Effects of reduced food intake on the parameters of toxicity evaluation in dogs

Abstract

-It is crucial to evaluate the variations in the toxicity parameters in experimental animals during the development of new drugs. Reduced food intake has been reported to have an impact on the toxicity parameters in rats; however, there are few reports of such studies in dogs. The aim of this study was to clarify the effects of reduced food intake on the general toxicity parameters and their reversibility in dogs. Male beagle dogs were fed 300 g/day of diet for 12 weeks in the control group, and 150 g/day for the first 8 weeks and 200 g/day for the subsequent 4 weeks in the low feeding group. During the following 4-week recovery period, the amount of feeding was set at 300 g/day. There were no clinical changes in any of the dogs. The low feeding group showed a body weight loss of 9.0%, 16.7% and 14.3% relative to the pre-test values at Week 4, 8 and 12, respectively. The following changes from the pre-test values and/or the control group in the examined parameters were observed in this group: decreased heart rate, prolonged PR interval on the ECG, decreased leukocyte count, and increased serum free fatty acid and γ-glutamyl transpeptidase levels. Significant changes of these parameters were not observed any more during the recovery period. This fact supports biological or physiological reaction to reduced food intake. These results are considered to represent useful information for toxicologists to distinguish between the direct effects of drugs and the changes attributable to reduced food intake.

Effects of reduced food intake for 4 weeks on physiological parameters in toxicity studies in dogs

“…The blood chemistry results showed a decrease in the ALP level, similar to previously reported findings (Morita et al, 2015;Takamatsu et al, 2015). In the present study, ALP isozymes were assayed to confirm which organs were affected by the reduced food intake.…”

“…In dogs, transient increases in the RBC count and the HGB and HCT levels, suggestive of hemoconcentration, were observed at week 4 in a previously reported reduced feeding study (Morita et al, 2015). In the present study, the hemoconcentration was also thought to have been caused by reduced food intake; however, the decrease in erythropoiesis was considered to be a stronger effect than the hemoconcentration.…”

“…The experimental period simulated a 4-week toxicity study in dogs, consisting of a 5-week pre-test period before the group assignment and a 4-week reduced feeding period. A reduced feeding period of 4 weeks was selected because changes in parameters related to a reduced food intake, such as a decreased body weight, ALP level, leukocyte count and HR, were observed at week 4 in a previous 12-week study (Morita et al, 2015).…”

“…This amount was considered to be sufficient based on the reported energy requirements of beagle dogs (Durrer and Hannon, 1962) and is the amount usually provided in general toxicity studies performed in dogs so as not to affect evaluations of the test compounds. During the reduced feeding period, dogs in the LF group received 150 g/day, based on the results of a previous study (Morita et al, 2015). Dogs in the control group were fed 300 g/day throughout the experimental period.…”

“…A treatment-related decrease in food intake is often observed in repeated-dose animal toxicity studies, and this decrease can exert secondary effects on the toxicological parameters. In dogs, we previously reported that a reduced food intake for 12 weeks affected many physiological parameters commonly measured in toxicity studies (Morita et al, 2015), resulting in decreases in body weight, alkaline phosphatase (ALP) level, leukocyte count, and heart rate (HR). However, the effects of a decreased food intake on some parameters, such as the effect of a decreased ALP level on bone growth and the effects of a diet-induced decrease in body weight on the circulating blood volume, remain unclear.…”