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At least 19 recordsLinked to original sources
PubMed1975

Drug interactions: the effects of alcohol and meprobamate applied singly and jointly in human subjects. IV. The concentrations of alcohol and meprobamate in the blood.

The absorption and elimination of alcohol and meprobamate from the blood during Experiments IV (E-IV) and V (E-V) of Carpenter et al. [J. Stud. Alc., Suppl. No. 7, pp. 54-139, 1975] were studied by means of mathematical models representing the relation between doses, concentration in the blood and time elapsing since drug ingestion. The blood concentrations of samples taken 2 and 5.5 hr after beginning to drink in E-IV and 1, 1.5, 2, 2.5, 3.5 and 4.5 hr in E-V were analyzed. The presence of meprobamate did not affect blood alcohol concentration (BAC) in either experiment. At 2 hr the mean BACS after 0.25, 0.50, 0.75 and 1.00 g of alcohol per kg were 6.8, 20.9, 37.7 and 53.7 mg per 100 ml in E-IV; 5.0, 34.1, 42.0 and 72.0 mg per 100 ml in E-V; and 8.1, 32.6, 41.3 and 71.3 mg per 100 ml when calculated by regression from E-V data. The calculated elimination rate of the 2 highest doses of alcohol in E-IV was 6.0 and 7.1 mg per 100 ml per hr; in E-V the mean calculated rates after 0.25-0.75 and after 1.00 g of alcohol per kg were 6.6 and 11.0 mg per 100 ml per hr. The blood meprobamate concentrations (BMC) in E-IV were not affected by alcohol. In E-V, 2.5 and 5.5 hr after meprobamate administration, the combination of 28 mg of meprobamate per kg and 0.75 g of alcohol per kg resulted in significantly lower BMC (7.83 and 12.63 mug per 100 ml) than after same dose of meprobamate with the other doses of alcohol (14.23 and 20.02 mug per 100 ml). The differences between these results and the findings of Carpenter et al. are discussed.

Dose-Response Relationship, Drug↗
PubMed1975

Drug interactions: the effects of alcohol and meprobamate applied singly and jointly in human subjects. III. The concentrations of alcohol and meprobamate in the blood and their effects on performance; application of mathematical models.

The relations between the levels of alcohol and meprobamate in the blood and performance on a visual-motor coordination tracking task were analyzed by a general system of mathematical models, using data from Experiment V by Carpenter et al. [J. Stud. Alc., Suppl. No. 7, pp. 54-139, 1975]. The derivation of the models is described. In general, the relationship between blood alcohol concentration (BAC) and performance was nonmonotonic: best performance occurred at BACS of 10 to 20 mg per 100 ml. The relationship between meprobamate concentration (BMC) and performance was monotonic: performance deteriorated with increasing BMC. The results of the reaction latency measure, howevr, showed no consistent relationship with BAC or BMC. The action of alcohol can be represented by a model which involves 2 distinct sites of action; that of meprobamate, 1 site. It could not be determined whether the site of action of meprobamate is distinct from those of alcohol because the blood levels of the drugs were not high enough. The implications of the results are discussed, with particular reference to the quantitative description of the joint action of drugs and the design of future experiments.

Drug Combinations↗
PubMed1975

Drug interactions: the effects of alcohol and meprobamate applied singly and jointly in human subjects. II. Five experiments.

Five experiments were conducted to study the effects of alcohol and meprobamate, administered singly and in combination, at doses up to 1.20 g of alcohol per kg of body weight and up to 30 mg of meprobamate per kg. Most of the 158 men were of college age (range, 21-49). In all experiments it appeared to the subjects that both drugs were administered, alcohol as a 25% solution in orange juice and meprobamate as 10 tablets. One hour after the men took the meprobamate they had 1 hr to drink the beverage. Before and at 1/2 hr intervals after administration of the drugs blood samples were taken and behavioral response measured by means of a visual-motor coordination tracking task (Stressalyzer). An experimental session lasted 6 hr. In Experiment I (E-I) each of 12 men was tested on 2 days, after 0, 1.00 or 1.20 g of alcohol per kg and 0 or 25 mg of meprobamate per kg. In Experiment II (E-II) 56 men were tested (8 per group) after 0, 5, 10, 15, 20, 25 or 30 mg of meprobamate per kg and alcohol placebo. In Experiment III (E-III) 40 men were tested (8 per group) after 0, 0.25, 0.50, 0.75, or 1.00 g of alcohol per kg and meprobamate placebo. In Experiment IV (E-IV) 25 men (5 per group) received meprobamate 3 times a day (total daily dosage, 0, 7, 14, 21 or 28 mg per kg) for 12 days. On days 8 to 12 all subjects drank alcohol, as in E-III. In Experiment V (E-V) 25 subjects (5 per group) were tested on 5 days, drinking each day the same doses of alcohol as in E-III and all received the same doses of meprobamate as in E-IV.

