This article describes the development of a mild, general, and highly reproducible method for the radiofluorination of (hetero)aryl iodide, bromide, and chloride substrates. This transformation proceeds via sequential Pd-catalysed Miyaura borylation with B2Pin2 followed by in situ Cu-mediated radiofluorination of the (hetero)aryl-BPin intermediate with K18F. Successful implementation of this method required identifying and replacing/removing components of the borylation reaction that impede the radiofluorination step. This method is applied to electronically and sterically diverse (hetero)aryl halides and enables the synthesis of 18F-labelled analogues of bioactive molecules such as indomethacin, dimethomorph, and metaxalone. In addition, this sequence is effective for the radiofluorination of a variety of amino acids and peptides.

N-Glycosylated heterocycles play important roles in biological systems and drug development. The synthesis of these compounds heavily relies on ionic N-glycosylation, which is usually constrained by factors such as labile glycosyl donors, precious metal catalysts, and stringent conditions. Herein, we report a dehydroxylative radical method for synthesizing N-glycosides by leveraging copper metallaphotoredox catalysis, in which stable and readily available 1-hydroxy carbohydrates are activated for direct N-glycosylation. Our method employs inexpensive photo- and copper- catalysts and can tolerate some extent of water. The reaction exhibits a broad substrate scope, encompassing 76 examples, and demonstrates high stereoselectivity, favoring 1,2-trans selectivity for furanoses and α-selectivity for pyranoses. It also exhibits high site-selectivity for substrates containing multiple N-atoms. The synthetic utility is showcased through the late-stage functionalization of bioactive compounds and pharmaceuticals like Olaparib, Axitinib, and Metaxalone. Mechanistic studies prove the presence of glycosyl radicals and the importance of copper metallaphotoredox catalysis.

Concurrent use of skeletal muscle relaxants (SMRs) and opioids has been linked to an increased risk of injury. However, it remains unclear whether the injury risks differ by specific SMR when combined with opioids. We conducted nine retrospective cohort studies within a US Medicaid population. Each cohort consisted exclusively of person-time exposed to both an SMR and one of the three most dispensed opioids-hydrocodone, oxycodone, and tramadol. Opioid users were further divided into three cohorts based on the initiation order of SMRs and opioids-synchronically triggered, opioid-triggered, and SMR-triggered. Within each cohort, we used Cox proportional hazard models to compare the injury rates for different SMRs compared to methocarbamol, adjusting for covariates. We identified 349,543, 139,458, and 218,967 concurrent users of SMRs with hydrocodone, oxycodone, and tramadol, respectively. In the oxycodone-SMR-triggered cohort, the adjusted hazard ratios (HRs) were 1.86 (95% CI, 1.23-2.82) for carisoprodol and 1.73 (1.09-2.73) for tizanidine. In the tramadol-synchronically triggered cohort, the adjusted HRs were 0.69 (0.49-0.97) for metaxalone and 0.62 (0.42-0.90) for tizanidine. In the tramadol-SMR-triggered cohort, the adjusted HRs were 1.51 (1.01-2.26) for baclofen and 1.48 (1.03-2.11) for cyclobenzaprine. All other HRs were statistically nonsignificant. In conclusion, the relative injury rate associated with different SMRs used concurrently with the three most dispensed opioids appears to vary depending on the specific opioid and the order of combination initiation. If confirmed by future studies, clinicians should consider the varying injury rates when prescribing SMRs to individuals using hydrocodone, oxycodone, and tramadol.

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 Fmn2deletion 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.

Drug-induced immune hemolytic anemia (DIIHA) is a relatively uncommon cause of anemia, and its diagnosis can be challenging. Although beta-lactam antimicrobial agents are often associated with DIIHA, any medication can potentially cause it. We describe a patient presenting with yellow skin discoloration and orange-colored urine after starting metaxalone for treatment of lumbosacral sprain. Laboratory studies were consistent with warm hemolytic anemia. Symptoms improved remarkably after discontinuation of metaxalone, coupled with initiation of glucocorticoids and rituximab.

