Hidrasec Adults 9-11-07

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

INTRODUCTION
PRESENTATION OUTLINE
Fluid 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
0%
rs 0% 0% 0%
rs
rs
rs
te
te
te
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Li
Li
Li
Li
2
9
FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES
DAILY WATER EXCHANGES
Water absorption
Exogenous sources: Endogenous sources:

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

Duodenum / Colon/
Ileum
Jejunum Rectum
2 liters
5.5 liters 1.3 liters
Food and fluid Stool

intake (<5ml/kg – children)
(drinks, meals…) (< 200 ml – adults)
2 liters
7 liters
Endogenous secretions: intestinal, pancreatic,
salivary, biliary and gastric juices
Sellin JH. Intestinal electrolyte absorption and secretion. In: Feldman M, et al, eds. Sleisenger & Fordtrans.
Gastrointestinal and Liver Disease. 8th ed. 2006
WATER FOLLOWS THE MOVEMENT OF

ELECTROLYTES AND GLUCOSE
Glucose, Na+, K+, Cl-, Water
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.
NORMAL STATE
Villus Tip: Absorption
Crypt: Secretion
Farthing M. Digestive Diseases (Review Article) 2006;24:47-58

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.

MECHANISMS OF INTESTINAL SECRETION
Endogenous 5-HT – potent intestinal secretagogue; has a key role in

secretagogues 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 Functions independently of the CNS through a variety

System of neurotransmitters: VIP and enkephalins

REGULATION OF INTESTINAL SECRETION
Enkephalin - opioid neurotransmitter that binds to delta receptors

to reduce the levels of cAMP
Enkephalinase - enzyme that degrades enkephalins
VIP (Vasoactive Intestinal Peptide)

- increase cAMP levels
Prostaglandin E2
Cyclic AMP - induces secretion of water and electrolytes
Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79

OPIOIDS AND THEIR RECEPTORS
Opioids Opioid receptors
µ (mu) δ (delta)
has inhibitory effects on decreases cAMP formation
intestinal smooth muscles
Exogenous
- Morphine +++ +
- Loperamide +++ +
Endogenous
- Enkephalins + +++

REGULATION OF WATER AND

ELECTROLTYE SECRETION
– NORMAL STATE
Delta receptor
c-AMP
VIP
Prostaglandins
ATP
Enkephalins
Enkephalinase

DIARRHEA
What is Diarrhea?
A. Passage of
abnormally liquid
stools at increased
frequency
B. Stool weight > 200
grams/day
C. Both 0% 0% 0%
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DIARRHEA
DIARRHEA
Passage of abnormally liquid or unformed stools at an increased

frequency
Stool weight > 200 grams / day
Harrison’s Principles of Internal Medicine 16th Edition. Volume 1. 2005

DIARRHEA
DIARRHEA
Over-secretion of water leads to diarrhea.
Secretion Absorption Hypersecretion Absorption
Normal State
DIARRHEA (> 200 grams /day)
It’s considered acute diarrhea if the
duration is?
A. < 2 weeks
B. 2 – 4 weeks
C. > 4 weeks
0% 0% 0%
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DIARRHEA
ACUTE, PERSISTENT, AND CHRONIC

DIARRHEA
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

DIARRHEA
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
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
week
0% 0% 0%
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3
BURDEN OF DIARRHEA
BURDEN OF DIARRHEA
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
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
DIARRHEA IN THE PHILIPPINES
2nd leading cause of morbidity (general population)
1000
7 7 0 .9 M a le
800 7 4 8 .2
6 9 5 .0 F e m a le
6 5 5 .0 6 3 9 .6 6 7 7 .0
600
R a tes*
5 0 3 .1
4 5 5 .4
4 2 0 .7
400 3 2 5 .4
200
0
A cu te L o w e r R T I D ia rrh e a s B r o n c h it is/ In f lu e n z a H y p e r t e n si o n
a n d P n e u m o n ia B ro n ch io lit is
*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
What Drugs/Management do you
utilized in your practice?
A. ORS
B. Antibiotics
C. Loperamide
D. Racecadotril
E. Others
0% 0% 0% 0% 0%
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MANAGEMENT OF DIARRHEA
APPROACH TO THE PATIENT WITH ACUTE

DIARRHEA
The 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

MANAGEMENT OF DIARRHEA
THE TREATMENT OF ACUTE DIARRHEA
Fluid 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
UNMET MEDICAL NEEDS IN THE TREATMENT OF ACUTE DIARRHEA
LIMITATIONS OF CURRENT THERAPY
Fluid - No significant reduction of diarrhea

replacement - Diarrhea may continue
“Antidiarrheals” - Limited efficacy

- CNS effects
- Bloating
- Rebound constipation
Antibiotics - Resistance
- Unwanted adverse effects

