AIMS:Fazamorexant is a dual orexin receptor antagonist being developed for the treatment of insomnia. This study aims to determine the dose-exposure-response relationship of single-dose fazamorexant vs. zolpidem in young adult and elderly healthy Chinese volunteers. METHODS:This single-centre, randomized, double-blind, double-dummy, placebo- and active-controlled, 4-period crossover study administered fazamorexant (40 mg/80 mg to young adults; 20 mg/40 mg to the elderly) and zolpidem (10 mg). Pharmacokinetics, pharmacodynamics (primary endpoint: SPV) and safety were assessed. RESULTS:Following a single 40 mg oral dose of fazamorexant in elderly and young adults, the geometric least‑squares mean (GLSM) values for Cmax were 1527.05 ng/mL (95% CI: 1268.66-1838.06) in the elderly and 1652.52 ng/mL (95% CI: 1420.41-1922.56) in young adults. The corresponding GLSM AUC0-t values were 7815.91 h·ng/mL (95% CI: 5985.56-10205.97) and 8351.15 h·ng/mL (95% CI: 6716.38-10383.84), respectively. There was no significant pharmacokinetic difference between young adults and the elderly with fazamorexant (Cmax GMR 92.41% [90% CI: 75.84-112.59]; AUC0-t GMR 93.59% [90% CI: 70.43-124.37]). In general, high-dose fazamorexant caused similar or less impairment vs. zolpidem in eye movements (SPV: young adults: 110.4 ± 80.1 vs. 108.3 ± 82.7 deg/sec；elderly: 145.1 ± 64.2 vs. 185.5 ± 63.0 deg/sec), choice-reaction-time performance, body sway and memory tests in young and elderly cohorts. The effects of low-dose fazamorexant on these psychomotor and cognitive measurements were significantly smaller than those of high-dose fazamorexant and zolpidem in both age cohorts. Despite of similarity in exposure, fazamorexant demonstrated larger effects on the pharmacodynamic measurements in the elderly than in young adults, suggesting an age-related increase of pharmacological sensitivity. CONCLUSIONS:Clinically hypnotic doses of fazamorexant induced less balance, judgement and memory impairment in healthy adults and elderly volunteers compared to the comprehensive suppression of zolpidem on the neurological system. These preliminary results suggest that fazamorexant is a potentially safer drug for insomnia. No age-related pharmacokinetic difference was identified with fazamorexant.

BACKGROUND AND AIMS:Previous studies found elevated platelet count (PLT), especially long-term persist high or increased PLT was associated with less likelihood disability-free survival (DFS). However, whether grip strength affects the relationship between them is still not elucidated.METHODS:A total of 6252 participants were recruited in the analysis based on the China Health and Retirement Longitudinal Study. The primary outcome was DFS, evaluated by a composite endpoint based on the first occurrence of either disability (having difficulty in at least one of the 6 activities of daily living: namely, dressing, bathing, continence, eating, getting into or out of bed, and toileting) or all-cause mortality.RESULTS:The association of PLT with primary outcome was significantly modified by grip strength (pinteraction = 0.022). The rates of primary outcome were significantly lower among participants with lower baseline PLT in participants with normal grip strength (multivariable odds ratio [OR], 0.67; 95% confidence interval [CI], 0.54-0.84; ptrend < 0.001), but not in those with low grip strength (multivariable OR, 1.70; 95% CI, 0.88-3.15; ptrend = 0.135), for the lowest quartile vs the highest quartile. Adding baseline PLT (quartiles or continuous) to a model containing conventional risk factors significantly improved risk reclassification for primary outcome among those with normal grip strength (most of p < 0.05).CONCLUSION:An inverse dose-response association of PLT with DFS was found among participants with normal grip strength, but not among those with low grip strength. Low grip strength might weaken the benefit of low PLT on DFS among middle-aged and older Chinese.

