Diurnal changes in capecitabine clock-controlled metabolism enzymes are responsible for its pharmacokinetics in male mice

The circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target tissues to the active form of the drug and cytotoxicity display variations depending on the chronopharmacokinetics. For anticancer drugs with narrow therapeutic ranges and dose-limiting side effects, it is particularly important to know the temporal changes in pharmacokinetics. A previous study indicated that pharmacokinetic profile of capecitabine was different depending on dosing time in rat. However, it is not known how such difference is attributed with respect to diurnal rhythm. Therefore, in this study, we evaluated capecitabine-metabolizing enzymes in a diurnal rhythm-dependent manner. To this end, C57BL/6J male mice were orally treated with 500 mg/kg capecitabine at ZT1, ZT7, ZT13, or ZT19. We then determined pharmacokinetics of capecitabine and its metabolites, 5 '-deoxy-5-fluorocytidine (5 ' DFCR), 5 '-deoxy-5-fluorouridine (5 ' DFUR), 5-fluorouracil (5-FU), in plasma and liver. Results revealed that plasma C-max and AUC(0-6h) (area under the plasma concentration-time curve from 0 to 6 h) values of capecitabine, 5 ' DFUR, and 5-FU were higher during the rest phase (ZT1 and ZT7) than the activity phase (ZT13 and ZT19) (p < 0.05). Similarly, C-max and AUC(0-6h) values of 5 ' DFUR and 5-FU in liver were higher during the rest phase than activity phase (p < 0.05), while there was no significant difference in liver concentrations of capecitabine and 5 ' DFCR. We determined the level of the enzymes responsible for the conversion of capecitabine and its metabolites at each ZT. Results indicated the levels of carboxylesterase 1 and 2, cytidine deaminase, uridine phosphorylase 2, and dihydropyrimidine dehydrogenase (p < 0.05) are being rhythmically regulated and, in turn, attributed different pharmacokinetics profiles of capecitabine and its metabolism. This study highlights the importance of capecitabine administration time to increase the efficacy with minimum adverse effects.Istanbul Universit

Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice

Cryptochromes are negative transcriptional regulators of the circadian clock in mammals. It is not clear how reducing the level of endogenous CRY1 in mammals will affect circadian rhythm and the relation of such a decrease with apoptosis. Here, we discovered a molecule (M47) that destabilizes Cryptochrome 1 (CRY1) both in vitro and in vivo. The M47 selectively enhanced the degradation rate of CRY1 by increasing its ubiquitination and resulted in increasing the circadian period length of U2OS Bmal1-dLuc cells. In addition, subcellular fractionation studies from mice liver indicated that M47 increased degradation of the CRY1 in the nucleus. Furthermore, M47-mediated CRY1 reduction enhanced oxaliplatin-induced apoptosis in Ras-transformed p53 null fibroblast cells. Systemic repetitive administration of M47 increased the median lifespan of p53−/− mice by ~25%. Collectively our data suggest that M47 is a promising molecule to treat forms of cancer depending on the p53 mutation

A Cross-sectional Study of Clinical Characteristics and Outcomes among Adults with Laboratory-confirmed SARS-CoV-2 Infection with Omicron Variant

The emergence of the SARS-CoV-2 Omicron variant has raised concerns due to its increased transmissibility and potential implications on clinical characteristics and outcomes in infected individuals. The aims of this report were to study the profile of SARS-CoV-2 infection with omicron variant, investigate the infection outcome, reinfection rates with associated factors, antibody levels, and explore the associations between biochemical markers and disease severity. This prospective cohort study was conducted in Duhok city in the Northern of Iraq. All volunteers with confirmed SARS-CoV-2 RT–PCR and confirmed Omicron infection who were older than 18 years old and agreed to participate were recruited for this study. The study was carried out from January to April 2022. There were 234 cases of confirmed SARS-CoV-2 RT–PCR Omicron infection. The mean age was 48.12±17.3 years, 43.2% were vaccinated, and 40.2% were male. Among the recruited patients, 99.1% recovered and did not need hospitalization. In this study, (38.9%) had a history of previously confirmed COVID-19 infection. Reinfection was significantly higher in females than males (p=0.04; OR= 0.56). It was found that the IgG antibody levels were higher in patients who received Pfizer-BioNTech than in those who received other vaccines (p=0.001). The levels of IgG were also significantly higher in patients with mild infection (p=0.046), whereas the levels of D-dimer were significantly higher in patients with severe cases of the infection compared to those with mild or moderate cases (p=0.001). Additionally, the levels of C-reactive protein (CRP) were observed to be higher in individuals with moderate cases of infection than in mild and severe cases (0.001). Individuals who contracted the Omicron strain generally had positive outcomes. Reinfection with the Omicron variant was relatively high. IgG levels were higher in patients with mild disease, implying that they were associated with decreased disease severity. We found significant associations between D-dimer levels and the severity of the disease. Additional research is required to investigate the long-term effects of Omicron infection