Chiropractic and Naturopathic Medicine for the

Transcription

Chiropractic and Naturopathic Medicine
for the Promotion of Optimal Health
and Alleviation of Pain and Inflammation
A Detailed Review of Current “Daily Use” Research with
Implications for Clinical Practice and Healthcare Policy
Alex Vasquez, D.C., N.D.
Updated: January 11, 2006
Updated PDF available at: http://www.OptimalHealthResearch.com/monograph05
Copyright © 2005 by Dr. Alex Vasquez
Updated January 11, 2006
Objective:
Data
Sources:
Results:
Conclusions:
This article has four major objectives: 1) to discuss modern chiropractic and naturopathic
primary care and wellness promotion within the American healthcare context, 2) to review new
research on the physiology and biochemistry of the inflammatory cascade with an emphasis on
safe and effective nutritional and botanical interventions appropriate for clinical use, 3) to present
an integrated model wherein spinal manipulation and nutritional interventions are hypothesized
to break the self-perpetuating cycle of immunogenic and neurogenic inflammation, and 4) to
correlate current research and documentation with logical implications for clinical practice and
healthcare policy.
Several hundred sources of information were identified, the vast majority from peer-reviewed
biomedical journals as identified via numerous Medline searches. Authoritative textbooks by
research scholars are also cited, as are published texts and periodicals documenting historical
fact. To the extent possible, emphasis is placed on controlled clinical trails, especially those that
allow comparison between pharmaceutical vs. natural treatments and/or those that provide data
regarding efficacy, safety, adverse effects, and cost-effectiveness.
The scientific rationale and clinical basis for the nutritional, non-pharmacologic treatment of
many common painful inflammatory disorders is well established in the peer-reviewed
biomedical research. Many natural treatments (ie, spinal manipulation, interventional nutrition,
and botanical medicines) appear superior to pharmacologic drugs in terms of efficacy, cost,
safety, and overall health promotion. Whereas most pharmacologic treatments for pain and
inflammation carry numerous adverse effects and thus contribute directly to increases in patient
suffering and healthcare expenses, several of the nutritional and botanical interventions described
in this comprehensive review appear relatively devoid of adverse effects and have been shown in
long-term follow-up studies to favorably modify the course of disease and in several instances to
reduce overall mortality and healthcare expenses.
Given the superior cost-effectiveness, relative lack of adverse effects, and additional “sidebenefits” of natural treatments used by chiropractic/naturopathic physicians, the
chiropractic/naturopathic management of outpatient musculoskeletal pain with
comprehensive treatment plans that integrate carefully selected nutritional and botanical
interventions as described in this review appears clinically, financially, and ethically
superior to those interventions commonly employed by allopathic medical physicians.
Research has shown that many of the drug and surgical interventions (over)utilized by
medical physicians for the treatment of musculoskeletal pain are dangerous, expensive,
and/or ineffective. The recent rofecoxib/Vioxx catastrophe demonstrates that neither FDA
approval nor routine allopathic utilization of a drug sanctifies its efficacy and safety. Scope
of practice laws and healthcare/insurance policies should be protected and amended to
ensure that ailing patients have access to science-based natural healthcare interventions.
This review will provide chiropractic/naturopathic physicians with clinically useful
information to help their patients attain improved health and well-being. Increased
professional involvement by all chiropractic and naturopathic physicians combined with
ever-growing public support should be immediately leveraged to effect widespread
healthcare reform in favor of natural medicine. Given that 493 American patients die as a
direct consequence—“side effect”—of allopathic medical interventions on a daily basis,
decreasing reliance on medical treatments by increasing access to chiropractic and
naturopathic physicians should be treated as a public health priority. Political action and
collaboration between the chiropractic and naturopathic professions will be required to
obtain: 1) national licensure for naturopathic physicians who have graduated from
residential 4-6 year doctorate programs, 2) limited prescriptive authority for chiropractic
physicians at least for the purpose of legally discontinuing and thereby protecting their
patients from pharmaceutical drugs known to significantly increase the risk of injury and
death, 3) the nation-wide passage and enforcement of "every category of provider laws" to
empower the public with financial access to and insurance coverage for nondrug
nonsurgical healthcare providers.
A Detailed Review of Current Research with Implications for Clinical Practice and Healthcare Policy - Alex Vasquez, D.C., N.D. Copyright © 2005.
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Introduction
As primary care providers with specialized training in musculoskeletal medicine, chiropractic physicians
typically play a dual role in clinical practice on a daily basis, generally striving to simultaneously accomplish
two related goals in each patient: 1) promoting overall wellness and professionally-supervised patientimplemented preventive healthcare, and 2) alleviating acute and chronic musculoskeletal pain. Both of these
goals are important given the tremendous financial and social impact of musculoskeletal pain and the
progressive deterioration of Americans’ health. At any given time, nearly thirty percent of the American
population suffers from musculoskeletal pain, joint swelling, or limitation of movement1, and approximately 1
of every 7 (14% of total) visits to a primary healthcare provider is for the treatment of musculoskeletal pain or
dysfunction.2 Resulting in more than $100 billion in US healthcare costs each year, back pain is the most
prevalent medical problem in the US, is the leading cause of long-term disability, and is the second leading
cause of restricted activity and the use of prescription and non-prescription drugs.3 The preventive healthcare
and wellness promotion advocated and implemented by chiropractic and naturopathic physicians is now more
important than ever since the health of the American population is consistently and progressively declining:
obesity and diabetes are “ever-growing” epidemics among children and adults4,5, infant mortality has recently
increased for the first time in 40 years6, and self-reported health status and health-related quality of life among
adults are declining.7 In the 25 years between 1975 and 2000, the incidence of cancer increased significantly,
and the number of people diagnosed with cancer is expected to double in the next several decades.8 Despite
these negative health trends, America spends more on healthcare than does any other nation—an unprecedented
$1.55 trillion, which is roughly 15% of the US gross domestic product.9 From the perspective of costeffectiveness, the healthcare system in America, currently dominated and “lead” by the allopathic medical
community, delivers a very poor return on investment, and it appears that assertive wellness promotion and
increased utilization of chiropractic and naturopathic healthcare may provide improved outcomes and decreased
overall healthcare costs.10, 11
American citizens, families, businesses, and communities are burdened by expensive medical management,
assessments, and interventions. Indeed, compared to those in other nations, impressive discrepancies exist
between healthcare investments and outcomes in America, and the generalization that Americans patients spend
more money for worse health outcomes12 has been termed “the American paradox” by the current author.13
Compared to citizens of other nations, Americans spend more on medical care and receive more drugs and
medical procedures14,15, yet paradoxically we experience the overall worst health outcomes among citizens of
industrialized nations. In 2000, the Director of World Health Organization’s Global Program on Evidence for
Health Policy, Christopher Murray MD PhD16, concluded, “Basically, you die earlier and spend more time
disabled if you're an American rather than a member of most other advanced countries." According to the 1999
review by Anderson and Poullier17, the average annual income for allopathic medical physicians in America (at
approximately $200,000 per year) is disproportionately higher than the income for physicians in other countries
(approximately $100,000 per year), especially considering the superior health outcomes that are commonplace
in other nations that spend much less per capita. Recent data has shown that one in seven households—almost
20 million American families—faces significant financial hardships due to medical bills, and of these almost
1) Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ. 2003;81(9):646-56
2) American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Guidelines for the initial evaluation of the adult patient with acute musculoskeletal symptoms. Arthritis Rheum. 1996 Jan;39(1):1-8
3) Legorreta AP, Metz RD, Nelson CF, Ray S, Chernicoff HO, Dinubile NA. Comparative analysis of individuals with and without chiropractic coverage: patient characteristics, utilization, and costs. Arch Intern Med.
2004;164:1985-92
4) Bloomgarden ZT. Type 2 diabetes in the young: the evolving epidemic. Diabetes Care. 2004;27:998-1010
5) Rizvi AA. Type 2 diabetes: epidemiologic trends, evolving pathogenic concepts, and recent changes in therapeutic approach. South Med J. 2004;97(11):1079-87
6) Nelson R. US infant mortality shows first rise in 40 years. Lancet. 2004;363(9409):626
7) Zack MM, Moriarty DG, Stroup DF, Ford ES, Mokdad AH. Worsening trends in adult health-related quality of life and self-rated health-United States, 1993-2001. Public Health Rep. 2004;119:493-505
8) Weir HK, Thun MJ, Hankey BF, Ries LA, Howe HL, Wingo PA, Jemal A, Ward E, Anderson RN, Edwards BK. Annual report to the nation on the status of cancer, 1975-2000, featuring the uses of surveillance data for cancer
prevention and control. J Natl Cancer Inst. 2003;95(17):1276-99
9) US health care: a state lottery? Lancet. 2004 Nov 20;364(9448):1829-30
2004;164:1985-92
11) Orme-Johnson DW, Herron RE. An innovative approach to reducing medical care utilization and expenditures. Am J Manag Care. 1997 Jan;3(1):135-44
12) "The results of the study demonstrate that, over the past four decades, the United States has been spending more and accomplishing less when compared with other industrialized nations." Shi L. Health care spending,
delivery, and outcome in developed countries: a cross-national comparison. Am J Med Qual 1997;12(2):83-93
13) Vasquez A. Natural Medicine: an overview and review of effective treatments for a wide range of conditions. Presented at Memorial-Hermann Healthcare System Consortium 2003. Made available at
www.OptimalHealthResearch.com/oldpresentation on December 24, 2004
14) “Though the U.S. has slightly fewer doctors per capita than the typical developed nation, we have almost twice as many MRI machines and perform vastly more angioplasties. …at least 31 percent of all the incremental
income we'll earn between 1999 and 2010 will go to health care.” Regnier P. Healthcare myth: We spend too much. Money Magazine. October 13, 2003: 11:29 AM EDT http://money.cnn.com/2003/10/08/pf/health_myths_1/
Accessed Monday, July 12, 2004
15) Reinhardt UE, Hussey PS, Anderson GF. U.S. health care spending in an international context. Health Aff (Millwood). 2004;23:10-25
16) “Basically, you die earlier and spend more time disabled if you're an American rather than a member of most other advanced countries." Christopher Murray MD PhD, Director of World Health Organization’s Global Program
on Evidence for Health Policy http://www.who.int/inf-pr-2000/en/pr2000-life.html Accessed July 12, 2004
17) Anderson GF, Poullier JP. Health spending, access, and outcomes: trends in industrialized countries. Health Aff (Millwood). 1999;18(3):178-92
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two-thirds (about 13 million families) report difficulty paying for other basic necessities—rent, mortgage
payments, transportation or food—as a result of medical debt.18 The toll of medical coverage is a heavy burden
for American small businesses, too; in 2003 health care costs rose about 15% for businesses with fewer than 200
workers vs. 13.5% for those with 500 or more, and many small employers cited increases of 20% or more,
leading USA Today19 to conclude, “That's made [medical/healthcare] insurance the No. 1 small business
problem.” Among Medicare recipients, more than one in seven (14%) report financial difficulties that result
from medical bills.20 In response to the rhetorical question “What do we get for our money?” Money
Magazine21 published in 2003 that, “For a start, [we get] lots of technology. Though the U.S. has slightly fewer
doctors per capita than the typical developed nation, we have almost twice as many MRI machines and perform
vastly more angioplasties. We also get an extraordinarily rich health-care industry: Last year, for example,
shareholders in the drugmaker Pfizer saw after-tax earnings of $9.2 billion, reflecting a net profit margin of 28
percent…” A 2004 article in the Washington Post22 summarized, “Although they spend more on health care than
patients in any other industrialized nation, Americans receive the right treatment less than 60 percent of the
time, resulting in unnecessary pain, expense and even death…” This discrepancy between exorbitant costs and
inferior results23 suggests the need to reconsider the paradigms and policies that shape American healthcare,
especially if underutilized options exist for immediate implementation that can effect widespread health
improvements at comparatively reduced costs.
Americans also suffer an astoundingly high level of iatrogenic (doctor-induced) morbidity and mortality in the
process of receiving medical care. Drug interactions, drug “side effects”, prescription errors, unnecessary
surgeries, nosocomial infections, and “hospital errors” are a leading cause of death in America. The number of
deaths due to “medication errors” more than doubled from 1983 to 1993.24 Lazarou et al25 published a landmark
report in JAMA in 1998 showing that hospital-supervised administration of drugs leads to adverse effects in
more than 2.2 million American patients and directly results in more than 100,000 deaths, thus “making these
reactions between the fourth and sixth leading cause of death." An article by Starfield26 published in JAMA in
2000 documented that allopathic medicine is the third leading cause of death in America after heart disease and
cancer; this article can be paraphrased as stating, “iatrogenic causes” result in “225,000 deaths per year”
constituting “the third leading cause of death in the United States.” Other estimates have been more
conservative, such as the 1997 review by Holland and Degury27 in American Family Physician, wherein the
authors note, "Recent estimates suggest that each year more than 1 million patients are injured while in the
hospital and approximately 180,000 die because of these injuries. Furthermore, drug-related morbidity and
mortality are common and are estimated to cost more than $136 billion a year." Thus, according to these
authoritative reviews, we can reasonably conclude that not less than 110,000 and up to 225,000 American
patients are killed every year by adverse drug effects, hospital errors, and other “side-effects” of allopathic
medicine. Placing this into a public health context, we see that more people die every year from iatrogenic
disease than from cerebrovascular disease (168,000), diabetes (69,000), influenza or pneumonia (65,000).28 If it
were not for the politics involved—that is, if allopathic iatrogenesis were an infectious disease rather than a
consequence of professional error—major public health campaigns would be directed to alert the public about
risk-reduction measures for this underappreciated major cause of death. Likewise, medical organizations such
as the American Medical Association would fight vehemently for improved patient care, rather than focusing on
limiting malpractice liability for allopathic doctors sued for harm or negligence.
Numerous adverse effects are produced as a direct result of medical/pharmaceutical management of benign
musculoskeletal pain. According to a 1998 review by Singh29, “Conservative calculations estimate that
18) Center for Studying Health System Change. Medical Debt a Problem for Almost 20 Million American Families: Many Face Tough Trade-offs Between Food, Shelter and Medical Care. News Release June 30, 2004.
http://www.hschange.org/CONTENT/690/ Accessed on January 4, 2005
19) Hopkins J. Health care tops taxes as small business cost drain. USA TODAY. http://www.usatoday.com/news/health/2003-04-20-small-business-costs_x.htm. Accessed January 4, 2005
20) A Large Majority Of Medicare Beneficiaries Struggle With Low Incomes Or Health Problems: Many Beneficiaries Face Financial Burdens Due To Medical Bills. The Commonwealth Fund.
http://www.cmwf.org/newsroom/newsroom_show.htm?doc_id=223628 Accessed on January 4, 2005
21) Regnier P. Healthcare myth: We spend too much. Money Magazine. October 13, 2003: 11:29 AM EDT http://money.cnn.com/2003/10/08/pf/health_myths_1/ Accessed January 4, 2005
22) Connolly C. U.S. Patients Spend More but Don't Get More, Study Finds: Even in Advantaged Areas, Americans Often Receive Inadequate Health Care. Washington Post, May 5, 2004; Page A15. On-line at
http://www.washingtonpost.com/ac2/wp-dyn/A1875-2004May4 accessed on July 28, 2004
24) Phillips DP, Christenfeld N, Glynn LM. Increase in US medication-error deaths between 1983 and 1993. Lancet. 1998;351(9103):643-4
25) Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998;279:1200-5
26) Starfield B. Is US health really the best in the world? JAMA. 2000;284(4):483-5
27) Holland EG, Degruy FV. Drug-induced disorders. Am Fam Physician. 1997;56(7):1781-8, 1791-2
28) Mokdad AH, Marks JS, Stroup DF, Gerberding JL. Actual causes of death in the United States, 2000. JAMA. 2004;291(10):1238-45
29) Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med. 1998;105(1B):31S-38S
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approximately 107,000 patients are hospitalized annually for nonsteroidal anti-inflammatory drug (NSAID)related gastrointestinal (GI) complications and at least 16,500 NSAID-related deaths occur each year among
arthritis patients alone. The figures for all NSAID users would be overwhelming, yet the scope of this problem
is generally under-appreciated.” More recently following the withdrawal of the arthritis drug rofecoxib (Vioxx)
in late September 2004, Topol30 extrapolated that as many as 160,000 adverse cardiovascular events (including
stroke, myocardial infarction, and death) may have resulted from the collusion of Merck’s intentional failure to
withdraw what was known for years to be a dangerous drug, the FDA’s failure to enforce regulatory standards to
protect the public, and the overutilization of Vioxx by the medical profession, which was well informed of the
lethality of Vioxx for several years31 before Merck’s confessionary and belated withdrawal of the drug. Soon
thereafter, several other so-called “anti-inflammatory drugs” such as valdecoxib (Bextra)32, celecoxib
(Celebrex)33, and naproxen (Aleve)34 were likewise associated with excess cardiovascular injury and death.
Although the advertising-induced feeding frenzy on Celebrex made it the most successful drug launch in US
history with more than 7.4 million prescriptions written within its first 6 months35, within 2 years of its release
evidence linking the drug to increased cardiovascular events (including death) was accumulating36, and the drug
has since been linked to a wide range of adverse effects such as membranous glomerulopathy and acute
interstitial nephritis37, acute cholestatic hepatitis38, and toxic epidermal necrolysis.39,40 Current guidelines hold
that patients must be informed of the excess cardiovascular risk associated with this drug and and that its use
should be limited to the lowest dose for the shortest time possible (weeks).41 When compared with placebo in
cardiac surgery patients, Bextra/valdecoxib is associated with a 3-fold to 4-fold increased risk of heart attack,
stroke, and death42, and recently 7 million arthritis patients, many of whom were already at high risk for
cardiovascular disease, were being treated with this drug.43 Use of Bextra was also strongly associated with
toxic epidermal necrolysis, a potentially fatal condition.44 Due primarily to the adverse cardiovascular effects45,
in the interest of protecting the public from additional adverse effects and unnecessary deaths, in April 2005 the
FDA ordered that Bextra/valdecoxib be taken off the market in the US46 and Health Candada followed suit by
removing the drug from Canadian markets.47 It is inexcusable that these drugs were so highly utilized (due to
aggressive marketing) despite evidence of relative analgesic inefficacy (not better than earlier NSAIDs like
aspirin), exorbidant costs (US $90-180 per month48) and clear evidence of danger (e.g., cardiovascular death) by
two well-identified mechanisms: inhibiting the formation of vasodilating and anti-aggregatory prostacyclin, and
shuting arachidonate toward leukotriene formation by blocking cyclooxygenase.
Allopathic medical education has recently been described as “woefully inadequate” in preparing medical doctors
for the diagnosis and treatment of musculoskeletal conditions49, and these deficits stem from the paucity of
didactic and clinical training provided to medical students in musculoskeletal diagnosis and treatment. In their
2004 review published in Physician and Sportsmedicine, Joy and Van Hala50 describe the formal training of a
sample of 85 recent medical graduates, “…the average time spent in rotations or courses devoted to orthopedics
during medical school was only 2.1 weeks. One third of these examinees graduated without any formal training
in orthopedics. As would be expected, these data suggest that limited educational experience contributes to poor
30) Topol EJ. Failing the public health--rofecoxib, Merck, and the FDA. N Engl J Med. 2004 Oct 21;351(17):1707-9
31) Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286(8):954-9
32) Ray WA, Griffin MR, Stein CM. Cardiovascular toxicity of valdecoxib. N Engl J Med. 2004;351(26):2767
33) "Patients in the clinical trial taking 400 mg. of Celebrex twice daily had a 3.4 times greater risk of CV events compared to placebo. For patients in the trial taking 200 mg. of Celebrex twice daily, the risk was 2.5 times greater.
The average duration of treatment in the trial was 33 months." FDA Statement on the Halting of a Clinical Trial of the Cox-2 Inhibitor Celebrex. http://www.fda.gov/bbs/topics/news/2004/NEW01144.html Available on January
4, 2005
34) "Preliminary information from the study showed some evidence of increased risk of cardiovascular events, when compared to placebo, to patients taking naproxen." FDA Statement on Naproxen.
http://www.fda.gov/bbs/topics/news/2004/NEW01148.html Available on January 4, 2005
35) Monsanto, Pfizer celebrate Celebrex. St. Louis Business Journal. July 20, 1999 http://www.bizjournals.com/stlouis/stories/1999/07/19/daily5.html Accessed on January 5, 2005
36) Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001 Aug 22-29;286(8):954-9
37) Markowitz GS, Falkowitz DC, Isom R, Zaki M, Imaizumi S, Appel GB, D'Agati VD. Membranous glomerulopathy and acute interstitial nephritis following treatment with celecoxib. Clin Nephrol. 2003;59(2):137-42
38) Grieco A, Miele L, Giorgi A, Civello IM, Gasbarrini G. Acute cholestatic hepatitis associated with celecoxib. Ann Pharmacother. 2002;36(12):1887-9
39) Berger P, Dwyer D, Corallo CE. Toxic epidermal necrolysis after celecoxib therapy. Pharmacotherapy. 2002 Sep;22(9):1193-5.
40) Friedman B, Orlet HK, Still JM, Law E. Toxic epidermal necrolysis due to administration of celecoxib (Celebrex). South Med J. 2002;95(10):1213-4
41) "Celecoxib should be used in the lowest effective doses for short periods (weeks) only. A risk–benefit discussion is necessary for those requiring the drug for a longer period." Cotter J, Wooltorton E. New restrictions on
celecoxib (Celebrex) use and the withdrawal of valdecoxib (Bextra). CMAJ. 2005 May 10;172(10):1299. Epub 2005 Apr 15 http://www.cmaj.ca/cgi/content/full/172/10/1299 Accessed September 28, 2005
42) Lenzer J. Pfizer criticised over delay in admitting drug's problems. BMJ. 2004;329(7472):935
44) "There is a strong association between Stevens-Johnson syndrome/toxic epidermal necrolysis and the use of the sulfonamide COX-2 inhibitors, particularly valdecoxib." La Grenade L, Lee L, Weaver J, Bonnel R, Karwoski C,
Governale L, Brinker A. Comparison of Reporting of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Association with Selective COX-2 Inhibitors. Drug Saf. 2005;28(10):917-24
45) Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, Boyce SW, Verburg KM. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med. 2005 Mar
17;352(11):1081-91. Epub 2005 Feb 15
46) "On April 7, the Food and Drug Administration requested that Pfizer suspend sales of BEXTRA in the United States. As a result, BEXTRA will no longer be available to patients in the United States... In light of the FDA's
position that there is an increased cardiovascular risk for all prescription non-steroidal anti-inflammatory arthritis medicines, as well as the increased rate of rare, serious skin reactions with BEXTRA, the FDA has requested that
sales of BEXTRA be suspended." http://www.bextra.com/ Accessed September 28, 2005
47) Sibbald B. Pfizer withdraw valdecoxib (Bextra) at Health Canada's request. CMAJ. 2005 May 10;172(10):e1298. Epub 2005 Apr 7 http://www.cmaj.ca/cgi/reprint/172/10/e1298 Accessed September 28, 2005
48) http://www.walgreens.com/library/finddrug/druginfo1.jsp?particularDrug=Celebrex&id=15102 Accessed September 29, 2005
49) Joy EA, Hala SV. Musculoskeletal Curricula in Medical Education: Filling In the Missing Pieces. The Physician and Sportsmedicine. 2004; 32: 42-45
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performance.” In 1998, Freedman and Bernstein51 published a landmark study in Journal of Bone and Joint
Surgery wherein they administered a validated musculoskeletal competency examination to 85 recent medical
graduates who had begun their hospital residency; 82% of these medical doctors failed to demonstrate basic
competency on the examination, leading the authors to conclude, “We therefore believe that medical school
preparation in musculoskeletal medicine is inadequate.” They repeated their study in 2002, and this time the
examination questions, which had previously been validated by orthopedic specialists, were validated by
directors of internal medicine departments; their conclusions stated, “According to the standard suggested by the
program directors of internal medicine residency departments, a large majority of the examinees once again
failed to demonstrate basic competency in musculoskeletal medicine on the examination. It is therefore
reasonable to conclude that medical school preparation in musculoskeletal medicine is inadequate.”52 In
February 2005, Matzkin et al53 administered a standardized test of musculoskeletal competency to 334 medical
students, residents, and staff physicians; the conclusion from their study reads as follows: “Seventy-nine percent
of the participants failed the basic musculoskeletal cognitive examination. This suggests that training in
musculoskeletal medicine is inadequate in both medical school and nonorthopaedic residency training
programs.” Again in August 2005, Schmale54 from the University of Washington showed that when a
standardized musculoskeletal examination was administered “…less than 50% of fourth-year students showed
competency. Students who completed a musculoskeletal clinical elective scored higher and were more
competent (78%) than students who did not take an elective. These results suggested that the curricular approach
toward teaching musculoskeletal medicine at this medical school was insufficient..." These results are
particularly alarming because the University of Washington consistently ranks as the best medical school in
America.55 If medical schools across the nation are failing to prepare doctors to evaluate and thus treate patients
with musculoskeletal complaints, then would this not present a danger to the public health? What might be the
consequences of such widespread professional ineptness? Insufficient training in musculoskeletal management
might be expected to produce negative clinical consequences and an increased reliance on stereotypic and
simplistic (rather than personalized and comprehensive) treatments such as the overutilization of so-called “antiinflammatory” drugs. Furthermore, such a high level of incompetence among recently graduated medical
doctors in basic musculoskeletal assessment may represent a public health risk to patients seeking care. The
overutilization of surgical treatments for musculoskeletal disorders also places an unjustified burden on the
nation’s healthcare system; for example, arthroscopic knee surgery is performed on at least 225,000 middle-age
and older Americans each year at a cost of several billion dollars to Medicare, the Department of Veterans
Affairs and private insurers56 yet the results are no better than those obtained from placebo.57 In their 2003
review of the literature on this topic, Bernstein and Quach58 concluded, “Arthroscopy for degenerative
conditions of the knee is among the most commonly employed orthopedic procedures, but its effectiveness (like
the effectiveness of many surgical operations) has never been proven in prospective trials.”
In contrast, chiropractic and naturopathic physicians receive extensive training in the management of outpatient
musculoskeletal disorders during their course of graduate healthcare training, which typically lasts from 4-6
years. Although some differences exist between the naturopathic and chiropractic professions in terms of
philosophy and clinical interventions, physicians in these professions share almost identical clinical goals: to
help patients become as healthy as possible without the use of drugs and surgery via the implementation of
comprehensive treatment plans that emphasize safe and effective natural interventions such as personalized
diets, therapeutic exercise, nutritional supplementation, and preventive, holistic healthcare.59 Following the
basic science courses which are similar in medical, osteopathic, naturopathic, and chiropractic schools60,
doctorate students in the health sciences learn different clinical therapeutics. Allopathic students learn to use
drugs and surgery as their main interventional tools. Osteopathic students learn the use of drugs, surgery, and
manual physical manipulation. Naturopathic students receive training in manual physical manipulation
(including spinal manipulation), therapeutic diets, clinical and interventional nutrition, botanical medicines,
51) Freedman KB, Bernstein J. The adequacy of medical school education in musculoskeletal medicine. J Bone Joint Surg Am. 1998;80(10):1421-7
52) Freedman KB, Bernstein J. Educational deficiencies in musculoskeletal medicine. J Bone Joint Surg Am. 2002;84-A(4):604-8
53) Matzkin E, Smith ME, Freccero CD, Richardson AB. Adequacy of education in musculoskeletal medicine. J Bone Joint Surg Am. 2005 Feb;87-A(2):310-4
54) Schmale GA. More evidence of educational inadequacies in musculoskeletal medicine. Clin Orthop Relat Res. 2005 Aug;(437):251-9
55) http://www.usnews.com/usnews/edu/grad/rankings/med/brief/mdprank_brief.php Accessed September 27, 2005
56) Gina Kolata. A Knee Surgery for Arthritis Is Called Sham. The New York Times, July 11, 2002
57) Moseley JB, O'Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall DH, Hollingsworth JC, Ashton CM, Wray NP. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med. 2002;347:81-8
58) Bernstein J, Quach T. A perspective on the study of Moseley et al: questioning the value of arthroscopic knee surgery for osteoarthritis. Cleve Clin J Med. 2003;70(5):401, 405-6, 408-10
59) Vasquez A. Integrative Orthopedics: The Art of Creating Wellness While Managing Acute and Chronic Musculoskeletal Disorders. Houston; Natural Health Consulting Corp. (www.OptimalHealthResearch.com): 2004
60) Smith MJ, Logan AC. Naturopathy. Med Clin North Am. 2002 Jan;86(1):173-84
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lifestyle counseling, environmental medicine, and other modalities, and licensed naturopathic physicians
commonly practice as generalists and family doctors.61,62,63,64 Chiropractic students learn clinical nutrition, and
receive extensive training in manual physical manipulation and physical rehabilitation and therapeutic exercise.
In accord with this comprehensive training in musculoskeletal management, numerous sources of evidence
demonstrate that chiropractic management is much safer and less expensive than allopathic medical treatment,
particularly for treatment of low-back pain. In their extensive review of the literature, Manga et al65 published
in 1993 that chiropractic management of low-back pain is superior to allopathic medical management in terms
of greater safety, greater effectiveness, and reduced cost; they concluded, "There is an overwhelming body of
evidence indicating that chiropractic management of low-back pain is more cost-effective than medical
management." and "There would be highly significant cost savings if more management of LBP [low-back pain]
was transferred from medical physicians to chiropractors." In a randomized trial involving 741 patients, Meade
et al66 showed, “Chiropractic treatment was more effective than hospital outpatient management, mainly for
patients with chronic or severe back pain… The benefit of chiropractic treatment became more evident
throughout the follow up period. Secondary outcome measures also showed that chiropractic was more
beneficial.” A 3-year follow-up study by these same authors67 in 1995 showed, “At three years the results
confirm the findings of an earlier report that when chiropractic or hospital therapists treat patients with low-back
pain as they would in day to day practice those treated by chiropractic derive more benefit and long term
satisfaction than those treated by hospitals.” Most recently, in 2004 Legorreta et al68 reported that the
availability of chiropractic care was associated with significant cost savings among 700,000 patients with
chiropractic coverage compared to 1 million patients whose insurance coverage was limited to allopathic
medical treatments. Simple extrapolation of the average savings per patient in this study ($208 annual savings
associated with chiropractic coverage) to the US population (295 million citizens in 200569) suggests that, if
fully implemented in a nation-wide basis, America could save $61,360,000,000 (more than $61 billion per year)
in healthcare annual expenses by ensuring chiropractic for all citizens in contrast to failing to provide such
coverage; obviously extrapolations such as this should consider other variables, such as the relatively higher
prevalence of injury and death among patients treated with drugs and surgery.70,71 A literature review by Dabbs
and Lauretti72 showed that spinal manipulation is safer than the use of NSAIDs in the treatment of neck pain.
Contrasting the rates of manipulation-associated cerebrovascular accidents to the dangers of medical and
surgical treatments for spinal disorders, Rosner73 noted, “These rates are 400 times lower than the death rates
observed from gastrointestinal bleeding due to the use of nonsteroidal anti-inflammatory drugs and 700 times
lower than the overall mortality rate for spinal surgery.” Similarly, in his review of the literature comparing the
safety of chiropractic manipulation in patients with low-back pain associated with lumbar disc herniation,
Oliphant74 showed that, “The apparent safety of spinal manipulation, especially when compared with other
[medically] accepted treatments for [lumbar disk herniation], should stimulate its use in the conservative
treatment plan of [lumbar disk herniation].”
Increasingly aware of the negative effects of pharmaceutical management of musculoskeletal pain, patients and
healthcare providers alike are looking to natural treatments and chiropractic healthcare75,76 with the hopes of
avoiding the risks of iatrogenic disease, such as drug-induced renal failure77,78, hepatotoxicity79,80,
61) Boon HS, Cherkin DC, Erro J, Sherman KJ, Milliman B, Booker J, Cramer EH, Smith MJ, Deyo RA, Eisenberg DM. Practice patterns of naturopathic physicians: results from a random survey of licensed practitioners in two US
States. BMC Complement Altern Med. 2004;4(1):14
63) Cherkin DC, Deyo RA, Sherman KJ, Hart LG, Street JH, Hrbek A, Davis RB, Cramer E, Milliman B, Booker J, Mootz R, Barassi J, Kahn JR, Kaptchuk TJ, Eisenberg DM. Characteristics of visits to licensed acupuncturists,
chiropractors, massage therapists, and naturopathic physicians. J Am Board Fam Pract. 2002 Nov-Dec;15(6):463-72
64) Cherkin DC, Deyo RA, Sherman KJ, Hart LG, Street JH, Hrbek A, Cramer E, Milliman B, Booker J, Mootz R, Barassi J, Kahn JR, Kaptchuk TJ, Eisenberg DM. Characteristics of licensed acupuncturists, chiropractors,
massage therapists, and naturopathic physicians. J Am Board Fam Pract. 2002 Sep-Oct;15(5):378-90
65) Manga P, Angus D, Papadopoulos C, et al. The Effectiveness and Cost-Effectiveness of Chiropractic Management of Low-Back Pain. Richmond Hill, Ontario: Kenilworth Publishing; 1993
66) Meade TW, Dyer S, Browne W, Townsend J, Frank AO. Low-back pain of mechanical origin: randomised comparison of chiropractic and hospital outpatient treatment. BMJ. 1990;300(6737):1431-7
67) Meade TW, Dyer S, Browne W, Frank AO. Randomised comparison of chiropractic and hospital outpatient management for low-back pain: results from extended follow up. BMJ. 1995;311(7001):349-5
2004;164:1985-92
69) US Census Bureau http://factfinder.census.gov/home/saff/main.html?_lang=en Accessed January 12, 2005
70) Rosner AL. Evidence-based clinical guidelines for the management of acute low-back pain: response to the guidelines prepared for the Australian Medical Health and Research Council. J Manipulative Physiol Ther.
2001;24(3):214-20
72) Dabbs V, Lauretti WJ. A risk assessment of cervical manipulation vs. NSAIDs for the treatment of neck pain. J Manipulative Physiol Ther. 1995;18:530-6
73) Rosner AL. Evidence-based clinical guidelines for the management of acute low-back pain: response to the guidelines prepared for the Australian Medical Health and Research Council. J Manipulative Physiol Ther.
2001;24(3):214-20
74) Oliphant D. Safety of spinal manipulation in the treatment of lumbar disk herniations: a systematic review and risk assessment. J Manipulative Physiol Ther. 2004;27:197-210
75) The Growth of Chiropractic and CAM: More Bad News for Medicine. Dynamic Chiropractic October 8, 2001, Volume 19, Issue 21 http://www.chiroweb.com/archives/19/21/03.html accessed November 11, 2004
76) Kessler RC, Davis RB, Foster DF, Van Rompay MI, Walters EE, Wilkey SA, Kaptchuk TJ, Eisenberg DM. Long-term trends in the use of complementary and alternative medical therapies in the United States. Ann Intern Med.
2001 Aug 21;135(4):262-8
77) “Patients with chronic arthritis who consume excessive amount of NSAIDs are at risk of developing renal papillary necrosis and chronic renal impairment.” Segasothy M, Chin GL, Sia KK, Zulfiqar A, Samad SA. Chronic
nephrotoxicity of anti-inflammatory drugs used in the treatment of arthritis. Br J Rheumatol. 1995 Feb; 34(2): 162-5
78) Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs. N Engl J Med. 1994 Dec 22;331(25):1675-9
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gastrointestinal ulceration and hemorrhage81,82,83,84, osteonecrosis85,86, joint degeneration87, hypertension88,
myocardial infarction89, and premature death90,91 that are associated with the non-steroidal anti-inflammatory
drugs (“NSAIDs”), non-NSAID analgesics such as acetaminophen, and the relatively new selective
cyclooxygenase-2 inhibitors (cox-2 inhibitors, or “coxibs”). It is tragically paradoxical that many of the
pharmaceutical drugs used for the suppression of arthritis symptoms and advertised as “arthritis relief” actually
exacerbate joint destruction and chronic inflammation by interfering with the biosynthesis of the
glycosaminoglycans that are essential components of joint cartilage while also promoting destruction of
subchondral bone.92,93,94,95 This places chiropractic physicians in an ethical dilemma when helping patients who
have been prescribed potentially dangerous medications by their medical doctors. On the one hand, chiropractic
physicians are aware of the research showing that, for example, coxibs provide little clinical benefit while
promoting increased cardiovascular mortality and other potentially lethal adverse effects. On the other hand, if a
chiropractic physician advises discontinuation of the medication, he or she may be reprimanded for “practicing
medicine.” It appears that chiropractic physicians will need to obtain limited prescription rights for the sake of
helping protect their patients from iatrogenic and drug-induced disease. Given that chiropractic physicians are
already duly trained in basic and clinical sciences sufficient for primary care, post-graduate certification courses
in pharmacology would be sufficient if additional training is deemed necessary to obtain these prescription
rights.
Despite the long-standing historical precedent in which human disease was treated by natural means (ie, diet
modification, botanical medicines, physical modalities) for the majority of human existence, the current
healthcare paradigm in America and other Western/industrialized nations is such that treatment with drugs and
surgery is labeled “conventional” while natural treatment as with nutritional, botanical, and physical
interventions is now described “alternative” and “unconventional.” This unfortunate inversion of terms causes
confusion among doctors and patients alike while it connotes scientific superiority and cultural sanctification of
pharmaceutical and surgical interventions, including those that are dangerous, ineffective, and unduly
expensive.96 Furthermore, the ongoing impact of the slanderous campaign by the American Medical
Association (AMA) and other organizations against non-medical healthcare professionals97—particularly
chiropractic physicians98,99,100—and inaccurate medical “research” and publications which continue to
intentionally denigrate chiropractic and naturopathic medicine in the eyes of the public and other healthcare
professionals101,102,103 form additional barriers which subtly yet effectively disenfranchises chiropractic
79) O'Connor N, Dargan PI, Jones AL. Hepatocellular damage from non-steroidal anti-inflammatory drugs. QJM. 2003 Nov;96(11):787-91
80) Tolman KG. Hepatotoxicity of non-narcotic analgesics. Am J Med. 1998 Jul 27;105(1B):13S-19S
81) “NSAIDs cause small intestinal inflammation in 65% of patients receiving the drugs long-term.” Bjarnason I, Macpherson AJ. Intestinal toxicity of non-steroidal anti-inflammatory drugs. Pharmacol Ther. 1994 Apr-May;62(12):145-57
82) “Endoscopic studies indicate that up to 30% of chronic NSAID users will develop gastroduodenal ulceration.” Blower AL. Considerations for nonsteroidal anti-inflammatory drug therapy: safety. Scand J Rheumatol Suppl.
1996;105:13-24
83) “ASA (1,500 mg/day for 5 days) caused about a 6-fold increase in blood loss. Four days after withdrawal of ASA, faecal blood was still about twice as high as in faeces of subjects given ibuprofen and indoprofen.” Porro GB,
Corvi G, Fuccella LM, Goldaniga GC, Valzelli G. Gastro-intestinal blood loss during administration of indoprofen, aspirin and ibuprofen. J Int Med Res 1977;5(3):155-60
84) “Non-steroidal anti-inflammatory drugs (NSAIDs) may adversely affect the colon, either by causing a non-specific colitis or by exacerbating a preexisting colonic disease. … Local and/or systemic effects of NSAIDs on
mucosal cells might lead to an increased intestinal permeability, which is a prerequisite for colitis.” Faucheron JL, Parc R. Non-steroidal anti-inflammatory drug-induced colitis. Int J Colorectal Dis. 1996;11:99-101
85) “The case of a young healthy man, who developed avascular necrosis of head of femur after prolonged administration of indomethacin, is reported here.” Prathapkumar KR, Smith I, Attara GA. Indomethacin induced
avascular necrosis of head of femur. Postgrad Med J. 2000 Sep; 76(899): 574-5
86) “This highly significant association between NSAID use and acetabular destruction gives cause for concern, not least because of the difficulty in achieving satisfactory hip replacements in patients with severely damaged
acetabula.” Newman NM, Ling RS. Acetabular bone destruction related to non-steroidal anti-inflammatory drugs. Lancet. 1985 Jul 6; 2(8445): 11-4
87) “At…concentrations comparable to those… in the synovial fluid of patients treated with the drug, several NSAIDs suppress proteoglycan synthesis… These NSAID-related effects on chondrocyte metabolism … are much
more profound in osteoarthritic cartilage than in normal cartilage, due to enhanced uptake of NSAIDs by the osteoarthritic cartilage.” Brandt KD. Effects of nonsteroidal anti-inflammatory drugs on chondrocyte metabolism in
vitro and in vivo. Am J Med. 1987 Nov 20; 83(5A): 29-34
88) "Systolic blood pressure increased significantly in 17% of rofecoxib- compared with 11% of celecoxib-treated patients (P = 0.032) at any study time point." Whelton A, Fort JG, Puma JA, Normandin D, Bello AE, Verburg KM;
SUCCESS VI Study Group.Cyclooxygenase-2--specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther 2001 MarApr;8(2):85-95
89) “The results from VIGOR showed that the relative risk of developing a confirmed adjudicated thrombotic cardiovascular event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or
unexplained death, ischemic stroke, and transient ischemic attacks) with rofecoxib treatment compared with naproxen was 2.38.” Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective
COX-2 inhibitors. JAMA 2001; 286(8):954-9
91) Ray WA, Griffin MR, Stein CM. Cardiovascular Toxicity of Valdecoxib. N Engl J Med. 2004; 351: 2767
93) “The case of a young healthy man, who developed avascular necrosis of head of femur after prolonged administration of indomethacin, is reported here.” Prathapkumar KR, Smith I, Attara GA. Indomethacin induced
avascular necrosis of head of femur. Postgrad Med J. 2000 Sep; 76(899): 574-5
94) “This highly significant association between NSAID use and acetabular destruction gives cause for concern, not least because of the difficulty in achieving satisfactory hip replacements in patients with severely damaged
acetabula.” Newman NM, Ling RS. Acetabular bone destruction related to non-steroidal anti-inflammatory drugs. Lancet. 1985 Jul 6; 2(8445): 11-4
95) Vidal y Plana RR, Bizzarri D, Rovati AL. Articular cartilage pharmacology: I. In vitro studies on glucosamine and non steroidal antiinflammatory drugs. Pharmacol Res Commun. 1978 Jun;10(6):557-69
96) MacIntosh A. Understanding the Differences Between Conventional, Alternative, Complementary, Integrative and Natural Medicine. Townsend Letter for Doctors and Patients. 1999; July #192: 60-62
97) Carter JP. Racketeering in Medicine: The Suppression of Alternatives. Norfolk: Hampton Roads Pub; 1993
98) Wilk CA. Medicine, Monopolies, and Malice: How the Medical Establishment Tried to Destroy Chiropractic. Garden City Park: Avery, 1996
99) Trever W. In the Public Interest. Los Angeles; Scriptures Unlimited; 1972
100) Getzendanner S. Permanent injunction order against AMA. JAMA. 1988 Jan 1;259(1):81-2
101) Terrett AG. Misuse of the literature by medical authors in discussing spinal manipulative therapy injury. J Manipulative Physiol Ther. 1995 May;18(4):203-10
102) Morley J, Rosner AL, Redwood D. A case study of misrepresentation of the scientific literature: recent reviews of chiropractic. J Altern Complement Med. 2001 Feb;7(1):65-78
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physicians from the larger healthcare community and from the patients who are legally entitled to—yet socially
discouraged and financially restricted from—chiropractic and naturopathic healthcare. Despite these limitations
and barriers to care, Americans are demanding alternatives to drugs and surgery for their healthcare needs, even
if they are forced to pay “out of pocket.” The landmark article by Eisenberg et al104 published in 1993 showed
that the use of natural forms of healthcare in the US was far higher than previously recognized, and a follow-up
study also lead by Eisenberg105 in 1998 showed that utilization of natural healthcare has continued to increase.
