Search

Obstructive hypertrophic cardiomyopathy (oHCM) is a subtype of HCM characterized by left ventricular outflow tract obstruction resulting from cardiac muscle hypertrophy and anatomic alterations in the mitral valve and apparatus. Mavacamten, a cardiac myosin inhibitor metabolized primarily by CYP2C19 in the liver, is the first and only targeted medication approved for the treatment of symptomatic New York Heart Association (NYHA) class II–III oHCM. Previous pharmacokinetic (PK) results of mavacamten in healthy Caucasian, Japanese, and Asian participants demonstrated that mavacamten exposure was affected by CYP2C19 metabolism status. This open‐label, parallel‐group, phase I trial aimed to determine the PK and safety of mavacamten in healthy Chinese participants with different CYP2C19 genotypes. The primary outcome was to define the PK of mavacamten in healthy Chinese participants; the secondary outcome was to examine safety and tolerability. After a single oral dose of 15 or 25 mg mavacamten in fasted healthy adult Chinese individuals, Cmax was reached within a median Tmax of 0.6–1.5 h, indicating rapid absorption. Inter‐individual variability was moderate, and individuals carrying non‐functional CYP2C19 alleles (*2/*2, *3/*3, or *2/*3) exhibited longer half‐life and increased total exposure. After stratification of CYP2C19 genotypes, total mavacamten exposures were similar among different ethnic groups when compared with prior PK studies. No significant adverse events were observed in this study. Single oral administration of mavacamten at 15 mg was well tolerated across all CYP2C19 genotypes, and 25 mg dose was well tolerated in healthy participants with CYP2C19 genotypes UM/RM/NM. The PK profile of mavacamten in the healthy Chinese population was consistent with that in other healthy populations. [ABSTRACT FROM AUTHOR]

BACKGROUND: Temperature is a primary factor that determines the eco‐geographical distribution and population development of invasive insects. Temperature stress leads to various negative effects, including excess reactive oxygen species (ROS), and catalase (CAT) is a key enzyme against ROS in the antioxidant pathway. The whitefly Bemisia tabaci MED is a typical invasive pest that causes damage worldwide. Our previous studies have shown that CAT promotes whitefly adaptation to high temperature by eliminating ROS. However, the mechanism underlying the low‐temperature adaptation of whiteflies is still unknown. RESULTS: In this study, we investigated the role of CAT in the low‐temperature tolerance of B. tabaci MED by analyzing its survival rate, reproduction, and ROS levels at 25 °C (as a control, suitable temperature), 20 °C (moderately decreased temperature), and 4 °C (severely decreased temperature). Silencing of BtCAT1, BtCAT2, or BtCAT3 reduced the viability of whiteflies under a short‐term severely decreased temperature (4 °C), which manifested as decreases in survival and fecundity accompanied by significant increases in ROS levels. Moreover, even at a moderately decreased temperature (20 °C), silencing of BtCAT1 led to high ROS levels and low survival rates in adults. CONCLUSION: Silencing of BtCATs significantly increased the sensitivity of B. tabaci MED to low temperatures. BtCAT1 is likely more essential than other BtCATs for low‐temperature tolerance in whiteflies. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]