BACKGROUND: Warfarin is a widely used oral anticoagulant with broad within- and between-individual dose requirements. Warfarin concentrations can be monitored by assessing its pharmacologic effects on International Normalized Ratio (INR). However, this approach has not been applied in the routine clinical management of patients receiving warfarin therapy. We performed a plasma warfarin assay using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) to determine if such an assay can be utilized in routine clinical practice. METHODS: We included a total of 105 patients with atrial fibrillation, and who were receiving warfarin for more than 1 yr. The plasma concentrations of total warfarin and 7-hydroxywarfarin were determined by HPLC-MS/MS (Waters, UK). We assessed the association between warfarin dose, concentration, and INR as well as the effects of these factors on warfarin concentrations. RESULTS: The mean maintenance dose of warfarin in 105 patients was 4.1+/-1.3 mg/day (range, 1.7-8.0 mg/day) and their mean plasma warfarin concentration was 1.3+/-0.5 mg/L. We defined a concentration range of 0.6-2.6 mg/L (corresponding to the 2.5th to 97.5th percentile range of the Plasma warfarin levels in the 74 patients showing INR within target range) as the therapeutic range for warfarin. The correlation of warfarin dose with warfarin concentration (r2=0.259, P<0.001) was higher than that with INR (r2=0.029, P=0.072). CONCLUSIONS: There was a significant correlation between warfarin dose and plasma warfarin concentrations in Korean patients with atrial fibrillation. Hence, plasma warfarin monitoring can help determine dose adjustments and improve our understanding of individual patient response to warfarin treatment.
Adult ; Aged ; Aged, 80 and over ; Anticoagulants/*blood/therapeutic use ; Asian Continental Ancestry Group ; Atrial Fibrillation/drug therapy ; Chromatography, High Pressure Liquid ; Female ; Humans ; Male ; Middle Aged ; Republic of Korea ; Tandem Mass Spectrometry ; Warfarin/analogs & derivatives/*blood/metabolism/therapeutic use

OBJECTIVEUsing two antithrombotic treatment (clopidogrel vs. clopidogrel combined warfarin) strategies after femoral-popliteal artery angioplasty prospectively, to evaluate which strategy is more effective for the restenosis prevention.

METHODSTotally 50 patients referred for endovascular treatment (including the percutaneous transluminal angioplasty (PTA) and stent implantation) of the superficial femoral artery and popliteal artery from January 2008 to May 2009 were randomly divided into clopidogrel group (group A, 25 cases, 30 limbs) and clopidogrel plus warfarin group (group B, 25 cases, 33 limbs) before operation. Clinical outcomes and restenosis rate of the target lesions were evaluated at 3, 6 and 12 months after operation.

RESULTSTotally 88 patients were screened for participation in the study, 56 patients were included after the follow-up of 12 months. At 3 months, the rates of restenosis were 16.7% in group A and 18.2% in group B (χ² = 0.025, P = 0.874). At 6 months, the accumulated restenosis rates were 36.7% in group A and 36.4% in group B (χ² = 0.001, P = 0.98). At 12 months, the accumulated restenosis rates were 53.3% in group A and 42.4% in group B (χ² = 0.75, P = 0.387). Analysis for the critical limb ischemia sub-group showed that follow-up of 12 months, the accumulated restenosis rate was 8/10 in group A and 6/12 in group B (χ² = 1.023, P = 0.312).

CONCLUSIONThe clopidogrel alone treatment for PTA or PTA plus stent implantation of femoral popliteal artery has no statistically significant difference in comparison with the clopidogrel combined warfarin treatment in terms of the cumulative vascular restenosis rate at 3, 6, 12 months postoperatively.

Adult ; Aged ; Aged, 80 and over ; Angioplasty, Balloon ; Arterial Occlusive Diseases ; etiology ; prevention & control ; Female ; Femoral Artery ; surgery ; Humans ; Male ; Middle Aged ; Popliteal Artery ; surgery ; Postoperative Complications ; prevention & control ; Prospective Studies ; Ticlopidine ; analogs & derivatives ; therapeutic use ; Warfarin ; therapeutic use

The present study was designed to determine the effects of puerarin pre-treatment on the pharmacokinetics of the oral anticoagulant agent warfarin and the antiplatelet agent clopidogrel in rats. In the treatment group, rats was gavaged with warfarin or clopidogrel after repeated treatment with puerarin at intraperitoneal doses of 20, 60, or 200 mg·kg(-1) for 7 days, while rats in the control group were administrated only with the same dose warfarin or clopidogrel. Plasma samples were obtained at the prescribed times and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). The results showed that rats treated with puerarin at all the test doses of 20, 60 and 200 mg·kg(-1) were found to affect the pharmacokinetics of warfarin, but not clopidogrel, suggesting a potential herb-drug interaction between puerarin and warfarin.
Animals ; Anticoagulants ; pharmacokinetics ; Chromatography, Liquid ; Clopidogrel ; Drug Administration Schedule ; Herb-Drug Interactions ; Injections, Intraperitoneal ; Isoflavones ; administration & dosage ; pharmacology ; Male ; Platelet Aggregation Inhibitors ; pharmacokinetics ; Rats ; Rats, Wistar ; Tandem Mass Spectrometry ; Ticlopidine ; analogs & derivatives ; pharmacokinetics ; Vasodilator Agents ; administration & dosage ; pharmacology ; Warfarin ; pharmacokinetics

