Method development and validation of sildenafil, N-desmethylsildenafil and N1,N4-desmethylsildenafil by LC-MS/MS and its application.

This study aimed to develop an LC-MS/MS method for determining sildenafil and its metabolites N-desmethylsildenafil and N1,N4-desmethylsildenafil in human plasma and applying it to a pharmacokinetic study of sildenafil in healthy volunteers. Sildenafil-d8 was used as the internal standard. Plasma samples were pretreated via protein precipitation with acetonitrile. The extractives were then separated on an ACQUITY UPLC BEH C18 (50-mm × 2.1-mm, 1.7-µm) column using gradient elution. The aqueous and organic mobile phases were ammonium formate 2 mM supplemented with 0.1% formic acid in water and acetonitrile, respectively, and the flow rate was 0.3 mL/min. An electrospray ionization source was applied, and multiple reaction monitoring was operated in the positive mode with selective channels at m/z 475.30 â†’ 100.10, 461.20 â†’ 283.30, 483.30 â†’ 108.10, and 449.00 â†’ 283.00 for sildenafil, sildenafil-d8, N-desmethylsildenafil, and N1,N4-desmethylsildenafil, respectively. The linear calibration curves of sildenafil and its metabolites spanned 1.0-1000 ng/mL. The lower limit of quantification was 1.0 ng/mL. The extractive recovery of analytes from the biological matrix was more than 90% and the matrix effect complied with relevant provisions. The intra- and inter-day precisions of sildenafil and its metabolite were <10%. The intra- and inter-day accuracy of sildenafil, N-desmethylsildenafil, and N1,N4-desmethylsildenafil was more than 99%. The method is highly sensitive and selective, and it was successfully applied to the bioequivalence studies of 100-mg sildenafil citrate tablets in 40 healthy Chinese volunteers.

Vaccinated or not? Survey on attitude toward 'approach-avoidance conflict' under uncertainty.

Vaccinated or not? This is an attitude survey for 'approach-avoidance conflict' under uncertainty. Therefore, measuring people's attitude toward COVID-19 vaccination is relatively distinctive from an attitude over a general conflict. An online survey of 3123 respondents from 30 provincial-level regions - out of 31 - on the Chinese mainland was conducted from January 22 to 27, 2021 to measure their willingness to be vaccinated. We found that over half of the respondents chose the options 'not to be vaccinated now' and 'wait and see before making a vaccination decision,' thereby indicating that people's willingness to be vaccinated is not as optimistic as anticipated in the early stage of vaccination in China. Hence, investigators should carefully select the measuring method to assess the 'true' levels of willingness to accept COVID-19 vaccines. Lastly, the relevant departments should fully predict obstacles to achieve immunity coverage and prepare for the 'vaccine hesitancy' of people in need.

Pharmacokinetics of Flunarizine Hydrochloride After Single Oral Doses in Healthy Subjects: Bioequivalence Study and Food Effects.

We designed a study to compare the newly developed 5-mg flunarizine hydrochloride capsules (test) to that of its marketed counterpart (5-mg; reference) among healthy adult Chinese volunteers. We performed an open-label, single-center study that consisted of 2 randomized, crossover trials, including a fasting trial and a fed trial. In each part of the study, the subjects were randomly assigned to either receive the test or reference products (5-mg flunarizine) in a 1:1 ratio. Subjects then received the alternative products, following a 14-day washout period. Concentrations of plasma flunarizine were analyzed using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters (noncompartmental model) were evaluated using the WinNonlin software. The analysis of variance and Food and Drug Administration bioequivalence statistical criterion of 90% confidence interval for 80% to 125% range (set at P ≤ .05) of geometric means ratios of test: reference product for peak plasma concentration, area under the plasma concentration-time curve (AUC) from time 0 to time t, and AUC from time 0 to infinity were determined. Tolerability was evaluated during the entire study period. Overall, 23 volunteers completed the fasting study, while 40 volunteers completed the fed study. The test formulation was found to be bioequivalent to the marketed formulation, as the 90% confidence interval for the ratio of geometric means of peak plasma concentration (fasting: 87.61%-101.67%; fed: 87.38%-104.06%), AUC from time 0 to time t (fasting: 89.44%-99.92%; fed: 92.65%-98.28%), and AUC from time 0 to infinity (fasting: 95.02%-104.33%; fed: 90.41%-96.96%) were within equivalence limits (80-125%) under both the fasting and fed conditions. When flunarizine was given alongside high-fat meals, time to maximum concentration was delayed ≈3.5 hours compared to fasting conditions. Meantime, high-fat meals increased its exposure by nearly 50%. Furthermore, there were no serious adverse events found among the subjects. This study confirmed that test and reference flunarizine hydrochloride capsules were bioequivalent under fasting and postprandial conditions.

Comparison of Kinematic Alignment and Mechanical Alignment in Total Knee Arthroplasty: A Meta-analysis of Randomized Controlled Clinical Trials.

The aim of this study was to estimate whether kinematic alignment (KA) improves knee function or clinical outcomes compared with mechanical alignment (MA) in the short term after total knee arthroplasty (TKA). We searched the literature for randomized controlled trials published before January 2020 from PubMed, EMBASE, Google, Web of Science, Cochrane Library, and other databases. The observation markers included "The Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index," "Knee Society Score (KSS)," "Oxford Knee Score (OKS)," "combined Knee Society Score (KSS)," "Knee injury and Osteoarthritis Outcome Score (KOOS)," "European Quality of Life Measure-5 Domain-5-Level (EQ-5D-5L)," range of motion (ROM), lower limb alignment, ligament release, and complications. A total of 11 randomized controlled trial studies were included in the study. During the follow-up of 6-24 months, the KA-TKA group was superior to the MA-TKA group in terms of WOMAC scores, combined KSS, KSS, knee function scores, and knee range of flexion, but there was no significant difference in EQ-5D-5L, KOOS, KOOS (symptoms, pain, ADL, sports, and quality of life), complications, knee range of extension, hip-knee-ankle (HKA) angle, tibial component slope angle, lateral distal femoral angle (LDFA) or medial proximal tibial angle (MPTA) angle between the MA-TKA group and the MA-TKA group (P > 0.05). Our meta-analysis revealed that the incidence of ligament release in the MA-TKA group was higher than that in the KA-TKA group. This meta-analysis shows that the KA-TKA group had better clinical outcomes and knee range of flexion than the MA-TKA group at short-term follow-up.