Biomedical - International Academy of Homotoxicology

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J o urnal o f
Biomedical
Therapy
Volume 6, Number 1 ) 2012
Integrating Homeopathy
and Conventional Medicine
Gastrointestinal
Disorders
• Irritable Bowel Syndrome – A Review Article
• Bioregulatory Treatment of Hepatitis C
© iStockphoto.com/Ostill
Content
I n Fo c u s
Irritable Bowel Syndrome – A Review Article . . . . . . . . . . . . . .4
Around the Globe
European Congress of Integrative Medicine . . . . . . . . . . . . . .11
W h a t E l s e i s N e w . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
© iStockphoto.com/Rosemarie
Gearhart Stafford
© iStockphoto.com/Dawna
From the Practice
Bioregulatory Treatment of Hepatitis C . . . . . . . . . . . . . . . . . . 14
Re f r e s h Yo u r H o m o t ox i c o l o g y
Gut Feelings Revisited: Evidence
for a Brain-Gut Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18
Meet the Expert
Dr. Sergio Vaisman Weinstein . . . . . . . . . . . . . . . . . . . . . . . . . 23
Practical Protocols
Bioregulatory Management of Peptic Ulcer Disease . . . . . . .24
E x p a n d y o u r Re s e a r c h K n o wl e d g e
Noninterventional Studies: An Overview . . . . . . . . . . . . . . . .27
Re s e a r c h H i g h l i g h t s
A Multicomponent Medication
Triggers Multiple Beneficial Effects
Related to Cognition and Neuronal Function . . . . . . . . . . . . 30
Cover © Naeblys/Fotolia.com
)2
Published by/Verlegt durch: International Academy for Homotoxicology GmbH, Bahnackerstraße 16,
76532 Baden-Baden, Germany, www.iah-online.com, e-mail: [email protected]
Editor in Chief/verantwortlicher Redakteur: Dr. Alta A. Smit
Editor: Dr. David W. Lescheid
Managing Editor: Silvia Bartsch
Print/Druck: Dinner Druck GmbH, Schlehenweg 6, 77963 Schwanau, Germany
© 2012 International Academy for Homotoxicology GmbH, Baden-Baden, Germany
© iStockphoto.com/Milena Lachowicz
)
)
The Importance of the Gut
Dr. Alta A. Smit
T
he importance of the gut in
health and disease is currently
attracting much attention in medicine. Gastroenterology is one of the
forefronts at which integrative medicine plays a prominent role.
Not only gastrointestinal, but also
systemic diseases are closely related
to the function of the epithelial barrier, the gut microbiome (ie, the collection of all the genes of the commensal microbiota and the corresponding
proteins and metabolites), and the
brain-gut axis.1
A new trend in medicine is the socalled network disease, and systems
biology, in which the recognition of
the complex interactions between different molecular, tissue, and organ
networks is in the foreground.2,3
Recently, it has been elucidated that
normal development of neural networks, immune networks, and also
neuroendocrine and metabolic networks depends on the integrity of the
microbiome and the brain-gut axis.4,5
Therefore, we have devoted considerable space to the introduction of this
topic, from the focus article on irritable bowel syndrome, in which the
disturbance of the brain-gut axis
plays a major role, to a more detailed
introduction of the various levels of
connectivity between the brain and
the gut by Dr. David W. Lescheid.
Irritable bowel syndrome is a perfect
example of multiple networks playing a role and interacting with each
other to produce a complex pathophysiological picture. Thus, the conventional medical treatment of this
syndrome is difficult because it
cannot be reduced to a single-product, single-target approach. Bioregulating therapies, through their multitarget, multicomponent approach,
offer a viable solution for intervention
in these kinds of syndromes. The importance of this topic is further to be
seen in the section “What Else Is
New?”
The emergence of congresses devoted
to integrative medicine is a sign of
the importance of this topic for health
care practitioners; however, as can be
seen from the article by Dr. Kerstin
Röska and Dr. Bernd Seilheimer, the
topic also met with a lot of interest in
a purely conventional scientific congress.
Dr. Alta A. Smit
Bioregulating medicines can have a
powerful adjuvant effect on seemingly difficult-to-treat diseases. The case
report by Dr. Arturo O’Byrne is evidence of this, in which biological
therapies have been used to successfully treat a refractory case of hepatitis C.
We continue our series on research
methods by Dr. Robbert van Haselen,
and our expert in this issue is Dr. Sergio Vaisman, who has had a longstanding impact on the development
of homotoxicology in Chile and Latin America.
Journal of Biomedical Therapy 2012 ) Vol. 6, No. 1
References
1. Grenham S, Clarke G, Cryan JF, Dinan
TG. Brain-gut-microbe communication in
health and disease. Front Physiol. 2011;2:94.
doi:10.3389/fphys.2011.00094.
2. Barabási AL, Gulbahce N, Loscalzo J.
Network medicine: a network-based approach to human disease. Nat Rev Genet.
2011;12(1):56-68. doi:10.1038/nrg2918.
3. del Sol A, Balling R, Hood L, Galas D.
Diseases as network perturbations. Curr
Opin Biotechnol.
2010;21(4):566-571.
doi:10.1016/j.copbio.2010.07.010.
4. Manco M. Gut microbiota and developmental programming of the brain: from
evidence in behavioral endophenotypes to
novel perspective in obesity. Front Cell Infect Microbiol. 2012;2:109. doi:10.3389/
fcimb.2012.00109.
5. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota
on brain and behaviour. Nat Rev Neurosci. 2012;13(10):701-712. doi:10.1038/
nrn3346.
)3
) I n Fo c u s
Irritable Bowel Syndrome –
A Review Article
By David W. Lescheid,
PhD, ND
Introduction
functional diarrhea, and functional
abdominal pain syndrome.4 It is part
of a cluster of syndromes termed central sensitivity disorders or functional somatic disorders that include fibromyalgia, chronic fatigue syndrome,
temporomandibular disorder, restless
legs syndrome,7,8 and interstitial cystitis/painful bladder syndrome.9 Irritable bowel syndrome coexists with
other functional gastrointestinal tract
(GIT) disorders, especially gastroesophageal reflux disease10 and dyspepsia.11 There also is close association between celiac disease and IBS,12
as well as increased risk of experiencing migraines.13
Irritable bowel syndrome (IBS) is a
functional bowel disorder characterized by common symptoms of abdominal pain or cramping (with variability in location and intensity),
abdominal distension and/or sensation of bloating, excessive flatulence,
diarrhea or constipation (or alteration
between the 2 states), and mucous in
stools.1,2 These symptoms can be relatively constant but most often relapsing and remitting, according to the
presence or absence of specific environmental triggers.1,3,4 Usually, the
disease remains chronic and recurring, with 40% of patients having the
diagnosis for 10 years or longer and
70% experiencing symptoms for 1 to
9 days each month.5 Symptoms that
are independently associated with
IBS include the following: lethargy
(relative risk [RR], 6.7), incomplete
evacuation (RR, 5.2), backache (RR,
2.0), early satiety (RR, 1.8), and increased frequency of micturition (RR,
1.8).6 Irritable bowel syndrome is not
a life-threatening condition but can
have a serious impact on a patient’s
daily activities and quality of life,1 including periodic bouts of pain, suffering, and direct medical expenses as
well as substantial potential social
and job-related consequences.2
)4
Irritable bowel syndrome is only one
of several functional bowel disorders,
including functional abdominal
bloating, functional constipation,
Epidemiology
Based on conservative estimates and
strict Rome-based diagnostic criteria,
7% to 10% of adults have IBS worldwide,2,14 but that number has been
estimated to be closer to 15% to 20%,
depending on different diagnostic
criteria and country-specific data.5
The prevalence of IBS is considerably
higher among the white US population than other ethnic groups, with
approximately 1500 cases per
100,000 in the white population,
300 cases per 100,000 in US Hispanics, and 170 cases per 100,000 in
African Americans. A clear explanation for those differences has not yet
been identified.2 This variability in
prevalence might reflect differences
in diagnostic patterns of health care
practitioners in various countries, cultural differences in seeking medical
care for this condition, or some as yet
undefined contributing factor. Furthermore, there are several different
relatively subjective criteria used to
diagnose IBS (as described later), and
this has been shown to affect prevalence, with the highest number using
the Manning criteria, followed by the
Rome I and then the Rome II criteria.5
In Westernized countries, IBS is 2
to 3 times more common in women
than in men. However, IBS is not
simply a disorder of women, especially in the Indian subcontinent, where
70% to 80% of the patients with IBS
are male.1 Women are more likely
to report abdominal pain and constipation-related symptoms, whereas men are more likely to report
diarrhea-related symptoms. The differences between sexes in IBS symptoms are modest; although female sex
hormones have been shown to in
fluence the severity of symptoms, this
contribution needs to be confirmed
in more clinical studies.15
Irritable bowel syndrome is usually a
disorder of young people, with half
of the patients experiencing symptom
onset before the age of 35 years, and
only 40% of patients aged 35 to 50
years when symptoms begin.2 More
than 75% of IBS cases occur in persons between the ages of 25 and 64
years.1,2 Children with recurrent ab-
) I n Fo c u s
Esophagus
Stomach
Liver
Duodenum
Pancreas
Transverse colon
Descending colon
Ascending colon
Cecum
Sigmoid colon
Appendix
Rectum
Human Digestive System
dominal pain are more likely to develop IBS during adolescence and
young adulthood,1 with 14% of high
school students and 6% of middle
school students reported to have
symptoms of the disease.1 Elderly
persons have been identified as an
underdiagnosed and overlooked population with IBS.16
Diagnosis
The diagnosis of IBS was previously
considered as a diagnosis of exclusion, but most current guidelines
amend this and acknowledge that it is
a distinct disease, albeit with a broad
differential diagnosis.2 There are no
consistent laboratory tests, imaging
studies, or biological markers to diagnose IBS; therefore, symptom-based
criteria, such as the Manning or Rome
III criteria (currently considered the
gold standard), are commonly used.
To diagnose IBS using the Rome III
criteria, patients must have “recurrent
abdominal pain or discomfort accompanied by at least two of three additional symptoms (pain relieved by
defecation, onset of pain associated
with a change in stool form, or onset
of pain associated with change in
stool frequency).”17 It should be noted that neither of these criteria have
been sufficiently validated in prospective studies; therefore, their diagnostic accuracy is unknown.17 Furthermore, it is probably more accurate to
consider IBS as a complex of concurrent symptoms, with each one separately having limited diagnostic value.18 A recent systematic review states
that “With none of the criteria showing sufficiently homogeneous and favourable results, organic disease cannot be accurately excluded by
symptom-based IBS criteria alone.”19
The relative subjectivity and variability of diagnostic criteria limit their
utility in clinical practice and restrict
the direct transferability between research studies.
