Anticoagulant Activity Of Warfarin Research Articles

Efficacy and safety of edoxaban in patients with chronic thromboembolic pulmonary hypertension: protocol for a multicentre, randomised, warfarin-controlled, parallel group trial - KABUKI trial

IntroductionChronic thromboembolic pulmonary hypertension (CTEPH) is a complication of prior pulmonary thromboembolism (PE), caused by incomplete clot dissolution after PE. In patients with CTEPH, lifelong anticoagulation is mandatory to prevent...

The joint physician- and pharmacist-managed anticoagulation clinic is aiming to improve warfarin management in outpatients with atrial fibrillation in China: A prospective observational study

Background: Anticoagulation clinic (AC) is aimed at improving anticoagulation control and outcomes in patients with atrial fibrillation (AF). There is little published data on the benefits of providing an AC in China even if Asians have a higher risk of hemorrhage and stroke when taking warfarin. This study attempts to assess the impact of the AC on warfarin management in the Chinese population. Subjects and Methods: This prospective observational study was conducted in the First Affiliated Hospital of Nanjing Medical University and consecutively enrolled 42 AF patients from the joint physician-and pharmacist-managed AC from March 2017 to April 2018. The study protocol was approved by the Institutional Review Board of the First Affiliated Hospital of Nanjing Medical University. Patients already on warfarin for at least 6 months before coming to the AC and unwilling to receive AF ablation or switch to non-Vitamin K antagonist oral anticoagulants were included. The anticoagulant activity of warfarin was monitored using the international normalized ratio (INR). The primary outcome of this study was INR control, which was defined by the time-in-therapeutic range (TTR). The TTR before and after visiting the AC was compared. Results: The mean age of the enrolled 42 patients was 68.3 ± 10.6 years and 25 (59.5%) were women. The mean CHA2DS2-VASc score and the mean HAS-BLED score were 3.43 ± 1.29 and 1.86 ± 0.80, respectively, in 28 (66.7%) patients with nonvalvular AF. The median follow-up time after visiting the AC was 298.5 days (interquartile range: 151.8–441.8 days). The TTR (% days) before and after visiting the AC was 44.1% ± 27.5% and 69.7% ± 23.3% (P < 0.001), respectively. Meanwhile, 6 (14.3%) and 25 (59.5%) patients had TTR (% days) >65% before and after visiting the AC (P = 0.001), respectively. Conclusions: TTR values were higher in AF patients taking warfarin after the AC. More patients reached satisfactory warfarin control after visiting the AC.

Real –life International Normalized Ratio (INR) profile ; Egyptian study

Warfarin remains widely used by patients with cardiovascular diseases[.Due to high interindividual variability, the anticoagulant activity of warfarin has to be monitored using the international normalized ratio (INR).The most widely recommended approach for evaluating the quality and safety of anticoagulation is to estimate the percentage of time in therapeutic range (TTR). It was a single center, cross-sectional observational study that was conducted at cardiology department at Benha University Hospital. This study was designed to: Study the INR values in patients on VKAs in the selected area., Calculation of the time in the therapeutic range (TTR) when is possible according to the number of INR/Patient., Find out which patient characteristics that are associated with good INR control. Patients were subdivided into two sub groups; sub group I : patients with TTR ≥ 65% , sub group II : patients with TTR < 65% .The study was designed to screen not less than 2000 INR laboratory tests from these patients. Mean TTR was 60.27%+_24.48% for the Rosendaal method. After multivariate adjustment,variables associated with good anticoagulation control were university studies (OR: 1.99, 95% CI: 1.08-3.64), chronic hepatic disease (OR: 8.15, 95% CI: 1.57-42.24), low comorbidity expressed as Charlson index(OR: 0.87, 95% CI: 0.76-0.99) , no previous cardiac disease (OR: 0.64, 95% CI: 0.41-0.98), lower risk of bleeding assessed as hypertension, abnormal enal/liver function, stroke, bleeding history or predisposition, rlabile international normalized ratio, elderly age, and use of drugs or alcohol { HAS-BLED} (OR: 0.81, 95% CI: 0.69-0.95), and lower heart rate OR: 0.99, 95% CI: 0.98-0.99). Our study shows a rate of inadequate control with AVKs of 54%, and 46% of the patients spent more than half the time outside the therapeutic range. .In our study, having a university degree was associated with adequate anticoagulation control.We believe that higher education helps patients to understand the importance of anticoagulant treatment adherence.

