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Otilonium bromide
Otilonium bromideChemistry & structural formula
The prototype of a class of 2-aminoethyl-N-benzoyl-aminobenzoatequaternary salts, endowed with spasmolytic activity on the intestinal
smooth muscle
Chemical name: diethylmethyl{2-[4-(2-octyloxybenzamido)benzoyloxy]-ethyl}ammonium bromideMolecular formula: C29H43BrN2O4
Molecular weight: 563.6
Otilonium bromideTherapeutic indications
Otilonium bromide is used as an antispasmodicfor treating spastic painful conditions of the distal section of the intestinal tract, including IBS
It is also effective in reducing intestinal spasmduring endoscopy
Otilonium bromideMechanism of action
Otilonium bromide restores physiological motility and enhances painthreshold to intestinal stimuli
ACh: acetylcholine, SP: substance P; NKA: neurokine A; NK1 and NK2: tachykinins
- OB modulates calcium entry in the intestinal smooth muscle cells (extra-cellular)
- OB inhibits Ca++ release from sarcoplasmic reticulum (intra-cellular)
- OB antagonizes tachykinin receptors
Otilonium bromideMechanism of action
Otilonium bromide modulates calcium fluxesin the intestinal smooth muscle cells
Decrease of calcium current
Farrugia, ICUR-Meeting 2003
Otilonium bromideMechanism of action
Relevant antisecretory effects on colonic crypts isolatedfrom human samples
- Perfusion of colonic crypts with acetylcholine produces an increase in intra-cellular calcium- Pretreatment with otilonium bromide inhibits human colonic crypt calcium signals
(marked by change in the color and then the redness of the crypt)
Williams, ICUR-Meeting 2003
Otilonium bromideMechanism of action
Otilonium bromide antagonizes tachykinin receptorson the intestinal smooth muscle cells and afferent nervous terminations,
thus modulating the development of intestinal hyperalgesia
Otilonium bromideMechanism of action (Summary)
Intense antispasmodic effect on the smooth muscles of the digestive tract: inhibition of basal and stimulated gastrointestinal motility in response to contractingagents of different nature, either chemical or physical
A combination of Ca++ channel blocking properties(INTRA- and EXTRA-CELLULAR fluxes) and mild antimuscarinic effects seems to better explain the pharmacological action
Modulation of intestinal hyperalgesia development
Otilonium bromideSelective intestinal uptake
Tissue distribution of [14C]-otilonium bromide after oral administrationof 2 mg/kg in rats
Evangelista, Drug Metab Dispos 2000;28:643-647
Otilonium bromideSelective intestinal uptake
Otilonium bromide is poorly absorbedafter oral administration (<3%)
The small absorbed fraction is rapidly eliminated
from the circulation through the biliary tract
The drug does not cross the blood-brain barrier
The most important route of elimination
is represented by the feces
Otilonium bromideToxicology
In animal models, otilonium bromide has proven minimal toxicity; therefore, overdoseshould not be a concern
In addition, no embryotoxicity, teratogenic, or mutagenic effects were observed in animal studies
Otilonium bromideClinical pharmacology
Preliminary studies involving healthy subjects and IBS patients demonstrated that:
1 - Otilonium bromide significantly reduced the magnitude and duration of the impaired gastrocolonic response to food
2 - Otilonium bromide showed a dose-dependent, rapid, and sustained effect on abdominal pain and visceral hypersensitivity
Sutton, Eur J Clin Pharmacol 1997;52:365-369
Otilonium bromideEffects on impaired colonic response
In IBS patients, otilonium bromide significantly reduced the magnitude and duration of the impaired gastrocolonic response to food
Narducci, Dig Dis Sci 1986;31:241-246
Otilonium bromideAbdominal pain control
Dose-dependent effect on abdominal pain
Duration of analgesia
Busachi, data on file at Menarini Ricerche 1974
Otilonium bromideAbdominal pain control
Rapid and sustained pain control
Medi-sphere 1995
Otilonium bromideModulation of visceral hypersensitivity
Otilonium bromide increases pressure threshold for pain and maximumtolerable distension (MTD) during barostat stimulation of patients with IBS
Bueno, ICUR-Meeting 2003
Otilonium bromideModulation of visceral hypersensitivity
Otilonium bromide increases volume threshold for pain and maximumtolerable distension (MTD) during barostat stimulation of patients with IBS
Bueno, ICUR-Meeting 2003
Otilonium bromideClinical efficacy in IBS
The clinical efficacy of otilonium bromide in patients with IBS has been documented in more than 20 trials involving at least 2,600 patients
