The acute toxicity of hydrocortisone 17-butyrate 21-propionate (HBP), hydrocortisone 17-butyrate (HB17) and hydrocortisone 21-butyrate (HB21) were investigated by three administration routes (s.c., i.p. and p.o.) in mice, rats and dogs. In the case of HBP, LD50 by oral administration was the highest, and followed by subcutaneous and intraperitoneal administration in mice and rats. And LD50 of HB17 and HB21 were not different from HBP in mice by subcutaneous administration. The deppression of spontaneous movement and respiratory rate, ptosis, larcrymation and the collapse were commonly observed in all drugs, and it was independent of administration routes. The autopsy revealed the atrophy of thymus, spleen and adrenal glands, the supprative nodules of heart and liver and the ulcers of alimentary tract in mice and rats. But the changes observed in mice and rats were recognized when 1000 mg/kg of HBP was administered to dogs subcutaneously. Many of these changes were common to glucocorticoids, and the LD50 of HBP was rather high compaired with other synthetic steroids ; therefore, HBP was among less toxic steroid.
Subacute toxicity of hydrocortisone 17-butyrate 21-propionate (HBP), a new synthetic corticosteroid, was studied in rats, using betamethasone 17-valerate (BV) and hydrocortisone 17-butyrate (HB) as the reference drugs. HBP was subcutaneously injected to rats at the daily doses of 0.08, 0.4, 2.0, 10 and 50 mg/kg for 30 days. BV and HB were also administered at the daily doses of 0.08, 0.4 and 2.0 mg/kg. The recovery test was performed for 4 weeks after administrations of HBP, BV and HB. The suppression of body weight gain by HBP was observed at the doses more than 0.08 mg/kg in male and more than 2.0 mg/kg in female rats. In addition, at the doses more than 0.4 mg/kg of HBP induced the dose-dependent symptoms such as decrease in the number of circulating white blood cells, lymphocyte counts and S-ALP level, increase in total cholesterol, GOT and GPT level of serum, and regressive changes in adrenals, lymphatic and hematopoietic tissues. There were fatal cases in rats given 50 mg/kg of HBP. These changes are considered to be common phenomena to other corticosteroids, and less toxic in female than male rats. Changes of symptoms caused by the administration of HBP 2.0 mg/kg were almost recovered after withdrawal. The toxicities of three corticosteroids were in the order of BV > HB ≥ HBP in strength. As the result, the maximum non-toxic dose of HBP was estimated to be 0.08mg/kg in female and lower than that in male rats.
Subacute toxicity of hydrocortisone 17-butyrate 21-propionate (HBP) was studied in rats. HBP was percutaneously given to rats with 0.1% and 0.5% creame (0.1% HBP-C, 0.5% HBP-C) and ointment (0.1% HBP-O, 0.5% HBP-O) at the daily dose level of 150 mg per 100 g body weight for 1 month. Rats receiving HBP-C and HBP-O showed some dose-dependent symptoms such as the suppression of body weight gain, emaciation, decrease in the number of white blood cells, hemoglobin, hematocrit and serum total cholesterol level, regressive changes in adrenals, skin, lymphatic and hematopoietic tissues, which are known as toxic effects of synthetic corticosteroids. These symptoms were comparatively high toxic in male rats and in cream groups, and almost disappeared in rats elapsed recovery time of 1 month after withdrawal of HBP.
Chronic toxicity of hydrocortisone 17-butyrate 21-propionate (HBP), a new synthetic corticosteroid, was studied in rats. HBP was subcutaneously injected to rats as the daily doses of 0.001, 0.01, 0.1, 1.0 and 3.0mg/kg for 6 months, and the following recovery test was carried out for 4 weeks. Hydrocortisone 17-butyrate (HB) and betamethasone 17-valerate (BV) were used as the referance drugs at the doses of 0.1, 1.0 and 3.0 mg/kg. The suppression of body weight gain by the administration of HBP was observed at the doses more than 1.0 mg/kg in male and more than 0.1 mg/kg in female, and the dead animals were seen at the hightest dose of HB and BV. Mainly at the doses more than 0.1 mg/kg HBP induced the dose-dependent symptoms such as decrease in the number of white blood cells and total protein level in serum, and increase in total cholesterol, GOT and GPT level in serum, and atrophic changes of adrenals, lymphatic tissues, skin and subsexual organs. No usual abnormality was recognized at the doses less than 0.01 mg/kg of HBP. These symptoms were more toxic in male, and the strength of toxicity was in the order of BV > HB > HBR Many of these findings have known as common effects of corticosteroids. The changes observed in this study were almost recovered after withdrawal of HBP at the doses less than 0.1 mg/kg. As the result, it was suggested that the maximum non-toxic dose of HBP was 0.001 mg/kg.
