ABSTRACT
Ionizable lipids with branched tails have been used in lipid nanoparticles (LNPs)-based messenger RNA (mRNA) therapeutics like COVID-19 vaccines. However, due to the limited commercial availability of branched ingredients, a systematic analysis of how the branched tails affect LNP quality has been lacking to date. Herein, a-branched tail lipids are focused, as they can be synthesized from simple commercially available chemicals, and the length of each chain can be independently controlled. Furthermore, symmetry and total carbon number can be used to describe a-branched tails, facilitating the design of a systematic lipid library to elucidate "structure-property-function" relationships. Consequently, a lipid library is developed containing 32 different types of a-branched tails. This library is used to demonstrate that branched chains increase LNP microviscosity and headgroup ionization ability in an acidic environment, which in turn enhances the stability and in vivo efficacy of mRNA-LNPs. Of the branched lipids, CL4F 8-6 LNPs carrying Cas9 mRNA and sgRNA could achieve 54% genome editing and 77% protein reduction with a single dose of 2.5 mg kg(-1). This mechanism-based data on branched lipids is expected to provide insights into rational lipid design and effective gene therapy in the future.
ABSTRACT
Background. Ensitrelvir is a novel oral SARS-CoV-2 3C-like protease inhibitor, and under late clinical development stage for COVID-19 diseases. Ensitrelvir exhibited an inhibition potency for organic cation transporter 1 (OCT1) and multidrug and toxin extrusion protein 1 (MATE1) in in vitro study and clinical drug-drug interaction (DDI) study is required judging fromDDI guidance.Metformin is widely used for treatment of diabetes, and is a sensitive substrate for OCT1 and MATE1. We evaluated the effect of ensitrelvir on the pharmacokinetics (PK) ofmetformin with physiologically-based pharmacokinetic (PBPK) modeling and simulation and clinical DDI study. Methods. The PBPK model of ensitrelvir was developed based on the physicochemical parameters, in vitro transporter inhibition parameters, and estimated PK parameters for human. DDI simulations between ensitrelvir and metformin were performed. Simcyp PBPK Simulator (Version 20, Certara UK Limited, UK) was used to develop PBPK model and simulate the DDIs. The in vitro 50% inhibitory concentration (IC50) values of each transporter were used as inhibition constant (Ki) for DDI simulations. Based on the PBPK analysis, the clinical DDI study planed. Results. PBPK analysis: As the result of DDI simulation, ensitrelvir increased the area under the curve (AUC) of metformin by 12%. The result suggests that in vivo DDI potency of ensitrelvir via inhibition of OCT1 or MATE1 would be low at a single dose of ensitrelvir 1000 mg. Clinical DDI study: The plasma concentration-time profile of metformin and ensitrelvir were monitored after 96 hours from a single dose of metformin with or without ensitrelvir. Ensitrelvir does not have effect on the PK of metformin (a geometric mean of AUC ratio was 1.02, Japanese healthy subjects, N=14), suggesting no MATE1 and OCT1 inhibition by ensitrelvir at a clinical dose. The PBPK analysis could well predict the clinical DDI study result. Conclusion. The results of PBPK analysis and the clinical DDI study suggest that no OCT1 and MATE1 inhibition by ensitrelvir is in the clinical dose. Therefore, ensitrelvir does not have a clinically meaningful effect on the pharmacokinetic profile of OCT1 and/or MATE1 substrates including metformin.
