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PubMed2004

Impairment due to intake of carisoprodol.

BACKGROUND: Carisoprodol is a centrally acting muscle relaxant commonly used for lower back pain. It is a drug of abuse and has been detected among impaired drivers. Carisoprodol's active metabolite meprobamate is thought to act through the GABA(A) receptor complex and produces a well-known impairing effect. It is unclear whether therapeutic intake of carisoprodol leads to impairment, and the effect of supratherapeutic doses has not been investigated. Possible impairment could further be a product of the parent drug and/or the metabolite meprobamate. The present study aimed to investigate if carisoprodol had an impairing effect by it self. METHODS: From the database at the Norwegian Institute of Public Health, Division for Forensic Toxicology and Drug Abuse 62 cases containing carisoprodol and meprobamate as only drugs were identified. These cases constituted our material. RESULTS: Impaired drivers (73%) had higher blood carisoprodol concentration than not impaired drivers (27%), but no difference in blood meprobamate concentration was found for all the drivers viewed together. Amongst occasional users of carisoprodol, however, there was difference in blood meprobamate concentration between not impaired and impaired drivers. The risk of being judged impaired rose with increasing blood carisoprodol concentration, but not with increasing blood meprobamate concentration. The clinical effects of carisoprodol as measured by the clinical test for impairment (CTI) resembled those of benzodiazepines with some important differences such as tachycardia, involuntary movements, hand tremor and horizontal gaze nystagmus, which may be specific carisoprodol effects. CONCLUSION: Carisoprodol probably has an impairing effect by itself, at least at blood concentration levels above which can be seen after therapeutic intake of the drug.

Analysis of Variance↗
PubMed2004

Comparison of patient questionnaires and plasma assays in intentional drug overdoses.

Our aim was to explore the agreement between clinically collected information on purported drug intake and plasma data in intentional drug overdose. We included all subjects with intentional drug overdose above 15 years of age consecutively admitted to the Emergency Department of the University Hospital during 4 months. Information about drugs used and sources of this information was collected and compared to presence of drug in plasma, concerning four drugs with high toxic potential (tricyclic antidepressants, meprobamate, paracetamol and ethanol). Sensitivity, specificity, predictive positive and negative values of all sources of information pooled were assessed for each drug. 413 intentional drug overdoses were included, 66% with more than one drug. According to clinical information, 8% took tricyclic antidepressants, 11% meprobamate, 9% paracetamol and 41% ethanol. Systematic plasma assays confirmed this in 59% of cases for tricyclic antidepressants, 76% for meprobamate and ethanol, and 77% for paracetamol. Plasma concentrations were considered toxic in 28% of cases for tricyclic antidepressants, 65% for meprobamate, 43% for ethanol and never for paracetamol. Tricyclic antidepressants and meprobamate were found unexpectedly in 3%, paracetamol in 7% and ethanol in 6%. Toxic concentrations were found only with meprobamate. The risk of erroneous, clinically collected information was greater by excess (25 to 40% false positives) than by lack (3 to 7% false negatives). Thus, the consequences of erroneous, clinically collected information were probably more excess cost for the institution than medical risk for the patients. However these results found at the population level may not be true at an individual level.

Acetaminophen↗
PubMed1994

Carisoprodol elimination in humans.

The elimination of the muscle relaxant drug, carisoprodol, was examined in 10 healthy volunteers after an oral dose of 700 mg. In nine subjects, carisoprodol was rapidly eliminated, with a mean half-life of 99 +/- 46 min, and extensively converted to meprobamate. Within 2.5 h after carisoprodol intake, meprobamate serum concentrations exceeded those of carisoprodol. Serum levels of meprobamate recorded (15-25 mumol/L) indicate that meprobamate might contribute to the effect(s) of carisoprodol. One subject eliminated carisoprodol with an overall half-life of 376 min, and only small amounts of meprobamate were recorded. This subject was found to be a poor metabolizer of mephenytoin. In spiked human sera, protein binding of carisoprodol was in the range of 41-67%, whereas meprobamate was bound to a lesser extent, 14-24%.

