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PubMed1981

The present status of meprobamate ingestion. A five-year review of cases with serum concentrations and clinical findings.

Fifty-seven cases of meprobamate ingestion from 1974 through 1979 were reviewed. Serum meprobamate concentrations, clinical findings, and epidemiologic data were studied to determine the present status of the abuse of this compound. The average patient was a 37-year-old woman who ingested meprobamate and at least one other drug (usually a benzodiazepine, a barbiturate, ethanol, or an opiate) in a suicide attempt of gesture. She arrived at the hospital either alert or lethargic with equal frequency. Half of the time she was seen only in the emergency room, and half of the time she was hospitalized. She was usually treated with supportive care alone and survived the ingestion. Serum meprobamate concentrations exceeding 12 mg/dl were consistent with coma. Dysarthria, hypotension, tachycardia, and ataxia were the most common physical findings. Meprobamate addiction was present in six patients.

Adolescent↗

PubMed1996

Formation of meprobamate from carisoprodol is catalysed by CYP2C19.

Carisoprodol is a muscle relaxant analgesic, which has an active metabolite i.e. meprobamate. We conducted an open three-panel single-dose administration study with 15 healthy volunteers: five poor metabolizers of mephenytoin, five poor metabolizers of debrisoquine and five extensive metabolizers of both substrates. The aim was to investigate if the elimination of carisoprodol and meprobamate is dependent on the two metabolic polymorphisms of mephenytoin and debrisoquine. The subjects were given single oral doses of 700 mg carisoprodol and 400 mg meprobamate on separate occasions. The disposition of carisoprodol was clearly correlated to the mephenytoin hydroxylation phenotype. The mean serum clearance of carisoprodol was four times lower in poor metabolizers of mephenytoin than in extensive metabolizers, which confirms the hypothesis from our previous study that N-dealkylation of carisoprodol cosegregates with the mephenytoin hydroxylation polymorphism. However, mean serum clearance of meprobamate did not differ between the two groups. Also, polymorphic debrisoquine hydroxylation did not influence the elimination of carisoprodol or meprobamate. Poor metabolizers of mephenytoin thus have a lower capacity to metabolize carisoprodol and may therefore have an increased risk of developing concentration dependent side-effects such as drowsiness and hypotension, if treated with ordinary doses of carisoprodol.

Administration, Oral↗

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↗

PubMed1958

Action of meprobamate on spinal monosynaptic reflexes and on inhibitory pathways.

Meprobamate was administered intravenously to spinal cats, in cumulative doses of 30 to 40 mg./kg. each. Initial doses may have a variable action on monosynaptic reflexes. At times some reflexes are depressed, while others are enhanced or unaffected. When dose levels of 100 mg./kg. or higher are reached, monosynaptic reflexes, both flexor and extensor, are depressed. Monosynaptic reflexes can be strongly depressed by meprobamate, their input-output relations often remaining unchanged. In such cases there is thus no change in the spatial summation requirements of those motoneurons remaining in the excitable zone. Inhibitory pathways, both direct and disynaptic, are highly resistant to the action of meprobamate. The drug does not distinguish between the direct and disynaptic pathways. It is suggested that meprobamate acts as a general depressant of excitatory synaptic transmission.

Animals↗

PubMed1960

Recurrent conditioning in the cat spinal cord. Differential effect of meprobamate on recurrent facilitation and inhibition.

The action of cumulative doses of meprobamate on antidromic conditioning has been studied in spinal cats. Recurrent facilitation is greatly reduced or completely abolished by total doses ranging from 210 to 400 mg./kg. The depth of recurrent inhibition is not affected in a consistent manner by meprobamate, but the duration of inhibition is markedly increased in all experiments. This differential action of meprobamate on facilitation and inhibition can be utilized to study conditioning effects consisting of combined inhibition and facilitation. If conditioning starts with an inhibitory phase, variable in duration, followed by facilitation, meprobamate depresses the facilitation and reveals an extended inhibitory curve. Facilitation, however, is not always accompanied by inhibition, since in some cases facilitation is depressed and no inhibition is uncovered. The results of these experiments are discussed in relation to the various types of conditioning that have been produced by antidromic stimulation.

Animals↗

PubMed1961

Effect of meprobamate on the multiplication of Brucella abortus in monocytes.

Peritoneal mononuclear phagocytes (monocytes) obtained from guinea pigs that had been treated with meprobamate do not support, in vitro, the intracellular growth of smooth Brucella abortus that is characteristic of monocytes from untreated animals. This modification of intracellular events appears to be due to an indirect action of the drug, since meprobamate does not produce any effects following direct exposure of monocytes or bacteria to the drug in vitro. Furthermore, the brucellacidal activity of serum from animals exposed to meprobamate is not increased. An interaction between monocytes and a component in the serum of animals exposed to meprobamate is required for the altered intracellular events.

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↗

PubMed1982

A study of the plasma levels of pentaerythritol mononitrate following administration of pentaerythritol tetranitrate in combination with meprobamate and diphenhydramine.

The systemic absorption of meprobamate, diphenhydramine and pentaerythritol tetranitrate (PETN) has been demonstrated following oral administration of a formulation containing all three drug substances to human volunteers. A study undertaken in dogs has also been made of the pharmacokinetics of the major nitrated metabolite of PETN when the parent drug is administered with and without meprobamate and diphenhydramine. Pentaerythritol mononitrate shows a six-fold increase in both peak plasma concentrations and area under the 0-12 hour plasma concentration-time curve when PETN is co-administered with a combination of meprobamate, diphenhydramine and nicotinic acid. No such increase is apparent when either meprobamate or diphenhydramine is excluded from the dose. Further increases in pentaerythritol mononitrate plasma levels and AUC 0-12 h are observed when all of the drugs are administered as the formulated coated tablet (VisanoCor).

Adult↗

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↗