racecadotril

A Novel Approach in the Treatmentof Acute Diarrhea

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

Clinical trials

Safety and tolerability profile

Conclusions

PRESENTATION OUTLINE

INTRODUCTION

FLUID ANDELECTROLYTEBALANCE IN THE INTESTINES

How much fluid passes through the intestine each day?

2 L

iters

5 L

iters

7 L

iters

9 L

iters

0% 0%0%0%

A. 2 Liters

B. 5 Liters

C. 7 Liters

D. 9 Liters

DAILY WATER EXCHANGES

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

Duodenum /Jejunum5.5 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. 8th ed. 2006

Ileum2 liters

Colon/Rectum1.3 liters

Stool(<5ml/kg – children)(< 200 ml – adults)

Food and fluid intake

(drinks, meals…)2 liters


DAILY WATER EXCHANGES

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.

Crypt: Secretion

Villus Tip: Absorption

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

NORMAL STATE


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

Endogenoussecretagogues

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



Functions independently of the CNS through a variety of neurotransmitters: VIP and enkephalins

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 E2

- increase cAMP levels

Cyclic AMP - induces secretion of water and electrolytes

Enkephalinase - enzyme that degrades enkephalins


OPIOIDS AND THEIR RECEPTORS

Exogenous

- Morphine- Loperamide

µ (mu)has inhibitory effects on

intestinal smooth muscles

(delta)decreases cAMP formation

++++++

++

Endogenous

- Enkephalins + +++


Opioids Opioid receptors


c-AMP

ATP

VIPProstaglandins


Enkephalins

REGULATION OF WATER AND ELECTROLTYE SECRETION– NORMAL STATE

Enkephalinase

Delta receptor


DIARRHEA

What is Diarrhea?

Pas

sage

of a

bnorm

ally

...

Sto

ol wei

ght >

200

g...

Both

0% 0%0%

A. Passage of abnormally liquid stools at increased frequency

B. Stool weight > 200 grams/day

C. Both

Passage of abnormally liquid or unformed stools at an increased frequency

Stool weight > 200 grams / day

DIARRHEA

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

DIARRHEA

Over-secretion of water leads to diarrhea.

Hypersecretion

DIARRHEA (> 200 grams /day)

SecretionSecretion AbsorptionAbsorption AbsorptionAbsorption

Normal State

DIARRHEA

DIARRHEA

It’s considered acute diarrhea if the duration is?

< 2

wee

ks

2 –

4 w

eeks

> 4

wee

ks

0% 0%0%

A. < 2 weeks

B. 2 – 4 weeks

C. > 4 weeks

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

DIARRHEA


ACUTE WATERY DIARRHEA (Infectious)1,2

1. Farthing M. Digestive Diseases (Review Article) 2006;24:47-582. 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

Bacteria: - ETEC- V. cholerae, V. parahaemolyticus- Aeromonas, Plesiomonas, Shigella, Salmonella, EHEC

Viruses: - Rotavirus- Enteric adenovirus (types 40 & 41)- SRSVs

Protozoa: - C. parvum, G. intestinalisDuration: < 14 days; lasts several hours or days

DIARRHEA

NORMAL VILLI BLUNTED VILLI

ACUTE WATERY DIARRHEA (Infectious)

DIARRHEA

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

BURDEN OF DIARRHEA

How many cases of Diarrhea do you see in your clinic?

1 p

atie

nt a w

eek

3 –

4 p

atie

nts

a w

eek

> 7

pat

ients

a w

eek

0% 0%0%

A. 1 patient a week

B. 3 – 4 patients a week

C. > 7 patients a week

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

BURDEN OF DIARRHEA


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)

1000

800

600

400

200

0Acute Lower RTIand Pneumonia

Ra

tes*

770.9695.0

639.6

455.4

325.4

748.2

655.0 677.0

503.1

420.7

Diarrheas Bronchitis/Bronchiolitis

Influenza Hypertension

M ale

Female

BURDEN OF DIARRHEA

MANAGEMENTOF DIARRHEA

What Drugs/Management do you utilized in your practice?

ORS

Antib

iotic

s

Loper

amid

e

Rac

ecad

otril

Oth

ers

0% 0% 0%0%0%

A. ORS

B. Antibiotics

C. Loperamide

D. Racecadotril

E. Others

APPROACH TO THE PATIENT WITH ACUTE DIARRHEA

Indications for evaluation:profuse diarrhea with dehydrationgrossly bloody stoolsfever ≥ 38.5oCduration > 48 hours without improvementnew community outbreakssevere abdominal pain in patients > 50 years, and elderly or immunocompromised patients

MANAGEMENT OF DIARRHEA

The decision to evaluate acute diarrhea depends on its severity and duration, and on various host factors.


