Kinetics of anti-SARS-CoV-2 IgG antibody levels and potential influential factors in subjects with COVID-19: A 11-month follow-up study.

We aim to study kinetics of anti-SARS-CoV-2 IgG antibody levels in subjects with COVID-19 for up to 11 months and the potential influential factors. The study was a prospective longitudinal study. The analyses were based on 77 serum/plasma samples with a mean of 4 samples per participant (range 1 - 18) in 20 participants with at least one positive Polymerase Chain Reaction testing result from 19 March 2020 up to 10 February 2021. Among the subjects (median age 34.5 years, 65% male), IgG level declined with the follow-up time (per month; geometric mean ratio [GMR] 0.73; 95% CI, 0.72 - 0.74). In a small sample of subjects from the general population with COVID-19, IgG levels declined non-linearly from month 2 to 11 with individual heterogeneity in quantity and changing speed and may be associated with gender, race and the loss of smell and taste.

Confirmation of the cardiac safety of nolasiban in a randomised cohort of healthy female volunteers.

Nolasiban is an orally active oxytocin receptor antagonist being developed to increase the efficiency of assisted reproductive technologies. This study evaluated the pharmacokinetics, pharmacodynamics, and cardiac safety of nolasiban in 45 healthy women of child-bearing age. Nolasiban was administered in a fasted state with a standardised lunch served 4.5 h post-dose. Concentration-effect modelling was used to assess the effect of two dosages of nolasiban (900 mg and 1800 mg) on QTc following single-dose administration. We found no significant change in QTc at all tested dosages. Two-sided 90% confidence intervals of geometric mean Cmax for estimated QTc effects of nolasiban were below the threshold of regulatory concern. The sensitivity of the assay to detect small changes in QTc was confirmed by a significant shortening of QTc between 2 and 4 h after consumption of a meal, which served to validate the model. Independent of the nolasiban assessment, this study also explored the effects of sex hormones on ECG parameters, especially QT subintervals. We found a significant relationship between JTpc and oestradiol. Heart rate was negatively correlated with progesterone. This study confirms the cardiovascular safety of nolasiban and describes relationships of sex hormones and ECG parameters.

Time- and Race-Specific Haematological Reference Intervals for Healthy Volunteer Trials: A Retrospective Analysis of Pooled Data From Multiple Phase I Trials.

Most UK hospitals, laboratories, and research institutions use uniform reference intervals (RI) that do not take into account known diurnal and racial variation in total white blood cells (WBC) count and its constituent parameters. These risks of excluding potentially suitable ethnic minority volunteers from participating in phase I clinical trials could call into question the validity of a trial's findings or limit its scientific applications and ability to accurately observe drug effects upon WBC parameters. This study pools data from multiple phase I trials, assesses the effects of race and time of day on WBC count, and compares it to the existing literature to establish race and time-specific RIs. A total 13,332 venous blood samples obtained from 7,157 healthy male and female volunteers at the time of screening or admission (predosing) who took part in 35 phase I trials over a period of seven years were pooled and the data were analyzed using generalised estimating equation models. Adjusted RI of total WBC count and its individual parameters were then calculated according to time of day (morning vs. evening) for both black and nonblack populations. This study indicates that black individuals on average had lower total WBC, neutrophil, monocyte, eosinophil, and basophil counts than individuals from nonblack racial groups. Black volunteers had higher mean lymphocyte counts relative to their nonblack counterparts. These differences were deemed statistically significant. Statistically significant increases in total WBC, neutrophil, lymphocyte, and monocyte counts were also observed over the course of daily sampling. Eosinophil counts decreased during this time period, but this finding was only statistically significant in the nonblack population. Despite an observed mild diurnal increase in basophil count in both populations, this was not considered statistically significant. This high-powered study adds significant weight to the known evidence for diurnal and racial variation in WBC parameters. Importantly, it proposes specific RIs that more precisely reflect race and time of day. These could ensure increased participation of black volunteers in clinical trials for improved population representation. Furthermore, the proposed RIs allow for more accurate postdose safety monitoring and reporting, and ensure improved monitoring of postdose WBC count changes.

Effects of the Fluoroquinolones Moxifloxacin and Levofloxacin on the QT Subintervals: Sex Differences in Ventricular Repolarization.

Women are associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. The purpose of this study was to characterize the differences in cardiac electrophysiology between moxifloxacin and levofloxacin in men and women and to assess the balance of inward and outward currents through the analysis of QT subintervals. Data from 2 TQT studies were used to investigate the impact of moxifloxacin (400 mg) and levofloxacin (1000 and 1500 mg) on QT subintervals using algorithms for measurement of J-Tpeak and Tpeak -Tend intervals. Concentration-effect analyses were performed to establish potential relationships between the ECG effects and the concentrations of the 2 fluoroquinolones. Moxifloxacin was shown to be a more potent prolonger of QT interval corrected by Fredericia (QTcF) and had a pronounced effect on J-Tpeak c. Levofloxacin had little effect on J-Tpeak c. For moxifloxacin, the concentration-effect modeling showed a greater effect for women on QTcF and J-Tpeak c, whereas for levofloxacin the inverse was true: women had smaller QTcF and J-Tpeak c effects. The different patterns in repolarization after administration of both drugs suggested a sex difference, which may be related to the combined IKs and IKr inhibitory properties of moxifloxacin versus IKr suppression only of levofloxacin. The equipotent inhibition of IKs and IKr appears to affect women more than men. Sex hormones are known to influence cardiac ion channel expression and differences in QT duration. Differences in IKr and IKs balances, influenced by sex hormones, may explain the results. These results support the impact of sex differences on the cardiac safety assessment of drugs.

The Cardiovascular Effects of a Meal: J-Tpeak and Tpeak -Tend Assessment and Further Insights Into the Physiological Effects.

Meal intake leads to a significant and prolonged increase in cardiac output to supply the splanchnic vasculature. A meal is associated with sympathetic activation of the cardiovascular system, and food ingestion is correlated with an increase in heart rate, an increase in cardiac stroke volume, and QTc interval shortening for up to 7 hours. Given the complexity of the system, one or several of many mechanisms could explain this observation. The shortening of the QTc interval was correlated with a rise of C-peptide following food ingestion, but the mechanisms by which C-peptide may be involved in the modulation of cardiac repolarization are still unknown. This shortening of the myocardial action potential caused by the ingestion of food was further investigated in the present study by measuring the QRS, J-Tpeak , and Tpeak -Tend intervals in search of further clues to better understand the underlying mechanisms. A retrospective analysis was conducted based on data collected in a formal thorough QT/QTc study in which 32 subjects received a carbohydrate-rich "continental" breakfast, moxifloxacin without food, and moxifloxacin with food. We assessed the effect of food on T-wave morphology using validated algorithms for measurement of J-Tpeak and Tpeak -Tend intervals. Our findings demonstrate that a standardized meal significantly shortened J-Tpeak for 4 hours after a meal and to a much lesser extent and shorter duration (up to 1 hour) prolonged the Tpeak -Tend and QRS intervals. This suggests that the QTc shortening occurs mainly during phase 2 of the cardiac action potential. As there was no corresponding effect on Tpeak -Tend beyond the first hour, we conclude that a meal does not interfere with the outward correcting potassium channels but possibly with Ca2+ currents. An effect on mainly Ca2+ aligns well with our understanding of physiology whereby an increase in stroke volume, as observed after a meal, is associated with changes in Ca2+ cycling in and out of the sarcoplasmic reticulum during cardiac myocyte contraction.