Hidrasec Adults 9-11-07
Hidrasec Adults 9-11-07
Hidrasec Adults 9-11-07
in the Treatment
of Acute Diarrhea
PRESENTATION OUTLINE
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
te
Li
Li
Li
Li
2
9
FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES
Water absorption
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
FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES
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
FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES
Gut lumen
Enterocyte
NORMAL STATE
Crypt: Secretion
µ (mu) δ (delta)
has inhibitory effects on decreases cAMP formation
intestinal smooth muscles
Exogenous
- Morphine +++ +
- Loperamide +++ +
Endogenous
- Enkephalins + +++
Delta receptor
c-AMP
VIP
Prostaglandins
ATP
Enkephalins
Enkephalinase
A. Passage of
abnormally liquid
stools at increased
frequency
B. Stool weight > 200
grams/day
C. Both 0% 0% 0%
...
h
ot
ly
..
g.
al
B
m
0
20
or
bn
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a
gh
of
ei
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lw
ag
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ss
St
Pa
DIARRHEA
DIARRHEA
DIARRHEA
Over-secretion of water leads to diarrhea.
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%
ks
ks
ks
ee
ee
ee
w
w
w
4
2
4
–
<
>
2
DIARRHEA
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
Defective absorption
Hypersecretion:
Vibrio cholerae, rotavirus,
ETEC, shigella
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%
k
k
ee
ee
ee
w
w
a
a
s
nt
s
nt
nt
t ie
tie
tie
pa
pa
pa
1
7
–
>
3
BURDEN OF DIARRHEA
BURDEN OF DIARRHEA
BURDEN OF DIARRHEA
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
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%
rs
RS
l
tri
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id
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o
O
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O
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A
Lo
R
MANAGEMENT OF DIARRHEA
Antibiotics - Resistance
- Unwanted adverse effects
Edelman R. Prevention and treatment of infectious diarrhea. Speculations on the next 10 years.
Am J Med 1985;78:99-106.
UNMET MEDICAL NEEDS IN THE TREATMENT OF ACUTE DIARRHEA
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%
s
o
Ye
N
RACECADOTRIL:
AN INTESTINAL
ANTISECRETORY
AGENT
RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT
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
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)
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 )
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.
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
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
D u ra t io n o f D ia rr h e a (h r)
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
Racecadotril + ORS 10
Placebo + ORS 7
The incidence of vomiting did not differ between the racecadotril and
placebo groups.
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
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
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
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 )
Racecadotril + ORS 10
Placebo + ORS 11
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
Rac eca dot ril with those of Lo per amide in pat ient s wi th
acu te diarrh ea .
ADULTS
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
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
A MULTINATIONAL COMPARISON OF
RACECADOTRIL AND LOPERAMIDE IN
THE TREATMENT OF ACUTE DIARRHEA
IN ADULTS (Prado D.)
TREATMENT
– Racecadotril: 100 mg, 3 times daily / Loperamide: 2 mg, 3
times daily
ANALYZED POPULATION
– Racecadotril: 461 patients / Loperamide: 454 patients
A MULTINATIONAL COMPARISON OF
RACECADOTRIL AND LOPERAMIDE IN
THE TREATMENT OF ACUTE DIARRHEA
IN ADULTS (Prado D.)
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)
Prado D. Scand J Gastroenterol 2002;37:656-61
ADULTS
A MULTINATIONAL COMPARISON OF
RACECADOTRIL AND LOPERAMIDE IN
THE TREATMENT OF ACUTE DIARRHEA
IN ADULTS (Prado D.)
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
A MULTINATIONAL COMPARISON OF
RACECADOTRIL AND LOPERAMIDE IN
THE TREATMENT OF ACUTE DIARRHEA
IN ADULTS (Prado D.)
CONCLUSION
Racecadotril resolved the symptoms of acute diarrhea rapidly and
effectively, and produced more rapid resolution of abdominal
symptoms and less constipation than loperamide.
PHARMACOVIGILANCE
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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SAFETY AND TOLERABILITY
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
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
SAFETY AND TOLERABILITY
A. ORS/Fluid
Replacement
B. Racecadotril
C. Loperamide 0% 0% 0% 0%
D. Antibiotics
s
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tri
t ic
id
o
m
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io
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ra
ce
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pe
nt
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A
Lo
R
R
id
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/Fl
RS
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%
t ic
l
h
tri
ot
io
o
B
ad
ib
nt
ec
A
ac
R
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
m
a
y
...
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R
SUMMARY AND
CONCLUSIONS
OVERALL CONCLUSIONS
Fluid Fluid
replacement replacement
Racecadotril
OVERALL CONCLUSIONS
RACECADOTRIL VERSUS
LOPERAMIDE
Efficacy variable Racecadotril Loperamide
Motility1 - +++
Secretion2 +++ +
Bacterial overgrowth1 - +
Constipation2 - ++
CNS effects1 - +
RACECADOTRIL
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
RACECADOTRIL