Biomedical - International Academy of Homotoxicology

d 2.00 • US $ 2.00 • CAN $ 3.00 

Journal of 

Biomedical 

Therapy 

Integrating 

Volume 6, Number 1 ) 2012 

Homeopathy 

and Conventional Medicine 

Gastrointestinal 

Disorders 

• Irritable Bowel Syndrome – A Review Article 

• Bioregulatory Treatment of Hepatitis C

) 

Content 

© iStockphoto.com/Milena Lachowicz 

© iStockphoto.com/Ostill 

In Focus 

Irritable Bowel Syndrome – A Review Article . . . . . . . . . . . . . . 4 

Around the Globe 

European Congress of Integrative Medicine . . . . . . . . . . . . . . 11 

What Else is New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 

© iStockphoto.com/Rosemarie © iStockphoto.com/Dawna Gearhart Stafford 

From the Practice 

Bioregulatory Treatment of Hepatitis C . . . . . . . . . . . . . . . . . . 14 

Refresh Your Homotoxicology 

Gut Feelings Revisited: Evidence 

for a Brain-Gut Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 

Meet the Expert 

Dr. Sergio Vaisman Weinstein . . . . . . . . . . . . . . . . . . . . . . . . . 23 

Practical Protocols 

Bioregulatory Management of Peptic Ulcer Disease . . . . . . . 24 

Expand your Research Knowledge 

Noninterventional Studies: An Overview . . . . . . . . . . . . . . . . 27 

Research Highlights 

A Multicomponent Medication 

Triggers Multiple Beneficial Effects 

Related to Cognition and Neuronal Function . . . . . . . . . . . . 30 

Cover © Naeblys/Fotolia.com 

) 2 

Published by/Verlegt durch: International Academy for Homotoxicology GmbH, Bahnackerstraße 16, 

76532 Baden-Baden, Germany, www.iah-online.com, e-mail: journal@iah-online.com 

Editor in Chief/verantwortlicher Redakteur: Dr. Alta A. Smit 

Editor: Dr. David W. Lescheid 

Managing Editor: Silvia Bartsch 

Print/Druck: Dinner Druck GmbH, Schlehenweg 6, 77963 Schwanau, Germany 

© 2012 International Academy for Homotoxicology GmbH, Baden-Baden, Germany

) 

The Importance of the Gut 

Dr. Alta A. Smit 

The importance of the gut in 

health and disease is currently 

attracting much attention in medicine. 

Gastroenterology is one of the 

forefronts at which integrative medicine 

plays a prominent role. 

Not only gastrointestinal, but also 

systemic diseases are closely related 

to the function of the epithelial barrier, 

the gut microbiome (ie, the collection 

of all the genes of the commensal 

microbiota and the corresponding 

proteins and metabolites), and the 

brain-gut axis. 1 

A new trend in medicine is the socalled 

network disease, and systems 

biology, in which the recognition of 

the complex interactions between different 

molecular, tissue, and organ 

networks is in the foreground. 2,3 

Recently, it has been elucidated that 

normal development of neural networks, 

immune networks, and also 

neuroendocrine and metabolic networks 

depends on the integrity of the 

microbiome and the brain-gut axis. 4,5 

Therefore, we have devoted considerable 

space to the introduction of this 

topic, from the focus article on irritable 

bowel syndrome, in which the 

disturbance of the brain-gut axis 

plays a major role, to a more detailed 

introduction of the various levels of 

connectivity between the brain and 

the gut by Dr. David W. Lescheid. 

Irritable bowel syndrome is a perfect 

example of multiple networks playing 

a role and interacting with each 

other to produce a complex pathophysiological 

picture. Thus, the conventional 

medical treatment of this 

syndrome is difficult because it 

cannot be reduced to a single-product, 

single-target approach. Bioregulating 

therapies, through their multitarget, 

multicomponent approach, 

offer a viable solution for intervention 

in these kinds of syndromes. The importance 

of this topic is further to be 

seen in the section “What Else Is 

New?” 

Bioregulating medicines can have a 

powerful adjuvant effect on seemingly 

difficult-to-treat diseases. The case 

report by Dr. Arturo O’Byrne is evidence 

of this, in which biological 

therapies have been used to successfully 

treat a refractory case of hepatitis 

C. 

We continue our series on research 

methods by Dr. Robbert van Haselen, 

and our expert in this issue is Dr. Sergio 

Vaisman, who has had a longstanding 

impact on the development 

of homotoxicology in Chile and Latin 

America. 

The emergence of congresses devoted 

to integrative medicine is a sign of 

the importance of this topic for health 

care practitioners; however, as can be 

seen from the article by Dr. Kerstin 

Röska and Dr. Bernd Seilheimer, the 

topic also met with a lot of interest in 

a purely conventional scientific congress. 

Dr. Alta A. Smit 

References 

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

TG. Brain-gut-microbe communication in 

health and disease. Front Physiol. 2011;2:94. 

doi:10.3389/fphys.2011.00094. 

2. Barabási AL, Gulbahce N, Loscalzo J. 

Network medicine: a network-based approach 

to human disease. Nat Rev Genet. 

2011;12(1):56-68. doi:10.1038/nrg2918. 

3. del Sol A, Balling R, Hood L, Galas D. 

Diseases as network perturbations. Curr 

Opin Biotechnol. 2010;21(4):566-571. 

doi:10.1016/j.copbio.2010.07.010. 

4. Manco M. Gut microbiota and developmental 

programming of the brain: from 

evidence in behavioral endophenotypes to 

novel perspective in obesity. Front Cell Infect 

Microbiol. 2012;2:109. doi:10.3389/ 

fcimb.2012.00109. 

5. Cryan JF, Dinan TG. Mind-altering microorganisms: 

the impact of the gut microbiota 

on brain and behaviour. Nat Rev Neurosci. 

2012;13(10):701-712. doi:10.1038/ 

nrn3346. 

) 3 

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

) In Focus 

Irritable Bowel Syndrome – 

A Review Article 

By David W. Lescheid, 

PhD, ND 

) 4 

Introduction 

Irritable bowel syndrome (IBS) is a 

functional bowel disorder characterized 

by common symptoms of abdominal 

pain or cramping (with variability 

in location and intensity), 

abdominal distension and/or sensation 

of bloating, excessive flatulence, 

diarrhea or constipation (or alteration 

between the 2 states), and mucous in 

stools. 1,2 These symptoms can be relatively 

constant but most often relapsing 

and remitting, according to the 

presence or absence of specific environmental 

triggers. 1,3,4 Usually, the 

disease remains chronic and recurring, 

with 40% of patients having the 

diagnosis for 10 years or longer and 

70% experiencing symptoms for 1 to 

9 days each month. 5 Symptoms that 

are independently associated with 

IBS include the following: lethargy 

(relative risk [RR], 6.7), incomplete 

evacuation (RR, 5.2), backache (RR, 

2.0), early satiety (RR, 1.8), and increased 

frequency of micturition (RR, 

1.8). 6 Irritable bowel syndrome is not 

a life-threatening condition but can 

have a serious impact on a patient’s 

daily activities and quality of life, 1 including 

periodic bouts of pain, suffering, 

and direct medical expenses as 

well as substantial potential social 

and job-related consequences. 2 

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 central 

sensitivity disorders or functional somatic 

disorders that include fibromyalgia, 

chronic fatigue syndrome, 

temporomandibular disorder, restless 

legs syndrome, 7,8 and interstitial cystitis/painful 

bladder syndrome. 9 Irritable 

bowel syndrome coexists with 

other functional gastrointestinal tract 

(GIT) disorders, especially gastroesophageal 

reflux disease 10 and dyspepsia. 

11 There also is close association 

between celiac disease and IBS, 12 

as well as increased risk of experiencing 

migraines. 13 

Epidemiology 

Based on conservative estimates and 

strict Rome-based diagnostic criteria, 

7% to 10% of adults have IBS worldwide, 

2,14 but that number has been 

estimated to be closer to 15% to 20%, 

depending on different diagnostic 

criteria and country-specific data. 5 

The prevalence of IBS is considerably 

higher among the white US population 

than other ethnic groups, with 

approximately 1500 cases per 

100,000 in the white population, 

300 cases per 100,000 in US Hispanics, 

and 170 cases per 100,000 in 

African Americans. A clear explanation 

for those differences has not yet 

been identified. 2 This variability in 

prevalence might reflect differences 

in diagnostic patterns of health care 

practitioners in various countries, cultural 

differences in seeking medical 

care for this condition, or some as yet 

undefined contributing factor. Furthermore, 

there are several different 

relatively subjective criteria used to 

diagnose IBS (as described later), and 

this has been shown to affect prevalence, 

with the highest number using 

the Manning criteria, followed by the 

Rome I and then the Rome II criteria. 

5 

In Westernized countries, IBS is 2 

to 3 times more common in women 

than in men. However, IBS is not 

simply a disorder of women, especially 

in the Indian subcontinent, where 

70% to 80% of the patients with IBS 

are male. 1 Women are more likely 

to report abdominal pain and constipation-related 

symptoms, whereas 

men are more likely to report 

diarrhea-related symptoms. The differences 

between sexes in IBS symptoms 

are modest; although female sex 

hormones have been shown to influence 

the severity of symptoms, this 

contribution needs to be confirmed 

in more clinical studies. 15 

Irritable bowel syndrome is usually a 

disorder of young people, with half 

of the patients experiencing symptom 

onset before the age of 35 years, and 

only 40% of patients aged 35 to 50 

years when symptoms begin. 2 More 

than 75% of IBS cases occur in persons 

between the ages of 25 and 64 

years. 1,2 Children with recurrent ab- 


) In Focus 

Esophagus 

Liver 

Stomach 

Duodenum 

Pancreas 

Transverse colon 

Descending colon 

Ascending colon 

Small intestine 

Human Digestive System 

Cecum 

Appendix 

Rectum 

Sigmoid colon 

© Andrea Danti/Fotolia.com 

dominal pain are more likely to develop 

IBS during adolescence and 

young adulthood, 1 with 14% of high 

school students and 6% of middle 

school students reported to have 

symptoms of the disease. 1 Elderly 

persons have been identified as an 

underdiagnosed and overlooked population 

with IBS. 16 

Diagnosis 

The diagn osis of IBS was previously 

considered as a diagnosis of exclusion, 

but most current guidelines 

amend this and acknowledge that it is 

a distinct disease, albeit with a broad 

differential diagnosis. 2 There are no 

consistent laboratory tests, imaging 

studies, or biological markers to diagnose 

IBS; therefore, symptom-based 

criteria, such as the Manning or Rome 

III criteria (currently considered the 

gold standard), are commonly used. 

To diagnose IBS using the Rome III 

criteria, patients must have “recurrent 

abdominal pain or discomfort accompanied 

by at least two of three additional 

symptoms (pain relieved by 

defecation, onset of pain associated 

with a change in stool form, or onset 

of pain associated with change in 

stool frequency).” 17 It should be noted 

that neither of these criteria have 

been sufficiently validated in prospective 

studies; therefore, their diagnostic 

accuracy is unknown. 17 Furthermore, 

it is probably more accurate to 

consider IBS as a complex of concurrent 

symptoms, with each one separately 

having limited diagnostic value. 

18 A recent systematic review states 

that “With none of the criteria showing 

sufficiently homogeneous and favourable 

results, organic disease cannot 

be accurately excluded by 

symptom-based IBS criteria alone.” 19 

The relative subjectivity and variability 

of diagnostic criteria limit their 

utility in clinical practice and restrict 

the direct transferability between research 

studies. 

An additional challenge of using 

symptom-based criteria for diagnosis 

is that the symptoms of IBS are 

shared by numerous other organic 

conditions; therefore, certain pathologies 

should be excluded, including 

inflammatory bowel disease, bile acid 

diarrhea, small-intestinal bacterial 

overgrowth, celiac disease, microscopic 

colitis, exocrine pancreatic insufficiency, 

and infectious colitis. 17 

The identification of a significant 

psychosomatic component and comorbidity 

with various other conditions 

also add difficulty to the diagnosis. 

1,3,17 

Four different bowel patterns are 

commonly recognized in those with 

IBS: persons with greater than 25% 

of bowel movements with loose or 

watery stools (diarrhea subtype or 

IBS-D) or greater than 25% of bowel 

movements with hard or lumpy stools 

(constipation subtype or IBS-C), persons 

with mixed constipation and diarrhea 

(IBS-M), and persons who alternate 

between diarrhea and 

constipation (IBS-A). 1,3 Another subtype, 

termed unsubtyped IBS (IBS-U), 

was recently identified in a multicenter 

study in China 20 and in other 

randomized controlled trials 21 using 

the Rome III criteria. The usefulness 

of this distinct categorization has 

been questioned because within 1 

) 5 


) In Focus 

) 6 

year, 75% of patients change subtypes, 

and 29% switch between constipation- 

and diarrhea-predominant 

IBS. 22 A recent review suggests that 

the reported variability in subtyping 

would be more consistent if the period 

recommended for recording stool 

frequency and consistency patterns 

was extended to 2 weeks. 21 Although 

there have been some reports of a 

predominance of specific subtypes of 

IBS, a systematic review elucidated 

that there is no consistent predominance 

of any one subtype and concluded 

that “IBS clinical subtypes distribution 

differs depending on the 

population evaluated, the geographical 

location, and the criteria employed 

to define IBS and bowel habit subtypes.” 