Adult↗
PubMed1985

Effect of tranquilizers on the total acetylcholine content and acetylcholinesterase activity in the brain tissue of Arvicanthis niloticus.

The effect of reserpine and meprobamate on the total acetylcholine content and acetylcholinesterase activity in the brain tissue of the kusu rat, Arvicanthis niloticus, was studied. The total acetylcholine content and acetylcholinesterase activity were determined 1 hr after i.p. injection of different doses of reserpine (0.25, 0.5 and 1 mg/ml/100 g body wt) and meprobamate (6.25, 12.5 and 25 mg/ml/100 g body wt). The effect of different time intervals (1, 10, 30 min, 1, 2.5, 5, 8, 12, 24 and 48 hr) on the total acetylcholine content and acetylcholinesterase activity was investigated after i.p. injection of 0.5 mg of reserpine and 12.5 mg of meprobamate/ml/100 g body wt. Both reserpine and meprobamate caused an increase in the total ACh content in the brain tissue of Arvicanthis niloticus which was suggested to be due to a decrease in the release of ACh, since both reserpine and meprobamate inhibited AChE activity after some tested periods. The effect of meprobamate was observed to be stronger than that of reserpine.

Acetylcholine↗
PubMed2003

Simultaneous determination of carisoprodol and acetaminophen in an attempted suicide by liquid chromatography-mass spectrometry with positive electrospray ionization.

An adult female ingested a considerable quantity of carisoprodol/acetaminophen tablets, which are not commercially available in Japan, in an attempt to commit suicide. Generally, because of lack of the appreciable ultraviolet absorbance or fluorescence, carisoprodol and its major metabolite meprobamate are determined by gas chromatography or gas chromatography-mass spectrometry. Complicated derivatization is, however, necessary to that methodology. Thus, we investigated the derivatization-free, highly sensitive, and simultaneous determination of carisoprodol, meprobamate, and acetaminophen by means of liquid chromatography-mass spectrometry (LC-MS) with positive electrospray ionization. A semi-micro ODS column was used. Ammonium acetate solution (10mM) and acetonitrile were used as mobile phase at a flow rate of 150 microL/min using gradient elution. MS parameters were as follows: capillary voltage, 3.5 kV; cone voltage, +30 V; extractor voltage, 5 kV; and ion source temperature, 100 degrees C. Urine samples pretreated by Oasis HLB cartridge, or plasma samples deproteinized by adding ice-cold acetonitrile were analyzed by LC-MS. The limits of quantitation for each compound were as follows: 0.50 ng/mL for carisoprodol; 10 ng/mL for acetaminophen; and 1.0 ng/mL for meprobamate. In the present case, carisoprodol and acetaminophen were the only drugs detected. Meprobamate was also found as the metabolite of carisoprodol in both urine and plasma. The plasma levels of carisoprodol, acetaminophen, and meprobamate on arrival were 29.5, 245, and 46.7 microg/mL, respectively. These levels were extremely high compared with therapeutic plasma concentrations. Despite the high plasma concentrations of these drugs, which correspond to fatal levels, the patient survived.

Acetaminophen↗
PubMed1964

THE ACTION OF SODIUM 4-HYDROXYBUTYRATE ON SPINAL REFLEXES.

