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Racecadortril

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for management of diarrhoea

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Racecadortril

  1. 1. Racecadortril Management of diarrhea
  2. 2. 2 Diarrhea
  3. 3. Fluid and electrolyte balance and diarrhea Burden of diarrhea and its management Racecadotril – an intestinal antisecretory agent Clinical trials Safety and tolerability profile Conclusions Presentation outline INTRODUCTION
  4. 4. Fluid and electrolyte balance in the intestines
  5. 5. How much fluid passes through the intestine each day? A. 2 Liters B. 5 Liters C. 7 Liters D. 9 Liters 2 Liters 5 Liters 7 Liters 9 Liters 0% 0%0%0%
  6. 6. Daily water exchanges Food Fluid intake Water absorption Water secretion (<5ml/kg – children) (< 200 ml – adults) Endogenous sources: (7 liters) Saliva Gastric juices Intestinal secretions Pancreatic juices Biliary secretions Sleisenger & Fordtrans Gastrointestinal and Liver Disease. 8th ed. 2006
  7. 7. Duodenum / Jejunum 5.5 liters Endogenous secretions: intestinal, pancreatic, salivary, biliary and gastric juices 7 liters Ileum 2 liters Colon/ Rectum 1.3 liters Stool (<5ml/kg – children) (< 200 ml – adults) Food and fluid intake (drinks, meals…) 2 liters Daily water exchanges Sleisenger & Fordtrans Gastrointestinal and Liver Disease. 8th ed. 2006
  8. 8. Glucose, Na+, K+, Cl-, Water Water follows the movement of electrolytes and glucose Gut lumen Enterocyte 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.
  9. 9. Crypt: Secretion Villus Tip: Absorption Normal state Farthing M. Digestive Diseases (Review Article) 2006;24:47-58
  10. 10. 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
  11. 11. Mechanisms of intestinal secretion Endogenous secretagogues 5-HT – potent intestinal secretagogue; has a key role in cholera toxin (CT) induced intestinal secretion PGE2 – potent intestinal secretagogue; CT- induced secretion is inhibited by a COX-2 inhibitor but not by a COX-1 inhibitor Enteric Nervous System Farthing M. Digestive Diseases (Review Article) 2006;24:47-58 Functions independently of the CNS through a variety of neurotransmitters: VIP and enkephalins
  12. 12. Regulation of intestinal secretion Enkephalin - opioid neurotransmitter that binds to delta receptors to reduce the levels of cAMP VIP (Vasoactive Intestinal Peptide) Prostaglandin E2 - increase cAMP levels Cyclic AMP - induces secretion of water and electrolytes Enkephalinase - enzyme that degrades enkephalins Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79
  13. 13. Opioids and their receptors Exogenous - Morphine - Loperamide µ (mu) has inhibitory effects on intestinal smooth muscles d (delta) decreases cAMP formation +++ +++ + + Endogenous - Enkephalins + +++ Opioids Opioid receptors Farthing M. Digestive Diseases (Review Article) 2006;24:47-58
  14. 14. c-AMP ATP VIP Prostaglandins Enkephalins Regulation of water and electroltye secretion - normal state Enkephalinase Delta receptor Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79
  15. 15. Originator information- Racecadortril  Brand name- Tiorfanor® /Tiorfast®  Company- Bioprojet pharma http://adisinsight.springer.com/drugs/800003 626
  16. 16. Originator- Drug description  Racecadotril,formerly known as acetorphan,is a prodrug,which is converted to the active metabolite thiorphan . Acetyl-thiorphanisan other active metabolite of racecadotril but yields only low potency NEP inhibitio.  Tiorfan® (Racecadotril) capsules was launched in France in 1993 for adult and Tiorfan® (Racecadotril) granulated powder in sachet in 2000 for children and infants. Front Pharmacol. 2012 May 30;3:93.
  17. 17. Dosage Forms And Strengths • Infants and children (together with ORS): • – Dose according to body weight —1.5 mg/kg per dose • Adults: – One 100 mg capsule initially regardless of time of day followed by one 100 mg capsule three-times daily, preferably before meals. • Continue treatment until two normal stools are recorded, do not exceed 7 days. Long-term treatment is not recommended.
