Cytochrome P-450 2C9 (CYP2C9) polymorphisms (CYP2C9*2 and CYP2C9*3) reduce the clearance of warfarin, increase the risk of bleeding, and prolong the time to stable dosing. Whether prospective use of a retrospectively developed algorithm that incorporates CYP2C9 genotype and nongenetic factors can ameliorate the propensity to bleeding and delay in achieving a stable warfarin dose is unknown. We initiated warfarin therapy in 48 orthopedic patients tailored to the following variables: CYP2C9 genotype, age, weight, height, gender, race, and use of simvastatin or amiodarone. By using pharmacogenetics-based dosing, patients with a CYP2C9 variant achieved a stable, therapeutic warfarin dose without excessive delay. However compared to those without a CYP2C9 variant, patients with a variant continued to be at increased risk (hazard ratio 3.6, 95% confidence interval 1.4-9.5, p = 0.01) for an adverse outcome (principally INR > 4), despite pharmacogenetics-based dosing. There was a linear relationship (R(2) = 0.42, p < 0.001) between the pharmacogenetics-predicted warfarin doses and the warfarin maintenance doses, prospectively validating the dosing algorithm. Prospective, perioperative pharmacogenetics-based dosing of warfarin is feasible; however, further evaluation in a randomized, controlled study is recommended.
To predict possible effects of global climatic change (via changes in ambient water temperatures and suspended sediments) on two exotic bivalves (zebra mussel, Dreissena polymorpha, and quagga mussel, Dreissena bugensis), we evaluated survival and growth at three temperatures (ambient, ambient + 2°C, and ambient + 4°C) and two turbidities (ambient and twice ambient) in outdoor tanks for approximately 3 months during both warm and cool seasons. We compared responses of zebra and quagga mussels from southwestern Lake Erie and zebra mussel from the Ohio River at Louisville, Kentucky. Experimental increases in temperature significantly enhanced growth rates in fall - early winter but not during summer - early fall. Elevated temperatures increased mortality in the warm season but not in the cool season. Zebra mussel survived better (especially the Ohio River population) than did quagga mussel at high temperatures. Inorganic turbidity had few detectable effects; relationships, where significant, varied with temperature and species. Based on these experiments and related laboratory studies, we predict that populations of Dreissena in the Ohio River and farther south will suffer overall if water temperatures increase. In contrast, more northern populations of Dreissena will probably benefit from predicted climatic change and may extend their range to higher latitudes and altitudes.
Subjects who have been titrated to a consistent target INR demonstrate comparable plasma S-warfarin concentrations independent of CYP2C9 genotype. The warfarin dose required to maintain a consistent target INR between subjects differs as a function of S-warfarin clearance which is decreased by both CYP2C9*2 and or CYP2C9*3 variant alleles. The variables of CYP2C9 genotype and age can be applied to restrict the dosage range considered for individual patients.
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