S-16924 [(R)-2-[1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]- pyrrolidin-3yl]-1-(4-fluorophenyl)-ethanone], a novel, potential antipsychotic with marked serotonin1A agonist properties: III. Anxiolytic actions in comparison with clozapine and haloperidol.
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S-16924 is a potential antipsychotic that displays agonist and antagonist properties at serotonin (5-HT)1A and 5-HT2A/2C receptors, respectively. In a pigeon conflict procedure, the benzodiazepine clorazepate (CLZ) increased punished responses, an action mimicked by S-16924, whereas the atypical antipsychotic clozapine and the neuroleptic haloperidol were inactive. Similarly, in a Vogel conflict paradigm in rats, CLZ increased punished responses, an action shared by S-16924 but not by clozapine or haloperidol. This action of S-16924 was abolished by the 5-HT1A antagonist WAY-100,635. Ultrasonic vocalizations in rats were inhibited by CLZ, S-16924, clozapine, and haloperidol. However, although WAY-100,635 abolished the action of S-16924, it did not affect clozapine and haloperidol. In a rat elevated plus-maze, CLZ, but not S-16924, clozapine, and haloperidol, increased open-arm entries. Like CLZ, S-16924 increased social interaction in rats, whereas clozapine and haloperidol were inactive. WAY-100,635 abolished this action of S-16924. CLZ, S-16924, clozapine, and haloperidol decreased aggressive interactions in isolated mice, but this effect of S-16924 was not blocked by WAY-100, 635. All drugs inhibited motor behavior, but the separation to anxiolytic doses was more pronounced for S-16924 than for CLZ. Finally, in freely moving rats, CLZ and S-16924, but not clozapine and haloperidol, decreased dialysis levels of 5-HT in the nucleus accumbens: this action of S-16924 was blocked by WAY-100,165. In conclusion, in contrast to haloperidol and clozapine, S-16924 possessed a broad-based profile of anxiolytic activity at doses lower than those provoking motor disruption. Its principal mechanism of action was activation of 5-HT1A (auto)receptors. (+info)
Use of micellar mobile phases for the chromatographic determination of clorazepate, diazepam, and diltiazem in pharmaceuticals.
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An ODS-2 column, a micellar mobile phase of high elution strength containing 0.1M sodium dodecyl sulfate and 3% (v/v) butanol, and ultraviolet detection at 230 nm are used for the determination of either of two benzodiazepines (clorazepate and diazepam) and a benzothiazepine (diltiazem) in pharmaceuticals. The procedure is shown to be competitive against conventional chromatography with methanol-water mobile phases, especially for diltiazem. The composition of the micellar mobile phase is selected using a predictive strategy based on an accurate retention model and assisted by computer simulation. Calibration graphs are linear at least in the 2.5 to 20 microg/mL, 4 to 20 microg/mL, and 5 to 40 microg/mL ranges for clorazepate, diazepam, and diltiazem, respectively. The intra- and interday repeatabilities (%) are clorazepate (1.7, 5.2), diazepam (0.43, 3.7), and diltiazem (0.36, 3.1). Limits of detection are well below the concentrations of the drugs found in the commercial pharmaceutical preparations analyzed. The drug contents evaluated with the proposed procedure are compared with the declared contents given by the manufacturers. The achieved percentages of label claim are usually between 95 and 104%. (+info)
Flumazenil-sensitive dose-related physical dependence in planarians produced by two benzodiazepine and one non-benzodiazepine benzodiazepine-receptor agonists.
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Two benzodiazepine (midazolam and clorazepate) and one non-benzodiazepine (zolpidem) benzodiazepine-receptor agonists produced dose-related physical dependence, as evidenced by abstinence-induced decrease in planarian locomotor velocity (pLMV) when drug-exposed planarians were placed into drug-free water, but not when they were placed into drug-containing water (i.e., an abstinence-induced withdrawal, since the effect was only obtained in the removal of drug and not in the continued presence of drug). We have previously shown that the decrease in pLMV is associated with specific and transient withdrawal signs. In the present study, the selective benzodiazepine-receptor antagonist flumazenil significantly antagonized (P<0.05), by co-application, the ability of each agonist to produce the withdrawal. These results: (1) suggest that benzodiazepine-receptor agonists, for two different chemical categories, produce dose-related physical dependence manifested as abstinence-induced withdrawal in this simple and convenient model, and (2) in the absence of cloning or radioligand binding literature, suggest a possible specific interaction site (receptor?) for these compounds in planarians. (+info)
Generalized skin drug eruption to natalizumab in a patient with multiple sclerosis.
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We report a generalized skin eruption in a young man being treated with natalizumab, a new drug used in patients with multiple sclerosis. (+info)
Differential behavioral profile induced by the injection of dipotassium chlorazepate within brain areas that project to the nucleus accumbens septi.