The actions of sodium 4-hydroxybutyrate, gamma-aminobutyric acid and meprobamate have been studied in unanaesthetized animals, in local anaesthetic tests, on isolated organ preparations, on convulsions induced by picrotoxin and strychnine, and on monosynaptic (patellar) and polysynaptic (plantar) reflexes of the spinal cord. Sodium 4-hydroxybutyrate induced a sleep-like state with three unusual features: the righting reflex was remarkably persistent, respiration was good throughout and recovery was abrupt. gamma-Aminobutyric acid was inactive and meprobamate caused flaccid paralysis with loss of the righting reflex. None of the agents affected the responses of the rat diaphragm either to direct stimulation of the muscle or to indirect stimulation through the phrenic nerve. Only meprobamate reduced the responses of theguinea-pig isolated ileum preparation, showed local anaesthetic action and had an anticonvulsant action. All three compounds were capable, after intravenous or topical application, of blocking plantar reflexes in doses which did not affect the patellar reflex. The spinal animal responded in the same way, to the same dose of sodium 4-hydroxybutyrate, as the decerebrate preparation. Topical application to the motor cortex had no effect on spinal reflexes. We conclude that sodium 4-hydroxybutyrate acts preferentially on the internuncial neurones in the spinal cord but differs from meprobamate in its other actions. The similarity between the actions of sodium 4-hydroxybutyrate and of gamma-aminobutyric acid provides furtherevidence in support of the hypothesis that sodium 4-hydroxybutyrate is involved in the gamma-aminobutyric acid metabolic pathways.

Aminobutyrates↗
PubMed2001

Transfer of carisoprodol to breast milk.

There is no published information on the transfer of the centrally acting muscle relaxant carisoprodol and its active metabolite meprobamate into breast milk. The objective of this study was to quantify the excretion of carisoprodol and meprobamate in human milk and estimate the dose received by breast-fed infants. The concentrations of carisoprodol and meprobamate were measured in breast milk on 4 consecutive days at steady-state conditions in one woman using carisoprodol 2100 mg/d. The average milk concentrations were 0.9 microg/mL for carisoprodol and 11.6 microg/mL for meprobamate. Based on the milk concentrations measured, the absolute dose ingested by an exclusively breast-fed infant could be estimated at 1.9 mg/kg per day, and the relative dose would be 4.1% of the weight-adjusted maternal dose. No adverse effects were observed in the infant, but the infant was partly fed with formula because of insufficient maternal milk production. Thus, the authors consider that at least during prolonged use, lactation is generally inadvisable until more clinical data are available.

Adult↗
PubMed1975

Alteration of drug metabolism during cholestasis in man.

The morphological and functional alterations of the smooth endoplasmic reticulum of the liver cell related to biliary stasis have brought attention to drug biotransformation during cholestasis. The metabolism of meprobamate, pentobarbital and tolbutamide was assessed in subjects with intrahepatic recurrent cholestasis (3), cholestatic hepatitis (6), extrahepatic biliary obstruction (7) and normal controls (16). In the patients with recurrent intrahepatic cholestasis no differences in drug metabolism were noted as compared to the control group. In cholestatic hepatitis the plasma half-lives of meprobamate (828 +/- 422 min.) and pentobarbital (39+-65) were significantly longer than in in controls (444 +/- 37 and 25.4 +/- 1.1 respectively). Tolbutamide plasma half-life appeared unchanged. The most striking variations were observed in the patients with extrahepatic biliary obstruction. In such cases while meprobamate half-life was unchanged, pentobarbital half-life was significantly prolonged (31.2 +/- 2.5) and the in vitro metabolism of the drug, using liver preparations, was decreased to less than 50% of the control value. In contrast the metabolism of tolbutamide was accelerated as evidenced by a significant decrease of plasma half-life (165 +/- 48 min. versus 384 +/- 76 of the controls) and an enhanced urinary excretion of the drug's metabolites. However the metabolism of tolbutamide in vitro did not show any difference between normal and cholestatic liver. Whatever the mechanism of the peculiar behaviour of tolbutamide in extrahepatic biliary obstruction it seems to be related to the increased bile dalt concentration during cholestasis. In fact the low values of plasma half-life increase significantly either relieving the biliary obstruction or producing a bile salt depletion with cholestyramine. Preliminary results in vitro suggest the bile salt could displace tolbutamide from albumin binding thus increasing the amount of free drug available for biotransformation by the liver. In conclusion cholestasis may affect drug metabolism depending on the degree of biliary stasis, liver cell injury and the type of drug tested. The mechanism could be that of an impaired biotransformation in the smooth endoplasmic reticulum or could involve extrahepatic factors.