23 

Pathophysiology 

The pathogenic mechanisms contributing 

to IBS are still incompletely 

known, 24 although it is evident that 

dysfunction in any part of the braingut 

axis (eg, alterations in the central 

nervous system caused by psychological 

or other factors, abnormal gastrointestinal 

motility, or heightened visceral 

sensations) can contribute to its 

development. It is well understood 

that this condition is heterogeneous, 

with an undoubtedly multifactorial 

cause. 25 

Several recent studies buttress the 

view that IBS, at least in part, has an 

organic component that can be readily 

and easily recognized. 3 A commonly 

considered hypothesis is that 

IBS is a 3-part complex of altered 

GIT motility, visceral hyperalgesia, 

and psychopathology. 2,5 There are 

distinct aberrations in the motility 

of the small and large bowel and a 

proposed generalized hyperresponsiveness 

within the smooth muscle 

layer. This helps explain the often associated 

(50% of patients) symptoms 

of increased urinary symptoms (eg, 

frequency, urgency, and nocturia). 1,2 

There also have been more recent 

reports that dysfunction in the endocannabinoid 

system could contribute 

to the onset and persistence of symptoms 

associated with IBS, 26 including 

perturbations in motility, secretion, 

and hypersensitivity. 27 Hyperalgesia 

within the GIT can be secondary to 

hyperexcitability of neurons in the 

dorsal horn in response to peripheral 

tissue irritation or to descending 

influences from the brain stem. 

Multiple factors are proposed to alter 

the function of neuroreceptors and 

afferent spinal neurons, including 

genetics, inflammation, mechanical 

irritation of local nerves, dysfunction 

of motility, and psychological 

influences. 1,2 There is still no clear association 

between psychiatric disturbances 

and pathogenesis of IBS, with 

considerable debate on whether psychopathology 

incites development of 

IBS or vice versa. In some studies, patients 

who seek medical care for IBS 

symptoms have a higher incidence 

of panic disorder, major depression, 

anxiety disorder, and hypochondriasis. 

These psychological disturbances 

are not commonly believed to cause 

or initiate the symptoms of IBS but 

are thought to influence the patient’s 

perception of the symptoms and affect 

the clinical outcome. 1,2 There is 

also a higher prevalence of physical 

and sexual abuse in patients with 

IBS. 1,2 It is evident that various interpersonal 

relationships, both positive 

and negative, can have an impact on 

the course of IBS. 28 The importance 

of the genetic contribution to IBS remains 

in dispute. 2,29 

There are several potential dietary 

factors that are identified as contributing 

to the development of IBS in 

susceptible people, 30 including intolerances 

to certain foods, 31,32 ingestion 

of malabsorbed sugars (ie, sorbitol, 

fructose, and lactose) and fructans, 33,34 

gluten sensitivity, 18 and abnormal intake 

of certain types of dietary fats (in 

particular, those rich in arachidonic 

acid, a precursor to several proinflammatory 

eicosanoids). 35 Immunoglobulin 

G antibodies to ingested food 

may be playing a role in IBS, and 

food elimination can be effective in 

reducing its symptoms. 2 Other lifestyle 

factors that are correlated with 

the development of IBS include 

smoking, 36 alcohol abuse and/or dependency, 

37 and poor sleep quality. 38 

Excessive intake of caffeine and/or 

legumes and inadequate daily intake 

of water also might exacerbate symp- 


) In Focus 

• Reduces pain-induced stress 

• Reduces stress-induced 

motility disorders 

Balancing 

the nervous system 

Parasympathetic 

nervous system 

Sympathetic 

nervous system 

Relaxing 

smooth muscles 

• Reduces spasms and cramps 

• Reduces spasm- and cramprelated 

pain 

• Reduces susceptibility 

to diarrhea and 

abdominal bloating 

• Reduces mucus production 

Restoring 

bowel function 

© iStockphoto.com/Clinton Johnston 

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

toms in susceptible persons. 2 All of 

these environmental factors, and the 

psychosocial factors previously discussed, 

could have a notable impact 

on the course of IBS, possibly via 

their ability to influence epigenetic 

mechanisms. 39 

Recent studies have identified additional 

pathophysiological mechanisms. 

Dysregulation of the brain-gut 

axis; GIT infection; low-grade infiltration 

and activation of mast cells 

in the intestinal mucosa, with consequent 

release of bioactive substances; 

and altered serotonin metabolism are 

some emerging factors of IBS pathogenesis. 

Modification of small-bowel 

and colonic microflora (ie, so-called 

intestinal dysbiosis) and altered gas 

balance may be of relevance in some 

subgroups of patients with IBS. 24,25 

The brain-gut axis is a bidirectional 

pathway that links higher cortical 

centers with visceral afferent sensation 

and intestinal motor function. 

Regulation of these connections occurs 

via numerous neurotransmitters 

found in the brain and gut (eg, 

cholecystokinin, vasoactive intestinal 

peptide, substance P, and serotonin 

[5-hydroxytryptamine]) that act at 

different sites, with varied effects on 

gastrointestinal motility, pain control, 

emotional behavior, and immunity. 

Studies have shown that IBS symptoms 

may be related to imbalance in 

mucosal 5-hydroxytryptamine availability 

caused by defects in 5-hydroxytryptamine 

production, serotonin 

receptors, or transporters. 2 

The concept of microscopic inflammation, 

possibly at a subclinical lowgrade 

level, 40 preceding the development 

of IBS 25 is groundbreaking and 

challenges the previous theories of 

this syndrome having no demonstrable 

pathological alterations. Lowgrade 

mucosal inflammation, in particular 

involving abnormal activation 

) 7 


) In Focus 

) 8 

of mast cells, has been identified as a 

contributing factor in the pathogenesis 

of IBS in a recent systematic review. 

41 The cause of this persistent 

nonresolving inflammation might be 

a breakdown in the integrity of the 

epithelial barrier because recent evidence 

has demonstrated an increase 

in colonic permeability, release of mediators 

from mucosal mast cells, and 

allergic disposition in patients with 

the disease. 42 Both colonic inflammation 

and small-bowel inflammation 

have been substantiated in a subset of 

patients with IBS and in patients with 

the onset of IBS after infectious enteritis, 

known as postinfectious IBS. 

The risk of developing IBS increases 

6-fold after GIT infection (10%-15% 

of adult patients) and remains elevated 

for at least 2 to 3 years after infection. 

An exposure to pathogenic organisms 

(eg, Campylobacter, Shigella, 

Salmonella, and Escherichia coli) may 

disrupt intestinal barrier function, alter 

neuromuscular function, and trigger 

chronic inflammation, which sustain 

IBS symptoms. 2,43 Factors that 

increase the risk of developing 

postinfectious IBS include severe and 

prolonged infection, female sex, 

younger age, antibiotic treatment for 

this infection, and concomitant presence 

of anxiety. 2,43 Further findings of 

small-bowel bacterial overgrowth 

and disrupted numbers, distribution, 

and types of fecal microflora in patients 

with IBS have been heralded as 

a unifying mechanism for the symptoms 

of bloating and distension common 

to this condition. 24,44 The abnormal 

bacterial overgrowth is believed 

to induce fermentation, leading to 

production of excess gas, which has 

led to effective treatments with probiotics 

and antibiotics. 7 Individuals 

who are carriers of the intestinal protozoan 

parasite, Blastocystis, also have 

been recently shown to have an increased 

risk of developing IBS, especially 

if they have single-nucleotide 

polymorphisms in the genes encoding 

interleukins 8 and 10. 45 

Treatment 

The prevailing mainstream medicine 

approach is to treat the dominant IBS 

symptoms, using antispasmodics, antidiarrheals, 

or laxatives, often with 

off-label use of pharmaceutical drugs. 

However, it is clear that, in many cases, 

this approach is unsystematic and 

associated with a limited therapeutic 

potential. Moreover, the use of more 

than one drug to treat different symptoms 

increases the risk of adverse effects. 

46 Furthermore, there is concern 

that several agents used to treat IBS 

symptoms may exacerbate some IBS 

symptoms and, therefore, need to be 

used with caution (eg, some antidepressants 

can cause constipation). A 

recent survey in the United States 

found that conventional therapies for 

IBS-C (eg, antidepressants, antispasmodics, 

laxatives, fiber, and stool softeners) 

are associated with adverse ef- 

fects that negatively affect the lives of 

those with IBS and lead to many patients 

seeking medical care or missing 

work/school or social activities as a 

result of this iatrogenesis. 47 Overall, 

there is limited evidence for the efficacy, 

safety, and tolerability of therapies 

currently available for the treatment 

of IBS. 48 Most mainstream 

medical therapies used to treat IBS 

target only one symptom, despite a 

European survey indicating that less 

than 25% of patients have complete 

relief of any one symptom with existing 

treatments. 5 

Therefore, from previous descriptions, 

IBS is a complex disease affecting 

many networks in the body. To 

treat this disease optimally, we need 

an approach that is multitargeted and 

multicomponent. 49 Treatment should 

thus not only concentrate on the 

symptoms of IBS, but also take into 

account the different network perturbations 

and deficiencies. 

Complementary and alternative medical 

therapies, such as homeopathy, 

acupuncture, special diets, herbal 

medication, and several forms of psychological 

treatments and hypnotherapy, 

are sought by many patients and 

are being offered by physicians as 

treatment options, either alone or in 

conjunction with conventional forms 

of therapy in patients with refractory 

symptoms. There also is considerable 

evidence of efficacy with comple- 


) In Focus 

Treat constipation, 

bloating, and nausea: Nux 

vomica- 

Homaccord 

Figure 2. Additional 

Individualized Treatment of 

Irritable Bowel Syndrome 

Treat mucosal 

membrane 

dysfunction: 

Mucosa compositum 

and Coenzyme 

compositum* 

Spascupreel 

Treat diarrhea: 

Diarrheel 

Treat comorbid 

dyspepsia: 

Gastricumeel 

Treat stress and 

sleep disturbances: 

Neurexan 

or Nervoheel 

mentary and alternative medical therapies, 

including well-designed randomized 

controlled trials with several 

of these therapies, such as peppermint 

oil and probiotics, as well as turmeric 

extract, artichoke leaf extract, combination 

herbal medicine products, traditional 

Chinese medicines and acupuncture, 

and various forms of 

mind-body medicine. (The article by 

Yoon et al 18 provides tables summarizing 

the evidence base for complementary 

and alternative medical therapies 

in the treatment of IBS.) 

The ability of medications with bioregulatory 

properties, and other natural 

health products, to influence multiple 

targets simultaneously positions 

them well as a potentially effective 

approach to such a complex disorder. 

Spascupreel is a multitargeted, multicomponent 

medication that offers a 

holistic approach, both treating the 

spasmodic component and potentially 

addressing the brain-gut axis. It is, 

thus, one of the cornerstone treatments 

in the condition (Figure 1). 

Other treatments can then be added, 

according to the patient’s specific 

needs, as an individualized treatment 

(Figure 2). 

Conclusion 

Irritable bowel syndrome is a complex 

disease that cannot be solved with a 

linear approach. A multitargeted, 

multicomponent therapy is necessary 

to target the networks involved in this 

disease. Medications acting in a bioregulatory 

manner address the pathophysiology 

of the disease and have an 

excellent tolerability profile. Therefore, 

they are a promising approach in 

providing adequate treatment to patients 

with IBS.| 

References 

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Medscape Reference Web site. http:// 

emedicine.medscape.com/article/930844- 

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Reference Web site. http://emedicine. 

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of 40,000 subjects. Aliment Pharmacol Ther. 

2003;17(5):643-650. 

6. Maxton DG, Morris J, Whorwell PJ. More accurate 

diagnosis of irritable bowel syndrome 

by the use of “non-colonic” symptomatology. 

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8. Yunus MB. The prevalence of fibromyalgia in 

other chronic pain conditions. Pain Res Treat. 

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) 9 

* In Canada, replace Coenzyme compositum by Ubicoenzyme. 


) In Focus 

) 10 

9. Nickel JC, Tripp DA, Pontari M, et al. Interstitial 

cystitis/painful bladder syndrome and 

associated medical conditions with an emphasis 

on irritable bowel syndrome, fibromyalgia 

and chronic fatigue syndrome. J Urol. 

