Doc 73578

Volume 6, Number 1 ) 2012

Gastrointestinal Disorders• Irritable Bowel Syndrome – A Review Article• Bioregulatory Treatment of Hepatitis C

d 2.00 • US $ 2.00 • CAN $ 3.00

Journal of

BiomedicalTherapy Integrating Homeopathy

and Conventional Medicine

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Published by/Verlegt durch: International Academy for Homotoxicology GmbH, Bahnackerstraße 16, 76532 Baden-Baden, Germany, www.iah-online.com, e-mail: [email protected] Editor in Chief/verantwortlicher Redakteur: Dr. Alta A. SmitEditor: Dr. David W. Lescheid Managing Editor: Silvia BartschPrint/Druck: Dinner Druck GmbH, Schlehenweg 6, 77963 Schwanau, Germany© 2012 International Academy for Homotoxicology GmbH, Baden-Baden, Germany

Cover © Naeblys/Fotolia.com

I n Fo c u sIrritable Bowel Syndrome – A Review Article . . . . . . . . . . . . . . 4

A r o u n d t h e G l o b e European Congress of Integrative Medicine . . . . . . . . . . . . . . 11

Wh a t E l s e i s N e w . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Fr o m t h e P ra c t i c e Bioregulatory Treatment of Hepatitis C . . . . . . . . . . . . . . . . . . 14

Re f r e s h Yo u r H o m o t ox i c o l o g yGut Feelings Revisited: Evidence for a Brain-Gut Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

M e e t t h e E x p e r tDr. Sergio Vaisman Weinstein . . . . . . . . . . . . . . . . . . . . . . . . . 23

P ra c t i c a l P r o t o c o l sBioregulatory Management of Peptic Ulcer Disease . . . . . . . 24

E x p a n d yo u r Re s e a r ch K n o wl e d g eNoninterventional Studies: An Overview . . . . . . . . . . . . . . . . 27

Re s e a r ch H i g h l i g h t s A Multicomponent Medication Triggers Multiple Beneficial Effects Related to Cognition and Neuronal Function . . . . . . . . . . . . 30

Content

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Dr. Alta A. Smit

Journal of Biomedical Therapy 2012 ) Vol. 6, No. 1

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The importance of the gut in health and disease is currently

attracting much attention in medi-cine. Gastroenterology is one of the forefronts at which integrative medi-cine plays a prominent role.

Not only gastrointestinal, but also systemic diseases are closely related to the function of the epithelial bar-rier, the gut microbiome (ie, the collec-tion of all the genes of the commen-sal microbiota and the corresponding proteins and metabolites), and the brain-gut axis.1

A new trend in medicine is the so-called network disease, and systems biology, in which the recognition of the complex interactions between dif-ferent molecular, tissue, and organ networks is in the foreground.2,3

Recently, it has been elucidated that normal development of neural net-works, immune networks, and also neuroendocrine and metabolic net-works depends on the integrity of the microbiome and the brain-gut axis.4,5

Therefore, we have devoted consider-able space to the introduction of this topic, from the focus article on irrita-ble bowel syndrome, in which the disturbance of the brain-gut axis plays a major role, to a more detailed introduction of the various levels of connectivity between the brain and the gut by Dr. David W. Lescheid.

Irritable bowel syndrome is a perfect example of multiple networks play-ing a role and interacting with each other to produce a complex patho-physiological picture. Thus, the con-ventional medical treatment of this syndrome is difficult because it cannot be reduced to a single-prod-uct, single-target approach. Bioregu-lating therapies, through their multi-target, multicomponent approach, offer a viable solution for intervention in these kinds of syndromes. The im-portance of this topic is further to be seen in the section “What Else Is New?”

Bioregulating medicines can have a powerful adjuvant effect on seeming-ly difficult-to-treat diseases. The case report by Dr. Arturo O’Byrne is evi-dence of this, in which biological therapies have been used to success-fully treat a refractory case of hepati-tis C.

We continue our series on research methods by Dr. Robbert van Haselen, and our expert in this issue is Dr. Ser-gio Vaisman, who has had a long-standing impact on the development of homotoxicology in Chile and Lat-in America.

The emergence of congresses devoted to integrative medicine is a sign of the importance of this topic for health care practitioners; however, as can be seen from the article by Dr. Kerstin Röska and Dr. Bernd Seilheimer, the topic also met with a lot of interest in a purely conventional scientific con-gress.

Dr. Alta A. Smit

References 1. Grenham S, Clarke G, Cryan JF, Dinan

TG. Brain-gut-microbe communication in health and disease. Front Physiol. 2011;2:94. doi:10.3389/fphys.2011.00094.

2. Barabási AL, Gulbahce N, Loscalzo J. Network medicine: a network-based ap-proach to human disease. Nat Rev Genet. 2011;12(1):56-68. doi:10.1038/nrg2918.

3. del Sol A, Balling R, Hood L, Galas D. Diseases as network perturbations. Curr Opin Biotechnol. 2010;21(4):566-571. doi:10.1016/j.copbio.2010.07.010.

4. Manco M. Gut microbiota and develop-mental programming of the brain: from evidence in behavioral endophenotypes to novel perspective in obesity. Front Cell In-fect Microbiol. 2012;2:109. doi:10.3389/fcimb.2012.00109.

5. Cryan JF, Dinan TG. Mind-altering micro-organisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neuro-sci. 2012;13(10):701-712. doi:10.1038/nrn3346.

The Importance of the Gut

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Introduction

Irritable bowel syndrome (IBS) is a functional bowel disorder character-ized by common symptoms of ab-dominal pain or cramping (with vari-ability in location and intensity), abdominal distension and/or sensa-tion of bloating, excessive flatulence, diarrhea or constipation (or alteration between the 2 states), and mucous in stools.1,2 These symptoms can be rela-tively constant but most often relaps-ing and remitting, according to the presence or absence of specific envi-ronmental triggers.1,3,4 Usually, the disease remains chronic and recur-ring, with 40% of patients having the diagnosis for 10 years or longer and 70% experiencing symptoms for 1 to 9 days each month.5 Symptoms that are independently associated with IBS include the following: lethargy (relative risk [RR], 6.7), incomplete evacuation (RR, 5.2), backache (RR, 2.0), early satiety (RR, 1.8), and in-creased frequency of micturition (RR, 1.8).6 Irritable bowel syndrome is not a life-threatening condition but can have a serious impact on a patient’s daily activities and quality of life,1 in-cluding periodic bouts of pain, suffer-ing, and direct medical expenses as well as substantial potential social and job-related consequences.2

Irritable bowel syndrome is only one of several functional bowel disorders, including functional abdominal bloating, functional constipation,

functional diarrhea, and functional abdominal pain syndrome.4 It is part of a cluster of syndromes termed cen-tral sensitivity disorders or functional so-matic disorders that include fibromyal-gia, chronic fatigue syndrome, temporomandibular disorder, restless legs syndrome,7,8 and interstitial cys-titis/painful bladder syndrome.9 Irri-table bowel syndrome coexists with other functional gastrointestinal tract (GIT) disorders, especially gastro-esophageal reflux disease10 and dys-pepsia.11 There also is close associa-tion between celiac disease and IBS,12 as well as increased risk of experienc-ing migraines.13

Epidemiology

Based on conservative estimates and strict Rome-based diagnostic criteria, 7% to 10% of adults have IBS world-wide,2,14 but that number has been estimated to be closer to 15% to 20%, depending on different diagnostic criteria and country-specific data.5 The prevalence of IBS is considerably higher among the white US popula-tion than other ethnic groups, with approximately 1500 cases per 100,000 in the white population, 300 cases per 100,000 in US His-panics, and 170 cases per 100,000 in African Americans. A clear explana-tion for those differences has not yet been identified.2 This variability in prevalence might reflect differences in diagnostic patterns of health care

practitioners in various countries, cul-tural differences in seeking medical care for this condition, or some as yet undefined contributing factor. Fur-thermore, there are several different relatively subjective criteria used to diagnose IBS (as described later), and this has been shown to affect preva-lence, with the highest number using the Manning criteria, followed by the Rome I and then the Rome II crite-ria.5

In Westernized countries, IBS is 2 to 3 times more common in women than in men. However, IBS is not simply a disorder of women, especial-ly in the Indian subcontinent, where 70% to 80% of the patients with IBS are male.1 Women are more likely to report abdominal pain and con-stipation-related symptoms, where-as men are more likely to report diarrhea-related symptoms. The dif-ferences between sexes in IBS symp-toms are modest; although female sex hormones have been shown to in-fluence the severity of symptoms, this contribution needs to be confirmed in more clinical studies.15

Irritable bowel syndrome is usually a disorder of young people, with half of the patients experiencing symptom onset before the age of 35 years, and only 40% of patients aged 35 to 50 years when symptoms begin.2 More than 75% of IBS cases occur in per-sons between the ages of 25 and 64 years.1,2 Children with recurrent ab-

Irritable Bowel Syndrome – A Review Article By David W. Lescheid, PhD, ND

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defecation, onset of pain associated with a change in stool form, or onset of pain associated with change in stool frequency).”17 It should be not-ed that neither of these criteria have been sufficiently validated in prospec-tive studies; therefore, their diagnos-tic accuracy is unknown.17 Further-more, it is probably more accurate to consider IBS as a complex of concur-rent symptoms, with each one sepa-rately having limited diagnostic val-ue.18 A recent systematic review states that “With none of the criteria show-ing sufficiently homogeneous and fa-vourable results, organic disease can-not be accurately excluded by symptom-based IBS criteria alone.”19 The relative subjectivity and variabil-ity of diagnostic criteria limit their utility in clinical practice and restrict the direct transferability between re-search studies.

An additional challenge of using symptom-based criteria for diagnosis is that the symptoms of IBS are shared by numerous other organic conditions; therefore, certain pathol-ogies should be excluded, including

inflammatory bowel disease, bile acid diarrhea, small-intestinal bacterial overgrowth, celiac disease, micro-scopic colitis, exocrine pancreatic in-sufficiency, and infectious colitis.17 The identification of a significant psychosomatic component and co-morbidity with various other condi-tions also add difficulty to the diag-nosis.1,3,17

Four different bowel patterns are commonly recognized in those with IBS: persons with greater than 25% of bowel movements with loose or watery stools (diarrhea subtype or IBS-D) or greater than 25% of bowel movements with hard or lumpy stools (constipation subtype or IBS-C), per-sons with mixed constipation and di-arrhea (IBS-M), and persons who al-ternate between diarrhea and constipation (IBS-A).1,3 Another sub-type, termed unsubtyped IBS (IBS-U), was recently identified in a multi-center study in China20 and in other randomized controlled trials21 using the Rome III criteria. The usefulness of this distinct categorization has been questioned because within 1

dominal pain are more likely to de-velop IBS during adolescence and young adulthood,1 with 14% of high school students and 6% of middle school students reported to have symptoms of the disease.1 Elderly persons have been identified as an underdiagnosed and overlooked pop-ulation with IBS.16

Diagnosis

The diagn osis of IBS was previously considered as a diagnosis of exclu-sion, but most current guidelines amend this and acknowledge that it is a distinct disease, albeit with a broad differential diagnosis.2 There are no consistent laboratory tests, imaging studies, or biological markers to diag-nose IBS; therefore, symptom-based criteria, such as the Manning or Rome III criteria (currently considered the gold standard), are commonly used. To diagnose IBS using the Rome III criteria, patients must have “recurrent abdominal pain or discomfort accom-panied by at least two of three addi-tional symptoms (pain relieved by

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year, 75% of patients change sub-types, and 29% switch between con-stipation- and diarrhea-predominant IBS.22 A recent review suggests that the reported variability in subtyping would be more consistent if the peri-od recommended for recording stool frequency and consistency patterns was extended to 2 weeks.21 Although there have been some reports of a predominance of specific subtypes of IBS, a systematic review elucidated that there is no consistent predomi-nance of any one subtype and con-cluded that “IBS clinical subtypes dis-tribution differs depending on the population evaluated, the geographi-cal location, and the criteria employed to define IBS and bowel habit sub-types.”23

