Non-benzodiazepine Anxiolytic Agent Research Articles

Buspirone decreases the activity of 5-hydroxytryptamine-containing dorsal raphe neurons in-vitro.

Buspirone, a non-benzodiazepine anxiolytic agent, produced a dose-dependent decrease in the activity of 5-HT-containing dorsal raphe neurons recorded from mouse brain slices. The response was not changed in a low calcium/high magnesium incubation medium, indicating that the observed effects were the result of a direct action of buspirone on raphe neurons. These data are discussed within the context of the anxiolytic effects of buspirone.

Metabolism of the new nonbenzodiazepine anxiolytic agent, RWJ-51204, in mouse, rat, dog, monkey and human hepatic S9 fractions, and in rats, dogs and humans

The in vitro and in vivo metabolism of the nonbenzodiazepine anxiolytic agent, RWJ-51204 was investigated after incubation with mice, rat, dog, monkey, and human hepatic S9 fractions in the presence of NADPH-generating system, and a single oral dose administration to rats (100 mg/kg), dogs (5 mg/kg), and humans (2.5 mg/subject). Plasma and red blood cells (2 h, rat) and urine samples (0-24 h, rat, dog and human) were obtained postdose. Unchanged RWJ-51204 (39-93% of the sample in vitro; < or =5% of the sample in vivo) plus 14 metabolites were profiled, quantified and tentatively identified on the basis of API-MS and MS/MS data, and by comparison of synthetic samples. The in vitro and in vivo metabolic pathways for RWJ-51204 are proposed, and the metabolite formations are via the following five pathways: 1. phenyl oxidation, 2. pyrido-oxidation, 3. N-deethoxymethylation, 4. dehydration, and 5. glucuronidation. Pathway 1 formed 4-hydroxy-2-fluoro-phenyl-RWJ-51204 (M1, 7-24% in vitro; 5-60% in vivo) in major amounts, OH-benzimidazole-RWJ-51204 (M2, 5-8% in vitro and in vivo) and diOH-phenyl-RWJ-51204 (< or =5-16% in vitro and in vivo); in conjunction with pathway 5 produced M1 glucuronide (60% in rat & dog; 17% in human), M2 glucuronide (16% in human). Pathways 2-4 formed minor/trace oxidized, and dehydrated metabolites. RWJ-51204 is extensively metabolized in vitro (except dog) and in vivo in rats, dogs and humans.

Psychopharmacology in supportive care of cancer: a review for the clinician. IV. Other psychotropic agents.

Besides benzodiazepine, antidepressant and neuroleptic agents, all of which have established roles in supportive care, other psychotropic drugs deserve consideration in selected conditions affecting patients with advanced cancer. This article briefly reviews relevant aspects of miscellaneous psychotropics available for secondline treatment, including nonbenzodiazepine sedative, hypnotic and anxiolytic drugs, anaesthetic agents, stimulants, and analgesic adjuvants acting on the central nervous system. The proper use of such subsidiary psychotropic agents requires that both their specificities and the particular characteristics of palliative care patients are taken into account.

Which patients presenting with clinical anxiety will abuse benzodiazepines?

Although benzodiazepines represent much safer alternatives to the old generation of sedative-hypnotics, in contemporary practice a minority of patients still abuse them. Many physicians are leery of prescribing benzodiazepines for fear of inadvertently contributing to such abuse. In the present investigation of a stratified sample of 134 adult patients from anxiety and chemical dependency clinics in two university medical centers were systematically evaluated in semi-structured interviews based on a modification of Washington University criteria. Sedative (mostly benzodiazepines) abuse was significantly associated with such indicators of long-term maladjustment as antisocial personality and somatization hysteria, labile moods, temper outbursts, unstable interpersonal relationships, alcoholism, and a history of suicide attempts. Family history of alcoholism was not significant when controlled for familial antisocial personality. Neither depression, nor its chronicity or family history for depression, had any bearing on abuse of benzodiazepines. Logistic regression identified unstable tempestuous relationships and family history of antisocial behavior as the most powerful predictors; in particular, absence of such history correctly classified 80 per cent of those who did not abuse these drugs. Our data can help physicians decide which clinically anxious patients can be prescribed benzodiazepines with relative peace of mind. Apart from the foregoing patient characteristics, physicians must consider pharmacokinetic factors which suggest that benzodiazepines with longer half-lives are least likely to result in dependence. Finally, non-benzodiazepine anxiolytic agents—such as hydroxyzine and SSRIs—should receive serious consideration as less problematic agents in the clinical management of anxiety disorders. Whenever available, brief psychotherapeutic approaches should also be provided. Copyright © 1999 John Wiley & Sons, Ltd.

