1. A Novel Approach in the Treatment of Acute Diarrhea Maria Teresita Andal-Gamutan, MD,FPCP,FPSG,FPSDE

3. FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES

5. DAILY WATER EXCHANGES Sellin JH. Intestinal electrolyte absorption and secretion. In: Feldman M, et al, eds. Sleisenger & Fordtrans Gastrointestinal and Liver Disease . 8 th ed. 2006 FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES Food Fluid intake Water absorption Water secretion (<5ml/kg – children) (< 200 ml – adults) Exogenous sources: (2 liters) Endogenous sources: (7 liters) Saliva Gastric juices Intestinal secretions Pancreatic juices Biliary secretions

6. Duodenum / Jejunum 5.5 liters Endogenous secretions: intestinal, pancreatic, salivary, biliary and gastric juices 7 liters Sellin JH. Intestinal electrolyte absorption and secretion. In: Feldman M, et al, eds. Sleisenger & Fordtrans. Gastrointestinal and Liver Disease . 8 th ed. 2006 Ileum 2 liters Colon/ Rectum 1.3 liters Stool (<5ml/kg – children) (< 200 ml – adults) Food and fluid intake (drinks, meals…) 2 liters FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES DAILY WATER EXCHANGES

7. Glucose, Na + , K + , Cl - , Water WATER FOLLOWS THE MOVEMENT OF ELECTROLYTES AND GLUCOSE Gut lumen Enterocyte FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES Fluid is required to solubilize complex foods in preparation for digestion and to produce an istonoic absorbate consisting of small molecules by which nutrient absorption can take place.

8. Crypt: Secretion Villus Tip: Absorption Farthing M. Digestive Diseases (Review Article) 2006;24:47-58 NORMAL STATE FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES

9. MECHANISMS OF INTESTINAL SECRETION Enterocyte Intestinal fluid secretion results from the active secretion of chloride and bicarbonate ions. Active chloride ion secretion has several components that maintain its secretion from the apical membrane of the enterocyte. The final common secretory pathway occurs through the chloride channel . FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES Farthing M. Digestive Diseases (Review Article) 2006;24:47-58

10. MECHANISMS OF INTESTINAL SECRETION Endogenous secretagogues 5-HT – potent intestinal secretagogue; has a key role in cholera toxin (CT) induced intestinal secretion PGE 2 – potent intestinal secretagogue; CT-induced secretion is inhibited by a COX-2 inhibitor but not by a COX-1 inhibitor Enteric Nervous System FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES Farthing M. Digestive Diseases (Review Article) 2006;24:47-58 Functions independently of the CNS through a variety of neurotransmitters: VIP and enkephalins

11. REGULATION OF INTESTINAL SECRETION Enkephalin - opioid neurotransmitter that binds to delta receptors to reduce the levels of cAMP Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79 VIP (Vasoactive Intestinal Peptide) Prostaglandin E 2 - increase cAMP levels Cyclic AMP - induces secretion of water and electrolytes Enkephalinase - enzyme that degrades enkephalins FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES

12. OPIOIDS AND THEIR RECEPTORS Exogenous - Morphine - Loperamide µ (mu) has inhibitory effects on intestinal smooth muscles  (delta) decreases cAMP formation +++ +++ + + Endogenous - Enkephalins + +++ Farthing M. Digestive Diseases (Review Article) 2006;24:47-58 Opioids Opioid receptors FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES

13. c-AMP ATP VIP Prostaglandins Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79 Enkephalins REGULATION OF WATER AND ELECTROLTYE SECRETION – NORMAL STATE Enkephalinase Delta receptor FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES

14. DIARRHEA

17. Over-secretion of water leads to diarrhea. Hypersecretion DIARRHEA (> 200 grams /day) Secretion Absorption Absorption Normal State DIARRHEA DIARRHEA

21. NORMAL VILLI BLUNTED VILLI ACUTE WATERY DIARRHEA (Infectious) DIARRHEA

22. 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 ACUTE WATERY DIARRHEA (Infectious) DIARRHEA

23. BURDEN OF DIARRHEA

25. More 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 DIARRHEA Harrison’s Principles of Internal Medicine 16 th Edition. Volume 1. 2005

26. 100 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 BURDEN OF DIARRHEA Harrison’s Principles of Internal Medicine 16 th Edition. Volume 1. 2005

27. DIARRHEA IN THE PHILIPPINES *rate/100,000 of sex-specific population 2003 Annual Report Field Health Service Information System, 2000 Philippine Health Statistics, Department of Health, Philippines 2nd leading cause of morbidity (general population) BURDEN OF DIARRHEA

