1. Homeopathic Products Principle of analogy or Law of Similars Small or infinitesimal doses (3X-30C) –Avogadro’s number=6x10 23 = ~23X Succussion and potentization (see http://www.boiron.com/en/htm/02_medi_hom eo/prepa_medi.htm) http://www.boiron.com/en/htm/02_medi_hom eo/prepa_medi.htm Ultra-high dilution effects Final product World Market USA

2. Evidence?? In vitro studies Animal studies Human studies Meta-analyses of human studies Implausibility, entrenched skeptics and overenthusiastic zealots

3. In: Vallance AK. J Alt Compl Med 1998;4:49-76.

6. Linde et al. Lancet 1997;350:834-843

7. Reilly et al. Lancet 1994;344:1601-06

8. Jacobs et al. J Alt Compl Med 2000;6:131-139 n=126 in Nepal

9. Jacobs et al. J Alt Compl Med 2000;6:131-139 n=126 in Nepal Jacobs et al. Pediatrics 1994;93:719-725. N=81 Nicaraqua

10. Jacobs et al. Pediatr Infec Dis 2001;20:177-183. N=75

13. Shang et al. Lancet 2005;366:726-732

17. Odds ratio for large, high quality trials (the lower the value the higher the benefit): Homeopath. N=8 OR=0.88 Conventional. N=6OR=0.58 Conclusions: “clinical effects of homeopathy are placebo effects” Critique: how about giving the OR for all included studies and also the OR for the”higher quality” studies (n=21 for homeopathy and n=9 for conventional). The selection of “clinical topics” for study seem to favor conventional drugs, e.g. respiratory infections. Shang et al. Lancet 2005;366:726-732

20. http://www.homeopathicpharmacy.org/index. htm

22. Probiotics Terms: Probiotic – P robiotics are live microorganisms (bacteria or yeasts) which, when administered in adequate amounts, confer a health benefit on the host Prebiotic - nutritional supplement taken to increase the amounts of beneficial bacterial in the gut or vagina. Example “FOS” (fructose oligosaccharides) Biotherapeutic agent - microorganism used for specific therapeutic activity in humans Nutriceutical - food products with beneficial effects in preventing or treating diseases

23. Predominant Flora: Stomach Stomach (0-10 3 cfu/ml): Gram+ aerobes, Lactobacillus & Streptococcus

24. Predominant Flora: Vagina Vagina: diverse aerobes & anaerobes including Lactobacillus jensenii, Lactobacillus acidophilus, Lactobacillus casei.

25. Predominant Flora: Urinary Tract Kidneys: sterile Bladder: sterile Urethra: 10 1 -10 2 E. coli

26. Predominant Flora: Intestines Small intestine: Proximal ileum (10 3 -10 4 cfu/ml) aerobic Gram+ Distal ileum (10 11 -10 12 cfu/ml) Gram- anaerobes Colon (10 11 -10 12 cfu/ml): Bacteroides, Eubacteria, Peptostreptococci, E. coli, Bifidobacterium, Fusobacteria

27. Functions of Normal Flora Digestion Production of vitamins Mucosal maturation Stimulate Immune System Attachment Intestinal transit Colonization resistance

28. Use of Probiotics for infections in Controlled Trials in Humans Prevention of Diarrhea Antibiotic associated diarrhea infantile diarrhea traveler’s diarrhea Treatment of Diarrhea Clostridium difficile disease HIV associated diarrhea acute diarrhea Prevention of vaginitis Miscellaneous situations

29. Stop Antibiotic Start Antibiotic Start yeast or placebo Stop Study yeast or placebo continued for 14d Saccharomyces boulardii and Antibiotic Associated Diarrhea in Hospitalized Patients N=180; site: University of Washington

30. Surawicz et al., Gastroenterol. 1989;96:981

31. Stop Antibiotic Start Antibiotic Start yeast or placebo Stop Study yeast or placebo continued for 3d Saccharomyces boulardii and Beta lactam Antibiotic Associated Diarrhea in Hospitalized Patients N=193; site: University of Washington, University of Kentucky

32. McFarland et al. Am J Gastroenterol 1995;90:439- 448

33. Lactobacillus GG and AAD in children Vanderhoof et al. J. Pediatrics 135:564-568,1999 n=202 outpaitnet children receiving oral antibioitcs diarrhea=26%P, 8%T

34. D’Souza et al., BMJ 2002;324:1361

35. Lactobacillus GG & Prevention of Infantile Nosocomial Diarrhea [Methods] DBPC in Poland 81 hospitalized children (1-36 months old) No diarrhea on admission Randomized during stay: – L. GG (12 x 10 9 CFU/d) – Placebo Szajewska H. J Pediatr 2001;138:361-5.