Roles of CYP2C9 and its variants (CYP2C9*2 and CYP2C9*3) in the metabolism of 6-methoxy-2-napthylacetic acid, an active metabolite of the prodrug nabumetone

Nabumetone is a prodrug, used as an anti-inflammation agent and having the active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA). The role of the polymorphic enzyme responsible for the 6-O-demethylation of 6-MNA to 6-hydroxy-2-naphtylacetic acid (6-HNA) was studied using recombinant cytochrome CYP2C9 microsomes (CYP2C9.1, CYP2C9.2 and CYP2C9.3) and human liver microsomes of known genotypes of CYP2C9. Utilizing recombinant CYP2C9.1, Vmax and Vmax/Km values of 6.3 ± 3.3 pmol/min/pmol P450 and 12.4 ± 4.7 nL/min/pmol P450, respectively, were obtained for the 6-MNA metabolism, and were almost similar to those in CYP2C9.2. In contrast, the Vmax/Km value in recombinant CYP2C9.3 was about one-third that of CYP2C9.1. In kinetic studies using liver microsomes of humans genotyped for the CYP2C9 genes, a sample genotyped as *3/*3 revealed about 4- to sixfold lower intrinsic clearance for 6-HNA formation than did samples genotyped as *1/*1. No appreciable differences were observed in kinetic parameters for 6-HNA formation in *1/*2 and *1/*3, while *2/*2 microsomes was comparable to wild type microsomes. In addition, S-warfarin 7-hydroxylation by recombinant CYP2C9.1 and CYP2C9.3 was inhibited by 6-MNA in a mixed manner. The apparent Ki value of 6-MNA on S-warfarin 7-hydroxylation by CYP2C9.3 was higher than that by CYP2C9.1. These results may provide valuable information for optimizing the anticoagulant activity of warfarin when nabumetone is co-administrated to patients.

Effect of vitamin K2 on the anticoagulant activity of warfarin during the perioperative period of catheter ablation: Population analysis of retrospective clinical data.

BackgroundCatheter ablation is a non-medication therapy for atrial fibrillation, and during the procedure, warfarin is withdrawn in the preoperative period to prevent the risk of bleeding. In case of emergency, vitamin K2 can be intravenously administered to antagonize the anticoagulant activity of warfarin. The aims of this study were to conduct population pharmacokinetic/pharmacodynamic modeling for retrospective clinical data and to investigate the effect of vitamin K2 on the anticoagulant activity of warfarin in the perioperative period of catheter ablation.MethodsA total of 579 international normalized ratio (INR) values of prothrombin time from 100 patients were analyzed using the nonlinear mixed-effects modeling program NONMEM. A 1-compartment model was adapted to the pharmacokinetics of warfarin and vitamin K2, and the indirect response model was used to investigate the relationship between plasma concentration and the pharmacodynamic response of warfarin and vitamin K2. Since no plasma concentration data for warfarin and vitamin K2 were available, 3 literally available pharmacokinetic parameters were used to simultaneously estimate 1 pharmacokinetic parameter and 5 pharmacodynamic parameters.ResultsThe population parameters obtained not only successfully explained the observed INR values, but also indicated an increase in sensitivity to warfarin in patients with reduced renal function. Simulations using these parameters indicated that vitamin K2 administration of more than 20 mg caused a slight dose-dependent decrease in INR on the day of catheter ablation and a delayed INR elevation after warfarin re-initiation.ConclusionsA pharmacokinetic/pharmacodynamic model was successfully built to explain the retrospective INR data during catheter ablation. Simulation studies suggest that vitamin K2 should be administered with care and that more than 20 mg is unnecessary in the preoperative period of catheter ablation.

Prolonged effects of miconazole oral gel on warfarin anticoagulation even after treatment withdrawal.

We investigated the effect of terminating miconazole oral gel (MOG) treatment on the anticoagulant activity of warfarin by evaluating changes in international normalized ratio levels (INR). Data were collected from the medical records of 6 patients treated with warfarin and MOG. Following cessation of MOG treatment, increased INR and INR/dose levels were observed for an average of 15 days, showing that the anticoagulant activity of warfarin was increased for ~ 2 weeks. Closer monitoring of INR levels for at least 2 weeks may be required upon withdrawal of MOG treatment in patients treated with warfarin.

Kinetics of drug action in disease states: towards physiology-based pharmacodynamic (PBPD) models.

