Acute hand ischemia after intra-arterial injection of meprobamate powder.

BACKGROUND: Meprobamate tablets contain microcrystalline cellulose, a potent embolic agent that has been shown to cause gangrene in animal studies. Microvascular embolization caused by microcrystalline cellulose can contribute to the ischemic process. OBJECTIVE: We report a case of acute hand ischemia after accidental intra-arterial injection of crushed meprobamate powder in a 23-year-old male drug abuser. CASE REPORT: The distal tips of the patient's right thumb, index finger, ring finger, and little finger continued to develop gangrene despite medical therapy with heparinization, low molecular-weight dextran infusion, corticosteroid administration, and hyperbaric oxygen therapy. CONCLUSION: We believe this is the first case of acute limb ischemia caused by intra-arterial injection of meprobamate powder documented in humans. Emergency physicians should be aware that accidental intra-arterial injection of crushed oral drug formulations is potentially limb threatening and prompt recognition of similar clinical scenarios is of vital importance.

Sleep complaints: Whenever possible, avoid the use of sleeping pills.

(1) Most sleep complaints involve difficulties in getting to sleep or staying asleep, or not feeling refreshed on awakening. Misconceptions and worrying over the lack of sleep and its consequences can contribute to reinforcing these disorders; (2) How can patients who complain of poor-quality sleep be helped, without resorting to treatments that can have adverse effects? To answer this question, we conducted a systematic review of the literature based on the standard Prescrire procedure; (3) One effective approach is to explain the basic physiology of sleep, to discuss misconceptions, and to adopt a strategy of "stimulus control". This method has a similar efficacy to prescribing a benzodiazepine. and the effect is longer lasting; (4) Moderate, regular physical exercise, especially in the morning, seems to help some patients, but the evidence is weak; (5) Some clinical trials of phytotherapy have shown a positive risk-benefit balance of weak aqueous or hydroalcoholic valerian extracts. Efficacy is limited, however; (6) A meta-analysis of placebo-controlled trials showed that benzodiazepines and related drugs increase the duration of sleep and help patients to fall asleep sooner. However, none of these trials provides comparative data spanning periods of more than two weeks. Efficacy is uncertain in the longer term, as patients quickly develop a tolerance to the hypnotic effects of benzodiazepines; (7) The adverse effects of benzodiazepines include frequent memory disorders, daytime drowsiness, falls, fractures and road accidents, and a withdrawal syndrome after treatment cessation. Related drugs such as zolpidem and zopiclone provoke similar adverse effects; (8) Sedative antihistamines have not been as well-evaluated as benzodiazepines in this setting. Small comparative trials of doxylamine and diphenhydramine showed no major difference in efficacy versus benzodiazepines and related drugs. The main adverse effects of sedative antihistamines are daytime drowsiness and altered vigilance, and atropinic effects; (9) Case-control studies showed a statistical link between benzodiazepine use in early pregnancy and birth defects such as cleft lip. In contrast, data on the use of doxylamine during pregnancy are reassuring; (10) Other sedative psychotropics have not been adequately tested in this setting or have been shown to have a negative risk-benefit balance; (11) In practice, patients who complain of poor-quality sleep should be given appropriate information on the mechanisms of normal sleep and related misconceptions, on the best methods for getting to sleep, and on the dangers of sedative psychotropics (dependence, withdrawal syndrome). When prescribing or dispensing a benzodiazepine to a woman of child-bearing age, the risk of birth defects, although not clearly demonstrated, must be mentioned.

Something old, something new: a successful case of meprobamate withdrawal.

Meprobamate, a benzodiazepine-like drug, was commonly prescribed for anxiety in the 1960s and 1970s, but fell out of favour, at least in part, due to the risk of dependence, for which there is little published evidence to guide clinical management. We discuss a 70-year-old man with a 45-year history of meprobamate dependency and multiple failed previous withdrawal attempts who was successfully withdrawn from meprobamate using diazepam during a 2-week inpatient stay on a specialist Addictions ward. An appropriate diazepam dose was established using the Clinical Institute Withdrawal Assessment scale for benzodiazepines (CIWA-B). This dose was then slowly reduced over 12 days. Multidisciplinary input, especially psychological therapy tackling his underlying anxiety disorder during his admission, was thought to be particularly helpful.

Different effects of psychotropic drugs on delayed hypersensitivity responses in mice.

The influence of certain psychotropic drugs on the delayed-type hypersensitivity (DTH) response to sheep red blood cells in BALB/c mice was studied. The effects on the overall response and the induction and elicitation phases were evaluated, using two alternative dosage schedules for each agent. It was found that diazepam had no effect on the DTH reaction but the administration of imipramine, haloperidol, chlorpromazine or meprobramate all resulted in depression of the response, impairing both the induction or elicitation phases. The results indicate that psychotropic drugs may produce in vivo depression of cell-mediated immunity by different mechanisms.

Relative bioavailability of meprobamate tablets in humans.

The relative bioavailability of 400-mg meprobamate tablets manufactured by 11 different firms was evaluated in two groups of healthy male subjects. Each group of six subjects received a reference standard product and five test products given at 1-week intervals. Plasma meprobamate concentrations at 1, 2, 3, 4, 6, 8, 10, 24, and 32 hr after dosing were determined using a GLC assay. Analysis of variance of the plasma level--time profiles revealed no statistically significant differences between any of the products in terms of plasma levels at the various sample times, time of peak plasma level, peak plasma level, and area under the plasma level--time curve. It was concluded that the 11 400-mg products could be considered bioequivalent.