28. MANAGEMENT OF DIARRHEA

31. Fluid and electrolyte replacement are of central importance to all forms of acute diarrhea. MANAGEMENT OF DIARRHEA THE TREATMENT 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. Harrison’s Principles of Internal Medicine 16 th Edition. Volume 1. 2005

32. UNMET MEDICAL NEEDS IN THE TREATMENT OF ACUTE DIARRHEA

33. LIMITATIONS OF CURRENT THERAPY Fluid replacement - No significant reduction of diarrhea - Diarrhea may continue “ Antidiarrheals” - Limited efficacy - CNS effects - Bloating - Rebound constipation Antibiotics - Resistance - Unwanted adverse effects Farthing M. Digestive Diseases (Review Article) 2006;24:47-58 UNMET MEDICAL NEEDS IN THE TREATMENT OF ACUTE DIARRHEA

34. 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 potential Edelman R. Prevention and treatment of infectious diarrhea. Speculations on the next 10 years. Am J Med 1985;78:99-106. UNMET MEDICAL NEEDS IN THE TREATMENT OF ACUTE DIARRHEA THE IDEAL TREATMENT FOR ACUTE DIARRHEA

35. Prevention of Dehydration and Control of Diarrhea Fluid replacement alone Fluid replacement with anti-secretory agent UNMET MEDICAL NEEDS IN THE TREATMENT OF ACUTE DIARRHEA THE IDEAL TREATMENT FOR ACUTE DIARRHEA

36. 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 potential Racecadotril 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 THE IDEAL TREATMENT FOR ACUTE DIARRHEA 1 UNMET MEDICAL NEEDS IN THE TREATMENT OF ACUTE DIARRHEA

38. RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT

39. REGULATION OF INTESTINAL SECRETION Enkephalin - opioid neurotransmitter that binds to delta receptors to reduce the levels of cAMP Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79 VIP (Vasoactive Intestinal Peptide) Prostaglandin E 2 - increase cAMP levels Cyclic AMP - induces secretion of water and electrolytes Enkephalinase - enzyme that degrades enkephalins RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT

40. c-AMP ATP VIP Prostaglandins Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79 Enkephalins REGULATION OF WATER AND ELECTROLTYE SECRETION – NORMAL STATE Enkephalinase Delta receptor RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT

41. c-AMP ATP Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79 Enkephalins Enkephalinase Delta receptor Toxic peptides from viruses / bacteria REGULATION OF INTESTINAL SECRETION - HYPERSECRETORY STATE RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT

42. c-AMP ATP Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79 Enkephalins Enkephalinase Delta receptor Toxic peptides from viruses / bacteria Racecadotril MODE OF ACTION OF RACECADOTRIL - NORMALIZATION OF SECRETION RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT

43. METABOLISM OF RACECADOTRIL Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79 RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT RACECADOTRIL THIORPHAN (potent-enkephalinase inhibitor) (Non-specific esterase) Hydrolysis

44. RACECADOTRIL (pro-drug) THIORPHAN (active metabolite) Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79 RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT METABOLISM OF RACECADOTRIL

45. Enkephalinase inhibition kinetics in healthy volunteers after a single oral dose (100 mg) Lecomte JM. International Journal of Antimicrobial Agents 14 (2000) 81-87 ONSET OF ACTION OF RACECADOTRIL RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT

46. CLINICAL TRIALS

52. Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463-467 CONCLUSION The results of this study provide evidence that racecadotril, as an adjunct to oral rehydration solution, is effective and well tolerated in reducing the duration and severity of acute watery diarrhea in hospitalized infants and children. The antidiarrheal effect is obtained more rapidly than with oral rehydration alone, particularly in infants with rotavirus infection. RACECADOTRIL IN THE TREATMENT OF ACUTE WATERY DIARRHEA IN CHILDREN (Salazar-Lindo et al.) INFANTS AND CHILDREN

58. Cézard JP et al. Gastroenterology 2001;120:799-805. CONCLUSION EFFICACY AND TOLERABILITY OF RACECADOTRIL IN ACUTE DIARRHEA IN CHILDREN ( Cézard et al.) INFANTS AND CHILDREN This study demonstrates the efficacy (up to 50% reduction in stool output) and tolerability of racecadotril as an adjunct therapy to oral rehydration solution in the treatment of severe diarrhea in infants and children.

59. ADULTS A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE DIARRHEA IN ADULTS David Prado for the Global Adult Racecadotril Study Group Scandinavian Journal of Gastroenterology 2002 AIM: to compare the efficacy, safety and tolerability of Racecadotril with those of Loperamide in patients with acute diarrhea.

62. Duration of Diarrhea ADULTS A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE DIARRHEA IN ADULTS (Prado D.) Prado D. Scand J Gastroenterol 2002;37:656-61

63. Treatment-related adverse events with an incidence of more than 1% Prado D. Scand J Gastroenterol 2002;37:656-61 ADULTS A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE DIARRHEA IN ADULTS (Prado D.)

