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250 CHEMOTHERAPY APR. 1986 Fig. 1 Chemical structure of T-2588 pivaloyloxymethyl (+)-(6 R, 7 R)-7 -a 2 )-2 -(2-amino- 4-thiazolyl)-2-methoxyiminoacetamido]-3-[(5-methyl- 2 H-tetrazol-2-yl) meth yl ]- 8 -oxo- 5 -thia- 1 - azabicyclo [4. 2. 0] oct- 2- ene- 2- carboxylate

VOL. 34 S-2 CHEMOTHERAPY

CHEMOTHERAPY

VOL. 34 S-2 CHEMOTHERAPY Fig. 4 Water intake of dams administered T-2588 orally Table 1 Organ weight of dams administered T-2588 orally (dissected on day 21 of gestation) Significantly different from control * p<0.05, ** p<0.01

CHEMOTHERAPY Table 2 Absolute and relative organ weight of dams administered T-2588 orally (dissected after weaning ), Significantly different from control * p<0.05, ** p<0.01 Table 3 Cesarean section data of dams administered T-2588 orally (dissected on day 21 of gestation) Significantly different from control * p<0.05, ** p<0.01

VOL. 34 S-2 CHEMOTHERAPY Photo. 1 Wavy ribs (T-2588 1, 000 mg/kg, Fetus) Table 4 Skeletal observation on fetuses obtained from dams administered T-2588 orally (dissected on day 21 of gestation) Significantly different from control * p<0.05

CHEMOTHERAPY Table 5 Visceral observation on fetuses obtained from dams administered T-2588 orally (dissected on day 21 of gestation) Significantly different from control * p<0.05, ** p<0.01. The umbilical artery passes to the right of the urinary bladder in most cases. In a few instances it passes to the left of the urinary bladder. Table 6 Observation of delivery and viability of pups obtained from dams administered T-2588 orally ( No. of pups born alive/no, of implantations) ~100 No. of 4 days old pups before culling/no, of pups born alive No. of pups at 3rd week/no. of 4 days old pups after culling No. of pups at 6th week/no. of 4 days old pups after culling Significantly different from control * p<0.05, ** p<0.01

VOL. 34 S-2 CHEMOTHERAPY Table 7 Body weight changes of F1 (Male) obtained from dams administered T-2588 orally Significantly different from control * p<0.05 Table 8 Body weight changes of F, (Female) obtained from dams administered T-2588 orally Significantly different from control * p<0.05

CHEMOTHERAPY Table 9 Postnatal development of F1 observed from dams administered T-2588 orally Photo. 2 Nodulated ribs (T-2588 1, 000 mg/kg, Neonate)

VOL. 34 S-2 CHEMOTHERAPY Table 10 Skeletal observation on pups obtained from dams administered T-2588 orally (culled at 4 days old) and middle phalanges Significantly different from control * p<0.05 Table 11 Absolute and relative organ weight of F1 (Male) obtained from dams administered T-2588 orally (dissected at 6 weeks old) Significantly different from control * p<0.05, **p<0.01

CHEMOTHERAPY Table 12 Absolute and relative organ weight of F1 (Female) obtained from dams administered T-2588 orally (dissected at 6 weeks old) Significantly different from control * p<0.05, ** p<0.01 Table 13 Open field test of F, (Male) obtained from dams administered T-2588 orally Significantly different from control * p<0.05

VOL; 34 S-2 CHEMOTHERAPY 261 Table 14 Open field test of F1 (Female) obtained from dams administered T-2588 orally Significantly different from control * p<0.05, ** p<0.01 Table 15 Reproductive performance of F1 obtained from dams administered T-2588 orally (dissected on day 20 of gestation)

262 CHEMOTHERAPY APR. 1986 Fig, 5 Water multiple T-maze test of F1 obtained from dams administered T-2588 orally (No. of errors) Fig. 6 Water multiple T-maze test of F1 obtained from dams administered T-2588 orally (Swimming time)

VOL. 34 S-2 CHEMOTHERAPY 263 4) DAWSON, A. B.: A note on the staining of the skeleton of cleared specimens with alizarine red S. Stain. Tech. 1 : 123 `424, 1926 5) WILSON, J. G.: Method for administering agents and detecting malformation in experimental animals. Chicago Univ. press, Teratology (WILSON, J. G. and J. WARKANY) pp. 262 `272, 1965 7) BUTCHER, R. E.; W. J. SCOTT, K. KAZMAIER & E. J. RITTER: Postnatal effects in rats of prenatal treatment with hydroxyurea. Teratology 7: 161 `466, 1973 8) BIEL, W. C.: Early age differences in maze performance in the albino rat. J. Genet. Psychol. 56 : 439 `453, 1940 13) SAEGUSA, T.; Y. SANEKO, T. SATO, I. NARA- MA & Y. SEJIMA : BD40A induced wavy ribs in rats. Cong. Anom. 20: 214 `215, 1980 14) NISHIMURA, M. ; M. IIZUKA, S. IWAKI & A. KAST : Repairability of drug-induced "wavy ribs" in rat offspring. Arzneim.-Forsch. (Drug Res.) 32 (II) : 1518 `4522, 1982 15) HAYASAKA, I. ; F. TAMAKI, K. UCHIYAMA, Z. KATO & K. MURAKAMI : Azosemide-induced fetal wavy ribs and their disappearance after birth in rats. Cong. Anom. 25 : 121 `127, 1985 16) OHURA, K.; S. TAKAYAMA : Repairability of insulin induced wavy ribs in rat offspring. Cong. Anom. 25 : 218, 1985

264 CHEMOTHERAPY APR. lead TERATOLOGICAL STUDY OF T-2588 IN RATS NORIHISA KOMAE, HIROKO NAKADA, SHOZO NAKAMURA and TOYOAKI YONEDA Research Laboratory, Toyama Chemical Co., Ltd. Teratological study on T-2588 was carried out in Sprague-Dawly strain rats. T-2588 was administered orally to pregnant rats from day 7 to 17 of gestation at the daily doses of 250, 500 and 1000 mg/kg as a suspension in 0. 5%CMC and 0. 1%HPC-L solution. Of 34 to 37 pregnant rats in each group, 20 pregnant rats were sacrificed on day 21 of gestation and remaining rats were allowed to deliver naturally. Dams, fetuses and offspring were examined. Following results were obtained. 1. After administration of T-2588, in pregnant rats, soft feces and transient decrease in food intake at all doses of T-2588, increase in water intake at the doses of 500 and 1000 mg/kg and depression of body weight gain at the dose of 1000 mg/kg were observed. 2. In the examination of fetuses, there were no significant differences in number and body weight of live fetuses, number of dead fetuses and sex ratio between the T-2588 treated groups and the control group. No external abnormality was observed in the T-2588 treated groups. In 1000 mg/kg treated group, however, significant increase of the prevalence of skeletal and visceral abnormality (wavy ribs, left umbilical artery) were observed. 3. In the postnatal examination, there were no significant differences in duration of gestation, number and body weight of newborn offspring, external development, function of sensory, reflex, learning ability and reproductive performance between the T-2588 treated groups and the control group. In 1000 mg/kg treated group, however, decrease in weaning rate and increase in number of rearing and ambulation, of female in open field test were observed. 4. From these results, the maximum non-effective dose of T-2588 on dam, fetus and offspring is estimated to be 500 mg/kg.

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