Comparative Study of the Effects of Captodiamine and Lorazepam on Car Driving Ability

Objective: To compare the effects of lorazepam, a benzodiazepine-type anxiolytic agent, with those of captodiamine, a non-benzodiazepine anxiolytic agent, on vigilance and on driving behaviour. Design: Randomised, double-blind, crossover trial. Study Participants: Sixteen healthy male volunteers, aged 29 to 44 years, medically qualified to drive, holding a driving licence for more than 5 years, and driving more than 15 000km per year. Intervention: Lorazepam 0.5mg in the morning and at lunchtime, 1mg at bedtime, for 7 days; captodiamine 50mg in the morning, at lunchtime and at bedtime, for 7 days. Outcome Measures: Principal criterion: driving test on a 900m circuit with assessment of the number of errors resulting from clumsiness, excessive inhibition and disinhibition. Other criteria: psychometric tests (visual and auditory reaction times, tremometric test) and measurement by visual analogue scales of the degree of internal stress, anxiety, drowsiness and reduction of physical and mental capacity. All measurements were made before and after 7 days of treatment. Results: During the driving test a reduction in the number of errors resulting from clumsiness and disinhibition was observed with captodiamine, whereas an increase in the number of errors was seen with lorazepam (p < 0.001). A trend towards a shortening of auditory reaction time was noted in favour of captodiamine (p < 0.10). The reduction in internal stress was significantly greater with lorazepam compared with captodiamine (p < 0.05). Atendency to drowsiness was noted with lorazepam (p < 0.10). No other trend or significant difference was observed between the two drugs. Conclusion: Compared with lorazepam, captodiamine improved the concentration and dexterity of individuals when driving, without inducing a tendency to drowsiness.

Concentrations and effects of buspirone are considerably reduced by rifampicin

Aims The effects of rifampicin on the pharmacokinetics and pharmacodynamics of buspirone, a non-benzodiazepine anxiolytic agent, were investigated. Methods In a randomized, placebo-controlled cross-over study with two phases, 10 young healthy volunteers took either 600 mg rifampicin or matched placebo once daily for 5 days. On day 6, 30 mg buspirone was administered orally. Plasma buspirone concentrations and effects of buspirone were measured up to 10 h. Results The total area under the plasma buspirone concentration-time curve after rifampicin was 10.4% (95% CI, 6.3–14.5%) of that after placebo (1.64±0.35 ng ml−1 h vs 22.0±15.1 ng ml−1 h (mean±s.d.); P<0.01). Rifampicin decreased the peak plasma concentration of buspirone from 6.6±3.7 ng ml−1 to 0.84±0.23 ng ml−1 (P<0.01) and the half-life from 2.8±0.7 h to 1.3±0.5 h (P<0.01). A significant (P<0.05) reduction in the effects of buspirone was observed in three of the six psychomotor tests employed (postural sway test with eyes closed, subjective drowsiness and overall drug effect) after rifampicin pretreatment. Conclusions The strong interaction between rifampicin and buspirone is probably mostly due to enhanced CYP3A4-mediated first-pass metabolism of buspirone. Buspirone will most likely show a greatly reduced anxiolytic effect when used together with rifampicin or other potent inducers of CYP3A4 such as phenytoin and carbamazepine.

Development of 5-HT 1 A receptor antagonists

The discovery that non-benzodiazepine anxiolytic agents such as buspirone bind with high affinity to the 5-HT 1 A receptor has stimulated the development of selective 5-HT 1 A receptor ligands as potential drug candidates. However, the lack of selective 5-HT 1 A receptor antagonists has hampered the elucidation of the mechanism of action of these agents, indeed, it is still unclear whether buspirone exerts its anxiolytic effects via an agonist action at presynaptic (somatodendritic) or an antagonist action at postsynaptic 5-HT 1 A receptors. Ligands that have been used previously to define the 5-HT 1 A receptor are either non-selective or have agonist activity at the presynaptic 5-HT 1 A receptor. It is only in the past three years that selective and silent 5-HT 1 A receptor antagonistshave emerged. This overview compares the profiles of the first selective 5-HT 1 A receptor antagonists in models of pre- and postsynaptic 5-HT 1 A receptor function. In addition, it highlights some of the problems associated with the development of selective 5-HT 1 A receptor antagonists.