2010;184(4):1358-1363. 

10. Gasiorowska A, Poh CH, Fass R. Gastroesophageal 

reflux disease (GERD) and irritable 

bowel syndrome (IBS): is it one disease 

or an overlap of two disorders? Dig Dis Sci. 

2009;54(9):1829-1834. 

11. Ford AC, Marwaha A, Lim A, Moayyedi P. 

Systematic review and meta-analysis of the 

prevalence of irritable bowel syndrome in 

individuals with dyspepsia. Clin Gastroenterol 

Hepatol. 2010;8(5):401-409. 

12. Ford AC, Chey WD, Talley NJ, Malhotra A, 

Spiegel BM, Moayyedi P. Yield of diagnostic 

tests for celiac disease in individuals with 

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Arch Intern Med. 2009;169(7):651-658. 

13. Cole JA, Rothman KJ, Cabral HJ, Zhang Y, 

Farraye FA. Migraine, fibromyalgia and depression 

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study. BMC Gastroenterol. 2006;6:26. 

14. Brandt LJ, Chey WD, Foxx-Orenstein AE, 

et al; American College of Gastroenterology 

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15. Adeyemo MA, Spiegel BMR, Chang L. Meta-analysis: 

do irritable bowel symptoms vary 

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Ther. 2010;32(6):738-755. 

16. Agrawal A, Khan MH, Whorwell PJ. Irritable 

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problem? Dig Liver Dis. 2009;41(10):721- 

724. 

17. Suares NC, Ford AC. Diagnosis and treatment 

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Med. 2011;11(60):425-433. 

18. Yoon SL, Grundmann O, Koepp L, Farrell 

L. Management of irritable bowel syndrome 

(IBS) in adults: conventional and complementary/alternative 

approaches. Altern Med 

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19. Jellema P, van der Windt DA, Schellevis FG, 

van der Horst HE. Systematic review: accuracy 

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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 online 

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. Shortterm 

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 irritable 

bowel syndrome: baseline results from 

LOGIC (Longitudinal Outcomes Study of 

Gastrointestinal Symptoms in Canada), a naturalistic 

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 microflora, 

gas production and gut motility. Eur Rev 

Med Pharmacol Sci. 2008;12(suppl 1):111- 

117. 

25. Sainsbury A, Ford AC. Treatment of irritable 

bowel syndrome: beyond fiber and 

antispasmodic agents. Ther Adv Gastroenterol. 

2011;4(2):115-127. 

26. Storr M, Allescher HD. Irritable bowel syndrome: 

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 system 

in the pathophysiology and treatment of 

irritable bowel syndrome. Neurogastroenterol 

Motil. 2008;20(8):857-868. 

28. Gerson MJ, Gerson CD. The importance of 

relationships in patients with irritable bowel 

syndrome: a review. Gastroenterol Res Pract. 

2012;2012:157340. 

29. Longstreth GF, Thompson WG, Chey WD, 

Houghton LA, Mearin F, Spiller RC. Functional 

bowel disorders. Gastroenterology. 

2006;130(5):1480-1491. 

30. Tighe MP, Cummings JR, Afzal NA. Nutrition 

and inflammatory bowel disease: primary 

or adjuvant therapy. Curr Opin Clin Nutr 

Metab Care. 2011;14(5):491-496. 

31. Eswaran S, Tack J, Chey WD. Food: the forgotten 

factor in the irritable bowel syndrome. 

Gastroenterol Clin North Am. 2011;40(1):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 Gastroenterol 

Rep. 2009;11(5):368-374. 

34. Gibson PR, Newnham E, Barrett JS, Shepherd 

SJ, Muir JG. Review article: fructose 

malabsorption and the bigger picture. Aliment 

Pharmacol Ther. 2007;25(4):349-363. 

35. Clarke G, Fitzgerald P, Hennessy AA, et al. 

Marked elevations in pro-inflammatory polyunsaturated 

fatty acid metabolites in females 

with irritable bowel syndrome. J Lipid Res. 

2010;51(5):1186-1192. 

36. Fujiwara Y, Kubo M, Kohata Y, et al. Cigarette 

smoking and its association with overlapping 

gastroesophageal reflux disease, 

functional dyspepsia, or irritable bowel syndrome. 

Intern Med. 2011;50(21):2443-2447. 

37. Masand PS, Sousou AJ, Gupta S, Kaplan DS. 

Irritable bowel syndrome (IBS) and alcohol 

abuse or dependence. Am J Drug Alcohol 

Abuse. 1998;24(3):513-521. 

38. Bellini M, Gemignani A, Gambaccini D, et 

al. Evaluation of latent links between irritable 

bowel syndrome and sleep quality. World J 

Gastroenterol. 2011;17(46):5089-5096. 

39. Dinan TG, Cryan J, Shanahan F, Keeling PW, 

Quigley EM. IBS: an epigenetic perspective. 

Nat Rev Gastroenterol Hepatol. 2010;7(8):465- 

471. 

40. Keohane J, O’Mahony C, O’Mahony L, 

O’Mahony S, Quigley EM, Shanahan F. Irritable 

bowel syndrome-type symptoms in patients 

with inflammatory bowel disease: a real 

association or reflection of occult inflammation? 

Am J Gastroenterol. 2010;105(8):1789- 

1794. 

41. Ford AC, Talley NJ. Mucosal inflammation 

as a potential etiological factor in irritable 

bowel syndrome: a systematic review. J Gastroenterol. 

2011;46(4):421-431. 

42. Vivinus-Nebot M, Dainese R, Anty R, et al. 

Combination of allergic factors can worsen 

diarrheic irritable bowel syndrome: role of 

barrier defects and mast cells. Am J Gastroenterol. 

2012;107(1):75-81. 

43. Thabane M, Marshall JK. Post-infectious irritable 

bowel syndrome. World J Gastroenterol. 

2009;15(29):3591-3596. 

44. Lin HC, Pimentel M. Bacterial concepts in 

irritable bowel syndrome. Rev Gastroenterol 

Disord. 2005;5(suppl 3):S3-S9. 

45. Olivo-Diaz A, Romero-Valdovinos M, 

Gudiño-Ramirez A, et al. Findings related 

to IL-8 and IL-10 gene polymorphisms in 

a Mexican patient population with irritable 

bowel syndrome infected with Blastocystis 

[published online ahead of print January 28, 

2012]. Parasitol Res. 2012;111(1):487-491. 

doi:10.1007/s00436-012-2830-0 

46. Goettsch WG, van den Boom G, Breekveldt- 

Postma NS, Smout AJ, Herings RM. Treatment 

patterns and health care costs of 

mebeverine-treated IBS patients: a casecontrol 

study. Pharmacoepidemiol Drug Saf. 

2004;13(11):803-810. 

47. Lembo A. Irritable bowel syndrome medications 

side effects survey. J Clin Gastroenterol. 

2004;38(9):776-781. 

48. Tack J, Fried M, Houghton LA, Spicak J, 

Fisher G. Systematic review: the efficacy of 

treatments for irritable bowel syndrome – a 

European perspective. Aliment Pharmacol Ther. 

2006;24(2):183-205. 

49. Whorwell PJ. Irritable bowel syndrome. Altern 

Ther Health Med. 2011;17(2)(suppl):S4-S6. 


) Around the Globe 

European Congress 

of Integrative Medicine 

Breakaway Session on Bioregulatory Medicine 

By Ghassan Andraos, MD 

Bioregulatory medicine is an 

emerging science. The aim of 

the scientific symposium “The Bioregulatory 

Medicine Approach: From 

Genomics to Clinical Application” 

was to update the 420 registered participants 

to the third European Congress 

of Integrative Medicine on the 

most recent changes and findings in 

this field. 

Sometimes described as “the bridge 

between natural medicine and conventional 

medicine,” this therapeutic 

approach seeks to improve patient 

care by offering a wide range of therapeutic 

and diagnostic tools, leading 

to a more personalized therapeutic 

approach. 

In her opening remarks, Alta Smit, 

MD, highlighted the novel and increasingly 

supported shift in medical 

thinking towards complexity. This 

includes the underlying single and 

multiple networks in the disease process. 

With this increased complexity 

in thinking, there also is a necessity to 

incorporate new technologies, with 

an improved ability to diagnose complexity, 

and for therapeutic drugs that 

have multiple biological targets. 

Bernd Seilheimer, PhD, then explained 

how genomic profiling can 

be used as a tool to substantiate the 

action of a multitargeted medication 

at a cellular level. The genomic and 

deep-sequencing data demonstrated 

that these multicomponent medications 

do indeed have multiple targets 

within a model disease system. After 

showing that there is a scientifically 

validated technology, with reproducible, 

credible evidence identifying the 

targets of multicomponent medications, 

a more complex pathological 

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

and Bernd Wolfarth, MD. 

process, such as the inflammatory cascade, 

can be investigated. 

Manfred Schmolz, PhD, presented 

the inflammatory cascade as a model 

for the value of network medicine, 

showing that inflammation is a defense 

mechanism that fits into the systems 

biology thinking and complexity 

and that it needs to be regulated, 

rather than suppressed. Possible intervention 

points were identified along 

the inflammatory cascade, and the 

value of a multitargeted therapeutic 

approach to modulate the inflammation 

(ie, upregulate some targets and 

downregulate others) to promote 

synergy and avoid adverse effects, 

while sustaining its therapeutic benefits, 

was substantiated. 

Bernd Wolfarth, MD, associate professor 

of sports medicine, highlighted 

the clinical evidence of Traumeel in 

the care of musculoskeletal disorders. 

He discussed the preclinical knowledge 

about its multitargeted mechanism 

of action, including a proof of 

concept from scientific support for 

relevant components, together with a 

body of clinical research built over 

the years and his own clinical experience 

and practice. He confirms that, 

for him, Traumeel is definitely a firstline 

therapy for musculoskeletal disorders. 

This conference confirms the potential 

of Bioregulatory Medicine as an 

effective first-line therapy with minimal 

adverse effects.| 

) 11 


) What Else is New 

Nutritional intervention may help 

restore homeodynamics in 

the intestine. 

© iStockphoto.com/Ostill 

Recent studies have discussed the role 

of the enteric microbiota in the 

treatment of gastrointestinal disorders. 

Intestinal Inflammatory 

Factors Affect Elderly 

Individuals 

Elderly individuals are often characterized 

by having chronic low levels of 

inflammation and immune system impairment 

that affect both their overall 

health and survival. This review describes 

intestinal components that receive 

and provide signals that play a 

role in local and systemic inflammation 

and immunity. These components include 

the following: sentinel cells, such 

as macrophages, dendritic cells, and 

mast cells concentrated in the splanchnic 

area, which receive simultaneous 

signals from commensal bacteria as 

well as physiological and pathological 

metabolic processes; endogenous immune 

system molecules in the intestine, 

such as natural killer cells and 

dendritic cells, which are affected by 

aging and stress; and exogenous molecules 

in the intestine, such as the evolutionarily 

conserved molecules from 

bacteria. All of these signals interact in 

a network that either promotes the restoration 

of homeodynamics or chronic 

inflammation if there is failed resolution 

of inflammation, long-lasting tissue 

injury, or persistent infections by 

pathogens. Supplementation by specific 

nutrients, including probiotics, prebiotics, 

and certain vitamins, minerals, 

and dietary substances, may contribute 

to restoring homeodynamics in the intestine 

and, therefore, in the whole 

body, by modifying the inflammatory 

pathways and by repairing any increased 

permeability of the epithelial 

barrier. 

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

Gut Microbiota 

Communicate With the Brain 

Human health is affected by a bidirectional 

communication system between 

gut microbiota and the brain. Although 

most previous research has focused on 

how the brain affects the gut microflora, 

there is increasing evidence that signals 

from the commensal and pathogenic 

bacteria in the gut also affect the 

brain and behavior. This particular article 

discusses recent studies, including 

those with germ-free mice. Because 

there is a definite signal (axis) between 

the brain and the gastrointestinal tract, 

study of the factors that affect it is important. 

The agents that decrease the 

amount of gut microbiota include antimicrobials. 

Future studies should focus 

on the molecular, cellular, and physiological 

aspects of the gut microbiota– 

brain communication. 

Neurogastroenterol Motil. 

2011;23(3):187-192. 

doi:10.1111/j.1365-2982.2010.01664.x 

) 12 

FOR PROFESSIONAL USE ONLY 

The information contained in this journal is meant for professional use only, is meant to convey general and/or specific worldwide scientific information relating to the 

products or ingredients referred to for informational purposes only, is not intended to be a recommendation with respect to the use of or benefits derived from the products 

and/or ingredients (which may be different depending on the regulatory environment in your country), and is not intended to diagnose any illness, nor is it intended to 

replace competent medical advice and practice. IAH or anyone connected to, or participating in this publication does not accept nor will it be liable for any medical 

or legal responsibility for the reliance upon or the misinterpretation or misuse of the scientific, informational and educational content of the articles in this journal. 

