Search

The notable unbiased of this research work was to evaluate the well-being and effectiveness of metaxalone by administering the newly developed test and reference drug. A two-period, two-categorization, crossover bioavailability study in fed conditions. Eleven participants were dosed and completed the trial successfully. The drugs were administered by way of a schedule. Samples collected in both periods for pharmacokinetic evaluation. Plasma samples analyzed using a validated method. Pharmacokinetic parameters for investigational and reference products were calculated using the metaxalone drug concentration and safety of the participants monitored by measurement of vital sign. Relative estimation factors calculated for Cmax, Tmax, area under the curve (AUC) t, AUC inf, K el, half-life, and 90% confidence intervals applied for to check for whether reference and test products are equivalent. The experimental part of the study was completed with no major adversarial event. No losses or stern adverse events transpired throughout the course of the experiment. The assessment product is analogous to reference product in relation to degree and extent of absorption. The outcome of this study indicates the newly developed drug is equivalent to the innovator drug and medication was well tolerated by all participants.

Background: Low back pain (LBP) causes 2.6 million visits to U.S. emergency departments (EDs) annually. These patients are often treated with skeletal muscle relaxants (SMRs).Objectives: The goal of this study was to determine whether efficacy of SMRs is associated with age, sex, or baseline LBP severity.Methods: This was a planned analysis of data from 4 randomized studies of patients with acute nonradicular LBP. Patients were enrolled during an ED visit and followed-up 1 week later. The primary outcome was improvement in the Roland-Morris Disability Questionnaire (RMDQ) between ED discharge and the 1-week follow-up. We compared the change in RMDQ among 8 groups: placebo, baclofen, metaxalone, tizanidine, diazepam, orphenadrine, methocarbamol, and cyclobenzaprine. All patients also received a nonsteroidal anti-inflammatory drug. We performed analysis of variance to determine statistically significant differences between medications and linear regression to determine the association of age, sex, and baseline severity with the primary outcome.Results: The mean improvement in RMDQ per group was placebo 10.5 (95% confidence interval [CI] 9.5-11.5), baclofen 10.6 (95% CI 8.6-12.7), metaxalone 10.3 (95% CI 8.1-12.4), tizanidine 11.5 (95% CI 9.5-13.4), diazepam 11.1 (95% CI 9-13.2), orphenadrine 9.5 (95% CI 7.4-11.5), methocarbamol 8.1 (95% CI 6.1-10.1), and cyclobenzaprine 10.1 (95% CI 8.3-12). The between-group differences were not statistically significantly different. Results were similar regardless of age, sex, and baseline severity. Higher baseline RMDQ was associated with greater clinical improvement (B coefficient 5.7, p < 0.01). Adverse medication effects were more common with cyclobenzaprine than with placebo (p < 0.01).Conclusions: Among patients in the ED with acute LBP treated with a nonsteroidal anti-inflammatory drug, SMRs do not improve outcomes more than placebo. Neither age, sex, nor baseline impairment impacts these results. [ABSTRACT FROM AUTHOR]

The notable unbiased of this research work was to evaluate the well-being and effectiveness of metaxalone by administering the newly developed test and reference drug. A two-period, two-categorization, crossover bioavailability study in fed conditions. Eleven participants were dosed and completed the trial successfully. The drugs were administered by way of a schedule. Samples collected in both periods for pharmacokinetic evaluation. Plasma samples analyzed using a validated method. Pharmacokinetic parameters for investigational and reference products were calculated using the metaxalone drug concentration and safety of the participants monitored by measurement of vital sign. Relative estimation factors calculated for Cmax, Tmax, area under the curve (AUC) t, AUC inf, K el, half-life, and 90% confidence intervals applied for to check for whether reference and test products are equivalent. The experimental part of the study was completed with no major adversarial event. No losses or stern adverse events transpired throughout the course of the experiment. The assessment product is analogous to reference product in relation to degree and extent of absorption. The outcome of this study indicates the newly developed drug is equivalent to the innovator drug and medication was well tolerated by all participants. [ABSTRACT FROM AUTHOR]

