Leritrelvir for the treatment of mild or moderate COVID-19 without co-administered ritonavir: a multicentre randomised, double-blind, placebo-controlled phase 3 trial.

Background: Leritrelvir is a novel α-ketoamide based peptidomimetic inhibitor of SARS-CoV-2 main protease. A preclinical study has demonstrated leritrelvir poses similar antiviral activities towards different SARS-CoV-2 variants compared with nirmatrelvir. A phase 2 clinical trial has shown a comparable antiviral efficacy and safety between leritrelvir with and without ritonavir co-administration. This trial aims to test efficacy and safety of leritrelvir monotherapy in adults with mild-to-moderate COVID-19. Methods: This was a randomised, double-blind, placebo-controlled, multicentre phase 3 trial at 29 clinical sites in China. Enrolled patients were from 18 to 75 years old, diagnosed with mild or moderate COVID-19 and not requiring hospitalization. Patients had a positive SARS-CoV-2 nucleic acid test (NAT) and at least one of the COVID-19 symptoms within 48 h before randomization, and the interval between the first positive SARS-CoV-2 NAT and randomization was ≤120 h (5 days). Patients were randomly assigned in a 1:1 ratio to receive a 5-day course of either oral leritrelvir 400 mg TID or placebo. The primary efficacy endpoint was the time from the first dose to sustained clinical recovery of all 11 symptoms (stuffy or runny nose, sore throat, shortness of breath or dyspnea, cough, muscle or body aches, headache, chills, fever ≥37 °C, nausea, vomiting, and diarrhea). The safety endpoint was the incidence of adverse events (AE). Primary and safety analyses were performed in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT05620160. Findings: Between Nov 12 and Dec 30, 2022 when the zero COVID policy was abolished nationwide, a total of 1359 patients underwent randomization, 680 were assigned to leritrelvir group and 679 to placebo group. The median time to sustained clinical recovery in leritrelvir group was significantly shorter (251.02 h [IQR 188.95-428.68 h]) than that of Placebo (271.33 h [IQR 219.00-529.63 h], P = 0.0022, hazard ratio [HR] 1.20, 95% confidence interval [CI], 1.07-1.35). Further analysis of subgroups for the median time to sustained clinical recovery revealed that (1) subgroup with positive viral nucleic acid tested ≤72 h had a 33.9 h difference in leritrelvir group than that of placebo; (2) the subgroup with baseline viral load >8 log 10 Copies/mL in leritrelvir group had 51.3 h difference than that of placebo. Leritrelvir reduced viral load by 0.82 log10 on day 4 compared to placebo. No participants in either group progressed to severe COVID-19 by day 29. Adverse events were reported in two groups: leritrelvir 315 (46.46%) compared with placebo 292 (43.52%). Treatment-relevant AEs were similar 218 (32.15%) in the leritrelvir group and 186 (27.72%) in placebo. Two cases of COVID-19 pneumonia were reported in placebo group, and one case in leritrelvir group, none of them were considered by the investigators to be leritrelvir related. The most frequently reported AEs (occurring in ≥5% of participants in at least one group) were laboratory finding: hypertriglyceridemia (leritrelvir 79 [11.7%] vs. placebo 70 [10.4%]) and hyperlipidemia (60 [8.8%] vs. 52 [7.7%]); all of them were nonserious. Interpretation: Leritrelvir monotherapy has good efficacy for mild-to-moderate COVID-19 and without serious safety concerns. Funding: This study was funded by the National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine, Guangdong Science and Technology Foundation, Guangzhou Science and Technology Planning Project and R&D Program of Guangzhou Laboratory.

Physiologically Based Pharmacokinetic Modeling for Multiple Oral Administration Labetalol in Pregnant Women.

BACKGROUND: Labetalol has an irreplaceable role in treating Hypertensive disorders of pregnancy (HDP), a common disease during pregnancy with a prevalence of 5.2-8.2%. However, there were big differences in dosage regimens between various guidelines. PURPOSE: A physiologically-based pharmacokinetics (PBPK) model was established and validated to evaluate the existing oral dosage regimens, and to compare the difference in plasma concentration between pregnant and non-pregnant women. METHODS: First, non-pregnant woman models with specific plasma clearance or enzymatic metabolism (UGT1A1, UGT2B7, CYP2C19) were established and validated. For CYP2C19, slow, intermediate, and rapid metabolic phenotypes were considered. Then, a pregnant model with proper structure and parameters adjustment was established and validated against the multiple oral administration data. RESULTS: The predicted labetalol exposure captured the experimental data well. The following simulations with criteria lowering 15 mmHg blood pressure (corresponding to around 108 ng/ml plasma labetalol) found that the maximum daily dosage in the Chinese guideline may be insufficient for some severe HDP patients. Moreover, similar predicted steady-state trough plasma concentration was found between the maximum daily dosage in the American College of Obstetricians and Gynecologists (ACOG) guideline, 800 mg Q8h and a regimen of 200 mg Q6h. Simulations comparing non-pregnant and pregnant women found that the difference in labetalol exposure highly depended on the CYP2C19 metabolic phenotype. CONCLUSIONS: In summary, this work initially established a PBPK model for multiple oral administration of labetalol for pregnant women. This PBPK model may lead to personalized labetalol medication in the future.

