Search

What Is Already Known About This Subject: • Inhibition of cholesteryl ester transfer protein (CETP) is a potential new mechanism for the treatment of dyslipidaemia. Anacetrapib is a novel CETP inhibitor in development. Warfarin is a commonly prescribed anticoagulant that has a narrow therapeutic index. A drug interaction study for warfarin with a novel CETP inhibitor is expected to be helpful in defining dosing regimens. WHAT THIS STUDY: ADDS • This is the first study to show that there is no clinically meaningful pharmacokinetic interaction between anacetrapib and warfarin. The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib., Aim: Anacetrapib is currently being developed for the treatment of dyslipidaemia. Since warfarin, an anticoagulant with a narrow therapeutic index, is expected to be commonly prescribed in this population, a drug interaction study was conducted., Methods: In a randomized, open-label, two-period fixed-sequence design, 12 healthy male subjects received two different treatments (treatment A followed by treatment B). In treatment A, a single oral dose of 30 mg warfarin (3 × 10 mg Coumadin(TM) ) was administered on day 1. After a washout interval, subjects began treatment B, where they were given daily 100 mg doses of anacetrapib (1 × 100 mg) beginning on day -14 and continuing through day 7, with concomitant administration of 30 mg warfarin (3 × 10 mg) on day 1. All anacetrapib and warfarin doses were administered with a standard low fat breakfast. After warfarin concentrations and prothrombin time were measured, standard pharmacokinetic, pharmacodynamic and statistical (linear mixed effects model) analyses were applied., Results: Anacetrapib was generally well tolerated when co-administered with warfarin in the healthy males in this study. The geometric mean ratios (GMRs) for warfarin + anacetrapib : warfarin alone and 90% confidence interval (CIs) for warfarin AUC((0-∞)) were 0.94 (0.90, 0.97) for the R(+) warfarin enantiomer and 0.93 (0.87, 0.98) for the S(-) warfarin enantiomer, both being contained in the interval (0.80, 1.25), supporting the primary hypothesis of the study. The GMRs warfarin + anacetrapib : warfarin alone and 90% CIs for the statistical comparison of warfarin C(max) were 1.01 (0.97, 1.05) for both the R(+) warfarin and the S(-) warfarin enantiomers, and were also contained in the interval (0.80, 1.25). The GMR (warfarin + anacetrapib : warfarin alone) and 90% CI for the statistical comparison of INR AUC((0-168 h)) was 0.93 (0.89, 0.96)., Conclusion: The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib., (© 2012 Merck & Co., Inc. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Genetic parameters were estimated with restricted maximum likelihood for individual test-day milk, fat, and protein yields and somatic cell scores with a random regression cubic spline model. Test-day records of Holstein cows that calved from 1994 through early 1999 were obtained from Dairy Records Management Systems in Raleigh, North Carolina, for the analysis. Estimates of heritability for individual test-days and estimates of genetic and phenotypic correlations between test-days were obtained from estimates of variances and covariances from the cubic spline analysis. Estimates were calculated of genetic parameters for the averages of the test days within each of the ten 30-day test intervals. The model included herd test-day, age at first calving, and bovine somatropin treatment as fixed factors. Cubic splines were fitted for the overall lactation curve and for random additive genetic and permanent environmental effects, with five predetermined knots or four intervals between days 0, 50, 135, 220, and 305. Estimates of heritability for lactation one ranged from 0.10 to 0.15, 0.06 to 0.10, 0.09 to 0.15, and 0.02 to 0.06 for test-day one to test-day 10 for milk, fat, and protein yields and somatic cell scores, respectively. Estimates of heritability were greater in lactations two and three. Estimates of heritability increased over the course of the lactation. Estimates of genetic and phenotypic correlations were smaller for test-days further apart.

The objective was to examine the direct and correlated responses of linear type, yield traits, and somatic cell scores (SCS) to divergent selection for predicted transmitting ability for type (PTAT) in Holsteins, while maintaining selection for yield traits across lines. For four generations, one-half of the University of Nebraska research Holstein herd was bred to Holstein sires with PTAT > 1.50 and the other half to sires with PTAT < 1.25, with nearly equal predicted transmitting abilities for yield traits for both groups. Estimates of genetic and residual correlations and heritabilities were obtained from REML estimates of (co)variance components. Model for type traits included fixed effect of date cows were classified, effects of age in days at freshening, and stage of lactation at classification. Year-season when cows freshened was fixed effect in model for yield and SCS. Animal genetic and residual effects were random. Final score, milk, fat, and protein yields, and SCS had heritability estimates of 0.38, 0.13,0.22, 0.09, and 0.38, respectively. Heritability estimates for type traits ranged from 0.04 to 0.52. Estimates of genetic correlations of final score with SCS and milk, fat, and protein yields were -0.64, 0.01, -0.18, and 0.06, respectively. Estimates of genetic correlations among linear type traits ranged from -0.77 to 1.00. Means of estimated breeding values for final score, stature, strength, body depth, fore udder attachment, rear udder height and width, udder cleft, udder depth, and front teat placement were significantly different between lines in the third generation. Milk, fat, and protein yields were not significantly different between lines in third generation, whereas SCS was significantly different. Estimate of genetic correlation between final score and SCS suggest that selection on PTAT would result in a change for SCS. In this study, divergent selection on PTAT of sires had a significant effect on udder and body traits, but little or no effect on feet and leg traits.

An attempt was made to isolate a bacteriophage T4 mutant generally disturbed in its ability to exclude the localized exclusion sensitivity determinants of T2 from the progeny of crosses. The method used was a modification of that used previously, which revealed T4 mutants unable to exclude more than one of the T2 sensitive sites specifically. One out of 1000 isolates from a mutagenized T4 am56:am32 stock was found to be mutated in its exclusion properties. However, the mutant was not generally exclusion deficient. Its properties were similar to those of a double mutant T4 ex 56:ex32, specifically unable to exclude the T2 sensitive sites near gene 56 and gene 32. The failure to isolate a generally excluding mutant at a frequency down to 10(-3) renders the occurrence of a general exclusion locus unlikely.