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Meprobamate-tranquilizer or anxiolytic? A historical perspective.

Meprobamate was the first successful anti-anxiety drug of the modern era. On the 50th anniversary of its introduction, the authors trace the development of its synthesis, marketing and runaway success to understand the scientific and socio-political factors that may have shaped its use in clinical psychiatry. The relationship of this drug to the earlier development of chlorpromazine is explored to clarify the imperatives of drug classification in modern psychiatry.

Anti-Anxiety Agents↗

Persistence of drug experience in rats formerly dependent on phenobarbital or meprobamate.

The rats of groups I, II, III and IV were treated orally with phenobarbital, meprobamate, codeine and vehicle, respectively, for total 21 days, and then drugs were withdrawn. All these rats were given again orally phenobarbital for 5 days starting from 70 days after the withdrawal. In comparison with groups III and IV, groups I and II showed larger weight gain during phenobarbital re-administration and longer-lasting weight loss and an larger increase in body temperature after the termination. These results suggested that the drug experience on sedative-hypnotics persisted over two months after the withdrawal and that did not cross to that of narcotics.

Animals↗

Naloxone blocks the effect of diazepam and meprobamate on conflict behaviour in rats.

The effect of naloxone on the anticonflict action of diazepam was studied in a model involving foot shock-induced suppression of food-rewarded operant behaviour. Both 1 and 10 mg/kg naloxone SC abolished the increase in punished responding produced by diazepam and chlordiazepoxide. Naloxone also blocked the anticonflict effect of meprobamate. These observations are discussed in terms of a possible involvement of endogenous opioid peptides in the anxiolytic effects of tranquillizers.

Animals↗

Gas chromatographic determination of meprobamate in serum or plasma after solid-phase extraction.

This gas chromatographic technique of determining meprobamate is based on a solid-phase extraction permitting a time reduction of the analysis and improving sensitivity. Quantification is realized on 500 microliters of plasma. The method uses etidocaine as internal standard and does not require derivatization. Thus it is simple, rapid, sensitive and applicable in forensic and clinical toxicological laboratories.

Chromatography, Gas↗

Gas chromatographic determination of meprobamate in human plasma.

A simplified and rapid gas chromatographic method has been developed for the determination of meprobamate in human plasma. The procedure includes a single-step extraction of alkalinized sample with chloroform, and chromatography on a non-polar fused-silica capillary column with flame ionization detection. The method is accurate (97.7 +/- 5.7% at 20 mg/l) and precise (maximum coefficient of variation of 9.5%). It provides an alternative to existing methods and is particularly suitable for toxicological studies.

Aged↗

Occurrence of barbiturate, benzodiazepine, meprobamate, methaqualone and phenothiazine in car occupants killed in traffic accidents in the south of Sweden.

An investigation of the following psychoactive drugs: barbiturate, benzodiazepine, meprobamate, methaqualone and phenothiazine, was performed on all automobile occupants killed in accidents in southern Sweden during 1977 and 1978. Of 122 drivers and 55 passengers analysed, low concentrations of these drugs were found in nine drivers and in five passengers. Thus, 7.3% of the drivers were driving under the influence of drugs and, of these, two drivers (1.6% of all analysed drivers) were also inebriated. Twenty-three per cent of the drivers were inebriated only. According to the circumstances in the accidents and the number of drivers whose analyses proved positive, drug influence seldom seems to be the cause of fatal traffic accidents.

Accidents, Traffic↗

Naloxone potentiates anxiolytic-like actions of diazepam, pentobarbital and meprobamate but not those of Ro19-8022 in the rat.

The elevated plus-maze test was used to determine if the opiate antagonist naloxone could potentiate the anxiolytic-like effects of the benzodiazepine diazepam, the barbiturate pentobarbital, the propanediol carbamate meprobamate and the partial benzodiazepine receptor agonist [R]-1-[(10-chloro-4-oxo-3-phenyl-4H-benzo[a]quinolizin-1-yl) carbonyl]-2-pyrrolidine-methanol (Ro19-8022) in the rat. A subeffective dose of each of these compounds was combined with naloxone, 10 mg/kg. Naloxone had no effect by itself, but potentiated all drugs except Ro19-8022. The proportion of entries on the open arm increased while the total number of arms entries was not modified. These results coincide with and extend data previously obtained in the mouse. One possible explanation for naloxone's effect could be that it blocks opioid inhibition of GABAergic (gamma-aminobutyric acid) neurons thereby enhancing the effects of benzodiazepines. Another possibility is that naloxone blocks opioid effects on adenosinergic systems.

