montirelin and Body-Weight

The effects on cataplexy and daytime sleep of acute and chronic oral administration of CG-3703, a potent TRH analog were assessed in canine narcolepsy. CG-3703 was found to be orally active and to reduce cataplexy (0.25 to 16 mg/kg) and sleep (8 and 16 mg/kg) in a dose-dependent manner. Two-week oral administration of CG-3703 (16 mg/kg) significantly reduced cataplexy and daytime sleep. The anticataplectic effects of CG-3703 were not associated with changes in general behavior, heart rate, blood pressure, rectal temperature, blood chemistry and thyroid function. Although drug tolerance for the effects on cataplexy and sleep were observed during the second week of chronic drug administration, therapeutic efficacy on cataplexy was improved with individual dose adjustment (final dose range: 16 to 28 mg/kg, p.o.). These results suggest that TRH analogs could be a promising new form of treatment for human narcolepsy.

Topics: Animals; Blood Proteins; Body Weight; Catalepsy; Dogs; Female; Male; Narcolepsy; Sleep Stages; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine; Wakefulness

Spontaneously epileptic rats (SER), which represent a double mutation (zi/zi, tm/tm), spontaneously exhibit both tonic and absence-like seizures. We examine the long-term effects of a thyrotropin-releasing hormone (TRH) analogue, CNK-602A, acute administration of which was effective inhibiting both types of seizures in SER, to determine if this agent could be used to treat epilepsy for long periods. Food pellets containing 0.001% CNK-602A were given ad libitum to SER from age 7 weeks. CNK-602A significantly inhibited tonic convulsions and prolonged survival. There were no alterations in body weight or plasma levels of triiodotHyronine (T3) and thyroxine (T4). These findings indicate that chronic intake of CNK-602A in a dose that does not affect plasma levels of T3 and T4 inhibits tonic convulsions in SER and suggest that this drug may be an effective treatment for convulsive seizures in patients with epilepsy.

Topics: Administration, Oral; Animals; Behavior, Animal; Body Weight; Disease Models, Animal; Eating; Epilepsy; Female; Humans; Male; Rats; Rats, Inbred SHR; Seizures; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine

The single dose toxicity studies of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, were conducted in Slc:ddY mice, Slc:SD rats, and beagle dogs of both sexes. The drug was administered intravenously (i.v.) to mice, rats and dogs, and intramuscularly (i.m.) to mice and rats. The animals were observed for 14 days after administration. LD50 values were more than 500 mg/kg and 200 mg/kg in mice and rats, respectively, by the i.v. route, and more than 20 mg/kg in both animal species by the i.m. route. In dogs, the minimum lethal dose was more than 200 mg/kg by the i.v. route. Mice that received more than 125 mg/kg by the i.v. route showed tremor and a decrease in locomotor activity during administration and for 30 min thereafter. Mice that received more than 5 mg/kg by the i.m. route showed tremor 5 min after administration and for 2 hr thereafter. Rats that received more than 50 mg/kg by the i.v. route showed tremor, and those that received 200 mg/kg by the same route showed a decrease in locomotor activity and ataxic gait, during and immediately after administration. Rats that received more than 5 mg/kg by the i.m. route showed tremor, and those that received 20 mg/kg by the same route showed salivation 5 min after administration and for 30 min thereafter. Dogs that received more than 12.5 mg/kg by the i.v. route revealed excitement, biting, vocalization, mydriasis, salivation, urination, defecation, licking chops, vomiting, increase in heart rate, panting, hyperthermia, tremor and conjunctival injection during administration and for 6 hr thereafter. The body weight, food consumption and water consumption, and pathological findings showed no changes attributable to the dosing of montirelin hydrate in any animal.

Topics: Animals; Body Weight; Dogs; Drinking; Eating; Female; Injections, Intramuscular; Injections, Intravenous; Lethal Dose 50; Locomotion; Male; Mice; Organ Size; Rats; Rats, Sprague-Dawley; Salivation; Thyrotropin-Releasing Hormone; Tremor