Adolescent↗
PubMed1985

Auto-titration technique using intracranial self-stimulation and effects of antianxiety drugs.

In order to study effects of antianxiety drugs on the threshold of intracranial self-stimulation (ICSS), the auto-titration technique was used in the two lever Skinner box. This procedure consisted of conventional ICSS except the brain stimulation current intensity was decreased after every 20 lever press for ICSS, and the animal could press the another reset lever (at any time) to reset the stimulation current intensity to the preseted level. The current intensity at which the animal pressed the reset lever (reset current) was defined as the threshold of ICSS. Since reset currents that the animals showed were very stable during this experiment, the effects of chlordiazepoxide, diazepam and meprobamate were studied. The reset current was significantly lowered by 5.0 mg/kg chlordiazepoxide, p.o., at 1 hr after administration accompanied by the significant increase of ICSS, and the reset current was significantly lowered by 20.0 mg/kg of chlordiazepoxide. On the other hand, diazepam did not lower the reset current, although a significant increase of ICSS was observed at 1.0 mg/kg, p.o. The reset current was lowered by meprobamate at 100 mg/kg, p.o., accompanied by the increase of ICSS, and a significant increase of ICSS was observed at 200 mg/kg but not accompanied by lowered reset current. From these results, increased susceptibility to the brain stimulation current may be involved in the facilitating effects of chlordiazepoxide and meprobamate on ICSS.

Animals↗
PubMed1991

[Electroencephalographic silence after intoxication with a carbamate tranquilizer].

A case of acute meprobamate poisoning in a 43 year-old-woman is reported. Twenty five hours after admission in the intensive care unit, deep coma and cerebral electrical silence were observed whereas the meprobamate plasmatic concentration was 250 mg/l. The patient recovery was uneventful. Meprobamate analysis must be performed for unexplained coma with isoelectric EEG.

Adult↗
PubMed1979

Acute metabolic interaction of ethanol and drugs.

Addition of ethanol in vitro was found to inhibit the microsomal metabolism of a variety of drugs such as meprobamate, aminopyrine, pentobarbital and zoxazolamine. In all cases, a mixed type of inhibition was obtained. When the concentration of alcohols of different chain lengths required to inhibit 50% of the metabolism of drugs was plotted against their corresponding octanol-water partition coefficients (Po/w) it was found that the inhibitory potency of alcohols is linearly related to the partition coefficients, with a slope of 0.98. In vivo acute administration of ethanol also resulted in decreased whole body metabolism of meprobamate, aminopyrine, pentobarbital, zoxazolamine and aniline. In vitro addition of pentobarbital, phenobarbital and meprobamate had no significant effect on ethanol metabolism by liver slices. Acute pretreatment with these drugs also had no effect on the rate of ethanol metabolism in vivo as measured in the whole body or as estimated from the rate of decrease of blood ethanol concentration. It appears therefore that acute metabolic interaction of ethanol and drugs is a one sided phenomenon, i.e. ethanol inhibits drug metabolism, whereas drugs do not inhibit ethanol metabolism. Ethanol inhibition of drug metabolism in vitro appears to result from a modification of the lipophilic milieu that surrounds the cytochrome P-450 in the microsomal membrane. Interference with the hydrophobic sites may either directly or indirectly affect the catalytic activities of the microsomal enzyme.

Animals↗
PubMed1980

[Pulmonary artery pressure measurement for assessment of bioavailability of isosorbide dinitrate and pentaerythritol tetranitrate (author's transl)].

