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[Psychopharmacology since 1952].

When chlorpromazine was introduced into psychiatric therapy in 1952 and thus the modern psychopharmacological era was started, the situation in psychiatry was deplorable. The psychiatric hospitals were overcrowded and obsolete, complementary institutions were widely missing. In Germany, even after introducing the neuroleptic era and the beginning of the thymoleptic epoch in 1957, no decisive improvement took place at first. As late as in the 70s successes of psychiatric reform efforts in the sense of humanization became visible, along with modern psychopharmacotherapy making an important contribution to these improvements. With the social attitude towards the mentally ill changing, this contribution became effective. In 1954 the antipsychotic efficacy of Rauwolfia alkaloids was described; in 1958 the butyrophenones, especially haloperidol, were introduced. In 1957 the antidepressive efficacy of imipramine was discovered, in the same year the psychiatric importance of monoaminoxidase inhibitors was defined. In 1949 Cade published his findings on the antimanic effect of lithium salts. As tranquilizers meprobamate (1955) and chlordiazepoxide (1960) were made available. In 1966 clozapine was introduced. Objections to psychopharmacotherapy, which were not always objective, were often raised. The biochemical research in cooperation with psychopharmacology has made progress, yet the target of clarification of the pathophysiology of the main psychoses has not been reached as yet. At present there is considerable resistance towards a further expansion of psychopharmacology, research being hampered by legal reglementation and bureaucracy. This development must be faced. Psychopharmacotherapy is not yet sufficiently effective and safe; it must be improved.

Europe↗

Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists.

In preparing this Position Statement, all relevant scientific literature was identified and reviewed critically by acknowledged experts using agreed criteria. Well-conducted clinical and experimental studies were given precedence over anecdotal case reports and abstracts were not usually considered. A draft Position Statement was then produced and subjected to detailed peer review by an international group of clinical toxicologists chosen by the American Academy of Clinical Toxicology and the European Association of Poisons Centres and Clinical Toxicologists. The Position Statement went through multiple drafts before being approved by the Boards of the two societies. The Position Statement includes a summary statement for ease of use and is supported by detailed documentation which describes the scientific evidence on which the Statement is based. Although many studies in animals and volunteers have demonstrated that multiple-dose activated charcoal increases drug elimination significantly, this therapy has not yet been shown in a controlled study in poisoned patients to reduce morbidity and mortality. Further studies are required to establish its role and the optimal dosage regimen of charcoal to be administered. Based on experimental and clinical studies, multiple-dose activated charcoal should be considered only if a patient has ingested a life-threatening amount of carbamazepine, dapsone, phenobarbital, quinine, or theophylline. With all of these drugs there are data to confirm enhanced elimination, though no controlled studies have demonstrated clinical benefit. Although volunteer studies have demonstrated that multiple-dose activated charcoal increases the elimination of amitriptyline, dextropropoxyphene, digitoxin, digoxin, disopyramide, nadolol, phenylbutazone, phenytoin, piroxicam, and sotalol, there are insufficient clinical data to support or exclude the use of this therapy. The use of multiple-dose charcoal in salicylate poisoning is controversial. One animal study and 2 of 4 volunteer studies did not demonstrate increased salicylate clearance with multiple-dose charcoal therapy. Data in poisoned patients are insufficient presently to recommend the use of multiple-dose charcoal therapy for salicylate poisoning. Multiple-dose activated charcoal did not increase the elimination of astemizole, chlorpropamide, doxepin, imipramine, meprobamate, methotrexate, phenytoin, sodium valproate, tobramycin, and vancomycin in experimental and/or clinical studies. Unless a patient has an intact or protected airway, the administration of multiple-dose activated charcoal is contraindicated. It should not be used in the presence of an intestinal obstruction. The need for concurrent administration of cathartics remains unproven and is not recommended. In particular, cathartics should not be administered to young children because of the propensity of laxatives to cause fluid and electrolyte imbalance. In conclusion, based on experimental and clinical studies, multiple-dose activated charcoal should be considered only if a patient has ingested a life-threatening amount of carbamazepine, dapsone, phenobarbital, quinine, or theophylline.