Objective To examine the prevalence and duration of skeletal muscle relaxant (SMR) treatment among commercially insured adults in the United States. Methods We used the MarketScan Research Database to identify a cohort of adults 18 to 64 years who had ≥2-year continuous enrollment between 2005 and 2018. We estimated the prevalence of SMR treatment using a repeated cross-sectional design and derived treatment duration using the Kaplan-Meier method. Analyses were stratified by age group, sex, geographic region, individual SMR agent, and musculoskeletal disorder. Results 48.7 million individuals were included. Treatment prevalence ranged from 61.5 to 68.3 per 1,000. About one-third of users did not have a preceding musculoskeletal disorder diagnosis. Cyclobenzaprine was the dominant agent accounting for >50% of prescriptions. The considerable growth in the use of baclofen, tizanidine, and methocarbamol paralleled with a decline in carisoprodol and metaxalone use. The prevalence was highest in the South while lowest in the Northeast. The median treatment duration was 14 days with 4.0%, 1.9%, and 1.0% of individuals using SMRs for more than 90, 180, and 365 days, respectively. Compared with cyclobenzaprine, patients initiating baclofen, tizanidine, and carisoprodol had longer treatment duration. Conclusions SMRs are widely used in the United States. Their use slightly increased in recent years, but trends varied among individual agents, patient groups, and geographic regions. Despite limited evidence to support efficacy, a sizable number of U.S. adults used SMRs for long-term and off-label conditions. Further study is needed to understand determinants of treatment as well as outcomes associated with such use. [ABSTRACT FROM AUTHOR]

Metaxalone is oxazolidin-2-one derivative, biopharmaceutics classification system class II drug, available in the market as a central muscle relaxant drug, used to alleviate discomforts associated with severe, painful musculoskeletal conditions. The major drawbacks associated with formulation of solid oral dosage forms of metaxalone are its poor aqueous solubility, poor flow property and low compressibility. The aim of present study was to develop different crystalline forms of metaxalone in order to overcome these drawbacks and consequently enhance its dissolution and bioavailability. For this purpose two different approaches were adopted namely cocrystallization and melt sonocrystallization. Cocrystals of metaxalonesaccharin and metaxalone-lactic acid were prepared, with saccharin and lactic acid as coformers, by using solvent evaporation method. Melt sonocrystallization technique was applied for preparation of melt sonocrystallized form of metaxalone. The percentage yield, melting point, particle size, flow property, crystallinity index, solubility and dissolution profiles of developed crystals were evaluated and compared with original metaxalone. Further the developed forms of metaxalone were characterized by differential scanning calorimetry, fourier transform infrared spectroscopy, X-ray diffraction and scanning electron microscopy. The sharp peak of differential scanning calorimetry thermograms and fourier transform infrared spectroscopy spectras indicate towards the formation of crystalline forms with retention of characterstic functionality of original metaxalone. The particle size and crystallinity index of the developed metaxalone crystals were significantly reduced in comparison to the original form. In addition, there was significant enhancement in the flow and compressibility of developed crystals, as indicated by the value of angle of repose, Carr's index and Hausner ratio. The solubility of prepared crystals was much higher as compared to metaxalone and progressively increased in the following order: metaxalonesaccharin< metaxalone-lactic acid

Context: Serotonin toxicity is a reported complication associated with both therapeutic use and overdose of metaxalone while on therapeutic doses of serotonergic drugs such as serotonin reuptake inhibitors. Monoamine oxidase A (MAO-A) inhibition by metaxalone has been proposed as the etiology of this toxicity. Metaxalone concentrations reported with cases of serotonin toxicity range from 31 to 61 mcg/ml (140–276 µM). We investigated the effect of metaxalone on MAO-A activity using an in vitro model. Methods: Metaxalone at concentrations ranging from 1.56 to 400 µM were incubated with a proprietary MAO substrate and recombinant human MAO-A for 1 h. After that, an esterase and luciferase were added and luminescence measured. Clorgyline, a known MAO-A inhibitor, was used as a positive control. Luminescence was measured using a Biotek Synergy HT microplate reader. Results: Metaxalone demonstrated significant dose-related inhibition of MAO-A activity. Four-parameter logistic regression analysis demonstrated a strong dose-response relationship at increasing concentrations. Conclusions: Our in vitro model shows that at toxic concentrations similar to those reported in case reports metaxalone shows significant MAO-A inhibition. Clinicians should be aware of this mechanism and understand the potentially lethal interactions metaxalone can have when prescribed with other serotonergic drugs and consider this as a potential cause of serotonin toxicity, especially in overdose scenarios. [ABSTRACT FROM AUTHOR]

