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Analysis of results of toxicological examinations performed by coroners' or medical examiners' laboratories in 2000 drug-involved deaths in nine major U. S. cities.

Data were collected on 2000 deaths in which psychoactive drugs were involved. The data were submitted by medical examiners or coroners in nine U. S. cities from their case files. The 2000 cases comprise a representative sample from each of these cities of deaths from psychoactive drugs between 1972 through 1974. This report details inter-city differences in methods and practices of the toxicological examination as well as the type and numbers of drugs reported. Even when the same analytical method was used in various cities, there were differences in extraction solvent and extraction pH. Of the 3909 drugs detected, 2945 were quantitated; the number of drugs quantitatively measured per case studied ranged from a low of 0.82 for New York to a high of 2.20 for Washington, D.C. The number of different drugs quantitatively measured varied from 16 for New York to 30 for San Francisco; however, New York qualitatively assayed for the presence of a total of 25 drugs. The number and type of drugs found per case varied. Methadone, for example, was found in 60% of the cases reported by New York and in 49% of the cases from Washington, D.C., but in only about 10% of cases reported by Philadelphia, Dallas, Miami, and San Francisco, and in less than 1% of Los Angeles and Cleveland cases; it was not reported by Chicago. Phenmetrazine-caused deaths were reported only by Dallas (one case) and Washington, D.C. (29 cases). From the data as a whole, information is presented for 33 drugs as to the concentration in physiological tissues and fluids. Analysis of single psychoactive drug cases and single-drug-plus-ethanol cases shows that, in the presence of ethanol, the toxic blood concentration of imipramine, amytriptyline, meprobamate, thioridazine, morphine, propoxyphene, methaqualone, and all barbiturates was decreased by an average of 50%.

Forensic Medicine↗

[Amphetamine--induced rage reaction in mice and its mechanism].

Rage reaction was induced in mice by ip amphetamine sulfate (APT) 15 mg/kg. Mice appeared hyperreactive after 6 min and then squeaked and fought each other. These manifestations were most distinct in 15-30 min and subsided after 40-70 min. At 20 degrees C and 25 degrees C, the occurrence of rage reaction was 85.0% and 90.0% respectively. The ED50 of APT for eliciting rage reaction was 11.8 +/- 2.1 mg/kg ip. No significant difference in the induction of rage reaction was observed between male and female mice but ambient temperature affected the occurrence of this reaction. Neuroleptic drugs (chlorpromazine, haloperidol, tardan and clozapine), anxiolytic drugs (diazepam and meprobamate) and reserpine suppressed the rage reaction induced by APT in mice. Phenobarbital and pentobarbital (at sedative doses), atropine, scopolamine, phentolamine and propranolol exerted no influence on APT--induced rage reaction. Amantadine, levodopa and apomorphine at lower doses potentiated the rage inducing effect of APT. Moreover, at higher doses amantadine or levodopa alone also evoked rage reaction similar to that induced by APT. Therefore, it may be deduced that the APT-induced rage reaction results from increased release of dopamine in limbic system and has nothing to do with the simultaneous epinephrine release. The available data indicate that the APT--induced rage reaction in mice deserves to be recommended as an animal model for screening potential neuroleptic drugs. The merits and shortcomings of this new model are discussed.

Amphetamine↗

Inhibition of carbonic anhydrases I and II by N-unsubstituted carbamate esters.

We previously showed that the zinc metalloenzyme carbonic anhydrases (CA I and II isozymes) bind "neutral" amides and related compounds as anions through coordination of their deprotonated amide nitrogen to the active site zinc (Rogers, J. I., Mukherjee, J., and Khalifah, R. G. (1987) Biochemistry 26, 5672-5679). Urethan, the ethyl carbamate ester, was among such compounds. The present study was designed to test whether other N-unsubstituted carbamate esters of pharmacological interest (as sedatives, hypnotics, anxiolytics, and skeletal muscle relaxants) were capable of binding to CA in the same manner. We studied the interaction of human CA I and II with urethan, phenyl carbamate, ethinamate, meprobamate, and methocarbamol. Phenyl carbamate studies were greatly complicated by its uncatalyzed hydrolysis via an elimination mechanism to form cyanate, a powerful CA inhibitor. In general, the compounds display: 1) slow on-off inhibition binding kinetics in the seconds range, 2) maximal inhibitor affinity at alkaline pH, and 3) characteristic three-band visible spectra of their complexes with cobalt-substituted CA I. These properties are shared with the previously studied amide inhibitors and are taken as evidence that the deprotonated carbamate nitrogen coordinates to the active site metal ion. CA I appeared to bind carbamate esters more tightly than CA II, an unusual 1000-fold selectivity being seen in the case of methocarbamol. The inhibition by these drugs is not sufficiently strong to implicate CA I and II in their mechanism of action. However, it does suggest the possible existence of previously unsuspected similarities between binding to CA and to their physiological receptors or targets, particularly the involvement of zinc.