Acute Disease↗

The effect of sodium bisulfite on the removal of drugs and their metabolites interfering with the Porter-Silber reaction in the determination of urinary 17-hydroxycorticosteroids.

In the determination of urinary 17-hydroxycorticosteroids, the urine is saturated with NaHSO3 after hydrolysis with beta-glucuronidase and then extracted with methylene chloride. Sodium bisfulfite removes almost all non-steroidal impurities in the urines from patients medicated with acetylspiramycin, leucomycin, erythromycin, triacetylolenadomycin, rifampicin and tranquilizers such as chlorpromazine, which interfere with the absorption at 410 nm. in the subsquent Porter-Silber reaction. In order to increase the specificity of a routine method, a procedure conducted by Allen has been often employed: The sum of 370- and 450-nm. absorbances is subtracted from twice absorbance at 410 nm. However, the procedure could not be used in the medicated urines mentioned above, because the spectral absorption curve of these drugs and their metabolites in the Porter-Silber reaction was not a straight but a strongly convex or concave line in the 370-450-nm. range. Using the present method, interference with the Porter-Silber reaction was not found in the urines from patients medicated with chloramphenicol, minocycline, chlordiazepoxide, meprobamate, methyprylon, nitrazepam, synthetic penicillins such as hetacillin, oxacillin and cloxacillin, or cephalosporins such as cephalexin and cephalothin. However, to obtain correct values in urines from patients medicated with spironolactone, it was necessary to subject the urines to treatment with methylene chloride before enzyme hydrolysis.

17-Hydroxycorticosteroids↗

Drug-related information generates placebo and nocebo responses that modify the drug response.

OBJECTIVE: Administration of the muscle relaxant carisoprodol and placebo was crossed with information that was agonistic or antagonistic to the effect of carisoprodol. It was investigated whether information alone induced physiological and psychological responses, and whether information modified the response to the drug. METHODS: Half of the subjects received capsules containing 525 mg carisoprodol together with information that the drug acted in a specific way (Groups Relaxant/C, Stimulant/C, and No Information/C). The other half of the subjects received lactose (Groups Relaxant/L, Stimulant/L, and No Information/L). Dependent variables were blink reflexes and skin conductance responses, subjective measures of tension and sleepiness, and serum carisoprodol and meprobamate concentrations. Recordings were made between 15 and 130 minutes after administration of the capsules. RESULTS: The Stimulant/L group reported more tension compared with the other two groups, and carisoprodol increased tension even more in the Stimulant/C group. The Relaxant/C group displayed higher levels of carisoprodol serum concentration compared with the other groups that received carisoprodol. CONCLUSIONS: Reported tension was modulated in the direction suggested by the stimulant information. The effect of carisoprodol on tension was also modulated by stimulant information. Increased carisoprodol absorption in the group that received relaxant information could be a mechanism in the placebo response.

Adolescent↗

Further pharmacological validation of the BALB/c neophobia in the free exploratory paradigm as an animal model of trait anxiety.

The present experiments were aimed at investigating the ability of established or putative anxiolytics to reduce the neophobia exhibited by BALB/c mice in the free exploratory paradigm. Results confirm the anxiolytic effects of the benzodiazepine receptor full agonist chlordiazepoxide (2.5-7.5 mg/kg), of meprobamate (15-60 mg/kg) and of ethanol (0.5-1.5 g/kg) and extend the pharmacological action of these compounds to a test situation devoid of anxiogenic components, that is to trait anxiety. The non-competitive NMDA antagonist MK 801 (0.04-0.16 mg/kg) elicited very similar behavioural effects. However, the alpha 2-adrenoceptor antagonists yohimbine (0.5-2 mg/kg) and idazoxan (0.3-2.7 mg/kg), the barbiturate pentobarbital (3.75-30 mg/kg), the mixed 5HT2 receptor antagonist ritanserin (0.25-4 mg/kg) and the D2 dopaminergic antagonist sulpiride (8-32 mg/kg) failed to decrease neophobia in BALB/c mice. The discussion focuses on the adequacy of this animal model of human pathology. The BALB/c neophobia may not model panic attacks because of the absence of worsening by the panic-provoking agent yohimbine and the lack of attenuation by CCK-B receptor antagonists. Because of its chronicity, this paradigm may model generalized anxiety, a pathology that has been suggested to overlap trait anxiety.