Peripheral nerves regenerate successfully; however, clinical outcome after injury is poor. We demonstrated that low-dose ionizing radiation (LDIR) promoted axon regeneration and function recovery after peripheral nerve injury (PNI). Genome-wide CpG methylation profiling identified LDIR-induced hypermethylation of the Fmn2 promoter, exhibiting injury-induced Fmn2 downregulation in dorsal root ganglia (DRGs). Constitutive knockout or neuronal Fmn2 knockdown accelerated nerve repair and function recovery. Mechanistically, increased microtubule dynamics at growth cones was observed in time-lapse imaging of Fmn2 -deficient DRG neurons. Increased HDAC5 phosphorylation and rapid tubulin deacetylation were found in regenerating axons of neuronal Fmn2 -knockdown mice after injury. Growth-promoting effect of neuronal Fmn2 knockdown was eliminated by pharmaceutical blockade of HDAC5 or neuronal Hdac5 knockdown, suggesting that Fmn2 deletion promotes axon regeneration via microtubule post-translational modification. In silico screening of FDA-approved drugs identified metaxalone, administered either immediately or 24-h post-injury, accelerating function recovery. This work uncovers a novel axon regeneration function of Fmn2 and a small-molecule strategy for PNI. [Display omitted] • LDIR promotes intrinsic axonal growth, function recovery, and Fmn2 hypermethylation • Fmn2 as a regulator of injury response, axon regeneration, and microtubule dynamics • Fmn2 deletion promotes axon regeneration via HDAC5-mediated tubulin deacetylation • FDA drug metaxalone recapitulates growth-promoting effects of Fmn2 deletion for PNI Proximal peripheral nerve injury (PNI) results in poor clinical outcomes. Au et al. reveal that ionizing radiation induces intrinsic growth of injured neurons and Fmn2 downregulation. Fmn2 deletion enhances microtubule dynamics, axon regeneration, and function recovery. Using gene signature of Fmn2 deletion identifies FDA-approved metaxalone recapitulating growth-promoting effects of Fmn2 deletion for PNI. [ABSTRACT FROM AUTHOR]

A simple and rapid method using liquid chromatography–mass spectrometry (LC-MS) for the determination of metaxalone in human plasma has been developed and validated. Letrozole was used as the internal standard (IS). The plasma samples were simply treated with acetonitrile which allowed the precipitation of plasma proteins. The chromatographic separation was achieved on a Sapphire C18 (2.1 mm × 150 mm, 5 µm, Newark, USA) column using the mobile phase (5 mM ammonium acetate containing 0.01% formic acid: acetonitrile (45:55, v/v)) at a flow rate of 0.3 ml/min. The selected ion monitoring (SIM) in the positive mode was used for the determination of [M + H]+ m/z 222.1 and 286.1 for metaxalone and letrozole, respectively. The standard curve obtained was linear (r2 ≥ 0.99) over the concentration range of 30.24−5040 ng/ml. Meanwhile, no interfering peaks or matrix effect was observed. The method established was simple and successfully applied to a pharmacokinetic study of metaxalone in healthy Chinese volunteers after a single oral dose administration of 800 mg metaxalone. The main pharmacokinetic parameters of metaxalone were as follow: Cmax, (1664 ± 1208) ng/ml and (2063 ± 907) ng/ml; AUC0−36, (13925 ± 6590) ng/ml h and (18620 ± 5717) ng/ml h; t1/2, (13.6 ± 7.7) h and (20.3 ± 7.7) h for the reference and test tablets, respectively. These pharmacokinetic parameters of metaxalone in healthy Chinese volunteers were reported for the first time.

Abstract Supramolecular reactions between a muscle relaxant drug, Metaxalone, 5-[(3,5-dimethylphenoxy)methyl]-2-oxazolidinone with a few carboxamides like nicotinamide, isonicotinamide, salicylamide and carboxylic acid coformers such as 3-hydroxybenzoic acid, 4-hydroxybenzoic acid resulted binary cocrystals. The cocrystals were initially characterized by PXRD, FT˗IR, ss-NMR, DSC and finally confirmed by single crystal X-ray diffraction. Surprisingly, all the novel cocrystals exhibited melting endotherm lower than the drug and coformer, which is not so common (29%) in the literature. Vibrational spectroscopy suggests the possible stoichiometry of the drug cocrystals based on the number of carbonyl stretching frequencies and hydrate formation in case of 4-hydroxybenzoic acid cocrystal. 13C-ssNMR spectroscopy of metaxalone–salicylamide cocrystal indicates the possibility of more symmetry independent molecule of the drug in the starting material to less in the cocrystal and molecular conformation was also reflected in the spectrum. The corresponding crystal structure consists of one molecule each of metaxalone and salicylamide in the asymmetric unit. Similar to the thermodynamically stable form of the drug and cocrystals with mono/di-carboxylic acids, metaxalone forms centrosymmetric N H⋯O hydrogen bonded imide-imide homodimer in this cocrystal. Salicylamide molecules also form centrosymmetric amide-amide homosynthon. Both the homodimers are perpendicularly (79°) interlinked via bifurcated carbonyl oxygen of the drug, which results 1D chain along the crystallographic b -axis. Auxiliary C˗H⋯O interactions further stabilize the bonding between the drug and salicylamide. Binding energy calculation of metaxalone/salicylamide homodimer and metaxalone‒salicylamide heterodimer using B3LYP/6-311++G** method and in addition, the stacking energy interactions in the API suggest the most preferred API homodimer synthon in the reported polymorphs and cocrystals. The pharmaceutical cocrystals of metaxalone with amide functionalities are reported for the first time in the literature. Graphical abstract The pharmaceutical cocrystals of Metaxalone (MTX) with nicotinamide (NCT), salicylamide (SAM), isonicotinamide (INA), 3-hydroxybenzoic acid (3HBA) and 4-hydroxybenzoic acid (4HBA) exhibited lower melting points than both the API and coformers, which is less common (29%) among the reported cocrystals. Image 1 Highlights • First time, we have reported Metaxalone cocrystals with amide functionalities. • All the pharmaceutical cocrystals exhibited lower melting points than the drug and coformers which are rare in the database. • Vibrational spectroscopy is utilized to predict the synthons and further stoichiometry in the cocrystals. • Crystal structure of metaxalone‒salicylamide is reported. • Binding energy and stacking energy calculations supported the dominance of API homodimer in the cocrystals. [ABSTRACT FROM AUTHOR]