Adult↗
PubMed1989

Interactive effects of acute ethanol administration on meprobamate levels in blood and brain of rabbit and rat.

In the simultaneous administration of meprobamate and ethanol to rabbits, the blood meprobamate concentration (BMC) increased greatly when the maximum blood ethanol concentration (BECmax) exceeded 1.0 mg/ml. Thus, we subjected the rabbits to continuous infusion of ethanol so as to make the blood ethanol concentration (BEC) constant and administered meprobamate by intravenous injection. Elimination of meprobamate became slow at about the BEC of 0.5 mg/ml and the degree reached almost maximum around the BEC of 1.0 mg/ml. The elimination rate did not change any more even when the BEC was raised higher. In the study conducted to elucidate the relationship between the BMC and brain meprobamate concentration (BrMC) using rats, it was found that meprobamate would show similar movements and its level would rise extremely by an acute administration of ethanol. It was indicated that the effect of ethanol on reinforcement of meprobamate activity would appear strongly by potentiation effect.

Animals↗
PubMed1987

Meprobamate kinetics during and after terminated hemoperfusion in acute intoxications.

We report four cases of severe meprobamate intoxication. Maximal plasma levels reached 800 (176), 816 (180), 863 (190) and 923 mumol/l (203 mg/l). All patients survived without sequelae including one patient resuscitated from cardiac arrest. The clinical course was complicated by coma, hypotension, and hypothermia in all patients. Three cases were treated with charcoal hemoperfusion with mean hemoperfusion clearance ranging from 134-164 ml/min compared to 174 ml/min in one case treated with resin filter and the same blood flow of 200 ml/min. In two cases, a mean renal meprobamate clearance of 15 and 23 ml/min was calculated comprising only 9-15% of the hemoperfusion clearance. The amount of meprobamate removed by hemoperfusion ranged from 1.6-6.2 g. In one case, the half-life of plasma meprobamate during hemoperfusion was 2.6 hours compared to 8.3 hours after hemoperfusion. Thus the half-life was reduced more than 3-fold. These data show that hemoperfusion may be indicated in severe meprobamate intoxication.

Adult↗
PubMed1992

Effect of long-term ethanol administration on meprobamate level in brain of rat.

Effect of long-term ethanol administration on brain meprobamate concentration (BrMC) was investigated using rats. In ethanol-non-pretreated rats, the average ratio of the maximum BrMC (BrMCmax) to the maximum blood meprobamate concentration (BMCmax) was 0.75 when 25 mg/kg meprobamate were intraperitoneally administered to rats singly or together with ethanol (2 g/kg or 4 g/kg). By a pretreatment of the animals with ethanol at the daily dose of 0.4 g or 0.6 g for 25 days, the average ratio of BrMCmax to BMCmax was 0.91 when the same dose of meprobamate were given into the abdominal cavity. It was considered that by long-term ethanol administration the permeability of blood-brain barrier to meprobamate might be accelerated, resulting in an increase in BrMC.

Animals↗
PubMed1984

The pharmacokinetics of meprobamate following its oral and rectal administration as a series of combinations with diphenhydramine, acetylsalicylic acid, codeine and pentaerythritol tetranitrate.

Studies in human volunteers of the pharmacokinetics of the active drugs in the formulations Visano-mini (meprobamate and diphenhydramine HCl), DoloVisano (meprobamate, diphenhydramine HCl, acetylsalicylic acid and codeine phosphate) and VisanoCor (meprobamate, diphenhydramine HCl and pentaerythritol tetranitrate (PETN], have demonstrated systemic absorption of each of the drugs from all of the formulations. Bioequivalence of meprobamate is indicated despite the drug combinations involved. Some differences in diphenhydramine pharmacokinetics are, however, apparent. The bioavailability of meprobamate administered rectally to human volunteers as the marketed preparations DoloVisano Suppositories and Dolo-Visano Suppositories sine codeino, is similar to that observed following oral administration.

Administration, Oral↗
PubMed1977

Use of hemodialysis in meprobamate overdosage.

