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Cardiovascular Drugs and Therapy Oct 2019To study whether polypharmacy or drug-drug interactions have differential effect on safety and efficacy in patients treated with direct oral anticoagulants (DOACs)... (Meta-Analysis)
Meta-Analysis
PURPOSE
To study whether polypharmacy or drug-drug interactions have differential effect on safety and efficacy in patients treated with direct oral anticoagulants (DOACs) versus warfarin.
METHODS
We performed a systematic review and meta-analysis of studies that randomized patients with atrial fibrillation to DOACs or warfarin stratified by the number of concomitant drugs. Outcomes included stroke or systemic embolism (SE), all-cause mortality, major bleeding, and intracranial hemorrhage. Risk ratios (RR) were calculated and Mantel-Haenszel random effects were applied.
RESULTS
Two high-quality studies were eligible, including 32,465 participants who received apixaban, rivaroxaban, or warfarin, with a median follow-up of 1.9 years. Of participants, 29% used < 5 drugs, 55% used 5-9 drugs, and 16% used ≥ 10 drugs. Drugs interacting with DOACs (P-glycoprotein/CYP3A4) were used by 6460 (20%) of patients. Patients with higher number of drugs (0-4 vs 5-9 vs ≥ 10) had higher rates of mortality (5.8%, 7.9%, 10.0%) and major bleeding (3.4%, 4.8%, 7.7%). Comparative efficacy or safety of DOACs versus warfarin was not affected by polypharmacy status or P-glycoprotein/CYP3A4 inhibitor use. However, the presence of polypharmacy (p = 0.001) or glycoprotein/CYP3A4-modulating drugs (p = 0.03) was correlated with increased risk of major bleeding when compared with warfarin. Overall, DOAC use was associated with a lower risk of stroke/SE (RR, 0.84; 95%CI, 0.74-0.94), all-cause mortality (RR, 0.91; 95%CI, 0.84-0.98), and intracranial hemorrhage (RR, 0.51; 95%CI, 0.38-0.70) compared with warfarin.
CONCLUSIONS
DOACs were more effective than warfarin, and at least as safe. Polypharmacy was associated with adverse outcomes and attenuated the advantage in risk of major bleeding among rivaroxaban users, particularly in the presence of P-glycoprotein/CYP3A4-modulating drugs.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Female; Hemorrhage; Humans; Male; Middle Aged; Polypharmacy; Risk Assessment; Risk Factors; Stroke; Treatment Outcome
PubMed: 31520256
DOI: 10.1007/s10557-019-06907-8 -
Phytomedicine : International Journal... Jul 2019Artemisinin was isolated and identified in 1972, which was the starting point for a new era in antimalarial drug therapy. Furthermore, numerous studies have demonstrated...
BACKGROUND
Artemisinin was isolated and identified in 1972, which was the starting point for a new era in antimalarial drug therapy. Furthermore, numerous studies have demonstrated that artemisinin and its derivatives exhibit considerable anticancer activity both in vitro, in vivo, and even in clinical Phase I/II trials. P-glycoprotein (P-gp) mediated multi-drug resistance (MDR) is one of the most serious causes of chemotherapy failure in cancer treatment. Interestingly, many artemisinin derivatives exhibit excellent ability to overcome P-gp mediated MDR and even show collateral sensitivity against MDR cancer cells. Furthermore, some artemisinin derivatives show P-gp-mediated MDR reversal activity. Therefore, the interaction between P-gp and artemisinin derivatives is important to develop novel combination treatment protocols with artemisinin derivatives and established anticancer drugs that are P-gp substrates.
PURPOSE
This systematic review provides an updated overview on the interaction between artemisinin derivatives and P-gp and the effect of artemisinin derivatives on the P-gp expression level.
RESULTS
Artemisinin derivatives exhibit multi-specific interactions with P-gp. The currently used artemisinin derivatives are not transported by P-gp. However, some of novel synthetized artemisinin derivatives exhibit P-gp substrate properties. Furthermore, many artemisinin derivatives act as P-gp inhibitors, which exhibit the potential to reverse MDR towards clinically used anticancer drugs.
CONCLUSION
Therefore, studies on the interaction between artemisinin derivatives and P-gp provide important information for the development of novel anti-cancer artemisinin derivatives to reverse P-gp mediated MDR and for the design of rational artemisinin-based combination therapies against cancer.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Artemisinins; Drug Resistance, Multiple; Humans; Neoplasms
PubMed: 31301971
DOI: 10.1016/j.phymed.2019.152998 -
Endocrinology Aug 2019Anaplastic thyroid cancer (ATC) is an aggressive type of thyroid cancer with a high mortality rate. Cytotoxic drugs are among the treatment modalities usually used for...
Anaplastic thyroid cancer (ATC) is an aggressive type of thyroid cancer with a high mortality rate. Cytotoxic drugs are among the treatment modalities usually used for ATC treatment. However, systemic chemotherapies for ATC have not been shown to have remarkable efficacy. ATP-binding cassette (ABC) transporters have been suggested as a possible mechanism in ATC resistance to chemotherapy. This systematic review was aimed to define the possible roles of ABC transporters in ATC resistance to chemotherapy. Numerous databases, including Scopus, Web of Science, PubMed, Cochrane Library, Ovid, ProQuest, and EBSCO, were searched for papers published since 1990, with predefined keywords. The literature searches were updated twice, in 2015 and 2017. All identified articles were reviewed, and 14 papers that met the inclusion criteria were selected. In the eligible studies, the roles of 10 out of 49 ABC transporters were evaluated; among them, three pumps (ABCB1, ABCC1, and ABCG2) were the most studied transporters in ATC samples. ABCC1 and ABCG2 had the highest expression rates in ATC, and ABCB1 ranked second among the inspected transporters. In conclusion, ABC transporters are the major determinants of ATC resistance to chemotherapy. By identifying these transporters, we can tailor the best treatment approach for patients with ATC. Additional studies are needed to define the exact role of each ABC transporter and other mechanisms in ATC drug resistance.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Animals; Drug Resistance, Neoplasm; Humans; Neoplastic Stem Cells; Signal Transduction; Thyroid Carcinoma, Anaplastic
PubMed: 31271419
DOI: 10.1210/en.2019-00241 -
The Journal of International Medical... Jul 2019A relationship between polymorphisms rs1128503 and rs1045642 in the multidrug resistance 1 gene () and susceptibility to hepatocellular carcinoma (HCC) has been reported... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
A relationship between polymorphisms rs1128503 and rs1045642 in the multidrug resistance 1 gene () and susceptibility to hepatocellular carcinoma (HCC) has been reported but is inconclusive. This study was performed to explore the significance of polymorphisms rs1128503 and rs1045642 in screening and diagnosis of HCC.
METHODS
Studies of association analyses between gene polymorphisms rs1128503 and rs1045642 and HCC were selected from three foreign language databases (PubMed, Cochrane, and Embase) and three Chinese databases (Wanfang, China National Knowledge Infrastructure, and China Knowledge Network) and subjected to meta-analysis.
RESULTS
We found no significant relationship between the rs1128503 polymorphism and susceptibility to HCC in 4 cohorts and no significant relationship between the rs1045642 polymorphism and susceptibility to HCC in 3 cohorts.
CONCLUSIONS
There was no relationship between polymorphisms rs1128503 or rs1045642 of the gene and susceptibility to HCC.
Topics: ATP Binding Cassette Transporter, Subfamily B; Carcinoma, Hepatocellular; Genetic Predisposition to Disease; Humans; Liver Neoplasms; Polymorphism, Single Nucleotide; Prognosis
PubMed: 31234681
DOI: 10.1177/0300060519855869 -
Clinical Pharmacokinetics Oct 2019Enzyme-mediated biotransformation of pharmacological agents is a crucial step in xenobiotic detoxification and drug disposition. Herein, we investigated the metabolism...
Physicochemical Properties, Biotransformation, and Transport Pathways of Established and Newly Approved Medications: A Systematic Review of the Top 200 Most Prescribed Drugs vs. the FDA-Approved Drugs Between 2005 and 2016.
BACKGROUND
Enzyme-mediated biotransformation of pharmacological agents is a crucial step in xenobiotic detoxification and drug disposition. Herein, we investigated the metabolism and physicochemical properties of the top 200 most prescribed drugs (established) as well as drugs approved by the US Food and Drug Administration (FDA) between 2005 and 2016 (newly approved).
OBJECTIVE
Our objective was to capture the changing trends in the routes of administration, physicochemical properties, and prodrug medications, as well as the contributions of drug-metabolizing enzymes and transporters to drug clearance.
METHODS
The University of Washington Drug Interaction Database (DIDB) as well as other online resources (e.g., CenterWatch.com, Drugs.com, DrugBank.ca, and PubChem.ncbi.nlm.nih.gov) was used to collect and stratify the dataset required for exploring the above-mentioned trends.
RESULTS
Analyses revealed that ~ 90% of all drugs in the established and newly approved drug lists were administered systemically (oral or intravenous). Meanwhile, the portion of biologics (molecular weight > 1 kDa) was 15 times greater in the newly approved list than established drugs. Additionally, there was a 4.5-fold increase in the number of compounds with a high calculated partition coefficient (cLogP > 3) and a high total polar surface area (> 75 Å) in the newly approved drug vs. the established category. Further, prodrugs in established or newly approved lists were found to be converted to active compounds via hydrolysis, demethylases, and kinases. The contribution of cytochrome P450 (CYP) 3A4, as the major biotransformation pathway, has increased from 40% in the established drug list to 64% in the newly approved drug list. Moreover, the role of CYP1A2, CYP2C19, and CYP2D6 were decreased as major metabolizing enzymes among the newly approved medications. Among non-CYP major metabolizers, the contribution of alcohol dehydrogenases/aldehyde dehydrogenases (ADH/ALDH) and sulfotransferases decreased in the newly approved drugs compared with the established list. Furthermore, the highest contribution among uptake and efflux transporters was found for Organic Anion Transporting Polypeptide 1B1 (OATP1B1) and P-glycoprotein (P-gp), respectively.
CONCLUSIONS
The higher portion of biologics in the newly approved drugs compared with the established list confirmed the growing demands for protein- and antibody-based therapies. Moreover, the larger number of hydrophilic drugs found in the newly approved list suggests that the probability of toxicity is likely to decrease. With regard to CYP-mediated major metabolism, CYP3A5 showed an increased involvement owing to the identification of unique probe substrates to differentiate CYP3As. Furthermore, the contribution of OATP1B1 and P-gp did not show a significant shift in the newly approved drugs as compared to the established list because of their broad substrate specificity.
Topics: Animals; Biological Transport; Biotransformation; Drug Approval; Humans; Prescription Drugs; United States; United States Food and Drug Administration
PubMed: 30972694
DOI: 10.1007/s40262-019-00750-8 -
Journal of Cardiology Jun 2019Amiodarone, which inhibits CYP2C9 and P-glycoprotein, is commonly prescribed with non-vitamin K antagonist oral anticoagulants (NOACs) and polypharmacy in high-risk... (Meta-Analysis)
Meta-Analysis
Non-vitamin K antagonist oral anticoagulants with amiodarone, P-glycoprotein inhibitors, or polypharmacy in patients with atrial fibrillation: Systematic review and meta-analysis.
BACKGROUND
Amiodarone, which inhibits CYP2C9 and P-glycoprotein, is commonly prescribed with non-vitamin K antagonist oral anticoagulants (NOACs) and polypharmacy in high-risk atrial fibrillation (AF) patients. We studied efficacy and safety of NOACs in AF patients receiving amiodarone, P-glycoprotein inhibitor, or polypharmacy.
METHODS
After a systematic database search (Medline, EMBASE, CENTRAL, SCOPUS, and Web of Science), four phase-III randomized trials comparing NOACs and warfarin in "with/without amiodarone," "with/without P-glycoprotein inhibitors," or "with/without multiple (≥5, polypharmacy) concomitant drugs" subgroups were included. The outcomes were pooled using a random-effects model to determine the relative risks (RRs) for stroke/systemic thromboembolism (SSTE), major bleeding (MB), intracranial hemorrhage (ICH), and all-cause mortality.
RESULTS
Among patients taking amiodarone, superiority of NOACs over warfarin in non-amiodarone users disappeared in terms of SSTE (p=0.11), MB (p=0.95), ICH (p=0.26), and mortality (p=0.32). No safety benefit (MB) of NOACs compared to warfarin was shown in patients taking P-glycoprotein inhibitors (p=0.47), but SSTE prevention was still superior with NOACs compared to warfarin in the same patient group [RR=0.78 (0.61-0.99), p=0.04, I=11%]. In AF patients with polypharmacy, NOACs showed a lower risk of SSTE [RR=0.82 (0.71-0.96), p=0.01, I=0%] and mortality [RR=0.91 (0.83-0.99), p=0.04, I=0%], but not MB (p=0.81) compared to warfarin.
CONCLUSIONS
NOACs were equivalent to warfarin among AF patients with concomitant amiodarone use in terms of efficacy, safety, and mortality. There was no safety benefit of NOACs over warfarin in patients using polypharmacy or P-glycoprotein inhibitors.
SYSTEMATIC REVIEW REGISTRATION
The protocol of this meta-analysis was registered on PROSPERO under CRD42018104808 (https://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42018104808).
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Oral; Adult; Aged; Amiodarone; Anticoagulants; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Female; Hemorrhage; Humans; Male; Middle Aged; Polypharmacy; Randomized Controlled Trials as Topic; Stroke; Thromboembolism; Treatment Outcome
PubMed: 30770140
DOI: 10.1016/j.jjcc.2018.12.018 -
Current Medicinal Chemistry 2019P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with...
P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Flavonoids; Humans; Molecular Structure; Structure-Activity Relationship
PubMed: 30277144
DOI: 10.2174/0929867325666181001115225 -
Journal of Interventional Cardiac... Jan 2019Amiodarone is a potent inhibitor of the CYP450:3A4 and inhibitor of the P-glycoprotein, both of which metabolize new oral anticoagulants (NOACs). Patients who are on... (Comparative Study)
Comparative Study
PURPOSE
Amiodarone is a potent inhibitor of the CYP450:3A4 and inhibitor of the P-glycoprotein, both of which metabolize new oral anticoagulants (NOACs). Patients who are on NOACs and are concomitantly treated with amiodarone may have a higher risk of major bleeding according to recent retrospective trials. Whether this increased risk outweighs the benefits of NOACs compared to warfarin is unknown. We aimed to compare clinical outcomes between NOACs and warfarin in patients with atrial fibrillation (AF) being treated with amiodarone.
METHODS
We performed a systematic review of MEDLINE, Cochrane, and Embase for randomized controlled trials that compared NOACs to warfarin for prophylaxis of ischemic stroke/thromboembolic events (TEs) in patients with AF and reported outcomes on TE, major bleeding, and intracranial bleeding (ICB). Risk ratio (RR) and 95% confidence intervals were measured using the Mantel-Haenszel method. Fixed effects model was used, and if heterogeneity (I2) was > 25%, effects were analyzed using a random model.
RESULTS
A total of four studies comparing NOACs to warfarin were included in the analysis. The total number of patients on amiodarone was 6197. Mean follow up was 23 ± 5 months. No statistically significant difference for TE prevention (RR, 0.73; 95% CI 0.50-1.07), major bleeding (RR, 1.02; 95% CI 0.68-1.53), or ICB outcomes (RR, 0.58; 95% CI 0.22-1.51) between patients on NOACs + amiodarone when compared to patients on warfarin + amiodarone.
CONCLUSION
Among patients with AF taking amiodarone, there is no increased risk of stroke, major bleeding, or ICB with NOACs compared to warfarin.
Topics: Administration, Oral; Aged; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Female; Humans; Male; Middle Aged; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Stroke; Survival Rate; Thromboembolism; Treatment Outcome; Warfarin
PubMed: 30128801
DOI: 10.1007/s10840-018-0427-y -
Phytomedicine : International Journal... May 2018Fuzi, which is the processed lateral roots of Aconitum carmichaeli Debx. (Ranunculaceae), is a traditional herbal medicine that is well known for its excellent... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Fuzi, which is the processed lateral roots of Aconitum carmichaeli Debx. (Ranunculaceae), is a traditional herbal medicine that is well known for its excellent pharmacological effects and acute toxicity. Aconitum alkaloids are responsible for its pharmacological activity and toxicity. Although a large number of studies on Fuzi have been reported, no comprehensive review on its pharmacokinetics has yet been published.
PURPOSE
This paper seeks to present a comprehensive review regarding the phytochemistry, pharmacokinetic features and toxicity of Fuzi. The regulation of drug-metabolizing enzymes (DMEs) and efflux transporters (ETs) by Fuzi is also concluded. Additionally, the use of Fuzi as a personalized medicine based on the bioavailability barrier (BB), which mainly comprises DMEs and ETs, is discussed.
METHODS
All available information on Fuzi was collected by searching for key words in PubMed, ScienceDirect, CNKI, Google Scholar, Baidu Scholar, and Web of Science.
RESULTS
Aconitum alkaloids, which mainly include diester-diterpene alkaloids (DDAs), monoester-diterpene alkaloids (MDAs) and unesterified-diterpene alkaloids (UDAs), could be detected after Fuzi ingestion in vivo. The Aconitum alkaloids are rapidly absorbed in the intestine and extensively distributed in the body. DMEs, especially CYP3A4/5, are responsible for various types of metabolic reactions of the Aconitum alkaloids. ETs, including P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), are involved in the efflux of the DDAs and MDAs. The kidney is the most important organ involved in the excretion of the Aconitum alkaloids. DDAs are the main toxic compounds present in Fuzi, and their acute toxicity is mainly due to their effects on the voltage-dependent sodium channels. Furthermore, Fuzi can substantially regulate DMEs and ETs.
CONCLUSIONS
The toxicity of DDAs is acute. However, further investigations are necessary to determine the exact toxicological mechanisms. The significant impact of Fuzi on DMEs and ETs suggests that the co-administration of Fuzi with drugs that are substrates of DMEs and/or ETs may cause herb-drug interactions (HDIs). The BB network controlled exposure to the Aconitum alkaloids in vivo. Polymorphisms of DMEs and ETs in different individuals contribute to the differences in the efficacy and toxicity of Fuzi ingestion. In the future, the use of Fuzi as personalized medicine based on the BB network is necessary and practical to achieve ideal therapeutic efficacy with minimal toxicity.
Topics: Aconitum; Alkaloids; Animals; Biological Availability; Chromatography, High Pressure Liquid; Diterpenes; Drugs, Chinese Herbal; Herb-Drug Interactions; Humans; Inactivation, Metabolic; Phytotherapy; Plant Extracts; Precision Medicine; Tissue Distribution
PubMed: 29526584
DOI: 10.1016/j.phymed.2018.03.001 -
The American Journal of Medicine May 2018Direct oral anticoagulants (DOACs) and amiodarone are widely used in the treatment of nonvalvular atrial fibrillation. The DOACs are P-glycoprotein (P-gp) and cytochrome...
BACKGROUND
Direct oral anticoagulants (DOACs) and amiodarone are widely used in the treatment of nonvalvular atrial fibrillation. The DOACs are P-glycoprotein (P-gp) and cytochrome p-450 (CYP3A4) substrates. Direct oral anticoagulant levels may be increased by the concomitant use of potent dual P-gp/CYP3A4 inhibitors, such as amiodarone, which can potentially translate into adverse clinical outcomes. We aimed to assess the efficacy and safety of drug-drug interaction by the concomitant use of DOACs and amiodarone.
METHODS
We performed a systematic review of MEDLINE, the Cochrane Central Register of Clinical Trials, and Embase, limiting our search to randomized controlled trials of patients with atrial fibrillation that have compared DOACs versus warfarin for prophylaxis of stroke or systemic embolism, to analyze the impact on stroke or systemic embolism, major bleeding, and intracranial bleeding risk in patients with concomitant use of amiodarone. Risk ratio (RR) 95% confidence intervals were measured using the Mantel-Haenszel method. The fixed effects model was used owing to heterogeneity (I) < 25%.
RESULTS
Four trials with a total of 71,683 patients were analyzed, from which 5% of patients (n = 3212) were concomitantly taking DOAC and amiodarone. We found no statistically significant difference for any of the clinical outcomes (stroke or systemic embolism [RR 0.85; 95% CI, 0.67-1.06], major bleeding [RR 0.91; 95% CI, 0.77-1.07], or intracranial bleeding [RR 1.10; 95% CI, 0.68-1.78]) among patients taking DOAC and amiodarone versus DOAC without amiodarone.
CONCLUSION
On the basis of the results of this meta-analysis, co-administration of DOACs and amiodarone, a dual P-gp/CYP3A4 inhibitor, does not seem to affect efficacy or safety outcomes in patients with atrial fibrillation.
Topics: Administration, Oral; Amiodarone; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Drug Interactions; Drug Therapy, Combination; Hemorrhage; Humans; Randomized Controlled Trials as Topic
PubMed: 29274758
DOI: 10.1016/j.amjmed.2017.11.047