A reversed-phase high-performance liquid chromatographic (RP-HPLC) method based on ion pair formation is demonstrated for the simultaneous determination of Metaxalone (MTX) and Diclofenac potassium (DCP) in commercial formulations. MTX (pKa=12.24) and DCP (pKa=4.00) are hydrophilic ionic substances that make the separation critical due to distinct pKa values. Addition of ionic additives (ion-pairing reagents or chaotropic agents) to the mobile phase allowed a significant improvement in retention of the ionic analytes. However, finding the suitable condition of the Ion-Pair Chromatography (IPC) to achieve desirable separation was challenging and often rebellious to influential chromatographic parameters. The judicious selection of eluent pH, flow rate, acidic modifiers and organic modifier, detector wavelength was performed with the aid of Plackett-Burman design and Box-Behnken design. Desired separation of MTX and DCP was achieved using an Inertsil ODS2 (250x4.6mm; 5ìm) column equilibrated with 10mM phosphate buffer (pH-5.0): acetonitrile (42: 58%v/v) containing 0.4% triethylamine and 0.5% tetrabutyl ammonium hydroxide as an eluent at a flow rate of 1.20 mL/min. Under optimal condition, the detection limits are 0.306ìg/mL and 0.807ìg/mL and limits of quantification 0.927ìg/mL and 2.44ìg/mL for MTX and DCP respectively. Subsequently, the plausible retention behavior of both analytes was predicted in the ion interaction condition. [ABSTRACT FROM AUTHOR]

Most of the analytical method required, fast and reliable analytical technique as per current requirement of pharmaceutical industry. Hence a simple rugged and cost effective method was developed and validated for Metaxalone. By using this HPLC method, the time for analysis is reduced sensationally as compared to other method published in most of the literatures published. The method was set on Ascentis express C8 column (10cm x 4.0mm, 2.7μ) using 0.1% Triethylamine as a buffer (pH 3.0 with per chloric acid) and acetonitrile as organic modifier. The flow rate was set at 1.0ml\min and analysis time was 4 minutes with gradient elution. The detection was conducted at 210nm. The method was validated as per International Conference of Harmonization (ICH) Guidelines in terms of Specificity linearity and range, precision and robustness. Sample and standard concentration of metaxalone was 0.5mg/ml. linearity of standard was covered from 0.4mg/ml to 0.6mg/ml. [ABSTRACT FROM AUTHOR]

A simple, rapid, sensitive, and selective liquid chromatography-tandem mass spectrometry (MS) method was developed and validated for the quantification of Metaxalone, a skeletal muscle relaxant, in human plasma using Metaxalone -D6 as Internal Standard (IS). Following Liquid-Liquid Extraction (LLE), the analytes were separated using an isocratic mobile phase on a reverse phase C18 column (Chromatopak peerless basic 50× 4.6mm× 3.0µm) and analyzed by MS in the multiple reaction monitoring mode using the respective [M+H]+ ions, m/z 222.14 / 160.98 for Metaxalone and m/z 228.25 /167.02 for the IS. The assay exhibited a linear dynamic range of 25.19 -2521.313 ng/mL for metaxalone in human plasma. The goodness of fit was consistently greater than 0.98 during the course of validation. The range of accuracy and precision of the back-calculated concentrations of the standard curve points was from 94.1% to 104.4% and 0.3% to 5.6% for metaxalone A run time of 2.0 min for each sample and injection volume is 5 µl. The validated method has been successfully used to analyze human plasma samples for application in pharmacokinetic, bioavailability, or bioequivalence studies. [ABSTRACT FROM AUTHOR]