Metaxalone (MTX) is a central nervous system (CNS) depressant used for the treatment of acute skeletal muscle pain. Several cases of fatal overdose deaths in the clinical use of MTX, along with the presence of ischemic hepatitis in deceased patients, have been documented. The present study aimed to investigate the metabolic activation of MTX and to define the possible correlation between the metabolic activation and cytotoxicity of MTX. An oxidative metabolite (M1) and a GSH conjugate (M2) were observed in S9 fraction incubations as well as in rat primary hepatocyte culture after exposure to MTX. M1 and M2 were also observed in bile of MTX-treated rats. CYP2A6 was found to dominate the oxidation of MTX. Both methoxsalen (MTS, a CYP2A6 inhibitor) and 2,6-dichloro-4-nitrophenol (DCNP, a sulfotransferase inhibitor) dramatically decreased the formation of M2. Pre-treatment of primary hepatocytes with DCNP or MTS significantly decreased the susceptibility to the cytotoxicity of MTX.

A biocatalytic approach for the synthesis of metaxalone and its analogues was developed based on the reaction of epoxides and cyanate catalyzed by halohydrin dehalogenase. Gram-scale synthesis of chiral and racemic metaxalone was achieved with 44% (98% ee) and 81% yields, respectively, by protein engineering of the halohydrin dehalogenase HHDHamb from Acidimicrobiia bacterium. Additionally, various metaxalone analogues were synthesized at 28-40% yields (90-99% ee) for chiral forms and 77-92% yields for racemic forms.

Aryl thiocyanates are flexible synthetic intermediates that can be used in the preparation of a diverse range of arene building blocks for medicinal chemistry. Here, we report a fast and efficient Lewis acid-catalyzed method for the regioselective thiocyanation of arenes. Iron(III) chloride was found to be an effective Lewis acid for the activation of N-thiocyanatosaccharin and the subsequent thiocyanation of a wide range of activated arenes. The procedure was applicable for the thiocyanation of biologically active compounds such as metaxalone and an estradiol derivative and was used as part of a one-pot tandem iron-catalytic process for the regioselective, dual functionalization of an arene building block.

Background and Objectives: Warfarin and a skeletal muscle relaxant are co-treatments in nearly a quarter-million annual United States (US) office visits. Despite international calls to minimize patient harm arising from anticoagulant drug interactions, scant data exist on clinical outcomes in real-world populations. We examined effects of concomitant use of warfarin and individual muscle relaxants on rates of hospitalization for thromboembolism among economically disadvantaged persons. Materials and Methods: Using 1999−2012 administrative data of four US state Medicaid programs, we conducted 16 retrospective self-controlled case series studies: half included concomitant users of warfarin + one of eight muscle relaxants; half included concomitant users of an inhaled corticosteroid (ICS) + one of eight muscle relaxants. The ICS analyses served as negative control comparisons. In each study, we calculated incidence rate ratios (IRRs) comparing thromboembolism rates in the co-exposed versus warfarin/ICS-only exposed person-time, adjusting for time-varying confounders. Results: Among ~70 million persons, we identified 8693 warfarin-treated subjects who concomitantly used a muscle relaxant, were hospitalized for thromboembolism, and met all other inclusion criteria. Time-varying confounder-adjusted IRRs ranged from 0.31 (95% confidence interval: 0.13−0.77) for metaxalone to 3.44 (95% confidence interval: 1.53−7.78) for tizanidine. The tizanidine finding was robust after quantitatively adjusting for negative control ICS findings, and in numerous prespecified secondary analyses. Conclusions: We identified a potential >3-fold increase in the rate of hospitalized thromboembolism in concomitant users of warfarin + tizanidine vs. warfarin alone. Alternative explanations for this finding include confounding by indication, a native effect of tizanidine, or chance.