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

DIARRHEA
Prevention of Dehydration and Control of Diarrhea
Fluid replacement with

Fluid replacement alone
anti-secretory agent

DIARRHEA 1
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
Are you aware that Racecadotril was
already in the market in late 90’s?
A. Yes
B. No
0% 0%
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Ye
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RACECADOTRIL:
AN INTESTINAL
ANTISECRETORY
AGENT
RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT
REGULATION OF INTESTINAL SECRETION
Enkephalin - opioid neurotransmitter that binds to delta receptors

to reduce the levels of cAMP
Enkephalinase - enzyme that degrades enkephalins
VIP (Vasoactive Intestinal Peptide)

- increase cAMP levels
Prostaglandin E2
Cyclic AMP - induces secretion of water and electrolytes

REGULATION OF WATER AND

ELECTROLTYE SECRETION
– NORMAL STATE
Delta receptor
c-AMP
VIP
Prostaglandins
ATP
Enkephalins
Enkephalinase

REGULATION OF INTESTINAL
SECRETION - HYPERSECRETORY
STATE
Delta receptor
c-AMP
Toxic peptides
from viruses /
ATP bacteria
Enkephalins
Enkephalinase

MODE OF ACTION OF RACECADOTRIL -

NORMALIZATION OF SECRETION
Delta
receptor
c-AMP
Toxic peptides
from viruses /
ATP bacteria
Enkephalins
Racecadotril
Enkephalinase

METABOLISM OF RACECADOTRIL
H 2O H 2O
H 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
A c - S - C H RACECADOTRIL
(B z ) - C O - N H - C H 2- C O 2- B z
A c - S - C H (B z ) - C O - N H - C H 2- C O 2- B z
(Non-specific
( N o n - s p e c i f i cesterase)
e st e r a se ) Hydrolysis
(N o n - sp e c if i c e st e r a se )
H S - C H ( B z ) - C O -(potent-enkephalinase
THIORPHAN N H -C H 2-C O 2-H
H S-C H (B z )-C O -N H -C H -C O -H
t - e n k e p h a l i n a s2e i n h i b2 i t o r )
T h i o r p h a n ( p o t e ninhibitor)
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 )

METABOLISM OF RACECADOTRIL
O O
O h y d r o ly sis OH
N N
H H O H H O
S HS
O
H 3C
RACECADOTRIL THIORPHAN
(pro-drug) (active metabolite)

ONSET OF ACTION OF RACECADOTRIL
Enkephalinase inhibition kinetics in healthy volunteers

after a single oral dose (100 mg)
500
400
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 )
300
**
200
** * * p <0 .0 1
**
100 R A CE CA D O T R IL
** P la ce b o
0
0 30 60 120 240 480 24 h rs
T im e (m in )
Lecomte JM. International Journal of Antimicrobial Agents 14 (2000) 81-87

CLINICAL TRIALS
INFANTS AND CHILDREN
RACECADOTRIL IN THE TREATMENT OF

ACUTE WATERY DIARRHEA IN CHILDREN
(Salazar-Lindo et al.)
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
TREATMENT
– Oral rehydration + racecadotril 1.5 mg/kg t.i.d.
– Oral rehydration + placebo t.i.d.
Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463-467


Total stool output / body weight (g/kg)
P < 0 .0 0 1
P <0 .0 0 1
400
350
T o t a l S t o o l O u t p u t ( g /k g )
300
53% 56%
250
200
150
100
50
0
R A CE CA D O T R IL P la ce b o R A CE CA D O T R IL P la ce b o
+ O R S (n =6 8 ) + O R S (n =6 7 ) + O R S (n =3 4 ) + O R S (n =3 9 )
In t e n t io n t o t re a t g ro u p R o t a v i r u s -P o s i t i v e S u b g r o u p


Time to recovery
100
P ro b a b ilit y o f U n re so lv e d D ia r r h e a (% )
R o t a v ir u s- p o sit iv e b o y s
80
R A CE C A D O T R IL + O R S
A ll b o y s P la ce b o + O R S
60
40
R o t a v i r u s - p o si t i v e b o y s
A ll b o y s
20
0 10 20 30 40 50 60 70 80 90 100 110 120
D u ra t io n o f D ia rr h e a (h r)


Total intake of oral rehydration
700
solution
600
O R S co n su m p t io n (m l)
p < 0 .0 0 1
500
400
300
R A CE CA D O T R IL
200 + O R S (n =6 8 )
P la ce b o + O R S (n = 6 7 )
100
0
Day 1 Day 2


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


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.

EFFICACY AND TOLERABILITY OF

RACECADOTRIL IN ACUTE DIARRHEA
IN CHILDREN (Cézard et al.)
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
Cézard JP et al. Gastroenterology 2001;120:799-805.


