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Glenn H Dillon - One of the best experts on this subject based on the ideXlab platform.
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Assessment of direct gating and allosteric modulatory effects of Meprobamate in recombinant GABAA receptors
European Journal of Pharmacology, 2016Co-Authors: Manish Kumar, Glenn H DillonAbstract:Meprobamate is a schedule IV anxiolytic and the primary metabolite of the muscle relaxant carisoprodol. Meprobamate modulates GABAA (??-aminobutyric acid Type A) receptors, and has barbiturate-like activity. To gain insight into its actions, we have conducted a series of studies using recombinant GABAA receptors. In ??x??z??2 GABAA receptors (where x=1-6 and z=1-3), the ability to enhance GABA-mediated current was evident for all ?? subunit isoforms, with the largest effect observed in ??5-expressing receptors. Direct gating was present with all ?? subunits, although attenuated in ??3-expressing receptors. Allosteric and direct effects were comparable in ??1??1??2 and ??1??2??2 receptors, whereas allosteric effects were enhanced in ??1??2 compared to ??1??2??2 receptors. In "extrasynaptic" (??1??3?? and ??4??3??) receptors, Meprobamate enhanced EC20 and saturating GABA currents, and directly activated these receptors. The barbiturate antagonist bemegride attenuated direct effects of Meprobamate. Whereas pentobarbital directly gated homomeric ??3 receptors, Meprobamate did not, and instead blocked the spontaneously open current present in these receptors. In wild type homomeric ??1 receptors, pentobarbital and Meprobamate were ineffective in direct gating; a mutation known to confer sensitivity to pentobarbital did not confer sensitivity to Meprobamate. Our results provide insight into the actions of Meprobamate and parent therapeutic agents such as carisoprodol. Whereas in general actions of Meprobamate were comparable to those of carisoprodol, differential effects of Meprobamate at some receptor subtypes suggest potential advantages of Meprobamate may be exploited. A re-assessment of previously synthesized Meprobamate-related carbamate molecules for myorelaxant and other therapeutic indications is warranted.
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Carisoprodol-Mediated Modulation of GABAA Receptors: In Vitro and in Vivo Studies.
The Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: L A Gonzalez, Cynthia M Taylor, Cathy L Bell-Horner, Michael B Gatch, M J Forster, Glenn H DillonAbstract:Carisoprodol is a frequently prescribed muscle relaxant. In recent years, this drug has been increasingly abused. The effects of carisoprodol have been attributed to its metabolite, Meprobamate, a controlled substance that produces sedation via GABAA receptors (GABAARs). Given the structural similarities between carisoprodol and Meprobamate, we used electrophysiological and behavioral approaches to investigate whether carisoprodol directly affects GABAAR function. In whole-cell patch-clamp studies, carisoprodol allosterically modulated and directly activated human α1β2γ2 GABAAR function in a barbiturate-like manner. At millimolar concentrations, inhibitory effects were apparent. Similar allosteric effects were not observed for homomeric ρ1 GABA or glycine α1 receptors. In the absence of GABA, carisoprodol produced picrotoxin-sensitive, inward currents that were significantly larger than those produced by Meprobamate, suggesting carisoprodol may directly produce GABAergic effects in vivo. When administered to mice via intraperitoneal or oral routes, carisoprodol elicited locomotor depression within 8 to 12 min after injection. Intraperitoneal administration of Meprobamate depressed locomotor activity in the same time frame. In drug discrimination studies with carisoprodol-trained rats, the GABAergic ligands pentobarbital, chlordiazepoxide, and Meprobamate each substituted for carisoprodol in a dose-dependent manner. In accordance with findings in vitro, the discriminative stimulus effects of carisoprodol were antagonized by a barbiturate antagonist, bemegride, but not by the benzodiazepine site antagonist, flumazenil. The results of our studies in vivo and in vitro collectively suggest the barbiturate-like effects of carisoprodol may not be due solely to its metabolite, Meprobamate. Furthermore, the functional traits we have identified probably contribute to the abuse potential of carisoprodol.