64. ADULTS CONCLUSION Racecadotril resolved the symptoms of acute diarrhea rapidly and effectively, and produced more rapid resolution of abdominal symptoms and less constipation than loperamide. Prado D. Scand J Gastroenterol 2002;37:656-61 A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE DIARRHEA IN ADULTS (Prado D.)

65. RACECADOTRIL’S SAFETY AND TOLERABILITY PROFILE

66. PHARMACOVIGILANCE 13 th Periodic Safety Update Report for Active Substance: Racecadotril. May 2007 Laboratoires Bioprojet Pharma. Adults Infants & Children TOTAL Period covered # of reported adverse events Prevalence March 1993 to March 2007 November 2000 to March 2007 75 30 105 0.00047 % 0.00032 % 0.00042 % Prevalence of adverse events associated with Racecadotril (France) Most common AE for adults and children: “Cutaneous disorders and miscellaneous allergic reactions” SAFETY AND TOLERABILITY

68. E. Coli content of the proximal jejunum (gnotobiotic piglets) Duval-Iflah Y. Et al., Alimentary Pharmacology , 1999; (suppl. 6); 9-14 EFFECTS OF RACECADOTRIL AND LOPERAMIDE ON BACTERIAL PROLIFERATION ( Duval-Iflah Y. et al.) SAFETY AND TOLERABILITY

69. 1. Lecomte JM, Int.J. Of Antimicrobial Agents , 2000; 14:81-87 2. Scwartz J-C, Int.J. Of Antimicrobial Agents , 2000; 14:75-79 3. Duval-Iflah Y. Et al., Alimentary Pharmacology , 1999; (suppl. 6): 9-14 4. Bergmann JF et al, Alimentary Pharmacology and Therapeutics , 1992; 6:305-313 5. Knisely JS, Drug and Alcohol Dependence ,1989;23:143-151 Blood-Brain Barrier Astrocyte processes Lipid soluble transport Carrier-mediated transport Does not induce CNS Toxicity 1,2,3 Racecadotril RACECADOTRIL DOES NOT CROSS THE BLOOD-BRAIN BARRIER Does not impair mental performance 4 Has no potential for abuse or physical dependence 5 SAFETY AND TOLERABILITY

70. Therapeutic Index = LD 50 ED 50 Lecomte JM, Int.J. Of Antimicrobial Agents , 2000; 14:81-87 100 mg TID (adults) 20 times this dose was given to healthy adults with no ill effects Therapeutic dose Relevance of high therapeutic index The higher the Therapeutic Index, the lower the risk of overdose. RACECADOTRIL HAS A HIGH THERAPEUTIC INDEX (median lethal dose) (median effective dose) SAFETY AND TOLERABILITY

74. SUMMARY AND CONCLUSIONS

75. Prevention of Dehydration and Control of Diarrhea Normalization Diarrhea OVERALL CONCLUSIONS RACECADOTRIL IN THE TREATMENT OF ACUTE DIARRHEA Diarrhea Fluid replacement Racecadotril Fluid replacement

76. Loperamide Racecadotril Efficacy variable Motility 1 Secretion 2 Bacterial overgrowth 1 CNS effects 1 Constipation 2 - +++ - - - +++ + + + ++ RACECADOTRIL VERSUS LOPERAMIDE 1. Duval-Iflah Y. Et al., Alimentary Pharmacology , 1999; (suppl. 6); 9-14 2. D. Turck et al. Aliment Pharmacol Ther 1999; 13 (Suppl. 6), 27-32.   OVERALL CONCLUSIONS

77. Active metabolite - Thiorphan Indication - treatment of acute diarrhea Recommended dose - 100 mg capsule every 8 hours Total daily dose: - should not exceed 300 mg Duration of treatment: - should not exceed 7 days Certificate of Product Registration of Racecadotril, Bureau of Food and Drugs, Department of Health. 2005 Racecadotril summary of product characteristics RACECADOTRIL OVERALL CONCLUSIONS

78. Absorption - Rapid Maximum concentration - Maintained for at least four hours Concentration in plasma - Maintained for at least eight hours after administration RACECADOTRIL OVERALL CONCLUSIONS Racecadotril summary of product characteristics

79. Efficacy - together with ORS, significantly reduces stool output and duration of diarrhea in infants and children Safety and tolerability - similar to placebo - fewer adverse events compared with loperamide - does not induce CNS toxicity - high therapeutic index RACECADOTRIL OVERALL CONCLUSIONS

80. Racecadotril: A Novel Approach in the Treatment of Acute Diarrhea

81. Thank you