IntroductionHydroxychloroquine (HCQ), 4-aminoquinoline, is an antimalarial drug and has become a basic therapy for rheumatic disease treatment. It can stabilize the condition of SLE patients and reduce the chances of patient relapse through its immunosuppressive function and antiinflammatory effects. This drug was absorbed completely and rapidly by oral administration, but has a prolonged half-life for elimination. The objective of this study was to evaluate the pharmacokinetic parameters and relative bioequivalence of a new generic (test) formulation with the branded (reference) formulation of HCQ in healthy Chinese male volunteers. This study was designed to acquire regulatory approval for the test formulation.MethodsThis study was conducted with a randomized, single-dose, two-period, and crossover design. The male subjects were randomly assigned to two groups at a 1:1 ratio to receive 0.2 g hydroxychloroquine sulfate tablets (0.1 g/piece) of the two formulations after a 3-month washout period then administered the alternate formulation. Study drugs were administered after overnight fasting (over 10 h). Plasma concentrations of hydroxychloroquine were measured by a validated LC-MS/MS method. The following pharmacokinetic properties were determined by a noncompartmental pharmacokinetic method: Cmax, Tmax, AUC0–t, AUC0–∝, and t1/2. The bioequivalence between the test and reference products was assessed based on the following parameters: Cmax, AUC0–60d, and AUC0–∝ using the ANOVA method. If the 90% CI for AUC0–t was within 80–125% and for Cmax was within 70–143% of the statistical interval proposed by the SFDA, the two formulations were assumed bioequivalent. Concerning the main pharmacokinetic charateristics of hydroxychloroquine, a long half-life drug, the pharmacokinetic parameters of 0–72 h were determined according to the FDA. Furthermore, a comparison was made between the parameters at 0–60 days and 0–72 h to evaluate whether a truncated AUC method can be applied to estimate the relative bioavailability of HCQ. Tolerability was assessed by monitoring vital signs and laboratory tests and by questioning subjects about adverse events.ResultsThe 90% CI of Cmax for HCQ is 103.8–142.3%; the AUC0–60 is 100–114.2% and AUC0–∝ 100–115.5%. Both met the criteria according to the SFDA’s guidelines for bioequivalence. The relative bioavailability was 109.5% (according to AUC0–60d) and 110.7% (according to AUC0–∝). No serious or unexpected adverse events were observed.ConclusionsIn this study, the pharmacokinetic studies and results were conducted so that the test and reference formulations of HCQ met the Chinese criteria for assuming bioequivalence. Both formulations were well tolerated in the population studies.

No abstract

No abstract

The present study examines the hypothesis that endogenous neural progenitor cells isolated from the neocortex of ischemic brain can differentiate into neurons or glial cells and contribute to neural regeneration. We performed middle cerebral artery occlusion to establish a model of cerebral ischemia/reperfusion injury in adult rats. Immunohistochemical staining of the cortex 1, 3, 7, 14 or 28 days after injury revealed that neural progenitor cells double-positive for nestin and sox-2 appeared in the injured cortex 1 and 3 days post-injury, and were also positive for glial fibrillary acidic protein. New neurons were labeled using bromodeoxyuridine and different stages of maturity were identified using doublecortin, microtubule-associated protein 2 and neuronal nuclei antigen immunohistochemistry. Immature new neurons coexpressing doublecortin and bromodeoxyuridine were observed in the cortex at 3 and 7 days post-injury, and semi-mature and mature new neurons double-positive for microtubule-associated protein 2 and bromodeoxyuridine were found at 14 days post-injury. A few mature new neurons coexpressing neuronal nuclei antigen and bromodeoxyuridine were observed in the injured cortex 28 days post-injury. Glial fibrillary acidic protein/bromodeoxyuridine double-positive astrocytes were also found in the injured cortex. Our findings suggest that neural progenitor cells are present in the damaged cortex of adult rats with cerebral ischemic brain injury, and that they differentiate into astrocytes and immature neurons, but most neurons fail to reach the mature stage.

Background and PurposeAbout 20.1% of intracranial aneurysms (IAs) carriers are multiple intracranial aneurysms (MIAs) patients with higher rupture risk and worse prognosis. A prediction model may bring some potential benefits. This study attempted to develop and externally validate a dynamic nomogram to assess the rupture risk of each IA among patients with MIA.MethodWe retrospectively analyzed the data of 262 patients with 611 IAs admitted to the Hunan Provincial People's Hospital between November 2015 and November 2021. Multivariable logistic regression (MLR) was applied to select the risk factors and derive a nomogram model for the assessment of IA rupture risk in MIA patients. To externally validate the nomogram, data of 35 patients with 78 IAs were collected from another independent center between December 2009 and May 2021. The performance of the nomogram was assessed in terms of discrimination, calibration, and clinical utility.ResultSize, location, irregular shape, diabetes history, and neck width were independently associated with IA rupture. The nomogram showed a good discriminative ability for ruptured and unruptured IAs in the derivation cohort (AUC = 0.81; 95% CI, 0.774–0.847) and was successfully generalized in the external validation cohort (AUC = 0.744; 95% CI, 0.627–0.862). The nomogram was calibrated well, and the decision curve analysis showed that it would generate more net benefit in identifying IA rupture than the “treat all” or “treat none” strategies at the threshold probabilities ranging from 10 to 60% both in the derivation and external validation set. The web-based dynamic nomogram calculator was accessible on https://wfs666.shinyapps.io/onlinecalculator/.ConclusionExternal validation has shown that the model was the potential to assist clinical identification of dangerous aneurysms after longitudinal data evaluation. Size, neck width, and location are the primary risk factors for ruptured IAs.