An additional challenge of using
symptom-based criteria for diagnosis
is that the symptoms of IBS are
shared by numerous other organic
conditions; therefore, certain pathologies should be excluded, including
© Andrea Danti/Fotolia.com
Small intestine
inflammatory bowel disease, bile acid
diarrhea, small-intestinal bacterial
overgrowth, celiac disease, microscopic colitis, exocrine pancreatic insufficiency, and infectious colitis.17
The identification of a significant
psychosomatic component and comorbidity with various other conditions also add difficulty to the diagnosis.1,3,17
Four different bowel patterns are
commonly recognized in those with
IBS: persons with greater than 25%
of bowel movements with loose or
watery stools (diarrhea subtype or
IBS-D) or greater than 25% of bowel
movements with hard or lumpy stools
(constipation subtype or IBS-C), persons with mixed constipation and diarrhea (IBS-M), and persons who alternate between diarrhea and
constipation (IBS-A).1,3 Another subtype, termed unsubtyped IBS (IBS-U),
was recently identified in a multicenter study in China20 and in other
randomized controlled trials21 using
the Rome III criteria. The usefulness
of this distinct categorization has
been questioned because within 1
)5
) I n Fo c u s
year, 75% of patients change subtypes, and 29% switch between constipation- and diarrhea-predominant
IBS.22 A recent review suggests that
the reported variability in subtyping
would be more consistent if the period recommended for recording stool
frequency and consistency patterns
was extended to 2 weeks.21 Although
there have been some reports of a
predominance of specific subtypes of
IBS, a systematic review elucidated
that there is no consistent predominance of any one subtype and concluded that “IBS clinical subtypes distribution differs depending on the
population evaluated, the geographical location, and the criteria employed
to define IBS and bowel habit subtypes.”23
Pathophysiology
The pathogenic mechanisms contributing to IBS are still incompletely
known,24 although it is evident that
dysfunction in any part of the braingut axis (eg, alterations in the central
nervous system caused by psychological or other factors, abnormal gastrointestinal motility, or heightened visceral sensations) can contribute to its
development. It is well understood
that this condition is heterogeneous,
with an undoubtedly multifactorial
cause.25
)6
Several recent studies buttress the
view that IBS, at least in part, has an
organic component that can be readily and easily recognized.3 A commonly considered hypothesis is that
IBS is a 3-part complex of altered
GIT motility, visceral hyperalgesia,
and psychopathology.2,5 There are
distinct aberrations in the motility
of the small and large bowel and a
proposed generalized hyperresponsiveness within the smooth muscle
layer. This helps explain the often associated (50% of patients) symptoms
of increased urinary symptoms (eg,
frequency, urgency, and nocturia).1,2
There also have been more recent
reports that dysfunction in the endocannabinoid system could contribute
to the onset and persistence of symptoms associated with IBS,26 including
perturbations in motility, secretion,
and hypersensitivity.27 Hyperalgesia
within the GIT can be secondary to
hyperexcitability of neurons in the
dorsal horn in response to peripheral tissue irritation or to descending influences from the brain stem.
Multiple factors are proposed to alter
the function of neuroreceptors and
afferent spinal neurons, including
genetics, inflammation, mechanical
irritation of local nerves, dysfunction of motility, and psychological
influences.1,2 There is still no clear association between psychiatric distur
bances and pathogenesis of IBS, with
considerable debate on whether psychopathology incites development of
IBS or vice versa. In some studies, patients who seek medical care for IBS
symptoms have a higher incidence
of panic disorder, major depression,
anxiety disorder, and hypochondriasis. These psychological disturbances
are not commonly believed to cause
or initiate the symptoms of IBS but
are thought to influence the patient’s
perception of the symptoms and affect the clinical outcome.1,2 There is
also a higher prevalence of physical
and sexual abuse in patients with
IBS.1,2 It is evident that various interpersonal relationships, both positive
and negative, can have an impact on
the course of IBS.28 The importance
of the genetic contribution to IBS remains in dispute.2,29
There are several potential dietary
factors that are identified as contributing to the development of IBS in
susceptible people,30 including intolerances to certain foods,31,32 ingestion
of malabsorbed sugars (ie, sorbitol,
fructose, and lactose) and fructans,33,34
gluten sensitivity,18 and abnormal intake of certain types of dietary fats (in
particular, those rich in arachidonic
acid, a precursor to several proinflammatory eicosanoids).35 Immunoglobulin G antibodies to ingested food
may be playing a role in IBS, and
food elimination can be effective in
reducing its symptoms.2 Other lifestyle factors that are correlated with
the development of IBS include
smoking,36 alcohol abuse and/or dependency,37 and poor sleep quality.38
Excessive intake of caffeine and/or
legumes and inadequate daily intake
of water also might exacerbate symp-
) I n Fo c u s
• Reduces pain-induced stress
• Reduces stress-induced motility disorders
Balancing
the nervous system
Parasympathetic
nervous system
Sympathetic
nervous system
Relaxing
smooth muscles
• Reduces susceptibility to diarrhea and abdominal bloating
• Reduces mucus production
Restoring
bowel function
© iStockphoto.com/Clinton Johnston
• Reduces spasms and cramps
• Reduces spasm- and cramp-
related pain
Figure 1. Therapeutic Action of Spascupreel in the Treatment of Irritable Bowel Syndrome
toms in susceptible persons.2 All of
these environmental factors, and the
psychosocial factors previously discussed, could have a notable impact
on the course of IBS, possibly via
their ability to influence epigenetic
mechanisms.39
Recent studies have identified additional pathophysiological mechanisms. Dysregulation of the brain-gut
axis; GIT infection; low-grade infiltration and activation of mast cells
in the intestinal mucosa, with consequent release of bioactive substances;
and altered serotonin metabolism are
some emerging factors of IBS patho-
genesis. Modification of small-bowel
and colonic microflora (ie, so-called
intestinal dysbiosis) and altered gas
balance may be of relevance in some
subgroups of patients with IBS.24,25
The brain-gut axis is a bidirectional
pathway that links higher cortical
centers with visceral afferent sensation and intestinal motor function.
Regulation of these connections occurs via numerous neurotransmitters found in the brain and gut (eg,
cholecystokinin, vasoactive intestinal
peptide, substance P, and serotonin
[5-hydroxytryptamine]) that act at
different sites, with varied effects on
gastrointestinal motility, pain control,
emotional behavior, and immunity.
Studies have shown that IBS symptoms may be related to imbalance in
mucosal 5-hydroxytryptamine availability caused by defects in 5-hydroxytryptamine production, sero
tonin receptors, or transporters.2
The concept of microscopic inflammation, possibly at a subclinical lowgrade level,40 preceding the development of IBS25 is groundbreaking and
challenges the previous theories of
this syndrome having no demonstrable pathological alterations. Lowgrade mucosal inflammation, in particular involving abnormal activation
)7
) I n Fo c u s
)8
of mast cells, has been identified as a
contributing factor in the pathogenesis of IBS in a recent systematic review.41 The cause of this persistent
nonresolving inflammation might be
a breakdown in the integrity of the
epithelial barrier because recent evidence has demonstrated an increase
in colonic permeability, release of mediators from mucosal mast cells, and
allergic disposition in patients with
the disease.42 Both colonic inflammation and small-bowel inflammation
have been substantiated in a subset of
patients with IBS and in patients with
the onset of IBS after infectious enteritis, known as postinfectious IBS.
The risk of developing IBS increases
6-fold after GIT infection (10%-15%
of adult patients) and remains elevated for at least 2 to 3 years after infection. An exposure to pathogenic organisms (eg, Campylobacter, Shigella,
Salmonella, and Escherichia coli) may
disrupt intestinal barrier function, alter neuromuscular function, and trigger chronic inflammation, which sustain IBS symptoms.2,43 Factors that
increase the risk of developing
postinfectious IBS include severe and
prolonged infection, female sex,
younger age, antibiotic treatment for
this infection, and concomitant presence of anxiety.2,43 Further findings of
small-bowel bacterial overgrowth
and disrupted numbers, distribution,
and types of fecal microflora in patients with IBS have been heralded as
a unifying mechanism for the symp-
toms of bloating and distension common to this condition.24,44 The abnormal bacterial overgrowth is believed
to induce fermentation, leading to
production of excess gas, which has
led to effective treatments with probiotics and antibiotics.7 Individuals
who are carriers of the intestinal protozoan parasite, Blastocystis, also have
been recently shown to have an increased risk of developing IBS, especially if they have single-nucleotide
polymorphisms in the genes encoding interleukins 8 and 10.45
fects that negatively affect the lives of
those with IBS and lead to many patients seeking medical care or missing
work/school or social activities as a
result of this iatrogenesis.47 Overall,
there is limited evidence for the efficacy, safety, and tolerability of therapies currently available for the treatment of IBS.48 Most mainstream
medical therapies used to treat IBS
target only one symptom, despite a
European survey indicating that less
than 25% of patients have complete
relief of any one symptom with existing treatments.5
Treatment
The prevailing mainstream medicine
approach is to treat the dominant IBS
symptoms, using antispasmodics, antidiarrheals, or laxatives, often with
off-label use of pharmaceutical drugs.
However, it is clear that, in many cases, this approach is unsystematic and
associated with a limited therapeutic
potential. Moreover, the use of more
than one drug to treat different symptoms increases the risk of adverse effects.46 Furthermore, there is concern
that several agents used to treat IBS
symptoms may exacerbate some IBS
symptoms and, therefore, need to be
used with caution (eg, some antidepressants can cause constipation). A
recent survey in the United States
found that conventional therapies for
IBS-C (eg, antidepressants, antispasmodics, laxatives, fiber, and stool softeners) are associated with adverse ef-
Therefore, from previous descriptions, IBS is a complex disease affecting many networks in the body. To
treat this disease optimally, we need
an approach that is multitargeted and
multicomponent. 49 Treatment should
thus not only concentrate on the
symptoms of IBS, but also take into
account the different network perturbations and deficiencies.
Complementary and alternative medical therapies, such as homeopathy,
acupuncture, special diets, herbal
medication, and several forms of psychological treatments and hypnotherapy, are sought by many patients and
are being offered by physicians as
treatment options, either alone or in
conjunction with conventional forms
of therapy in patients with refractory
symptoms. There also is considerable
evidence of efficacy with comple-
) I n Fo c u s
Treat constipation,
bloating, and nausea: Nux
vomicaHomaccord
Figure 2. Additional
Treat mucosal
membrane
dysfunction:
Mucosa compositum
and Coenzyme
compositum*
Treat diarrhea:
Diarrheel
Spascupreel
Individualized Treatment of
Irritable Bowel Syndrome
Treat comorbid
dyspepsia:
Gastricumeel
mentary and alternative medical therapies, including well-designed randomized controlled trials with several
of these therapies, such as peppermint
oil and probiotics, as well as turmeric
extract, artichoke leaf extract, combination herbal medicine products, traditional Chinese medicines and acupuncture, and various forms of
mind-body medicine. (The article by
Yoon et al18 provides tables summarizing the evidence base for complementary and alternative medical therapies in the treatment of IBS.)
The ability of medications with bioregulatory properties, and other natural health products, to influence multiple targets simultaneously positions
them well as a potentially effective
approach to such a complex disorder.
Spascupreel is a multitargeted, multicomponent medication that offers a
holistic approach, both treating the
spasmodic component and potentially addressing the brain-gut axis. It is,
thus, one of the cornerstone treatments in the condition (Figure 1).
Other treatments can then be added,
according to the patient’s specific
needs, as an individualized treatment
(Figure 2).
Conclusion
Irritable bowel syndrome is a complex
disease that cannot be solved with a
linear approach. A multitargeted,
multicomponent therapy is necessary
to target the networks involved in this
disease. Medications acting in a bioregulatory manner address the pathophysiology of the disease and have an
excellent tolerability profile. Therefore, they are a promising approach in
providing adequate treatment to patients with IBS.|
Treat stress and
sleep disturbances:
Neurexan
or Nervoheel
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) I n Fo c u s
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2011;4(2):115-127.
26. Storr M, Allescher HD. Irritable bowel syndrome: a dysfunction of the endocannabinoid
system? Gastroenterology. 2012;142(2):406408.
27.Storr MA, Yüce B, Andrews CN, Sharkey
KA. The role of the endocannabanoid system in the pathophysiology and treatment of
irritable bowel syndrome. Neurogastroenterol
Motil. 2008;20(8):857-868.
28. Gerson MJ, Gerson CD. The importance of
relationships in patients with irritable bowel
syndrome: a review. Gastroenterol Res Pract.
2012;2012:157340.
29. Longstreth GF, Thompson WG, Chey WD,
Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology.
2006;130(5):1480-1491.
30. Tighe MP, Cummings JR, Afzal NA. Nutrition and inflammatory bowel disease: primary or adjuvant therapy. Curr Opin Clin Nutr
Metab Care. 2011;14(5):491-496.