Dissatisfaction with the costs and results obtained with drug- and surgery-based healthcare is a major reason that
many patients are seeking natural healthcare solutions.106,107
In order to document and solidify a large body of interconnected research that has day-to-day relevance for
chiropractic and naturopathic physicians, this review will provide an update on the ongoing progress that
increasingly supports if not favors the use of natural therapeutics in the management of patients with disorders
associated with chronic pain and inflammation. Chiropractic and naturopathic physicians should appreciate the
benefits and limitations of natural treatments, as well as nutrient-drug interactions (if any) that may arise in
patients using both drug and non-drug treatments. In addition to reviewing the biochemistry of inflammation
and eicosanoid metabolism, this article reviews the most commonly used and well-researched nutritional and
botanical interventions for the treatment of pain and inflammation, namely “essential fatty acids”, vitamin D,
glucosamine and chondroitin sulfate, niacinamide, proteolytic enzymes, Devil’s Claw (Harpagophytum
procumbens), Cat’s Claw (Uncaria spp), Willow bark (Salix spp), Boswellia (Boswellia serrata), and ginger
(Zingiber officiniale). This review will provide chiropractic and naturopathic physicians with clinically useful
information to help their patients attain improved health and well-being. Osteoarthritis and chronic low-back
pain, the two most prevalent musculoskeletal afflictions, will serve as prototypes for this discussion.
The Biochemistry of Inflammation: From NF-kappaB to Eicosanoids
Numerous influences and pathways are involved in the processes of inflammation. Clinicians are tasked with
appreciating these contributions while maintaining a conceptual overview that facilitates effective clinical
intervention.108 As the processes of inflammation have been elucidated with increasing clarity and precision in
the past several years, most clinicians will benefit from a brief review of the current understanding of
inflammation. Simplistic, linear models of inflammatory processes must be discarded in favor of
conceptualizations that incorporate the biochemical, nutritional/botanical, neurogenic inflammation, and
psychogenic contributions to inflammation modulation.
The process of inflammation may be said to begin with the translation of an environmental trigger into a
biochemical signal that initiates the inflammatory pathway. As discussed in more detail in the paragraphs that
follow, environmental triggers can include injury, radiation, infection, oxidative stress, and certain foods,
particularly those high in fat and those with a high glycemic index (ie, “simple sugars”). Regardless of the
original locus or etiology, each of these stimuli may lead to activation of the NF-kappaB cascade, which is a
major pathway for the amplification of inflammatory processes.109,110 A ubiquitous nuclear transcription factor
that promotes the activation of genes that encode for inflammatory mediators and enzymes, NF-kappaB can be
thought of as the major intracellular “amplifier” which ultimately increases the production of the direct
mediators of inflammation such as cytokines, prostaglandins, leukotrienes, nitric oxide and other reactive
oxygen species (“free radicals”). Preparation for the process of inflammation begins when two subunit
proteins—p50 and p65—merge in the cytoplasm to form NF-kappaB, which is kept in an inactive state by
inhibitor kappaB (IkB). When triggered by any of the common stimuli listed above, IkB is phosphorylated and
destroyed by inhibitor kappaB kinase (IKK). The destruction of IkB allows NF-kappaB to move into the
nucleus of the cell where it activates genes encoding for inflammatory responses. These genes then elaborate
their inflammatory products such as interleukin-1 (IL-1), IL-6, tumor necrosis factor, and the proinflammatory
103) American Medical Association. Report 12 of the Council on Scientific Affairs (A-97) Full Text. http://www.ama-assn.org/ama/pub/category/13638.html Accessed on January 16, 2005
104) Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL. Unconventional medicine in the United States. Prevalence, costs, and patterns of use. N Engl J Med 1993;328:246-52
105) Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M, Kessler RC.Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA. 1998;280:1569-75
106) van Haselen RA, Reiber U, Nickel I, Jakob A, Fisher PA. Providing Complementary and Alternative Medicine in primary care: the primary care workers' perspective. Complement Ther Med. 2004;12:6-16
107) Yussman SM, Ryan SA, Auinger P, Weitzman M. Visits to complementary and alternative medicine providers by children and adolescents in the United States. Ambul Pediatr. 2004;4:429-35
108) Vasquez A. Integrative Orthopedics: The Art of Creating Wellness While Managing Acute and Chronic Musculoskeletal Disorders. Houston; Natural Health Consulting Corp. (www.OptimalHealthResearch.com): 2004
109) D'Acquisto F, May MJ, Ghosh S. Inhibition of Nuclear Factor Kappa B (NF-B):: An Emerging Theme in Anti-Inflammatory Therapies. Mol Interv. 2002 Feb;2(1):22-35 Available at
http://molinterv.aspetjournals.org/cgi/reprint/2/1/22 on November 9, 2004
110) Tak PP, Firestein GS. NF-kappaB: a key role in inflammatory diseases. J Clin Invest. 2001;107(1):7-11
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destructive enzymes including nitric oxide synthase, lipoxygenase, cyclooxygenase, and matrix
metalloproteinases including collagenase and gelatinase, which destroy connective tissue. Nitric oxide synthase
catalyses the formation of nitric oxide (NO-), which plays an important role in the development of peripheral
osteoarthritis111 and spinal disc degeneration112 via oxidative destruction of articular tissues. Cyclooxygenase
transforms arachidonic acid into prostaglandins and thromboxanes, which recruit leukocytes to the area of
inflammation, exacerbate edema, sensitize peripheral neurons to increased pain perception, and ultimately
facilitate the liberation of proteinases, such as matrix metaloproteinases, (MMP) which destroy joint structures.
Present in several isoforms, the lipoxygenase enzyme acts on arachidonic acid to produce leukotrienes that also
increase inflammation, joint destruction, and production of MMP. Overall, this same inflammatory response
plays a part in the genesis and perpetuation of numerous inflammatory disorders, such as osteoarthritis, cancer,
rheumatoid arthritis and other autoimmune diseases, and numerous conditions associated with pain and
inflammation. This process of NF-kappaB activation and modulation of genetic expression is illustrated in
Figures 1 and 2.
111) Pelletier JP, Martel-Pelletier J. Therapeutic targets in osteoarthritis: from today to tomorrow with new imaging technology. Ann Rheum Dis. 2003;62 Suppl 2:ii79-82
112) Kohyama K, Saura R, Doita M, Mizuno K. Intervertebral disc cell apoptosis by nitric oxide: biological understanding of intervertebral disc degeneration. Kobe J Med Sci. 2000;46(6):283-95
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Figure 1. The creation and activation of NF-kappaB—a crucial step in the amplification of proinflammatory gene
expression. Adapted from Vasquez A. Integrative Orthopedics. Natural Health Consulting Corp. (OptimalHealthResearch.com): 2004
subunit
p65
NF-kappaB is made from two subunit
proteins: p65 and p50.
subunit
p50
IkB:
NF-kappaB
In the cytosol, NF-kappaB is made
"inactive" by inhibitor KappaB.
inhibitor of NF
kappaB
P
P
P
IKK: IkB kinase
(alpha, beta,
and gamma)
P
P
IkB:
NF-kappaB
Exposure to 'stressful stimuli'
such as LPS or oxidative stress,
activates "inhibitory kappaB kinase",
which phosphorylates IkB for destruction.
inhibitor of NF
kappaB
P
Once IkB is destroyed, then
NF-kappaB is free to bind with DNA.
NF-kappaB
NF-kappaB enters the nucleus and binds with DNA
to activate genes which encode for the
increased production of inflammatory mediators.
IL-6
CRP
Prostaglandins
Cyclooxygenase-2
Thromboxanes
NF-kappaB
Inflammatory
genes
IL-1
Collagenase/MMP
Lipoxygenase
Inducible nitric
oxide synthase
TNF-a
Leukotrienes
Nitric oxide
Health problems:
Pain
Inflammation
Cardiovascular
disease,
thrombosis
Insulin resistance
Autoimmune and
rheumatic disease
Cancer
Neurodegeneration
Adhesion molecules
Increased production of inflammatory mediators
- such as cytokines, prostaglandins, leukotrienes promotes cellular dysfunction and tissue destruction.
11 of 58
Figure 2. Translation of environmental traumas into biochemical inflammation. Note the self-perpetuating “vicious
cycle” where inflammatory mediators promote additional inflammation via activation of NF-kappaB.
Environment and triggers
(highly variable and modifiable) Translation
Environmental stim uli:
"Stress"
Radiation
Oxidative stress
Injury
Bacterial LPS from
infection or "leaky gut"
Food and environmental
allergens
Viral infections
Consumption of
macronutrients: sugars >
lipids > protein
Arachidonic acid
metabolites such as
PG-E2
Nutrient-poor processed
food diet w ith insufficient
phytonutrition,
antioxidants, ALA, EPA,
DHA, GLA
Mediators
(modifiable w ith vitamins, minerals, foods,
fatty acids, botanicals, and drugs)
Genetic expression
(variable among individuals)
IL-6
Activation of
NF-KappaB
Increased expression
of pro-inflammatory
and anti-apoptotic
genes coding for
production of
cytokines, adhesion
molecules, and
pro-inflammatory
enzymes: iNOs, Cox,
Lipox
Events
CRP
Prostaglandins (PG-E2)
Cyclooxygenase-2
Thromboxanes
IL-1
Collagenase/MMP
Lipoxygenase
Inducible nitric
oxide synthase
Leukotrienes
Nitric oxide
TNF-a
Health problem s:
Pain
Inflammation
Cardiovascular
disease,
thrombosis
Insulin resistance
Autoimmune and
rheumatic disease
Cancer
Neurodegeneration
Adhesion molecules
IL-1, PG-E2
reactive oxygen species and oxidative stress
tumor necrosis factor and CRP
Activation of NF-kappaB results in the upregulation of genes which encode for the production of inflammatory
cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and IL-6 as well as enzymes with
generally proinflammatory effects such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2)
and the lipoxygenases (LIPOX). IL-6 stimulates production of C-reactive protein (CRP), which is a sensitive
serum marker of inflammation (such as in osteoarthritis and rheumatoid arthritis) and which is associated with
an increased risk of cardiovascular disease, progressively deteriorating health and “rapid biological aging” in
men and women.113,114 INOS increases production of the free radical nitric oxide which is elevated in
degenerating spinal discs115 and peripheral joints116 and which contributes directly to joint destruction via
destructive oxidation of articular tissues.117 COX-2 is responsible for the conversion of arachidonic acid to
prostaglandins, several of which increase the perception of pain by sensitizing peripheral nociceptors118 in
addition to having a central hyperalgesic effect119 and promoting the destruction of articular structures by
increasing production of proteolytic enzymes, variously named collagenases, gelatinases, and matrix
metalloproteinases.120 Similarly, LIPOX catalyzes the conversion of arachidonate to the leukotrienes, which,
promote swelling, inflammation, chemotaxis, and tissue destruction via release of increased quantities of
proteolytic enzymes. In their anti-inflammatory roles, LIPOX and COX also act on gamma-linolenic acid for
the production of the anti-inflammatory 15-HETrE and prostaglandin E-1, respectively, as well as on the omega3 fatty acids EPA and DHA for the production of anti-inflammatory prostaglandins, leukotrienes, docosatrienes,
and resolvins as discussed in the sections that follow. Our discussion of the mechanisms of anti-inflammatory
nutritional interventions must also include mention of the phytonutraceutical activation of peroxisome
proliferator-activated receptors (PPARs), since fatty acids and selected botanical medicines exert their actions at
least in part by activation of PPAR-alpha and PPAR-gamma, which then mediate health-promoting and antiinflammatory effects that are clinically significant. As fatty acid receptors that influence genetic expression via
113) Kushner I. C-reactive protein elevation can be caused by conditions other than inflammation and may reflect biologic aging. Cleve Clin J Med. 2001 Jun;68(6):535-7
114) Black S, Kushner I, Samols D. C-reactive Protein. J Biol Chem. 2004 Nov 19;279(47):48487-90
115) Kohyama K, Saura R, Doita M, Mizuno K. Intervertebral disc cell apoptosis by nitric oxide: biological understanding of intervertebral disc degeneration. Kobe J Med Sci. 2000;46(6):283-95
116) Pelletier JP, Martel-Pelletier J. Therapeutic targets in osteoarthritis: from today to tomorrow with new imaging technology. Ann Rheum Dis. 2003;62 Suppl 2:ii79-82
117) Amin AR, Dave M, Attur M, Abramson SB. COX-2, NO, and cartilage damage and repair. Curr Rheumatol Rep. 2000;2:447-53
118) Schaible HG, Ebersberger A, Von Banchet GS. Mechanisms of pain in arthritis. Ann N Y Acad Sci. 2002;966:343-54
119) Grubb BD. Peripheral and central mechanisms of pain. Br J Anaesth. 1998 Jul;81(1):8-11
120) Mertz PM, DeWitt DL, Stetler-Stevenson WG, Wahl LM. Interleukin 10 suppression of monocyte prostaglandin H synthase-2. Mechanism of inhibition of prostaglandin-dependent matrix metalloproteinase production. J Biol
Chem. 1994;269:21322-9
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suppression of NF-kappaB activation as well as via NF-kappaB-independent pathways, PPARs when activated
in moderation induce numerous beneficial physiologic responses, including direct and indirect antiinflammatory, anti-cancer, and cardioprotective effects.121,122,123 The biochemical flowchart beginning with the
dietary intake of fatty acids and ending in the catalyzed production of lipoxygenases and prostaglandins is
provided in Figure 3 for omega-3 fatty acids and in Figure 4 for omega-6 fatty acids.
Figure 3: Metabolism of omega-3 fatty acids and related eicosanoids.
From Vasquez A. Integrative Orthopedics. Natural
Health Consulting Corp. (OptimalHealthResearch.com): 2004
Physiologic and
nutrigenomic effects
Eicosanoid metabolism
Appears to
downregulate
inflammation (CRP,
IL-6) and prostaglandin
production
independently of its
actions on COX and
LOX; reduces nitric
oxide production
Omega-3
fatty acids
Alpha-linolenic acid
ALA 18:3n3
"essential fatty acid"
flax seed oil
delta-6-desaturase
very slow rate-limiting conversion
Requires: Zn, Mg, pyridoxine, iron
Facilitated by: vitamin C
Inhibited by: EPA, DHA, catecholamines
Stearidonic acid
18:4n3
small amount found in
black currant oil;
inhibits 5-lipoxygenase
3-series prostaglandins and thromboxanes
General actions: lower blood pressure, prevent clots,
block formation of 2-series PGs (which raise blood
pressure, promote clots, etc) from omega-6
elongase
Numerous nutrigenomic
effects which are generally
anti-inflammatory,
antiproliferative, and
anticarcinogenic; probably
modulates
neurotransmitter
production and reception;
reduces intracellular
calcium levels (thus
modifying muscle tone
and genetic expression);
suppression of NF-kappaB
and COX-2 expression via
PPARα and PPARγ
activation; reduces nitric
oxide production
n-3 Eicosatetraenoic
acid
20:4n3
PG-D3
Cyclooxygenase
inhibited by: ginger,
aspirin, DHA
PG-G3
delta-5-desaturase
PG-E3
peroxidase
liberation from
phospholipids by
phospholipase-A2
is reduced by prednisone,
cortisol, quercetin
and rutin
Eicosapentaenoic acid
EPA 20:5n3
fatty fish, fish oil, cod liver oil
elongase
Lipoxygenase
PG-H3
PG-F3a
PG-I3: reduces
arrhythmia,
fibrillation;
anti-inflammatory
5-series leukotrienes
TX-A3: reduces
arrhythmia and
fibrillation
LT-A5
LT-B5: inactive or anti-inflammatory
n-3 docosapentaenoic acid
n-3 DPA 22:5n3
production is increased by
n-6 fatty acids and by n-3 deficiency
Numerous nutrigenomic
effects which are
generally
anti-inflammatory,
antiproliferative, and
anticarcinogenic;
modulates
neurotransmitter
production and
reception; reduces
nitric oxide production
LT-C5
delta-4-desaturase
(very slow conversion)
Docosahexaenoic acid
DHA 22:6n3
fatty fish, fish oil, cod
liver oil, microalgae
liberation by phospholipase-A2
followed by actions of
lipoxygenase, cyclooxygenase,
random events, and
cell-cell interactions
Docosatrienes and resolvins:
reduce inflammation by inhibiting
cytokine expression and
neutrophil chemotaxis
121) Vanden Heuvel JP. Peroxisome proliferator-activated receptors: a critical link among fatty acids, gene expression and carcinogenesis. J Nutr. 1999 Feb;129(2S Suppl):575S-580S
122) Chinetti G, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors and inflammation: from basic science to clinical applications. Int J Obes Relat Metab Disord. 2003;27 Suppl 3:S41-5
123) Vamecq J, Latruffe N. Medical significance of peroxisome proliferator-activated receptors. Lancet. 1999;354(9173):141-8
13 of 58
Figure 4. Metabolism of omega-6 fatty acids and related eicosanoids.
From Vasquez A. Integrative Orthopedics. Natural
Health Consulting Corp. (OptimalHealthResearch.com): 2004
Physiologic and
nutrigenomic effects
activates
NF-kappaB;
tumor promoter;
displaces
arachidonate
from cell
membranes
Eicosanoid metabolism
Omega-6
fatty acids
Linoleic acid
LA 18:2n-6
nut, seed, and vegetable oils:
safflower oil (76%), sunflower oil
(71%), corn oil (57%), soybean oil
(54%), canola oil (21%)
13-S-HODE: possibly anticarcinogenic
15-lipoxygenase-1
delta-6-desaturase
very slow rate-limiting conversion
Impaired with deficiency of: Zn, Mg, pyridoxine,
iron, ascorbate, niacin, and riboflavin
Inhibited by: EPA, DHA, catecholamines
directly or
indirectly: favorably
modulates
?
adhesion
molecules and
hormone receptors;
mediates selective
cytotoxicity and
(re)differentiation;
activation of
PPAR-γ
Gamma-linolenic acid
GLA 18:3n-6
evening primrose oil, borage seed
oil, hemp oil, black currant seed oil
Vitamin C increases GLA
production from LA; EPA inhibits
GLA formation
PG-G1
PG-H1
PG-F1a
Cyclooxygenase
inhibited by:
ginger, turmeric,
holy basil, NSAIDs
elongase: rapid conversion
Dihomo gamma-linolenic acid
DGLA 20:3n-6
breast milk
phospholipase
A2
15-Lipoxygenase
Arachidonic acid
ARA 20:4n-6
(membrane bound)
Found in land animal fats:
beef, liver, pork, poultry, lamb.
Formation of ARA is inhibited
by EPA
Adrenic acid
22:4n-6
PG-I2 (prostacyclin): produced by
COX-2; decreases platelet
aggregation; lowers blood pressure;
increases pain and neonatal
adipogenesis
LO X
-2
5-Lipoxygenase
inhibited by Boswellia
hase
PGE synt
PG
synth F
ase
D
PG
thromboxane A
synthase
e
as
nth
sy
Prostaglandin E2 (PG-E2): promotes
inflam mation, chemotaxis, and edema;
sensitizes neurons to increased duration
and intensity of pain perception; induces
fever in the hypothalamus, protects
gastric mucosa, reduces apoptosis and
promotes cancer, induces COX, increases
IgE production; upregulates arom atase;
increased by nitric oxide
Thromboxane A2:
produced by COX-1;
increases platelet
aggregation
PG-A2
5-HPETE:
promotes
tissue
destruction
via lysozymes
LT-A4
synthase
5-HETE
PG-H2
rapid platelet
aggregation
12-HPETE
12-S-HETE: certainly
procarcinogenic
12-HPETE
12-R-HETE:
procarcinogenic
15-HPETE
15-S-HETE: possibly
anticarcinogenic
15-
PG-G2
rapid platelet
aggregation
Prostaglandin hydroperoxidase
(PGH synthase,
requires two glutathione)
PG
synth I
ase
LO
8OX
S -L
1 212-R-LOX
free
arachidonic acid
delta-4-desaturase
n-6 docosapentaenoic acid
22:5n-6
8-HETE: procarcinogenic
X
nonenzymatic
peroxidation
liberation from
phospholipids by
phospholipase-A2
Inhibited by
prednisone,cortisol,
quercetin, rutin, DHA
Cyclooxygenase
inhibited by:
NSAIDs, ginger,
turmeric, EPA,
gamma-tocopherol
elongase
15-HETrE: strongly reduces production of
5-lipoxygenase arachidonate metabolites
8-iso-PG-E2 and
8-iso-PG-F2-alpha:
increase pain and
inflammation
delta-5-desaturase
(very slow conversion, inhibited by EPA and DHA;
most arachidonic acid comes directly from the diet)
inhibited by: catecholamines
activates NF-kappaB;
increases superoxide
generation; impairs
several pathways of
cytochrome P450
detoxification
peroxidase
Prostaglandin E-1: PGE-1
Production is promoted by
melatonin, ethanol,
vitamin C.
Actions: antiinflammatory,
vasodilation, inhibits
platelet aggregation.
Collagenases/ matrix
metaloproteinases
facilitate j oint
destruction; promoted by
PG-F2a and 5-HPET E;
formation is inhibited by
EPA and inhibition of
COX and LIPOX
PG-F2a: increases uterine
contractions, increased
levels associated with
dysmenorrhea, formation
suppressed by vitamin C
PG-D2: exacerbates allergies;
promotes cartilage generation
LT-A4*: in general,
all of the series-4
leukotrienes are
pro-inflammatory
12-LOX
or
15-LOX
Lipoxin
A4
and
B4
LT -B4
synthase
LT-C4*: form ation
requires glutathione;
promotes muscle
contraction,
bronchoconstriction,
edema
LT-D4*: promotes
muscle contraction,
bronchoconstriction,
edema
LT-E4*: sm ooth muscle
contraction, more
powerful than histamine,
elevated in asthma
LT-B4: im munosuppressive;
increases edema and
chemotaxis; induces
release of lysosomal
enzymes, increases
reactive oxygen
species, enhances
production of TNF-a,
IL-1, and IL-6;
procarcinogenic
*cysteinyl leukotrienes are
key mediators of allergic
inflammation
PG-J2: possible upregulation
of angiogenesis and MMP-1
T X-B2: inactive
PG-B2
14 of 58
The process of inflammation is not unalterable, nor must pharmaceutical drugs always be employed to modify
its course. Numerous dietary, nutritional, and botanical medicines can favorably influence this pathway and the
resultant clinical sequelae. Unlike pharmaceutical drugs which are generally designed to target a specific,
isolated event along the cascade (as seen with selective cox-2 inhibitors), natural therapeutics generally
intervene at numerous junctures, thus allowing for safe yet powerful clinical benefit, generally with nonexistent
or negligible adverse effects. Now that readers have a conceptual overview of the inflammatory process,
understanding the mechanisms of action for each of the clinical therapeutics listed below will be greatly
facilitated.
Nutrition Against Disease: Interventional Nutrition for the Natural Alleviation of Inflammation and
Promotion of Optimal Health
An altruistic interest in our patients’ care and adherence to scientific principles converge to direct us against the
use of popular symptom-suppressing and anti-inflammatory chemical drugs which all-too-often accelerate joint
destruction124 and premature mortality125,126 and to instead choose a more rational and holistic approach that
improves long-term health outcomes.127,128,129 It is important to note that inflammation is a systemic, body-wide
phenomenon which is more appropriately and effectively ameliorated by whole-body improvements than it is to
single-intervention therapies that target isolated enzymes and biochemical processes.
The pro-inflammatory nature of the standard American diet: The typical American/Western diet is
proinflammatory in nature and contributes directly to the initiation and exacerbation of chronic inflammation
and disorders such as joint destruction, diabetes mellitus, cardiovascular disease, and cancer.130,131,132,133 The
chiropractic physician Dr. David Seaman134 deserves recognition and accolades for his 2002 review of the
literature published wherein he proposed the proinflammatory nature of the standard Western diet—typified by
the common American diet with an abundance of omega-6 and trans fatty acids, simple sugars and starches, and
nutritionally-depleted convenience foods and a serious deficiency of vitamins, minerals, omega-3 fatty acids,
and phytonutrients. The concepts that Dr. Seaman promoted as a hypothesis a mere 3 years ago have by this
time been scientifically validated in clinical trials in humans. While it has long-been documented that increased
consumption of refined grains and carbohydrates correlated with the rapid and population-wide onset of
“diseases of Western civilization” such as diabetes, arthritis, cardiovascular disease, cancer, and
neuropsychiatric illness135, we are only now beginning to understand the biochemical and physiologic
mechanisms by which dietary components influence physiologic function and, ultimately, health and disease.
Consumption of refined “simple” carbohydrates such as sugar, white bread, pastry, candy, and fruit juice
generally leads to a rapid increase in blood glucose followed by an accompanying increase in insulin. While it
is well known that elevation in blood glucose following consumption of sugar or fruit juice results in oxidative
stress136 and to suppression of immune function (inhibition of neutrophil-mediated bacterial phagocytosis137) for
several hours, only recently has glucose consumption (75 grams; 300 calories) been shown to directly promote
inflammation and to increase expression of chondrolytic enzymes such as MMP-2 and MMP-9138, higher levels
of which correlate with and appear to contribute to the progression of joint destruction.139 Wheat consumption
126) Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med. 1998 Jul 27; 105(1B): 31S-38S
127) Knoops KT, de Groot LC, Kromhout D, Perrin AE, Moreiras-Varela O, Menotti A, van Staveren WA. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA.
2004 Sep 22;292(12):1433-9
129) O'Keefe JH Jr, Harris WS. From Inuit to implementation: omega-3 fatty acids come of age. Mayo Clin Proc. 2000 Jun;75(6):607-14
130) Aljada A, Mohanty P, Ghanim H, Abdo T, Tripathy D, Chaudhuri A, Dandona P. Increase in intranuclear nuclear factor kappaB and decrease in inhibitor kappaB in mononuclear cells after a mixed meal: evidence for a
proinflammatory effect. Am J Clin Nutr. 2004;79(4):682-90
2004 Sep 22;292(12):1433-9
132) Seaman DR. The diet-induced proinflammatory state: a cause of chronic pain and other degenerative diseases? J Manipulative Physiol Ther. 2002;25(3):168-79
133) Cordain L. The Paleo Diet: Lose Weight and Get Healthy by Eating the Food You Were Designed to Eat. Indianapolis; John Wiley and Sons, 2002
135) Price WA. Nutrition and Physical Degeneration: A Comparison of Primitive and Modern Diets and Their Effects. Santa Monica; Price-Pottinger Nutrition Foundation: 1945
136) Mohanty P, Hamouda W, Garg R, Aljada A, Ghanim H, Dandona P. Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J Clin Endocrinol Metab. 2000;85(8):2970-3
137) Sanchez A, Reeser JL, Lau HS, Yahiku PY, Willard RE, McMillan PJ, Cho SY, Magie AR, Register UD. Role of sugars in human neutrophilic phagocytosis. Am J Clin Nutr. 1973;26(11):1180-4
138) Aljada A, Ghanim H, Mohanty P, Syed T, Bandyopadhyay A, Dandona P. Glucose intake induces an increase in activator protein 1 and early growth response 1 binding activities, in the expression of tissue factor and matrix
metalloproteinase in mononuclear cells, and in plasma tissue factor and matrix metalloproteinase concentrations. Am J Clin Nutr 2004 Jul;80(1):51-7
139) Marini S, Fasciglione GF, Monteleone G, Maiotti M, Tarantino U, Coletta M. A correlation between knee cartilage degradation observed by arthroscopy and synovial proteinases activities. Clin Biochem. 2003;36:295-304
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has been shown to trigger migraine headaches140 in certain patients, and in recent experimental studies the wheat
protein gliadin was shown to induce a pro-inflammatory effect via activation of NF-kappaB.141,142 Cow’s milk
can contribute to adverse effects that can include migraine headache143, otitis media144, and joint
inflammation145,146, and it is a rich source of emulsified arachidonic acid which is the precursor to prostaglandins
and leukotrienes and their pain-enhancing and joint-destroying properties via prostaglandin-E2 (PG-E2), PG-I2
and PG-F2α, leukotriene-B4, and 5-HETE as illustrated in Figure 4. Rich sources of arachidonic acid such as
cow’s milk, beef, liver, pork, and other grain-fed land animal meats add fuel to the inflammatory fire by
providing the biochemical precursor (arachidonic acid) which is necessary for the production of prostaglandins,
thromboxanes, and leukotrienes that promote and perpetuate processes such as atherosclerosis147, cancer148,
arthritis and joint destruction.149 To demonstrate the pro-inflammatory effect of a typical Western meal, Aljada
et al150 administered a single meal of egg and sausage muffin sandwiches with 2 hash browns and documented a
postprandial increase of 150% for NF-kappaB (from ~190 to ~510 AUC) which lasted for approximately 2
hours and was associated with increases in oxidative stress and the inflammatory marker CRP. Thus, data are
consistent with the general conclusion that typical Western dietary components including refined carbohydrates,
cow’s milk, wheat, and arachidonate-rich animal products will promote pain, free-radical damage,
immunosuppression, inflammation, and numerous diseases via molecular, immunologic, and biochemical
mechanisms. By extension, treatment of “inflammatory diseases” without addressing the proinflammatory
nature of the patient’s diet becomes questionable; anti-inflammatory efficacy almost always improved following
dietary improvements as described here.
The Supplemented Paleo-Mediterranean Diet: The health-promoting diet of choice for the majority of
people is a diet based on abundant consumption of fruits, vegetables, seeds, nuts, omega-3 and monounsaturated
fatty acids, lean meats and fish. This diet prohibits and obviates overconsumption of chemical preservatives,
artificial sweeteners, and carbohydrate-dominant foods such as candies, pastries, breads, potatoes, grains, and
other foods with a high glycemic load and high glycemic index. This “Paleo-Mediterranean Diet” is a
combination of the “Paleolithic” or “Paleo diet” and the well-known “Mediterranean diet”, both of which are
well described in peer-reviewed journals and the lay press. The Mediterranean diet is characterized by increased
proportions of legumes, nuts, seeds, whole grain products, fruits, vegetables (including potatoes), fish and lean
meats, and monounsaturated and n-3 fatty acids.151 Consumption of this diet is consistently associated with
improvements in insulin sensitivity and reductions in cardiovascular disease, diabetes, cancer, and all-cause
mortality.152 The Paleolithic diet detailed by collaborators Eaton153, O’Keefe154, and Cordain155 is similar to the
Mediterranean diet except for stronger emphasis on fruits and vegetables (preferably raw or minimally cooked),
omega-3-rich lean meats, and reduced consumption of starchy foods such as potatoes and grains, the latter of
which were not staples in the human diet until the last few thousand years. Emphasizing the olive oil and red
wine of the Mediterranean diet and the absence of grains and potatoes per the Paleo diet appears to be the way to
get the best of both dietary worlds; the remaining diet is characterized by fresh whole fruits, vegetables, nuts
(especially almonds), seeds, olive oil, lean meats rich in n-3 fatty acids, and red wine in moderation. In sum,
this dietary plan along with the inclusion of garlic and dark chocolate (a rich source of cardioprotective,
140) Grant EC. Food allergies and migraine. Lancet. 1979; 1(8123):966-9
141) Maiuri MC, De Stefano D, Mele G, Iovine B, Bevilacqua MA, Greco L, Auricchio S, Carnuccio R. Gliadin increases iNOS gene expression in interferon-gamma-stimulated RAW 264.7 cells through a mechanism involving NFkappa B. Naunyn Schmiedebergs Arch Pharmacol. 2003;368(1):63-71
142) Jelinkova L, Tuckova L, Cinova J, Flegelova Z, Tlaskalova-Hogenova H. Gliadin stimulates human monocytes to production of IL-8 and TNF-alpha through a mechanism involving NF-kappaB. FEBS Lett. 2004;571:81-5
143) Grant EC. Food allergies and migraine. Lancet. 1979; 1(8123):966-9
144) Juntti H, Tikkanen S, Kokkonen J, Alho OP, Niinimaki A. Cow's milk allergy is associated with recurrent otitis media during childhood. Acta Otolaryngol. 1999;119:867-73
145) Panush RS, Stroud RM, Webster EM. Food-induced (allergic) arthritis. Inflammatory arthritis exacerbated by milk. Arthritis Rheum. 1986;29(2):220-6
146) Golding DN. Is there an allergic synovitis? J R Soc Med. 1990;83(5):312-4
147) Dwyer JH, Allayee H, Dwyer KM, Fan J, Wu H, Mar R, Lusis AJ, Mehrabian M. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med. 2004;350(1):29-37
148) Romano M, Claria J. Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: implications for cancer therapy. FASEB J. 2003 Nov;17(14):1986-95
149) Mertz PM, DeWitt DL, Stetler-Stevenson WG, Wahl LM. Interleukin 10 suppression of monocyte prostaglandin H synthase-2. Mechanism of inhibition of prostaglandin-dependent matrix metalloproteinase production. J Biol
Chem. 1994;269:21322-9
150) Aljada A, Mohanty P, Ghanim H, Abdo T, Tripathy D, Chaudhuri A, Dandona P. Increase in intranuclear nuclear factor kappaB and decrease in inhibitor kappaB in mononuclear cells after a mixed meal: evidence for a
proinflammatory effect. Am J Clin Nutr. 2004;79(4):682-90
151) Curtis BM, O'Keefe JH Jr. Understanding the Mediterranean diet. Could this be the new "gold standard" for heart disease prevention? Postgrad Med. 2002 Aug;112(2):35-8, 41-5
http://www.postgradmed.com/issues/2002/08_02/curtis.htm
2004 Sep 22;292(12):1433-9
153) Eaton SB, Shostak M, Konner M. The Paleolithic Prescription: A program of diet & exercise and a design for living, New York: Harper & Row, 1988
154) O'Keefe JH Jr, Cordain L. Cardiovascular disease resulting from a diet and lifestyle at odds with our Paleolithic genome: how to become a 21st-century hunter-gatherer. Mayo Clin Proc. 2004 Jan;79(1):101-8
155) Cordain L. The Paleo Diet: Lose Weight and Get Healthy by Eating the Food You Were Designed to Eat. Indianapolis; John Wiley and Sons, 2002
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antioxidative, and anti-inflammatory polyphenolic flavonoids156,157) is expected to reduce adverse cardiovascular
events by more than 76%.158
Biochemical justification for this type of diet is ample and is well supported by numerous long-term studies in
humans wherein both Mediterranean and Paleolithic diets result in dramatic reductions in disease-specific and
all-cause mortality.159,160,161,162 Diets rich in fruits and vegetables are sources of more than 5,000
phytochemicals, many of which have antioxidant, anti-inflammatory, and anti-cancer properties.163 Oleic acid,
squalene, and phenolics in olive oil and phenolics and resveratrol in red wine have antioxidant, antiinflammatory, and anti-cancer properties and also protect against cardiovascular disease.164 N-3 fatty acids have
numerous health benefits via multiple mechanisms as described in the sections that follow. Increased intake of
dietary fiber from fruits and vegetable favorably modifies gut flora, promotes xenobiotic elimination (via flora
modification, laxation, and overall reductions in enterohepatic recirculation), and is associated with reductions
in morbidity and mortality. Such a “Paleolithic diet” can also lead to urinary alkalinization (average urine pH of
≥ 7.5 according to Sebastian et al165) which increases renal retention of minerals for improved musculoskeletal
health166,167,168 and which increases urinary elimination of many toxicants and xenobiotics for a tremendous
reduction in serum levels and thus adverse effects from chemical exposure or drug overdose.169 Furthermore,
therapeutic alkalinization was recently shown in an open trial with 82 patients to reduce symptoms and disability
associated with low-back pain and to increase intracellular magnesium concentrations by 11%.170 Ample intake
of amino acids via dietary proteins supports phase-2 detoxification (amino acid and sulfate conjugation) for
proper xenobiotic elimination171,172, provides amino acid precursors for neurotransmitter synthesis and
maintenance of mood, memory, and cognitive performance173,174,175,176, and prevents the immunosuppression and
decrements in musculoskeletal status caused by low-protein diets.177
Described here for the first time, the “supplemented Paleo-Mediterranean diet” provides patients the best of
current knowledge in nutrition by relying on a foundational diet plan of fresh nuts, seeds, fruits, vegetables, fish,
and lean meats which is adorned with olive oil for its squalene, phenolic antioxidant/anti-inflammatory and
monounsaturated fatty acid content. Inclusive of medical foods such as red wine, garlic, and dark chocolate
which may synergize to effect at least a 76% reduction in cardiovascular disease178, this diet is supplemented
with rational doses of additional vitamins, minerals, and fatty acids for reasons described in the sections that
follow.
Multivitamin/multimineral supplementation (excluding iron and excess vitamin A and including
additional vitamin D): Leading pioneers in the science of nutritional medicine include the late Roger Williams,
whose classic texts Biochemical Individuality179 in 1956 and Nutrition Against Disease180 in 1971 established
156) Schramm DD, Wang JF, Holt RR, Ensunsa JL, Gonsalves JL, Lazarus SA, Schmitz HH, German JB, Keen CL. Chocolate procyanidins decrease the leukotriene-prostacyclin ratio in humans and human aortic endothelial
cells. Am J Clin Nutr. 2001;73(1):36-40
157) Engler MB, Engler MM, Chen CY, et al. Flavonoid-rich dark chocolate improves endothelial function and increases plasma epicatechin concentrations in healthy adults. J Am Coll Nutr. 2004;23(3):197-204
158) Franco OH, Bonneux L, de Laet C, Peeters A, Steyerberg EW, Mackenbach JP. The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%.
BMJ. 2004;329(7480):1447-50
159) de Lorgeril M, Salen P, Martin JL, Monjaud I, Boucher P, Mamelle N. Mediterranean dietary pattern in a randomized trial: prolonged survival and possible reduced cancer rate. Arch Intern Med. 1998 Jun 8;158(11):1181-7
2004 Sep 22;292(12):1433-9
161) Lindeberg S, Cordain L, and Eaton SB. Biological and clinical potential of a Paleolithic diet. J Nutri Environ Med 2003; 13:149-160
162) O'Keefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004 Jun 2;43(11):2142-6
163) Liu RH. Health benefits of fruit and vegetables are from additive and synergistic combinations of phytochemicals. Am J Clin Nutr. 2003 Sep;78(3 Suppl):517S-520S
164) Alarcon de la Lastra C, Barranco MD, Motilva V, Herrerias JM. Mediterranean diet and health: biological importance of olive oil. Curr Pharm Des. 2001;7:933-50
165) Sebastian A, Frassetto LA, Sellmeyer DE, Merriam RL, Morris RC Jr. Estimation of the net acid load of the diet of ancestral preagricultural Homo sapiens and their hominid ancestors. Am J Clin Nutr 2002;76:1308-16
166) Sebastian A, Harris ST, Ottaway JH, Todd KM, Morris RC Jr. Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate. N Engl J Med. 1994;330(25):1776-81
167) Tucker KL, Hannan MT, Chen H, Cupples LA, Wilson PW, Kiel DP. Potassium, magnesium, and fruit and vegetable intakes are associated with greater bone mineral density in elderly men and women. Am J Clin Nutr.
1999;69(4):727-36
168) Whiting SJ, Boyle JL, Thompson A, Mirwald RL, Faulkner RA. Dietary protein, phosphorus and potassium are beneficial to bone mineral density in adult men consuming adequate dietary calcium. J Am Coll Nutr.
2002;21(5):402-9
169) Proudfoot AT, Krenzelok EP, Vale JA. Position Paper on urine alkalinization. J Toxicol Clin Toxicol. 2004;42(1):1-26
170) "The results show that a disturbed acid-base balance may contribute to the symptoms of low back pain. The simple and safe addition of an alkaline multimineral preparate was able to reduce the pain symptoms in these
patients with chronic low back pain." Vormann J,Worlitschek M,Goedecke T,Silver B. Supplementation with alkaline minerals reduces symptoms in patients with chronic low back pain. J Trace Elem Med Biol. 2001;15(2-3):179-83
171) Liska DJ. The detoxification enzyme systems. Altern Med Rev. 1998;3:187-9
172) Anderson KE, Kappas A. Dietary regulation of cytochrome P450. Annu Rev Nutr. 1991;11:141-67
173) Rogers RD, Tunbridge EM, Bhagwagar Z, Drevets WC, Sahakian BJ, Carter CS. Tryptophan depletion alters the decision-making of healthy volunteers through altered processing of reward cues.
Neuropsychopharmacology. 2003;28:153-62 Accessed at http://www.acnp.org/sciweb/journal/Npp062402336/default.htm on November 10, 2004
174) Arnulf I, Quintin P, Alvarez JC, Vigil L, Touitou Y, Lebre AS, Bellenger A, Varoquaux O, Derenne JP, Allilaire JF, Benkelfat C, Leboyer M. Mid-morning tryptophan depletion delays REM sleep onset in healthy subjects.
Neuropsychopharmacology. 2002;27(5):843-51 Accessed at http://www.acnp.org/sciweb/journal/Npp042502293/default.htm on November 10, 2004
175) Thomas JR, Lockwood PA, Singh A, Deuster PA. Tyrosine improves working memory in a multitasking environment. Pharmacol Biochem Behav. 1999;64:495-500
176) Markus CR, Olivier B, Panhuysen GE, Van Der Gugten J, Alles MS, Tuiten A, Westenberg HG, Fekkes D, Koppeschaar HF, de Haan EE. The bovine protein alpha-lactalbumin increases the plasma ratio of tryptophan to the
other large neutral amino acids, and in vulnerable subjects raises brain serotonin activity, reduces cortisol concentration, and improves mood under stress. Am J Clin Nutr. 2000;71:1536-44
177) Castaneda C, Charnley JM, Evans WJ, Crim MC. Elderly women accommodate to a low-protein diet with losses of body cell mass, muscle function, and immune response. Am J Clin Nutr. 1995;62:30-9
178) Franco OH, Bonneux L, de Laet C, Peeters A, Steyerberg EW, Mackenbach JP. The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%.
BMJ. 2004;329(7480):1447-50
179) Williams RJ. Biochemical Individuality : The Basis for the Genetotrophic Concept. Austin and London: University of Texas Press, 1956
180) Williams RJ. Nutrition Against Disease: Environmental Prevention. New York: Pitman Publishing. 1971
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the scientific and conceptual rationale for the use of interventional nutrition for the preservation of health and in
the treatment of human disease, and Linus Pauling, whose concept of using the “right molecules” such as
vitamins, minerals, and other dietary factors opened the field of “orthomolecular medicine.”181,182 More recently,
Robert Heaney183 advanced our understanding of the adverse effects of chronic subclinical nutritional
deficiencies with the phrase “long-latency deficiency diseases”, and Bruce Ames has helped us appreciate the
importance and biochemical/physiologic mechanisms of optimal nutrition184 and high-dose vitamin
supplementation185, respectively. Although practitioners of natural healthcare have long advocated the use of
supplemental vitamins and minerals, the value of this health-promoting practice has only recently been
conceded by allopathic groups such as Harvard Medical School and the American Medical Association186 who
stated in 2002 that, “Most people do not consume an optimal amount of all vitamins by diet alone” and “…it
appears prudent for all adults to take vitamin supplements.” Vitamin and mineral supplementation helps
compensate for inadequacies of foods grown in depleted soils or by non-organic techniques187,188, and to ensure
adequate nutritional intake during times of dietary indiscretion (reduced intake) or illness (increased utilization
or excretion). Since vitamins commonly function as enzyme cofactors, their daily consumption is required to
maintain enzymatic activities, and their provision in supraphysiologic quantities can be used to overcome
genotrophic defects and facilitate activity in variant (ie, “slow” or “defective”) enzymes.189 Vitamin E
supplementation must be in the form of mixed tocopherols and include a high (~40%) percentage of gammatocopherol190 to avoid the purported adverse effects of alpha-tocopherol when used alone191, and vitamin E
appears to improve the action of insulin192 and to ameliorate neurodegenerative disorders193, osteoarthritis
pain194,195, inflammation in diabetics196, and may provide protection against the effects of urban pollution.197
Excess vitamin A clearly carries a risk of hepatotoxicity198 and is controversially associated with an increased
risk for birth defects when consumed in doses greater than 10,000 IU per day by pregnant women. The most
notable exception to the generally health-promoting benefits of mineral supplementation is iron, which should
not be administered to those who are not iron deficient due to its oxidative and oncogenic properties.199 Indeed,
iron overload is quite common in the general population200 and particularly among patients with musculoskeletal
pain201,202,203 and is causatively associated with numerous maladies including cardiovascular disease204,205,
cancer206,207, diabetes mellitus208, hypogonadism and infertility209, thyroid disorders210, infectious disease211, and
spinal and peripheral arthropathy.212,213,214,215
Vitamin D deserves special attention in the discussion of vitamins, particularly in light of the recent upsurge in
research documenting its manifold health benefits216,217 and the importance of obtaining and maintaining optimal serum
181) Pauling L. Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease. Science. 1968;160:265-71
182) Pauling L, Wyatt RJ, Klein DF, Lipton MA. On the orthomolecular environment of the mind: orthomolecular theory. Am J Psychiatry. 1974;131:1251-67
183) Heaney RP. Long-latency deficiency disease: insights from calcium and vitamin D. Am J Clin Nutr. 2003;78:912-9
184) Ames BN. The metabolic tune-up: metabolic harmony and disease prevention. J Nutr. 2003 May;133(5 Suppl 1):1544S-8S
185) Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms. Am J Clin Nutr.
