摘要:

AbstractThe review begins by outlining some of the animal models of anxiety that have been used to evaluate anxiolytic activity. Whereas acute screening tests such as antagonism of chemically induced convulsions and foot shock‐induced aggression in mice have proved to be useful in the selection of compounds chemically related to known anxiolytics, more sophisticated animal models of anxiety (e.g., the various conflict models) appear to be required if the essential features of human anxiety are to be simulated in the laboratory. The review summarizes our experience with such a model and also critically assesses the value of “open‐field” induced stress in rats as a model of anxiety that is relatively simple but which enables the investigator to try to find biochemical correlates of anxiolytic action. Using the open‐field' model, we have examined the effects of a number of anxiolytics (diazepam, clobazam, and nicotinamide, the putative endogenous ligand of benzodiazepine receptors) on behaviour and neurotransmitter function in different regions of the rat brain. Evidence is presented that anxiolytics act primarily by facilitating gamma‐aminobutyric (GABA)‐ergic transmission in limbic regions of the brain. The review concludes by outlining some of the mechanisms whereby both the 1,5‐ and 1,4‐benzodiazepines may exert their effects at the cellular level. Whereas there is substantial experimental evidence suggesting that GABA‐ergic activity is facilitated by the anxiolytic displacing a specific protein (GABA‐modulin) from some of the GABA‐receptor sites, thereby facilitating chloride transport into the neurons (hyperpolarization), the distribution of the benzodiazepine receptors on nonneuronal elements (glia) suggests that these drugs have more complex actions than is generally stated. Furthermore, the interactions between the benzodiazepines, GABA, and the enkephalins in subcortical regions of the brain suggest that the pharmacological profile of these drugs cannot be explained only in terms of a facilitation of

ISSN:0272-4391    

DOI:10.1002/ddr.430010703

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractA brief review is given of the current evidence for multiple benzodiazepine receptors in the brain. The existence of a heterogeneous receptor population may imply that the various pharmacological effects of the benzodiazepines are dissociable. Since GABA receptors are believed to be closely linked to benzodiazepine receptors, it is of interest to know whether this is always the case and whether GABA is involved in the expression of all the different benzodiazepine activities.

ISSN:0272-4391    

DOI:10.1002/ddr.430010704

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractClobazam is a 1, 5‐benzodiazepine with significant activity in preclinical tests predictive of potential clinical antianxiety activity. Clinical efficacy equivalent to diazepam has been established with minimal effects on psychomotor performance. Clobazam has also been found to have a broad spectrum of anticonvulsant activity with acceptable toxicity and to be active in suppressing aggressive behavior in rodents. This compound appears to have less of an effect on motor coordination, muscle tone, behavioral depression and hyporeflexia than standard reference compounds in various species as well as little or no apparent effect on memory and learning in animals and humans. The major metabolite, desmethylclobazam, is also an anxiolytic candidate approximately 10 times less potent than diazepam and a potent anticonvulsant with a complete lack of sedation. These compounds represent a new classification of pharmaceutical agents in which antianxiety and anticonvulsant effects can be achieved without sedative or depressive side effect

ISSN:0272-4391    

DOI:10.1002/ddr.430010705

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

Abstract1,4‐benzodiazepines (BDZs) are known to induce mild but consistent dysmnesia in several animal models and in humans, whereas the 1,5‐BDZ clobazam is claimed to be devoid of this adverse effect. Systematic animal studies comparing 1,5‐ to 1,4‐BDZs in this field are lacking. The “threshold” conditioned escape response (t‐CER) in the Wistar rat, a recently described learning and memory model, is known to discriminate between 1,5‐ and 1,4‐ BDZs. In this model it has been shown that: all 1,4‐BDZs studied induce a definite dysmnesia (retention and/or acquisition impairments and, with the exception of diazepam, retrieval impairment); 1,4‐BDZ dysmnesia is not due to an eventual state‐dependency learning; many other psychotropic drugs, in usual doses, do not impair t‐CER performances; 1,5‐ BDZs (clobazam and triflubazam) do not interfere, even in high do

ISSN:0272-4391    

DOI:10.1002/ddr.430010706

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractThe anticonvulsant action of N‐desmethylclobazam, the metabolite of clobazam, has been evaluated acutely in DBA/2 mice with audiogenic seizures and in baboons (Papio papio) with photosensitive epilepsy, and compared with the effect of clobazam. In mice, desmethylclobazam appears less potent than clobazam, in terms of the ED50 for abolition of the tonic or clonic phase of the seizure response, but it has a longer time course of action. In baboons, desmethylclobazam, 1 to 4 mg/kg i.v., has a protective action against photically‐induced myoclonus comparable to that seen after similar doses of clobazam. After clobazam, 4 mg/kg, plasma clobazam concentration shows a rapid, approximately exponential, clearance (t1/2= 2.0 to 2.5 hr), and plasma desmethylclobazam content increases progressively to a peak at 6 hr or later. Plasma concentrations of desmethylclobazam after clobazam injection rapidly exceed those associated with potent anticonvulsant action when desmethylclobazam itself is administered. It is concluded that in the baboon and probably also in man the metabolite desmethylclobazam is responsible for a substantial part of the antiepileptic effect of cloba

