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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↗
PubMed1997

Barbiturate-like actions of the propanediol dicarbamates felbamate and meprobamate.

Felbamate and meprobamate are structurally related propanediol dicarbamates that possess distinct pharmacological profiles. Felbamate is a minimally sedative, broad-spectrum anticonvulsant, whereas meprobamate is a strong sedative-anxiolytic agent. Previously, we reported that felbamate potentiates gamma-aminobutyric acid(A) (GABA(A)) receptor Cl- currents and inhibits N-methyl-D-aspartate (NMDA) receptor currents. Here we further characterized the interaction of the two dicarbamates with GABA(A) receptors to determine the basis for their pharmacological differences. In whole-cell voltage-clamp recordings from cultured rat hippocampal neurons, meprobamate enhanced GABA-evoked responses in a concentration-dependent manner and, at high concentrations (>1 mM), exhibited a separate channel-blocking effect that limited the magnitude of GABA(A) receptor potentiation. At equivalent concentrations, meprobamate produced substantially greater potentiation than did felbamate. Furthermore, meprobamate (but not felbamate), in the absence of GABA, directly activated Cl- currents that could be attenuated by the GABA(A) receptor antagonists bicuculline and picrotoxin. The mean deactivation time constant of whole-cell currents evoked by 10 mM meprobamate (110 ms) or 1 and 3 microM GABA (180 ms) were faster than the deactivation time constant of 10 mM meprobamate (490 ms) or 3 mM felbamate (470 ms) in the presence of GABA. Meprobamate and felbamate prolonged the mean burst duration of GABA-activated unitary currents in excised outside-out membrane patches. In addition, at high (supratherapeutic) concentrations, meprobamate blocked NMDA-activated currents. We conclude that felbamate and meprobamate have barbiturate-like modulatory actions on GABA(A) receptors, but meprobamate has greater activity and, unlike felbamate, is able to directly activate the receptor.

Animals↗
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↗
PubMed2000

Anxiolytic-like effects of meprobamate. Interactions with an opiate antagonist in Swiss and BALB/c mice.

Naloxone has previously been shown to block the effects of benzodiazepines in the Swiss but not in the BALB/c strain. We have also reported that naloxone potentiates subeffective doses of benzodiazepines in Swiss mice. In the present studies we first determined whether naloxone could block anxiolytic-like effects of meprobamate in Swiss and BALB/c mice. Then we evaluated if subeffective doses of meprobamate could be potentiated in Swiss as well as in BALB/c mice. The elevated plus-maze test and the light/dark choice procedure were used. The lowest dose of meprobamate with anxiolytic-like effects was 60 mg/kg in the BALB/c mice. This dose was effective in both the plus-maze and in the light/dark choice procedure. In Swiss mice the same dose was effective in the plus-maze, whereas 120 mg/kg was required in the light/dark choice procedure. When an effective dose of meprobamate was combined with naloxone, 10 mg/kg, no blockade of anxiolytic-like effects was obtained in any strain in any procedure. To the contrary, when a subeffective dose of meprobamate was combined with naloxone, 10 mg/kg, an anxiolytic-like effect was obtained in both strains in both procedures. The present series of experiment shows that the ability of naloxone to block anxiolytic-like drug effects do not apply to meprobamate. However, the naloxone-induced potentiation of subeffective doses previously observed after treatment with benzodiazepines or buspirone was present also after treatment with meprobamate. Moreover, although blockade of anxiolytic-like drug effects with naloxone has not been observed in BALB/c mice, potentiation was as evident in that strain as in the Swiss. This suggests that the mechanisms behind naloxone's blockade of anxiolytic-like effects are independent from those behind its potentiation of such effects.

Animals↗
PubMed2003

Comparative abuse liability and pharmacological effects of meprobamate, triazolam, and butabarbital.

