In Focus - Traumeel
Transcription
In Focus - Traumeel
d 2.00 • US $ 2.00 • CAN $ 3.00 Biomedical Therapy J o urnal o f Volume 3, Number 2 ) 2009 Integrating Homeopathy and Conventional Medicine Mucosal Distress • Intestinal Permeability and Its Role in Disease • Differential Treatment of Chronic Rhinosinusitis Contents I n Fo c u s Intestinal Permeability and Its Role in Disease . . . . . . . . . . . .4 W h a t E l s e I s N e w ? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12 Re f r e s h Yo u r H o m o t ox i c o l o g y The Mucosal Immune System: Functional Properties and Potential Clinical Implications . . 14 Specialized Applications Immune Modulation With Microdose Combination Products . . . . . . . . . . . . . . . . . 17 Meet the Expert Dr. Bert Hannosset . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19 Practical Protocols Chronic Rhinosinusitis With and Without Polyps: Differential Treatment With Bioregulatory Medicines . . . . .20 M a r ke t i n g Yo u r P r a c t i c e Think About the Future! . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Re s e a r c h H i g h l i g h t s Gastrointestinal Cramps in Children: Spascupreel Comparable to Hyoscine Butylbromide . . . . . . 24 Making of ... Manufacturing of Traumeel Injection Solution Part II: Sterilization, Quality Control, Labeling, and Packaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26 Cover photograph © MedicalRF.com/Getty Images )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 charge/verantwortlicher Redakteur: Dr. Alta A. Smit Print/Druck: VVA Konkordia GmbH, Dr.-Rudolf-Eberle-Straße 15, 76534 Baden-Baden, Germany © 2009 International Academy for Homotoxicology GmbH, Baden-Baden, Germany © H. P. Hoff/artbotanica ) ) A Block to Bioregulation Dr. Alta A. Smit W hy devote an entire issue to mucous membranes? The body’s mucosal surfaces have often been compared to a sixth sense, and as evolution progressed from unicellular organisms to complex structures, the mucosae had to adapt to become both barriers to harmful substances and selective sieves permitting passage of nutrients and other beneficial substances. The mucous membranes therefore constitute one of the body’s most sophisticated immune organs. The role of the epithelium itself in the immune process is also the subject of intense research.1 The mucosal immune system in all its complexity makes up the largest part of our immune system, and research is increasing our knowledge not only of how immune responses in general are evoked, but also of how the mucosal system is linked to the systemic immune system. Recent years have seen a major shift in how we view disease in relation to the mucosal immune system: Certain diseases once classified as autoimmune disorders are now understood as autoinflammatory disorders, and conventional medical literature is also beginning to view a lack of acute inflammatory response as a cause of disease, as bioregulatory practitioners have known for decades.2 It is thus no wonder that mucosal distress span many specialties, from gastroenterology to gynecology; more surprising, though, is the interest of disciplines such as neurology and rheumatology (see focus article). Bioregulatory medicine, moreover, sees mucosal distress as one of the major blocks to bioregulation and therefore an essential consideration in developing any treatment regimen. We begin our investigation with a focus article on gut permeability by Dr. David Lescheid, followed by an overview article on mucosal immunity by Dr. Doris Ottendorfer, a recognized specialist in this field. The rubric Specialized Applications illustrates how this knowledge can be applied, and the column Practical Protocols demonstrates how modern immune research into debilitating conditions such as chronic rhinosinusitis can aid in refining our bioregulatory microdose therapy. Mary Kingzette summarizes a cohort study that compares Spascupreel to the reference drug hyoscine butylbromide and concludes that the microdose product is just as effective as the conventional drug in treating spasms in children. The Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 Making of … presents the second part of ampoule manufacturing (although mucosal distress, of course, is more likely to benefit from direct sublingual or intranasal administration rather than injections). As usual, marketing specialist Marc Deschler has excellent advice for practitioners, this time writing about the importance of adequate financial planning. Last but not least, we continue revealing our experts in a new light, this time with Dr. Bert Hannosset, the vice president of the International Society of Homotoxicology and Homeopathy. Dr. Alta A. Smit References: 1. Schleimer RP, Kato A, Kern R, Kuperman D, Avila PC. Epithelium: at the interface of innate and adaptive immune responses. J Allergy Clin Immunol. 2007;120(6):1279-1284. 2. Marks DJ, Harbord MW, MacAllister R, et al. Defective acute inflammation in Crohn’s disease: a clinical investigation. Lancet. 2006;367(9511):668-678. )3 ) I n Fo c u s Intestinal Permeability and Its Role in Disease By David Lescheid, PhD, ND Maintaining integrity in the gastrointestinal (GI) tract is of paramount importance in our overall health. The commonly recognized functions of the GI tract (digestion, secretion, absorption, and motility) can occur effectively only if there are intact epithelial membranes. These functions must occur properly to provide us with the nutrients that we need to support our activities of daily living. T )4 he mucous membranes of the GI tract also provide compartmentalization, protecting the relatively fragile, homeodynamic internal milieu from the relatively harsh environment of the intestinal lumen. Mucosal membranes include many different structures and cells with unique roles in maintaining the physical, chemical, and immunological barrier functions.1 Another major function of the GI tract is immunity. The epithelial cells of the GI tract provide the first line of defense, protecting us from the potentially dangerous or foreign substances brought into our body via our food and drink. Furthermore, most pathogenic microbes, including many medically important viruses,2 must cross a mucosal barrier to cause disease. It is estimated that up to 80% of the immune system cells are initiated in the GI tract or spend a good portion of their life there. The gut-associated lymphatic system (GALT) is part of an interdependent mucosal immune system termed the mucosa-associated lymphatic system (MALT). Immunocompetent cells that develop in the GALT are transported via the lymphatic system to the circulatory system to be carried to other mucous membranes, such as the respiratory and urogenital tracts, to provide protection. This interdependence between all mucous membranes in the body is important because it means that by using bioregulatory medicines to restore integrity in the GI tract, we can influence the overall immune system and general health. The immunological barrier function is a very dynamic and complex one, with roles not only in protection from substances that are foreign and/or potentially dangerous but also in tolerance to commensal microflora and the nutrients that are Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 digested and absorbed to maintain normal body functions (Figure). In the healthy GI tract, with intact mucous membranes, tolerance is the predominant immunological function. Therefore, we do not react to the daily nutrients that we need to support our physiological functions. If the GI tract barrier is compromised, there is a breakdown in tolerance, leading to increased reactivity, chronic activation of immune system cells, and production of cytokines that can have localized and systemic effects. Some of the more common diseases associated with a breakdown in the integrity of the GI tract include the inflammatory bowel diseases3 and certain autoimmune diseases, such as ankylosing spondylitis, IgA nephropathy and multiple sclerosis,4 type 1 diabetes mellitus,5 and autism.6 Other conditions associated with a hyperpermeable GI tract include congestive heart failure,7 chronic venous insufficiency and the development of leg ulcers,8 major depressive disorder,9 chronic fatigue immune deficiency syndrome,10 gallstones,11 and progression of human immunodeficiency virus (HIV) infection.12 The documented relationship between a “leaky gut” and so many important diseases, as described, speaks to the importance of medical interventions that can safely and effectively promote healing in a timely manner. This article will describe ) I n Fo c u s the scientific support for the use of antihomotoxic medicines in treating a hyperpermeable GI tract and restoring optimal health. Using homotoxicology to treat a hyperpermeable GI tract One of the inherent strengths in homotoxicology is that it provides a very well thought out, logical approach to the progression of diseases and of disease regression. The Disease Evolution Table (DET) outlines a framework from which to position a disease in relation to its status of regulation and deregulation and to which germ layer of tissue has been affected. It also provides a relative guide as to the prognosis of the disease and the phases that might occur during healing. On the DET, a leaky gut is classified on the vertical axis in the section on endodermal tissue, just to the right of the regulation/compensation division in the impregnation phase. It means that it will take some time to restore gut integrity and that all 3 pillars of homotoxicology (i.e., organ regulation and cellular activation, immunomodulation, and detoxification) will have to be used to provide complete resolution. In any disease, it is important to first examine the broader picture and ask what external influences might be contributing to the disease or acting as obstacles to cure the disease. For example, we know that many substances (e.g., gluten, certain food additives, heavy metals, and inhalants) affect the permeability of the GI tract. Microbial infections and aging also can increase permeability. Excessive, regular consumption of alcohol13,14 and high fructose corn syrup15 are also associated with the development of a leaky gut in susceptible people. It is important to discontinue this external supply of toxins as a first step towards resolution. Discontinuing these toxins supports the 4-S approach to detoxification: Stop (the external supply of Blood stream toxins), Support (the organs of detoxification and drainage), Stimulate (elimination of toxins), and Sensitize (the patient for detoxification). Other toxins that affect the permeability of the GI tract include pharmaceutical drugs, such as proton pump inhibitors16 and nonsteroidal antiinflammatory drugs (e.g., cyclooxy genase [COX] 2 inhibitors).17,18 Zeel has been shown to be as effective as COX-2 inhibitors in a clinical trial of patients with mild to moderate arthritis of the knee.19 There are numerous clinical trials demonstrating that topical Traumeel effectively manages pain in many different musculoskeletal disorders, including acute symptomatic treatment of tendinopathy.20 These studies suggest that antihomotoxic medicines can be used as anti-inflammatory agents that will not damage the GI tract. The permeability of the GI tract is not only affected by physical toxins, but also by lifestyle events or stressors on mental