In a double-blind cross-over study with 9 patients suffering from ischemic cardiomyopathy with cardiac failure, the effect of 3 different drug preparations on pulmonary artery pressure (PA-pressure) was studied. Iso-Ameritrat is a new drug-combination consisting of a sweet-tasting wrap containing 2.5 mg Isosorbide Dinitrate (ISDN) and of a bitter-tasting core containing 10 mg Pentaerythritol Tetranitrate (PETN) and 200 mg Meprobamate. A statistically significant decrease of PA-pressure values could be observed already 3 minutes after administration of Iso-Ameritrat. Within the next minutes this decrease even augmented and lasted over the whole period of measurement (30 minutes). After administration of the second drug preparation (Ameritrat), containing 10 mg PETN and 200 mg Meprobamate in the core, but not any nitrate in the wrap a slight but also statistically significant decrease of PA-pressure values could be documented. Therefore a sublingual resorption of PETN can be assumed. The precise beginning of the effect of PETN couldn't be assured, but it must be within 5 minutes. A thir preparation, containing only 200 mg Meprobamate in the bitter tasting core caused no significant decrease of PA-pressure values.

Adult↗
PubMed1993

Carisoprodol (Soma): a new and cautious perspective on an old agent.

Carisoprodol (Soma, others) is a commonly prescribed, noncontrolled, skeletal muscle relaxant whose active metabolite is meprobamate. Patients for whom carisoprodol is prescribed are at risk for meprobamate dependence; several such cases have been reported. Toxicity and withdrawal associated with the use of meprobamate is high and has led to abandonment of this agent in clinical practice. Because carisoprodol possesses the same risks it should be avoided when possible, and it should be given schedule IV controlled substance status.

Carisoprodol↗
PubMed1988

Absence of amnesia induction in mice with hydroxyzine in comparison with three other minor tranquillizers.

Hydroxyzine (Atarax) was compared with three traditional anxiolytics (diazepam, meprobamate, triazolam) for potential amnesic activity in a step-through passive avoidance task in the mouse. The doses investigated were: hydroxyzine (4, 8 and 16 mg/kg); diazepam (0.25, 0.5 and 1 mg/kg); meprobamate (8, 16 and 32 mg/kg); triazolam (0.0015, 0.003 and 0.006 mg/kg). The doses investigated were chosen on the basis of prior experiments for not having sedative effects as measured in a photo-cell activity meter. All drugs were administered i.p. 30 min before the first trial of the passive avoidance task. The compounds were also investigated for eventual analgesic activity using the hot plate test. The results indicated that hydroxyzine up to sedative doses was devoid of amnesic activity, whereas clear signs of amnesia were induced by diazepam, meprobamate and triazolam at doses at least 8 times lower than those which reduced spontaneous motor activity. None of the compounds showed analgesic activity in the hot plate test suggesting that the signs of amnesia observed in the passive avoidance test were not due to reduced sensitivity to aversive stimulation.

Amnesia↗
PubMed1981

[Effects of afloqualone, a new centrally acting muscle relaxant, on DRL response and CER in rats (author's transl)].

In gross-behavioral observations, chlordiazepoxide, diazepam, meprobamate, and pentobarbital-Na produced excitatory behavior at 5 and 10, 1 and 2, 100 and 200, and 10 and 20 mg/kg p.o., respectively whereas afloqualone produced no excitatory behavior at doses up to 20 mg/kg p.o., these doses induce muscle relaxation and motor depression. Afloqualone depressed DRL response at 10 and 20 mg/kg p.o. Similar effects were seen with chlorpromazine (5, 10, 20 mg/kg p.o.). Chlordiazepoxide, meprobamate, and pentobarbital-Na facilitated DRL response at doses producing excitatory behavior. Methamphetamine (0.5, 1, 2 mg/kg p.o.) facilitated the response, dose-dependently. In CER, chlordiazepoxide (5, 10, 20 mg/kg p.o.), diazepam (1, 2, 5 mg/kg p.o.), and meprobamate (50, 100, 200 mg/kg p.o.) dose-dependently increased the response during the alarm period, regardless of the response during the safe period. Pentobarbital-Na (5, 10, 20 mg/kg p.o.) had much the same effect. Afloqualone slightly increased the response during the alarm period in one out of 3 rats at 5, 10, and 20 mg/kg p.o., respectively. Chlorpromazine and methamphetamine had no influence on the response during the alarm period at doses up to 20 and 2 mg/kg p.o., respectively. These results suggest that the pharmacological properties of afloqualone, as related to behavior differ from those of anti-anxiety drugs, hypnotics, and stimulants.

