The incidence of LZD-related thrombocytopenia in the Chinese population is much higher than that suggested by the drug instructions. Low pretreatment platelet count, low body weight, low serum albumin concentration, long-term drug administration, advanced age, renal insufficiency, and concomitant use of caspofungin, levofloxacin, and meropenem have been identified as risk factors. Although predictors have been proposed for use in clinical practice to screen for patients at high risk who require intensified monitoring, further research on the dosage-based pharmacokinetics and pharmacodynamics of LZD are urgently needed.

This study was aimed to elucidate the roles of inhibition of related JAK/STAT pathways in regulating cytotoxicity induced by cisplatin in non-small-cell lung cancer (NSCLC) cell. We treated five non-small-cell lung cancer cell lines with cisplatin alone or with cisplatin and Jak2 inhibitor (ruxolitinib) and assessed cell viability, expression of Jak2 and STAT3 and cell apoptosis. We also investigated the effect of combination treatment inhibited tumor xenograft growth in two human NSCLC xenograft models bearing the cisplatin resistant (H1299) and sensitive (A549) cells. Different cell lines with different genetic background showed half-maximal inhibitory concentrations (IC50) of cisplatin from 4.66 to 68.28 µmol/L. They could be divided into cisplatin intrinsic resistant and cisplatin sensitive cell lines. In cisplatin-resistant cells with higher Jak2 and STAT3 expression, cisplatin and ruxolitinib combination dramatically suppressed the cell growth, down-regulated the expression of phosphorylated STAT3 and induced cleaved caspase-3 expression. Moreover combination with cisplatin and ruxolitinib also significantly inhibited the growth of resistant cell H1299, A549/DDP and H2347 in soft agar model. Finally, combination group significant inhibited the tumor growth and induced the caspase-3 expression compared with either single agent alone (P < 0.05) on the resistant cell xenografts model. The present study indicates that further study is warranted to determine the effectiveness of combination treatment with cisplatin and Jak2/stat3 pathway inhibitor for platinum-resistant NSCLC.

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BackgroundFluoroquinolone-related hepatotoxicity is rare but serious and is attracting increasing attention. We explored the incidence, clinical features and risk factors of acute liver injury associated with fluoroquinolone use.Materials and methodsBased on the Adverse Drug Events Active Surveillance and Assessment System that we developed, we carried out a case-control study by enrolling patients who were hospitalized and received fluoroquinolones to treat or prevent infections at the Chinese People’s Liberation Army General Hospital from Jan 2016 to Dec 2017. The incidence of fluoroquinolone-induced acute liver injury was estimated, and logistic regression was used to reveal the risk factors of this adverse reaction.ResultsWe found that 17,822 patients received fluoroquinolones, and 13,678 of them met the inclusion criteria. A total of 91 patients developed acute liver injury after receiving the medication, and 369 controls were matched to these patients. The overall incidence of fluoroquinolone-induced acute liver injury in the Chinese population is approximately 6–7 cases per 1,000 individuals annually. Multivariate logistic regression analysis showed that older age slightly decreased the risk of hepatotoxicity (OR, 0.98; 95% CI, 0.96–0.99). The male sex (OR, 2.19; 95% CI, 1.07–4.48), alcohol abuse (OR, 2.91; 95% CI, 1.39–6.11) and hepatitis B carrier status (OR, 2.38; 95% CI, 1.04–5.48) increased the risk of liver injury. Concurrent use of cephalosporins or carbapenems was also associated with an increased risk.ConclusionIncreased risk of fluoroquinolone-related hepatotoxicity may be associated with youth, the male sex, alcohol abuse, hepatitis B carrier status and the concurrent use of cephalosporins or carbapenems.

According to the updated Roussel Uclaf Causality Assessment Method (RUCAM), drug-induced liver injury (DILI) is currently defined based on thresholds of alanine aminotransferase (ALT) levels above 5 × the upper limit of normal (ULN) and/or alkaline phosphatase (ALP) levels greater than 2 × the ULN. However, many parameters with different thresholds are also currently used in the clinic. We therefore performed a comparative analysis to evaluate which set of criteria was the most appropriate to detect DILI. We enrolled hospitalized patients who received fluoroquinolones to treat or prevent infections. Three liver test criteria were used to diagnose DILI in these patients. RUCAM criteria were defined as the gold standard, and the other two criteria were as follows: 1) ALT or aspartate aminotransferase (AST) levels greater than 5 × the ULN on two consecutive occasions and/or ALP levels greater than 2 × the ULN on two consecutive occasions [issued by DILI Network (DILIN)]; 2) ALT levels greater than 1 × the ULN on two consecutive occasions or ALT levels greater than 2 × the ULN [issued by the National Medical Products Administration (NMPA) of China]. We found that the RUCAM criteria resulted in 657 warnings, DILIN criteria resulted in 358, NMPA criteria resulted in 1,377, and the positive predictive value (PPV) were 9.74%, 10.89%, and 9.73% ( P = 0.80), respectively. The levels of agreement of the DILIN and NMPA criteria with the RUCAM criteria were moderate, but the agreement between the DILIN criteria and NMPA criteria was poor. In conclusion, the NMPA criteria with relatively lax thresholds for the parameters require much more labor to determine the diagnosis, making them unsuitable for clinical practice. Conversely, the DILIN criteria employing stricter thresholds for the parameters were more effective but would miss some positive cases, and the cases it identified were usually quite serious, which is not conductive to early intervention. Therefore, we still recommend the use of the RUCAM criteria in clinical practice.