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Carisoprodol-Mediated Modulation of GABAA Receptors: In Vitro and in Vivo Studies
2009Co-Authors: L A Gonzalez, Cynthia M Taylor, Cathy L Bell-Horner, Michael B Gatch, Michael J. Forster, Glenn H DillonAbstract:Carisoprodol is a frequently prescribed muscle relaxant. In recent years, this drug has been increasingly abused. The effects of carisoprodol have been attributed to its metabolite, Meprobamate, a controlled substance that produces sedation via GABAA receptors (GABAARs). Given the structural similari-ties between carisoprodol and Meprobamate, we used electro-physiological and behavioral approaches to investigate whether carisoprodol directly affects GABAAR function. In whole-cell patch-clamp studies, carisoprodol allosterically modulated and directly activated human 122 GABAAR function in a barbiturate-like manner. At millimolar concentra-tions, inhibitory effects were apparent. Similar allosteric effects were not observed for homomeric 1 GABA or glycine 1 receptors. In the absence of GABA, carisoprodol produce
Brookie M. Best - One of the best experts on this subject based on the ideXlab platform.
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Factors affecting carisoprodol metabolism in pain patients using urinary excretion data
Journal of Analytical Toxicology, 2014Co-Authors: Stephanie A. Tse, Joseph D. Ma, Rabia S. Atayee, Brookie M. BestAbstract:Carisoprodol is a skeletal muscle relaxant prescribed to treat pain. Carisoprodol is metabolized to Meprobamate, an active metabolite with anxiolytic effects, by the genetically polymorphic CYP2C19 enzyme. Concomitant use of CYP2C19 substrates or inhibitors may alter carisoprodol metabolism, with therapeutic and/or toxic implications for effectively treating patients with pain. This was a retrospective analysis of urinary excretion data collected from patients with pain from March 2008 to May 2011. Carisoprodol and Meprobamate urine concentrations were measured by liquid chromatography-tandem mass spectrometry, and the metabolic ratio (MR) of Meprobamate to carisoprodol concentrations was determined in 14,965 subjects. The MR geometric mean and 95% confidence interval (95% CI) of the young group (105, 95% CI = 99.1-113) were ∼47.4% higher than the middle-aged group (71.9, 95% CI = 70-73.8) and nearly two times higher than the elderly group (54.4, 95% CI = 51.3-57.6). Females had a 20.7% higher MR compared with males. No significant change in the MR was observed with overall CYP2C19 inhibitor or substrate use. However, evaluation of individual inhibitors showed co-administration with esomeprazole or fluoxetine was associated with a 31.8 and 24.6% reduction in MR, respectively, compared with controls (P < 0.05). Omeprazole did not significantly affect the MR. Patient-specific factors such as age, sex and co-medications may be important considerations for effective carisoprodol therapy.
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Evaluating the relationship between carisoprodol concentrations and Meprobamate formation and inter-subject and intra-subject variability in urinary excretion data of pain patients
Journal of Analytical Toxicology, 2012Co-Authors: Stephanie A. Tse, Rabia S. Atayee, Brookie M. Best, Amadeo J PesceAbstract:Using urinary carisoprodol data from pain patients, our objectives were to determine the relationship between carisoprodol concentration and its conversion to Meprobamate, and quantify the intra-subject and inter-subject variability in carisoprodol metabolism. Liquid chromatography-tandem mass spectrometry was used to quantitate carisoprodol and Meprobamate concentrations in urine specimens. The log creatinine-corrected carisoprodol versus log creatinine-corrected Meprobamate showed a marginal positive relationship (R(2) = 0.395), with a 29.1-fold variance between subjects at the mean carisoprodol concentration. The geometric mean carisoprodol and Meprobamate urine concentrations were 0.519 ± 3.38 mg and 28.2 ± 2.34 mg analyte per gram creatinine, respectively. The log metabolic ratio (MR) versus log creatinine-corrected carisoprodol displayed a marginal positive correlation. A subpopulation of outliers with higher carisoprodol and lower Meprobamate levels were considered poor metabolizers and represented 0.483% (n = 21) of the study population. Using a curve-fit mathematical model, we estimated 0.318% (n = 10) to be ultra-rapid metabolizers. The inter-subject population geometric standard deviation (SD) of the MR was 3.64. The intra-subject geometric median and mean SD of the MR were 1.60 (interquartile range: 1.28, 2.07) and 1.72 ± 1.60, respectively. Inter-subject variability was 2.27 times greater than the median intra-subject variability. With a better understanding of urine carisoprodol and Meprobamate concentrations and variability, urine drug testing provides a useful monitoring reference for clinicians.
Stephanie A. Tse - One of the best experts on this subject based on the ideXlab platform.