The efficacy of Chinese patent medicine combined with entecavir for the treatment of chronic HBV-related liver fibrosis or cirrhosis: Protocol for a systematic review and meta-analysis of randomized controlled trials or prospective cohort studies.

BACKGROUND: There are currently no FDA-approved biological or chemical drugs for the treatment of HBV-related liver fibrosis or cirrhosis. Some Chinese patent medicines have proven to be effective in this area. OBJECTIVE: The network meta-analysis (NMA) is to evaluate whether entecavir combined with Chinese patent medicine, such as "fuzhenghuayu capsules," "anluohuaxian pills," "fufangbiejiaruangan tablets," shows superior efficiency compared with entecavir alone for the treatment of chronic HBV-related liver fibrosis or cirrhosis. To evaluate which Chinese patent medicine is the most effective at improving liver fibrosis or cirrhosis in chronic hepatitis B-infected patients? METHODS: Registration of protocol: the protocol was published in the PROSPERO database (identification number: CRD42018112547). We will search PubMed, EMbase, Medline, Cochrane, China Network Knowledge Infrastructure (CNKI), and Wanfang for randomized controlled trials (RCTs) or "prospective cohort studies" of "fuzhenghuayu capsules," "anluohuaxian pills," "fufangbiejiaruangan tablets" respectively combined with entecavir in the treatment of chronic HBV-related liver fibrosis or cirrhosis from their inception to September 30, 2018. R 3.3.3 and GeMTC 0.14.3 software will be used for data analysis.

Polymorphism of R353Q (rs6046) in factor VII and the risk of myocardial infarction: A systematic review and meta-analysis.

OBJECTIVE: Genetic components substantially contribute to the development of myocardial infarction (MI), and R353Q polymorphism (rs6046) in FVII gene has been suspected to be associated with the risk of MI. METHODS: A meta-analysis was conducted on the links between R353Q polymorphism and the susceptibility of MI. A comprehensive literature search was performed on 8 electronic databases. The main effects of the genotypes were estimated using a logistic regression approach. The odds ratios with 95% confidence intervals were calculated using the conventional summary method meta-analysis. The possible sources of heterogeneity among the included studies were explored using meta-regression analysis and subgroup analysis. RESULTS: A total of 18 eligible case-control studies, comprising of 4701 cases and 5329 controls, were included. No overall statistical relationship was identified between R353Q and MI by any of the genetic models. The meta-regression demonstrated that the Asian population, body mass index (BMI) category, and diabetes affected the heterogeneity. In addition, subgroup analyses showed that heterogeneities were identified in Asian population and BMI category, which highly agree with the results of meta-regression. CONCLUSIONS: The current meta-analysis suggested that R353Q polymorphism was not associated with the MI risk. Asian population, BMI category, and diabetes might be related to the incidence of MI. However, large-scale, case-control studies with rigorous designs are essential to provide accurate evidence.

[Value of multi-slice spiral CT in the diagnosis and therapeutic effect evaluation of gastrointestinal stromal tumors].

OBJECTIVE: To analyze the CT manifestations of gastrointestinal stromal tumors, and explore the value of CT in the diagnosis and therapeutic effect evaluation of these tumors. METHODS: A retrospectively analysis of the medical imaging data was conducted in 39 cases of gastrointestinal stromal tumors confirmed by surgery and pathology in comparison with the pathological findings. RESULTS: Of the 39 patients with gastrointestinal stromal tumors, 2 had esophageal stromal tumors, 23 had gastric stromal tumor, 7 had duodenal stromal tumor, 4 had jejunal stromal tumors, 2 had ileal stromal tumors, and 1 had colon stromal tumor. Twenty-five patients were found to have highly malignant tumors, and 11 had low-grade tumors, with the other 3 having tumors of unidentifiable nature. CT displayed exogenous or endogenous mass in these cases, and the tumors had a maximum diameter ranging from 3 to 45 cm (<5 cm in 12 cases and >or=5 cm in 27 cases). Of the 27 cases with a tumor diameter over 5 cm, 23 had malignant stromal tumors, and the tumor mass showed heterogeneous density with central necrosis and cystic and the solid portion of the tumor exhibited mild to moderate enhancement. Six patients were found to have intratumoral punctate calcification, and 17 with malignant tumors showed high peripheral enhancement, with the solid portion of the tumors showing delayed enhancement. The 6 patients with unresectable tumors received chemotherapy resulting in significantly reduced tumor diameter and cystic and necrotic foci in the tumor. CONCLUSION: Multi-slice spiral CT allows precise localization and qualitative assessment of gastrointestinal stromal tumors, and also helps in the evaluation of the therapeutic effect.