Hidrasec Adults 9-11-07

A Novel Approach in the Treatment of Acute DiarrheaMaria Teresita Andal-Gamutan, MD,FPCP,FPSG,FPSDE

INTRODUCTION

PRESENTATION OUTLINEFluid and electrolyte balance and diarrhea Burden of diarrhea and its management Racecadotril an intestinal antisecretory agent Clinical trials Safety and tolerability profile Conclusions

FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES

How much fluid passes through the intestine each day? A. 2 Liters B. 5 Liters C. 7 Liters D. 9 Liters

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FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES

DAILY WATER EXCHANGESWater absorption Exogenous sources: (2 liters) Food Fluid intake Endogenous sources: (7 liters) Saliva Gastric juices Intestinal secretions Pancreatic juices Biliary secretions

Sellin JH. Intestinal electrolyte absorption and secretion. In: Feldman M, et al, eds. Sleisenger & Fordtrans Gastrointestinal and Liver Disease. 8th ed. 2006

Water secretion (

DIARRHEA

DIARRHEAPassage of abnormally liquid or unformed stools at an increased frequency Stool weight > 200 grams / day

Harrisons Principles of Internal Medicine 16th Edition. Volume 1. 2005

DIARRHEA

DIARRHEAOver-secretion of water leads to diarrhea.

Secretion

Absorption

Hypersecretion Absorption

Normal State DIARRHEA(> 200 grams /day)

Its considered acute diarrhea if the duration is? A. < 2 weeks B. 2 4 weeks C. > 4 weeks

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4 weeks duration - needs further evaluation to exclude serious underlying pathology - usually non-infectious in originHarrisons Principles of Internal Medicine 16th Edition. Volume 1. 2005

DIARRHEA

ACUTE WATERY DIARRHEA (Infectious)Bacteria: - ETEC - V. cholerae, V. parahaemolyticus - Aeromonas, Plesiomonas, Shigella, Salmonella, EHEC Viruses: - Rotavirus - Enteric adenovirus (types 40 & 41) - SRSVs Protozoa: - C. parvum, G. intestinalis Duration: < 14 days; lasts several hours or days

1,2

1. Farthing M. Digestive Diseases (Review Article) 2006;24:47-58 2. The Treatment of Diarrhea: A manual for physicians and other senior health workers, Department of Child and Adolescent Health and Development, World Health Organization 2005

DIARRHEA

ACUTE WATERY DIARRHEA (Infectious)

NORMAL VILLI

BLUNTED VILLI

DIARRHEA

ACUTE WATERY DIARRHEA (Infectious)Destruction of enterocytes: EIEC, rotavirus, shigella

Defective absorption

Hypersecretion: Vibrio cholerae, rotavirus, ETEC, shigella

IMBALANCE BETWEEN ABSORPTION AND SECRETION

The Treatment of Diarrhea: A manual for physicians and other senior health workers, Department of Child and Adolescent Health and Development, World Health Organization 2005

BURDEN OF DIARRHEA

How many cases of Diarrhea do you see in your clinic? A. 1 patient a week B. 3 4 patients a week C. > 7 patients a week0%k w ee w

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BURDEN OF DIARRHEA

BURDEN OF DIARRHEAMore than 1 billion people suffer one or more episodes of acute diarrhea each year. Because of poor sanitation and more limited access to health care, acute infectious diarrhea remains one of the most common causes of mortality in developing countries.


BURDEN OF DIARRHEA

BURDEN OF DIARRHEA100 million people affected annually in the US - nearly 50% must restrict activities - 10% consult physicians - 250,000 require hospitalization - roughly 3,000 die (primarily the elderly)


BURDEN OF DIARRHEA

DIARRHEA IN THE PHILIPPINES2nd leading cause of morbidity (general population)10007 7 0 .9 M a le

800

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6 9 5 .0

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F e m a le 6 3 9 .6 6 7 7 .0 5 0 3 .1 4 2 0 .7 3 2 5 .4

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*rate/100,000 of sex-specific population

2003 Annual Report Field Health Service Information System, 2000 Philippine Health Statistics, Department of Health, Philippines

MANAGEMENT OF DIARRHEA

A. B. C. D. E.

What Drugs/Management do you utilized in your practice?ORS Antibiotics Loperamide Racecadotril Others

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APPROACH TO THE PATIENT WITH ACUTE DIARRHEAThe decision to evaluate acute diarrhea depends on its severity and duration, and on various host factors.Indications for evaluation: profuse diarrhea with dehydration grossly bloody stools fever 38.5oC duration > 48 hours without improvement new community outbreaks severe abdominal pain in patients > 50 years, and elderly or immunocompromised patients



THE TREATMENT OF ACUTE DIARRHEAFluid and electrolyte replacement are of central importance to all forms of acute diarrhea.