Animals↗
PubMed1964

SOME ACTIONS OF CENTRALLY ACTIVE AND OTHER DRUGS ON THE TRANSMISSION OF SINGLE NERVE IMPULSES THROUGH THE ISOLATED SUPERIOR CERVICAL GANGLION PREPARATION OF THE RABBIT.

The effect of some centrally-active and other drugs on the transmission of single nerve impulses through the isolated superior cervical ganglion preparation of the rabbit has been studied by recording both preganglionic and postganglionic action potentials. Block of conduction in the axon could be distinguished from block of the synaptic mechanism. The drugs did not appear to exert any one characteristic form of blocking action. A continuous spectrum of drug action linked an agent such as meprobamate which acted predominantly on the synapse to benactyzine which acted mainly by blocking axonal conduction. The drugs have been divided into three groups. Group I: hexamethonium, meprobamate, paraldehyde, amylobarbitone, methylpentynol and azacyclonal; these acted relatively selectively at the ganglion. Group II: N714C (the cis-isomer of chlorprothixene), prochlorperazine, methylpentynol carbamate, pipradrol, promethazine, perphenazine and procaine; the action of these drugs on the ganglion could be accounted for entirely in terms of their axonal depressant action. Group III: chlorprothixene, promazine, N720 (dihydrochlorprothixene), chlorpromazine, hydroxyzine and benactyzine; these drugs also blocked axonal conduction but in addition they appeared to exert a "facilitating" action at the ganglionic synapse. The actions of adrenaline, adrenochrome, iproniazid, ergotoxine, mescaline and lysergic acid diethylamide on transmission were also studied. The implications of the modifications of ganglionic transmission produced by these drugs is discussed.

Action Potentials↗
PubMed1975

Conditioned learning in young rats born of drug-addicted parents and raised on addictive drugs.

Ratlings born of six drug-addicted and a control group of parent rats were raised under the influence of the same drugs administered in drinking water. They were trained in a conditioned avoidance paradigm (CAR) from the 7th week when the drugs were withdrawn except in two subgroups of flurazepam and morphine. The growth rate was not appreciably impaired except for temporary slowness in morphine and alcohol-raised rats; it was faster in phenobarbitone and meprobamate-raised rats. The CAR-acquisition rates of the treatment groups were quite close and parallel to that of the controls except for the morphine, meprobamate, medazepam and the two drug-trained subgroups; whereas, the rats raised on low-dose morphine showed a faster than control acquisition rate. No evidence of state-dependent learning was obtained from this study.

Animals↗
PubMed1975

[Influence of the administration of psychopharmacological compounds on the take up time of an alimentary material in the hamster and a study of the associated behaviour (author's transl)].

The take up time of a standardized alimentary material is a simple component of hamster hoarding behaviour. This value was modified by administrations of the following compounds: diazepam, chlorpromazine, meprobamate, apomorphine, d-amphetamine, piribedil, fenfluramine, sulpiride, imipramine, phenobarbital, clonidine and morphine. The change consisted of a varying increase in the take up time, dependent upon the substance and dosage. High doses of chlorpromazine, apomorphine and fenfluramine inhibited the take up. A behavioural study connected with alimentary take up was included in the experiment. Some behavioural modifications (increase or decrease in motor activity, myorelaxation, stereotyped exploration, reciprocating movements) demonstrated differences between the studied compounds related to their pharmacological properties. The immediate consumption of food, without take up and hoarding behaviour, observed with meprobamate treatment, was an interesting and unexpected change in hamster behaviour. The measurement of the take up time and analysis of behavioural modifications may be useful in comparing and preliminary screening of new psychopharmacological compounds.

Animals↗