A repeated dose toxicity study of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in Sprague-Dawley rats. Male and female rats were given the drug intravenously for 5 weeks at doses of 0 (control), 0.05, 0.5, 5 and 50 mg/kg. After discontinuation of the treatment, a 4-week recovery test was also conducted in the 0, 0.5 and 50 mg/kg groups. No deaths related to the treatment were observed. Tremor was seen in the 50 mg/kg group. Polyuria was observed in the 5 and 50 mg/kg groups. There were decreases in body weight gain in the 0.5 mg/kg group and over of males, and in food consumption in all male dose groups and increase in water consumption in the 5 and 50 mg/kg groups. In blood chemical examination, decrease in triglyceride was observed in the 5 and 50 mg/kg groups of males. Urinalysis showed increase in urine volume in the 0.5 mg/kg group and over. Ophthalmoscopic and hematologic examinations failed to show any abnormalities attributable to the treatment. Pathological examination disclosed serous cell hypertrophy of the submandibular gland in all dose groups and increase in its organ weight in the 0.5 mg/kg group and over. The changes mentioned above were satisfactorily reversible except for the serous cell hypertrophy of the submandibular gland in the 50 mg/kg group. The decrease in food consumption and serous cell hypertrophy of the submandibular gland in the 0.05 mg/kg group were considered to be of no toxicological significance. These results show that the NOAEL of montirelin hydrate is 0.05 mg/kg for 5-week repeated dose toxicity in rats.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Drinking; Eating; Female; Injections, Intravenous; Male; Rats; Rats, Sprague-Dawley; Submandibular Gland; Thyrotropin-Releasing Hormone; Time Factors; Tremor; Triglycerides

A repeated dose toxicity study of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in Sprague-Dawley rats. Male and female rats were given the drug intravenously for 26 weeks at doses of 0 (control), 0.0004, 0.02, 1 and 50 mg/kg. After discontinuation of the treatment, a 9-week recovery test was also conducted in the 0, 1 and 50 mg/kg groups. No deaths related to the treatment were observed. Tremor and polyuria were seen in the 50 mg/kg group. There were decrease in body weight gain, and increase in water consumption in the 1 and 50 mg/kg groups. In those dose groups of males, decrease in food consumption was observed. Ophthalmoscopic examination failed to show any abnormalities attributable to the treatment. Blood chemical examination disclosed decrease in total cholesterol in the 50 mg/kg group. There were also decreases in phospholipid in the 50 mg/kg group of females, and in triglyceride in the 1 and 50 mg/kg groups of males. Urinalysis and hematologic examination failed to show any abnormalities attributable to the treatment. In pathological examination, serous cell hypertrophy and increase in organ weight of the submandibular gland were observed in the 1 and 50 mg/kg groups, and increase in organ weight of thyroid was revealed in the 0.02 mg/kg group and over. The changes mentioned above were satisfactorily reversible except for the decrease in food consumption in the 50 mg/kg group of males. Increased thyroid weight in the 0.02 mg/kg group was considered to be of no toxicological significance. These results show that the NOAEL of montirelin hydrate is 0.02 mg/kg for 26-week repeated dose toxicity in rats.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Drinking; Eating; Female; Injections, Intravenous; Lipids; Male; Organ Size; Rats; Rats, Sprague-Dawley; Submandibular Gland; Thyrotropin-Releasing Hormone; Time Factors; Tremor

A repeated dose toxicity study of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in beagle dogs. Male and female dogs were given the drug intravenously for 26 weeks at doses of 0 (control), 0.02, 0.2, 2 and 20 mg/kg. After discontinuation of the treatment, a 9-week recovery test was also conducted. No deaths related to the treatment were observed. Nasal discharge in all dose groups, and tremor, salivation and emesis in the 0.2 mg/kg group and over were seen. Decrease in body weight gain was observed in the 2 and 20 mg/kg groups. There were no abnormalities in body temperature, and food and water consumptions. Urinalysis and electrocardiographic, ophthalmoscopic and hematologic examinations failed to show any abnormalities attributable to the treatment. In blood chemical examination, increase in T3 level was observed in the 2 and 20 mg/kg groups of females. There were no pathological findings attributable to the treatment. The changes mentioned above were satisfactorily reversible. The nasal discharge seen in the 0.02 mg/kg group was considered to be of no toxicological significance. These results show that the NOAEL of montirelin hydrate is 0.02 mg/kg for 26-week repeated dose toxicity in dogs.

Topics: Animals; Body Weight; Dogs; Dose-Response Relationship, Drug; Female; Heart Rate; Injections, Intravenous; Male; Salivation; Thyrotropin-Releasing Hormone; Time Factors; Tremor; Triiodothyronine; Vomiting

A study of fertility and early embryonic development to implantation of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in Sprague-Dawley rats. Male rats were given the drug intravenously from 63 days before mating to the end of mating period and female rats from 14 days before mating to day 7 of pregnancy; the dose levels for both males and females were 0 (control), 0.02, 1 and 50 mg/kg. The females were sacrificed on day 20 of pregnancy for examination of their fetuses. In the 50 mg/kg group, tremor, disappeared within some minutes, was observed during administration period in all animals. Food and water consumptions increased in the females and body weight gain was suppressed in the males. Moreover prolonged estrus cycle was observed at early period of the administration in the females, but it recovered at late period of the administration. However, there were no toxicities in the males and females in the 1 mg/kg or less groups. The drug had no adverse effects on reproductive function of the parent animals, or on development of fetuses. These results show that the NOAEL of montirelin hydrate are 1 mg/kg for general toxicity in parent animals, and 50 mg/kg for reproductive function of the parent animals and for development of fetuses.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Drinking; Eating; Embryonic and Fetal Development; Estrus; Female; Fertility; Fetus; Injections, Intravenous; Male; Pregnancy; Rats; Rats, Sprague-Dawley; Thyrotropin-Releasing Hormone; Tremor