2002 Apr;75(4):616-58
186) Fletcher RH, Fairfield KM. Vitamins for chronic disease prevention in adults: clinical applications. JAMA. 2002;287:3127-9
187) Worthington V. Nutritional quality of organic versus conventional fruits, vegetables, and grains. J Altern Complement Med. 2001;7:161-73
188) Ren H, Endo H, Hayashi T. The superiority of organically cultivated vegetables to general ones regarding antimutagenic activities. Mutat Res. 2001 Sep 20;496(1-2):83-8
2002 Apr;75(4):616-58
190) Jiang Q, Christen S, Shigenaga MK, Ames BN. gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr. 2001;74:714-22
191) Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality. Ann Intern Med. 2004 Nov 10; [Epub ahead of print
at http://www.annals.org on November 10, 2004]
192) Caballero B. Vitamin E improves the action of insulin. Nutr Rev. 1993;51:339-40
193) Di Matteo V,Esposito E.Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer's disease, Parkinson's disease,and amyotrophic lateral sclerosis.Curr Drug Targets CNS Neurol Disord.2003;2:95-107
194) Edmonds SE, Winyard PG, Guo R, Kidd B, Merry P, Langrish-Smith A, Hansen C, Ramm S, Blake DR. Putative analgesic activity of repeated oral doses of vitamin E in the treatment of rheumatoid arthritis. Results of a
prospective placebo controlled double blind trial. Ann Rheum Dis. 1997;56:649-55
195) Machtey I, Ouaknine L. Tocopherol in Osteoarthritis: a controlled pilot study. J Am Geriatr Soc. 1978 Jul;26(7):328-30
196) Upritchard JE, Sutherland WH, Mann JI. Effect of supplementation with tomato juice, vitamin E, and vitamin C on LDL oxidation and products of inflammatory activity in type 2 diabetes. Diabetes Care. 2000;23:733-8
197) Menzel DB. Nutritional needs in environmental intoxication: vitamin E and air pollution, an example. Environ Health Perspect. 1979;29:105-14
198) "The smallest continuous daily consumption leading to cirrhosis was 25,000 IU during 6 years, whereas higher daily doses (greater than or equal to 100,000 IU) taken during 2 1/2 years resulted in similar histological lesions.
... The data also indicate that prolonged and continuous consumption of doses in the low "therapeutic" range can result in life-threatening liver damage." Geubel AP, De Galocsy C, Alves N, Rahier J, Dive C. Liver damage
caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases. Gastroenterology. 1991 Jun;100(6):1701-9
199) Hollan S, Johansen KS. Adequate iron stores and the 'Nil nocere' principle. Haematologia (Budap). 1993;25(2):69-84
200) Olynyk JK, Bacon BR. Hereditary hemochromatosis. Detecting and correcting iron overload. Postgrad Med. 1994;96(5):151-8, 161, 165
201) M'Seffar A, Fornasier VL, Fox IH. Arthropathy as the major clinical indicator of occult iron storage disease. JAMA. 1977;238:1825-8
202) Axford JS, Bomford A, Revell P, Watt I, Williams R, Hamilton EB. Hip arthropathy in genetic hemochromatosis. Radiographic and histologic features. Arthritis Rheum. 1991;34(3):357-61
203) Olynyk J, Hall P, Ahern M, Kwiatek R, Mackinnon M. Screening for genetic haemochromatosis in a rheumatology clinic. Aust N Z J Med. 1994;24(1):22-5
204) Salonen JT, Nyyssonen K, Korpela H, Tuomilehto J, Seppanen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation. 1992;86(3):803-11
205) Sullivan JL. Iron and the sex difference in heart disease risk. Lancet. 1981;1(8233):1293-4
206) Stevens RG, Graubard BI, Micozzi MS, Neriishi K, Blumberg BS. Moderate elevation of body iron level and increased risk of cancer occurrence and death. Int J Cancer. 1994;56(3):364-9
207) Stevens RG, Jones DY, Micozzi MS, Taylor PR. Body iron stores and the risk of cancer. N Engl J Med. 1988 Oct 20;319(16):1047-52
208) Phelps G, Chapman I, Hall P, Braund W, Mackinnon M. Prevalence of genetic haemochromatosis among diabetic patients. Lancet. 1989;2(8657):233-4
209) Tweed MJ, Roland JM. Haemochromatosis as an endocrine cause of subfertility. BMJ. 1998;316(7135):915-6
210) Edwards CQ, Kelly TM, Ellwein G, Kushner JP. Thyroid disease in hemochromatosis. Increased incidence in homozygous men. Arch Intern Med. 1983;143(10):1890-3
211) Brock JH. Iron and the outcome of infection. Br Med J (Clin Res Ed). 1986;293(6546):518-20
212) Bywaters EG, Hamilton EB, Williams R. The spine in idiopathic haemochromatosis. Ann Rheum Dis. 1971;30(5):453-6
213) M'Seffar A, Fornasier VL, Fox IH. Arthropathy as the major clinical indicator of occult iron storage disease. JAMA. 1977;238:1825-8
214) Axford JS, Bomford A, Revell P, Watt I, Williams R, Hamilton EB. Hip arthropathy in genetic hemochromatosis. Radiographic and histologic features. Arthritis Rheum. 1991;34(3):357-61
215) Olynyk J, Hall P, Ahern M, Kwiatek R, Mackinnon M. Screening for genetic haemochromatosis in a rheumatology clinic. Aust N Z J Med. 1994;24(1):22-5
216) Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004;79:362-71
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levels.218 Although cholecalciferol is a prehormone naturally produced in the skin by chemical reactions induced by
exposure to sunlight (UVB radiation), it is also found in small amounts in a few foods and is therefore also referred to as
“vitamin D.” Insufficient dietary sources of vitamin D along with insufficient sun exposure have created an epidemic of
vitamin D deficiency in America219 and other industrialized nations220 which contributes to the development of mental
depression221,222,223, diabetes mellitus224,225, cancer226,227, hypertension228,229, cardiovascular disease230, polycystic ovary
syndrome231, migraine headaches232,233, and autoimmune/inflammatory disorders234 such as type-1 diabetes235, and multiple
sclerosis.236 The research indicates that risk for and severity of many of these and other illnesses can be safely reduced with
the use of vitamin D in daily doses of 1,000 IU for infants, 2,000 IU for children, and up to 4,000 IU for adults as we have
recently justified elsewhere237 provided that serum calcium is periodically assessed monitor for hypercalcemia, the most
reliable sign of vitamin D excess. Doctors can easily assess vitamin D status with measurement of serum 25-OH-vitamin
D, and we recently proposed that serum levels of 40 - 65 ng/mL (100 - 160 nmol/L) as shown in Figure 5 from Vasquez238
and Vasquez et al239 will provide optimal protection from the many diseases associated with vitamin D deficiency while
minimizing risk for adverse effects. Chiropractic and naturopathic physicians are aware that vitamin D deficiency is
common in patients with generalized musculoskeletal pain240 and low-back pain241, that vitamin D has anti-inflammatory
benefits242,243,244, and that treatment with vitamin D can safely lead to dramatic reductions in musculoskeletal pain in a large
percentage of patients.245,246
Figure 5. Proposed normal and optimal ranges for serum 25(OH)D levels based on
current research. From Vasquez A. Integrative Orthopedics.. (OptimalHealthResearch.com): 2004
Excess vitamin D > 80 ng/mL (200 nmol/L)
Proposed optimal range 40 - 65 ng/mL (100 - 160 nmol/L)
Insufficiency range < 20- 40 ng/mL (50 - 100 nmol/L)
Deficiency < 20 ng/mL (50 nmol/L)
217) Zittermannn A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr. 2003;89(5):552-72
218) Vasquez A, Manso G, Cannell J. The Clinical Importance of Vitamin D (Cholecalciferol): A Paradigm Shift with Implications for All Healthcare Providers. Alternative Therapies in Health and Medicine 2004; 10: 28-37
219) Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, Vamvakas EC, Dick IM, Prince RL, Finkelstein JS. Hypovitaminosis D in medical inpatients. N Engl J Med. 1998;338:777-83
220) Kauppinen-Makelin R, Tahtela R, Loyttyniemi E, Karkkainen J, Valimaki MJ. A high prevalence of hypovitaminosis D in Finnish medical in- and outpatients. J Intern Med. 2001;249(6):559-63
221) Gloth FM 3rd, Alam W, Hollis B. Vitamin D vs broad spectrum phototherapy in the treatment of seasonal affective disorder. J Nutr Health Aging 1999;3(1):5-7
222) Lansdowne AT, Provost SC. Vitamin D3 enhances mood in healthy subjects during winter. Psychopharmacology (Berl). 1998;135:319-23
223) Vieth R, Kimball S, Hu A, Walfish PG. Randomized comparison of the effects of the vitamin D3 adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients. Nutr J. 2004;3(1):8
224) Chiu KC, Chu A, Vay LWG, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr. 2004; 79:820-5
225) Borissova AM, Tankova T, Kirilov G, Dakovska L, Kovacheva R. The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int J Clin Pract. 2003;57(4):258-61
226) Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer. 2002;94(6):1867-75
227) Grant WB. Ecologic studies of solar UV-B radiation and cancer mortality rates. Recent Results Cancer Res. 2003;164:371-7
228) Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C. Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab.
2001;86(4):1633-7
229) Krause R, Buhring M, Hopfenmuller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet. 1998;352(9129):709-10
230) Scragg R, Jackson R, Holdaway IM, Lim T, Beaglehole R. Myocardial infarction is inversely associated with plasma 25-hydroxyvitamin D3 levels: a community-based study. Int J Epidemiol. 1990;19(3):559-63
231) Thys-Jacobs S, Donovan D, Papadopoulos A, Sarrel P, Bilezikian JP. Vitamin D and calcium dysregulation in the polycystic ovarian syndrome. Steroids. 1999;64(6):430-5
232) Thys-Jacobs S. Alleviation of migraines with therapeutic vitamin D and calcium. Headache. 1994 Nov-Dec;34(10):590-2
233) Thys-Jacobs S. Vitamin D and calcium in menstrual migraine. Headache. 1994 Oct;34(9):544-6
234) Cantorna MT. Vitamin D and autoimmunity: is vitamin D status an environmental factor affecting autoimmune disease prevalence? Proc Soc Exp Biol Med. 2000;223(3):230-3
235) Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001;358(9292):1500-3
236) Munger KL, Zhang SM, O'Reilly E, Hernan MA, Olek MJ, Willett WC, Ascherio A. Vitamin D intake and incidence of multiple sclerosis. Neurology. 2004;62:60-5
237) Vasquez A, Manso M, Cannell J. The Clinical Importance of Vitamin D (Cholecalciferol): A Paradigm Shift with Implications for All Healthcare Providers. Alternative Therapies in Health and Medicine 2004; 10: 28-37
238) Vasquez A. Integrative Orthopedics: The Art of Creating Wellness While Managing Acute and Chronic Musculoskeletal Disorders. Houston; Natural Health Consulting Corporation. (www.OptimalHealthResearch.com): 2004
239) Vasquez A, Manso M, Cannell J. The Clinical Importance of Vitamin D (Cholecalciferol): A Paradigm Shift with Implications for All Healthcare Providers. Alternative Therapies in Health and Medicine 2004; 10: 28-37
240) Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc. 2003;78(12):1463-70
241) Al Faraj S, Al Mutairi K. Vitamin D deficiency and chronic low-back pain in Saudi Arabia. Spine. 2003;28:177-9
242) Timms PM, Mannan et al.. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM. 2002;95:787-96
243) Van den Berghe G, Van Roosbroeck D, Vanhove P, Wouters PJ, De Pourcq L, Bouillon R. Bone turnover in prolonged critical illness: effect of vitamin D. J Clin Endocrinol Metab. 2003;88(10):4623-32
244) Tetlow LC, Woolley DE. The effects of 1 alpha,25-dihydroxyvitamin D(3) on matrix metalloproteinase and prostaglandin E(2) production by cells of the rheumatoid lesion. Arthritis Res. 1999;1:63-70
246) Masood H, Narang AP, Bhat IA, Shah GN. Persistent limb pain and raised serum alkaline phosphatase the earliest markers of subclinical hypovitaminosis D in Kashmir. Indian J Physiol Pharmacol. 1989;33:259-61
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Generally speaking, vitamin/mineral supplementation has been shown in clinical trials to improve nutritional
status and reduce the risk for chronic diseases247,248, improve mood249, enhance wellbeing250, potentiate
antidepressant drug treatment251, alleviate migraine headaches (when used with diet improvement and fatty
acids252), improve immune function and infectious disease outcomes in the elderly253 (especially diabetics254),
reduce morbidity and mortality in patients with HIV infection255,256, alleviate premenstrual syndrome257,258,
ameliorate bipolar disorder259, reduce violence and antisocial behavior in children260 and incarcerated young
adults (when used with essential fatty acids261), improve scores of intelligence in children262, and to benefit
children with attention deficit and hyperactivity disorder.263 Vitamin supplementation has anti-inflammatory
benefits as evidenced by significant reduction in CRP in a double-blind placebo-controlled trial.264 In an
increasingly toxic world265,266,267 wherein the average American shows a body burden of more than a dozen
different pesticides268,269 and where toxic metal accumulation is commonplace270,271,272, vitamin and mineral
supplementation becomes even more necessary to help protect against oxidative damage caused by pollution and
heavy metals273,274,275,276,277 and to support the nutrient-dependent detoxification reactions that are required for
the proper elimination of xenobiotics.278,279,280,281,282 Of course, dietary modification and nutritional
supplementation needs to be tailored to the needs, goals, health status, and pharmacotherapy (if any) of each
individual patient; however, the recommendations included in this article will be safe and beneficial for the vast
majority of patients. An overview of vitamin and mineral supplementation is provided in Appendix A.
“Essential fatty acids”: To the extent that most fatty acids are neither produced de novo or not produced in
sufficient amounts for the attainment of optimal health, nearly all of the dietary fatty acids discussed here can be
considered “essential” insofar as they must be supplied from diet or supplementation. Strictly speaking, the
term “essential fatty acids” (EFA) refers only to n-3 alpha-linolenic acid and n-6 linoleic acid, both of which are
the “first in line” in their respective n-3 and n-6 categories.
Fatty acids obtained from diet, supplements, and endogenous production effect powerful biological actions via
numerous mechanisms such as 1) altering cell membrane/receptor function, 2) modulating gene transcription, 3)
modulating hormone production and reception, and 4) shifting eicosanoid metabolism from proinflammatory to
247) McKay DL, Perrone G, Rasmussen H, Dallal G, Hartman W, Cao G, Prior RL, Roubenoff R, Blumberg JB. The effects of a multivitamin/mineral supplement on micronutrient status, antioxidant capacity and cytokine
production in healthy older adults consuming a fortified diet. J Am Coll Nutr. 2000;19(5):613-21
248) McKay DL, Perrone G, Rasmussen H, Dallal G, Blumberg JB. Multivitamin/mineral supplementation improves plasma B-vitamin status and homocysteine concentration in healthy older adults consuming a folate-fortified diet.
J Nutr. 2000;130:3090-6
249) Benton D, Haller J, Fordy J. Vitamin supplementation for 1 year improves mood. Neuropsychobiology. 1995;32(2):98-105
250) Vieth R, Kimball S, Hu A, Walfish PG. Randomized comparison of the effects of the vitamin D3 adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients. Nutr J. 2004;3(1):8
251) Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000;60:121-30
252) Wagner W, Nootbaar-Wagner U. Prophylactic treatment of migraine with gamma-linolenic and alpha-linolenic acids. Cephalalgia. 1997;17:127-30
253) Langkamp-Henken B, Bender BS, Gardner EM, Herrlinger-Garcia KA, Kelley MJ, Murasko DM, Schaller JP, Stechmiller JK, Thomas DJ, Wood SM. Nutritional formula enhanced immune function and reduced days of
symptoms of upper respiratory tract infection in seniors. J Am Geriatr Soc. 2004;52:3-12
254) Barringer TA, Kirk JK, Santaniello AC, Foley KL, Michielutte R. Effect of a multivitamin and mineral supplement on infection and quality of life. A randomized, double-blind, placebo-controlled trial. Ann Intern Med.
2003;138:365-71
255) Fawzi WW, Msamanga GI, Spiegelman D, et al. A randomized trial of multivitamin supplements and HIV disease progression and mortality. N Engl J Med 2004;351:23-32
256) Burbano X, Miguez-Burbano MJ, McCollister K, Zhang G, Rodriguez A, Ruiz P, Lecusay R, Shor-Posner G. Impact of a selenium chemoprevention clinical trial on hospital admissions of HIV-infected participants. HIV Clin
Trials. 2002;3:483-91
257) Abraham GE. Nutritional factors in the etiology of the premenstrual tension syndromes. J Reprod Med 1983;28(7):446-64
258) Stewart A. Clinical and biochemical effects of nutritional supplementation on the premenstrual syndrome. J Reprod Med. 1987;32:435-41
259) Kaplan BJ, Simpson JS, Ferre RC, Gorman CP, McMullen DM, Crawford SG. Effective mood stabilization with a chelated mineral supplement: an open-label trial in bipolar disorder. J Clin Psychiatry. 2001;62:936-44
260) Kaplan BJ, Crawford SG, Gardner B, Farrelly G. Treatment of mood lability and explosive rage with minerals and vitamins: two case studies in children. J Child Adolesc Psychopharmacol. 2002;12(3):205-19
261) Gesch CB, Hammond SM, Hampson SE, Eves A, Crowder MJ.Influence of supplementary vitamins, minerals and essential fatty acids on the antisocial behaviour of young adult prisoners. Randomised, placebo-controlled
trial. Br J Psychiatry. 2002;181:22-8
262) Benton D. Micro-nutrient supplementation and the intelligence of children. Neurosci Biobehav Rev 2001; 25: 297–309
263) Harding KL, Judah RD, Gant C.Outcome-based comparison of Ritalin versus food-supplement treated children with AD/HD. Altern Med Rev. 2003;8:319-30
264) Church TS, Earnest CP, Wood KA, Kampert JB. Reduction of C-reactive protein levels through use of a multivitamin. Am J Med. 2003;115:702-7
265) Spicer PE, Kereu RK. Organochlorine insecticide residues in human breast milk: a survey of lactating mothers from a remote area in Papua New Guinea. Bull Environ Contam Toxicol. 1993;50:540-6
266) Sherman JD. Chemical exposure and disease: diagnostic and investigative techniques. Princeton NJ: Princeton Scientific Publishing Company, 1994.
267) Philp RB. Environmental hazards and human health. Boca Raton; CRC Lewis Publishers, 1995
268) Pesticide Action Network North America (PANNA). Chemical Trespass: Pesticides in Our Bodies and Corporate Accountability. Accessed from http://www.panna.org/campaigns/docsTrespass/chemicalTrespass2004.dv.html
on November 10, 2004
269) “In a study led by Mount Sinai School of Medicine in New York, in collaboration with the Environmental Working Group and Commonweal, researchers at two major laboratories found an average of 91 industrial compounds,
pollutants, and other chemicals in the blood and urine of nine volunteers, with a total of 167 chemicals found in the group.” Accessed at http://www.ewg.org/reports/bodyburden/es.php on November 10, 2004
270) Schober SE, Sinks TH, Jones RL, Bolger PM, McDowell M, Osterloh J, Garrett ES, Canady RA, Dillon CF, Sun Y, Joseph CB, Mahaffey KR. Blood mercury levels in US children and women of childbearing age, 1999-2000.
JAMA. 2003;289(13):1667-74
271) Nash D, Magder L, Lustberg M, Sherwin RW, Rubin RJ, Kaufmann RB, Silbergeld EK. Blood lead, blood pressure, and hypertension in perimenopausal and postmenopausal women. JAMA. 2003;289(12):1523-32
272) Bradstreet J, Geier DA, Kartzinel JJ, Adams JB, Geier MR. A Case-Control Study of Mercury Burden in Children with Autistic Spectrum Disorders. J Am Phys Surgeons 2003; 8: 76-9
273) Mahaffey KR, Vanderveen JE. Nutrient-toxicant interactions: susceptible populations. Environ Health Perspect. 1979;29:81-7
274) Levander OA. Lead toxicity and nutritional deficiencies. Environ Health Perspect. 1979;29:115-25
275) Menzel DB. Nutritional needs in environmental intoxication: vitamin E and air pollution, an example. Environ Health Perspect. 1979;29:105-14
276) Simon JA, Hudes ES. Relationship of ascorbic acid to blood lead levels. JAMA. 1999 Jun 23-30;281(24):2289-93
277) Dawson EB, Evans DR, Harris WA, Teter MC, McGanity WJ. The effect of ascorbic acid supplementation on the blood lead levels of smokers. J Am Coll Nutr. 1999 Apr;18(2):166-70
278) Bidlack WR, Smith CH. The effect of nutritional factors on hepatic drug and toxicant metabolism. J Am Diet Assoc. 1984;84:892-8
279) Bland JS, Barrager E, Reedy RG, Bland K. A Medical Food-Supplemented Detoxification Program in the Management of Chronic Health Problems. Altern Ther Health Med. 1995;1:62-71
280) Bland JS, Bralley JA. Nutritional upregulation of hepatic detoxification enzymes. J Appl Nutr. 1992 44: 2-15
281) Liska DJ. The detoxification enzyme systems. Altern Med Rev. 1998;3:187-9
282) Anderson KE, Kappas A. Dietary regulation of cytochrome P450. Annu Rev Nutr. 1991;11:141-67
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relatively less inflammatory and perhaps “anti-inflammatory.” Three major groups of unsaturated fatty acids are
present in the human diet—n-3 (ALA, EPA, DHA), n-6 (linoleic acid, GLA, arachidonic acid), and n-9 (oleic
acid). Based on a survey of the literature including recent reviews by Vasquez283,284,285 and Larsson et al286, we
may reasonably conclude that the fatty acids with the most clinically significant health-promoting benefits are
the n-3 fatty acids ALA, EPA, and DHA, the n-6 fatty acid GLA, and the n-9 fatty acid oleic acid, as
summarized in the sections that follow. The n-6 fatty acids linoleic acid and arachidonic acid show
proinflammatory, hyperalgesic, atherosclerotic, and oncogenic properties via numerous mechanisms and should
be minimized in the diet of most patients.287,288,289,290
alpha-linolenic acid (ALA): ALA is an essential fatty acid as it is the “first in line” in the family of omega-3
polyunsaturated fatty acids (PUFA). Sources include flaxseed oil (57% ALA), canola oil (9% ALA), soy oil,
breast milk, English/black walnuts, soybeans, pine nuts, green vegetables, and beans. Conversion of ALA to the
more biologically active EPA and DHA does not reliably or efficiently occur in humans.291 No increase in DHA
has been consistently observed in humans after supplementation of ALA292; in fact, supplementation with flax
seed oil has actually been shown to reduce DHA levels in humans.293 Although ALA can reduce blood pressure
and cardiovascular mortality294, it does not reduce serum lipids as do EPA and DHA. In a study of men with
metabolic syndrome, ALA was shown to have anti-inflammatory benefits independent of its conversion to EPA
or DHA.295 The mechanism of action appears to be downregulation of NF-KappaB (the main “amplifier” for the
expression of proinflammatory gene products296) rather than the direct modulation of eicosanoid biosynthesis.
One study using flaxseed oil as a source of ALA to treat rheumatoid arthritis found no clinical or biochemical
benefit (i.e., no change in Hgb, CRP, ESR)297; however, the poor results of this study may have been due to the
inferior quality of the flaxseed oil product that was used which only supplied 32% ALA compared with the
much higher concentration of 57% found in most products. Moderate intakes of ALA from flaxseed oil
profoundly reduce production of proinflammatory prostaglandins (e.g., PG-E2, measured by urinary excretion)
by 52% to 85% in humans298 which is superior to the 42% reduction induced by rofecoxib (the drug “Vioxx”).299
In summary, increased intake of ALA appears to provide cardioprotective300 and anti-inflammatory
benefits301,302, and ALA can help reduce the frequency and severity of migraine headaches when used as part of
a comprehensive natural treatment plan that includes diet change and nutritional supplementation.303
Eicosapentaenoic acid: EPA, 20:5n3: EPA is essentially absent in vegan diets since the major dietary source is
fish oil. Dietary EPA is incorporated into cell membranes where it modulates neurotransmitter and hormone
receptor function and where it is stored before liberation by phospholipase for eicosanoid production. EPAderived eicosanoids have anti-inflammatory properties, including a reduction in the production of proinflammatory eicosanoids such as LT-B4, PAFs, and cytokines such as TNF-alpha and IL-1, and a large
284) Vasquez A. Reducing Pain and Inflammation Naturally. Part 1: New Insights into Fatty Acid Biochemistry and the Influence of Diet. Nutr Perspect 2004; October: 5, 7-10, 12, 14
285) Vasquez A. Reducing Pain and Inflammation Naturally. Part 2: New Insights into Fatty Acid Supplementation and Its Effect on Eicosanoid Production and Genetic Expression. Nutr Perspect 2005; January: 5-16
286) Larsson SC, Kumlin M, Ingelman-Sundberg M, Wolk A. Dietary long-chain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms. Am J Clin Nutr. 2004;79(6):935-45
287) Rusyn I, Bradham CA, Cohn L, Schoonhoven R, Swenberg JA, Brenner DA, Thurman RG. Corn oil rapidly activates nuclear factor-kappaB in hepatic Kupffer cells by oxidant-dependent mechanisms. Carcinogenesis.
1999;20(11):2095-100
289) Dwyer JH, Allayee H, Dwyer KM, Fan J, Wu H, Mar R, Lusis AJ, Mehrabian M. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med. 2004;350(1):29-37
290) Adam O, Beringer C, Kless T, Lemmen C, Adam A, Wiseman M, Adam P, Klimmek R, Forth W. Anti-inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis. Rheumatol Int. 2003
Jan;23(1):27-36
291) "Indu and Ghafoorunissa showed that while keeping the amount of dietary LA constant, 3.7 g ALA appears to have biological effects similar to those of 0.3 g long-chain n-3 PUFA with conversion of 11 g ALA to 1 g longchain n-3 PUFA." Simopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr. 1999 Sep;70(3 Suppl):560S-569S
292) Francois CA, Connor SL, Bolewicz LC, Connor WE. Supplementing lactating women with flaxseed oil does not increase docosahexaenoic acid in their milk. Am J Clin Nutr. 2003 Jan;77(1):226-33
293) “Linear relationships were found between dietary alpha-LA and EPA in plasma fractions and in cellular phospholipids. … There was an inverse relationship between dietary alpha-LA and docosahexaenoic acid
concentrations in the phospholipids of plasma, neutrophils, mononuclear cells, and platelets.” Mantzioris E, James MJ, Gibson RA, Cleland LG. Differences exist in the relationships between dietary linoleic and alphalinolenic acids and their respective long-chain metabolites. Am J Clin Nutr. 1995 Feb;61(2):320-4
294) Simopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr. 1999 Sep;70(3 Suppl):560S-569S
295) “CONCLUSIONS: Dietary supplementation with ALA for 3 months decreases significantly CRP, SAA and IL-6 levels in dyslipidaemic patients. This anti-inflammatory effect may provide a possible additional mechanism for
the beneficial effect of plant n-3 polyunsaturated fatty acids in primary and secondary prevention of coronary artery disease.” Rallidis LS, Paschos G, Liakos GK, Velissaridou AH, Anastasiadis G, Zampelas A. Dietary alphalinolenic acid decreases C-reactive protein, serum amyloid A and interleukin-6 in dyslipidaemic patients. Atherosclerosis. 2003 Apr;167(2):237-42
296) Tak PP, Firestein GS. NF-kappaB: a key role in inflammatory diseases. J Clin Invest. 2001 Jan;107(1):7-11
297) “Thus, 3-month's supplementation with alpha-LNA did not prove to be beneficial in rheumatoid arthritis.” Nordstrom DC, Honkanen VE, Nasu Y, Antila E, Friman C, Konttinen YT. Alpha-linolenic acid in the treatment of
rheumatoid arthritis. A double-blind, placebo-controlled and randomized study: flaxseed vs. safflower seed. Rheumatol Int. 1995;14(6):231-4
298) Adam O, Wolfram G, Zollner N. Effect of alpha-linolenic acid in the human diet on linoleic acid metabolism and prostaglandin biosynthesis. J Lipid Res. 1986 Apr;27(4):421-6
299) Van Hecken A, Schwartz JI, Depre M, De Lepeleire I, Dallob A, Tanaka W, Wynants K, Buntinx A, Arnout J, Wong PH, Ebel DL, Gertz BJ, De Schepper PJ. Comparative inhibitory activity of rofecoxib, meloxicam,
diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol. 2000 Oct;40(10):1109-20
300) Hu FB, Stampfer MJ, Manson JE, Rimm EB, Wolk A, Colditz GA, Hennekens CH, Willett WC. Dietary intake of alpha-linolenic acid and risk of fatal ischemic heart disease among women. Am J Clin Nutr. 1999
May;69(5):890-7
301) “CONCLUSIONS: Dietary supplementation with ALA for 3 months decreases significantly CRP, SAA and IL-6 levels in dyslipidaemic patients. This anti-inflammatory effect may provide a possible additional mechanism for
the beneficial effect of plant n-3 polyunsaturated fatty acids in primary and secondary prevention of coronary artery disease.” Rallidis LS, Paschos G, Liakos GK, Velissaridou AH, Anastasiadis G, Zampelas A. Dietary alphalinolenic acid decreases C-reactive protein, serum amyloid A and interleukin-6 in dyslipidaemic patients. Atherosclerosis. 2003 Apr;167(2):237-42
303) Wagner W, Nootbaar-Wagner U. Prophylactic treatment of migraine with gamma-linolenic and alpha-linolenic acids. Cephalalgia. 1997 Apr;17(2):127-30
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reduction in PG-E2 and TX-B2.304 Unfortunately, EPA can decrease production of DGLA, the metabolite of
GLA that has health-promoting properties.305 EPA doses of at least 4 grams per day are needed to increase
bleeding time.306 EPA supplementation reduces urinary excretion of calcium in patients with hypercalciuria and
may therefore help prevent the development of calcium urolithiasis.307 Due to its anti-inflammatory, membraneenhancing, and other nutrigenomic benefits, EPA supplementation has proven beneficial for patients with
lupus,308 cancer309, borderline personality disorder310, mental depression311,312,313, schizophrenia314, and
osteoporosis (when used with GLA).315
Docosahexaenoic acid: DHA, 20:6n-3: DHA is found only in plants of the sea, phytoplankton/microalgae, and
consumers of microalgae (such as fish). Like EPA, DHA is an important component of cell membranes and
generally appears to improve cell membrane function via improving receptor function and signal transduction.
In late 2003, bioactive metabolites of DHA—the docosatrienes and resolvins—were discovered to mediate
potent anti-inflammatory benefits.316 Animal studies have shown that induction of DHA deficiency causes
memory deficits and a reduction in hippocampal cell size317, and DHA deficiency in humans is consistently
associated with mental depression, learning disorders (e.g., ADD/ADHD), and other neuropsychiatric disorders
such as schizophrenia—these findings are consistent with the view that the nervous system has an absolute
requirement for DHA for proper function.318 DHA appears essential for optimal cognitive function in infants
and adults, and DHA in fish oil provides some protection against thrombosis, arrhythmia, cardiovascular death,
Alzheimer’s disease319, otitis media (when used with nutritional supplementation320), and coronary restenosis
following angioplasty.321 Supplementation with DHA (often in the form of fish oil, which includes EPA) has
been shown to benefit patients with bipolar disorder322, Crohn’s disease323, rheumatoid arthritis324,325,326, lupus327,
cardiovascular disease328, psoriasis329, and cancer.330 DHA appears to have an “anti-stress” benefit manifested
by 30% reductions in norepinephrine and improved resilience to psychoemotional stress.331,332 Supplementation
with EPA+DHA in fish oil is extremely safe and reduces all-cause mortality.333
Gamma (γ)-linolenic acid: GLA, 18:3n6: The most powerful health-promoting n-6 fatty acid, GLA is found in
varying concentrations in evening primrose oil, borage seed oil, hemp seed oil, and black currant seed oil. Most
if not all of the actions of GLA are mediated following its elongation to the biologically active DGLA, from
which eicosanoids that have cardioprotective and anti-inflammatory benefits are derived. Low levels of DGLA
304) Tapiero H, et al. Polyunsaturated fatty acids (PUFA) and eicosanoids in human health and pathologies. Biomed Pharmacother. 2002 Jul;56(5):215-22
305) Horrobin DF. Interactions between n-3 and n-6 essential fatty acids (EFAs) in the regulation of cardiovascular disorders and inflammation. Prostaglandins Leukot Essent Fatty Acids. 1991 Oct;44(2):127-31
306) “A dose of 1.8 g EPA/d did not result in any prolongation in bleeding time, but 4 g/d increased bleeding time and decreased platelet count with no adverse effects. In human studies, there has never been a case of clinical
bleeding…” Simopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr. 1999 Sep;70(3 Suppl):560S-569S
307) Yasui T, Tanaka H, Fujita K, Iguchi M, Kohri K. Effects of eicosapentaenoic acid on urinary calcium excretion in calcium stone formers. Eur Urol. 2001 May;39(5):580-5
308) Duffy EM, Meenagh GK, McMillan SA, Strain JJ, Hannigan BM, Bell AL. The clinical effect of dietary supplementation with omega-3 fish oils and/or copper in systemic lupus erythematosus. J Rheumatol. 2004
Aug;31(8):1551-6
309) Wigmore SJ, Barber MD, Ross JA, Tisdale MJ, Fearon KC. Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer. 2000;36(2):177-84
310) Zanarini MC, Frankenburg FR. omega-3 Fatty acid treatment of women with borderline personality disorder: a double-blind, placebo-controlled pilot study. Am J Psychiatry. 2003 Jan;160(1):167-9
311) Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 2002 Mar;159(3):477-9
312) Puri BK, Counsell SJ, Hamilton G, Richardson AJ, Horrobin DF.Eicosapentaenoic acid in treatment-resistant depression associated with symptom remission, structural brain changes and reduced neuronal phospholipid
turnover. Int J Clin Pract. 2001 Oct;55(8):560-3
313) Peet M, Horrobin DF.A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry. 2002
Oct;59(10):913-9
314) Emsley R, Myburgh C, Oosthuizen P, van Rensburg SJ. Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am J Psychiatry. 2002 Sep;159(9):1596-8
315) Kruger MC, Coetzer H, de Winter R, Gericke G, van Papendorp DH. Calcium, gamma-linolenic acid and eicosapentaenoic acid supplementation in senile osteoporosis. Aging (Milano). 1998 Oct;10(5):385-94
316) Hong S, Gronert K, Devchand PR, Moussignac RL, Serhan CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J
Biol Chem. 2003 Apr 25;278(17):14677-87
317) Ahmad A, Murthy M, Greiner RS, Moriguchi T, Salem N Jr. A decrease in cell size accompanies a loss of docosahexaenoate in the rat hippocampus. Nutr Neurosci. 2002 Apr;5(2):103-13
318) Salem N Jr, Niebylski CD. The nervous system has an absolute molecular species requirement for proper function. Mol Membr Biol. 1995;12(1):131-4
319) Horrocks LA, Yeo YK. Health benefits of docosahexaenoic acid (DHA). Pharmacol Res. 1999 Sep;40(3):211-25
320) Linday LA, Dolitsky JN, Shindledecker RD, Pippenger CE. Lemon-flavored cod liver oil and a multivitamin-mineral supplement for the secondary prevention of otitis media in young children: pilot research. Ann Otol Rhinol
Laryngol. 2002 Jul;111(7 Pt 1):642-52
321) Bairati I, Roy L, Meyer F. Double-blind, randomized, controlled trial of fish oil supplements in prevention of recurrence of stenosis after coronary angioplasty. Circulation. 1992 Mar;85(3):950-6
322) Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry. 1999
May;56(5):407-12
323) Belluzzi A, Brignola C, Campieri M, Pera A, Boschi S, Miglioli M. Effect of an enteric-coated fish-oil preparation on relapses in Crohn's disease. N Engl J Med. 1996 Jun 13;334(24):1557-60
324) Adam O, Beringer C, Kless T, Lemmen C, Adam A, Wiseman M, Adam P, Klimmek R, Forth W. Anti-inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis. Rheumatol Int. 2003
Jan;23(1):27-36
325) Lau CS, Morley KD, Belch JJ. Effects of fish oil supplementation on non-steroidal anti-inflammatory drug requirement in patients with mild rheumatoid arthritis--a double-blind placebo controlled study. Br J Rheumatol. 1993
Nov;32(11):982-9
326) Kremer JM, Jubiz W, Michalek A, Rynes RI, Bartholomew LE, Bigaouette J, Timchalk M, Beeler D, Lininger L. Fish-oil fatty acid supplementation in active rheumatoid arthritis. A double-blinded, controlled, crossover study.
Ann Intern Med. 1987 Apr;106(4):497-503
327) Walton AJ, Snaith ML, Locniskar M, Cumberland AG, Morrow WJ, Isenberg DA. Dietary fish oil and the severity of symptoms in patients with systemic lupus erythematosus. Ann Rheum Dis. 1991 Jul;50(7):463-6
328) “The recent GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico)-Prevention study of 11,324 patients showed a 45% decrease in risk of sudden cardiac death and a 20% reduction in all-cause
mortality in the group taking 850 mg/d of omega-3 fatty acids.” O'Keefe JH Jr, Harris WS. From Inuit to implementation: omega-3 fatty acids come of age. Mayo Clin Proc. 2000 Jun;75(6):607-14
329) Bittiner SB, Tucker WF, Cartwright I, Bleehen SS. A double-blind, randomised, placebo-controlled trial of fish oil in psoriasis. Lancet. 1988;1(8582):378-80
330) Gogos CA, Ginopoulos P, Salsa B, Apostolidou E, Zoumbos NC, Kalfarentzos F. Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore immunodeficiency and prolong survival for severely ill patients with
generalized malignancy: a randomized control trial. Cancer. 1998 Jan 15;82(2):395-402
331) Hamazaki T, Itomura M, Sawazaki S, Nagao Y. Anti-stress effects of DHA. Biofactors. 2000;13(1-4):41-5
332) Sawazaki S, Hamazaki T, Yazawa K, Kobayashi M. The effect of docosahexaenoic acid on plasma catecholamine concentrations and glucose tolerance during long-lasting psychological stress: a double-blind placebocontrolled study. J Nutr Sci Vitaminol (Tokyo). 1999 Oct;45(5):655-65
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are associated with increased risk for stroke and myocardial infarction.334 DGLA metabolites reduce the
formation of the arachidonate-derived 2-series prostaglandins, 4-series leukotrienes and platelet-activating
factor.335 GLA supplementation results in the formation of two biologically active metabolites from DGLA
formed by cyclooxygenase and lipoxygenase. Prostaglandin E-1 (PG-E1) is the main metabolite formed from
DGLA by cyclooxygenase and its production is increased by vitamin C.336 PG-E1 decreases platelet
aggregation337, inhibits vascular smooth muscle cell proliferation in vitro338, causes vasodilation339, and thus
helps lower blood pressure.340 PG-E1 has anti-inflammatory benefits and is probably the most potent
prostaglandin with respect to bronchodilation.341 Production of PG-E1 is increased by n-3 fatty acids.342 15HETrE is the second main metabolite from GLA/DGLA and is formed from DGLA via 15-lipoxygenase. 15HETrE has potent anti-inflammatory action by inhibiting the conversion of arachidonic acid to leukotrienes via
inhibition of 5-lipoxygenase and 12-lipoxygenase.343,344 Clinically, this is very important because several
common and serious health problems including allergy, asthma, cardiovascular disease, and cancer are at least
partially dependent upon the function of lipoxygenase for the production of leukotrienes. Notably, prostate
cancer cells can be rapidly killed in vitro by lipoxygenase inhibition.345 Clinical benefit associated with GLA
supplementation is seen in patients with, eczema346, breast cancer (when used with tamoxifen347), premenstrual
syndrome348, rheumatoid arthritis349,350, diabetic neuropathy351, migraine headaches (when used with ALA352),
and respiratory distress syndrome (when used with EPA).353
Oleic acid: N-9 oleic acid appears to have health-promoting benefits, namely cardioprotection and antiinflammation which are both partially mediated via suppression of NF-kappaB.354 Most clinical trials in humans
have used olive oil as a source of oleic acid, and since olive oil is a complex mixture of oleic acid, squalene, and
phenolic antioxidants/anti-inflammatories, therefore, determination of the benefits of oleic acid alone (i.e.,
without squalene and phenolics) is difficult. Other sources of oleic acid include flax seed oil and borage oil.
Olive oil should be consumed in the diet to attain sufficient quantity of oleic acid along with the healthpromoting, anti-inflammatory, anti-cancer, and cardioprotective squalene and phenolic antioxidants. Dietary
consumption of olive oil is consistently associated with reductions in cancer and cardiovascular disease,
particularly when used as a component of a health-promoting diet.355,356
Nutrigenomics: Modulation of Genetic Expression via Interventional Nutrition
The study of how dietary components and nutritional supplements influence genetic expression is referred to as
“nutrigenomics” or “nutritional genomics” and has been described as “the next frontier in the postgenomic
era.”357 Various nutrients have been shown to modulate genetic expression and thus alter phenotypic
manifestations of disease by upregulating or downregulating specific genes, interacting with nuclear receptors,
altering hormone receptors, and modifying the influence of transcription factors, such as proinflammatory NFkappaB and the anti-inflammatory peroxisome-proliferator activated receptors (PPARs).358,359,360,361 Indeed, the
previous view that nutrients only interact with human physiology at the metabolic/post-transcriptional level
335) Fan YY, Chapkin RS. Importance of dietary gamma-linolenic acid in human health and nutrition. J Nutr. 1998 Sep;128(9):1411-4
336) Horrobin DF. Ascorbic acid and prostaglandin synthesis. Subcell Biochem. 1996;25:109-15
339) Tapiero H, et al. Polyunsaturated fatty acids (PUFA) and eicosanoids in human health and pathologies. Biomed Pharmacother. 2002 Jul;56(5):215-22
341) Horrobin DF. Ascorbic acid and prostaglandin synthesis. Subcell Biochem. 1996;25:109-15
342) Rubin D, Laposata M. Cellular interactions between n-6 and n-3 fatty acids: a mass analysis of fatty acid elongation/desaturation, distribution among complex lipids, and conversion to eicosanoids. J Lipid Res. 1992
Oct;33(10):1431-40
343 Horrobin DF. Interactions between n-3 and n-6 essential fatty acids (EFAs) in the regulation of cardiovascular disorders and inflammation. Prostaglandins Leukot Essent Fatty Acids. 1991 Oct;44(2):127-31
345) Ghosh J, Myers CE. Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13182-7
346) Fiocchi A, Sala M, Signoroni P, Banderali G, Agostoni C, Riva E. The efficacy and safety of gamma-linolenic acid in the treatment of infantile atopic dermatitis. J Int Med Res. 1994 Jan-Feb;22(1):24-32
347) Kenny FS, Pinder SE, Ellis IO, Gee JM, Nicholson RI, Bryce RP, Robertson JF. Gamma linolenic acid with tamoxifen as primary therapy in breast cancer. Int J Cancer. 2000 Mar 1;85(5):643-8
348) Puolakka J, Makarainen L, Viinikka L, Ylikorkala O. Biochemical and clinical effects of treating the premenstrual syndrome with prostaglandin synthesis precursors. J Reprod Med. 1985 Mar;30(3):149-53
349) Brzeski M, Madhok R, Capell HA. Evening primrose oil in patients with rheumatoid arthritis and side-effects of non-steroidal anti-inflammatory drugs. Br J Rheumatol. 1991 Oct;30(5):370-2
350) Rothman D, DeLuca P, Zurier RB. Botanical lipids: effects on inflammation, immune responses, and rheumatoid arthritis. Semin Arthritis Rheum. 1995 Oct;25(2):87-96
351) Jamal GA, Carmichael H. The effect of gamma-linolenic acid on human diabetic peripheral neuropathy: a double-blind placebo-controlled trial. Diabet Med. 1990 May;7(4):319-23
352) Wagner W, Nootbaar-Wagner U. Prophylactic treatment of migraine with gamma-linolenic and alpha-linolenic acids. Cephalalgia. 1997 Apr;17(2):127-30
353) Pacht ER, DeMichele SJ, Nelson JL, Hart J, Wennberg AK, Gadek JE. Enteral nutrition with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants reduces alveolar inflammatory mediators and protein influx in
patients with acute respiratory distress syndrome. Crit Care Med. 2003 Feb;31(2):491-500
354) Massaro M, Carluccio MA, De Caterina R. Direct vascular antiatherogenic effects of oleic acid: a clue to the cardioprotective effects of the Mediterranean diet. Cardiologia. 1999 Jun;44(6):507-13
355) de Lorgeril M, Salen P, Martin JL, Monjaud I, Boucher P, Mamelle N. Mediterranean dietary pattern in a randomized trial: prolonged survival and possible reduced cancer rate. Arch Intern Med. 1998 Jun 8;158(11):1181-7
356) Alarcon de la Lastra C, Barranco MD, Motilva V, Herrerias JM. Mediterranean diet and health: biological importance of olive oil. Curr Pharm Des. 2001 Jul;7(10):933-50
357) Kaput J, Rodriguez RL. Nutritional genomics: the next frontier in the postgenomic era. Physiol Genomics. 2004 Jan 15;16(2):166-77
358) Vamecq J, Latruffe N. Medical significance of peroxisome proliferator-activated receptors. Lancet. 1999;354:141-8
359) Ehrmann J Jr, Vavrusova N, Collan Y, Kolar Z. Peroxisome proliferator-activated receptors (PPARs) in health and disease. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2002 Dec;146(2):11-4
360) Kliewer SA, Xu HE, Lambert MH, Willson TM. Peroxisome proliferator-activated receptors: from genes to physiology. Recent Prog Horm Res. 2001;56:239-63
361) Delerive P, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol. 2001;169(3):453-9
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must be updated in light of current research showing that nutrients can, in fact, modify human physiology and
phenotype at the genetic/pre-transcriptional level.