Animals↗

Determination of halothane-induced sleeping time in the rat: effect of prior administration of centrally active drugs.

A method is described for the determination of halothane-induced sleeping time in the rat. 2 The sleeping time exhibited a diurnal variation which was due, at least in part, to a change in the sensitivity of the central nervous system (CNS) to the anaesthetic. 3 Tolerance to halothane did not develop in rats repeatedly exposed to the anaesthetic over a period of over 48 hours. 4 Repeated sleeping time determinations have been used to follow changes in the sensitivity of the CNS to the anaesthetic occurring with time. 5 A tolerance to halothane was induced by pretreatment of rats with doses of amylobarbitone, pentobarbitone or meprobamate sufficient to keep animals anaesthetized for approximately 12 hours. This tolerance was followed by a period of halothane-hypersensitivity. 6 Halothane-tolerant animals awakened with higher brain halothane concentrations and were also tolerant to intracerebroventricularly administered pentobarbitone. 7 Halothane-hypertensive rats awakened with lower brain halothane concentrations and were also hypersensitivity to intracerebroventricularly administered pentobarbitone. 8 The possibility that the induction of cross-tolerance to halothane may be indicative of a drug's potential to produce dependence is discussed.

Animals↗

Convulsions induced by centrally administered NMDA in mice: effects of NMDA antagonists, benzodiazepines, minor tranquilizers and anticonvulsants.

1. Convulsions were induced reproducibly by intracerebroventricular injection of N-methyl-D-aspartic acid (NMDA) to conscious mice. 2. Competitive (carboxypiperazine-propylphosphonic acid, CPP; 2-amino-7-phosphonoheptanoic acid, AP7) and non-competitive (MK801; phencyclidine, PCP; thienylcyclohexylpiperidine, TCP; dextrorphan; dextromethorphan) NMDA antagonists prevented NMDA-induced convulsions. 3. Benzodiazepine receptor agonists and partial agonists (triazolam, diazepam, clonazepam, Ro 16-6028), classical anticonvulsants (diphenylhydantoin, phenobarbitone, sodium valproate) and meprobamate were also found to prevent NMDA-induced convulsions. 4. Flumazenil (a benzodiazepine receptor antagonist) and the GABA agonists THIP and muscimol (up to subtoxic doses) were without effect. 5. Flumazenil reversed the anticonvulsant action of diazepam, but not that of MK801. 6. Results obtained in this model differ somewhat from those described in a seizure model with systemic administration of NMDA. An explanation for this discrepancy is offered. 7. This model is a simple test for assessing the in vivo activity of NMDA antagonists and also expands the battery of chemically-induced seizure models for characterizing anticonvulsants not acting at NMDA receptors.

Animals↗

Abusive prescription of psychostimulants: a study of two cases.

Because psychostimulants have serious possible side effects and particular potential for abuse, their therapeutic indications are today exclusively limited to disorders such as obesity, narcolepsy, or attention deficit/hyperactivity disorder. We report two cases of abusive prescription of these drugs. The first concerns a woman who was treated for a 3 kg weight gain with fenproporex for 5 years and presented a withdrawal syndrome when this drug was no longer marketed in France. In the second case, a woman who complained of atypical sleep problems was prescribed modafinil, methylphenidate, clobazam, lormetazepam, meprobamate, and aceprometazine, and was found dead in her home a few weeks later in unexplained circumstances. For these two patients, neither the indications, nor the contraindications, nor the prescribing rules for these restricted drugs had been complied with. This case report highlights the extreme danger of these substances and stresses the importance of adhering to the rules of prescription.

Adult↗

Effects of calcium "antagonists" on vertebrate skeletal muscle cells.

