Variation in the CYP2D6 genotype is not associated with carvedilol dose changes in patients with heart failure.

WHAT IS KNOWN AND OBJECTIVE: Carvedilol is the standard of care for heart failure (HF) patients. Carvedilol is partially metabolized by the highly polymorphic enzyme, CYP2D6. To reach an effective dose while avoiding adverse drug reactions (ADRs), testing of CYP2D6 genotype prior to carvedilol initiation may be considered. The objectives of this study were to determine CYP2D6 metabolic genotypes in an Israeli cohort of HF patients and to investigate the relationship between genotype, carvedilol dose and number of ADRs to determine the importance of CYP2D6 genotyping prior to treatment initiation. METHODS: Ninety-three patients with HF on carvedilol were CYP2D6 genotyped and classified as poor (PM), intermediate (IM), extensive (EM) or ultrarapid (UM) metabolizers. Carvedilol dose and ADRs were calculated and correlated with genotype using linear regression statistic analysis. RESULTS AND DISCUSSION: The distribution of the CYP2D6 phenotype in the Israeli population with HF is similar to the European general population. There were no significant differences of carvedilol dose and number of ADRs among genotype groups. Genotype group affiliation and number of adverse drug reactions were not predictive of carvedilol dose changes. WHAT IS NEW AND CONCLUSION: Genotype group affiliation and number of adverse drug reactions were not predictive of carvedilol dose during therapy for patients with HF. The Israeli CYP2D6 phenotype distribution in HF patients was consistent with the frequency in the general European population.

Ibuprofen use and clinical outcomes in COVID-19 patients.

OBJECTIVE: It was recently suggested that ibuprofen might increase the risk for severe and fatal coronavirus disease 2019 (COVID-19) and should therefore be avoided in this patient population. We aimed to evaluate whether ibuprofen use in individuals with COVID-19 was associated with more severe disease, compared with individuals using paracetamol or no antipyretics. METHODS: In a retrospective cohort study of patients with COVID-19 from Shamir Medical Centre, Israel, we monitored any use of ibuprofen from a week before diagnosis of COVID-19 throughout the disease. Primary outcomes were mortality and the need for respiratory support, including oxygen administration and mechanical ventilation. RESULTS: The study included 403 confirmed cases of COVID-19, with a median age of 45 years. Of the entire cohort, 44 patients (11%) needed respiratory support and 12 (3%) died. One hundred and seventy-nine (44%) patients had fever, with 32% using paracetamol and 22% using ibuprofen, for symptom-relief. In the ibuprofen group, 3 (3.4%) patients died, whereas in the non-ibuprofen group, 9 (2.8%) patients died (p 0.95). Nine (10.3%) patients from the ibuprofen group needed respiratory support, compared with 35 (11%) from the non-ibuprofen group (p 1). When compared with exclusive paracetamol users, no differences were observed in mortality rates or the need for respiratory support among patients using ibuprofen. CONCLUSIONS: In this cohort of COVID-19 patients, ibuprofen use was not associated with worse clinical outcomes, compared with paracetamol or no antipyretic.

Escape from a fluctuating system: a master equation and trapping approach.

We present a general solution for the mean exit time in a system with on-site fluctuations between two configurations described by a master equation. The coupled configurations represent a spatially discretized version of an escape over a fluctuating barrier [C. R. Doering and J. C. Gadoua, Phys. Rev. Lett. 69, 2318 (1992)], and passage through modulating channels. Based on the general properties of the mean exit time, we obtain a simple solution for a coupled "birth" and "death" case that exhibits resonant activation. Within this exactly solvable model we derive analytically the optimal fluctuating rate, which is sensitive to the initial condition and scales as 1/n, where n is the system size. Our approach unifies a number of escape problems and points towards the generality of resonant activation.