Fatty acids and their end-products modulate genetic expression in several ways, as these examples will illustrate.
In general, n-3 fatty acids decrease inflammation and promote health while n-6 fatty acids (except for GLA,
which is generally health-promoting) increase inflammation, oxidative stress, and the manifestation of disease.
Corn oil, probably as a result of its high n-6 LA (linoleic acid) content, rapidly activates NF-kappaB and thus
promotes tumor development, atherosclerosis, and elaboration of pro-inflammatory mediators such as
TNFa.362,363,364 Similarly n-6 arachidonic acid increased production of the free radical superoxide approximately
4-fold when added to isolated Kupffer cells in vitro. Prostaglandin-E2 is produced from arachidonic acid by
cyclooxygenase and increases genetic expression of cyclooxygenase and IL-6; thus, inflammation manifested by
an increase in PG-E2 leads to additive expression of cyclooxygenase, which further increases inflammation and
elevates C-reactive protein.365 Some of the unique health-promoting effects of GLA are nutrigenomically
mediated via activation of PPAR-gamma, resultant inhibition of NF-kappaB, and impairment of estrogen
receptor function.366,367 Supplementation with ALA leads to a dramatic reduction of prostaglandin formation in
humans368, and this effect is probably mediated by downregulation of proinflammatory transcription, as
evidenced by reductions in CRP, IL-6, and serum amyloid A.369 EPA appears to exert much of its antiinflammatory benefit by suppressing NF-kappaB activation and thus reducing elaboration of proinflammatory
mediators.370,371 EPA also indirectly modifies gene expression and cell growth by reducing intracellular calcium
levels and thus activating protein kinase R which impairs eukaryotic initiation factor-2alpha and inhibits protein
synthesis at the level of translation initiation, thereby mediating an anti-cancer benefit.372 DHA is the precursor
to docosatrienes and resolvins which downregulate gene expression for proinflammatory IL-1, inhibit of TNFa,
and reduce neutrophil entry to sites of inflammation.373 Oxidized EPA activates PPAR-alpha and thereby
suppresses NF-kappaB and the activation of proinflammatory genes.374,375 Other nutrients that inhibit the
activation of NF-kappaB include vitamin D376 377, lipoic acid378, green tea379, rosemary380, grape seed extract381,
resveratrol382,383, caffeic acid phenethyl ester (CAPE) from bee propolis384, indole-3-carbinol385, N-acetyl-L-
362) Rusyn I, Bradham CA, Cohn L, Schoonhoven R, Swenberg JA, Brenner DA, Thurman RG. Corn oil rapidly activates nuclear factor-kappaB in hepatic Kupffer cells by oxidant-dependent mechanisms. Carcinogenesis. 1999
Nov;20(11):2095-100
363) Rose DP, Hatala MA, Connolly JM, Rayburn J. Effect of diets containing different levels of linoleic acid on human breast cancer growth and lung metastasis in nude mice. Cancer Res. 1993 Oct 1;53(19):4686-90
364) Dichtl W, Ares MP, Jonson AN, Jovinge S, Pachinger O, Giachelli CM, Hamsten A, Eriksson P, Nilsson J. Linoleic acid-stimulated vascular adhesion molecule-1 expression in endothelial cells depends on nuclear factorkappaB activation. Metabolism. 2002 Mar;51(3):327-33
365) Bagga D, Wang L, Farias-Eisner R, Glaspy JA, Reddy ST. Differential effects of prostaglandin derived from omega-6 and omega-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion. Proc Natl Acad Sci U
S A. 2003 Feb 18;100(4):1751-6. Available at http://www.pnas.org/cgi/reprint/100/4/1751.pdf
366) Menendez JA, Colomer R, Lupu R. Omega-6 polyunsaturated fatty acid gamma-linolenic acid (18:3n-6) is a selective estrogen-response modulator in human breast cancer cells: gamma-linolenic acid antagonizes estrogen
receptor-dependent transcriptional activity, transcriptionally represses estrogen receptor expression and synergistically enhances tamoxifen and ICI 182,780 (Faslodex) efficacy in human breast cancer cells. Int J Cancer.
2004 May 10;109(6):949-54
367) Jiang WG, Redfern A, Bryce RP, Mansel RE. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) mediates the action of gamma linolenic acid in breast cancer cells. Prostaglandins Leukot Essent Fatty Acids.
2000 Feb;62(2):119-27
369) Rallidis LS, Paschos G, Liakos GK, Velissaridou AH, Anastasiadis G, Zampelas A. Dietary alpha-linolenic acid decreases C-reactive protein, serum amyloid A and interleukin-6 in dyslipidaemic patients. Atherosclerosis.
2003 Apr;167(2):237-42
370) Zhao Y, Joshi-Barve S, Barve S, Chen LH. Eicosapentaenoic acid prevents LPS-induced TNF-alpha expression by preventing NF-kappaB activation. J Am Coll Nutr. 2004 Feb;23(1):71-8
371) Mishra A, Chaudhary A, Sethi S. Oxidized omega-3 fatty acids inhibit NF-kappaB activation via a PPARalpha-dependent pathway. Arterioscler Thromb Vasc Biol. 2004 Sep;24(9):1621-7
372) Palakurthi SS, Fluckiger R, Aktas H, Changolkar AK, Shahsafaei A, Harneit S, Kilic E, Halperin JA. Inhibition of translation initiation mediates the anti-cancer effect of the n-3 polyunsaturated fatty acid eicosapentaenoic acid.
Cancer Res. 2000 Jun 1;60(11):2919-25
373) “These results indicate that DHA is the precursor to potent protective mediators generated via enzymatic oxygenations to novel docosatrienes and 17S series resolvins that each regulate events of interest in inflammation
and resolution.” Hong S, Gronert K, Devchand PR, Moussignac RL, Serhan CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in antiinflammation. J Biol Chem. 2003 Apr 25;278(17):14677-87
374) Mishra A, Chaudhary A, Sethi S. Oxidized omega-3 fatty acids inhibit NF-kappaB activation via a PPARalpha-dependent pathway. Arterioscler Thromb Vasc Biol. 2004 Sep;24(9):1621-7
375) Delerive P, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol. 2001;169(3):453-9
376) “1Alpha,25-dihydroxyvitamin D3 (1,25-(OH)2-D3), the active metabolite of vitamin D, can inhibit NF-kappaB activity in human MRC-5 fibroblasts, targeting DNA binding of NF-kappaB but not translocation of its subunits p50
and p65.” Harant H, Wolff B, Lindley IJ. 1Alpha,25-dihydroxyvitamin D3 decreases DNA binding of nuclear factor-kappaB in human fibroblasts. FEBS Lett. 1998 Oct 9;436(3):329-34
377) “Thus, 1,25(OH)2D3 may negatively regulate IL-12 production by downregulation of NF-kB activation and binding to the p40-kB sequence.” D'Ambrosio D, Cippitelli M, Cocciolo MG, Mazzeo D, Di Lucia P, Lang R, Sinigaglia
F, Panina-Bordignon P. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest. 1998 Jan 1;101(1):252-62
378) “ALA reduced the TNF-alpha-stimulated ICAM-1 expression in a dose-dependent manner, to levels observed in unstimulated cells. Alpha-lipoic acid also reduced NF-kappaB activity in these cells in a dose-dependent
manner.” Lee HA, Hughes DA.Alpha-lipoic acid modulates NF-kappaB activity in human monocytic cells by direct interaction with DNA. Exp Gerontol. 2002 Jan-Mar;37(2-3):401-10
379) “In conclusion, EGCG is an effective inhibitor of IKK activity. This may explain, at least in part, some of the reported anti-inflammatory and anti-cancer effects of green tea.” Yang F, Oz HS, Barve S, de Villiers WJ, McClain
CJ, Varilek GW. The green tea polyphenol (-)-epigallocatechin-3-gallate blocks nuclear factor-kappa B activation by inhibiting I kappa B kinase activity in the intestinal epithelial cell line IEC-6. Mol Pharmacol. 2001
Sep;60(3):528-33
380) “These results suggest that carnosol suppresses the NO production and iNOS gene expression by inhibiting NF-kappaB activation, and provide possible mechanisms for its anti-inflammatory and chemopreventive action.”
Lo AH, Liang YC, Lin-Shiau SY, Ho CT, Lin JK. Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthase through down-regulating nuclear factor-kappaB in mouse macrophages. Carcinogenesis. 2002
Jun;23(6):983-91
381) “Constitutive and TNFalpha-induced NF-kappaB DNA binding activity was inhibited by GSE at doses > or =50 microg/ml and treatments for > or =12 h.” Dhanalakshmi S, Agarwal R, Agarwal C. Inhibition of NF-kappaB
pathway in grape seed extract-induced apoptotic death of human prostate carcinoma DU145 cells. Int J Oncol. 2003 Sep;23(3):721-7
382) “Resveratrol's anticarcinogenic, anti-inflammatory, and growth-modulatory effects may thus be partially ascribed to the inhibition of activation of NF-kappaB and AP-1 and the associated kinases.” Manna SK, Mukhopadhyay
A, Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J
Immunol. 2000 Jun 15;164(12):6509-19
383) “Both resveratrol and quercetin inhibited NF-kappaB-, AP-1- and CREB-dependent transcription to a greater extent than the glucocorticosteroid, dexamethasone.” Donnelly LE, Newton R, Kennedy GE, Fenwick PS, Leung
RH, Ito K, Russell RE, Barnes PJ. Anti-inflammatory Effects of Resveratrol in Lung Epithelial Cells: Molecular Mechanisms. Am J Physiol Lung Cell Mol Physiol. 2004 Jun 4 [Epub ahead of print]
384) “Caffeic acid phenethyl ester (CAPE) is an anti-inflammatory component of propolis (honeybee resin). CAPE is reportedly a specific inhibitor of nuclear factor-kappaB (NF-kappaB).” Fitzpatrick LR, Wang J, Le T. Caffeic acid
phenethyl ester, an inhibitor of nuclear factor-kappaB, attenuates bacterial peptidoglycan polysaccharide-induced colitis in rats. J Pharmacol Exp Ther. 2001 Dec;299(3):915-20
385) Takada Y, Andreeff M, Aggarwal BB. Indole-3-carbinol suppresses NF-{kappa}B and I{kappa}B{alpha} kinase activation causing inhibition of expression of NF-{kappa}B-regulated antiapoptotic and metastatic gene products
and enhancement of apoptosis in myeloid and leukemia cells. Blood. 2005 Apr 5; [Epub ahead of print]
24 of 58
cysteine386, selenium387, and zinc.388 Therefore, we see that fatty acids and nutrients directly affect gene
expression by complex and multiple mechanisms, as graphically demonstrated in Figure 6, and the synergism
and potency of these numerous anti-inflammatory nutraceuticals supports the rationale for the use of nutrition
and select botanicals for the safe and effective treatment of inflammatory disorders.
Figure 6. An integrated model of fatty acid effects on eicosanoid production and nutrigenomics. Used here
with permission of Vasquez. (Vasquez A. Reducing Pain and Inflammation Naturally. Part 2: New Insights into Fatty Acid
Supplementation and Its Effect on Eicosanoid Production and Genetic Expression. Nutr Perspect 2005; January: 5-16)
Linoleic acid, arachidonic acid, and
hyperglycemia upregulate NF-kappaB,
which influences DNA to produce
more COX and LIPOX, which then
utilize arachidonic acid to create
pro-inflammatory mediators
hyperglycemia; consumption
of foods with high glycemic
load and high glycemic index
DNA
NF-KappaB
activation
proinflammatory
prostaglandins
upregulate
COX-2
cell membrane
phospolipids
linoleic acid
ins
ostagland
2-series pr
4-series leukotrienes
arachidonic acid
COX-2
ALA
and
EPA
3-series prostagla
oleic acid
GLA / DGLA
Vitamin D
Lipoic acid
Green tea
Rosemary
Grape seed extract
Bee propolis (CAPE)
Resveratrol
Curcumin
Selenium
N-acetyl-cysteine
ndins, 5-series leu
kotrienes
docosatrien
es, resolvin
s
PG-E1
a nd 15
-HETrE
PPARα
suppresses
COX-2
expression
NF-KappaB
inhibition
PPARγ
activation
molecules that inhibit pain,
inflammation,
and cancer; reduction in
disease-promoting molecules
HEALTH
promotion
//
PPARα
activation
DISEASE
promotion
mutual antagonism
Lipoxygenase
DHA
chemicals that generally
promote pain, inflammation,
and cancer
Reduction in
NO synthase,
gelatinase B,
IL-6, prostaglandin E2, and TNF-α
//
NF-KappaB
inhibition
DNA
//
ALA, EPA, DHA, oleic acid,
and GLA are generally
health-promoting because
they favorably modify gene
expression for a relative
reduction in pro-inflammatory
mediators
favorable modification of gene expression and
suppression of inflammatory gene activation
promotes homeostasis and health
386) Paterson RL, Galley HF, Webster NR. The effect of N-acetylcysteine on nuclear factor-kappa B activation, interleukin-6, interleukin-8, and intercellular adhesion molecule-1 expression in patients with sepsis. Crit Care Med.
2003 Nov;31(11):2574-8
387) Faure P, Ramon O, Favier A, Halimi S. Selenium supplementation decreases nuclear factor-kappa B activity in peripheral blood mononuclear cells from type 2 diabetic patients. Eur J Clin Invest. 2004;34(7):475-81
388) Uzzo RG, Leavis P, Hatch W, Gabai VL, Dulin N, Zvartau N, Kolenko VM. Zinc inhibits nuclear factor-kappa B activation and sensitizes prostate cancer cells to cytotoxic agents. Clin Cancer Res. 2002;8(11):3579-83
25 of 58
Selected Nutritional and Botanical Therapeutics for the Alleviation of Joint Pain and Inflammation
Subsequent to the overall health improvement and anti-inflammatory benefits provided by the supplemented
Paleo-Mediterranean diet described above, many patients who require additional anti-inflammatory
interventions can be safely and effectively treated with the following phytonutraceuticals, each of which is
supported by experimental and clinical data in humans. Mechanism(s) of action, indications, contraindications,
dosage, and common drug interactions (if any) are listed for each.
Glucosamine and chondroitin sulfate: Glucosamine and chondroitin are the “building blocks” from
which cartilage is built and oral supplementation is intended to enhance cartilage anabolism and to thus
counteract the enhanced cartilage catabolism seen in destructive arthritis processes.389 Clinical trials with
glucosamine and chondroitin sulfates have shown consistently positive results in clinical trials involving patients
with osteoarthritis of the hands, hips, knees, temporomandibular joint, and low-back.390,391,392,393,394,395,396 For
example, glucosamine sulfate was superior to placebo for pain reduction and preservation of joint space in a 3year clinical trial in patients with knee osteoarthritis.397 Arguments against the use of glucosamine due to
inflated concern about inefficacy or exacerbation of diabetes398 are without scientific merit399,400 as evidenced by
a 90-day trial of diabetic patients consuming 1500 mg of glucosamine hydrochloride with 1200 mg of
chondroitin sulfate which showed no significant alterations in serum glucose or hemoglobin A1c401 and by the
previously cited 3-year study which found significant clinical benefit and no adverse effects on glucose
homeostasis.402 The adult dose of glucosamine sulfate is generally 1500-2000 mg per day in divided doses, and
the dose of chondroitin sulfate is approximately 1000 mg daily. Both treatments are safe for multiyear use, and
rare adverse effects include allergy and nonpathologic gastrointestinal upset. Clinical benefit is generally
significant following 4-6 weeks of treatment and is maintained for the duration of treatment. In contrast to
coxib and other mislabeled “anti-inflammatory ” drugs that consistently elevate the incidence of cardiovascular
disease, death, and other adverse effects403,404,405,406,407, supplementation with chondroitin sulfate appears to
safely reduce the pain and disability associated with osteoarthritis while simultaneously reducing incidence of
cardiovascular morbidity and mortality.408,409
In a study with animals that spontaneously develop
410
atherosclerosis , administration of chondroitin sulfate appears to have induced regression of existing
atherosclerosis. In a six-year study with 120 patients with established cardiovascular disease, 60 chondroitintreated patients suffered 6 coronary events and 4 deaths compared to 42 events and 14 deaths in a comparable
group of 60 patients receiving “conventional” therapy; chondroitin-treated patients reported enhancement of
well-being while no adverse clinical or laboratory effects were noted during the 6 years of treatment. 411
390) “…patients taking GS had a significantly greater decrease in TMJ pain with function, effect of pain, and acetaminophen used between Day 90 and 120 compared with patients taking ibuprofen.” Thie NM, Prasad NG, Major
PW. Evaluation of glucosamine sulfate compared to ibuprofen for the treatment of temporomandibular joint osteoarthritis: a randomized double blind controlled 3 month clinical trial. J Rheumatol. 2001;28(6):1347-55
391) Braham R, Dawson B, Goodman C. The effect of glucosamine supplementation on people experiencing regular knee pain. Br J Sports Med. 2003;37(1):45-9
392) “…oral glucosamine therapy achieved a significantly greater improvement in articular pain score than ibuprofen, and the investigators rated treatment efficacy as 'good' in a significantly greater proportion of glucosamine than
ibuprofen recipients. In comparison with piroxicam, glucosamine significantly improved arthritic symptoms after 12 weeks of therapy...” Matheson AJ, Perry CM. Glucosamine: a review of its use in the management of
osteoarthritis. Drugs Aging. 2003; 20(14): 1041-60
393) Uebelhart D, Malaise M, Marcolongo R, DeVathaire F, Piperno M, Mailleux E, Fioravanti A, Matoso L, Vignon E. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind,
multicenter study versus placebo. Osteoarthritis Cartilage. 2004;12:269-76
394) van Blitterswijk WJ, van de Nes JC, Wuisman PI. Glucosamine and chondroitin sulfate supplementation to treat symptomatic disc degeneration: biochemical rationale and case report. BMC Complement Altern Med.
2003;3(1):2
395) Morreale P, Manopulo R, Galati M, Boccanera L, Saponati G, Bocchi L. Comparison of the antiinflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis. J Rheumatol.
1996;23(8):1385-91
396) Mazieres B, Combe B, Phan Van A, Tondut J, Grynfeltt M. Chondroitin sulfate in osteoarthritis of the knee: a prospective, double blind, placebo controlled multicenter clinical study. J Rheumatol. 2001;28(1):173-81
397) Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, Giacovelli G, Henrotin Y, Dacre JE, Gossett C. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled
clinical trial. Lancet. 2001;357(9252):251-6
398) Adams ME. Hype about glucosamine. Lancet. 1999;354(9176):353-4
399) Cumming A. Glucosamine in osteoarthritis. Lancet. 1999;354(9190):1640-1
400) Rovati LC, Annefeld M, Giacovelli G, Schmid K, Setnikar I. Glucosamine in osteoarthritis. Lancet. 1999;354(9190):1640
401) Scroggie DA, Albright A, Harris MD. The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized
clinical trial. Arch Intern Med. 2003;163(13):1587-9
402) Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, Giacovelli G, Henrotin Y, Dacre JE, Gossett C. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled
clinical trial. Lancet. 2001;357(9252):251-6
4, 2005
407) "Preliminary information from the study showed some evidence of increased risk of cardiovascular events, when compared to placebo, to patients taking naproxen." FDA Statement on Naproxen.
http://www.fda.gov/bbs/topics/news/2004/NEW01148.html Available on January 4, 2005
408) Morrison LM. Treatment of coronary arteriosclerotic heart disease with chondroitin sulfate-A: preliminary report. J Am Geriatr Soc. 1968;16(7):779-85
409) Morrison LM, Branwood AW, Ershoff BH, Murata K, Quilligan JJ Jr, Schjeide OA, Patek P, Bernick S, Freeman L, Dunn OJ, Rucker P. The prevention of coronary arteriosclerotic heart disease with chondroitin sulfate A:
preliminary report. Exp Med Surg. 1969;27(3):278-89
410) Morrison LM, Bajwa GS. Absence of naturally occurring coronary atherosclerosis in squirrel monkeys (Saimiri sciurea) treated with chondroitin sulfate A. Experientia. 1972 Dec 15;28(12):1410-1
411) Morrison LM, Enrick N. Coronary heart disease: reduction of death rate by chondroitin sulfate A. Angiology. 1973 May;24(5):269-87
26 of 58
Niacinamide: Niacinamide is a form of vitamin B3 that was first shown to be highly effective in the
treatment of osteoarthritis by Kaufman more than 50 years ago.412 Furthermore, Kaufman’s documentation of
an “anti-aging” effect of vitamin supplementation in general and niacinamide therapy in particular413 is
consistent with recent experimental data demonstrating rapid reversion of aging phenotypes by niacinamide
through possible modulation of histone acetylation.414 A recent double-blind placebo-controlled repeat study
found that niacinamide therapy improved joint mobility, reduced objective inflammation as assessed by ESR,
reduced the impact of the arthritis on the activities of daily living, and allowed a reduction in medication use.415
While the mechanism of action is probably multifaceted, inhibition of joint-destroying nitric oxide appears to be
an important benefit.416 The standard dose of 500 mg given orally 6 times per day is more effective than 1,000
mg 3 times per day. Hepatic dysfunction is rare when daily doses are kept below 3,000 mg per day, yet Gaby417
suggests measurement of liver enzymes after 3 months of treatment and yearly thereafter. Antirheumatic benefit
is generally significant following 2-6 weeks of treatment, and patients may also notice an anxiolytic benefit,
which is probably due to the binding of niacinamide to GABA/benzodiazepine receptors.418
Vitamin D (cholecalciferol): Vitamin D insufficiency is epidemic in the United States419,420,421 and is
extremely prevalent (>90%) among patients with chronic musculoskeletal pain422, limb pain423, and low-back
pain.424 The mechanism by which this pain is produced has been clearly elucidated: 1) vitamin D deficiency
causes a reduction in calcium absorption, 2) production of parathyroid hormone (PTH) is increased to maintain
blood calcium levels, 3) PTH results in increased urinary excretion of phosphorus, which leads to
hypophosphatemia, 4) insufficient calcium phosphate results in deposition of unmineralized collagen matrix on
the endosteal (inside) and periosteal (outside) of bones, 5) when the collagen matrix hydrates and swells, it
causes pressure on the sensory-innervated periosteum resulting in pain.425 In patients with vitamin D deficiency,
oral supplementation with vitamin D clearly produces anti-inflammatory benefits426,427, and treatment with
vitamin D can safely lead to dramatic reductions in musculoskeletal pain in a large percentage of patients.428,429
Routine annual measurement of vitamin D status should be the standard of care430 since failure to diagnose
vitamin D deficiency and to provide adequate replacement doses are both ethically questionable431,432 and
scientifically unjustifiable in light of the low cost, manifold benefits, rare adverse effects, and high prevalence of
vitamin D deficiency.433 Physiologic requirements are approximately 4,000 IU per day in men434 and can only
be achieved with high-dose oral supplementation or full-body sun exposure on a frequent or preferably daily
basis. As reviewed in the recent monograph by Vasquez et al435, relative contraindications include the use of
thiazide diuretics or presence of a vitamin D hypersensitivity syndrome such as primary hyperparathyroidism,
adrenal insufficiency, hyperthyroidism, hypothyroidism, or granulomatous disease such as sarcoidosis, Crohn’s
disease, or tuberculosis). Serum calcium is periodically monitored in patients receiving moderate doses of
vitamin D (adult range 4,000 – 10,000 IU per day), as hypercalcemia is the best laboratory indicator of vitamin
D excess. High doses of vitamin D (up to 100,000 IU per day) have been safely used during pregnancy436,437,438;
periodic testing of serum calcium is required to monitor for hypercalcemia.
412) Kaufman W. Niacinamide therapy for joint mobility. Therapeutic reversal of a common clinical manifestation of the “normal” aging process. Conn State Med J 1953;17:584-591
413) Kaufman W. The use of vitamin therapy to reverse certain concomitants of aging. J Am Geriatr Soc 1955;3:927-936
414) Matuoka K, Chen KY, Takenawa T. Rapid reversion of aging phenotypes by nicotinamide through possible modulation of histone acetylation. Cell Mol Life Sci. 2001;58(14):2108-16
415) Jonas WB, Rapoza CP, Blair WF. The effect of niacinamide on osteoarthritis: a pilot study. Inflamm Res 1996 Jul;45(7):330-4
416) McCarty MF, Russell AL. Niacinamide therapy for osteoarthritis--does it inhibit nitric oxide synthase induction by interleukin 1 in chondrocytes? Med Hypotheses. 1999;53(4):350-60
417) Gaby AR. Literature review and commentary: Niacinamide for osteoarthritis. Townsend Letter for Doctors and Patients. 2002: May; 32
418) Mohler H, Polc P, Cumin R, Pieri L, Kettler R. Nicotinamide is a brain constituent with benzodiazepine-like actions. Nature. 1979; 278(5704): 563-5
419) Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, Vamvakas EC, Dick IM, Prince RL, Finkelstein JS. Hypovitaminosis D in medical inpatients. N Engl J Med. 1998;338(12):777-83
420) Gordon CM, DePeter KC, Feldman HA, Grace E, Emans SJ. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med 2004;158(6):531-7
421) Nesby-O'Dell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW, Looker AC, Allen C, Doughertly C, Gunter EW, Bowman BA. Hypovitaminosis D prevalence and determinants among African American and white women of
reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr 2002;76:187-92
422) Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc. 2003;78(12):1463-70
425) Holick MF. Vitamin D deficiency: what a pain it is. Mayo Clin Proc. 2003 Dec;78(12):1457-9
426) Timms PM, Mannan et al.. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM. 2002;95:787-96
427) Van den Berghe G, Van Roosbroeck D, Vanhove P, Wouters PJ, De Pourcq L, Bouillon R. Bone turnover in prolonged critical illness: effect of vitamin D. J Clin Endocrinol Metab. 2003;88(10):4623-32
430) Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004;79(3):362-71
431) Heaney RP. Vitamin D, nutritional deficiency, and the medical paradigm. J Clin Endocrinol Metab. 2003;88(11):5107-8
432) Hollis BW, Wagner CL. Assessment of dietary vitamin D requirements during pregnancy and lactation. Am J Clin Nutr. 2004;79(5):717-26
434) Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003;77(1):204-10
436) Hollis BW, Wagner CL. Assessment of dietary vitamin D requirements during pregnancy and lactation. Am J Clin Nutr. 2004;79(5):717-26
437) O'Leary JA, Klainer LM, Neuwirth RS. The management of hypoparathyroidism in pregnancy. Am J Obstet Gynecol. 1966;94(8):1103-7
438) Goodenday LS, Gordon GS. No risk from vitamin D in pregnancy. Ann Intern Med. 1971;75(5):807-8
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Proteolytic enzymes: Oral administration of proteolytic enzymes (such as pancreatin, bromelain,
papain, trypsin and alpha-chymotrypsin) for therapeutic purposes is well established on physiologic,
biochemical, and clinical grounds, and a brief review of their historical use is warranted. One of the first
experimental studies was published by Beard in 1906 in the British Medical Journal wherein he showed that
proteolytic enzymes significantly inhibited tumor growth in mice with implanted tumors439, and a year later in
that same journal, Cutfield440 reported tumor regression and other objective improvements in a patient treated
with proteolytic enzymes. In the American research literature, anti-cancer effects of proteolytic enzymes were
reported during this same time in the Journal of the American Medical Association in anecdotal case reports of
patients with fibrosarcoma441, breast cancer442, and head and neck malignancy443—all of whom responded
positively to the administration of proteolytic enzymes; no adverse effects were seen. Although nearly a century
would pass before Beard’s study and results were replicated with modern techniques444,445, by now it is well
established that orally administered proteolytic enzymes are well absorbed from the gastrointestinal tract into the
systemic circulation446,447 and that the anti-tumor, anti-metastatic, anti-infectious, anti-inflammatory , analgesic,
and anti-edematous actions result from synergism between a variety of mechanisms of action, including the
dose-dependent stimulation of reactive oxygen species production and anti-cancer cytotoxicity in human
neutrophils448, a pro-differentiative effect449, reduction in PG-E2 production450, reduction in substance P
production451, modulation of adhesion molecules and cytokine levels452, fibrinolytic effects and a antithrombotic effect mediated at least in part by a reduction in 2-series thromboxanes.453
Unfortunately,
enthusiasm for the enzyme treatment of cancer waned prematurely when trypsin was judged to not be a “miracle
cure”, when the mechanism of action could not be determined, and as enthusiasm surrounding drug and
radiation treatments grabbed the attention of allopaths.454 However, modern controlled clinical trials in cancer
patients have established the value of enzyme therapy, which produces important clinical benefit (e.g., symptom
reduction and prolonged survival) for little cost and with negligible adverse effects.455,456,457,458 Research in
other clinical applications for proteolytic enzymes has consistently shown benefit when properly formulated and
manufactured preparations are administered appropriately in the treatment of cellulitis, diabetic ulcers, sinusitis,
and bronchitis.459 For example, in a double-blind placebo-controlled trial with 59 patients, Taub460 documented
that oral administration of bromelain significantly promoted the resolution of congestion, inflammation, and
edema in patients with acute and chronic refractory sinusitis; no adverse effects were seen in any patient.
When not treating patients with cancer or infectious disease, chiropractic and naturopathic physicians
today use these enzymes mostly for the treatment of inflammatory and injury-related disorders. Reporting from
the Tulane University Health Service Center, Trickett461 reported that a papain-containing preparation benefited
40 patients with various injuries (e.g., contusions, sprains, lacerations, strains, fracture, surgical repair, and
muscle tears); no adverse effects were seen. In a recent open trial of patients with knee pain, Walker et al462
found a dose-dependent reduction in pain and disability as well as a significant improvement in psychological
well-being in patients consuming bromelain orally. Most of the bromelain studies reviewed by Brien et al463
were suggestive of a positive benefit in patients with knee osteoarthritis, but inadequate dosing clearly
prohibited the attainment of optimal results. Bromelain also attenuates experimental contraction-induced
439) Beard J. The action of trypsin upon the living cells of Jensen's mouse-tumour. Br Med J 1906; 4 (Jan 20): 140-1
440) Cutfield A. Trypsin Treatment in Malignant Disease. Br Med J. 1907; 5: 525
441) Wiggin FH. Case of Multiple Fibrosarcoma of the Tongue, With Remarks on the Use of Trypsin and Amylopsin in the Treatment of Malignant Disease." Journal of the American Medical Association 1906; 47: 2003-8
442) Goeth RA. Pancreatic treatment of cancer, with report of a cure. Journal of the American Medical Association 1907; (March 23) 48: 1030
443) Campbell JT. Trypsin Treatment of a Case of Malignant Disease. Journal of the American Medical Association 1907; 48: 225-226
444) Saruc M, Standop S, Standop J, Nozawa F, Itami A, Pandey KK, Batra SK, Gonzalez NJ, Guesry P, Pour PM. Pancreatic enzyme extract improves survival in murine pancreatic cancer. Pancreas. 2004;28(4):401-12
445) Batkin S, Taussig SJ, Szekerezes J. Antimetastatic effect of bromelain with or without its proteolytic and anticoagulant activity. J Cancer Res Clin Oncol. 1988;114(5):507-8
446) Gotze H, Rothman SS. Enteropancreatic circulation of digestive enzymes as a conservative mechanism. Nature 1975; 257(5527): 607-609
447) Liebow C, Rothman SS. Enteropancreatic Circulation of Digestive Enzymes. Science 1975; 189(4201): 472-474
448) Zavadova E, Desser L, Mohr T. Stimulation of reactive oxygen species production and cytotoxicity in human neutrophils in vitro and after oral administration of a polyenzyme preparation. Cancer Biother. 1995;10(2):147-52
449) Maurer HR, Hozumi M, Honma Y, Okabe-Kado J. Bromelain induces the differentiation of leukemic cells in vitro: an explanation for its cytostatic effects? Planta Med. 1988 Oct;54(5):377-81
450) Brien S, Lewith G, Walker A, Hicks SM, Middleton D. Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies. Evidence-based Complementary and Alternative Medicine. 2004;1(3)251–257
451) Gaspani L, Limiroli E, Ferrario P, Bianchi M. In vivo and in vitro effects of bromelain on PGE(2) and SP concentrations in the inflammatory exudate in rats. Pharmacology. 2002;65(2):83-6
452) Leipner J, Saller R. Systemic enzyme therapy in oncology: effect and mode of action. Drugs. 2000 Apr;59(4):769-80
453) Vellini M, Desideri D, Milanese A, Omini C, Daffonchio L, Hernandez A, Brunelli G. Possible involvement of eicosanoids in the pharmacological action of bromelain. Arzneimittelforschung. 1986;36(1):110-2
454) The trypsin treatment of cancer. British Medical Journal 1907; March 2: 519-20
455) Gonzalez NJ, Isaacs LL. Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nutr Cancer. 1999;33(2):117-24
456) Sakalova A, Bock PR, Dedik L, Hanisch J, Schiess W, Gazova S, Chabronova I, Holomanova D, Mistrik M, Hrubisko M. Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with
multiple myeloma. Cancer Chemother Pharmacol. 2001 Jul;47 Suppl:S38-44
457) Popiela T, Kulig J, Hanisch J, Bock PR. Influence of a complementary treatment with oral enzymes on patients with colorectal cancers--an epidemiological retrolective cohort study. Cancer Chemother Pharmacol. 2001;47
Suppl:S55-63
459) Taussig SJ, Yokoyama MM, Chinen A, Onari K, Yamakido M. Bromelain: a proteolytic enzyme and its clinical application. A review. Hiroshima J Med Sci. 1975;24(2-3):185-93
460) Taub SJ. The use of bromelains in sinusitis: a double-blind clinical evaluation. Eye Ear Nose Throat Mon. 1967 Mar;46(3):361-5
461) Trickett P. Proteolytic enzymes in treatment of athletic injuries. Appl Ther. 1964;30:647-52
462) Walker AF, Bundy R, Hicks SM, Middleton RW. Bromelain reduces mild acute knee pain and improves well-being in a dose-dependent fashion in an open study of otherwise healthy adults.Phytomedicine.2002;9:681-6
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skeletal muscle injury464, reduces production of hyperalgesic PG-E2 and substance P465, is generally effective in
the amelioration of trauma-induced injury, edema, and inflammation, and is practically non-toxic. Although
bromelain may be used in isolation, enzyme therapy is generally delivered in the form of polyenzyme
preparations containing pancreatin, bromelain, papain, amylase, lipase, trypsin and alpha-chymotrypsin.
Devil’s Claw (Harpagophytum procumbens): Harpagophytum has a long history of use in the treatment
of musculoskeletal complaints, and recent clinical trials have substantiated its role as an effective analgesic
suitable for clinical utilization. At least 12 clinical trials have been published on the use of Harpagophytum in
the treatment of musculoskeletal pain, and all trials have found the botanical to be clinically valuable and with
adverse effects comparable to placebo.466 Harpagophytum’s clinical benefit appears to derive chiefly from its
analgesic effect which appears to be mediated at least in part by activating antinociceptive neurons located in the
periaqueductal gray467, and administration of the herb does not alter eicosanoid production in humans.468,469 In
patients with osteoarthritis of the hip and knee, Harpagophytum is just as effective yet safer and better tolerated
than the drug diacerhein.470,471 In a study involving 183 patients with low-back pain, Harpagophytum was found
to be safe and moderately effective in patients with “severe and unbearable pain” and radiating pain with
neurologic deficit.472 Most recently, Harpagophytum was studied in a head-to-head clinical trial with the
formerly popular but dangerous selective cox-2 inhibitor Vioxx (rofecoxib); the data indicate that
Harpagophytum was safer and at least as effective.473 About 8% of patients may experience diarrhea or other
mild gastrointestinal effects, and fewer patients may experience dizziness; Harpagophytum may potentiate
anticoagulants. Treatment should be continued for at least 4 weeks, and many patients will continue to improve
after 8 weeks from the initiation of treatment.474 Products are generally standardized for the content of
harpagosides, with a target dose of at least 30 and preferably up to 60 mg harpagoside per day.475,476 However,
the whole plant is considered to contain effective constituents, not only the iridoid glycosides.477 Chrubasik478
noted that while Harpagophytum appears to be safe and moderately effective for the treatment musculoskeletal
pain, different proprietary products show significant variances in potency and clinical effectiveness. Data
suggest that Harpagophytum is better than placebo and at least as good as commonly used NSAIDs479,
suggesting that Harpagophytum should be clinically preferred over NSAIDs due to the lower cost and greater
safety.480
Cat’s Claw (Uncaria spp): Thirty patients with osteoarthritis of the knees benefited from highlyconcentrated freeze-dried aqueous extraction of U. guianensis dosed at 1 capsule of 100 mg daily.481 Reduction
in pain was approximately 36% at 4 weeks. A year-long study of patients with active rheumatoid arthritis (RA)
treated with sulfasalazine or hydroxychloroquine showed “relative safety and modest benefit” of Uncaria
tomentosa (UT).482 Uncaria inhibits NF-κB, TNFα, COX-2, and thus PGE-2 production.483 No major adverse
effects have been noted; however, headache and dizziness are more common in patients receiving Uncaria than
464) Walker JA, Cerny FJ, Cotter JR, Burton HW. Attenuation of contraction-induced skeletal muscle injury by bromelain. Med Sci Sports Exerc. 1992 Jan;24(1):20-5
466) Gagnier JJ, Chrubasik S, Manheimer E. Harpgophytum procumbens for osteoarthritis and low-back pain: a systematic review. BMC Complement Altern Med. 2004 Sep 15;4(1):13
467) Shin MC, Chang HK, Jang HM, Kim CJ, Kim Y, Kim EH. Modulation of Harpagophytum procumbens on ion channels in acutely dissociated periaquedeuctal gray neurons of rats. Korean J Meridian Acupoint 2003; 20: 17-29
468) Whitehouse LW, Znamirowska M, Paul CJ. Devil's Claw (Harpagophytum procumbens): no evidence for anti-inflammatory activity in the treatment of arthritic disease. Can Med Assoc J 1983 Aug 1;129(3):249-51
469) Moussard C, Alber D, Toubin MM, Thevenon N, Henry JC. A drug used in traditional medicine, harpagophytum procumbens: no evidence for NSAID-like effect on whole blood eicosanoid production in human. Prostaglandins
Leukot Essent Fatty Acids 1992 Aug;46(4):283-6
470) Chantre P, Cappelaere A, Leblan D, Guedon D, Vandermander J, Fournie B. Efficacy and tolerance of Harpagophytum procumbens versus diacerhein in treatment of osteoarthritis. Phytomedicine 2000;7(3):177-83
471) Leblan D, Chantre P, Fournie B. Harpagophytum procumbens in the treatment of knee and hip osteoarthritis. Four-month results of a prospective, multicenter, double-blind trial versus diacerhein. Joint Bone Spine
2000;67(5):462-7
472) “…subgroup analyses suggested that the effect was confined to patients with more severe and radiating pain accompanied by neurological deficit. …a slightly different picture, with the benefits seeming, if anything, to be
greatest in the H600 group and in patients without more severe pain, radiation or neurological deficit.” Chrubasik S, Junck H, Breitschwerdt H, Conradt C, Zappe H. Effectiveness of Harpagophytum extract WS 1531 in the
treatment of exacerbation of low-back pain: a randomized, placebo-controlled, double-blind study. Eur J Anaesthesiol 1999 Feb;16(2):118-29
473) Chrubasik S, Model A, Black A, Pollak S. A randomized double-blind pilot study comparing Doloteffin and Vioxx in the treatment of low-back pain. Rheumatology (Oxford). 2003 Jan;42(1):141-8 See
www.OptimalHealthResearch.com /articles.htm for the full-text of this article.
474) Chrubasik S, Thanner J, Kunzel O, Conradt C, Black A, Pollak S. Comparison of outcome measures during treatment with the proprietary Harpagophytum extract doloteffin in patients with pain in the lower back, knee or hip.