ABSTRACT
Background. Ensitrelvir is a new drug candidate to treat COVID-19 disease. According to the in vitro drug-drug interaction (DDI) study, time-dependent inhibition by ensitrelvir was observed on cytochrome P450 3A (CYP3A). The purpose of this study was to evaluate the effect of ensitrelvir on the pharmacokinetics (PK) of CYP3A substrates by clinial DDI studies and physiologically-based pharmacokinetic (PBPK) analyses. Methods. Clinical studies: The effect of once daily multiple-doses of ensitrelvir with the loading dose on Day 1/ maintenance dose (750/250 mg) for 6 days on the PK of midazolam (MDZ) was assessed. MDZ was administered on Days -2 and 6. The effects of once daily multiple-doses of ensitrelvir with 750/250 mg for 5 days on the PK of dexamethasone (DXS) and prednisolone (PLS) were also assessed because these corticosteroids were also CYP3A substrates. DXS and PLS were administered on Days -2, 5 (co-administration with ensitrelvir), 9 and 14 to evaluate the effects after the last dose of ensitrelvir. PBPK analyses: The effects of once daily multiple-doses of ensitrelvir with another dose regimen (the loading dose/mentenance dose [375/125 mg] for 5 days) on the PK of CYP3A substrates were predicted using Simcyp PBPK Simulator (Version 20, Certara UK Limited, UK). Results. The AUC0-inf of MDZ co-administered with ensitrelvir was increased by 8.80-fold compared to those of MDZ alone, indicating that ensitrelvir is a strong CYP3A inhibitor with 750/250 mg for 6 days. The AUC0-inf of DXS on Day 5 was increased 3.47-fold and the effect of ensitrelvir on the PK of DXS was diminished over time after the last dose of ensitrelvir. The AUC0-inf of PLS on Day 5 was increased 1.25-fold and no clinically meaningful effect of ensitrelvir on the PK of PLS was observed. The PBPK analyses predicted that the co-administration of ensitrelvir increased the AUC of MDZ by 3.83-fold and the AUC of DXS by 2.49-fold following ensitrelvir at 375/125 mg for 5 days. A clinical study with MDZ under the analyses conditions is underway to confirm the PBPK results. Conclusion. The clinical study revealed that ensitrelvir affects the PK of CYP3A substrates with 750/250 mg for 5 or 6 days. The PBPK analyses suggests that ensitrelvir is expected to a moderate inhibitor of CYP3A with 375/125 mg for 5 days.
ABSTRACT
The main target of anti-inflammatory drug therapies for coronavirus disease 2019 (COVID-19) is reducing the risk of acute respiratory distress syndrome (ARDS), an important risk factor for acute death. In the RECOVERY trial, 6 mg/day of dexamethasone for up to 10 days improved 28-day mortality compared with those who received usual care alone. Here, we present three COVID-19 cases who improved after treatment with methylprednisolone (MPSL) and/or following prednisolone (PSL) for acute progression of respiratory failure. Three male COVID-19 patients, aged 56, 84, and 49 years old, developed acute respiratory failure after admission. MPSL therapy (500 mg/day for 3 days) was started for these patients at 4, 4, and, 2 days after admission, respectively, when oxygen administration was required. Following this therapy, two of the three present cases received 30 or 40 mg/day of PSL for an additional 6 and 8 days, respectively. The remaining case discontinued corticosteroid after MPSL therapy. All three cases survived, had fever reduction at 6, 2, and 1 days after start of MPSL therapy, could discontinue oxygen therapy at 6, 6, and 11 days after start of MPSL therapy, and showed negative results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction at 8, 6, and 22 days after start of MPSL therapy, respectively. No serious side effects due to drug discontinuation of treatment for COVID-19 were observed. MPSL is a candidate drug for corticosteroid therapy for COVID-19. Corticosteroid therapy should be started in the early stage of respiratory failure. Optimal drug selection, timing of intervention, dose, and duration of corticosteroid therapy for COVID-19 should be analyzed in the further studies. © Journal of Xiangya Medicine. All rights reserved.
ABSTRACT
This paper describes a programming environment for classes of our university. It consists of a web server software at the front end and a virtual machine at the back end. Using OpenID Connect technology for its authentication enables us to operate the system securely. Since the system can be accessed via a web browser, the user does not have to install any other software additionally. We will explain the configuration details as well as the result of two-month operations. © 2021, Springer Nature Switzerland AG.