Bioequivalence and Safety of Levetiracetam Granules and Oral Solution: A Randomized, Single-Dose, 2-Period Crossover Study in Healthy Chinese Volunteers Under a Fasting Condition.

The bioequivalence and safety of levetiracetam granules (test formulation) and oral solution (reference formulation) were evaluated in Chinese healthy volunteers under a fasting condition. A total of 24 subjects randomly received the test or reference formulation at the rate of 1:1. The alternative formulation was administered after a 7-day washout period. The blood samples were collected at designated time points. Liquid chromatography-tandem mass spectrometry was applied to determine the plasma concentrations of levetiracetam. Adverse events were monitored and recorded. The 90% CIs for the geometric mean ratios of maximum plasma concentration, area under the plasma concentration-time curve from time 0 to the last quantifiable concentration, and area under the plasma concentration-time curve from time 0 to infinity between test preparation and reference preparation were 95.5% to 110.7%, 100.2% to 105.3%, and 100.3% to 105.7%, respectively, all within an acceptable bioequivalence range of 80.00% 125.00%. Both test and reference preparations were well tolerated. The trial confirmed that a single dose of 500-mg levetiracetam granules was bioequivalent to oral solution under a fasting condition, and may serve as a new dosage form of levetiracetam for clinical practice.

Applying machine learning methods to develop a successful aging maintenance prediction model based on physical fitness tests.

AIM: The purpose of this study was to develop a machine learning prediction model for successful aging (SA) based on physical fitness tests. METHODS: A total of 3657 community-dwelling adults aged ≥60 years from Nanchang city were recruited in this study. A 3-year follow-up test was carried out for all the participants to determine whether they turn to non-SA. Developed questionnaires and physical fitness tests were used to obtain overall health condition, balance, agility, speed, reactions and gait. Four machine learning models (logistic regression, deep learning, random forest and gradient boosting decision tree) were applied to develop the prediction models, the analyzed sample was 890. RESULTS: The baseline prevalence of successful aging was 26.99%, The average annual incidence rate of SA to non-SA was 11.04%. There were significant differences between the SA and non-SA groups for all physical fitness tests at baseline. The accuracy and area under the curve of all four machine learning models was >85%, the positive predictive value and sensitivity was >75%, and the specificity was >86% on the average. The deep learning model outperformed the other model, with area under the curve 90.00%, accuracy 89.3%, positive predictive value 85.8% and specificity 93.1%, respectively. Compared with other models, the logistic regression model performed best in sensitivity. Age, arm curl, 30-s sit-to-stand and reaction time were important predictors in all models. CONCLUSION: The deep learning model is ideal in the prediction of SA maintenance, and the corresponding physical fitness interventions are essential to ensuring SA. Geriatr Gerontol Int 2020; ••: ••-••.

Reference value for the TUGT in healthy older people: A systematic review and meta-analysis.

The timed up and go test (TUGT) was recently proposed as a strong predictor of adverse outcomes. Few reviews have been conducted to identify a standard for the TUGT in healthy older people, and the aims of this study were to explore the source of heterogeneity and evaluate the range of reference values for the TUGT in healthy people over 60 years old stratified by age and sex. The VIP, EMBASE, Web of Science and PubMed databases were searched from January 1, 2000, to December 31, 2018. A subgroup analysis and meta-regression were used to assess heterogeneity. Thirty-four eligible studies were included. The mean TUGT results for the total population, males and females in the sample were 9.21 s [95% CI (9.11, 9.31)], 9.33 s [95% CI (7.82, 11.08)] and 8.87 s [95% CI (8.40, 9.38)], respectively. The mean TUGT results for older people in their 60 s, 70 s, and 80 s were 7.91 s [95% CI (6.62, 9.20)], 8.67 s [95% CI (7.23, 10.12)] and 11.68 s [95% CI (8.11, 15.26)], respectively. The meta-regression analysis results showed that the heterogeneity was related to age (P < 0.01). Age affects the results of the TUGT, and it is necessary to take age into consideration when conducting stratified physical evaluations for the evaluation of older people individuals' physical fitness.

Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy.

VEGF/VEGFR signal axis has been proven to be an important target for development of novel cancer therapies. One challenging aspect in small molecular VEGFR inhibitors is to achieve sustained target inhibition at tolerable doses previously seen only with the long-acting biologics. It would require high potency (low effective drug concentrations) and sufficient drug exposures at tolerated doses so that the drug concentration can be maintained above effective drug concentration for target inhibition within the dosing period. Fruquintinib (HMPL-013) is a small molecule inhibitor with strong potency and high selectivity against VEGFR family currently in Phase II clinical studies. Analysis of Phase I pharmacokinetic data revealed that at the maximum tolerated dose of once daily oral administration fruquintinib achieved complete VEGFR2 suppression (drug concentrations were maintained above that required to produce >85% inhibition of VEGFR2 phosphorylation in mouse) for 24 hours/day. In this article, the preclinical data for fruquintinib will be described, including kinase enzyme activity and selectivity, cellular VEGFR inhibition and VEGFR-driven functional activity, in vivo VEGFR phosphorylation inhibition in the lung tissue in mouse and tumor growth inhibition in a panel of tumor xenograft and patient derive xenograft models in mouse. Pharmacokinetic and target inhibition data are also presented to provide a correlation between target inhibition and tumor growth inhibition.

Alteration of airway responsiveness mediated by receptors in ovalbumin-induced asthmatic E3 rats.

AIM: Airway hyperresponsiveness is a constant feature of asthma. The aim of the present study was to investigate airway hyperreactivity mediated by contractile and dilative receptors in an ovalbumin (OVA)-induced model of rat asthma. METHODS: Asthmatic E3 rats were prepared by intraperitoneal injection with OVA/aluminum hydroxide and then challenged with intranasal instillation of OVA-PBS two weeks later. The myograph method was used to measure the responses of constriction and dilatation in the trachea, main bronchi and lobar bronchi. RESULTS: In asthmatic E3 rats, beta(2) adrenoceptor-mediated relaxation of airway smooth muscle pre-contracted with 5-HT was inhibited, and there were no obvious difference in relaxation compared with normal E3 rats. Contraction of lobar bronchi mediated by 5-HT and sarafotoxin 6c was more potent than in the trachea or main bronchi. Airway contractions mediated by the endothelin (ET)(A) receptor, ET(B) receptor and M(3) muscarinic receptor were augmented, and the augmented contraction was most obvious in lobar bronchi. The order of efficacy of contraction for lobar bronchi induced by agonists was ET-1, sarafotoxin 6c>ACh>5-HT. OX8 (an antibody against CD8(+) T cells) strongly shifted and OX35 (an antibody against CD4(+) T cells) modestly shifted isoprenaline-induced concentration-relaxation curves in a nonparallel fashion to the left with an increased R(max) in asthmatic rats and sarafotoxin 6c-induced concentration-contractile curves to the right with a decreased E(max). CONCLUSION: The inhibition of airway relaxation and the augmentation of contraction mediated by receptors contribute to airway hyperresponsiveness and involve CD8(+) and CD4(+) T cells.Acta Pharmacologica Sinica (2009) 30: 965-972; doi: 10.1038/aps.2009.61.