Pathophysiology

The pathogenic mechanisms contrib-uting to IBS are still incompletely known,24 although it is evident that dysfunction in any part of the brain-gut axis (eg, alterations in the central nervous system caused by psycholog-ical or other factors, abnormal gastro-intestinal motility, or heightened vis-ceral sensations) can contribute to its development. It is well understood that this condition is heterogeneous, with an undoubtedly multifactorial cause.25

Several recent studies buttress the view that IBS, at least in part, has an

organic component that can be read-ily and easily recognized.3 A com-monly considered hypothesis is that IBS is a 3-part complex of altered GIT motility, visceral hyperalgesia, and psychopathology.2,5 There are distinct aberrations in the motility of the small and large bowel and a proposed generalized hyperrespon-siveness within the smooth muscle layer. This helps explain the often as-sociated (50% of patients) symptoms of increased urinary symptoms (eg, frequency, urgency, and nocturia).1,2 There also have been more recent reports that dysfunction in the endo-cannabinoid system could contribute to the onset and persistence of symp-toms associated with IBS,26 including perturbations in motility, secretion, and hypersensitivity.27 Hyperalgesia within the GIT can be secondary to hyperexcitability of neurons in the dorsal horn in response to periph-eral tissue irritation or to descend-ing influences from the brain stem. Multiple factors are proposed to alter the function of neuroreceptors and afferent spinal neurons, including genetics, inflammation, mechanical irritation of local nerves, dysfunc-tion of motility, and psychological influences.1,2 There is still no clear as-sociation between psychiatric distur-bances and pathogenesis of IBS, with considerable debate on whether psy-chopathology incites development of IBS or vice versa. In some studies, pa-tients who seek medical care for IBS symptoms have a higher incidence

of panic disorder, major depression, anxiety disorder, and hypochondria-sis. These psychological disturbances are not commonly believed to cause or initiate the symptoms of IBS but are thought to influence the patient’s perception of the symptoms and af-fect the clinical outcome.1,2 There is also a higher prevalence of physical and sexual abuse in patients with IBS.1,2 It is evident that various inter-personal relationships, both positive and negative, can have an impact on the course of IBS.28 The importance of the genetic contribution to IBS re-mains in dispute.2,29

There are several potential dietary factors that are identified as contrib-uting to the development of IBS in susceptible people,30 including intol-erances to certain foods,31,32 ingestion of malabsorbed sugars (ie, sorbitol, fructose, and lactose) and fructans,33,34 gluten sensitivity,18 and abnormal in-take of certain types of dietary fats (in particular, those rich in arachidonic acid, a precursor to several proinflam-matory eicosanoids).35 Immunoglob-ulin G antibodies to ingested food may be playing a role in IBS, and food elimination can be effective in reducing its symptoms.2 Other life-style factors that are correlated with the development of IBS include smoking,36 alcohol abuse and/or de-pendency,37 and poor sleep quality.38 Excessive intake of caffeine and/or legumes and inadequate daily intake of water also might exacerbate symp-

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toms in susceptible persons.2 All of these environmental factors, and the psychosocial factors previously dis-cussed, could have a notable impact on the course of IBS, possibly via their ability to influence epigenetic mechanisms.39

Recent studies have identified ad-ditional pathophysiological mecha-nisms. Dysregulation of the brain-gut axis; GIT infection; low-grade infil-tration and activation of mast cells in the intestinal mucosa, with conse-quent release of bioactive substances; and altered serotonin metabolism are some emerging factors of IBS patho-

genesis. Modification of small-bowel and colonic microflora (ie, so-called intestinal dysbiosis) and altered gas balance may be of relevance in some subgroups of patients with IBS.24,25 The brain-gut axis is a bidirectional pathway that links higher cortical centers with visceral afferent sensa-tion and intestinal motor function. Regulation of these connections oc-curs via numerous neurotransmit-ters found in the brain and gut (eg, cholecystokinin, vasoactive intestinal peptide, substance P, and serotonin [5-hydroxytryptamine]) that act at different sites, with varied effects on gastrointestinal motility, pain control,

emotional behavior, and immunity. Studies have shown that IBS symp-toms may be related to imbalance in mucosal 5-hydroxytryptamine avail-ability caused by defects in 5-hy-droxytryptamine production, sero-tonin receptors, or transporters.2

The concept of microscopic inflam-mation, possibly at a subclinical low-grade level,40 preceding the develop-ment of IBS25 is groundbreaking and challenges the previous theories of this syndrome having no demonstra-ble pathological alterations. Low-grade mucosal inflammation, in par-ticular involving abnormal activation

Figure 1. Therapeutic Action of Spascupreel in the Treatment of Irritable Bowel Syndrome

• Reducespain-inducedstress• Reducesstress-induced

motilitydisorders

• Reducesspasmsandcramps• Reducesspasm-andcramp-

relatedpain

• Reducessusceptibilitytodiarrheaandabdominalbloating

• Reducesmucusproduction

Balancingthenervoussystem

Relaxingsmoothmuscles

Restoringbowelfunction

Parasympatheticnervoussystem

Sympatheticnervoussystem

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of mast cells, has been identified as a contributing factor in the pathogene-sis of IBS in a recent systematic re-view.41 The cause of this persistent nonresolving inflammation might be a breakdown in the integrity of the epithelial barrier because recent evi-dence has demonstrated an increase in colonic permeability, release of me-diators from mucosal mast cells, and allergic disposition in patients with the disease.42 Both colonic inflamma-tion and small-bowel inflammation have been substantiated in a subset of patients with IBS and in patients with the onset of IBS after infectious en-teritis, known as postinfectious IBS. The risk of developing IBS increases 6-fold after GIT infection (10%-15% of adult patients) and remains elevat-ed for at least 2 to 3 years after infec-tion. An exposure to pathogenic or-ganisms (eg, Campylobacter, Shigella, Salmonella, and Escherichia coli) may disrupt intestinal barrier function, al-ter neuromuscular function, and trig-ger chronic inflammation, which sus-tain IBS symptoms.2,43 Factors that increase the risk of developing postinfectious IBS include severe and prolonged infection, female sex, younger age, antibiotic treatment for this infection, and concomitant pres-ence of anxiety.2,43 Further findings of small-bowel bacterial overgrowth and disrupted numbers, distribution, and types of fecal microflora in pa-tients with IBS have been heralded as a unifying mechanism for the symp-

toms of bloating and distension com-mon to this condition.24,44 The abnor-mal bacterial overgrowth is believed to induce fermentation, leading to production of excess gas, which has led to effective treatments with probi-otics and antibiotics.7 Individuals who are carriers of the intestinal pro-tozoan parasite, Blastocystis, also have been recently shown to have an in-creased risk of developing IBS, espe-cially if they have single-nucleotide polymorphisms in the genes encod-ing interleukins 8 and 10.45

Treatment

The prevailing mainstream medicine approach is to treat the dominant IBS symptoms, using antispasmodics, an-tidiarrheals, or laxatives, often with off-label use of pharmaceutical drugs. However, it is clear that, in many cas-es, this approach is unsystematic and associated with a limited therapeutic potential. Moreover, the use of more than one drug to treat different symp-toms increases the risk of adverse ef-fects.46 Furthermore, there is concern that several agents used to treat IBS symptoms may exacerbate some IBS symptoms and, therefore, need to be used with caution (eg, some antide-pressants can cause constipation). A recent survey in the United States found that conventional therapies for IBS-C (eg, antidepressants, antispas-modics, laxatives, fiber, and stool soft-eners) are associated with adverse ef-

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fects that negatively affect the lives of those with IBS and lead to many pa-tients seeking medical care or missing work/school or social activities as a result of this iatrogenesis.47 Overall, there is limited evidence for the effi-cacy, safety, and tolerability of thera-pies currently available for the treat-ment of IBS.48 Most mainstream medical therapies used to treat IBS target only one symptom, despite a European survey indicating that less than 25% of patients have complete relief of any one symptom with exist-ing treatments.5

Therefore, from previous descrip-tions, IBS is a complex disease affect-ing many networks in the body. To treat this disease optimally, we need an approach that is multitargeted and multicomponent. 49 Treatment should thus not only concentrate on the symptoms of IBS, but also take into account the different network pertur-bations and deficiencies.

Complementary and alternative med-ical therapies, such as homeopathy, acupuncture, special diets, herbal medication, and several forms of psy-chological treatments and hypnother-apy, are sought by many patients and are being offered by physicians as treatment options, either alone or in conjunction with conventional forms of therapy in patients with refractory symptoms. There also is considerable evidence of efficacy with comple-

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Figure 2. Additional

Individualized Treatment of

Irritable Bowel Syndrome

mentary and alternative medical ther-apies, including well-designed ran-domized controlled trials with several of these therapies, such as peppermint oil and probiotics, as well as turmeric extract, artichoke leaf extract, combi-nation herbal medicine products, tra-ditional Chinese medicines and acu-puncture, and various forms of mind-body medicine. (The article by Yoon et al18 provides tables summa-rizing the evidence base for comple-mentary and alternative medical ther-apies in the treatment of IBS.)

The ability of medications with bio-regulatory properties, and other natu-ral health products, to influence mul-tiple targets simultaneously positions them well as a potentially effective approach to such a complex disorder. Spascupreel is a multitargeted, multi-component medication that offers a holistic approach, both treating the

spasmodic component and potential-ly addressing the brain-gut axis. It is, thus, one of the cornerstone treat-ments in the condition (Figure 1). Other treatments can then be added, according to the patient’s specific needs, as an individualized treatment (Figure 2).

Conclusion

Irritable bowel syndrome is a complex disease that cannot be solved with a linear approach. A multitargeted, multicomponent therapy is necessary to target the networks involved in this disease. Medications acting in a bio-regulatory manner address the patho-physiology of the disease and have an excellent tolerability profile. There-fore, they are a promising approach in providing adequate treatment to pa-tients with IBS.|

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SpaScupReel

Treatdiarrhea:Diarrheel

Treatconstipation,bloating,andnausea:Nux

vomica-Homaccord

Treatstressandsleepdisturbances:

NeurexanorNervoheel

Treatcomorbiddyspepsia:Gastricumeel

Treatmucosalmembranedysfunction:

MucosacompositumandCoenzymecompositum*

* In Canada, replace Coenzyme compositum by Ubicoenzyme.

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18. Yoon SL, Grundmann O, Koepp L, Farrell L. Management of irritable bowel syndrome (IBS) in adults: conventional and comple-mentary/alternative approaches. Altern Med Rev. 2011;16(2):134-151.

19. Jellema P, van der Windt DA, Schellevis FG, van der Horst HE. Systematic review: accu-racy of symptom-based criteria for diagnosis of irritable bowel syndrome in primary care. Aliment Pharmacol Ther. 2009;30(7):695-706.

20. Yao X, Yang YS, Cui LH, et al. Subtypes of irritable bowel syndrome on Rome III criteria: a multi-center study [published on-line ahead of print September 19, 2011]. J Gastroenterol Hepatol. doi:10.1111/j.1440-1746.2011.06930.x.

21. Engsbro AL, Simren M, Bytzer P. Short-term stability of subtypes in irritable bowel syndrome. Aliment Pharmacol Ther. 2012;35(3):350-359.

22. Paré P, Gray J, Lam S, et al. Health-related quality of life, work productivity, and health care resource utilization of subjects with ir-ritable bowel syndrome: baseline results from LOGIC (Longitudinal Outcomes Study of Gastrointestinal Symptoms in Canada), a nat-uralistic study. Clin Ther. 2006;28(10):1726-1735.

