Mining and analysis of lorlatinib-induced adverse drug event signals / 中国药房

OBJECTIVE To provide references for the safe use of lorlatinib in clinical practice. METHODS The reporting odds ratio （ROR） method， Medicines and Healthcare Products Regulatory Agency comprehensive standard method （referred to as “MHRA method”） and the Bayesian confidence propagation neural network （BCPNN） method were used to detect adverse drug events （ADEs） signals of lorlatinib in the FDA Adverse Event Reporting System from the first quarter of 2019 to the fourth quarter of 2022. RESULTS & CONCLUSIONS Totally 114 overlapping ADEs signals of lorlatinib were detected by the three methods， among which there were 73 new suspicious ADEs signals which were not covered in the instruction of lorlatinib. When using loratinib in clinical practice， special attention should be paid to ADEs with a high number of cases and signals， such as various neurological diseases， psychiatric diseases， respiratory system， thoracic and mediastinal diseases； clinical manifestations included cerebral edema， cerebral infarction， pulmonary hypertension， mutism， decreased sexual desire， pleural effusion. The signals of mobile thrombophlebitis， radiation necrosis， mutism， vesicoureteral reflux not mentioned in the instructions were all strong in BCPNN detection with high specificity， to which we should pay attention in clinical application.

Literature analysis of drug-induced autoimmune hepatitis induced by tumor necrosis factor-α inhibitor / 中国药房

OBJECTIVE To analyze the characteristics of drug-induced autoimmune hepatitis （DIAIH） induced by tumor necrosis factor-α inhibitor （TNFi）， and to provide reference for clinical drug treatment. METHODS Retrieved from PubMed， Embase， China Academic Journal full-text Database， VIP and Wanfang database， the case reports of TNFi-induced DIAIH were collected to conduct descriptive analysis. RESULTS A total of 33 case reports involving 44 patients were collected， including 31 females and 13 males， with an average age of （41.14±2.20） years old， mostly aged 30 to 60 years （77.27%）. The primary diseases were Crohn disease （CD）， ulcerative colitis （UC） and rheumatoid arthritis （RA） （68.18%）. Of the 44 patients， 35 were treated with infliximab （IFX）， 7 with adalimumab， and 2 with etanercept. The dosage of 37 patients was within the scope of the instructions， and 31 received other drugs additionally； DIAIH mainly occurred ≤24 weeks after medication （68.18%）； 21 patients （47.73%） had no clinical manifestations； alanine aminotransferase and aspartate aminotransferase were abnormally elevated in all patients； anti-nuclear antibodies were positive in 38 patients. Except for 3 patients who required liver transplantation， all the other patients improved after drug withdrawal and/or symptomatic treatment such as glucocorticoid therapy. CONCLUSIONS TNFi- induced DIAIH is more common in female patients and can occur with conventional doses， with significant differences in occurrence time. However， the intervention measures are basically the same for DIAIH induced by different types of TNFi. Clinical use of TNFi， especially the use of IFX， requires close attention to the clinical manifestations， liver function and autoantibody level， and a detailed evaluation should be conducted to detect DIAIH as soon as possible. If liver function continues to not improve， it is necessary to stop taking medicine as soon as possible and receive symptomatic treatment to avoid developing acute or severe DIAIH or liver failure.

Data mining of severe cutaneous adverse reactions related to immune checkpoint inhibitors in the FAERS / 中国药房

OBJECTIVE To mine and analyze severe cutaneous adverse reaction signals of 5 commonly used immune checkpoint inhibitors （ICIs）， and to provide reference for clinically safe use of drugs. METHODS Based on the FDA adverse events reporting system （FAERS） database，adverse drug events （ADEs） reports about severe cutaneous adverse reactions related to ipilimumab， nivolumab， pembrolizumab， atezolizumab and durvalumab were collected from listing in the United States to the fourth quarter of 2022. The ADE signals were mined and analyzed with reporting odds ratio （ROR） and Bayesian confidence propagation neural network （BCPNN）. RESULTS A total of 5 726 reports of severe cutaneous adverse reactions were collected， including 3 037 reports for nivolumab，1 465 reports for pembrolizumab， 130 reports for durvalumab， 429 reports for atezolizumab and 665 reports for ipilimumab. All 5 kinds of ICIs caused positive signals， the correlation degree of which was as follows： pembrolizumab＞atezolizumab＞nivolumab＞ipilimumab＞durvalumab. Stevens-Johnson syndrome（SJS） and toxic epidermal necrolysis （TEN） have been reported for all 5 ICIs， and the association was the strongest with pembrolizumab. CONCLUSIONS All 5 kinds of ICIs are associated with the risk of severe skin adverse reactions， and close attention should be paid to their clinical use， especially being cautious when using pembrolizumab. The combination of ICIs should be avoided as much as possible.