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Factors affecting carisoprodol metabolism in pain patients using urinary excretion data
Journal of Analytical Toxicology, 2014Co-Authors: Stephanie A. Tse, Joseph D. Ma, Rabia S. Atayee, Brookie M. BestAbstract:Carisoprodol is a skeletal muscle relaxant prescribed to treat pain. Carisoprodol is metabolized to Meprobamate, an active metabolite with anxiolytic effects, by the genetically polymorphic CYP2C19 enzyme. Concomitant use of CYP2C19 substrates or inhibitors may alter carisoprodol metabolism, with therapeutic and/or toxic implications for effectively treating patients with pain. This was a retrospective analysis of urinary excretion data collected from patients with pain from March 2008 to May 2011. Carisoprodol and Meprobamate urine concentrations were measured by liquid chromatography-tandem mass spectrometry, and the metabolic ratio (MR) of Meprobamate to carisoprodol concentrations was determined in 14,965 subjects. The MR geometric mean and 95% confidence interval (95% CI) of the young group (105, 95% CI = 99.1-113) were ∼47.4% higher than the middle-aged group (71.9, 95% CI = 70-73.8) and nearly two times higher than the elderly group (54.4, 95% CI = 51.3-57.6). Females had a 20.7% higher MR compared with males. No significant change in the MR was observed with overall CYP2C19 inhibitor or substrate use. However, evaluation of individual inhibitors showed co-administration with esomeprazole or fluoxetine was associated with a 31.8 and 24.6% reduction in MR, respectively, compared with controls (P < 0.05). Omeprazole did not significantly affect the MR. Patient-specific factors such as age, sex and co-medications may be important considerations for effective carisoprodol therapy.
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Evaluating the relationship between carisoprodol concentrations and Meprobamate formation and inter-subject and intra-subject variability in urinary excretion data of pain patients
Journal of Analytical Toxicology, 2012Co-Authors: Stephanie A. Tse, Rabia S. Atayee, Brookie M. Best, Amadeo J PesceAbstract:Using urinary carisoprodol data from pain patients, our objectives were to determine the relationship between carisoprodol concentration and its conversion to Meprobamate, and quantify the intra-subject and inter-subject variability in carisoprodol metabolism. Liquid chromatography-tandem mass spectrometry was used to quantitate carisoprodol and Meprobamate concentrations in urine specimens. The log creatinine-corrected carisoprodol versus log creatinine-corrected Meprobamate showed a marginal positive relationship (R(2) = 0.395), with a 29.1-fold variance between subjects at the mean carisoprodol concentration. The geometric mean carisoprodol and Meprobamate urine concentrations were 0.519 ± 3.38 mg and 28.2 ± 2.34 mg analyte per gram creatinine, respectively. The log metabolic ratio (MR) versus log creatinine-corrected carisoprodol displayed a marginal positive correlation. A subpopulation of outliers with higher carisoprodol and lower Meprobamate levels were considered poor metabolizers and represented 0.483% (n = 21) of the study population. Using a curve-fit mathematical model, we estimated 0.318% (n = 10) to be ultra-rapid metabolizers. The inter-subject population geometric standard deviation (SD) of the MR was 3.64. The intra-subject geometric median and mean SD of the MR were 1.60 (interquartile range: 1.28, 2.07) and 1.72 ± 1.60, respectively. Inter-subject variability was 2.27 times greater than the median intra-subject variability. With a better understanding of urine carisoprodol and Meprobamate concentrations and variability, urine drug testing provides a useful monitoring reference for clinicians.
Michael J. Forster - One of the best experts on this subject based on the ideXlab platform.
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Carisoprodol pharmacokinetics and distribution in the nucleus accumbens correlates with behavioral effects in rats independent from its metabolism to Meprobamate.
Neuropharmacology, 2020Co-Authors: Theresa M. Carbonaro, Michael B Gatch, Michael J. Forster, Vien Nguyen, Laszlo ProkaiAbstract:Abstract Carisoprodol (Soma®) is a centrally-acting skeletal-muscle relaxant frequently prescribed for treatment of acute musculoskeletal conditions. Carisoprodol's mechanism of action is unclear and is often ascribed to that of its active metabolite, Meprobamate. The purpose of this study was to ascertain whether carisoprodol directly produces behavioral effects, or whether metabolism to Meprobamate via cytochrome P450 (CYP450) enzymatic reaction is necessary. Rats were trained to discriminate carisoprodol (100 mg/kg) to assess time course and whether a CYP450 inhibitor (cimetidine) administered for 4 days would alter the discriminative effects of carisoprodol. Additionally, pharmacokinetics of carisoprodol and Meprobamate with and without co-administration of cimetidine were assessed via in vivo microdialysis combined with liquid-chromatography–tandem mass spectrometry from blood and nucleus accumbens (NAc). The time course of the discriminative-stimulus effects of carisoprodol closely matched the time course of the levels of carisoprodol in blood and NAc, but did not match the time course of Meprobamate. Administration of cimetidine increased levels of carisoprodol and decreased levels of Meprobamate consistent with its interfering with metabolism of carisoprodol to Meprobamate. However, cimetidine failed to alter the discriminative-stimulus effects of carisoprodol. Carisoprodol penetrated into brain tissue and directly produced behavioral effects without being metabolized to Meprobamate. These findings indicate that understanding the mechanism of action of carisoprodol independently of Meprobamate will be necessary to determine the validity of its clinical uses.
