calcipotriene and Corneal-Opacity

A 4-week repeated percutaneous dose toxicity of calcipotriol (MC903), an anti-psoriasic agent, followed by a recovery for 4 weeks was studied in Slc:SD rats at doses of 4, 20 and 100 micrograms/kg/day as low, mid and high dose levels. 1. One male and female at high dose died probably due to stress and circulatory failure. One female at mid dose died with clonic convulsion considered to be results in attached error of a neck collar. Survival of rats showed reddish tear, reddening and desquamation of the skin at application site, and vocalization at all groups including control. Furthermore, abnormal gait, dirty hair, emaciation and opacity of the eyeball surface in both sexes were observed at high dose. 2. A decreased body weight and a slight increased water consumption in both sexes, and a decreased food consumption in males were observed at high dose. 3. An increased incidence of corneal opacity was noted significantly in both sexes as compared with control at high dose. Urinalysis revealed an increased Ca excretion in both sexes at more than mid dose, and lower pH in females at mid dose and in both sexes at high dose, and a decreased urinary volume in males at high dose. The increases of neutrophil and serum beta-globulin ratios in females, and serum Ca level in both sexes were observed at high dose. The increased mineralization of the cornea in males at mid dose and in both sexes at high dose, and of the Kidney in males at high dose were observed. At the skin of application site, cellular infiltration in the epidermis and dermis in both sexes at more than mid dose was observed. Furthermore, hyperplasia of the squamous cell in females, and hyperkeratosis in the epidermis and hypertrophy of the sebaceous gland in both sexes were observed at high dose. 4. After a 4-week recovery period, the changes related with application disappeared except for opacity of the eyeball surface and cornea, and mineralization of organs. 5. On the basis of results obtained in the present study, it is considered that 4 micrograms/kg/day is the no-toxic dose of MC903 applied percutaneously in both sexes of rats.

Topics: Administration, Cutaneous; Animals; Beta-Globulins; Body Weight; Calcitriol; Calcium; Corneal Opacity; Dermatologic Agents; Drug Administration Schedule; Female; Hyperplasia; Leukocyte Count; Male; Neutrophils; Rats; Rats, Sprague-Dawley; Skin

A 26-week repeated subcutaneous dose toxicity of calcipotriol (MC903), an anti-psoriasic agent, followed by a recovery for 5 weeks was studied in Slc:SD rats at doses of 0.4, 2 and 10 micrograms/kg/day as low, mid and high dose levels. 1. No mortality during the experimental period was observed in both sexes of all groups including control. An increased incidence of opacity of the eyeball surface in males was noted at high dose. There were no difference in body weight and food consumption between control. An increased water consumption in both sexes was observed at high dose. 2. An increased incidence of the corneal opacity was noted significantly at high dose in both sexes compared with that observed in control. Urinalysis revealed the increased excretions of Ca at more than mid dose, and Na, Cl and IP in males at high dose, and an decreased urinary volume in females and lower pH in both sexes at high dose. An increased serum Ca level in males at mid dose and in both sexes at high dose, and an elevated ALP activity in males at high dose were observed. The increased weights of the kidney in males at more than mid dose and adrenal gland in both sexes at high dose were observed. The increased incidence of mineralization of the cornea and kidney was noted significantly in males at more than mid dose as compared with control. Dilatation of endoplasmic reticulum of distal tubular cells of the kidney in both sexes was observed at high dose on electron microscopic examination. 3. After a 5-week recovery period, the changes related with the treatment of MC903 almost disappeared except for mineralizations of the cornea and kidney. 4. On the basis of results obtained in the present study, it is considered that 0.4 microgram/kg/day is the no-toxic dose of MC903 administered subcutaneously in both sexes of rats.

Topics: Adrenal Glands; Alkaline Phosphatase; Animals; Calcitriol; Calcium; Cornea; Corneal Opacity; Dermatologic Agents; Drug Administration Schedule; Female; Injections, Subcutaneous; Kidney; Male; Minerals; Organ Size; Rats

Calcipotriol (MC903), an anti-psoriasic agent, was given subcutaneously at dose levels of 1, 5 and 25 micrograms/kg/day during the pre-pairing period (9 weeks prior to pairing in males and 2 weeks prior to pairing in females) and the pairing period to male and female rats and in the early stage of pregnancy (day 0 through 7 of gestation) to female rats, and the effects of the test compound on male and female reproductive performance and fetal development were evaluated. 1. In the male 25 micrograms/kg group, opacity of the eyeball surface was observed, and depression of body weight gain, and decreases of body weight and food consumption, and increases in the weight of the kidney were statistically significant in comparison with vehicle controls. 2. In the female 25 micrograms/kg group, depression of body weight gain and food consumption were statistically significant in comparison with vehicle controls. 3. No changes in parameters of reproductive performance were seen in any dosed groups. 4. No changes in parameters of implantation performance were seen. There were no treated-related abnormalities in fetal mortality, weights of fetuses, and external, visceral and skeletal examinations. Based on there results, it is considered that in the present study the no-toxic dose levels of MC903 were 5 micrograms/kg/day for parents, 25 micrograms/kg/day for reproductive performance and fetal development.

Topics: Animals; Body Weight; Calcitriol; Corneal Opacity; Dermatologic Agents; Eating; Embryonic and Fetal Development; Female; Fertility; Injections, Subcutaneous; Kidney; Male; Organ Size; Pregnancy; Rats

A 26-week repeated percutaneous dose toxicity of calcipotriol (MC903), an anti-psoriasic agent, was studied in Slc:SD rats at doses of 0.8, 4 and 20 micrograms/kg/day as low, mid and high dose levels. 1. No mortality were observed in both sexes of all groups including control. An increased water consumption was observed in females at mid dose and in both sexes at high dose. 2. An increased incidence of the corneal opacity in males at mid dose and in both sexes at high dose was noted significantly as compared with that observed in control. Urinalysis revealed a slight increased urinary volume, increased excretions of Ca and IP, and lower pH in both sexes at more than mid dose. Levels of the serum IP in females and Ca in both sexes were elevated at high dose. 3. The increased weights of the kidney in males and adrenal gland in females were observed at high dose. The kidney in females at mid dose and in both sexes at high dose showed a higher incidence of mineralization than in control. Furthermore, osteosclerosis of the sternum and femur in both sexes, and hyperkeratosis of the skin at application site in females at high dose were observed. Electron microscopic examination revealed no abnormality in the liver and kidney. 4. On the basis of results obtained in the present study, it is considered that 0.8 microgram/kg/day is the no-toxic dose of MC903 applied percutaneously in both sexes of rats.

Topics: Administration, Cutaneous; Animals; Calcitriol; Calcium; Corneal Opacity; Dermatologic Agents; Drug Administration Schedule; Female; Keratosis; Kidney; Male; Minerals; Organ Size; Phosphates; Rats; Rats, Sprague-Dawley