Gerhard Levy started his investigations on the “Kinetics of Drug Action in Disease States” in the fall of 1980. The objective of his research was to study inter-individual variation in pharmacodynamics. To this end, theoretical concepts and experimental approaches were introduced, which enabled assessment of the changes in pharmacodynamics per se, while excluding or accounting for the cofounding effects of concomitant changes in pharmacokinetics. These concepts were applied in several studies. The results, which were published in 45 papers in the years 1984–1994, showed considerable variation in pharmacodynamics. These initial studies on kinetics of drug action in disease states triggered further experimental research on the relations between pharmacokinetics and pharmacodynamics. Together with the concepts in Levy’s earlier publications “Kinetics of Pharmacologic Effects” (Clin Pharmacol Ther 7(3): 362–372, 1966) and “Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin” (Clin Pharmacol Ther 10(1): 22–35, 1969), they form a significant impulse to the development of physiology-based pharmacodynamic (PBPD) modeling as novel discipline in the pharmaceutical sciences. This paper reviews Levy’s research on the “Kinetics of Drug Action in Disease States”. Next it addresses the significance of his research for the evolution of PBPD modeling as a scientific discipline. PBPD models contain specific expressions to characterize in a strictly quantitative manner processes on the causal path between exposure (in terms of concentration at the target site) and the drug effect (in terms of the change in biological function). Pertinent processes on the causal path are: (1) target site distribution, (2) target binding and activation and (3) transduction and homeostatic feedback.

Establishment of pharmacogenomic algorithm for predicting stable warfarin dose in Chinese patients

BackgroundGenetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated....

Evaluation of the Effect of Lime Fruit Juice on the Anticoagulant Effect of Warfarin

Aim:Citrus aurantifolia (Family Rutaceae) is commonly known as a familiar food and medicine, and s therapeutic effectiveness in a variety of diseases has been suggested in traditional medicine. Various complementary and alternative medicines (CAM) have been shown to interact with orthodox medicines. Hence, the aim of this study is to investigate such a phenomenon particularly the interaction of lime fruit juice with warfarin.Materials and Method:Wistar strain albino rats of both sexes weighing between 190 and 230g were administered with oral doses of the respective drugs used depending on the groups of animals. Effects on the anticoagulant activity of warfarin were determined by standard laboratory methods.Result:Lime fruit juice caused a reduction in the anticoagulant activity of warfarin.Conclusion:This finding has shown that CAM can interact with orthodox medicines hence, warfarin prescribers need to be aware of the usage of CAM and monitor the international normalized ratio (INR) of their patients more frequently.

Risk of clinically relevant bleeding in warfarin‐treated patients—influence of SSRI treatment

To investigate the risk of clinically relevant bleeding in warfarin-treated patients with or without concomitant treatment with selective serotonin reuptake inhibitors (SSRIs). A cohort study was performed in patients treated with warfarin due to atrial fibrillation. Exposed patients were defined as patients treated with SSRI at any time between January 1999 and September 2005 (n = 117). Unexposed patients without SSRI-treatment were randomly selected and matched for age and sex (1:1). The primary endpoint was hospital admission due to bleeding during the same time period. Bleeding occurred in 17 exposed patients (totally 23 bleedings) and in two unexposed patients (totally two bleedings) (p = 0.0003). A total of 11 bleedings occurred during treatment with the combination of warfarin and SSRI, and 14 during treatment with warfarin only. The total incidences of bleedings per 1000 treatment years were 51.4 (25.7-92.0) and 23.9 (13.1-40.1), respectively, and the unadjusted incidence rate ratio (IRR) 2.15 (0.88-5.11). Cox regression analysis including first bleedings revealed an adjusted hazard ratio of 3.49 (1.37-8.91) for bleeding during treatment with a combination of SSRI and warfarin compared with treatment with warfarin only. Initiation of SSRI therapy was not associated with a change in dose of warfarin or with a change in international normalized ratio (INR) (p = 0.48 and p = 0.31, respectively). Addition of SSRI to warfarin-treated patients may be associated with an increased risk of clinically relevant bleeding. The effect seems not to be associated with a direct influence of SSRI on the anti-coagulant activity of warfarin.

Drug Interaction Studies with Dexlansoprazole Modified Release (TAK-390MR), a Proton Pump Inhibitor with a Dual Delayed-Release Formulation

