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
Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [125I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors. 相似文献
We examined the association between three inflammatory markers (Interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) and incident lung cancer using baseline, updated, and averaged inflammatory measures in older adults.
Methods
We fitted multivariable Cox models to assess whether circulating levels of inflammation markers were associated with incident lung cancers in the Health Aging, Body and Composition (HealthABC) prospective cohort of 3075 older adults aged 70–79?years at baseline. IL-6 and CRP were measured biennially, whereas TNF-α was measured at baseline.
Results
Baseline levels of IL-6 were significantly associated with incident lung cancer risk in a model that adjusted for age, gender, race, and site (Model 1) (Hazard RatioT3 vs. T1: 3.34, 95% Confidence Interval: 1.91, 5.85) and in a model adjusted for health factors linked to chronic inflammation (Model 2) (HR T3 vs. T1: 2.57, 95% CI: 1.41, 4.65). The associations observed in time-updated IL-6 (HR T3 vs. T1: 2.47, 95% CI: 1.43, 4.28), cumulatively averaged IL-6 (HR T3 vs. T1: 2.47, 95% CI: 1.43, 4.35), and baseline CRP levels (HR T3 vs. T1: 1.85, 95% CI: 1.11, 3.08) with incident lung cancer in Model 1 were not statistically significant in Model 2.
Conclusions
Baseline CRP and IL-6 levels were associated with increased risk of lung cancer in Model 1 and both models, respectively. Chronic IL-6 inflammation, as quantified by repeated measures was associated with incident lung cancer in Model 1, but not Model 2. Further research is needed to understand the role of CRP and IL-6 in lung carcinogenesis. 相似文献
The prognosis of pancreatic cancer is poor with the overall 5-year survival rate of less than 5% changing minimally over the past decades and future projections predicting it developing into the second leading cause of cancer related mortality within the next decade. Investigations into the mechanisms of pancreatic cancer development, progression and acquired chemoresistance have been constant for the past few decades, thus resulting in the identification of human nucleoside transporters and factors affecting cytotoxic uptake via said transporters. This review summaries the aberrant expression and role of human nucleoside transports in pancreatic cancer, more specifically human equilibrative nucleoside transporter 1/2 (hENT1, hENT2), and human concentrative nucleoside transporter 1/3 (hCNT1, hCNT3), while briefly discussing the connection and importance between these nucleoside transporters and mucins that have also been identified as being aberrantly expressed in pancreatic cancer. The review also discusses the incidence, current diagnostic techniques as well as the current therapeutic treatments for pancreatic cancer. Furthermore, we address the importance of chemoresistance in nucleoside analogue drugs, in particular, gemcitabine and we discuss prospective therapeutic treatments and strategies for overcoming acquired chemoresistance in pancreatic cancer by the enhancement of human nucleoside transporters as well as the potential targeting of mucins using a combination of mucolytic compounds with cytotoxic agents. 相似文献
ObjectiveTo investigate the impact on cardiovascular events (CVEs) in a real-world population of patients with atrial fibrillation (AF) by implementing the Atrial fibrillation Better Care (ABC: A, Avoid stroke with anticoagulation; B, better symptom management; C, Cardiovascular and comorbidity risk management) pathway.Patients and MethodsThis prospective single-center cohort study included 907 consecutive patients with nonvalvular AF on vitamin K antagonists from February 2008 to December 2016. The A, B, and C groups were defined as follows: “A” by a Time in Therapeutic Range ≥65%; “B” by a European Heart Rhythm Association (EHRA) symptom scale I-II, and “C” as optimized cardiovascular comorbidity management. Primary end point was a composite outcome of CVEs.ResultsDuring a median follow-up of 36.9 months (interquartile range [IQR] 20.0-57.5; 3022 patient-years), 118 CVEs occurred (3.9% per year; 95% confidence interval [CI], 3.2-4.7). Symptomatic patients (EHRA III-IV) had a higher risk of CVEs compared with those in EHRA I (hazard ratio [HR], 2.73, 95% CI, 1.61-4.63, P<.001). Optimally managed patients in the ABC group (n=198) had a lower risk of CVEs (1.8 [95% CI, 0.9-3.0] vs 4.5% [95% CI, 3.7-5.5] per year, P=.001) compared with those presenting with at least 1 suboptimal ABC factor (HR, 0.40, 95% CI, 0.22-0.74, P=.003). This association was evident using multivariate Cox proportional regression analysis (HR, 0.44, 95% CI, 0.24-0.80, P=.007).ConclusionIntegrated care management according to the ABC pathway resulted in a significantly lower rate of CVEs, suggesting a clear benefit of a holistic approach to optimize the management of patients with AF.Trial Registrationclinicaltrials.gov Identifier: NCT01882114相似文献
Lilly Laboratories cell porcine kidney 1 (LLC-PK1) cells transfected with human P-glycoprotein (LLC-PK1-P-gp) are widely used in transport assays to identify drug candidates that function as substrates of this efflux transporter. Endogenous transporters expressed in LLC-PK1 cells may complicate the interpretation of findings from P-gp-mediated transport assays. We investigated the impact of porcine breast cancer resistance protein (Bcrp) in P-gp-mediated transport assays in LLC-PK1 cells. Porcine Bcrp mRNA was detected in both LLC-PK1 wildtype (WT) and LLC-PK1-P-gp cells by quantitative RT-PCR. To investigate the activity and impact of porcine Bcrp, we conducted transport assays using 6 typical BCRP substrates in LLC-PK1 cells. Efflux ratios (ER) of the 6 BCRP substrates in LLC-PK1 WT cells were >2, and were reduced in the presence of the BCRP inhibitor Ko143. The efflux activities of the 6 BCRP substrates were confirmed using MDCKII cells transfected with human BCRP. Net ERs of prazosin and fluvastatin, dual substrates of P-gp and BCRP, determined by dividing ERs in LLC-PK1-P-gp cells by those in LLC-PK1 WT cells, were <2, but increased to >2 in the presence of Ko143. These results indicated that endogenous Bcrp in LLC-PK1 cells was involved in the transport of BCRP substrates and may interfere with the identification of P-gp substrates. 相似文献
Rodent models mimic the heterogeneity of head and neck cancer (HNC) malignancies and are used to investigate HNC-associated biomarkers and evaluate drug responses. To assess the utility of patient-derived xenografts (PDXs) as an HNC model, 18 tumour samples were obtained from surgical specimens of patients with HNC and implanted into non-obese diabetic severe combined immunodeficient mice. The histological features of PDXs and corresponding patient samples were compared. Furthermore, the present study investigated how PDX responses to anticancer drugs mimic patient clinical responses, as well as the expression of adenosine triphosphate-binding cassette transporters through chemotherapy in an HNC-PDX model. A total of five PDXs from patients with HNC exhibiting high correspondence with histopathological features of the original patient samples were established (establishment rate, 28%). The responses of three PDXs to cisplatin were associated with clinical responses of the patients. ABC transporter expression was augmented in one PDX model after anticancer drug treatment, but not in PBS-treated passaged PDXs. PDX models exhibited similar biological and chemosensitive characteristics to those of the primary tumours. PDXs could be a useful preclinical tool to test novel therapeutic agents and identify novel targets and biomarkers in HNC. 相似文献