Serum retinol binding protein as a novel marker for clearance and dosage optimization: pharmacokinetics study of voriconazole in a cirrhosis population

Background and ObjectiveVoriconazole (VRC) exhibits nonlinear pharmacokinetic (PK) characteristics and a narrow therapeutic window. Consequently, standardized dosage regimens are insufficient to achieve the targeted therapeutic exposure in patients with cirrhosis. While numerous population pharmacokinetic (PPK) studies on VRC have been conducted, data on the cirrhosis demographic remain limited.This study aimed to explore the PK characteristics of VRC and its covariates in a cirrhosis population, with the objective of recommending individualized dosing regimens.MethodsData collected from routine therapeutic drug monitoring (TDM) of patients with recorded VRC plasma concentrations during a period of therapy between September 2022 and August 2024 were included. A population pharmacokinetic (PPK) model was constructed using nonlinear mixed-effects modeling (NONMEM). Monte Carlo simulation was used to predict the target trough concentrations of VRC under steady-state conditions based on the final model parameters, thereby facilitating tailored dosage recommendations.ResultsA total of 151 trough concentrations were obtained from 78 patients enrolled in the PPK study of VRC. A one-compartment model featuring first-order absorption and first-order elimination was optimal in describing the PK characteristics, additionally incorporating Child-Pugh grades and retinol-binding protein (RBP) as covariates affecting the central ventricular clearance rate (CL) of VRC. In the final model, the CL was determined as 6.96 L/h. For patients classified as Child-Pugh A and B with RBP ≥25 mg/L, the recommended dosages were 400 mg/d and 200 mg/d, respectively. At RBP levels <25 mg/L, the recommended dosages for Child-Pugh A and C patients were 200 mg/d and 100 mg/d, respectively, while for Child-Pugh B patients, both 200 mg/d and 100 mg/d were recommended.ConclusionOur results support the utility of RBP as a novel marker associated with VRC clearance. This biomarker may offer a practical option for VRC dosage optimization. The clinical dosage of VRC could be tailored according to the Child-Pugh grades and RBP levels of patients. While numerous unexplained factors potentially influence the pharmacokinetic properties of VRC, the application of PPK model-guided TDM is crucial for achieving precision in individualized medication regimens

Attenuation of immobilization stress-induced hypertension by temperature-controllable warm needle acupuncture in rats and the peripheral neural mechanisms

IntroductionWe and others have shown that electrical stimulation of the PC-6 acupoint over the wrist relieves hypertension by stimulating afferent sensory nerve fibers and activating the central endogenous opioid system. Warm needle acupuncture has long been utilized to treat various diseases in clinics.MethodsHere, we developed a temperature-controllable warm needle acupuncture instrument (WAI) and investigated the peripheral mechanism underlying the effect of warm needle acupuncture at PC-6 on hypertension in a rat model of immobilization stress-induced hypertension.ResultsStimulation with our newly developed WAI and traditional warm needle acupuncture attenuated hypertension development. Such effects were reproduced by capsaicin (a TRPV1 agonist) injection into PC-6 or WAI stimulation at 48°C. In contrast, PC-6 pretreatment with the TRPV1 antagonist capsazepine blocked the antihypertensive effect of WAI stimulation at PC-6. WAI stimulation at PC-6 increased the number of dorsal root ganglia double-stained with TRPV1 and CGRP. QX-314 and capsaicin perineural injection into the median nerve for chemical ablation of small afferent nerve fibers (C-fibers) prevented the antihypertensive effect of WAI stimulation at PC-6. Additionally, PC-6 pretreatment with RTX ablated the antihypertensive effect of WAI stimulation.ConclusionThese findings suggest that warm needle acupuncture at PC-6 activates C-fiber of median nerve and the peripheral TRPV1 receptors to attenuate the development of immobilization stress-induced hypertension in rats

Dynamics Analysis of Avian Influenza A(H7N9) Epidemic Model

The avian influenza A(H7N9) virus has certain fatal effects on human. In this paper, a mathematical model describing the transmission dynamics of avian influenza A(H7N9) between human and poultry is investigated. The basic reproduction number of the model is obtained by applying the method of the next generation matrix. Then the local and global stability of the equilibria are proven. At last, we use numerical simulations to verify the theoretical results

Dynamics Analysis of an Avian Influenza A (H7N9) Epidemic Model with Vaccination and Seasonality

H7N9 virus in the environment plays a role in the dynamics of avian influenza A (H7N9). A nationwide poultry vaccination with H7N9 vaccine program was implemented in China in October of 2017. To analyze the effect of vaccination and environmental virus on the development of avian influenza A (H7N9), we establish an avian influenza A (H7N9) transmission model with vaccination and seasonality among human, birds, and poultry. The basic reproduction number for the prevalence of avian influenza is obtained. The global stability of the disease-free equilibrium and the existence of positive periodic solution are proved by the comparison theorem and the asymptotic autonomous system theorem. Finally, we use numerical simulations to demonstrate the theoretical results. Simulation results indicate that the risk of H7N9 infection is higher in colder environment. Vaccinating poultry can significantly reduce human infection

Hepatic dysfunction events associated with voriconazole: a real-world study from FDA adverse event reporting system (FAERS) database

Aims: Although voriconazole-induced hepatotoxicity has been reported previously, the direct cause-effect relationship in the real world remains to be established. The aim of this study was to investigate the association between voriconazole and hepatic dysfunction based on the FAERS database. Methods: Data from January 2004 to March 2022 in FAERS were retrieved. We estimate the association between the hepatic dysfunction and voriconazole using reporting odds ratios (RORs) for mining the adverse event report signals and compare voriconazole with the full database and other antifungal drugs. Results: 646 reports of hepatic dysfunction related to voriconazole as the primary suspect drug were collected totally. The median time to event of the hepatic dysfunction events was 8 (interquartile range [IQR] 2-28) days. 62.20% hepatic-related adverse events appeared within the first 15 days since the initiation of voriconazole administration. The overall ROR (95% CI) for hepatic-related adverse events was 6.82 (95% CI 6.26-7.42). Comparing to other antifungal drugs, the RORs for hepatic-related adverse events of fluconazole, isavuconazole and amphotericin B were 2.19 (95% CI 1.94-2.47), 2.31 (95% CI 1.66-3.33) and 1.26 (95% CI 1.08-1.48), respectively. Conclusions: We observed strong signals of higher frequency of reporting hepatic dysfunction events associated with voriconazole in the events of hepatic dysfunction. Since the risk of developing liver injury and possible hepatic dysfunction by voriconazole depends on several factors including underlying hepatic disease, close clinical and laboratory monitoring, including therapeutic drug monitoring (TDM), are essential to prevent or promptly recognize further deterioration of the hepatic function.</jats:p