Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used for the treatment of Inlammator dimseas, but sg t side effects such as g oi l erosion and renal damage lmit their use. NSAIDs Inhibit the enzyme cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid to p (PGs) and thromboxane. Two forms of COX have been identlfled-COX-1, which is constitutively expressed in most tissues and organs, and the Inducible enzyme, COX-2, whih has been localized primarily to ilmmatory cells and tsues. In an animal model of acute inflammation (Injection ofcarrageenan into the footpad), edema was produced that was associated with marked accumulation of COX-2 mRNA and thromboxane. A selective inhibitor of COX-2 (SC-58125) inhibited edema at the inmatory site and was analgesic but had no effect on PG production In the stomach and did not cause gastric toxicity. These data suggest that selective inhibition of COX-2 may produce superior an mmatory drugs with substantial safety advantages over existing NSAIDs. bone density, fluid and electrolyte imbalance, and "Cushinglike" symptoms. These untoward effects limit glucocorticoid use in chronic inflammatory disorders such as rheumatoid arthritis (13).Studies were designed to evaluate the role ofCOX-2 in vivo at the site of inflammation. We report that in a model of inflammation useful in the characterization of NSAIDs, the carrageenan-injected rat paw, COX-2 was expressed locally in response to the proinflammatory stimulus and that the induction of COX-2 mRNA coincided with the synthesis of proinflammatory PGs and the development of edema and hyperalgesia. COX-1 mRNA was detectable in the normal rat paw, but its expression did not change following the onset of the inflammatory reaction. Furthermore, a selective inhibitor of COX-2 {SC-58125: 1-[(4-methylsulfonyl)phenyll-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole} blocked edema and hyperalgesia in vivo following an inflammatory insult, without causing gastric mucosal damage.

Background: Osteosarcoma, a primary malignant bone tumor derived from mesenchymal tissue, is the most common type of pleomorphic tumor that occurs in children and adolescents. The aim of this study was to compare the efficacy and safety of high-dose methotrexate (M), doxorubicin (D), cisplatin (C), and ifosfamide (I) in the management of osteosarcoma. Methods: Electronic databases including PubMed, Cochrane Library, and Embase database were searched for studies published from when the databases were established to July 13, 2019. The network meta-analysis was performed using software R 3.3.2 and STATA version 41.0 after demographic and outcome data extraction. The ranks based on probabilities of interventions for each outcome were performed. In addition, the consistency of direct and indirect evidence was assessed by node splitting. Results: The network meta-analysis results revealed that MDCI had a significant lower hazard risk of overall survival [MDCI vs MDC: HR = 0.74, 95% CrI (0.23, 0.87); MDCI vs DC: HR = 0.60, 95% CrI (0.16, 0.92)]. In addition, MDCI had a clearly longer progression-free survival time than that of DC [MDCI: HR = 0.88, 95% CrI (0.46, 0.98)]. No significant difference was detected in MDC and DC in OS, PFS, and AEs. The probabilities of rank plot showed that MDCI ranked first in OS (73.12%) and PFS (52.43%). DC was the best treatment in safety, ranked first (75.43%). Conclusions: MDCI showed its superiority among all chemotherapeutic agents in relation to efficacy and safety, followed by MDC. In addition, MDCI was associated with an increased risk of AEs. According to our analysis, DC was less effective but safer for MDC and MDCI.