Binding Sites↗

Evaluation of psychopharmacological effects of petroleum ether extract of Cuscuta reflexa Roxb. stem in mice.

The petroleum ether extract of Cuscuta reflexa Roxb. stem (PECR) was evaluated for its psychopharmacological activities in several experimental models using Swiss albino mice. The PECR was found to cause significant reduction in spontaneous activity and exploratory behavioral profiles. It also showed reduction in muscle relaxant activity by rotarod, 30 degrees inclined screen tests and showed significant analgesic properties as well as potentiated remarkably the pentobarbitone sodium, diazepam and meprobamate--induced sleeping time. All these results were compared with respective controls for the evaluation of significance. The presence of steroids in the PECR might he responsible for psychopharmacological activities.

Alkanes↗

Gender differences in suicide attempters in Hungary: retrospective epidemiological study.

AIM: To determine gender differences in suicidal behavior and investigate the factors associated with suicide attempts. METHODS: In the framework of the WHO/Euro Multicenter Study on Suicidal Behavior, 1,158 suicide attempts have been registered and analyzed retrospectively in Pecs center, Hungary. Descriptive statistics and logistic regression analysis were performed to compare the characteristics of male and female suicide attempters. RESULTS: A "typical" female suicide attempter could be characterized as follows: retired or economically inactive (OR=2.38), widowed (OR=6.55), divorced (OR=1.64), or with depression in her personal history (OR=1.27). Female attempters were mainly repeaters, using the method of self-poisoning, mostly with benzodiazepines. Among men, unemployment, living alone, never having been married, and problems with addiction were the main risk factors, while violent methods characterized the typical attempt In the cases of self-poisoning, men were more likely to take meprobamate or carbamazepine. CONCLUSION: Significant differences were found in the risk factors for suicide attempts between men and women. Since suicide is a multi-causal phenomenon, its therapy and prevention should be complex and gender differences should be taken into consideration while building up our helping strategies.

Adolescent↗

CNS activities of Celesia coromandeliane Vahl. in mice.

The dried extracts of aerial parts of Celesia coromandeliane Vahl. (Scrophulariaceae) were evaluated for CNS activities in mice. The methanol extract of aerial part of Celesia coromandeliane (MECC) was found to cause significant depression in general as well as exploratory behavioral profiles in mice. MECC showed reduction in muscle relaxant activity by 30 degrees inclined screen test, as well as potential remarkably the pentobarbitone sodium-, diazepam- and meprobamate-induced sleeping time of mice. The petroleum ether extract of aerial parts of Celesia coromandeliane (PECC) showed significant analgesic properties as evidenced by the significant reduction in the number of writhes and stretches induced in mice by 1.2% acetic acid solution. Pretreatment with PECC caused significant protection against strychnine- and leptazol-induced convulsions. All these results were compared with respective controls for the evaluation of significance. The presence of steroids in PECC and saponins in MECC might be responsible for respective CNS activities in mice.

Analgesics↗

[Benzodiazepine receptors during various treatments of alcohol withdrawal].

Drugs most commonly used in the treatment of alcoholic withdrawal are antianxiety agents, namely benzodiazepines. Some similarities may be found between the mechanism of action of such active principles and that of alcohol at the GABAergic transmission level. In mice with physical dependence, in vivo binding of [3H]-RO 15-1788 to central benzodiazepine receptors increases during the initial period, but then tends to taper down to its basal value in the course of withdrawal. Neurochemical treatment with alpha-adrenergic drugs or with agents than can stimulate serotonergic transmission, as opposed to meprobamate therapy, promotes faster recovery of basal levels. In man, these data may be referred to decreased benzodiazepine consumption in the course of alcohol withdrawal. The results suggest that both noradrenergic and serotonergic treatments may be associated with significantly lower risks for newly induced benzodiazepine dependence.

