Analgecine regulates microglia polarization in ischemic stroke by inhibiting NF-κB through the TLR4 MyD88 pathway.

Therapeutic strategies used to attenuate inflammation and to increase recovery of neurons after a stroke include microglia anti-inflammatory (M2) polarization and repression of proinflammatory (M1). Extracts isolated from Vaccina variola-inoculated rabbit skin, for example analgecine (AGC), have been used as a therapy for patients experiencing lower back pain associated with degenerative diseases of the spine for about twenty years. In the study presented here, neuroprotective effect associated with AGC was analyzed as well as the anti-inflammatory mechanism linked to AGC in terms of attenuating microglia-mediated neuronal damage. Rats were intravenously injected with AGC after middle cerebral artery occlusion (MCAO), which showed to suppress neuronal loss and reduce neurological deficits. In addition, AGC inhibited pro-inflammatory cytokine release and increased anti-inflammatory cytokines. Furthermore, this study revealed that treatment with AGC supported microglia transition from M1 to M2 in both oxygen-glucose deprivation/reperfusion (OGD/R) and LPS/IFN-γ induced microglia cells, as well as indirectly inhibited LPS/IFN-γ-induced neuronal damage through the modulation of microglial polarization. It is also important to note that AGC inhibited NF-κB p65 phosphorylation through repressing TLR4/Myd88/TRAF6 signaling pathway. In addition, we found that TLR4 inhibition by AGC depended on Myd88. Altogether, this work supports that AGC inhibits M1 microglial polarization and promotes anti-inflammation independently and dependently on TLR4/MyD88. Since it is shown to have neuroprotective effects in this study, AGC has great potential to be used in the clinic to reduce inflammation and aid in recovery after stroke.

Pharmacokinetics and Bioequivalence of Clopidogrel Hydrogen Sulfate Tablets in Fed and Fasted Conditions: An Open-Label, Randomized, Semireplicated Crossover Study in Healthy Chinese Volunteers.

Clopidogrel is an antiplatelet drug with high intraindividual variability in systemic exposure and efficacy. It has been used for treating atherosclerosis and acute coronary syndrome and in preventing stent restenosis and thrombotic complications after stent implantation in clinical practice for nearly 20 years. In this study we aimed to evaluate the bioequivalence of 2 clopidogrel hydrogen sulfate formulations (75-mg tablets) under fed (n = 66) and fasted (n = 66) conditions by using the reference-scaled average bioequivalence method. An open-label, randomized, 3-sequence and 3-period crossover (3×3), semireplicated study was designed and conducted. Clopidogrel concentration of plasma samples was measured by high-precision liquid chromatography and tandem mass spectrometry. The pharmacokinetic parameters were derived by a noncompartmental model. In the fed condition the geometric least-squares mean ratios of peak concentration (Cmax ) and area under the concentration-time curve (AUC0-t ) were, respectively, 103.38% and 98.97%, and the corresponding 90%CIs were 95.68% to 111.70% and 94.67% to 103.47%. In the fasted condition the geometric least squares mean ratios of Cmax and AUC0-t were, respectively, 106.53% and 105.77%, and the corresponding 90%CIs were 97.62% to 116.25% and 96.96% to 115.38%. According to the criteria for bioequivalence (80.00% to 125.00%), the test formulations of clopidogrel and Plavix were determined to be bioequivalent.

A Two-Sequence, Four-Period, Crossover, Replicate Study to Demonstrate Bioequivalence of Warfarin Sodium Tablet in Healthy Chinese Subjects Under Fasting and Fed Conditions.

Warfarin is a narrow therapeutic index anticoagulant drug, and several generic formulations have been approved worldwide. However, there has been no report evaluating the bioequivalence of warfarin sodium according to US Food and Drug Administration draft guidance. We designed a 2-sequence and 4-period crossover study to compare the pharmacokinetic profile and assess bioequivalence between the test warfarin sodium tablet and reference product Coumadin (2.5 mg) in 56 healthy Chinese subjects under fasting and fed conditions. The plasma concentration of warfarin was analyzed by a validated liquid chromatography-tandem mass spectrometry assay, and the reference-scaled procedure was used to determine bioequivalence for the pharmacokinetics parameters. The results showed that the point estimate of geometric mean ratios of Cmax and AUC0-t for warfarin were 103.21% and 99.31%, respectively, in the fasting condition and 100.62% and 98.98%, respectively, in the fed condition, and the 90% confidence intervals were all within the range of 90.00%-111.11%. The upper limit of the 90% confidence interval of estimated within-subject variation ratios of the test and reference products was 1.33 for Cmax and 2.22 for AUC0-t under the fasting condition and 1.68 for Cmax and 2.15 for AUC0-t under the fed condition. Overall, bioequivalence of the 2 warfarin sodium products was demonstrated.

Pharmacokinetics and bioequivalence of generic and branded abiraterone acetate tablet: a single-dose, open-label, and replicate designed study in healthy Chinese male volunteers.

PURPOSE: Abiraterone acetate is a highly variable drug and has been approved for the treatment of patients with metastatic castration-resistant prostate cancer in many countries. This study was conducted to compare the pharmacokinetic profile between the test product (abiraterone acetate tablet) and reference product ZYTIGA® (250 mg) mainly. METHODS: To overcome the high intra-subject variability of abiraterone, a two-sequence and four-period crossover study was designed to assess bioequivalence between the two products in 32 healthy male Chinese subjects under fasting conditions. The plasma concentration of abiraterone was analyzed by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) assay and the reference-scaled procedure was used to determine bioequivalence for the pharmacokinetics parameters. RESULTS: The point estimate of geometric mean ratios with 90% confidence interval (CI) of maximum observed concentration (Cmax) and the area under the concentration-time curve (AUC0t) for abiraterone in the test and reference products were 100.19% (90% CI 87.05-115.32%) and 105.99% (90% CI 96.34-116.62%), respectively, and were both within the range of 80.00-125.00%. The 95% confidence upper limit bound for [Formula: see text] was - 0.1079 for Cmax and was - 0.0515 for AUC0t. CONCLUSIONS: Bioequivalence was demonstrated between the two abiraterone acetate products. The study also confirmed high intra-subject variability, for abiraterone: coefficient of variation (CV, %) of Cmax values for the test and reference products were 40.33% and 46.58%, while for AUC0t were 24.02% and 34.16%, respectively. TRIAL REGISTRATION: http://www.chinadrugtrials.org.cn/ : CTR20170997.