OBJECTIVE To analyze and identify the metabolites of pirtobrutinib （PTN） in rats， and clarify the possible metabolic pathways of PTN in rats. METHODS Six rats were intragastrically administered with 10 mg/kg PTN suspension. Blood samples were collected from the rats 30 minutes before administration and at 0.25， 0.5， 1， 2， 4， 6， 8， 12， 24 hours after administration. Urine and feces samples were collected 12 hours before administration and 24 hours after administration. UHPLC- Orbitrap Exploris 240 system combined with Compound Discoverer 3.0 and Xcalibur 2.0 software were adopted for structural identification and metabolic pathway analysis of PTN metabolites in rat plasma， urine， and feces. RESULTS A total of 29 PTN metabolites were identified， including 17， 19 and 22 metabolites in plasma， urine and feces， respectively. The metabolic pathways of PTN mainly included oxidation， sulfation， glucuronidation， etc.， and its metabolites were mostly combination products of two or more different metabolic forms. In detail， a total of 26 metabolites were associated with phase Ⅰ metabolic reactions （14 oxidation metabolites， 9 reduction/dehydrogenation metabolites， 8 demethylation metabolites， and 5 hydrolysis metabolites）. Meanwhile， a total of 20 products were involved in phase Ⅱ metabolites （14 sulfation metabolites and 8 glucuronic acid binding metabolites）. CONCLUSIONS PTN exhibits a diverse range of metabolites in rat fecal samples， with the primary metabolic pathways being oxidation， sulfation， glucuronidation， and others.

Objective:To mine and compare the adverse event (AE) signals of allopurinol and febuxostat and provide reference for the rational and safe use of the 2 drugs in clinic.Methods:The AE reports on allopurinol and febuxostat from January 1, 2009 to December 31, 2021 were collected by searching the US Food and Drug Administration Public Data Open Project (openFDA) database. AEs were classified using preferred term (PT) and systemic organ class (SOC) of the International Medical Terminology Dictionary 25.0. The AE risk signals of allopurinol and febuxostat were mined using the reporting odds ratio ( ROR) method. The number of AE reports ≥3 and the lower limit of the 95% confidence interval ( CI) of the ROR>1 was defined as a positive signal. The new AE risk signals of allopurinol and febuxostat were screened according to the drug labels. The radar chart was drawn according to the number of allopurinol and febuxostat risk signals. The positive PT signals were descriptively and statistically analyzed. Results:The number of AE reports of allopurinol and febuxostat were 105 532 and 9 949, respectively. The analysis of the top 100 AE reports were as follows. There were 82 positive PT signals of allopurinol, involving 14 SOCs, and 61 AEs were not recorded in the drug labels; there were 86 positive PT signals of febuxostat, involving 18 SOCs, and 25 AEs were not recorded in the drug labels. The top 5 PTs in the signal strength of allopurinol were drug reaction with eosinophilia and systemic symptoms, end-stage renal disease, hypercalcemia, acute kidney injury, and chronic kidney disease; the top 5 PTs in the signal strength of febuxostat were enthesopathy, granuloma skin, blood parathyroid hormone decreased, tenosynovitis and alanine aminotransferase abnormal. The 2 drugs had a total of 49 overlapping signals. More AE signals of allopurinol were detected in SOCs of metabolic and nutritional diseases, blood and lymphatic system diseases etc.; more AE signals of febuxostat were detected in SOCs of skin and subcutaneous tissue diseases, various musculoskeletal, and connective tissue diseases, etc.Conclusions:Allopurinol has a higher risk of causing AEs related to kidney and urinary system, blood and lymphatic system, and metabolic system, while febuxostat has a higher risk of causing AEs related to skin and subcutaneous tissue, musculoskeletal and connective tissue, and hepatobiliary system. It is suggested that patients with gout accompanied by renal insufficiency, urinary system diseases or blood diseases should be careful with allopurinol, and the patients with gout accompanied by liver dysfunction should be careful with febuxostat.

Objective:To explore the feasibility of pulse wave recording in the pharmacodynamics and safety evaluation in clinical trials of sedative-hypnotics.Methods:The subjects were male healthy subjects who were publicly recruited by the research ward of Beijing Friendship Hospital, Capital Medical University from April 11 to June 11, 2022. The pharmacokinetic parameters of the single or combined use of midazolam were calculated based on the pharmacokinetic parameter analysis set. The occurrence of adverse events during the trial were recorded. Healthy subjects wore pulse wave recording watches for 24 hours in states of without medication, midazolam alone, and midazolam combined with itraconazole, and the subjects′ heart rate and body movement data were recorded, and pharmacodynamic evaluation indicators such as sleep duration, sleep depth and multiple dreams were compared with safety evaluation indicators such as mental state, circadian rhythm and life vitality.Results:A total of 12 healthy male subjects were included, aged (34±6) years. When using midazolam alone, the median Tmax was 0.5 hour, Cmax was (19.10±5.35) μg/L, AUC 0-t was (45.41±13.88) min·μg/L, and AUC 0-∞ was (46.99±14.74) min·μg/L. After combination with itraconazole, the median Tmax was still 0.5 hour, Cmax was (61.05±19.0) μg/L, AUC 0-t was (394.36±60.26) min·μg/L, and AUC 0-∞ was (553.10±178.87) min·μg/L. The 90% confidence interval for the geometric mean ratio of the AUC 0-t between midazolam combined with itraconazole and midazolam alone was 735.24% to 1 061.57%. Among the 12 subjects, 9 had a total of 26 adverse events, all of which were mild. The results of pulse wave recording showed statistically significant differences in sleep duration[(5.40±1.35), (6.50±1.85), and (8.05±0.8) hours, P=0.001], sleep depth [(14.13±5.15), (19.00±4.62), and (24.32±3.66) points, P=0.005] and life vitality[40.00(38.00,41.00), 36.50(35.25,38.75), and 32.50(30.00,36.00) points, P<0.001] in subjects in states of without medication, midazolam alone, and midazolam combined with itraconazole. Conclusion:Pulse wave recording can be used for a real-time, objective, quantitative assessment of the pharmacodynamics and safety of sedative-hypnotics.