Aged ; Aged, 80 and over ; Anticoagulants ; therapeutic use ; Aspirin ; therapeutic use ; Atrial Fibrillation ; complications ; drug therapy ; Brain Ischemia ; etiology ; prevention & control ; Dabigatran ; therapeutic use ; Dipyridamole ; therapeutic use ; Female ; Guideline Adherence ; statistics & numerical data ; Humans ; Male ; Middle Aged ; Platelet Aggregation Inhibitors ; therapeutic use ; Practice Guidelines as Topic ; Primary Prevention ; statistics & numerical data ; Pyrazoles ; therapeutic use ; Pyridones ; therapeutic use ; Rivaroxaban ; therapeutic use ; Stroke ; etiology ; prevention & control ; Ticlopidine ; analogs & derivatives ; therapeutic use ; Warfarin ; therapeutic use

Deep venous thrombosis (DVT) poses a major challenge to public health worldwide. Endothelial cell injury evokes inflammatory and oxidative responses that contribute to thrombus formation. Tea polyphenol (TP) in the form of epigallocatechin-3-gallate (EGCG) has anti-inflammatory and oxidative effect that may ameliorate DVT. However, the precise mechanism remains incompletely understood. The current study was designed to investigate the anti-DVT mechanism of EGCG in combination with warfarin (an oral anticoagulant). Rabbits were randomly divided into five groups. A DVT model of rats was established through ligation of the inferior vena cava (IVC) and left common iliac vein, and the animals were orally administered with EGCG, warfarin, or vehicle for seven days. In vitro studies included pretreatment of human umbilical vein endothelial cells (HUVECs) with different concentrations of EGCG for 2 h before exposure to hydrogen peroxide. Thrombus weight and length were examined. Histopathological changes were observed by hematoxylin-eosin staining. Blood samples were collected for detecting coagulation function, including thrombin and prothrombin times, activated partial thromboplastin time, and fibrinogen levels. Protein expression in thrombosed IVCs and HUVECs was evaluated by Western blot, immunohistochemical analysis, and/or immunofluorescence staining. RT-qPCR was used to determine the levels of AGTR-1 and VEGF mRNA in IVCs and HUVECs. The viability of HUVECs was examined by CCK-8 assay. Flow cytometry was performed to detect cell apoptosis and ROS generation was assessed by 2',7'-dichlorofluorescein diacetate reagent. In vitro and invivo studies showed that EGCG combined with warfarin significantly reduced thrombus weight and length, and apoptosis in HUVECs. Our findings indicated that the combination of EGCG and warfarin protects HUVECs from oxidative stress and prevents apoptosis. However, HIF-1α silencing weakened these effects, which indicated that HIF-1α may participate in DVT. Furthermore, HIF-1α silencing significantly up-regulated cell apoptosis and ROS generation, and enhanced VEGF expression and the activation of the PI3K/AKT and ERK1/2 signaling pathways. In conclusion, our results indicate that EGCG combined with warfarin modifies HIF-1α and VEGF to prevent DVT in rabbits through anti-inflammation via the PI3K/AKT and ERK1/2 signaling pathways.
Animals ; Anticoagulants/pharmacology* ; Catechin/analogs & derivatives* ; Eosine Yellowish-(YS)/pharmacology* ; Fibrinogen/pharmacology* ; Hematoxylin/pharmacology* ; Human Umbilical Vein Endothelial Cells ; Humans ; Hydrogen Peroxide/pharmacology* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; MAP Kinase Signaling System ; Phosphatidylinositol 3-Kinases/metabolism* ; Polyphenols/pharmacology* ; Proto-Oncogene Proteins c-akt/metabolism* ; RNA, Messenger ; Rabbits ; Rats ; Reactive Oxygen Species/metabolism* ; Signal Transduction ; Sincalide/pharmacology* ; Tea ; Thrombin/pharmacology* ; Vascular Endothelial Growth Factor A/metabolism* ; Venous Thrombosis/pathology* ; Warfarin/pharmacology*

Pharmacogenetic testing for clinical applications is steadily increasing. Correct and adequate use of pharmacogenetic tests is important to reduce unnecessary medical costs and adverse patient outcomes. This document contains recommended pharmacogenetic testing guidelines for clinical application, interpretation, and result reporting through a literature review and evidence-based expert opinions for the clinical pharmacogenetic testing covered by public medical insurance in Korea. This document aims to improve the utility of pharmacogenetic testing in routine clinical settings.
Anticoagulants/therapeutic use ; Antidepressive Agents/therapeutic use ; Antimetabolites, Antineoplastic/therapeutic use ; Antitubercular Agents/therapeutic use ; Arylamine N-Acetyltransferase/genetics ; Coronary Artery Disease/drug therapy/genetics ; Cytochrome P-450 CYP2C19/genetics ; Cytochrome P-450 CYP2C9/genetics ; Cytochrome P-450 CYP2D6/genetics ; Depressive Disorder/drug therapy/genetics ; Genotype ; Isoniazid/therapeutic use ; Laboratories, Hospital/standards ; Methyltransferases/genetics ; Pharmacogenomic Testing/*methods/standards ; Platelet Aggregation Inhibitors/therapeutic use ; Pulmonary Embolism/drug therapy/genetics ; Ticlopidine/analogs & derivatives/therapeutic use ; Tuberculosis/drug therapy/genetics ; Vitamin K Epoxide Reductases/genetics ; Warfarin/therapeutic use