ADR Signal Mining and Analysis of Adverse Drug Reaction of Ceritinib / 中国药房

OBJECTIVE：To initially evaluate the safety of ceritinib after it is marketed ，and to provide reference for the rational use of drug. METHODS The report odd ratio method and proportional reporting ratio method were used to mine the signals of ceritinib-related adverse events from FDA adverse event reporting system （FAERS）during the second quarter of 2014 to the third quarter of 2019. The patients ’gender，age，body weight ，daily dose and course of treatment were collected. SPSS 26.0 software was used to test the number of ADR cases of this system group and other system groups by chi square test. RESULTS ：A total of 10 318 ADR reports with ceritinib as the first suspicious drug were collected ， and 236 ADR signals of seretinib were excavated. After excluding the ineffective treatment ，187 ADR signals were obtained ，involving 16 systems. Inaddition to those mentioned in the drug instructions ，the signals also included various nervous disease ，blood and lymph system disease ，infections and infectious disease ，etc.，such as hand-foot-genital syndrome ，mutation of anaplatic lymphoma kinase gene. Among them ，the ADR reports of gastrointestinal diseases were the most （576 cases）. Compared with ADR of other systems ，gender，age，body weight，daily dose and treatment course had significant effects on ADR of gastrointestinal diseases （P＜0.05）. Most of the patient with gastrointestinal ADR after using ceritinih were female （59.9％），45 years old and above （70.3％），body weight ≤65 kg （68.1％），daily dose 451-750 mg/d（50.2％），and medication duration less than 3 months（75.7％）. CONCLUSIONS ：The risk of gastrointestinal ADR in female patients over 45 years old and with body weight less than 65 kg after using seretinib is relatively high. This kind of ADRs are also related to daily dose ，and most of which occur within 3 months. Therefore ，great importance should be attached to drug monitoring during clinical use.

Effects of PPARαactivation on AngⅡ-induced cardiomyocyte hypertro-phy and interaction of NFATc4 with p65-NFκB / 中国病理生理杂志

AIM: To investigate the effects of fenofibrate on angiotensin Ⅱ ( AngⅡ)-induced cardiomyocyte hypertrophy .METHODS:Primary neonatal cardiomyocytes were pretreated with fenofibrate (10μmol/L) for 1 h followed by stimulation with AngⅡ(100 nmol/L).The mRNA levels of ANF, BNP andβ-MHC were measured by real-time PCR. Western blotting was employed to determine the nuclear translocations of NFATc 4 and p65-NFκB.Co-immunoprecipitation was used to investigate the interaction of NFATc 4 with p65-NFκB in the nucleus of cardiomyocytes .In addition, the DNA binding activity of NFATc4 on the BNP promoter was determined by EMSA .RESULTS:Fenofibrate significantly inhibited AngⅡ-induced cardiomyocyte hypertrophy .Fenofibrate treatment inhibited the nuclear translocations of NFATc 4 and p65-NFκB, as well as the interactions of NFATc 4 with p65-NFκB in the nucleus of cardiomyocytes induced by AngⅡ.Fenofi-brate inhibited the binding activity of NFATc 4 with the BNP promoter , which was strengthened by AngⅡ.CONCLU-SION:Fenofibrate enhances the interaction of NFATc 4 with PPARα, decreases the interaction of NFATc 4 with p65-NFκB in the nucleus of cardiomyocytes , and inhibits the DNA binding activity of NFATc 4 induced by AngⅡ, which may be the important mechanisms of fenofibrate on inhibiting cardiac hypertrophy .