Receptor theory predicts that fixed-proportion mixtures of a competitive, reversible agonist (e.g., fentanyl) and antagonist (e.g., naltrexone) at a common receptor [e.g., mu-opioid receptors (MORs)] will result in antagonist proportion-dependent decreases in apparent efficacy of the agonist/antagonist mixtures and downward shifts in mixture dose-effect functions. The present study tested this hypothesis by evaluating behavioral effects of fixed-proportion fentanyl/naltrexone mixtures in a warm-water tail-withdrawal procedure in rhesus monkeys ( = 4). Fentanyl (0.001-0.056 mg/kg) alone, naltrexone (0.032-1.0 mg/kg, i.m.) alone, and fixed-proportion mixtures of fentanyl/naltrexone (1:0.025, 1:0.074, and 1:0.22) were administered in a cumulative-dosing procedure, and the proportions were based on published fentanyl and naltrexone values at MOR in monkey brain. Fentanyl alone produced dose-dependent antinociception at both 50 and 54°C thermal intensities. Up to the largest dose tested, naltrexone alone did not alter nociception. Consistent with receptor theory predictions, naltrexone produced a proportion-dependent decrease in the effectiveness of fentanyl/naltrexone mixtures to produce antinociception. The maximum effects of fentanyl, naltrexone, and each mixture were also used to generate an efficacy-effect scale for antinociception at each temperature, and this scale was evaluated for its utility in quantifying 1) efficacy requirements for antinociception at 50 and 54°C and 2) relative efficacy of six MOR agonists that vary in their efficacies to produce agonist-stimuated GTPS binding in vitro (from lowest to highest efficacy: 17-cyclopropylmethyl-3,14-dihyroxy-4,5-epoxy-6-[(3'-isoquinolyl)acetamindo]morphine, nalbuphine, buprenorphine, oxycodone, morphine, and methadone). These results suggest that fixed-proportion agonist/antagonist mixtures may offer a useful strategy to manipulate apparent drug efficacy for basic research or therapeutic purposes.

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Fast inhibitory neurotransmission in the brain is mediated by wide range of GABAA receptor (GABAAR) and glycine receptor (GlyR) isoforms, each with different physiological and pharmacological properties. Because multiple isoforms are expressed simultaneously in most neurons, it is difficult to define the properties of individual isoforms under synaptic stimulation conditions in vivo. Although recombinant expression systems permit the expression of individual isoforms in isolation, they require exogenous agonist application which cannot mimic the dynamic neurotransmitter profile characteristic of native synapses. We describe a neuron-HEK293 cell co-culture technique for generating inhibitory synapses incorporating defined combinations of GABAAR or GlyR subunits. Primary neuronal cultures, prepared from embryonic rat cerebral cortex or spinal cord, are used to provide presynaptic GABAergic and glycinergic terminals, respectively. When the cultures are mature, HEK293 cells expressing the subunits of interest plus neuroligin 2A are plated onto the neurons, which rapidly form synapses onto HEK293 cells. Patch clamp electrophysiology is then used to analyze the physiological and pharmacological properties of the inhibitory postsynaptic currents mediated by the recombinant receptors. The method is suitable for investigating the kinetic properties or the effects of drugs on inhibitory postsynaptic currents mediated by defined GABAAR or GlyR isoforms of interest, the effects of hereditary disease mutations on the formation and function of both types of synapses, and synaptogenesis and synaptic clustering mechanisms. The entire cell preparation procedure takes 2–5 weeks.

Mu opioid receptor antagonists have clinical utility and are important research tools. To develop nonpeptide and highly selective mu opioid receptor antagonist, a series of 14-O-heterocyclic-substituted naltrexone derivatives were designed, synthesized, and evaluated. These compounds showed subnanomolar-to-nanomolar binding affinity for the mu opioid receptor. Among them, compound 1 exhibited the highest selectivity for the mu opioid receptor over the delta and kappa receptors. These results implicated an alternative 'address' domain in the extracellular loops of the mu opioid receptor. KeywordsOpioid; Mu opioid receptor; Antagonist; Naltrexone Opioid receptors were generally classified into three subtypes based on the pharmacological, behavioral, and biochemical studies. [1][2][3] Opioid antagonists have played very important roles in the study of opioid receptors. In fact, an agonist is characterized as opioid-receptor-mediated only if its effect is competitively inhibited by an opioid antagonist.4 , 5 It is important to have receptor-selective opioid antagonists as tools to identify the receptor types related to the interaction with opioid agonists.4 -6 The mu opioid receptor (MOR) is the major type that mediates opioid analgesic effects of morphine, although all three opioid receptors can be involved in analgesia. The characterization of the MOR structure-function relationship is essential because it has been found that morphine's analgesic effect, addictive properties, and other major side effects are abolished in MOR knock-out mice.7 , 8 Moreover, it has been demonstrated that the analgesic effects and the adverse side effects (including addiction and abuse liability) of morphine are primarily due to its interaction with the MOR.4 In fact, naltrexone, an opioid antagonist with moderate selectivity for the MOR, has been shown to block relapse and curb drug craving in post-dependent opiate addicts.9 , 10 Recent research results also indicate that MOR antagonists can be used in the treatment of obesity, psychosis and Parkinson's disease.11 Furthermore, highly selective MOR antagonists can be used as probes to characterize the MOR-binding pocket. Yet the lack of a non-peptidyl, highly selective, and potent MOR antagonist limits our understanding of the structure-function relationship of the MOR, the interaction of non-peptidyl MOR agonists with the receptor, and more specifically, the activation mechanism of the receptor related to its role in drug abuse and addiction.Schwyzer et al. proposed the 'message-address' concept in his analysis of the structure-activity relationship of ACTH, adrenocorticotropic hormone, and related hormones.12 By applying the 'message-address' concept, highly selective non-peptide antagonists for the kappa opioid receptor (KOR) (e.g., norbinaltorphimine (norBNI) and 5′-guanidinonaltrindole (GNTI)),13 , 14 and for the delta opioid receptor (DOR) (e.g., naltrindole (NTI))15 were designed and synthesized several years ago (Fig. 1). Thus far no potent and highly selective antagon...

