PubMed Health⌕ Search

Biomedical subjects

Bonny L Bukaveckas

Publications and source records attributed to Bonny L Bukaveckas.

7 recordsLinked to original sources
PubMed2005

Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype.

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.

Adult↗
PubMed2003

Manganese distribution across the blood-brain barrier. I. Evidence for carrier-mediated influx of managanese citrate as well as manganese and manganese transferrin.

Manganese (Mn) is an essential element and a neurotoxicant. Regulation of Mn movement across the blood-brain barrier (BBB) contributes to whether the brain Mn concentration is functional or toxic. In plasma, Mn associates with water, small molecular weight ligands and proteins. Mn speciation may influence the kinetics of its movement through the BBB. In the present work, the brain influx rates of 54Mn2+, 54Mn citrate and 54Mn transferrin (54Mn Tf) were determined using the in situ brain perfusion technique. The influx rates were compared to their predicted diffusion rates, which were determined from their octanol/aqueous partitioning coefficients and molecular weights. The in situ brain perfusion fluid contained 54Mn2+, 54Mn citrate or 54Mn Tf and a vascular volume/extracellular space marker, 14C-sucrose, which did not appreciably cross the BBB during these short experiments (15-180 s). The influx transfer coefficient (Kin) was determined from four perfusion durations for each Mn species in nine brain regions and the lateral ventricular choroid plexus. The brain Kin was (5-13) x 10(-5), (3-51) x 10(-5), and (2-13) x 10(-5) ml/s/g for 54Mn2+, 54Mn citrate, and 54Mn Tf, respectively. Brain Kin values for any one of the three Mn species generally did not significantly differ among the nine brain regions and the choroid plexus. However, the brain Kin for Mn citrate was greater than Mn2+ and Mn Tf Kin values in a number of brain regions. When compared to calculated diffusion rates, brain Kin values suggest carrier-mediated brain influx of 54Mn2+, 54Mn citrate and 54Mn Tf. 55Mn citrate inhibited 54Mn citrate uptake, and 55Mn2+ inhibited 54Mn2+ uptake, supporting the conclusion of carrier-mediated brain Mn influx. The greater Kin values for Mn citrate than Mn2+ and its presence as a major non-protein-bound Mn species in blood plasma suggest Mn citrate may be a major Mn species entering the brain.

Animals↗
PubMed2003

Manganese distribution across the blood-brain barrier. II. Manganese efflux from the brain does not appear to be carrier mediated.

There is concern about manganese (Mn) neurotoxicity. Mn can enter the brain by carrier-mediated influx. There have been no previous reports of investigation of Mn efflux from the brain. We used an established method that determines the rate of efflux out of the brain across the blood-brain barrier (BBB) from the product of the brain distribution volume (Vbrain) and the apparent elimination rate constant (Kel). Vbrain is determined as 54Mn uptake into rat parietal brain slices versus time. Kel is determined from the percentage of 54Mn remaining in the brain at various times after its discrete injection into the parietal cortex, compared to a reference compound which is expected to very slowly diffuse out of the brain. The Mn ion, Mn citrate and Mn transferrin (Mn Tf) were studied. 14C-sucrose and 14C-dextran were used as reference compounds. The volume of distribution of the Mn species in brain slices was approximately 3-5 ml/g, indicating concentrative uptake. Mn, as the Mn ion or Mn citrate, was injected into the brain with sucrose or dextran to determine Kel. Based on the rapid exchange rate of Mn with ligands and on thermodynamic calculations, injection of Mn ion or Mn citrate into the brain would be expected to result in rapid formation of the same Mn species, predominantly the Mn ion, Mn citrates and Mn phosphate, in brain extracellular fluid. After injection into the brain Mn did not efflux from the brain more rapidly than sucrose or dextran, which diffuse across the BBB. Brain capillary diffusion of the Mn ion and Mn citrate would be expected to be slower than sucrose or dextran. The rate of Mn efflux from the brain is consistent with diffusion.

Animals↗
PubMed2002

Warfarin dose adjustments based on CYP2C9 genetic polymorphisms.

BACKGROUND: The dose response relationship of warfarin is unpredictable. Polymorphism of the Cytochrome P4502C9 enzyme leads to warfarin hypersensitivity presumably due to decreased metabolism of the S-enantiomer. The purpose of this study was to further characterize the relationship between CYP2C9 genotype and phenotype and to develop a basis for guidelines to interpret CYP2C9 genotype for warfarin dosing. METHODS AND RESULTS: Patients stabilized on warfarin therapy were recruited from an anticoagulation clinic. Patients were genotyped for CYP2C9*2, CYP2C9*3 and CYP2C9*5 alleles by standard methods of polymerase chain reaction amplification and restriction endonuclease digestion. Phenotype was determined by; dose (mg/kg/d) required to maintain anticoagulation, (INR 2.0-3.0), oral plasma S-warfarin clearance, and the plasma S:R-warfarin ratio. In this cohort, no subjects were found to have the CYP2C9*5 allele. The plasma S-warfarin concentration did not differ with age, dose or CYP2C9 genotype. Both CYP2C9*2 and *3 alleles were associated with lower maintenance dosages, lower total and R-warfarin plasma concentrations, decreased oral clearance of S-warfarin, increased plasma S:R-warfarin ratio and extended S-warfarin elimination half-life. Advancing age was found to decrease Warfarin maintenance dose in subjects with the common active CYP2C9*1/*1 genotype but did not influence dose requirement of subjects with one or more variant CYP2C9 alleles. CONCLUSIONS: 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.

Adult↗