Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several revascularisation methods are effective in patients with acute coronary syndromes. Standard antithrombotic treatment combines heparin and aspirin during the acute phase, followed by long-term aspirin therapy. The only proven advantage of adding clopidogrel is for patients who undergo angioplasty with stenting. Ticagrelor is an antiplatelet drug belonging to a different chemical class than clopidogrel. Its chemical structure resembles that of adenosine. Ticagrelor has been authorised in the European Union for patients with acute coronary syndromes, in combination with aspirin. Clinical evaluation is mainly based on a double-blind randomised trial comparing ticagrelor + aspirin versus clopidogrel + aspirin in 18 624 patients who underwent angioplasty (64% of patients), coronary artery bypass grafting (10%), or who received medical treatment only. Half of the patients were treated for at least 9 months. After 12 months of treatment, compared to the clopidogrel group, overall mortality appeared to be significantly lower in the ticagrelor group (4.5% versus 5.9%), along with cardiovascular mortality (4.0% versus 5.1%). Symptomatic myocardial infarction was also less frequent (5.8% versus 6.9%), but not stroke (about 1.4% in both groups). Ticagrelor did not statistically significantly reduce overall mortality in patients who had angioplasty with stenting, but stent thrombosis was less frequent than with clopidogrel (2.9% versus 3.8%). In combination with aspirin, ticagrelor provoked more bleeding than clopidogrel, based on the definition used in the trial (16.1% versus 14.6%). In contrast, the rate of major bleeding was similar in the two groups (11.5%), including fatal bleeding (0.3%). The adverse effect profile of ticagrelor resembles that of adenosine in certain respects. For example, dyspnoea was more frequent with ticagrelor than with clopidogrel (13.8% versus 7.8%), as were conduction disorders and ventricular pauses at the beginning of treatment (5.8% versus 3.6%). There were also more cases of hyperuricaemia and elevated creatinine levels with ticagrelor. Ticagrelor and its active metabolite are substrates and inhibitors of cytochrome P450 isoenzymes and P-glycoprotein, creating a risk of multiple pharmacokinetic interactions. Pharmacodynamic interactions are also likely to occur, especially with antithrombotic agents and heart-rate-lowering drugs. In practice, in patients with an acute coronary syndrome treated with angioplasty and stenting, and who are also receiving aspirin, it remains to be shown whether the harm-benefit balance of ticagrelor is clearly better than that of clopidogrel. In other settings, there is no firm evidence that ticagrelor is better than aspirin alone.
...
PMID:Ticagrelor. Acute coronary syndromes: nothing new. 2197 81

Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.
...
PMID:Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. 2237 Nov 4

Edoxaban is a novel, orally available, highly specific direct inhibitor of factor Xa and is currently being developed for the treatment and prevention of venous thromboembolism and prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The objectives of the present analyses were to characterise edoxaban population pharmacokinetics (PPK) and identify potential intrinsic and extrinsic factors affecting variability in edoxaban exposure, determine if there are relationships between edoxaban pharmacokinetics or biomarkers and the risk of bleeding in patients with NVAF using an exposure-response model, and to use the PPK and exposure-response model to support dose selection for a phase III trial of edoxaban in patients with NVAF. PPK analysis of data from 1,281 edoxaban-dosed subjects with intrinsic factors such as renal impairment or NVAF and extrinsic factors such as concomitant medications revealed significant effects of renal impairment and concomitant strong P-glycoprotein (P-gp) inhibitors on the pharmacokinetics of edoxaban. Exposure-response analysis found that in patients with NVAF, the incidence of bleeding events increased significantly with increasing edoxaban exposure, with steady-state minimum concentration (Cmin,ss) showing the strongest association. Clinical trial simulations of bleeding incidence were used to select 30 mg and 60 mg once-daily edoxaban with 50% dose reductions for patients with moderate renal impairment or receiving concomitant strong P-gp inhibitors as the treatment regimens in the ENGAGE AF-TIMI 48 (NCT00781391) trial.
...
PMID:Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation. 2239 55