Objective:To mine and compare the adverse event (AE) signals of allopurinol and febuxostat and provide reference for the rational and safe use of the 2 drugs in clinic.Methods:The AE reports on allopurinol and febuxostat from January 1, 2009 to December 31, 2021 were collected by searching the US Food and Drug Administration Public Data Open Project (openFDA) database. AEs were classified using preferred term (PT) and systemic organ class (SOC) of the International Medical Terminology Dictionary 25.0. The AE risk signals of allopurinol and febuxostat were mined using the reporting odds ratio ( ROR) method. The number of AE reports ≥3 and the lower limit of the 95% confidence interval ( CI) of the ROR>1 was defined as a positive signal. The new AE risk signals of allopurinol and febuxostat were screened according to the drug labels. The radar chart was drawn according to the number of allopurinol and febuxostat risk signals. The positive PT signals were descriptively and statistically analyzed. Results:The number of AE reports of allopurinol and febuxostat were 105 532 and 9 949, respectively. The analysis of the top 100 AE reports were as follows. There were 82 positive PT signals of allopurinol, involving 14 SOCs, and 61 AEs were not recorded in the drug labels; there were 86 positive PT signals of febuxostat, involving 18 SOCs, and 25 AEs were not recorded in the drug labels. The top 5 PTs in the signal strength of allopurinol were drug reaction with eosinophilia and systemic symptoms, end-stage renal disease, hypercalcemia, acute kidney injury, and chronic kidney disease; the top 5 PTs in the signal strength of febuxostat were enthesopathy, granuloma skin, blood parathyroid hormone decreased, tenosynovitis and alanine aminotransferase abnormal. The 2 drugs had a total of 49 overlapping signals. More AE signals of allopurinol were detected in SOCs of metabolic and nutritional diseases, blood and lymphatic system diseases etc.; more AE signals of febuxostat were detected in SOCs of skin and subcutaneous tissue diseases, various musculoskeletal, and connective tissue diseases, etc.Conclusions:Allopurinol has a higher risk of causing AEs related to kidney and urinary system, blood and lymphatic system, and metabolic system, while febuxostat has a higher risk of causing AEs related to skin and subcutaneous tissue, musculoskeletal and connective tissue, and hepatobiliary system. It is suggested that patients with gout accompanied by renal insufficiency, urinary system diseases or blood diseases should be careful with allopurinol, and the patients with gout accompanied by liver dysfunction should be careful with febuxostat.

Objective:To explore the feasibility of pulse wave recording in the pharmacodynamics and safety evaluation in clinical trials of sedative-hypnotics.Methods:The subjects were male healthy subjects who were publicly recruited by the research ward of Beijing Friendship Hospital, Capital Medical University from April 11 to June 11, 2022. The pharmacokinetic parameters of the single or combined use of midazolam were calculated based on the pharmacokinetic parameter analysis set. The occurrence of adverse events during the trial were recorded. Healthy subjects wore pulse wave recording watches for 24 hours in states of without medication, midazolam alone, and midazolam combined with itraconazole, and the subjects′ heart rate and body movement data were recorded, and pharmacodynamic evaluation indicators such as sleep duration, sleep depth and multiple dreams were compared with safety evaluation indicators such as mental state, circadian rhythm and life vitality.Results:A total of 12 healthy male subjects were included, aged (34±6) years. When using midazolam alone, the median Tmax was 0.5 hour, Cmax was (19.10±5.35) μg/L, AUC 0-t was (45.41±13.88) min·μg/L, and AUC 0-∞ was (46.99±14.74) min·μg/L. After combination with itraconazole, the median Tmax was still 0.5 hour, Cmax was (61.05±19.0) μg/L, AUC 0-t was (394.36±60.26) min·μg/L, and AUC 0-∞ was (553.10±178.87) min·μg/L. The 90% confidence interval for the geometric mean ratio of the AUC 0-t between midazolam combined with itraconazole and midazolam alone was 735.24% to 1 061.57%. Among the 12 subjects, 9 had a total of 26 adverse events, all of which were mild. The results of pulse wave recording showed statistically significant differences in sleep duration[(5.40±1.35), (6.50±1.85), and (8.05±0.8) hours, P=0.001], sleep depth [(14.13±5.15), (19.00±4.62), and (24.32±3.66) points, P=0.005] and life vitality[40.00(38.00,41.00), 36.50(35.25,38.75), and 32.50(30.00,36.00) points, P<0.001] in subjects in states of without medication, midazolam alone, and midazolam combined with itraconazole. Conclusion:Pulse wave recording can be used for a real-time, objective, quantitative assessment of the pharmacodynamics and safety of sedative-hypnotics.