Clinically potent skeletal muscle relaxants are used primarily for their effects on the central nervous system. But they also have direct effects on muscle contraction that possibly involve Ca2+ channels. We compared the effects of dantrolene, an agent known to have a direct action on vertebrate skeletal muscle, with other substances used as (1) relaxants and (2) antagonists of Ca-dependent excitation-contraction coupling. Isolated intact frog muscle cells were injected with the photoprotein aequorin, and membrane potential changes, intracellular Ca2+ transients, and contractile force were measured. Dantrolene (10(-8) to 10(-5) M) decreased the amplitude of Ca2+ transients, did not affect their rates of decay, and reduced contractile force. We also used an integrated digital-imaging system to record microscopic changes, namely, active shortening in myofibrils and changes in striation spacing. Dantrolene did not increase the time between contraction in myofibrils near the surface compared with myofibrils near the center of a cell. Hence dantrolene does not suppress Ca2+ transients by disturbing current flow in the transverse tubular system. Each of the following actually increased Ca2+ transients and contractile force evoked by action potentials: baclofen (10(-7) to 10(-5) M) less than flordipine (10(-6) M) less than meprobamate (10(-7) to 10(-3) M) less than chlordiazepoxide (10(-5) X 10(-4) M) less than procaine (10(-5) to 5 X 10(-4] less than GABA (10(-5) M) less than D-600 (10(-6) M) less than nylidrin (10(-5) M)--in order of increasing potency. Ca2+ channels in the sarcoplasmic reticulum of intact skeletal muscle are evidently inhibited by dantrolene but not by Ca2+ antagonists.

Animals↗

The antinicotinic effects of drugs with clinically useful sedative-antianxiety properties.

Mice were given a drug per os and 2 h later were challenged with an intravenous LD95 of nicotine. Amitriptyline, imipramine, doxepin, meprobamate, chlordiazepoxide, diazepam, trifluoroperazine, haloperidol, thioridazine, chlorpromazine, phenobarbital, propranolol and diphenylhydantoin were all active in protecting mice from extensor convulsions and lethality. Iproniazid, tranylcypromine, atropine, benztropine and trimethadione were inactive. There appears to be a relationship between blockage of nicotine-induced extensor convulsions and lethality in mice and sedative-antianxiety effects in man. This relationship is especially good for drugs designated antidepressant, antianxiety and antipsychotic.

Animals↗

Pharmacobezoar: an evolving new entity.

Pharmacobezoars, bezoars comprised of medications, are unusual entities. Medications reported to cause bezoars include aluminum hydroxide gel, enteric-coated aspirin, sucralfate, guar gum, cholestyramine, enteral feeding formulas, psyllium preparations, nifedipine XL, and meprobamate. They most often occur, as do bezoars of any type, in a background of altered motility or anatomy of the gastrointestinal tract. Bowel hypoactivity, dehydration, and concomitant use of anticholinergics and narcotis appear to contribute to the propensity for bezoar formation by aluminum hydroxide gel and Isocal. The hygroscopic properties of psyllium and guar gum appear to contribute to their propensity to form bezoars. Insolubility of the carrying vehicle of enteric-coated aspirin and nifedipine is the setting in which these medications form bezoars. In contrast to nonmedication bezoars, pharmacobezoars may produce additional symptoms, those related to the release of their active ingredients. In patients with suspected gastrointestinal tract emptying problems, whether esophageal, gastric, small bowel, or colonic, the astute clinician should consider pharmacobezoar in the differential diagnosis.

Bezoars↗

Psychotropic drug use in an ambulatory elderly population.

Medication histories were obtained from 3,192 ambulatory elderly persons participating in a health screening program. A total of 2,009 (63%) women and 1,183 (37%) men were included in the drug use study. Flurazepam, pentobarbital and the combination of amobarbital and secobarbital were used by 4.5, 0.6 and 0.4% of participants, respectively, and these three agents accounted for 87.6% of all prescribed hypnotic drugs. Diazepam, meprobamate and chlordiazepoxide were the most commonly used minor tranquilizers. Barbiturates were contained in nearly one fourth of minor tranquilizers used by these elderly subjects. Less than 1% (0.5%) of the participants in this program reported the use of a neuroleptic. Approximately 3% of the participants reported the use of an antidepressant drug. Nearly 90% of participants who reported the daily use of a hypnotic agent state they had been using the product on a daily basis for longer than 1 year.

