UPLC-MS/MS assay for the simultaneous determination of pyrotinib and its oxidative metabolite in rat plasma: Application to a pharmacokinetic study.

Pyrotinib is an irreversible EGFR/HER2 inhibitor that has been approved for the treatment of breast cancer. The aim of this work was to establish a quantification method for the simultaneous determination of pyrotinib and its metabolite pyrotinib-lactam in rat plasma using UPLC-MS/MS. After simple protein precipitation with acetonitrile, the analytes and internal standard (neratinib) were separated on an ACQUITY BEH C18 column (2.1 × 50 mm, 1.7 µm) using a mobile phase of water containing 0.1% formic acid and acetonitrile. The detection was performed using selected reaction monitoring mode with precursor-to-product ion transitions at m/z 583.2 > 138.1 for pyrotinib, m/z 597.2 > 152.1 for pyrotinib-lactam, and m/z 557.2 > 112.1 for internal standard. The assay exhibited excellent linearity in the concentration range of 0.5-1000 ng/mL for pyrotinib and pyrotinib-lactam. The assay met the criteria of the United States Food and Drug Administration-validated bioanalytical methods and was successfully applied to a pharmacokinetic study of pyrotinib and its metabolite for the first time. Our results demonstrated that pyrotinib rapidly converted into pyrotinib-lactam, whose in vivo exposure was 21% that of pyrotinib.

Genetically predicted circulating levels of cytokines and the risk of osteoarthritis: A mendelian randomization study.

Background: The association between inflammatory cytokines and osteoarthritis (OA) has been reported in several observational studies, but the causal relationship between these two remains unknown. Hence, we performed this two-sample Mendelian randomization (MR) to confirm the causal relationship between circulating levels of inflammatory factors and osteoarthritis risk. Method: We used genetic variants associated with cytokine circulation levels from a meta-analysis of genome-wide association studies (GWASs) in 8,293 Finns as instrumental variables and obtained OA data from the United Kingdom Biobank, including a total of 345,169 subjects of European ancestry (66,031 diagnosed OA cases and 279,138 controls). Inverse variance weighting (IVW), MR-Egger, Wald Ratio, weighted median, and MR multiplicity residual sums with outliers (MR-PRESSO) were used. Result: We found a causal relationship between circulating levels of macrophage inflammatory protein-1beta (MIP-1ß) and risk of OA (OR = 0.998, 95% CI = 0.996-0.999p = 9.61 × 10-5); tumour necrosis factor beta (TNF-ß) was also causally associated with risk of OA (OR = 0.996,95%CI = 0.994-0.999, p = 0.002); finally we found a suggestive association between C-C motif chemokine ligand 5(CCL5, also called Rantes) and OA risk (OR = 1.013, 95%CI = 1.002-1.024,p = 0.016). Conclusion: Our findings offer promising leads for the development of new therapeutic targets in the treatment of osteoarthritis. By identifying the role of inflammatory cytokines in this debilitating condition through a genetic epidemiological approach, our study contributes to a better understanding of the underlying disease mechanisms. These insights may ultimately pave the way for more effective treatments that improve patient outcomes.

Ketorolac Administration After Colorectal Surgery Increases Anastomotic Leak Rate: A Meta-Analysis and Systematic Review.

OBJECTIVE: This meta-analysis aimed to evaluate whether ketorolac administration is associated with an increased anastomotic leak rate after colorectal surgery. METHODS: The literature was searched using the Web of Science, Embase, and PubMed databases, and the search ended on May 31, 2020. The Newcastle-Ottawa Scale was used to assess methodological quality. Statistical heterogeneity was assessed using the Chi-square Q test and I 2 statistics. Subgroup analysis was performed, and Egger's test was used to assess publication bias. RESULTS: This meta-analysis included seven studies with 400,822 patients. Our results demonstrated that ketorolac administration after surgery increases the risk of anastomotic leak [OR = 1.41, 95% CI: 0.81-2.49, Z = 1.21, P = 0.23]. Low heterogeneity was observed across these studies (I 2 = 0%, P = 0.51). The results of subgroup analysis showed that the use of ketorolac in case-control and retrospective cohort studies significantly increased the risk of anastomotic leak (P < 0.05). Furthermore, the subgroup analysis revealed that ketorolac use increased anastomotic leak rate in patients in the United States and Canada, and ketorolac plus morphine use did not increase anastomotic leak rate in Taiwanese patients (P < 0.05). No significant publication bias was observed (P = 0.126). Moreover, the analysis of risk factors related to anastomotic leak rate indicated that the total use of ketorolac did not increase the risk of anastomotic leak similar to the control group (P > 0.05). CONCLUSION: The meta-analysis indicates that the use of ketorolac increases the risk of anastomotic leak after colorectal surgery. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, identifier CRD42020195724.