Physician patterns in the provision of health care to their own employees.

To determine the level of medical and mental health care that family physicians provide to employees. Mailed survey. Family practices in Oklahoma. Two hundred ninety-one of 735 physicians assessed via the membership roster of the Oklahoma Academy of Family Physicians. The majority of physician respondents (55.6%) reported providing routine health care always or most of the time to employees. Rural practice sites were associated with the provision of broader medical services (Spearman's p = -.35, P < .00001); 51.7% of respondents reported providing routine health care always or most of the time to employees' families. Breast and genital examinations were more likely to be undertaken in family members (67.2%) compared with employees (50.0%). Only a minority of physician respondents (12.3%) reported providing mental health care always or most of the time to employees; 53% never or rarely provided this service. When mental health care was addressed, respondents provided counseling alone (28.6%), prescription of psychotropic medication alone (8.8%), or both (62.7%). Antidepressants (50.7%) and nonbenzodiazepine anxiolytic agents (36.2%) were most frequently prescribed. When asked about ideal conditions, a significant minority of physician respondents (41.3%) preferred to refer employees to colleagues for medical care, and 59.8% preferred to refer for mental health care. The majority of family physicians in this study reported providing medical care to their employees, whereas only a minority provide mental health care.

The psychopharmacology of clobazam

The psychopharmacology of clobazam, specifically its effects on CNS arousal, cognitive and memory functions and psychomotor performance, is reviewed. Compared with the 1,4-benzodiazepine tranquillizers, clobazam is characterized by a lack of sedative and amnestic effects and no impairment of psychomotor skills including car driving, both in volunteer and clinically anxious patient populations. Clobazam also compares favourably with buspirone, a nonbenzodiazepine anxiolytic agent. Differentiation of the psychopharmacological profile of clobazam from the 1,4-benzodiazepines suggests important pharmacodynamic differences between the two groups. These in turn represent significant advantages for the clinical use of clobazam in the management of ambulant patients with anxiety.

High-performance liquid chromatographic method for determination of DN-2327, a novel non-benzodiazepine anxiolytic, and/or its active metabolite in human plasma and urine.

A sensitive and precise high-performance liquid chromatographic procedure has been developed for the determination of a new non-benzodiazepine anxiolytic agent, DN-2327 (I), and its pharmacologically active metabolite, MII (II), in human plasma and urine. Extraction of I, II, and the internal standard from plasma and urine samples were achieved using solid-phase extraction. Separation of the analytes was performed on a reversed-phase C18 column. The effluent was monitored with fluorescence detection at excitation and emission maxima of 328 and 367 nm, respectively. The work-up procedure was reproducible and recovered more than 92% of I and II from either plasma or urine. The chromatographic system for plasma and urine extracts allowed complete resolution of I and II from the internal standard with excellent selectivity. For each analyte, the lower detection limits were 0.1 and 1 ng/ml in plasma and urine, respectively. For each analyte, standard curves were linear in the ranges of 0.1-50 and 1-500 ng/ml in plasma and urine, respectively. The method was highly precise, with coefficients of variation for each analyte in quality controls that were generally below 7 and 5% for plasma and urine samples, respectively. The accuracy of the method was good with the deviations between added and calculated concentrations of each analyte being typically within +/- 10% and +/- 5.6% for plasma and urine samples, respectively. The stability of I and II in standard solutions, plasma and urine samples protected from laboratory light was excellent, with no evidence of degradation after 72 h at room temperature, five months at 4 degrees C, or three months at -20 degrees C.

Use of a conflict procedure in pigeons to characterize anxiolytic drug activity: Evaluation of N-methyl-d-aspartate antagonists

Because of its apparent effectiveness in detecting non-benzodiazepine anxiolytic agents, a recently introduced conflict procedure in pigeons was used to evaluate possible anti-punishment activity of various N-methyl-d-aspartate (NMDA) antagonists. Punished responding was significantly increased by competitive NMDA antagonists (CPP, CGS 19755), but not by noncompetitive NMDA antagonists acting at either the ion channel (PCP, ketamine, MK-801), the glycine site (kynurenic acid, 7-chlorokynurenic acid, ACPC), or the polyamine site (ifenprodil) of the NMDA receptor complex; the proposed glutamate antagonist, riluzole, was also ineffective.