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Mass spectrometric analysis of carisoprodol and Meprobamate in rat brain microdialysates.
Journal of mass spectrometry : JMS, 2016Co-Authors: Laszlo Prokai, Vien Nguyen, Petr Fryčák, Michael J. ForsterAbstract:We report the evaluation of several mass spectrometry-based methods for the determination of carisoprodol and Meprobamate in samples obtained from the rat brain by in vivo intracranial microdialyis. Among the techniques that aspire to perform analyses without chromatographic separation and thereby increase throughput, chip-based nanoelectrospray ionization and the use of an atmospheric pressure solids analysis probe fell short of requirements because of insufficient detection sensitivity and hard ionization, respectively. Although direct analysis in real time provided the required soft ionization, shortcomings of a tandem mass spectrometry-based assay also included inadequate detection sensitivity and, in addition, poor quantitative reproducibility. Therefore, liquid chromatography coupled with atmospheric pressure chemical ionization tandem mass spectrometry was developed to determine carisoprodol and Meprobamate from artificial cerebrospinal fluid as the medium. No desalting and/or extraction of the samples was necessary. The assay, combined with in vivo sampling via intracranial microdialyis, afforded time-resolved concentration profiles for the drug and its major metabolite from the nucleus accumbens region of the brain in rats after systemic administration of carisoprodol. Copyright © 2016 John Wiley & Sons, Ltd.
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Carisoprodol-Mediated Modulation of GABAA Receptors: In Vitro and in Vivo Studies
2009Co-Authors: L A Gonzalez, Cynthia M Taylor, Cathy L Bell-Horner, Michael B Gatch, Michael J. Forster, Glenn H DillonAbstract:Carisoprodol is a frequently prescribed muscle relaxant. In recent years, this drug has been increasingly abused. The effects of carisoprodol have been attributed to its metabolite, Meprobamate, a controlled substance that produces sedation via GABAA receptors (GABAARs). Given the structural similari-ties between carisoprodol and Meprobamate, we used electro-physiological and behavioral approaches to investigate whether carisoprodol directly affects GABAAR function. In whole-cell patch-clamp studies, carisoprodol allosterically modulated and directly activated human 122 GABAAR function in a barbiturate-like manner. At millimolar concentra-tions, inhibitory effects were apparent. Similar allosteric effects were not observed for homomeric 1 GABA or glycine 1 receptors. In the absence of GABA, carisoprodol produce
Jørg Mørland - One of the best experts on this subject based on the ideXlab platform.
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Carisoprodol intoxications and serotonergic features.
Clinical toxicology (Philadelphia, Pa.), 2005Co-Authors: Jorgen G Bramness, Hanne Kristin Sørlid, Jørg Mørland, Nina Rudberg, Dag JacobsenAbstract:The symptoms and signs of carisoprodol intoxications do not resemble those caused by its metabolite Meprobamate. Meprobamate most probably produces its effects through the GABAergic neurotransmitter system. The signs and symptoms of carisoprodol intoxications, however, are not easily explained by interaction with this neurotransmitter system. In the present study, four cases of carisoprodol intoxications are presented with emphasis on the presence of serotonergic signs and symptoms. All four cases fulfilled three different sets of criteria for the diagnosis of serotonin syndrome. These findings could indicate that an increased serotonin level in the central nervous system could explain some of the symptoms and signs of carisoprodol intoxications. This may have implications for the clinical evaluation and treatment of such intoxications. Since few laboratories routinely screen for carisoprodol it is important to keep this drug in mind when encountering intoxications displaying serotonergic symptoms.
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Impairment due to intake of carisoprodol
Drug and Alcohol Dependence, 2004Co-Authors: Jorgen G Bramness, Svetlana Skurtveit, Jørg MørlandAbstract: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 GABAA 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. © 2004 Elsevier Ireland Ltd. All rights reserved.
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Carisoprodol elimination in humans.
Therapeutic drug monitoring, 1994Co-Authors: Harald Olsen, Gunnar Alvan, E Koppang, Jørg MørlandAbstract: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%.