36. Lactobacillus GG & Prevention of Infantile Nosocomial Diarrhea [Results] 6.7* 2.2* 33.3 16.7 *p<0.05 L. GG (n=45) Placebo (n=36) Szajewska H. J Pediatr 2001;138:361-5.

37. Probiotic Prevention of Traveler’s Diarrhea NYC travelers to developing countries; n=225 (Hilton et al. J. Travel Med 1997;4:41-43) 7.4%/exposure day for placebo 3.9%/exposure day for Lactobacillus GG (p=0.05) Austrian travelers to Turkey; n-1016 (Kollaritsch et al. Fortschr Med 1993;111:152-156) 39.1% placebo 28.7% S. boulardii (p=0.02)

38. Lactobacilli and Pediatric Diarrhea Treatment (L. rhamnosus and L. reuteri in hospital setting) N=69 Rosenfeldt et al., Pediatr Infec Dis 2002;21:411

39. Huang, et al., Digestive Diseases and Sciences, Vol.47, No. 11 (Nov 2002)

43. McFarland et al., JAMA; 271, 1913-1918, (1994).

44. S. boulardii & High Dose Vancomycin for Recurrent C. difficile Disease 50% 16.7% * Surawicz CM. Clin Infect Dis 2000;31:1012-7. S. boulardii (n=18) Placebo (n=14) *p=0.05

45. Other Uses for Probiotics – Crohn’s Disease Ulcerative Colitis Pouchitis Allergy/Exema Irritable Bowel SyndromeDental caries* High Cholesterol*Urinary Tract Infections* Helicobacter pylori* Lactose Intolerance Candida vaginal infections* Bacterial Vaginosis * Limited evidence

46. Table 6.1. Controlled clinical trials evaluating probiotics and Crohn’s disease Probiotic N Result Ref L. rhamnosus GG 4510.5% placebo 16.6% LGG, ns Prantera 7 L. rhamnosus GG112/4 relapse placebo 3/5 relapse LGG, ns Schultz 8 Saccharomyces boulardii174.6 stools/day placebo 3.3 stools/day in Sb* Plein 9 Saccharomyces boulardii 326/16 relapse in mesalamine 1/16 relapse in mesalamine/Sb Guslandi 10 E. coli Nissle 1917287/12 relapse in prednisone 4/12 relapse in prednisone/EcMalchow 11 * probiotic significantly better than control, p<0.05; ns=probiotic not significantly different than control

47. Table 6.2. Clinical trials evaluating probiotics and ulcerative colitis ProbioticNResult Ref E. coli (Nissle 1917)11673% relapse in mesalamine 67% relapse in Ec, ns Rembacken 16 E. coli (Nissle 1917)10311% relapse in mesalamine 16% relapse in Ec, nsKruis 17 E. coli (Nissle 1917)32736% relapse in mesalamine 45% relapse in Ec, nsKruis 18 Saccharomyces boulardii2417/24 had successful outcomeGuslandi 10 VSL#3 (mix)2015/20 had no relapse in 12 monthsVenturi 19 ns= probiotic not significantly different than standard treatment

48. Lactobacillus GG to Prevent Infantile Atopic Disease DBPC in Finland Family history atopic disease (eczema, allergic rhinitis, asthma) Mothers randomized: – Lactobacillus GG (1 x 10 10 CFU/d) – Placebo Mothers treated 2-4 weeks before delivery Infants treated for 6 months Followed for 2 years Kalliomaki M. Lancet 2001;357:1076-9

49. Lactobacillus GG and Infantile Atopic Disease [Results] 23% * 46% Kalliomaki M. Lancet 2001;357:1076-9 *p=0.008 L. GG (n=64) Placebo (n=68)

51. Multiple Mechanisms of Action Resistance is Infrequent Use May Reduce Exposure to Antibiotics Delivery of Microbial Enzymes Well Tolerated Benefit to Risk Ration is Favorable Few Controlled Trials Persistence Possible Translocation Possible Transfer of Resistance Plasmids? Infection Possible Quality Control Issues Regulatory Issues in USA AdvantagesDisadvantages Potential Advantages and Disadvantages of Probiotics

52. Evidence supporting commercially available (USA) probiotics* AADUnevenGood Acute Adult ??Good Acute pediatric ??Good Traveler diarrhea ??Fair C. dif??LimitedGood BVGood**Good***?? condition L. acidophilus L. reueri LGGSb L. acidophilus=Lactinex; L. reueri=Probiotica; LGG=Culturelle; Sb=Florastor; ** strains tested not yet available in USA

53. Probiotics Summary Living microorganisms with multiple mechanisms of action Good safety profile Some applications to prevent and treat infectious diseases An alternative to antibiotics in some situations May have other applications, e.g. allergy, cancer, colitis, Crohn’s Disease, Ulcerative Colitis, IBS Product selection is very important