  18. 18. Approximate number of sachets per administration according to the body weight of the child: WHO Essential medicines list for children: Racecadotril
  19. 19. Summary of Originator product  Brand Name: Tiorfanor® /Tiorfast®  Company- Bioprojet pharma  Strength: 1.5 mg/kg per dose  Dosage Form: capsule and tablets  Route of Administration: oral http://adisinsight.springer.com/drugs/800003 626
  20. 20. Approved indications  Acute diarrhoea 1.http://www.cimsasia.com/ 2. Drugs. April 2000, Volume 59, Issue 4, pp 829-835
  21. 21. Diarrhea
  22. 22. What is Diarrhea? A. Passage of abnormally liquid stools at increased frequency B. Stool weight > 200 grams/day C. Both Passage ofabnorm all... Stoolw eight> 200 g... B oth 0% 0%0%
  23. 23. Passage of abnormally liquid or unformed stools at an increased frequency Stool weight > 200 grams / day Diarrhea DIARRHEA Harrison’s Principles of Internal Medicine 16th Edition. Volume 1. 2005
  24. 24. Over-secretion of water leads to diarrhea. Hypersecretion Diarrhea (> 200 grams /day) Secretion Absorption Absorption Normal State Diarrhea
  25. 25. It’s considered acute diarrhea if the duration is? < 2 w eeks 2 – 4 w eeks > 4 w eeks 0% 0%0% A. < 2 weeks B. 2 – 4 weeks C. > 4 weeks
  26. 26. Acute diarrhea - < 2 weeks duration - more than 90% are caused by infectious agents - often accompanied by vomiting, fever, and abdominal pain Persistent diarrhea - 2 to 4 weeks duration Chronic diarrhea - > 4 weeks duration - needs further evaluation to exclude serious underlying pathology - usually non-infectious in origin Acute, persistent, and chronic diarrhea Harrison’s Principles of Internal Medicine 16th Edition. Volume 1. 2005
  27. 27. Acute watery diarrhea (infectious) 1,2 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.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
  28. 28. Acute watery diarrhoea – lasts several hours or days, and includes cholera; Acute bloody diarrhoea – also called dysentery; and Persistent diarrhoea – lasts 14 days or longer
  29. 29. Normal villi Blunted villi Acute watery diarrhea (Infectious)
  30. 30. Destruction of enterocytes: EIEC, rotavirus, shigella Defective absorption Hypersecretion: Vibrio cholerae, rotavirus, ETEC, shigella Imbalance between absorption and secretion Acute watery diarrhea (Infectious)
  31. 31. Prevalance of diarrhea  Diarrhea is widely recognized as a major cause of childhood morbidity and mortality in many developing countries, particularly in sub-Saharan Africa. According to World Health Organization (WHO) report in the African region, diarrheal diseases are still leading causes of mortality and morbidity in children under five years of age. This same report indicates that each child in the said region has five episodes of diarrhea per year and that 800,000 die each year from diarrhea and dehydration.  Diarrhoeal disease is the second leading cause of death in children under five years old. It is both preventable and treatable.  Each year diarrhoea kills around 760 000 children under five.  A significant proportion of diarrhoeal disease can be prevented through safe drinking-water and adequate sanitation and hygiene.  Globally, there are nearly 1.7 billion cases of diarrhoeal disease every year.  Diarrhoea is a leading cause of malnutrition in children under five years old. 1. Ending preventable deaths from pneumonia and diarrhoea by 2025, WHO ; unicef 2. Ann Afr Med.2012 Oct-Dec;11(4):217-21.
