Dextofisopam in the Treatment of Patients With IBS
Dextofisopam in the Treatment of Patients With IBS
Background: Dextofisopam modulates stimulated activity in animal models of stress, altered bowel motility, and visceral hypersensitivity.
Aim: To evaluate the effects of dextofisopam in men and women with diarrhoea-predominant or alternating irritable bowel syndrome (IBS) (d-IBS or a-IBS).
Methods: In this double-blind, placebo-controlled study, patients were randomly assigned to receive dextofisopam 200 mg b.d. or placebo for 12 weeks. The prospectively defined primary endpoint was number of months of adequate overall relief of IBS symptoms. Bowel function was assessed primarily via stool frequency and consistency.
Results: Of 140 enrolled patients, 66 received dextofisopam and 74 placebo; 73% of the patients were women, and 78% had d-IBS. Dextofisopam was superior to placebo on the primary endpoint (P = 0.033). In d-IBS patients treated with dextofisopam, both men and women had improved stool consistency, but stool frequency was reduced only in women. Benefit diminished over time on the primary endpoint, but persisted on frequency and consistency. Dextofisopam and placebo had similar rates and types of adverse events, with more events of worsening abdominal pain with dextofisopam (12% vs. 4%) and more headaches with placebo (12% vs. 5%). Constipation was rare.
Conclusion: Dextofisopam should be further evaluated as a new treatment for men and women with d-IBS and a-IBS.
Irritable bowel syndrome (IBS) is defined by a constellation of symptoms that includes abdominal pain or discomfort accompanied by diarrhoea, constipation, or an alternation between the two. Based on the predominant bowel disturbance, IBS patients are usually categorized as either 'diarrhoea-predominant', 'constipation-predominant', or 'alternating' between diarrhoea and constipation.
Irritable bowel syndrome is a common disorder, with prevalence estimated at 6-20% in North America, Europe, and Asia. Higher prevalence rates are reported for women than for men (two to three times greater). IBS has been shown to have a large negative impact on patients' function and quality of life, with significant social and economic costs.
Dextofisopam is the R-enantiomer of tofisopam, a nonsedating agent used for the treatment of a variety of illnesses associated with autonomic instability. With nitrogen atoms in the 2,3 position of its benzodiazepine ring, dextofisopam differs from typical benzodiazepines, which have nitrogen atoms in either the 1,4 or 1,5 position. Recent studies have indicated that dextofisopam binds to a novel binding site within the central nervous system that may be responsible for mediating its actions. This receptor has been characterized as the 2,3-benzodiazepine receptor, which is distinct from the classical 1,4 or 1,5-benzodiazepine receptor. Dextofisopam has no significant binding at other receptors or ion channels. In contrast to classical benzodiazepine receptors, which are primarily located in cortical areas, the 2,3-benzodiazepine receptors are concentrated in the subcortical ganglia, substantia nigra, and hypothalamus, and do not appear to be present in the gastrointestinal tract. It has been postulated that 2,3-benzodiazepine receptors may be important in the modulation of autonomic function, including gastrointestinal motor and sensory activity, and produce no sedation or altered sensorium, as occurs with classical 1,5-benzodiazepine agonists. Dextofisopam has been shown to decrease stimulated transit in animal models, reduce visceral pain in colorectal distension models, and have limited effects on basal transit.
Based on the profile above, a randomized, double-blind, placebo-controlled, parallel-group trial was conducted to assess the efficacy, safety, and tolerability of dextofisopam (200 mg b.d.) in men and women with diarrhoea-predominant or alternating IBS (d-IBS or a-IBS).
Summary and Introduction
Summary
Background: Dextofisopam modulates stimulated activity in animal models of stress, altered bowel motility, and visceral hypersensitivity.
Aim: To evaluate the effects of dextofisopam in men and women with diarrhoea-predominant or alternating irritable bowel syndrome (IBS) (d-IBS or a-IBS).
Methods: In this double-blind, placebo-controlled study, patients were randomly assigned to receive dextofisopam 200 mg b.d. or placebo for 12 weeks. The prospectively defined primary endpoint was number of months of adequate overall relief of IBS symptoms. Bowel function was assessed primarily via stool frequency and consistency.
Results: Of 140 enrolled patients, 66 received dextofisopam and 74 placebo; 73% of the patients were women, and 78% had d-IBS. Dextofisopam was superior to placebo on the primary endpoint (P = 0.033). In d-IBS patients treated with dextofisopam, both men and women had improved stool consistency, but stool frequency was reduced only in women. Benefit diminished over time on the primary endpoint, but persisted on frequency and consistency. Dextofisopam and placebo had similar rates and types of adverse events, with more events of worsening abdominal pain with dextofisopam (12% vs. 4%) and more headaches with placebo (12% vs. 5%). Constipation was rare.
Conclusion: Dextofisopam should be further evaluated as a new treatment for men and women with d-IBS and a-IBS.
Introduction
Irritable bowel syndrome (IBS) is defined by a constellation of symptoms that includes abdominal pain or discomfort accompanied by diarrhoea, constipation, or an alternation between the two. Based on the predominant bowel disturbance, IBS patients are usually categorized as either 'diarrhoea-predominant', 'constipation-predominant', or 'alternating' between diarrhoea and constipation.
Irritable bowel syndrome is a common disorder, with prevalence estimated at 6-20% in North America, Europe, and Asia. Higher prevalence rates are reported for women than for men (two to three times greater). IBS has been shown to have a large negative impact on patients' function and quality of life, with significant social and economic costs.
Dextofisopam is the R-enantiomer of tofisopam, a nonsedating agent used for the treatment of a variety of illnesses associated with autonomic instability. With nitrogen atoms in the 2,3 position of its benzodiazepine ring, dextofisopam differs from typical benzodiazepines, which have nitrogen atoms in either the 1,4 or 1,5 position. Recent studies have indicated that dextofisopam binds to a novel binding site within the central nervous system that may be responsible for mediating its actions. This receptor has been characterized as the 2,3-benzodiazepine receptor, which is distinct from the classical 1,4 or 1,5-benzodiazepine receptor. Dextofisopam has no significant binding at other receptors or ion channels. In contrast to classical benzodiazepine receptors, which are primarily located in cortical areas, the 2,3-benzodiazepine receptors are concentrated in the subcortical ganglia, substantia nigra, and hypothalamus, and do not appear to be present in the gastrointestinal tract. It has been postulated that 2,3-benzodiazepine receptors may be important in the modulation of autonomic function, including gastrointestinal motor and sensory activity, and produce no sedation or altered sensorium, as occurs with classical 1,5-benzodiazepine agonists. Dextofisopam has been shown to decrease stimulated transit in animal models, reduce visceral pain in colorectal distension models, and have limited effects on basal transit.
Based on the profile above, a randomized, double-blind, placebo-controlled, parallel-group trial was conducted to assess the efficacy, safety, and tolerability of dextofisopam (200 mg b.d.) in men and women with diarrhoea-predominant or alternating IBS (d-IBS or a-IBS).
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