The purpose of the Journal of Biomedical Therapy is to share worldwide scientific information about successful protocols from orthodox and complementary practitioners. 

The intent of the scientific information contained in this journal is not to “dispense recipes” but to provide practitioners with “practice information” for a better understanding 

of the possibilities and limits of complementary and integrative therapies. 

Some of the products referred to in articles may not be available in all countries in which the journal is made available, with the formulation described in any article or available 

for sale with the conditions of use and/or claims indicated in the articles. It is the practitioner’s responsibility to use this information as applicable and in a 

manner that is permitted in his or her respective jurisdiction based on the applicable regulatory environment. We encourage our readers to share their complementary 

therapies, as the purpose of the Journal of Biomedical Therapy is to join together like-minded practitioners from around the globe. 

Written permission is required to reproduce any of the enclosed material. The articles contained herein are not independently verified for accuracy or truth. They have been 

provided to the Journal of Biomedical Therapy by the author and represent the thoughts, views and opinions of the article’s author. 


© iStockphoto.com/Selvanegra 

Exposure to traffic air pollution 

increases the risk of dying 

from gastric cancer. 

b 

© iStockphoto.com/Tony Tremblay 

Emotions Affect Food Intake 

This study attempted to determine some 

of the specific connections between human 

emotions and feeding behavior by 

examining the relationship between gut 

signaling from specific nutrients and 

externally created emotions. Functional 

magnetic resonance imaging was used 

to measure the effects in the brain. The 

study included 12 healthy male and female 

volunteers who were not obese. 

“Nutrient-induced gut-brain signaling” 

was determined after the subjects received 

an infusion of fatty acid or saline. 

An important part of this study was 

that, because the volunteers received an 

infusion, it bypassed the taste receptors, 

texture, sight, and mouth-end feel associated 

with fatty foods, showing for the 

first time in humans the direct effect of 

the composition of the food itself on 

emotions. Sad emotion was induced by 

validated sad or neutral classical music 

and facial expressions. The subjects 

then rated their feelings of hunger, fullness, 

and mood. The results indicated 

that sad emotion was “attenuated by 

fatty acid infusion.” These findings increase 

the understanding of the relationships 

among emotions, hunger/ 

food intake, meal-induced sensations 

and obesity, eating disorders, functional 

dyspepsia, and depression. Furthermore, 

this study helps support the validity 

of phrases such as “emotional 

overeating” and “comfort feeding.” 

Cancer-Associated Death 

Is Affected by Density 

of Petroleum Stations 

In Taiwan, a case-control study on air 

pollution and death from gastric cancer 

was conducted from 2004 to 2008. 

Data were obtained from case deaths 

affected by gastric cancer and control 

deaths affected by variables other than 

tumors and gastrointestinal tract diseases. 

Cases and controls were matched 

by sex, birth year, and death year; 

2 substantial petroleum companies 

provided data for number of petroleum 

stations in the municipalities. The 

density of petroleum stations in 

municipalities determined the exposure 

to “benzene and other hydrocarbons 

present in ambient evaporative 

losses of petroleum or to air emissions 

from motor vehicles.” The study determined 

that persons who lived in municipalities 

with the highest density of 

petroleum stations (>75th percentile) 

had an increased risk of death associated 

with gastric cancer, when compared 

with persons who lived in municipalities 

with the lowest density of 

petroleum stations (≤25th percentile). 

In the future, studies should seek to determine 

the specific ways that traffic air 

pollution causes gastric cancer. 

J Toxicol Environ Health A. 

2011;74(18):1215-1224. 

Enterotypes Determined 

for Human Gut Microbiome 

There is rapidly expanding knowledge 

of both the species and functional features 

of the human gut microbiome. 

The present study analyzed data from 

adult fecal samples of 4 different countries 

and 22 newly sequenced fecal 

metagenomes and combined them 

with previous data from 2 other countries 

to identify 3 enterotypes (robust 

clusters of related bacteria) that are not 

specific to a country or continent. 

These enterotypes represent well-balanced, 

defined microbial communities 

with a relatively high degree of phylogenetic 

and functional association 

between them. Although the individual 

composition can be affected 

differently by diet and drugs, they are 

not explained by differences in body 

mass index, sex, age, and nationality. 

However, several marker genes (eg, 

12 genes that associate with age) or 

functional variables (eg, 3 modules that 

associate with body mass index) were 

determined and could be useful for diagnosis 

and possible prediction of the 

risk of different human disorders. The 

robustness and predictability of the 

clusters also suggest that they could be 

used as a guide for how different human 

groups would respond differently 

to drug and diet intake. 

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

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

doi:10.1172/JCI46380 

) 13 


) From the Practice 

Bioregulatory Treatment 

of Hepatitis C 

A Clinical Case Report 

By Arturo O’Byrne, MD 

) 14 

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

RNA virus that causes acute and chronic hepatitis 

C in humans. 1 More than 170 million people worldwide 

are infected with HCV, covering approximately 

3.3% of the world’s population. 2,3 

Chronic progression of this disease 

is characterized by progressive 

development of fibrosis and 

cirrhosis of the liver after 20 to 25 

years in 2% to 35% of those affected. 4 

Furthermore, patients with cirrhosis 

are exposed to life-threatening complications, 

including end-stage liver 

disease, esophageal variceal hemorrhage, 

and the development of hepatocellular 

carcinoma (HCC), which 

occurs at an incidence of 4% to 5% 

per year in these patients. 5,6 With 

chronic HCV infection being the 

leading cause of HCC and the first 

indication of liver transplantation in 

industrialized countries, this poses an 

enormous threat to worldwide public 

health. 5,7 Hepatitis C virus has also 

rapidly surpassed human immunodeficiency 

virus as a cause of death in 

the United States, with almost 75% of 

HCV-related deaths occurring among 

adults between the ages of 45 and 64 

years. 7 

Transmission of the virus is parenteral 

and sexual, with needle sharing, 

unscreened blood transfusions, nonsterile 

tattooing or acupuncture, and 

vertical and sexual transmission being 

among some of the means of viral 

exposure. However, intravenous drug 

use remains the most common cause 

of HCV infection, especially in developed 

countries. 7,8 There are 6 genotypes 

of HCV, 52 subtypes within 

these genotypes, and a diverse population 

of mutant viruses known as 

quasispecies within each infected individual. 

3 Genotype 1 (subtypes 1a and 

1b) is reported to be the most frequent 

genotype worldwide, accounting 

for 40% to 80% of all isolates, 

but unlike HCV genotypes 2 and 3, 

which respond more favorably to 

treatment, genotypes 1 and 4 are 

more difficult to eradicate using current 

conventional medications. 1,3,7 

Genotype 1 also may be associated 

with more severe liver disease and a 

higher risk of HCC. 7 The ability of 

the virus to incorporate adaptive mutations 

in the host and exist as genetically 

distinct quasispecies, in addition 

to disrupting the host’s defense 

by blocking phosphorylation and 

function of interferon (IFN) regulatory 

factor-3, an antiviral signalling 

molecule, poses a major challenge to 

the immune-mediated control of 

HCV. 1 This may also explain the variable 

clinical course of the disease, 

difficulties in vaccine development, 

and the variable results of treatment. 

1,8 Current pharmacological intervention 

includes antiviral agents 

that specifically target viral function, 

collectively termed direct-acting antivirals, 

in addition to host-targeted agents 

that aim to inhibit HCV replication. 8 

The aim behind all treatment options 

is to eradicate HCV viremia, thereby 

increasing quality of life and reducing 

the risk of cirrhosis and HCC. 7,8 

Combination therapy of pegylated 

IFN-α and ribavirin is the current 

mainstay of treatment, resulting in 

sustained clearance of serum HCV- 

RNA. However, this treatment causes 

many adverse effects (eg, flulike 

symptoms, insomnia, hair loss, mood 

changes, pruritus, dermatitis, and hematological 

abnormalities, including 

neutropenia, anemia, and thrombocytopenia) 

and is only efficacious in 

approximately 50% of patients, with 

possible relapses at the end of treatment. 

8-10 Several host factors, such as 

age, stage of liver fibrosis, body mass 

index, liver steatosis, insulin resistance, 

ethnicity, and interleukin 28B 

single-nucleotide polymorphisms, 

and viral genotype are reported to 

influence the treatment outcome. 1,2,5,11 

Patients infected with both acute 

and chronic hepatitis are usually 

asymptomatic, making early diagnosis 

difficult. 4 Once symptoms occur, 



Photograph by Dr. Christian Schüttler; licensed under the Creative Commons 

Namensnennung-Weitergabe unter gleichen Bedingungen Deutschland 

(http://creativecom-mons.org/licenses/by-sa/2.0/de/legalcode); http://de. 

wikipedia.org/w/index.php?title=Datei:HCV_particles.jpg&filetimesta 

mp=20060703221106 

Possible hepatitis C virus particles from human serum after chromatographic purification 

they tend to be nonspecific, with fatigue 

and/or malaise being the most 

commonly reported, in addition to a 

general decrease in quality of life. 4,7 

Thereafter, symptoms often develop 

as clinical findings of extrahepatic 

manifestations of HCV and most 

commonly involve the joints, muscle, 

and skin (ie, arthralgias, paresthesias, 

myalgias, pruritus, and sicca 

syndrome). Patients with ongoing 

pathology associated with chronic 

hepatitis C that eventually results in 

organ failure can present with symptoms 

and signs related to synthetic 

dysfunction and portal hypertension 

(ie, ankle edema, abdominal distention, 

hematemesis or melena, palmar 

erythema, and yellowing of the 

eyes). 7 The natural history of chronic 

hepatitis is ill defined because of the 

long latent period between inoculum 

and development. Severity and progression 

are variable but generally 

slow; however, host and environmental 

factors play a vital role in disease 

progression. 8,11 

Clinical Case 

In July 2006, a 55-year-old male patient 

presented to the clinic with 

symptoms of skin irritation and pruritus. 

Investigations undertaken 6 

months earlier reported altered levels 

of liver enzymes; features of fatty 

liver on ultrasonography, in addition 

to positive antibodies; an increased 

HCV RNA assay result of 697,000 

IU/mL; and a genotype test result of 

type 1 subtype 1b. These features all 

confirmed a diagnosis of chronic 

hepatitis C infection. 

The patient’s medical history included 

having abnormal coagulation 

factor X since the age of 35 years, 

for which he received many transfusions 

(plasma and isolated X factor) 

in the past several years, which may 

have caused the HCV transmission 

and infection. The patient also reported 

previous and current treatment 

for metabolic syndrome, anxiety, 

and several adverse effects 

potentially caused by his conventional 

hepatitis drug therapy (ie, articular 

pain, insomnia, and emotional 

irritability). The patient has 

received weekly injections of 180 µg 

peginterferon alfa-2a, in addition to 

an oral dose of 5 tablets of ribavirin 

per day for the past 5 months. The 

patient was also taking a combination 

angiotensin II receptor blocker 

and diuretic drug (candesartan); a 

statin/3-hydroxy-3-methyl glutaryl–coenzyme 

A reductase inhibitor 

(atorvastatin); an antihyperglycemic 

drug (metformin); an antifibrinolytic 

(tranexamic acid); 2 antidepressants 

(sertraline and mirtazapine); an acetaminophen- 

and codeine-based analgesic, 

in addition to a sedative 

(zolpidem); and a mood-stabilizing 

agent (levomepromazine). 

By March 2006, the hypertension 

and coagulation disorders were controlled; 

however, despite the conventional 

hepatitis C treatment, the viral 

load increased to greater than 

700,000 IU/mL, with loss of appetite 

and sexual desire added to the 

adverse effects of the conventional 

drugs still felt by the patient. After 

5 months of conventional treatment 

with no effect on the hepatitis C, 

the patient turned to bioregulatory 

therapy. 

In light of the chronicity of the infection, 

the extensive list of conventional 

drugs and their adverse effects, 

in addition to the multiple 

concomitant disease processes pres- 

) 15 



) 16 

ent all at the same time, it was clear 

that a carefully orchestrated therapy 

scheme, providing a combination of 

detoxification, supportive, reparative, 

and immune-enhancing activities, 

was to be initiated. After the first consultation 

in July 2006, a combination 

of medications (eg, Hepar compositum, 

Engystol, and Galium-Heel) was 

given parenterally for immediate immunomodulation 

and tissue support, 

in addition to extensive nutritional 

supplementation (eg, vitamin B complex). 

The intravenous method of administering 

the bioregulating medications, 

together with the nutritional 

supplements, has evoked greater systemic 

effects in our clinic. The patient 

was also prescribed an oral combination 

of medications targeted at assisting 

with the reparative processes of 

the body, providing the necessary 

cellular and organ support, in particular 

for the hepatic, hematological, 

and splenic organs, and assisting 

with the activation of the immune 

system. Hepeel, Engystol, and a combination 

of products composed of 

Chelidonium-Homaccord and products 

containing porcine tissue materials 

(eg, liver, spleen, and bone marrow) 

and 2 bioregulatory metabolic 

factors (Acidum succinicum-Injeel 

and Acidum fumaricum-Injeel) were 

prescribed 3 times a day at specific 

intervals. Gentle detoxification was 

also started with the use of Hepeel 

and other prescribed liver cleanse 

formulas. At the follow-up visit 2 

weeks later, Valerianaheel was prescribed 

to assist with the insomnia, 

followed by homeopathically prepared 

ribavirin (D8 potency) and pegylated 

IFN (D8 potency) 2 weeks 

after that to assist with the adverse 

effects of the conventional counterparts. 

The latter were to be taken 

each once a day for 2 weeks, followed 

by 10 drops 3 times a week thereafter. 

After receiving neural therapy during 

the fourth consultation in September, 

the patient developed hematomas 

in all the injected sites, 24 

hours after the injection therapy. 

These were seen as a positive development 

in the patient’s movement 

towards health, and an acute posology 

of oral Cinnamomum-Homaccord 

was prescribed for the next 1.5 

days, in addition to Traumeel acting 

as an adjunct for the management of 

the inflammatory process. The patient 

responded well after 48 hours 

of the initial crisis, displaying positive 

disease evolution changes. 

By using the electroacupuncture 

system, developed by Reinhold Voll, 

MD, and Fritz Kramer, MD, in Germany 

60 years ago, the measurement 

of bioimpedance in the patient’s 

acupuncture points was 

assessed throughout the rest of the 

consultations, which was also used 

to confirm the physician’s choice of 

medicines. After being evaluated in 

early October, autologous blood 

therapy was administered a few days 

later into the indicated acupuncture 

points (ie, large intestine, liver, and 

lungs), in conjunction with several 

combination medications acting in a 

bioregulating manner and nutritional 

supplementation. The medications 

chosen continued to provide extensive 

tissue and organ support (eg, 

Hepar suis-Injeel, Pulmo suis-Injeel, 

and Bronchus suis-Injeel), with constant 

immunomodulation (eg, Galium-Heel, 

Engystol, and Traumeel) 

and activation of regulatory and enzymatic 

processes (eg, Ubichinon 

compositum and Acidum fumaricum-Injeel). 

Detoxification and 

drainage systems were also being 

assisted, while other medicines continued 

to work on repair and improvement 

of symptoms. On the day 

of receipt of the first autologous 

blood injection therapy, the patient 

developed acute pharyngitis, which 

resolved spontaneously, displaying a 

positive lymphodermal disease evolution. 

By the seventh visit in mid-October, 

the patient reported a significant improvement 

in the skin pruritus, in 

addition to improved and more regulated 

sleep patterns. The patient 

was advised to stop his antifibrinolytic 

medication (tranexamic acid) in 

early October, with no ill effect on 

his current hematological values, indicating 

normal prothrombin time 

(PT) and partial thromboplastin 

time (PTT) levels and improved levels 

of neutrophils (from 110,000 to 



197,000 cells/µL). The patient continued 

to receive autologous blood 

injection therapy each week until 

the follow-up visit a month later. At 

this time, the patient reported complete 

absence of the pruritus, increased 

energy levels, vastly improved 

appetite, and a general 

feeling of being more encouraged 

and emotionally more positive. 

Blood test results indicated further 

increases in eosinophil numbers and 

PT and PTT values (10.6 and 26.7 

seconds, respectively), in addition to 

normal fasting glucose levels, but 

liver enzyme levels were still altered 

(ie, increased alanine aminotransferase 

level). One month later, in early 

December, electroacupuncture control 

testing was performed, with 

continued administration of weekly 

autologous blood injection therapy. 

The gastrointestinal system was being 

targeted, using a combination of 

medications, including Podophyllum 

compositum. By mid-December, 

the patient displayed an ectodermalpositive 

disease evolution, with dry 

scaly skin developing on the right 

foot, which, after the application of 

Traumeel cream, started secreting 

and resolving after a further 2 days. 

By January 10, 2007, polymerase 

chain reaction HCV levels were 43 

IU RNA/mL, with PT and PTT levels 

at 16.3 and 39.9 seconds, respectively. 

The patient started to progressively 

reduce his IFN treatment, 

which was then completely discontinued, 

in addition to the ribavirin, 

under the advice of the patient’s hepatologist 

in March 2007. Repeat 

blood tests in September 2007 confirmed 

the same minimal viral load 

and regulated PT and PTT levels, at 

10.00 and 26.6 seconds, respectively. 

Twenty months later, in early 

2009, an ultrasonographic investigation 

revealed no evidence of past 

fatty liver changes, and liver function 

test results were normal. A recent 

blood test, performed in July 2012, 

once again revealed results with a 

minimal viral load, indicating no 

signs of relapse and that the patient 

was maintaining self-regulation. 

Conclusion 

Hepatitis C infections, in particular 

with the genotype 1, subtype 1b, 

can be challenging to treat because 

the mutating virus is difficult to 

eradicate and the risk of developing 

severe liver disease and HCC is 

much higher in this group of patients. 

This 55-year-old patient was 

treated with several modalities because 

of the complexity of his health 

status, but medicines acting in a bioregulating 

manner provided the 

mainstay of the multilevel intervention 

that was necessary in this case. 

The host assisted in launching an 

effective and sustained immune response 

toward an evasive adversary, 

but the medicines also provided the 

necessary organ and tissue support 

for detoxification, tissue repair, and 

regeneration, resulting in normal 

hepatic structure and function, with 

minimal adverse reactions.| 

References 

1. Carcamo WC, Nguyen CQ. Advancement 

in the development of models 

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 hepatitis 

C. Dtsch Arztebl Int. 2012;109(19):352- 

358. doi:10.3238/arztebl.2012.0352. 

3. Imran M, Waheed Y, Manzoor S, et al. Interaction 

of hepatitis C virus proteins with 

pattern recognition receptors [published 

online ahead of print June 22, 2012]. Virol 

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 interferon, 

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]. Virol 

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 effectiveness 

and quality of life considerations 

in the treatment of hepatitis C infection. 

Clinicoecon Outcomes Res. 2010;2:87-96. 

doi:10.2147/CEOR.S7283. 

9. Salloum S, Tai AW. Treating hepatitis C 

infection by targeting the host. Transl Res. 

2012;159(6):421-429. doi:10.1016/j. 

trsl.2011.12.007. 

10. Baraldi S, Hepgul N, Mondelli V, Pariante 

CM. Symptomatic treatment of interferonα-induced 

depression in hepatitis C: a 

systematic review. J Clin Psychopharmacol. 

2012;32(4):531-543. 

11. Sievert W. Management issues in chronic viral 

hepatitis: hepatitis C. J Gastroenterol Hepatol. 

2002;17(4):415-422. 

) 17 


) Refresh Your Homotoxicology 

Gut Feelings Revisited: 

Evidence for a Brain-Gut Axis 


PhD, ND 

) 18 

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. Expressions 

such as “gut feelings” or 

“follow your gut” have been commonly 

used for many years. The scientific 

support for these expressions 

is being substantiated, with considerable 

support for direct communication 

between the brain and the gastrointestinal 

tract (GIT). This article 

will discuss some of the recent evidence 

for the presence of the braingut 

axis, including some of the bestdescribed 

features, such as the 

cholinergic anti-inflammatory pathway 

and the influence of the microbiome 

* and macronutrients directly 

on the central nervous system (CNS). 

Recent studies buttressing the therapeutic 

potential of influencing this 

brain-gut axis also will be discussed. 

Role of the Cholinergic 

Anti-inflammatory Pathway 

Cranial nerve X, the vagus nerve, is 

well-known for its ability to influence 

multiple targets outside the 

CNS. Many of its fibers leave the vertebral 

column at the cervical spine 

and wander (Latin vagari means 

“wandering”) throughout the thoracic 

and abdominal cavities to innervate 

numerous visceral organs, including 

the esophagus, stomach, 

small intestine, proximal half of the 

colon as well as the heart and lungs. 

It supplies parasympathetic nervous 

system input to the liver, gallbladder, 

pancreas, kidneys, and upper region 

of the ureters and is an important relay 

of sensory information from the 

head, neck, abdomen, and thorax to 

the brain. 1 The primary neurotransmitter 

used for communication between 

the synapses of the vagus 

nerve and its targets is acetylcholine, 

a signaling molecule with widespread 

function in the parasympathetic 

and sympathetic nervous systems. 

1 

A pathway between the brain and the 

gut, using the vagus nerve as a conduit 

of communication, has been described 

as the cholinergic anti-inflammatory 

pathway. 2-4 In this 

pathway, afferent nerve fibers from 

the vagus nerve receive signals from 

the organs and tissues they are situated 

in and carry these signals to the 

brain. Some of these signals are messages 

about injury, ischemia, and 

pathogens, as well as the levels and 

activities of proinflammatory cytokines 

in the local microenvironment. 

In the brain, processing and sorting 

of these signals occurs, and the appropriate 

message is carried via the 

efferent vagus nerve fibers back to 

the site of origin. The activation of 

the appropriate acetylcholine receptors, 

including the α7 nicotinic acetylcholine 

receptors on immunocompetent 

cells, results in either a 

decrease of the local proinflammatory 

message or a possible increase in 

inflammation. In this way, the brain 

can play an active part in controlling 

an inflammatory response at a distal 

site and preventing the damaging 

consequences of an excessive innate 

immune system response. 2-4 

This complete circuit of sensors of 

infection or injury (the vagus afferent 

nerve fibers in visceral tissues), relay 

system, and integrator (brain and 

other parts of the CNS) and effectors 

(vagus efferent nerve fibers, acetylcholine, 

and the target cells) is clearly 

involved in the maintenance of 

immune system homeodynamics and 

has been recently proposed as an inflammatory 

reflex. 5 This system 

could function in a similar manner to 

reflex arcs in other complex organ 

systems and suggests that it is important 

to consider sensory nerves as an 

integral part of the control of innate 

immune system responses. 6 Also, it 

might be possible to eventually map 

an inflammatory homunculus in the 

brain, with specific regions controlling 

different components of the inflammatory 

response. 7 

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

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



The practical ramification of this 

brain-gut axis, outlined by the cholinergic 

anti-inflammatory pathway, 

is that therapeutic interventions, including 

acupuncture, biofeedback, 

mindfulness meditation, body work, 

cervical adjustments, and specific 

natural health products, that could 

potentially modify the activity of the 

autonomic nervous system (and, 

therefore, input and output of the 

vagus nerve) might help modify the 

nonresolving inflammation associated 

with chronic diseases, such as inflammatory 

bowel disease, rheumatoid 

arthritis, and type 2 diabetes 

mellitus. 8 Moreover, because the afferent 

vagus nerve fibers bind to acetylcholine 

receptors that influence 

the heart, it may be possible to treat 

inflammation by controlling the activity 

of the vagus nerve, via an electronic 

device similar to a pacemaker, 

and to assess the effect via a heart 

rate monitor. 9 The potential value of 

this approach is supported by recent 

evidence demonstrating that heart 

rate variability is an independent 

marker of systemic inflammatory responses 

and correlates well with certain 

biomarkers of systemic inflammation, 

including high-sensitivity 

C-reactive protein (hs-CRP) and interleukin 

6. 10-12 

Role of the Microbiome 

It is well substantiated that billions 

of microorganisms exist within our 

GIT and that many of them have important 

roles to play in our overall 

metabolism and health, including 

modulation of both innate and adaptive 

immune systems and synthesis 

and metabolism of important vitamins, 

hormones, and short-chain 

fatty acids with beneficial function. 