or emotional levels. Blood flow to the liver Figure. Intestinal mucosa. The mucosal Lymph node barrier prevents harmful substances (e.g., toxins, pathogenic bacteria, and in- CRH and TRH receptor flammatory mediators) from entering the body. At the same time, it serves as a highly selective filter, ensuring the absorption of useful substances (e.g., food particles) through tight junctions and epithelial cells. Food particles Bacteria CRH NSAIDs Alcohol Probiotic bacteria Unstirred water Tight junction Enterocyte Abbreviations: CRH, corticotropin-reEpithelial barrier Mucus layer leasing hormone; NSAID, nonsteroidal anti-inflammatory drug; TRH, thyrotropin-releasing hormone. )5 Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 ) I n Fo c u s )6 For example, it has been shown that even a short period of sleep deprivation in mice will cause a profound change in permeability of the GI tract and translocation of bacteria to normally sterile sites, such as the mesenteric lymph nodes, spleen, pancreas, and blood.21 Chronic insomnia in humans is also associated with the production of proinflammatory cytokines and the reduction of antioxidant systems and hormones that can lead to hyperpermeability in the GI tract.22 Neurexan is an antihomotoxic medicine that is useful in treating insomnia and helping to relax persons who are overstimulated by the stressors of daily living.23 Modulating stressors, such as insomnia, can be an important part of treating a leaky gut because it has been shown in animal studies that chronic psychological stress will cause hyperpermeability in the GI tract and predispose the animals to hypersensitivity and illness.24,25 We have known for years that there is a connection between the nervous, endocrine, and immune systems via shared signaling molecules, receptors, and anatomical locations.26,27 This field of psychoneuroimmunology has provided the scientific proof that there is a gut-brain connection and that physiological or pathological changes in one of these organs profoundly influence the function of the other organ. Recently, a parasympathetic anti-inflammatory pathway has been described; this pathway connects the cytokine signals in the GI tract with vagus nerve fibers, the brain, acetylcholine and its receptors on macrophages, and further changes in cytokine signals.28,29 This pathway, termed the cholinergic anti-inflammatory pathway, provides the evidence needed to support the role that modulating parasympathetic nervous system output from the brain can play in healing the leaky gut. Several effective methods of modulating this pathway include acupuncture, biofeedback, mindfulness meditation, various forms of physical therapies, and chiropractic techniques.28,29 Furthermore, there are a number of antihomotoxic medications that have been shown to be very effective in modulating the psychosomatic influences on disease states. These include Nervoheel, for anxiousness and irritability23,30; Neuro-Injeel/ Neuro-Heel, for deeper pathologies, particularly for someone who has never been well since a specific life event; and Tonico-Injeel/TonicoHeel, for physical and mental exhaustion from overwork.23 Correcting any dysregulation in the brain is an important component of healing a leaky gut. This healing can occur indirectly by modulating shared signaling molecules, such as cytokines, between the organs, as described previously. Alternately, this restoration can occur directly because there is recent evidence that physical structures previously thought to be found only in the central nervous system are also found in the GI tract.31 This is the so-called brain-gut axis. It is suggested that “cellular interactions previously thought to be unique to the blood-brain barrier, also regulate gut epithelial permeability.”31 This evidence provides further support to the potential of using medicines commonly considered to be nervous system specific as adjuncts to healing the GI tract. Once the external factors contributing to the development of a leaky gut, or interfering with self-regulation, have been identified and addressed, it is important to begin treatments using the 3 pillars of homotoxicology. Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 Cross section of gut mucosa 1. Organ regulation and cellular activation There are a number of different antihomotoxic medicines that will support and regulate the organs of the GI tract. One of the key structures contributing to the physical barrier function of the GI tract is the tight junction between the epithelial cells. These tight junctions ensure that most of the substances that are absorbed follow the intracellular pathway rather than the paracellular pathway. By following the intracellular pathway, they are carefully processed by the intracellular enzymes and biochemical pathways of the epithelial cells before they enter the lymphatic or circulatory systems to be carried to the rest of the body. Two important processes in GI epithelial cells are the cytochrome P450 enzyme sys- ) I n Fo c u s tems,32,33 which are involved in the phase I and phase II detoxification of substances; and the p-glycoprotein and cation/anion transporter systems,34,35 which act as phase III transporters regulating the influx and efflux of certain drugs, metals, and toxins. The function of both of these systems can be supported by Mucosa compositum. Furthermore, these intracellular processes are energy dependent and, therefore, the use of Coenzyme compositum is indicated to help support the Krebs/ tricarboxylic acid cycle generation of adenosine triphosphate (ATP). The tight junctions are also complex, dynamic structures that can be influenced by many different types of stimuli,36 possibly including antihomotoxic medicines. A breakdown in the integrity of tight junctions has been associated with many different diseases.37 The tight-junctional complex consists of a number of different proteins, including zonulins, occludins, and claudins; a number of different kinases; and a junctional adhesion protein, which is a member of the immunoglobulin superfamily.38 The claudins and the occludins form extracellular loops that span the gap between the cells. The claudin proteins are water-filled pores that carefully select substances that enter the paracellular pathway based on charge and size. Zonulins act as tethering proteins linking the claudins to the intracellular matrix via their attachment to actin and myosin. This structural arrangement of the tight-junctional complex means that changes in the intracellular matrix, via actin-myosin interactions, can affect the opening and closing of the claudin pores and, therefore, the integrity of the epithelial barrier. The myosin heads have ATPase activity and, therefore, hydrolyze ATP to provide the energy to help them move along the actin strands.39 This energy-dependent process can be supported by the use of Coenzyme compositum, an antihomotoxic medicine that is thought to generate ATP via its influence on the intracellular Krebs/tricarboxylic acid cycle. 2. Immunoregulation If the tight-junctional complexes become permeable, macromolecules, including substances in food and drink that have not been thoroughly processed and microflora and their endotoxins, cross into the supporting aerolar connective tissue and interact with the immune system cells located there. These interactions result in the synthesis and secretion of inflammatory cytokines, such as interleukin (IL) 1b, tumor necrosis factor (TNF) α, and interferon g. These cytokines also directly affect the tight-junctional architecture to further increase permeability.38,40 A positive feedback loop is set up, with increased intestinal permeability up-regulating the synthesis and secretion of proinflammatory cytokines that increase permeability even further. Reversing a leaky gut requires repairing the physical tight-junctional structure, as described previously, in addition to modulating the inflammatory cytokines that are further impairing the healing process. According to a number of animal and human observational studies, it appears that the actual physical damage to the mucosal epithelial cell barrier occurs prior to the induction of excessive proinflammatory cytokines.41 This further strengthens the importance of structural and functional organ support, as described previously, as an initial strategy to treating the leaky gut. Once substances have crossed the mucosal epithelial cell barriers, antigen-presenting cells (e.g., dendritic cells) collect them, process them, Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 and present them to naïve T cells. Depending on the nature of these substances, their dose, and the extent of interaction, different types of cytokines are synthesized and secreted. These cytokines influence the direction of T-cell development towards either T-helper cell type 1 (Th1)-dominant (cell-mediated) immunity or Th2-dominant (humoral) immunity. Other T cells, termed Th3 and/or Treg cells, play a role in ensuring that the immune system shift in either direction is moderated and not too vigorous or persistent. A detailed description of Th1/Th2/ Th3/Treg immunity is beyond the scope of this article and is reviewed in detail elsewhere.42-45 An enhanced understanding of the cytokines involved in the pathogenesis of various diseases will assist in the development and use of safe, effective methods of modulating these cytokines and recreating balance in the immune system to promote healing. Immunomodulation is an important step in the healing of the leaky gut. Two of the most important cyto kines directly contributing to increased permeability in the GI tract are IL-1b46 and TNF-α.38 There are a number of specific targets for these cytokines in mainstream medicine, including the monoclonal antibodies to TNF-α, infliximab and adalimumab; however, both of these medicines have a substantial number of potentially severe adverse effects.47 A safer, effective way to modulate these cytokines is by using the antihomotoxic medicine Traumeel. Using in vitro studies, the extent of modulation of TNF-α and IL-1b by Traumeel is significant, ranging from 54% to 70%, respectively.48 Echinacea compositum is an antihomotoxic medicine that has been shown to effectively prevent postoperative infections.49 There is re- )7 ) I n Fo c u s )8 cent evidence that the alkylamides from extracts of the root of Echinacea species modulate TNF-α, via the endogenous cannabinoid receptors.50,51 The N-alkylamides of Echinacea purpurea work synergistically to not only decrease the expression of TNF-α but also to increase the expression of IL-10,52 a cytokine known for its immunosuppressive effects on Th1-dominant diseases such as Crohn’s disease. Because of the ability of Echinacea extracts to shift the immune system towards Th2-dominant immunity, it is important to use them with caution and only in conditions in which they are unlikely to aggravate signs and symptoms. For example, ulcerative colitis is considered a Th2dominant disease53 and, therefore, any medical intervention (e.g., with Echinacea extracts) that promotes further development of Th2 cells might cause an aggravation of symptoms. Furthermore, persons who are sensitive to plants in the Asteraceae family also might be sensitive to Echinacea extracts. Finally, because Echinacea species extracts, in particular the aerial parts, have immunostimulatory activity, it is suggested that they are not administered in full concentrations to persons with autoimmune conditions. A homeopathic concentration of D4 (1:10,000) is considered safe for oral use and, therefore, the use of Echinacea compositum drinking ampoules is safe in autoimmune and proliferative conditions. Even before substances in the GI tract lumen reach the epithelial cells or tight-junctional complexes, they must diffuse through a mucous layer. The mucous layer is not simply a static physical structure. It is highly dynamic, with a meshwork of many different interdependent proteins and carbohydrates. Two of the best-characterized components of the mucous layer are trefoil factor peptides (TFFs) and mucin.54 Both of these components are synthesized and secreted by the goblet cells interspersed throughout the mucous membrane. They migrate onto the luminal side of the epithelial cells to provide an extra viscous layer of protection and selective filtration.55,56 The synthesis and release of TFFs is diurnal, with a peak time during the nocturnal hours. This protective rhythm is disrupted by aging, a Helicobacter pylori infection, sleep deprivation,57 and celiac disease.58 Furthermore, there is evidence that modulating proinflammatory cytokines, such as TNF-α, also helps maintain optimal levels of TFFs,59 suggesting that this might be another mechanism by which Traumeel can act to help in the restoration of gut integrity. 