Single dose toxicity studies of landiolol hydrochloride (ONO-1101), a novel ultra short acting β-blocker, were conducted in Sprague-Dawley (SD) rats and beagle dogs. ONO-1101 was administered intravenously at a dose level of 37.5, 75, 150 or 300mg/kg to rats of both sexes and 25, 50 or 100 mg/kg to male dogs. In the rat study, 5/6 males in the 150 mg/kg group and all animals in the 300 mg/kg group died during or right after administration. Survivors in the 150 mg/kg group showed temporal hypoactivity, bradypnea, dyspnea, tremor, loss of righting reflex and reddish lacrimation up to 5 min after injection. One male in the 150 mg/kg group had a tendency of suppression on body weight gain. No effects on clinical signs and body weight gain were seen in the 75 mg/kg group or lower. Necropsy findings showed only red tear in the majority of the decedents. In the dog study, all animals died within 6 min after administration in the 100 mg/kg group, showed ataxic gait, rolling and tachypnea followed by bradypnea and gasping/apnea. Incontinence of urine, defecation and vocalization were also seen in each one of two animals before death. Temporal hypoactivity was seen 1 min after administration in the 50 mg/kg group. No clinical signs were seen in the 25 mg/kg group. ONO-1101 did not affect bodyweight or food consumption. Necropsy findings of the decedents showed no abnormalities. It is indicated that the minimum lethal doses are 150 mg/kg in rats and 100 mg/kg in dogs.

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4-week repeated dose toxicity study with 4-week recovery test of landiolol hydrochloride (ONO-1101), a novel ultra short acting β-blocker, was conducted in Sprague-Dawley (SD) rats. ONO-1101 was administered intravenously to rats of both sexes at a dose level of 0 (control), 12.5, 25, 50 or 100 mg/kg/day. In the 100 mg/kg/day group, bradypnea or dyspnea was seen in all animals, pale in ear, eye and foot, tremor, reddish lacrimation and loss of righting reflex were also observed in some animals right after administration, and then those signs disappeared within 1 min after administration. During the treatment period, 3/20 animals of each sex in the 100 mg/kg/day showed clonic convulsion and died within 2 min after administration. No clinical changes were seen in the 50 mg/kg/day group or lower. Histopathological findings showed atrophy of the submaxillary gland in females and vessel-wall thickening and perivascular fibrosis of the injection site (tail) in both sexes at 100 mg/kg/day, however those changes were reversible. ONO-1101 did not effect on body weight, food consumption, ophthalmology, urinalysis, hematology, blood chemistry, organ weights or necropsy at any doses. These results indicate that the no-adverse-effect level of ONO-1101 in rats is 50 mg/kg/day for both sexes in this study.

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4-week repeated dose toxicity study with 4-week recovery test of landiolol hydrochloride (ONO-1101), a novel ultra short acting β-blocker, was conducted in beagle dogs. ONO-1101 was administered intravenously to dogs of both sexes at a dose level of 0(control), 12.5, 25 or 50 mg/kg/day. No deaths occurred throughout the treatment period. Transitory licking chops, vomiting, nausea, diarrhea and soft feces were observed occasionally in both sexes dosed 25 and 50 mg/kg/day and the incidence seemed dose-dependent. However, those incidence declined in the course of the treatment period. Hematology showed a decrease in red blood cell count, hematocrit and hemoglobin value in both sexes receiving 25 and 50 mg/kg/day. ONO-1101 did not effect on body weight, food consumption, respiratory rate, pulse, rectal temperature, heart rate, blood pressure, electrocardiography, renal or hepatic function, ophthalmology, urinalysis, occult blood in feces, blood chemistry, organ weights, necropsy and microscopic findings at any doses. These results indicate that the no-adverse-effect level of ONO-1101 in dogs is 12.5 mg/kg/day for both sexes in this study.

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A fertility study of landiolol hydrochloride (ONO-1101), a novel ultra short acting β-blocker, was conducted in Sprague-Dawley (SD) rats. ONO-1101 was administered intravenously to males from the 64th day before mating until necropsy, and to females from 15th day before mating until day 7 of gestation, at a dose level of 0 (control), 25, 50 or 100 mg/kg/day. On day 20 of gestation, all dams were sacrificed and their fetuses were examined. In the 100 mg/kg/day group, hypoactivity, clonic convulsion, bradypnea/apnea and reddish lacrimation were observed after administration in both sexes, and 3 males and 2 females died. Reddish lacrimation was occasionally seen in males at late stage of the treatment period in 50 mg/kg/day group. In the 100 mg/kg/day group, body weight gain suppressed in females from the premating through the gestation period, and food consumption decreased in females during the premating period, and mean thymus weight decreased in males. ONO-1101 did not affect estrous cycle, copulatory or fertility in both sexes or external, skeletal or visceral features of the fetuses. From the above results, it is estimated that the no-toxic dose level of ONO-1101 under these experimental conditions is 50 mg/kg/day for general toxicity in parents, and 100 mg/kg/day for the reproductive performance in parents and for the development of fetuses.

