Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dabigatran is a novel oral direct thrombin inhibitor that has been shown to have beneficial outcomes in the prevention of thromboembolic stroke in patients with atrial fibrillation. Its advantages compared with warfarin may include decreased laboratory monitoring (e.g., international normalized ratio), minimal cytochrome P450 drug interactions, lack of dietary interactions, and faster onset of action. However, dabigatran is still associated with drug interactions, as will be reviewed through a patient case. Consultant pharmacists should carefully review a patient&s medication profile and evaluate the pros and cons of dabigatran therapy as its use becomes more prevalent.
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PMID:Evaluating and assessing dabigatran drug interactions. 2291 Jan 32

The human cytochrome P450 (CYP) superfamily includes at least 57 genes that encode enzymes with diverse metabolic and biosynthetic functions. This study was conducted in order to investigate the associations between polymorphisms in CYP superfamily genes (CYP11B2, CYP17A1, CYP2B6, CYP2C9, CYP2E1 and CYP7A1) and ischemic stroke (IS). Six single nucleotide polymorphisms (SNPs) of CYP superfamily genes were selected and genotyped by direct sequencing in 121 patients with IS and 321 control subjects. The genetic data were analyzed using SNPStats and SPSS 18.0. Multiple logistic regression models (codominant 1, codominant 2, dominant, recessive and log-additive) were used to evaluate odds ratios (ORs), 95% confidence intervals (CIs) and p-values. The rs179998 SNP of CYP11B2 was significantly associated with IS (p=0.0336 in a log-additive model). The rs3813867 SNP of CYP2E1 was significantly associated with smoking in IS (p=0.0336 in a log-additive model). The rs1799998 SNP of CYP11B2 and rs3808607 of CYP7A1 were related to diabetes mellitus in IS (p<0.05). CYP11B2, CYP2E1 and CYP7A1 SNPs were associated with IS in the population studied. Further study is required to confirm these associations and to determine their biological significance.
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PMID:Association between cytochrome P450 promoter polymorphisms and ischemic stroke. 2296 79

Unlike vitamin K antagonists (VKAs), the new oral anticoagulants (NOACs)-direct thrombin inhibitor, dabigatran, and direct activated factor X inhibitors, rivaroxaban, and apixaban-do not require routine INR monitoring. Compared to VKAs, they possess relatively rapid onset of action and short halflives, but vary in relative degrees of renal excretion as well as interaction with p-glycoprotein membrane transporters and liver cytochrome P450 metabolic enzymes. Recent completed phase III trials comparing NOACs with VKAs for stroke prevention in atrial fibrillation (AF)-the RE-LY, ROCKET AF, and ARISTOTLE trials-demonstrated at least noninferior efficacy, largely driven by significant reductions in haemorrhagic stroke. Major and nonmajor clinically relevant bleeding rates were acceptable compared to VKAs. Of note, the NOACs caused significantly less intracranial haemorrhagic events compared to VKAs, the mechanisms of which are not completely clear. With convenient fixed-dose administration, the NOACs facilitate anticoagulant management in AF in the community, which has hitherto been grossly underutilised. Guidelines should evolve towards simplicity in anticipation of greater use of NOACs among primary care physicians. At the same time, the need for caution with their use in patients with severely impaired renal function should be emphasised.
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PMID:Stroke prevention in atrial fibrillation: understanding the new oral anticoagulants dabigatran, rivaroxaban, and apixaban. 2299 73

Treatment of intracerebral hemorrhage is often pointless, although considerable effort has been devoted to developing treatments for ischemic stroke. The purpose of this study was to determine the influence of drugs in improving neurological outcomes with pharmaceutical therapy after intracerebral hemorrhage. The free-radical hypothesis for intracerebral hemorrhage is based on the cytotoxicity triggered by blood components and its degradation products, such as heme and iron as a potent pro-oxidant atom. Sulfaphenazole (SPZ) has a different mechanism such as reactive oxygen species scavenging, in addition to the inhibition of superoxide production by cytochrome P450. The present study investigated the properties of SPZ in collagenase-induced intracerebral hemorrhage rat brain damage. The results show that systemic SPZ treatment after intracerebral hemorrhage reduces striatal dysfunction, the elevation of lipid peroxidation, and brain edema in the rat. These results suggest that SPZ is a potentially effective therapeutic approach for intracerebral hemorrhage as the effect of SPZ was initiated for either 1 h or 3 d post-intracerebral hemorrhage.
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PMID:Effects of sulfaphenazole after collagenase-induced experimental intracerebral hemorrhage in rats. 2303 77

Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated.
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PMID:The new oral anticoagulants: a challenge for hospital formularies. 2308 1

Warfarin, at a dose adjusted according to the INR, is the standard prophylactic anticoagulant for patients with atrial fibrillation and a major risk of thrombosis. Dabigatran, a thrombin inhibitor, is an alternative when warfarin fails to maintain the INR within the therapeutic range most of the time. Warfarin and aspirin are reasonable choices for patients at moderate risk of thrombosis. Rivaroxaban, a factor Xa inhibitor, has been approved for the treatment of patients with atrial fibrillation and a moderate or major risk of thrombosis, but with no associated valve abnormalities. Clinical evaluation of rivaroxaban is mainly based on a double-blind, randomised, non-inferiority trial comparing rivaroxaban (20 or 15 mg taken once daily, according to renal function) versus adjusted-dose warfarin in 14 264 patients at high risk of thrombosis. Most patients were treated for at least 18 months. Overall mortality was not significantly different between the 2 groups (about 5% annually), nor was the incidence of stroke or systemic embolism (2% annually). Note that the dose of warfarin was not optimised in this trial. Indirect comparison with dabigatran is too fraught with methodological flaws to provide meaningful results. Overall, data on rivaroxaban are less convincing than those on dabigatran. About 35% of patients in the 2 groups stopped treatment prematurely, mainly because of adverse effects or withdrawal of consent. The overall incidence of bleeding was similar with rivaroxaban and warfarin (about 15%), including the incidence of serious bleeding (3.5%). Rivaroxaban was associated with fewer bleeding-related deaths (0.24% versus 0.48%), more cases of serious gastrointestinal bleeding (3.2% versus 2.02%) and fewer cases of intracranial haemorrhage (0.8% versus 1.2%). Combination with cytochrome P450 or P-glycoprotein inhibitors, or with drugs affecting renal function, boosts the effects of rivaroxaban. Combination with other antithrombotic drugs should be avoided. In practice, warfarin remains the standard prophylactic drug for patients with atrial fibrillation and a major risk of thrombosis, while dabigatran is an alternative in cases that are difficult to manage. In mid-2012, the data on rivaroxaban are not sufficiently convincing to challenge this standard.
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PMID:Rivaroxaban and atrial fibrillation: continue to use warfarin or in some cases, dabigatran. 2321 Feb 52

Atrial fibrillation (AF) is an independent risk factor for ischemic stroke occurrence, severity, recurrence, and mortality. Anticoagulation therapy for the prevention of thromboembolism is critical in patients with AF who are at risk of stroke. Warfarin has been an efficacious anticoagulant for this purpose, but its use has been limited by frequent laboratory monitoring, drug interactions, unpredictable individual response, delayed onset of action, and bleeding. Apixaban is the second oral direct selective factor Xa inhibitor approved for the prevention of stroke/systemic embolism in patients with nonvalvular AF. It was significantly better than aspirin in reducing stroke (ischemic or hemorrhagic) or systemic embolism without increasing the risk of major bleeding in patients with AF who were at increased risk of stroke and for whom warfarin was unsuitable. In a randomized, double-blind trial that was originally designed to test for noninferiority, apixaban was superior to warfarin (target international normalized ratio 2-3) in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality in patients with AF. Apixaban has a half-life of about 12 hours, and the normal dosage is 5 mg orally twice daily. However, it may be reduced to 2.5 mg twice daily based on individual factors of the patient (age, renal function, and body weight) and the concomitant use of potent dual inhibitors of cytochrome P450 3A4 and P-glycoprotein. Similar to other novel oral anticoagulants (dabigatran and rivaroxaban), apixaban has no reversal agent for its anticoagulant effect. Overall, apixaban is a safe and efficacious alternative for stroke prophylaxis in high-risk patients who have AF and who are unable to achieve therapeutic goals with warfarin therapy.
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PMID:Apixaban: a new factor Xa inhibitor for stroke prevention in patients with nonvalvular atrial fibrillation. 2353 30