Animals↗

Anti-anxiety drug usage in the United States, 1989.

In 1989 more than 36.4 million new prescriptions for minor tranquilizers (MTs) were written in the continental United States. These drugs were 81 percent of all tranquilizers prescribed; the majority of the MTs were benzodiazepines, with hydroxyzines, meprobamates and buspirones making up the remaining 19 percent. The predominant diagnosis associated with the total MT group of drugs was "anxiety states". This condition was listed as a reason for one in every four new prescriptions for MTs. Per capita new prescriptions averaged 232.3 per 1,000 population, with the highest rate reported in the East South Central area and the lowest in the Pacific states. Psychiatrists accounted for 20 percent of the new prescriptions, just behind internists with 21 percent.

Anti-Anxiety Agents↗

Consequences of the 1989 New York State triplicate benzodiazepine prescription regulations.

OBJECTIVE: Comparison of psychoactive medication prescribing and Medicaid expenditures before (1987 through 1988) and after (1989 through 1990) institution of the New York State triplicate benzodiazepine regulations. DATA SOURCES: The National Prescription Audit (IMS America, Plymouth Meeting, Pa), New York State Medicaid, and Blue Cross/Blue Shield fo the Rochester (NY) Area. RESULTS: From 1988 to 1989, New York State benzodiazepine prescribing decreased by 44%, 60%, and 30% as assessed by IMS America, Medicaid, and Blue Cross/Blue Shield, respectively. Prescribing of the following alternative sedative-hypnotics increased in New York State compared with decreases nationally (IMS America data): meprobamate, +125% vs -9%; methyprylon, +84% vs -15%; ethchlorvynol, +29% vs -18%; butabarbital, +31% vs -15%; hydroxyzine, +15% vs -1.1%; and chloralhydrate, +136% vs -0.4%. Increased prescribing of alternatives was also seen in the Medicaid and Blue Cross/Blue Shield data. Medicaid benzodiazepine expenditures decreased 52% from 1988 to 1989 ($21.7 million to $10.4 million). Alternative sedative expenditures increased 115% ($3.9 million to $8.4 million). Total Medicaid psychoactive medication expenditures remained nearly constant ($46.7 million to $45.6 million). CONCLUSION: Although the triplicate regulations have decreased benzodiazepine prescribing, an undesirable increase has occurred in the prescribing of less acceptable medications. The wider public health, patient care, and financial implications of triplicate benzodiazepine regulations are of concern and require further study before other jurisdictions undertake similar programs.

Anti-Anxiety Agents↗

[4-aminopyridine induced rage reaction in mice].

Rage reaction was induced in mice by sc 4-aminopyridine (4-AP) 6 mg . kg-1. Mice appeared hyperreactive after 8-12 min and then squeaked and fought each other. These manifestations were most distinct in 10-30 min and subsided after 40-60 min. The occurrence of rage reaction on this dose level was around 90%. At higher doses 4-AP caused convulsions and death after evocation of rage reaction. The ED50 of 4-AP for eliciting rage reaction was 4.7 +/- 0.7 mg . kg-1 sc. No significant difference in induction of rage reaction was seen between male and female mice of different body weights. Both neuroleptic drugs (chlorpromazine, haloperidol, tarden and clozapine) and anxiolytic drugs (diazepam, chlordiazepoxide, and meprobamate) inhibited 4-AP-induced rage reaction in mice. Barbiturates, Chloral hydrate, methaqualone, morphine hydrochloride, aspirin, phenytoin sodium, diphenhydramine hydrochloride, atropine sulfate, and procaine hydrochloride did not affect rage reaction. The 4-AP-induced aggressive behavior, similar to that induced by electric footshock or isolation, has the merits of convenience to deal with and time saving. Hence we recommended it as a screening method for drugs with neuroleptic and anxiolytic activities.

4-Aminopyridine↗

The role of serendipity in drug discovery.