  32. 32.  Every year:  6.9 million children die before their 5th birthday  - 3.0 million in the first month of life  - 2.0 million aged 1 – 12 months Integrated Global Action Plan for Pneumonia and Diarrhoea, 12 April 2013, Washington DC
  33. 33. Global Burden of Pneumonia and Diarrhoea in children under-five 2011  1.24 million pneumonia deaths 760,000 diarrhoea deaths  Incidence and mortality are higher in less developed countries Effective interventions exist for prevention and management 1) WHO. Global Health Observatory (http://www.who.int/gho/child_health/en/index.htm l) (2) *For undernutrition: Black et al. Lancet, 2008
  34. 34. Countries with the largest burden of diarrhoea deaths
  35. 35. Countries with the largest burden of diarrhoea deaths • 64% of global diarrheal deaths Integrated Global Action Plan for Pneumonia and Diarrhoea, 12 April 2013, Washington DC
  36. 36. The global burden of under-five deaths has fallen steadily since 1990 The UN Inter-agency Group for Child Mortality Estimation, 2012.
  37. 37. 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
  38. 38. The ideal treatment for acute diarrhea 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 Am J Med 1985;78:99-106.
  39. 39. Prevention of Dehydration and Control of Diarrhea Fluid replacement alone Fluid replacement with anti-secretory agent The ideal treatment for acute diarrhea
  40. 40. Racecadotril was developed specifically with these characteristics in mind.2 The ideal treatment for acute diarrhea 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 1. AmJ Med 1985;78:99-106. 2. Int J Antimicrob Agents. 14 (2000)
  41. 41. Racecadotril: an intestinal antisecretory agent
  42. 42. Regulation of intestinal secretion Enkephalin - opioid neurotransmitter that binds to delta receptors to reduce the levels of cAMP VIP (Vasoactive Intestinal Peptide) Prostaglandin E2 - increase cAMP levels Cyclic AMP - induces secretion of water and electrolytes Enkephalinase - enzyme that degrades enkephalins Int J Antimicrob Agents. 14 (2000) 75-79
  43. 43. Regulation of water and electroltye secretion – normal state Delta receptor Enkephalins Enkephalinase c-AMP ATP VIP Prostaglandins Int J Antimicrob Agents. 14 (2000) 75-79
  44. 44. Delta receptor Enkephalins Enkephalinase c-AMP ATP Toxic peptides from viruses / bacteria Regulation of intestinal secretion - hypersecretory state Int J Antimicrob Agents. 14 (2000) 75-79
  45. 45. Delta receptor Enkephalins Racecadotril Enkephalinase c-AMP ATP Toxic peptides from viruses / bacteria Mode of action of racecadotril - normalization of secretion Int J Antimicrob Agents. 14 (2000) 75-79
  46. 46. Metabolism of racecadotril Ac-S-CH(Bz)-CO-NH-CH-CO-Bz22 Thiorphan (potent-enkephalinaseinhibitor) (Non-specificesterase) RACECADOTRIL HS-CH(Bz)-CO-NH-CH-CO-H2 2 HO2 HO2 RACECADOTRIL THIORPHAN (potent-enkephalinase inhibitor) Ac-S-CH(Bz)-CO-NH-CH-CO-Bz22 Thiorphan (potent-enkephalinaseinhibitor) (Non-specificesterase) RACECADOTRIL HS-CH(Bz)-CO-NH-CH-CO-H2 2 HO2 HO2 (Non-specific esterase) Hydrolysis Int J Antimicrob Agents. 14 (2000) 75-79
  47. 47. O O H HH H N N O O O O OH HC3 hydrolysis S HS RACECADOTRIL (pro-drug) THIORPHAN (active metabolite) Metabolism of racecadotril Int J Antimicrob Agents. 14 (2000) 75-79
  48. 48. Onset of action of racecadotril Enkephalinase inhibition kinetics in healthy volunteers after a single oral dose (100 mg) 500 400 300 200 100 0 0 30 60 120 240 480 24 hrs ** p<0.01 Enkephalinaseactivity (pmol/ml/minute) Time (min) ** ** ** ** RACECADOTRIL Placebo Int J Antimicrob Agents. 14 (2000) 81-87
  49. 49. Clinical trials
  50. 50. Study design – Randomized, double-blind, placebo-controlled study with 2 parallel groups Objective – To assess the efficacy and safety of racecadotril as an adjunct to oral rehydration therapy for children with acute watery diarrhea Racecadotril in the treatment of acute watery diarrhea in children Treatment – Oral rehydration + racecadotril 1.5 mg/kg t.i.d. – Oral rehydration + placebo t.i.d. N Engl J Med. 2000 Aug 17;343(7):463-7.