23. Guilera M, Balboa A, Mearin F. Bowel habit subtypes and temporal patterns in irritable bowel syndrome: systematic review. Am J Gastroenterol. 2005;100(5):1174-1184.

24. Gasbarrini A, Lauritano EC, Garcovich M, Sparano L, Gasbarrini G. New insights into the pathophysiology of IBS: intestinal micro-flora, gas production and gut motility. Eur Rev Med Pharmacol Sci. 2008;12(suppl 1):111-117.

25. Sainsbury A, Ford AC. Treatment of ir-ritable bowel syndrome: beyond fiber and antispasmodic agents. Ther Adv Gastroenterol. 2011;4(2):115-127.

26. Storr M, Allescher HD. Irritable bowel syn-drome: a dysfunction of the endocannabinoid system? Gastroenterology. 2012;142(2):406-408.

27. Storr MA, Yüce B, Andrews CN, Sharkey KA. The role of the endocannabanoid sys-tem in the pathophysiology and treatment of irritable bowel syndrome. Neurogastroenterol Motil. 2008;20(8):857-868.

28. Gerson MJ, Gerson CD. The importance of relationships in patients with irritable bowel syndrome: a review. Gastroenterol Res Pract. 2012;2012:157340.

29. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Func-tional bowel disorders. Gastroenterology. 2006;130(5):1480-1491.

30. Tighe MP, Cummings JR, Afzal NA. Nutri-tion and inflammatory bowel disease: pri-mary or adjuvant therapy. Curr Opin Clin Nutr Metab Care. 2011;14(5):491-496.

31. Eswaran S, Tack J, Chey WD. Food: the for-gotten factor in the irritable bowel syndrome. Gastroenterol Clin North Am. 2011;40(1):141-162.

32. Morcos A, Dinan T, Quigley EM. Irritable bowel syndrome: role of food in pathogenesis and management. J Dig Dis. 2009;10(4):237-246.

33. Fernandez-Banares F, Esteve M, Viver JM. Fructose-sorbitol malabsorption. Curr Gastro-enterol Rep. 2009;11(5):368-374.

34. Gibson PR, Newnham E, Barrett JS, Shep-herd SJ, Muir JG. Review article: fructose malabsorption and the bigger picture. Aliment Pharmacol Ther. 2007;25(4):349-363.

35. Clarke G, Fitzgerald P, Hennessy AA, et al. Marked elevations in pro-inflammatory poly-unsaturated fatty acid metabolites in females with irritable bowel syndrome. J Lipid Res. 2010;51(5):1186-1192.

36. Fujiwara Y, Kubo M, Kohata Y, et al. Ciga-rette smoking and its association with over-lapping gastroesophageal reflux disease, functional dyspepsia, or irritable bowel syn-drome. Intern Med. 2011;50(21):2443-2447.

37. Masand PS, Sousou AJ, Gupta S, Kaplan DS. Irritable bowel syndrome (IBS) and alco-hol abuse or dependence. Am J Drug Alcohol Abuse. 1998;24(3):513-521.

38. Bellini M, Gemignani A, Gambaccini D, et al. Evaluation of latent links between irritable bowel syndrome and sleep quality. World J Gastroenterol. 2011;17(46):5089-5096.

39. Dinan TG, Cryan J, Shanahan F, Keeling PW, Quigley EM. IBS: an epigenetic perspective. Nat Rev Gastroenterol Hepatol. 2010;7(8):465-471.

40. Keohane J, O’Mahony C, O’Mahony L, O’Mahony S, Quigley EM, Shanahan F. Irri-table bowel syndrome-type symptoms in pa-tients with inflammatory bowel disease: a real association or reflection of occult inflamma-tion? Am J Gastroenterol. 2010;105(8):1789-1794.

41. Ford AC, Talley NJ. Mucosal inflammation as a potential etiological factor in irritable bowel syndrome: a systematic review. J Gas-troenterol. 2011;46(4):421-431.

42. Vivinus-Nebot M, Dainese R, Anty R, et al. Combination of allergic factors can worsen diarrheic irritable bowel syndrome: role of barrier defects and mast cells. Am J Gastroen-terol. 2012;107(1):75-81.

43. Thabane M, Marshall JK. Post-infectious ir-ritable bowel syndrome. World J Gastroenterol. 2009;15(29):3591-3596.

44. Lin HC, Pimentel M. Bacterial concepts in irritable bowel syndrome. Rev Gastroenterol Disord. 2005;5(suppl 3):S3-S9.

45. Olivo-Diaz A, Romero-Valdovinos M, Gudiño-Ramirez A, et al. Findings related to IL-8 and IL-10 gene polymorphisms in a Mexican patient population with irritable bowel syndrome infected with Blastocystis [published online ahead of print January 28, 2012]. Parasitol Res. 2012;111(1):487-491. doi:10.1007/s00436-012-2830-0

46. Goettsch WG, van den Boom G, Breekveldt-Postma NS, Smout AJ, Herings RM. Treat-ment patterns and health care costs of mebeverine-treated IBS patients: a case-control study. Pharmacoepidemiol Drug Saf. 2004;13(11):803-810.

47. Lembo A. Irritable bowel syndrome medica-tions side effects survey. J Clin Gastroenterol. 2004;38(9):776-781.

48. Tack J, Fried M, Houghton LA, Spicak J, Fisher G. Systematic review: the efficacy of treatments for irritable bowel syndrome – a European perspective. Aliment Pharmacol Ther. 2006;24(2):183-205.

49. Whorwell PJ. Irritable bowel syndrome. Altern Ther Health Med. 2011;17(2)(suppl):S4-S6.

) 11


) A r o u n d t h e G l o b e

European Congress of Integrative Medicine Breakaway Session on Bioregulatory Medicine By Ghassan Andraos, MD

Bioregulatory medicine is an emerging science. The aim of

the scientific symposium “The Bio-regulatory Medicine Approach: From Genomics to Clinical Application” was to update the 420 registered par-ticipants to the third European Con-gress of Integrative Medicine on the most recent changes and findings in this field.Sometimes described as “the bridge between natural medicine and con-ventional medicine,” this therapeutic approach seeks to improve patient care by offering a wide range of ther-apeutic and diagnostic tools, leading to a more personalized therapeutic approach.In her opening remarks, Alta Smit, MD, highlighted the novel and in-creasingly supported shift in medical thinking towards complexity. This

includes the underlying single and multiple networks in the disease pro-cess. With this increased complexity in thinking, there also is a necessity to incorporate new technologies, with an improved ability to diagnose com-plexity, and for therapeutic drugs that have multiple biological targets.Bernd Seilheimer, PhD, then ex-plained how genomic profiling can be used as a tool to substantiate the action of a multitargeted medication at a cellular level. The genomic and deep-sequencing data demonstrated that these multicomponent medica-tions do indeed have multiple targets within a model disease system. After showing that there is a scientifically validated technology, with reproduc-ible, credible evidence identifying the targets of multicomponent medica-tions, a more complex pathological

process, such as the inflammatory cas-cade, can be investigated.Manfred Schmolz, PhD, presented the inflammatory cascade as a model for the value of network medicine, showing that inflammation is a de-fense mechanism that fits into the sys-tems biology thinking and complexi-ty and that it needs to be regulated, rather than suppressed. Possible inter-vention points were identified along the inflammatory cascade, and the value of a multitargeted therapeutic approach to modulate the inflamma-tion (ie, upregulate some targets and downregulate others) to promote synergy and avoid adverse effects, while sustaining its therapeutic bene-fits, was substantiated.Bernd Wolfarth, MD, associate pro-fessor of sports medicine, highlighted the clinical evidence of Traumeel in the care of musculoskeletal disorders. He discussed the preclinical knowl-edge about its multitargeted mecha-nism of action, including a proof of concept from scientific support for relevant components, together with a body of clinical research built over the years and his own clinical experi-ence and practice. He confirms that, for him, Traumeel is definitely a first-line therapy for musculoskeletal dis-orders.This conference confirms the poten-tial of Bioregulatory Medicine as an effective first-line therapy with mini-mal adverse effects.|

From left to right: Alta Smit, MD; Bernd Seilheimer, PhD; Manfred Schmolz, PhD; and Bernd Wolfarth, MD.

) 12


Intestinal Inflammatory Factors Affect Elderly Individuals

Elderly individuals are often character-ized by having chronic low levels of inflammation and immune system im-pairment that affect both their overall health and survival. This review de-scribes intestinal components that re-ceive and provide signals that play a role in local and systemic inflammation and immunity. These components in-clude the following: sentinel cells, such as macrophages, dendritic cells, and mast cells concentrated in the splanch-nic area, which receive simultaneous signals from commensal bacteria as well as physiological and pathological metabolic processes; endogenous im-mune system molecules in the intes-tine, such as natural killer cells and

dendritic cells, which are affected by aging and stress; and exogenous mole-cules in the intestine, such as the evolu-tionarily conserved molecules from bacteria. All of these signals interact in a network that either promotes the res-toration of homeodynamics or chronic inflammation if there is failed resolu-tion of inflammation, long-lasting tis-sue injury, or persistent infections by pathogens. Supplementation by specif-ic nutrients, including probiotics, pre-biotics, and certain vitamins, minerals, and dietary substances, may contribute to restoring homeodynamics in the in-testine and, therefore, in the whole body, by modifying the inflammatory pathways and by repairing any in-creased permeability of the epithelial barrier.

Mutat Res. 2010;690(1-2):50-56.

Gut Microbiota Communicate With the Brain

Human health is affected by a bidirec-tional communication system between gut microbiota and the brain. Although most previous research has focused on how the brain affects the gut microflo-ra, there is increasing evidence that sig-nals from the commensal and patho-genic bacteria in the gut also affect the brain and behavior. This particular ar-ticle discusses recent studies, including those with germ-free mice. Because there is a definite signal (axis) between the brain and the gastrointestinal tract, study of the factors that affect it is im-portant. The agents that decrease the amount of gut microbiota include anti-microbials. Future studies should focus on the molecular, cellular, and physio-logical aspects of the gut microbiota–brain communication.

Neurogastroenterol Motil.

2011;23(3):187-192.

doi:10.1111/j.1365-2982.2010.01664.x

) W h a t E l s e i s N e w

Nutritional intervention may help

restore homeodynamics in

the intestine.

Recent studies have discussed the role

of the enteric microbiota in the

treatment of gastrointestinal disorders.

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F O R P R O F E S S I O N A L U S E O N L Y

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 avail-able 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 comple-mentary 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.

) 13


Emotions Affect Food Intake

This study attempted to determine some of the specific connections between hu-man emotions and feeding behavior by examining the relationship between gut signaling from specific nutrients and externally created emotions. Functional magnetic resonance imaging was used to measure the effects in the brain. The study included 12 healthy male and fe-male volunteers who were not obese. “Nutrient-induced gut-brain signaling” was determined after the subjects re-ceived an infusion of fatty acid or saline. An important part of this study was that, because the volunteers received an infusion, it bypassed the taste receptors, texture, sight, and mouth-end feel asso-ciated with fatty foods, showing for the first time in humans the direct effect of the composition of the food itself on emotions. Sad emotion was induced by validated sad or neutral classical music and facial expressions. The subjects then rated their feelings of hunger, full-ness, and mood. The results indicated that sad emotion was “attenuated by fatty acid infusion.” These findings in-crease the understanding of the rela-tionships among emotions, hunger/food intake, meal-induced sensations and obesity, eating disorders, functional dyspepsia, and depression. Further-more, this study helps support the va-lidity of phrases such as “emotional overeating” and “comfort feeding.”

