ABSTRACT
BACKGROUND AND AIM: Warfarin is the most frequently prescribed anticoagulant worldwide. However, warfarin therapy is associated with a high risk of bleeding and thromboembolic events because of a large interindividual dose-response variability. We investigated the effect of genetic and non genetic factors on warfarin dosage in a South Italian population in the attempt to setup an algorithm easily applicable in the clinical practice. MATERIALS AND METHODS: A total of 266 patients from Southern Italy affected by cardiovascular diseases were enrolled and their clinical and anamnestic data recorded. All patients were genotyped for CYP2C9 2, 3, CYP4F2 3, VKORC1 -1639 G>A by the TaqMan assay and for variants VKORC1 1173 C>T and VKORC1 3730 G>A by denaturing high performance liquid chromatography and direct sequencing. The effect of genetic and not genetic factors on warfarin dose variability was tested by multiple linear regression analysis, and an algorithm based on our data was established and then validated by the Jackknife procedure. RESULTS: Warfarin dose variability was influenced, in decreasing order, by VKORC1-1639 G>A (29.7%), CYP2C9 3 (11.8%), age (8.5%), CYP2C9 2 (3.5%), gender (2.0%) and lastly CYP4F2 3 (1.7%); VKORC1 1173 C>T and VKORC1 3730 G>A exerted a slight effect (<1% each). Taken together, these factors accounted for 58.4% of the warfarin dose variability in our population. Data obtained with our algorithm significantly correlated with those predicted by the two online algorithms: Warfarin dosing and Pharmgkb (p<0.001; R(2)â=â0.805 and p<0.001; R(2)â=â0.773, respectively). CONCLUSIONS: Our algorithm, which is based on six polymorphisms, age and gender, is user-friendly and its application in clinical practice could improve the personalized management of patients undergoing warfarin therapy.
Subject(s)
Anticoagulants/administration & dosage , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/genetics , Drug Administration Schedule , Pharmacogenetics/methods , Warfarin/administration & dosage , Aged , Algorithms , Alleles , Aryl Hydrocarbon Hydroxylases/genetics , Chromatography, High Pressure Liquid , Cytochrome P-450 CYP2C9 , Cytochrome P-450 Enzyme System/genetics , Cytochrome P450 Family 4 , Dose-Response Relationship, Drug , Female , Genotype , Humans , International Normalized Ratio , Italy , Male , Middle Aged , Polymerase Chain Reaction , Regression Analysis , Vitamin K Epoxide Reductases/geneticsABSTRACT
BACKGROUND: Pharmacogenetic testing for drug-metabolizing enzymes is not yet widely used in clinical practice. METHODS: In an attempt to facilitate the application of this procedure, we have compared two real-time PCR-based methods, the TaqMan and the LightCycler for the pharmacogenetic evaluation of CYP2C9*2/*3 polymorphisms. RESULTS AND CONCLUSION: Both procedures are suitable for pharmacogenetic studies. The TaqMan procedure was less expensive in terms of cost per sample, but the TaqMan apparatus is more expensive than the LightCycler apparatus.
Subject(s)
Aryl Hydrocarbon Hydroxylases/metabolism , Pharmacogenetics/methods , Polymorphism, Genetic , Taq Polymerase/metabolism , Alleles , Aryl Hydrocarbon Hydroxylases/genetics , Cytochrome P-450 CYP2C9 , Humans , Pharmacogenetics/economics , Polymerase Chain Reaction/methods , Sensitivity and Specificity , Taq Polymerase/genetics , TemperatureABSTRACT
Exercise training elicits an improvement in work capacity and in left-ventricular function in patients with coronary artery disease. An improvement in myocardial oxygen supply accounts for these effects. The aim of this study was to test the hypothesis that exercise training could favorably influence diastolic perfusion time, a major determinant of subendocardial perfusion. Twenty-two male patients with coronary artery disease were randomized to a training or control group. At the study entry and after one year, all patients underwent an exercise stress test. After one year, rest heart rate was lower and diastolic perfusion time was higher in the training group but not in the control group. At peak of exercise, diastolic perfusion time increased and ST-segment depression decreased significantly in the training group but not in the control group. A significant relation was found between the R-R interval and the diastolic perfusion time either before or after training, with a difference in the intercepts of two regressions. Training shifted updown-line regression, effecting a higher value of diastolic perfusion time for a given value of heart rate. Thus, training increases diastolic perfusion time, independently from the effect on heart rate. This mechanism may contribute to the improvement of myocardial perfusion.