EDITORIAL article Front. Neurosci., 23 May 2023Sec. Neuropharmacology Volume 17 - 2023 | https://doi.org/10.3389/fnins.2023.1198291

Objective: To identify factors related to poor prognosis in patients with cerebral infarction (CI) and to construct and validate a personalized prediction model based on these factors.Methods: A retrospective analysis was conducted on the clinical and follow-up data of 857 patients with CI who were diagnosed in the neurology department of a tertiary A hospital in Anhui Province, China from April 2020 to March 2022. Based on follow-up data and the Modified Rankin Scale (mRS) score one year after discharge, patients were divided into a good prognosis group (793 cases, mRS <= 2) and a poor prognosis group (64 cases, mRS >2). Multivariate logistic regression analysis was used to identify independent risk factors, which were then used to establish a nomogram model. The predictive performance of the model was evaluated using the area under the receiver operating characteristic curve (ROC, AUC), and the calibration curve was used to evaluate the calibration of the nomogram.Results: There was a statistically significant difference in the distribution of eight variables between the groups, including post-discharge use of biguanide hypoglycemic drugs, insulin, systolic blood pressure, exercise status, alcohol consumption, smoking status, age, and gender (P < 0.05). Multivariate logistic regression analysis suggested that gender, smoking after discharge, alcohol consumption, lack of exercise, and oral administration of biguanide hypoglycemic drugs are independent risk factors for poor prognosis in patients with CI (P < 0.05). The personalized poor prognosis nomogram constructed based on these five predictive factors showed good discriminative ability and predictive stability, with AUCs of 0.768 (95 % CI: 0.712-0.825) and 0.775 (95 % CI: 0.725-0.836) before and after internal validation, respectively. The calibration curve confirmed the accuracy and consistency of the nomogram (P = 0.956).Conclusion: Female gender, smoking, alcohol consumption, lack of exercise, and post-discharge use of biguanide hypoglycemic drugs are independent risk factors for poor prognosis in patients with CI. The constructed nomogram shows good predictive efficiency for post-discharge prognosis and can help in clinical decision-making.

We report the findings of a single-dose, randomized, three-period cross-over, clinical trial in healthy Chinese individuals (n = 24) comparing the pharmacokinetics of insulin degludec/liraglutide (IDegLira) with its individual components. Furthermore, we report a population pharmacokinetic analysis of a 26-week, phase III, treat-to-target, randomized trial of 720 Chinese individuals with type 2 diabetes. Participants were randomized to IDegLira, degludec or liraglutide, all once daily with metformin. The pharmacokinetic profiles of IDegLira were similar to its individual components. Dose proportionality was indicated for both IDegLira components. Although there were no relevant covariate effects on degludec exposure, liraglutide exposure was inversely correlated with bodyweight. In conclusion, for the Chinese population, the pharmacokinetics of the fixed-ratio combination IDegLira is similar to that of its individual components.

This study aimed to develop a deep learning (DL) model to improve the diagnostic performance of EIC and ASPECTS in acute ischemic stroke (AIS). Acute ischemic stroke patients were retrospectively enrolled from 5 hospitals. We proposed a deep learning model to simultaneously segment the infarct and estimate ASPECTS automatically using baseline CT. The model performance of segmentation and ASPECTS scoring was evaluated using dice similarity coefficient (DSC) and ROC, respectively. Four raters participated in the multi-reader and multicenter (MRMC) experiment to fulfill the region-based ASPECTS reading under the assistance of the model or not. At last, sensitivity, specificity, interpretation time and interrater agreement were used to evaluate the raters’ reading performance. In total, 1391 patients were enrolled for model development and 85 patients for external validation with onset to CT scanning time of 176.4 ± 93.6 min and NIHSS of 5 (IQR 2–10). The model achieved a DSC of 0.600 and 0.762 and an AUC of 0.876 (CI 0.846–0.907) and 0.729 (CI 0.679–0.779), in the internal and external validation set, respectively. The assistance of the DL model improved the raters’ average sensitivities and specificities from 0.254 (CI 0.22–0.26) and 0.896 (CI 0.884–0.907), to 0.333 (CI 0.301–0.345) and 0.915 (CI 0.904–0.926), respectively. The average interpretation time of the raters was reduced from 219.0 to 175.7 s (p = 0.035). Meanwhile, the interrater agreement increased from 0.741 to 0.980. With the assistance of our proposed DL model, radiologists got better performance in the detection of AIS lesions on NCCT.

Calcium-dependent, neuronal adenylyl cyclase subtype 1 (AC1) is critical for cortical potentiation and chronic pain. NB001 is a first-in-class drug acting as a selective inhibitor against AC1. The present study delineated the pharmacokinetic (PK) properties of human-used NB001 (hNB001) formulated as immediate-release tablet. This first-in-human (FIH) study was designed as randomized, double-blind, placebo-controlled trial. hNB001 showed placebo-like safety and good tolerability in healthy volunteers. A linear dose-exposure relationship was demonstrated at doses between 20 mg and 400 mg. The relatively small systemic exposure of hNB001 in human showed low bioavailability of this compound through oral administration, which can be improved through future dosage research. Food intake had minimal impact on the absorption of hNB001 tablet. Animal experiments further confirmed that hNB001 had strong analgesic effect in animal models of neuropathic pain. In brain slice prepared from the anterior cingulate cortex (ACC), bath application of hNB001 blocked the induction of long-term potentiation (LTP). These results from both rodents and human strongly suggest that hNB001 can be safely used for the future treatment of different types of chronic pain in human patients.

