P-glycoprotein (P-gp), encoded by the multiple drug resistance gene ABCB1 (also known as MDR1), is an integral component of the blood brain barrier crucial in limiting drug uptake into the central nervous system. Altered expression or function of P-gp, as seen in dogs of the collie lineage homozygous for the nt228(del4) mutation of the ABCB1 gene (ABCB1-1Delta), can result in potentially fatal neurotoxicosis, especially following administration of systemic macrocyclic lactones (SML). Occasionally, dogs from unrelated breeds develop subchronic signs of neurotoxicity when receiving SML to treat generalized demodicosis. It is possible that these dogs are heterozygous carriers of the ABCB1-1Delta mutation, resulting in decreased P-gp activity and central neurotoxicosis. Cheek swabs were collected from 28 dogs with generalized demodicosis that had shown subchronic signs of neurotoxicity following daily oral administration of ivermectin or other SML. Ten of these animals received concurrent systemic treatment with other confirmed or putative P-gp substrates. After DNA extraction, the relevant portion of the ABCB1 gene was amplified by polymerase chain reaction, and sequenced. Twenty-seven dogs were homozygous normal while one dog was heterozygous for the ABCB1-1Delta mutation. Therefore, with the exception of one dog, the observed neurotoxicity could not be attributed to the ABCB1-1Delta mutation. Possible explanations for the adverse reactions observed include pharmacological interactions (administration of SML with other P-gp substrates or inhibitors), excessively high doses, polymorphisms in P-gp expression, uncharacterized mutations in the ABCB1 gene or in another gene, or phenomena unrelated to the SML-P-gp interaction.

Ezetimibe coadministered with statins is effective in reducing LDL-C in patients who do not attain target LDL-C levels while on statin monotherapy.

IntroductionWhen a standard dose of statins fails to achieve lipid control in patients at high risk for coronary artery disease (CAD), increasing the statin dosage or co-administration of additional agents is recommended. The aim of this study was to compare the safety and lipid-lowering efficacy of doubling the standard statin dose (STAT2) to that of co-administering ezetimibe 10 mg/day (EZE+statin) in Canadian patients at high CAD risk with persistent hyperlipidemia upon statin treatment.Material and methodsSix-week, open-label, randomized, multicentre study. The primary outcome was the change in plasma LDL-C and secondary measures included the change in additional lipid parameters. Safety was assessed with the incidence of emergent adverse events (AEs).ResultsEight hundred eighty-five patients (EZE+statin, n=586; STAT2, n=299) completed the study. The mean (SD) percent change in low-density lipoprotein cholesterol (LDL-C) was – 30.9% (18.2) for the EZE+statin group and –18.4% (19.0) for the STAT2 group (p=0.001). Percent and absolute decreases in total cholesterol (TC), triglycerides and the TC to high-density lipoprotein cholesterol ratio (TC/HDL-C) were significantly greater for the EZE+statin group (p = 0.001). After 6 weeks of treatment, 70% of the patients in the EZE+statin group and 48% of patients in the STAT2 group (OR=2.45, p<0.001) achieved target LDL-C levels of<2.5 mmol/l. Incidence of AEs was similar between groups, with the exception of a higher incidence of muscle disorders in the STAT2 group.ConclusionsIn patients at high CAD risk who are above the LDL-C target while on statin monotherapy, co-administration of ezetimibe is well tolerated and more effective in improving the lipid profile compared to doubling the existing statin dose.

Objectives. The aim of this prospective cohort, multicentre study was to assess the effect of coadministrating ezetimibe 10 mg/day with an ongoing statin on the estimated risk for Cardiovascular (CVD) mortality in patients with persistently elevated LDL-C after statin monotherapy. Methods. The Systematic Coronary Risk Evaluation (SCORE) function was used to estimate the 10-year risk for cardiovascular mortality at baseline and 6 weeks. Primary outcome measures were absolute and percent changes in estimated Coronary Heart Disease (CHD) Mortality Risk, and general CVD Mortality Risk (Total CVD Mortality Risk). Results. 825 patients were included in the analysis. Mean (SD) age was 62 (10.5) years and 62.3% were males. The mean (SD) estimated Total CVD Mortality Risk decreased from 0.068 (0.059) at baseline to 0.053 (0.046) at 6 weeks (RR = 0.77; 95% CI:0.689–0.867), while the estimated CHD Mortality Risk decreased from 0.047 (0.040) at baseline to 0.034 (0.029) at 6 weeks (RR = 0.72; 95% CI:0.624–0.826). Conclusions. Co-administration of ezetimibe with a statin is effective in significantly reducing the estimated risk for cardiovascular mortality as measured by the SCORE model.