J Clin Invest. 2011;121(8):3094-3099.

doi:10.1172/JCI46380

Cancer-Associated Death Is Affected by Density of Petroleum Stations

In Taiwan, a case-control study on air pollution and death from gastric cancer was conducted from 2004 to 2008. Data were obtained from case deaths affected by gastric cancer and control deaths affected by variables other than tumors and gastrointestinal tract dis-eases. Cases and controls were matched by sex, birth year, and death year; 2 substantial petroleum companies provided data for number of petroleum stations in the municipalities. The density of petroleum stations in municipalities determined the expo-sure to “benzene and other hydrocar-bons present in ambient evaporative losses of petroleum or to air emissions from motor vehicles.” The study deter-mined that persons who lived in mu-nicipalities with the highest density of petroleum stations (>75th percentile) had an increased risk of death associ-ated with gastric cancer, when com-pared with persons who lived in mu-nicipalities with the lowest density of petroleum stations (≤25th percentile). In the future, studies should seek to de-termine the specific ways that traffic air pollution causes gastric cancer.

J Toxicol Environ Health A.

2011;74(18):1215-1224.

bExposure to traffic air pollution

increases the risk of dying

from gastric cancer.

Enterotypes Determined for Human Gut Microbiome

There is rapidly expanding knowledge of both the species and functional fea-tures of the human gut microbiome. The present study analyzed data from adult fecal samples of 4 different coun-tries and 22 newly sequenced fecal metagenomes and combined them with previous data from 2 other coun-tries to identify 3 enterotypes (robust clusters of related bacteria) that are not specific to a country or continent. These enterotypes represent well-bal-anced, defined microbial communities with a relatively high degree of phylo-genetic and functional association between them. Although the indi-vidual composition can be affected differently by diet and drugs, they are not explained by differences in body mass index, sex, age, and nationality. However, several marker genes (eg, 12 genes that associate with age) or functional variables (eg, 3 modules that associate with body mass index) were determined and could be useful for di-agnosis and possible prediction of the risk of different human disorders. The robustness and predictability of the clusters also suggest that they could be used as a guide for how different hu-man groups would respond differently to drug and diet intake.

Nature. 2011;473(7346):174-180.

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) F r o m t h e P r a c t i c e

Bioregulatory Treatment of Hepatitis C

A Clinical Case Report By Arturo O’Byrne, MD

Chronic progression of this dis-ease is characterized by pro-

gressive development of fibrosis and cirrhosis of the liver after 20 to 25 years in 2% to 35% of those affected.4 Furthermore, patients with cirrhosis are exposed to life-threatening com-plications, including end-stage liver disease, esophageal variceal hemor-rhage, and the development of hepa-tocellular carcinoma (HCC), which occurs at an incidence of 4% to 5% per year in these patients.5,6 With chronic HCV infection being the leading cause of HCC and the first indication of liver transplantation in industrialized countries, this poses an enormous threat to worldwide public health.5,7 Hepatitis C virus has also rapidly surpassed human immunode-ficiency virus as a cause of death in the United States, with almost 75% of HCV-related deaths occurring among adults between the ages of 45 and 64 years.7

Transmission of the virus is paren-teral and sexual, with needle sharing, unscreened blood transfusions, non-sterile tattooing or acupuncture, and

vertical and sexual transmission be-ing among some of the means of viral exposure. However, intravenous drug use remains the most common cause of HCV infection, especially in devel-oped countries.7,8 There are 6 geno-types of HCV, 52 subtypes within these genotypes, and a diverse popu-lation of mutant viruses known as quasispecies within each infected indi-vidual.3 Genotype 1 (subtypes 1a and 1b) is reported to be the most fre-quent genotype worldwide, account-ing for 40% to 80% of all isolates, but unlike HCV genotypes 2 and 3, which respond more favorably to treatment, genotypes 1 and 4 are more difficult to eradicate using cur-rent conventional medications.1,3,7 Genotype 1 also may be associated with more severe liver disease and a higher risk of HCC.7 The ability of the virus to incorporate adaptive mu-tations in the host and exist as ge-netically distinct quasispecies, in ad-dition to disrupting the host’s defense by blocking phosphorylation and function of interferon (IFN) regula-tory factor-3, an antiviral signalling molecule, poses a major challenge to

the immune-mediated control of HCV.1 This may also explain the vari-able clinical course of the disease, difficulties in vaccine development, and the variable results of treat-ment.1,8 Current pharmacological in-tervention includes antiviral agents that specifically target viral function, collectively termed direct-acting antivi-rals, in addition to host-targeted agents that aim to inhibit HCV replication.8 The aim behind all treatment options is to eradicate HCV viremia, thereby increasing quality of life and reduc-ing the risk of cirrhosis and HCC.7,8 Combination therapy of pegylated IFN-α and ribavirin is the current mainstay of treatment, resulting in sustained clearance of serum HCV-RNA. However, this treatment causes many adverse effects (eg, flulike symptoms, insomnia, hair loss, mood changes, pruritus, dermatitis, and he-matological abnormalities, including neutropenia, anemia, and thrombo-cytopenia) and is only efficacious in approximately 50% of patients, with possible relapses at the end of treat-ment.8-10 Several host factors, such as age, stage of liver fibrosis, body mass index, liver steatosis, insulin resis-tance, ethnicity, and interleukin 28B single-nucleotide polymorphisms, and viral genotype are reported to influence the treatment outcome.1,2,5,11

Patients infected with both acute and chronic hepatitis are usually asymptomatic, making early diagno-sis difficult.4 Once symptoms occur,

Hepatitis C virus (HCV) is a small positive-sense single-

stranded RNA virus that causes acute and chronic hepa-

titis C in humans.1 More than 170 million people world-

wide are infected with HCV, covering approximately

3.3% of the world’s population.2,3

) 15



they tend to be nonspecific, with fa-tigue and/or malaise being the most commonly reported, in addition to a general decrease in quality of life.4,7 Thereafter, symptoms often develop as clinical findings of extrahepatic manifestations of HCV and most commonly involve the joints, muscle, and skin (ie, arthralgias, paresthe-sias, myalgias, pruritus, and sicca syndrome). Patients with ongoing pathology associated with chronic hepatitis C that eventually results in organ failure can present with symp-toms and signs related to synthetic dysfunction and portal hypertension (ie, ankle edema, abdominal disten-tion, hematemesis or melena, palmar erythema, and yellowing of the eyes).7 The natural history of chronic hepatitis is ill defined because of the long latent period between inoculum and development. Severity and pro-gression are variable but generally slow; however, host and environ-mental factors play a vital role in dis-ease progression.8,11

Clinical Case

In July 2006, a 55-year-old male pa-tient presented to the clinic with

symptoms of skin irritation and pru-ritus. Investigations undertaken 6 months earlier reported altered levels of liver enzymes; features of fatty liver on ultrasonography, in addition to positive antibodies; an increased HCV RNA assay result of 697,000 IU/mL; and a genotype test result of type 1 subtype 1b. These features all confirmed a diagnosis of chronic hepatitis C infection.

The patient’s medical history includ-ed having abnormal coagulation factor X since the age of 35 years, for which he received many transfu-sions (plasma and isolated X factor) in the past several years, which may have caused the HCV transmission and infection. The patient also re-ported previous and current treat-ment for metabolic syndrome, anxi-ety, and several adverse effects potentially caused by his conven-tional hepatitis drug therapy (ie, ar-ticular pain, insomnia, and emotion-al irritability). The patient has received weekly injections of 180 µg peginterferon alfa-2a, in addition to an oral dose of 5 tablets of ribavirin per day for the past 5 months. The patient was also taking a combina-

tion angiotensin II receptor blocker and diuretic drug (candesartan); a statin/3-hydroxy-3-methyl gluta-ryl–coenzyme A reductase inhibitor (atorvastatin); an antihyperglycemic drug (metformin); an antifibrinolytic (tranexamic acid); 2 antidepressants (sertraline and mirtazapine); an acet-aminophen- and codeine-based an-algesic, in addition to a sedative (zolpidem); and a mood-stabilizing agent (levomepromazine).

By March 2006, the hypertension and coagulation disorders were con-trolled; however, despite the conven-tional hepatitis C treatment, the viral load increased to greater than 700,000 IU/mL, with loss of appe-tite and sexual desire added to the adverse effects of the conventional drugs still felt by the patient. After 5 months of conventional treatment with no effect on the hepatitis C, the patient turned to bioregulatory therapy.

In light of the chronicity of the in-fection, the extensive list of conven-tional drugs and their adverse ef-fects, in addition to the multiple concomitant disease processes pres-

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) 16



ent all at the same time, it was clear that a carefully orchestrated therapy scheme, providing a combination of detoxification, supportive, reparative, and immune-enhancing activities, was to be initiated. After the first con-sultation in July 2006, a combination of medications (eg, Hepar composi-tum, Engystol, and Galium-Heel) was given parenterally for immediate im-munomodulation and tissue support, in addition to extensive nutritional supplementation (eg, vitamin B com-plex). The intravenous method of ad-ministering the bioregulating medi-cations, together with the nutritional supplements, has evoked greater sys-temic effects in our clinic. The patient was also prescribed an oral combina-tion of medications targeted at assist-ing with the reparative processes of the body, providing the necessary cellular and organ support, in partic-ular for the hepatic, hematological, and splenic organs, and assisting with the activation of the immune system. Hepeel, Engystol, and a com-bination of products composed of Chelidonium-Homaccord and prod-ucts containing porcine tissue materi-als (eg, liver, spleen, and bone mar-row) and 2 bioregulatory metabolic factors (Acidum succinicum-Injeel and Acidum fumaricum-Injeel) were prescribed 3 times a day at specific intervals. Gentle detoxification was also started with the use of Hepeel and other prescribed liver cleanse formulas. At the follow-up visit 2 weeks later, Valerianaheel was pre-

scribed to assist with the insomnia, followed by homeopathically pre-pared ribavirin (D8 potency) and pe-gylated IFN (D8 potency) 2 weeks after that to assist with the adverse effects of the conventional counter-parts. The latter were to be taken each once a day for 2 weeks, followed by 10 drops 3 times a week thereaf-ter.

After receiving neural therapy dur-ing the fourth consultation in Sep-tember, the patient developed hema-tomas in all the injected sites, 24 hours after the injection therapy. These were seen as a positive devel-opment in the patient’s movement towards health, and an acute posol-ogy of oral Cinnamomum-Homac-cord was prescribed for the next 1.5 days, in addition to Traumeel acting as an adjunct for the management of the inflammatory process. The pa-tient responded well after 48 hours of the initial crisis, displaying posi-tive disease evolution changes.

By using the electroacupuncture system, developed by Reinhold Voll, MD, and Fritz Kramer, MD, in Ger-many 60 years ago, the measure-ment of bioimpedance in the pa-tient’s acupuncture points was assessed throughout the rest of the consultations, which was also used to confirm the physician’s choice of medicines. After being evaluated in early October, autologous blood therapy was administered a few days

later into the indicated acupuncture points (ie, large intestine, liver, and lungs), in conjunction with several combination medications acting in a bioregulating manner and nutrition-al supplementation. The medications chosen continued to provide exten-sive tissue and organ support (eg, Hepar suis-Injeel, Pulmo suis-Injeel, and Bronchus suis-Injeel), with con-stant immunomodulation (eg, Gali-um-Heel, Engystol, and Traumeel) and activation of regulatory and en-zymatic processes (eg, Ubichinon compositum and Acidum fumari-cum-Injeel). Detoxification and drainage systems were also being assisted, while other medicines con-tinued to work on repair and im-provement of symptoms. On the day of receipt of the first autologous blood injection therapy, the patient developed acute pharyngitis, which resolved spontaneously, displaying a positive lymphodermal disease evo-lution.