31. Eswaran S, Tack J, Chey WD. Food: the forgotten factor in the irritable bowel syndrome.
Gastroenterol Clin North Am. 2011;40(1):141162.
32.Morcos A, Dinan T, Quigley EM. Irritable
bowel syndrome: role of food in pathogenesis
and management. J Dig Dis. 2009;10(4):237246.
33.Fernandez-Banares F, Esteve M, Viver JM.
Fructose-sorbitol malabsorption. Curr Gastroenterol Rep. 2009;11(5):368-374.
34. Gibson PR, Newnham E, Barrett JS, Shepherd SJ, Muir JG. Review article: fructose
malabsorption and the bigger picture. Aliment
Pharmacol Ther. 2007;25(4):349-363.
35. Clarke G, Fitzgerald P, Hennessy AA, et al.
Marked elevations in pro-inflammatory polyunsaturated fatty acid metabolites in females
with irritable bowel syndrome. J Lipid Res.
2010;51(5):1186-1192.
36. Fujiwara Y, Kubo M, Kohata Y, et al. Cigarette smoking and its association with overlapping gastroesophageal reflux disease,
functional dyspepsia, or irritable bowel syndrome. Intern Med. 2011;50(21):2443-2447.
37. Masand PS, Sousou AJ, Gupta S, Kaplan DS.
Irritable bowel syndrome (IBS) and alcohol abuse or dependence. Am J Drug Alcohol
Abuse. 1998;24(3):513-521.
38. Bellini M, Gemignani A, Gambaccini D, et
al. Evaluation of latent links between irritable
bowel syndrome and sleep quality. World J
Gastroenterol. 2011;17(46):5089-5096.
39. Dinan TG, Cryan J, Shanahan F, Keeling PW,
Quigley EM. IBS: an epigenetic perspective.
Nat Rev Gastroenterol Hepatol. 2010;7(8):465471.
40.Keohane J, O’Mahony C, O’Mahony L,
O’Mahony S, Quigley EM, Shanahan F. Irritable bowel syndrome-type symptoms in patients with inflammatory bowel disease: a real
association or reflection of occult inflammation? Am J Gastroenterol. 2010;105(8):17891794.
41.Ford AC, Talley NJ. Mucosal inflammation
as a potential etiological factor in irritable
bowel syndrome: a systematic review. J Gastroenterol. 2011;46(4):421-431.
42. Vivinus-Nebot M, Dainese R, Anty R, et al.
Combination of allergic factors can worsen
diarrheic irritable bowel syndrome: role of
barrier defects and mast cells. Am J Gastroenterol. 2012;107(1):75-81.
43. Thabane M, Marshall JK. Post-infectious irritable bowel syndrome. World J Gastroenterol.
2009;15(29):3591-3596.
44. Lin HC, Pimentel M. Bacterial concepts in
irritable bowel syndrome. Rev Gastroenterol
Disord. 2005;5(suppl 3):S3-S9.
45.
Olivo-Diaz A, Romero-Valdovinos M,
Gudiño-Ramirez A, et al. Findings related
to IL-8 and IL-10 gene polymorphisms in
a Mexican patient population with irritable
bowel syndrome infected with Blastocystis
[published online ahead of print January 28,
2012]. Parasitol Res. 2012;111(1):487-491.
doi:10.1007/s00436-012-2830-0
46. Goettsch WG, van den Boom G, BreekveldtPostma NS, Smout AJ, Herings RM. Treatment patterns and health care costs of
mebeverine-treated IBS patients: a casecontrol study. Pharmacoepidemiol Drug Saf.
2004;13(11):803-810.
47. Lembo A. Irritable bowel syndrome medications side effects survey. J Clin Gastroenterol.
2004;38(9):776-781.
48.Tack J, Fried M, Houghton LA, Spicak J,
Fisher G. Systematic review: the efficacy of
treatments for irritable bowel syndrome – a
European perspective. Aliment Pharmacol Ther.
2006;24(2):183-205.
49. Whorwell PJ. Irritable bowel syndrome. Altern
Ther Health Med. 2011;17(2)(suppl):S4-S6.
) Around the Globe
European Congress
of Integrative Medicine
Breakaway Session on Bioregulatory Medicine
By Ghassan Andraos, MD
B
includes the underlying single and
multiple networks in the disease process. With this increased complexity
in thinking, there also is a necessity to
incorporate new technologies, with
an improved ability to diagnose complexity, and for therapeutic drugs that
have multiple biological targets.
Bernd Seilheimer, PhD, then explained how genomic profiling can
be used as a tool to substantiate the
action of a multitargeted medication
at a cellular level. The genomic and
deep-sequencing data demonstrated
that these multicomponent medications do indeed have multiple targets
within a model disease system. After
showing that there is a scientifically
validated technology, with reproducible, credible evidence identifying the
targets of multicomponent medications, a more complex pathological
ioregulatory medicine is an
emerging science. The aim of
the scientific symposium “The Bioregulatory Medicine Approach: From
Genomics to Clinical Application”
was to update the 420 registered participants to the third European Congress of Integrative Medicine on the
most recent changes and findings in
this field.
Sometimes described as “the bridge
between natural medicine and conventional medicine,” this therapeutic
approach seeks to improve patient
care by offering a wide range of therapeutic and diagnostic tools, leading
to a more personalized therapeutic
approach.
In her opening remarks, Alta Smit,
MD, highlighted the novel and increasingly supported shift in medical
thinking towards complexity. This
From left to right: Alta Smit, MD; Bernd Seilheimer, PhD; Manfred Schmolz, PhD;
and Bernd Wolfarth, MD.
process, such as the inflammatory cascade, can be investigated.
Manfred Schmolz, PhD, presented
the inflammatory cascade as a model
for the value of network medicine,
showing that inflammation is a defense mechanism that fits into the systems biology thinking and complexity and that it needs to be regulated,
rather than suppressed. Possible intervention points were identified along
the inflammatory cascade, and the
value of a multitargeted therapeutic
approach to modulate the inflammation (ie, upregulate some targets and
downregulate others) to promote
synergy and avoid adverse effects,
while sustaining its therapeutic benefits, was substantiated.
Bernd Wolfarth, MD, associate professor of sports medicine, highlighted
the clinical evidence of Traumeel in
the care of musculoskeletal disorders.
He discussed the preclinical knowledge about its multitargeted mechanism of action, including a proof of
concept from scientific support for
relevant components, together with a
body of clinical research built over
the years and his own clinical experience and practice. He confirms that,
for him, Traumeel is definitely a firstline therapy for musculoskeletal disorders.
This conference confirms the potential of Bioregulatory Medicine as an
effective first-line therapy with minimal adverse effects.|
) 11
) What Else is New
Nutritional intervention may help
restore homeodynamics in
© iStockphoto.com/Ostill
the intestine.
Intestinal Inflammatory
Factors Affect Elderly
Individuals
Elderly individuals are often characterized by having chronic low levels of
inflammation and immune system impairment that affect both their overall
health and survival. This review describes intestinal components that receive and provide signals that play a
role in local and systemic inflammation
and immunity. These components include the following: sentinel cells, such
as macrophages, dendritic cells, and
mast cells concentrated in the splanchnic area, which receive simultaneous
signals from commensal bacteria as
well as physiological and pathological
metabolic processes; endogenous immune system molecules in the intestine, such as natural killer cells and
Recent studies have discussed the role
of the enteric microbiota in the
treatment of gastrointestinal disorders.
dendritic cells, which are affected by
aging and stress; and exogenous molecules in the intestine, such as the evolutionarily conserved molecules from
bacteria. All of these signals interact in
a network that either promotes the restoration of homeodynamics or chronic
inflammation if there is failed resolution of inflammation, long-lasting tissue injury, or persistent infections by
pathogens. Supplementation by specific nutrients, including probiotics, prebiotics, and certain vitamins, minerals,
and dietary substances, may contribute
to restoring homeodynamics in the intestine and, therefore, in the whole
body, by modifying the inflammatory
pathways and by repairing any increased permeability of the epithelial
barrier.
Mutat Res. 2010;690(1-2):50-56.
Gut Microbiota
Communicate With the Brain
Human health is affected by a bidirectional communication system between
gut microbiota and the brain. Although
most previous research has focused on
how the brain affects the gut microflora, there is increasing evidence that signals from the commensal and pathogenic bacteria in the gut also affect the
brain and behavior. This particular article discusses recent studies, including
those with germ-free mice. Because
there is a definite signal (axis) between
the brain and the gastrointestinal tract,
study of the factors that affect it is important. The agents that decrease the
amount of gut microbiota include antimicrobials. Future studies should focus
on the molecular, cellular, and physiological aspects of the gut microbiota–
brain communication.
Neurogastroenterol Motil.
2011;23(3):187-192.
doi:10.1111/j.1365-2982.2010.01664.x
F O R P RO F E S S I ONA L U S E ON LY
) 12
The information contained in this journal is meant for professional use only, is meant to convey general and/or specific worldwide scientific information relating to the
products or ingredients referred to for informational purposes only, is not intended to be a recommendation with respect to the use of or benefits derived from the products
and/or ingredients (which may be different depending on the regulatory environment in your country), and is not intended to diagnose any illness, nor is it intended to
replace competent medical advice and practice. IAH or anyone connected to, or participating in this publication does not accept nor will it be liable for any medical
or legal responsibility for the reliance upon or the misinterpretation or misuse of the scientific, informational and educational content of the articles in this journal.
The purpose of the Journal of Biomedical Therapy is to share worldwide scientific information about successful protocols from orthodox and complementary practitioners.
The intent of the scientific information contained in this journal is not to “dispense recipes” but to provide practitioners with “practice information” for a better understanding
of the possibilities and limits of complementary and integrative therapies.
Some of the products referred to in articles may not be available in all countries in which the journal is made available, with the formulation described in any article or available for sale with the conditions of use and/or claims indicated in the articles. It is the practitioner’s responsibility to use this information as applicable and in a
manner that is permitted in his or her respective jurisdiction based on the applicable regulatory environment. We encourage our readers to share their complementary therapies, as the purpose of the Journal of Biomedical Therapy is to join together like-minded practitioners from around the globe.
Written permission is required to reproduce any of the enclosed material. The articles contained herein are not independently verified for accuracy or truth. They have been
provided to the Journal of Biomedical Therapy by the author and represent the thoughts, views and opinions of the article’s author.
© iStockphoto.com/Tony Tremblay
© iStockphoto.com/Selvanegra
Exposure to traffic air pollution
b
increases the risk of dying
from gastric cancer.
Emotions Affect Food Intake
This study attempted to determine some
of the specific connections between human emotions and feeding behavior by
examining the relationship between gut
signaling from specific nutrients and
externally created emotions. Functional
magnetic resonance imaging was used
to measure the effects in the brain. The
study included 12 healthy male and female volunteers who were not obese.
“Nutrient-induced gut-brain signaling”
was determined after the subjects received an infusion of fatty acid or saline.
An important part of this study was
that, because the volunteers received an
infusion, it bypassed the taste receptors,
texture, sight, and mouth-end feel associated with fatty foods, showing for the
first time in humans the direct effect of
the composition of the food itself on
emotions. Sad emotion was induced by
validated sad or neutral classical music
and facial expressions. The subjects
then rated their feelings of hunger, fullness, and mood. The results indicated
that sad emotion was “attenuated by
fatty acid infusion.” These findings increase the understanding of the relationships among emotions, hunger/
food intake, meal-induced sensations
and obesity, eating disorders, functional
dyspepsia, and depression. Furthermore, this study helps support the validity of phrases such as “emotional
overeating” and “comfort feeding.”
Cancer-Associated Death
Is Affected by Density
of Petroleum Stations
In Taiwan, a case-control study on air
pollution and death from gastric cancer
was conducted from 2004 to 2008.