Phytomedicine 2002 Apr;9(3):181-94
475) “They took an 8-week course of Doloteffin at a dose providing 60 mg harpagoside per day… Doloteffin is well worth considering for osteoarthritic knee and hip pain and nonspecific low-back pain.” Chrubasik S, Thanner J,
Kunzel O, Conradt C, Black A, Pollak S. Comparison of outcome measures during treatment with the proprietary Harpagophytum extract doloteffin in patients with pain in the lower back, knee or hip. Phytomedicine 2002
Apr;9(3):181-94
476) Gagnier JJ, Chrubasik S, Manheimer E. Harpgophytum procumbens for osteoarthritis and low-back pain: a systematic review. BMC Complement Altern Med. 2004 Sep 15;4(1):13
477) Wegener T. [Therapy of degenerative diseases of the musculoskeletal system with South African devil's claw (Harpagophytum procumbens DC)] [Article in German] Wien Med Wochenschr 1999;149(8-10):254-7
478) Chrubasik S, Conradt C, Roufogalis BD. Effectiveness of Harpagophytum extracts and clinical efficacy. Phytother Res. 2004 Feb;18(2):187-9
479) Chrubasik S, Conradt C, Black A. The quality of clinical trials with Harpagophytum procumbens. Phytomedicine. 2003;10(6-7):613-23
480) Chrubasik S, Junck H, Breitschwerdt H, Conradt C, Zappe H. Effectiveness of Harpagophytum extract WS 1531 in the treatment of exacerbation of low-back pain: a randomized, placebo-controlled, double-blind study. Eur J
Anaesthesiol 1999 Feb;16(2):118-29
481) Piscoya J, Rodriguez Z, Bustamante SA, Okuhama NN, Miller MJ, Sandoval M.Efficacy and safety of freeze-dried cat's claw in osteoarthritis of the knee: mechanisms of action of the species Uncaria guianensis. Inflamm
Res. 2001 Sep;50(9):442-8 This article is available on-line at www.OptimalHealthResearch.com /articles.htm
482) "This small preliminary study demonstrates relative safety and modest benefit to the tender joint count of a highly purified extract from the pentacyclic chemotype of UT in patients with active RA taking sulfasalazine or
hydroxychloroquine." Mur E, Hartig F, Eibl G, Schirmer M. Randomized double blind trial of an extract from the pentacyclic alkaloid-chemotype of uncaria tomentosa for the treatment of rheumatoid arthritis. J Rheumatol. 2002
Apr;29(4):678-81
483) Piscoya J, Rodriguez Z, Bustamante SA, Okuhama NN, Miller MJ, Sandoval M.Efficacy and safety of freeze-dried cat's claw in osteoarthritis of the knee: mechanisms of action of the species Uncaria guianensis. Inflamm
Res. 2001 Sep;50(9):442-8 This article is available on-line at www.OptimalHealthResearch.com /articles.htm
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in patients in placebo groups. This herb should probably not be used during pregnancy based on its historical
use as a contraceptive. Most products are between 250-500 mg and are standardized to 3.0% alkaloids and 15%
total polyphenols dosed 1-3 times per day. Other studies with Uncaria tomentosa have shown enhancement of
post-vaccination immunity484 and enhancement of DNA repair in humans.485
Willow bark (Salix spp): In a double-blind placebo-controlled clinical trial in 210 patients with
moderate/severe low-back pain (20% of patients had positive straight-leg raising test), extract of willow bark
showed a dose-dependent analgesic effect with benefits beginning in the first week of treatment.486 In a head-tohead study of 228 patients comparing willow bark (standardized for 240 mg salicin) with Vioxx (rofecoxib),
treatments were equally effective yet willow bark was safer and 40% less expensive.487 Because willow bark’s
salicylates were the original source for the chemical manufacture of acetylsalicylic acid (aspirin), researchers
and clinicians have erroneously mistaken willow bark to be synonymous with aspirin; this is certainly inaccurate
and therefore clarification of willow’s mechanism of action will be provided here. Aspirin has two primary
effects via three primary mechanisms of action: 1) anticoagulant effects mediated by the acetylation and
permanent inactivation of thromboxane-A synthase, which is the enzyme that makes the powerful
proaggregatory thromboxane-A2; 2) antiprostaglandin action via acetylation of both isoforms of cyclooxygenase
(COX-1 inhibition 25-166x more than COX-2) with widespread inhibition of prostaglandin formation, and 3)
antiprostaglandin formation via “retroconversion” of acetylsalicylate into salicylic acid which then inhibits
cyclooxygenase-2 gene transcription.488 Notice that the acetylation reactions are specific to aspirin and thus
actions #1 and #2 are not seen with willow bark; whereas #3—inhibition of COX-2 transcription by
salicylates—appears to be the major mechanism of action of willow bark extract. Proof of this principle is
supported by the lack of adverse effects associated with willow bark in the research literature. If willow bark
were pharmacodynamically synonymous with aspirin, then we would expect case reports of gastric ulceration,
hemorrhage, and Reye’s syndrome to permeate the research literature; this is not the case and therefore—with
the exception of possible allergic reactions in patients previously allergic to aspirin and salicylates—extensive
“warnings” on willow bark products489 are unnecessary.490 Salicylates are widely present in fruits, vegetables,
herbs and spices and are partly responsible for the anti-cancer, anti-inflammatory, and health-promoting benefits
of plant consumption.491,492 With willow bark products, the daily dose should not exceed 240 mg of salicin, and
products should include other components of the whole plant. Except for rare allergy in patients previously
sensitized to aspirin or salicylates, no adverse effects are known, yet use during pregnancy and with anticoagulant medication is discouraged.
Boswellia (Boswellia serrata): Boswellia shows anti-inflammatory action via inhibition of 5lipoxygenase493 with no apparent effect on cyclooxygenase.494 A recent clinical study showed that Boswellia
was able to reduce pain and swelling while increasing joint flexion and walking distance in patients with
osteoarthritis of the knees.495 While reports from clinical trials published in English are relatively rare, a recent
abstract from the German medical research496 stated, “In clinical trials promising results were observed in
patients with rheumatoid arthritis, chronic colitis, ulcerative colitis, Crohn's disease, bronchial asthma and
peritumoral brains edemas.” Additional recent studies have confirmed the effectiveness of Boswellia in the
treatment of asthma497 and ulcerative colitis.498 Minor gastrointestinal upset has been reported. Products are
484) "C-Med-100 is a novel nutraceutical extract from the South American plant Uncaria tomentosa or Cat's Claw which is known to possess immune enhancing and antiinflammatory properties in animals. However, statistically
significant immune enhancement for the individuals on C-Med-100 supplement was observed..." Lamm S, Sheng Y, Pero RW. Persistent response to pneumococcal vaccine in individuals supplemented with a novel water
soluble extract of Uncaria tomentosa, C-Med-100. Phytomedicine. 2001 Jul;8(4):267-74
485) "There was a statistically significant decrease of DNA damage and a concomitant increase of DNA repair in the supplement groups (250 and 350 mg/day) when compared with non-supplemented controls (p < 0.05)." Sheng
Y, Li L, Holmgren K, Pero RW. DNA repair enhancement of aqueous extracts of Uncaria tomentosa in a human volunteer study. Phytomedicine. 2001 Jul;8(4):275-82
486) Chrubasik S, Eisenberg E, Balan E, Weinberger T, Luzzati R, Conradt C. Treatment of low-back pain exacerbations with willow bark extract: a randomized double-blind study. Am J Med. 2000;109:9-14
487) Chrubasik S, Kunzel O, Model A, Conradt C, Black A. Treatment of low-back pain with a herbal or synthetic anti-rheumatic: a randomized controlled study. Willow bark extract for low-back pain. Rheumatology (Oxford).
2001;40:1388-93
488) Hare LG, Woodside JV, Young IS. Dietary salicylates. J Clin Pathol 2003 Sep;56(9):649-50
489) Clauson KA, Santamarina ML, Buettner CM, Cauffield JS. Evaluation of Presence of Aspirin-Related Warnings with Willow Bark (July/August). Ann Pharmacother. 2005 May 31; [Epub ahead of print]
490) Vasquez A, Muanza DN. Evaluation of Presence of Aspirin-Related Warnings with Willow Bark: Comment on the Article by Clauson et al. Ann Pharmacotherapy 2005 Oct;39(10):1763. Epub 2005 Aug 30
491) Lawrence JR, Peter R, Baxter GJ, Robson J, Graham AB, Paterson JR. Urinary excretion of salicyluric and salicylic acids by non-vegetarians, vegetarians, and patients taking low dose aspirin. J Clin Pathol. 2003
Sep;56(9):651-3
492) Paterson JR, Lawrence JR. Salicylic acid: a link between aspirin, diet and the prevention of colorectal cancer. QJM. 2001 Aug;94(8):445-8
493) Wildfeuer A, Neu IS, Safayhi H, Metzger G, Wehrmann M, Vogel U, Ammon HP. Effects of boswellic acids extracted from a herbal medicine on the biosynthesis of leukotrienes and the course of experimental autoimmune
encephalomyelitis. Arzneimittelforschung 1998 Jun;48(6):668-74
494) Safayhi H, Mack T, Sabieraj J, Anazodo MI, Subramanian LR, Ammon HP. Boswellic acids: novel, specific, nonredox inhibitors of 5-lipoxygenase. J Pharmacol Exp Ther 1992 Jun;261(3):1143-6
495) Kimmatkar N, Thawani V, Hingorani L, Khiyani R. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee--a randomized double blind placebo controlled trial. Phytomedicine. 2003
Jan;10(1):3-7
496) Ammon HP. [Boswellic acids (components of frankincense) as the active principle in treatment of chronic inflammatory diseases] [Article in German] Wien Med Wochenschr. 2002;152(15-16):373-8
497) Gupta I, Gupta V, Parihar A, Gupta S, Ludtke R, Safayhi H, Ammon HP. Effects of Boswellia serrata gum resin in patients with bronchial asthma: results of a double-blind, placebo-controlled, 6-week clinical study. Eur J Med
Res. 1998 Nov 17;3(11):511-4
498) Gupta I, Parihar A, Malhotra P, Singh GB, Ludtke R, Safayhi H, Ammon HP. Effects of Boswellia serrata gum resin in patients with ulcerative colitis. Eur J Med Res. 1997 Jan;2(1):37-43
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generally standardized to contain 37.5–65% boswellic acids, which are currently considered the active
constituents with clinical benefit. The target dose is approximately 150 mg of boswellic acids thrice daily; dose
and number of capsules/tablets will vary depending upon the concentration found in differing products.
Ginger (Zingiber officiniale): Ginger is a well known spice and food with a long history of
consumption and use as an anti-inflammatory and anti-nausea agent.499 Components of ginger have been shown
to reduce production of the leukotriene LTB4 by inhibiting 5-lipoxygenase and to reduce production of the
prostaglandin PG-E2 by inhibiting cyclooxygenase.500,501 With its dual action in the reduction of inflammationpromoting prostaglandins and leukotrienes, as well as its ability to inhibit nitric oxide production502, ginger has
been shown to safely reduce the pain and disability associated with osteoarthritis, rheumatoid arthritis, muscle
aches503,504, osteoarthritis of the knees505, and migraine headaches.506 Doses up to one gram of ginger per day
have been safely used during pregnancy to reduce the nausea and vomiting of pregnancy507 and hyperemesis
gravidarum508, while doses for the treatment of rheumatic conditions has ranged from 1 gram (one-half
teaspoon) of powdered ginger to up to 50 grams per day of fresh or lightly cooked root. 509,510 The pungent
principles of ginger often create a warm or burning sensation in the stomach that is mild, reducible with food
consumption, and not indicative of tissue irritation. In contrast with pharmaceutical NSAIDs, ginger appears to
have a protective benefit against gastric ulceration.511,512 No significant adverse effects due to ginger are
known; gall stones and the use of coumadin/Warfarin may possibly be relative contraindications due to the mild
cholagogic and anticoagulant actions, respectively.
MSM (Methylsulfonylmethane): MSM is a fairly popular nutritional supplement for the amelioration of
allergies, interstitial cystitis, and joint pain, although the research supporting its use is quite limited.513 MSM is
relatively inexpensive and appears safe, especially for short-term use; one clinical trial used 2,600 mg for 30
days with no major adverse effects.514 Doses of 1-3 grams per day appear safe and are reasonable for patients
who may derive benefit.
Spinal Manipulation: Mechanisms of Action and Synergism with Nutritional/Botanical Interventions
Using the state of the sciences before the year 1910, chiropractic was founded with a profound appreciation of
the integrated nature of health and the therapeutic focus was on spinal manipulation. In describing the
chiropractic model of health, DD Palmer515 wrote, “The human body represents the actions of three laws—
spiritual, mechanical, and chemical—united as one triune. As long as there is perfect union of these three, there
is health.” While the therapeutic focus of the profession has been spinal manipulation, from its inception the
chiropractic profession has emphasized a holistic, integrative model of therapeutic intervention, health, and
disease, and chiropractic was the first healthcare profession in America to specifically claim that the
optimization of health requires attention to spiritual/emotional/psychological, mechanical/physical/structural,
and biochemical/nutritional/hormonal/chemical considerations.
Accordingly, these cornerstones are
fundamental to the modern definition of the chiropractic profession recently articulated by the American
Chiropractic Association516: “Doctors of Chiropractic are physicians who consider man as an integrated being
and give special attention to the physiological and biochemical aspects including structural, spinal,
musculoskeletal, neurological, vascular, nutritional, emotional and environmental relationships.”
499) Langner E, Greifenberg S, Gruenwald J. Ginger: history and use. Adv Ther 1998 Jan-Feb;15(1):25-44
500) Kiuchi F, Iwakami S, Shibuya M, Hanaoka F, Sankawa U. Inhibition of prostaglandin and leukotriene biosynthesis by gingerols and diarylheptanoids. Chem Pharm Bull (Tokyo) 1992 Feb;40(2):387-91
501) Tjendraputra E, Tran VH, Liu-Brennan D, Roufogalis BD, Duke CC. Effect of ginger constituents and synthetic analogues on cyclooxygenase-2 enzyme in intact cells. Bioorg Chem 2001 Jun;29(3):156-63
502) Shen CL, Hong KJ, Kim SW. Effects of ginger (Zingiber officinale Rosc.) on decreasing the production of inflammatory mediators in sow osteoarthrotic cartilage explants. J Med Food. 2003 Winter;6(4):323-8
503) Srivastava KC, Mustafa T. Ginger (Zingiber officinale) in rheumatism and musculoskeletal disorders. Med Hypotheses. 1992 Dec;39(4):342-8
504) Srivastava KC, Mustafa T. Ginger (Zingiber officinale) and rheumatic disorders. Med Hypotheses. 1989 May;29(1):25-8
505) Altman RD, Marcussen KC. Effects of a ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum. 2001 Nov;44(11):2531-8
506) Mustafa T, Srivastava KC. Ginger (Zingiber officinale) in migraine headache. J Ethnopharmacol. 1990 Jul;29(3):267-73
507) Vutyavanich T, Kraisarin T, Ruangsri R. Ginger for nausea and vomiting in pregnancy: randomized, double-masked, placebo-controlled trial. Obstet Gynecol 2001 Apr;97(4):577-82
508) Fischer-Rasmussen W, Kjaer SK, Dahl C, Asping U. Ginger treatment of hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol. 1991 Jan 4;38(1):19-24
509) Srivastava KC, Mustafa T. Ginger (Zingiber officinale) in rheumatism and musculoskeletal disorders. Med Hypotheses. 1992 Dec;39(4):342-8
510) Srivastava KC, Mustafa T. Ginger (Zingiber officinale) and rheumatic disorders. Med Hypotheses. 1989 May;29(1):25-8
511) al-Yahya MA, Rafatullah S, Mossa JS, Ageel AM, Parmar NS, Tariq M. Gastroprotective activity of ginger zingiber officinale rosc., in albino rats. Am J Chin Med 1989;17(1-2):51-6
512) Yamahara J, Mochizuki M, Rong HQ, Matsuda H, Fujimura H. The anti-ulcer effect in rats of ginger constituents. J Ethnopharmacol. 1988;23:299-304
513) Methylsulfonylmethane (MSM). Monograph. Altern Med Rev. 2003 Nov;8(4):438-41
514) Barrager E, Veltmann JR Jr, Schauss AG, Schiller RN. A multicentered, open-label trial on the safety and efficacy of methylsulfonylmethane in the treatment of seasonal allergic rhinitis. J Altern Complement Med.
2002;8:167-73
515) Palmer DD. The Science, Art, and Phiosophy, of Chiropractic. Portland, OR; Portland Printing House Company, 1910: 107
516) American Chiropractic Association. What is Chiropractic? http://amerchiro.org/media/whatis/ Accessed January 9, 2005
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Applied to either the spine or peripheral joints, high-velocity low-amplitude joint manipulation appears to have
numerous physical and physiological effects, including but not limited to the following: 1) releasing entrapped
intraarticular menisci and synovial folds, 2) acutely reducing intradiscal pressure, thus promoting replacement of
decentralized disc material, 3) stretching of deep periarticular muscles to break the cycle of chronic autonomous
muscle contraction by lengthening the muscles and thereby releasing excessive actin-myosin binding, 4)
promoting restoration of proper kinesthesia and proprioception, 5) promoting relaxation of paraspinal muscles
by stretching facet joint capsules, 6) promoting relaxation of paraspinal muscles via “postactivation depression”,
which is the temporary depletion of contractile neurotransmitters, 7) temporarily elevating plasma betaendorphin, 8) temporarily enhancing phagocytic ability of neutrophils and monocytes, and 9) activation of the
diffuse descending pain inhibitory system located in the periaqueductal gray matter—this is an important aspect
of nociceptive inhibition by intense sensory/mechanoreceptor stimulation, which will be discussed in a
following section for its relevance to neurogenic inflammation. While this list of mechanisms-of-action is
certainly not complete, for purposes of this paper it is sufficient to have established that, indeed, joint
manipulation in general and spinal manipulation in particular have objective mechanistic effects that correlate
with their clinical benefits. Additional details are provided in numerous published reviews and primary
research517,518,519,520,521,522,523 and by Leach524, whose extensive description of the mechanisms of action of spinal
manipulative therapy is unsurpassed. Given such a wide base of experimental and clinical support published in
peer-reviewed journals and widely-available textbooks, denigrations directed toward spinal manipulation on the
grounds that it is “unscientific” or “unsupported by research” are unfounded and are indicative of selective
ignorance.
The clinical benefits and cost-effectiveness of chiropractic management of musculoskeletal conditions is
extensively documented, and that spinal manipulation generally shows superior safety to drug and surgical
treatment of back and neck pain is also well established.525,526,527,528,529,530,531 Adjunctive therapies such as postisometric relaxation532 and correction of myofascial dysfunction533 can lead to tremendous and rapid reductions
in musculoskeletal pain without the hazards and expense associated with pharmaceutical drugs.
Nonmusculoskeletal benefits of musculoskeletal/spinal manipulation include improved pulmonary function
and/or quality of life in patients with asthma534,535,536,537 and improvement or restoration of vision in patients with
post-traumatic visual loss.538,539,540,541,542,543,544,545 More research is required to quantify the potential benefits of
spinal manipulation in patients with wide-ranging conditions such as epilepsy546,547, attention-deficit
hyperactivity disorder548,549, and Parkinson’s disease.550 Given that most pharmaceutical drugs work on single
517) Maigne JY, Vautravers P. Mechanism of action of spinal manipulative therapy. Joint Bone Spine. 2003;70(5):336-41
518) Brennan PC, Triano JJ, McGregor M, Kokjohn K, Hondras MA, Brennan DC. Enhanced neutrophil respiratory burst as a biological marker for manipulation forces: duration of the effect and association with substance P and
tumor necrosis factor. J Manipulative Physiol Ther. 1992 Feb;15(2):83-9
519) Brennan PC, Kokjohn K, Kaltinger CJ, Lohr GE, Glendening C, Hondras MA, McGregor M, Triano JJ. Enhanced phagocytic cell respiratory burst induced by spinal manipulation: potential role of substance P. J Manipulative
Physiol Ther. 1991 Sep;14(7):399-408
520) Heikkila H, Johansson M, Wenngren BI. Effects of acupuncture, cervical manipulation and NSAID therapy on dizziness and impaired head repositioning of suspected cervical origin: a pilot study. Man Ther. 2000
Aug;5(3):151-7
521) Rogers RG. The effects of spinal manipulation on cervical kinesthesia in patients with chronic neck pain: a pilot study. J Manipulative Physiol Ther. 1997;20(2):80-5
522) Bergman, Peterson, Lawrence. Chiropractic Technique. New York: Churchill Livingstone 1993. An updated edition is now availabe published by Mosby.
523) Herzog WH. Mechanical and physiological responses to spinal manipulative treatments. JNMS: J Neuromusculoskeltal System 1995; 3: 1-9
524) Leach RA. (ed). The Chiropractic Theories: A Textbook of Scientific Research, Fourth Edition. Baltimore: Lippincott, Williams & Wilkins, 2004
525) Dabbs V, Lauretti WJ. A risk assessment of cervical manipulation vs. NSAIDs for the treatment of neck pain. J Manipulative Physiol Ther. 1995;18:530-6
526) Rosner AL. Evidence-based clinical guidelines for the management of acute low-back pain: response to the guidelines prepared for the Australian Medical Health and Research Council. J Manipulative Physiol Ther. 2001
Mar-Apr;24(3):214-20
527) Oliphant D. Safety of spinal manipulation in the treatment of lumbar disk herniations: a systematic review and risk assessment. J Manipulative Physiol Ther. 2004;27:197-210
528) Meade TW, Dyer S, Browne W, Townsend J, Frank AO. Low-back pain of mechanical origin: randomised comparison of chiropractic and hospital outpatient treatment. BMJ. 1990;300(6737):1431-7
529) Meade TW, Dyer S, Browne W, Frank AO. Randomised comparison of chiropractic and hospital outpatient management for low-back pain: results from extended follow up. BMJ. 1995;311(7001):349-5
530) Manga P, Angus D, Papadopoulos C, et al. The Effectiveness and Cost-Effectiveness of Chiropractic Management of Low-Back Pain. Richmond Hill, Ontario: Kenilworth Publishing; 1993
2004;164:1985-92
532) Lewit K, Simons DG. Myofascial pain: relief by post-isometric relaxation. Arch Phys Med Rehabil. 1984;65(8):452-6
533) Ingber RS. Iliopsoas myofascial dysfunction: a treatable cause of "failed" low-back syndrome. Arch Phys Med Rehabil. 1989 May;70(5):382-6
534) Nielson NH, Bronfort G, Bendix T, Madsen F, Wecke B. Chronic asthma and chiropractic spinal manipulation: a randomized clinical trial. Clin Exp Allergy 1995;25:80-8
535) Mein EA, Greenman PE, McMillin DL, Richards DG, Nelson CD. Manual medicine diversity: research pitfalls and the emerging medical paradigm. J Am Osteopath Assoc. 2001 Aug;101(8):441-4
536) “There were small increases (7 to 12 liters per minute) in peak expiratory flow in the morning and the evening in both treatment groups,… Symptoms of asthma and use of beta-agonists decreased and the quality of life
increased in both groups, with no significant differences between the groups.” Balon J, Aker PD, Crowther ER, Danielson C, Cox PG, O'Shaughnessy D, Walker C, Goldsmith CH, Duku E, Sears MR. A comparison of active
and simulated chiropractic manipulation as adjunctive treatment for childhood asthma. N Engl J Med. 1998 Oct 8;339(15):1013-20
537) Bronfort G, Evans RL, Kubic P, Filkin P. Chronic pediatric asthma and chiropractic spinal manipulation: a prospective clinical series and randomized clinical pilot study. J Manipulative Physiol Ther. 2001 Jul-Aug;24(6):369-77
538) Stephens D, Pollard H, Bilton D, Thomson P, Gorman F. Bilateral simultaneous optic nerve dysfunction after periorbital trauma: recovery of vision in association with chiropractic spinal manipulation therapy. J Manipulative
Physiol Ther. 1999 Nov-Dec;22(9):615-21
539) Stephens D, Gorman F, Bilton D. The step phenomenon in the recovery of vision with spinal manipulation: a report on two 13-yr-olds treated together. J Manipulative Physiol Ther. 1997 Nov-Dec;20(9):628-33
540) Stephens D, Gorman F. The association between visual incompetence and spinal derangement: an instructive case history. J Manipulative Physiol Ther. 1997 Jun;20(5):343-50.
541) Stephens D, Gorman RF. Does 'normal' vision improve with spinal manipulation? J Manipulative Physiol Ther. 1996 Jul-Aug;19(6):415-8
542) Gorman RF. Monocular scotomata and spinal manipulation: the step phenomenon. J Manipulative Physiol Ther. 1996 Jun;19(5):344-9
543) Gorman RF. Monocular visual loss after closed head trauma: immediate resolution associated with spinal manipulation. J Manipulative Physiol Ther. 1995 Jun;18(5):308-14
544) Gorman RF. The treatment of presumptive optic nerve ischemia by spinal manipulation. J Manipulative Physiol Ther. 1995;18(3):172-7
545) Gorman RF. Automated static perimetry in chiropractic. J Manipulative Physiol Ther. 1993 Sep;16(7):481-7
546) Elster EL.Treatment of bipolar, seizure, and sleep disorders and migraine headaches utilizing a chiropractic technique. J Manipulative Physiol Ther. 2004 Mar-Apr;27(3):E5
547) Alcantara J, Heschong R, Plaugher G, Alcantara J. Chiropractic management of a patient with subluxations, low-back pain and epileptic seizures. J Manipulative Physiol Ther. 1998;21(6):410-8
548) Giesen JM, Center DB, Leach RA. An evaluation of chiropractic manipulation as a treatment of hyperactivity in children. J Manipulative Physiol Ther. 1989 Oct;12(5):353-63
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biochemical pathways, spinal manipulation is discordant with the medical/drug paradigm because its effects are
numerous (rather than singular) and physical and physiological (rather than biochemical). Thus, when viewed
through the allopathic/pharmaceutical lens, spinal manipulation (like acupuncture and other physical
modalities), will be viewed as “unscientific” and “does not make sense.” In this case, the fault lies with the
viewer and the lens, not with the object.
Research documenting the systemic and “nonmusculoskeletal” benefits of spinal manipulation mandates that our
concept of “musculoskeletal” must be expanded to appreciate that musculoskeletal interventions benefit
nonmusculoskeletal body systems and physiologic processes. This conceptual expansion applies also to soft
tissue therapeutics such as massage, which can reduce adolescent aggression551, improve outcome in preterm
infants552, alleviate premenstrual syndrome553, and increase serotonin and dopamine levels in patients with lowback pain.554
Neurogenic inflammation causes catabolism of articular structures and thus promotes joint destruction555,556, a
phenomena that the current author has termed “neurogenic chondrolysis.”557 The biologic and scientific basis
for this concept rests on the following sequence of events which ultimately form a self-perpetuating cycle: 1)
tissue irritation by allergens, injury, degradation, or chemical xenobiotics results in the release of
proinflammatory mediators in local tissues (immunogenic inflammation); 2) nociceptive input is received
centrally and results in release of proinflammatory mediators from sensory neurons (neurogenic
inflammation558) and results in a neurologically-mediated catabolic effect in articular cartilage (neurogenic
chondrolysis559,560) and in tissues distant from the site of irritation (neurogenic switching561,562), 3) inflammation
and catabolism in articular structures mediated by the nervous system promotes joint destruction and thus
exacerbates immunogenic inflammation, 4) exacerbation of immunogenic inflammation promotes additional
neurogenic inflammation
Based on recently published research, an additional mechanism of action for musculoskeletal manipulation is
described here: the current author proposes that intense mechanoreceptor activation via high-velocity lowamplitude spinal manipulation inhibits C-fiber-mediated nociceptive input and thus suppresses neurogenic
inflammation. Since neurogenic chondrolysis is inhibited by interference with C-fiber (type IV) mediated
nociception563 and since it appears that chiropractic manipulation inhibits C-fiber mediated nociception564,565,
then chiropractic manipulation may promote health and wellness by reducing neurogenic inflammation and may
promote articular integrity by inhibiting neurogenic chondrolysis. This would explain the benefits of spinal
manipulation in the treatment of asthma566,567,568, since asthma is known to be mediated in large part by
neurogenic inflammation.569,570 Therefore, for the promotion of wellness and the treatment of inflammatory
disorders, I propose that the most effective means for inhibiting this self-perpetuating vicious cycle is
549) Bastecki AV, Harrison DE, Haas JW. Cervical kyphosis is a possible link to attention-deficit/hyperactivity disorder. J Manipulative Physiol Ther. 2004 Oct;27(8):e14
550) Elster EL. Upper cervical chiropractic management of a patient with Parkinson's disease: a case report. J Manipulative Physiol Ther. 2000 Oct;23(8):573-7
551) Diego MA, Field T, Hernandez-Reif M, Shaw JA, Rothe EM, Castellanos D, Mesner L. Aggressive adolescents benefit from massage therapy. Adolescence 2002 Fall;37(147):597-607
552) Mainous RO. Infant massage as a component of developmental care: past, present, and future. Holist Nurs Pract 2002 Oct;16(5):1-7
553) Hernandez-Reif M, Martinez A, Field T, Quintero O, Hart S, Burman I. Premenstrual symptoms are relieved by massage therapy. J Psychosom Obstet Gynaecol 2000 Mar;21(1):9-15
554) "RESULTS: By the end of the study, the massage therapy group, as compared to the relaxation group, reported experiencing less pain, depression, anxiety and improved sleep. They also showed improved trunk and pain
flexion performance, and their serotonin and dopamine levels were higher." Hernandez-Reif M, Field T, Krasnegor J, Theakston H. Lower back pain is reduced and range of motion increased after massage therapy. Int J
Neurosci 2001;106(3-4):131-45
555) Gouze-Decaris E, Philippe L, Minn A, Haouzi P, Gillet P, Netter P, Terlain B. Neurophysiological basis for neurogenic-mediated articular cartilage anabolism alteration. Am J Physiol Regul Integr Comp Physiol.
2001;280(1):R115-22
556) Decaris E, Guingamp C, Chat M, Philippe L, Grillasca JP, Abid A, Minn A, Gillet P, Netter P, Terlain B. Evidence for neurogenic transmission inducing degenerative cartilage damage distant from local inflammation. Arthritis
Rheum. 1999;42(9):1951-60
557) Vasquez A. Integrative orthopedics: exploring the structural aspect of the matrix. Applying Functional Medicine in Clinical Practice. Tampa, Florida November 29-December 4, 2004. Hosted by the Institute for Functional
Medicine: www.FunctionalMedicine.org
558) Meggs WJ.Mechanisms of allergy and chemical sensitivity. Toxicol Ind Health. 1999 Apr-Jun;15(3-4):331-8
2001;280(1):R115-22
560) Decaris E, Guingamp C, Chat M, Philippe L, Grillasca JP, Abid A, Minn A, Gillet P, Netter P, Terlain B. Evidence for neurogenic transmission inducing degenerative cartilage damage distant from local inflammation. Arthritis
Rheum. 1999;42(9):1951-60
561) Meggs WJ. Neurogenic Switching: A Hypothesis for a Mechanism for Shifting the Site of Inflammation in Allergy and Chemical Sensitivity. Environ Health Perspect 1995; 103:54-56
562) Meggs WJ. Mechanisms of allergy and chemical sensitivity. Toxicol Ind Health. 1999 Apr-Jun;15(3-4):331-8
2001;280(1):R115-22
564) Gillette, R. A speculative argument for the coactivation of diverse somatic receptor populations by forceful chiropractic adjustments. Man Med 1987; 3:1-14
565) Boal RW, Gillette RG. Central neuronal plasticity, low-back pain and spinal manipulative therapy. J Manipulative Physiol Ther. 2004;27(5):314-26
569) Renz H. Neurotrophins in bronchial asthma. Respir Res. 2001;2(5):265-8
570) Groneberg DA, Quarcoo D, Frossard N, Fischer A. Neurogenic mechanisms in bronchial inflammatory diseases. Allergy. 2004 Nov; 59(11): 1139-52
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therapeutic intervention directed toward as many of the loci of activity as possible—namely the inflamed
tissues, proinflammatory nerves, spinal cord, and the brain—and this can be accomplished with
phytonutraceutical antiinflammatories (as described in previous sections), meditative stress reduction571,
inhibition of nociception with spinal manipulation572,573 (and perhaps acupuncture574 and other physical
modalities), and by botanical and nutritional medicines that inhibit neurogenic inflammation575,576, respectively
(Figure 7). In addition to these biochemically- and neurologically-mediated effects, other health benefits
potentially mediated by piezoelectric physiology should also be considered.577,578,579
Figure 7: Hypothetical model of the vicious cycle of immunogenic and neurogenic inflammation and their
inhibition by multicomponent intervention.
clinical interventions
meditation, stress
reduction, relaxation,
healthy relationships,
social support,
meaning, "spirituality"
inhibition of noxious stimuli reception
by intense mechanoreceptor
activation
(e.g., spinal manipulation); additional
effects may be mediated by
piezoelectric phenomena
physiologic phenomena
"stress"
reception by (noxious stimulation
of) central nervous system
(spinal cord and brain)
neurologic
sensory
input
neurogenic
inflammation
"neurogenic
switching"
tissue degeneration,
local inflammation
anti-inflammatory
diet, nutritional and
botanical
anti-inflammatories
injury, pain,
allergen, or
noxious event
Furthermore, I propose that select nutritional interventions as surveyed in this paper may have enhanced effects
and benefits when combined with spinal manipulative therapy. For example, enhanced respiratory burst clearly
carries both antitumor and antimicrobial benefits, and this physiologic effect can be induced by oral
consumption of proteolytic enzymes580 as well as by chiropractic spinal manipulative therapy.581,582 Likewise,
we would expect synergism between spinal manipulative therapy583,584,585 and nutritional586 and botanical587,588
571) Lutgendorf S, Logan H, Kirchner HL, Rothrock N, Svengalis S, Iverson K, Lubaroff D. Effects of relaxation and stress on the capsaicin-induced local inflammatory response. Psychosom Med. 2000;62(4):524-34
572) Gillette, R. A speculative argument for the coactivation of diverse somatic receptor populations by forceful chiropractic adjustments. Man Med 1987; 3:1-14
573) Boal RW, Gillette RG. Central neuronal plasticity, low-back pain and spinal manipulative therapy. J Manipulative Physiol Ther. 2004;27(5):314-26
574) Joos S, Brinkhaus B, Maluche C, Maupai N, Kohnen R, Kraehmer N, Hahn EG, Schuppan D. Acupuncture and moxibustion in the treatment of active Crohn's disease: a randomized controlled study. Digestion.
2004;69(3):131-9
575) Jancso N, Jancso-Gabor A, Szolcsanyi J. Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. Br J Pharmacol. 1967 Sep;31(1):138-51
576) Miller MJ, Vergnolle N, McKnight W, Musah RA, Davison CA, Trentacosti AM, Thompson JH, Sandoval M, Wallace JL. Inhibition of neurogenic inflammation by the Amazonian herbal medicine sangre de grado. J Invest
Dermatol. 2001;117(3):725-30
577) Athenstaedt H. Pyroelectric and piezoelectric properties of vertebrates. Ann N Y Acad Sci. 1974;238:68-94
578) Athenstaedt H. "Functional polarity" of the spinal cord caused by its longitudinal electric dipole moment. Am J Physiol. 1984;247(3 Pt 2):R482-7
579) Lipinski B. Biological significance of piezoelectricity in relation to acupuncture, Hatha Yoga, osteopathic medicine and action of air ions. Med Hypotheses. 1977;3(1):9-12
581) Brennan PC, Triano JJ, McGregor M, Kokjohn K, Hondras MA, Brennan DC. Enhanced neutrophil respiratory burst as a biological marker for manipulation forces: duration of the effect and association with substance P and
tumor necrosis factor. J Manipulative Physiol Ther. 1992 Feb;15(2):83-9
Physiol Ther. 1991 Sep;14(7):399-408
586) Surette ME, Koumenis IL, Edens MB, Tramposch KM, Clayton B, Bowton D, Chilton FH. Inhibition of leukotriene biosynthesis by a novel dietary fatty acid formulation in patients with atopic asthma: a randomized, placebocontrolled, parallel-group, prospective trial. Clin Ther. 2003 Mar;25(3):972-9
587) Gupta I, Gupta V, Parihar A, Gupta S, Ludtke R, Safayhi H, Ammon HP. Effects of Boswellia serrata gum resin in patients with bronchial asthma: results of a double-blind, placebo-controlled, 6-week clinical study. Eur J Med
Res. 1998 Nov 17;3(11):511-4
588) Khayyal MT, el-Ghazaly MA, el-Khatib AS, Hatem AM, de Vries PJ, el-Shafei S, Khattab MM. A clinical pharmacological study of the potential beneficial effects of a propolis food product as an adjuvant in asthmatic patients.
Fundam Clin Pharmacol. 2003 Feb;17(1):93-102
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interventions in the treatment of asthma, particularly since these treatments are mediated primarily via different
mechanisms—namely the neurophysiologic inhibition of neurogenic inflammation (proposed) and the
biochemical reduction in pro-inflammatory mediators such as leukotrienes, respectively. As a final example,
synergism would be expected in the treatment of low-back pain when spinal manipulation, therapeutic exercise,
proprioceptive retraining, oral vitamin D supplementation, and botanical medicines such as Harpagophytum and
Willow Bark are used together in holistic, integrative, multicomponent treatment plans.589 Taken together, these
data form an integrative model that incorporates and mechanistically validates the chiropractic “triad of health”
(Figure 8).
Figure 8: The chiropractic “Triad of Health”: a conceptual model for understanding the interconnected
nature of various physiologic processes and systems.
Mental
Emotional
Neurological
Spiritual
Physical
Structural
Exercise
Nutritional
Biochemical
Hormonal
Chiropractic and Naturopathic Medicine within Healthcare Systems Tailored to the Medical Paradigm
The term “paradigm” refers to the unconsciously assumed “lens” by which individuals view and interact with
(their perception of) reality. Even before asked, questions are phrased and framed to within the conceptual
boundaries of the prevailing paradigm, and the end result is that the answers that appear “right” are the ones that
coincide with the underlying assumptions and which reinforce and support the status quo. A vicious cycle of
informational inbreeding is created that, unless acted upon by an influence outside of the paradigm, essentially
creates a “house of mirrors” where indoctrinated individuals cannot escape their own worldview and wherein
these same individuals repeatedly reflect to themselves and each other misinformation that is only “right”
insofar as it agrees with and sustains the prevailing modus operandi.590 In this regard, the allopathic medical
model of healthcare delivery is indeed its own paradigm—one that is increasingly described in articles that
discuss
its
characteristics,
influence,
shortcomings,
and
the
facility
with
which
is
591,592,593,594,595,596,597,598,599
misappropriated.
In theory and practice, the modern medical paradigm can be loosely
590) Aronson E. The Social Animal. San Fransico: WH Freeman and Company, 1972. See especially page 16. Updated editions available.
591) Micozzi MS. Double standards and double jeopardy for CAM research. J Altern Complement Med. 2001;7(1):13-4
592) Mein EA, Greenman PE, McMillin DL, Richards DG, Nelson CD. Manual medicine diversity: research pitfalls and the emerging medical paradigm. J Am Osteopath Assoc. 2001;101:441-4
593) Hyman M. Paradigm shift: the end of "normal science" in medicine understanding function in nutrition, health, and disease. Altern Ther Health Med. 2004;10(5):10-5, 90-4
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described as a system of healthcare that emphasizes the use of chemical drugs and invasive surgery as its
primary means of intervention; technological, “sophisticated” assessments and interventions are favored over
those of greater simplicity (ie, “unsophisticated”) and lower cost regardless of efficacy; patients are responsible
only for “compliance” to the doctor’s orders and are generally placed in a position of disempowerment because
the options presented (drugs and surgery) are outside of their control and understanding while self-directed
nonchemical nonsurgical options are either not discussed or are subtly or blatantly disdained; treatment of the
disease assumes predominance over the needs and uniqueness of the patient. 600,601,602,603 Within certain contexts,
this paradigm is appropriate and produces favorable results, namely in the treatment of acute trauma and
immediately life-threatening disease. However, when this paradigm is applied to the vast majority of outpatient
clinical encounters, it is generally inferior in cost-effectiveness and global impact than other approaches to
healthcare delivery that emphasize patient empowerment for the implementation of self-directed healing and
which improve underlying physiology so that health is restored and symptoms are alleviated, rather than merely
suppressed with drugs. Most medications are designed to block the body’s normal functioning, and this is
clearly indicated by the most popular categories of medications, e.g., calcium channel blockers, serotonin
antagonists604, HMG-CoA reductase inhibitors605, angiotensin converting enzyme (ACE) inhibitors, and
serotonin reuptake inhibitors. The near exclusive reliance upon “single pathway” drugs and surgery by our
current medical system is most ironic considering the complexity of disease and the powerful influence of
lifestyle and environment in the generation of the epidemics of today, namely heart disease, cancer, depression,
and autoimmune disease. Doctors who fail to appreciate the presentations and prevalence of nutritional
deficiencies/imbalances606 or who cannot escape their drug/surgery paradigm of intervention607 will by necessity
turn to drugs/surgery when clinical intervention is called for—not on the basis of the appropriateness of these
interventions but rather simply because they know no other options. The treatment of nutritional imbalances
and lifestyle diseases with drugs and surgery (rather than the correction of the underlying nutritional imbalance
or habit) appears illogical and potentially unethical, but it is no large leap of faith to extrapolate that it is a
common occurrence affecting millions of patients every day; this is true even if we limit the discussion to the
clinical consequences of vitamin D deficiency608,609 and fatty acid imbalance610,611, both of which are epidemic
and are the underlying causes of numerous “diseases” that, when viewed through the allopathic lens of most
practicing doctors, will be treated with pharmaceutical drugs, perhaps surgery. By the very nature of their
incongruence with reality and failure to intervene at the primary level of causality, defective paradigms will
repeatedly produce lackluster results regardless of the amount of effort, talent, or funding that is poured into
them.612 In this situation, additional investment of resources (intellectual, financial, material, and social) is not
the answer; what is needed is a “paradigm shift” that permeates the entirety of the system in question.613,614
Building upon phraseology offered by Wilson615 and the concepts solidified by Beckman et al616, one might
articulate that the required shift is that from materialistic reductionism and biomedical objectivism to what
integrative natural medicine practitioners have been espousing for decades—science-based integrative
subjectivism: the consideration of all data, influences, and possible interventions and the application of these
considerations within a broad-based nonexclusive context that foremost respects patient uniqueness and the
web-like matrix of interconnected biophysiologic, psychosocial, environmental, and neuromusculoskeletal
phenomena.
594) Heaney RP. Vitamin D, nutritional deficiency, and the medical paradigm. J Clin Endocrinol Metab. 2003;88:5107-8
595) Stevens CW, Glatstein E. Beware the Medical-Industrial Complex. Oncologist. 1996;1(4):IV-V
596) Wilson HJ. The myth of objectivity: is medicine moving towards a social constructivist medical paradigm? Fam Pract. 2000;17:203-9
597) van der Steen WJ, Ho VK. Drugs versus diets: disillusions with Dutch health care. Acta Biotheor. 2001;49(2):125-40
598) Drug-company influence on medical education in USA. Lancet. 2000 Sep 2;356(9232):781
599) Beckman JF, Fernandez CE, Coulter ID. A systems model of health care: a proposal. J Manipulative Physiol Ther. 1996 Mar-Apr;19(3):208-15
601) Hawk C. The wellness hypothesis. In Leach RA (ed). The Chiropractic Theories: A Textbook of Scientific Research, Fourth Edition. Baltimore: Lippincott, Williams & Wilkins, 2004, 399-415
604) "Lotronex was an early example of a new class of drug for irritable bowel, the 5-HT3 antagonists… At least five people had died after taking the drug… There had been 49 cases of ischemic colitis and … 34 patients had
required admission to hospital and ten needed surgery.” Horton R. Lotronex and the FDA: a fatal erosion of integrity. Lancet. 2001 May 19;357(9268):1544-5
605) "FDA has received reports of 31 U.S. deaths due to severe rhabdomyolysis associated with use of Baycol, 12 of which involved concomitant gemfibrozil use." US Food and Drug Administration. Bayer voluntarily withdraws
Baycol. http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01095.html on March 14, 2004
610) Vasquez A. Reducing Pain and Inflammation Naturally. Part 2: New Insights into Fatty Acid Supplementation and Its Effect on Eicosanoid Production and Genetic Expression. Nutr Perspect 2005; January: 5-16
611) Simopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr. 1999 Sep;70(3 Suppl):560S-569S
612) Breton D, Largent C. The Paradigm Conspiracy: Why Our Social Systems Violate Human Potential-And How We Can Change Them. Center City; Hazelden: 1996
613) Kuhn T. The Structure of Scientific Revolutions. Third Edition. Chicago: University of Chicago Press, 1996
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The pharmaceutical/drug paradigm rose to power following the questionable attribution of improvements in
societal health to the increased use of drugs, particularly antibiotics. Soon thereafter, the “external invader”
model of disease became accepted by the medical profession617,618, and patients were seen as victims of and
separate from their disease(s), and the roles of interventional nutrition, responsible lifestyle modification, and
other natural treatments were marginalized to obscurity and trivialized to quackery.619,620,621 More specifically,
this paradigm contends that chemical drugs are the only reasonable (ie, “scientific”, “proven” and “rational”)
means for treating and preventing disease. 622 Aided by ample funding from state and federal subsidies for
education and research, cash from the pharmaceutical industry, and the falsification of research that was and is
still used to denigrate chiropractic, the medical profession conspired to illegally destroy the osteopathic,
chiropractic, naturopathic professions, and the effects of these actions are still seen and felt
today.623,624,625,626,627,628,629 The naivety and acquiesce of the public also played a role, since the seductive
pharmaceutical paradigm generally supports that patients are exonerated from responsibility and discipline, save
for “compliance” (ie, “submission”) to life-long medicalization.
Although Kuhn630 is credited with introducing the term “paradigm” within the academic and intellectual arena, it
is the treatise by Breton and Largent631 that makes this concept and its implications relevant for the systems that
shape our lives and create our “reality” on a day-to-day basis. Early in their review (page 54), they note that one
of the ways that old systems maintain power is by ignoring the pain and suffering that they directly create, and
by justifying these “side effects” as “necessary evils”—i.e., that widespread suffering is justified for the
attainment of what is reported as widespread benefit. However, the data presented in this paper show that
widespread iatrogenic suffering is not justified for the illusion of widespread benefit. Almost all of the natural
treatments employed by chiropractic and naturopathic physicians as described in this paper provide clinically
significant relief of musculoskeletal symptoms while improving rather than detracting from overall health.