By the seventh visit in mid-October, the patient reported a significant im-provement in the skin pruritus, in addition to improved and more reg-ulated sleep patterns. The patient was advised to stop his antifibrinol-ytic medication (tranexamic acid) in early October, with no ill effect on his current hematological values, in-dicating normal prothrombin time (PT) and partial thromboplastin time (PTT) levels and improved lev-els of neutrophils (from 110,000 to

) 17


197,000 cells/µL). The patient con-tinued to receive autologous blood injection therapy each week until the follow-up visit a month later. At this time, the patient reported com-plete absence of the pruritus, in-creased energy levels, vastly im-proved appetite, and a general feeling of being more encouraged and emotionally more positive. Blood test results indicated further increases in eosinophil numbers and PT and PTT values (10.6 and 26.7 seconds, respectively), in addition to normal fasting glucose levels, but liver enzyme levels were still altered (ie, increased alanine aminotransfer-ase level). One month later, in early December, electroacupuncture con-trol testing was performed, with continued administration of weekly autologous blood injection therapy. The gastrointestinal system was be-ing targeted, using a combination of medications, including Podophyl-lum compositum. By mid-December, the patient displayed an ectodermal-positive disease evolution, with dry scaly skin developing on the right foot, which, after the application of Traumeel cream, started secreting and resolving after a further 2 days.

By January 10, 2007, polymerase chain reaction HCV levels were 43 IU RNA/mL, with PT and PTT lev-els at 16.3 and 39.9 seconds, respec-tively. The patient started to progres-sively reduce his IFN treatment, which was then completely discon-

tinued, in addition to the ribavirin, under the advice of the patient’s hep-atologist in March 2007. Repeat blood tests in September 2007 con-firmed the same minimal viral load and regulated PT and PTT levels, at 10.00 and 26.6 seconds, respective-ly. Twenty months later, in early 2009, an ultrasonographic investiga-tion revealed no evidence of past fatty liver changes, and liver function test results were normal. A recent blood test, performed in July 2012, once again revealed results with a minimal viral load, indicating no signs of relapse and that the patient was maintaining self-regulation.

Conclusion

Hepatitis C infections, in particular with the genotype 1, subtype 1b, can be challenging to treat because the mutating virus is difficult to eradicate and the risk of developing severe liver disease and HCC is much higher in this group of pa-tients. This 55-year-old patient was treated with several modalities be-cause of the complexity of his health status, but medicines acting in a bio-regulating manner provided the mainstay of the multilevel interven-tion that was necessary in this case. The host assisted in launching an effective and sustained immune re-sponse toward an evasive adversary, but the medicines also provided the necessary organ and tissue support for detoxification, tissue repair, and

regeneration, resulting in normal hepatic structure and function, with minimal adverse reactions.|

References 1. Carcamo WC, Nguyen CQ. Advance-

ment in the development of mod-els for hepatitis C research. J Biomed Biotechnol. 2012;2012:346761. doi:10.1155/2012/346761.

2. Hofmann WP, Sarrazin C, Zeuzem S. Current standards in the treatment of chronic hepati-tis C. Dtsch Arztebl Int. 2012;109(19):352-358. doi:10.3238/arztebl.2012.0352.

3. Imran M, Waheed Y, Manzoor S, et al. In-teraction of hepatitis C virus proteins with pattern recognition receptors [published online ahead of print June 22, 2012]. Vi-rol J. 2012;9(1):126. doi:10.1186/1743-422X-9-126.

4. Jamall IS, Yusuf S, Azhar M, Jamall S. Is pegylated interferon superior to inter-feron, with ribavarin, in chronic hepatitis C genotypes 2/3? World J Gastroenterol. 2008;14(43):6627-6631.

5. Hoffmann TW, Duverlie G, Bengrine A. MicroRNAs and hepatitis C virus: toward the end of miR-122 supremacy [published online ahead of print June 12, 2012]. Vi-rol J. 2012;9(1):109. doi:10.1186/1743-422X-9-109.

6. Pawlotsky JM. New antiviral agents for hepatitis C. F1000 Biol Rep. 2012;4:5. doi:10.3410/B4-5.

7. Mukherjee S. Hepatitis C. Medscape Web site. http://emedicine.medscape.com/article/177792-overview#a0101. Updated February 29, 2012. Accessed June 27, 2012.

8. Jafferbhoy H, Gashau W, Dillon J. Cost ef-fectiveness and quality of life considerations in the treatment of hepatitis C infection. Clinicoecon Outcomes Res. 2010;2:87-96. doi:10.2147/CEOR.S7283.

9. Salloum S, Tai AW. Treating hepatitis C infection by targeting the host. Transl Res. 2012;159(6):421-429. doi:10.1016/j.trsl.2011.12.007.

10. Baraldi S, Hepgul N, Mondelli V, Pariante CM. Symptomatic treatment of interferon-α-induced depression in hepatitis C: a systematic review. J Clin Psychopharmacol. 2012;32(4):531-543.

11. Sievert W. Management issues in chronic vi-ral hepatitis: hepatitis C. J Gastroenterol Hepa-tol. 2002;17(4):415-422.


) 18


) Re f r e s h Yo u r H o m o t ox i c o l o g y

Gut Feelings Revisited: Evidence for a Brain-Gut Axis By David W. Lescheid, PhD, ND

Introduction

It has been proposed since antiquity that the gut can either be a source of emotions or have a major influence on their character and intensity. Ex-pressions such as “gut feelings” or “follow your gut” have been com-monly used for many years. The sci-entific support for these expressions is being substantiated, with consider-able support for direct communica-tion between the brain and the gas-trointestinal tract (GIT). This article will discuss some of the recent evi-dence for the presence of the brain-gut axis, including some of the best-described features, such as the cholinergic anti-inflammatory path-way and the influence of the micro-biome* and macronutrients directly on the central nervous system (CNS). Recent studies buttressing the thera-peutic potential of influencing this brain-gut axis also will be discussed.

Role of the Cholinergic Anti-inflammatory Pathway

Cranial nerve X, the vagus nerve, is well-known for its ability to influ-ence multiple targets outside the CNS. Many of its fibers leave the ver-tebral column at the cervical spine and wander (Latin vagari means “wandering”) throughout the thorac-

ic and abdominal cavities to inner-vate numerous visceral organs, in-cluding the esophagus, stomach, small intestine, proximal half of the colon as well as the heart and lungs. It supplies parasympathetic nervous system input to the liver, gallbladder, pancreas, kidneys, and upper region of the ureters and is an important re-lay of sensory information from the head, neck, abdomen, and thorax to the brain.1 The primary neurotrans-mitter used for communication be-tween the synapses of the vagus nerve and its targets is acetylcholine, a signaling molecule with wide-spread function in the parasympa-thetic and sympathetic nervous sys-tems.1

A pathway between the brain and the gut, using the vagus nerve as a con-duit of communication, has been de-scribed as the cholinergic anti-in-flammatory pathway.2-4 In this pathway, afferent nerve fibers from the vagus nerve receive signals from the organs and tissues they are situ-ated in and carry these signals to the brain. Some of these signals are mes-sages about injury, ischemia, and pathogens, as well as the levels and activities of proinflammatory cyto-kines in the local microenvironment. In the brain, processing and sorting of these signals occurs, and the ap-propriate message is carried via the

efferent vagus nerve fibers back to the site of origin. The activation of the appropriate acetylcholine recep-tors, including the α7 nicotinic ace-tylcholine receptors on immunocom-petent cells, results in either a decrease of the local proinflammato-ry message or a possible increase in inflammation. In this way, the brain can play an active part in controlling an inflammatory response at a distal site and preventing the damaging consequences of an excessive innate immune system response.2-4

This complete circuit of sensors of infection or injury (the vagus afferent nerve fibers in visceral tissues), relay system, and integrator (brain and other parts of the CNS) and effectors (vagus efferent nerve fibers, acetyl-choline, and the target cells) is clear-ly involved in the maintenance of immune system homeodynamics and has been recently proposed as an in-flammatory reflex.5 This system could function in a similar manner to reflex arcs in other complex organ systems and suggests that it is impor-tant to consider sensory nerves as an integral part of the control of innate immune system responses.6 Also, it might be possible to eventually map an inflammatory homunculus in the brain, with specific regions control-ling different components of the in-flammatory response.7

* The microbiome refers to the collection of all the genes of the commensal microbiota and the corresponding proteins and metabolites (see Turnbaugh PJ, Ley RE, Hamady

M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007;449[7164]:804-810).

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The practical ramification of this brain-gut axis, outlined by the cho-linergic anti-inflammatory pathway, is that therapeutic interventions, in-cluding acupuncture, biofeedback, mindfulness meditation, body work, cervical adjustments, and specific natural health products, that could potentially modify the activity of the autonomic nervous system (and, therefore, input and output of the vagus nerve) might help modify the nonresolving inflammation associat-ed with chronic diseases, such as in-flammatory bowel disease, rheuma-toid arthritis, and type 2 diabetes mellitus.8 Moreover, because the af-ferent vagus nerve fibers bind to ace-tylcholine receptors that influence the heart, it may be possible to treat inflammation by controlling the ac-tivity of the vagus nerve, via an elec-tronic device similar to a pacemaker, and to assess the effect via a heart rate monitor.9 The potential value of this approach is supported by recent evidence demonstrating that heart rate variability is an independent marker of systemic inflammatory re-sponses and correlates well with cer-tain biomarkers of systemic inflam-mation, including high-sensitivity C-reactive protein (hs-CRP) and in-terleukin 6.10-12

Role of the Microbiome

It is well substantiated that billions of microorganisms exist within our GIT and that many of them have im-portant roles to play in our overall metabolism and health, including modulation of both innate and adap-tive immune systems and synthesis and metabolism of important vita-mins, hormones, and short-chain fatty acids with beneficial function. The gut flora has been described as a forgotten organ because many of its essential protective, structural, and metabolic functions have been un-derappreciated until recently.13 How-

ever, exciting new discoveries have validated the historical view of the benefit of commensal microflora and have described the human intestinal microbiome as a new frontier in hu-man biology.14 One of the most re-cent discoveries is the connection between the gut microbiome and the CNS to form what is termed the mi-

crobiome-gut-brain axis (Figure).15 This discovery and the studies that sup-port it suggest that the microbes within our GITs can influence more sophisticated nervous system func-tions, such as “affect, motivation and higher cognitive functions, including intuitive decision making.”16 This discovery also further establishes that the communication between the brain, gut, and associated microbes

plays an important role in health and disease.17 Recognition that the “hu-man microbiome serves as the inter-face between our genes and our his-tory of environmental exposures” has led to the possibility of a mind-body-microbial continuum that has an impact into neurodevelopment and development of unique behav-ioral phenotypes.18

In animal studies, the acquisition of appropriate bacteria from the mother in the immediate postnatal period is an important contributing factor to the development of normal gas-trointestinal, immune, neuroendo-crine, and metabolic systems. It has even been shown to be one of the key factors regulating the set point

Microbiota-gut interactions

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of the hypothalamic-pituitary-adre-nal (HPA) axis.19 Other studies have shown definitive changes within the brain, depending on the composition of bacteria in the GIT. For example, a recent study demonstrated that the presence or absence of commonly identified bacteria in the intestine in germ-free and specific pathogen-free mice affected the expression of N-methyl-D-aspartate receptor, brain-derived neurotrophic factor, and serotonin receptor in the different regions of the brain. These neuro-chemical changes were accompanied by observable changes in anxiety-like behavior.20 It was recently shown, us-ing a mouse model, that the ingestion of a strain-specific probiotic, termed Lactobacillus rhamnosus, influenced the expression of γ-aminobutyric acid receptors in different regions of the brain associated with anxiety and depression. The ingestion of these beneficial bacteria also reduced anxi-ety and depression-related behavior associated with long-term use of corticosterone in otherwise healthy animals. Both the neurochemical and behavioral benefits of the probiotic agent were negated if the vagus nerve was cut, suggesting that this nerve serves as an essential communication pathway between the brain and the gut. What this study demonstrates is that bacteria play an important role in influencing the brain. Also, it might be possible to select and use specific microorganisms as adjunctive therapies in stress-related disorders, such as anxiety and depression.21 It provides further support for an in-terdependent link between the brain and the gut flora.

