Homeopathic Products

• Principle of analogy or Law of Similars• Small or infinitesimal doses (3X-30C)

– Avogadro’s number=6x1023 = ~23X

• Succussion and potentization (see http://www.boiron.com/en/htm/02_medi_homeo/prepa_medi.htm)

• Ultra-high dilution effects• Final product• World Market• USA

Evidence??

• In vitro studies

• Animal studies

• Human studies

• Meta-analyses of human studies

• Implausibility, entrenched skeptics and overenthusiastic zealots

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

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

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

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

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

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

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

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

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

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

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

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

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

Odds ratio for large, high quality trials (the lower the value the higher the benefit):

Homeopath. N=8 OR=0.88

Conventional. N=6 OR=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

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

Probiotics Terms:

•Probiotic – Probiotics 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

Predominant Flora: Stomach

Stomach (0-103 cfu/ml): Gram+ aerobes, Lactobacillus & Streptococcus

Predominant Flora: Vagina

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

Predominant Flora: Urinary Tract

Kidneys: sterile

Bladder: sterile

Urethra: 101-102 E. coli

Predominant Flora: Intestines

Small intestine: Proximal ileum (103-104 cfu/ml) aerobic Gram+Distal ileum (1011-1012 cfu/ml) Gram- anaerobes

Colon (1011-1012 cfu/ml): Bacteroides, Eubacteria, Peptostreptococci, E. coli, Bifidobacterium, Fusobacteria

Functions of Normal Flora

• Digestion

• Production of vitamins

• Mucosal maturation

• Stimulate Immune System

• Attachment

• Intestinal transit

• Colonization resistance

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

Stop Antibiotic

Start Antibiotic

Start yeast or placebo

Stop Study

yeast or placebo continued for 14d

Saccharomyces boulardii and Antibiotic Associated Diarrhea in Hospitalized PatientsN=180; site: University of Washington

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

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 PatientsN=193; site: University of Washington, University of Kentucky

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

Lactobacillus GG and AAD in childrenVanderhoof et al. J. Pediatrics 135:564-568,1999

n=202 outpaitnet children receiving oral antibioitcs diarrhea=26%P, 8%T

D’Souza et al., BMJ 2002;324:1361

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 109 CFU/d) – Placebo

Szajewska H. J Pediatr 2001;138:361-5.

Lactobacillus GG & Prevention of Infantile Nosocomial Diarrhea [Results]

0

5

10

15

20

25

30

35

%

NDRotaviral

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.

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)

Lactobacilli and Pediatric Diarrhea Treatment (L. rhamnosus and L. reuteri in hospital setting)

05

1015

20

2530

3540

45

50

dur (h) d5 dia (%) d5 rota(%) hosp days

treated

control

N=69 Rosenfeldt et al., Pediatr Infec Dis 2002;21:411

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

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

S. boulardii & High Dose Vancomycin for Recurrent C. difficile

Disease

0

10

20

30

40

50

60

% C

DD

re

cu

rre

nc

es

50%

16.7%*

Surawicz CM. Clin Infect Dis 2000;31:1012-7.

S. boulardii (n=18)

Placebo(n=14)

*p=0.05

Other Uses for Probiotics –Limited Data

•Crohn’s Disease

•Ulcerative Colitis

•Pouchitis

•Allergy/Exema

•Irritable Bowel Syndrome Dental caries

•High Cholesterol Urinary Tract Infections

•Helicobacter pylori

• Lactose Intolerance

•Candida vaginal infections

•Bacterial Vaginosis

Table 6.1. Controlled clinical trials evaluating probiotics and Crohn’s disease

 

Probiotic N Result Ref

L. rhamnosus GG 45 10.5% placebo16.6% LGG, ns Prantera 7

L. rhamnosus GG 11 2/4 relapse placebo

3/5 relapse LGG, ns Schultz 8

Saccharomyces boulardii 17 4.6 stools/day placebo

3.3 stools/day in Sb* Plein 9

Saccharomyces boulardii 32 6/16 relapse in mesalamine

1/16 relapse in mesalamine/Sb Guslandi 10

E. coli Nissle 1917 28 7/12 relapse in prednisone 4/12 relapse in prednisone/Ec Malchow 11

 * probiotic significantly better than control, p<0.05; ns=probiotic not significantly different than control

Table 6.2. Clinical trials evaluating probiotics and ulcerative colitis

 

Probiotic N Result Ref

E. coli (Nissle 1917) 116 73% relapse in mesalamine

67% relapse in Ec, ns Rembacken 16

E. coli (Nissle 1917) 103 11% relapse in mesalamine

16% relapse in Ec, ns Kruis 17

E. coli (Nissle 1917) 327 36% relapse in mesalamine

45% relapse in Ec, ns Kruis 18

Saccharomyces boulardii 24 17/24 had successful outcome Guslandi 10

VSL#3 (mix) 20 15/20 had no relapse in 12 months Venturi 19

 

ns= probiotic not significantly different than standard treatment

Lactobacillus GG to PreventInfantile Atopic Disease

• DBPC in Finland• Family history atopic disease

(eczema, allergic rhinitis, asthma)• Mothers randomized:

– Lactobacillus GG (1 x 1010 CFU/d)

– Placebo

• Mothers treated 2-4 weeks before deliveryInfants treated for 6 months

• Followed for 2 years

Kalliomaki M. Lancet 2001;357:1076-9

Lactobacillus GG and Infantile Atopic Disease [Results]

0

5

10

15

20

25

30

35

40

45

50

% 2

yr

old

ch

ildre

n a

top

ic e

cze

ma

23%*

46%

Kalliomaki M. Lancet 2001;357:1076-9

*p=0.008

L. GG (n=64)

Placebo (n=68)

Table 3. Potential Mechanisms of Action of Probiotics

Mechanism Probiotic Microogranism Osbservation Reference

Production of Pathogeninhibitory substances

Lactobacillus reuteri

L. rhamnosus GG

In vitro

In vitro

90

91

Inhibition of pathogenattachment

Saccharomyces boulardii

L. Acidophilus

Human erythrocytes,in vitro

Piglet mucus, invitro

92

93

Inhibition of action ofmicrobial toxins

S. boulardii Rat ileal loops 94

95

96

Stimulation of IgA S. boulardii

L. rhamnosus GG

Rat intestine

Human serum

97

98

Trophic effects onintestinal mucosa

S. boulardii Rat intestineRat intestine

99

100

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

Advantages Disadvantages

Potential Advantages and Disadvantages of Probiotics

Lactobacillus rhamnosus GG Dietary Supplement: Culturelle

Saccharomyces boulardii Dietary Supplement: Florastor

Evidence supporting commercially available (USA) probiotics*

AAD Uneven Good Good Good

Acute Adult

? ? Good Good

Acute pediatric

? ? Good Good

Traveler diarrhea

? ? Fair Fair

C. dif ? ? Limited Good

BV Good** Good*** ? ?

condition L. acidophilus L. reueri LGG Sb

L. acidophilus=Lactinex; L. reueri=Probiotica; LGG=Culturelle; Sb=Florastor; ** strains tested not yet available in USA

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, IBS

•Product selection is very important