Insights into efficacy and safety of dapagliflozin treatment for the management in older adults with type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: This study aimed to evaluate the efficacy and safety of dapagliflozin as a monotherapy glucose-lowering drug treatment for older adults with diabetes. RESEARCH DESIGN & METHODS: Randomized controlled trial reports were retrieved from PubMed, Embase Cochrane Library, and Web of Science from database inception to 8 May 2021. Publication bias and heterogeneity were assessed using the Cochrane risk-of-bias tool and the Cochrane Q statistic, respectively. RESULTS: Compared with placebo, dapagliflozin as a monotherapy glucose-lowering drug did improve the control of glycosylated hemoglobin and fasting plasma glucose levels in older adults. Our analysis also confirmed that the body weight of older adults was well controlled under treatment of dapagliflozin as a monotherapy glucose-lowering drug. Patients in older adults with diabetes took a higher risk of genital infection and renal impairment or failure after treatment of dapagliflozin. In addition, treatment with dapagliflozin reduced the risk of hypoglycemia, and did not reveal increased risk of urinary tract infection and developing fractures compared to placebo in older adults. CONCLUSIONS: Dapagliflozin as a monotherapy glucose-lowering drug appeared to be an effective treatment for older adults with diabetes, although it might increase risk of genital infection and renal impairment or failure.

Validity of the association between five steroid hormones quantification and female infertility conditions: A new perspective for clinical diagnosis.

Quantification of endogenous steroids and their precursors is essential for diagnosis of a wide range of causes for female infertility. However, immunoassays often overestimate concentrations due to assay interference by other endogenous steroids, especially at low concentrations. In addition, it still lacks of diagnostic reference intervals for five sex steroid hormones, including estradiol (E2), 11-deoxycorticosterone (DOC), 17-hydroxyprogesterone (17-OHP4), pregnenolone (P5) and progesterone (P4), which are crucial for distinguishing between normal individuals and female infertility. Therefore, we developed and validated a reliable and rapid ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous determination and quantification of five sex hormones, giving the reference intervals to accurately evaluate and diagnose female infertility. Our results showed that the developed UPLC-MS/MS assay was fast, high throughput, reproducible, specific, accurate, highly sensitive, and fully validated for simultaneous determination of P5, P4, 17-OHP4, DOC and E2 in human follicular fluid. The simple sample preparation procedure in the current study gave reproducible and consistent recoveries. The validation results show that the UPLC-MS/MS assay has acceptable accuracy and precision at low concentrations, which permits their use in clinical study. In addition, our data gave the concentration range of five steroid hormones quantification in patients with female infertility and normal individuals. Our data can be used to accurately evaluate and diagnose female infertility.

Comparison of Hepatotoxicity Associated With New BCR-ABL Tyrosine Kinase Inhibitors vs Imatinib Among Patients With Chronic Myeloid Leukemia: A Systematic Review and Meta-analysis.

Importance: Although BCR-ABL fusion oncoprotein tyrosine kinase inhibitors (BCR-ABL TKIs) can substantially improve the survival rate of chronic myeloid leukemia (CML), they are clinically accompanied by severe hepatotoxicity. Objective: To compare the relative risk (RR) of hepatotoxicity of new-generation BCR-ABL TKIs with that of imatinib, and to provide an overall assessment of the clinical benefit. Data Sources: PubMed, Embase, Cochrane library databases, and ClinicalTrials.gov were searched for clinical trials published between January 2000 and April 2020. Study Selection: Study selection was conducted independently by 2 investigators according to the inclusion and exclusion criteria published previously in the protocol: only randomized phase 2 or phase 3 clinical trials that compared bosutinib, dasatinib, nilotinib, or ponatinib with imatinib were included. Among the 2666 records identified, 9 studies finally fulfilled the established criteria. Data Extraction and Synthesis: Two investigators extracted study characteristics and data independently using a standardized data extraction form. Data were extracted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. When substantial heterogeneity was observed, pooled estimates were calculated based on the random-effect model; otherwise, the fixed-effect model was used. Main Outcomes and Measures: Data extracted included study characteristics, baseline patient information, interventions and data on all-grade and high-grade (grades 3 and 4) elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, overall survival, and major molecular response (MMR). The RRs and 95% CIs were calculated using the inverse variance method. Results: Nine trials involving 3475 patients were analyzed; the median (range) age was 49 (18-91) years; 2059 (59.2%) were male patients. Increased risks were observed for each new-generation TKI except for dasatinib. Patients receiving new-generation TKIs were more likely to experience all grades of ALT elevation (pooled RR, 2.89; 95% CI, 1.78-4.69; P < .001) and grades 3 and 4 ALT elevation (pooled RR, 4.36; 95% CI, 2.00-9.50; P < .001) compared with those receiving imatinib. Patients receiving new-generation TKIs were also more likely to experience all grades of AST elevation (pooled RR, 2.20; 95% CI, 1.63-2.98; P < .001) and grades 3 and 4 AST elevation (pooled RR, 2.65; 95% CI, 1.59-4.42; P < .001) compared with those receiving imatinib. New-generation TKIs were associated with a significantly higher rate of MMR at 1 year compared with imatinib (pooled RR, 1.59; 95% CI, 1.44-1.75; P < .001). No statistical difference in overall survival at 1 year was found between new-generation TKIs and imatinib (pooled RR, 1.00; 95% CI, 1.00-1.01; P = .33). Conclusions and Relevance: When compared to imatinib, bosutinib, nilotinib, and ponatinib had higher relative risks of hepatotoxicity. Treatment with new-generation TKIs was associated with a higher MMR rate at 1 year but not with 1-year overall survival.