TREATMENT
– Oral rehydration + racecadotril 1.5 mg/kg t.i.d.
– Oral rehydration + placebo t.i.d.
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


Stool weight (g/hour) up to 48 hours
20
40%
S t o o l o u t p u t ( g /h o u r )
15
50%
**
10
***
* * p = 0 .0 0 9
5 * * * p = 0 .0 0 1
0
R a ce c a d o tr il P la ce b o R a ce ca d o tr il P la ce b o
+ ORS + O RS + ORS + O RS
(n =8 4 ) (n =8 2 ) (n =5 3 ) (n =6 3 )
Fu ll d a ta se t P e r -p r o t o c o l p o p u la t i o n


Time to recovery in rotavirus-positive patients
Duration of diarrhea [median, hours]
Racecadotril Placebo P
100
P ro b a b ilit y o f u n re s o lv e d d ia r rh e a (% )
[n = 32] [n = 35]
80
6.9 36 0.02
P la ce b o + O R S
60 R A C E C A D O TR IL + O R S
40
20
0
0 10 20 30 40 50 60 70 80 90
D u r a t io n o f d ia rr h e a (h o u r s )


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


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.

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 comp ar e the effi cac y, safe ty an d tol erab ility of
Rac eca dot ril with those of Lo per amide in pat ient s wi th
acu te diarrh ea .
ADULTS
RACECADOTRIL AND LOPERAMIDE IN
IN ADULTS (Prado D.)
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
Prado D. Scand J Gastroenterol 2002;37:656-61

ADULTS
TREATMENT
– Racecadotril: 100 mg, 3 times daily / Loperamide: 2 mg, 3
times daily
ANALYZED POPULATION
– Racecadotril: 461 patients / Loperamide: 454 patients

ADULTS
Duration of Diarrhea
100
P ro b a b ility o f u n re so lv e d
90
80 R A C E C A D O T R I L (N = 4 7 3 )
L o p e r a m i d e (N = 4 7 1 )
70
d ia rrh e a (% )
60
50 P =N S
40
30
20
10
0
0 20 40 60 80 100 120 140 160
T im e t o re s o lu t io n (h o u r s)
ADULTS
Treatment-related adverse events with an incidence of more than 1%
14
1 2 .5
12
R A C E C A D O T R I L (n =4 7 3 )
10 L o p e r a m id e (n =4 7 2 )
% o f P a tie n ts
8
6 .1
6
4 3.4
2 .3
1.7
2 0 .8
0
C o n st ip a t io n A b d o m in a l e n la r g e m e n t A n o re x ia

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.

RACECADOTRIL’S
SAFETY AND
TOLERABILITY
PROFILE
SAFETY AND TOLERABILITY
PHARMACOVIGILANCE
Prevalence of adverse events associated with Racecadotril (France)
Period covered # of reported Prevalence

adverse events
Adults March 1993 to March 2007 75 0.00047 %

Infants & Children November 2000 to March 2007 30 0.00032 %
TOTAL 105 0.00042 %
Most common AE for adults and children: “Cutaneous disorders

and miscellaneous allergic reactions”
13th Periodic Safety Update Report for Active Substance: Racecadotril. May 2007 Laboratoires Bioprojet Pharma.
Case Number 1:
A 35 year old male developed diarrhea and was
given Loperamide, his symptom improved but
after 2 days he consults you because of
recurrence of Diarrhea. What is the likely
explanation?
A. Re-infection with
a new
bacteria/virus
B. Bacterial
proliferation
0% 0% 0%
C. This is osmotic
Diarrhea
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EFFECTS OF RACECADOTRIL AND

LOPERAMIDE ON BACTERIAL
PROLIFERATION (Duval-Iflah Y. et al.)
E. Coli content of the proximal jejunum (gnotobiotic piglets)
p =0 .0 4
p =0 .8 6 p =0 .0 0 5
120
120
100
1 0 6 E . C o li / g co n t e n t
80
(m e d ia n )
R A CE CA D O T R IL
60 C o n tro l
L o p e ra m id e
40
20
1 4
0
Duval-Iflah Y. Et al.,Alimentary Pharmacology, 1999; (suppl. 6); 9-14

RACECADOTRIL DOES NOT CROSS

THE BLOOD-BRAIN BARRIER
Racecadotril
Does not induce CNS Toxicity1,2,3
Does not impair mental
Blood-Brain Barrier
performance4
Has no potential for abuse or
physical dependence5 Carrier-mediated
transport
Lipid soluble
transport
Astrocyte
1. Lecomte JM, Int.J. Of Antimicrobial Agents, 2000; 14:81-87 processes
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
RACECADOTRIL HAS A HIGH

THERAPEUTIC INDEX
LD50 (median lethal dose)
Therapeutic Index =
ED50 (median effective dose)
The higher the Therapeutic Index,

the lower the risk of overdose.
Therapeutic dose Relevance of high therapeutic index
100 mg TID (adults) 20 times this dose was given to healthy

adults with no ill effects
Lecomte JM, Int.J. Of Antimicrobial Agents, 2000; 14:81-87

