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ABSTRACTcially for evaluation of the teratogenicity, due to their small size, rapid development, transparency, and maintain them in culture plates, evaluate the teratogenicity in short term, conduct morphological assessment of each organ without any autopsy operation. The purpose of the present study was to improve an evaluation method for the teratogenicity of test compounds with high throughput ability and prediction -were exposed to test compounds from 5-6 to 144 hr post-fertilization, (hpf) corresponding to the organogenesis period. Morphological changes or functional abnormalities induced by test compound treatments were assessed and scored at 11 endpoints, and the potential of teratogenicity was judged based on the score. As a validation assay of the system, the potentials of 59 known teratogenic or non-teratogenic test -rectly predicted in 90% (53/59) of all compounds with low false negative and false positive rates. These valuable tool for early stage screening in drug discovery.

The pharmacological activity of DSP-6952, a novel compound was investigated, compared to that of clinically efficacious gastrointestinal (GI) prokinetic 5-hydroxytryptamine (5-HT) receptor agonists. DSP-6952 had a strong affinity of Ki = 51.9 nM for 5-HT receptor, and produced contraction in the isolated guinea pig colon with EC of 271.6 nM and low intrinsic activity of 57%, similar to tegaserod and mosapride. In the development of the 5-HT receptor agonists, cardiovascular risk was deliberately evaluated, because some related prokinetics were reported to cause with cardiovascular adverse events, such as ventricular arrhythmias or ischemia. DSP-6952 showed minimal effects up to 100 μM in human ether-a-go-go-related gene (hERG) channels or guinea pig cardiomyocytes. In telemetered conscious monkeys, DSP-6952 did not affect blood pressure or any electrocardiogram (ECG) up to 180 mg/kg, p.o.; however, DSP-6952 transiently increased heart rate, as well as in anesthetized dogs. The positive chronotropic effects of DSP-6952 were completely antagonized by a 5-HT receptor antagonist, and another 5-HT receptor agonist, TD-5108 also increased heart rate. These effects are considered a class effect seen in clinically developing and marketed 5-HT receptor agonists, and have not been regarded as a critical issue in clinical use. DSP-6952 did not induce contraction in the rabbit coronary artery up to 100 μM, which differed from tegaserod or sumatriptan. These results show that DSP-6952 does not have cardiac ischemic risk via coronary vasoconstriction. In conclusion, DSP-6952 is a promising GI prokinetic compound with partial 5-HT receptor agonistic activity as well as a favorable cardiovascular safety profile.

Historical control data on rabbit prenatal developmental toxicity studies, performed between 1994-2010, were obtained from 20 laboratories, including 11 pharmaceutical and chemical companies and nine contract laboratories, in Japan. In this paper, data were incorporated from a laboratory if the information was based on 10 studies or more. Japanese White rabbits and New Zealand White rabbits were used for prenatal developmental toxicity studies. The data included maternal reproductive findings at terminal cesarean sections and fetal findings including spontaneous incidences of morphological alterations. No noticeable differences between strains or laboratories were observed in the maternal reproductive and fetal developmental data. The inter-laboratory variations in the incidences of fetal external, visceral, and skeletal alterations seem to be due to differences in the selection of observation parameters, observation criteria, and classification of the findings, and terminology of fetal alterations.

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