Toxicologic Pathology Forum: Current Status on the Use of Animal Models of Human Disease in the Pharmaceutical Industry in Japan in Nonclinical Safety Assessment-Opinion Paper.

In nonclinical safety studies for new drug development, healthy animals have been commonly used. However, in some cases, the use of animal models of human disease is considered to be more favorable in evaluating risks in patients. To elucidate the current status of the use of animal models for nonclinical safety assessment, an internal questionnaire from the Japan Pharmaceutical Manufacturers Association and surveys (questionnaire period: August 27 to September 30, 2015) of both common technical documents and review reports of approved drugs (approval period: May 1999 to May 2017) disclosed by the Pharmaceutical and Medical Devices Agency were conducted.

Characteristics of structures and lesions of the eye in laboratory animals used in toxicity studies.

Histopathology of the eye is an essential part of ocular toxicity evaluation. There are structural variations of the eye among several laboratory animals commonly used in toxicity studies, and many cases of ocular lesions in these animals are related to anatomical and physiological characteristics of the eye. Since albino rats have no melanin in the eye, findings of the fundus can be observed clearly by ophthalmoscopy.

General considerations in ocular toxicity risk assessment from the toxicologists' viewpoints.

Humans commonly obtain approximately 80% of external information from vision. Since loss of vision markedly decreases quality of life, risk assessments for visual toxicity of new drugs are extremely important. However, the ICH S4 guideline for nonclinical toxicity study of new drugs only indicates a brief instruction for ophthalmologic examinations, and submitted data for drug approval according only to this guideline are not always considered sufficient in light of ocular toxicity risk assessments.

Effects of reduced food intake on toxicity study parameters in rats.

This study comprehensively describes the effects of various levels of food reduction on a wide range of toxicological parameters in dietary-optimized rats (fed with approximately 75% of ad libitum food consumption daily; 16 g and 22 g/day for females and males, respectively) that has been established as a nutritionally appropriate and well-controlled animal model in conducting toxicity studies. Toxicological parameters, including general condition, ophthalmology, clinical pathology and anatomic pathology, were examined in dietary-optimized Crl:CD(SD) female and male rats fed 16 g and 22 g/day (control), 12 g and 17 g/day (75% group), 8 g and 11 g/day (50% group), or 4 g and 6 g/day (25% group), respectively for 2 weeks. There was mortality and morbidity including reddish urine in 25% group females.

Cardiac involvement in Beagle-based canine X-linked muscular dystrophy in Japan (CXMDJ): electrocardiographic, echocardiographic, and morphologic studies.

Background: Cardiac mortality in Duchenne muscular dystrophy (DMD) has recently become important, because risk of respiratory failure has been reduced due to widespread use of the respirator. The cardiac involvement is characterized by distinctive electrocardiographic abnormalities or dilated cardiomyopathy, but the pathogenesis has remained obscure. In research on DMD, Golden retriever-based muscular dystrophy (GRMD) has attracted much attention as an animal model because it resembles DMD, but GRMD is very difficult to maintain because of their severe phenotypes.

Beneficial effect of moderate food restriction in toxicity studies in rats.

Moderate food restriction (FR) has been established as a nutritionally appropriate and well-controlled method with long-term beneficial effects in conducting toxicity and carcinogenicity studies in rodents. This study describes the early effects of moderate FR on toxicity study parameters in rats and on the variability of these parameters. Physical signs, body weight, food and water consumption, and clinical pathology parameters were examined in a 4-week study in which rats were moderately food-restricted or fed ad libitum (AL).

Major clinical and histopathological characteristics of canine X-linked muscular dystrophy in Japan, CXMDJ.

Canine X-linked muscular dystrophy (CXMD), which was found in a colony of golden retriever, is caused by a mutation in the dystrophin gene and it is a useful model of Duchenne muscular dystrophy (DMD). To investigate the pathogenesis and to develop therapy of DMD, we have established a beagle-based CXMD colony in Japan (CXMDJ) and examined their phenotypes. The mortality by 3 days of age in the third generation (G3) of CXMDJ dogs, 32.

Changes in plasma membrane Ca2+ -ATPase expression and ATP content in lenses of hereditary cataract UPL rats.

The UPL rat is a newly developed hereditary cataract model. We previously found that Ca2+ concentrations in UPL rat lenses increase with the development of cataract, and that the administration of disulfiram and aminoguanidine ameliorates the increase in Ca2+ and the development of cataract in UPL rats. In this study, we determined the expression and activity of plasma membrane Ca2+-ATPase (PMCA) in lenses of normal and UPL rats.

Transport of trace elements in lenses of normal and hereditary cataract UPL rats.

The multitracer technique was applied to the determination of the uptake of trace elements in the lenses of normal and hereditary cataract UPL rats to investigate the transport mechanisms of trace elements during cataract development. Be, Na, Sc, V, Cr, Mn, Fe, Co, Zn, As, Se, Rb, Sr, Y, Zr, Tc, Ru and Rh accumulate in normal and UPL cataract rat lenses. The rates of uptake of trace elements differ among species and also differ between normal and UPL rat lenses.

Canine X-linked muscular dystrophy in Japan (CXMDJ).

The purpose of this study was to develop a strain of canine X-linked muscular dystrophy (CXMD), a model of Duchenne muscular dystrophy, in Japan. A female beagle was artificially inseminated with frozen-thawed spermatozoa derived from an affected golden retriever. Subsequently, two carrier female dogs (G1 carriers) and four normal male littermates were produced.

Delay of cataract development in hereditary cataract UPL rats by disulfiram and aminoguanidine.

The UPL rat is a newly developed hereditary cataract model. We previously found that the administration of disulfiram, a dimer of diethyldithiocarbamate that possesses antioxidant activity, and aminoguanidine, which is known to inhibit inducible nitric oxide synthase, inhibits cataract development in selenite-induced cataract rats. In this study, we investigated the anti-cataract effects and mechanism of disulfiram and aminoguanidine on UPL rats.