Data were obtained from case deaths
affected by gastric cancer and control
deaths affected by variables other than
tumors and gastrointestinal tract diseases. Cases and controls were matched
by sex, birth year, and death year;
2 substantial petroleum companies
provided data for number of petroleum
stations in the municipalities. The
density of petroleum stations in
municipalities determined the exposure to “benzene and other hydrocarbons present in ambient evaporative
losses of petroleum or to air emissions
from motor vehicles.” The study determined that persons who lived in municipalities with the highest density of
petroleum stations (>75th percentile)
had an increased risk of death associated with gastric cancer, when compared with persons who lived in municipalities with the lowest density of
petroleum stations (≤25th percentile).
In the future, studies should seek to determine the specific ways that traffic air
pollution causes gastric cancer.
J Toxicol Environ Health A.
2011;74(18):1215-1224.
Enterotypes Determined
for Human Gut Microbiome
There is rapidly expanding knowledge
of both the species and functional features of the human gut microbiome.
The present study analyzed data from
adult fecal samples of 4 different countries and 22 newly sequenced fecal
metagenomes and combined them
with previous data from 2 other countries to identify 3 enterotypes (robust
clusters of related bacteria) that are not
specific to a country or continent.
These enterotypes represent well-balanced, defined microbial communities
with a relatively high degree of phylogenetic and functional association
between them. Although the indi
vidual composition can be affected
differently by diet and drugs, they are
not explained by differences in body
mass index, sex, age, and nationality.
However, several marker genes (eg,
12 genes that associate with age) or
functional variables (eg, 3 modules that
associate with body mass index) were
determined and could be useful for diagnosis and possible prediction of the
risk of different human disorders. The
robustness and predictability of the
clusters also suggest that they could be
used as a guide for how different human groups would respond differently
to drug and diet intake.
Nature. 2011;473(7346):174-180.
) 13
J Clin Invest. 2011;121(8):3094-3099.
doi:10.1172/JCI46380
) From the Practice
Bioregulatory Treatment
of Hepatitis C
A Clinical Case Report
By Arturo O’Byrne, MD
Hepatitis C virus (HCV) is a small positive-sense singlestranded RNA virus that causes acute and chronic hepa
titis C in humans.1 More than 170 million people worldwide are infected with HCV, covering approximately
3.3% of the world’s population.2,3
C
hronic progression of this disease is characterized by progressive development of fibrosis and
cirrhosis of the liver after 20 to 25
years in 2% to 35% of those affected.4
Furthermore, patients with cirrhosis
are exposed to life-threatening complications, including end-stage liver
disease, esophageal variceal hemorrhage, and the development of hepatocellular carcinoma (HCC), which
occurs at an incidence of 4% to 5%
per year in these patients.5,6 With
chronic HCV infection being the
leading cause of HCC and the first
indication of liver transplantation in
industrialized countries, this poses an
enormous threat to worldwide public
health.5,7 Hepatitis C virus has also
rapidly surpassed human immunodeficiency virus as a cause of death in
the United States, with almost 75% of
HCV-related deaths occurring among
adults between the ages of 45 and 64
years.7
) 14
Transmission of the virus is parenteral and sexual, with needle sharing,
unscreened blood transfusions, nonsterile tattooing or acupuncture, and
vertical and sexual transmission being among some of the means of viral
exposure. However, intravenous drug
use remains the most common cause
of HCV infection, especially in developed countries.7,8 There are 6 genotypes of HCV, 52 subtypes within
these genotypes, and a diverse population of mutant viruses known as
quasispecies within each infected individual.3 Genotype 1 (subtypes 1a and
1b) is reported to be the most frequent genotype worldwide, accounting for 40% to 80% of all isolates,
but unlike HCV genotypes 2 and 3,
which respond more favorably to
treatment, genotypes 1 and 4 are
more difficult to eradicate using current conventional medications.1,3,7
Genotype 1 also may be associated
with more severe liver disease and a
higher risk of HCC.7 The ability of
the virus to incorporate adaptive mutations in the host and exist as genetically distinct quasispecies, in addition to disrupting the host’s defense
by blocking phosphorylation and
function of interferon (IFN) regulatory factor-3, an antiviral signalling
molecule, poses a major challenge to
the immune-mediated control of
HCV.1 This may also explain the variable clinical course of the disease,
difficulties in vaccine development,
and the variable results of treatment.1,8 Current pharmacological intervention includes antiviral agents
that specifically target viral function,
collectively termed direct-acting antivirals, in addition to host-targeted agents
that aim to inhibit HCV replication.8
The aim behind all treatment options
is to eradicate HCV viremia, thereby
increasing quality of life and reducing the risk of cirrhosis and HCC.7,8
Combination therapy of pegylated
IFN-α and ribavirin is the current
mainstay of treatment, resulting in
sustained clearance of serum HCVRNA. However, this treatment causes
many adverse effects (eg, flulike
symptoms, insomnia, hair loss, mood
changes, pruritus, dermatitis, and hematological abnormalities, including
neutropenia, anemia, and thrombocytopenia) and is only efficacious in
approximately 50% of patients, with
possible relapses at the end of treatment.8-10 Several host factors, such as
age, stage of liver fibrosis, body mass
index, liver steatosis, insulin resistance, ethnicity, and interleukin 28B
single-nucleotide polymorphisms,
and viral genotype are reported to
influence the treatment outcome.1,2,5,11
Patients infected with both acute
and chronic hepatitis are usually
asymptomatic, making early diagnosis difficult.4 Once symptoms occur,
Photograph by Dr. Christian Schüttler; licensed under the Creative Commons
Namensnennung-Weitergabe unter gleichen Bedingungen Deutschland
(http://creativecom-mons.org/licenses/by-sa/2.0/de/legalcode); http://de.
wikipedia.org/w/index.php?title=Datei:HCV_particles.jpg&filetimesta
mp=20060703221106
) From the Practice
Possible hepatitis C virus particles from human serum after chromatographic purification
they tend to be nonspecific, with fatigue and/or malaise being the most
commonly reported, in addition to a
general decrease in quality of life.4,7
Thereafter, symptoms often develop
as clinical findings of extrahepatic
manifestations of HCV and most
commonly involve the joints, muscle,
and skin (ie, arthralgias, paresthesias, myalgias, pruritus, and sicca
syndrome). Patients with ongoing
pathology associated with chronic
hepatitis C that eventually results in
organ failure can present with symptoms and signs related to synthetic
dysfunction and portal hypertension
(ie, ankle edema, abdominal distention, hematemesis or melena, palmar
erythema, and yellowing of the
eyes).7 The natural history of chronic
hepatitis is ill defined because of the
long latent period between inoculum
and development. Severity and progression are variable but generally
slow; however, host and environmental factors play a vital role in disease progression.8,11
Clinical Case
In July 2006, a 55-year-old male patient presented to the clinic with
symptoms of skin irritation and pruritus. Investigations undertaken 6
months earlier reported altered levels
of liver enzymes; features of fatty
liver on ultrasonography, in addition
to positive antibodies; an increased
HCV RNA assay result of 697,000
IU/mL; and a genotype test result of
type 1 subtype 1b. These features all
confirmed a diagnosis of chronic
hepatitis C infection.
The patient’s medical history included having abnormal coagulation
factor X since the age of 35 years,
for which he received many transfusions (plasma and isolated X factor)
in the past several years, which may
have caused the HCV transmission
and infection. The patient also reported previous and current treatment for metabolic syndrome, anxiety, and several adverse effects
potentially caused by his conventional hepatitis drug therapy (ie, articular pain, insomnia, and emotional irritability). The patient has
received weekly injections of 180 µg
peginterferon alfa-2a, in addition to
an oral dose of 5 tablets of ribavirin
per day for the past 5 months. The
patient was also taking a combinaJournal of Biomedical Therapy 2012 ) Vol. 6, No. 1
tion angiotensin II receptor blocker
and diuretic drug (candesartan); a
statin/3-hydroxy-3-methyl glutaryl–coenzyme A reductase inhibitor
(atorvastatin); an antihyperglycemic
drug (metformin); an antifibrinolytic
(tranexamic acid); 2 antidepressants
(sertraline and mirtazapine); an acetaminophen- and codeine-based analgesic, in addition to a sedative
(zolpidem); and a mood-stabilizing
agent (levomepromazine).
By March 2006, the hypertension
and coagulation disorders were controlled; however, despite the conventional hepatitis C treatment, the viral
load increased to greater than
700,000 IU/mL, with loss of appetite and sexual desire added to the
adverse effects of the conventional
drugs still felt by the patient. After
5 months of conventional treatment
with no effect on the hepatitis C,
the patient turned to bioregulatory
therapy.
In light of the chronicity of the infection, the extensive list of conventional drugs and their adverse effects, in addition to the multiple
concomitant disease processes pres-
) 15
) From the Practice
) 16
ent all at the same time, it was clear
that a carefully orchestrated therapy
scheme, providing a combination of
detoxification, supportive, reparative,
and immune-enhancing activities,
was to be initiated. After the first consultation in July 2006, a combination
of medications (eg, Hepar compositum, Engystol, and Galium-Heel) was
given parenterally for immediate immunomodulation and tissue support,
in addition to extensive nutritional
supplementation (eg, vitamin B complex). The intravenous method of administering the bioregulating medications, together with the nutritional
supplements, has evoked greater systemic effects in our clinic. The patient
was also prescribed an oral combination of medications targeted at assisting with the reparative processes of
the body, providing the necessary
cellular and organ support, in particular for the hepatic, hematological,
and splenic organs, and assisting
with the activation of the immune
system. Hepeel, Engystol, and a combination of products composed of
Chelidonium-Homaccord and products containing porcine tissue materials (eg, liver, spleen, and bone marrow) and 2 bioregulatory metabolic
factors (Acidum succinicum-Injeel
and Acidum fumaricum-Injeel) were
prescribed 3 times a day at specific
intervals. Gentle detoxification was
also started with the use of Hepeel
and other prescribed liver cleanse
formulas. At the follow-up visit 2
weeks later, Valerianaheel was pre-
scribed to assist with the insomnia,
followed by homeopathically prepared ribavirin (D8 potency) and pegylated IFN (D8 potency) 2 weeks
after that to assist with the adverse
effects of the conventional counterparts. The latter were to be taken
each once a day for 2 weeks, followed
by 10 drops 3 times a week thereafter.
After receiving neural therapy during the fourth consultation in September, the patient developed hematomas in all the injected sites, 24
hours after the injection therapy.
These were seen as a positive development in the patient’s movement
towards health, and an acute posology of oral Cinnamomum-Homaccord was prescribed for the next 1.5
days, in addition to Traumeel acting
as an adjunct for the management of
the inflammatory process. The patient responded well after 48 hours
of the initial crisis, displaying positive disease evolution changes.
By using the electroacupuncture
system, developed by Reinhold Voll,
MD, and Fritz Kramer, MD, in Germany 60 years ago, the measurement of bioimpedance in the patient’s acupuncture points was
assessed throughout the rest of the
consultations, which was also used
to confirm the physician’s choice of
medicines. After being evaluated in
early October, autologous blood
therapy was administered a few days
later into the indicated acupuncture
points (ie, large intestine, liver, and
lungs), in conjunction with several
combination medications acting in a
bioregulating manner and nutritional supplementation. The medications
chosen continued to provide extensive tissue and organ support (eg,
Hepar suis-Injeel, Pulmo suis-Injeel,
and Bronchus suis-Injeel), with constant immunomodulation (eg, Galium-Heel, Engystol, and Traumeel)
and activation of regulatory and enzymatic processes (eg, Ubichinon
compositum and Acidum fumaricum-Injeel). Detoxification and
drainage systems were also being
assisted, while other medicines continued to work on repair and improvement of symptoms. On the day
of receipt of the first autologous
blood injection therapy, the patient
developed acute pharyngitis, which
resolved spontaneously, displaying a
positive lymphodermal disease evolution.
