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A 52 year old man admitted to hospital in a toxic state, was found to have agranulocytosis, which recovered when an analgesic containing meprobamate was stopped. The patient was known to have had similar symptoms 9 months previously when the drug was first used, thereby demonstrating an idiosyncratic reaction to meprobamate.
We present a randomized double-blind study on the efficacy of caroverine in the treatment of alcohol withdrawal symptoms. The group B Ca2+ channel blocking agent caroverine was tested against meprobamate in inpatient treatment of alcohol withdrawal. Patients of both groups were similar in age, weight, duration of drinking, ingested quantities of alcohol and intensity of withdrawal symptoms in both groups. The symptoms were quantified daily by Syndromkurztest (SKT), Nurses' Observation Scale for Inpatient Evaluation (NOSIE), NGI; the Webster scale was applied to rate tremor, speech and coping. Duration of study was scheduled for 5 days after which other medication, e.g., levopromazine was applied if needed. As caroverine is registered and used as a spasmolytic drug in Austria, patients' verbal consent was sufficient. In both compounds we registered no difference of clinical efficacy, though caroverine presented less sedative side effects. This may be an important factor in the treatment and management of alcohol withdrawal symptoms. Dose ranges were 120 mg/day vs. 2,400 mg/day of caroverine and meprobamate, respectively. Thus, drug loading and metabolism can be thoroughly reduced by the application of caroverine--another important point in treatment of alcoholism. In 4 cases of manifest delirium tremens the infusional application of caroverine was openly tested with dose ranges of 2.5-5.0 mg/kg (24 h). Clinical effects were estimated to be similar with oral application as was therapeutic efficacy. This novel indication of a group-B Ca2+ channel blocker presents an interesting feature, which seems to warrant further investigation.
A patient with severe meprobamate poisoning presented within 4 h after suicidal ingestion of an unknown amount of the drug. The patient was unconscious, unresponsive, and hypotensive. Continuous arteriovenous hemoperfusion with coated activated charcoal resulted in a clearance of 198.8 +/- 15.6 mL/min with an extraction ratio of 0.66 +/- 0.05 (n = 3). There was almost complete elimination of the drug from the blood by 16 h. Continuous arteriovenous hemoperfusion, which can be performed in areas where dialysis facilities are not available, may be an effective adjunct to the treatment of acute meprobamate intoxication, particularly in patients with profound hypotension.
This paper considers the pharmacology of the centrally acting muscle relaxant carisoprodol, and its metabolite meprobamate, which is also administered as an anxiolytic in its own right. Literature implicating these drugs in impaired driving is also reviewed. A series of 104 incidents in which these drugs were detected in the blood of drivers involved in accidents or arrested for impaired driving was considered, with respect to the analytical toxicology results, patterns of drug use in these subjects, the driving behaviors exhibited, and the symptoms observed in the drivers. Symptomatology and driving impairment were consistent with other CNS depressants, most notably alcohol. Reported driving behaviors included erratic lane travel, weaving, driving slowly, swerving, stopping in traffic, and hitting parked cars and other stationary objects. Drivers on contact by the police displayed poor balance and coordination, horizontal gaze nystagmus, bloodshot eyes, unsteadiness, slurred speech, slow responses, tendency to doze off or fall asleep, difficulty standing, walking or exiting their vehicles, and disorientation. Many of these cases had alcohol or other centrally acting drugs present also, making difficult the attribution of the documented impairment specifically to carisoprodol and meprobamate. In 21 cases, however, no other drugs were detected, and similar symptoms were present. Impairment appeared to be possible at any concentration of these two drugs; however, the most severe driving impairment and most overt symptoms of intoxication were noted when the combined concentration exceeded 10 mg/L, a level still within the normal therapeutic range.
The localization of meprobamate-like (MPB-like) molecules in the neuromuscular junction of rats has been investigated at light- and electron- microscopic levels with the peroxidase-antiperoxidase (PAP) immunohistochemical method, using a purified antiserum obtained from rabbits immunized with a meprobamate-bovine serum albumin (MPB-BSA) conjugate. The immunoreaction was found surrounding synaptic vesicles and in protuberant deposits situated in the post-synaptic membrane. These facts suggest the existence of endogenous MPB-like molecules in neuromuscular junction and that the immunostained protuberant deposits should mark the receptors of those molecules.