The gut flora has been described as a 

forgotten organ because many of its 

essential protective, structural, and 

metabolic functions have been underappreciated 

until recently. 13 However, 

exciting new discoveries have 

validated the historical view of the 

benefit of commensal microflora and 

have described the human intestinal 

microbiome as a new frontier in human 

biology. 14 One of the most recent 

discoveries is the connection 

between the gut microbiome and the 

CNS to form what is termed the microbiome-gut-brain 

axis (Figure). 15 This 

discovery and the studies that support 

it suggest that the microbes 

within our GITs can influence more 

sophisticated nervous system functions, 

such as “affect, motivation and 

higher cognitive functions, including 

intuitive decision making.” 16 This 

discovery also further establishes that 

the communication between the 

brain, gut, and associated microbes 

Influence of the brain on the intestinal microbiota 

Vagus nerve 

Figure. The Microbiome-Gut-Brain Axis 

Microbiota-gut 

interactions 

plays an important role in health and 

disease. 17 Recognition that the “human 

microbiome serves as the interface 

between our genes and our history 

of environmental exposures” has 

led to the possibility of a mindbody-microbial 

continuum that has 

an impact into neurodevelopment 

and development of unique behavioral 

phenotypes. 18 

In animal studies, the acquisition of 

appropriate bacteria from the mother 

in the immediate postnatal period 

is an important contributing factor 

to the development of normal gastrointestinal, 

immune, neuroendocrine, 

and metabolic systems. It has 

even been shown to be one of the 

key factors regulating the set point 

Gut-brain 

axis 

Influence of the microbiota on the brain and behavior 

© iStockphoto.com/David Marchal (digestive system) and © iStockphoto.com/Evgeny Terentev (human brain) 

) 19 



) 20 

of the hypothalamic-pituitary-adrenal 

(HPA) axis. 19 Other studies have 

shown definitive changes within the 

brain, depending on the composition 

of bacteria in the GIT. For example, 

a recent study demonstrated that the 

presence or absence of commonly 

identified bacteria in the intestine in 

germ-free and specific pathogen-free 

mice affected the expression of N- 

methyl-D-aspartate receptor, brainderived 

neurotrophic factor, and 

serotonin receptor in the different 

regions of the brain. These neurochemical 

changes were accompanied 

by observable changes in anxiety-like 

behavior. 20 It was recently shown, using 

a mouse model, that the ingestion 

of a strain-specific probiotic, termed 

Lactobacillus rhamnosus, influenced the 

expression of γ-aminobutyric acid 

receptors in different regions of the 

brain associated with anxiety and 

depression. The ingestion of these 

beneficial bacteria also reduced anxiety 

and depression-related behavior 

associated with long-term use of 

corticosterone in otherwise healthy 

animals. Both the neurochemical and 

behavioral benefits of the probiotic 

agent were negated if the vagus nerve 

was cut, suggesting that this nerve 

serves as an essential communication 

pathway between the brain and the 

gut. What this study demonstrates 

is that bacteria play an important 

role in influencing the brain. Also, it 

might be possible to select and use 

specific microorganisms as adjunctive 

therapies in stress-related disorders, 

such as anxiety and depression. 21 It 

provides further support for an interdependent 

link between the brain 

and the gut flora. 

Neurotransmitters released after 

commands from the CNS can affect 

the habitat of the microflora in several 

ways, including altering the motility 

of the GIT, affecting the production 

of mucin and the function of 

epithelial cells, and directly affecting 

the growth of different bacteria, 17 including 

pathogenic strains, such as 

Escherichia coli O157:H7. 22 Conversely, 

gut microbiota can influence 

brain and behavior via the production 

of metabolites that directly influence 

the CNS, activate innate and 

adaptive immune system responses 

with systemic effects, and modulate 

neural afferent circuits to the brain. 21 

Certain strains of probiotics also 

could influence the metabolism of 

tryptophan, a precursor to serotonin 

that has wide-ranging effects 

throughout the nervous system, including 

the CNS. 23 Finally, there is 

evidence that gut microbiota and 

probiotics 24 can influence the perception 

of visceral and even somatic 

pain, suggesting that they, or their 

metabolites, can modulate the sensitivity 

of the associated nerves. 23 

Enteric microflora and their toxins 

can affect enterochromaffin cells in 

the GIT. 25 Enterochromaffin cells 

help regulate communication between 

the gut lumen and the nervous 

system in several ways, including direct 

innervation by afferent fibers of 

the vagus nerve 26 and local secretion 

of corticotropin-releasing hormone 27 

(also termed corticotropin-releasing factor). 

This hormone is most commonly 

studied as being produced in the 

hypothalamus, where it is an important 

component of the HPA axis 

communication pathway. 1 Corticotropin-releasing 

factor and its related 

peptides have been demonstrated to 

be widely expressed in the colon of 

humans and rodents, 28 where they 

are integral mediators of the stress 

response in the brain-gut axis 29 and 

play an important role in the regulation 

of motility, 30 permeability, 31 and 

inflammation 32 in the intestines. It 

can be synthesized and released from 

dendritic cells of the innate immune 

system, a process that is enhanced by 

commensal bacteria, such as Bacteriodes 

vulgatus and Fusobacterium varum. 

33 A recent study in rats demonstrated 

that “chronic psychosocial 

stress triggers reversible inflammation, 

persistent epithelial dysfunction, 

and colonic hyperalgesia,” 

largely via upregulation of corticotropin-releasing 

factor receptor type 

1 in intestines. 34 This study provides 

support for the role of corticotropinreleasing 

factor as an important messenger 

in the brain-gut axis and suggests 

that this might be one of the 

mechanisms responsible for the observed 

effects of psychosocial stress 

on the symptoms of irritable bowel 

syndrome. 35 

Early life stressors, such as maternal 

separation, have been well studied in 

rodent models as examples of the 

pathological consequences of braingut 

axis dysfunction. 36 One of the 

consequences of the premature separation 

of rat pups from their mother 

during the neonatal period is immediate 

and prolonged changes in intestinal 

physiology. These functional 

abnormalities of the colon in rat pups 

after maternal deprivation can be 

ameliorated with the supplementation 

of strain-specific probiotics, at 

least partly because of the ability of 

these probiotics (Lactobacillus rhamnosus 

R0011 and Lactobacillus helveticus 

R0052) to normalize cortisone release, 

a marker of HPA axis activity. 37 

Another consequence of premature 

maternal separation is depressivelike 

symptoms, which have been shown 

to be reversed by the supplementation 

of a probiotic, Bifidobacterium infantis. 

In this case, the probiotic normalized 

interleukin 6 levels, restored 

noradrenaline concentrations in the 

brainstem, and reversed the observed 

behavioral deficits. 38 



Role of Macronutrients 

An intriguing study by Van Oudenhove 

et al 39 demonstrated that ingestion 

of fatty food by healthy nonobese 

volunteers, via an intragastic 

tube to avoid any influence of smell, 

taste, or feel, substantially reduced 

their response to experimentally induced 

sadness through appropriate 

music and pictures. Furthermore, exposure 

to the same music and pictures 

decreased their sense of fullness 

after ingestion of a fatty meal. 39 

These interesting results suggest that 

ingested macronutrients can directly 

influence CNS activity to affect emotions 

and, conversely, that the brain 

can affect our normal response to ingested 

meals. A thought-provoking 

commentary entitled “Was Feuerbach 

Right: Are We What We Eat?” discusses 

this possibility. 40 These results 

also support the idea of fatty foods as 

comfort foods. 

Although it was not examined in the 

study which specific neural and hormonal 

pathways were involved in relaying 

this information between the 

fatty food in the gut and the CNS, 

some likely candidates are ghrelin 

and cholecystokinin. Ghrelin is a 

hormone produced in the gut and 

other parts of the GIT that has been 

shown to have a wide variety of 

functions, including stimulating appetite, 

modulating inflammation, 

promoting sleep, reducing pain, and 

facilitating learning and memory. It 

also is associated with reward behaviors 

and mood regulation in animal 

models. 1 A recent animal study 

showed that persistent psychosocial 

stress in male mice increased levels of 

ghrelin and corticosteroid in addition 

to triggering behaviors to seek 

out high-fat foods. 41 These data suggest 

that ghrelin might be an important 

part of the repertory of hormones 

associated with the stress 

response. They also are an interesting 

support for a relatively common human 

behavior of preferring to eat 

calorie-dense comfort foods during 

times of high stress. Stimulation of 

parasympathetic nervous system terminals 

in the GIT by fatty acids, the 

corresponding release of cholecystokinin, 

and the subsequent secretion 

of pancreatic enzymes are well-established 

components of the digestive 

process. 1,42 The receptors for cholecystokinin 

are known for their roles 

in learning and memory and in modulating 

panic, anxiety, and appetite, 

further demonstrating that this hormone 

pathway could serve as part of 

the brain-gut axis. 1 

Conclusions 

There is clearly a network of interactions 

between the brain and the gut 

that can be described by various 

plausible connections, including the 

vagus nerve and its associated neurotransmitters, 

the gut microbiome 

and macronutrients, and their direct 

and indirect influences on CNS activity. 

It is intriguing to think that 

there might be further networks of 

interactions that could be included in 

a unifying model, including a gutbrain-skin 

axis, 43 a gut-brain-liver 

axis, 44 and a gut–brain–exocrine 

pancreas axis. 45 A more in-depth understanding 

of the interconnections 

between the brain and the gut will 

help illuminate potential therapeutic 

access points to treat diseases associated 

with a dysfunctional interaction 

between the CNS and the GIT, including 

irritable bowel syndrome, 46 

peptic ulcer disease, and gastroesophageal 

reflux disorder. 47 The existence 

of a brain-gut axis is clearly 

no longer a farrago of disjointed hypotheses, 

but an increasingly welldefined 

bidirectional communication 

pathway. 

The established presence of different 

networks contributing to the braingut 

axis supports the therapeutic use 

of multicomponent medications with 

the ability to affect more than one 

biological target simultaneously. 

Spascupreel is a product with evidence 

suggesting that it can target 

multiple receptors associated with 

this complex network, including 

muscarinic acetylcholine receptors 

(affecting smooth muscle contraction 

and motility), γ-aminobutyric acid-A 

(GABA type A) receptors (associated 

with CNS processing of mood disorders, 

including anxiety), and dopaminergic 

receptors type 2 (affecting 

central control of the pain response). 

It inhibits the enzyme monoamine 

oxidase B (MOA-B) (unpublished 

data), which is known to contribute 

to the regulation of levels of neurotransmitters, 

including dopamine. 

Furthermore, several of the ingredients 

of Spascupreel are documented 

in the scientific literature to modulate 

various central and peripheral targets 

of the brain-gut axis. However, the 

multicomponent medication Spascupreel 

could be considered as an important 

addition to a comprehensive 

therapeutic approach to any condition 

associated with a dysfunction of 

the brain-gut axis. Other bioregulating 

medications, such as Thalamus 

compositum (in central pain syndromes 

related to the GIT) and Tonsilla 

compositum (in disturbances of 

the HPA), are also used to influence 

the brain-gut axis.| 

) 21 



) 22 

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central and peripheral actions of brain-gut 

peptides: a basis for regulation of gastric 

function. Surgery. 1985;98(2):183-190. 

43. Arck P, Handjiski B, Hagen E, et al. Is 

there a “gut-brain-skin axis”? Exp Dermatol. 

2010;19(5):401-405. 

44. Wang PY, Caspi L, Lam CK, et al. Upper 

intestinal lipids trigger a gut-brain-liver 

axis to regulate glucose production. Nature. 

2008;452(7190):1012-1016. 

45. Konturek SJ, Zabielski R, Konturek JW, 

Czarnecki J. Neuroendocrinology of the 

pancreas: role of brain-gut axis in pancreatic 

secretion. Eur J Pharmacol. 2003;481(1):1- 

14. 

46. Kennedy PJ, Clarke G, Quigley EM, 

Groeger JA, Dinan TG, Cryan JF. Gut memories: 

towards a cognitive neurobiology of 

irritable bowel syndrome. Neurosci Biobehav 

Res. 2012;36(1):310-340. 

47. Konturek PC, Brzozowski T, Konturek 

SJ. Stress and the gut: pathophysiology, 

clinical consequences, diagnostic approach 

and treatment options. J Physiol Pharmacol. 

2011;62(6):591-599. 


) Meet the Expert 

Dr. Sergio Vaisman Weinstein 

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 musical 

theory. Unfortunately, in the 

fourth year of these studies, he had to 

stop playing the violin because of a 

broken arm and never recommenced. 

Both Sergio and his older brother 

shared their father’s interest in medicine. 

As youngsters, they accompanied 

him when he held his Sunday 

surgery at the hospital where he 

worked. After finishing secondary 

school at the Instituto Nacional 

in Santiago, Sergio studied medicine 

at the School of Medicine at the University 

of Chile and was awarded a 

Degree in Surgery before the age of 

24 years. 

Dr. Vaisman has passed his fascination 

with medicine and music down 

to the next generation: his eldest son 

is a traumatologist, and his youngest 

daughter is a student of cello and musical 

composition. 

Dr. Vaisman likes to be out in nature 

and, ever since he was a boy, has enjoyed 

going on camping trips. He has 

always been a keen sportsman, playing 

basketball when younger and jogging 

for the last 25 years. 

After 10 years as a physician, Dr. 