Serendipity is one of the many factors that may contribute to drug discovery. It has played a role in the discovery of prototype psychotropic drugs that led to modern pharmacological treatment in psychiatry. It has also played a role in the discovery of several drugs that have had an impact on the development of psychiatry. "Serendipity" in drug discovery implies the finding of one thing while looking for something else. This was the case in six of the twelve serendipitous discoveries reviewed in this paper, i.e., aniline purple, penicillin, lysergic acid diethylamide, meprobamate, chlorpromazine, and imipramine. In the case of three drugs, i.e., potassium bromide, chloral hydrate, and lithium, the discovery was serendipitous because an utterly false rationale led to correct empirical results; and in case of two others, i.e., iproniazid and sildenafil, because valuable indications were found for these drugs which were not initially those sought The discovery of one of the twelve drugs, chlordiazepoxide, was sheer luck.

Animals↗

Interaction between certain psychopharmaca and low-dose oral contraceptives.

The authors wanted to find answers to the question whether certain benzodiazepines and minor tranquillizers decrease the action of low-dose oral contraceptives due to interaction between these drugs by examining 72 women taking these drugs concurrently. Drug interaction causing pregnancy was not observed. Spotting was observed in an extremely high number of cases taking meprobamate or chlordiazepoxide. In 76.9% of these cases causal relation could be proved by the discontinuance of anxiolytic or by changing to another psychopharmacon.

Anti-Anxiety Agents↗

[Voluntary drug poisoning: epidemiology, performance and limits of the emergency laboratory].

The aim of this study is to determine the efficiency ot toxicologic screening (detection of barbiturates, benzodiazepines, tricyclic antidepressants, salicylates, phenothiazines, meprobamate and ethanol assay), during acute drug poisoning. In 1988, 898 patients are enclose in this study. Screenings are negative in 17% of cases; benzodiazepines, alcohol and antidepressants are often found. The recovery is very good for barbiturates and salicylates but it's not perfect for benzodiazepines, particularly flunitrazepam triazolam, loflazepate, oxazepam, and non tricyclic antidepressants. This failure probably depends on these emergency methods.

Clinical Laboratory Techniques↗

Past and future of neuropsychopharmacology.

The advent of what is called the chemotherapy of mental diseases goes back to the early fifties, when a series of clinical observations led medical research to reconsider this field, that at the time was not particularly developed. The use of chlorpromazine and of reserpine in the therapy of some psychotic syndromes dates back to that time. A few years later meprobamate was introduced and proved active against anxiety. The success obtained with these drugs was followed by a flourishing of research carried out in a joint effect by pharmacologists and clinicians. This cooperation gave birth to a new discipline, the neuropsychopharmacology. In the course of time, through a progressive refining of the techniques it has been possible to acquire methods particularly suitable for the identification of the effects of the various drugs acting on the CNS. If the sixties were the decade of the synapse, during the seventies the main interest of research was focused on receptors, and the eighties can be considered the decade of post-receptor intraneuronal mechanisms. As far as the future of research is concerned, priority must be given to scientific approaches that: a) explore in a new and original chemistry; b) use advanced pharmacological techniques; c) start from scientific hypotheses based on recent discoveries and if possible suggested by scientists. Recently, special attention has been devoted to the study of inhibitors of proteolitic enzymes responsible for the degradation of enkephalins which allegedly should reinforce the endogenous mechanisms for the control of pain. Encouraging data are already available but these preliminary results should be confirmed before going into more extended investigations.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

[Acute drug poisoning in suicidal elderly patients 70 years' old and over. 92 cases in a medical ICU].

