Rifamycins (rifampin, rifabutin, and rifapentine) play an essential role in the treatment of mycobacterial and some nonmycobacterial infections. They also induce the activity of various drug transporting and metabolizing enzymes, which can impact the concentrations and efficacy of substrates. Many anticoagulant and antiplatelet (AC/AP) agents are substrates of these enzymes and have narrow therapeutic indices, leading to risks of thrombosis or bleeding when coadministered with rifamycins. The objective of this systematic review was to evaluate the effects on AC/AP pharmacokinetics, laboratory markers, and clinical safety and efficacy of combined use with rifamycins. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidance was performed. The PubMed, Embase, and Web of Science databases were queried for English-language reports on combination use of rifamycins and AC/AP agents from database inception through August 2021. The 29 studies identified examined warfarin (n = 17), direct oral anticoagulants (DOACs) (n = 8), and antiplatelet agents (n = 4) combined with rifampin (n = 28) or rifabutin (n = 1). Eleven studies were case reports or small case series; 14 reported on pharmacokinetic or laboratory markers in healthy volunteers. Rifampin-warfarin combinations led to reductions in warfarin area under the curve (AUC) of 15%–74%, with variability by warfarin isomer and study. Warfarin dose increases of up to 3–5 times prerifampin doses were required to maintain coagulation parameters in the therapeutic range. DOAC AUCs were decreased by 20%–67%, with variability by individual agent and with rifampin versus rifabutin. The active metabolite of clopidogrel increased substantially with rifampin coadministration, whereas prasugrel was largely unaffected and ticagrelor saw decreases. Our review suggests most combinations of AC/AP agents and rifampin are problematic. Further studies are required to determine whether rifabutin or rifapentine could be safe alternatives for coadministration with AC/AP drugs. 相似文献
6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT1513 and NUDT1512 genotypes were at a 10–15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT1513 and NUDT1512, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients. 相似文献
The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with Ki values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with Km values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CLR) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CLR (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CLR of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates. 相似文献
Introduction: The sodium-glucose co-transporter 2 (SGLT2) is ascribed to target renal tubular glucose re-absorption, and its inhibition has been proved to induce glucosuria which improves the glycemic index. Accordingly, SGLT2 inhibitors have found to be the promising class of antidiabetic agents for the management of type 2 diabetes mellitus. A large number of SGLT2 inhibitors have developed through structural modification and investigated for their ability to selectivity inhibit SGLT2 transporters with better bioavailability.
Areas covered: This review comprises a summary of patent applications (2013–2018) of SGLT2 inhibitors with focus on chemical structural advancement and therapeutic potentials in the management of diabetes and related disorders.
Expert opinion: SGLT2 inhibitors exert multiple metabolic benefits, including reduced glycated hemoglobin (HbA1c), improved glycemic control (fasting and postprandial), reduced body weight, reduced systolic and diastolic blood pressure and improved HDL cholesterol. Due to the virtue of no interference with insulin action and secretion, their efficacy remains the same even in presence of progressive β cell failure in type 2 diabetes. Additionally, few members of this class have been reported to exhibit cardioprotective, renoprotective, and anticancer activity. However, more study on the long-term outcomes in patients taking SGLT2 inhibitors is warranted. 相似文献
Objective To investigate the effect of rapamycin on cholesterol homeostasis of glomerular mesangial cells and the underlying mechanism. Methods Glomerular mesangial cell line (HMCL) cells were cultured and divided into control group, IL-1β group and different concentration rapamycin groups. Intracellular cholesterol accumulation was observed and measured by oil O staining and HPLC. Real-time quantitative PCR and Western blot were used to detect the mRNA and protein expression of LDLR, PPARγ, LXRα, ABCA1 in HMCL after the treatment with IL-1β and rapamycin. Results Rapamycin had no significant influence on intracellular cholesterol concentration under normal condition. IL-1β significantly increased the intracellular cholesterol concentration by 143% of control (P<0.05), and 10, 50, 100 ?滋g/L rapamycin could significantly inhibit the effect of IL-1β (87%, 116%, 96% of control respectively, all P<0.05). Rapamycin could suppress the increased expression of LDLR caused by IL-1β on both mRNA and protein level in a dose-dependent manner(P<0.01). Rapamycin dose-dependently up-regulated the reduced mRNA and protein expression of ABCA1, the decreased mRNA expression of PPARγ and LXRα induced by IL-1β as well (P<0.01). Conclusion Rapamycin may contribute to the maintenance of intracellular cholesterol homeostasis in glomerular mesangial cells under inflammatory state by both reducing cholesterol uptake and promoting cholesterol efflux. 相似文献
We report on the effect of age and chronic caloric restriction (CR) on insulin binding and glucose transporter content in both diaphragm and heart muscle membrane of young (11 months), mid-age (17 months), and old (29 month) ad libitum fed and CR Brown-Norway rats. The control animals received rat chow ad lib and CR animals were allowed 60% of ad libitum food. The CR regimen was initiated at four months of age and the animals were maintained on their respective diets until necropsy. There was no effect of age on insulin binding for either ad libitum or CR animals at each age evaluated. Caloric restriction significantly lowered insulin levels at each age studied when compared to the ad libitum-fed rats. However, CR animals were noted to have increased insulin binding (p < 0.001) compared to ad libitum-fed animals at each age for diaphragm muscle. For the heart, there appeared to be a decreased binding, particularly at higher insulin concentrations, in CR-fed animals. There was no net change in Glut-1 or Glut-4 levels for heart muscle membrane, or Glut-4 levels for diaphragm muscle membrane between ad libitum or CR animals. This data indicates that caloric restriction may have tissue-specific effects for insulin receptor binding, and that the improved insulin sensitivity in CR states is not a result of altered glucose transporter protein content. 相似文献