A study of the effect of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, during the period of organogenesis was conducted in Sprague-Dawley rats. Female rats were given the drug intravenously at dose levels of 0 (control), 0.02, 1 and 50 mg/kg from day 7 to day 17 of pregnancy. Twenty-three or twenty-five female rats per dose level were sacrificed on day 20 of pregnancy for examination of their fetuses, and the pregnant rats (13-15 per dose levels) were allowed to deliver naturally for postnatal examination of their offspring. In the 1 or 50 mg/kg group, water consumption and the weights of adrenals of the dams increased and the weights of the thymus of the dams decreased. In addition, tremor, disappeared within some minutes, was observed from day 7 to day 16 of pregnancy in all dams given 50 mg/kg. Moreover, food consumption increased and the weights of the submaxillary glands of the dams given 50 mg/kg increased. The drug had no effect on the number of corpora lutea and implantations, on fetal mortality, on fetal body weights, on sex ratio, or on external, visceral and skeletal development of the fetuses. The drug also did not affect delivery. The drug did not have any adverse effects on the newborn such as the number of live newborns, birth index and body weights of live newborn, or on the postnatal development of the first generation offspring (F1) such as differentiation, functional development, emotionality, motor ability, learning ability or reproductive performance. The drug also had no adverse effects of the second generation offspring (F2). These results show that the NOAEL of montirelin hydrate are 0.02 mg/kg for general toxicity in mother animals, 50 mg/kg for pregnancy and delivery of mother animals and 50 mg/kg for development of their offspring.

Topics: Animals; Behavior, Animal; Body Weight; Drinking; Eating; Embryonic and Fetal Development; Female; Fetus; Injections, Intravenous; Labor, Obstetric; Male; Organ Size; Pregnancy; Rats; Rats, Sprague-Dawley; Reproduction; Thyrotropin-Releasing Hormone

A study of the effect of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, during the period of organogenesis was conducted in New Zealand white rabbits. Female rabbits were given the drug intravenously at dose levels of 0 (control), 0.01, 0.1 and 1 mg/kg from day 6 to day 18 of pregnancy. Female rabbits were sacrificed on day 29 of pregnancy for examination of their fetuses. In the 0.1 mg/kg group, food consumption decreased slightly. In the 1 mg/kg group, tachypnea, salivation and rhinorrhea were observed, and body weight and food consumption decreased and water consumption increased. The drug had no effect on the number of corpora lutea and implantations, or on fetal mortality, on fetal body weights, on placental weight, on sex ratio, or on external, visceral and skeletal development of the fetuses. These results show that the NOAEL of montirelin hydrate are 0.1 mg/kg for general toxicity in mother animals, and 1 mg/kg for pregnancy of mother animals and for development of fetuses.

Topics: Animals; Body Weight; Eating; Embryonic and Fetal Development; Female; Fetus; Injections, Intravenous; Male; Organ Size; Pregnancy; Rabbits; Thyrotropin-Releasing Hormone

A study of the effect of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, during the perinatal and lactation periods was conducted in Sprague-Dawley rats. Female rats were given the drug intravenously at dose levels of 0 (control), 0.02, 1 and 50 mg/kg from day 17 of pregnancy to day 21 after delivery. All pregnant rats were allowed to deliver naturally for postnatal examination of their offspring. In the 1 and 50 mg/kg groups, food and water consumptions decreased after delivery and the weights of adrenals of the dams increased. In addition, tremor, disappeared within some minutes, was observed during administration period in all dams given 50 mg/kg. Moreover, body weight gain was suppressed after delivery, and the weights of submaxillary glands increased, and the weights of thymus and liver decreased in the dams given 50 mg/kg. The drug did not affect delivery. The drug did not have any adverse effects on the newborn including the number of live newborns, birth index and body weights of live newborn. In the 1 or 50 mg/kg group, body weight gains were suppressed and food consumption decreased in the offspring. The drug did not have any adverse effects on the postnatal development of the offspring such as differentiation, functional development, emotionality, motor ability, learning ability or reproductive performance. These results show that the NOAEL of montirelin hydrate are 0.02 mg/kg for general toxicity in mother animals, 50 mg/kg for reproductive function in mother animals and 0.02 mg/kg for their offspring.

Topics: Animals; Animals, Newborn; Behavior, Animal; Body Weight; Dose-Response Relationship, Drug; Drinking; Eating; Female; Injections, Intravenous; Lactation; Male; Organ Size; Pregnancy; Rats; Rats, Sprague-Dawley; Reproduction; Thyrotropin-Releasing Hormone