Implementation of regulations to control the prescribing of benzodiazepines in New York State in 1989 resulted in a 55% decrease in benzodiazepine prescribing, with a concomitant increase in the rates of prescribing older sedative-hypnotic compounds such as butabarbital (30% increase) and meprobamate (125% increase). In a double-blind, crossover, placebo-controlled study, we compared the behavioral and pharmacological effects of triazolam, meprobamate, and butabarbital in 14 recreational drug users. Placebo and three doses each of triazolam, meprobamate, and butabarbital were administered to each subject in a random order. Objective tests (motor performance, concentration) and subjective response questionnaires measured drug effects. Triazolam, meprobamate, and butabarbital showed comparable negative dose-response slopes on the objective measures. On the basis of these objective data, equivalent doses for the three compounds were determined to be as follows: 0.5 mg triazolam = 2,400 mg meprobamate = 400 mg butabarbital. Subjective effects data on equivalent doses show that butabarbital produced the highest peak score on Cole/ARCI Abuse Potential, ARCI Pentobarbital Chlorpromazine Alcohol Group (PCAG), and "drug strength" scales. Triazolam and butabarbital produced equivalent results on ARCI Morphine Benzedrine Group (MBG), Cole/ARCI Euphoria, and "drug liking" scales. Meprobamate was indistinguishable from placebo on euphoria and abuse potential scales. Behavioral economics analysis indicated a price crossover point two times higher for butabarbital (400 mg) than for any other drug condition. These data indicate a comparative abuse liability of butabarbital > triazolam > or = meprobamate, suggesting that the prescribing restrictions on benzodiazepines had little net benefit on abuse risk in the population and may have increased the risk of overdose morbidity and mortality.

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↗
PubMed1997

Felbamate and meprobamate: a comparison of their anticonvulsant properties.

The anticonvulsant effect of felbamate and meprobamate were compared in a series of models for seizure activity and regarding their neurotoxic action. In the MES test, felbamate was active below neurotoxic doses. Meprobamate had an ED50 in the range of neurotoxic doses. The s.c. PTZ test was influenced by meprobamate in a fairly low dosage (ED50 66 mg/kg), but for felbamate no clearly dose-related effect could be shown up to 150 mg/kg. Reflex epilepsy in gerbils was stronger suppressed by meprobamate (ED50 34 mg/kg) than by felbamate (ED50 63 mg/kg). In amygdala kindled rats, meprobamate proved to be the most active compound, both regarding treatment of fully kindled rats, development of kindling and independent discharges from a mirror focus (secondary epileptogenesis), which were fully suppressed by oral treatment with 80 mg/kg for 30 days. Both drugs were weakly effective in a model for absence epilepsy in rats. The unexpectedly high activity of meprobamate justifies a second look at the anticonvulsant properties of the drug, especially since it was extensively used as an anxiolytic drug in the past with few obvious serious side effects.

Animals↗
PubMed2003

Association between blood carisoprodol:meprobamate concentration ratios and CYP2C19 genotype in carisoprodol-drugged drivers: decreased metabolic capacity in heterozygous CYP2C19*1/CYP2C19*2 subjects?

Carisoprodol is metabolized to meprobamate by the cytochrome P450 enzyme CYP2C19, encoded by the polymorphic CYP2C19 gene. Most studies on carisoprodol metabolism have been carried out on individuals phenotyped for CYP2C19 activity using the probe drug S-mephenytoin. We aimed to investigate whether the ratio of carisoprodol to meprobamate in a 'real life' setting could be predicted by CYP2C19 genotype or, more specifically, if high carisoprodol : meprobamate ratios in drugged drivers could be ascribed to the presence of mutant CYP2C19 alleles. From original material comprising 358 blood samples from apprehended drivers, two polarized groups were selected; a high-ratio group of 11 subjects where the carisoprodol : meprobamate ratio was >1 and a low-ratio control group of 23 subjects where the ratio was <0.31. Genotyping was carried out for the CYP2C19*2, CYP2C19*3 and CYP2C19*4 alleles. DNA samples from 94 healthy blood donors were used as reference material. The number of mutant alleles in the high-ratio and low-ratio groups was significantly higher and lower, respectively, than in the reference material. The increased number of mutant alleles in the high-ratio group was not due to the presence of many poor metabolizers, but to a high number of heterozygous individuals with the genotype CYP2C19*1/*2. This result indicates a gene dosage effect where the carisoprodol : meprobamate ratio reflects the number of active CYP2C19 alleles. The metabolism of carisoprodol to meprobamate is dependent on CYP2C19 genotype. Heterozygous individuals with the CYP2C19*1/*2 genotype have a reduced capacity for metabolizing carisoprodol, and should probably be regarded as intermediate metabolizers of this drug.

Adult↗