Toxicokinetics and toxicity of atorvastatin in dogs.

HMG-CoA reductase inhibitors (e.g., statins) are an important clinical option to lower cholesterol and treat co-morbidities. Atorvastatin is the most prescribed statin and has obtained generic status. We recently had a clinical development program evaluating a combination of atorvastatin with a GPR119 agonist as a treatment for dyslipidemia, where toxicological evaluations in dogs were completed. There were several challenges related to selecting doses for atorvastatin, including understanding the dose-exposure relationship from different drug forms used by the innovator in their general toxicology studies, bioanalytical assays that did not separate and quantify parent from metabolites, and high variability in the systemic exposures following oral dosing. The studies in this report characterized the toxicokinetics and toxicity of atorvastatin in the dog for up to 13-weeks. Overall, there were no notable differences in the toxicokinetics of atorvastatin or the two active hydroxylated metabolites between the sexes at Week 13. However, systemic exposures were markedly lower at Week 13 compared to that observed at Week 4, suggesting induction of metabolism or reduced absorption from the gastrointestinal tract following oral dosing. Changes in laboratory chemistries included increased liver enzyme levels and lower cholesterol levels. Histopathologic evaluation revealed multifocal minimal to slight hemorrhages in the submucosa of the gallbladder; all findings were reversible. The information from these studies along with the existing clinical experience with atorvastatin can be used to design robust toxicology studies in dogs and reduce animal use.

Determination of mycophenolic acid and its phenol glucuronide metabolite in human plasma and urine by high-performance liquid chromatography.

Simultaneous determination of mycophenolic acid (MPA) and mycophenolate phenol glucuronide (MPAG) in plasma and urine was accomplished by isocratic HPLC with UV detection. Plasma was simply deproteinated with acetonitrile and concentrated, whereas urine was diluted prior to analysis. Linearity was observed from 0.2 to 50 microg/ml for both MPA and MPAG in plasma and from 1 to 50 microg/ml of MPA and 5 to 2000 microg/ml MPAG in urine with extraction recovery from plasma greater than 70%. Detection limits using 0.25 ml plasma were 0.080 and 0.20 microg/ml for MPA and MPAG, respectively. The method is more rapid and simple than previous assays for MPA and MPAG in biological fluids from patients.

Functional equivalence of autistic leading and communicative pointing: analysis and treatment.

Several studies have demonstrated that behavior problems can be reduced by teaching new, socially desirable responses that serve the same function as the undesirable behaviors being replaced. The present study was undertaken to extend this strategy systematically to a different area of child development, specifically, language disorder. A less desirable form of requesting, autistic leading, was treated by strengthening a more desirable form of requesting, pointing. The study was conducted using a multiple baseline design across four children with autism. Intervention included verbal and physical prompting of the pointing response as well as tangible reinforcement for child-initiated instances of that response. In a later phase, verbal requesting was also taught to accompany the pointing. Following intervention, response generalization was observed; that is, as pointing became frequent, leading became rare. In addition, stimulus generalization was observed; that is, pointing was exhibited in the presence of new adults, new settings, and new tangible objects. Results are discussed with respect to the principle that functional equivalence and response efficiency can be combined procedurally to treat a variety of undesirable behaviors in an educationally constructive manner.