A case of meprobamate overdosage successfully treated with hemodialysis is described. The patient was admitted 4 hours after an overdosage of meprobamate (30-40 g) deeply unconscious, hypotensive, in respiratory failure and with a serum meprobamate level of 50 mg/100 ml. Hemodialysis was instituted using a Gambro parallel flow dialyzer and a portable re-circulating dialyzate delivery system (Redy, CCi Life Systems). Meprobamate removal with hemodialysis was 672+/-167 mg/hr with a corresponding clearance of 61.97+/-9.9 ml/min. Drug removal with forced diuresis was 177+/-23.4 mg/hr. Metabolic degradation of the drug was approximately 482 mg/hr with a plasma disappearance rate of 5.2%/hr. No drug could be detected in the dialyzate fluid after its passage through the Redy re-circulating dialyzate system. Because of the rapidity of metabolic degradation of meprobamate, we feel that hemodialysis should be reserved for severe clinical intoxication and either compromised normal excretory routes or progressive clinical deterioration.

Female↗
PubMed1987

Influence of meprobamate and phenobarbital upon local cerebral glucose utilization: parallelism with effects of the anxiolytic diazepam.

The [1-14C]2-deoxyglucose technique was employed for an evaluation of the regional pattern of alteration of brain metabolism induced by the anxiolytics phenobarbital (which is described in small doses as anxiolytic agent) and meprobamate. Their effects were compared with those produced by the anxiolytic benzodiazepine diazepam which we have described in a previous study. In low doses, both meprobamate (30 mg/kg i.v.) and phenobarbital (5 mg/kg i.v.) elicited a regional pattern of changes similar to those seen with diazepam. Thus, the local cerebral glucose utilization (LCGU) of the mammillary nuclei, the lateral and ventral thalamic nuclei, the anterior thalamic nuclei and the geniculate nuclei was significantly decreased. A doubling of the dose (meprobamate 60 mg/kg i.v.; phenobarbital 10 mg/kg i.v.), however, resulted in a decrement in LCGU in virtually every brain region examined. Further, at this higher dose, phenobarbital significantly increased LCGU in the interpeduncular nucleus. These data demonstrate that both meprobamate and phenobarbital, in moderate doses induce selective alterations in LCGU in particular brain regions with the pattern of changes similar to that induced by diazepam. The structures affected may be of general importance for the expression of the anxiolytic actions of each of those classes of minor tranquilizers in clinical use.

Animals↗
PubMed1975

Drug interactions: the effect of alcohol and meprobamate applied singly and jointly in human subjects. V. Summary and conclusions.

The design, analysis and conclusions of the series of experiments by Carpenter et al., Ashford and Cobby, and Cobby and Ashford [J. Stud. Alc., Suppl. No. 7, pp. 54-176, 1975] are reviewed. Mathematical models of the joint action of drugs were developed and data obtained to test the models by studying the action of alcohol and meprobamate singly and in combination in human subjects. The data proved to be too limited in the range of drug concentrations in the blood necessary to identify the single most appropriate model. Carpenter et al. analyzed the data by analysis of variance, which involves assumptions about the structure of the observation and the form of the distribution of the error terms. The analyses of Ashford and Cobby and Cobby and Ashford used the mathematical models, which represented pharmacological and physiological actions of the drugs. The majority of the results of the two analyses agreed; however in Experiment V Carpenter et al. combined drugs, doses and blood samples in one analysis anf found a significant influence of meprobamate dose on blood alcohol concentration (BAC) and homogeneous error terms. Cobby and Ashford analyzed absorption and elimination phases of each alcohol dose separately and found no influence of meprobamate on BAC and significant heterogeneity in the residual error terms. Both sets of analyses found a complex interaction between the pattern of abosorption and elimination of meprobamate and dose of alcohol. Carpenter et al. related the results of behavioral measures to drug doses, Ashford and Cobby to the concentrations of the drugs in the blood. Theoretically the models can analyze the pattern of behavioral results at each combination of doses but the data available were insufficient for the purpose. The modifications in experimental design and analytical techniques necessary to continue research in developing mathematical models are discussed.

Behavior↗
PubMed1977

Meprobamate overdosage: a continuing problem.

Meprobamate was implicated in 50 (6.5%) of 773 admissions to Massachusetts General Hospital due to psychotropic drug overdosage between 1962 and 1975. Estimated doses ingested reached as high as 40 gm. Serious intoxication was common. In 25 cases deep coma (grade 3 or 4) was reached; 23 patients became hypotensive, and 16 required assisted ventilation. Two patients died, one of whom ingested an estimated 12 to 20 gm of meprobamate apparently with no other drugs. The findings indicate that overdosage with meprobamate, even when taken alone, produces intoxication that is often serious and sometimes fatal. Although meprobamate is a relatively inexpensive anti-anxiety agent, its questionable efficacy and the potential for life-threatening intoxication are important drawbacks to the clinical use of this drug.