Neurotransmitters released after commands from the CNS can affect the habitat of the microflora in sev-eral ways, including altering the mo-tility of the GIT, affecting the pro-

duction of mucin and the function of epithelial cells, and directly affecting the growth of different bacteria,17 in-cluding pathogenic strains, such as Escherichia coli O157:H7.22 Con-versely, gut microbiota can influence brain and behavior via the produc-tion of metabolites that directly in-fluence the CNS, activate innate and adaptive immune system responses with systemic effects, and modulate neural afferent circuits to the brain.21 Certain strains of probiotics also could influence the metabolism of tryptophan, a precursor to serotonin that has wide-ranging effects throughout the nervous system, in-cluding the CNS.23 Finally, there is evidence that gut microbiota and probiotics24 can influence the percep-tion of visceral and even somatic pain, suggesting that they, or their metabolites, can modulate the sensi-tivity of the associated nerves.23

Enteric microflora and their toxins can affect enterochromaffin cells in the GIT.25 Enterochromaffin cells help regulate communication be-tween the gut lumen and the nervous system in several ways, including di-rect innervation by afferent fibers of the vagus nerve26 and local secretion of corticotropin-releasing hormone27 (also termed corticotropin-releasing fac-

tor). This hormone is most common-ly studied as being produced in the hypothalamus, where it is an impor-tant component of the HPA axis communication pathway.1 Cortico-tropin-releasing factor and its related peptides have been demonstrated to be widely expressed in the colon of humans and rodents,28 where they are integral mediators of the stress response in the brain-gut axis29 and play an important role in the regula-tion of motility,30 permeability,31 and inflammation32 in the intestines. It can be synthesized and released from

dendritic cells of the innate immune system, a process that is enhanced by commensal bacteria, such as Bacteri-

odes vulgatus and Fusobacterium var-

um.33 A recent study in rats demon-strated that “chronic psychosocial stress triggers reversible inflamma-tion, persistent epithelial dysfunc-tion, and colonic hyperalgesia,” largely via upregulation of cortico-tropin-releasing factor receptor type 1 in intestines.34 This study provides support for the role of corticotropin-releasing factor as an important mes-senger in the brain-gut axis and sug-gests that this might be one of the mechanisms responsible for the ob-served effects of psychosocial stress on the symptoms of irritable bowel syndrome.35

Early life stressors, such as maternal separation, have been well studied in rodent models as examples of the pathological consequences of brain-gut axis dysfunction.36 One of the consequences of the premature sepa-ration of rat pups from their mother during the neonatal period is imme-diate and prolonged changes in in-testinal physiology. These functional abnormalities of the colon in rat pups after maternal deprivation can be ameliorated with the supplementa-tion of strain-specific probiotics, at least partly because of the ability of these probiotics (Lactobacillus rhamno-

sus R0011 and Lactobacillus helveticus

R0052) to normalize cortisone re-lease, a marker of HPA axis activity.37 Another consequence of premature maternal separation is depressivelike symptoms, which have been shown to be reversed by the supplementa-tion of a probiotic, Bifidobacterium in-

fantis. In this case, the probiotic nor-malized interleukin 6 levels, restored noradrenaline concentrations in the brainstem, and reversed the observed behavioral deficits.38

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Role of Macronutrients

An intriguing study by Van Ouden-hove et al39 demonstrated that inges-tion of fatty food by healthy non-obese volunteers, via an intragastic tube to avoid any influence of smell, taste, or feel, substantially reduced their response to experimentally in-duced sadness through appropriate music and pictures. Furthermore, ex-posure to the same music and pic-tures decreased their sense of fullness after ingestion of a fatty meal.39 These interesting results suggest that ingested macronutrients can directly influence CNS activity to affect emo-tions and, conversely, that the brain can affect our normal response to in-gested meals. A thought-provoking commentary entitled “Was Feuerbach Right: Are We What We Eat?” dis-cusses this possibility.40 These results also support the idea of fatty foods as comfort foods.

Although it was not examined in the study which specific neural and hor-monal pathways were involved in re-laying this information between the fatty food in the gut and the CNS, some likely candidates are ghrelin and cholecystokinin. Ghrelin is a hormone produced in the gut and other parts of the GIT that has been shown to have a wide variety of functions, including stimulating ap-petite, modulating inflammation, promoting sleep, reducing pain, and facilitating learning and memory. It also is associated with reward behav-iors and mood regulation in animal models.1 A recent animal study showed that persistent psychosocial stress in male mice increased levels of ghrelin and corticosteroid in addi-tion to triggering behaviors to seek out high-fat foods.41 These data sug-gest that ghrelin might be an impor-tant part of the repertory of hor-mones associated with the stress

response. They also are an interesting support for a relatively common hu-man behavior of preferring to eat calorie-dense comfort foods during times of high stress. Stimulation of parasympathetic nervous system ter-minals in the GIT by fatty acids, the corresponding release of cholecysto-kinin, and the subsequent secretion of pancreatic enzymes are well-estab-lished components of the digestive process.1,42 The receptors for chole-cystokinin are known for their roles in learning and memory and in mod-ulating panic, anxiety, and appetite, further demonstrating that this hor-mone pathway could serve as part of the brain-gut axis.1

Conclusions

There is clearly a network of interac-tions between the brain and the gut that can be described by various plausible connections, including the vagus nerve and its associated neu-rotransmitters, the gut microbiome and macronutrients, and their direct and indirect influences on CNS ac-tivity. It is intriguing to think that there might be further networks of interactions that could be included in a unifying model, including a gut-brain-skin axis,43 a gut-brain-liver axis,44 and a gut–brain–exocrine pancreas axis.45 A more in-depth un-derstanding of the interconnections between the brain and the gut will help illuminate potential therapeutic access points to treat diseases associ-ated with a dysfunctional interaction between the CNS and the GIT, in-cluding irritable bowel syndrome,46 peptic ulcer disease, and gastro-esophageal reflux disorder.47 The ex-istence of a brain-gut axis is clearly no longer a farrago of disjointed hy-potheses, but an increasingly well-defined bidirectional communication pathway.

The established presence of different networks contributing to the brain-gut axis supports the therapeutic use of multicomponent medications with the ability to affect more than one biological target simultaneously. Spascupreel is a product with evi-dence suggesting that it can target multiple receptors associated with this complex network, including muscarinic acetylcholine receptors (affecting smooth muscle contraction and motility), γ-aminobutyric acid-A (GABA type A) receptors (associated with CNS processing of mood disor-ders, including anxiety), and dopa-minergic receptors type 2 (affecting central control of the pain response). It inhibits the enzyme monoamine oxidase B (MOA-B) (unpublished data), which is known to contribute to the regulation of levels of neu-rotransmitters, including dopamine. Furthermore, several of the ingredi-ents of Spascupreel are documented in the scientific literature to modulate various central and peripheral targets of the brain-gut axis. However, the multicomponent medication Spascu-preel could be considered as an im-portant addition to a comprehensive therapeutic approach to any condi-tion associated with a dysfunction of the brain-gut axis. Other bioregulat-ing medications, such as Thalamus compositum (in central pain syn-dromes related to the GIT) and Ton-silla compositum (in disturbances of the HPA), are also used to influence the brain-gut axis.|

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21. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regu-lates emotional behaviour and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011;108(3):16050-16055.

22. Freestone PP, Sandrini SM, Haigh RD, Lyte M. Microbial endocrinology: how stress in-fluences susceptibility to infection. Trends Microbiol. 2008;16(2):55-64.

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Dr. Sergio Vaisman Weinstein was born in Santiago de Chile.

His father was a dermatologist, and his mother was a concert pianist. From the latter, Sergio inherited his love for music and, at the age of 8 years, started studying violin and mu-sical theory. Unfortunately, in the fourth year of these studies, he had to stop playing the violin because of a broken arm and never recommenced.Both Sergio and his older brother shared their father’s interest in medi-cine. As youngsters, they accompa-nied him when he held his Sunday surgery at the hospital where he worked. After finishing secondary school at the Instituto Nacional in Santiago, Sergio studied medicine at the School of Medicine at the Uni-versity of Chile and was awarded a Degree in Surgery before the age of 24 years. Dr. Vaisman has passed his fascina-tion with medicine and music down to the next generation: his eldest son is a traumatologist, and his youngest daughter is a student of cello and mu-sical composition. Dr. Vaisman likes to be out in nature and, ever since he was a boy, has en-joyed going on camping trips. He has always been a keen sportsman, play-ing basketball when younger and jog-ging for the last 25 years.

After 10 years as a physician, Dr. Vaisman fulfilled one of his child-hood dreams and began studying for his pilot’s license. He continued to make progress with this hobby, pass-ing his instrumental flying examina-tion and subsequently qualifying to fly a multiengine aircraft. Proud own-er of a twin-engine aircraft with room for 6 passengers, he has covered the country from its Northern-most point (Arica) to its Southern-most point (Punta Arenas), sometimes taking sleeping bags and tents on board to allow him to combine his passions for camping and flying.After more than 30 years as a pedia-trician, Dr. Vaisman felt the need to explore new avenues. This happened in light of his frustration at treating a group of patients whose conditions could only be relieved, but not cured, by conventional medicine. At this crossroads in his career, he was invit-ed to study for a Diploma in Biologi-cal Medicine, which he accepted to explore new possibilities. He soon

) M e e t t h e E x p e r t

realized that this was the opportunity that he had been seeking, and he con-tinued to study at all the levels offered by the International Academy for Homotoxicology. His initial attempts to treat patients using this new ap-proach allowed him to see for himself the excellent results obtained when applying bioregulatory therapy to pe-diatric patients. Because he was com-pletely convinced that a combination of conventional medicine and bio-regulation was the ideal solution, and taking advantage of his long teaching career at the University of Chile, he began to give talks to different groups of physicians throughout the country to make them aware of this approach and increase the number of profes-sionals with an understanding of this therapy. These talks led him to coor-dinate a Diploma in Homotoxicology in a School of Medicine at a univer-sity in Santiago de Chile.He has also spoken at conferences and symposia and taught diploma courses in Chile, Colombia, Peru, and Portugal.His scientific contribution and sup-port of the International Academy for Homotoxicology was recognized at the International Symposium on Bio-regulatory Medicine, held in Bogota in March 2012.|

Dr. Sergio Vaisman Weinstein

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) P r a c t i c a l P r o t o c o l s

Bioregulatory Management of Peptic Ulcer Disease By David W. Lescheid, PhD, ND

Peptic ulcer disease is the cause of mucosal defects in the portions of

the gastrointestinal tract (GIT) that are exposed to acid and pepsin. These mucosal defects are termed ulcers if they extend through the muscularis mucosae. A further delineation into gastric or duodenal ulcers is used if they occur in the stomach or duodenum, respectively.1

In the United States, PUD affects ap-proximately 4.5 million people per year, with an annual prevalence of 1.8%.1 The frequency of PUD varies considerably between different coun-tries (eg, Japan has an annual inci-dence of approximately 1 case, Nor-way has an annual incidence of approximately 1.5 cases, and Scotland has an annual incidence of approxi-mately 2.7 cases per 1000 population) and is determined mainly by associa-tion with the major reported causes: infection by the bacterium Helicobacter

pylori and use of nonsteroidal anti-in-flammatory drugs (NSAIDs).1 In gen-eral, the frequency of PUD is decreas-ing in the developed world but increasing in developing countries.1

Peptic ulcer disease was previously considered as a disease primarily of males, but current estimates suggest more of an even distribution, with a male to female ratio of approximately 1:1. However, the average lifetime risk of developing PUD is still slightly higher in men (11%-14%) than in women (8%-11%).1 The average age of diagnosis for duodenal ulcers is be-tween 30 and 50 years, whereas the prevalence of gastric ulcers peaks in those aged 50 to 70 years.1 Younger patients are more likely to have non–H pylori, non-NSAID gastric ulcers than are more elderly patients.2