The concomitant use of prescription opioids and skeletal muscle relaxants has been associated with opioid overdose, but little data exist on the head-to-head safety of these drug combinations. The objective of this study was to compare the risk of opioid overdose among patients on long-term opioid therapy who concurrently initiate skeletal muscle relaxants.

As the population ages, spine-related pain is increasingly common in older adults. While medications play an important role in pain management, their use has limitations in geriatric patients due to reduced liver and renal function, comorbid medical problems, and polypharmacy. This review will assess the evidence basis for medications used for spine-related pain in older adults, with a focus on drug metabolism and adverse drug reactions. A PubMed/OVID search crossing common spine, neck, and back pain terms with key words for older adults and geriatrics was combined with common drug classes and common drug names and limited to clinical trials and age over 65 years. The results were then reviewed with identification of commonly used drugs and drug categories: nonsteroidal anti-inflammatories (NSAIDs), acetaminophen, corticosteroids, gabapentin and pregabalin, antispastic and antispasmodic muscle relaxants, tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tramadol, and opioids. Collectively, 138 double-blind, placebo-controlled trials were the focus of the review. The review found a variable contribution of high-quality studies examining the efficacy of medications for spine pain primarily in the geriatric population. There was strong evidence for NSAID use with adjustments for gastrointestinal and renal risk factors. Gabapentin and pregabalin had mixed evidence for neuropathic pain. SNRIs had good evidence for neuropathic pain and a more favorable safety profile than TCAs. Tramadol had some evidence in older patients, but more so in persons aged < 65 years. Rational therapeutic choices based on geriatric spine pain diagnosis are helpful, such as NSAIDs and acetaminophen for arthritic and myofascial-based pain, gabapentinoids or duloxetine for neuropathic and radicular pain, antispastic agents for myofascial-based pain, and combination therapy for mixed etiologies. Tramadol can be well tolerated in older patients, but has risks of cognitive and classic opioid side effects. Otherwise, opioids are typically avoided in the treatment of spine-related pain in older adults due to their morbidity and mortality risk and are reserved for refractory severe pain. Whenever possible, beneficial geriatric spine pain pharmacotherapy should employ the lowest therapeutic doses with consideration of polypharmacy, potentially decreased renal and hepatic metabolism, and co-morbid medical disorders.

Muscle relaxant and pain reliever metaxalone (MET) is a biopharmaceutical classification systems (BCS) class II drug with poor aqueous solubility and high permeability. The presence of an aromatic skeleton and cyclic carboxamate moiety are the probable reasons for the decreased aqueous solubility, which impacts on its low bioavailability. A high dose (800 mg) of the drug often creates adverse side effects on the central nervous system that needs urgent remedy. Cocrystallization of MET with nicotinamide (NAM), salicylamide (SAM), and 4-hydroxybenzoic acid (HBA) resulted in multicomponent solids that were characterized by PXRD, DSC and single crystal X-ray diffraction. Cocrystals with SAM and NAM form 2D isostructural cocrystals, whereas with HBA the result is a differently packed cocrystal hydrate (or anisole hemisolvate) depending upon the crystallization medium. Similar to the reported MET cocrystals, these cocrystals also confirm the preference for an imide⋯imide homosynthon in the drug. The dominance of the drug-drug homodimer over drug-coformer heterodimers was demonstrated based on binding energy calculations. Further, powder dissolution experiments in pH 6.8 phosphate buffer indicate that the cocrystals improved the apparent solubility compared to the native drug by 3-9 fold. The absence of stronger heterosynthons between MET and the coformers, their lower melting points and the high solubility of the coformers are the probable reasons for the enhanced solubility of the bioactive component. The MET-NAM cocrystal exhibited the highest solubility/dissolution rate among the three binary solid forms, which may offer improved bioavailability and a lower dose with minimal side effects.

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.