Supplemental Digital Content is available in the text. Background and Purpose: Edaravone dexborneol, comprised of 2 active ingredients, edaravone and (+)-borneol, has been developed as a novel neuroprotective agent with synergistic effects of antioxidant and anti-inflammatory in animal models. The present clinical trial aimed at testing the effects of edaravone dexborneol versus edaravone on 90-day functional outcome in patients with acute ischemic stroke (AIS). Methods: A multicenter, randomized, double-blind, comparative, phase III clinical trial was conducted at 48 hospitals in China between May 2015 and December 2016. Inclusion criteria included patients diagnosed as AIS, 35 to 80 years of age, National Institutes of Health Stroke Scale Score between 4 and 24, and within 48 hours of AIS onset. AIS patients were randomized in 1:1 ratio into 2 treatment arms: 14-day infusion of edaravone dexborneol or edaravone injection. The primary end point was the proportion of patients with modified Rankin Scale score ≤1 on day 90 after randomization. Results: One thousand one hundred sixty-five AIS patients were randomly allocated to the edaravone dexborneol group (n=585) or the edaravone group (n=580). The edaravone dexborneol group showed significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization, compared with the edaravone group (modified Rankin Scale score ≤1, 67.18% versus 58.97%; odds ratio, 1.42 [95% CI, 1.12–1.81]; P=0.004). The prespecified subgroup analyses indicated that a greater benefit was observed in female patients than their male counterparts (2.26, 1.49–3.43 versus 1.14, 0.85–1.52). Conclusions: When edaravone dexborneol versus edaravone was administered within 48 hours after AIS, 90-day good functional outcomes favored the edaravone dexborneol group, especially in female patients. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02430350.

Background and Purpose: Edaravone dexborneol, comprised of 2 active ingredients, edaravone and (+)-borneol, has been developed as a novel neuroprotective agent with synergistic effects of antioxidant and anti-inflammatory in animal models. The present clinical trial aimed at testing the effects of edaravone dexborneol versus edaravone on 90-day functional outcome in patients with acute ischemic stroke (AIS). Methods: A multicenter, randomized, double-blind, comparative, phase III clinical trial was conducted at 48 hospitals in China between May 2015 and December 2016. Inclusion criteria included patients diagnosed as AIS, 35 to 80 years of age, National Institutes of Health Stroke Scale Score between 4 and 24, and within 48 hours of AIS onset. AIS patients were randomized in 1:1 ratio into 2 treatment arms: 14-day infusion of edaravone dexborneol or edaravone injection. The primary end point was the proportion of patients with modified Rankin Scale score ≤1 on day 90 after randomization. Results: One thousand one hundred sixty-five AIS patients were randomly allocated to the edaravone dexborneol group (n=585) or the edaravone group (n=580). The edaravone dexborneol group showed significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization, compared with the edaravone group (modified Rankin Scale score ≤1, 67.18% versus 58.97%; odds ratio, 1.42 [95% CI, 1.12–1.81]; P =0.004). The prespecified subgroup analyses indicated that a greater benefit was observed in female patients than their male counterparts (2.26, 1.49–3.43 versus 1.14, 0.85–1.52). Conclusions: When edaravone dexborneol versus edaravone was administered within 48 hours after AIS, 90-day good functional outcomes favored the edaravone dexborneol group, especially in female patients. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02430350.