Introduction: Serotonin syndrome is a potentially life-threatening entity associated with pro-serotonergic medications in therapeutic use, in overdose, or when co-administered with other drugs. A broad range of drugs and drug combinations have been associated with serotonin syndrome. Metaxalone overdose associated with serotonin syndrome has not been previously reported. Case Report: ( Case 1) A 23-year-old female overdosed on tramadol and metaxalone. She developed dysautonomia, diaphoresis, lower extremity rigidity and spontaneous clonus, flaccid upper extremities, and hyperthermia 5 h after ingestion. Her course was complicated by status epilepticus. ( Case 2) A 56-year-old female overdosed on metaxalone and was found unresponsive. She developed dysautonomia, lower extremity rigidity and spontaneous clonus, flaccid upper extremities, rhabdomyolysis, acute renal failure, and hyperthermia. Non-depolarizing neuromuscular blockade and cooling blankets were required to control hyperthermia in both cases. Serum metaxalone levels were markedly elevated in both cases. Conclusion: These are the first reported cases of metaxalone overdose associated with serotonin syndrome, which may be related to monoamine oxidase inhibition. [ABSTRACT FROM AUTHOR]

Owing to know the complexity in reverse phase high performance liquid chromatography (RP-HPLC) method optimization; i.e., the selection of optimum combination of input variables for achieving the desired separation, a mathematical relationship between the experimental variables with the responses is to be established by response surface methodology. The paper aims to describe the use of the Box–Behnken experimental design to identify the significant variables effects influencing the separation of metaxalone (MTX) and its two base hydrolytic impurities (DP-1 and DP-2) in a stability indicating RP-HPLC method. Influence variables such as column temperature, buffer pH, and buffer concentration, each at three levels were screened for the desirability of responses like theoretical plates, resolution (MTX-DP-1), capacity factor of MTX, tailing factor at 10% (MTX), and analysis time (Rtof DP-2). A statistical program (Design Expert 8.0) was used to calculate and optimize the five responses simultaneously by means of a multiple response optimization algorithm. The optimum conditions are established including the robustness of the method using a Box–Behnken design, as part of the validation exercise. 10 mM phosphate buffer with pH 4.7 at 31°C column temperature was found to be the optimized condition to produce desirable responses. System suitability limits were defined based on the results of the robustness test. The RP-HPLC method was further validated with respect to linearity, range, precision, specificity, accuracy, limit of detection, and limit of quantification, according to the current regulatory requirements. The optimized method gives rapid and efficient separation with complete resolution between the three peaks, and represents an improvement over the existing reported methods. [ABSTRACT FROM AUTHOR]

Purpose: To develop a simple, highly sensitive, precise and accurate high-performance liquid chromatographic method with photodiode array detection and validated for the rapid quantification of metaxalone in rat plasma samples. Method: Following Liquid-Liquid Extraction (LLE), metaxalone and the internal standard Phenytoin (PHY) were extracted from an aliquot of 200 mL of plasma. Chromatographic separation was carried out using Phenomenex Luna C8 column (250 mmµ 4.6 mmµ 5 mm) with mobile phase composed of phosphate buffer, pH 7 and acetonitrile in 35:65, v/v ratio. The analyte was monitored with UV detector at 219 nm. The developed method was validated with respect to linearity, accuracy, precision, specificity and stability. The peak area ratio of MET to that of internal standard, PHY was used for the quantification of samples. Results: The retention time of MET and PHY were found to be 2.30 and 3.02 min respectively. The calibration curve was linear (r²> or=0.99) ranging from 1.505-538.254 ng/ml and the lower limit of quantification was 1.505 ng/ mL. Interday and Intraday precision were lower than 5% (CV) and accuracy ranged from 95 to 105% in terms of percent accuracy. Mean extraction recovery was found to be above 94%. Conclusion: A simple, alternative, reproducible and sensitive HPLC-DAD method was developed for MET that can be used in preclinical pharmacokinetics. [ABSTRACT FROM AUTHOR]

Highlights: [•] Solvent-assisted grinding can easily create a cocrystal formation. [•] Metaxalone and n =2 of short-chain dicarboxylic acids can form cocrystal. [•] The cocrystal formation is also easily induced by a unique DSC-FTIR microspectroscopy. [ABSTRACT FROM AUTHOR]

