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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]

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]

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.

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]