The benzodiazepines chlorodiazepoxide, diazepam and flurazepam and meprobamate depress the response of the guinea-pig ileum to acetylcholine, histamine and 5-hydroxytryptamine. As compared to the benzodiazepines the action of meprobamate is very weak. Chlorodiazepoxide has a weaker anti-acetylcholine activity than diazepam and flurazepam. On the other hand chlorodiazepoxide possesses a realtively strong anti-histamine activity. The three benzodiazeptines tested are about equally effective in reducing the contraction of the guinea-pig ileum caused by 5-hydroxytryptamine. The potency of diazepam and flurazepam in blocking the effect of the three smooth muscle stimulants appears to be rather similar.
A case of suicidal overdose from the ingestion of Palpipax (meprobamate and sparteine) is presented. The drugs were quantified in biological fluids and tissues using gas chromatography. The blood concentrations of meprobamate and sparteine were found to be 88.2 and 40.4 micrograms/ml, respectively. Results are discussed in the light of the existing literature.
Imipramine, diazepam, chlordiazepoxide, and meprobamate inhibit incorporation of 3H-thymidine in human lymphocytes in culture. For the first three drugs, 50% inhibition occurs at a concentration of 5 X 10(-5) M, and for meprobamate at a concentration of 10(-3 M. Ethanol has no action up to 10(-1) M.
The influence of minor tranquilizers (diazepam, meprobamate and beuactizine) on the hypothalamically elicited emotional responses was studied in chronic experiments on rabbits. The positive self-stimulation elicited from the lateral hypothalamus was facilitated by all used tranquilizers. On the first day of administration of the drugs the rate of self-stimulation increased markedly. The rate of self-stimulation was still mildly enhanced on the second day and returned to its initial value on the third day. The avoidance behaviour elicited from the medial hypothalamus changed to obvious self-stimulation after the administration of diazepam and meprobamate. The reversed behaviour preserved on the second day, while on the third day the animals resumed their avoidance behaviour. It was depressed by benactizine injection and some activation of exploratory behaviour was observed.
Behavioral tolerance to meprobamate was demonstrated in a cat, on an FI schedule, without behavior taking place during the chronic treatment. Behavioral factors, such as the development of corrective patterns of behavior, do not explain behavioral tolerance in this case.
Mebutamate, a propanediol derivative, has recently been introduced as an antihypertensive agent. In a double-blind, controlled study of 33 patients, the antihypertensive effect of mebutamate was not found to differ significantly from that of a placebo.The psychosedative properties of mebutamate did not differ from those of meprobamate. Reserpine, when given orally, lowered blood pressure and its antihypertensive activity was independent of its sedative properties.
A rapid near IR spectrophotometric method was developed for determining meprobamate in tablets, sustained-release capsules, suspensions, and injectables. The absorbance of a chloroform solution of the drug is obtained at about 1.96 mum for quantitation. Assay of nine commercial products from four different manufacturers gave results ranging from 97 to 104% of label claim. Coefficients of variation of 0.7 and 1.3% were obtained on the tablets and a sustained-release product, respectively.
The selectivity and sensitivity provided by a wall-coated open tubular column coupled with a nitrogen-selective detector allowed rapid, accurate determination of diazepam, meprobamate, phenylbutazone, and thioridazine in serum in the same chromatographic system using 100--200 microliters of sample.
A case is described in which voluntary ingestion of 72 g meprobamate (mpb) was complicated by shock ascribed to cardiac failure and vasodilation, documented by hemodynamic monitoring. Forced diuresis and cardiac inotropic support were added to the therapy. We recommend Swan-Ganz monitoring in any case of mpb overdosage associated with hypotension and suggest that forced diuresis is not contraindicated if appropriate assessment of the patient's hemodynamic condition is performed.
Most pharmacopoeial methods for meprobamate are based on acid hydrolysis, followed by determination of the ammonia formed. In order to find optimum conditions the hydrolysis was studied with the aid of TLC. Various types and concentrations of acid were tested. Refluxing with 25% (wt/vol) HCl for two hours proved to be sufficient to achieve complete hydrolysis (99.4 +/- 1%). This method is less time-consuming than that of the European Pharmacopoeia and the hydrolysate does not turn brown as is the case with high concentrations of H2SO4.
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.
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.
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.