Dabigatran, rivaroxaban, and apixaban are the new oral anticoagulants (NOAC) which have been investigated in patients with atrial fibrillation (AF) for primary and secondary prevention of stroke and thromboembolism. In these trials NOAC had a similar efficacy and safety profile compared to traditional vitamin-K-antagonists such as warfarin. We advise caution in the use of NOAC in patients with stroke or cerebral hemorrhage because of the following reasons: 1) Patients with cerebral bleeding were excluded from the trials. 2) Stroke within 14 days and severe stroke within 6 months before screening were exclusion criteria in the trials investigating dabigatran and rivaroxaban. 3) There is no antidote for reversal and no reliable laboratory monitoring of the anticoagulant effect for emergency situations. 4) NOAC are either substrates of the P-glycoprotein (P-gp) or are metabolized by the cytochrome P450 (CYP) system, or both. Drug-drug interactions between NOAC and P-gp and CYP-affecting drugs are largely unknown. 5) Long-term effects of thrombin generation inhibition on the occurrence of infections, malignancies, dementia, and other diseases are unknown. Based on these considerations it is our opinion that studies of NOAC in patients with stroke compared with other prevention strategies, as well as more post marketing surveillance data, are required.
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PMID:Reservations against new oral anticoagulants after stroke and cerebral bleeding. 2362 64

Clopidogrel, an antiplatelet agent, is increasingly prescribed for patients with recent stroke, myocardial infarction, acute coronary syndrome, and/or patients post-coronary stent insertion to prevent recurrent cardiovascular events. Since clopidogrel can increase the risk of gastrointestinal hemorrhage, co-administration of proton pump inhibitors (PPIs) has been recommended, particularly in patients at high risk. In 2009, the FDA issued warnings about potential interactions between clopidogrel and PPIs, given the fact that both drugs are metabolized via the cytochrome P450 pathway. Prior studies have demonstrated significant reduction in platelet inhibition when PPI therapy is administered to subjects on clopidogrel therapy. Two meta-analyses were published in 2010 and 2011, the first suggesting association of PPIs with adverse cardiovascular events when observational studies were examined, but noting that the results were limited by the presence of significant heterogeneity. The second meta-analysis did not find a significant increase in the risk of adverse primary events (which included all cause mortality, cardiovascular death, myocardial infarction, or stroke), and concluded that analysis of the data from two randomized controlled trials yielded a risk difference of zero. An updated literature search was performed to assess clinical studies describing interactions between PPIs and clopidogrel published from 2011-2012. The majority of these studies did not show significant interactions when primary cardiac outcomes were considered. More importantly, the newer data demonstrated that PPI usage independently was a risk factor for adverse CV outcomes, since most PPI users were older patients who were more likely to have concomitant co-morbid conditions. Two updated reviews also concluded that the presence of confounding factors likely explained differences in results between studies, and that there were no significant differences in effects on clopidogrel between individual proton pump inhibitors. Overall, clinicians can assure their patients that combination therapy is safe when indicated in a patient at high risk of GI bleeding, but they should also stop PPI therapy if it is not clinically indicated.
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PMID:Proton pump inhibitors and potential interactions with clopidogrel: an update. 2369 47

Oxygen deprivation followed by reoxygenation causes pathological responses in many disorders, including ischemic stroke, heart attacks, and reperfusion injury. Key aspects of ischemia-reperfusion can be modeled by a Caenorhabditis elegans behavior, the O2-ON response, which is suppressed by hypoxic preconditioning or inactivation of the O2-sensing HIF (hypoxia-inducible factor) hydroxylase EGL-9. From a genetic screen, we found that the cytochrome P450 oxygenase CYP-13A12 acts in response to the EGL-9-HIF-1 pathway to facilitate the O2-ON response. CYP-13A12 promotes oxidation of polyunsaturated fatty acids into eicosanoids, signaling molecules that can strongly affect inflammatory pain and ischemia-reperfusion injury responses in mammals. We propose that roles of the EGL-9-HIF-1 pathway and cytochrome P450 in controlling responses to reoxygenation after anoxia are evolutionarily conserved.
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PMID:Cytochrome P450 drives a HIF-regulated behavioral response to reoxygenation by C. elegans. 2381 Dec 25


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