ABSTRACT A stability-indicating reverse-phase high-performance liquid chromatography-mass spectrometric method was developed and validated for the assay of metaxalone through forced degradation under acidic, alkaline, photo, oxidative and peroxide stress conditions. Separation of degradation products was accomplished on a reverse-phase Phenomenex C18 (250 × 4.6 mm, 5 µm) column thermostated at 25°C using 10 mM aqueous ammonium acetate: methanol (35:65 v/v) as mobile phase in an isocratic mode of elution. The eluents were detected at 275 nm by photo diode array detector and mass detectors connected in series. Two unknown base hydrolysis products of metaxalone were identified and characterized as (a) methyl 3-(3,5-dimethylphenoxy)-2-hydroxypropylcarbamate and (b) 1-(3,5-dimethylphenoxy)-3-aminopropan-2-ol by MS, 1H NMR and FTIR spectroscopy. The method was validated as per International Conference on Harmonization guidelines and metaxalone was selectively determined in presence of its degradation impurities, demonstrating its stability-indicating nature. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: An isocratic stability indicating RP-HPLC–UV method is presented for the determination of metaxalone (MET) in the presence of its degradation products. The method uses Dr. Maisch C18 column (250mm×4.6mm, 5μm) with mobile phase consisting of acetonitrile–potassium dihydrogen orthophosphate buffer with 4mL of 0.4% triethyl amine (pH 3.0; 10mM) (58:42, v/v) at a flow rate of 1.0mL/min. pH of the buffer was adjusted with o-phosphoric acid. UV detection was performed at 225nm. The method was validated for specificity, linearity, precision, accuracy, limit of detection, limit of quantification and robustness. The calibration plot was linear over the concentration range of 1–100μg/mL having a correlation coefficient (r 2) of 0.999. Limits of detection and quantification were 0.3 and 1μg/mL, respectively. Intra-day and inter-day precision (% RSD) was 0.65 and 0.79 respectively. The proposed method was used to investigate the degradation kinetics of MET under different stress conditions employed. Degradation of MET followed a pseudo-first-order kinetics, and rate constant (K), time left for 50% potency (t 1/2), and time left for 90% potency (t 90) were calculated. [Copyright &y& Elsevier]

Abstract: Metaxalone is a skeletal muscle relaxant, an approved drug for pain relief. Published bioanalytical methods lacked detailed stability evaluation in blood and plasma. An accurate, precise, high-throughput tandem mass spectroscopic method has been developed and validated. Following solid phase extraction (SPE), metaxalone and the internal standard metaxalone-d3 were extracted from an aliquot of 200μL of human plasma. Chromatographic separation achieved on an Ascentis Express C18 column (50mm×4.6mm i.d., 2.7μm particle size) with mobile phase is a mixture of 10mM ammonium acetate buffer (pH 4.5)–methanol–acetonitrile (20:50:30, v/v/v), at an isocratic flow rate of 0.7mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source. The mass transitions of metaxalone and metaxalone-d3 were m/z 222.3→161.2 and m/z 225.3→163.3, respectively. The linear calibration curves were obtained in the concentration range of 0.105–10.081μg/mL (r 2 ≥0.99) with a lower limit of quantification (LLOQ) of 0.105μg/mL. The intra- and inter-day precisions and relative error were all within 6%. Despite achieving high mean recovery (>78%), no interference peaks or matrix effects were observed. Detailed stability exercises including drug stability in blood, hemolyzed, lipemic and normal plasma were conducted to extend the method applicability in vast majority of clinical studies using 800mg metaxalone extended release oral dosage form. [Copyright &y& Elsevier]

A simple, precise and accurate isocratic RP-HPLC stability-indicating assay method has been developed to determine diclofenac potassium and metaxalone in their combined dosage forms. Isocratic separation was achieved on a Hibar-C18, Lichrosphere-100® (250 mm × 4.6 mm i.d., particle size 5 μm) column at room temperature in isocratic mode, the mobile phase consists of methanol: water (80:20, v/v) at a flow rate of 1.0 ml/min, the injection volume was 20 μl and UV detection was carried out at 280nm.The drug was subjected to acid and alkali hydrolysis, oxidation, photolysis and heat as stress conditions. The method was validated for specificity, linearity, precision, accuracy, robustness and system suitability. The method was linear in the drug concentration range of 2.5-30 μg/ml and 20-240 μg/ml for diclofenac potassium and metaxalone, respectively. The precision (RSD) of six samples was 0.83 and 0.93% for repeatability, and the intermediate precision (RSD) among six-sample preparation was 1.63 and 0.49% for diclofenac potassium and metaxalone, respectively. The mean recoveries were between 100.99-102.58% and 99.97-100.01% for diclofenac potassium and metaxalone, respectively. The proposed method can be used successfully for routine analysis of the drug in bulk and combined pharmaceutical dosage forms. [ABSTRACT FROM AUTHOR]