Animals↗

Immunolocalization of meprobamate-like molecules in rat cerebellar cortex.

The localization of meprobamate-like (MPB-like) molecules in the cerebellar cortex of the rat was investigated with the peroxidase-antiperoxidase (PAP) immunocytochemical method using an antiserum raised in rabbits. The positive immunoreaction for MPB in several nervous structures and in the wall of blood capillaries suggest the presence of endogenous MPB-like molecules.

Animals↗

Antenatal exposure to meprobamate and chlordiazepoxide in relation to malformations, mental development, and childhood mortality.

In a follow-up study of 50,282 pregnancies (lasting at least five lunar months) and the offspring, malformations identified before the first birthday, or at death before the fourth birthday, were identified in 3248 children (6.5 per cent). A total of 1870 children exposed in utero to meprobamate or chlordiazepoxide were compared with 48,412 children who were not. No significant differences were found either overall or in specific outcomes; rates were also similar when exposures occurred during the first trimester or at other times during pregnancy. Deaths (stillbirth to the fourth birthday) occurred in 2227 children (4.4 per cent), and there was no evidence that antenatal exposure to either drug increased the death rate. Finally, as judged by mental and motor scores at the age of eight months, and intelligence quotient scores at four years, there was no evidence that the drugs cause brain damage.

Abnormalities, Drug-Induced↗

A rapid and sensitive gas chromatographic analysis of meprobamate or carisoprodol in urine and plasma.

A method for the identification and quantification of meprobamate or carisoprodol in plasma by GC/FID is presented. The method employs vinylbarbital as the internal standard and requires no derivatization. After a single extraction, analysis is achieved in 7 min. This method is thus rapid, sensitive, reproducible, selective, and applicable to forensic and clinical toxicological analyses.

Carisoprodol↗

Impaired brain functions due to diazepam and meprobamate abuse in a 53-year-old-male.

The following case study demonstrates the important influence of diazepam and meprobamate on a patient's neuropsychological test performance. This article includes: a brief medical history and summary of previous physical examinations; brief description of the neuropsychological test battery; formulation of the original neuropsychological test findings; follow-up neuropsychological testing; and discussion. The profound interaction effect of these prescribed drugs revealed severe cognitive, memory, and motor function deficits in a 53-year-old male. These findings are in contrast to reports in the literature.

Cognition Disorders↗

Meprobamate reduces accuracy of physiological detection of deception.

Normal male subjects attempted to deceive an experimenter recording electrodermal, respiratory, an cardiovascular activity. Those who had ingested a placebo or nothing were detected with statistically significant frequency on the basis of their phasic electrodermal responses, which clearly distinguished them from truthful suspects. That was not the case with deceptive subjects who had ingested 400 milligrams of meprobamate, nor did the examiner detect which subjects had received the drug.

Blood Pressure↗

Management of the prescription-drug-dependent adult: case of meprobamate abuse and its treatment.

Misuse of prescription drugs in the elderly can be a serious problem that is difficult to manage. Prescriptions for non-narcotic central nervous system (CNS) depressants (e.g., anxiolytics and sedative-hypnotics) are commonly written, and their use is associated with severe intoxication and withdrawal effects. The presence of comorbid psychiatric conditions (e.g., depression or panic disorder), for which these agents are prescribed frequently, complicates the clinical picture. This paper, using case examples of meprobamate abuse, describes how physicians can recognize, manage, and treat a patient who is abusing a non-narcotic CNS depressant.

Adult↗

Arterial-venous plasma concentration differences of meprobamate in acute human poisonings.

