Copovidone-related Cutaneous Response in the Dog.

A cutaneous response (localized swelling and/or erythema of the skin) has been noted in dog toxicology studies in which multiple, unrelated compounds were administered orally with copovidone as a vehicle. The response has been noted in studies with 6 different test items that are structurally unrelated and span several different therapeutic indications spanning an approximate 6-year period (2009-2015). A factor common among the studies is the formulation-a copovidone amorphous solid dispersion (ASD). Cutaneous responses have not been observed in dogs administered non-ASD formulations of the same test items but have occasionally been noted in placebo (copovidone control) dogs. Polyvinylpyrrolidone (a polymer of one of the primary components of copovidone) has been reported to result in similar findings in dogs when administered by the intravenous route. Considerations for the role of copovidone and the potential role of histamine in the cutaneous changes are outlined.

Studying navitoclax, a targeted anticancer drug, in healthy volunteers--ethical considerations and risk/benefit assessments and management.

BACKGROUND: Biopharmaceutical studies for anti-cancer drugs are typically conducted in cancer patients due to unacceptable toxicities to healthy volunteers. Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor that has been studied in cancer patients. METHODS: A strategy that integrated the evaluation of non-clinical toxicology data and clinical data in cancer patients was employed to assess the feasibility, determine doses and establish risk management plans for studying navitoclax in healthy volunteers. Two relative bioavailability/food effect studies with either a 25 mg dose or 50 and 100 mg doses of navitoclax were conducted sequentially in healthy female volunteers of non-childbearing potential. RESULTS/CONCLUSION: Navitoclax was well-tolerated in both studies in healthy volunteers, and did not impose risks beyond the minimal levels expected in healthy volunteer studies. Compared to a similar study in cancer patients, the studies in healthy volunteers generated higher quality data in a short period of time to support formulation selection.

Comparison of technicians' ability to detect clinical signs in rats housed in wire-bottom versus solid-bottom cages with bedding.

Rodent toxicology studies have historically been performed in wire-bottom cages, but the 1996 Guide for the Care and Use of Laboratory Animals recommends solid-bottom caging with bedding. Some investigators have expressed concern that changing to solid-bottom cages would interfere with technicians' ability to detect clinical signs. To test this hypothesis, rats were housed in both types of caging and given compounds to induce a variety of subtle clinical signs common to toxicology studies including chromodacryorrhea, soft stool, stereotypic behaviors, mild hypoactivity, abnormal postures, and discolored urine. For one comparison, fecal pellets were removed to simulate decreased production of feces. Technicians, blinded from knowing which animals had been treated, observed the rats and recorded the clinical signs they detected. The technicians who administered the treatments verified that clinical signs were present before and after the blinded technicians made their observations. The number of animals observed with clinical signs divided by the number of animals verified with signs was calculated for each compound and compared between the cage types by using the Fisher Exact Test. The only statistically significant difference observed was a diminished ability to detect discolored, dark urine from rats in wire-bottom cages. These results suggest that concerns about technical staff's inability to detect clinical signs in toxicity tests should not prevent investigators from using solid-bottom cages with bedding.

Urine acidification has no effect on peroxisome proliferator-activated receptor (PPAR) signaling or epidermal growth factor (EGF) expression in rat urinary bladder urothelium.

We previously reported prevention of urolithiasis and associated rat urinary bladder tumors by urine acidification (via diet acidification) in male rats treated with the dual peroxisome proliferator-activated receptor (PPAR)alpha/gamma agonist muraglitazar. Because urine acidification could potentially alter PPAR signaling and/or cellular proliferation in urothelium, we evaluated urothelial cell PPARalpha, PPARdelta, PPARgamma, and epidermal growth factor receptor (EGFR) expression, PPAR signaling, and urothelial cell proliferation in rats fed either a normal or an acidified diet for 5, 18, or 33 days. A subset of rats in the 18-day study also received 63 mg/kg of the PPARgamma agonist pioglitazone daily for the final 3 days to directly assess the effects of diet acidification on responsiveness to PPARgamma agonism. Urothelial cell PPARalpha and gamma expression and signaling were evaluated in the 18- and 33-day studies by immunohistochemical assessment of PPAR protein (33-day study only) and quantitative real-time polymerase chain reaction (qRT-PCR) measurement of PPAR-regulated gene expression. In the 5-day study, EGFR expression and phosphorylation status were evaluated by immunohistochemical staining and egfr and akt2 mRNA levels were assessed by qRT-PCR. Diet acidification did not alter PPARalpha, delta, or gamma mRNA or protein expression, PPARalpha- or gamma-regulated gene expression, total or phosphorylated EGFR protein, egfr or akt2 gene expression, or proliferation in urothelium. Moreover, diet acidification had no effect on pioglitazone-induced changes in urothelial PPARgamma-regulated gene expression. These results support the contention that urine acidification does not prevent PPARgamma agonist-induced bladder tumors by altering PPARalpha, gamma, or EGFR expression or PPAR signaling in rat bladder urothelium.