site (initially termed "BZD receptor") of the GABAA receptor chloride ionophore complex or exhibit a GABAA receptor subtype-selectivity are thought to have advantages vs. full agonists such as diazepam and most other clinically used BZDs in that such compounds have less adverse effects and reduced or absent tolerance and dependence liability. One of such compounds, abecarnil, has been clinically evaluated as a novel anxiolytic drug, but, despite its potent preclinical anti-seizure activity, it has not yet been evaluated in patients with epilepsy. In the present proof-of-concept study, we performed a within-subject placebo-controlled, single oral dose study of abecarnil in patients with photosensitive epilepsy. Flumazenil, which is generally considered a BZD receptor antagonist, but has slight
The first double-blind, placebo-controlled trial of a partial benzodiazepine agonist abecarnil (ZK 112-119) in generalized anxiety disorder. This is the first reported controlled trial of a partial benzodiazepine agonist, abecarnil, utilized in the treatment of generalized anxiety disorder (GAD). It was a sequential dose-finding study comparing 15-30 mg/day, 7.5-15 mg/day, and 3-9 mg/day and Hamilton Anxiety Scale (HAM-A) scores. At Week 3, 61 percent of the abecarnil 3-9 mg/day group was rated as at least 50 percent improved on the HAM-A, compared to 30 percent of the placebo group. With abrupt discontinuation there were mild to moderate withdrawal symptoms and loss of efficacy in the two higher dose groups. However, in the 3-9 mg/day abecarnil group, there were few withdrawal symptoms
Double-blind, placebo-controlled trial of two doses of abecarnil for geriatric anxiety. We studied the tolerability and efficacy of abecarnil, a new partial benzodiazepine agonist, for short-term relief of anxiety in geriatric patients. After a 1-week placebo lead-in, 182 outpatients (mean +/- SD age = 68.3 +/- 5.8; range, 59-85 years) were randomly assigned in a double-blind, parallel-group design to high-dosage abecarnil (7.5-17.5 mg daily), low-dosage abecarnil (3.0-7.0 mg daily), or placebo for 6 weeks of acute treatment followed by abrupt discontinuation and a 2-week follow-up. During the acute treatment period, the discontinuation rate from adverse events was greater for the group treated with high-dosage abecarnil (44%) than for the groups treated with low-dosage abecarnil (14
Abecarnil for the treatment of generalized anxiety disorder: a placebo-controlled comparison of two dosage ranges of abecarnil and buspirone. The development of effective and well-tolerated anxiolytic agents is an area of critical clinical importance. Abecarnil, a beta carboline, is a partial benzodiazepine-receptor agonist that has demonstrated promise as an anxiolytic agent. In this study, we examine the efficacy, safety, and discontinuation-related effects of abecarnil, buspirone, and placebo in the acute and long-term treatment of patients who have generalized anxiety disorder. This is a double-blind, placebo-controlled study of two dosages of abecarnil and buspirone. In total, 464 patients were randomized. After a placebo run-in week, patients entered a 6-week double-blind treatment
A double-blind evaluation of the safety and efficacy of abecarnil, alprazolam, and placebo in outpatients with generalized anxiety disorder. Abecarnil Work Group. In a placebo-controlled, multicenter study, 180 male and female outpatients, ages 18-65, with DSM-III-R generalized anxiety disorder, were treated with abecarnil (a partial benzodiazepine agonist), alprazolam, or placebo for 4 weeks . This was followed by a rapid (1-week) taper, during which patients were assessed for any taper-related symptoms. All patients were identified via a structured clinical interview for DSM-III-R and randomly assigned to one of the three treatment groups. More than 70% of each treatment group completed the study. In the acute-treatment phase, both abecarnil and alprazolam showed evidence for efficacy
Human studies on abecarnil a new beta-carboline anxiolytic: safety, tolerability and preliminary pharmacological profile. 1. Abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate), a beta-carboline with high affinity for benzodiazepine receptors, was tested in healthy male subjects; single doses of abecarnil were given in five dosage levels (1 mg, 5 mg, 10 mg, 20 mg, 40 mg and biochemical and haematological screening. Drug effects were estimated utilizing a bipolar visual analogue scale (poles: 'sleepy'-'alert') and a psychomotor task, the digit symbol substitution task. The pharmacokinetics of single and multiple doses were also determined in the multiple dose study. 3. Abecarnil was generally well tolerated. In the single dose study the most frequently reported side effects
Abecarnil and alprazolam in humans: behavioral, subjective and reinforcing effects. Abecarnil, a novel beta-carboline, is under development for the treatment of Generalized Anxiety Disorder. This study compared the behavioral, subjective and reinforcing effects of abecarnil to those of the benzodiazepine alprazolam in 14 healthy males with histories of sedative drug abuse. Placebo, abecarnil (10 , 20, 40 mg) and alprazolam (1.0, 2.0, 4.0 mg) were administered p.o. in a double-blind, cross-over design. Abecarnil and alprazolam produced comparable dose-dependent decreases in behavioral performance on balance, circular lights, digit-recall and digit-symbol-substitution tasks that peaked 2-4 hr after drug administration. Both drugs produced a profile of sedative effects and were categorized