Few data exist on potentially adverse metaxalone (Skelaxin®) ingestions in adults. All metaxalone ingestions involving patients aged ≥20 years during 2000-2006 were retrieved from Texas poison control centers. Exclusion criteria were lack of follow-up or multiple substance ingestion. Cases were analyzed for selected demographic and clinical factors. Of the 142 patients, 66.2% were female. Dose ingested was reported for 61 patients. Of those cases with a reported dose, distribution by management site was 29.5% on-site, 59.0% already at/en route to health care facility, and 11.5% referred to health care facility. Final medical outcome was 'no effect' for 50.8% cases, 'minor effect' for 31.1%, and 'moderate effect' for 18.0%. The more common adverse clinical effects reported were drowsiness (27.9%), tachycardia (6.6%), agitation (6.6%), nausea (4.9%), dizziness (4.9%), slurred speech (4.9%), and tremor (4.9%). A moderate medical outcome occurred in 13.6% of ingestions of ≤2400 mg and 20.5% of ingestions of >2400 mg. Management involved a health care facility in 18.2% of ingestions of ≤2400 mg and 100.0% of ingestions of >2400 mg. This study found that adult ingestions of higher doses of metaxalone, particularly >2400 mg, were associated with more serious medical outcomes and were managed at health care facilities. This study also proposes triage guidelines for when ingestions can be safely managed at home. [ABSTRACT FROM AUTHOR]

Abstract: Metaxalone (Met), a drug for treatment of pain and stiffness due to muscular injuries, was covalently linked to poly(ethylene glycols) (PEG) via a chloroacetyl chloride spacer. The average weight molecular weights used for PEG are 4000, 6000 and 10,000, respectively, and the procedure of chemical modification for PEGs was conducted by a two-step protocol: (1) synthesis of N-chloroacetyl-metaxalone; (2) synthesis of PEG4000–Met, PEG6000–Met and PEG10000–Met. The controlled drug release studies were performed in buffer solutions with pH values equal to 1.1, 7.4 and 10.0. The results demonstrate that, in the same condition, the rate of hydrolysis for PEG10000–Met is the slowest among three prodrugs, and more amount of metaxalone can be detected releasing from prodrug matrices at the presence of α-chymotrypsin in a buffer solution with pH 8.0. It was also found that these novel prodrugs can effectively improve the metaxalone''s pharmacokinetics, and furthermore can markedly increase its half-life period. [Copyright &y& Elsevier]

Low back pain is a leading reason for primary care visits. Many treatment options are available, but some lack scientific support.The aim of this review was to discuss the etiology of low back pain and the relative risks and benefits of muscle relaxants commonly prescribed for the management of back pain.We searched Intercontinental Marketing Services data for January 2003 through January 2004 to determine the most commonly prescribed agents for the management of musculoskeletal pain. Carisoprodol, cyclobenzaprine hydrochloride, and metaxalone represented >45% of all such prescriptions. Cochrane Library, MEDLINE, and EMBASE databases were searched (time frame: 1960 through January 2004; search terms: back pain, carisoprodol, cyclobenzaprine, metaxalone, muscle relaxants, and pharmacotherapy) and reference lists of identified articles were hand-searched.Three trials of carisoprodol (N = 197) were located in the Cochrane Library database. Two double-blind, randomized, placebo-controlled trials evaluating the safety and efficacy of cyclobenzaprine hydrochloride (N = 1405) were identified in the literature. Three double-blind, placebo-controlled trials were identified for metaxalone (N = 428) in 2 reports. The types of adverse events seen with these agents involved the central nervous system, including drowsiness/sedation, fatigue, and dizziness. However, the efficacy of cyclobenzaprine hydrochloride was shown to be independent of its sedative effects, which were dose related. The potential for abuse with carisoprodol is of growing concern.Analgesic pain management for low back pain due to muscle spasm may be combined with a muscle relaxant. Cyclobenzaprine hydrochloride has the most recent and largest clinical trials demonstrating its benefit, but carisoprodol and metaxalone also appear to be effective. However, carisoprodol''s usefulness is mitigated by its potential for abuse. [Copyright &y& Elsevier]