Chronic toxicity of a new synthetic corticosteroid, hydrocortisone 17-butyrate 21-propionate (HBP), was investigated in rats of both sexes. HBP was percutaneously given to rats with 0.1%, 0.5% cream and ointment at the daily dose level of 150 mg per100 g body weight for 6 months. For the comparison, the percutaneous toxicity with 0.12% betamethasone 17-valerate (BV) creame and ointment, and 0.1% hydrocortisone 17-butyrate (HB) cream and ointment at the daily dose level of 150 mg per100 g body weight were studied. Rats receiving HBP showed the dose-dependent changes such as the suppressions of body weight gain and food intake, emaciation, decrease in the number of white blood cells and lymphocytes, total protein, increase in the number of red cells, hematocrit, hemoglobin, blood sugar and total cholesterol, regressive changes in adrenal cortex, lymphatic and hematopoietic tissues and skin, and gastric erosion, which have been well known as toxic effects of synthetic corticosteroids. These findings were comparatively high toxic in male, and almost disappeared in rats elapsed recovery time of 1 month after withdrawal of HBP. The toxicities of HBP, BV and HB were qualitatively same. However, the grade of effects of HBP toxicity was similar to that of HB, weaker than of BV.
The percutaneous subacute toxicity of 0.1% and 0.5% hydrocortisone 17-butyrate 21-propionate ointment (0.1% HBP, 0.5% HBP) were studied in beagle dogs for 3 months at the daily dose level of 200 mg per kilogram of body weight, using 0.1% and 0.5% hydrocortisone 17-buyrate ointment (0.1% HB, 0.5% HB), 0.12% and 0.5% betamethasone 17-butyrate ointment (0.12% BV, 0.5% BV) as the reference drugs. The results in this study were as follows : 1) In the sites applied HBP, HB and BV, acne-like changes and inhibition of hair growth wore found. 2) Body weight, food and water consumptions increased in the groups of 0.5% ointment, and in these dogs obesity by accumlation of subcutaneous fat was observed. 3) In hematological examination, biochemical examination and urinalysis, decrease in the number of lymphocytes and eosinophils, and increase in total cholesterol, triglyceride, urine-volume and urine-potassium were observed at 0.5% ointment groups. 4) In autopsy, dose-induced weight loss of thymus and adrenals, and hemorrhage of gastromucosa were found in dogs applied HBP, HB and BV. 5) In histopathological examination, the atrophy of adrenal cortex, lymphatic tissues, bone marrow, prostate, uterus and skin were found in dogs applied HBP, HB and BV. Further more, enlargement of hepatocytes was found. The above changes common other corticosteroids, which have been already reported, returned to normal after I month recovery period at 0.1% or 0.12% ointment groups. The percutaneous toxicity study of HBP compared with HB and BV was perfofmed. As the result, HBP and HB were almost samely toxic, but slightly less toxic than BV.
The visual toxicity and the ototoxicity of hydrocortisone 17-butyrate 21-propionate (HBP), a newly synthesized anti-inflammatory steroid, was investigated using rats and dogs. (1) Electroretinogram (ERG) and visually evoked potential (VEP) in rats were not changed when HBP was administered intravenously and intraperitoneally, even at the semilethal doses. Consequently, it was suggested that HBP had no effect on the visual nervous system. (2) Similar to other corticosteroids, the intra ocular pressure rose in the dogs received HBP. Nevertheless, these dogs showed neither the remarkable changes in ERG, in the fundus of the eye, in the histological examination, nor the turbidity of the cornae and the lens. Based on these facts, it was reasonable to think that the rise in the intra ocular pressure caused by HBP was not so severe that induce the secondary influence to other visual functions. (3) The rats received HBP did not show any changes in the auditory function by the audiometory. As the result, HBP was thought to be one of the rather safety corticosteroids concerning the visual toxicity and the ototoxicity.
The present experiments were undertaken to determine the antigenicity and other toxicities of HBP ; such as phototoxicity, photosensitivity, ulcerogenicity, androgenic-myotropic, estrogenic and progestational activities, and mutagenicity. No antibody formation and delayed type skin reaction of HBP were seen in rabbits. Active systemic anaphylaxis was not observed in guinea pigs challenged by HBP. In the phototoxicity and photosensitivity test, 0.1% HBP ointment, 0.1% HBP cream and 10% HBP acetone solution did not show any skin reaction with or without irradiation of ultraviolet light. Repeated subcutaneous administrations of HBP irritated the gastric and intestinal mucosa dose dependently in rats as hydrocortisone 17-butyrate and betamethasone 17-valerate (BV). HBP had netiher androgenic-myotropic nor estrogenic activity, but antiestrogenic activity was observed. The progestational activity of HBP in immature rabbit pretreated with estrone was less potent than BV. In the mutagenicity test of HBP investigated by the reverse mutation according to the method by Ames, no significant increase in the number of revertants was observed in the presence or absence of S9 mixture.