Tolerability of oral sorafenib in pet dogs with a diagnosis of cancer.

Sorafenib is a multi-target small molecule inhibitor of the RAF kinase family and VEGFR-2/PDGFR. The US Food and Drug Administration approved sorafenib in human patients with liver, thyroid, or renal carcinoma. The aim of this study was to help guide future pharmacokinetic (PK) studies of sorafenib in dogs with a cancer diagnosis. Client-owned dogs were eligible if they had a cytologic or histologic diagnosis of cancer. Patients were enrolled at escalating doses of sorafenib. Patients were evaluable for the study if they received at least one dose of sorafenib and presented 1 week later for a follow-up examination, blood work, and assessment of drug tolerability. The goal of this study was not to define a maximum tolerated dose as may be reasonable in conventional cytotoxic chemotherapy drugs, but rather to describe the tolerability of this drug in dogs with a cancer diagnosis, as a prequel to future sorafenib PK studies. No patients in the study had any evidence of adverse events that were attributable to sorafenib. Doses of 3 mg/kg were well tolerated and associated with a suggestion of clinical activity, supportive of future PK, and pharmacodynamic analysis. Such future studies are recommended at this dose to define the associated exposure achieved and determine a reasonable schedule for sorafenib administration.

The effects of erythropoietin dose titration during high-fat diet-induced obesity.

Erythropoietin (Epo) is a pleotropic cytokine with several nonhematopoietic tissue effects. High-dose Epo treatment-mediated effects on body weight, fat mass and glucose tolerance have recently been reported, thus extending its pleotropic effects to fat and glucose metabolism. However, the exact dose range of Epo treatment required for such effects remains unidentified to date. We investigated Epo dosage effect (up to 1000 U/kg) on hematocrit, body weight, body composition, glucose metabolism, food intake, and physical activity, during high-fat diet-induced obesity. We report that Epo doses (1000, 600, 300, and 150 U/kg) significantly reduced body weight gain and fat mass, while, only Epo doses of 300 U/kg and higher significantly affected glucose tolerance. None of the tested Epo doses showed any detectable effects on food intake, and only 1000 U/kg dose significantly increased physical activity, suggesting that these parameters may only be partially responsible for the metabolic effects of Epo treatment.