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.


UNMET MEDICAL NEEDS IN THE TREATMENT OF ACUTE DIARRHEA

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



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.


THE IDEAL TREATMENT FOR ACUTE DIARRHEA

Prevention of Dehydration and Control of Diarrhea

Fluid replacement alone

Fluid replacement with

anti-secretory agent


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

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 DIARRHEA1


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

Yes N

o

0%0%

A. Yes

B. No

RACECADOTRIL:AN INTESTINALANTISECRETORY AGENT

c-AMP

ATP

VIPProstaglandins


Enkephalins

REGULATION OF WATER AND ELECTROLTYE SECRETION– NORMAL STATE

Enkephalinase

Delta receptor

RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT

c-AMP

ATP


Enkephalins

Enkephalinase

Delta receptor

Toxic peptides from viruses /

bacteria

REGULATION OF INTESTINAL SECRETION - HYPERSECRETORY STATE


c-AMP

ATP


Enkephalins

Enkephalinase

Delta receptor

Toxic peptides from viruses /

bacteria

Racecadotril

MODE OF ACTION OF RACECADOTRIL -NORMALIZATION OF SECRETION


METABOLISM OF RACECADOTRIL


Ac-S-CH(Bz)-CO-NH-CH -CO -Bz22

Th io rphan (potent-enkephalinase inhibitor)

(Non-specific esterase)

RACECADOTRIL

HS-CH(Bz)-CO-NH-CH -CO -H2 2

H O2 H O2

RACECADOTRIL

THIORPHAN (potent-enkephalinase inhibitor)

Ac-S-CH(Bz)-CO-NH-CH -CO -Bz22

Th io rphan (potent-enkephalinase inhibitor)

(Non-specific esterase)

RACECADOTRIL

HS-CH(Bz)-CO-NH-CH -CO -H2 2

H O2 H O2

(Non-specific esterase) Hydrolysis


O O

H HH H

N N

O

O O

O OH

H C3

hydrolysis

S HS

RACECADOTRIL(pro-drug)

THIORPHAN(active metabolite)



METABOLISM OF RACECADOTRIL

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

500

400

300

200

100

00 30 60 120 240 480 24 hrs

** p<0.01

En

ke

ph

ali

na

se a

ctiv

ity

(pm

ol/

ml/

min

ute

)

Tim e (m in)

**

**

**

**

RA CECA DOT RIL

Placebo


CLINICAL TRIALS

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 (Salazar-Lindo et al.)

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

INFANTS AND CHILDREN

Total stool output / body weight (g/kg)

400

350

300

250

200

150

100

50

0RA CECA DOT R IL

+ ORS (n=68)

Intent io n to t reat g ro up Ro tavirus-Posit ive Subg roup

RA CECA DOT R IL(n=34)+ ORS

Placebo+ ORS (n=67)

P<0.001

P<0.001

Placebo+ ORS (n=39)

Tota

l S

too

l O

utp

ut

(g/k

g)

53% 56%




Time to recovery

0 10 20 30 40 50 60 70 80 90 100 110 120

20

40

60

80

100

Durat ion o f Diarrhea (hr)

Rotavirus-positive boys

All boys

All boys

Rotavirus-positive boys

RA CECA DOT RIL + ORSPlacebo + ORS

Pro

ba

bil

ity

of

Un

reso

lve

d D

iarr

he

a (

%)





700

600

500

400

300

200

100

0

OR

S c

on

sum

pti

on

(m

l) p<0.001

Day 1 Day 2

RA CECA DOT RIL+ ORS (n=68)

Placebo + ORS (n=67)

Total intake of oral rehydration solution



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.

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.




Stool weight (g/hour) up to 48 hours

20

15

10

5

0Racecadotr i l

+ ORS(n=84)

Fu l l data set Per-p ro toco l po pu lat ion

Racecadotr i l

(n=53)+ ORS

Placebo+ ORS(n=82)

Placebo+ ORS(n=63)

**

***

Sto

ol

ou

tpu

t (g

/ho

ur)

** p = 0.009*** p = 0.001

40%

50%




Time to recovery in rotavirus-positive patients


100

80

60

40

20

00 10 20 30 40 60 70 80 9050

Pro

ba

bil

ity

of

un

reso

lve

d d

iarr

he

a (

%)

Placebo + ORS

RA CECA DOTRIL + ORS

Durat io n o f d iarrhea (hours)



Duration of diarrhea [median, hours]

Racecadotril[n = 32]

Placebo[n = 35]

P

6.9 36 0.02

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 ADULTSDavid 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.

