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Otilonium bromide

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Page 1: Spasm Omen

Otilonium bromide

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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

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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

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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

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Otilonium bromideMechanism of action

Otilonium bromide modulates calcium fluxesin the intestinal smooth muscle cells

Decrease of calcium current

Farrugia, ICUR-Meeting 2003

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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

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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

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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

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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

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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

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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

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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

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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

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Otilonium bromideAbdominal pain control

Dose-dependent effect on abdominal pain

Duration of analgesia

Busachi, data on file at Menarini Ricerche 1974

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Otilonium bromideAbdominal pain control

Rapid and sustained pain control

Medi-sphere 1995

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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

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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

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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

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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

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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

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Otilonium bromideGlobal efficacy

Treatment with otilonium bromide resulted in a betterglobal efficacy outcome vs. placebo

Battaglia, Aliment Pharmacol Ther 1998;12:1003-1010

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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

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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

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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

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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

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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

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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

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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

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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

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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