A double-blind, placebo-controlled trial of abecarnil and diazepam in the treatment of patients with generalized anxiety disorder. In a multicenter, double-blind trial, 310 patients who had received a diagnosis of generalized anxiety disorder were treated for 6 weeks with either abecarnil, diazepam, or placebo at mean daily doses of 12 mg of abecarnil or 22 mg of diazepam administered three times daily. Patients who were improved at 6 weeks could volunteer to continue double-blind treatment for a total of 24 weeks. The maintenance treatment phase allowed the comparison of taper results for the three treatments at several study periods (0-6 weeks, 7-12 weeks, and more than 12 weeks). Slightly more diazepam (77%) and placebo (75%) patients completed the 6-week study than abecarnil patients (66
Abecarnil, a new beta-carboline, in the treatment of anxiety disorders. Abecarnil, a novel anxiolytic beta-carboline, was investigated in five four-week double-blind, European multicentre studies. Overall 451 patients with generalised anxiety disorder were randomised to abecarnil, 461 to placebo and 464 to active controls. Data includes inferential statistics based on individual studies and descriptive analysis of 323 patients in open-label abecarnil long-term continuation up to 52 weeks. Abecarnil was safe, the most frequent adverse event being drowsiness. Onset of effect was at week 1. At week 4 the Hamilton Anxiety Scale score had improved by 12-13 points on average. Due to notably large and variable placebo effects abecarnil was not consistently superior to placebo. No rebound
A double-blind comparison of abecarnil and diazepam in the treatment of uncomplicated alcohol withdrawal. Treatment of the alcohol withdrawal syndrome is best accomplished using pharmacologic agents that have minimal interaction with alcohol, have limited adverse effects, and are without abuse potential. The partial benzodiazepine receptor agonist beta-carboline compound, abecarnil, has been shown in animal and human studies to possess a number of these characteristics and to be useful in the reduction of alcohol withdrawal convulsions in mice. In this study, 49 alcohol-dependent inpatients who exhibited at least moderate symptoms of uncomplicated alcohol withdrawal were treated over a 5-day detoxification period with abecarnil or diazepam and rated daily for alcohol withdrawal symptoms
Psychomotor effects of the anxiolytic abecarnil: a comparison with lorazepam. Abecarnil is a metabolically stable beta-carboline that binds with high affinity and selectivity to central benzodiazepine receptors. The effects on cognitive and psychomotor skills of abecarnil (ZK 112-119), 2.5 mg and 5.0 mg, were compared with lorazepam 2.0 mg and placebo. Twenty-four healthy, young males participated in a double-blind, four-way Latin square design and performed batteries of behavioral tests at predrug and at 20, 40, 60, 80, 100, 120, 180, 240, 360 and 480 min after drug administration. Abecarnil 5.0 mg and lorazepam 2.0 mg displayed similar impairment profiles in tests of cognitive functions including memory encoding. Abecarnil 2.5 mg was substantially less impairing than lorazepam
and Healthcare products Regulatory Agency (MHRA). We found 52 systematic reviews, RCTs, or observational studies that met our inclusion criteria. In this systematic review we present information relating to the effectiveness and safety of the following interventions: abecarnil, antidepressants (imipramine, opipramol, paroxetine, sertraline, escitalopram and venlafaxine), antipsychotic drugs (trifluoperazine
Alprazolam dependence prevented by substituting with the β-carboline abecarnil Abrupt termination of the treatment of humans with benzodiazepines (BDZs) leads to a rapid onset of discontinuation syndrome characterized by anxiety, muscle spasms, and occasionally convulsions. For this reason, it is recommended in clinical practice to reduce the dose of the BDZs gradually at the end of treatment , and seizures between days 1 and 28 after termination of the treatment. Replacement of alprazolam with the beta-carboline abecarnil for 7 days prevented the occurrence of the signs of dependence. In contrast, substitution of the beta-carboline antagonist ethyl-5-isopropoxy-4-methyl-beta-carboline-3-carboxylate (ZK93426) for alprazolam worsened the discontinuation syndrome. Replacement therapy with abecarnil
, pregnenolone and progesterone, in both brain and plasma of handling-habituated rats, whereas handling in naive rats increased the concentrations of these steroids only in brain. 4. Pretreatment of handling-habituated rats with the anxiolytic beta-carboline derivative abecarnil, a positive allosteric modulator of GABAA receptors, which per se failed to affect the AP concentration in brain or plasma, prevented
at an alpha/beta subunit interface. Structural intermediates of ZK 91085 and the beta-carboline abecarnil, the latter of which only slightly potentiated GABA currents in alpha1/beta2, were analysed to determine structural requirements for modulation. ZK 91085 thus allosterically stimulates the GABA(A) receptor through two sites of action: the benzodiazepine site and the loreclezole site in contrast
Pharmacokinetics of abecarnil in patients with renal insufficiency. To characterize the pharmacokinetics of a single 5 mg oral dose of abecarnil in subjects with varying degrees of renal impairment. Twenty-six subjects were enrolled in this open-label parallel-group study. Ten subjects had normal renal function (NRF; creatinine clearance [CLCR] > or = 85 ml/min/1.73 m2), six subjects had mild to moderate renal insufficiency (MMRI; CLCR between 25 and 73 ml/min/1.73 m2), and 10 subjects had severe renal insufficiency (SRI; CLCR < or = 10 ml/min/1.73 m2). Abecarnil plasma concentrations were determined by means of HPLC, and plasma protein binding was determined by use of ultracentrifugation. Pharmacokinetic parameters were obtained with use of model-independent and model-dependent methods