3. Detoxification Once the organs of the GI tract have been supported and the proinflammatory cytokines have been modulated to the point at which they can self-regulate, it is important to ensure that all remaining endotoxins and exotoxins are detoxified and drained. Clearing toxins also helps to activate physiological systems that protect the GI tract from further damage. In addition to the TFFs, another important component of the mucous layer is mucin. Mucins are large extracellular proteins that are heavily glycosylated with a bottle brush-like structure. The mucins play a number of roles, including control of cell growth, signal transduction from the lumen to the intracellular structures, adhesion of commensal and potentially pathogenic microbes, and protection.60 Their protective function is due in part to the ability of the glycoproteins to act as a molecular sieve, carefully regulating diffusion of substances Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 based on their charge and size. For this careful, selective process to occur optimally, the mucins need to be relatively free of toxins. Furthermore, regulating proinflammatory cytokines also helps mucins to assemble and function appropriately.61 It can be postulated that using Lymphomyosot and Traumeel might help to keep the mucin structures clear and able to perform their functions optimally; this is an important contributing factor to healing a hyperpermeable GI tract. Many of the immune system cells of the GALT are present in the loose areolar connective tissue just below the epithelial cells.1 For these immune cells to work optimally, there must be a relatively clear pathway for antigens to be able to be received by them. Furthermore, these immune system cells must have a relatively high degree of mobility to move to where they are needed to mount an appropriate immune response. In my opinion, using drainage preparations, such as Lymphomyosot, may help keep this loose areolar connective tissue relatively free of exotoxins and endotoxins; this is an important part of ensuring that an appropriate immune response occurs. It is important to recognize that there is a closely regulated, interdependent relationship between the GI tract and the liver. The stomach, intestine, spleen, and pancreas drain to the liver via the hepatic portal system. Therefore, many of the toxins from a leaky gut will end up in the liver, where they need to be processed. Furthermore, if the detoxification mechanisms in the liver are not functioning adequately, excess or insufficiently processed toxins are recycled back into the duodenum of the GI tract via the bile duct. Using Nux vomica-Homaccord or Hepar compositum to support liver detoxification systems and Coenzyme ) I n Fo c u s compositum to support the energy demands of these systems is thus important. The addition of Berberis-Homaccord reduces the toxin burden even further by supporting the detoxification and drainage functions of the kidneys and liver. Animal studies14,62 have shown that excess alcohol consumption causes direct damage to hepatocytes and leads to the development of a leaky gut. The increased toxin load, subsequent to this increased GI tract permeability, further contributes to liver damage, stressing the importance of addressing the health of the liver and GI tract simultaneously. Conclusions Because of the paramount importance of the mucosa in systemic immune responses and the connectivity between all of the mucosal barriers in the body, repairing a leaky gut can be an important access point in the management of many diseases. Management begins by discontinuing the intake of potentially damaging toxins or lifestyle choices and replacing or repairing them with antihomotoxic medicines that will not cause any further damage. It is important to support the ability of the various organs to perform their physiological functions (using Mucosa compositum, Nux vomica-Homaccord, and Coenzyme compositum) and to immunomodulate cytokines, such as IL-1b and TNF-α (using Traumeel and Echinacea compositum). This will halt the positive feedback loop of increased permeability, production of excess proinflammatory cytokines, and further permeability. It is also important to recognize that there is a definitive gut-brain connection and, therefore, it is essential to address any mental and/or emotional disturbances (using Neurexan, Neuro-Heel/Neuro-Injeel, Nervoheel, or Tonico-Heel/Tonico-Injeel) that could be interfering with restoration of mucosal integrity. Finally, it is important to remove toxins and to activate the organs, so that they maintain optimal detoxification pathways even after therapy has been discontinued. The science and art of homotoxicology provides us with a scientifically supported, logical framework to heal a hyperpermeable GI tract and, therefore, support maximal health in our patients. One of the additional strengths of antihomotoxic medicine is that the medications can be used synergistically with other natural health products to support timely and effective healing. Other natural health products shown to be useful in healing the leaky gut include probiotics,62-64 quercetin,65-68 L-glutamine,69-71 zinc,72-74 zinc carnosine,75 vitamin A,76 vitamin D,77,78 melatonin,79 curcumin,80-83 and licorice extracts.84| Hans-Heinrich Reckeweg Award 2010 Join in – have your experience rewarded Heel annually honors outstanding scientific research in the field of a unique homeotherapeutic system (homotoxicology) with the Hans-Heinrich Reckeweg Award. The main award (€ 10,000) is presented for scientific work of fundamental theoretical and/or practical significance in antihomotoxic medicine in the fields of human and veterinary medicine. The incentive award (€ 5,000) is presented for promising results arising from clinical, case-based or fundamental research in antihomotoxic medicine in the fields of human and veterinary medicine. The prize money is intended to fund further research. Both prizes are awarded for research carried out in a laboratory or registered practice. All results must be new, convincing and previously unpublished, and research should not have involved animal testing. The deadline for submissions is May 31, 2010. For more information contact: Biologische Heilmittel Heel GmbH, Department of Research, 76532 Baden-Baden, Germany Phone +49 7221 501-227, Fax +49 7221 501-660, [email protected], www.heel.com Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 )9 ) I n Fo c u s ) 10 References: 1. Bourlioux P, Koletzko B, Guarner F, Braesco V. The intestine and its microflora are partners for the protection of the host: report on the Danone Symposium “The Intelligent Intestine,” held in Paris, June 14, 2002. Am J Clin Nutr. 2003;78(4):675-683. 2. Williams JE. Portal to the interior: viral pathogenesis and natural compounds that restore mucosal immunity and modulate inflammation. Alt Med Rev. 2003;8(4):395-409. 3. Laukoetter MG, Nava P, Nusrat A. 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Systematic review: the lower gastrointestinal adverse events of non-steroidal antiinflammatory drugs. Aliment Pharmacol Ther. 2006;24(5):751-767. 19. Birnesser H, Klein P, Weiser M. A modern homeopathic medication works as well as COX2 inhibitors [in German]. Der Allgemeinarzt. 2003;25(4):261-264. Translated from German at http://www.heel.ca/pdf/studies/Zeel%20comp%20vs%20Cox%202.pdf. Accessed November 4, 2009. 20. Schneider C, Klein P, Stolt P, Oberbaum M. A homeopathic ointment preparation compared with 1% diclofenac gel for acute symptomatic treatment of tendinopathy. Explore. 2005;1(6):446-452. 21. Everson CA, Toth LA. Systemic bacterial invasion induced by sleep deprivation. Am J Physiol Regul Integr Comp Physiol. 2000;278(4):R905-R916. 22. Irwin MR, Wang M, Campomayor CO, Collado-Hidalgo A, Cole S. Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med. 2006;166(16):1756-1762. 23. Smit A. Homotoxicological approach to psychosomatic disease. J Biomed Ther. Spring 2007:5-8. 24. Buret AG. How stress induces intestinal hypersensitivity. Am J Pathol. 2006;168(1):3-5. 25. Yang PC, Jury J, Söderholm JD, Sherman PM, McKay DM, Perdue MH. Chronic psychological stress in rats induces intestinal sensitization to luminal antigens. Am J Pathol. 2006;168(1):104-114. 26. Rossi EL. Mind modulation of the immune system. In: Rossi EL. Psychobiology of MindBody Healing: New Concepts of Therapeutic Hypnosis. New York, NY: WW Norton & Co Inc; 2003:chap 9. 27. Reiche EM, Morimoto HK, Nunes SM. Stress and depression-induced immune dysfunction: implications for the development and progression of cancer. Int Rev Psychiatry. 2005;17(6):515-527. 28. Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405(6785):458-462. 29. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007;117(2):289-296. 30. Milopolskaya IM. Therapeutic possibilities of the preparation Nervoheel in the treatment of patients with somatic conditions suffering from anxiety disorders [in Russian]. Biologicheskaya Meditsina. 2002;(1):30-34. 31. Savidge TC, Sofroniew MV, Neunlist M. Starring roles for astroglia in barrier pathologies of gut and brain. Lab Invest. 2007;87(8):731736. Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 32. Thelen K, Dressman JB. Cytochrome P450mediated metabolism in the human gut wall. J Pharm Pharmacol. 2009;61(5):541-558. 33. Choi MK, Song IS. Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences. Drug Metab Pharmacokinet. 2008;23(4):243-253. 34. Ding X, Kaminsky LS. Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annu Rev Pharmacol Toxicol. 2003;43:149-173. 35. Bressler JP, Olivi L, Cheong JH, Kim Y, Maerten A, Bannon D. Metal transporters in intestine and brain: their involvement in metalassociated neurotoxicities. Hum Exp Toxicol. 2007;26(3):221-229. 36. Shen L, Turner JR. Role of epithelial cells in initiation and propagation of intestinal inflammation: eliminating the static: tight junction dynamics exposed. Am J Physiol Gastrointest Liver Physiol. 