Glycine receptors (GlyRs) containing the α2 subunit regulate cortical interneuron migration. Disruption of the GlyR α2 subunit gene (Glra2) in mice leads to disrupted dorsal cortical progenitor homeostasis, leading to a depletion of projection neurons and moderate microcephaly in newborn mice. In humans, rare variants in GLRA2, which is located on the X chromosome, are associated with autism spectrum disorder (ASD) in the hemizygous state in males. These include a microdeletion (GLRA2∆ex8-9) and missense mutations in GLRA2 (p.N109S and p.R126Q) that impair cell-surface expression of GlyR α2, and either abolish or markedly reduce sensitivity to glycine. We report the functional characterization of a third missense variant in GLRA2 (p.R323L), associated with autism, macrocephaly, epilepsy and hypothyroidism in a female proband. Using heterosynapse and macroscopic current recording techniques, we reveal that GlyR α2R323L exhibits reduced glycine sensitivity, but significantly increased inhibitory postsynaptic current (IPSC) rise and decay times. Site-directed mutagenesis revealed that the nature of the amino acid switch at position 323 is critical for impairment of GlyR function. Single-channel recordings revealed that the conductance of α2R323Lβ channels was higher than α2β channels. Longer mean opening durations induced by p.R323L may be due to a change in the gating pathway that enhances the stability of the GlyR open state. The slower synaptic decay times, longer duration active periods and increase in conductance demonstrates that the GlyR α2 p.R323L mutation results in an overall gain of function, and that GlyR α2 mutations can be pathogenic in the heterozygous state in females.

Background: Several recent studies have reported the reliable prognostic effect of hematological biomarkers in various tumors. Yet, the prognostic value of these hematological markers in soft tissue sarcoma (STS) remains inconclusive. Thus, the aim of this meta-analysis was to check the effect of hematological markers on the prognosis of STS. Methods: We systematically searched for relevant papers published before October 2019 in the PubMed and EMBASE databases. Overall survival (OS) and disease-specific survival (DSS) were the primary outcome, whereas disease-free survival was the secondary outcome. A thorough study of hazard ratios (HR) and 95% of confidence intervals (CIs) was done for determining the prognostic significance. Results: We performed 23 studies that comprised of 4,480 patients with STS. The results revealed that higher neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), and platelet-to-lymphocyte ratio (PLR) were associated with poor OS/DFS (HR = 2.08/1.72, for NLR; HR = 1.92/1.75, for CRP, and HR = 1.86/1.61, for PLR). In contrast, a low lymphocyte-to-monocyte ratio (LMR) was relate to worse OS/DFS (HR = 2.01/1.90, for LMR). Moreover, pooled analysis illustrated that elevated NLR and CRP represents poor DSS, with HRs of 1.46 and 2.06, respectively. In addition, combined analysis revealed that higher Glasgow prognostic score (GPS) was linked to an adverse OS/DSS (HR = 2.35/2.77). Conclusion: Our meta-analysis suggested that hematological markers (NLR, CRP, PLR, LMR, and GPS) are one of the important prognostic indicators for patients affected by high-grade STS and patients with the STS being located in the extremity.