What Breton and Largent say of dysfunctional paradigms can be seen to apply to the medical paradigm and the
system of medical healthcare that results: “Sick paradigms make sick institutions that make sick people…” In
this case, the “sick paradigm” is the medical model in which chronic diseases caused by unhealthy lifestyles
and/or nutritional deficiencies are “treated” with drugs and surgery. The “sick institutions are the exorbitantly
expensive medical systems that kill 180,000 Americans per year—493 patients per day. The “sick people” are
the American population with progressively deteriorating health status, as well as members within the healthcare
community. Medical physicians consistently show higher rates of suicide and depression than the general
population.632,633,634
North and Ryall635 noted, “More than half of female physicians may experience a
psychiatric illness during their lifetime. Depression is by far the most common such disorder, and the suicide
rate is alarmingly high. However, female physicians appear to be at lower risk for substance abuse than male
physicians.”
Relegating the modern chiropractic profession to a marginalized position in the healthcare arena simply because
some (not all) of the founding assumptions of the profession c.1903 have since been determined to be simplistic
or inaccurate would be as ridiculous as it would be to castigate the entire allopathic profession as incompetent
simply because their forebears utilized treatments such as “bloodletting”, administration of “therapeutic
mercury”, refusing care to African-Americans with syphilis, or, more recently, injections of cancer cells into
620) Barrett S, Herbert V. The Vitamin Pushers: How the ‘Health Food’ Industry is Selling America a Bill of Goods. Amherst; Prometheus Press, 1994
628) Morley J, Rosner AL, Redwood D. A case study of misrepresentation of the scientific literature: recent reviews of chiropractic. J Altern Complement Med. 2001 Feb;7(1):65-78
630) Kuhn T. The Structure of Scientific Revolutions. Third Edition. Chicago: University of Chicago Press, 1996
631) Breton D, Largent C. The Paradigm Conspiracy: Why Our Social Systems Violate Human Potential-And How We Can Change Them. Center City; Hazelden: 1996
632) Schernhammer ES, Colditz GA. Suicide rates among physicians: a quantitative and gender assessment (meta-analysis). Am J Psychiatry. 2004;161(12):2295-302
633) Center C, Davis M, Detre T, Ford DE, Hansbrough W, Hendin H, Laszlo J, Litts DA, Mann J, Mansky PA, Michels R, Miles SH, Proujansky R, Reynolds CF 3rd, Silverman MM. Confronting depression and suicide in
physicians: a consensus statement. JAMA. 2003 Jun 18;289(23):3161-6
634) Bogs W. Physicians Face Elevated Suicide Risk. http://www.medscape.com/viewarticle/496595 Accessed December 25, 2004
635) North CS, Ryall JE. Psychiatric illness in female physicians. Are high rates of depression an occupational hazard? Postgrad Med. 1997 May;101(5):233-6, 239-40, 242
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hospital patients without their consent for the sake of conducting research on the course of the disease.636 It is a
malicious act to continue denigrating (and thereby restricting) the modern chiropractic profession based on
scientific shortcomings that were inherent in all of the healthcare professions 100 years ago, or even 40 years
ago. To this day, the American Medical Association continues to berate the entire chiropractic profession based
on controversial and politically influenced reports which found “deficits” in chiropractic education in the
1960’s; these shortcomings that occurred more than 40 years ago are used as justification to restrict the
profession even now.637 Furthermore, since it appears that most allopathic medical doctors have received
inadequate training in fundamental musculoskeletal medicine638,639,640, they would therefore not be expected to
be aware of the complex physiological effects of spinal manipulation and modern integrative chiropractic care
(reviewed previously; see Leach641, Haldeman642, Bergman et al643, and Vasquez644 for more details). In his
noteworthy, critique of his own profession, former JAMA editor George Lundberg MD645, even though he
admits to having been taught essentially nothing but misinformation about chiropractic in his formal medical
education, had an occasion of uncommon insight which allowed him to distinguish pre-scientific chiropractic
theory from contemporary chiropractic practice. He writes, “Putting aside my early bias against chiropractic, it
is important for me to note the distinction between theory and practice. [Early chiropractic theory] may be one
thing, but [the modern chiropractic profession] may be something entirely different.” Likewise, it is incumbent
upon policymakers and other healthcare professionals to relinquish their simplistic and inaccurate perceptions of
the chiropractic profession and to access current articles and texts so that they can become informed of the
developments that have modernized the chiropractic profession in the course of the past 100 years since its
inception. Selective misunderstanding and intentional ignorance of chiropractic by medical organizations and
policymakers serves only to maintain the status quo and to justify resistance to the full inclusion of chiropractic
physicians into the healthcare system despite overwhelming and consistent evidence that chiropractic care is
safe, effective, and more cost-effective than allopathic management.
In contrast to the promulgations decreed by those aligned with the drug/medical paradigm, the body of evidence
supporting the majority of natural therapeutics is uniquely solid and consistent. For example, evidence supports
that the anxiolytic herb Kava kava has superior safety and cost-effectiveness when compared to pharmaceutical
anxiolytics646,647, and that St. John’s Wort has shown antidepressant efficacy that is equal or superior to that of
the more expensive pharmaceutical antidepressants648,649,650, and it does not appear to increase the risk for
suicide as do the commonly used “antidepressant” drugs.651,652,653,654,655 Alan Goldhamer, a chiropractic
physician, appears to have created the most effective treatment plan for chronic hypertension that has ever been
documented656,657—yet most insurance companies will not pay for chiropractic management of hypertension,
and most allopathic cardiologists remain clinically ignorant of non-drug treatments for hypertension. Preventive
research by Orme-Johnson and Herron658 utilizing a “multicomponent prevention program” that included
meditation, yoga, herbal dietary supplements, and diet recommendations documented that total medical
expenses were reduced by 59% over 4 years and by 63% over 11 years compared to patients under
‘conventional’ medical care; hospital admission rates were reduced by 11.4-fold for cardiovascular disease, 3.3fold for cancer, and 6.7-fold for mental health and substance abuse. Simple nutritional supplementation of
patients in intensive care units dramatically reduces infection rates, mortality, and hospital
636) Lerner BH. Sins of omission--cancer research without informed consent. N Engl J Med. 2004;351(7):628-30
638) Freedman KB, Bernstein J. The adequacy of medical school education in musculoskeletal medicine. J Bone Joint Surg Am. 1998;80(10):1421-7
641) Leach RA (ed). The Chiropractic Theories: A Textbook of Scientific Research, Fourth Edition. Baltimore: Lippincott, Williams & Wilkins, 2004
642) Haldeman S (ed). Principles and practice of chiropractic. Second Edition. Norwalk; Appleton and Lange, 1992
643) Bergman, Peterson, Lawrence. Chiropractic Technique. New York: Churchill Livingstone 1993. An updated edition is now availabe published by Mosby.
645) Lundberg GD. Severed trust: why American healthcare hasn’t been fixed. Updated and revised. New York; Basic Books 2002.
646) Vasquez A. Kava: Piper methysticum--Dangerous drug, or safe herb? http://wellbodybook.com/kava.htm on November 24, 2004 See also: Schmidt M. Analysis of Kava Side Effects Reports Concerning the Liver. Nov.
2001. (Translated from German by M. Lindenmaier M and J. Brinckmann; Dec. 31, 2001)
647) Clouatre DL. Kava kava: examining new reports of toxicity. Toxicol Lett. 2004;150(1):85-96
648) Schrader E. Equivalence of St John's wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol 2000;15(2):61-8
649) Vorbach EU, Arnoldt KH, Hubner WD. Efficacy and tolerability of St. John's wort extract LI 160 versus imipramine in patients with severe depressive episodes according to ICD-10. Pharmacopsychiatry 1997;30 Suppl 2:81-5
650) Philipp M, Kohnen R, Hiller KO. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks. BMJ. 1999 Dec 11;319(7224):1534-8
651) Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA. 2004 Jul 21;292(3):338-43
652) Lenzer J. FDA to review risks of antidepressants in adults. BMJ. 2004 Oct 9;329(7470):816
653) Lenzer J. FDA panel urges "black box" warning for antidepressants. BMJ. 2004 Sep 25;329(7468):702
654) Lenzer J. Secret US report surfaces on antidepressants in children. BMJ. 2004 Aug 7;329(7461):307
655) Gunnell D, Ashby D. Antidepressants and suicide: what is the balance of benefit and harm. BMJ. 2004 Jul 3;329(7456):34-8
656) Goldhamer A, Lisle D, Parpia B, Anderson SV, Campbell TC.. Medically supervised water-only fasting in the treatment of hypertension. J Manipulative Physiol Ther 2001 Jun;24(5):335-9
657) Goldhamer AC, Lisle DJ, Sultana P, Anderson SV, Parpia B, Hughes B, Campbell TC. Medically supervised water-only fasting in the treatment of borderline hypertension. J Altern Complement Med. 2002;8(5):643-50
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expenses659,660,661,662,663,664, and this benefit is so significant and consistent that failure to implement nutritional
intervention in acutely ill patients should be deemed unethical and clear grounds for malpractice litigation.
Based on these and other illustrative examples described elsewhere by the current author665, it is reasonable to
conclude that American healthcare would be more effective, more affordable, and safer if providers of holistic
natural healthcare were fully integrated into the healthcare system rather than being politically excluded (e.g.,
restrictive licensure laws) or functionally excluded (e.g., discriminatory CPT codes and HMO policies666) by a
system of drug- and surgery-based medicine that financially depletes the people667, business668, and communities
of our nation669,670 while failing to deliver competent healthcare671 and cost-effective nation-wide health
improvements672 that are proportional to the continuous increase in spending.673 The current author has referred
to this disparity of investment and reward as the “American paradox”—Americans spend more on healthcare
than any other nation in the world, yet the health status of Americans is the worst among developed nations and
is continuing to decline despite ever-increasing technological sophistication, overall expenses, and iatrogenic
morbidity and mortality.674,675 Thus it appears that spending and technology may not be the answers to our
national healthcare dilemma, and that conservative natural treatments deserve more attention—by extension, this
implies that physicians trained in natural lower-cost therapeutics should be afforded greater opportunities to
contribute to national healthcare efforts.
The pharmaceutical industry aggressively promotes its own interests in medical schools and in post-graduate
medical education for physicians676 including the use of misleading advertising677,678 and the direct influence of
patients with direct-to-consumer advertising.679 Drug companies spend $8,000 - $15,000 per doctor per year to
advertise their products to their sales force: medical physicians.680 In their prophetic 2001 review criticizing the
overuse of pharmaceutical “anti-inflammatory drugs”, Van der Steen and Ho681 write, “Unofficial and official
sources tend to inform the general public that the drugs promote human health. We argue that their being used
on a massive scale is actually a medical disaster. The health of many patients would be served better if the drugs
they take were replaced by proper forms of diet, but the pharmaceutical industry, the most potent force affecting
medication policies, appears to prevent a shift in the balance from over-medicalization towards healthy life
styles… In any case, the overuse of drugs has become a serious problem in modern society.”
Despite consistent evidence that pharmaceutical/medical interventions kill not less than 180,000 and up to
225,000 Americans per year682,683, doctorate-level providers of nonallopathic healthcare such as chiropractic,
659) Falcao de Arruda IS, de Aguilar-Nascimento JE. Benefits of early enteral nutrition with glutamine and probiotics in brain injury patients. Clin Sci (Lond). 2004;106(3):287-92
660) Garrel D, Patenaude J, Nedelec B, Samson L, Dorais J, Champoux J, D'Elia M, Bernier J. Decreased mortality and infectious morbidity in adult burn patients given enteral glutamine supplements: a prospective, controlled,
randomized clinical trial. Crit Care Med. 2003;31(10):2444-9
661) Houdijk AP, Rijnsburger ER, Jansen J, Wesdorp RI, Weiss JK, McCamish MA, Teerlink T, Meuwissen SG, Haarman HJ, Thijs LG, van Leeuwen PA. Randomised trial of glutamine-enriched enteral nutrition on infectious
morbidity in patients with multiple trauma. Lancet. 1998 Sep 5;352(9130):772-6
662) Jones C, Palmer TE, Griffiths RD. Randomized clinical outcome study of critically ill patients given glutamine-supplemented enteral nutrition. Nutrition. 1999;15(2):108-15
663) Griffiths RD, Jones C, Palmer TE. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition. 1997;13(4):295-302
664) Senkal M, Mumme A, Eickhoff U, Geier B, Spath G, Wulfert D, Joosten U, Frei A, Kemen M. Early postoperative enteral immunonutrition: clinical outcome and cost-comparison analysis in surgical patients. Crit Care Med.
1997;25(9):1489-96
666) "The Solla plaintiffs argued that each HMO defendant is "by itself a combination in restraint of trade, and that there is no concerted action requirement for an illegal combination." Solla Case DISMISSED! Dynamic
Chiropractic; August 24, 1998, Volume 16, Issue 18 http://www.chiroweb.com/archives/16/18/22.html on July 12, 2004
667) “A national study released today reports 20 million American families — or one in seven families — faced hardships paying medical bills last year, which forced many to choose between getting medical attention or paying
rent or buying food…” Freeman, Liz. 'Working poor' struggle to afford health care. Naples Daily News. Published in Naples, Florida and online at
http://www.naplesnews.com/npdn/news/article/0,2071,NPDN_14940_3000546,00.html Accessed July 28, 2004
668) “The USA's 5.8 million small companies… Health care costs are rising about 15% this year for those with fewer than 200 workers vs. 13.5% for those with 500 or more… But many small employers cite increases of 20% or
more. That's made insurance the No. 1 small business problem…” Jim Hopkins. Health care tops taxes as small business cost drain. USA TODAY. http://www.usatoday.com/news/health/2003-04-20-small-businesscosts_x.htm. Accessed July 28, 2004
669) “In 1994, we spent $1 trillion on health care in the US, or, more accurately, we spent most of this astounding sum on disease treatment. This represents an increase of 300% in the last 15 years. Health care costs now
consume 15% of the gross national product (GNP), with the percentage of GNP spent on health care continuing to increase at twice the rate of inflation. If the rate of increase continues, health care costs will consume the
entire GNP within 50 years. Corporations now spend an incredible 48% of their after-tax profits on health care, and it is projected that by the year 2000, healthcare costs will equal 60% of after-tax profit at the average
Fortune 500 company.” Pizzorno JE. Total Wellness. Rocklin: Prima; 1996 page 7
income we'll earn between 1999 and 2010 will go to health care.” Regnier P. Healthcare myth: We spend too much. Money Magazine. October 13, 2003: 11:29 AM EDT http://money.cnn.com/2003/10/08/pf/health_myths_1/
Accessed Monday, July 12, 2004
671) “Although they spend more on health care than patients in any other industrialized nation, Americans receive the right treatment less than 60 percent of the time, resulting in unnecessary pain, expense and even death…”
Ceci Connolly. U.S. Patients Spend More but Don't Get More, Study Finds: Even in Advantaged Areas, Americans Often Receive Inadequate Health Care. Washington Post, May 5, 2004; Page A15. On-line at
http://www.washingtonpost.com/ac2/wp-dyn/A1875-2004May4 accessed on July 28, 2004
672) US health care: a state lottery? Lancet. 2004 Nov 20;364(9448):1829-30
675) Zack MM, Moriarty DG, Stroup DF, Ford ES, Mokdad AH. Worsening trends in adult health-related quality of life and self-rated health-United States, 1993-2001. Public Health Rep. 2004;119:493-505
676) Drug-company influence on medical education in USA. Lancet. 2000 Sep 2;356(9232):781
677) Villanueva P, Peiro S, Librero J, Pereiro I. Accuracy of pharmaceutical advertisements in medical journals. Lancet. 2003 Jan 4;361(9351):27-32
678) Wilkes MS, Doblin BH, Shapiro MF. Pharmaceutical advertisements in leading medical journals: experts' assessments. Ann Intern Med. 1992;116(11):912-9
679) Mintzes B, Barer ML, Kravitz RL, Kazanjian A, Bassett K, Lexchin J, Evans RG, Pan R, Marion SA. Influence of direct to consumer pharmaceutical advertising and patients' requests on prescribing decisions: two site cross
sectional survey. BMJ. 2002; 324(7332): 278-9
680) Blumenthal D. Doctors and drug companies. N Engl J Med. 2004;351:1885-90
682) Holland EG, Degruy FV. Drug-induced disorders. Am Fam Physician. 1997 Nov 1;56(7):1781-8, 1791-2
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naturopathic and (to a much lesser extent) osteopathic physicians continue to be denigrated684, discriminatorily
misbranded as “nonphysicians”685,686 and are legislatively, financially, and politically limited from the
opportunity to fully provide evidence-based healthcare with equitable payment and insurance coverage allowed
for medical doctors.687 According to internal reviews by allopathic physicians and epidemiologists, allopathic
physicians commonly deliver care that is “substandard”688 and which poses “serious threats to the health of the
American public.”689 Unless we are intentionally choosing to pay more money and to “die earlier and spend
more time disabled"690, then we must enact nationwide healthcare reform to mandate the complete integration
of, access to, and reimbursement for chiropractic and naturopathic physicians in the American healthcare
system. Allopathic/pharmaceutical hegemony of the American healthcare system might possibly justified if its
particular style of diagnosis and treatment provided superior overall outcomes at reduced cost; however this has
never been proven. Rather, to the contrary, the American system of allopathic/pharmaceutical healthcare is
wantonly expensive, delivers care that is commonly “substandard”691 and which poses “serious threats to the
health of the American public”692 and which is a direct cause of death for approximately 493 Americans each
day.
The healthcare landscape of America has been dominated by the allopathic medical community and
pharmaceutical industry, which formerly sought to monopolize healthcare delivery by disenfranchising and
slandering other healthcare providers with the goal of extinguishing the chiropractic, naturopathic, and
osteopathic professions.693,694,695 Due in large part to the successful anti-trust lawsuit brought by Chester Wilk et
al against the American Medical Association and other medical groups696, this conspiracy was formally ended
by court injunction in the late 1980s, yet its negative political, financial, and social consequences are ongoing.
Medical journals have historically allowed and thus condoned many biased, unfounded, and fraudulent
“research” articles by medical authors which denigrate chiropractic and other natural forms of healthcare
through the repeated misuse of references, misleading statements, highly selective use of certain published
papers, failure to refer to relevant literature, inaccurate reporting of the contents of published work, and errors in
citation.697,698
Given that the biomedical information system is strongly biased in favor of
pharmaceutical/surgical interventions and sharply against biologic/natural interventions699,700, there is an
extreme shifting of “the balance of evidence” in favor of the medical paradigm; this creates a self-serving and
self-perpetuating vicious cycle wherein prevailing paradigms are supported by a biased database of articles
which systematically create the illusion that comparatively little research exists to support “alternative”
conceptualizations and interventions. Adherence to high standards of intellectual integrity and academic
propriety is frequently sidelined in slanderous “critical reviews” of chiropractic and naturopathic medicine that
range from subdued to venomous in tone and tact.701 Recent examples are plentiful, including biased and
occasionally profane polemics listed as “book reviews” published by the American Medical Association702
which condone such positions as “I almost never initiate a referral to a non-allopathic physician” and offensive
and intellectually paradoxical statements such as “That’s the kind of crap I would not believe in, even if it were
true.”703 Harvard Medical School recently stepped into the libelous unscientific fray in a 2004 promotional
mailing704 that included the unreferenced statement “…about half the people who seek spinal manipulation from
a chiropractor experience problems caused by the treatment.” The 2003 unbridled ambush against chiropractic
683) Starfield B. Is US health really the best in the world? JAMA. 2000 Jul 26;284(4):483-5
685) Druss BG, Marcus SC, Olfson M, Tanielian T, Pincus HA. Trends in care by nonphysician clinicians in the United States. N Engl J Med. 2003 Jan 9;348(2):130-7
686) Cooper RA, Henderson T, Dietrich CL. Roles of nonphysician clinicians as autonomous providers of patient care. JAMA. 1998 Sep 2;280(9):795-802
687) Gaumer G, Koren A, Gemmen E. Barriers to expanding primary care roles for chiropractors: The role of chiropractic as primary care gatekeeper. J Manipulative Physiol Ther. 2002;25:427-49
688) Brennan TA, Leape LL, Laird NM, Hebert L, Localio AR, Lawthers AG, Newhouse JP, Weiler PC, Hiatt HH. Incidence of adverse events and negligence in hospitalized patients: results of the Harvard Medical Practice Study
I. 1991. Qual Saf Health Care. 2004 Apr;13(2):145-51
689) McGlynn EA, Asch SM, Adams J, Keesey J, Hicks J, DeCristofaro A, Kerr EA. The quality of health care delivered to adults in the United States. N Engl J Med. 2003 Jun 26;348(26):2635-45
692) McGlynn EA, Asch SM, Adams J, Keesey J, Hicks J, DeCristofaro A, Kerr EA. The quality of health care delivered to adults in the United States. N Engl J Med. 2003 Jun 26;348(26):2635-45
697) Morley J, Rosner AL, Redwood D. A case study of misrepresentation of the scientific literature: recent reviews of chiropractic. J Altern Complement Med. 2001;7:65-78
699) Micozzi MS. Double standards and double jeopardy for CAM research. J Altern Complement Med. 2001;7:13-4
700) Resch KI, Ernst E, Garrow J. A randomized controlled study of reviewer bias against an unconventional therapy. J R Soc Med. 2000;93(4):164-7
701) Micozzi MS. Double standards and double jeopardy for CAM research. J Altern Complement Med. 2001;7:13-4
702) Iserson KV, Uzich L, Barnett LM. Books, Journals, New Media. JAMA 1998; 280: 1633-5
703) Clarfield AM. Book review of “Nature Cures: The History of Alternative Medicine in America” JAMA 2003; 290: 2741-2 http://jama.ama-assn.org/cgi/content/full/290/20/2741 Accessed September 29, 2005
704) Harvard Health Letter promotion: 26 Health Revelations You Need to Know. Harvard Medical School: Boston, MA, 2004. For discussion see http://amerchiro.org/media/releases/122004.shtml accessed on January 18, 2005
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and naturopathic medicine by WebMD and Medscape705 publicly disclosed their lack of objectivity and peer
review of this so-called “trustworthy, credible, and timely” internet journal, and these polemics have been
authoritatively redressed in a two-part article in American Journal of Family Practice (Pizzorno, Dunne et al; in
press). The on-going polemic by Stephen Barrett MD at www.chirobase.org constantly reaches new lows in
professionalism and objectivity, finding every negative aspect of anything related to chiropractic and presenting
it as if it were reflective of the entire profession and each of its members. Institutionalized violence such as
these attacks against their fellow healthcare providers is what fuels animosity and mistrust against what is
perceived to be “the medical establishment.”706 This is particularly true when, according to the American
Medical Association707, “organized medicine” is “ready to fight their efforts” whenever
naturopathic/chiropractic physicians seek to implement the holistic broad-spectrum care they are trained to
provide, and when medical organizations such as the AMA use the rhetoric of “patient safety” as the
justification to impose restrictions on naturopathic/chiropractic physicians and to resist the implementation of
meaningful change in a healthcare system that is unduly expensive, disempowering, and lethal. “Patient safety”
was the same façade used by the AMA during the decades in which chiropractic and naturopathic medicine were
crushed to the point of near extinction by what was later made clear to be a system-wide conspiracy which
violated America’s anti-trust laws and threatened to create a medical monopoly over US healthcare by
destroying other healthcare professions.708, 709 The osteopathic profession—labeled as “cultists” by the American
Medical Association, which stated in 1953 that “…all voluntary associations with osteopaths are unethical”—
was likewise faced with extinction, until merger with allopathic medicine was the only remaining strategy—a
strategy which the medical profession believed would eventually destroy the osteopathic profession. In his
review of osteopathic history, Gevitz710 writes, “…the M.D.’s gradually came to believe that the only way to
destroy osteopathy was through the absorption of D.O.’s, much as the homeopaths and eclectics had been
swallowed up early in the century.” Even today, the AMA continues to list osteopathic medicine under
“alternative medicine”711 even though several osteopathic medical colleges have consistently provided training
that is superior to most “conventional” medical schools.712
The image of the superiority of medical physicians and medical education was conjured at a time when the vast
majority of the population had no access to higher education or health-related information. Public policies,
legislative acts, and systems of government subsidization of medical schools and the pharmaceutical industry
were enacted decades ago during times of primitive comprehensions of disease processes and the blind faith that
we would achieve “better living through chemistry” and that drugs were the solutions to our healthcare
problems. Medical doctors were socially deified by the public acceptance of their self-purported elitism and
their condemnation of other competitors in the healthcare arena, namely those physicians brazen enough to
refute the pharmaceutical paradigm by studying and advocating such things as nutrition, exercise, and effective
yet conservative and low-cost options to drugs and surgery. Now, however, the accumulated research
documents the fallacy of applying the drug/surgery paradigm to most chronic, lifestyle-generated diseases713,714,
and past and current medical education is now acknowledged as “inadequate” for the treatment of chronic
diseases in general715 and musculoskeletal conditions in particular.716,717 If we accept recent authoritative
publications concluding that “medical education is failing to prepare students adequately for their future
practice”718 and that, in another article published by the American Medical Association, medical education “is
currently being held together by peanut butter and bubble gum”719 then the only logical and responsible action
that can be taken to provide patients with immediate and equitable access to physicians with training in the
management of chronic illness is to remove the outdated financial and legislative barriers that restrict patients
from access to the scientific, cost-effective, patient-centered and patient-driven healthcare that chiropractic and
705) Atwood IV KC. Naturopathy: A Critical Appraisal. Medscape.com Posted 12/30/2003 Available at www.medscape.com on December 25, 2004
707) Croasdale M. Nonphysicians eager to pick up prescription pad. Empowered by recent victories, nonphysicians gear up for 2005 legislative efforts to expand their scope. American Medical News. Feb. 7, 2005.
http://www.ama-assn.org/amednews/2005/02/07/prl10207.htm#top Accessed February 6, 2005
710) Gevitz N. The D.O.'s: Osteopathic Medicine in America. Johns Hopkins University Press; 1991; pages 100-103
711) American Medical Association. Report 12 of the Council on Scientific Affairs (A-97) Full Text http://www.ama-assn.org/ama/pub/category/13638.html on February 15, 2005
712) Special report. America's best graduate schools. Schools of Medicine. The top schools: primary care. US News World Rep. 2004 Apr 12;136(12):74
715) Holman H. Chronic disease--the need for a new clinical education. JAMA. 2004;292:1057-9
719) DeAngelis CD. Professors not professing. JAMA. 2004;292:1060-1
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naturopathic physicians have been duly trained to deliver in their 4-5 years of graduate education. Any
suggestion that “improvements in medical education” will effect significant change in the healthcare landscape
of America within our lifetime is illogical insofar as it will require decades to implement effective changes in
medical education and for these graduates to then infiltrate and replace the existing physicians educated under
the aforementioned inadequate system. In general, it takes about 50 years for new scientific truths to be
accepted and implemented by the medical community720,721; if we wait another 50 years to implement
progressive change in healthcare, we will have allowed and thus condoned the deaths of another 10,000,000 (ten
million) Americans to iatrogenic disease. Given a conservative estimate of 200,000 medicine-induced deaths
per year722,723, we see that more Americans die every 3.5 months as a direct result of allopathic medicine than
the total number of military deaths during the entire 11 years of the Vietnam War (approximately 58,200).724
Critics of chiropractic/naturopathic medicine consistently berate and denigrate natural medicine practitioners
and interventions as “unproven” and “unscientific.” Authors who make broad-based statements like these are
publicly confessing their ignorance of relevant medical research and their inability to effectively access
biomedical databases such as Medline. Their ignorance of the science is assumed to imply a lack of science.
Failure to have learned the science supporting natural medicine does not make natural medicine “unscientific.”
Encapsulating this phenomenon with simple wit, the American orator Upton Sinclair once noted, “It is difficult
to get a man to understand something when his salary depends upon his not understanding it.” Indeed, if the
allopathic medical community were to objectively evaluate chiropractic solely on the basis of its therapeutic
indices (e.g., ratio of benefit to risk and expense), there is little question that chiropractic management in general
and spinal manipulation in particular would become one of the favored treatments for musculoskeletal pain. But
because chiropractic is not a “drug” and perhaps because referring patients to “other” physicians might connote
that they are peers rather than subordinates, chiropractic continues to be allowed within but not fully integrated
into the American healthcare arena. There is no scientific basis for this continued exclusion, and evidence
repeatedly shows that chiropractic management is associated with superior cost-effectiveness compared to
medical management for many conditions. Now that the data on the “coxibs” has been made public,
comparative cost-effectiveness data should be recalculated to include the financial and human costs associated
with drug-related morbidity and mortality manifested as myocardial infarction, unstable angina, cardiac
thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, transient ischemic attacks,
hypertension, and so-called idiosyncratic reactions.725,726,727,728
In the end, chiropractic/naturopathic
management will be found to be clearly superior.
A favored tool for enforcing inertia in healthcare is the claim that alternative healthcare providers must meet
“the same high standards” as “conventional” medicine.729 Declaring accountability to an undefined “standard”
is an obfuscatory tool ready to be leveraged for corruption, exploitation, the postponement of meaningful
dialogue, and additional procrastination in the face of urgently needed change. What standards? Created,
endorsed, enforced, reviewed, and updated by whom? In consideration of which options and “alternatives”?
Which of the following examples from the allopathic community meets high standards of excellence in
healthcare to which all healthcare providers should aspire and be held accountable?
A) Most antidepressant drugs increase the risk of suicide and have long lists of other “side effects” in
children and adults.730,731 A 2004 review by Jick et al732 published in JAMA showed that “The risk of
suicidal behavior after starting antidepressant treatment is similar among users of amitriptyline,
721) Bland JS. Jeffrey S. Bland, PhD, FACN, CNS: functional medicine pioneer. Altern Ther Health Med. 2004;10(5):74-81
722) Holland EG, Degruy FV. Drug-induced disorders. Am Fam Physician. 1997;56(7):1781-8, 1791-2
724) Vietnam War (1964-1975) "Battle Deaths: 47,410; Other Deaths (In Theater): 10,788" http://www.va.gov/pressrel/amwars.htm; Vietnam War Deaths 47,369 + 10,799 http://www.cwc.lsu.edu/cwc/other/stats/warcost.htm;
Statistical information about casualties of the Vietnam conflict. Reference Report #18: Inquiry: Statistical information about casualties of the Vietnam conflict. “The CACCF as of December 1998 has 58,193 records of U.S.
military personnel who died as a result of the conflict in Southeast Asia, including those declared dead from a missing or captured status.”
http://www.archives.gov/research_room/research_topics/vietnam_war_casualty_lists/statistics.html Accessed January 11, 2006
4, 2005
729) White House Commission on Complementary and Alternative Medicine Policy. http://www.whccamp.hhs.gov/es.html Accessed January 7, 2005
730) Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet.
2004;363(9418):1341-5
731) Gunnell D, Ashby D. Antidepressants and suicide: what is the balance of benefit and harm. BMJ. 2004;329(7456):34-8
732) Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA. 2004 Jul 21;292(3):338-43
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B)
C)
D)
E)
fluoxetine, and paroxetine compared with the risk among users of dothiepin. The risk of suicidal
behavior is increased in the first month after starting antidepressants, especially during the first 1 to 9
days.”
Many antipsychotic drugs have a dubious record of long-term efficacy733 and concentrate in the
myocardium734 to produce a 2.4-fold to 3.5-fold increased the risk of sudden cardiovascular death,
mostly due to arrhythmia.735 Recently, Straus et al736 noted, “Current use of antipsychotics in a general
population is associated with an increased risk of sudden cardiac death, even at a low dose and for
indications other than schizophrenia. Risk of sudden cardiac death was highest among recent users but
remained elevated during long-term use.” Tricyclic antidepressants when used at “higher” doses also
cause increased sudden death.737 Surely, most patients are not advised of this.
Cox-2 inhibitors for the treatment of osteoarthritis are exorbitantly expensive compared to older
NSAIDs, do not have increased efficacy compared with the older drugs, do not cure arthritic disease,
increase the risk of cardiovascular death, and are overall clinically less reasonable than many “natural
alternatives.” In contrast, for example, the simple anti-inflammatory treatment known as “fish oil”
reduces pain in patients with rheumatoid arthritis738 739, and carries additional “side-benefits” such as
alleviating mental depression740,741,742 and reducing cardiovascular and total mortality in patients with
cardiovascular disease.743,744,745 Likewise, chondroitin sulfate safely alleviates arthritic disease746,747,748
while simultaneously reducing incidence of cardiovascular morbidity and mortality.749,750,751,752
Type-2 diabetes and obesity generally result from dietary indiscretion (macronutrient excess),
subclinical nutritional deficiencies (micronutrient insufficiency), and lack of exercise which results in
insulin resistance and sarcopenia. Rather than nutritional supplementation and aggressive diet and
lifestyle modification, the medical treatment for diabetogenic obesity focuses on drugs (e.g., metformin)
and surgery (e.g., gastroplasty and biliopancreatic diversion). Davies and Jenkinson753 remark,
“Treating obesity with drugs is about as honest and effective as treating jaundice with camouflage
cream.”
Despite billions of dollars and accolades to the contrary, the consensus is that—overall—the “war on
cancer” is being lost754,755, the incidence of cancer has increased significantly since the 1970s756, the
incidence of childhood cancers is accelerating757, and several commonly used chemotherapy and
radiation interventions increase the likelihood of “secondary neoplasms”—that is: medical treatments
such as chemotherapy and radiation actually cause a secondary/iatrogenic cancer to develop in a
significant proportion of cancer patients.758,759,760,761 Philpott et al762 reported, “With the increasing use
733) Whitaker R. The case against antipsychotic drugs: a 50-year record of doing more harm than good. Med Hypotheses. 2004;62(1):5-13
734) Titier K, Canal M, Deridet E, Abouelfath A, Gromb S, Molimard M, Moore N. Determination of myocardium to plasma concentration ratios of five antipsychotic drugs: comparison with their ability to induce arrhythmia and
sudden death in clinical practice. Toxicol Appl Pharmacol. 2004;199(1):52-60
735) Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT. Antipsychotics and the risk of sudden cardiac death. Arch Gen Psychiatry. 2001;58(12):1161-7
736) Straus SM, Bleumink GS, Dieleman JP, van der Lei J, 't Jong GW, Kingma JH, Sturkenboom MC, Stricker BH. Antipsychotics and the risk of sudden cardiac death. Arch Intern Med. 2004 Jun 28;164(12):1293-7
737) Ray WA, Meredith S, Thapa PB, Hall K, Murray KT. Cyclic antidepressants and the risk of sudden cardiac death. Clin Pharmacol Ther. 2004;75(3):234-41
738) Adam O, Beringer C, Kless T, Lemmen C, Adam A, Wiseman M, Adam P, Klimmek R, Forth W. Anti-inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis. Rheumatol Int.
2003;23(1):27-36
739) Volker D, Fitzgerald P, Major G, Garg M. Efficacy of fish oil concentrate in the treatment of rheumatoid arthritis. J Rheumatol. 2000;27(10):2343-6
740) Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 2002 Mar;159(3):477-9
741) Puri BK, Counsell SJ, Hamilton G, Richardson AJ, Horrobin DF.Eicosapentaenoic acid in treatment-resistant depression associated with symptom remission, structural brain changes and reduced neuronal phospholipid
turnover. Int J Clin Pract. 2001 Oct;55(8):560-3
742) Peet M, Horrobin DF.A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry. 2002
Oct;59(10):913-9
744) Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet.
1999;354(9177):447-55
745) Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R, Franzosi MG, Geraci E, Levantesi G, Maggioni AP, Mantini L, Marfisi RM, Mastrogiuseppe G, Mininni N, Nicolosi GL, Santini M, Schweiger C, Tavazzi
L, Tognoni G, Tucci C, Valagussa F; GISSI-Prevenzione Investigators. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo
Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002;105(16):1897-903
748) van Blitterswijk WJ, van de Nes JC, Wuisman PI. Glucosamine and chondroitin sulfate supplementation to treat symptomatic disc degeneration: biochemical rationale and case report. BMC Complement Altern Med.
2003;3(1):2
752) Morrison LM, Bajwa GS. Absence of naturally occurring coronary atherosclerosis in squirrel monkeys (Saimiri sciurea) treated with chondroitin sulfate A. Experientia. 1972 Dec 15;28(12):1410-1
753) Davies P, Jenkinson S. How tainted is medicine? Lancet. 2002 May 18;359(9319):1775
754) Leaf C. Why We're Losing the War on Cancer—and How to Win It. Fortune. 2004; March 9
756) Weir HK, Thun MJ, Hankey BF, Ries LA, Howe HL, Wingo PA, Jemal A, Ward E, Anderson RN, Edwards BK. Annual report to the nation on the status of cancer, 1975-2000, featuring the uses of surveillance data for cancer
prevention and control. J Natl Cancer Inst. 2003;95(17):1276-99
757) Steliarova-Foucher E, Stiller C, Kaatsch P, Berrino F, Coebergh JW, Lacour B, Parkin M. Geographical patterns and time trends of cancer incidence and survival among children and adolescents in Europe since the 1970s
(the ACCISproject): an epidemiological study. Lancet. 2004 Dec 11;364(9451):2097-105
758) Relling MV, Rubnitz JE, Rivera GK, Boyett JM, Hancock ML, Felix CA, Kun LE, Walter AW, Evans WE, Pui CH. High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet. 1999 Jul
3;354(9172):34-9
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F)
G)
H)
I)
J)
of chemotherapy for many different primary malignancies, secondary or therapy-related acute myeloid
leukaemias (AML) and myelodysplastic syndromes (MDS) are becoming more common. The risk of
developing sAML has been estimated to be between 2% and 10%, depending upon the type, duration
and dosage of previous therapy. It is therefore one of the most serious long-term complications of
current cancer treatment and is likely to increase as longer survival rates for the primary tumour are
achieved.”
Drug treatment for hypertension typically lowers blood pressure by 12/6, whereas dietary modification
and exercise achieves a reduction of 17/13, and diet modification with fasting under chiropractic
supervision achieves average reductions of 37/13 and can achieve reductions of 60/17 in severely
hypertensive patients.763,764 Chiropractic physicians are the only nationally licensed physicians with
extensive training in therapeutic nutrition, yet insurance will not generally cover chiropractic
management of hypertension, despite its clearly superior cost-effectiveness compared to pharmaceutical
management. Hypertension as an industry in the United States is valued at more than $23 billion per
year.765
Cardiovascular disease is the leading cause of death in America and results in direct and indirect
healthcare expenses that reach into the billions of dollars. Associated interventions, technologies, and
consequences include angioplasty, cardiac catheterization, heart transplant, pacemakers, heart scans,
cholesterol-lowering drugs, anti-hypertensive drugs, stroke, heart failure, and sudden cardiac death. In
societies were people exercise regularly and eat healthy natural diets, cardiovascular disease does not
exist. The average cholesterol level of most animals and most humans who obtain sufficient exercise
and eat a natural diet is approximately 130 mg/dL, whereas among Americans, the average cholesterol
level is 205 mg/dL766, which leads to astronomical expenses for medications, doctor visits, loss of
patient work, transportation, laboratory tests, etc.
At a cost of approximately $4,000 per intervention, surgical “treatment” for recurrent otitis media is no
better than placebo767 and appears to be far more dangerous, far more expensive, and less effective than
so-called “naturopathic treatment”768 or nutritional prevention with vitamins, minerals, and cod-liver
oil.769
Corticosteroids are advised as standard care for the treatment of idiopathic pulmonary fibrosis yet this
treatment carries undue risk such as infection and osteoporosis, expedites declines in pulmonary
function, and leads to more rapid death than does nontreatment—placebo.770,771 In another recent
clinical trial, compared with patients who received no treatment, patients treated with corticosteroids
and cyclophosphamide died faster.772
Giving post-menopausal women biodivergent estrogen extracted from horse urine along with synthetic
biodivergent progesterone derivative (“progestins”) was dubiously labeled “hormone replacement
therapy” despite that both of these substances are foreign to the human body. Equine estrogen is a
known carcinogen773,774,775, and progestins are well known to be prothrombotic. The medical profession
759) Lenz G, Dreyling M, Schiegnitz E, Haferlach T, Hasford J, Unterhalt M, Hiddemann W. Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell
transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol. 2004 Dec 15;22(24):4926-33
760) "The leukemia risk associated with partial-body radiotherapy for uterine corpus cancer was small; about 14 excess leukemia cases were due to radiation per 10,000 women followed for 10 years." Curtis RE, Boice JD Jr,
Stovall M, Bernstein L, Holowaty E, Karjalainen S, Langmark F, Nasca PC, Schwartz AG, Schymura MJ, et al. Relationship of leukemia risk to radiation dose following cancer of the uterine corpus. J Natl Cancer Inst. 1994
Sep 7;86(17):1315-24
761) “Platinum-based treatment of ovarian cancer increases the risk of secondary leukemia.” Travis LB, Holowaty EJ, Bergfeldt K, Lynch CF, Kohler BA, Wiklund T, Curtis RE, Hall P, Andersson M, Pukkala E, Sturgeon J, Stovall
M. Risk of leukemia after platinum-based chemotherapy for ovarian cancer. N Engl J Med. 1999 Feb 4;340(5):351-7
762) Philpott NJ, Elebute MO, Powles R, Treleaven JG, Gore M, Dainton MG, Min T, Swansbury GJ, Catovsky D. Platinum agents and secondary myeloid leukaemia: two cases treated only with platinum-based drugs. Br J
Haematol. 1996 Jun;93(4):884-7
763) Goldhamer A, Lisle D, Parpia B, Anderson SV, Campbell TC. Medically supervised water-only fasting in the treatment of hypertension. J Manipulative Physiol Ther 2001 Jun;24(5):335-9
764) Goldhamer AC, Lisle DJ, Sultana P, Anderson SV, Parpia B, Hughes B, Campbell TC. Medically supervised water-only fasting in the treatment of borderline hypertension. J Altern Complement Med. 2002;8(5):643-50
765) Pardell H, Tresserras R, Armario P, Hernandez del Rey R. Pharmacoeconomic considerations in the management of hypertension. Drugs. 2000;59 Suppl 2:13-20
766) O'Keefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004 Jun 2;43(11):2142-6
767) Koivunen P, Uhari M, Luotonen J, Kristo A, Raski R, Pokka T, Alho OP. Adenoidectomy versus chemoprophylaxis and placebo for recurrent acute otitis media in children aged under 2 years: randomised controlled trial. BMJ.
2004;328(7438):487
768) Sarrell EM, Cohen HA, Kahan E. Naturopathic treatment for ear pain in children. Pediatrics. 2003 May;111(5 Pt 1):e574-9
769) Linday LA, Dolitsky JN, Shindledecker RD, Pippenger CE. Lemon-flavored cod liver oil and a multivitamin-mineral supplement for the secondary prevention of otitis media in young children: pilot research. Ann Otol Rhinol
Laryngol. 2002 Jul;111(7 Pt 1):642-52
770) "...worse survival was associated with prednisone therapy compared with no therapy..." Douglas WW, Ryu JH, Schroeder DR. Idiopathic pulmonary fibrosis: Impact of oxygen and colchicine, prednisone, or no therapy on
survival. Am J Respir Crit Care Med. 2000 Apr;161(4 Pt 1):1172-8
771) "Subjects treated with high-dose prednisone alone experienced a higher incidence of serious side effects and also exhibited a trend to more rapid decline of pulmonary function and shortened survival than did those treated
with colchicine alone." Douglas WW, Ryu JH, Swensen SJ, Offord KP, Schroeder DR, Caron GM, DeRemee RA. Colchicine versus prednisone in the treatment of idiopathic pulmonary fibrosis. A randomized prospective
study. Members of the Lung Study Group. Am J Respir Crit Care Med. 1998 Jul;158(1):220-5
772) Collard HR, Ryu JH, Douglas WW, Schwarz MI, Curran-Everett D, King TE Jr, Brown KK. Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest. 2004
Jun;125(6):2169-74.
773) Zhang F, Chen Y, Pisha E, Shen L, Xiong Y, van Breemen RB, Bolton JL. The major metabolite of equilin, 4-hydroxyequilin, autoxidizes to an o-quinone which isomerizes to the potent cytotoxin 4-hydroxyequilenin-oquinone. Chem Res Toxicol. 1999 Feb;12(2):204-13
774) Pisha E, Lui X, Constantinou AI, Bolton JL. Evidence that a metabolite of equine estrogens, 4-hydroxyequilenin, induces cellular transformation in vitro. Chem Res Toxicol. 2001 Jan;14(1):82-90
775) Zhang F, Swanson SM, van Breemen RB, Liu X, Yang Y, Gu C, Bolton JL. Equine estrogen metabolite 4-hydroxyequilenin induces DNA damage in the rat mammary tissues: formation of single-strand breaks, apurinic sites,
stable adducts, and oxidized bases. Chem Res Toxicol. 2001 Dec;14(12):1654-9
44 of 58
strongly advocated this “treatment” for millions of women before it was finally publicly disclosed that
these drugs increase the risk for breast cancer, ovarian cancer, gall bladder disease, urinary
incontinence, and cardiovascular death.776,777,778,779
K) Only 30-50% of medial interventions are supported by evidence-based research from randomized
clinical trials.780,781
L) Documentation of subtle and overt corruption within the medical-pharmaceutical-regulatory triad is
consistently reported in first-tier “conventional” medical journals782,783,784,785,786,787, the popular
press788,789,790,791,792 and internet websites.793,794,795,796 Writing in the New England Journal of Medicine,
Blumenthal797 noted, “When a great profession and the forces of capitalism interact, drama is likely to
result… On display in the relationship between doctors and drug companies are the grandeur and
weaknesses of the medical profession — its noble aspirations and its continuing inability to fulfill
them.”
Yes, indeed we need high standards in healthcare; but those standards should be designed and enforced for the
protection of patients, not for the protection of paradigms, medical hegemony, and the maintenance of the status
quo. Indeed, nearly every routine ambulatory outpatient condition can be either cured or ameliorated by
nonsurgical nonpharmacologic means; the evidence in support of these natural treatments is already published in
peer-reviewed medical journals. An integrative mindset and willingness to deflate the expansive illusions of
complexity that surround many illnesses are prerequisites to the successful acquisition and implementation of
this data. This monograph represents only a very small portion of the research supporting natural treatments for
a wide range of conditions.
Medicolegal considerations deserve mention any time that clinical practice and scientific research are at odds
with each other, and the importance of “voluntary informed consent” has been internationally established since
the Nuremberg Medical Trial of 1946-1947 that condemned medical experiments on unconsenting prisoners.798
Minimum requirements for informed consent include 1) competence—the patient must be coherent and have the
mental and emotional faculties to make rational decisions, 2) procedures—the patient is informed of the
procedures involved and “what will be done”, 3) options—the patient is informed of the alternatives and options
that are available for the treatment of the condition, 4) risk—the patient is informed of the risks and expenses
involved, 5) benefits—the patient is given a realistic appraisal of the nature (e.g., breadth, duration) of the
potential benefits resulting from the procedure(s), and 6) voluntariness—the patient is the ultimate decisionmaker with respect to his/her body. Voluntariness requires that options be presented in a manner and within a
context that makes these options equally accessible. Based on these minimal criteria for informed consent, and
given the extensive documentation substantiating the effectiveness and safety of natural treatments for pain and
inflammation, we can reasonably conclude that patients suffering from painful musculoskeletal disorders are
entitled to receive from their healthcare providers information about these treatments as valid and reasonable
options in the management of their health concerns. Failure to provide patients with non-drug non-surgical
options for the management of their musculoskeletal symptoms is therefore ethically questionable and
medicolegally untenable. For example, a physician who tells his patient “There is no research to support
‘alternative’ treatments for your [painful musculoskeletal disorder]” has clearly misrepresented the facts and has
776) Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E.Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and
Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998 Aug 19;280(7):605-13
777) Lacey JV Jr, Mink PJ, Lubin JH, Sherman ME, Troisi R, Hartge P, Schatzkin A, Schairer C. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA. 2002 Jul 17;288(3):334-41
778) Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA. 2000 Jan 26;283(4):485-91
779) Grady D, Brown JS, Vittinghoff E, Applegate W, Varner E, Snyder T; HERS Research Group. Postmenopausal hormones and incontinence: the Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol. 2001
Jan;97(1):116-20
780) "Half of the interventions used in routine clinical practice amongst medical inpatients are supported by results from randomized controlled trials." Nordin-Johansson A, Asplund K. Randomized controlled trials and consensus
as a basis for interventions in internal medicine. J Intern Med. 2000 Jan;247(1):94-104
781) Gill P, Dowell AC, Neal RD, Smith N, Heywood P, Wilson AE. Evidence based general practice: a retrospective study of interventions in one training practice. BMJ. 1996 Mar 30;312(7034):819-21
782) Horton R. Lotronex and the FDA: a fatal erosion of integrity. Lancet. 2001;357(9268):1544-5
783) Just how tainted has medicine become? Lancet. 2002 Apr 6;359(9313):1167
784) Vento S. How tainted is medicine? Lancet. 2002 May 18;359(9319):1775
785) Wheatley D. How tainted is medicine? Lancet. 2002 May 18;359(9319):1775-6
787) Brennan TA. Buying editorials. N Engl J Med. 1994;331:673-5
791) Wolinsky H, Brune T. The Serpent on the Staff : The Unhealthy Politics of the American Medical Association. New York; Putnam Books, 1994
792) Mendelsohn RS. Confessions of a medical heretic. Chicago; Contemporary Books.1979
793) Rost P. Big Pharma's Dirty Little Secret. www.commondreams.org/views04/1226-29.htm Accessed February 7, 2005
794) Steinreich D. 100 Years of Medical Robbery. http://www.mises.org/fullstory.aspx?control=1547 Accessed February 7, 2005
795) Mercola J. The AMA's 100 Years of Robbing You Blind 6/30/04 www.mercola.com/2004/jun/30/ama_money.htm Accessed February 7, 2005
796) Hockenberry J. Drug giant accused of false claims. Whistleblower alleges illegal encouragement of off-label use. http://msnbc.com/news/937302.asp?0sl=-42&cp1=1 Accessed February 7, 2005
797) Blumenthal D. Doctors and drug companies. N Engl J Med. 2004;351(18):1885-9
798) Roelcke V. Nazi medicine and research on human beings. Lancet 2004; 364 (Special Issue: Medicine, Crime, and Punishment): 6-7
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mislead the patient into believing that the only available options are surgical and pharmaceutical. Should the
patient suffer injury as a result of the ensuing pharmaceutical/surgical management of their health concern,
he/she would have a reasonable argument that informed consent was not obtained and that the injury might have
been avoided had he/she been fully informed of safer “alternatives.” Additionally, healthcare systems that
essentially make drugs and surgery cost-free or available for a nominal “co-payment” while forcing patients to
pay out-of-pocket for nondrug nonsurgical “alternatives” have obfuscated the patient’s ability to chose the best
option—if all other variables are equal, then of course the patient will use the treatment that is subsidized and
available at lesser cost. Since most insurance policies cover drugs and surgery but do not cover natural
treatments as described in this paper, most patients’ “voluntary consent” is invalidated because it has been
financially leveraged. Drugs and surgery are invariably covered by insurance if deemed to be “medically
necessary.” The only way to ensure that patients have equal access to their healthcare options and to provide
the opportunity for valid and authentic voluntary informed consent is to remove the unfair financial
subsidization of pharmaceutical/surgical treatments; this will require legislative enactment of "every category of
provider laws"—these laws provide that patients have equal access to healthcare providers of different
disciplines.799,800
Conclusions
The chiropractic profession continues to develop and mature over time and with advances in research that
further our understanding of health and disease and the value of diet, nutrition, exercise, spinal manipulation and
other natural therapeutics. In contrast to their allopathic counterparts, chiropractic and naturopathic physicians
are the only healthcare providers trained to consider each patient as an integrated being and to give specific
attention to the physiological and biochemical aspects of health and disease, including structural, spinal,
musculoskeletal, neurological, vascular, nutritional, emotional and environmental relationships.801,802
Accordingly, chiropractic and naturopathic physicians are in progressively greater demand for the provision of
healthcare that includes and yet increasingly extends beyond the relatively narrow scope of musculoskeletal
specialization. Research documenting the visceral and systemic benefits of spinal manipulation mandates that
our concept of “musculoskeletal” must be expanded to appreciate that musculoskeletal interventions benefit
nonmusculoskeletal body systems and systemic processes.803,804,805,806,807,808
To that end, this article has
provided a review of the nutritional aspects of a health-promoting lifestyle, characterized by proper ergonomics
and abundant physical activity, the selective use and skilled application of noninvasive natural therapeutics, and
the supplemented Paleo-Mediterranean diet which is characterized by intake of lean meats, fresh fruits and
vegetables, supplemental vitamins and minerals (excluding excess iron and vitamin A, and with physiologic
doses of vitamin D), and balanced broad-spectrum fatty acid supplementation. The anti-inflammatory and
analgesic nutritional and botanical medicines described in this review are generally appropriate for the treatment
of inflammatory and degenerative musculoskeletal conditions, and they comprise an attractive alternative to the
too-often lethal effects of pharmacologic anti-inflammatory and anti-rheumatic drugs.
If we consider that medical/surgical interventions result in an excess of 110,000 – 225,000 iatrogenic American
deaths each year809,810, we could reasonably conclude that undue restriction of chiropractic and naturopathic
physicians to practice preventive healthcare and the discriminatory legal and financial barriers that inhibit
patients from accessing alternatives to drugs and surgery are unethical and may represent a violation of patients’
[human] rights insofar as these restrictions ultimately deny patients’ access to safe, effective, cost-effective,
empowering, affordable healthcare by simultaneously restricting them to interventions that carry greater risk for
799) “Most health insurance plans in Washington state must provide access to every category of licensed health-care provider.” Mike Kreidler, Washington Insurance Commissioner. Every Category Law and Your Health
Insurance. http://www.insurance.wa.gov/factsheets/factsheet_detail.asp?FctShtRcdNum=54 Accessed February 17, 2005
800) Washington State Chiropractic Association. "Maintain and Protect “Every Category of Provider” Law: As always, the WSCA’s top priority is to maintain a patient’s right to choose the provider of their choice for the treatment
of conditions covered in a health insurance plan." http://www.chirohealth.org/legislation/legislationAgendaDetails.htm Accessed February 17, 2005
802) American Chiropractic Association. What is Chiropractic? http://amerchiro.org/media/whatis/ Accessed January 9, 2005
803) Mein EA, Greenman PE, McMillin DL, Richards DG, Nelson CD. Manual medicine diversity: research pitfalls and the emerging medical paradigm. J Am Osteopath Assoc. 2001;101(8):441-4
804) Balon J, Aker PD, Crowther ER, Danielson C, Cox PG, O'Shaughnessy D, Walker C, Goldsmith CH, Duku E, Sears MR. A comparison of active and simulated chiropractic manipulation as adjunctive treatment for childhood
asthma. N Engl J Med. 1998;339(15):1013-20
Physiol Ther. 1991;14(7):399-408
806) Gorman RF. Monocular visual loss after closed head trauma: immediate resolution associated with spinal manipulation. J Manipulative Physiol Ther. 1995;18(5):308-14
807) Wingfield BR, Gorman RF. Treatment of severe glaucomatous visual field deficit by chiropractic spinal manipulative therapy: a prospective case study and discussion. J Manipulative Physiol Ther. 2000;23:428-34
808) Radjieski JM, Lumley MA, Cantieri MS. Effect of osteopathic manipulative treatment of length of stay for pancreatitis: a randomized pilot study. J Am Osteopath Assoc. 1998 May;98(5):264-72
809) Starfield B. Is US health really the best in the world? JAMA. 2000 Jul 26;284(4):483-5
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harm and greater financial expense. With ever-increasing costs and ever-worsening health outcomes, the
American healthcare system is destined for collapse unless we change the model upon which our healthcare
system is founded—namely that surgery and chemical drugs are the solutions to chronic diseases induced by
nutritional deficiencies, oxidative stress, impaired detoxification, defects in fatty acid metabolism, altered
gastrointestinal function, and neuromusculoskeletal dysfunction. We have reached an irrevocable impasse in
which our current healthcare system dominated by drugs and surgery is no longer consistent with the balance of
scientific research.
The time has come for patients and practitioners of natural healthcare to demand change and equitable access
within the healthcare arena. Financial and legislative barriers imposed upon the general population which
impede access to the safer and more cost-effective healthcare are intolerable if we intend to reverse the welldocumented trends of progressive decline in American health and the escalating costs of medical health services.
Rapid policy and legislative changes should be enacted to facilitate the public’s access to the healthcare services
provided by chiropractic and naturopathic physicians so that we can reverse current trends enacted by
overutilization of overpriced and hazardous medical interventions that threaten to bankrupt the nation and kill
200,000 Americans per year. If we assume that current trends will continue for the next five years as they have
over the past several decades, then failure to enact progressive changes in national healthcare policy will
continue to have adverse financial effects on the people811, business812, and communities of our nation813,814 and
will precipitate an additional one million American deaths due to iatrogenic causes (200,000 deaths per year for
five years = 1 million iatrogenic deaths). If the community of healthcare providers is to succeed in its purported
altruistic mission of enacting improvements in healthcare delivery and improving the health of our fellow
citizens and patients, and if we are to reverse the ongoing crises in American health and healthcare, we must
actualize tangible and authentic reform as quickly as possible for the sake of our patients’ and the nation’s
health. “Authentic reform” in this context specifically implies but is not limited to 1) naturopathic licensure
with autonomous prescriptive authority for the remaining 37 states that currently deny their citizens access to the
healthcare providers with the most training in therapeutic diets, interventional nutrition, botanical medicines,
and lifestyle counseling, 2) limited prescriptive authority for chiropractic physicians at least for the purpose of
legally discontinuing and thereby protecting their patients from pharmaceutical drugs known to significantly
increase the risk of injury and death, 3) the nation-wide passage and enforcement of "every category of provider
laws" to empower the public with financial access to and insurance coverage for nondrug nonsurgical healthcare
providers.
The claim that “alternative medicine” is “unscientific” is no longer intellectually defensible. The American
healthcare system is an exorbitantly expensive healthcare system that is failing to improve national health and is
failing protect our citizens from a holocaust of iatrogenic morbidity and mortality while imposing an impressive
financial burden on the citizens, families, communities, and small businesses of our nation. The only
scientifically responsible action is to effect political change to empower equitable access to duly trained
doctorate-level physicians. Each and every day, approximately 493 American patients die prematurely as a
direct consequence—“side effect”—of allopathic medical care, and the numbers of patients who receive
inefficacious, inadequate, inappropriate, and/or substandard medical care reaches into the millions; these are not
issues for contention or debate—they are consistently documented and reported in mainstream, first-tier
conservative “conventional” medical journals, such as JAMA815,816,817,818, New England Journal of
Medicine819,820,821, American Family Physician822, American Journal of Medical Quality823, and Quality and
811) “A national study released today reports 20 million American families — or one in seven families — faced hardships paying medical bills last year, which forced many to choose between getting medical attention or paying
rent or buying food…” Freeman, Liz. 'Working poor' struggle to afford health care. Naples Daily News. Published in Naples, Florida and online at
http://www.naplesnews.com/npdn/news/article/0,2071,NPDN_14940_3000546,00.html Accessed July 28, 2004
812) “The USA's 5.8 million small companies… Health care costs are rising about 15% this year for those with fewer than 200 workers vs. 13.5% for those with 500 or more… But many small employers cite increases of 20% or
more. That's made insurance the No. 1 small business problem…” Jim Hopkins. Health care tops taxes as small business cost drain. USA TODAY. http://www.usatoday.com/news/health/2003-04-20-small-businesscosts_x.htm. Accessed July 28, 2004
813) “In 1994, we spent $1 trillion on health care in the US, or, more accurately, we spent most of this astounding sum on disease treatment. This represents an increase of 300% in the last 15 years. Health care costs now
consume 15% of the gross national product (GNP), with the percentage of GNP spent on health care continuing to increase at twice the rate of inflation. If the rate of increase continues, health care costs will consume the
entire GNP within 50 years. Corporations now spend an incredible 48% of their after-tax profits on health care, and it is projected that by the year 2000, healthcare costs will equal 60% of after-tax profit at the average
Fortune 500 company.” Pizzorno JE. Total Wellness. Rocklin: Prima; 1996 page 7
income we'll earn between 1999 and 2010 will go to health care.” Pat Regnier, Money Magazine. Healthcare myth: We spend too much. October 13, 2003: 11:29 AM EDT
http://money.cnn.com/2003/10/08/pf/health_myths_1/ Accessed Monday, July 12, 2004
818) DeAngelis CD. Professors not professing. JAMA. 2004;292:1060-1
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Safety in Health Care.824 Each chiropractic and naturopathic physician should commit to effective action or
material contribution to organized efforts on a regular basis. Safe, effective, natural healthcare is what the
public wants and what the public is demanding. The research has been and will continue to be in our favor
because our low-cost, low-risk interventions effectively intervene at the primary level of disease causality rather
than masking the symptoms of underlying dysfunction with higher-cost higher-risk chemical drugs. Direct and
indirect support of the medical hegemony that unduly limits chiropractic and naturopathic physicians from
access to patients and which results in unnecessary financial burdens on a large percentage of the individuals,
families, businesses, and communities of this nation while killing with "side-effects" approximately 493
Americans per day is no longer scientifically, ethically, or financially defensible. Rectification of this situation
requires primarily three components: 1) national licensure for naturopathic physicians who have graduated from
residential 4-6 year doctorate programs825,826,827,828, 2) limited prescriptive authority for chiropractic physicians at
least for the purpose of legally discontinuing and thereby protecting their patients from pharmaceutical drugs
known to significantly increase the risk of injury and death, 3) the nation-wide passage and enforcement of
"every category of provider laws" to empower the public with financial access to and insurance coverage for
nondrug nonsurgical healthcare providers.829,830 Progressively expensive medical costs absorb nearly 25% of
America’s economic growth potential831 while medical treatments kill 493 Americans per day. Clearly, in the
interests of patient care and national economic stability and growth, the time for change is now.
820) Ray WA, Griffin MR, Stein CM. Cardiovascular Toxicity of Valdecoxib. N Engl J Med. 2004; 351: 2767
821) Moseley JB, O'Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall DH, Hollingsworth JC, Ashton CM, Wray NP. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med 2002 Jul
11;347(2):81-8
825) Boon HS, Cherkin DC, Erro J, Sherman KJ, Milliman B, Booker J, Cramer EH, Smith MJ, Deyo RA, Eisenberg DM. Practice patterns of naturopathic physicians: results from a random survey of licensed practitioners in two
US States. BMC Complement Altern Med. 2004;4(1):14
827) Cherkin DC, Deyo RA, Sherman KJ, Hart LG, Street JH, Hrbek A, Davis RB, Cramer E, Milliman B, Booker J, Mootz R, Barassi J, Kahn JR, Kaptchuk TJ, Eisenberg DM. Characteristics of visits to licensed acupuncturists,
chiropractors, massage therapists, and naturopathic physicians. J Am Board Fam Pract. 2002 Nov-Dec;15(6):463-72
828) Cherkin DC, Deyo RA, Sherman KJ, Hart LG, Street JH, Hrbek A, Cramer E, Milliman B, Booker J, Mootz R, Barassi J, Kahn JR, Kaptchuk TJ, Eisenberg DM. Characteristics of licensed acupuncturists, chiropractors,
massage therapists, and naturopathic physicians. J Am Board Fam Pract. 2002 Sep-Oct;15(5):378-90
829) “Most health insurance plans in Washington state must provide access to every category of licensed health-care provider.” Mike Kreidler, Washington Insurance Commissioner. Every Category Law and Your Health
Insurance. http://www.insurance.wa.gov/factsheets/factsheet_detail.asp?FctShtRcdNum=54 Accessed February 17, 2005
830) Washington State Chiropractic Association. "Maintain and Protect “Every Category of Provider” Law: As always, the WSCA’s top priority is to maintain a patient’s right to choose the provider of their choice for the treatment
of conditions covered in a health insurance plan." http://www.chirohealth.org/legislation/legislationAgendaDetails.htm Accessed February 17, 2005
831) Sager A, Socolar D. Health Costs Absorb One-Quarter of Economic Growth, 2000-2005; Recent Federal Report Unintentionally Obscures Massive Rise, Physicians' Decisions Key to Controlling Cost, 9 February 2005.
Accessible from http://dcc2.bumc.bu.edu/hs/ushealthreform.htm on February 17, 2005
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Appendix A: Clinical and Physiologic Considerations of Vitamins and Minerals832
Nutrients
Vitamin A
♦
Physiology, toxicity, and contraindications
Vitamin A comes in different forms with different
characteristics; of these, all-trans retinol is the most
common, and retinol palmitate is one of the least
toxic. The richest dietay source of vitamin A is liver.
Vitamin A has little or no antioxidant activity;
carotenes are antioxidants.
♦ Daily dose is should generally be <10,000 IU/d.
Most patients should not consume more than 20,000
IU of vitamin A per day without express supervision
by a healthcare provider. Vitamin A is present in
some multivitamins, in cod liver oil, and in other
supplements—read labels to ensure that the total
daily intake is not greater than 20,000 IU per day.
Approximately 200 cases of vitamin A toxicity are
reported worldwide each year—a miniscule fraction of
adverse effects compared to the number of people
taking vitamin A supplements and compared to the
number of people poisoned or killed by
pharmaceutical drugs each year.
♦ Vitamin A is necessary for proper immune function,
vision, cell growth and differentiation (especially
epithelial tissue). Insufficiency of vitamin A causes
epithelial tissue to produce excess keratin; hence the
keratinization of the eye and skin in patients with
vitamin A deficiency.
♦ Manifestations of vitamin A deficiency are night
blindness (flash blindness), follicular hyperkeratosis,
frequent infections, and poor wound healing. Tissue
damage (ie, burns and trauma) and infections greatly
increase the requirement for and tolerability of vitamin
A supplementation.
Clinical applications and notes (for adult patients)
Short-term prescription of 100,000 – 200,000 IU
per day is common in children and adults. Vitamin A
toxicity is seen with chronic ingestion of therapeutic
doses (for example: 25,000 IU per day for 6 years, or
100,000 IU per day for 2.5 years833). Do not
administer high doses to patients on numerous
medications or with liver disease.
♦ Doses of vitamin A ≥ 10,000 IU are controversially
associated with an increased risk for birth defects;
therefore women who are pregnant or might soon
become pregnant should keep their daily intake of
vitamin A below 10,000 IU from all sources.
♦ Clinical applications for supraphysiologic
doses of vitamin A include: adult acne,
menorrhagia, and viral infections, especially
measles.
♦ Patients must be advised of limited duration of
use (e.g., 1 week) and to reduce or stop
supplementation if signs of toxicity occur such as
skin problems (dry skin, flaking skin, chapped or split
lips, red skin rash, hair loss), joint pain, bone pain,
headaches, anorexia (loss of appetite), edema (water
retention, weight gain, swollen ankles, difficulty
breathing), fatigue, and/or liver damage.
♦ Clinical experience: Any time you prescribe highdose vitamin A (ie, greater than 25,000-50,000 IU per
day), you must clearly define the time limit of this
treatment in writing so that the patient will not
mistakenly continue taking the vitamin and end up
with vitamin A toxicity.
Carotenoids
♦
Carotenoids are antioxidants and have additional
specific functions. Fewer than 10% of carotenoids can
serve as precursors to vitamin A; of these, beta-,
alpha-, and gamma-carotene are the most efficient.
Provitamin carotenoids are converted to all-trans
retinal which is then converted to retinyl ester.
♦ Carotenoids are generally administered in
microgram doses and should be delivered in a broadspectrum combination including: beta carotene, alpha
carotene, zeaxanthin, cryptoxanthin, and lutein.
♦ Virtually non-toxic when administered in rational
doses from natural sources and in balanced
combination. Conversion of carotenes to vitamin A is
impaired in patients with diabetes and
hypothyroidism.
♦
♦
♦
Antioxidant
Immunosupportive (eg, in HIV)
832) Liska A, Quinn S, Lukaczer D, Jones DS, Lerman RH (eds). Clinical Nutrition: A Functional Approach. Second Edition. Gig Harbor; The Institute for Functional Medicine: 2004: 97-149
833) Geubel AP, De Galocsy C, Alves N, Rahier J, Dive C. Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases. Gastroenterology. 1991 Jun;100(6):1701-9
49 of 58
Appendix A: Clinical and Physiologic Considerations of Vitamins and Minerals—continued
Nutrients
Vitamin D3
(cholecalciferol)
Vitamin E
Vitamin D deficiency is well documented to be
extremely common: ~40% of the general population
and >90% of patients with musculoskeletal pain.
♦ The physiologic requirement for vitamin D3 is
approximately 4,000 IU per day in adult men. Clinical
guidelines for supplementation are as follows: 1,000 –
2,000 IU for infants; 2,000 IU for children and
adolescents; 2,000-4,000 IU for adults, may go up to
10,000 IU per day for adults for up to 6 months and/or
with laboratory supervision. Dietary sources of
vitamin D are insufficient to meet physiologic needs—
vitamin D needs can only be met by sun exposure
(full-body, without sunscreen, near equatorial, near
noon, for 10-20 minutes) or by high-dose vitamin D
supplementation.
♦ Physiologic doses are non-toxic except in patients
with vitamin D hypersensitivity or those taking certain
medications that induce hypercalcemia.
♦ The thiazide class of diuretics (including
hydrochlorothiazide) can induce hypercalcemia.
Correction of underlying hypovitaminosis D may
precipitate hypercalcemia.
♦ “Vitamin D hypersensitivity” is seen in
granulomatous diseases including tuberculosis,
sarcoidosis, Crohn’s disease, and some types of
cancer; also adrenal failure, hypothyroidism and
hyperthyroidism.
♦
Deficiency of vitamin E is rarely recognized but can
present as ataxia and neurologic dysfunction,
especially in patients with malabsorption. Best dietary
sources are seed and nut oils, especially sesame
seeds, almonds, sunflower seeds, and wheat germ
oil.
♦ A reasonable preventive dose is 200-800 IU per
day. Doses up to 3,200 IU per day are generally
considered nontoxic.
♦ Vitamin E is commonly described as a “chain
breaking antioxidant” with special importance in
protecting cell membranes and lipoproteins from
oxidative damage.
♦
Implement vitamin D replacement in all patients
unless contraindicated. Vitamin D assessment and
administration is becoming the standard of care and
failure to implement vitamin D therapy may be
grounds for malpractice.834,835
♦ Assess vitamin D status with 25-OH-vitamin D.
♦ Monitor for vitamin D toxicity by measuring serum
calcium.
♦
Conditions Associated with Vitamin D Deficiency:
♦ Rickets (children) and osteomalacia (adults)
♦ osteoporosis
♦ diabetes mellitus
♦ osteoarthritis
♦ hypertension
♦ cardiovascular disease
♦ metabolic syndrome
♦ depression
♦ multiple sclerosis
♦ rheumatoid arthritis
♦ Grave’s disease
♦ ankylosing spondylitis
♦ systemic lupus erythematosus
♦ cancers of the breast, prostate, and colon
♦ polycystic ovary syndrome
♦ musculoskeletal pain
♦ epilepsy
♦ migraine headaches
♦ Chronic low-back pain
♦ Inflamation
“Vitamin E” is a family of related chemicals
including:
DL-tocopherol: this is synthetic and should
never be used. Don’t even give this to your dog.
Alpha-tocopherol: commonly used but it
depletes the body of the more important
gamma-tocopherol.836
Beta-tocopherol:
Delta-tocopherol:
Gamma-tocopherol: this is the most
important form of vitamin E and should be
provided at approximately 40% when “mixed
tocopherols” are consumed.
Tocopherol succinate: specific for improving
mitochondrial function and for its anti-cancer
effect.837
Tocotrienols: appear protective against
breast cancer
♦
834) Heaney RP. Vitamin D, nutritional deficiency, and the medical paradigm. J Clin Endocrinol Metab. 2003 Nov;88(11):5107-8
835) Al Faraj S, Al Mutairi K. Vitamin D deficiency and chronic low back pain in Saudi Arabia. Spine. 2003 Jan 15;28(2):177-9
836) Jiang Q, Christen S, Shigenaga MK, Ames BN. gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr. 2001 Dec;74(6):714-22
837) Prasad KN, Kumar B, Yan XD, Hanson AJ, Cole WC. Alpha-tocopheryl succinate, the most effective form of vitamin E for adjuvant cancer treatment: a review. J Am Coll Nutr. 2003 Apr;22(2):108-17
50 of 58
Nutrients
Vitamin K1
(phylloquinone):
from plants
Vitamin K2
(menaquinone):
from animals and
bacteria
Vitamin K3
(menadione):
synthetic
Vitamin K1 (phylloquinone)—this is the form of
vitamin K found in plants
♦ Vitamin K2 (menaquinone)—found in animal
tissues and synthesized by bacteria
♦ Vitamin K3 (menadione)—synthetic form that
must be alkylated in the body prior to use; this form of
vitamin K is difficult to obtain and is generally not
used for nutritional supplementation.
♦ 500-1000 mcg is a common supplemental dose.
♦ Vitamin K must not be taken by patients needing
anticoagulation and taking coumadin-warfarinheparin. Vitamin K is necessary for the production of
clotting factors: factor II (prothrombin), factor VII,
factor IX, and factor X.
♦ Vitamin K is also necessary for the formation of
osteocalcin—a calcium-binding protein in bone.
Vitamin K is necessary for bone formation and
blood clotting, thus obvious clinical applications
include osteoporosis/osteopenia and
menorrhagia/ecchymosis.
♦ Vitamin K1 (phylloquinone)—doses of at least
1,000 IU per day of K1 are needed in order to
optimize carboxylation of osteocalcin.838
♦ Vitamin K2 (menaquinone)—A recent study with
21 patients in the treatment group published in JAMA
used 45 mg/d (forty five milligrams per day = 45,000
mcg per day) of vitamin K2 for an 80% reduction in
liver cancer in patients with viral cirrhosis:
“Compliance with vitamin K2 in the treatment group
was good; no patient had adverse reactions or
dropped out of the study.”839
♦
♦
B-1 (thiamine)
♦
Classic deficiency is dry beriberi (central and
peripheral neurologic dysfunction, dementia,
psychosis, weakness, neuropathy) and wet beriberi
(congestive heart failure). The classic CNS
manifestations of thiamine/magnesium deficiency
seen in alcoholics is Wernecke-Korsakoff syndrome.
♦ Conversion from the inactive form to the active
form of the vitamin requires magnesium.
♦ Functions include: enzyme cofactor, aldehyde
transfer, modulates chloride ion channels in the CNS,
energy production in hexose monophosphate shunt,
phagocytic respiratory burst, neurotransmitter
synthesis and release.
♦ Anaphylaxis to parenteral thiamine has been
reported.
20-100 mg is a common supplemental dose; one
study used 5,000 mg to find evidence of a cholinergic
effect.840 The densest food source of thiamine is
brewer’s yeast.
♦ Thiamine insufficiency is common in patients with
cardiomyopathy.841,842 Alleviates congestive heart
failure in some patients, especially when used with
CoQ10 and magnesium.843
♦ Deficiency is common in the demented elderly;
alleviates “Alzheimer’s disease” in some patients
B-2 (riboflavin)
♦
♦
Classic deficiency: angular stomatitis
20-200 mg is a common supplemental dose. The
richest dietary sources are yeast and liver.
♦ Several studies have used 400 mg per day in
patients with migraine and have not reported any
serious adverse effects.
♦ Functions include: enzyme cofactor (especially for
energy production as FAD in the electon transport
chain), drug/xenobiotic detoxification via support of
Cy-P450, antioxidant functions via glutathione
reductase.
♦
♦
400 mg per morning is safe and effective for the
alleviation of migraine.844
838) Binkley NC, Krueger DC, Kawahara TN, Engelke JA, Chappell RJ, Suttie JW. A high phylloquinone intake is required to achieve maximal osteocalcin gamma-carboxylation. Am J Clin Nutr. 2002 Nov;76(5):1055-60
839) Habu D, Shiomi S, Tamori A, Takeda T, Tanaka T, Kubo S, Nishiguchi S. Role of vitamin K2 in the development of hepatocellular carcinoma in women with viral cirrhosis of the liver. JAMA. 2004 Jul 21;292(3):358-61
840) Meador KJ, Nichols ME, Franke P, Durkin MW, Oberzan RL, Moore EE, Loring DW. Evidence for a central cholinergic effect of high-dose thiamine. Ann Neurol. 1993 Nov;34(5):724-6
841) da Cunha S, Albanesi Filho FM, da Cunha Bastos VL, Antelo DS, Souza MM. Thiamin, selenium, and copper levels in patients with idiopathic dilated cardiomyopathy taking diuretics. Arq Bras Cardiol. 2002 Nov;79(5):454-65
842) Wohl MG, Brody M, Shuman CR, Turner R, Brody J. Thiamine and cocarboxylase concentration in heart, liver and kidney, of patients with heart failure. J Clin Invest. 1954 Nov;33(11):1580-6
843) Shimon I, Almog S, Vered Z, Seligmann H, Shefi M, Peleg E, Rosenthal T, Motro M, Halkin H, Ezra D. Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving longterm furosemide therapy. Am J Med. 1995 May;98(5):485-90
844) Boehnke C, Reuter U, Flach U, Schuh-Hofer S, Einhaupl KM, Arnold G. High-dose riboflavin treatment is efficacious in migraine prophylaxis: an open study in a tertiary care centre. Eur J Neurol. 2004 Jul;11(7):475-7
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Nutrients
B-3: niacin
♦
Classic deficiency is pellagra: depression,
dermatitis, dementia, diarrhea, death. Endogenous
production requires 60 mg tryptophan to make 1 mg
niacin. Richest dietary sources are yeast, rice bran,
wheat bran, liver, and poultry breast meat.
♦ 20-100 mg is a common supplemental dose; doses
up to 2,000 mg per day in divided doses are used for
the treatment of hypercholesterolemia and must be
monitored with lab tests to assess for possible liver
dysfunction. Up to 6 grams (6,000 mg) per day in
divided doses has been used safely.
♦ Liver damage has been seen with doses > 2,000
mg per day. Patients on high doses must be
monitored with periodic measurements of liver
enzymes; not to be used in patients with liver disease.
“Time-release niacin” is the most hepatotoxic form of
niacin.
♦
B-3:
niacinamide
♦
♦
20-100 mg is a common supplemental dose.
500 mg 4-6 times per day for 2,000 – 3,000 mg per
day is safe and effective for osteoarthritis.
♦ Toxicity is rare; however monitoring liver enzymes
at 1 and 4 months and yearly thereafter is
encouraged when doses ≥ 2000 mg are used.
anti-aging (reveral of aging phenotypes via
histone acetylation)
♦ osteoarthritis
B-3: inositol
hexaniacinate
(“no-flush niacin”)
♦
2000 mg per day in divided doses of 500-1000 mg
each is common.
♦ 4,000 mg per day safely improves circulation in
patients with Raynaud’s phenomenon846
B-5 (pantothenic
acid)
♦
Deficiency is generally unrecognized, but may
include depression, acne, anemia, and weight gain;
richest dietary sources are yeast and liver.
♦ Main physiologic functions include its structural
role in the formation of the Coenzyme A molecule.
20-100 mg is a common supplemental dose, and
doses of 10,000 mg calcium pantothenate have been
used safely; it is virtually non-toxic.
♦ May help alleviate fatigue in some patients.
♦ May alleviate acne.
This is a slow release form of vitamin B3 that
allows supplementation with niacin at high doses
without the flushing and hepatotoxicity seen with plain
niacin. However, despite one enthusiastic article
stating that this is the preferred form of B3 for treating
lipid disorders, inositol hexaniacinate appears
clinically ineffective for the treatment of dyslipidemia.
Dyslipidemia: Niacin at 2000-3000 mg per day in
divided doses can lower total and LDL cholesterol,
fibrinogen, triglyceride levels, and raise HDL. In a
head-to-head study 2,000 mg niacin was more
powerful than 1,200 mg gemfibrozil for favorably
modifying lipids.845
♦
♦
♦
845) Sprecher DL. Raising high-density lipoprotein cholesterol with niacin and fibrates: a comparative review. Am J Cardiol. 2000 Dec 21;86(12A):46L-50L
846) Sunderland GT, Belch JJ, Sturrock RD, Forbes CD, McKay AJ. A double blind randomised placebo controlled trial of hexopal in primary Raynaud's disease. Clin Rheumatol. 1988 Mar;7(1):46-9
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Nutrients
B-6
♦
B-12 (cobalamin)
Classic deficiency manifests as megaloblastic
anemia, dorsal column lesions (ie, loss of pedal
vibration and proprioception), mental depression,
fatigue, peripheral neuropathy. “Pernicious
anemia” is a type of B12 deficiency caused by
autoimmune atrophic gastritis wherein parietal cells
are destroyed, leaving the host without intrinsic
factor. Best dietary sources are liver, clams, and
kidneys—vegetarian diets are notoriously deficient
in B12.
♦ 100 – 2,000 mcg is a common supplemental
dose; at least 2,000 mcg per day is required to
increase blood levels in patients with B12
deficiency and malabsorption
♦ essentially non-toxic
♦ cyanocobalamin contains cyanide and should
be avoided; anaphylaxis to parenteral b12 has
been reported
Deficiency can cause widespread—subtle or
severe—problems and manifestations since this
cofactor is used in more than 100 enzymatic
reactions. Modest dietary sources are yest,
sunflower seeds, and wheat germ. Deficiency of B6
can be induced by the drug Isoniazid.
♦ 20-100 mg is a common supplemental dose;
250 mg per day with breakfast is safe and
reasonable when higher doses are needed; this
should be co-administered with a
multivitamin/multimineral supplement that supplies
other vitamins and minerals, especially
replacement doses (200-600 mg) of magnesium.
Very high doses of vitamin B6 (600-900 mg) are
supported by the literature for the treatment of
specific conditions, and doses ≤ 1,000 mg per day
have been used safely with doctor supervision.847
♦ Peripheral sensory (and motor) neuropathy has
been reported in patients taking gram doses for
several years. Most of these reports appear
associated with synthetic pyridoxine HCl and the
toxicity is likely due to untreated magnesium
deficiency which impairs conversion of neurotoxic
pyridoxine HCl into the safe and active pyridoxal 5'
phosphate. Doses of B6 greater than 150 mg may
suppress prolactin and lactation.
“Active” and
biologically useful
forms of this vitamin:
♦ Hydroxycobalamin
also called
hydroxocobalamin
♦ Adenosylcobalamin
♦ Methylcobalamin
Cyanocobalamin
contains cyanide,
which is poisonous at
high doses848
♦
♦
Clinical applications and notes (for adult
patients)
♦ Pyridoxine HCl is synthetic and somewhat
neurotoxic until it is converted to pyridoxal 5'
phosphate which requires magnesium. Pyridoxine
HCl must always be coadministered with
magnesium.
♦ Clinical applications: carpal tunnel
syndrome, autism, epilepsy, PMS, calcium
oxalate nephrolithiasis, nausea/vomiting of
pregnancy.
♦ Vitamin B6 is commonly used to promote
various forms of detoxification; however high
doses may paradoxically inhibit the
sulfotransferase aspect of detoxification.
Cyanocobalamin contains cyanide and should
be avoided as it can contribute to chronic cyanide
toxicity and loss of vision (tobacco-alcohol
amblyopia)—the treatment for the latter problem is
administration of nutrients with an emphasis on
hydroxocobalamin
♦ “active” forms include methylcobalamin and
hydroxocobalamin
♦ At least 2,000 mcg per day is required to
increase blood levels in patients with B12
deficiency to the same levels that can be obtained
with standard regimens of
parenteral/intramuscular administration.849
♦ Vitamin B12 in high doses appears to help
alleviate low-back pain850: this study used
intramuscular administration, but high-dose
oral supplementation should be superior if
doses >2,000 mcg are used.
♦ Can alleviate fatigue, especially neurogenic
fatigue in patients with chronic infections
♦
2002 Apr;75(4):616-58
848) Reidenberg MM. Cyanocobalamin--a case for withdrawal. J R Soc Med. 1993 May;86(5):309
849) Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998 Aug 15;92(4):1191-8
850) Mauro GL, Martorana U, Cataldo P, Brancato G, Letizia G. Vitamin B12 in low back pain: a randomised, double-blind, placebo-controlled study. Eur Rev Med Pharmacol Sci. 2000 May-Jun;4(3):53-8
53 of 58
Nutrients
Biotin
♦
Folic acid
♦
Found in low doses in foliage. Numerous functions include
the transfer of methyl groups, necessary for the formation of
myelin, neurotransmitters, and for the protection of DNA.
Brewer’s yeast is clearly the densest dietary source of folic
acid. Deficiency causes macrocytic anemia, fatigue,
depression, and hyperhomocysteinemia. B12 and folic acid
should be coadministered.
♦ 800 mcg is a reasonable supplemental dose and should be
considered the minimal supplemental dose. Doses of 5, 10,
and 20 mg (ie, up to 20,000 mcg) are commonly used and are
generally safe.
♦ Use folic acid cautiously in patients with a history of seizure
or those who are taking anti-seizure medications. Anti-seizure
medications induce deficiency of folate, and if folate is
replaced, then anti-seizure protection may be lost.
Always use with B-12 and other b-vitamins
Potentiates antidepressants by
addressing the previously undiagnosed
folic acid deficiency
♦ Improves efficacy and reduces toxicity of
methotrexate
♦ Lowers homocysteine levels, may also
require B12, B6, NAC, etc.
Vitamin C
♦
Classic deficiency is scurvy: bleeding gums, subcutaneous
bleeding (ecchymoses, petechiae), weak and friable skin and
mucus membranes, reduced immunity, corkscrew hairs, and
follicular hyperkeratosis. Vitamin C has some function as an
antioxidant, in immune support, and in (dopaminergic)
neurotransmission. The best dietary sources are fresh fruits
and vegetables, which also contain the phytochemicals
necessary to optimize the function of vitamin C.
♦ 500-1,000 mg is a reasonable daily dosage for preventive
healthcare;
♦ High doses cause benign loose stools; this varies from
patient to patient and time to time; some patients get loose
stools with 500 mg while others can tolerate 10,000 mg with no
problems.
♦ Intravenous ascorbate can induce hemolysis in patients
with G6PD deficiency
♦ Oral supplementation can exacerbate cardiac complications
of iron overload.854
Anti-allergy benefits in high doses due to
mechanisms including ~40% reductions in
serum histamine
♦ 6,000 mg/d in divided doses has been
shown to have anti-stress benefits.855
♦ Anticancer effects may require boweltolerance dosing or intravenous
administration.
♦ High doses benefit autistic children via a
dopaminergic mechanism856
Necessary for fatty acid metabolism and mitochondrial
function. Deficiency can include hyperlactatemia, ataxia,
seizures, hypotonia, seborheic dermatitis, and hair loss.
Richest dietary source is brewer’s yeast. Deficiency is
uncommon in the general population however it is commonly
seen in patients taking inadequate parenteral nutrition.
♦ Virtually non-toxic: In 2001, the Food and Nutrition Board
(FNB) reported that no adverse effects had been documented
due to either dietary or supplemental consumption of biotin,
and this document was still presented as accurate/current as
of September 2005.851
♦ Avidin in raw egg whites irreversibly binds to biotin and
prevents absorption
Clinical applications and notes (for adult
patients)
♦ 50 – 3,000 mcg is a common supplemental
dose.
♦ May provide benefit to diabetics,
especially for the treatment/prevention of
peripheral neuropathy852
♦ Biotin deficiency during pregnancy is
common may result in birth defects;
supplementation of pregnant women with
~300 mcg is warranted853
♦
♦
♦
851) Food and Nutrition Board (FNB). Dietary Reference Intakes-Vitamins. http://www.nal.usda.gov/fnic/etext/000105.html and http://www.iom.edu/Object.File/Master/7/296/0.pdf On Sept 6, 2005
852) Koutsikos D, Agroyannis B, Tzanatos-Exarchou H. Biotin for diabetic peripheral neuropathy. Biomed Pharmacother. 1990;44(10):511-4
853) Mock DM, Quirk JG, Mock NI. Marginal biotin deficiency during normal pregnancy. Am J Clin Nutr. 2002 Feb;75(2):295-9
854) McLaran CJ, Bett JH, Nye JA, Halliday JW. Congestive cardiomyopathy and haemochromatosis--rapid progression possibly accelerated by excessive ingestion of ascorbic acid. Aust N Z J Med. 1982 Apr;12(2):187-8
855) Brody S, Preut R, Schommer K, Schurmeyer TH. A randomized controlled trial of high dose ascorbic acid for reduction of blood pressure, cortisol, and subjective responses to psychological stress. Psychopharmacology
(Berl). 2002 Jan;159(3):319-24
856) Dolske MC, Spollen J, McKay S, Lancashire E, Tolbert L. A preliminary trial of ascorbic acid as supplemental therapy for autism. Prog Neuropsychopharmacol Biol Psychiatry. 1993 Sep;17(5):765-74
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Nutrients
Calcium
500 - 1,500 mg is the common supplemental dose.
1,000 - 1,500 mg is the recommended
supplemental dose in patients with osteopenia
♦ may promote constipation, especially if not
balanced with magnesium, supplementation should
provide a 1:2 to 1:1 ratio of calcium to magnesium
♦ do not administer with certain medications,
especially antibiotics such as tetracycline, due to the
binding effect which renders the drug systemically
unavailable and can result in death in patients with
life-threatening infections like pneumonia
can promote constipation
always use with magnesium
alleviates bruxism
alleviates PMS
significantly lowers blood pressure when used
with vitamin D
♦
♦
♦
♦
♦
♦
♦
Magnesium
♦
Magnesium deficiency is clearly one of the most
common nutritional deficiencies in all populations.
♦ 200 -800 mg is a common supplemental dose;
high doses cause loose stools.
♦ Do not administer high doses to patients with
severe constipation or with renal failure due to
potential for hypermagnesemia.
♦ Do not administer with certain medications,
especially antibiotics such as tetracycline, due to the
binding effect; spironolactone is a magnesium-sparing
diuretic that can potentiate hypermagnesemia.
♦
♦
♦
♦
♦
♦
Zinc
♦
♦
10 – 25 mg per day is common in supplements;
Doses up to 150 mg can be used therapeutically,
preferably for short-term only or used with 2-4 mg
copper
♦ Excess or imbalanced zinc supplementation can
promote copper deficiency by competition for
absorption
♦ Do not use high-dose zinc in patients with
Alzheimers disease.857
♦ Must be administered with food in order to avoid
stomach irritation
Improves mucosal integrity in patients with
Crohn’s disease when used at 150 mg per day
♦ Promotes tissue healing: trauma, diabetic
ulcers
Copper
♦
♦
2 mg is the most common supplemental dose
Excess or imbalanced copper supplementation can
promote zinc deficiency by competition for absorption
♦ Wilson’s disease is a type of copper toxicity
associated with liver disease and neuropsychiatric
disorder
A good multivitamin should have enough so that
you don’t have to use a separate supplement.
♦ up to 4 mg per day can be used in patients
with connective tissue disorders such as
Marfan’s syndrome and/or to promote healing
Chromium
♦
♦
♦
200 is the most common supplemental dose
500 mcg is commonly used in diabetics
doses up to 1,000 mcg have been used safely in
diabetics
♦ may potentiate diabetic medications; start slowly
and with 6xdaily glucose monitoring in severe
diabetics
A good multivitamin should have enough so
that you don’t have to use a separate supplement
unless you have to use high doses in diabetic
patients
♦ Can alleviate diabetes
♦ Can alleviate hypoglycemia
alleviates bruxism
alleviates PMS
alleviates migraine headaches
alleviates constipation
alleviates muscle spasm and hypertonicity
helps with asthma, hypertension, insomnia,
irritability, anxiety, detoxification,
♦
♦
♦
857) Vasquez A. A brief review of two potential adverse effects of zinc supplementation: cognitive deterioration in patients with Alzheimer's disease, and copper deficiency. Nutritional Perspectives 1995; 18: 11, 19
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Nutrients
Iodide
And
Iodine
♦
♦
Necessary for the formation of thyroid hormone
May benefically modulate estrogen metabolism in
women
♦
Daily doses greater than 750 mcg iodide
contribute to exacerbation of hypothyroidism in
patients with pre-existing thyroid disorders or
borderline thyroid function.858
♦ High doses of iodine 3-6 mg per day can
reduce breast pain during 6 months of
treatment859; long-term safety and efficacy have
not been demonstrated with high-dose oral
supplementation.
♦ Lecithin-bound iodine moduates cytokine release
and may improve symptoms in patients with
asthma860
♦ At least one author/researcher/clinician has
advocated the use of high-dose iodine
supplementation (“orthoiodosupplementation”) and
has used 50 mg per day (fifty milligrams per day) in
patients; it may be that the toxicity associated with
iodine-containing drugs (Amiodarone: antiarrythmic)
is due to the drug itself and not the iodine.861
Rationale for “high dose” iodine supplementation is
suggested by the increased prevalence of
halogenated/brominated pesticides/herbicides and
other pollutants in our environment which are known
to have adverse health effects.
Potassium
♦
get this from fruits and vegetables, not from
supplements
♦ high-normal intake of potassium from fruits and
vegetables can cause fatal hyperkalemia in patients with
renal failure such as due to diabetes
lowers blood pressure
reduces risk of stroke independently from its
ability to lower blood pressure
♦ promotes urinary alkalinization, which is
important for mineral retention and increased
excretion of most xenobiotics
Selenium
♦
200 mcg is considered the standard supplemental and
therapeutic dose
♦ daily doses should be kept below 800 mcg
♦
♦
♦
♦
♦
antioxidant
protects against cancer and heart disease
immunosupportive; powerfully inhibits risk of
serious infection in patients with HIV
858) Chow CC, Phillips DI, Lazarus JH, Parkes AB. Effect of low dose iodide supplementation on thyroid function in potentially susceptible subjects: are dietary iodide levels in Britain acceptable? Clin Endocrinol (Oxf). 1991
May;34(5):413-6
859) Kessler JH. The effect of supraphysiologic levels of iodine on patients with cyclic mastalgia. Breast J. 2004 Jul-Aug;10(4):328-36
860) Kawano Y, Saeki T, Noma T. Effect of lecithin-bound iodine on the patients with bronchial asthma. Int Immunopharmacol. 2005 Apr;5(4):805-10
861) Abraham GE. Serum inorganic iodide levels following ingestion of a tablet form of Lugol solution: evidence for an enterohepatic circulation of iodine. The Original Internist. 2004; 11: 29-35
56 of 58
Nutrients
Iron
Iron supplementation should not be used in patients unless
their iron levels are low, and this is determined by measuring
serum ferritin—not by performing a CBC which can show
anemia that is unrelated to iron deficiency and which may be
associated with iron overload.
♦ The finding of iron deficiency in any adult patient requires
that the patient be referred to a gastroenterologist for
endoscopic evaluation. Failure to make a timely referral for
any adult patient with iron deficiency is grounds for
malpractice litigation.
♦ Iron promotes the formation of “free radicals” and is thus
implicated in several diseases, such as infections, cancer,
liver disease, diabetes, and cardiovascular disease. Iron
supplements should not be consumed except by people who
have been definitively diagnosed with iron deficiency by
measurement of serum ferritin. See
http://vix.com/menmag/alexiron.htm
♦
Screen
asymptomatic
patients.
♦ Never use iron supplementation without first
testing serum ferritin.862,863
♦ Replacement dose for iron deficiency is 60-180
mg of iron per day. 40-60 mg 3x per day is
reasonable for correcting iron deficiency; may
promote constipation and stomach upset;
consume with food, especially meat;
♦ All adult patients with iron deficiency have a
gastrointestinal lesion such as cancer until
proven otherwise. YOU MUST REFER THESE
PATIENTS TO A GASTROENTEROLOGIST.864
See diagram below from Integrative
Orthopedics: www.OptimalHealthResearch.com
♦
Follow-up abnormal laboratory results.
(high serum iron, elevated liver enzymes, high blood glucose, etc.)
Screen high-risk
and symptomatic
patients.
Assess iron status with transferrin saturation and serum ferritin.
Use fasting morning specimen.
IRON-DEFICIENCY
serum ferritin:<10-15
in women, <20 in
men, transferrin
saturation:<16%
In adults with no
obvious cause of
blood loss: Assume
pathologic
gastrointestinal
bleeding until proven
otherwise. Simply
testing for occult blood
in the stool is
insufficient. Refer for
complete (endoscopic)
evaluation.
POSSIBLE SEVERE IRON
OVERLOAD
transferrin saturation: >40%
and/or
serum ferritin: >160 in
women; >200 in men
"HEALTHY IRON STATUS"
transferrin saturation:25-30%
serum ferritin: 30-70
"MODERATE IRON OVERLOAD"
transferrin saturation: >33-45%
serum ferritin: 80-160
Periodically assess iron
status as part of routine
health assessment.
Consider assessment for
impending iron deficiency.
Consider periodic blood
donation and low-iron diet
to maintain healthy iron
status.
No treatment is mandatory.
Periodically assess iron status
as part of routine health
assessment. Consider low-iron
diet and regular blood donation
to reduce risk of cancer and
myocardial infarction.
Repeat tests with fasting
morning specimen. Consider
other causes of elevated
transferrin saturation or
elevated serum ferritin.*
Second assessment suggests
"healthy iron status" or
"moderate iron overload":
Average results and/or
reassess within 1 month, or
periodically assess iron status
as part of routine health
assessment.
PROBABLE SEVERE IRON
OVERLOAD
Ferritin >200 in women, or
Ferritin >300 in men.
Confirm with diagnostic
phlebotomy, or liver biopsy, or
MRI.
*Factors that alter iron assessment tests:
False elevations of transferrin saturation: cancer,
liver disease, inflammation, infection, excess alcohol
consumption, non-fasting specimens.
False elevations of ferritin: inflammation, infection,
cancer, excess alcohol consumption, liver disease,
early pregnancy, hyperthyroidism, tissue necrosis,
hyperferremia-cataract syndrome and other rare
genetic/congenital syndromes.
Copyright  1999-2005
Dr. Alex Vasquez
OptimalHealthResearch.com
Refer as needed (usually
gastroenterologist,
hematologist, or internist) for
phlebotomy therapy and/or
deferoxamine chelation.
862) Vasquez A. Integrative Orthopedics: Concepts, Algorithms, and Therapeutics. The art of creating wellness while effectively managing acute and chronic musculoskeletal disorders. Natural Health Consulting
Corporation: www.OptimalHealthResearch.com 2004, Revised edition August 2004
863) Hollan S, Johansen KS. Adequate iron stores and the 'Nil nocere' principle. Haematologia (Budap). 1993;25(2):69-84
864) Green BT, Rockey DC. Gastrointestinal endoscopic evaluation of premenopausal women with iron deficiency anemia. J Clin Gastroenterol. 2004 Feb;38(2):104-9
57 of 58
Resources
The American Association of Naturopathic
Physicians
3201 New Mexico Avenue, NW Suite 350
Washington, DC 20016
Toll free: 1-866-538-2267
Local: 202-895-1392
Fax: 202-274-1992
Website: www.naturopathic.org
American Chiropractic Association
1701 Clarendon Blvd, Arlington, VA 22209
Phone 800/986-4636
Website: www.amerchiro.org
Worstpills.org
Public Citizen
1600 20th Street, North West
Washington, DC 20009
Website: www.WorstPills.org
58 of 58
About the Author: Alex Vasquez, B.S., D.C., N.D.
Dr. Alex Vasquez began his professional studies at Texas Chiropractic College and later graduated from Western States Chiropractic College with his
Bachelor of Science and Doctor of Chiropractic degrees. Following graduation and chiropractic licensure, Dr. Vasquez attended the Bastyr University to
complete his Doctor of Naturopathic Medicine degree. He maintained a private practice of chiropractic and naturopathic medicine in Seattle while serving
as Adjunct Professor of Orthopedics, Rheumatology, and Radiographic Interpretation before returning to Houston in 2001. He is a licensed naturopathic
physician with prescriptive authority in Washington and Oregon and is a licensed chiropractic doctor in Texas. Dr. Vasquez is the author of more than 20
scientific articles and a 486-page textbook, Integrative Orthopedics: The Art of Creating Wellness while Effectively Managing Acute and Chronic
Musculoskeletal Disorders. His plans for the future include pursuing an MD or DO degree and completing his upcoming textbooks in Rheumatology and
Oncology.
Publications and Presentations—an incomplete listing:
Vasquez A, Cannell J. Calcium and vitamin D in preventing fractures: data are not sufficient to show inefficacy.[letter] BMJ: British Medical
Journal 2005;331:108-9
Vasquez A. High-Dose Vitamin D - One of the Best Nutritional Supplements on the Market. Nutritional Wellness July, 2006
Vasquez A. Reducing pain and inflammation naturally - Part 4: Nutritional and Botanical Inhibition of NF-kappaB, the Major Intracellular
Amplifier of the Inflammatory Cascade. A Practical Clinical Strategy Exemplifying Anti-Inflammatory Nutrigenomics. Nutritional
Perspectives July 2005; 5-12
Vasquez A. Subphysiologic Doses of Vitamin D are Subtherapeutic: Comment on the Study by The Record Trial Group. TheLancet.com June
16, 2005
Vasquez A, Cannell J. Subphysiologic Doses of Vitamin D are Subtherapeutic: Comment on the Study by Porthouse and colleagues. [Rapid
response] http://bmj.bmjjournals.com/cgi/eletters/330/7498/1003#105711 BMJ: British Medical Journal 2005, May 4
Vasquez A. Reducing pain and inflammation naturally - Part 3: Improving overall health while safely and effectively treating musculoskeletal
pain. Nutritional Perspectives 2005; 28: 34-38, 40-42
Vasquez A. Healthcare for our bones: A practical nutritional approach to preventing osteoporosis. [Letter]. Journal of Manipulative and
Physiological Therapeutics 2005; 28: 213
Vasquez A. Reducing Pain and Inflammation Naturally. Part 2: New Insights into Fatty Acid Supplementation and Its Effect on Eicosanoid
Production and Genetic Expression. Nutritional Perspectives 2005; January: 5-16
Dave N. Muanza, Ph.D., Alex Vasquez, John Cannell, M.D., William P Grant, Ph.D. Isoflavones and Postmenopausal Women. JAMA:
Journal of the American Medical Association 2004; 292: 2337
Vasquez A. Vitamin D Supplementation in the Treatment of Musculoskeletal Pain. The Original Internist 2004; 11: 7-9
Vasquez A. Reducing Pain and Inflammation Naturally. Part 1: New Insights into Fatty Acid Biochemistry and the Influence of Diet.
Nutritional Perspectives 2004; October: 5, 7-10, 12, 14
Alex Vasquez, D.C., N.D., Gilbert Manso, M.D., John Cannell, M.D. The Clinical Importance of Vitamin D (Cholecalciferol): A Paradigm
Shift with Implications for All Healthcare Providers. Integrative Medicine: A Clinician's Journal 2004; 3: 44-54
Vasquez A, John Cannell, MD. Better Bones and Beyond: Vitamin D Plays Role in Inflammatory and Metabolic Disease. Holistic Primary
Care 2004; (Fall) 5: 3,6,7
Vasquez A. Integrative Orthopedics and Vitamin D: Testing, Administration, and New Relevance in the Treatment of Musculoskeletal Pain.
Townsend Letter for Doctors and Patients 2004; October, 75-77
Vasquez A, Gilbert Manso, M.D., John Cannell, M.D. The Clinical Importance of Vitamin D (Cholecalciferol): A Paradigm Shift with
Implications for All Healthcare Providers. Alternative Therapies in Health and Medicine 2004; 10: 28-37
John Cannell, MD and Vasquez A. Measuring Your Vitamin D Levels: Your Most Important Blood Test?
http://www.mercola.com/2004/jul/3/vitamin_d_levels.htm 2004, July 3
Vasquez A. Integrative Orthopedics: Concepts, Algorithms, and Therapeutics. The art of creating wellness while effectively managing
acute and chronic musculoskeletal disorders. Natural Health Consulting Corporation: www.OptimalHealthResearch.com 2004, Revised
edition August 2004.
Vasquez A. Alternative Treatments for Hepatitis. Hepatitis Magazine Conference in Houston, Texas November 9,2002
Vasquez A. Holistic and Natural Approaches to Helping People with Narcolepsy. Narcolepsy Network's Convention in Las Vegas, Nevada
2002, October 18-20
Vasquez A. Natural Approaches to Menopause. Impressions - A publication of The Women's Fund for Health Education and Research
2002 Fall, page 10
Vasquez A. “The Clinical Management of Hemochromatosis and Iron Overload in Naturopathic Practice.” 16th Annual National Convention
of the American Association of Naturopathic Physicians Tucson, Arizona 2001, August 22-25
Vasquez A. Gender inequality in health and healthcare. Wingspan 1999; April-June, 8-9
Vasquez A. Men’s Health: Valuing gender equality in health and healthcare. MEN Magazine 1997; August: 10-11, 19
Vasquez A. Men’s Health: Meditation for health of mind, body, and soul: the need for re-creation and the art of building a walled garden.
MEN Magazine 1997; July: 10-11
Vasquez A. Men’s Health: The five most common cancers in men: strategies for prevention. MEN Magazine 1997; June: 10-11,23
Vasquez A. Men’s Health: Iron in men: why men store this nutrient in their bodies and the harm that it does. MEN Magazine
http://www.vix.com/menmag/alexiron.htm 1997; January: 11, 21-23
Vasquez A. Musculoskeletal disorders and iron overload disease: comment on the American College of Rheumatology guidelines for the
initial evaluation of the adult patient with acute musculoskeletal symptoms. Arthritis & Rheumatism—Official Journal of the American
College of Rheumatology 1996; 39:1767-8
Vasquez A. Hereditary Hemochromatosis: It’s not just for Caucasians.Townsend Letter for Doctors and Patients 1996;July:88
Vasquez A. Zinc treatment for reduction of hyperplasia of prostate. Townsend Letter for Doctors and Patients 1996; January: 100
Vasquez A. Knowledge of hemochromatosis is prerequisite to its diagnosis and treatment. Townsend Letter for Doctors and Patients 1995;
December: 96-8
Vasquez A. Iron in Men: Why men store this nutrient in their bodies and the harm that it does. Mentor 1995; Fall: 24-25
Vasquez A. A brief review of two potential adverse effects of zinc supplementation: cognitive deterioration in patients with Alzheimer's
disease, and copper deficiency. Nutritional Perspectives 1995; 18: 11, 19
Vasquez A.High body iron stores: causes, effects, diagnosis, and treatment. Nutritional Perspectives 1994;17:13,15-7,19,21,28
Vasquez A. Hemochromatosis and iron. Townsend Letter for Doctors 1994; August/September: 914-6
59 of 58
The following section describes some of the
nutritional and botanical products
from Biotics Research Corporation (BioticsResearch.com)
that might be used for clinical implementation
of the concepts described in this paper.
The new high-potency
multivitamin/multimineral from Biotics
The most potent
broad-spectrum
multivitamin and
multimineral
supplement
on the professional
market.
Includes Green Tea,
Quercetin, and
Bioflavonoids.
Piperine—from black
peper—enhances
nutrient absorption.
Dose: 3 capsules twice per day
Vitamin A (palmitate)
Mixed carotenoids
Vitamin E: tocopherol succinate
with mixed tocopherols
Vitamin D3 (cholecalciferol)
Vitamin C
Vitamin K1
Thiamin (B1) active cocarboxylase
Riboflavin (B2)
Riboflavin-5-phosphate (B2)
Vitamin B3: Niacinamide
Inositol hexaniacinate (niacin)
Pantothenic Acid
Vitamin B6 (pyridoxine HCL)
Vitamin B6 (active form P5P)
Folic Acid
B-12: Hydroxocobalamin
Biotin
Calcium (citrate)
Magnesium (citrate/ oxide)
Zinc (citrate)
Selenomethionine
Sodium selenite
Copper (citrate)
Manganese (citrate)
Molybdenum (glycinate)
Chromium picolinate
Iodine (potassium iodide)
Boron (gluconate)
Vanadium (aspartate)
Green tea extract
Quercetin
Citrus Bioflavonoids
Piperine
serving
2,500 IU
5,000 IU
(highest RDA) %
150%
1333%
400 IU
2,000 IU
500 mg
1000 mcg
50 mg
50 mg
100 mg
50 mg
200 mg
25 mg
25 mg
1,000 mcg
1,000 mcg
800 mcg
400 mg
200 mg
20 mg
200 mcg
(600 IU) 333%
(120mg) 416%
(120mcg) 833%
(1.4mg) 3571%
(1.6 mg) 3125%
(18mg) 883%
(7mg) 2850%
(2mg) 2,500%
(600mcg) 166%
(2.8mcg) 35,714%
(30 mcg) 2,666%
(1000 mg) 40%
(400mg) 50%
(12mg) 166%
(70) 285%
1.3 mg
5 mg
100 mcg
200 mcg
200 mcg
1.5 mg
25 mcg
25 mg
50 mg
20 mg
1 mg
1.3mg) 100%
(2.6mg) 192%
(50mcg) 200%
(45mcg) 444%
100%
-
No fillers, no colors, no allergens, no sugar, no junk
3 capsules 2 times per day provides the most potent multivitamin and multimineral on the
Professional healthcare market. It is as simple as that—this is an excellent multivitamin
supplement: potent, balanced, and with bioflavonoids. Includes piperine for increased
nutrient absorption.
Notes from Dr. Vasquez
http://www.OptimalHealthResearch.com/monograph05
Page 2
CHONDROSAMINE PLUS
CHONDROSAMINE-S
Joint cartilage is dynamic, living tissue that requires a constant
supply of many nutrients to maintain structure and function and to
resist degeneration from traumatic injury and from normal "wear and
tear" which occurs with everyday activities.
CHONDROSAMINE PLUS:
Capsules per bottle: 90
Product code: # 7815
CHONDROSAMINE-S:
Three (3) capsules supply:
• Vitamin C (as ascorbic acid) 180 mg
• Niacin (as niacinamide) 50 mg
• Pantothenic Acid (as calcium pantothenate) 45 mg
• Folic Acid 200 mcg
• Vitamin B12 (as cobalamin) 3 mcg
• Manganese (as manganese gluconate) 6 mg
• Purified chondroitin sulfate (bovine) 500 mg
• MSM (methylsulfonylmethane) 100 mg
• Saccharum Officinarum extract (shoots) 25 mg
• Superoxide Dismutase (vegetable culture) 20 mcg
• Catalase (from vegetable culture) 20 mcg
• CHONDROSAMINE PLUS provides Glucosamine (1000 mg
elemental) derived from glucosamine HCL
• CHONDROSAMINE-S provides Glucosamine (600 mg
elemental) derived from glucosamine sulfate
3 capsules 2 times per day of Chondrosamine Plus or Chondrosamine-S provides proven doses
of chondroprotective nutrients and is an excellent treatment for osteoarthritis.865,866,867,868
3 capsules once per day is sufficient for “maintenance” once acute symptoms of osteoarthritis
have subsided.
Research also suggests that purified chondroitin sulfate can protect against cardiovascular
disease and myocardial infarction. 869,870,871,872
No drug interactions are known.
Allergy to chondroitin/glucosamine has been reported once or twice in the research.
866) van Blitterswijk WJ, ... Glucosamine and chondroitin sulfate supplementation to treat symptomatic disc degeneration: biochemical rationale and case report. BMC Complement Altern Med. 2003;3(1):2
867) Morreale P, …. Comparison of the antiinflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis. J Rheumatol. 1996;23(8):1385-91
868) Mazieres B, Combe B, Phan Van A, Tondut J, Grynfeltt M. Chondroitin sulfate in osteoarthritis of the knee: a prospective, double blind, placebo controlled multicenter clinical study. J Rheumatol. 2001;28(1):173-81
871) Morrison LM, Bajwa GS. Absence of naturally occurring coronary atherosclerosis in squirrel monkeys (Saimiri sciurea) treated with chondroitin sulfate A. Experientia. 1972;28(12):1410-1
Page 3
Intenzyme Forte
Proteolytic enzymes are known to break-down proteins into amino
acids. Therefore, proteolytic enzymes can be used to support the
body's digestion of protein-containing foods.
Proteolytic enzymes have also been shown to facilitate tissue healing
after injury by breaking-down products of inflammation.
Tablets per bottle: 50
Product code: 1207
Product code: 1201
Product code: 1202
Each tablet supplies:
• Pancreatin 4X (from porcine) 100 mg
• Bromelain 50 mg
• Papain 50 mg
• Lipase 10 mg
• Amylase 10 mg
• Trypsin & Alpha Chymotrypsin (from porcine) 100 mg
• Superoxide Dismutase (from vegetable culture) 10 mcg
• Catalase (from vegetable culture) 10 mcg
Orally administered proteolytic enzymes are well absorbed from the gastrointestinal tract
into the systemic circulation.873,874 The anti-tumor, anti-metastatic, anti-infectious,
anti-inflammatory , analgesic, and anti-edematous actions result from the dose-dependent
(about 8 tablets 3 times per day) stimulation of reactive oxygen species production and
anti-cancer cytotoxicity in human neutrophils875, a pro-differentiative effect876, reduction in
PG-E2 production877, reduction in substance P production878, modulation of adhesion molecules
and cytokine levels879, fibrinolytic effects and a anti-thrombotic effect mediated at least in
part by a reduction in 2-series thromboxanes.880
8 tablets 3 times per day between meals is reasonable for clinical use in adults. Lower doses
(such as 2 tablets 2-3 times per day) are also effective, especially for treating benign
conditions like osteoarthritis or bursitis.
873) Gotze H, Rothman SS. Enteropancreatic circulation of digestive enzymes as a conservative mechanism. Nature 1975; 257(5527): 607-609
874) Liebow C, Rothman SS. Enteropancreatic Circulation of Digestive Enzymes. Science 1975; 189(4201): 472-474
876) Maurer HR, Hozumi M, Honma Y, Okabe-Kado J. Bromelain induces the differentiation of leukemic cells in vitro: an explanation for its cytostatic effects? Planta Med. 1988 Oct;54(5):377-81
880) Vellini M, Desideri D, Milanese A, Omini C, Daffonchio L, Hernandez A, Brunelli G. Possible involvement of eicosanoids in the pharmacological action of bromelain. Arzneimittelforschung. 1986;36(1):110-2
Page 4
Bio-D-Mulsion and Bio-D-Mulsion Forte
Vitamin D has a well-established role in calcium homeostasis and the
maintenance of bone health. Biotics’ Bio-D-Mulsion has excellent absorption
due to the unique emulsification process. Previous research with
emulsification showed that absorption of CoQ-10 was greatly increased by
emulsification, resulting in higher serum levels and improved costeffectiveness. 881,882,883,884
Recent articles indicate that the prevalence of vitamin D deficiency is much
higher than previously recognized (more than 90% in patients with chronic
pain, according to a recent study published by the Mayo Clinic), and that
vitamin D supplementation is much safer than previously recognized (up to
4,000 IU rather than 400 IU for adults). Recent articles have also suggested
that vitamin D may have a role in the prevention and treatment of many
chronic diseases. We are clearly on the verge of a paradigm shift with regard
to our understanding and clinical use of vitamin D.885
Bio-D-Mulsion
Servings per bottle: 750
Bio-D-Mulsion: Each drop supplies 400 IU of vitamin D in the form of
cholecalciferol.
Bio-D-Mulsion Forte
Servings per bottle: 750
Bio-D-Mulsion Forte: Each drop supplies 2,000 IU of vitamin D in the form
of cholecalciferol
Dr Vasquez generally recommends 800-1,200 IU of vitamin D per day for infants based on
research showing that this is safe and results in a dramatic reduction in the incidence of
type-1 diabetes.886 The emulsified drop/liquid form of Bio-D-Mulsion is perfect for
infants and children, who commonly have problems with pills and capsules.
The dose for children is 2,000 IU per day, while the requirement for adults is approximately
4,000 IU per day.887 Nutritional interventions for treatment and preventive
healthcare should be supervised by clinicians trained in nutrition. Specifically, serum calcium
should be monitored periodically.888 These high/physiologic doses of vitamin D must be used
cautiously—if at all—in patients taking thiazide diuretics and those with granulomatous diseases
such as Crohn’s disease, tuberculosis, sarcoidosis, lymphoma and other types of cancer. It is
absolutely imperative that these patients be monitored closely with measurement of serum
calcium every 2-4 weeks.
881) Bucci LR, Pillors M, Medlin R, Klenda B, Robol H, Stiles JC, Sparks WS. Enhanced blood levels of coenzyme Q-10 from an emulsified oral form. In Faruqui SR and Ansari MS (editors). Second Symposium on Nutrition and
Chiropractic Proceedings. April 15-16, 1989 in Davenport, Iowa
882) Bucci LR, Pillors …. Enhanced uptake in humans of coenzyme Q10 from an emulsified form. Third International Congress of Biomedical Gerontology; Acapulco, Mexico: June 1989
883) Joint Meeting of the American Institute of Nutrition, American Society for Clinical Nutrition, Canadian Society of Nutritional Sciences. University of California Davis. July 20-24, 1986
884) Bucci LR, Sparks WS. Comparison of vitamin A absorption from commercial oil emulsified and micellized products. Am J Clin Nutr 1986; 116(6): 27
885) Vasquez A, Gilbert Manso, M.D., John Cannell, M.D. The Clinical Importance of Vitamin D (Cholecalciferol): A Paradigm Shift with Implications for All Healthcare Providers. Alternative Therapies in Health and Medicine
2004; 10: 28-37
886) Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001;358(9292):1500-3
887) Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003;77:204-10
888) Vasquez A, Gilbert Manso, M.D., John Cannell, M.D. The Clinical Importance of Vitamin D (Cholecalciferol): A Paradigm Shift with Implications for All Healthcare Providers. Alternative Therapies in Health and Medicine
2004; 10: 28-37
Page 5
Cautions
Dose reduction is appropriate when patients experience significant sun exposure, since sun exposure can easily
induce production of 10,000 IU.
Serum testing of 25-OH-vitamin D is advisable during treatment, and levels tend to plateau after about 8 weeks of
supplementation.
Patients should be tested for hypercalcemia (and/or screened for hyperparathyroidism) before the initiation of
treatment and monitored for hypercalcemia and/or hypervitaminosis D during treatment.
Causes of hypercalcemia include: hyperparathyroidism, cancer, sarcoidosis, adrenal insufficiency, and thyroid
disease.
Drug interactions
Several drugs increase the risk for and severity of vitamin D deficiency.
A few drugs may cause adverse effects when administered with vitamin D.
Patients with gout have been shown to have reduced levels of the active form of vitamin D 1,25dihydroxycholecalciferol.
The use of anti-convulsant drugs is associated with an increased risk for vitamin D deficiency and
osteomalacia.
Allopurinol
Anticonvulsants
Bile Acid
Sequestrants
Bile acid sequestrants impair fat absorption and thus impair absorption of fat-soluble vitamins.
Cimetidine
Cimetidine might reduce the formation of active 1,25- dihydroxycholecalciferol.
Colestipol
Bile acid sequestrants impair fat absorption and thus impair absorption of fat-soluble vitamins.
Oral
Corticosteroids
Estradiol,
Estrogens
Gabapentin
Corticosteroids increase the risk of osteoporosis, reduce calcium absorption in the intestine, and
appear to inhibit the formation of 1,25- dihydroxycholecalciferol.
Estrogen supplementation appears to make vitamin D deficiency less common.
Heparin
Hydroxychloroquine
Indapamide
Isoniazid
Thiazide diuretics enhance the actions of vitamin D and therefore patients taking vitamin D
should do so only under the supervision of a health practitioner who monitors clinical status and
laboratory tests—serum calcium and 25-OH-vitamin D.
Drug may interfere with action of vitamin.
Mineral Oil
Interferes with absorption
Neomycin
Drug reduces absorption
Orlistat
Drug reduces absorption
Phenobarbital
Thiazide
Diuretics (See
text)
osteomalacia.
Thiazide diuretics enhance the actions of vitamin D and therefore patients taking vitamin D
should do so only under the supervision of a health practitioner who monitors clinical status and
laboratory tests—serum calcium and 25-OH-vitamin D.
Valproic Acid
osteomalacia.
Verapamil
Vitamin D supplementation may interfere with the action of verapamil.
Warfarin
Only one case report has been published suggesting that vitamin D may potentiate
warfarin/coumadin; this may increase the risk for bleeding. Patients taking coumadin/Warfarin
along with changes in vitamin D intake should be monitored clinically and with lab tests to
ensure that INR is stable. Frequent monitoring of anticoagulation is required to maintain the
International Normalized Ratio (INR) between 2.0 to 3.5 for most clinical indications.
osteomalacia.
Heparin interferes with vitamin D function and increases the risk for osteomalacia and
osteoporosis.
Clinical and laboratory monitoring is necessary, especially among patients with sarcoidosis, who
have an increased prevalence of hypercalcemia.
Page 6
Bio-Multi Plus
Multivitamin and multimineral support available with iron,
without iron, and without iron and copper
BioMultiPlus
Product code: 1161
Iron- and Copper-free
BioMultiPlus
Product code: 1163
Product code: 1162
Iron-free BioMultiPlus
Product code: 1168
Product code: 1169
Product code: 1164
Contents: Three (3) tablets supply:
• Vitamin A (as palmitate and natural mixed
carotenoids) 7,500 IU
• Vitamin C (as mixed ascorbates) 100 mg
• Vitamin D (as cholecalciferol) 400 IU
• Vitamin E (as d-alpha tocopheryl acetate) 30 IU
• Vitamin K (as phytonadione) 35 mcg
• Thiamin (B1) (as mononitrate) 10 mg
• Riboflavin (B2) 10 mg
• Niacin (as niacinamide) 20 mg
• Vitamin B6 (as pyridoxine HCI) 10 mg
• Folic Acid 400 mcg
• Vitamin B12 (as resin-bound cobalamin) 10 mcg
• Biotin 300 mcg
• Pantothenic Acid (as calcium pantothenate) 25 mg
• Calcium (as citrate) 200 mg
• Iron (as gluconate) 18 mg (optional)
• Iodine (from kelp) 150 mcg
• Magnesium (as aspartate, gluconate, glycinate)
100 mg
• Zinc (as gluconate, aspartate) 15 mg
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Selenium (from vegetable cultures) 50 mcg
Copper (as gluconate, aspartate) 2 mg
Manganese (as gluconate, aspartate) 2 mg
Chromium (from vegetable culture) 50 mcg
Molybdenum (from vegetable culture) 10 mcg
Potassium (as gluconate, chloride, aspartate) 99
mg
Boron (as calcium borogluconate) 1 mg
Lithium (from vegetable culture) 20 mcg
Rubidium (from vegetable culture) 25 mcg
Vanadium (from vegetable culture) 5 mcg
Citrus Bioflavonoids 10 mcg
L-Lysine (as L-Lysine HCI) 30 mg
L-Methionine 30 mg
N-Acetyl-L-Cysteine 10 mg
Coenzyme Q10 1 mg
Superoxide Dismutase (from vegetable culture) 20
mcg
Catalase (from vegetable culture) 20 mcg
An excellent general purpose multivitamin and multimineral supplement: 3 tablets twice per
day with meals is customary.
Most adults in America (and other industrialized nations)
do not consume sufficient amounts of vitamins and minerals from diet alone and therefore
nutritional supplements are necessary. 889
889) Fletcher RH, Fairfield KM. Vitamins for chronic disease prevention in adults: clinical applications. JAMA. 2002;287:3127-9
Page 7
Optimal EFAs
A new combination fatty acid product comprised of the finest fish oil, flaxseed oil, and borage seed oil, which
provides ALA, EPA, DHA, GLA, and oleic acid.
Product Information: liquid
Servings per bottle: 36 teaspoons
Product Information: capsules
Servings per bottle: 120 capsules, 2 capsules per
serving
Product Information: liquid, PER TEASPOON
Product Information: liquid, per TWO CAPSULES
* ALA: 420 mg
* EPA: 238 mg
* DHA: 158 mg
* GLA: 168 mg
* Oleic acid: 306 mg
* ALA: 280 mg
* EPA: 159 mg
* DHA: 105 mg
* GLA: 112 mg
* Oleic acid: 204 mg
For prevention, 3-6 caps per day is reasonable. When using fatty acids for therapeutic and
interventional purposes, higher doses are commonly required and therefore the liquid form
(which can be mixed in juice or a smoothie) is preferred for both palatability and practicality.
One to two tablespoons per day is reasonable for treatment and preventive medicine, and
doses up to 8 TBS per day would be within the safe parameters delineated in peerreviewed research. High doses such as 8 TBS per day must be supervised by a knowledgeable
clinician and must be appropriate for the clinical situation.
Page 8
KappArest
NF-kappaB is a molecule inside each cell that becomes activated to
stimulate the production of inflammatory chemicals that promote
pain, inflammation, and variety of diseases such as cancer, arthritis,
heart disease, and autoimmune diseases such as lupus and
rheumatoid arthritis.
Modulation of NF-kappaB is emerging as a primary clinical goal in
the management of inflammatory disorders.890
Serving Size: 3 Capsules
Servings Per Container: 60
Contains:
Code #: 7855
180 Capsules
® BioPerine is a registered trademark
of Sabinsa Corporation.
Other ingredients: Cellulose, gelatin,
water and glycerin.
RECOMMENDATION: Three (3)
capsules taken two (2) times daily as a
dietary supplement or as otherwise
directed by a health care professional.
Amount Per Serving
Proprietary Blend 1,150 mg
Curcumonoids (turmeric extract)(rhizome)*
Boswellia serrata extract (gum)*
Propolis*
Green tea extract (camellia sinensis)(leaves)*
Ginger extract (rhizome)*
Rosemary extract (leaves)*
Celery seed extract*
Resveratrol (polygonium cuspidatum extract)(root)*
Alpha Lipoic acid*
Saccharium officinarium extract (shoots)*
Phytolens™ (lens esculenta extract)(husks)*
BioPerine® (from piper nigrum)*
*Daily Values not established
4 capsules 2-3 times per day is the customary dose. Can be taken with food if necessary.
Piperine is required for the absorption of curcumin/turmeric in humans.
Without piperine, nearly all of the health benefits of curcumin/turmeric are not available to
humans due to low absorption of curcumin/turmeric.891 Piperine also increases the absorption
of other nutrients and medications. Therefore, products with piperine must be used judiciously
in patients taking pharmaceutical medications, especially those detoxified via CYP3A4, CYP2D6,
and CYP1A2 such theophylline and propranolol.
890) D'Acquisto F, May MJ, Ghosh S. Inhibition of Nuclear Factor Kappa B (NF-B): An Emerging Theme in Anti-Inflammatory Therapies. Mol Interv. 2002 Feb;2(1):22-35
891) Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998;64(4):353-6
Page 9
KappArest
ingredient
Quote/example from the research literature
Turmeric-curcumin
(requires piperine
for absorption)
•
“Curcumin, EGCG and resveratrol have been shown to suppress activation of NFkappa B.”892
Lipoic acid
•
“ALA reduced the TNF-alpha-stimulated ICAM-1 expression in a dose-dependent
manner, to levels observed in unstimulated cells. Alpha-lipoic acid also reduced
NF-kappaB activity in these cells in a dose-dependent manner.”893
Green tea extract
•
“In conclusion, EGCG is an effective inhibitor of IKK activity. This may explain,
at least in part, some of the reported anti-inflammatory and anticancer effects of
green tea.”894
Rosemary
•
“These results suggest that carnosol suppresses the NO production and iNOS gene
expression by inhibiting NF-kappaB activation, and provide possible mechanisms
for its anti-inflammatory and chemopreventive action.”895
Propolis
•
“Caffeic acid phenethyl ester (CAPE) is an anti-inflammatory component of
propolis (honeybee resin). CAPE is reportedly a specific inhibitor of nuclear
factor-kappaB (NF-kappaB).”896
Resveratrol
•
“Resveratrol's anticarcinogenic, anti-inflammatory, and growth-modulatory
effects may thus be partially ascribed to the inhibition of activation of NF-kappaB
and AP-1 and the associated kinases.”897
•
“Both resveratrol and quercetin inhibited NF-kappaB-, AP-1- and CREBdependent transcription to a greater extent than the glucocorticosteroid,
dexamethasone.”898
Phytolens (Biotics
exclusive; patented)
•
Phytolens is Biotics’ patented polyphenolic extract from lentils. Published
experimental research has documented the in vivo antioxidant activity against
superoxide other free radicals.899
Celery seed extract
•
Contains antiinflammatory components
Ginger
•
Contains antiinflammatory components with long history of empiric and clinical
use
892) Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, Lee SS. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through
suppression of NF-kappa B activation. Mutat Res. 2001 Sep 1;480-481:243-68
893) Lee HA, Hughes DA.Alpha-lipoic acid modulates NF-kappaB activity in human monocytic cells by direct interaction with DNA. Exp Gerontol. 2002 Jan-Mar;37(2-3):401-10
894) Yang F, Oz HS, Barve S, de Villiers WJ, McClain CJ, Varilek GW. The green tea polyphenol (-)-epigallocatechin-3-gallate blocks nuclear factor-kappa B activation by inhibiting I kappa B kinase activity in the intestinal
epithelial cell line IEC-6. Mol Pharmacol. 2001 Sep;60(3):528-33
895) Lo AH, Liang YC, Lin-Shiau SY, Ho CT, Lin JK. Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthase through down-regulating nuclear factor-kappaB in mouse macrophages. Carcinogenesis.
2002 Jun;23(6):983-91
896) Fitzpatrick LR, Wang J, Le T. Caffeic acid phenethyl ester, an inhibitor of nuclear factor-kappaB, attenuates bacterial peptidoglycan polysaccharide-induced colitis in rats. J Pharmacol Exp Ther. 2001 Dec;299(3):915-20
897) Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and
lipid peroxidation. J Immunol. 2000 Jun 15;164(12):6509-19
898) Donnelly LE, Newton R, Kennedy GE, Fenwick PS, Leung RH, Ito K, Russell RE, Barnes PJ.Anti-inflammatory Effects of Resveratrol in Lung Epithelial Cells: Molecular Mechanisms. Am J Physiol Lung Cell Mol Physiol.
2004 Jun 4 [Epub ahead of print]
899) Sandoval M, Ronzio RA, Muanza DN, Clark DA, Miller MJ. Peroxynitrite-induced apoptosis in epithelial (T84) and macrophage (RAW 264.7) cell lines: effect of legume-derived polyphenols (phytolens). Nitric Oxide.
1997;1(6):476-83
Page 10
Bio-Allay
Biotics Research Corporation recently produced a new product
combing well-researched herbs known to support normal neurologic
function and inflammatory balance.
Servings per bottle: 120 capsules
Product Information:
Contents per capsule: Proprietary blend containing 950 mg
1. White Willow (Salix Alba) bark900
2. Devil's Claw extract (Harpagophytum procumbens)901,902
3. Boswellia (Boswellia serrata)903
These three herbs were specifically selected based on peer-reviewed research documenting
their effectiveness in the treatment of low-back pain and osteoarthritis.904
2-4 capsules 2 times per day is a reasonable dose. Do not use this product in patients with
a history of allergy to aspirin or salycilates. There seems to be no need to worry about
other aspirin-related adverse effects since these are generally the result of acetylation
which occurs only with acetylsalicylate and not with the salicylic acid derivatives resultant
from willow bark supplementation.905
900) Chrubasik S, Eisenberg E, Balan E, Weinberger T, Luzzati R, Conradt C. Treatment of low-back pain exacerbations with willow bark extract: a randomized double-blind study. Am J Med. 2000;109:9-14
901) Chantre P, Cappelaere A, Leblan D, Guedon D, Vandermander J, Fournie B. Efficacy and tolerance of Harpagophytum procumbens versus diacerhein in treatment of osteoarthritis. Phytomedicine 2000;7(3):177-83
902) Leblan D, Chantre P, Fournie B. Harpagophytum procumbens in the treatment of knee and hip osteoarthritis. Four-month results of a prospective, multicenter, double-blind trial versus diacerhein. Joint Bone Spine
2000;67(5):462-7
903) Kimmatkar N, Thawani V, Hingorani L, Khiyani R. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee--a randomized double blind placebo controlled trial. Phytomedicine. 2003;10(1):3-7
904) Vasquez A. Reducing pain and inflammation naturally - Part 3: Improving overall health while safely and effectively treating musculoskeletal pain. Nutritional Perspectives 2005; 28: 34-38, 40-42 Available at
http://www.optimalhealthresearch.com/reprints
905) Vasquez A, Muanza DN. Evaluation of Presence of Aspirin-Related Warnings with Willow Bark: Comment on the Article by Clauson et al. Ann Pharmacotherapy 2005 Oct;39(10):1763. Epub 2005 Aug 30
Page 11

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