NEW THERAPIES FOR GI DISORDERS
| THE ROLE OF PROBIOTICS IN GI DISORDERS —Martin H. Floch, MD, Clinical Professor of Medicine, Yale University
School of Medicine, New Haven, CT
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| Use of probiotics: definition—live microbial organisms ingested in foods or supplements that benefit host; come from
humans (part of anaerobic flora); benefits—improve immune response; prevent and shorten infections; able to get
through stomach (not affected by gastric acid, bile acids, and pancreatic enzymes); once in ileum, have adherent substances
that allow them to live in mucus layer, and produce antibacterial substances antagonistic to carcinogenic and
pathogenic flora; healthy individuals have own probiotic flora; fiber—fermented by probiotics in colon; not all fibers
same; soluble (fermented) and insoluble (not fermented); soluble fibers found in fruits and vegetables; produce short-
chain fatty acids (butyric, propionic, and acetic); butyric acid main fuel for colon; other short-chain fatty acids produced
in smaller amounts
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| Literature: 20 organisms used in studies (1980-2004); bacterial flora in humans stable but varies with diet, eg, vegetarian
vs meat eating; probiotic organisms include Bifidobacterium, Lactobacillus, and Streptococcus; Saccharomyces (yeast)
listed as probiotic organism
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| Guidelines for probiotic use: recommendations—A (strong evidence in literature); B (suggestive evidence); C (too
few studies to be certain)
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| In childhood and adult diarrhea: meta-analysis and literature analysis show strong evidence for use (A recommendation);
organisms include Lactobacillus reuteri, Lactobacillus rhamnosus GG, Lactobacillus casei, Lactobacillus acidophilus
, Saccharomyces, and Bifidobacterium; use in childhood diarrhea—19 randomized studies and 1 open trial plus 1
meta-analysis; probiotics administered to children with acute diarrhea in developed countries safe and shorten duration of
diarrhea by ≈1 day (30 hr); effect seen mostly in young children when given early at doses of at least 1010 organisms; evidence
best in viral (ie, rotavirus) infections and less in bacterial infections; stimulates immune response in viral infections;
diarrhea in adults—7 studies; shorter course demonstrated; variety of doses and clinical conditions; no meta-
analysis (B recommendation)
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| Antibiotic-associated diarrhea: Clostridium difficile proven responsible for 26% to 50% of cases (number probably
higher, but diagnosis often missed); typical scenario of patient on antibiotics; clindamycin originally implicated, but now
any antibiotic may precipitate syndrome; patient develops diarrhea and, if persistent, sigmoidoscopy reveals typical colitis
with ulcers and membranes; onset of watery diarrhea; toxin A and toxin B found in stool; C difficile—anaerobic
spore-forming rod; ubiquitous; not always pathogen; carried by 20% of infants and 3% of adults; community-associated
diarrhea found in 7 of 100,000 ambulatory patients and in 20 of 100,000 hospital patients; risks include taking antibiotics
(alter intestinal flora) and being hospital patient (setting exposure for patient); treatment includes stopping antibiotic, providing
supportive care, and confirming diagnosis; metronidazole (first-line therapy) given orally or intravenously (IV) for
10 to 14 days; if drug intolerance occurs or symptoms persist, give vancomycin; recurrence or relapse—8% to 50% of
cases; single recurrence usually followed by increase in recurrences, and refractory cases (65%); risks include older individual,
intensive care unit (ICU) patient, new antibiotics, albumin <2.5 g/dL; hospital stay longer than 16 to 30 days, and
new strains (epidemic outbreaks of C difficile B1/NAP1); literature—13 controlled studies (8 definitely positive and 5
negative or equivocal); meta-analysis of 9 studies (1214 patients) revealed probiotics effective; doses and products varied,
but Saccharomyces boulardii most effective; L rhamnosus GG also effective; recommendation A (strong evidence) for