Adolescent↗
PubMed1987

Effects of meprobamate on plasma lipids, lipoproteins, and experimental atherosclerosis.

The effects of the tranquilizer meprobamate (Equanil) on plasma lipids, lipoproteins, and atherogenesis in cockerels fed an atherogenic diet have been investigated. Gross gradings (visually assessed blindly) of the atherosclerosis of the thoracic and abdominal aortas of the meprobamate-treated plain mash were significantly more severe than the untreated plain mash controls. There were no significant differences in the gradings of thoracic and abdominal aortic lesions in the atherogenic groups, whether treated with meprobamate or not. Microscopic examination of the coronary arteries of birds on the atherogenic regimen treated with meprobamate revealed that these birds had atherosclerosis similar to the atherogenic diet group.

Animals↗
PubMed1983

Dissolution of meprobamate from various tablet formulations.

The effect of some formulation variables on the release of meprobamate from compressed tablets has been investigated. Possible interaction among the various variables was also studied. As a diluent, lactose produced a better dissolution rate than did starch. Tablets made with starch paste as the binder produced a faster release of meprobamate than those made with gelatin solution. Acacia proved to be the best disintegrating agent when compared to microcrystalline cellulose or starch, especially when the formulation already contained starch as the diluent. Under these conditions, microcrystalline cellulose was a better disintegrating agent than starch. Magnesium stearate or talc when used as a lubricant did not reduce the rate of release of meprobamate. Formulations containing a large proportion of starch (about 50%) did not produce a fast release of meprobamate.

Excipients↗
PubMed1976

The influence of meprobamate on heart rate in the conscious dog.

The effects of meprobamate on heart rate in the unanesthetized dog were compared under two experimental conditions: (1) In the animal equipped with a telemetry device, in which the heart rate was on average 70/min over a 24 hour period, i.v. injection of 20 mg/kg of meprobamate tended to increase heart rate, a dose of 50 mg/kg provoking a significant tachycardia; (2) In the untrained dog restrained on a table, in which the heart rate ranged from 100 to 110/min, i.v. doses of 20 and 30 mg/kg of meprobamate did not lower heart rate, notwithstanding a significant sedative effect whereas a dose of 50 mg/kg provoked tachycardia; atropine-induced cardio-acceleration was not influenced by these doses of meprobamate.

Animals↗
PubMed1984

A purinergic component in the central actions of meprobamate.

The anxiolytic propanediol carbamate, meprobamate, potentiates the depressant actions of adenosine on the firing of rat cerebral cortical neurons. Meprobamate inhibits the uptake of adenosine by rat cortical synaptosomes at concentrations within the therapeutic range. Potentiation of endogenously released adenosine can account for many of the central actions of meprobamate.

Action Potentials↗
PubMed1985

A possible role of endogenous adenosine in the sedative action of meprobamate.

The behavioral interaction of intraperitoneal (i.p.) injections of meprobamate with intracerebroventricular (i.c.v.) injections of adenosine or 5'-N-ethylcarboxamidoadenosine (NECA) was examined on spontaneous locomotor activity in mice. The locomotor depressant effect of meprobamate, an adenosine uptake inhibitor, was potentiated by adenosine, but not by NECA, an uptake-resistant adenosine analogue. These findings suggest that heightened endogenous adenosine levels could mediate some of the central actions of meprobamate.

Adenosine↗
PubMedDate not supplied

Determination of meprobamate in pharmaceutical dosage forms also containing carbromal by liquid chromatography and indirect photometric detection.

In a pharmaceutical form also containing carbromal, meprobamate could not be quantified selectively by classical methods described in pharmacopoeias due to a significant interference from carbromal. Consequently, reversed-phase HPLC methods have been developed to separate the two active ingredients using indirect photometric detection to visualize and determine meprobamate which has very poor chromophoric properties. Different parameters influencing the sensitivity of the indirect response, such as the nature of the highly absorbing compound added to the mobile phase (the marker) as well as the methanol content and the pH of this phase, have been studied. Two chromatographic systems containing benzoic acid or cinnamic acid as the marker, have been optimized and validated. Good linearity and reproducibility have been obtained with both systems but the cinnamic acid method has the advantage that meprobamate and carbromal can be determined simultaneously at 273 nm.

Benzoates↗