2006;290(4):G577-G582. 37. Liu Z, Li N, Neu J. Tight junctions, leaky intestines, and pediatric diseases. Acta Paediatr. 2005;94(4):386-393. 38. Clayburgh DR, Shen L, Turner JR. A porous defense: the leaky epithelial barrier in intestinal disease. Lab Invest. 2004;84(3):282-291. 39. Barrett KE. New ways of thinking about (and teaching about) intestinal epithelial function. Adv Physiol Educ. 2008;32(1):25-34. 40. Forsyth CB, Farhadi A, Jakate SM, Tang Y, Shaikh M, Keshavarzian A. Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative stress, gut leakiness, and liver injury in a rat model of alcoholic steatohepatitis. Alcohol. 2009;43(2):163-172. 41. Schulzke JD, Ploeger S, Amasheh M, et al. Epithelial tight junctions in intestinal inflammation. Ann NY Acad Sci. 2009;1165:294300. 42. Poritz LS, Garver KI, Green C, Fitzpatrick L, Ruggiero F, Koltun WA. Loss of the tight junction protein ZO-1 in dextran sulfate sodium induced colitis. J Surg Res. 2007;140(1):12-19. 43. Neurath MF, Finotto S, Glimcher LH. The role of Th1/Th2 polarization in mucosal immunity. Nat Med. 2002;8(6):567-573. 44. Schmolz M, Ottendorf D. The immune system, our personal bodyguard. J Biomed Ther. 2008;2(3):4-9. 45. Vojdani A, Erde J. Regulatory T cells, a potent immunoregulatory target for CAM researchers: the ultimate antagonist (I). Evid Based Complement Alternat Med. 2006;3(1):25-30. 46. Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev. 2003;8(3):223-246. 47. Scheinfeld N. A comprehensive review and evaluation of the side effects of the tumor necrosis factor alpha blockers etanercept, infliximab and adalimumab. J Dermatolog Treat. 2004;15(5):280-294. 48. Al-Sadi RM, Ma TY. IL-1β causes an increase in intestinal epithelial tight junction permeability. J Immunol. 2007;178(7):4641-4649. 49. Porozov S, Cahalon L, Weiser M, Branski D, Lider O, Oberbaum M. Inhibition of IL-1β and TNF-α secretion from resting and activated human immunocytes by the homeo- ) I n Fo c u s pathic medication Traumeel S. Clin Dev Immunol. 2004;11(2):143-149. 50. Bonini M, La Torre G, De Cesare A, et al. A randomized clinical trial of the effect of Echinacea compositum S on the prophylaxis of post-operative infections. J Prev Med Hygiene. 2001;42:30-35. 51. Gertsch J, Schoop R, Kuenzle U, Suter A. Echinacea alkylamides modulate TNF-alpha gene expression via cannabinoid receptor CB2 and multiple signal transduction pathways. FEBS Lett. 2004;577(3):563-569. 52. Raduner S, Majewska A, Chen JZ, et al. Alkylamides from Echinacea are a new class of cannabinomimetics: cannabanoid type 2 receptor-dependent and -independent immunomodulatory effects. J Biol Chem. 2006;281(20):14192-14206. 53. Chicca A, Raduner S, Pellati F, et al. Synergistic immunopharmacological effects of N-alkylamides in Echinacea purpurea herbal extracts. Int Immunopharmacol. 2009;9(78):850-858. 54. Owczarek D, Cibor D, Szczepanek M, Mach T. Biological therapy of inflammatory bowel disease. Pol Arch Med Wewn. 2009;119(12):84-88. 55. Kindon H, Pothoulakis C, Thim L, LynchDevaney K, Podolosky DK. Trefoil peptide protection of intestinal epithelial barrier function: cooperative interaction with mucin glycoprotein. Gastroenterology. 1995;109(2):516-523. 56. Taupin D, Podolsky DK. Trefoil factors: initiators of mucosal healing. Nat Rev Mol Cell Biol. 2003;4(9):721-732. 57. Plaut AG. Trefoil peptides in defense of the gastrointestinal tract. N Engl J Med. 1997;336(7):506-507. 58. Johns CE, Newton JL, Westley BR, May FE. The diurnal rhythm of the cytoprotective human trefoil protein TFF2 is reduced by factors associated with gastric mucosal damage: ageing, Helicobacter pylori infection, and sleep deprivation. Am J Gastroenterol. 2005;100(7):1491-1497. 59. Ciacci C, Di Vizio D, Seth R, et al. Selective reduction of intestinal trefoil factor in untreated coeliac disease. Clin Exp Immunol. 2002;130(3):526-531. 60. Loncar MB, Al-azzeh ED, Sommer PS, et al. Tumour necrosis factor α and nuclear factor κB inhibit transcription of human TFF3 encoding a gastrointestinal healing peptide. Gut. 2003;52(9):1297-1303. 61. Hollingsworth MA, Swanson BJ. Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 2004;4(1):45-60. 62. Heazlewood CK, Cook MC, Eri R, et al. Abberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med. 2008;5(3):e54. 63. Mennigen R, Nolte K, Rijcken E, et al. Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis. Am J Physiol Gastrointest Liver Physiol. 2009;296(5):G1140-G1149. 64. Ukena SN, Singh A, Dringenberg U, et al. Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity. PLoS One. 2007;2(12):e1308. 65. Farhadi A, Fields JZ, Keshavarzian A. Mucosal mast cells are pivotal elements in inflammatory bowel disease that connect the dots: stress, intestinal hyperpermeability and inflammation. World J Gastroenterol. 2007;13(22):3027-3030. 66. Bischoff SC. Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data. Nat Rev Immunol. 2007;7(2):93-104. 67. Penissi AB, Rudolph MI, Piezzi RS. Role of mast cells in gastrointestinal mucosal defense. Biocell. 2003;27(2):163-172. 68. Amasheh M, Schlichter S, Amasheh S, et al. Quercetin enhances epithelial barrier function and increases claudin-4 expression in Caco-2 cells. J Nutr. 2008;138(6):10671073. 69. Reeds PJ, Burrin DG. Glutamine and the bowel. J Nutr. 2001;131(suppl 9):2505S2508S. 70. Li Y, Yu Z, Liu F, Tan L, Wu B, Li J. Oral glutamine ameliorates chemotherapy-induced changes of intestinal permeability and does not interfere with the antitumor effect of chemotherapy in patients with breast cancer: a prospective randomized trial. Tumori. 2006;92(5):396-401. 71. Li N, Lewis P, Samuelson D, Liboni K, Neu J. Glutamine regulates Caco-2 cell tight junction proteins. Am J Physiol Gastrointest Liver Physiol. 2004;287(3):G726-G733. 72. Prasad AS. Zinc in human health: effect of zinc on immune cells. Mol Med. 2008;14(56):353-357. 73. Sturniolo GC, Fries W, Mazzon E, Di Leo V, Barollo M, D’Incà R. Effect of zinc supplementation on intestinal permeability in experimental colitis. J Lab Clin Med. 2002;139(5):311-315. 74. Maggini S, Wintergest ES, Beveridge S, Hornig DH. Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses. Br J Nutr. 2007;98(suppl 1): S29-S35. 75. Mahmood A, FitzGerald AJ, Marchbank T, et al. Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. Gut. 2007;56(2):168-175. 76. Beum PV, Basma H, Bastola DR, Cheng PW. Mucin biosynthesis: upregulation of core 2 β1,6 N-acetylglucosaminyltransferase by retinoic acid and Th2 cytokines in a human airway epithelial cell line. Am J Physiol Lung Cell Mol Physiol. 2005;288(1):L116-L124. 77. Kong J, Zhang Z, Musch MW, et al. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am J Physiol Gastrointest Liver Physiol. 2008;294(1):G208-G216. 78. Chirayath MV, Gajdzik L, Hulla W, Graf J, Cross HS, Peterlik M. Vitamin D increases tight-junction conductance and paracellular Ca2+ transport in Caco-2 cell cultures. Am J Physiol. 1998;274(2, pt 1):G389-G396. 79. Konturek SJ, Konturek PC, Brzozowska I, et al. Localization and biological activities of melatonin in intact and diseased gastrointestinal tract (GIT). J Physiol Pharmacol. 2007;58(3):381-405. Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 80. Chan MM. Inhibition of tumor necrosis factor by curcumin, a phytochemical. Biochem Pharmacol. 1995;49(11):1551-1556. 81. Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as “Curecumin”: from kitchen to clinic. Biochem Pharmacol. 2008;75(4):787809. 82. Aggarwal BB, Sundaram C, Malani N, Ichikawa H. Curcumin: the Indian solid gold. In: Aggarwal BB, Surh YJ, Shishodia S, eds. The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease. New York, NY: Springer-Verlag; 2007. Advances in Experimental Medicine and Biology; vol 595:1-75. 83. Song WB, Zhang ZS, Xiao B, et al. Protective effect of curcumin against methotrexateinduced small intestinal damage in rats [in Chinese]. Nan Fang Yi Ke Da Xue Xue Bao. 2008;28(1):119-121. 84. Aly AM, Al-Alousi L, Salem HA. Licorice: a possible anti-inflammatory and anti-ulcer drug. AAPS PharmSciTech. 2005;6(1):E74E82. ) 11 ) What Else Is New? Eating a poor diet when pregnant or breastfeeding may cause long-lasting health damage to the child. No fast food during pregnancy! To slim down, get enough sleep A mother’s heavy consumption of fast food during pregnancy increases the likelihood that her child will develop unhealthy eating habits. At least, that’s what British animal experiments suggest. During pregnancy and lactation, rats were fed either normal lab rations or a junk-food diet consisting of potato chips, chocolate, and high-fat cheese. The results indicate that offspring subjected to high levels of fat and sugar in utero also tended to select unhealthy foods later, when given a choice. The effects on body mass and blood lipid and insulin levels were predictable. There is considerable evidence that these findings also apply to humans, so pregnant and nursing women should pay special attention to healthy eating. Children and adolescents who do not get enough sleep risk becoming overweight, according to an American study in which 335 youngsters aged 7 to 17 years underwent three successive nights of standard polysomnography. Overweight children slept an average of 22 minutes less than their normal-weight age peers and had significantly shorter periods of REM sleep. The researchers calculated that the risk of overweight is doubled by sleeping one hour less each night and tripled by losing an hour of REM sleep. Arch Gen Psychiatry. 2008;65(8):924-932. Musical aptitude and social competence are genetically linked Musically gifted people are also likely to be socially adept. That’s an oversimplified statement of the findings of a recent Finnish research study. Scientists from Helsinki discovered that social competencies such as human bonding and attachment are encoded on the same gene as the ability to carry a tune and keep a beat. The study analyzed the genetic makeup of 19 families whose members included professional musicians and/or active amateurs. The results demonstrated that the testconfirmed musicality of individual family members could be traced to two variants of the arginine-vasopressin receptor 1A, a gene also associated with human bonding and altruism. PLoS ONE 4(5):e5534. doi:10.1371/journal.pone.0005534. J Physiol. 2008;586(13):3219-3230. 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. Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 © iStockphoto.com/Armin Hinterwirth ) What Else Is New? Latest research findings suggest that the cells responsible for the axolotl’s famed ability to regenerate limbs, organs, and even parts of the brain do not undergo dedifferentiation into a pluripotent state. Can French kissing cause cancer? The Mexican salamander: a “miracle of regeneration” According to an American study, oral sex and open-mouthed kissing are associated with the development of oral human papillomavirus (HPV) infection and may therefore be responsible for increases in HPV-positive oropharyngeal cancers, which have tripled in the last 40 years and are predicted to double in each successive decade. Formerly, most oropharyngeal cancers were caused by heavy smoking, but the human papillomavirus is now the single greatest factor. The case-control study provides a possible explanation for this shift. Oral HPV infection was discovered in 4.8 percent of 332 control patients in an ENT outpatient clinic. In another study, oral HPV infection was found in 2.9 percent of 210 male students, aged 18 to 23 years. Among the control patients, the risk of infection increased with the lifetime number of sex partners; the trend was significantly more pronounced with oral sex than with vaginal contacts. Among the college students, HPV infection increased with the number of oral sex partners and openmouthed kissing partners but not with vaginal sexual contacts. Research scientists at Dresden Technological University’s Center for Regenerative Therapies have discovered how the axolotl (Ambystoma mexicanum) replaces severed limbs. Contrary to previous assumptions, the basis of limb regeneration in the axolotl is not pluripotent cells with unrestricted potential, but rather cells that can only develop into specific tissues, as in mammals. Nonetheless, the axolotl is able to regenerate complete and functional limbs, organs, and even parts of the brain. “Our research demonstrates for the J Infect Dis. 2009;199(9):1263-1269. first time that axolotl cells behave like the cells in mammals and are not so different from our own,” emphasizes Professor Elly Tanaka, who headed the Dresden study. By integrating a fluorescent protein into the axolotl’s genotype and tracking the further development of individual cells and tissues, the Dresden scientists were able to show that in axolotls, different types of progenitor cells with restricted developmental potential formed at the site of an injury. “Most cells are restricted to their own tissue identity,” explains Tanaka. According to the authors, these findings open up completely new perspectives for regenerative medicine. Nature. 2009;460(7251):60-65. Now avai lable on li n e! The International Academy for Homotoxicology is pleased to announce that the Journal of Biomedical Therapy is now also available online at www.iah-online.com. Visitors of the IAH web site can download the current issue, peruse back issues, or look for articles in the “List of published topics.” Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 ) 13 ) Re f r e s h Yo u r H o m o t ox i c o l o g y The Mucosal Immune System Functional Properties and Potential Clinical Implications By Doris Ottendorfer, PhD Introduction Mucosa-associated organs represent the physical interface to the environment. They are, therefore, particularly vulnerable to damage by infectious pathogens or noxious agents. This is why all mucosae are under constant surveillance by a specifically organized mucosa-associated lymphoid tissue (MALT). Notably, mucosal immune responses differ functionally from systemic immunity against blood-borne antigens. For example, mucosal antigen uptake and handling induce antigenspecific mucosal immune responses, but normally suppress systemic immunity against most orally ingested antigens. An explanation of these differences is given in the following sections. ) 14 Oral tolerance The above-mentioned difference between systemic and mucosal immune responses reflects the distinct challenges that mucosal surfaces face from being directly exposed to the external environment. To protect mucosal surfaces from injury and subsequently from organ damage and severe diseases, the mucosal immune system must be able to discriminate efficiently between potential pathogens on one side and to tolerate the tremendous number of commensal microbes and harmless food antigens on the other side.1,2 This phenomenon, called oral tolerance, has emerged as a fundamental aspect of mucosal immunity, contributing highly to intestinal homeostasis and human health. Structural properties of the mucosal immune system Oral tolerance is defined as a state of “systemic hyporesponsiveness” to orally administered harmless anti gen(s) on subsequent antigen challenge. The breakdown of this delicate balance provokes uncontrolled mucosal inflammation due to unlimited antigen contact with the MALT.3 For example, in newborns, some regulatory pathways of mucosal immunity might not be fully matured, allowing for greater sensitization to harmless dietary antigens instead of suppression. Therefore, food allergies can occur. Presumably, probiotic bacteria, with their numerous mechanisms of action, may represent a hopeful therapy to treat allergic disorders, as recently reviewed.4,5 The complexity of the mucosal barrier deserves some attention, considering the anatomical aspects of tolerance against luminal antigens.6 Both cellular and noncellular components cooperate to maintain mucosal barrier function. Among noncellular components, luminal enzyme activities, antimicrobial factors (e.g., defensins), and secretory IgA antibodies are present in large amounts in the mucous layer covering the mucosal surface. These components neutralize bacteria and viruses.6 The proteolytic cleavage of Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 food antigens from egg, soy, fish, or nuts minimizes their immunogenic properties. Mucin glycoproteins lining the intestinal epithelium contribute substantially to mucosal barrier function. Remarkably, intestinal epi thelial cells and luminal commensal bacteria closely interact to terminate and/or limit mucosal immune responses at a complex molecular level.7 For example, it has been demonstrated that recognition by intestinal epithelial cells of selected probiotic bacteria strongly down-regulates an important proinflammatory signaling cascade, the nuclear factor-κB pathway.7 Even the composition and functional activities of the gut microbiota crucially affect the structure and functions of the mucosal immune system.8 Immunological networks The efficient recognition of potential pathogens as one task of mucosal immunity includes inductive sites, such as Peyer’s patches, where T-helper type 2 (Th2) cells provide cytokine help for B lymphocytes to switch to IgA antibody production.9,10 The lamina propria, as an effector site of mucosal tissues, contains many mature B plasma cells secreting secretory IgA delivered for mucosal protection against potential pathogens. Numerous T-helper cells and cytotoxic T cells in the lamina propria mediate cell-mediated immunity against microbes and viruses. For active oral tolerance to occur, ) Re f r e s h Yo u r H o m o t ox i c o l o g y Table. Overview of T-regulatory Cells (adapted from Shevach12) Variable “Natural” Treg Cells “Induced” Treg Cells Inducing stimuli TCR stimulation with self-peptides TCR stimulation with peripheral (auto) antigens, foreign antigens, dietary antigens, or pathogens Type of APC, mode of antigen presentation, and cytokine milieu are also important Origin Derived from the thymus Conversion and/or expansion of nonregulatory peripheral CD4+ naïve, memory, or effector T cells Phenotype FOXP3 positive CD25 positive Highly variable coexpression of FOXP3 and CD25 Mechanisms of suppression T-cell–T-cell–contact and/or T-cell–APC–contact dependent Cell-contact–dependent, cell-bound TGF-b and, in some cases, soluble TGF-b Cytokines (IL-10 and TGF-b) Other cytokines (IL-2, IL-4, IL-6, IL-13, IFN-g, and TGF-b) Accessory molecules (e.g., CTLA-4 and GITR) Th3 cells (soluble TGF-b and/or IL-10) Tr1 cells (IL-10) CD8+ Treg cells (not well defined, cell-contact–dependent, ILT3 and ILT4) Abbreviations: APC, antigen-presenting cell; CTLA, cytotoxic T-lymphocyte antigen; FOX, fork head box; GITR, glucocorticoidinduced tumor necrosis factor receptor; IFN, interferon; IL, interleukin; ILT, immunoglobulinlike transcript; TCR, T-cell receptor; TGF, transforming growth factor; Th, T-helper cell; Treg, T regulatory; Tr1, T-regulatory cell type 1. more than one mechanism presumably prevents uncontrolled mucosal immune responses against harmless antigens. Functionally distinct T-cell populations interact with differently specialized subtypes of antigen-presenting cells (APCs) in distinct mucosal compartments. In this context, it is reasonable to assume that the maturation and activation stage of locally present APCs, such as dendritic cells, dictates the fate of mucosal T-cell activation.11 Additional T cells with profound immunosuppressive functions, summarized under the term regulatory T cells, have been identified (Table).12 These include T-regulatory 1 (Tr1) cells and Th3 cells. From experimental models for autoimmune encephalomyelitis (EAE), Weiner and colleagues13 coined the term Th3 cells to explain their results. In mice orally fed myelin basic protein as an autoantigen for multiple sclerosis in humans, the peripheral immune response against the same antigen was inhibited on challenge. As responsible cell types, Th3 regulatory cells were detected, secreting large amounts of the cytokine transforming growth factor β. Interestingly, higher antigen doses favored T-cell anergy and/or depletion, whereas lower antigen doses seemed to generate tolerance mediated by these Th3 cells.13 Other regulatory T-cell populations such as Tr1 cells differed from classic Th1 cells by their secretion of larger amounts of the immunosuppressvie cytokine interleukin 10. Interleukin 10 controls Th1 cell activation and several macrophage functions. Clinical implications for oral tolerance Altogether, oral tolerance mechanisms represent a continuous natural immunological event driven by Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 exogenous antigens. For therapeutic purposes, it seems logical to assume that some human autoimmune diseases, such as multiple sclerosis or type 1 diabetes mellitus, may be prevented by orally given self-antigens. However, recently reviewed work on this topic indicated that this immunological concept functions well in animal disease models, but yielded inconsistent results in human clinical trials.14 In contrast, sublingual immunotherapy (SLIT) with oral allergen extracts for allergic rhinitis and conjunctivitis considerably improved symptom relief of these disorders.15 Ongoing research efforts on the basic mechanisms of this fascinating part of mucosal immunity hopefully will help prevent some pitfalls, so that the use of oral tolerance pathways may in the future become an inherent part of immune therapy.| ) 15 References: 1. Wittig BM, Zeitz M. The gut as an organ of immunology. Int J Colorectal Dis. 2003;18(3):181-187. 2. Sansonetti PJ. War and peace at mucosal surfaces. Nat Rev Immunol. 2004;4(12):953964. 3. Sampson HA. Food allergy: when mucosal immunity goes wrong. J Allergy Clin Immunol. 2005;115(1):139-141. 4. Sherman PM, Ossa JC, Johnson-Henry K. Unraveling mechanisms of action of probiotics. Nutr Clin Pract. 2009;24(1):1014. 5. Kullen MJ, Bettler J. The delivery of probiotics and prebiotics to infants. Curr Pharm Des. 2005;11(1):55-74. 6. Baumgart DC, Dignass AU. Intestinal barrier function. Curr Opin Clin Nutr Metab Care. 2002;5(6):685-694. 7. Neish AS. The gut microflora and intestinal epithelial cells: a continuing dialogue. Microbes Infect. 2002;4(3):309-317. 8. O’Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep. 2006;7(7):688-693. 9. Mayer L. Mucosal immunity. Pediatrics. 2003;111(6, pt 3):1595-1600. 10. MacDonald TT. The mucosal immune system. Parasite Immunol. 2003;25(5):235246. 11. Shortman K, Naik SH. Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol. 2007;7(1):19-30. 12. Shevach EM. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity. 2006;25(2):195-201. 13. Miller A, Lider O, Roberts AB, Sporn MB, Weiner HL. Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor beta after antigenspecific triggering. Proc Natl Acad Sci USA. 1992;89(1):421-425. 14. Weiner HL. Current issues in the treatment of human diseases by mucosal tolerance. Ann N Y Acad Sci. 2004;1029:211-224. 15. Kuo CH, Wang WL, Chu YT, Lee MS, Hung CH. Sublingual immunotherapy in children: an updated review. Pediatr Neonatol. 2009;50(2):44-49. 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. For MDs and licensed healthcare practitioners only Free of charge ) 16 www.iah-online.com Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 ) Specialized Applications Immune Modulation With Microdose Combination Products By Alta A. Smit, MD T Three properties seem to make microdose bioregulatory products ideal for modulation of the mucosal immune system. he importance of the mucosal immune system has been addressed by several authors in this journal. The complexity of this immune system and its effects on the systemic immune system make it an attractive target for addressing local immune problems, such as inflammatory bowel disease and allergy. These properties can also be used for systemic immune dysregulation, such as adjuvant therapy for autoimmune diseases, in which case the corresponding tissue extract is used in an oral form. sponse in the mucosa. The arrows indi- and the dotted arrows, differentiation; red relates to regular activation or inhi- Plants1 and organ preparations have a combination chemistry that can be efficiently used to address multiple targets. This fits the complexity of the immune system in the mucosa. bition, whereas orange indicates pro- cesses that are predominantly found in allergy. Abbreviations: DC, dendritic cell; Ig, im- munoglobulin; IFN, interferon; IL, inter- leukin; TGF, transforming growth factor; Th, T-helper cell; Treg, T-regulatory cell. DC Th0 Lymph node IL-2 TGF-ß Th2 IL-2 IFN-γ Th1 IL-3 IL-4 Mast cell Y Y IgE Y Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 IgG4 Y Y YY Histamine Leukotrienes Cytokines Plasma cell Y Y Peripheral tissues Basophil Y IL-3 IL-4 IL-5 Y IL-3 IL-5 Treg Y Eosinophil Histamine Leukotrienes Cytokines cate secretion; the blunt lines, inhibition; 1. Multitarget regulation Allergen/Antigen Peptides Leukotrienes Cytokines Figure. Deployment of the T-cell re- IgA ) 17 ) Specialized Applications Table 1. Medications Used to Induce Local Tolerance Medication Target Tissue (Local) Medication Target Tissue (Systemic) Mucosa compositum Universal for mucosae Traumeel General Euphorbium compositum Nasal mucosa Tonsilla compositum Podophyllum compositum Gut mucosa Reticuloendothelial tissue (including bone marrow) Solidago compositum Urogenital tract Cerebrum compositum Brain Gynäcoheel Female reproductive tract Hepar compositum Liver Ovarium compositum Ovarium Thyreoidea compositum Thyroid 2. The microdose ) 18 Table 2. Medications Used to Induce Systemic Tolerance It also seems that microdose preparations will have an effect on the immune system, which tends toward regulation rather than stimulation or suppression. The mucosal immune system is especially geared towards tolerance, especially in the face of microdoses of food.2 The main carriers of the antigen are in the first instance dendritic cells.3 These cells will carry the antigen to the mesenteric lymph node,4 where this response takes place. The mechanism is depicted in the Figure. The main cell involved in the tolerance reaction is the T-regulatory cell, which plays a pivotal role in the downregulation of both T-helper cell type 1 (Th1) and Th2. The induction of Th3 and transforming growth factor β by microdose preparations was shown on blood culture results.5 Furthermore, Traumeel was shown in vitro to down-regulate proinflammatory cytokines from T cells and colon epithelial cells.6 3. Possibility of sublingual administration It seems that the oral mucosa has special features that make it ideal for oral tolerance. Sublingual immunotherapy used in allergy is more efficient if it is given sublingually or nasally, but not intraintestinally.7 Furthermore, the oral mucosal interface, also called the “gateway to the gut,”8 seems to have a special relationship to tolerance because of the number of bacterial species living there.9 The medications listed in Table 1 and Table 2 are examples used to induce local and systemic tolerance, respectively.| Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 References: 1. McChesney JD, Venkataraman SK, Henri JT. Plant natural products: back to the future or into extinction? Phytochemistry. 2007;68(14):2015-2022. 2. Wershil BK, Furuta GT. Gastrointestinal mucosal immunity. J Allergy Clin Immunol. 2008;121(suppl 2):380S-383S. 3. Worbs T, Bode U, Yan S, et al. Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. J Exp Med. 2006;203(3):519-527. 4. Macpherson AJ, Smith K. Mesenteric lymph nodes at the center of immune anatomy. J Exp Med. 2006;203(3):497-500. 5. Heine H, Schmolz M. Induction of the immunological bystander reaction by plant extracts. Biomed Ther. 1998;16(3):224-226. 6. Porozov S, Cahalon L, Weiser M, Branski D, Lider O, Oberbaum M. Inhibition of IL-1b and TNF-α secretion from resting and activated human immunocytes by the homeopathic medication Traumeel S. Clin Dev Immunol. 2004;11(2):143-149. 7. Mascarell L, Van Overtvelt L, Moingeon P. Novel ways for immune intervention in immunotherapy: mucosal allergy vaccines. Immunol Allergy Clin North Am. 2006;26(2):283306, vii-viii. 8. Pennisi E. A mouthful of microbes. Science. 2005;307(5717):1899-1901. 9. Cutler CW, Jotwani R. Dendritic cells at the oral mucosal interface. J Dent Res. 2006;85(8):678-689. ) Meet the Expert Dr. Bert Hannosset By Catherine E. Creeger B these disciplines. Bert was so enthusiastic about his new discoveries that he stopped practicing conventional medicine in 1988 and quickly learned all he could about homeopathy and phytotherapy. Having established himself in complementary medical circles, he went on to study neural therapy (1991-1992). These studies in turn introduced him to antihomotoxic medicines. Dr. Hannosset’s connection to homotoxicology continued to develop. Eager to spread the word and give others a chance to learn about it, he gladly accepted an offer to lecture on homotoxicology. In the past five years, he has had the opportunity to give several courses on homotoxicology and antihomotoxic medications and has even become the president of both the Belgian Homo toxicological Society and Belgium’s largest school of clinical homeopathy. He truly enjoys teaching other medical doctors and especially fostering knowledge of homotoxicology and clinical homeopathy among an ever-growing group of Belgian MDs. Since August 2008, he has served as vice president on the board of the International Society of Homotoxicology and Homeopathy. At the moment, teaching continuing-education courses is his major ert Hannosset was born in 1960 in a village of only 600 residents in the Hesbaye (Haspen gouw) district of Belgium, one of the country’s most productive agricultural regions. He grew up on a small farm, where he developed a love of nature and learned early on the meaning of hard physical labor. Perhaps this is why he decided at age ten that he wanted to become a medical doctor rather than a veterinarian – the hard and dirty aspect of treating animals was not terribly appealing to him! After seven years of boarding school education, he began his medical studies in 1978, obtaining his MD degree in 1985 from the University of Leuven (Belgium). 1985 was a particularly big year for Bert: He also got married that year and started a private practice in conventional medicine together with his wife, also an MD, whom he had met during his fourth year of medical school. Today they have three young-adult children and still work together as a team, but their practice has evolved to emphasize complementary medicine (homeopathy, phytotherapy, neural therapy, and biopuncture, among others). In 1986, disappointed with the failure of conventional medicine in treating his young son, Dr. Hannosset was introduced to homeopathy and phytotherapy by a chance encounter with another doctor who had several years’ experience in Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 “hobby,” which really doesn’t leave him much time for other recreational activities, except for walking and bicycling with his wife and friends out in nature on weekends. But who knows what the future may bring?| ) 19 ) Practical Protocols Chronic Rhinosinusitis With and Without Polyps Differential Treatment With Bioregulatory Medicines By Alta A. Smit, MD C hronic rhinosinusitis (CRS) is one of the most commonly reported diseases. More than 24 million office visits for CRS were described as far back as 1992, and this incidence has probably increased rather than decreased.1 In the United States, the incidence of CRS is more than 10% in the general population.2 The pathogenesis of CRS is poorly understood. There is evidence for the role of bacteria and fungi as well as the presence of a deranged immune response in the sinuses and upper airways.2 Deficiencies in the epithelial immune barrier function might compromise the interaction between the host and external stimuli, which may lead to an increased susceptibility to bacterial and fungal colonization in patients with CRS. Chronic rhinosinusitis is defined as a group of disorders characterized by inflammation of the mucosa of the nose and the paranasal sinuses of at least 12 weeks’ duration. Two classes of CRS exist, and these can be divided according to the T-cell responses seen in the mucosa. According to Joe and Thakkar,3 it is best to think of these as inflammation from either a neutrophilic or an eosinophilic origin. The eosinophilic classification refers to CRS with nasal polyps (CRSwNP), also associated with aspirin-exacerbated respiratory disease, asthma, and allergic fungal rhinosinusitis. The neutrophilic subtype refers to CRS without nasal polyps (CRSsNP). Children seem to experience CRSwNP more often.4 This is also reflected in the cytokine profiles: CRSwNP has an up-regulated T-helper cell type 2 (Th2) profile and low Tregulatory cells, whereas CRSsNP has a Th1 profile5 (see Figure). The pathogenesis of CRSwNP is described in Table 1. Table 1. Pathogenesis of Chronic (Eosinophilic) Rhinosinusitis With Polyps. ) 20 • Hypersensitivity immune reaction • The initiating antigen is a fungus (non-invasive) • Antigen-presenting cells secrete interleukin 10, recruit T cells • Th1/Th2 imbalance • A regulation rigidity into a Th2 profile occurs • Eosinophilia ensues • Eosinophils surround fungus • Eosinophils secrete major basic protein, which chemically damages the mucosa • Basophils and mast cells add to inflammation Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 Thus, it is important to adjust bioregulatory treatment in patients with these conditions. In CRSwNP, the immunomodulation is performed with Engystol. Engystol is used in this case because it has been shown to increase interferon-γ, which will support the Th1 profile and balance the Th2 rigidity.6 In CRSsNP, the immunomodulation is performed with Traumeel. Traumeel has been shown to downregulate the proinflammatory cyto kines interleukin 1, interleukin 8, and tumor necrosis factor a.7 The rest of the treatment stays the same for the two types, as illustrated with the protocol in Table 2.