For patients with atrial fibrillation and a high risk of thrombosis, the standard prophylaxis is warfarin, an anticoagulant, at a dose adjusted to the INR. Warfarin and aspirin are both reasonable choices for patients with a moderate risk of thrombosis. Dabigatran, an oral anticoagulant that inhibits thrombin, has been authorised for patients with atrial fibrillation and a moderate or high risk of thrombosis, without associated valvular abnormalities. Clinical evaluation of dabigatran is based on a randomised "non-inferiority" trial comparing two doses of dabigatran (110 mg and 150 mg) taken twice daily, and adjusted-dose warfarin, in 18 113 patients treated for an average of 21 months. Overall mortality was about 4% per year and did not differ between the 3 groups. There was a greater reduction in the annual incidence of stroke or systemic embolism with the higher dose of dabigatran (1.1%) than with warfarin (1.7%). This is not the case for the lower dose (1.5%). In patients with good INR control, the difference in favour of the higher dose of dabigatran was no longer statistically significant. All-cause treatment discontinuation rates were higher with dabigatran than with warfarin (21% versus 17%, p<0.001). The incidence of serious bleeding did not differ statistically between warfarin and the higher dose of dabigatran (3.57% versus 3.32%), but was lower with the lower dose of dabigatran (2.87%). Compared with warfarin, dabigatran appears to be associated with about a 0.2% excess of myocardial infarction (0.73% versus 0.53%). Dyspepsia is also more frequent with dabigatran (6% versus 1.4%). Hepatic adverse effects appear to be mild but need to be monitored. The effects of dabigatran are potentiated by combination with P-glycoprotein inhibitors and drugs that impair renal function. Combination with other antithrombotic agents should also be avoided. Treatment with dabigatran does not require monitoring of haemostasis, whereas vitamin K inhibitors necessitate close INR monitoring. In contrast, renal function must be monitored, as renal impairment increases the risk of bleeding. Unlike vitamin K antagonists, there is no antidote for dabigatran overdose. In practice, warfarin remains the standard drug for patients with atrial fibrillation and a moderate or high risk of thrombosis. Aspirin is an alternative for moderate-risk patients. When the risk is significant and the INR cannot be maintained within the target range despite close monitoring, dabigatran is the alternative to warfarin, provided the patient is closely monitored, especially for changes in renal function.
...
PMID:Dabigatran and atrial fibrillation: the alternative to warfarin for selected patients. 2241 15

Therapy with vitamin K antagonists (VKA) is especially feared because of its variable therapeutic effect. Direct thrombin inhibitors have been demonstrated to be safe and effective in preventing stroke in patients with atrial fibrillation (AF) eligible for inclusion in the RE-LY trial. Dabigatran provides equal or superior efficacy to VKA (110mg BID) and is much safer than VKA, with a similar safety margin (150mg BID). Dabigatran does not lead to liver dysfunction and does not require monitoring. The choice of dose should be based on specific patient characteristics (coronary disease, decreased renal function, age, low body weight, administration of other drugs for AF or P-glycoprotein inhibitors, history of gastrointestinal bleeding). Dabigatran is a viable alternative to VKA that provides many advantages over these drugs and is certainly preferred by most patients due to the problems of VKA follow-up.
...
PMID:[Dabigatran: a new therapeutic alternative in the prevention of stroke]. 2268 9

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.
...
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.
...
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.
...
PMID:Reservations against new oral anticoagulants after stroke and cerebral bleeding. 2362 64

Rivaroxaban is the first agent available within a new class of anticoagulants called direct factor Xa inhibitors. Rivaroxaban is approved for use in the United States for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, for the prevention of deep vein thrombosis in patients undergoing total hip replacement and total knee replacement, for the treatment of deep vein thrombosis and pulmonary embolism, and for the reduction in risk of recurrence of deep vein thrombosis and pulmonary embolism (with additional indications under review). Rivaroxaban dose and frequency of administration vary depending on the indication. As of result of predictable pharmacokinetics and pharmacodynamics, a fixed dose of rivaroxaban is administered without routine coagulation testing. Rivaroxaban has a short half-life, undergoes a dual mode of elimination (hepatic and renal), and is a substrate for P-glycoprotein. Rivaroxaban has a lower potential for drug interactions compared with warfarin. Despite the advantages of a once/day fixed-dose oral agent, in many clinical situations limited evidence is available to guide optimal management of rivaroxaban therapy. In this article, we review the available evidence and provide recommendations where possible for such situations including the desire to monitor the anticoagulation intensity, use in special patient populations, managing drug interactions, and transitioning across anticoagulant agents. Potential strategies for reversing rivaroxaban's anticoagulant effect are reviewed. Health systems will need to perform a systematic safety evaluation and ensure that numerous hospital policies related to anticoagulation are updated to include rivaroxaban. A comprehensive approach to education is needed for clinicians, patients, and technical support personnel involved in patient interactions to ensure safe use.
...
PMID:Rivaroxaban: practical considerations for ensuring safety and efficacy. 2371 87

Warfarin has been the mainstay oral anticoagulant (OAC) medication prescribed for stroke prevention in atrial fibrillation (AF) patients. However, warfarin therapy is challenging because of marked interindividual variability in dose and response, requiring frequent monitoring and dose titration. These limitations have prompted the clinical development of new OACs (NOACs) that directly target the coagulation cascade with rapid onset/offset of action, lower risk for drug-drug interactions, and more predictable response. Recently, NOACs dabigatran (direct thrombin inhibitor), and rivaroxaban and apixaban (factor Xa [FXa] inhibitors) have gained regulatory approval as alternative therapies to warfarin. Though the anticoagulation efficacy of these NOACs has been characterized, differences in their pharmacokinetic and pharmacodynamic profiles have become a significant consideration in terms of drug selection and dosing. In this review, we outline key pharmacokinetic and pharmacodynamic features of each compound and provide guidance on selection and dosing of the 3 NOACs relative to warfarin when considering OAC therapy for AF patients. Importantly, we show that by better understanding the effect of clinical variables such as age, renal function, dosing interval, and drug metabolism (CYP3A4) and transport (P-glycoprotein), we might be able to better predict the risk for sub- and supratherapeutic anticoagulation response and individualize OAC selection and dosing.
...
PMID:Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. 2379 May 95


<< Previous 1 2 3 4 5 6 7 Next >>

---