use; L rhamnosus and S boulardii confirmed as adjuvant therapy in recent meta-analysis of 25 studies; S boulardii sold as
Florastor; L rhamnosus GG no longer available (but in drink for children called Danimals); S boulardii—yeast; has
trophic effect on enterocytes; stimulates effect of IgA secretion; reduction in intestinal nitric oxide production; eradicates
spores; in initial study of 180 participants, 1 g/day used at onset of antibiotic use and stopped after 2 wk; 21.8% of controls
developed diarrhea and only 9.5% of those treated; L acidophilus (Lactinex)—ineffective; L rhamnosus GG— varied
effects; effective in yogurt in those with diarrhea caused by erythromycin; effective in children; effective in open study;
ineffective for prevention in 267 hospital patients in controlled study
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| Treatment of recurrence: repeated doses of metronidazole; pulsed or tapered doses of vancomycin; rifampin; nitazoxinide;
combined antibiotics; remove contacts; adjuvant probiotic
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| Inflammatory bowel disease (IBD): pouchitis—after ileoanal bypass, reduced counts of lactobacilli and bifidobacteria
in stool; study by Gionchetti—random trial of 40 participants in remission; used probiotic VSL#3, 6 g/day for 9 mo;
300 billion organisms/g; all 20 patients who did not receive VSL relapsed (only 3 in 20 treated relapsed); strong evidence
for use of VSL#3 in prevention and treatment (Recommendation A); costly ($3 per pill)
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| Immunologic modulation: classic experiments by Isolauri in Finland showed increase in IgA in rotavirus infections;
numerous animal experiments and analysis of literature on humans show increase in IgA, stimulation of dendritic cells,
increase in interleukin (IL)-10, and barrier protection; B recommendation (too few clinical studies); definitely stimulates
immune process; organisms include L acidophilus, Lactobacillus plantarum, Bifidobacterium lactis, L casei, L rhamnosus
GG, and Lactobacillus johnsonii; food company manufacturing drink with L casei (DanActive); for radiation-induced diarrhea,
vaginosis, ulcerative colitis (UC), IBD, and irritable bowel syndrome (IBS), C recommendation (not enough literature)
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| Radiation-induced diarrhea: only 3 studies in literature (all effective); in one study, participants given large doses of
VSL at start of irradiation (3 tablets of 450 billion organisms); only 8 of 95 patients developed diarrhea, compared to 52
of 95 controls; more studies needed
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| Helicobacter pylori: worldwide problem; only 8 probiotic studies with varied protocols; 4 used L johnsonii in milk vehicle;
gastritis and bacterial load decreased but none cured; however, reports of higher cure rate when adjuvant probiotics
used; when probiotics used, lesser number of recoverable H pylori; of questionable benefit at present; meta-analysis of 6
studies and 180 patients showed no disappearance with probiotic only
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| Probiotics in UC: Escherichia coli vs mesalamine; reported in Lancet in 1999; random study in mild, moderate, and severe
UC; 116 participants treated with prednisone and when in remission, treated with 1.2 g mesalamine or 2 capsules of
nonpathogenic E coli; no difference in remission
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| Probiotics in IBD: 10 controlled studies (as of 2004; 3 in chronic UC [CUC], 4 in Crohn’s disease, and 3 in pouchitis);
varied organisms and varied doses; for CUC, E coli Nissle strain effective in all 3 studies (E coli Nissle not produced in
United States); for Crohn’s disease, Saccharomyces found effective in 2 studies and VSL#3 in 1 study; L rhamnosus GG
ineffective; for pouchitis, VSL#3 found effective in all 3 studies; conclusion—probiotics effective but with varying responses;
not enough literature to make firm recommendations; strong evidence (recommendation A) for use in prevention
and treatment of pouchitis, but C recommendation for UC and Crohn’s disease
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| Probiotics in IBS: study by Nobaek—randomized trial of 60 participants given 400 mL of 50 million Lactobacillus