| References: 1. Cherry WB, Li JT. Chronic rhinosinusitis in adults. Am J Med. 2008;121(3):185-189. 2. Tieu DD, Kern RC, Schleimer RP. Alterations in epithelial barrier function and host defense responses in chronic rhinosinusitis. J Allergy Clin Immunol. 2009;124(1):37-42. 3. Joe SA, Thakkar K. Chronic rhinosinusitis and asthma. Otolaryngol Clin North Am. 2008;41(2):297-309, vi. 4. Coffinet L, Chan KH, Abzug MJ, Simões EA, Cool C, Liu AH. Immunopathology of chronic rhinosinusitis in young children. J Pediatr. 2009;154(5):754-758. 5. Van Bruaene N, Pérez-Novo CA, Basinski TM, et al. T-cell regulation in chronic paranasal sinus disease. J Allergy Clin Immunol. 2008;121(6):1435-1441,1441.e1-e3. 6. Enbergs H. Effects of the homeopathic preparation Engystol on interferon-γ production by human T-lymphocytes. Immunol Invest. 2006;35(1):19-27. 7. Porozov S, Cahalon L, Weiser M, Branski D, Lider O, Oberbaum M. Inhibition of IL-1β and TNF-α secretion from resting and activated human immunocytes by the homeopathic medication Traumeel S. Clin Dev Immunol. 2004;11(2):143-149. ) Practical Protocols Cor ti A DHE sol Figure. Th1/Th2 balance. Abbreviations: DHEA, dehydroepiandrosterone; IFN, interferon; IL, interleukin; TGF, transforming growth factor; Th, T-helper cell; TNF, tumor necrosis factor. IL-2 IFN-γ TNF Inflammation IL-4, IL-13 IL-5 IL-10 TGF-β Inhibition Allergy Table 2. Treatment for Chronic Rhinosinusitis With Nasal Polyps (CRSwNP) and Without Nasal Polyps (CRSsNP). DET Phase Basic and/or Symptomatic Orodermal • Degeneration Euphorbium compositum S/SN* D&D (CRSwNP and CRSsNP) Regulation Therapya Optional • • Echinacea Advanced supportive de- toxification and drainageb followed by or impregnation (depending on • Basic detoxification and • CRSwNP: • CRSsNP: the severity) IM compositum (if there is severe infection) drainage: Detox-Kitc Engystol N tablets Traumeel S tablets also as biopuncture (using the ampoules) OR • • • Mucosa compositum Coenzyme compositum Ubichinon compositum Dosages: Euphorbium compositum: 1 spray in each nostril up to 5 times per day. Regulation therapy: tablets: 1 tablet 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 liters of water; drink throughout the day. a Antihomotoxic regulation therapy consists of a three-pillar approach: detoxification and drainage (D&D), immunomodulation (IM), and organ regulation (OR). b Advanced supportive detoxification and drainage consists of Hepar compositum (liver), Solidago compositum (kidney), and Thyreoidea compositum (connective tissue). The Detox-Kit consists of Lymphomyosot, Nux vomica-Homaccord, and Berberis-Homaccord. c ) 21 * Marketed as Sinusin in the United States. Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 ) M a r k e t i n g Yo u r P r a c t i c e Think About the Future! By Marc Deschler Marketing specialist Toward year’s end, we all typically reflect on the year that is drawing to a close and begin to wonder about the next. Being well-prepared means fewer surprises in the future, so I’d like to suggest two topics that deserve serious thought. 1. Do you have a plan for 2010? For any business – including a medical practice – planning must be understood first and foremost as an attempt to shape the future. The classical definition of planning is systematic, future-oriented thinking that sets goals and outlines how to implement them. With last year’s expense statement in front of you, you’ll need to ask the following questions to come up with a meaningful plan for the near future (e.g., for the coming year): • Does the category “other expenses” include expenditures incurred only in this particular year, such as consultants’ fees? • Does the statement include expenses actually belonging to an earlier year, perhaps because a supplier was very late in billing you? • Were there any costs unrelated to the operation of the practice, such as vandalism repairs? • Did you acquire any durable assets that will be paid off only in the next year or later? This process identifies nonrecurring expenditures and costs unrelated to running your business. Simply carrying them over into the future would falsify your projections. In times of economic downturn, effective cost containment is more important than ever. Understanding the basics of business administration and being ) 22 aware of your practice expenses will allow you to react faster to changing circumstances. Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 The next step is to develop a reasonable budget based on your cleanedup figures for the past year. At this point, there are additional factors to consider: • Do you anticipate any salary changes for your assistants? • Ask your tax advisor whether there is any advantage to switching from straight-line to declining-balance depreciation of assets. • Consider the state of the financial market and discuss refinancing loans with your bank. Interest rates are often flexible. • Take into account any fundamental upcoming changes in your practice – a pregnancy, extensive renovations, etc. • The inflation rate should also be included in your calculations. Prices for consumer goods rarely go down. At this point, you’ve already taken a big step toward controlling costs. During the planning year, note whether your predictions are accurate and investigate any discrepancies. At times when your income changes almost daily or the economic headlines are bad, planning of this sort may seem either unnecessary or not worth the effort. Keep in mind, though, that the only way to change your income situation in the future is through effective cost containment. First of all, this means under- © iStockphoto.com/Zsolt Nyulaszi Group or joint practices share expenses for staff, office space, and equipment. This can significantly increase the profitability of the joint enterprise. standing the basics and being aware of the expenses and organization of your practice. Having a good grasp of them allows you to react significantly more quickly to changing circumstances. 2. Inter-practice cooperation In times of declining revenue, many solo practitioners begin to think about some form of group or joint practice. To a large extent, outer circumstances will determine whether sharing staff and/or facilities with others is possible or practical. A shared practice spends less on staff and office space than two (or more) individual practices would. Since each practitioner’s total expenses are lower, his or her income is also higher. In other words, the same profit is possible from a lower volume of business. And sharing expensive diagnostic equipment, for example, results in a much larger return on the investment. Several factors need to be considered to ensure a successful partnership, but new, creative models of cooperation are definitely worth considering. Equipment sharing is the least binding form of association between two or more practitioners. The closer the association, the more important careful planning and weighing the pros and cons becomes. What are the advantages of sharing a practice? • The partners complement each other, resulting in both an expansion of the practice’s expert knowledge and competence and in entrepreneurial synergies that produce economic advantages for both parties. This can be true not only of a practice adding a junior partner but also of longestablished practices joining forces. • The partners can step in for each other. The practice is covered during vacation times and on sick days, reducing the burden of expenses. In addition, the extended office hours that may be possible with multiple partners make the practice more interesting to patients. • Two can accomplish more than one, and four eyes are better than two. Doubling the number of responsible parties cuts business risks in half. • Partnerships make financing easier. Two partners may mean more owner equity, and many banks have more confidence in partnerships than in sole proprietors. There are several fundamental prerequisites, however, to achieving a workable partnership. Play it safe and take your time finding the right person. The human factor is as important in a business partnership as it is in a marriage. If the two partners aren’t on the same wavelength, separation eventually becomes in- Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 evitable. The partnership must be absolutely fair and based on fundamental principles of trust and openness, even if the partners are not equally invested. Mistrust can destroy any partnership. Discuss the future goals of the partnership and what each of you expect from it – not just once, but repeatedly and frankly. Here, too, sharing ideas has a stimulating effect. It’s also important to discuss all aspects of your future interaction – distribution of ownership, compensation and profit sharing, division of labor, competencies, vacation times, decision-making procedures – and set them down in writing. Decide on a timetable and commit to specific action steps so the partnership can start up on time. It is highly recommended to seek legal advice and to carefully consi der the following points in the contract: staff hiring; terms of severance, including non-competition clauses and terms of payment, the latter of which could be drawn out in order to ensure the liquidity of the practice. Moonlighting as a factor should be under rules of contract to ensure equality in the time the partners spend in the practice. If it becomes obvious already at an early stage that a partnership will require greater adjustment on your part than you are willing to make, do not simply adopt a “wait and see” attitude; end the association before it starts.| ) 23 ) Re s e a r c h H i g h l i g h t s Gastrointestinal Cramps in Children Spascupreel Comparable to Hyoscine Butylbromide By Mary A. Kingzette Introduction Gastrointestinal cramps and spasms are common in children and adults. In Germany, approximately 10 million prescriptions and an unknown number of over-the-counter selfmedications are used annually for these symptoms. In the United States, $1.2 billion was spent on over-thecounter antacids, antidiarrhetics, and antigas products in 2002. Hyoscine butylbromide is an alkaloid medication with spasmolytic and parasympatholytic properties; it is frequently used to treat acute colic. One disadvantage of this treatment is that hyoscine (scopolamine)containing treatments can be infrequently associated with dry mouth, urinary retention, and increases in ocular pressure. Natural medicines are increasingly used as suitable solutions for acute and chronic disease. Spascupreel is a homeopathic medication that consists of plant and mineral extracts in microdose (10−2 to 10−6). It has been used empirically in over 50 countries primarily for spasms of smooth muscles of the stomach, intestines, bladder, and uterus. In the present study, conducted in Germany, the effects of Spascupreel were compared with those of the conventional medication hyoscine butylbromide in children younger than 12 years who had gastrointestinal or urethral spasms. Methods This cohort study was prospective, observational, and non-interventional. A total of 204 children were enrolled from 57 centers. Each child received either Spascupreel or hyoscine butylbromide orally (both in tablet form). The practitioner determined the treatment for each patient. Doses were determined according to patient age and recommendations of the product information sheet. The maximum study duration