  51. 51. 400 350 300 250 200 150 100 50 0 RACECADOTRIL + ORS (n=68) Intention to treat group Rotavirus-Positive Subgroup RACECADOTRIL (n=34)+ ORS Placebo +ORS(n=67) P<0.001 P<0.001 Placebo +ORS(n=39) TotalStoolOutput(g/kg) 53% 56%
  52. 52. Time to recovery 0 10 20 30 40 50 60 70 80 90 100 110 120 20 40 60 80 100 Duration of Diarrhea (hr) Rotavirus-positiveboys All boys All boys Rotavirus-positiveboys RACECADOTRIL + ORS Placebo + ORS ProbabilityofUnresolvedDiarrhea(%)
  53. 53. 700 600 500 400 300 200 100 0 ORSconsumption(ml) p<0.001 Day 1 Day 2 RACECADOTRIL + ORS (n=68) Placebo +ORS(n=67) Total intake of oral hydration solution
  54. 54. Tolerability Adverse Events (%) Racecadotril + ORS 10 Placebo + ORS 7 The incidence of vomiting did not differ between the racecadotril and placebo groups.
  55. 55. 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.
  56. 56. Efficacy and tolerability of racecadotril in acute diarrhea in children Study design – Randomized, double-blind, placebo-controlled, multicenter study Inclusion criteria – Severe acute diarrhea – Aged 3 months to 4 years – 3 or more watery stools per day – Onset of diarrhea - less than 3 days Population – Racecadotril + ORS: 84 patients – Placebo + ORS: 82 patients Gastroenterology. 2001 Mar;120(4):799-805.
  57. 57. Evaluation criteria – Stool output during the first 48 hrs (primary end point) – Stool output during the first 24 hrs – Dehydration status at 24 hrs (Urine Na+ / K+ ratio) – Duration of diarrhea – Number and characteristics of stools Treatment – Oral rehydration + racecadotril 1.5 mg/kg t.i.d. – Oral rehydration + placebo t.i.d.
  58. 58. 20 15 10 5 0 Racecadotril + ORS (n=84) Full data set Per-protocol population Racecadotril (n=53) + ORS Placebo +ORS (n=82) Placebo +ORS (n=63) ** *** Stooloutput(g/hour) ** p =0.009 *** p =0.001 40% 50%
  59. 59. Time to recovery in rotavirus-positive patients 100 80 60 40 20 0 0 10 20 30 40 60 70 80 9050 Probabilityofunresolveddiarrhea(%) Placebo +ORS RACECADOTRIL + ORS Duration of diarrhea (hours) Duration of diarrhea [median, hours] Racecadotril [n = 32] Placebo [n = 35] P 6.9 36 0.02
  60. 60. Tolerability Number of Adverse Events (AE) Racecadotril + ORS 10 Placebo + ORS 11 The incidence of adverse events was similar in both groups of patients. Most common AE: Vomiting
  61. 61. Conclusion 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
  62. 62. A multinational comparison of racecadotril and loperamide in the treatment of acute diarrhea in adults Aim: To compare the efficacy, safety and tolerability of Racecadotril with those of Loperamide in patients with acute diarrhea. Study design single, blind, randomized – Multicenter (21 centers in 14 countries) – Parallel groups – Ambulatory patients Inclusion criteria – 3 or more watery stools, with no visible blood, in the last 24 hours – onset of diarrhea of presumed infectious origin, of at least 24 hours and less than 5 days Scand J Gastroenterol. 2002 Jun;37(6):656-61.