A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE DIARRHEA IN ADULTS (Prado D.)

STUDY DESIGN single, blind, randomized– Multicenter (21 centers in 14 countries) – Parallel groups – Ambulatory patients

Prado D. Scand J Gastroenterol 2002;37:656-61

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

ADULTS

TREATMENT – Racecadotril: 100 mg, 3 times daily / Loperamide: 2 mg, 3

times daily

ADULTS

ANALYZED POPULATION – Racecadotril: 461 patients / Loperamide: 454 patients



Duration of Diarrhea

ADULTS


100

90

80

70

60

50

40

30

20

10

0

Pro

ba

bil

ity

of

un

reso

lve

dd

iarr

he

a (

%)

Tim e to reso lut ion (hours)

0 20 40 60 80 100

P=NS

120 140 160

RA CECA DOT R IL (N=473)

Loperamide (N=471)


Treatment-related adverse events with an incidence of more than 1%


ADULTS

1 4

1 2

1 0

8

6

4

2

0Constipation Abdominal enlargement Anorexia

% o

f P

ati

en

ts

RA CECA DOT RIL (n=473)Loperamide (n=472)

3.4

1.70 .8

12.5

6.1

2.3


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

PHARMACOVIGILANCE

13th Periodic Safety Update Report for Active Substance: Racecadotril. May 2007 Laboratoires Bioprojet Pharma.

Adults

Infants & Children

TOTAL

Period covered # of reportedadverse 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

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?

Re-

infe

ctio

n with

a n

..

Bac

teria

l pro

lifer

atio

n

This

is o

smotic

Dia

rrhe

a

0% 0%0%

A. Re-infection with a new bacteria/virus

B. Bacterial proliferation

C. This is osmotic Diarrhea

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.)

120

100

80

60

40

20

0

10

/

g c

on

ten

t(m

ed

ian

)

6E

. C

oli

RA CECA DOT RILControlLoperamide

p=0.04

p=0.86 p=0.005

1 4

120


1. Lecomte JM, Int.J. Of Antimicrobial Agents, 2000; 14:81-872. Scwartz J-C, Int.J. Of Antimicrobial Agents, 2000; 14:75-793. Duval-Iflah Y. Et al.,Alimentary Pharmacology, 1999; (suppl. 6): 9-144. Bergmann JF et al, Alimentary Pharmacology and Therapeutics, 1992; 6:305-3135. Knisely JS,Drug and Alcohol Dependence,1989;23:143-151

Blood-Brain Barrier

Astrocyteprocesses

Lipid solubletransport

Carrier-mediatedtransport

Does not induce CNS Toxicity1,2,3

Racecadotril

RACECADOTRIL DOES NOT CROSS THE BLOOD-BRAIN BARRIER

Does not impair mental performance4

Has no potential for abuse or physical dependence5


Therapeutic Index = LD50

ED50

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)


Case Number 2A 20 y/o Female develops diarrhea, voluminous

but not blood streaked. She is afebrile but dehydrated, your treatment of choice would be?

ORS/F

luid

Rep

lace

men

t

Rac

ecad

otril

Loper

amid

e

Antib

iotic

s

0% 0%0%0%

A. ORS/Fluid Replacement

B. Racecadotril

C. Loperamide

D. Antibiotics

Case Number 3A 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?

Rac

ecad

otril

Antib

iotic

Both

0% 0%0%

A. Racecadotril

B. Antibiotic

C. Both

Case Number 4A 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?

Rep

eat M

etro

nidaz

ole...

Ba

Enema

Colo

nosco

py

Sto

ol Exa

m

0% 0%0%0%

A. Repeat Metronidazole at higher dose

B. Ba Enema

C. Colonoscopy

D. Stool Exam

SUMMARY AND CONCLUSIONS

Prevention of Dehydration and Control of Diarrhea

NormalizationDiarrhea

OVERALL CONCLUSIONS

RACECADOTRIL IN THE TREATMENT OF ACUTE DIARRHEA

Diarrhea

Fluid replacement

Racecadotril

Fluid replacement

LoperamideRacecadotrilEfficacy variable

Motility1

Secretion2

Bacterial overgrowth1

CNS effects1

Constipation2

-

+++

-

-

-

+++

+

+

+

++

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

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. 2005Racecadotril summary of product characteristics

RACECADOTRIL

OVERALL CONCLUSIONS

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

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

Racecadotril: A Novel Approachin the Treatment of Acute Diarrhea

Thank you

racecadotril

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