Age Factors↗

Screening of 16 common therapeutic drugs. Possible association with the Ah locus.

16 common therapeutic agents were screened for differences in sedation or lethality between C57BL/6N and DBA/2N inbred mouse strains that had been previously treated with beta-naphthoflavone. No differences were observed for meprobamate, valium, promethazine, valproic acid, lincomycin, imipramine, terbutaline, propoxyphene, nitrofurantoin, amphotericin B, or diphenhydramine. C57BL/6N mice appeared to be more resistant than DBA/2N mice to the lethal effects of isoxsuprine, niridazole, pentazocine, isoniazid, and hydralazine. None of these latter five drugs had any capacity to displace [3H-1,6]2,3,7,8-tetrachlorodibenzo-p-dioxin from the liver cytosolic Ah receptor in C57BL/6N mice. With the use of beta-naphthoflavone-pretreated offspring from the (C57BL/6N) (DBA/2N)F1 X DBA/2N backcross, a strict correlation (100% of 24 individuals in each case) was found between the Ahb allele and resistance to the lethal effects of isoxsuprine or niridazole. No correlation between the Ah locus and pentazocine, hydralazine, or isoniazid lethality was apparent. These results indicate that presence of the Ahb allele is associated with increased protection against isoxsuprine and niridazole lethality. This increased protection may reflect enhanced detoxication metabolic pathways (e.g., induced cytochrome P1-450 and/or uridine diphosphate glucuronosyltransferase controlled by the Ah locus). The increased protection is not related to interaction of these drugs with the Ah receptor. It should be kept in mind that gene-environment interactions involving the Ah locus and isoxsuprine or niridazole may be important in certain clinical instances.

Animals↗

Depression, psychotropic medication, and risk of myocardial infarction. Prospective data from the Baltimore ECA follow-up.

BACKGROUND: There is suggestive evidence that depression increases risk of myocardial infarction (MI), but there are no prospective studies in which the measure of depression corresponds to clinical criteria. This study examines prospectively whether a major depressive episode increases the risk of incident MI and evaluates the role of psychotropic medication use in this relationship. METHODS AND RESULTS: The study is based on a follow-up of the Baltimore cohort of the Epidemiologic Catchment Area Study, a survey of psychiatric disorders in the general population. A history of major depressive episode, dysphoria (2 weeks of sadness), and psychotropic medication use were assessed in 1981, and self-reported MI was assessed in 1994. Sixty-four MIs were reported among 1551 respondents free of heart trouble in 1981. Compared with respondents with no history of dysphoria, the odds ratio for MI associated with a history of dysphoria was 2.07 (95% CI, 1.16 to 3.71), and the odds ratio associated with a history of major depressive episode was 4.54 (95% CI, 1.65 to 12.44), independent of coronary risk factors. In multivariate models, use of barbiturates, meprobamates, phenothiazines, and lithium was associated with an increased risk of MI, whereas use of tricyclic antidepressants and benzodiazepines was not. Among individuals with no history of dysphoria, only lithium use was significantly associated with MI. CONCLUSIONS: These data suggest that a history of dysphoria and a major depressive episode increase the risk of MI. The association between psychotropic medication use and MI is probably a reflection of the primary relationship between depression and MI.

Adolescent↗

Clinical course in acute self-poisonings: a prospective study of 1125 consecutively hospitalised adults.