  63. 63. Treatment – Racecadotril: 100 mg, 3 times daily / Loperamide: 2 mg, 3 times daily Analyzed population – Racecadotril: 461 patients / Loperamide: 454 patients
  64. 64. Duration of Diarrhea 100 90 80 70 60 50 40 30 20 10 0 Probabilityofunresolved diarrhea(%) Time to resolution (hours) 0 20 40 60 80 100 P=NS 120 140 160 RACECADOTRIL (N=473) Loperamide(N=471)
  65. 65. Treatment-related adverse events with an incidence of more than 1% 14 12 10 8 6 4 2 0 Constipation Abdominal enlargement Anorexia %ofPatients RACECADOTRIL (n=473) Loperamide(n=472) 3.4 1.7 0.8 12.5 6.1 2.3
  66. 66. Conclusion Racecadotril resolved the symptoms of acute diarrhea rapidly and effectively, and produced more rapid resolution of abdominal symptoms and less constipation than loperamide.
  67. 67. Effect of racecadotril in the management of acute diarrhea in infants and children Racecadotril and rehydration was compared with rehydration alone . Children aged 3 months to 3 years who had acute diarrhoea . Evaluated in an emergency department (Hôpital Necker Enfants Malades, Paris, France). Primary end point : . Number of medical visits during the week after starting treatment. Secondary end points : . Number of stools during the first 48 hours . Duration of the diarrhoea and the weight on day 7 Arch Pediatr. 2002 Aug;9(8):774-9.
  68. 68. Clinical characteristics at admission Population Group racecadotril + rehydration Group rehydration alone Total number (M / F) 81 (51 / 33) 83 (43 / 40) Age (months)* 12 ± 6.1 12.1 ± 7.2 Start of diarrhoea (h)* 41.5 ± 26.3 39.9 ± 28.3 Average number of stools in the previous 24 h 8.5 8.1 Weight loss in % 5.0 ± 3.9 5.0 ± 3.5 * = mean ± SD
  69. 69. Efficacy results Criteria * Group racecadotril + rehydration Group rehydration alone P Number of stools in the first 48 hours 6.8 ± 3.8 9.5 ± 4.5 < 0.001 Total duration of diarrhea (hours) 97.2 ± 35.6 137.7 ± 42.4 < 10 -9 * = mean ± SD
  70. 70. Further visits after Day 2 racecadotril + rehydration (n = 81) rehydration alone (n = 83) P Total 14 / 76 (18.4%) 27 / 78 (34.6%) < 0.05 Initial hydration - PO 10 / 41 15 / 41 NS - IV 4 / 35 12 / 37 < 0.05 Reason for consultation - Same episode of diarrhoea 8 / 76 21 / 78 < 0.05 Concern Worsening Secondary hospitalisation 6 2 2 8 13 8 - Other reason 6 6 Days of hospitalisation for infusion (number of children) 37 (37) 45 (43)
  71. 71. Results  One hundred and sixty-six children were alternatively randomized to the treated and the control groups. There was no difference for age, degree of dehydration and length of illness before the first visit between the groups. Whatever type of rehydration (oral or i.v.), the treated group had a significant lower number of stools (p < 0.001) and a faster recovery (p < 10(-9)). The children receiving racecadotril needed less additional ED visits for the same episode (p < 0.05). There was no difference for the weight-gain on day 7.
  72. 72. Conclusions  This study demonstrates the efficacy of racecadotril as adjuvant therapy to oral and i.v. rehydration in the treatment of acute diarrhoea and a fewer emergency department second visit before recovery.
  73. 73. Comparision of racecadotril and loperamide in children with acute diarrhoea Study design . Double placebo . Parallel groups Inclusion criteria . Ambulatory children from 2 to 10 years . More than 3 loose stools in the last 24 h . Onset of diarrhea of less than 5 days Analysed population . Racecadotril : 52 children . Loperamide : 50 children Evaluation criteria . Number of diarrheic stools assessed from diary card (main criterion) . Duration of diarrhea . Evolution of abdominal circumference Aliment Pharmacol Ther. 1999 Dec;13 Suppl 6:27-32.
  74. 74. Duration of diarrhea Racecadotril Loperamide Racecadotril is as efficient as loperamide 0 5 10 15 Stool number 0 1 2 3 4 hours Numberofstools
  75. 75. Racecadotril Loperamide Racecadotril is better tolerated than loperamide 0 10 20 30 40 50 60 0 10 20 30 40 50 Constipated patients * * P = 0.03 %ofpatients %ofpatients * * P = 0.04
  76. 76. Conclusions  Racecadotril and loperamide were equally effective in treating acute diarrhoea in these children, and racecadotril had a superior tolerability and safety profile.