Efficacy and safety of levetiracetam versus (fos)phenytoin for second-line treatment of epilepticus: a meta-analysis of latest randomized controlled trials.

OBJECTIVES: To assess the efficiency and safety profiles of levetiracetam and (fos)phenytoin (phenytoin or fosphenytoin) for second-line treatment of seizures by performing a meta-analysis of RCTs. METHODS: We systematically searched PubMed, Embase, Cochrane, FDA.gov, and ClinicalTrials.gov for RCTs (published before July 31, 2020; no language restrictions). Two independent reviewers screened abstracts and titles against inclusion and exclusion criteria published previously in the PROSPERO: CRD42020202736. Eleven studies fulfilled the established criteria. We assessed pooled data by using a random-effects model. Quality analysis was performed by using version 2 of the Cochrane risk-of-bias tool (RoB 2). RevMan v.5.3 was used to perform statistical analyses, and publication bias (egger's test) was assessed with Stata MP v.14.0. RESULTS: Levetiracetam was similar to (fos)phenytoin in seizure termination rate (risk ratio [RR] 0.94; 95% CI 0.87 to 1.01), time of seizure termination (mean difference [MD] 0.44; -0.60 to 1.49), and drug resistance ([RR] 1.12, 0.86 to 1.45). The safety outcome showed a significant statistical difference between fosphenytoin group and levetiracetam group ([RR] 1.44, 1.14 to 1.81), while there was no significant difference observed between phenytoin treatment and levetiracetam treatment ([RR] 1.26, 0.99 to 1.60). CONCLUSION: Levetiracetam was similar to (fos)phenytoin in cessation rate convulsive status epilepticus, and drug resistance, while it was superior (fos)phenytoin in pooled safety outcome. Further exploration is still needed as to whether it is the first choice for second-line drugs.

In vitro inhibition of human UDP-glucuronosyltransferase (UGT) 1A1 by osimertinib, and prediction of in vivo drug-drug interactions.

Osimertinib is the only third-generation epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) approved by Food and Drug Administration (FDA). This study aimed to know the inhibitory effect of osimertinib on human UDP-glucosyltransferases (UGTs) and human liver microsomes (HLMs), as well as to identify its potential to cause drug-drug interaction (DDI) arising from the modulation of UGT activity. High inhibitory effect of osimertinib was shown towards UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A10, 2B7 and 2B15. Especially, osimertinib exhibited competitive inhibition against UGT1A1 with a Ki,u of 0.87 ± 0.12 µM. It also noncompetitively inhibited SN-38 glucuronidation in pooled HLMs with a Ki,u of 3.32 ± 0.25 µM. Results from quantitative prediction study indicated that osimertinib administered at 80 mg/day may result in a 4.83 % increase in the AUC of drugs mainly metabolized by UGT1A1, implying low risk of DDI via liver metabolism. However, the ratios of [I]gut/Ki,u are much higher than 11 in HLMs and recombinant UGT1A1, indicating a risk for interaction in intestine. The effects of osimertinib on intestinal UGT should be paid more attention on to avoid unnecessary clinical DDI risks.

Inhibition of human UDP-glucuronosyltransferase enzymes by midostaurin and ruxolitinib: implications for drug-drug interactions.

Cancer therapy with tyrosine kinase inhibitors (TKIs) is a rapidly developing field, and several TKIs have been reported to have an impact on the activities of UDP-glucosyltransferases (UGTs), implying a potential risk for drug-drug interaction (DDI). Herein, we investigated the inhibitory effects of two commonly used TKIs, midostaurin and ruxolitinib, on human UGTs and quantitatively evaluated their DDI potential via UGT inhibition. It was found that midostaurin was a potent inhibitor of the majority of human UGTs, including UGT1A3, 1A4, 1A7, 1A8, 1A9, 1A10, 2B7, 2B15, and 2B17, with IC50 values lower than 4 µM (IC50 0.0128-3.85 µM), while ruxolitinib exhibited weak inhibition towards the activity of almost all the tested UGT isoforms. Furthermore, based on reversible inhibition, the co-administration of midostaurin at the clinical available dose was predicted to increase the plasma exposure to sensitive UGT1A3, 1A7, and 1A8 substrates by at least 61.4%, 25.6%, and 651%, respectively. In summary, our data identify that midostaurin is a potent inhibitor of the majority of human UGTs and may bring a potential risk of DDI via inhibition against UGT1A3, 1A7, and 1A8, while ruxolitinib cannot trigger UGT-mediated DDI due to its weak inhibition towards UGTs.