Most proton pump inhibitors are extensively metabolized by cytochrome P450 (CYP) isoenzymes, as are many other drugs, giving rise to potential drug-drug interactions. Dexlansoprazole modified release (MR) [TAK-390MR] is a modified-release formulation of dexlansoprazole (TAK-390), an enantiomer of lansoprazole, which employs an innovative Dual Delayed Release technology designed to prolong the plasma dexlansoprazole concentration-time profile following once-daily oral administration. As with lansoprazole, dexlansoprazole is metabolized mainly by CYP3A and CYP2C19. Based on in vitro studies, dexlansoprazole has the potential to inhibit activity of these isoenzymes and also may induce human hepatic CYP1A and CYP2C9 activity. To determine whether dexlansoprazole has an effect on these isoenzymes in vivo, drug interaction studies with dexlansoprazole MR were conducted. Four separate randomized, double-blind, two-way crossover, placebo-controlled, single-centre studies were conducted in healthy volunteers to evaluate the effect of dexlansoprazole on the pharmacokinetics of four test substrates (diazepam, phenytoin, theophylline [administered as intravenous aminophylline] and warfarin), which were selected based on in vitro and/or in vivo data that suggest a potential drug interaction with CYP isoenzymes or potentially coadministered narrow therapeutic index drugs. In each study, dexlansoprazole MR 90 mg or placebo was administered once daily for 9 or 11 days in each period. Subjects received a single dose of test substrate in each study period. Pharmacokinetic parameters of the test substrates were estimated using noncompartmental methods. A conclusion of no effect of dexlansoprazole MR on the test substrate was made if the 90% confidence intervals (CIs) for the ratios of the central values for the observed maximum plasma drug concentration (C(max)) and the area under the plasma concentration-time curve (AUC) of test substrate administered with dexlansoprazole MR versus placebo were within 0.80-1.25 based on an analysis of variance model. The potential for a pharmacodynamic interaction was also assessed for warfarin using prothrombin time, measured as the international normalized ratio. Routine safety assessments were conducted in these studies. Mean C(max) and AUC values were generally similar for each test substrate when administered with multiple once-daily doses of dexlansoprazole MR or placebo. The 90% CIs for the bioavailability of these test substrates administered with dexlansoprazole MR relative to that obtained when the substrates were administered with placebo were within the bioequivalency range of 0.80-1.25, indicating that multiple doses of dexlansoprazole MR had no effect on the pharmacokinetics of these drugs. Additionally, dexlansoprazole MR had no effect on the pharmacodynamics of warfarin. Administration of these drugs with dexlansoprazole MR 90 mg or placebo was well tolerated; the only serious adverse event, which led to a subject's discontinuation from the study, was considered unrelated to study drugs. Coadministration of dexlansoprazole MR with diazepam, phenytoin or theophylline did not affect the pharmacokinetics of these drugs, and therefore is unlikely to alter the pharmacokinetic profile of other drugs metabolized by CYP2C19, CYP2C9, CYP1A2 and perhaps CYP3A. Additionally, dexlansoprazole MR coadministered with warfarin did not affect the pharmacokinetics of the warfarin enantiomers and had no effect on the anticoagulant activity of warfarin. Dexlansoprazole MR was well tolerated in these trials of healthy subjects.

Pharmacokinetic and pharmacodynamic study of interaction of Rhodiola rosea SHR‐5 extract with warfarin and theophylline in rats

Significant pharmacokinetic/pharmacodynamic interactions between various herbal products and drugs being substrates of cytochrome P450 have recently been reported. The aim of this study was to determine whether Rhodiola rosea SHR-5 extract interacts with warfarin and theophylline when administered concomitantly. Thus, concomitant treatment of rats with theophylline and SHR-5 did not give rise to significant effects on the pharmacokinetics of theophylline. Simultaneous administration of SHR-5 and warfarin did not alter significantly the pharmacokinetics or the anticoagulant activity of warfarin. It is concluded that SHR-5 might be of value in the treatment of patients with mild or moderate depression, and that its interaction with co-administered drugs is likely to be negligible.

Evaluation of a Potential Tigecycline‐Warfarin Drug Interaction

To evaluate the potential for a clinically significant drug interaction between tigecycline and warfarin by using pharmacokinetic and anticoagulant assessments. Open-label, nonrandomized study. Inpatient clinical pharmacology unit. Nineteen healthy male volunteers were enrolled; eight completed all study assessments. All subjects received a single oral dose of warfarin 25 mg (day 1). Seven days later (day 8), they received a 100-mg loading dose of intravenous tigecycline, followed by 50 mg every 12 hours for eight additional doses. On day 12, they received another single oral dose of warfarin 25-mg with their last dose of tigecycline. Serum tigecycline and plasma R- and S-warfarin concentrations were determined by high-performance liquid chromatography with tandem mass spectroscopy. Pharmacokinetic parameters were calculated by using noncompartmental methods and analyzed by the two 1-sided tests equivalence procedure. Pharmacodynamic analyses were based on anticoagulant parameters derived from international normalized ratios of prothrombin times. Tigecycline peak concentration, trough concentration, area under the concentration-time curve (AUC) from 0-12 hrs, and clearance were not affected by single-dose warfarin. In contrast, R- and S-warfarin AUC from time zero extrapolated to infinity was increased by 68% and 29%, respectively, and clearance was decreased by 40% and 23%, respectively, when warfarin was administered after eight doses of tigecycline. Nevertheless, tigecycline did not alter the anticoagulant effects of warfarin, which is consistent with a mechanism based only on increased warfarin protein binding. These results suggest that a dosage adjustment of either drug is not necessary during coadministration of tigecycline and warfarin. However, consistent with good medical practice, the anticoagulant activity of warfarin should be monitored during coadministration with tigecycline.

