This document provides information on racecadotril, an intestinal antisecretory agent for the management of diarrhea. It discusses fluid and electrolyte balance in the intestines, the burden of diarrhea, and limitations of current therapy. Racecadotril works by inhibiting the enzyme enkephalinase, reducing intestinal fluid secretion. Clinical trials showed racecadotril significantly reduced stool output and shortened time to recovery when used with oral rehydration therapy in children with acute watery diarrhea compared to placebo. Racecadotril has a rapid onset of action and good safety profile.

1. Racecadortril
Management of diarrhea

2. 2
Diarrhea

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. Fluid and electrolyte balance in the
intestines

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. 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. 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. 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. Crypt: Secretion
Villus Tip: Absorption
Normal state
Farthing M. Digestive Diseases
(Review Article) 2006;24:47-58

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. 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. 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. 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. 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. Originator information- Racecadortril
 Brand name- Tiorfanor® /Tiorfast®
 Company- Bioprojet pharma
http://adisinsight.springer.com/drugs/800003
626

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. 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.

19. Approximate number of sachets per administration
according to the body weight of the child:
WHO Essential medicines list for
children: Racecadotril

20. 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

21. Approved indications
 Acute diarrhoea
1.http://www.cimsasia.com/
2. Drugs. April 2000, Volume 59, Issue 4, pp 829-835

22. Diarrhea

23. 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%

24. 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

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

26. 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

27. 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

28. 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

29. 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

30. Normal villi Blunted villi
Acute watery diarrhea (Infectious)

31. Destruction of enterocytes:
EIEC, rotavirus, shigella
Defective absorption
Hypersecretion:
Vibrio cholerae, rotavirus,
ETEC, shigella
Imbalance between absorption and secretion
Acute watery diarrhea (Infectious)

32. 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.

33.  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

34. 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

35. Countries with the largest burden of
diarrhoea deaths

36. 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

37. The global burden of under-five deaths
has fallen steadily since 1990
The UN Inter-agency Group for Child
Mortality Estimation, 2012.

38. 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

39. 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.

40. Prevention of Dehydration and Control of Diarrhea
Fluid replacement alone
Fluid replacement with
anti-secretory agent
The ideal treatment for acute diarrhea

41. 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)

42. Racecadotril:
an intestinal
antisecretory agent

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

49. 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

50. Clinical trials

51. 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.

52. 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%

53. 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(%)

54. 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

55. Tolerability
Adverse Events (%)
Racecadotril + ORS 10
Placebo + ORS 7
The incidence of vomiting did not differ between the racecadotril
and placebo groups.

56. 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.

57. 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.

58. 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.

59. 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%

60. 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

61. 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

62. 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

63. 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.

64. Treatment
– Racecadotril: 100 mg, 3 times daily /
Loperamide: 2 mg, 3 times daily
Analyzed population
– Racecadotril: 461 patients / Loperamide:
454 patients

65. 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)

66. 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

67. Conclusion
Racecadotril resolved the symptoms of acute diarrhea
rapidly and effectively, and produced more rapid
resolution of abdominal symptoms and less constipation
than loperamide.

68. 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.

69. 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

70. 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

71. 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)

72. 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.

73. 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.

74. 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.

75. Duration of diarrhea
Racecadotril
Loperamide
Racecadotril is as efficient as loperamide
0
5
10
15
Stool number
0
1
2
3
4
hours
Numberofstools

76. 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

77. Conclusions
 Racecadotril and loperamide were equally effective in
treating acute diarrhoea in these children, and
racecadotril had a superior tolerability and safety profile.

78. 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

79.  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

80. 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.

81. 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.

83. conclusion
 Conclusions Racecadotril acts rapidly to resolve acute
diarrhoea and has an incidence of adverse events similar to
that of placebo.

84. 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

85. 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
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5. Knisely JS,Drug and Alcohol Dependence,1989;23:143-151

86. Summary and conclusions

87. Prevention of Dehydration and
Control of Diarrhea
Fluid
replacement
Diarrhea Diarrhea Normalization
Fluid
replacement
Racecadotril in the treatment of acute
diarrhea
Racecadotril

88. LoperamideRacecadotrilEfficacy variable
Motility1
Secretion2
Bacterial overgrowth1
CNS effects1
Constipation2
-
+++
-
-
-
+++
+
+
+
++
Racecadotril versus loperamide


1.Alimentary Pharmacology, 1999; (suppl.
6); 9-14

89. 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

90. Absorption - Rapid
Maximum concentration - Maintained for at least four
hours
Concentration in plasma - Maintained for at least eight
hours after administration
Racecadotril

91. 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