Arterial-venous plasma concentration differences of meprobamate were studied on admission of acute overdose in man. The patients were divided in two groups. In the control group (n = 25) two successive blood samples were collected from the same vessel. In the study group (n = 35) femoral arterial and venous blood samples were collected simultaneously. In the control group the differences were not significant. In the study group the differences were statistically significant (P less than 0.01). The present study suggests that the origin of blood samples should be stated for toxicological studies and that the toxicokinetics may be more complex than those recognized previously.

Adolescent↗

The use of a kymograph in a comparative trial of flunitrazepam and meprobamate in elderly patients.

A double-blind crossover trial was carried out in 31 hospitalized elderly patients receiving night-time sedation to compare the effects of flunitrazepam (0.5 mg) and meprobamate (200 mg). After 1 week on placebo, patients received 1-week's treatment with each drug in random order. Quality of sleep was assessed by a nurse at hourly intervals over 8 hours each night. In 11 patients, the results were compared with those from kymographic recordings measuring patient restlessness (motility index). No statistically significant difference was found between the two active drug treatments, and there was a close correlation between the two methods of assessment. It is suggested that the kymograph may well be a useful and economic method of evaluating the effectiveness of hypnotics.

Aged↗

Effects of diazepam, meprobamate, chlorpromazine and apomorphine on a quickly learned conditioned suppression in mice.

Mice exhibited a marked suppression of motor activity when placed into the same environment in which they had previously received electric foot shocks. Apomorphine-HCl (0.1 - 10 mg/kg) produced a dose-dependent reduction of the conditioned suppression of activity, but did not increase activity in non-shocked mice. Diazepam (0.2, 1, and 5 mg/kg), meprobamate (25 and 50 mg/kg), and chlorpromazine-HCl (2 and 5 mg/kg) did not reduce conditioned suppression. Thus, the conditioned suppression caused by a quick conditioning technique does not produce similar results to those using the conditioned emotional response involving suppression of operant lever-pressing behavior.

Animals↗

Physical dependence on meprobamate after repeated oral administration in rats.

The physical dependence potential of meprobamate (MPB) was compared with that of phenobarbital (PHB) and codeine (COD) to ascertain whether MPB produces definite physical dependence in the rat. Rats were treated orally with MPB (maintenance dosage = 800 mg/kg X 2/day), PHB (100 X 2) or COD (50 X 2) twice a day (10:00 a.m. and 5:00 p.m.) for a total of 21 days; the treatment was ceased for 3 days after administration for 7 days, and the last dosing was performed on day 27. During intoxication and after the withdrawal, the MPB treated rats exhibited behaviour and withdrawal signs similar to those seen in the PHB treated rats, but not the COD treated rats. After withdrawal of drugs, definite weight loss was observed in all the rats given drugs, and the recovery of the MPB and PHB treated rats was clearly later than that of the COD treated rats. A long-lasting increase in rectal temperature was observed after the withdrawal in the MPB and PHB treated rats; a decrease was seen in the COD treated rats. From these results, it is concluded that definite physical dependence on MPB, similar to that on PHB but different from that on COD, was developed after repeated oral administration for a total of 21 days in the rat.

Administration, Oral↗

Drug interactions: the effects of alcohol and meprobamate applied singly and jointly in human subjects. I. Theoretical considerations and literature review.

The considerations necessary to describe the effects of combinations of drugs in a biological system are reviewed. The terms which express these effects-additive, potentiative, antagonistic, synergistic-have not had specific operations applied to them and mathematical models have been sought to define these operations. The models should (1) describe the nature of the action of single drugs, (2) classify the results of drug combinations, (3) provide a set of operations for deciding the outcome of combinations, and (4) predict all possible results of a combination from a knowledge of each drug acting alone. Research on the effects of alcohol and meprobamate and their interactions is reviewed, including behavioral and pharmacological studies and also some studies of the interaction of alcohol with other drugs. The task of characterizing the relation between the drug and response is formidable because complex physiological and biochemical processes determine the relationship between administered and effective dose and are further complicated by route of drug administration and various time relations. The descriptions of biochemical and physiological events seem well advanced; those of behavior are not. Much of the behavioral research assumes that a single dose is representative of all doses of the drug, and that combinations of the drugs and additivity of effects can be determined without a rigorous definition or means of application. [Bibliography of 249 items.]

Animals↗