plantarium; L plantarium recovered from feces; decrease in flatulence and pain in treated patients; authors felt strongly
that results significant; in all IBS studies so far, symptoms measured (but difficult to interpret); 6 other controlled studies
(1985-2004; 3 positive and 3 negative); no conclusions drawn
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| Bifidobacterium infantis: randomized placebo-controlled study showed increase in cytokines, although numbers too few
to be significant; 3 doses used (106 , 108 , and 1010 ); 108 dose effective by Symptom Global Assessment; 106 and 1010 ineffective;
found product not formulated properly
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| Dose of probiotics: important; varies greatly with product; live- and active-culture yogurts must contain >108 organisms/g;
L rhamnosus GG tablets have 1010 ; VSL#3 has 300 to 450 billion organisms/packet; over-the-counter products
have unknown quality and quantity; in Crohn’s disease studies, 12 billion organisms of L rhamnosus GG did not prevent
recurrence in postoperative placebo-controlled study; 300 billion Saccharomyces effective; 3 billion of 8 organisms in
VSL#3 effective
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| Probiotic products marketed to physicians: L rhamnosus GG in Danimals; S boulardii (Florastor); L acidophilus, L
paracasei, Bifidobacterium, and Streptococcus thermophilus in Flora-Q (no clinical studies); responses vary with different
diseases and different species and strains
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| HCV FUTURE THERAPIES —Fred Poordad, MD, Chief, Hepatology and Liver Transplantation, Comprehensive Transplant
Center, Cedars-Sinai Medical Center, Los Angeles, CA
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| Update on therapy: pegylated interferon (PEG-IFN) and ribavirin will be used for long time to treat hepatitis C virus
(HCV); new concept rapid viral response (RVR); should check 4-wk polymerase chain reaction (PCR); in 12-wk PCR, if
2-log drop present in genotype-1 patient, but patient still viremic (partial early virologic response [EVR]), patient has
<20% chance of sustained virologic response (SVR); if virus completely undetectable at 12 wk, patient has 80% chance
of SVR (good negative predictor because if 2-log drop absent, SVR zero); look at details of EVR (if still viremic, chances
not good); some physicians extending therapy >1 yr in these individuals; study—500 participants; if negativity not
achieved at 4 wk, therapy given for 1 or 1.5 yr; results showed 1.5 yr of therapy better in genotype 1 for participants not
negative at 4 wk; another study showed that if negative at 8 wk, 1 yr as good as 1.5 yr of therapy; if not negative at 12 wk,
extended therapy of benefit; can shorten therapy in small subset of genotype-1 patients; if patient starting out with
<600,000 IU of virus, treated, and negative (<50 IU of virus) at 4 wk, 24 wk of therapy gives same response as full year;
with these patients, therapy not stopped at 6 mo, but dose reduced if side effects present
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| Differences between genotypes 2 and 3: genotype 2—if negativity achieved at 4 wk, and patient treated for 12 to 14
wk, 85% SVR obtained (90% with 6 mo; 5% SVR lost by truncating therapy); if negativity not achieved at 4 wk and
treated for 6 mo, 70% SVR obtained; genotype 3—negative at 4 wk (RVR), SVR with shorter therapy still as good as
with genotype 2 (85%); with no RVR and 6 mo of therapy, SVR worse than for genotype 1; slow-responding genotype-3
patient different from slow-responding genotype-2 patient, but rapid-responding genotype-2 and -3 patients behave same;
study—retrospective; in genotype-2 and -3 patients who did not achieve RVR and treated for 6 mo or 1 yr with low-dose
ribavirin, relapse rate only 4% (if treated for 1 yr) and SVR ≈10% higher; prospective study not yet done
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| Retreatment of nonresponders: study—400 participants, genotype 1, treatment-naive, with high viral load; given
PEG-IFN á-2a (Pegasys) vs PEG-IFN á-2b (Peg-Intron) and same dose of ribavirin for 12 wk; viral response exactly