By the seventh visit in mid-October,
the patient reported a significant improvement in the skin pruritus, in
addition to improved and more regulated sleep patterns. The patient
was advised to stop his antifibrinolytic medication (tranexamic acid) in
early October, with no ill effect on
his current hematological values, indicating normal prothrombin time
(PT) and partial thromboplastin
time (PTT) levels and improved levels of neutrophils (from 110,000 to
) From the Practice
197,000 cells/µL). The patient continued to receive autologous blood
injection therapy each week until
the follow-up visit a month later. At
this time, the patient reported complete absence of the pruritus, increased energy levels, vastly improved appetite, and a general
feeling of being more encouraged
and emotionally more positive.
Blood test results indicated further
increases in eosinophil numbers and
PT and PTT values (10.6 and 26.7
seconds, respectively), in addition to
normal fasting glucose levels, but
liver enzyme levels were still altered
(ie, increased alanine aminotransferase level). One month later, in early
December, electroacupuncture control testing was performed, with
continued administration of weekly
autologous blood injection therapy.
The gastrointestinal system was being targeted, using a combination of
medications, including Podophyllum compositum. By mid-December,
the patient displayed an ectodermalpositive disease evolution, with dry
scaly skin developing on the right
foot, which, after the application of
Traumeel cream, started secreting
and resolving after a further 2 days.
By January 10, 2007, polymerase
chain reaction HCV levels were 43
IU RNA/mL, with PT and PTT levels at 16.3 and 39.9 seconds, respectively. The patient started to progressively reduce his IFN treatment,
which was then completely discon-
tinued, in addition to the ribavirin,
under the advice of the patient’s hepatologist in March 2007. Repeat
blood tests in September 2007 confirmed the same minimal viral load
and regulated PT and PTT levels, at
10.00 and 26.6 seconds, respectively. Twenty months later, in early
2009, an ultrasonographic investigation revealed no evidence of past
fatty liver changes, and liver function
test results were normal. A recent
blood test, performed in July 2012,
once again revealed results with a
minimal viral load, indicating no
signs of relapse and that the patient
was maintaining self-regulation.
Conclusion
Hepatitis C infections, in particular
with the genotype 1, subtype 1b,
can be challenging to treat because
the mutating virus is difficult to
eradicate and the risk of developing
severe liver disease and HCC is
much higher in this group of patients. This 55-year-old patient was
treated with several modalities because of the complexity of his health
status, but medicines acting in a bioregulating manner provided the
mainstay of the multilevel intervention that was necessary in this case.
The host assisted in launching an
effective and sustained immune response toward an evasive adversary,
but the medicines also provided the
necessary organ and tissue support
for detoxification, tissue repair, and
regeneration, resulting in normal
hepatic structure and function, with
minimal adverse reactions.|
References
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site.
http://emedicine.medscape.com/
article/177792-overview#a0101. Updated
February 29, 2012. Accessed June 27, 2012.
8. Jafferbhoy H, Gashau W, Dillon J. Cost effectiveness and quality of life considerations
in the treatment of hepatitis C infection.
Clinicoecon Outcomes Res. 2010;2:87-96.
doi:10.2147/CEOR.S7283.
9. Salloum S, Tai AW. Treating hepatitis C
infection by targeting the host. Transl Res.
2012;159(6):421-429.
doi:10.1016/j.
trsl.2011.12.007.
10.Baraldi S, Hepgul N, Mondelli V, Pariante
CM. Symptomatic treatment of interferonα-induced depression in hepatitis C: a
systematic review. J Clin Psychopharmacol.
2012;32(4):531-543.
11. Sievert W. Management issues in chronic viral hepatitis: hepatitis C. J Gastroenterol Hepatol. 2002;17(4):415-422.
) 17
) Re f r e s h Yo u r H o m o t ox i c o l o g y
Gut Feelings Revisited:
Evidence for a Brain-Gut Axis
PhD, ND
Introduction
ic and abdominal cavities to innervate numerous visceral organs, including the esophagus, stomach,
small intestine, proximal half of the
colon as well as the heart and lungs.
It supplies parasympathetic nervous
system input to the liver, gallbladder,
pancreas, kidneys, and upper region
of the ureters and is an important relay of sensory information from the
head, neck, abdomen, and thorax to
the brain.1 The primary neurotransmitter used for communication between the synapses of the vagus
nerve and its targets is acetylcholine,
a signaling molecule with widespread function in the parasympathetic and sympathetic nervous systems.1
It has been proposed since antiquity
that the gut can either be a source of
emotions or have a major influence
on their character and intensity. Expressions such as “gut feelings” or
“follow your gut” have been commonly used for many years. The scientific support for these expressions
is being substantiated, with considerable support for direct communication between the brain and the gastrointestinal tract (GIT). This article
will discuss some of the recent evidence for the presence of the braingut axis, including some of the bestdescribed features, such as the
cholinergic anti-inflammatory pathway and the influence of the microbiome* and macronutrients directly
on the central nervous system (CNS).
Recent studies buttressing the therapeutic potential of influencing this
brain-gut axis also will be discussed.
Role of the Cholinergic
Anti-inflammatory Pathway
Cranial nerve X, the vagus nerve, is
well-known for its ability to influence multiple targets outside the
CNS. Many of its fibers leave the vertebral column at the cervical spine
and wander (Latin vagari means
“wandering”) throughout the thorac-
) 18
A pathway between the brain and the
gut, using the vagus nerve as a conduit of communication, has been described as the cholinergic anti-inflammatory pathway.2-4 In this
pathway, afferent nerve fibers from
the vagus nerve receive signals from
the organs and tissues they are situated in and carry these signals to the
brain. Some of these signals are messages about injury, ischemia, and
pathogens, as well as the levels and
activities of proinflammatory cytokines in the local microenvironment.
In the brain, processing and sorting
of these signals occurs, and the appropriate message is carried via the
efferent vagus nerve fibers back to
the site of origin. The activation of
the appropriate acetylcholine receptors, including the α7 nicotinic acetylcholine receptors on immunocompetent cells, results in either a
decrease of the local proinflammatory message or a possible increase in
inflammation. In this way, the brain
can play an active part in controlling
an inflammatory response at a distal
site and preventing the damaging
consequences of an excessive innate
immune system response.2-4
This complete circuit of sensors of
infection or injury (the vagus afferent
nerve fibers in visceral tissues), relay
system, and integrator (brain and
other parts of the CNS) and effectors
(vagus efferent nerve fibers, acetylcholine, and the target cells) is clearly involved in the maintenance of
immune system homeodynamics and
has been recently proposed as an inflammatory reflex.5 This system
could function in a similar manner to
reflex arcs in other complex organ
systems and suggests that it is important to consider sensory nerves as an
integral part of the control of innate
immune system responses.6 Also, it
might be possible to eventually map
an inflammatory homunculus in the
brain, with specific regions controlling different components of the inflammatory response.7
* The microbiome refers to the collection of all the genes of the commensal microbiota and the corresponding proteins and metabolites (see Turnbaugh PJ, Ley RE, Hamady
M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007;449[7164]:804-810).
Gut-brain
axis
Vagus nerve
Microbiota-gut
interactions
Figure. The Microbiome-Gut-Brain Axis
© iStockphoto.com/David Marchal (digestive system) and © iStockphoto.com/Evgeny Terentev (human brain)
It is well substantiated that billions
of microorganisms exist within our
GIT and that many of them have important roles to play in our overall
metabolism and health, including
modulation of both innate and adaptive immune systems and synthesis
and metabolism of important vitamins, hormones, and short-chain
fatty acids with beneficial function.
The gut flora has been described as a
forgotten organ because many of its
essential protective, structural, and
metabolic functions have been underappreciated until recently.13 How-
In animal studies, the acquisition of
appropriate bacteria from the mother
in the immediate postnatal period
is an important contributing factor
to the development of normal gastrointestinal, immune, neuroendocrine, and metabolic systems. It has
even been shown to be one of the
key factors regulating the set point
Influence of the microbiota on the brain and behavior
Role of the Microbiome
plays an important role in health and
disease.17 Recognition that the “human microbiome serves as the interface between our genes and our history of environmental exposures” has
led to the possibility of a mindbody-microbial continuum that has
an impact into neurodevelopment
and development of unique behavioral phenotypes.18
ever, exciting new discoveries have
validated the historical view of the
benefit of commensal microflora and
have described the human intestinal
microbiome as a new frontier in human biology.14 One of the most recent discoveries is the connection
between the gut microbiome and the
CNS to form what is termed the microbiome-gut-brain axis (Figure).15 This
discovery and the studies that support it suggest that the microbes
within our GITs can influence more
sophisticated nervous system functions, such as “affect, motivation and
higher cognitive functions, including
intuitive decision making.”16 This
discovery also further establishes that
the communication between the
brain, gut, and associated microbes
Influence of the brain on the intestinal microbiota
The practical ramification of this
brain-gut axis, outlined by the cholinergic anti-inflammatory pathway,
is that therapeutic interventions, including acupuncture, biofeedback,
mindfulness meditation, body work,
cervical adjustments, and specific
natural health products, that could
potentially modify the activity of the
autonomic nervous system (and,
therefore, input and output of the
vagus nerve) might help modify the
nonresolving inflammation associated with chronic diseases, such as inflammatory bowel disease, rheumatoid arthritis, and type 2 diabetes
mellitus.8 Moreover, because the afferent vagus nerve fibers bind to acetylcholine receptors that influence
the heart, it may be possible to treat
inflammation by controlling the activity of the vagus nerve, via an electronic device similar to a pacemaker,
and to assess the effect via a heart
rate monitor.9 The potential value of
this approach is supported by recent
evidence demonstrating that heart
rate variability is an independent
marker of systemic inflammatory responses and correlates well with certain biomarkers of systemic inflammation, including high-sensitivity
C-reactive protein (hs-CRP) and interleukin 6.10-12
) 19
of the hypothalamic-pituitary-adrenal (HPA) axis.19 Other studies have
shown definitive changes within the
brain, depending on the composition
of bacteria in the GIT. For example,
a recent study demonstrated that the
presence or absence of commonly
identified bacteria in the intestine in
germ-free and specific pathogen-free
mice affected the expression of Nmethyl-D-aspartate receptor, brainderived neurotrophic factor, and
serotonin receptor in the different
regions of the brain. These neurochemical changes were accompanied
by observable changes in anxiety-like
behavior.20 It was recently shown, using a mouse model, that the ingestion
of a strain-specific probiotic, termed
Lactobacillus rhamnosus, influenced the
expression of γ-aminobutyric acid
receptors in different regions of the
brain associated with anxiety and
depression. The ingestion of these
beneficial bacteria also reduced anxiety and depression-related behavior
associated with long-term use of
corticosterone in otherwise healthy
animals. Both the neurochemical and
behavioral benefits of the probiotic
agent were negated if the vagus nerve
was cut, suggesting that this nerve
serves as an essential communication
pathway between the brain and the
gut. What this study demonstrates
is that bacteria play an important
role in influencing the brain. Also, it
might be possible to select and use
specific microorganisms as adjunctive
therapies in stress-related disorders,
such as anxiety and depression.21 It
provides further support for an interdependent link between the brain
and the gut flora.
) 20
Neurotransmitters released after
commands from the CNS can affect
the habitat of the microflora in several ways, including altering the motility of the GIT, affecting the pro-
duction of mucin and the function of
epithelial cells, and directly affecting
the growth of different bacteria,17 including pathogenic strains, such as
Escherichia coli O157:H7.22 Conversely, gut microbiota can influence
brain and behavior via the production of metabolites that directly influence the CNS, activate innate and
adaptive immune system responses
with systemic effects, and modulate
neural afferent circuits to the brain.21
Certain strains of probiotics also
could influence the metabolism of
tryptophan, a precursor to serotonin
that has wide-ranging effects
throughout the nervous system, including the CNS.23 Finally, there is
evidence that gut microbiota and
probiotics24 can influence the perception of visceral and even somatic
pain, suggesting that they, or their
metabolites, can modulate the sensitivity of the associated nerves.23
Enteric microflora and their toxins
can affect enterochromaffin cells in
the GIT.25 Enterochromaffin cells
help regulate communication between the gut lumen and the nervous
system in several ways, including direct innervation by afferent fibers of
the vagus nerve26 and local secretion
of corticotropin-releasing hormone27
(also termed corticotropin-releasing factor). This hormone is most commonly studied as being produced in the
hypothalamus, where it is an important component of the HPA axis
communication pathway.1 Corticotropin-releasing factor and its related
peptides have been demonstrated to
be widely expressed in the colon of
humans and rodents,28 where they
are integral mediators of the stress
response in the brain-gut axis29 and
play an important role in the regulation of motility,30 permeability,31 and
inflammation32 in the intestines. It
can be synthesized and released from
dendritic cells of the innate immune
system, a process that is enhanced by
commensal bacteria, such as Bacteriodes vulgatus and Fusobacterium varum.33 A recent study in rats demonstrated that “chronic psychosocial
stress triggers reversible inflammation, persistent epithelial dysfunction, and colonic hyperalgesia,”
largely via upregulation of corticotropin-releasing factor receptor type
1 in intestines.34 This study provides
support for the role of corticotropinreleasing factor as an important messenger in the brain-gut axis and suggests that this might be one of the
mechanisms responsible for the observed effects of psychosocial stress
on the symptoms of irritable bowel
syndrome.35
Early life stressors, such as maternal
separation, have been well studied in
rodent models as examples of the
pathological consequences of braingut axis dysfunction.36 One of the
consequences of the premature separation of rat pups from their mother
during the neonatal period is immediate and prolonged changes in intestinal physiology. These functional
abnormalities of the colon in rat pups
after maternal deprivation can be
ameliorated with the supplementation of strain-specific probiotics, at
least partly because of the ability of
these probiotics (Lactobacillus rhamnosus R0011 and Lactobacillus helveticus
R0052) to normalize cortisone release, a marker of HPA axis activity.37
Another consequence of premature
maternal separation is depressivelike
symptoms, which have been shown
to be reversed by the supplementation of a probiotic, Bifidobacterium infantis. In this case, the probiotic normalized interleukin 6 levels, restored
noradrenaline concentrations in the
brainstem, and reversed the observed
behavioral deficits.38
Role of Macronutrients
An intriguing study by Van Oudenhove et al39 demonstrated that ingestion of fatty food by healthy nonobese volunteers, via an intragastic
tube to avoid any influence of smell,
taste, or feel, substantially reduced
their response to experimentally induced sadness through appropriate
music and pictures. Furthermore, exposure to the same music and pictures decreased their sense of fullness
after ingestion of a fatty meal.39
These interesting results suggest that
ingested macronutrients can directly
influence CNS activity to affect emotions and, conversely, that the brain
can affect our normal response to ingested meals. A thought-provoking
commentary entitled “Was Feuerbach
Right: Are We What We Eat?” discusses this possibility.40 These results
also support the idea of fatty foods as
comfort foods.
Although it was not examined in the
study which specific neural and hormonal pathways were involved in relaying this information between the
fatty food in the gut and the CNS,
some likely candidates are ghrelin
and cholecystokinin. Ghrelin is a
hormone produced in the gut and
other parts of the GIT that has been
shown to have a wide variety of
functions, including stimulating appetite, modulating inflammation,
promoting sleep, reducing pain, and
facilitating learning and memory. It
also is associated with reward behaviors and mood regulation in animal
models.1 A recent animal study
showed that persistent psychosocial
stress in male mice increased levels of
ghrelin and corticosteroid in addition to triggering behaviors to seek
out high-fat foods.41 These data suggest that ghrelin might be an important part of the repertory of hormones associated with the stress
response. They also are an interesting
support for a relatively common human behavior of preferring to eat
calorie-dense comfort foods during
times of high stress. Stimulation of
parasympathetic nervous system terminals in the GIT by fatty acids, the
corresponding release of cholecystokinin, and the subsequent secretion
of pancreatic enzymes are well-established components of the digestive
process.1,42 The receptors for cholecystokinin are known for their roles
in learning and memory and in modulating panic, anxiety, and appetite,
further demonstrating that this hormone pathway could serve as part of
the brain-gut axis.1
Conclusions
There is clearly a network of interactions between the brain and the gut
that can be described by various
plausible connections, including the
vagus nerve and its associated neurotransmitters, the gut microbiome
and macronutrients, and their direct
and indirect influences on CNS activity. It is intriguing to think that
there might be further networks of
interactions that could be included in
a unifying model, including a gutbrain-skin axis,43 a gut-brain-liver
axis,44 and a gut–brain–exocrine
pancreas axis.45 A more in-depth understanding of the interconnections
between the brain and the gut will
help illuminate potential therapeutic
access points to treat diseases associated with a dysfunctional interaction
between the CNS and the GIT, including irritable bowel syndrome,46
peptic ulcer disease, and gastroesophageal reflux disorder.47 The existence of a brain-gut axis is clearly
no longer a farrago of disjointed hypotheses, but an increasingly welldefined bidirectional communication
pathway.
The established presence of different
networks contributing to the braingut axis supports the therapeutic use
of multicomponent medications with
the ability to affect more than one
biological target simultaneously.
Spascupreel is a product with evidence suggesting that it can target
multiple receptors associated with
this complex network, including
muscarinic acetylcholine receptors
(affecting smooth muscle contraction
and motility), γ-aminobutyric acid-A
(GABA type A) receptors (associated
with CNS processing of mood disorders, including anxiety), and dopaminergic receptors type 2 (affecting
central control of the pain response).
It inhibits the enzyme monoamine
oxidase B (MOA-B) (unpublished
data), which is known to contribute
to the regulation of levels of neurotransmitters, including dopamine.
Furthermore, several of the ingredients of Spascupreel are documented
in the scientific literature to modulate
various central and peripheral targets
of the brain-gut axis. However, the
multicomponent medication Spascupreel could be considered as an important addition to a comprehensive
therapeutic approach to any condition associated with a dysfunction of
the brain-gut axis. Other bioregulating medications, such as Thalamus
compositum (in central pain syndromes related to the GIT) and Tonsilla compositum (in disturbances of
the HPA), are also used to influence
the brain-gut axis.|
) 21
) 22
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) Meet the Expert
Dr. Sergio Vaisman Weinstein
D
r. Sergio Vaisman Weinstein
was born in Santiago de Chile.
His father was a dermatologist, and
his mother was a concert pianist.
From the latter, Sergio inherited his
love for music and, at the age of 8
years, started studying violin and musical theory. Unfortunately, in the
fourth year of these studies, he had to
stop playing the violin because of a
broken arm and never recommenced.
Both Sergio and his older brother
shared their father’s interest in medicine. As youngsters, they accompanied him when he held his Sunday
surgery at the hospital where he
worked. After finishing secondary
school at the Instituto Nacional
in Santiago, Sergio studied medicine
at the School of Medicine at the University of Chile and was awarded a
Degree in Surgery before the age of
24 years.
Dr. Vaisman has passed his fascination with medicine and music down
to the next generation: his eldest son
is a traumatologist, and his youngest
daughter is a student of cello and musical composition.
Dr. Vaisman likes to be out in nature
and, ever since he was a boy, has enjoyed going on camping trips. He has
always been a keen sportsman, playing basketball when younger and jogging for the last 25 years.
After 10 years as a physician, Dr.
Vaisman fulfilled one of his childhood dreams and began studying for
his pilot’s license. He continued to
make progress with this hobby, passing his instrumental flying examination and subsequently qualifying to
fly a multiengine aircraft. Proud owner of a twin-engine aircraft with room
for 6 passengers, he has covered the
country from its Northern-most point
(Arica) to its Southern-most point
(Punta Arenas), sometimes taking
sleeping bags and tents on board to
allow him to combine his passions for
camping and flying.
After more than 30 years as a pediatrician, Dr. Vaisman felt the need to
explore new avenues. This happened
in light of his frustration at treating a
group of patients whose conditions
could only be relieved, but not cured,
by conventional medicine. At this
crossroads in his career, he was invited to study for a Diploma in Biological Medicine, which he accepted to
explore new possibilities. He soon
realized that this was the opportunity
that he had been seeking, and he continued to study at all the levels offered
by the International Academy for
Homotoxicology. His initial attempts
to treat patients using this new approach allowed him to see for himself
the excellent results obtained when
applying bioregulatory therapy to pediatric patients. Because he was completely convinced that a combination
of conventional medicine and bioregulation was the ideal solution, and
taking advantage of his long teaching
career at the University of Chile, he
began to give talks to different groups
of physicians throughout the country
to make them aware of this approach
and increase the number of professionals with an understanding of this
therapy. These talks led him to coordinate a Diploma in Homotoxicology
in a School of Medicine at a university in Santiago de Chile.
He has also spoken at conferences
and symposia and taught diploma
courses in Chile, Colombia, Peru, and
Portugal.
His scientific contribution and support of the International Academy for
Homotoxicology was recognized at
the International Symposium on Bioregulatory Medicine, held in Bogota
in March 2012.|
) 23
) Practical Protocols
Bioregulatory Management
of Peptic Ulcer Disease
PhD, ND
Peptic ulcer disease (PUD) is a complex, multifactorial
disease of the gastrointestinal systems common in
industrialized nations.