In moderately severe, non-febrile and non-bloody diarrhea, antimotility antisecretory agents can be useful adjuncts to control symptoms. Judicious use of antibiotics is appropriate in selected instances of acute diarrhea.


UNMET MEDICAL NEEDS IN THE TREATMENT OF ACUTE DIARRHEA


LIMITATIONS OF CURRENT THERAPYFluid replacement Antidiarrheals - No significant reduction of diarrhea - Diarrhea may continue - Limited efficacy - CNS effects - Bloating - Rebound constipation - Resistance - Unwanted adverse effects

Antibiotics

Farthing M. Digestive Diseases (Review Article) 2006;24:47-58


THE IDEAL TREATMENT FOR ACUTE DIARRHEAinhibits fluid secretion by intestinal mucosa has a rapid onset of action has limited constipating effects has a high therapeutic index has minimal central nervous system effects has low abuse potential

Edelman R. Prevention and treatment of infectious diarrhea. Speculations on the next 10 years. Am J Med 1985;78:99-106.


THE IDEAL TREATMENT FOR ACUTE DIARRHEAPrevention of Dehydration and Control of Diarrhea

Fluid replacement with Fluid replacement alone anti-secretory agent


THE IDEAL TREATMENT FOR ACUTE DIARRHEA1

inhibits fluid secretion by intestinal mucosa has a rapid onset of action has limited constipating effects has a high therapeutic index has minimal central nervous system effects has low abuse potentialRacecadotril was developed specifically with these characteristics in mind.2

1. Edelman R. Prevention and treatment of infectious diarrhea. Speculations on the next 10 years. Am J Med 1985;78:99-106. 2. Lecomte JM. International Journal of Antimicrobial Agents 14 (2000) 81-87

Are you aware that Racecadotril was already in the market in late 90s?

A. Yes B. No

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RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT


REGULATION OF INTESTINAL SECRETIONEnkephalin - opioid neurotransmitter that binds to delta receptors to reduce the levels of cAMP

Enkephalinase - enzyme that degrades enkephalins VIP (Vasoactive Intestinal Peptide) Prostaglandin E2 Cyclic AMP - increase cAMP levels

- induces secretion of water and electrolytes

Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79


REGULATION OF WATER AND ELECTROLTYE SECRETION NORMAL STATE

Delta receptor

c-AMPATPEnkephalins

VIP Prostaglandins

Enkephalinase



REGULATION OF INTESTINAL SECRETION - HYPERSECRETORY STATE

Delta receptor

c-AMPToxic peptides from viruses / bacteria

ATPEnkephalins

Enkephalinase



MODE OF ACTION OF RACECADOTRIL NORMALIZATION OF SECRETION

Delta receptor

c-AMPToxic peptides from viruses / bacteria

ATPEnkephalins Racecadotril

Enkephalinase



METABOLISM OF RACECADOTRILH 2O H 2O R A C E C A D O T R IL R A C E C A D O T R IL H 2O H 2O

A c - S - C H RACECADOTRIL2 - C O 2 - B z (B z )-C O -N H -C H A c - S - C H (B z ) - C O - N H - C H 2- C O 2- B z(N o n -sp e c if e st e r a se ) (Non-specifici cesterase) (N o n - sp e c if i c e st e r a se )

Hydrolysis

H S - C H (B z )-C N H -C H 2-C O 2-H THIORPHANO -(potent-enkephalinase2 T h i o r p h a n ( p o t e ninhibitor)h a l i n a s2e i n h i b i t o r ) t -e n k e p T h i o r p h a n (p o t e n t - e n k e p h a li n a se in h ib it o r )

H S-C H (B z )-C O -N H -C H -C O -H



METABOLISM OF RACECADOTRIL

O N H S O H 3C H O O

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h y d r o ly sisH HS

N H O

OH

RACECADOTRIL (pro-drug)

THIORPHAN (active metabolite)



ONSET OF ACTION OF RACECADOTRILEnkephalinase inhibition kinetics in healthy volunteers after a single oral dose (100 mg)500

E n k e p h a lin a se a ct iv it y ( p m o l /m l / m i n u t e )

400

300 ** 200 ** 100 ** 0 ** * * p

Hidrasec Adults 9-11-07

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