Vaisman fulfilled one of his childhood 

dreams and began studying for 

his pilot’s license. He continued to 

make progress with this hobby, passing 

his instrumental flying examination 

and subsequently qualifying to 

fly a multiengine aircraft. Proud owner 

of a twin-engine aircraft with room 

for 6 passengers, he has covered the 

country from its Northern-most point 

(Arica) to its Southern-most point 

(Punta Arenas), sometimes taking 

sleeping bags and tents on board to 

allow him to combine his passions for 

camping and flying. 

After more than 30 years as a pediatrician, 

Dr. Vaisman felt the need to 

explore new avenues. This happened 

in light of his frustration at treating a 

group of patients whose conditions 

could only be relieved, but not cured, 

by conventional medicine. At this 

crossroads in his career, he was invited 

to study for a Diploma in Biological 

Medicine, which he accepted to 

explore new possibilities. He soon 

realized that this was the opportunity 

that he had been seeking, and he continued 

to study at all the levels offered 

by the International Academy for 

Homotoxicology. His initial attempts 

to treat patients using this new approach 

allowed him to see for himself 

the excellent results obtained when 

applying bioregulatory therapy to pediatric 

patients. Because he was completely 

convinced that a combination 

of conventional medicine and bioregulation 

was the ideal solution, and 

taking advantage of his long teaching 

career at the University of Chile, he 

began to give talks to different groups 

of physicians throughout the country 

to make them aware of this approach 

and increase the number of professionals 

with an understanding of this 

therapy. These talks led him to coordinate 

a Diploma in Homotoxicology 

in a School of Medicine at a university 

in Santiago de Chile. 

He has also spoken at conferences 

and symposia and taught diploma 

courses in Chile, Colombia, Peru, and 

Portugal. 

His scientific contribution and support 

of the International Academy for 

Homotoxicology was recognized at 

the International Symposium on Bioregulatory 

Medicine, held in Bogota 

in March 2012.| 

) 23 


) Practical Protocols 

Bioregulatory Management 

of Peptic Ulcer Disease 


PhD, ND 

) 24 

Peptic ulcer disease (PUD) is a complex, multifactorial 

disease of the gastrointestinal systems common in 

industrialized nations. 

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 approximately 

4.5 million people per 

year, with an annual prevalence of 

1.8%. 1 The frequency of PUD varies 

considerably between different countries 

(eg, Japan has an annual incidence 

of approximately 1 case, Norway 

has an annual incidence of 

approximately 1.5 cases, and Scotland 

has an annual incidence of approximately 

2.7 cases per 1000 population) 

and is determined mainly by association 

with the major reported causes: 

infection by the bacterium Helicobacter 

pylori and use of nonsteroidal anti-inflammatory 

drugs (NSAIDs). 1 In general, 

the frequency of PUD is decreasing 

in the developed world but 

increasing in developing countries. 1 

Peptic ulcer disease was previously 

considered as a disease primarily of 

males, but current estimates suggest 

more of an even distribution, with a 

male to female ratio of approximately 

1:1. However, the average lifetime risk 

of developing PUD is still slightly 

higher in men (11%-14%) than in 

women (8%-11%). 1 The average age of 

diagnosis for duodenal ulcers is between 

30 and 50 years, whereas the 

prevalence of gastric ulcers peaks in 

those aged 50 to 70 years. 1 Younger 

patients are more likely to have non– 

H pylori, non-NSAID gastric ulcers 

than are more elderly patients. 2 

The pathogenesis of PUD is multifactorial, 

with contributions from several 

factors, including excessive acid and 

pepsin in the gastric lumen, defective 

defensive mucosal barrier components 

(eg, mucus, bicarbonate, and leaky intercellular 

junctions), impaired mucosal 

blood flow, cellular restitution, and 

epithelial cell turnover. 1 However, the 

most commonly recognized causes are 

persistent infections by H pylori, the 

use of NSAIDs, and aspirin. 1 Chronic 

overwhelming stress was identified 

historically as a major initiating factor 

but is now generally considered secondary 

to an infection by H pylori. 3 

There is renewed interest in defining 

the psychosocial etiology of PUD, 4 

with the recognition that the combined 

effect of H pylori and stress on 

the development of ulcers is paramount. 

5 This heterogeneity of causes 

of PUD is exemplified by numerous 

other contributing factors identified, 

including the genetic predisposition 

of the host and environmental factors 

(eg, cigarette smoking, 6 excessive alcohol 

intake, and extreme emotional or 

physical stress, 1,7 including childhood 

physical abuse 8 ). Moreover, other 

medications that have been associated 

with the development of the gastritis 

preceding PUD include potassium and 

iron supplements and ethanol in both 

chronic and binge drinkers. 1 

The most common symptom of PUD 

is epigastric pain, often described as a 

gnawing, burning sensation that occurs 

2 to 3 hours after a meal and is 

relieved by food and/or antacids. 1,9 

This pain might wake the patient at 

night and possibly radiate into the 

back. Other symptoms may include 

nausea, heartburn, abdominal bloating, 

belching, intolerance to fatty 

foods, and chest discomfort. Vomiting 

may occur if there is partial or complete 

obstruction of the gastric outlet, 

and hematemesis or melena can accompany 

bleeding in the GIT. In addition 

to epigastric tenderness, signs of 

melena and succussion splash also occur 

because of GIT bleeds and/or gas- 



tric outlet obstructions. 1 Ulcers induced 

by NSAID use might have no 

overt symptoms or nonspecific physical 

findings, similar to uncomplicated 

PUD. 1 

The major complications of PUD include 

GIT bleeds and perforations of 

ulcers, with the potential development 

to peritonitis and sepsis. 1 Infection by 

H pylori also has been identified as one 

of the complex host and environmental 

factors that increase the risk of gastric 

adenocarcinoma, 9 possibly because 

of its ability to initiate and 

sustain chronic nonresolving inflammation. 

10 Although the mortality rate 

of PUD is relatively low, it can significantly 

impair a patient’s well-being 

and quality of life and is associated 

with high costs for employers and 

health care systems. 11 

In most patients with uncomplicated 

PUD, routine laboratory tests are not 

helpful in the diagnosis, and radiographic 

and endoscopic imaging techniques 

are needed for confirmation. 1 

Establishing that there is an overwhelming 

infection by H pylori is considered 

of primary importance in most 

patients with peptic ulcers. This can be 

measured using endoscopic and invasive 

testing (eg, rapid urease test, histopathological 

analysis, and culture) 

or nonendoscopic and noninvasive 

testing (eg, serum H pylori antibody 

detection, fecal antigen tests, and urea 

breath tests). 1,12 An endoscopic examination 

of the upper GIT is the preferred 

diagnostic test in the evaluation 

of patients with suspected PUD, 

whereas other tests for suspected 

Zollinger-Ellison syndrome include a 

fasting serum gastrin level and secretin 

stimulation tests. Chest x-ray, electrocardiographic, 

and computed tomographic 

scan results are used to exclude 

other conditions, such as 

detecting free abdominal air in the 

case of a perforation and myocardial 

infarction. 1 

Given the current understanding of 

the pathogenesis of PUD, most patients 

with PUD are treated for H pylori 

infection (with initial estimates of 

success in 85%-90% of cases, but values 

decreasing to

Photograph by Samir; licensed under the Creative Commons 

Attribution-Share Alike 3.0 Unported license; http://en.wikipedia.org/wiki/Image:Deep_gastric_ulcer.png. 


Gastric ulcer 

) 26 

for 7 to 14 days as the first-line treatment. 

1 Also, proton pump inhibitors 

exacerbate NSAID-induced small intestinal 

injury, possibly by inducing 

dysbiosis, suggesting that it would be 

prudent to avoid NSAIDs during this 

treatment. 13 Because of increasing resistance 

of H pylori to antibiotics, there 

are reports of “unacceptably low treatment 

success” and accompanying proposals 

to alter the therapy to potentially 

increase therapeutic value. 14,15 

The presence of H pylori needs to be 

initially confirmed and then shown to 

be eradicated because ulcers have been 

shown to relapse in unsuccessful H pylori 

elimination. 1,12 

There are insufficient data to support 

any special diet in assisting with the 

healing of PUD, although some studies 

demonstrate that the consumption 

of common spices in food (eg, clove, 

cinnamon, oregano, black pepper, turmeric, 

and ginger) and supplementation 

with certain herbal medicines can 

have definite beneficial effects on the 

gastric mucosa and may be of great 

benefit for the prevention of gastric 

ulcers. 1,16 With the success of medical 

therapy, surgery has a very limited role 

in the management of PUD and is 

only recommended in refractory cases 

and complications of PUD (eg, obstructions, 

perforations, penetration, 

and massive GIT bleeding). 1,17 With 

the declining success rates of conventional 

triple-therapy treatments, it is 

evident that there is an opportunity 

for medications with bioregulatory 

properties, and other natural health 

products, to be used as adjunctive 

therapies in the treatment and prevention 

of recurrence of peptic ulcers. 

Bioregulatory Intervention 

A small interventional trial using medications 

with bioregulatory properties 

(ie, Gastricumeel, Nux vomica- 

Homaccord, Lymphomyosot, and Coenzyme 

compositum/Ubichinon compositum) 

demonstrated that this also 

was an effective method of eradicating 

H pylori and, therefore, treating one of 

the recognized causes of PUD. 18 As 

previously described, there are several 

potential networks that can contribute 

to the development of PUD. The bioregulatory 

medical approach to treatment 

is shown in the Table.| 

References 

1. Anand BS. Peptic ulcer disease. Medscape 

Reference Web site. http://emedicine.medscape.com/article/181753-overview. 

Accessed 

March 29, 2011. 

2. Xia HH, Phung N, Kalantar JS, Talley NJ. 

Demographic and endoscopic characteristics 

of patients with Helicobacter pylori positive 

and negative peptic ulcer disease. Med J Aust. 

2000;173(10):515-519. 

3. Gustafson J, Welling D. “No acid, no ulcer”–100 

years later: a review of the history 

of peptic ulcer disease. J Am Coll Surg. 

2010;210(1):110-116. 

4. Jones MP. The role of psychosocial factors 

in peptic ulcer disease: beyond Helicobacter 

pylori and NSAIDs. J Psychosom Res. 

2006;60(4):407-412. 

5. Fink G. Stress controversies: post-traumatic 

stress disorder, hippocampal volume, gastroduodenal 

ulceration. J Neuroendocrinol. 

2011;23(2):107-117. 

6. Zhang L, Ren JW, Wong CC, et al. Effects 

of cigarette smoke and its active components 

on ulcer formation and healing in 

the gastrointestinal mucosa. Curr Med Chem. 

2012;19(1):63-69. 

7. Leong RW. Differences in peptic ulcer between 

the East and the West. Gastroenterol 

Clin North Am. 2009;38(2):363-379. 

8. Fuller-Thomson E, Bottoms J, Brennenstuhl 

S, Hurd M. Is childhood physical abuse 

associated with peptic ulcer disease? Findings 

from a population-based study. J Interpers 

Violence. 2011;26(16):3225-3247. 

9. Pritchard DM, Crabtree JE. Helicobacter pylori 

and gastric cancer. Curr Opin Gastroenterol. 

2006;22(6):620-625. 

10. Polk DB, Peek RM Jr. Helicobacter pylori: 

gastric cancer and beyond. Nat Rev Cancer. 

2010;10(6):403-414. 

11. Barkun A, Leontiadis G. Systematic review of 

the symptom burden, quality of life impairment 

and costs associated with peptic ulcer 

disease. Am J Med. 2010;123(4):358-366. 

e352. 

12. Costa F, D’Elios MM. Management of Helicobacter 

pylori infection. Expert Rev Anti Infect 

Ther. 2010;8(8):887-892. 

13. Wallace JL, Syer S, Denou E, et al. Proton 

pump inhibitors exacerbate NSAID-induced 

small intestinal injury by inducing dysbiosis. 

Gastroenterology. 2011;141(4):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 Gastroenterol. 

2010;16(22):2710-2719. 

17. Stewart DJ, Ackroyd R. Peptic ulcers 

and their complications. Surgery (Oxford). 

2008;26(11):452-457. 

18. Ricken K-H. Clinical treatment of functional 

dyspepsia and Helicobacter pylori gastritis. 

Biomed Ther. 1997;15(3):76-81. 


) Expand Your Research Knowledge 

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. 

Noninterventional studies, also 

called nonexperimental studies, 

are studies that do not involve any 

intervention (experimental or otherwise) 

on the part of the investigator. 

Such studies have in common the 

use of an observational research design. 

In the conduct of noninterventional 

studies, the same rigor must be 

applied as in experimental studies. 1,2 

The main types of noninterventional 

studies are summarized in Table 1. 

Noninterventional studies fall under 

the header of “observational epidemiology,” 

in which the main exposures 

(eg, environmental factors or 

treatments) are not under the direct 

control of the epidemiologist. 