The clinical course in an unselected group of 1125 consecutively hospitalised self-poisonings was studied during 1 year in Oslo. Mortality was 0.5%, but only 0.3% in those admitted without cardiac and respiratory arrest. Mortality among those in grade IV coma was 4.2%. The deepest comas (grade III or IV) occurred in 25.1% of the admissions with a mean duration of the coma of 5.8 h (range 1-80). Complications occurred in 21.7% of the admissions and 6.9% suffered more than one complication of which the most frequent were respiratory depression (13.5%), hypotension (5.3%), pneumonia (4.4%), and hypothermia (1.6%). The complication rate was highest in poisonings with opiates (60.7%), meprobamate (37.5%) and antihistamines (30.0%). Arrhythmias and respiratory depression were closely associated with poisonings with antidepressants and opiates, respectively. Owing to frequent polydrug overdoses it was difficult to associate other complications with other main toxic agents. Administration of antidotes (20.6%), cuffed intubation (4.4%) and forced alkaline diuresis (3.4%) were the most frequent special therapeutic measures taken. The change in pattern of self-poisonings in Oslo focuses on antidote therapy and intensive care, especially outside hospital, but limits the need for haemodialysis and haemoperfusion which were performed in only 1.0% of the admissions.

Acute Disease↗

Buspirone: a new type of anxiolytic.

Buspirone is a member of a new class of agents known as azaspirodecanediones, and represents the first nonbenzodiazepine anxiolytic to be introduced in the U.S. in recent years. It does not resemble the benzodiazepines or older anxiolytics such as meprobamate and the barbiturates in pharmacologic profile. Buspirone lacks anticonvulsant activity, interacts minimally with central nervous system depressants such as alcohol, and does not cause muscle relaxation. The drug is reported to have minimal sedating effect, to cause no impairment of driving-related skills, and to have no euphoriant effect or addictive potential. With this low side-effect profile, buspirone should not require Drug Enforcement Agency scheduling controls. Clinical trials indicate buspirone is efficacious in the treatment of mild to moderate anxiety disorders. Answers to questions of possible side effects related to dopaminergic intractions must await post-marketing experience. Buspirone is a suitable addition to drug formularies as its pre-marketing data suggest several advantages compared with anxiolytics currently available.

Animals↗

A profile of alcohol and prescription drug abuse in a high-risk community-based elderly population.

Substance abuse among the elderly is relatively common but often remains undetected or ignored by health and social workers. Psychosocial and health factors related to the aging process are the major contributors to alcoholism and other drug abuse. It is estimated that between two and ten percent of individuals over the age of 60 suffer from alcoholism. This article profiles alcohol and prescription drug abuse among the geriatric clientele of Elderly Services of Spokane (ESS), a division of the Spokane (Washington) Community Mental Health Center. In addition to traditional channels, ESS uses a unique gatekeeper network to identify high-risk, community-based elderly. Elderly persons referred by gatekeepers are regarded as "hidden" elderly and at highest risk; notably, 37 percent of ESS clients are referred via this mechanism. Case management records of 1668 ESS clients were reviewed for a history of alcoholism, and a total of 161 persons (9.6 percent) were diagnosed with either primary or secondary alcohol abuse. Fifty subjects (about five percent of the average active ESS caseload) were referred for prescription drug abuse. Misused prescription drug classes were sedative-hypnotics, antianxiety agents, and analgesics. Diazepam, codeine, meprobamate, and flurazepam were the top four agents, and 92 percent of the subjects were found to have a duration of prescription drug abuse in excess of five years. A 60 percent correlation between prescription drug abuse and previous or active alcoholism was found. Additional characteristics of the geriatric study population are discussed in detail, including specific psychosocial factors, source of referral, age, gender, living situation, marital status, psychiatric history, and presence of polypharmacy.

Aged↗

Thirty years' war: a battle with insomnia.

A 72-year-old man with a 30-year complaint of intractable insomnia had a positive family history of depression. He first came to psychiatric attention in 1958, after attacking his wife. He was prescribed barbiturates, and later was given meprobamate and nitrazepam, but with no effect on his complaint. The patient tended to increase the dosage of any drug given, of his own accord. EEG sleep recording confirmed the diagnosis of nocturnal myoclonus. It was hoped that at the case conference further treatment stratagems would be suggested.

Aged↗