Plasma lipid profiling across species for the identification of optimal animal models of human dyslipidemia.

In an attempt to understand the applicability of various animal models to dyslipidemia in humans and to identify improved preclinical models for target discovery and validation for dyslipidemia, we measured comprehensive plasma lipid profiles in 24 models. These included five mouse strains, six other nonprimate species, and four nonhuman primate (NHP) species, and both healthy animals and animals with metabolic disorders. Dyslipidemic humans were assessed by the same measures. Plasma lipoprotein profiles, eight major plasma lipid fractions, and FA compositions within these lipid fractions were compared both qualitatively and quantitatively across the species. Given the importance of statins in decreasing plasma low-density lipoprotein cholesterol for treatment of dyslipidemia in humans, the responses of these measures to simvastatin treatment were also assessed for each species and compared with dyslipidemic humans. NHPs, followed by dog, were the models that demonstrated closest overall match to dyslipidemic humans. For the subset of the dyslipidemic population with high plasma triglyceride levels, the data also pointed to hamster and db/db mouse as representative models for practical use in target validation. Most traditional models, including rabbit, Zucker diabetic fatty rat, and the majority of mouse models, did not demonstrate overall similarity to dyslipidemic humans in this study.

Transurethral bladder catheterization of male rhesus macaques: a refinement of approach.

BACKGROUND: Successful transurethral bladder catheterization in male non-human primates can be challenging. An optimized approach for consistent and reproducible catheterization using a refined technique is described. METHODS: Under sedated and non-sedated conditions, transurethral bladder catheterization was performed on 25 male rhesus macaques of varying ages and body weights over time. A refined technique ensuring optimal lubrication of the urethral canal prior to catheter insertion was utilized along with various single and multiple lumen catheters. RESULTS: All animals were successfully catheterized. Sixty-five catheterization sessions were conducted with a high overall success rate (100%). The incidence of catheter (10%) and post-catheterization (2%) complications was low. CONCLUSIONS: The urinary bladder of male rhesus can be reliably and reproducibly catheterized with minimal complication using this approach. Successful catheterization was facilitated by thorough urethral lubrication and using suitable catheters. In addition, this approach may be performed without sedation on thoroughly conditioned animals.

Use of a rigid endoscope to teach urethral catheterization of the female dog.

Urethral catheterization of the female dog is known to be a challenging procedure. The authors describe a catheterization technique in which they use a rigid endoscope to visualize the canine urogenital vestibule during the procedure. The technique is particularly helpful as a training tool for students who are not yet experienced with the canine anatomy. The endoscope is attached to a video camera and monitor, allowing others to observe and learn the procedure.

Effects of anacetrapib on plasma lipids, apolipoproteins and PCSK9 in healthy, lean rhesus macaques.

Inhibition of cholesteryl ester transfer protein (CETP) has been vigorously pursued as a potential therapy to treat patients who are at an elevated risk for coronary artery disease. Anacetrapib, a novel CETP inhibitor, has been shown clinically to raise HDL cholesterol and reduce LDL cholesterol when provided as monotherapy or when co-administered with a statin. Preclinically, the effects of anacetrapib on the functionality and composition of HDL have been extensively studied. In contrast, the effects of anacetrapib on other parameters related to lipoprotein metabolism and cardiovascular risk have been difficult to explore. The aim of the present investigation was to evaluate the effects of anacetrapib in rhesus macaques and to compare these to effects reported in dyslipidemic humans. Our results from two separate studies show that administration of anacetrapib (150 mg/kg q.d. for 10 days) to rhesus macaques results in alterations in CETP activity (reduced by more than 70%) and HDL cholesterol (increased by more than 110%) which are similar to those reported in dyslipidemic humans. Levels of LDL cholesterol were reduced by more than 60%, an effect slightly greater than what has been observed clinically. Treatment with anacetrapib in this model was also found to lead to statistically significant reductions in plasma PCSK9 and to reduce cholesterol excursion in the combined chylomicron and remnant lipoprotein fraction isolated from plasma by fast protein liquid chromatography. Collectively, these data suggest that rhesus macaques may be a useful translational model to study the mechanistic effects of CETP inhibition.