Effects of Buspirone on Sleep and Respiration

Drugs used in the treatment of anxiety are frequently sedating and tend to be respiratory depressants. Buspirone, a nonbenzodiazepine anxiolytic agent, has little reported sedative effect. It has been shown to be a respiratory stimulant in an anesthetized, glomectomized cat model. In this study, we examined the effects of two intraperitoneal single doses (10 and 20 mg/kg) of buspirone on sleep and respiration in unanesthetized, intact, freely moving rats. Buspirone increased sleep latency (p less than 0.0001) and decreased total sleep (p less than 0.02) through reductions in both non-REM and REM sleep. Respiratory rate (p less than 0.0003) and ventilation (p less than 0.004) were significantly increased for 4 h after drug injection. The effects on respiration were independent of those on sleep; stimulation was evident in both waking and non-REM sleep. This study suggests that buspirone, in addition to being free of sedating and respiratory depressant side effects when prescribed for anxiety in humans, may be a respiratory stimulant whose effects persist in sleep.

Preclinical profile of the pyrimidinylpiperazinyl imide compound WY‐47,846: A potential anxiolytic

AbstractA preclinical anxiolytic profile of the pyrimidinylpiperazinyl imide compound Wy‐47,846, is presented. In an effort to achieve an orally active, nonbenzodiazepine anxiolytic agent, the compound Wy‐47,846 was synthesized and examined in various preclinical neurochemical, psychopharmacological and neurophysiological tests. Wy‐47,846 displayed high affinity at the 5‐HT‐1A receptor binding site (Ki = 16.7 nM) and had weak‐to‐modest affinities for D‐2 and 5‐HT‐2 receptors. Wy‐47,846 also was effective in binding to the 5‐HT‐1A site in ex vivo receptor binding studies, but did not alter D‐2 binding under these conditions. Wy‐47,846 was also weak to inactive at displacing adrenergic (alpha‐1, alpha‐2, and beta), cholinergic, histamine H‐1, opiate, and benzodiazepine receptor radioligands from their respective binding sites. Wy‐47,846 reduced 5‐HT‐2 receptor binding following subacute (3 week) treatment. In both shelf‐jump and discrete trial conditioned avoidance tests, Wy‐47,846 reduced avoidance responding while increasing escape responses. No sedative effects were noted at behaviorally active doses. Like other nonbenzodiazepine anxiolytics, Wy‐47,846 also did not release the suppression of punished responding in shock‐suppressed drinking nor in Geller‐Seifter conflict experiments. Wy‐47,846 also potently inhibited serotonergic neuronal activity in the dorsal raphe nucleus, suggesting agonist activity at the 5‐HT‐1A receptor and increased noradrenergic neuronal activity in the locus coeruleus by an unknown mechanism. These findings support the characterization of Wy‐47,846 as a nonbenzodiazepine anxiolytic agent.

Buspirone decreases the activity of serotonin-containing neurons in the dorsal raphe in freely-moving cats

Buspirone, a non-benzodiazepine anxiolytic agent, produced a dose-dependent decrease in the activity of serotonin-containing neurons in the dorsal raphe nucleus of freely-moving cats. The response ranged from no significant change at doses of 0.05 mg/kg to a nearly total suppression of activity at 1 mg/kg These data suggest that the anxiolytic properties of buspirone may be mediated, at least part, by an action on neurons in the dorsal raphe.

Double-blind comparison of buspirone and clorazepate in anxious outpatients

Buspirone, a new nonbenzodiazepine anxiolytic agent, was compared with clorazepate in a double-blind, multicenter trial conducted with 336 outpatients who had moderate to severe anxiety. The two treatments were equally effective for relief of symptoms, including anxiety with associated depression. Although both agents were generally well tolerated, the profile of side effects was dissimilar. Drowsiness and depression occurred significantly (p <0.055) more frequently with clorazepate, whereas nausea and headache occurred significantly (p <0.055) more frequently with buspirone. Clorazepate-treated patients were significantly (p <0.055) more likely to have had an adverse experience that was considered drug related or that interfered with the therapeutic effect. In this study, buspirone was shown to be an effective antianxiety agent, causing significantly less sedation than clorazepate.

Buspirone increases locus coeruleus noradrenergic neuronal activity in vitro

Buspirone, a non-benzodiazepine anxiolytic agent, produced dose-dependent increases in the activity of norepinephrine-containing locus coeruleus neurons recorded from mouse brain slices in vitro. The response was not changed in a low calcium/high magnesium incubation medium, indicating that the observed effects were the result of a direct action of buspirone on locus coeruleus neurons. These data suggest that noradrenergic neurons may not be as important in mediating anxiety states as previously suggested.