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BACKGROUND: The effect of the agonism on gamma-aminobutyric acid (GABA) receptors was studied within medial prefrontal cortex (mPFC), amygdala (AMY) and ventral hipocampus (VH) in the plus-maze test in male rats bilaterally cannulated. These structures send glutamatergic projections to the nucleus accumbens septi (NAS), in which interaction and integration between these afferent pathways has been described. In a previous study of our group, blockade of glutamatergic transmission within NAS induced an anxiolytic like effect. METHODS: Three rat groups received either saline or dipotassium chlorazepate (1 or 2 mug/1 mul solution) 15 min before testing. Time spent in the open arms (TSOA), time per entry (TPE), extreme arrivals (EA), open and closed arms entries (OAE, CAE) and relationship between open- and closed-arms quotient (OCAQ) were recorded. RESULTS: In the AMY injected group TSOA, OAE and EA were increased by the higher doses of dipotassium chlorazepate (p < 0.01). In the mPFC, TPE was decreased by both doses (p < 0.05). Injection within ventral hippocampus (VH) decreased TSOA, OAE and OCAQ with lower doses (p < 0.05). When the three studied saline groups were compared, TSOA, OAE, EA and OCAQ were enhanced in the VH group when compared to mPFC and AMY (p < 0.001). Insertion of inner canula (p < 0.001, p < 0.01, p < 0.01) and saline injection showed an increasing significant difference (p < 0.001 in all cases) with the action of guide cannula alone within VH in TSOA, OAE and EA. CONCLUSION: We conclude that the injection of dipotassium chlorazepate has a differential effect depending of the brain area, leading to facilitatory and inhibitory effects on anxiety processing. (+info)
Allosteric modulation by benzodiazepine receptor ligands of the GABAA receptor channel expressed in Xenopus oocytes.
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Chick brain mRNA was isolated and injected into Xenopus oocytes. This led to the expression in the surface membrane of functional GABA-activated channels with properties reminiscent of vertebrate GABAA channels. The GABA-induced current was analyzed quantitatively under voltage-clamp conditions. Picrotoxin inhibited this current in a concentration-dependent manner with IC50 = 0.6 microM. The allosteric modulation of GABA currents by a number of drugs acting at the benzodiazepine binding site was characterized quantitatively. In the presence of the benzodiazepine receptor ligands diazepam and clorazepate, GABA responses were enhanced, and in the presence of the convulsant beta-carboline compound methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), they were depressed. Maximal stimulation of the response elicited by 10 microM GABA was 160% with diazepam and 90% with clorazepate, and maximal inhibition was 42% with DMCM, 30% with methyl beta-carboline-3-carboxylate (beta-CCM), 15% with ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a][1,4]benzodiazepine-3-carboxylate (Ro 15-1788), and 12% with ethyl beta-carboline-3-carboxylate (beta-CCE). Half-maximal stimulation was observed with 20 nM diazepam and 390 nM clorazepate, respectively, and half-maximal inhibition with 6 nM DMCM. beta-CCM had a similar effect to DMCM, whereas beta-CCE and Ro 15-1788 showed only small inhibition at low concentrations (less than 1 microM). All the tested carboline compounds and Ro 15-1788 showed a biphasic action and stimulated GABA current at concentrations higher than 1 microM.(ABSTRACT TRUNCATED AT 250 WORDS) (+info)
Clorazepate use may prevent alcohol withdrawal convulsions.
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Clorazepate dipotassium was administered orally for the five-day prophylactic treatment of potential, incipient and overt withdrawal signs and symptoms in 226 patients on admission to an inpatient alcohol treatment unit. Conservative estimates based on these patients' histories and on literature reports predicted that between 7 and 40 (3% to 18%) of these persons would be expected to have a withdrawal convulsion. No patients experienced convulsions. This complete absence of seizures suggests that clorazepate is effective in counteracting convulsive and other manifestations of the alcohol withdrawal syndrome. (+info)
Single daily dose treatment of anxiety with clobazam or dipotassium clorazepate.
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1 Forty-four clinically anxious patients entered a comparative double-blind trial of clobazam 20 mg, clobazam 30 mg and dipotassium clorazepate 15 mg, all drugs given as a single dose at night. 2 Assessment by the Hamilton Anxiety Scale, Morbid Anxiety Inventory (Salkind) and a Visual Analogue Scale showed a statistically significant improvement for all treatment groups after 2 weeks, with continued improvement after a further 2 weeks. 3 Daytime drowsiness was the commonest side-effect in all treatment groups but there was a tendency for a lower incidence in patients on clobazam. There was no evidence of a dose-related incidence of drowsiness in the clobazam 20 mg and 30 mg groups. Other side-effects were few and nonspecific. 4 Clobazam is a 1,5-benzodiazepine with an elimination half-life of 18 hours. When given in single doses of 20-30 mg at night it has an equivalent effect to dipotassium clorazepate 15 mg. (+info)