P
eptic ulcer disease is the cause of
mucosal defects in the portions of
the gastrointestinal tract (GIT) that are
exposed to acid and pepsin. These
mucosal defects are termed ulcers if
they extend through the muscularis
mucosae. A further delineation into
gastric or duodenal ulcers is used if they
occur in the stomach or duodenum,
respectively.1
In the United States, PUD affects approximately 4.5 million people per
year, with an annual prevalence of
1.8%.1 The frequency of PUD varies
considerably between different countries (eg, Japan has an annual incidence of approximately 1 case, Norway has an annual incidence of
approximately 1.5 cases, and Scotland
has an annual incidence of approximately 2.7 cases per 1000 population)
and is determined mainly by association with the major reported causes:
infection by the bacterium Helicobacter
pylori and use of nonsteroidal anti-inflammatory drugs (NSAIDs).1 In general, the frequency of PUD is decreasing in the developed world but
increasing in developing countries.1
) 24
Peptic ulcer disease was previously
considered as a disease primarily of
males, but current estimates suggest
more of an even distribution, with a
male to female ratio of approximately
1:1. However, the average lifetime risk
of developing PUD is still slightly
higher in men (11%-14%) than in
women (8%-11%).1 The average age of
diagnosis for duodenal ulcers is between 30 and 50 years, whereas the
prevalence of gastric ulcers peaks in
those aged 50 to 70 years.1 Younger
patients are more likely to have non–
H pylori, non-NSAID gastric ulcers
than are more elderly patients.2
The pathogenesis of PUD is multifactorial, with contributions from several
factors, including excessive acid and
pepsin in the gastric lumen, defective
defensive mucosal barrier components
(eg, mucus, bicarbonate, and leaky intercellular junctions), impaired mucosal blood flow, cellular restitution, and
epithelial cell turnover.1 However, the
most commonly recognized causes are
persistent infections by H pylori, the
use of NSAIDs, and aspirin.1 Chronic
overwhelming stress was identified
historically as a major initiating factor
but is now generally considered sec-
ondary to an infection by H pylori.3
There is renewed interest in defining
the psychosocial etiology of PUD,4
with the recognition that the combined effect of H pylori and stress on
the development of ulcers is paramount.5 This heterogeneity of causes
of PUD is exemplified by numerous
other contributing factors identified,
including the genetic predisposition
of the host and environmental factors
(eg, cigarette smoking,6 excessive alcohol intake, and extreme emotional or
physical stress,1,7 including childhood
physical abuse8). Moreover, other
medications that have been associated
with the development of the gastritis
preceding PUD include potassium and
iron supplements and ethanol in both
chronic and binge drinkers.1
The most common symptom of PUD
is epigastric pain, often described as a
gnawing, burning sensation that occurs 2 to 3 hours after a meal and is
relieved by food and/or antacids.1,9
This pain might wake the patient at
night and possibly radiate into the
back. Other symptoms may include
nausea, heartburn, abdominal bloating, belching, intolerance to fatty
foods, and chest discomfort. Vomiting
may occur if there is partial or complete obstruction of the gastric outlet,
and hematemesis or melena can accompany bleeding in the GIT. In addition to epigastric tenderness, signs of
melena and succussion splash also occur because of GIT bleeds and/or gas-
tric outlet obstructions.1 Ulcers induced by NSAID use might have no
overt symptoms or nonspecific physical findings, similar to uncomplicated
PUD.1
The major complications of PUD include GIT bleeds and perforations of
ulcers, with the potential development
to peritonitis and sepsis.1 Infection by
H pylori also has been identified as one
of the complex host and environmental factors that increase the risk of gastric adenocarcinoma,9 possibly because of its ability to initiate and
sustain chronic nonresolving inflammation.10 Although the mortality rate
of PUD is relatively low, it can significantly impair a patient’s well-being
and quality of life and is associated
with high costs for employers and
health care systems.11
In most patients with uncomplicated
PUD, routine laboratory tests are not
helpful in the diagnosis, and radiographic and endoscopic imaging techniques are needed for confirmation.1
Establishing that there is an overwhelming infection by H pylori is considered of primary importance in most
patients with peptic ulcers. This can be
measured using endoscopic and invasive testing (eg, rapid urease test, histopathological analysis, and culture)
or nonendoscopic and noninvasive
testing (eg, serum H pylori antibody
detection, fecal antigen tests, and urea
breath tests).1,12 An endoscopic examination of the upper GIT is the preferred diagnostic test in the evaluation
of patients with suspected PUD,
whereas other tests for suspected
Zollinger-Ellison syndrome include a
fasting serum gastrin level and secretin
stimulation tests. Chest x-ray, electrocardiographic, and computed tomographic scan results are used to exclude other conditions, such as
detecting free abdominal air in the
case of a perforation and myocardial
infarction.1
Given the current understanding of
the pathogenesis of PUD, most patients with PUD are treated for H pylori infection (with initial estimates of
success in 85%-90% of cases, but values decreasing to <80%) and/or
avoidance of NSAIDs, along with the
appropriate use of antisecretory therapy. Eradication of H pylori is a prolonged and complicated process, most
commonly with a triple-therapy approach with either amoxicillin or metronidazole, clarithromycin, and a proton pump inhibitor given twice daily
Table. Bioregulatory Treatment of Peptic Ulcer Diseasea
DET-Phase
Endodermal
Mucodermal
Impregnation
Basic and/or Symptomatic
•
Gastricumeel
•
(gastric)
Duodenoheel
(duodenum)
Regulation Therapyb
Optional
D&D
•
•
Advanced detoxification and drainage,c
followed by
Basic detoxification and drainage: Detox-Kitd
•
IM
•
Traumeel
CTOS
•
•
•
Mucosa compositum
Coenzyme compositum*
Ubichinon compositum*
to degeneration
Atropinum compositum
(if there is acute pain)
Dosages: Basic therapy: 1 tablet 3 times per day. Regulation therapy: tablets, 1 tablet 3 times per day; drops, 10 drops 3 times per day;
ampoules, 1 ampoule of each medication, 1 to 3 times per week. Detox-Kit, 30 drops of each medication in 1.5 L of water (drink throughout
the day). Optional therapy: 1 ampoule 1 to 3 times per week.
Abbreviations: CTOS, cellular, tissue, and organ support; D&D, detoxification and drainage; DET, Disease Evolution Table; IM, immunomodulation.
a
As an adjunct to standard medical treatment.
b
Antihomotoxic regulation therapy consists of a 3-pillar approach: D&D, IM, and CTOS.
c
Advanced supportive detoxification and drainage consists of Hepar compositum (liver), Solidago compositum (kidney), and Thyreoidea
compositum (connective tissue).
d
The Detox-Kit consists of Lymphomyosot,† Nux vomica-Homaccord, and Berberis-Homaccord.
* In Canada, replace Coenzyme compositum and Ubichinon compositum by Ubicoenzyme.
† Marketed in Canada as “Lyphosot”.
) 25
Photograph by Samir; licensed under the Creative Commons
Attribution-Share Alike 3.0 Unported license; http://en.wikipedia.org/wiki/Image:Deep_gastric_ulcer.png.
Gastric ulcer
for 7 to 14 days as the first-line treatment.1 Also, proton pump inhibitors
exacerbate NSAID-induced small intestinal injury, possibly by inducing
dysbiosis, suggesting that it would be
prudent to avoid NSAIDs during this
treatment.13 Because of increasing resistance of H pylori to antibiotics, there
are reports of “unacceptably low treatment success” and accompanying proposals to alter the therapy to potentially increase therapeutic value.14,15
The presence of H pylori needs to be
initially confirmed and then shown to
be eradicated because ulcers have been
shown to relapse in unsuccessful H pylori elimination.1,12
) 26
There are insufficient data to support
any special diet in assisting with the
healing of PUD, although some studies demonstrate that the consumption
of common spices in food (eg, clove,
cinnamon, oregano, black pepper, turmeric, and ginger) and supplementation with certain herbal medicines can
have definite beneficial effects on the
gastric mucosa and may be of great
benefit for the prevention of gastric
ulcers.1,16 With the success of medical
therapy, surgery has a very limited role
in the management of PUD and is
only recommended in refractory cases
and complications of PUD (eg, obstructions, perforations, penetration,
and massive GIT bleeding).1,17 With
the declining success rates of conventional triple-therapy treatments, it is
evident that there is an opportunity
for medications with bioregulatory
properties, and other natural health
products, to be used as adjunctive
therapies in the treatment and prevention of recurrence of peptic ulcers.
Bioregulatory Intervention
A small interventional trial using medications with bioregulatory properties
(ie, Gastricumeel, Nux vomicaHomaccord, Lymphomyosot, and Coenzyme compositum/Ubichinon compositum) demonstrated that this also
was an effective method of eradicating
H pylori and, therefore, treating one of
the recognized causes of PUD.18 As
previously described, there are several
potential networks that can contribute
to the development of PUD. The bioregulatory medical approach to treatment is shown in the Table.|
References
1. Anand BS. Peptic ulcer disease. Medscape
Reference Web site. http://emedicine.medscape.com/article/181753-overview.
Accessed March 29, 2011.
2. Xia HH, Phung N, Kalantar JS, Talley NJ.
Demographic and endoscopic characteristics
of patients with Helicobacter pylori positive
and negative peptic ulcer disease. Med J Aust.
2000;173(10):515-519.
3. Gustafson J, Welling D. “No acid, no ulcer”–100 years later: a review of the history of peptic ulcer disease. J Am Coll Surg.
2010;210(1):110-116.
4. Jones MP. The role of psychosocial factors in peptic ulcer disease: beyond Helicobacter pylori and NSAIDs. J Psychosom Res.
2006;60(4):407-412.
5. Fink G. Stress controversies: post-traumatic
stress disorder, hippocampal volume, gastroduodenal ulceration. J Neuroendocrinol.
2011;23(2):107-117.
6. Zhang L, Ren JW, Wong CC, et al. Effects
of cigarette smoke and its active components on ulcer formation and healing in
the gastrointestinal mucosa. Curr Med Chem.
2012;19(1):63-69.
7. Leong RW. Differences in peptic ulcer between the East and the West. Gastroenterol
Clin North Am. 2009;38(2):363-379.
8. Fuller-Thomson E, Bottoms J, Brennenstuhl
S, Hurd M. Is childhood physical abuse
associated with peptic ulcer disease? Findings from a population-based study. J Interpers
Violence. 2011;26(16):3225-3247.
9. Pritchard DM, Crabtree JE. Helicobacter pylori and gastric cancer. Curr Opin Gastroenterol.
2006;22(6):620-625.
10.Polk DB, Peek RM Jr. Helicobacter pylori:
gastric cancer and beyond. Nat Rev Cancer.
2010;10(6):403-414.
11. Barkun A, Leontiadis G. Systematic review of
the symptom burden, quality of life impairment and costs associated with peptic ulcer
disease. Am J Med. 2010;123(4):358-366.
e352.
12. Costa F, D’Elios MM. Management of Helicobacter pylori infection. Expert Rev Anti Infect
Ther. 2010;8(8):887-892.
13.Wallace JL, Syer S, Denou E, et al. Proton
pump inhibitors exacerbate NSAID-induced
small intestinal injury by inducing dysbiosis. Gastroenterology. 2011;141(4):13141322,1322.e1-5.
14. Graham DY, Fischbach L. Helicobacter pylori
treatment in the era of increasing antibiotic
resistance. Gut. 2010;59(8):1143-1153.
15. Chuah SK, Tsay FW, Hsu PI, Wu DC. A new
look at anti-Helicobacter pylori therapy. World
J Gastroenterol. 2011;17(35):3971-3975.
16. Al Mofleh IA. Spices, herbal xenobiotics and
the stomach: friends or foes? World J Gastroenterol. 2010;16(22):2710-2719.
17.Stewart DJ, Ackroyd R. Peptic ulcers
and their complications. Surgery (Oxford).
2008;26(11):452-457.
18. Ricken K-H. Clinical treatment of functional
dyspepsia and Helicobacter pylori gastritis.
Biomed Ther. 1997;15(3):76-81.
) E x p a n d Yo u r Re s e a r c h K n o w l e d g e
Noninterventional Studies:
An Overview
By Robbert van Haselen,
MSc
In the previous article in this series, I further elaborated
on the different types of clinical trials; in this article,
I will provide a further overview of the main types of
noninterventional studies.
N
oninterventional studies, also
called nonexperimental studies,
are studies that do not involve any
intervention (experimental or otherwise) on the part of the investigator.
Such studies have in common the
use of an observational research design. In the conduct of noninterventional studies, the same rigor must be
applied as in experimental studies.1,2
The main types of noninterventional
studies are summarized in Table 1.
Noninterventional studies fall under
the header of “observational epidemiology,” in which the main exposures (eg, environmental factors or
treatments) are not under the direct
control of the epidemiologist.
Noninterventional studies can involve either populations or individual patients. The main comparative
noninterventional studies are cohort
studies and case-control studies. The
main descriptive noninterventional
studies are cross-sectional studies,
case series, and case reports.4
In Table 2, the main types and characteristics of noninterventional studies are summarized.
It should be noted that the temporal
perspective refers to the main temporal orientation of a particular epidemiological design and not to the
data collection process itself. For instance, in cohort studies, sometimes
the data are collected retrospectively
“after the event” (eg, by linking back
to records that enable the reliable
identification of different levels of
the exposure of interest). The latter
are often called historical cohort studies, but even such a study is prospective in terms of following up “the
march” of cohorts with different exposure levels to a health outcome of
interest. Historical cohort studies are
less common nowadays because of
the increasing ethical barrier of privacy/data protection.
Cohort studies that compare the
outcomes of differently treated cohorts are possible but are particularly
susceptible to selection bias: the cohorts are noncomparable with respect to other factors than the treatments of interest. The latter can be
partly addressed by recording/assessing all the relevant determinants
of outcome in both cohorts and then
adjusting for any confounding due
to these factors during the analysis.