Noninterventional studies can involve 

either populations or individual 

patients. The main comparative 

noninterventional studies are cohort 

studies and case-control studies. The 

main descriptive noninterventional 

studies are cross-sectional studies, 

case series, and case reports. 4 

In Table 2, the main types and characteristics 

of noninterventional studies 

are summarized. 

It should be noted that the temporal 

perspective refers to the main temporal 

orientation of a particular epidemiological 

design and not to the 

data collection process itself. For instance, 

in cohort studies, sometimes 

the data are collected retrospectively 

“after the event” (eg, by linking back 

to records that enable the reliable 

identification of different levels of 

the exposure of interest). The latter 

are often called historical cohort studies, 

but even such a study is prospective 

in terms of following up “the 

march” of cohorts with different exposure 

levels to a health outcome of 

interest. Historical cohort studies are 

less common nowadays because of 

the increasing ethical barrier of privacy/data 

protection. 

Cohort studies that compare the 

outcomes of differently treated cohorts 

are possible but are particularly 

susceptible to selection bias: the cohorts 

are noncomparable with respect 

to other factors than the treatments 

of interest. The latter can be 

partly addressed by recording/assessing 

all the relevant determinants 

of outcome in both cohorts and then 

adjusting for any confounding due 

to these factors during the analysis. 

The risk remains, however, that not 

all relevant determinants of outcome 

have been assessed and that the 

causal attribution of findings to a 

particular treatment remains biased. 

There is no real solution for this 

problem because it is, in practice, impossible 

to know and validly assess 

all the determinants of outcome. 

Therefore, in medicine, investigators 

often resort to the “next best” thing 

for managing ignorance: randomization. 

Provided there are sufficient 

patients included, the latter ensures 

that the known and unknown confounders 

are equally distributed 

(without selection bias) between the 

treatment groups. However, randomized 

studies are sometimes unnecessary, 

inappropriate, impossible, or 

inadequate 5 ; therefore, a need for 

noninterventional studies remains. 

More recently, so-called hybrid designs 

have been proposed, in which 

several clinical trials are embedded 

within a cohort study. 6 Such innovative 

mixed designs may be particularly 

suited when the assessment of 

the additional value of treatment is 

compared with “treatment as usual,” 

and this is often relevant in complementary 

and alternative medicine 

research. Although such designs 

hold promise, they may not always 

be feasible. 

) 27 


© iStockphoto.com/Mutlu Kurtbas 

Case-control studies are primarily 

used for etiological research. They 

used to be termed retrospective because, 

conceptually, the temporal 

orientation is from the disease onset 

backward to the postulated causal 

factors. Yet, cases and controls in a 

case-control study are often accumulated 

prospectively. A further variant 

is the so-called nested case-control 

study, in which the cases and controls 

are drawn from the population 

of a larger cohort study. An advantage 

of such nested designs is that, 

because of the larger cohort study, 

more detailed and reliable information 

on the environmental (eg, nutritional) 

factors on the cases and controls 

can be obtained. 

Cross-sectional studies examine the 

presence or absence of disease in relation 

to the presence or absence of 

other variables in each member of a 

representative sample of the study 

population at a particular point in 

time. In this manner, potential correlations 

between the presence or 

absence (or level) of variables in the 

diseased versus the nondiseased 

members can be determined. However, 

the presence of a correlation 

does not necessarily imply causation. 

The classic example of this in epidemiology 

is the correlation between 

more storks and larger families in 

rural areas compared with urban areas. 

This does not necessarily imply 

that the storks carry the babies! For 

causal attribution, biological plausibility 

and prospectively collected 

data are a precondition. 

Noninterventional studies are all 

“observational,” but this should not 

be confused with qualitative observational 

studies that are different 

from the studies listed in Table 2. 

Observational methods used in the 

social sciences involve the systematic, 

detailed observation of behavior 

and talk: the qualitative researcher 

systematically watches people and 

events to find out about behaviors 

and interactions in natural settings. 

Observation, in this sense, represents 

the idea of the researcher as the research 

instrument, as someone who 

Table 1. Main Types of Noninterventional Studies a 

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. 

) 28 

Case series 

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

a 

Data adapted from Porta. 3 


) Expand Your Research Knowledge 

goes out into the field. 4 A further 

elaboration on qualitative research 

methods is outside the scope of this 

article. 

There are now reporting guidelines 

for most types of studies. For comparative 

and cross-sectional epidemiological 

studies, there is the 

STROBE guideline. 7 However, for 

case series and case reports, there are 

not yet reporting guidelines.| 

References 

1. Kelsey JL, Whittemore AS, Evans AS, Douglas 

Thompson W. Methods in Observational 

Epidemiology. 2nd ed. New York, NY: Oxford 

University Press; 1996. 

2. Schnetzler G, Hayward C. Overview of 

guidelines and recommendations for the 

planning, conduct and reporting of company-sponsored 

observational, noninterventional 

studies in Europe. Pharm Med. 

2011;25(4):235-244. 

3. Porta M, ed. A Dictionary of Epidemiology. 

5th ed. New York, NY: Oxford University 

Press; 2008. 

4. Mays N, Pope C. Qualitative research: observational 

methods in health care settings. 

BMJ. 1995;311(6998):182-184. 

5. Black N. Why we need observational studies 

to evaluate the effectiveness of health care. 

BMJ. 1996;312(7040):1215-1218. 

6. Relton C, Torgerson D, O’Cathain A, Nicholl 

J. Rethinking pragmatic randomised controlled 

trials: introducing the “cohort multiple 

randomised controlled trial” design. BMJ. 

2010;340:c1066. doi: 10.1136/bmj.c1066. 

7. von Elm E, Altman DG, Egger M, Pocock 

SJ, Gøtzsche PC, Vandenbroucke JP; 

STROBE Initiative. The Strengthening the 

Reporting of Observational Studies in Epidemiology 

(STROBE) statement: guidelines 

for reporting observational studies. Lancet. 

2007;370(9596):1453-1457. 

Table 2. Overview of Different Types of Noninterventional Studies 

Type of Study Study Base Temporal Perspective Focus Comment 

Cohort: 

2 or more 

cohorts 

Patient 

populations 

Prospective 

Analytical/hypothesis 

testing 

This type of cohort study is used to assess the 

health-related effects of environmental exposures 

or therapeutic interventions. 

Cohort: 

1 cohort 

Patient 

populations 

Prospective 

Descriptive 

This type of cohort study is often referred to as 

postmarketing surveillance study. In Germanspeaking 

countries, the term Anwendungsbeobachtungen 

is often used. 

Case-control 

Patient 

population 

Retrospective 

Analytical/hypothesis 

testing 

Case-control studies are used to investigate the 

potential relationship between a suspected risk 

factor or attribute and disease. 

Cross-sectional 

Patient 

populations 

Particular point in time 

Prevalence and correlations 

Cross-sectional studies are not suitable to determine 

a temporal sequence between cause 

and effect. 

Case series 

Patient 

populations 

Prospective or retrospective 

Descriptive 

Case series lack formal hypotheses and study 

protocols; if they had these characteristics, they 

would be cohort studies. 

Case reports 

Individual 

patients 

Prospective or retrospective 

Descriptive 

Case reports can serve among other educational, 

medical, safety monitoring, or hypothesisgenerating 

purposes. 

) 29 


) Research Highlights 

A Multicomponent Medication 

Triggers Multiple Beneficial Effects 

Related to Cognition and Neuronal 

Function 

By Kerstin Röska, PhD, 

and Bernd Seilheimer, PhD 

) 30 

Background 

During the Society for Neuroscience 

Congress in Washington, DC, 

which was held from November 12 

to 16, 2011, 3 posters on the beneficial 

effects of a multicomponent 

natural medication, termed HE-300, 

on cognitive dysfunction were presented. 

This meeting had more than 

30 000 participants and is the premier 

venue for neuroscientists from 

around the world to debut cuttingedge 

research on the brain and the 

nervous system. 

Introduction and 

Research Objective 

Disorders of cognition and memory, 

such as dementia, are complex, 

chronic, and multifactorial, with unknown 

etiology. The fact that we 

know little about the molecular 

pathways that result in cognitive decline 

and neuronal cell death led to 

the development of drugs lacking 

any disease-modifying effect. All 

therapeutic options currently available 

only treat the symptoms of the 

underlying disease. Another limiting 

factor comes along with modern 

drug discovery, which is based on a 

reductionist approach. The focus is 

always on a single target and a single 

molecule designed to block, activate, 

or modify it. To better mirror 

disease complexity, future drug discovery 

approaches should aim 

at multiple targets using multicomponent 

medications. Our study 

describes the use of HE-300, a multicomponent 

multitargeted me di cation, 

to treat cognitive dysfunction 

and its effects on neuronal function. 

Materials and Methods 

The study included a series of genomic, 

in vitro, ex vivo, and in vivo 

experiments related to neuronal 

function and cognitive impairment. 

First, a systematic gene analysis of 

the whole genome (“next-generation 

sequencing”) was performed in 

rats after treatment with HE-300. 

This single-molecule sequencing 

technology identified gene clusters 

affected by HE-300 that are involved 

in neuronal function and 

cognitive decline. Second, the gene 

analysis data were instrumental for 

the development of functional assays 

to determine the effect of HE- 

300 on neuronal outgrowth, synaptic 

transmission, and amyloid 

precursor protein (APP) processing. 

Third, several studies using a variety 

of behavioral animal models were 

performed to determine in vivo efficacy. 

HE-300 (1-2 mL/kg) was tested 

in learning and memory models, 

such as spatial memory (T-maze), 

olfactory memory (Social Transmission 

of Food Preference), and methods 

to test memory of fear (Passive 

Avoidance and Contextual Fear 

Conditioning). A synthetic drug for 

the treatment of dementive disorders, 

donepezil, was included in the 

investigations as a positive control. 

Two different species, mice and rats, 

were used in scopolamine-induced 

memory impairment. Scopolamine, 

an acetylcholinesterase inhibitor, 

was given before HE-300 treatment, 

reflecting the dementive state after 

loss of acetylcholine neurons. 

Results 

Our study revealed that the multicomponent 

multitargeted medication, 

HE-300, affects the expression 

of gene clusters associated with synaptic 

function in the rat hippocampus 

2 and 3 days after treatment 

(Figure). The gene networks associated 

with β-amyloid binding, cognition, 

and synaptic plasticity were 

mainly influenced. A significant effect 

on genes for APP and 

β-secretase, 2 proteins involved in 

the pathology of Alzheimer disease, 

could be observed. Furthermore, 

synaptophysin, a synaptic vesicle 

glycoprotein, and synaptotagmin 3, 

a membrane-trafficking protein, 


) Research Highlights 

Figure. Modeling Molecular Networks 1 

The illustration shows the gene network that plays a role in cognitive functions. The 

points marked in green display the genes that are influenced by the multicomponent 

natural medication, HE-300. HE-300 significantly reduces the gene expression of APP 

and BACE, which are responsible for the formation of β-amyloid plaques in Alzheimer 

disease. 

were highly influenced in their expression 

levels, indicating that 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 analysis. 

It is suggested that HE-300 influences 

the generation of β-amyloid 

protein, which hallmarks Alzheimer 

disease. Furthermore, HE-300 induces 

the elongation of dendrites of 

primary hippocampal neurons and 

restores age-related modifications of 

synaptophysin messenger RNA in 

the rat cortex. The behavioral tests 

confirmed the supporting effect of 

HE-300 on cognitive function: HE- 

300 not only significantly improved 

natural forgetfulness, but also scopolamine-induced 

deficits in learning 

and memory tests, such as the 

T-maze, Passive Avoidance, Contextual 

Fear Conditioning, and Social 

Transmission of Food Preference. 

HE-300 attained similar efficacy as 

the gold standard, donepezil, in all 

in vivo test systems and displayed 

beneficial effects on memory function 

in both species used. 

Discussion 

Our study shows that the multicomponent 

multitargeted medication, 

HE-300, enhances and improves 

cognitive functions on genomic, 

functional, and behavioral levels. 

The research results imply that this 

drug is able to influence the development 

and maintenance of dementive 

states. Because of the nature of 

the medication used, the biological 

and clinical effects may arise from 

different targeted biochemical pathways 

involved in cognition and 

learning. Therefore, HE-300 emerges 

as a true disease-modifying agent 

and may be an efficient and alternative 

option in the challenge to understand, 

treat, and defeat diseases 

associated with cognitive dysfunction. 

These data are a good foundation 

for future clinical studies to investigate 

the therapeutic effect of 

HE-300 in humans.| 

Reference 

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

A multicomponent medication (HE-300) 

targets the mechanisms related to Alzheimer 

disease: in-vitro & in-vivo assessment. Poster 

presented at: Neuroscience 2011; November 

12-16, 2011; Washington, DC. 

) 31 


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