Self-inflicted acute drug overdose in suicidal elderly patients appears to be a growing challenge to public health. To the best of our knowledge, little has been published on this topic. Thus we undertook a retrospective study, from January 1969 to October 1989, in a medical ICU. Ninety-two suicidal, elderly patients (54 women, 38 men) with a mean age of 77 years were included. The mean length of the hospital stay was 7 days (range: 1-45 days). Seventy-six percent of them were intubated and subjected to mechanical ventilation for a mean duration of 3 days. Overdosing on one drug occurred in 46 cases (50%). Toxicological analyses implicated the following medications: benzodiazepines, 50 cases; meprobamate, 26 cases; barbiturates, 24 cases; tricyclic anti-depressants, 17 cases; trichloroethylene, 1 case; insulin, 1 case. Psychiatric history, recorded for 47 patients, revealed previous suicide attempts by 20 of them. Complications were reported in 40 cases (43.5%): respiratory complications, 25 cases; shock, 13 cases; postanoxic coma, 2 cases. The incidence of mortality (13 cases) was 14%. Thirty-three patients were transferred to psychiatric units after release from ICU. During the same period, our ICU admitted 2,762 patients for acute drug poisoning and observed a 1% mortality rate. Thus, morbidity and mortality are higher in the elderly than in younger patients.

Acute Disease↗

[The ectophosphatase activity of cultured endothelial cells of calf aorta and the effect of drugs on ecto-ATPase].

Cultivated endothelial cells of calf aorta (line BKEz-7) possess an effective ectophosphatase system (enzyme activities: ATPase 38.0 +/- 10.2; ADPase 9.2 +/- 4.2; 5'-nucleotidase 4.1 +/- 2.6 fmol/cell.min). Drugs with central depressive activity such as promazine, chlorpromazine, and meprobamate inhibit the activity of the ecto-ATPase. A possible connection between the inhibitory activity on the ecto-ATPase and their central depressive effects is discussed.

5'-Nucleotidase↗

Discriminative stimulus properties of midazolam in the pigeon.

Five pigeons were trained to discriminate injections of midazolam (1.0 or 3.0 mg/kg i.m.) from saline with responding maintained under a fixed-ratio 30 schedule of food delivery. When other benzodiazepines were tested, they consistently produced greater than 80% of midazolam-appropriate responding. The order of potency for substituting for midazolam was triazolam greater than alprazolam = diazepam = lorazepam greater than midazolam greater than flurazepam = nitrazepam greater than nordiazepam. The barbiturate phenobarbital (10-100 mg/kg) substituted for midazolam in three of four pigeons whereas pentobarbital (1.0-30 mg/kg) substituted in only two of five pigeons. Several nonbenzodiazepine anxiolytics were also evaluated. Methaqualone (3.0-56 mg/kg) substituted in only one of four pigeons and meprobamate (30-100 mg/kg) failed to substitute in any pigeon tested. CL 218,872, when administered either i.m. (0.3-30 mg/kg) or p.o. (1.0-56 mg/kg), and buspirone (0.3-30 mg/kg) did not substitute for midazolam. Compounds from pharmacological classes not related to midazolam also failed to substitute for midazolam. Pretreatment with the benzodiazepine antagonist flumazenil (Ro 15-1788; 0.03-1.0 mg/kg) antagonized the discriminative stimulus properties of midazolam in a dose-related manner in all pigeons tested. However, this antagonism could not be overcome with increasing doses of midazolam in all pigeons. The results of the present study demonstrate that midazolam is an effective discriminative stimulus in the pigeon. Benzodiazepine anxiolytics, but not other compounds with sedative and/or anxiolytic properties, were found to reliably substitute for midazolam. These results suggest that the discriminative stimulus effects of midazolam are pharmacologically selective.

Animals↗

Drug therapy in the treatment of minimal brain dysfunction.

The pharmacotherapy of minimal brain dysfunction (MBD) is reviewed. Studies using central nervous system (CNS) stimulants (amphetamines and methylphenidate, deanol, pemoline, caffeine), antidepressants (imipramine and desipramine), anticonvulsants (phenytoin and primidone), antianxiety agents (chlordiazepoxide, hydroxyzine, meprobamate), antipsychotic agents (phenothiazines, thioxanthenes, butyrophenones) and miscellaneous agents (benztropine, thyrotropin-releasing hormone, megavitamins) are discussed. When drugs are indicated, the CNS stimulants are the agents of choice in the treatment of MBD. The use of tricyclic antidepressants in MBD is regarded as investigational and warrants careful monitoring to minimize toxicities. Anticonvulsants have been ineffective in controlling behavior problems; however, phenytoin may be helpful in auditory perception problems. Anti-anxiety and antipsychotic agents are not as desirable as the CNS stimulants for treatment since they do not decrease distractibility or increase attention spans.

Anti-Anxiety Agents↗