The risk remains, however, that not
all relevant determinants of outcome
have been assessed and that the
causal attribution of findings to a
particular treatment remains biased.
There is no real solution for this
problem because it is, in practice, impossible to know and validly assess
all the determinants of outcome.
Therefore, in medicine, investigators
often resort to the “next best” thing
for managing ignorance: randomization. Provided there are sufficient
patients included, the latter ensures
that the known and unknown confounders are equally distributed
(without selection bias) between the
treatment groups. However, randomized studies are sometimes unnecessary, inappropriate, impossible, or
inadequate5; therefore, a need for
noninterventional studies remains.
More recently, so-called hybrid designs have been proposed, in which
several clinical trials are embedded
within a cohort study.6 Such innovative mixed designs may be particularly suited when the assessment of
the additional value of treatment is
compared with “treatment as usual,”
and this is often relevant in complementary and alternative medicine
research. Although such designs
hold promise, they may not always
be feasible.
) 27
© iStockphoto.com/Mutlu Kurtbas
Case-control studies are primarily
used for etiological research. They
used to be termed retrospective because, conceptually, the temporal
orientation is from the disease onset
backward to the postulated causal
factors. Yet, cases and controls in a
case-control study are often accumulated prospectively. A further variant
is the so-called nested case-control
study, in which the cases and controls are drawn from the population
of a larger cohort study. An advantage of such nested designs is that,
because of the larger cohort study,
more detailed and reliable information on the environmental (eg, nutritional) factors on the cases and controls can be obtained.
Cross-sectional studies examine the
presence or absence of disease in relation to the presence or absence of
other variables in each member of a
representative sample of the study
population at a particular point in
time. In this manner, potential correlations between the presence or
absence (or level) of variables in the
diseased versus the nondiseased
members can be determined. However, the presence of a correlation
does not necessarily imply causation.
The classic example of this in epidemiology is the correlation between
more storks and larger families in
rural areas compared with urban areas. This does not necessarily imply
that the storks carry the babies! For
causal attribution, biological plausibility and prospectively collected
data are a precondition.
Noninterventional studies are all
“observational,” but this should not
be confused with qualitative observational studies that are different
from the studies listed in Table 2.
Observational methods used in the
social sciences involve the systematic, detailed observation of behavior
and talk: the qualitative researcher
systematically watches people and
events to find out about behaviors
and interactions in natural settings.
Observation, in this sense, represents
the idea of the researcher as the research instrument, as someone who
Table 1. Main Types of Noninterventional Studiesa
) 28
Type of Study
Description of Study
Cohort
A group of patients or subjects with defined characteristics, which is followed up (“marching
forward in time”). This type of study usually involves the identification of 2 or more cohorts of
patients, one receiving the exposure/treatment of interest and the other(s) not, and
following-up of these cohorts regarding the outcome of interest.
A noninterventional study with a single cohort of patients is also possible. Such studies
usually occur in routine clinical practice, with the aim to describe treatment and outcomes.
Case-control
A study that involves the identification of patients who have the outcome of interest and
control patients who do not have the outcome of interest and then reviewing to determine
if they had the exposure/treatment of interest.
Cross-sectional
A study that examines the relationship between diseases and other variables of interest as
they exist in a defined population in a particular point in time.
Case series
A report on a series of patients with an outcome of interest. No control group is involved.
Data adapted from Porta.3
a
) E x p a n d Yo u r Re s e a r c h K n o w l e d g e
goes out into the field.4 A further
elaboration on qualitative research
methods is outside the scope of this
article.
There are now reporting guidelines
for most types of studies. For comparative and cross-sectional epidemiological studies, there is the
STROBE guideline.7 However, for
case series and case reports, there are
not yet reporting guidelines.|
References
1. Kelsey JL, Whittemore AS, Evans AS, Douglas Thompson W. Methods in Observational
Epidemiology. 2nd ed. New York, NY: Oxford
University Press; 1996.
2. Schnetzler G, Hayward C. Overview of
guidelines and recommendations for the
planning, conduct and reporting of company-sponsored observational, noninterventional studies in Europe. Pharm Med.
2011;25(4):235-244.
3. Porta M, ed. A Dictionary of Epidemiology.
5th ed. New York, NY: Oxford University
Press; 2008.
4. Mays N, Pope C. Qualitative research: observational methods in health care settings.
BMJ. 1995;311(6998):182-184.
5. Black N. Why we need observational studies
to evaluate the effectiveness of health care.
BMJ. 1996;312(7040):1215-1218.
6. Relton C, Torgerson D, O’Cathain A, Nicholl J. Rethinking pragmatic randomised controlled trials: introducing the “cohort multiple randomised controlled trial” design. BMJ.
2010;340:c1066. doi: 10.1136/bmj.c1066.
7. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP;
STROBE Initiative. The Strengthening the
Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines
for reporting observational studies. Lancet.
2007;370(9596):1453-1457.
Table 2. Overview of Different Types of Noninterventional Studies
Type of Study
Study Base
Temporal Perspective
Focus
Comment
Cohort:
2 or more
cohorts
Patient
populations
Prospective
Analytical/hypothesis
testing
This type of cohort study is used to assess the
health-related effects of environmental exposures or therapeutic interventions.
Cohort:
1 cohort
Patient
populations
Prospective
Descriptive
This type of cohort study is often referred to as
postmarketing surveillance study. In Germanspeaking countries, the term Anwendungsbeobachtungen is often used.
Case-control
Patient
population
Retrospective
Analytical/hypothesis
testing
Case-control studies are used to investigate the
potential relationship between a suspected risk
factor or attribute and disease.
Cross-sectional
Patient
populations
Particular point in time
Prevalence and correlations
Cross-sectional studies are not suitable to determine a temporal sequence between cause
and effect.
Case series
Patient
populations
Prospective or retrospective
Descriptive
Case series lack formal hypotheses and study
protocols; if they had these characteristics, they
would be cohort studies.
Case reports
Individual
patients
Prospective or retrospective
Descriptive
Case reports can serve among other educational, medical, safety monitoring, or hypothesisgenerating purposes.
) 29
) Re s e a r c h H i g h l i g h t s
A Multicomponent Medication
Triggers Multiple Beneficial Effects
Related to Cognition and Neuronal
Function
By Kerstin Röska, PhD,
and Bernd Seilheimer, PhD
Background
tivate, or modify it. To better mirror
disease complexity, future drug discovery approaches should aim
at multiple targets using multicomponent medications. Our study
describes the use of HE-300, a multicomponent multitargeted medica
tion, to treat cognitive dysfunction
and its effects on neuronal function.
During the Society for Neuroscience Congress in Washington, DC,
which was held from November 12
to 16, 2011, 3 posters on the beneficial effects of a multicomponent
natural medication, termed HE-300,
on cognitive dysfunction were presented. This meeting had more than
30 000 participants and is the premier venue for neuroscientists from
around the world to debut cuttingedge research on the brain and the
nervous system.
Introduction and
Research Objective
) 30
Disorders of cognition and memory,
such as dementia, are complex,
chronic, and multifactorial, with unknown etiology. The fact that we
know little about the molecular
pathways that result in cognitive decline and neuronal cell death led to
the development of drugs lacking
any disease-modifying effect. All
therapeutic options currently available only treat the symptoms of the
underlying disease. Another limiting factor comes along with modern
drug discovery, which is based on a
reductionist approach. The focus is
always on a single target and a single molecule designed to block, ac-
Materials and Methods
The study included a series of genomic, in vitro, ex vivo, and in vivo
experiments related to neuronal
function and cognitive impairment.
First, a systematic gene analysis of
the whole genome (“next-generation sequencing”) was performed in
rats after treatment with HE-300.
This single-molecule sequencing
technology identified gene clusters
affected by HE-300 that are involved in neuronal function and
cognitive decline. Second, the gene
analysis data were instrumental for
the development of functional assays to determine the effect of HE300 on neuronal outgrowth, synaptic transmission, and amyloid
precursor protein (APP) processing.
Third, several studies using a variety
of behavioral animal models were
performed to determine in vivo efficacy. HE-300 (1-2 mL/kg) was tested in learning and memory models,
such as spatial memory (T-maze),
olfactory memory (Social Transmission of Food Preference), and methods to test memory of fear (Passive
Avoidance and Contextual Fear
Conditioning). A synthetic drug for
the treatment of dementive disorders, donepezil, was included in the
investigations as a positive control.
Two different species, mice and rats,
were used in scopolamine-induced
memory impairment. Scopolamine,
an acetylcholinesterase inhibitor,
was given before HE-300 treatment,
reflecting the dementive state after
loss of acetylcholine neurons.
Results
Our study revealed that the multicomponent multitargeted medication, HE-300, affects the expression
of gene clusters associated with synaptic function in the rat hippocampus 2 and 3 days after treatment
(Figure). The gene networks associated with β-amyloid binding, cognition, and synaptic plasticity were
mainly influenced. A significant effect on genes for APP and
β-secretase, 2 proteins involved in
the pathology of Alzheimer disease,
could be observed. Furthermore,
synaptophysin, a synaptic vesicle
glycoprotein, and synaptotagmin 3,
a membrane-trafficking protein,
) Re s e a r c h H i g h l i g h t s
Figure. Modeling Molecular Networks1
The illustration shows the gene network that plays a role in cognitive functions. The
points marked in green display the genes that are influenced by the multicomponent
natural medication, HE-300. HE-300 significantly reduces the gene expression of APP
and BACE, which are responsible for the formation of β -amyloid plaques in Alzheimer
disease.
were highly influenced in their expression levels, indicating that HE300 affects synaptic transmission.
The functional assays demonstrated
that HE-300 significantly decreases
soluble APP levels in neuronal cells,
which was consistent for 72 hours.
These data confirmed and supported
the results from the genomic analysis. It is suggested that HE-300 influences the generation of β-amyloid
protein, which hallmarks Alzheimer
disease. Furthermore, HE-300 induces the elongation of dendrites of
primary hippocampal neurons and
restores age-related modifications of
synaptophysin messenger RNA in
the rat cortex. The behavioral tests
confirmed the supporting effect of
HE-300 on cognitive function: HE300 not only significantly improved
natural forgetfulness, but also scopolamine-induced deficits in learning and memory tests, such as the
T-maze, Passive Avoidance, Contextual Fear Conditioning, and Social
Transmission of Food Preference.
HE-300 attained similar efficacy as
the gold standard, donepezil, in all
in vivo test systems and displayed
beneficial effects on memory function in both species used.
Discussion
learning. Therefore, HE-300 emerges as a true disease-modifying agent
and may be an efficient and alternative option in the challenge to understand, treat, and defeat diseases
associated with cognitive dysfunction. These data are a good foundation for future clinical studies to investigate the therapeutic effect of
HE-300 in humans.|
Our study shows that the multicomponent multitargeted medication,
HE-300, enhances and improves
cognitive functions on genomic,
functional, and behavioral levels.
The research results imply that this
drug is able to influence the development and maintenance of dementive states. Because of the nature of
the medication used, the biological
and clinical effects may arise from
different targeted biochemical pathways involved in cognition and
Reference
1. Schnack C, Hellrung A, Seilheimer B, et al.
A multicomponent medication (HE-300)
targets the mechanisms related to Alzheimer
disease: in-vitro & in-vivo assessment. Poster
presented at: Neuroscience 2011; November
12-16, 2011; Washington, DC.
) 31
IAH Abbreviated
Course
An e-learning course leading to
certification in homotoxicology
from the International Academy for
Homotoxicology in just 40 hours.
1 Access the IAH website at www.iah-online.com. Select your language.
2 Click on Login and register.
3 Go to Education Program.
4 Click on The IAH abbreviated course.
5 When you have finished the course, click on Examination.
After completing it successfully, you will receive your
certificate by mail.
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Free of charge
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