same; undetectability at 4 wk and 12 wk same (slightly higher with Peg-Intron but not statistically different); study—
1000 participants; Peg-Intron nonresponders treated with 360 µg of Pegasys for 12 wk, followed by 1 or 1.5 yr of therapy
or standard dose of Pegasys for 1 or 1.5 yr; SVR 14% and 16% in group who received treatment for 1.5 yr; speaker believes
PEG-IFN failure should not be retreated with another PEG-IFN; maintenance therapy—4-yr trial comparing 90 µg
of Pegasys to nothing; death, decompensation, liver cancer, and fibrosis identical; however, alanine aminotransferase
(ALT) and viral RNA levels dropped significantly in treatment group
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New Therapies
| Background: structural proteins actual body of virus; nonstructural proteins responsible for assembling virus; NS5B region
polymerase responsible for replicating RNA; replicon system—in vitro system; incomplete piece of virus (has some, but not
all, of nonstructural elements); during testing of new drugs, if antiviral effect seen in replicon, human testing begun
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| Nucleoside and nonnucleoside inhibitors: inhibit NS5B polymerase; NM283 (valopicitabine; made by Idenix)—
studies originally done in vitro with parent compound (NM107); polymerase inhibitors in nonresponders to PEG-IFN and
ribavirin, SVR zero; had side effects of nausea, vomiting, and diarrhea; not approved by Food and Drug Administration;
end-of-treatment results in naive patients not promising; R1626 (Roche)—doses of 3000 or 4500 mg as monotherapy for 15
days, 3.5-log decline; had too many side effects, so can study only 1500-mg dose, which resulted in 1-log decline; ongoing
phase 1 study using 1500 mg bid with half-dose or full dose of Pegasys for 24 wk; HCV-796 (Wyeth)—dose-finding study
of 100 to 1000 mg with PEG-IFN; showed that non-1 genotypes had response; protease inhibitors only for genotype 1; side
effect profile included possible cardiac toxicity (put on hold); polymerase inhibitors fairly weak, compared to protease inhibitors
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| Protease inhibitors: 5 compounds; telaprevir and bocepravir going into phase 3 studies; proteases and polymerases—
proteins produced by nonstructural component of gene; proteases responsible for activating downstream nonstructural
proteins, cleaving them, and making them active; inhibiting protease inhibits virus assembly; inhibiting polymerase inhibits
RNA replication; viral NS3 protease inhibits human immune system, so dual benefit from inhibition, ie, improving
innate immune response and decreasing viral replication, possibly making patients more responsive to IFN; VX-950
(telaprevir)—as monotherapy, resistance developed in 1 to 2 wk; phase 2 trials for treatment-naive genotype-1 group;
drug only approved for 12 wk; if patient not virus-negative at 4 wk, must stop drug; 79% of patients PCR-negative at 4
wk on telaprevir, PEG-IFN, and ribavirin, compared to 11% with PEG-IFN and ribavirin group; at 12 wk, 40% negative
in PEG-IFN and ribavirin group and 70% negative in triple-regimen group; of 9 in triple-regimen, group who received
full 12 wk of therapy, 3 relapsed immediately and 6 achieved SVR (35%; same as with 1 yr of PEG-IFN and ribavirin);
more data upcoming; rash reason for most discontinuation (53% overall); SCH 503034 (bocepravir; Schering-Plough)—
in vitro, potent compound (stronger than VX-950); good oral bioavailability; dosed q8h; good dose-response curves;
only effective dose 800 mg; results showed 79% SVR in genotype-1 treatment-naïve participants given bocepravir for 12
wk vs 34% in group given PEG-IFN and ribavirin; in nonresponders, 14% SVR vs 2% in control group; ITMN-191 from
InterMune—protease inhibitor; just starting clinical trial; highly potent; NS3 region confers certain point mutations that
are cross-resistant; protease inhibitors have cross-resistance; polymerase inhibitors have own resistance issues; no cross-
resistance between protease inhibitors and polymerase inhibitors; little cross-resistance between polymerase inhibitors
(combination of polymerase inhibitors possible)
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Suggested Reading
Boyle RJ et al: Probiotic use in clinical practice: what are the risks? Am J Clin Nutr 83:1256, 2006; Buts JP et al: Effects
of Saccharomyces boulardii on intestinal mucosa. Dig Dis Sci 51:1485, 2006; Canani RB et al: Probiotics for treatment of
acute diarrhoea in children: randomised clinical trial of five different preparations. BMJ 335:340, 2007; Drusano GL et al:
A 48-week duration of therapy with pegylated interferon alpha 2b plus ribavirin may be too short to maximize long-term response
among patients infected with genotype-1 hepatitis C virus. J Infect Dis 189:964, 2004; Durai R: Epidemiology, pathogenesis,
and management of Clostridium difficile infection. Dig Dis Sci 52:2958, 2007; Eutamene H et al: Role of
probiotics in correcting abnormalities of colonic flora induced by stress. Gut 56:1495, 2007; Fiocchi C: Probiotics in inflammatory
bowel disease: yet another mechanism of action? Gastroenterology 131:2009, 2006; Friedrich MJ: Benefits of gut
microflora under study. JAMA 299:162, 2008; Hickson M et al: Use of probiotic Lactobacillus preparation to prevent diarrhoea
associated with antibiotics: randomised double blind placebo controlled trial. BMJ 335:80, 2007; Epub 2007 Jun 29. McFarland
LV: Diarrhoea associated with antibiotic use. BMJ 335:54, 2007; Patel K et al: Current therapies for chronic
hepatitis C. Drug combination achieves sustained response in more than half of patients. Postgrad Med 114:48, 2003;
Pawlotsky JM et al: The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology 132:1979,
2007; Rossi SJ et al: New developments in the treatment of hepatitis C. Gut 52:756, 2003; Sarrazin C et al: SCH
503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders. Gastroenterology
132:1270, 2007; Sheu BS et al: Pretreatment with Lactobacillus- and Bifidobacterium-containing yogurt can improve
the efficacy of quadruple therapy in eradicating residual Helicobacter pylori infection after failed triple therapy. Am J Clin
Nutr 83:864, 2006; Wilcox MH et al: Probiotics and diarrhea: Data are not widely applicable. BMJ 335:171, 2007.
Educational Objectives
| The goal of this program is to improve the management of gastrointestinal (GI) disorders and hepatitis C. After hearing and
assimilating this program, the clinician will be better able to:
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 | 1. Determine whether use of probiotics is helpful in a specific GI disorder by using current recommendations.
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| 2. Recognize the risk factors for relapse or recurrence of Clostridium difficile infection.
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| 3. Utilize appropriate doses of probiotics.
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| 4. Differentiate polymerase inhibitors from protease inhibitors in the treatment of hepatitis C.
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| 5. Describe drugs currently in development for treatment of hepatitis C.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts
of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health
care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Floch has
received grant and research support from Roche, Schering Plough, Valent, Idenix, Novartis, Intarcia, Human Genome Sciences,
BMS, Gilead, Arbios, NIH, and Vertix, is a consultant-advisor for Schering Plough, Gilead, Valeant, Idenix, Novartis,
and Vertex, and is on the Speakers’ Bureaus of BMS, Gilead, Schering, and Valeant. Dr. Poordad has received grant and
research support from Roche, Schering Plough, Vertex, Idenix, Novartis, HGS, Valent, Intarcia, GSK, Merck, and Arbios,
and is on the Speakers’ Bureaus of Schering, Gilead, Valent, Idenix, and Novartis. The planning committee reported nothing
to disclose.
Acknowledgements
Dr. Floch was recorded at the 17th Annual GI Symposium, held November 3, 2007, in New Bruswick, NJ, and sponsored
by the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Division of
Gastroenterology/Hepatology. Dr. Poordad was recorded at the 8th Annual Update in Gastroenterology, held October
26-28, 2007, in La Quinta, CA, and sponsored by Cedars-Sinai Medical Center, Division of Gastroenterology. The
Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
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