Metaxalone has only recently been associated with serotonin syndrome. The mechanism of action of this centrally acting muscle relaxant is unknown; however, the observation of serotonin syndrome in patients with metaxalone overdose suggests a role in the serotonergic pathway. Case report. (Case 1) A 29-year-old woman with overdose of metaxalone presented to the emergency department with altered mental status, seizure-like activity, hyperthermia, rigidity in the lower extremities, myoclonus, and hyperreflexia. Vital signs on arrival include blood pressure of 168/80 mmHg, heart rate of 208 beats per minute (bpm), respirations of 20/min, a temperature of 41.6° C rectally, and room air oxygen saturation of 97%. She was intubated and sedated with benzodiazepines, and actively cooled. Serum paroxetine concentration was 23 (therapeutic range: 20-200) ng/mL, and serum metaxalone concentration was 31 mcg/mL (peak plasma concentrations average 0.9 mcg/mL at 3.3 h following a single oral dose of 400 mg). (Case 2) A 27-year-old man presented to the emergency department with altered mental status, rigidity in his lower extremities, myoclonus, and hyperreflexia. Vital signs on arrival include blood pressure of 158/131 mmHg, heart rate of 126 bpm, respiratory rate of 20 breaths per minute, and temperature of 37.2°C, with oxygen saturation of 98% on room air. His medication list included metaxalone and escitalopram. He was managed aggressively with IV boluses of diazepam, in total 80 mg, in the emergency department. Serum escitalopram concentration was 24 ng/mL with a therapeutic range of 21-64 ng/mL, and serum metaxalone concentration was 58 mcg/mL. Conclusion. These two cases suggest that at supratherapeutic concentrations metaxalone has serotonergic effects. Severe serotonin toxicity may result from metaxalone abuse in individuals using a selective serotonin reuptake inhibitor therapeutically. [ABSTRACT FROM AUTHOR]

Experimental and clinical studies have suggested that several neurological disorders are associated with the occurrence of central nervous system neuroinflammation. Metaxalone is an FDA-approved muscle relaxant that has been reported to inhibit monoamine oxidase A (MAO-A). The aim of this study was to investigate whether metaxalone might exert antioxidant and anti-inflammatory effects in HMC3 microglial cells. An inflammatory phenotype was induced in HMC3 microglial cells through stimulation with interleukin-1β (IL-1β). Control cells and IL-1β-stimulated cells were subsequently treated with metaxalone (10, 20, and 40 µM) for six hours. IL-1β stimulated the release of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), but reduced the anti-inflammatory cytokine interleukin-13 (IL-13). The upstream signal consisted of an increased priming of nuclear factor-kB (NF-kB), blunted peroxisome proliferator-activated receptor gamma (PPARγ), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression. IL-1β also augmented MAO-A expression/activity and malondialdehyde levels and decreased Nrf2 mRNA expression and protein levels. Metaxalone decreased MAO-A activity and expression, reduced NF-kB, TNF-α, and IL-6, enhanced IL-13, and also increased PPARγ, PGC-1α, and Nrf2 expression. The present experimental study suggests that metaxalone has potential for the treatment of several neurological disorders associated with neuroinflammation. [ABSTRACT FROM AUTHOR]

Abstract: A case is presented of a 54-year-old white female found dead in a secured apartment. Postmortem toxicologic analysis of the heart blood identified acetaminophen (97mg/L), citalopram (0.4mg/L), gabapentin (24mg/L) and metaxalone (21mg/L). The metaxalone concentration is within the range of previously reported fatalities involving metaxalone. The medical examiner ruled that the cause of death was metaxalone and gabapentin intoxication and the manner of death was suicide. [Copyright &y& Elsevier]

Purpose: The aim of the present work was to classify metaxalone according to the Biopharmaceutics Classification System (BCS), to develop a clinically relevant dissolution method that can be used to predict the oral absorption of metaxalone and to establish an in vitro-in vivo correlation (IVIVC).Methods: Solubility of the drug was studied in different pH media and permeability studies were performed using a Caco-2 cell model. The in vitro dissolution and in vivo disposition of metaxalone from 3 different immediate release (IR) tablet formulations were investigated using USP 2 apparatus and a single dose, four-way, crossover bioequivalence study in healthy humans along with an oral solution of the drug, respectively. An IVIVC was established by using a direct, differential based method.Results: Metaxalone has been confirmed as a Class II drug according to BCS. Bioavailability studies performed in humans demonstrated that dissolution was the rate limiting step for bioavailability of the drug and one of the test products had significantly improved bioavailability compared to the marketed product Skelaxin®. An IVIVC model was developed that demonstrated an acceptable internal predictability.Conclusion: The IVIVC demonstrated that formulation factors play a significant role in dissolution and absorption of metaxalone. A pH 4.5 dissolution medium containing 0.5% NaCl with 0.2% SLS (USP apparatus 2 at 50 rpm) is clinically relevant to predict bioavailability of the drug and is superior to the USP method in terms of the Quality by Design (QbD) concept. [ABSTRACT FROM AUTHOR]