Case Number 2
A 20 y/o Female develops diarrhea, voluminous
but not blood streaked. She is afebrile but
dehydrated, your treatment of choice would be?
A. ORS/Fluid
Replacement
B. Racecadotril
C. Loperamide 0% 0% 0% 0%
D. Antibiotics
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O
Case Number 3
A 30 y/o male has been having Diarrhea for 5 days,
with 38 degree celcius temperature. He ingested
raw egg 2 days prior to developing diarrhea, your
treatment will be?
A. Racecadotril
B. Antibiotic
C. Both
0% 0% 0%
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Case Number 4
A 50 y/o male consults you due to diarrhea of
> 4 weeks. It is in small amounts and did not
respond to Antibiotics/Metronidazole.
What will be your next step?
A. Repeat
Metronidazole at
higher dose
B. Ba Enema
C. Colonoscopy
0% 0% 0% 0%
D. Stool Exam
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SUMMARY AND
CONCLUSIONS
OVERALL CONCLUSIONS

ACUTE DIARRHEA
Prevention of Dehydration and
Control of Diarrhea
Fluid Fluid
replacement replacement
Diarrhea Diarrhea Normalization
Racecadotril
OVERALL CONCLUSIONS
RACECADOTRIL VERSUS
LOPERAMIDE
Efficacy variable Racecadotril Loperamide
Motility1 - +++

Secretion2 +++ +

Bacterial overgrowth1 - +
Constipation2 - ++
CNS effects1 - +
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
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
Certificate of Product Registration of Racecadotril, Bureau of Food and Drugs, Department of Health. 2005
Racecadotril summary of product characteristics
OVERALL CONCLUSIONS
RACECADOTRIL
Absorption - Rapid
Maximum concentration - Maintained for at least four hours
Concentration in plasma - Maintained for at least eight hours after

administration
Racecadotril summary of product characteristics

OVERALL CONCLUSIONS
RACECADOTRIL
Efficacy - together with ORS, significantly reduces

stool output and duration of diarrhea in
infants and children
Safety and - similar to placebo

tolerability - fewer adverse events compared
with loperamide
- does not induce CNS toxicity
- high therapeutic index
Racecadotril: A Novel Approach
in the Treatment of Acute Diarrhea
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Hidrasec Adults 9-11-07

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A Novel Approach

Maria Teresita Andal-Gamutan, MD,FPCP,FPSG,FPSDE

Fluid and electrolyte balance and diarrhea

Burden of diarrhea and its management

Racecadotril – an intestinal antisecretory agent

DAILY WATER EXCHANGES

Exogenous sources: Endogenous sources:

DAILY WATER EXCHANGES

Food and fluid Stool

WATER FOLLOWS THE MOVEMENT OF

Glucose, Na+, K+, Cl-, Water

Fluid is required to solubilize complex foods in preparation for digestion

Villus Tip: Absorption

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

MECHANISMS OF INTESTINAL SECRETION

Enterocyte Intestinal fluid secretion results from the active

Active chloride ion secretion has several components

The final common secretory pathway occurs through

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

MECHANISMS OF INTESTINAL SECRETION

Endogenous 5-HT – potent intestinal secretagogue; has a key role in

PGE2 – potent intestinal secretagogue; CT-induced

Enteric Nervous Functions independently of the CNS through a variety

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

REGULATION OF INTESTINAL SECRETION

Enkephalin - opioid neurotransmitter that binds to delta receptors

Enkephalinase - enzyme that degrades enkephalins

VIP (Vasoactive Intestinal Peptide)

Cyclic AMP - induces secretion of water and electrolytes

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

OPIOIDS AND THEIR RECEPTORS

Opioids Opioid receptors

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

REGULATION OF WATER AND

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

Passage of abnormally liquid or unformed stools at an increased

Stool weight > 200 grams / day

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

Secretion Absorption Hypersecretion Absorption

ACUTE, PERSISTENT, AND CHRONIC

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

ACUTE WATERY DIARRHEA (Infectious) 1,2

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

ACUTE WATERY DIARRHEA (Infectious)

NORMAL VILLI BLUNTED VILLI

ACUTE WATERY DIARRHEA (Infectious)

IMBALANCE BETWEEN ABSORPTION AND SECRETION

More than 1 billion people suffer one or more episodes of acute

Because of poor sanitation and more limited access to health care,

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

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)

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

DIARRHEA IN THE PHILIPPINES

2nd leading cause of morbidity (general population)

*rate/100,000 of sex-specific population

APPROACH TO THE PATIENT WITH ACUTE

Indications for evaluation:

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

THE TREATMENT OF ACUTE DIARRHEA