Purpose: Remimazolam tosylate (HR-7056) is a novel ester-type benzodiazepine with ultrafast onset of effect. The compound is being developed for sedation induction and maintenance during anesthesia. It was approved for procedural anesthesia in December 2019 by the National Medical Products Administration of China. Previous studies have reported on remimazolam's effects on consciousness and cognition. Although the time to full psychomotor recovery after remimazolam-mediated sedation is critical for decisions regarding hospital discharge, relevant clinical evidence is still lacking. This study investigated the residual psychomotor effects of remimazolam and their recovery from sedating treatment in 2 simulated clinical settings: (1) single-dose administration for sedation initiation; and (2) constant rate infusion for sedation maintenance. Methods: A single-ascending-dose, parallel-group, midazolam-controlled study and a 2-way crossover study evaluating the reversal effect of flumazenil versus placebo after a 2-h constant rate infusion were conducted with HR-7056 in 87 Chinese healthy volunteers; the studies used a double-blind, randomized trial design. A battery of psychomotor tests was administered before dosing and several times postdose over 4-6 h. Pharmacokinetic, sedation, and safety assessments were performed throughout the studies. Findings: After bolus infusion, the Bispectral Index score decreased in a concentration-dependent manner with HR-7056, accompanied by a sharp drop of Modified Observer's Assessment of Alertness/Sedation score. The recovery of consciousness was much faster with HR-7056 than with midazolam. During the constant rate infusion, the Bispectral Index score was maintained between 40 and 60 with an average plasma remimazolam concentration of similar to 1000 ng/mL. Subjects' performance in saccadic and smooth pursuit eye movement, body sway, test of choice reaction time, and word recall was significantly impaired after single-dose midazolam and after constant rate infusion of remimazolam. The end-of-infusion injection of flumazenil shortened the median time to full alertness to 3.5 min and effectively reversed psychomotor and cardiovascular dysfunction. (C) 2020 The Authors. Published by Elsevier Inc.

Purpose: Edaravone is a free-radical scavenger with relatively favorable properties of brain penetration. It has been approved for the indications of acute ischemic stroke and amyotrophic lateral sclerosis (ALS). This study aimed to establish a pharmacokinetic (PK) model to fit the PK profile of edaravone after a single sublingual (SL) dose of a novel edaravone tablet and single IV infusion of injectable edaravone in healthy Chinese volunteers participating in a bioavailability study. The model is expected to be useful for predicting the concentration-time profiles of edaravone following different dosing regimens in a healthy Chinese population. The purposes were to identify an optimal dose and dosing regimen for the new SL formulation and to support future clinical exploration of this tablet product in its approved indications and other therapeutic fields being developed. Methods: The PK profiles after a single SL dose or IV infusion of edaravone 30 mg can be well described by a 3-compartment linear disposition model, on which a first-order absorption model with a lag time and a parameter for bioavailability was incorporated to fit the absorption phase of the SL dose. Performance of these PK models was evaluated for goodness of fit, residual trends, visual predictive checks, as well as precision of model predictions against external data. The validated models were employed for simulating the PK profiles of edaravone after a single SL dose of 60 mg and IV infusion of 60 mg for 60 min. Findings: The resultant estimates support the possibility and feasibility of demonstrating bioequivalence between an SL administration of edaravone 60 mg and the currently approved dosing regimen for ALS (ie, 60 mg IV over 60 min) once per day. The calculation of sample size suggested that the requirement for subject number was acceptable considering the general capacity of a Phase I study center, and so were the procedures defined in the protocol. (C) 2020 Elsevier Inc. All rights reserved.

SPT-07A is an intravenous injection of (+)-2-borneol being developed for the treatment of acute ischemic stroke. This study aimed to investigate the pharmacokinetics, pharmacodynamics, safety, tolerability, and mass balance of SPT-07A after sequentially administered single and multiple infusions of SPT-07A at 10 mg, 20 mg, or 40 mg. This phase I, double-blind, randomized, placebo-controlled, dose-escalation study was conducted in 36 Chinese healthy volunteers. Each cohort enrolled 12 eligible subjects, who were 9:3 randomized to receive SPT-07A or matching placebo during the two study occasions, that is, an initial single-dose occasion followed by a 7-day multiple-dose occasion with a dosing interval of 12 h. Pharmacokinetic, pharmacodynamic assessments regarding effects on the central nervous system (CNS) were performed pre-dose and several times post-dose. Safety and tolerability were evaluated throughout the study for each cohort. Following single intravenous (i.v.) administration of 10 mg to 40 mg SPT-07A, the plasma SPT-07A concentration reached its peak by the end of infusion. Thereafter, the plasma concentration declined in a multiphase exponential manner with an average terminal elimination half-life of 3.85 to 8.93 h. The exposure parameters of SPT-07A increased dose proportionally. Steady state of SPT-07A was reached after 12-hourly i.v. administrations for 4 days with minimal accumulations. No significant difference of change-from-baseline was observed in the pharmacodynamic measurements between each of the three SPT-07A-treated groups and the placebo group. A total of 41 adverse events (AEs) were reported in 77.8% subjects at 10 mg (7/9), 20 mg (7/9), and 40 mg (7/9), respectively. The AE incidence in placebo group was also 77.8% (7/9). All AEs were mild or moderate in severity and self-limited. SPT-07A was mainly excreted in human urine in glucuronic acid conjugate forms. The total urine recovery rate approximated 84.69% of the administered dose. SPT-07A was safe and well tolerated after single and multiple intravenous administrations of SPT-07A in the range of 10 mg to 40 mg. SPT-07A presented linear pharmacokinetics in human. Based on plasma exposure, the doses of 10–40 mg twice daily resulted in exposure levels comparable with those obtained at doses demonstrating potential efficacy on AIS animal models and were thus recommended as therapeutic exploratory doses in the phase II clinical trial.