Treatment of rats with the Pelargonium sidoides extract EPs® 7630 has no effect on blood coagulation parameters or on the pharmacokinetics of warfarin

Umckaloabo is a herbal drug for the treatment of respiratory tract infections. It contains an aqueous ethanolic extract from roots of Pelargonium sidoides DC (EPs) 7630) as the active ingredient. Polymeric polyphenols and coumarins have been identified as the principal ingredients of EPs 7630. In view of the coumarin content, it has been suggested that the administration of Umckaloabo could possibly be associated with an increased risk of bleeding. This study, therefore, investigated whether a change in blood coagulation parameters or an interaction with coumarin-type anticoagulants occurred after administration of EPs 7630 to rats. No effect on thromboplastin time (TPT), partial TPT (PTPT) or thrombin time (TT) was observed after oral administration of EPs 7630 (10, 75, 500 mg/kg) for 2 weeks, while treatment with warfarin (0.05 mg/kg) for the same period resulted in significant changes in TPT and PTPT. If EPs 7630 (500 mg/kg) and warfarin (0.05 mg/kg) were given concomitantly, the anticoagulant action of warfarin was not influenced. Similarly, the pharmacokinetics of warfarin were unchanged after pre-treatment with EPs 7630 for 2 weeks. Coumarin-type anticoagulants inhibit the synthesis of vitamin K-dependent coagulation factors via an identical mechanism in rat and man, and have a similar pattern of metabolism in both species. Moreover, as the coumarins so far identified in EPs 7630 do not posses the structural characteristics needed for anticoagulant activity, it appears unlikely that an increased tendency to haemorrhage arises in patients after intake of Umckaloabo.

Single-dose pharmacokinetics and anticoagulant activity of warfarin is unaffected by nebivolol in healthy volunteers

Background Studies have reported that nebivolol possesses distinct nitric oxide releasing/vasodilating properties. The role of nitric oxide on endothelial and platelet function is well established in the literature. Given these actions, the effects of steady-state nebivolol on the pharmacokinetic (PK) and anticoagulant activity of warfarin were studied. Methods This was an open-label study conducted in 12 healthy volunteers. Subjects were given a 10-mg dose of warfarin on Day 1 and Day 17. On Day 8-Day 22, 10 mg oral nebivolol was given QD. Blood samples for assessment of PK and anticoagulation (prothrombin time, INR) were taken at frequent intervals on Day 1 and Day 17. Results Administration of nebivolol resulted in no clinically significant changes in the PK of R- or S-warfarin being observed (see Table). Warfarin protein binding was unaffected by nebivolol. Similarly, nebivolol had no clinically significant effects on the anticoagulant activity of warfarin. Conclusion Once daily dosing of 10 mg nebivolol does not alter the single-dose PK or anticoagulant activity of warfarin. Clinical Pharmacology & Therapeutics (2005) 77, P39–P39; doi: 10.1016/j.clpt.2004.12.043 Table 1. Cmax AUC0-∞ Parameter Ratio 90% CI Ratio 90% CI R-warfarin 1.05 0.95–1.16 1.07 1.03–1.11 S-warfarin 1.09 0.97–1.23 1.10 1.03–1.18

Correction: effect of azathioprine on the anticoagulant activity of warfarin

Correction: effect of azathioprine on the anticoagulant activity of warfarin

Correction: effect of azathioprine on the anticoagulant activity of warfarin

Correction: effect of azathioprine on the anticoagulant activity of warfarin

Correction: Effect of Azathioprine on the Anticoagulant Activity of Warfarin

Correction: Effect of Azathioprine on the Anticoagulant Activity of Warfarin

Effect of azathioprine on the anticoagulant activity of warfarin

Effect of azathioprine on the anticoagulant activity of warfarin

Eprosartan does not affect the anticoagulant activity of warfarin,

Eprosartan does not affect the anticoagulant activity of warfarin,