ISSN:0272-4391    

DOI:10.1002/ddr.430010707

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractThe effects of clobazam and diazepam on oculomotor activity were measured using on‐line monitoring of saccadic eye movements. The study was carried out in ten healthy volunteers, under double‐blind conditions. Each volunteer received a single dose of diazepam 10 mg and 20 mg, clobazam 20 mg and 40 mg, and placebo, each separated by a 7‐day washout period. A “split” in drug effect between latency (polysynaptic reflex time) and velocity (muscular function) of eye movements was seen for clobazam, but not for

ISSN:0272-4391    

DOI:10.1002/ddr.430010708

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractThe effects of three dose regimens of HOE 8476, a combination of nomifensine (25 mg) and clobazam (7.5 mg), placebo, and a combination of amitriptyline (25 mg) and chlordiazepoxide (10 mg) were compared in a five‐period double‐blind randomised crossover study. Ten healthy volunteer drivers took part in the study, and were tested at weekly intervals preceded by a 48‐hr predosing period and followed by a 4‐day washout period. The sedative activity of amitriptyline/chlordiazepoxide (AMI/CHLOR) was shown on nearly all the subjective and objective measures of behavior employed, while, in contrast, there was a relative lack of sedation and performance impairment attributed to HOE 8476, except with complex tasks at the higher dose level. The results of the study confirm previous results in volunteers that HOE 8476 has psychotropic activity which differs from that of a standard antidepressant/benzodiazepine combination in that it is not accompanied by significant sedation or impairment of psychomotor perf

ISSN:0272-4391    

DOI:10.1002/ddr.430010709

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractThe effects of the 1, 5‐benzodiazepine derivative clobazam upon critical flicker fusion (CFF) values in normal subjects is reviewed. All studies reviewed were double‐blind and placebo controlled. Single acute doses of 10 or 20 mg did not lead to significant CFF changes, whereas repeated doses of 20 mg clobazam a day for 4 days produced a significant elevation in CFF thresholds. Possible pharmacokinetic reasons for this CFF elevation after repeated doses are discussed. Equivalent investigations of clobazam at higher dose levels (30 to 60 mg) showed a similar difference in the effects of acute versus repeated doses; single acute doses led to significant CFF decrements, while repeated administrations led to similar clobazam and placebo CFF levels. The patterns of CFF changes with this 1,5‐benzodiazepine anxiolytic agent seems to be different from the CFF changes generally reported with the 1,4‐benzodiazepine anxiolytic agents (generally CFF reductions), and suggests possible central nervous system alerting affects after repeated administration at the lower dose

ISSN:0272-4391    

DOI:10.1002/ddr.430010710

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractA commonly used method of evaluating critical flicker fusion (CFF) threshold—the Leeds psychomotor tester—has been assessed with regard to the influence of pupil‐size alteration on CFF measurements. Six healthy volunteers, (three males, three females) took part and were treated with saline, pilocarpine 2%, and homatropine 1% eye drops at intervals of one week according to a balanced crossover design. The regression of CFF threshold on pupil size, both measured up to 7 hr after treatment, was highly significant in all subjects. Increases of pupil size from 2 to 8 mm produced a rise in CFF threshold which varied between individuals but ranged from 2 to 9 Hz. In a separate study, the effect of clobazam 20 mg on binocular and monocular CFF, the latter both uncorrected and corrected for pupil size, was assessed over the 8‐hr period after treatment. No significant changes in either measure of CFF were observed. On a separate study day the same four subjects submitted to mydriasis/miosis induced by homatropine followed by pilocarpine eye drops. This procedure showed that the use of an artificial pupil of 2 mm adequately corrected for pupil‐size influences on CFF in all but on

ISSN:0272-4391    

DOI:10.1002/ddr.430010711

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractA selective review of benzodiazepine dependence studies in animals is presented, emphasizing areas of drug self‐injection, drug discrimination, and physiological dependence. Benzodiazepines as a class, as well as long‐acting barbiturates, appear to maintain drug self‐injection behavior less well than ultrashort‐acting barbiturates. The duration of action as well as the rapidity of onset of these drugs may be important determinants of their reinforcing efficacy. Drug discrimination procedures may allow evaluation of the relative rapidity at onset and duration of action of these drugs to evaluate this and related hyp

ISSN:0272-4391    

DOI:10.1002/ddr.430010712

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY