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Expert Opinion on Drug Safety Dec 2020The effects of the C3435T genetic polymorphism on clopidogrel responses are conflicting and inconclusive especially in patients undergoing percutaneous coronary... (Meta-Analysis)
Meta-Analysis
Effects of the C3435T single nucleotide polymorphism on major adverse cardiovascular events in acute coronary syndrome or coronary artery disease patients undergoing percutaneous coronary intervention and treated with clopidogrel: A systematic review and meta-analysis.
INTRODUCTION
The effects of the C3435T genetic polymorphism on clopidogrel responses are conflicting and inconclusive especially in patients undergoing percutaneous coronary intervention (PCI). This study examined the pooled risk of major adverse cardiovascular events (MACE) and bleeding events associated with the C3435T polymorphism in acute coronary syndrome or coronary artery disease patients undergoing PCI and treated with clopidogrel.
AREAS COVERED
Literature was searched in different resources for eligible studies. The pooled risk ratio was measured using RevMan software, with <0.05 (two-sided) set as statistically significant.
EXPERT OPINION
The C3435T homozygous mutant (TT) was associated with significantly increased risk of MACE compared to either wild type genotype (CC) or the combination of wild type and heterozygous genotypes (TT vs. CC: RR 1.33; 95% CI 1.06-1.68; =0.02; TT vs. CC+CT: RR 1.32; 95% CI 1.10-1.60; =0.004). Safety outcomes, i.e. bleeding events were not significantly different between the genetic models investigated (TT vs. CC: RR 1.93; 95% CI 0.86-4.35; =0.11; TT vs. CC+CT: RR 1.36; 95% CI 0.89-2.09; =0.16; CT+TT vs. CC: RR 1.20; 95% CI 0.59-2.44; =0.61). It is suggested that C3435T genotype should be tested for ACS/CAD patients undergoing PCI to ensure optimum therapy of clopidogrel.
Topics: ATP Binding Cassette Transporter, Subfamily B; Acute Coronary Syndrome; Cardiovascular Diseases; Clopidogrel; Coronary Artery Disease; Genotype; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Polymorphism, Single Nucleotide
PubMed: 33040624
DOI: 10.1080/14740338.2020.1836152 -
Pharmaceutical Research Sep 2020The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in apixaban...
PURPOSE
The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in apixaban disposition based on in vitro studies. Recommendations against co-administration of apixaban with inhibitors of these efflux transporters can be found throughout the literature as well as in the apixaban FDA label. However, the clinical relevance of such findings is questionable due to the high permeability and high solubility characteristics of apixaban.
METHODS
Using recently published methodologies to discern metabolic- from transporter- mediated drug-drug interactions, a critical evaluation of all published apixaban drug-drug interaction studies was conducted to investigate the purported clinical significance of efflux transporters in apixaban disposition.
RESULTS
Rational examination of these clinical studies using basic pharmacokinetic theory does not support the clinical significance of intestinal efflux transporters in apixaban disposition. Further, there is little evidence that efflux transporters are clinically significant determinants of systemic clearance.
CONCLUSIONS
Inhibition or induction of intestinal CYP3A4 can account for exposure changes of apixaban in all clinically significant drug-drug interactions, and lack of intestinal CYP3A4 inhibition can explain all studies with no exposure changes, regardless of the potential for these perpetrators to inhibit intestinal or systemic efflux transporters.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Biological Transport; Cytochrome P-450 CYP3A; Drug Interactions; Humans; Intestinal Absorption; Neoplasm Proteins; Pyrazoles; Pyridones
PubMed: 32996065
DOI: 10.1007/s11095-020-02927-4 -
Clinical Drug Investigation Nov 2020Direct oral anticoagulants (DOACs), as substrates of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein, are susceptible to drug-drug interactions (DDIs). Hepatitis C...
BACKGROUND
Direct oral anticoagulants (DOACs), as substrates of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein, are susceptible to drug-drug interactions (DDIs). Hepatitis C direct-acting antiviral agents (DAAs), via P-glycoprotein or CYP3A4 inhibition, may increase DOAC exposure with relevant bleeding risk. We performed a systematic review on DDIs between DOACs and DAAs.
METHODS
Two reviewers independently identified studies through electronic databases, until 7 July 2020, supplementing the search by reviewing conference abstracts and the ClinicalTrials.gov website.
RESULTS
Of 1386 identified references, four articles were finally included after applying the exclusion criteria. Three phase I clinical studies in healthy volunteers assessed interactions between dabigatran and glecaprevir/pibrentasvir, odalasvir/simeprevir, or sofosbuvir/velpatasvir/voxilaprevir, showing an increase in the dabigatran area under the concentration-time curve (AUC) by 138%, 103%, and 161%, respectively.
CONCLUSIONS
DOACs and DAAs are under-investigated for DDI risk. Real-world studies are needed to assess the clinical relevance of the pharmacokinetic interactions with dabigatran and describe the actual spectrum of possible DDIs between DAAs and other DOACs.
Topics: Anticoagulants; Antiviral Agents; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Hepatitis C; Humans
PubMed: 32809123
DOI: 10.1007/s40261-020-00962-y -
BMC Complementary Medicine and Therapies Jun 2020African Potato (hypoxis hemerocallidea), is used for enhancing immune system in Southern Africa. It is among the plants of intense commercial and scientific interest;...
BACKGROUND
African Potato (hypoxis hemerocallidea), is used for enhancing immune system in Southern Africa. It is among the plants of intense commercial and scientific interest; hence, the aim of this study was to describe its chemistry and pharmacology.
METHODS
PubMed, Cochrane Controlled Trials Register (CENTRAL) and Google Scholar were searched independently for relevant literature. The last search occurred in October 2018. Other research material was obtained from Google. The following search terms were used, but not limited to: "African Potato", "hypoxis", "hemerocallidea", "rooperol." Articles that were explaining the chemistry and pharmacology of hypoxis hemerocallidea were included.
RESULTS
Thirty articles from PubMed, Cochrane and Google Scholar were eligible. Three webpages were included from Google. Results showed that the tuberous rootstock (corm) of African Potato is used traditionally to treat wasting diseases, testicular tumours, insanity, barrenness, impotency, bad dreams, intestinal parasites, urinary infection, cardiac disease and enhancing immunity. The plant contains hypoxoside, which is converted rapidly to a potent antioxidant, rooperol in the gut. The corm contains sterols, sterol glycosides, stanols, terpenoids, saponins, cardiac glycosides, tannins and reducing sugars. A dose of 15 mg/kg/day of hypoxoside is reportedly therapeutic. Preclinical studies of African Potato have shown immunomodulation, antioxidant, antinociceptive, hypoglycaemic, anti-inflammatory, anticonvulsant, antibacterial, uterolytic, antimotility, spasmolytic and anticholinergic effects. The common side effects of African Potato are nausea and vomiting, which subside over time. In vitro, African Potato demonstrated inhibitory effects on CYP1A2, 2C9, 2D6, 3A4, 3A5, CYP19-metabolism and induction of P-glycoprotein. In vivo, it did not alter the pharmacokinetics of efavirenz or lopinavir/ritonavir.
CONCLUSION
African Potato is mainly used as an immunostimulant. The exact mechanisms of action for all the pharmacological actions are unknown. More research is required to substantiate claims regarding beneficial effects. There are many research gaps that require investigation including pharmacokinetic interactions with conventional drugs, especially those used in HIV/AIDS.
Topics: Africa; Catechols; Humans; Hypoxis; Medicine, African Traditional; Plant Extracts; Plants, Medicinal
PubMed: 32527245
DOI: 10.1186/s12906-020-02956-x -
Hamostaseologie Dec 2020Recombinant interleukin-2 (rIL-2) is indicated for metastatic renal cell carcinoma and melanoma. Over recent years low-dose rIL-2 has been studied for the treatment of...
Recombinant interleukin-2 (rIL-2) is indicated for metastatic renal cell carcinoma and melanoma. Over recent years low-dose rIL-2 has been studied for the treatment of autoimmune diseases and acute coronary syndrome because of its ability to expand and activate T regulatory (T) cells. However, several medical conditions potentially benefiting from rIL-2 administrations are characterized by an intrinsic prothrombotic risk, thus requiring concurrent anticoagulation. In our systematic review of the literature, we investigated the potential for drug interactions between oral anticoagulants and rIL-2 by assessing the influence of rIL-2 administration on transporters and cytochromes determining the pharmacokinetics of (direct) oral anticoagulants. We extracted data from 12 studies, consisting of 11 animal studies and one study in humans. Eight studies investigated the pharmacokinetics of P-glycoprotein (P-gp) substrates and reported that the intraperitoneal rIL-2 administration may inhibit intestinal P-gp. Four studies on hepatic cytochrome P450 yielded conflicting results. The only human study included in this systematic review concluded that rIL-2 suppresses the hepatic cytochrome P450, but only if given at higher doses. Based on the results from animal studies, the co-administration of rIL-2 and dabigatran etexilate, a substrate of intestinal P-gp, may lead to higher dabigatran plasma concentrations and bioavailability. Human studies should confirm whether this potential interaction is clinically relevant.
Topics: Animals; Drug Interactions; Factor Xa Inhibitors; Humans; In Vivo Dosimetry; Interleukin-2
PubMed: 32325520
DOI: 10.1055/a-1120-4064 -
Current Cancer Drug Targets 2020Breast cancer is the most probable cancer among women. However, the available treatment is based on targeting different stages of breast cancer viz., radiation therapy,...
PURPOSE
Breast cancer is the most probable cancer among women. However, the available treatment is based on targeting different stages of breast cancer viz., radiation therapy, hormonal therapy, chemotherapy, and surgical interventions, which have some limitations. The available chemotherapeutics are associated with problems like low solubility, low permeability, high first-pass metabolism, and P-glycoprotein efflux. Hence, the aforementioned restrictions lead to ineffective treatment. Multiple chemotherapeutics can also cause resistance in tumors. So, the purpose is to develop an effective therapeutic regimen for the treatment of breast cancer by applying a nanomedicinal approach.
METHODS
This review has been conducted on a systematic search strategy, based on relevant literature available on Pub Med, MedlinePlus, Google Scholar, and Sciencedirect up to November 2019 using keywords present in abstract and title of the review. As per our inclusion and exclusion criteria, 226 articles were screened. Among 226, a total of 40 articles were selected for this review.
RESULTS
The significant findings with the currently available treatment is that the drug, besides its distribution to the target-specific site, also distributes to healthy cells, which results in severe side effects. Moreover, the drug is less bioavailable at the site of action; therefore, to overcome this, a high dose is required, which again causes side effects and lower the benefits. Nanomedicinal approaches give an alternative approach to avoid the associated problems of available chemotherapeutics treatment of breast cancer.
CONCLUSION
The nanomedicinal strategies are useful over the conventional treatment of breast cancer and deliver a target-specific drug-using different novel drug delivery approaches.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Drug Delivery Systems; Female; Humans; Nanostructures; Theranostic Nanomedicine
PubMed: 32228423
DOI: 10.2174/1568009620666200331124113 -
Epilepsy Research May 2020Use of non-vitamin K antagonist oral anticoagulants (NOACs), including dabigatran etexilate, rivaroxaban, apixaban, edoxaban or betrixaban provides a safe and convenient...
Use of non-vitamin K antagonist oral anticoagulants (NOACs), including dabigatran etexilate, rivaroxaban, apixaban, edoxaban or betrixaban provides a safe and convenient alternative to the traditional anticoagulation with vitamin K antagonists or heparin derivatives. Many patients receiving long-term seizure prophylaxis with antiepileptic drugs (AEDs) may require anticoagulation with NOACs. Providers caring for these patients need to be informed about potential interactions between AEDs and NOACs and the relevant clinical consequences. A systematic review of the existing literature was conducted to elucidate current knowledge on the clinically relevant interactions between AEDs and NOACs and highlight areas in which further research is needed. The systematic review protocol was developed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. Ovid MEDLINE, Embase, The Cochrane Library and SciFinder were searched. Of the 630 non-duplicate items identified by the search, 13 met eligibility criteria. These 13 items included 8 case reports, 2 letters to the editor and 3 nonrandomized studies. The majority of pharmacokinetic interactions between NOACs and first generation AEDs occurred via the induction of the hepatic enzyme system and competition for the P-glycoprotein transporter and lead to decreased NOAC plasma levels and consequent thrombotic events. Only one article, a case report, was identified that focused on interactions between the second generation AED and a NOAC. At the present time, the limited evidence suggests that enzyme-inducing or inhibiting AEDs reduce the effectiveness of anticoagulation produced by several NOACs. This information may help providers anticipate possible interactions and guide therapy appropriately.
Topics: Administration, Oral; Anticoagulants; Anticonvulsants; Drug Interactions; Epilepsy; Humans
PubMed: 32155540
DOI: 10.1016/j.eplepsyres.2020.106304 -
Drug Resistance Updates : Reviews and... May 2020Multidrug resistance (MDR) is the dominant cause of the failure of cancer chemotherapy. The design of antitumor drugs that are able to evade MDR is rapidly evolving,...
Multidrug resistance (MDR) is the dominant cause of the failure of cancer chemotherapy. The design of antitumor drugs that are able to evade MDR is rapidly evolving, showing that this area of biomedical research attracts great interest in the scientific community. The current review explores promising recent approaches that have been developed with the aim of circumventing or overcoming MDR. Encouraging results have been obtained in the investigation of the MDR-modulating properties of various classes of natural compounds and their analogues. Inhibition of P-gp or downregulation of its expression have proven to be the main mechanisms by which MDR can be surmounted. The use of hybrid molecules that are able to simultaneously interact with two or more cancer cell targets is currently being explored as a means to circumvent drug resistance. This strategy is based on the design of hybrid compounds that are obtained either by merging the structural features of separate drugs, or by conjugating two drugs or pharmacophores via cleavable/non-cleavable linkers. The approach is highly promising due to the pharmacokinetic and pharmacodynamic advantages that can be achieved over the independent administration of the two individual components. However, it should be stressed that the task of obtaining successful multivalent drugs is a very challenging one. The conjugation of anticancer agents with nitric oxide (NO) donors has recently been developed, creating a particular class of hybrid that can combat tumor drug resistance. Appropriate NO donors have been shown to reverse drug resistance via nitration of ABC transporters and by interfering with a number of metabolic enzymes and signaling pathways. In fact, hybrid compounds that are produced by covalently attaching NO-donors and antitumor drugs have been shown to elicit a synergistic cytotoxic effect in a variety of drug resistant cancer cell lines. Another strategy to circumvent MDR is based on nanocarrier-mediated transport and the controlled release of chemotherapeutic drugs and P-gp inhibitors. Their pharmacokinetics are governed by the nanoparticle or polymer carrier and make use of the enhanced permeation and retention (EPR) effect, which can increase selective delivery to cancer cells. These systems are usually internalized by cancer cells via endocytosis and accumulate in endosomes and lysosomes, thus preventing rapid efflux. Other modalities to combat MDR are described in this review, including the pharmaco-modulation of acridine, which is a well-known scaffold in the development of bioactive compounds, the use of natural compounds as means to reverse MDR, and the conjugation of anticancer drugs with carriers that target specific tumor-cell components. Finally, the outstanding potential of in silico structure-based methods as a means to evaluate the ability of antitumor drugs to interact with drug transporters is also highlighted in this review. Structure-based design methods, which utilize 3D structural data of proteins and their complexes with ligands, are the most effective of the in silico methods available, as they provide a prediction regarding the interaction between transport proteins and their substrates and inhibitors. The recently resolved X-ray structure of human P-gp can help predict the interaction sites of designed compounds, providing insight into their binding mode and directing possible rational modifications to prevent them from becoming P-gp drug substrates. In summary, although major efforts were invested in the search for new tools to combat drug resistant tumors, they all require further implementation and methodological development. Further investigation and progress in the abovementioned strategies will provide significant advances in the rational combat against cancer MDR.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Acridines; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Drug Design; Drug Resistance, Neoplasm; Glycoconjugates; Humans; Nanoparticles; Neoplasms; Nitric Oxide; Plant Preparations; Polymers; Technology, Pharmaceutical
PubMed: 32087558
DOI: 10.1016/j.drup.2020.100682 -
Journal of Drug Targeting Jul 2020Cellular assays are essential in pharmaceutical development of protein-loaded nanomedicine. Cell lines provide robust and efficient models to characterise cytotoxicity,...