  77. 77. Prospective randomized double-blind trial of racecadotril compared with loperamide in elderly people with gastroenteritis  Design and Methods: a randomized, prospective, double-blind, and parallel group design from February 2008 to March 2009.  Patients of both sexes were randomly allocated to receive either one tablet of racecadotril 100 mg every 8 h or two tablets of loperamide 2.0 mg followed by one tablet after each unformed stool, up to four tablets in any 24-h period. Patients were treated until recovery, defined as the production of two consecutive normal stools or no stool production for a period of 12 h. Eur J Clin Pharmacol (2010) 66:137–144
  78. 78.  Results : Normal stools were collected 36±4 h after the beginning of racecadotril and in 63±6 h from the beginning of loperamide administration (P<0.01). The median time of abdominal pain in the intent-to-treat (ITT) population was 14 h for racecadotril and 28 h for loperamide. In the perprotocol (PP) population, the median time of abdominal pain was 14 h for racecadotril and 32 h for loperamide (P<0.01).  Conclusions: Racecadotril is more effective than loperamide− probably due to drug interaction with loperamide−and it is not related to pharmacogenetic susceptibility. Racecadotril is also more cost effective than loperamide. Eur J Clin Pharmacol (2010) 66:137–144
  79. 79. Racecadotril versus placebo in the treatment of acute diarrhoea in adults.  Methods: A two-centre, double-blind, parallel-group, randomized study was carried out to compare the efficacy and tolerability of racecadotril (100 mg three times daily) and placebo in 70 adult patients with acute diarrhoea. An objective criterion of antisecretory activity, stool weight, was used. Aliment Pharmacol Ther. 1999 Dec;13 Suppl 6:15-9.
  80. 80. When the two groups of patients were compared, the mean (± S.E.M.) stool weight in the racecadotril group was 355 ± 35 g, while the stool weight in placebo-treated patients was 499 ± 46 g (P = 0.025). Hence, a significant decrease in stool weight of 28.9% was achieved with racecadotril.
  81. 81. conclusion  Conclusions Racecadotril acts rapidly to resolve acute diarrhoea and has an incidence of adverse events similar to that of placebo.
  82. 82. E. Coli content of the proximal jejunum (gnotobiotic piglets) Effects of racecadotril and loperamide on bacterial proliferation 120 100 80 60 40 20 0 10/gcontent (median) 6 E.Coli RACECADOTRIL Control Loperamide p=0.04 p=0.86 p=0.005 1 4 120 Alimentary Pharmacology, 1999; (suppl. 6); 9-14
  83. 83. Blood-Brain Barrier Astrocyte processes Lipid soluble transport Carrier-mediated transport Does not induce CNS Toxicity1,2,3 Racecadotril Does not impair mental performance4 Has no potential for abuse or physical dependence5 Racecadotril does not cross the blood- brain barrier 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.Alimentary Pharmacology, 1999; (suppl. 6): 9-14 4. Alimentary Pharmacology and Therapeutics, 1992; 6:305-313 5. Knisely JS,Drug and Alcohol Dependence,1989;23:143-151
  84. 84. Summary and conclusions
  85. 85. Prevention of Dehydration and Control of Diarrhea Fluid replacement Diarrhea Diarrhea Normalization Fluid replacement Racecadotril in the treatment of acute diarrhea Racecadotril
  86. 86. LoperamideRacecadotrilEfficacy variable Motility1 Secretion2 Bacterial overgrowth1 CNS effects1 Constipation2 - +++ - - - +++ + + + ++ Racecadotril versus loperamide   1.Alimentary Pharmacology, 1999; (suppl. 6); 9-14
  87. 87. Racecadotril 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
  88. 88. Absorption - Rapid Maximum concentration - Maintained for at least four hours Concentration in plasma - Maintained for at least eight hours after administration Racecadotril
  89. 89. 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

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