was 1 week. The patients included were children younger than 12 years who had newly diagnosed or recurring gastrointestinal or urethral spasms. The patients excluded were those 12 years or older, those already receiving treatment for gastrointestinal spasms, or those for whom one of the study treatments was contraindicated. At the initial visit, the children were examined and data were collected (demographics; localization, intensity, and duration of spasms; etiology; auscultation findings; ultrasonographic findings; possible adjunctive diseases; possible earlier therapies; and presence of risk factors, including adiposity, asthma, diabetes mellitus, eczema, bronchitis, and decreased renal function). The effectiveness of the respective therapies was evaluated by the effect on severity of spasms and clinical symptoms, including pain/cramps, sleep disturbances, distress, eating Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 or drinking difficulties, and frequent crying. The scale for these variables was from 0 to 3 (0 indicates asymptomatic; 1, mild symptoms; 2, moderate symptoms; and 3, severe symptoms). Time to first improvement of symptoms was also recorded (after the first administration, after 12-24 hours of treatment, after 1-3 days of treatment, after > 3 days of treatment, and no improvement). The estimated total effect of treatment was determined by the physician, on a scale of 1 to 5 (1 indicates asymptomatic; 2, clear improvements; 3, moderate improvements; 4, no improvements; and 5, worsening of symptoms). Compliance was evaluated on a 4-point scale (ranging from very good to low), given by the physician, based on information from the patient or caregiver. Tolerability was Aconitum napellus © H. P. Hoff/artbotanica ) 24 © H. P. Hoff/artbotanica ) Re s e a r c h H i g h l i g h t s Monkshood or Wolfsbane (Aconitum napellus) and the False Helleborine, also known as White Hellebore (Veratrum album), are two of the active ingredients contained in Spascupreel. Veratrum album evaluated by the practitioner based on a 4-point scale (very good, good, moderate, and low). Very good tolerability indicates no tolerability complaints, and low tolerability indicates a reaction after each administration. Results There were 2 groups in this study: the Spascupreel group (n = 99) and the control (hyoscine butylbromide) group (n = 105). There were no statistically significant differences in sex between the 2 groups, but patients in the Spascupreel group tended to be younger and, therefore, also shorter and lighter than patients in the hyoscine butylbromide group. Patients were treated for a mean of 6.1 days in both groups. There were 15 patients in the Spascupreel group and 31 in the control group who discontinued treatment. In most cases, discontinuation occurred because of the disappearance of symptoms during therapy. The scores for all variables improved during treatment. The time to first improvement of symptoms was less than 1 day in 12% of the Spascupreel group and 13% of the control group. Most patients (80% in the Spascupreel group and 89% in the hyoscine butylbromide group) experienced an improvement in symptoms within 2 days of treatment, without significant differences between treatment groups. No improvement during the study period was noted for only 4% of the Spascupreel group and 2% of the control group. According to the physicians, treatment was successful (“very good”) in 75% of the Spascupreel group and 79% of the control group. Both groups had similar levels of overall satisfaction with treatment (P = 0.44). During the study, the patients shifted from having predominantly severe or medium symptoms to mostly being asymptomatic for all variables. The greatest effect was seen for pain/cramps and severity of symptoms. For total score, the mean change from baseline was −7.9 in the Spascupreel group versus −6.6 in the hyoscine butylbromide group (negative values indicate symptom improvement). Most patients reported “very good” tolerability with both treatments: 91% in the Spascupreel group and 93% in the hyoscine butylbromide group (P = 0.83). There were no adverse events reported for either treatment. Most patients also reported “very good” compliance in both groups: 72% in the Spascupreel group and 68% in the hyoscine butylbromide group (P = 0.44). Discussion This observational study of 2 groups of children younger than 12 years Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 indicates that Spascupreel (a homeopathic treatment) is comparable to hyoscine butylbromide (a conventional treatment) for gastrointestinal spasms. Alternative treatments for various conditions, including musculoskeletal conditions, vertigo, and respiratory and gastrointestinal disorders, are being used more commonly in the industrialized world. Reasons for the popularity of alternative medical practices include the generally lower rate of adverse events with these treatments and the closer interaction between patient and practitioner. In the present study, both Spascupreel and hyoscine butylbromide showed comparable improvements in the severity of symptoms. The tolerability of both treatments was also very good. Finally, there were no adverse effects with either treatment. Overall, the study showed that patients who opt for homeopathic therapy for gastrointestinal spasms can be treated successfully with Spascupreel. Spascupreel proved to be very good for treating gastrointestinal symptoms and showed very good tolerability and compliance as well.| Reference: Müller-Krampe B, Oberbaum M, Klein P, Weiser M. Effects of Spascupreel versus hyoscine butylbromide for gastrointestinal cramps in children. Pediatr Int. 2007;49(3):328-334. ) 25 ) Making of ... Manufacturing of Traumeel Injection Solution Part II: Sterilization, Quality Control, Labeling, and Packaging By Larissa Wörthwein-Mack With regard to both equipment and personnel, the production of Traumeel ampoules is subject to more stringent regulation than the production of non-sterile dosage forms such as ointment, tablets, or drops. Preparing the ingredients, producing and filtering the injection solution and filling it into glass ampoules all take place in Class C cleanrooms, which can be entered only by specially trained personnel wearing protective clothing. A fter filling, the ampoules are marked for identification, plac ed in stainless steel containers, and transferred to the Sterilization department, where they are autoclaved in accordance with the requirements of the European Pharmacopeia (Ph. Eur.). In this process, hot steam under pressure of 1 bar over atmospheric pressure is used to effectively kill all microorganisms. The sterilizers used in this process are very large, tall compartments of stainless steel that can be vented on two sides. The ampoules to be sterilized enter from a Class C cleanroom on one side and are discharged on the other. Duration, temperature, and pressure of the sterilization process are constantly and precisely monitored and recorded by measuring devices built into the sterilizer. In addition, the ampoules are marked with an indicator stripe showing that the required temperature has been attained. Only then is the sterilizer emptied. Samples are taken to monitor microbiological and chemical quality. Quality control testing In the next step, an optical testing procedure is used to monitor every ampoule (100 percent control) for ) 26 Device for testing ampoules for visible particles Journal of Biomedical Therapy 2008 ) Vol. 2, No. 1 Photos by Sonja Bell ) Making of ... Manual loading of ampoules into a sterilizer A star wheel feeding ampoules into the testing device for visible particles Right: Device for testing ampoules for leaks mobile and visible particles such as bits of glass that might develop when the ampoules are sealed. The testing device detects visible particles down to 50 µm in size. All defective ampoules are sorted out and destroyed. All the ampoules that pass this test are carried by a conveyor belt to the next testing site, where they are tested for leaks. Measuring conductivity under high voltage determines whether each ampoule is intact or cracked. Here, too, every ampoule is tested (100 percent). This machine can test up to approximately 200,000 ampoules per day. All of the intact ampoules then continue on to the labeling department, where self-adhesive labels are applied. Product-specific printing plates are first used to hot-stamp the required data on the blank labels. Immediately downstream, a camera system checks to ensure that the printing is complete and correct. The label is then detached from its carrier film, applied to an ampoule, and secured by a roller. A sensor uses a mark on each label to guide it into position. As each ampoule is discharged from the labeler, it is monitored by another sensor that confirms the presence of a label. This equipment can label about 330,000 ampoules per day. After labeling, the finished Traumeel ampoules are spot-checked for correctly applied and printed labels. Packaging The labeled ampoules still have to pass through one last department, namely, the Packaging department. A machine inserts the ampoules into special trays shaped out of heated plastic film. Another machine inserts each filled tray into a folded cardboard box along with a package insert. After a scanner confirms the identity of the secondary packaging (box and package insert), the batch number and expiration date are stamped on the box. At the end of the assembly line, the package is weighed to confirm that all components have been included in the box. The finished boxes are then bundled and packed into shipping cartons. The production head then checks the manufacturing report to confirm that the ampoules were produced in Journal of Biomedical Therapy 2009 ) Vol. 3, No. 2 accordance with the production instructions. The head of Quality Control also checks the report to confirm that all testing was conducted in accordance with the test instructions to ensure the required quality. As the very last step, the batch of medication is released by the Qualified Person in accordance with §15 of the German Pharmaceuticals Act (AMG). Now the Traumeel ampoules are ready to be shipped out to wholesalers and pharmacies in more than 50 countries around the globe. With a production of 100 million units per year, Heel is the world’s leading manufacturer of homeopathic injection medications.| Inserting ampoules into plastic trays on the assembly line ) 27 C a s e St u dy Co m p e t i t i o n Submit your case study on bioregulatory treatment for presentation at a scientific symposium in Baden-Baden, Germany! Authors of the two best case studies received by the International Academy for Homotoxicology (IAH): q will present their findings in person at the scientific symposium of the International Society of Homotoxicology and Homeopathy (ISOHH) during Medical Week in late October 2010 in Baden-Baden, Germany; q will have their studies published in a subsequent issue of the wellknown “Journal of Biomedical Therapy;” q will receive free travel and accommodations courtesy of the IAH. For criteria and conditions of entry, along with a sample case study and guidelines for writing up your research, visit the IAH website at www.iah-online.com and click on “Case study competition.” Let the world know about your expertise in bioregulatory medicine! www.iah-online.com