Cellular assays are essential in pharmaceutical development of protein-loaded nanomedicine. Cell lines provide robust and efficient models to characterise cytotoxicity, cellular uptake, absorption mechanism, intracellular stability, exocytosis mechanism and therapeutic effects of nanomedicine. GI epithelial cells and goblet cells have been employed to examine protein-loaded nanoparticles . However, the existence of different research protocols hampers the comparison of formulations and obtained results. Although advanced novel microscopy and fluorescent detection techniques are available for facilitating the development of nano-sized formulation, optimised research designs and validated instrument operation procedure are crucial to increase the reliability and validity of research findings. In the current review article, we examined a number of cellular assays, including cellular culture, cytotoxicity assay, cellular uptake assay, transepithelial studies, permeability assays, glucose consumption assays, and exocytosis and endocytosis studies, that have been widely employed for the development of orally administered insulin-loaded nanoparticles. Meanwhile, the role of various technologies, such as CLSM, flow cytometry, ELISA, fluorescence microscopy, microplate reader, and transmission electron microscopy, on visualisation of nanoparticle cellular uptake was evaluated. The following four challenges, including limited nanoparticle diffusion across mucus barrier, unwanted apical exocytosis, P-glycoprotein efflux pumps, endosomal entrapment and lysosomal degradation on protein-loaded nanoparticles, should be addressed in future studies. During formulation optimisation, strategies that can overcome the above hinderance are warranted to maximise oral bioavailability, minimise waste in research funding and facilitate the translation of therapeutic protein-loaded nanomedicine into clinical settings.
Topics: Administration, Oral; Cell Line, Tumor; Humans; Nanoparticles; Proteins
PubMed: 32013626
DOI: 10.1080/1061186X.2020.1726356 -
International Journal of Nanomedicine 2019The poor pharmacokinetic characteristics of most anticancer drugs have limited their clinical effectiveness. The application of nanoparticles as a novel drug delivery...
The poor pharmacokinetic characteristics of most anticancer drugs have limited their clinical effectiveness. The application of nanoparticles as a novel drug delivery system has provided opportunities to tackle the current challenges facing conventional drug delivery systems such as poor pharmacokinetics, lack of specificity to tumor cells, multidrug resistance, and toxicity. This systematic review aims to examine the application of pharmacokinetic studies of nanoparticles loaded in conventional drugs and herb-derived compounds for cancer therapy. The pharmacokinetic parameters of several herbal medicines and chemotherapeutic drugs loaded into nanoparticles were reported. This included area under the curve (AUC) of plasma concentration-time profile, maximum plasma concentration (C), time to maximum plasma concentration (T), volume of distribution (V or V), elimination half-life (t), and clearance (CL). The systematic review was conducted using information available in the PubMed and Science Direct databases up to February 2019. The search terms employed were: pharmacokinetics, pharmacokinetic study, nanoparticles, anticancer, traditional medicine, herbal medicine, herb-derived compounds, natural products, and chemotherapy. Overall, nanoparticle carriers not only significantly improved pharmacokinetics but also further enhanced permeability, solubility, stability, specificity, and selectivity of the carried anticancer drugs/herb-derived compounds to target tumor cells. Additionally, they also limited hepatic first-pass metabolism and P-glycoprotein (P-gp) efflux of the carried anticancer drugs/herb-derived compounds. Based on this systematic review, polymeric nanoparticles were the most commonly used nanocarrier to improve the pharmacokinetic parameters. The use of nanoparticles as a novel drug delivery system has the potential to improve both pharmacokinetics and cytotoxicity activity of the loaded drugs/herb-derived compounds for cancer therapy.
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Humans; Nanoparticles; Neoplasms; Plants, Medicinal
PubMed: 31632004
DOI: 10.2147/IJN.S213229