The pathogenesis of PUD is multifac-torial, with contributions from several factors, including excessive acid and pepsin in the gastric lumen, defective defensive mucosal barrier components (eg, mucus, bicarbonate, and leaky in-tercellular junctions), impaired muco-sal blood flow, cellular restitution, and epithelial cell turnover.1 However, the most commonly recognized causes are persistent infections by H pylori, the use of NSAIDs, and aspirin.1 Chronic overwhelming stress was identified historically as a major initiating factor but is now generally considered sec-

ondary to an infection by H pylori.3 There is renewed interest in defining the psychosocial etiology of PUD,4 with the recognition that the com-bined effect of H pylori and stress on the development of ulcers is para-mount.5 This heterogeneity of causes of PUD is exemplified by numerous other contributing factors identified, including the genetic predisposition of the host and environmental factors (eg, cigarette smoking,6 excessive alco-hol intake, and extreme emotional or physical stress,1,7 including childhood physical abuse8). Moreover, other medications that have been associated with the development of the gastritis preceding PUD include potassium and iron supplements and ethanol in both chronic and binge drinkers.1

The most common symptom of PUD is epigastric pain, often described as a gnawing, burning sensation that oc-curs 2 to 3 hours after a meal and is relieved by food and/or antacids.1,9 This pain might wake the patient at night and possibly radiate into the back. Other symptoms may include nausea, heartburn, abdominal bloat-ing, belching, intolerance to fatty foods, and chest discomfort. Vomiting may occur if there is partial or com-plete obstruction of the gastric outlet, and hematemesis or melena can ac-company bleeding in the GIT. In addi-tion to epigastric tenderness, signs of melena and succussion splash also oc-cur because of GIT bleeds and/or gas-

Peptic ulcer disease (PUD) is a complex, multifactorial

disease of the gastrointestinal systems common in

industrialized nations.

) 25



tric outlet obstructions.1 Ulcers in-duced by NSAID use might have no overt symptoms or nonspecific physi-cal findings, similar to uncomplicated PUD.1

The major complications of PUD in-clude GIT bleeds and perforations of ulcers, with the potential development to peritonitis and sepsis.1 Infection by H pylori also has been identified as one of the complex host and environmen-tal factors that increase the risk of gas-tric adenocarcinoma,9 possibly be-cause of its ability to initiate and sustain chronic nonresolving inflam-mation.10 Although the mortality rate of PUD is relatively low, it can signifi-cantly impair a patient’s well-being and quality of life and is associated with high costs for employers and health care systems.11

In most patients with uncomplicated PUD, routine laboratory tests are not helpful in the diagnosis, and radio-graphic and endoscopic imaging tech-niques are needed for confirmation.1 Establishing that there is an over-whelming infection by H pylori is con-sidered of primary importance in most patients with peptic ulcers. This can be measured using endoscopic and inva-sive testing (eg, rapid urease test, his-topathological analysis, and culture) or nonendoscopic and noninvasive testing (eg, serum H pylori antibody detection, fecal antigen tests, and urea breath tests).1,12 An endoscopic exami-nation of the upper GIT is the pre-ferred diagnostic test in the evaluation of patients with suspected PUD, whereas other tests for suspected Zollinger-Ellison syndrome include a fasting serum gastrin level and secretin

stimulation tests. Chest x-ray, electro-cardiographic, and computed tomo-graphic scan results are used to ex-clude other conditions, such as detecting free abdominal air in the case of a perforation and myocardial infarction.1

Given the current understanding of the pathogenesis of PUD, most pa-tients with PUD are treated for H py-

lori infection (with initial estimates of success in 85%-90% of cases, but val-ues decreasing to <80%) and/or avoidance of NSAIDs, along with the appropriate use of antisecretory thera-py. Eradication of H pylori is a pro-longed and complicated process, most commonly with a triple-therapy ap-proach with either amoxicillin or met-ronidazole, clarithromycin, and a pro-ton pump inhibitor given twice daily

DET-Phase Basic and/or Symptomatic Regulation Therapyb Optional

Endodermal Mucodermal

Impregnation

to degeneration

• Gastricumeel (gastric)• Duodenoheel (duodenum)

D&D • Advanceddetoxification and drainage,c

followed by• Basicdetoxificationand drainage: Detox-Kitd

• Atropinum compositum (if there is acute pain)

IM • Traumeel

CTOS • Mucosacompositum• Coenzymecompositum*• Ubichinoncompositum*

Dosages: Basic therapy: 1 tablet 3 times per day. Regulation therapy: tablets, 1 tablet 3 times per day; drops, 10 drops 3 times per day; ampoules, 1 ampoule of each medication, 1 to 3 times per week. Detox-Kit, 30 drops of each medication in 1.5 L of water (drink throughout the day). Optional therapy: 1 ampoule 1 to 3 times per week.

Abbreviations: CTOS, cellular, tissue, and organ support; D&D, detoxification and drainage; DET, Disease Evolution Table; IM, immunomodulation. aAs an adjunct to standard medical treatment.bAntihomotoxic regulation therapy consists of a 3-pillar approach: D&D, IM, and CTOS.cAdvanced supportive detoxification and drainage consists of Hepar compositum (liver), Solidago compositum (kidney), and Thyreoidea compositum (connective tissue).dThe Detox-Kit consists of Lymphomyosot,† Nux vomica-Homaccord, and Berberis-Homaccord.

Table. Bioregulatory Treatment of Peptic Ulcer Diseasea

* In Canada, replace Coenzyme compositum and Ubichinon compositum by Ubicoenzyme.

† Marketed in Canada as “Lyphosot”.

) 26



for 7 to 14 days as the first-line treat-ment.1 Also, proton pump inhibitors exacerbate NSAID-induced small in-testinal injury, possibly by inducing dysbiosis, suggesting that it would be prudent to avoid NSAIDs during this treatment.13 Because of increasing re-sistance of H pylori to antibiotics, there are reports of “unacceptably low treat-ment success” and accompanying pro-posals to alter the therapy to poten-tially increase therapeutic value.14,15 The presence of H pylori needs to be initially confirmed and then shown to be eradicated because ulcers have been shown to relapse in unsuccessful H py-

lori elimination.1,12

There are insufficient data to support any special diet in assisting with the healing of PUD, although some stud-ies demonstrate that the consumption of common spices in food (eg, clove, cinnamon, oregano, black pepper, tur-meric, and ginger) and supplementa-tion with certain herbal medicines can have definite beneficial effects on the gastric mucosa and may be of great benefit for the prevention of gastric ulcers.1,16 With the success of medical therapy, surgery has a very limited role in the management of PUD and is only recommended in refractory cases and complications of PUD (eg, ob-structions, perforations, penetration, and massive GIT bleeding).1,17 With the declining success rates of conven-tional triple-therapy treatments, it is evident that there is an opportunity for medications with bioregulatory

properties, and other natural health products, to be used as adjunctive therapies in the treatment and preven-tion of recurrence of peptic ulcers.

Bioregulatory Intervention

A small interventional trial using med-ications with bioregulatory properties (ie, Gastricumeel, Nux vomica-Homaccord, Lymphomyosot, and Co-enzyme compositum/Ubichinon com-positum) demonstrated that this also was an effective method of eradicating H pylori and, therefore, treating one of the recognized causes of PUD.18 As previously described, there are several potential networks that can contribute to the development of PUD. The bio-regulatory medical approach to treat-ment is shown in the Table.|

References1. Anand BS. Peptic ulcer disease. Medscape

Reference Web site. http://emedicine.med-scape.com/article/181753-overview. Ac-cessed March 29, 2011.

2. Xia HH, Phung N, Kalantar JS, Talley NJ. Demographic and endoscopic characteristics of patients with Helicobacter pylori positive and negative peptic ulcer disease. Med J Aust. 2000;173(10):515-519.

3. Gustafson J, Welling D. “No acid, no ul-cer”–100 years later: a review of the his-tory of peptic ulcer disease. J Am Coll Surg. 2010;210(1):110-116.

4. Jones MP. The role of psychosocial fac-tors in peptic ulcer disease: beyond Helico-bacter pylori and NSAIDs. J Psychosom Res. 2006;60(4):407-412.

5. Fink G. Stress controversies: post-traumatic stress disorder, hippocampal volume, gas-troduodenal ulceration. J Neuroendocrinol. 2011;23(2):107-117.

6. Zhang L, Ren JW, Wong CC, et al. Effects of cigarette smoke and its active compo-nents on ulcer formation and healing in the gastrointestinal mucosa. Curr Med Chem. 2012;19(1):63-69.

7. Leong RW. Differences in peptic ulcer be-tween the East and the West. Gastroenterol Clin North Am. 2009;38(2):363-379.

8. Fuller-Thomson E, Bottoms J, Brennenstuhl S, Hurd M. Is childhood physical abuse associated with peptic ulcer disease? Find-ings from a population-based study. J Interpers Violence. 2011;26(16):3225-3247.

9. Pritchard DM, Crabtree JE. Helicobacter pylo-ri and gastric cancer. Curr Opin Gastroenterol. 2006;22(6):620-625.

10. Polk DB, Peek RM Jr. Helicobacter pylori: gastric cancer and beyond. Nat Rev Cancer. 2010;10(6):403-414.

11. Barkun A, Leontiadis G. Systematic review of the symptom burden, quality of life impair-ment and costs associated with peptic ulcer disease. Am J Med. 2010;123(4):358-366.e352.

12. Costa F, D’Elios MM. Management of Heli-cobacter pylori infection. Expert Rev Anti Infect Ther. 2010;8(8):887-892.

13. Wallace JL, Syer S, Denou E, et al. Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dys-biosis. Gastroenterology. 2011;141(4):1314-1322,1322.e1-5.

14. Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut. 2010;59(8):1143-1153.

15. Chuah SK, Tsay FW, Hsu PI, Wu DC. A new look at anti-Helicobacter pylori therapy. World J Gastroenterol. 2011;17(35):3971-3975.

16. Al Mofleh IA. Spices, herbal xenobiotics and the stomach: friends or foes? World J Gastro-enterol. 2010;16(22):2710-2719.

17. Stewart DJ, Ackroyd R. Peptic ulcers and their complications. Surgery (Oxford). 2008;26(11):452-457.

18. Ricken K-H. Clinical treatment of functional dyspepsia and Helicobacter pylori gastritis. Biomed Ther. 1997;15(3):76-81.

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) E x p a n d Yo u r Re s e a r c h K n o w l e d g e

Noninterventional Studies: An Overview By Robbert van Haselen, MSc

In the previous article in this series, I further elaborated

on the different types of clinical trials; in this article,

I will provide a further overview of the main types of

noninterventional studies.

N oninterventional studies, also called nonexperimental studies,

are studies that do not involve any intervention (experimental or other-wise) on the part of the investigator. Such studies have in common the use of an observational research de-sign. In the conduct of noninterven-tional studies, the same rigor must be applied as in experimental studies.1,2

The main types of noninterventional studies are summarized in Table 1.

Noninterventional studies fall under the header of “observational epide-miology,” in which the main expo-sures (eg, environmental factors or treatments) are not under the direct control of the epidemiologist.

Noninterventional studies can in-volve either populations or individu-al patients. The main comparative noninterventional studies are cohort studies and case-control studies. The main descriptive noninterventional studies are cross-sectional studies, case series, and case reports.4 In Table 2, the main types and char-acteristics of noninterventional stud-ies are summarized.