The interchangeability evaluation for generic drugs formulated as intravenous injections normally only requires assessments of pharmaceutical equivalence (PE) when the medicinal products are simple small-molecule drugs. However, intravenously administered non-biological complex drugs (NBCDs), such as liposomes, microsphere suspension, or fat emulsion, have inherent passive disposition selectivity due to their special formulations, thereby the in vivo drug performances are improved. Because of the complexity in formulation, the in vitro pharmaceutical investigations of follow-on NBCDs are more complicated than those required for generic small-molecule drugs. In addition to qualitative and quantitative sameness of the active and inactive ingredients, it is required to comparatively study the static and kinetic microscopic particle-related physiochemical properties of the follow-on NBCDs versus the reference products. Moreover, for complex formulations that have a significant impact on the biodistribution of the drug compound, an in vivo bioequivalence (BE) study is also important. Since NBCDs that demonstrated bioequivalence through the conventional BE approach have been found inequivalent in efficacy or safety to the reference products, pivotal BE studies for follow-on NBCDs are required to take both encapsulated/total drug and free drug as the analytes to address release kinetics and biodistribution of the active pharmacological ingredient in the body. This manuscript reviews the 26 U.S. FDA published product-specific guidelines for intravenous injections. In general, these NBCDs can be stratified into four groups according to their release kinetics and ability of bio-membrane penetration. Group 1 consists of seven small-molecule, non-complex drugs; group 2 included four NBCDs with either microscale particle size or rapid dissolution property; group 3 include five loosely packed NBCDs (fat emulsions) and one quickly released ophthalmic liposomal drug; and the last group contains four cytotoxic liposomal or protein-bound NBCDs and five iron carbohydrate complexes. The requirements of the corresponding guidelines range from simple proof of PE between the test and the reference products, to a collection of studies that demonstrate the key manufacturing process (e.g. liposome loading), the particle- or vehicle-wise static and kinetic physiological characterizations, the dissolution test, and BE evaluation of both total/encapsulated drug form and free drug form between the follow-on NBCDs and their reference products. Such studies are challenging in implementation. Therefore, a variety of alternative approaches are proposed in this article.

A biosimilar is a biological agent highly similar to an approved reference biological drug in terms of efficacy, safety, and purity, that often has a relatively lower price. 1 European Medicines AgencyGuideline on similar biological medicinal products. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-rev1_en.pdfDate: 2015 Date accessed: August 16, 2019 Google Scholar The availability of biosimilars offers health systems a chance to strike a balance between the drive to control costs and the need to improve access—deemed fundamental to achieving the Sustainable Development Goals, in particular target 3.8: achieving universal health coverage. 2 Lyman GH Zon R Harvey RD Rationale, opportunities, and reality of biosimilar medications. N Engl J Med. 2018; 379: 694-695 Crossref PubMed Scopus (12) Google Scholar The remarkable expansion in the development of biosimilars over the last decade has led to a focus on gaining a complete picture of all approved anticancer biosimilars available worldwide, and the disparities in the availability among different countries. Understanding global anticancer biosimilar availability will provide essential data and insight into the possible causes of global health inequality and could support the development of strategies to address it.

目的 探讨高风险心房颤动(以下简称房颤)患者不同临床情况下的抗栓治疗策略.方法 回顾性分析1例房颤性卒中伴髋关节置换患者的诊治情况,并对患者不同病理情况下的抗栓治疗方案进行调整和药学监护.结果 临床药师介入高风险房颤患者诊治,通过药学循证,在患者多个治疗关键节点提供个体化用药建议,并对抗栓治疗患者建档进行规范化管理和随访,监护疗效和不良反应,最终患者病情得到有效控制,全程监护未发生不良反应.结论 临床药师通过对抗栓治疗患者的个体化用药指导和规范化管理,可保障抗栓治疗患者用药的安全性和有效性.

[This corrects the article DOI: 10.3389/fphar.2018.01316.].