CYP1A2 Polymorphism and Drug Co-administration Affect the Blood Levels and Adverse Effects of Pirfenidone.

BACKGROUND: Mutations in metabolic enzymes and co-administration of drugs may affect the blood concentration of pirfenidone effective in pulmonary fibrosis. To provide a basis for the precise clinical use of pirfenidone, the authors analyzed the correlation between steady-state pirfenidone trough concentration and adverse drug reactions (ADRs) and examined the impact of CYP1A2*1C (rs2069514) and *1F (rs762551) variants and co-administration on pirfenidone blood concentrations and ADRs. METHODS: Forty-four patients were enrolled. The blood concentration of pirfenidone was determined using high-performance liquid chromatography. CYP1A2*1C and *1F genotypes were determined using direct SNP sequencing. Additional information related to drug associations was collected to screen factors affecting drug metabolism. RESULTS: The highest predictive value of ADRs was observed when the steady-state trough concentration of pirfenidone was 3.18 mcg·mL-1 and the area under the receiver operating characteristic curve was 0.701 (P = 0.024). The pirfenidone concentration-to-dose ratio (C/D) in CYP1A2*1F homozygous AA mutants was lower than that in C carriers (CC+AC) (1.28 ± 0.85 vs. 2.03 ± 1.28 mcg·mL-1; P = 0.036). Adverse drug reaction (ADR) incidence in the homozygous AA mutant group (28.0%) was significantly lower than that in the C carriers (CC+AC) (63.2%; P = 0.020), and ADR incidence in the A carriers (AC+AA) was considerably lower than that in the CC group (85.7%; P = 0.039). The C/D value of the combined lansoprazole/rabeprazole group was lower than that of the noncombination group (P < 0.05). CONCLUSIONS: The ADR incidence was positively correlated with pirfenidone blood concentration. The CYP1A2 (rs762551) AA genotype is associated with lower pirfenidone concentrations and fewer ADRs. Lansoprazole/rabeprazole co-administration reduced pirfenidone concentrations. Randomized controlled trials should further explore personalized dosing of pirfenidone and combination therapies.

Hepatotoxic mechanism of cantharidin: insights and strategies for therapeutic intervention.

Cantharidin (CTD), a natural compound derived from Mylabris, is widely used in traditional Oriental medicine for its potent anticancer properties. However, its clinical application is restricted due to its high toxicity, particularly towards the liver. This review provides a concise understanding of the hepatotoxic mechanisms of CTD and highlights novel therapeutic strategies to mitigate its toxicity while enhancing its anticancer efficacy. We systematically explore the molecular mechanisms underlying CTD-induced hepatotoxicity, focusing on the involvement of apoptotic and autophagic processes in hepatocyte injury. We further discuss the endogenous and exogenous pathways implicated in CTD-induced liver damage and potential therapeutic targets. This review also summarizes the structural modifications of CTD derivatives and their impact on anticancer activity. Additionally, we delve into the advancements in nanoparticle-based drug delivery systems that hold promise in overcoming the limitations of CTD derivatives. By offering valuable insights into the hepatotoxic mechanisms of CTD and outlining potential avenues for future research, this review contributes to the ongoing efforts to develop safer and more effective CTD-based therapies.

Effects of dexmedetomidine on neurocognitive disturbance after elective non-cardiac surgery in senile patients: a systematic review and meta-analysis.

OBJECTIVE: Senile patients often experience neurocognitive disturbance after non-cardiac surgery. Several clinical trials have investigated if the perioperative intravenous use of dexmedetomidine has a positive effect on the prevention of neurocognitive dysfunction, but the results have been inconsistent. We performed a meta-analysis to investigate the effects of dexmedetomidine on neurocognitive disturbance after elective non-cardiac surgery in senile patients. METHODS: The PubMed, Cochrane Library, EMBASE and China National Knowledge Infrastructure databases were comprehensively searched for all randomized controlled trials published before 1 February 2020 that investigated the efficacy of dexmedetomidine in the prevention of postoperative delirium (POD) or postoperative cognitive dysfunction (POCD). RESULTS: Sixteen studies involving 4376 patients were included in this meta-analysis. Compared with the control (i.e., saline), the perioperative intravenous use of dexmedetomidine significantly reduced the incidence of POD and POCD. However, patients in the dexmedetomidine group were more likely to develop bradycardia and hypotension during the administration of dexmedetomidine than patients in the control group. There were no differences between the two groups in the incidence of nausea and vomiting or mortality rate. CONCLUSION: Dexmedetomidine has a positive effect on the prevention of neurocognitive disturbance in senile patients after elective non-cardiac surgery.