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.

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.

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.

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.]

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.

[The influence of the polymorphism of the active substance on the properties of tablets. Part 3. Compressional behaviour of meprobamate (author's transl)]. / Einfluss der Polymorphie des Wirkstoffes auf die Eigenschaften von Tabletten. 3. Mitteilung: Kompressionsverhalten von Meprobamat.

Three polymorphic meprobamate-modifications (I, II, III) of different particle size were compressed without other ingredients on a hydraulic press under 30, 60, 120, and 240 N/mm2. The rather soft substance shows a high degree of densification and above ca. 60 N/mm2 also good consolidation properties. The void volumes of the compacts obey the equation of Kawakita and are increasing in all cases in the sequence I leads to III leads to II. The radial breaking strength generally decreases in the same succession and depends linearly on the logarithm of compaction pressure. It is noteworthy, that the modification with the highest density (I) has the highest plasticity and is also compacted most easily. Modification II which is slightly harder and has a density between modifications I and III, shows the greatest differences in the compaction behaviour, as compared to modification I. Its breaking strength is also increasing faster with compaction pressure than the other modifications.

[Gender differences in suicidal behavior]. / Nemi különbségek a szuicid viselkedésben.

Gender-specific differences in suicidal behaviour have been analysed in a number of recent studies. According to these, several socioeconomic, demographic, psychiatric, familial, help-seeking differences can be identified in protective and risk factors between males and females. Gender is one of the most replicated predictors for suicide. In the framework of the WHO/EURO Multicentre Study on Suicidal Behaviour, more than fifty thousand suicide attempts have been registered so far. Until now data on more than 1200 monitored suicidal events have been collected in Pecs centre. In most countries male suicid rates are higher. In contrast to suicides, rates of suicide attempts are usually higher in females. Concerning the differences in methods, it is a recognised fact that males use violent methods of both suicide and attempted suicide more often than females. The summarised clinical impression suggests that compliance of male patients is poorer than that of females. According to our data, a typical male attempter is characterised as follows: unemployed, never married, lives alone. He tends to use violent methods; if he takes drugs, it is mostly meprobamate or carbamazepine. A lot of male attempters have alcohol problems or dependence. As for the females, we found high odds ratios in the following cases: divorced or widowed, economically inactive, depressive state in the anamnesis. Female attempters are mainly repeaters using the method of self-poisoning, mostly with benzodiazepines. As suicide is a multicausal phenomenon, its therapy and prevention should also be complex and gender differences should be taken into account in building up our helping strategies.

[Characteristics of the choice of psychotropic drugs in suicide attempts]. / A pszichofarmakonválasztás jellemzöi öngyilkossági kísérletekben.

UNLABELLED: Review of results of Pecs centre in WHO/EURO Multicentre Study on Suicidal Behaviour. OBJECTIVE: Studies concerning the choice of methods and psychotropics in the suicidal acts have a great importance because the outcome of suicides is decisively determined by the potential lethality of the method. In the sample of patients who attempted suicides, the features of overdoses have been investigated as well as their relations to the age, sex and repetition. METHOD: Within the framework of the WHO/EURO Multicentre Study on Suicidal Behaviour data, 1158 cases with suicide attempts were collected from 1997 to 2001. RESULTS: Among methods of suicide attempts the most frequents were overdoses, while cutting, and hanging were more rarely, and alcohol consumption associated with 15% of attempts. Psychotropics were found in three-quarters of overdoses. A more detailed analysis of the methods used by suicidal patients shows that benzodiazepines represented almost two-thirds of all the drugs taken followed by meprobamate, carbamazepine and antidepressants. Repeaters used frequently antidepressants, antipsychotics, carbamazepine, while benzodiazepines and meprobamate poisoning were rather typical of first-ever group. CONCLUSION: Considerable differences in the use of psychotropics for parasuicide related to gender, age and repetition were found. The results suggest, that the features of overdoses may be in connection with the availability of drugs and the special national characteristics of drug-prescribing. The differences of repeaters may reflect the insufficiency of the mental health care system. The authors emphasize the importance of these facts among the possibilities of prevention.

[Unsuspected danger of a medicinal preparation]. / Danger inattendu d'une préparation magistrale.

INTRODUCTION: Inhaled foreign bodies are commonly reported in childhood but less so among adults. We report the case of a patient who inhaled a medicinal preparation containing meprobamate and quinine sulfate. The consequence of this was caustic damage to the airways. CASE REPORT: A 64-year-old woman came to the emergency room because of dyspnea, oropharyngeal pain and sialorrhea. She reported that she had inhaled a capsule containing meprobamate and quinine sulfate the previous day. Flexible bronchoscopy showed evidence of caustic damage to the larynx and lower airways. The patient was treated by fasting, corticoids and intravenous broad-spectrum antibiotics. All the lesions recovered and she was discharged from the hospital 15 days after the event. CONCLUSIONS: Inhalation of drugs mostly leads to airway obstruction. Risk of harm is influenced by neurological status, the motility of the digestive system and the properties of the drug. To the best of our knowledge, this is the first time that caustic airway disease has been described following inhalation of a medicinal preparation containing meprobamate and quinine. It highlights the need to be familiar with the chemical properties of medications when prescribing them to patients who are at risk of aspiration.