It should be noted that the temporal perspective refers to the main tem-poral orientation of a particular epi-demiological design and not to the data collection process itself. For in-stance, in cohort studies, sometimes the data are collected retrospectively “after the event” (eg, by linking back to records that enable the reliable identification of different levels of the exposure of interest). The latter are often called historical cohort stud-ies, but even such a study is prospec-tive in terms of following up “the march” of cohorts with different ex-posure levels to a health outcome of interest. Historical cohort studies are less common nowadays because of the increasing ethical barrier of pri-vacy/data protection.

Cohort studies that compare the outcomes of differently treated co-horts are possible but are particularly susceptible to selection bias: the co-horts are noncomparable with re-spect to other factors than the treat-ments of interest. The latter can be partly addressed by recording/as-sessing all the relevant determinants

of outcome in both cohorts and then adjusting for any confounding due to these factors during the analysis. The risk remains, however, that not all relevant determinants of outcome have been assessed and that the causal attribution of findings to a particular treatment remains biased. There is no real solution for this problem because it is, in practice, im-possible to know and validly assess all the determinants of outcome. Therefore, in medicine, investigators often resort to the “next best” thing for managing ignorance: randomiza-tion. Provided there are sufficient patients included, the latter ensures that the known and unknown con-founders are equally distributed (without selection bias) between the treatment groups. However, random-ized studies are sometimes unneces-sary, inappropriate, impossible, or inadequate5; therefore, a need for noninterventional studies remains.

More recently, so-called hybrid de-signs have been proposed, in which several clinical trials are embedded within a cohort study.6 Such innova-tive mixed designs may be particu-larly suited when the assessment of the additional value of treatment is compared with “treatment as usual,” and this is often relevant in comple-mentary and alternative medicine research. Although such designs hold promise, they may not always be feasible.

) 28


Case-control studies are primarily used for etiological research. They used to be termed retrospective be-cause, conceptually, the temporal orientation is from the disease onset backward to the postulated causal factors. Yet, cases and controls in a case-control study are often accumu-lated prospectively. A further variant is the so-called nested case-control study, in which the cases and con-trols are drawn from the population of a larger cohort study. An advan-tage of such nested designs is that, because of the larger cohort study, more detailed and reliable informa-tion on the environmental (eg, nutri-tional) factors on the cases and con-trols can be obtained.

Cross-sectional studies examine the presence or absence of disease in re-lation to the presence or absence of other variables in each member of a representative sample of the study population at a particular point in time. In this manner, potential cor-relations between the presence or absence (or level) of variables in the diseased versus the nondiseased members can be determined. How-ever, the presence of a correlation does not necessarily imply causation. The classic example of this in epide-miology is the correlation between more storks and larger families in rural areas compared with urban ar-eas. This does not necessarily imply that the storks carry the babies! For

causal attribution, biological plausi-bility and prospectively collected data are a precondition.

Noninterventional studies are all “observational,” but this should not be confused with qualitative obser-vational studies that are different from the studies listed in Table 2. Observational methods used in the social sciences involve the systemat-ic, detailed observation of behavior and talk: the qualitative researcher systematically watches people and events to find out about behaviors and interactions in natural settings. Observation, in this sense, represents the idea of the researcher as the re-search instrument, as someone who

Type of Study Description of Study

Cohort A group of patients or subjects with defined characteristics, which is followed up (“marching forward in time”). This type of study usually involves the identification of 2 or more cohorts of patients, one receiving the exposure/treatment of interest and the other(s) not, and following-up of these cohorts regarding the outcome of interest.A noninterventional study with a single cohort of patients is also possible. Such studies usually occur in routine clinical practice, with the aim to describe treatment and outcomes.

Case-control A study that involves the identification of patients who have the outcome of interest and control patients who do not have the outcome of interest and then reviewing to determine if they had the exposure/treatment of interest.

Cross-sectional A study that examines the relationship between diseases and other variables of interest as they exist in a defined population in a particular point in time.

Case series A report on a series of patients with an outcome of interest. No control group is involved.

aData adapted from Porta.3

Table 1. Main Types of Noninterventional Studiesa

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) E x p a n d Yo u r Re s e a r c h K n o w l e d g e

goes out into the field.4 A further elaboration on qualitative research methods is outside the scope of this article.

There are now reporting guidelines for most types of studies. For com-parative and cross-sectional epide-miological studies, there is the STROBE guideline.7 However, for case series and case reports, there are not yet reporting guidelines.|

References1. Kelsey JL, Whittemore AS, Evans AS, Doug-

las Thompson W. Methods in Observational Epidemiology. 2nd ed. New York, NY: Oxford University Press; 1996.

2. Schnetzler G, Hayward C. Overview of guidelines and recommendations for the planning, conduct and reporting of com-pany-sponsored observational, noninter-ventional studies in Europe. Pharm Med. 2011;25(4):235-244.

3. Porta M, ed. A Dictionary of Epidemiology. 5th ed. New York, NY: Oxford University Press; 2008.

4. Mays N, Pope C. Qualitative research: ob-servational methods in health care settings. BMJ. 1995;311(6998):182-184.

5. Black N. Why we need observational studies to evaluate the effectiveness of health care. BMJ. 1996;312(7040):1215-1218.

6. Relton C, Torgerson D, O’Cathain A, Nich-oll J. Rethinking pragmatic randomised con-trolled trials: introducing the “cohort multi-ple randomised controlled trial” design. BMJ. 2010;340:c1066. doi: 10.1136/bmj.c1066.

7. von Elm E, Altman DG, Egger M, Po-cock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epi-demiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370(9596):1453-1457.

Type of Study Study Base Temporal Perspective Focus Comment

Cohort: 2 or more cohorts

Patient populations

Prospective Analytical/hypothesis testing

This type of cohort study is used to assess the health-related effects of environmental expo-sures or therapeutic interventions.

Cohort: 1 cohort

Patient populations

Prospective Descriptive This type of cohort study is often referred to as postmarketing surveillance study. In German-speaking countries, the term Anwendungs-beobachtungen is often used.

Case-control Patient population

Retrospective Analytical/hypothesis testing

Case-control studies are used to investigate the potential relationship between a suspected risk factor or attribute and disease.

Cross-sectional Patient populations

Particular point in time Prevalence and corre-lations

Cross-sectional studies are not suitable to de-termine a temporal sequence between cause and effect.

Case series Patient populations

Prospective or retrospec-tive

Descriptive Case series lack formal hypotheses and study protocols; if they had these characteristics, they would be cohort studies.

Case reports Individual patients

Prospective or retrospec-tive

Descriptive Case reports can serve among other education-al, medical, safety monitoring, or hypothesis-generating purposes.

Table 2. Overview of Different Types of Noninterventional Studies

) 30


A Multicomponent Medication Triggers Multiple Beneficial Effects Related to Cognition and Neuronal Function By Kerstin Röska, PhD, and Bernd Seilheimer, PhD

) Re s e a r c h H i g h l i g h t s

Background

During the Society for Neurosci-ence Congress in Washington, DC, which was held from November 12 to 16, 2011, 3 posters on the bene-ficial effects of a multicomponent natural medication, termed HE-300, on cognitive dysfunction were pre-sented. This meeting had more than 30 000 participants and is the pre-mier venue for neuroscientists from around the world to debut cutting-edge research on the brain and the nervous system.

Introduction and Research Objective

Disorders of cognition and memory, such as dementia, are complex, chronic, and multifactorial, with un-known etiology. The fact that we know little about the molecular pathways that result in cognitive de-cline and neuronal cell death led to the development of drugs lacking any disease-modifying effect. All therapeutic options currently avail-able only treat the symptoms of the underlying disease. Another limit-ing factor comes along with modern drug discovery, which is based on a reductionist approach. The focus is always on a single target and a sin-gle molecule designed to block, ac-

tivate, or modify it. To better mirror disease complexity, future drug dis-covery approaches should aim at multiple targets using multicom-ponent medications. Our study describes the use of HE-300, a mul-ticomponent multitargeted me di ca-tion, to treat cognitive dysfunction and its effects on neuronal function.

Materials and Methods

The study included a series of ge-nomic, in vitro, ex vivo, and in vivo experiments related to neuronal function and cognitive impairment. First, a systematic gene analysis of the whole genome (“next-genera-tion sequencing”) was performed in rats after treatment with HE-300. This single-molecule sequencing technology identified gene clusters affected by HE-300 that are in-volved in neuronal function and cognitive decline. Second, the gene analysis data were instrumental for the development of functional as-says to determine the effect of HE-300 on neuronal outgrowth, synap-tic transmission, and amyloid precursor protein (APP) processing. Third, several studies using a variety of behavioral animal models were performed to determine in vivo effi-cacy. HE-300 (1-2 mL/kg) was test-ed in learning and memory models,

such as spatial memory (T-maze), olfactory memory (Social Transmis-sion of Food Preference), and meth-ods to test memory of fear (Passive Avoidance and Contextual Fear Conditioning). A synthetic drug for the treatment of dementive disor-ders, donepezil, was included in the investigations as a positive control. Two different species, mice and rats, were used in scopolamine-induced memory impairment. Scopolamine, an acetylcholinesterase inhibitor, was given before HE-300 treatment, reflecting the dementive state after loss of acetylcholine neurons.

Results

Our study revealed that the multi-component multitargeted medica-tion, HE-300, affects the expression of gene clusters associated with syn-aptic function in the rat hippocam-pus 2 and 3 days after treatment (Figure). The gene networks associ-ated with β-amyloid binding, cog-nition, and synaptic plasticity were mainly influenced. A significant ef-fect on genes for APP and β-secretase, 2 proteins involved in the pathology of Alzheimer disease, could be observed. Furthermore, synaptophysin, a synaptic vesicle glycoprotein, and synaptotagmin 3, a membrane-trafficking protein,

) 31


) Re s e a r c h H i g h l i g h t s

were highly influenced in their ex-pression levels, indicating that HE-300 affects synaptic transmission. The functional assays demonstrated that HE-300 significantly decreases soluble APP levels in neuronal cells, which was consistent for 72 hours. These data confirmed and supported the results from the genomic analy-sis. It is suggested that HE-300 in-fluences the generation of β-amyloid protein, which hallmarks Alzheimer disease. Furthermore, HE-300 in-duces the elongation of dendrites of primary hippocampal neurons and restores age-related modifications of synaptophysin messenger RNA in the rat cortex. The behavioral tests confirmed the supporting effect of HE-300 on cognitive function: HE-300 not only significantly improved natural forgetfulness, but also sco-polamine-induced deficits in learn-ing and memory tests, such as the

T-maze, Passive Avoidance, Contex-tual Fear Conditioning, and Social Transmission of Food Preference. HE-300 attained similar efficacy as the gold standard, donepezil, in all in vivo test systems and displayed beneficial effects on memory func-tion in both species used.

Discussion

Our study shows that the multicom-ponent multitargeted medication, HE-300, enhances and improves cognitive functions on genomic, functional, and behavioral levels. The research results imply that this drug is able to influence the devel-opment and maintenance of demen-tive states. Because of the nature of the medication used, the biological and clinical effects may arise from different targeted biochemical path-ways involved in cognition and

learning. Therefore, HE-300 emerg-es as a true disease-modifying agent and may be an efficient and alterna-tive option in the challenge to un-derstand, treat, and defeat diseases associated with cognitive dysfunc-tion. These data are a good founda-tion for future clinical studies to in-vestigate the therapeutic effect of HE-300 in humans.|

Reference1. Schnack C, Hellrung A, Seilheimer B, et al.

A multicomponent medication (HE-300) targets the mechanisms related to Alzheimer disease: in-vitro & in-vivo assessment. Poster presented at: Neuroscience 2011; November 12-16, 2011; Washington, DC.

Figure. Modeling Molecular Networks1

The illustration shows the gene network that plays a role in cognitive functions. The points marked in green display the genes that are influenced by the multicomponent natural medication, HE-300. HE-300 significantly reduces the gene expression of APP and BACE, which are responsible for the formation of β-amyloid plaques in Alzheimer disease.

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