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A teratogenicity study of landiolol hydrochloride (ONO-1101), a novel ultra short acting β-blocker, was conducted in Sprague-Dawley (SD) rats. ONO-1101 was administered intravenously at a dose level of 0 (control), 25, 50 or 100 mg/kg/day to pregnant rats from day 7 to 17 of gestation, and effects of ONO-1101 on dams, fetuses and their offspring, were examined. In the 100 mg/kg/day group, hypoactivity, bradypnea, reddish lacrimation, clonic convulsion and loss of righting reflex were observed and 2 animals died. Food consumption in the 100 mg/kg/day group decreased during the treatment period. No drug-related changes were observed in dams for their body weights, necropsy findings or organ weights. Decrease in placental weight was seen in the 100 mg/kg/day group, but no effect was found in fetal weight. ONO-1101 had no effects on delivery and lactation. On day 4 after birth, viability of offspring were decrease in the 50 or 100 mg/kg/day group, and body weight of males were decreased in the 100 mg/kg/day group, but no change caused by the treatment was observed in growth of offspring thereafter. On skeletal examination in offsprings culled on day 4 after birth, increase in the incidence of unossificated talus were seen in the 50 or 100 mg/kg/day group. But no drug-related anomalies were observed in external, skeletal or visceral findings in fetuses. It was not also found any influence of ONO-1101 on external differentiations, functional, behavioral or leading abilities or reproductive performance in offspring. From the above results, it is estimated that the no-toxic dose level of ONO-1101 under these experimental conditions is 50 mg/kg/day for dams, and 25 mg/kg/day for their offspring.

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A teratogenicity study oflandiolol hydrochloride (ONO-1101), a novel ultra short acting β-blocker, was conducted in KAR:NZW rabbits. ONO-1101 was administered intravenously at a dose level of 0 (control), 25, 50 or 100 mg/kg/day to pregnant rabbit from day 6 to 18 of gestation to examine the effects on dams and fetuses. Death occurred on 3 animals in the 100mg/kg/day group and one animal in the 50 mg/kg/day group during the treatment period. Hypoactivity, bradypnea/apnea and clonic convulsion after administration was observed in animal dosed 100 mg/kg/day. No maternal effects were seen on body weight, food consumption, necropsy findings or organ weights. External, skeletal and visceral findings revealed no adverse effects of ONO-1101 on fetuses. From the above results, it is estimated that the no-toxic dose level of ONO-1101 under these experimental conditions is 25 mg/kg/day for dams and 100 mg/kg for fetuses.

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A perinatal and postnatal study of landiolol hydrochloride (ONO-1101), a novel ultra short acting β-blocker, was conducted in Sprague-Dawley (SD) rats. ONO-1101 was administered intravenously at a dose level of 0 (control), 25, 50 or 100 mg/kg/day from day 17 of gestation to day 20 after parturitation to examine the effects on pregnancy, delivery, lactation and the effects on postnatal growth and development of offspring. In the 100 mg/kg/day group, hypoactivity, reddish lacrimation, clonic convulsion and bradypnea/apnea were observed after administration and 5 animals died in the treatment period, and body weight on day 21 and food consumption on days 14-21 of dam at weaning were lower than control group. In the 50 mg/kg/day group, reddish lacrimation was occasionally seen in some animals. ONO-1101 had no effects on pregnancy, delivery, lactation and necropsy findings or organ weights of dams. In the 100 mg/kg/day group, viability of offspring on day 4 after birth decreased and body weight gain of the suckling suppressed, but those changes recovered after weaning. On the skeletal examination of offspring culled on day 4 after birth, decrease in the mean number of osiffied phalanges of hindpaw and increase in the incidence of unossified talus bone were seen in the 100 mg/kg/day group, however, no delay of ossification was found form the weanling. There were no influence of ONO-1101 on external differentiation, functional, behavioral or learning abilities or reproductive performance in offspring. From the above results, it is estimated that the no-toxic dose level of ONO-1101 under these experimental conditions is 50 mg/kg/day for dam and offspring.

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