- In the majority of these studies the standard therapeutic dose of 40 mg, three times a day, was used
Otilonium bromideComparison with placebo
Battaglia G et al. Aliment Pharmacol Ther 1998;12:1003-1010
Study design:Double-blind, placebo-controlled, randomized, 15-week study in patients with IBS
Endpoints:- Severity of symptoms - Investigator objective signs- Quality of life- Global assessment of efficacy by the investigators
Otilonium bromideClinical efficacy
A double-blind, placebo-controlled, 15-week study in Irritable Bowel Syndrome
Assessment of Efficacy
Patient
Symptoms
Abdominal pain
Abdominal distension
Bowel habits
Quality of life
Visual Analogue Scale (VAS)
Investigator
Objective signs
Tenderness of sigmoid colon
Pain evocation
Global assessment of efficacy
Battaglia, Aliment Pharmacol Ther 1998;12:1003-1010
Otilonium bromideGlobal efficacy
Treatment with otilonium bromide resulted in a betterglobal efficacy outcome vs. placebo
Battaglia, Aliment Pharmacol Ther 1998;12:1003-1010
Otilonium bromideAssessment of treatment efficacy
According to physicians, treatment with otilonium bromide was “Good or Excellent” in a higher percentage of IBS patients vs. placebo
Battaglia, Aliment Pharmacol Ther 1998;12:1003-1010
Otilonium bromideProportions of responders
Considering the 3 major endpoints (pain intensity, pain frequency,and presence of meteorism and distension), otilonium bromide showedsignificantly higher proportions of responders compared with placebo
Glende, Eur J Gastroenterol Hepatol 2002;14:1331-1338
Otilonium bromideEfficacy on diarrhea/constipation in IBS
An extended analysis of a large clinical trial demonstrated that otilonium bromide shows a significant therapeutic gain vs. placebo in reducing both frequency and intensity of pain,as well as discomfort, in patients who reportDIARRHEA, CONSTIPATION or an alternation of both as their dominant intestinal habit
Glende, Eur J Gastroenterol Hepatol 2002;14:1331-1338
Otilonium bromideSafety
Placebo-like tolerability
Otilonium bromide has a placebo-like tolerability without systemic anticholinergic effects
Otilonium bromide spasmolytic activity on the gastrointestinal tract is evident at doses that neither affect the gastric secretion nor produce the typical atropine-like side effects
Otilonium bromide Placebo
n° of treated patients 160 165
n° of patients with adverse events 2 1
Battaglia, Aliment Pharmacol Ther 1998;12:1003-1010
Otilonium bromideSafety
Clinical Expert Statements, 2000-2004
From January 2000 to December 2004, based on the packages/units sold, a total number of approximately 4,700,000 (3 tabs/die) to 7,000,000 (2 tabs/die) patients/month (30 days) treated with tablets, and more than 4,000 patients in which gastrointestinal endoscopy was performed using vials, have been estimated
Within the Periodic Safety Update Reports (PSURs) covering this period, only one suspected non-serious Adverse Drug Reaction (ADR) was reported
Otilonium bromideSafety
Otilonium bromide exerts its action locally, Without any considerable systemic side effect
Absorption following oral administration is very low
Otilonium bromide was highly safe both in short-term (2 weeks) and long-term (2 years) clinical trials
At therapeutic doses, the drug does not cause side effects- No drug interactions have been reported to date- Otilonium bromide has proven minimal toxicity in animals; therefore, overdose should not cause any particular problem in humans- Otilonium bromide can be safely given to patients with hepatic, renal, and cardiac diseases
Otilonium bromideAdministration
Dosage and administration
Each tablet contains 40 mg otilonium bromide
Dosage is one tablet two/three times a day,
according to physician’s discretion
Otilonium bromideConclusions
IBS is the most frequent cause of chronic recurrentabdominal pain, and it is associated with significantdisability and healthcare costs
Otilonium bromide is a quaternary ammonium derivativeendowed with an original mechanism of action
Otilonium bromide possesses distinct smooth musclefavorable properties and effects on visceral perception
Otilonium bromide shows a localized activity,as it is poorly absorbed and selectively taken upin the lower gastrointestinal tract
Otilonium bromideConclusions
Clinical trials demonstrated that otilonium bromide reduces abdominal pain and discomfort in patients with IBS
In controlled clinical trials, otilonium bromideefficacy and tolerability compared favorably vs. placeboand active comparators
Most IBS patients can be treated with otilonium bromidein a safe and effective manner
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