The relative potencies of 1,25-dihydroxycholecalciferol, 24-F-1,25-dihydroxycholecalciferol, and 24,24-F2-1,25-dihydroxycholecalciferol at three doses (25, 100 or 400 micrograms) were assessed in nonlactating Jersey cows. The 24,24-F2-1,25-dihydroxycholecalciferol induced a significantly greater hypercalcemia and hyperphosphatemia than did 1,25-dihydroxycholecalciferol. The 24-F-1,25-dihydroxycholecalciferol was intermediate in its hypercalcemic and hyperphosphatemic potency. Urinary hydroxyproline excretion rate and plasma hydroxyproline concentration were not significantly increased by treatment with any of the compounds. This indicates that these compounds did not stimulate bone resorption in nonlactating, nongravid cows. Renal function was significantly impaired in cows that received a 400-micrograms dose of any compound. There was a severe reduction in glomerular filtration rate (up to 42%) and urine specific gravity. Renal function was most severely affected in cows treated with 24,24-F2-dihydroxycholecalciferol and was evident even at the 100-micrograms dosage level.
Nine metabolites and analogs of cholecalciferol (CC) were tested for ability to increase tibia ash weight in chicks otherwise deprived of vitamin D. All of the compounds promoted bone mineralization in a linear log dose-response relationship. The maximal response obtained for any compound was an approximate doubling in bone ash weight compared to vehicle-treated controls. Relative potencies, based upon the calculated ash weight doubling dose, were as follows: 1 alpha, 25-(OH)2-CC = 1 alpha-OH-CC greater than CC greater than 25-OH-CC greater than 24R, 25-(OH)2-CC = 1 alpha,24R, 25-(OH)3- CC greater than 5,6-trans-25-OH-CC greater than 1 alpha, 24S, 25- (OH)3-CC greater than 5,6-trans-CC greater than 24S, 25-(OH)2-CC.
Topical application of 400 mug of cantharidin to the rat's ear caused an approximate doubling in the mean weight of uniform ear punch samples when compared to vehicle-treated controls at 72 hr, and produced a maximal response at 7 days. Dexamethasone reduced the increase in weight when applied topically, but was ineffective when given subcutaneously or orally at the same doses. Hydrocortisone, prednisolone, triamcinolone, betamethasone, flurometholone, paramethasone acetate, fluocinolone acetonide, fluocinonide, and flurandrenolide showed significant suppression of cantharidin-induced inflammation. Cholesterol, diphenhydramine, tripelennamine, chlorpheniramine, promethazine, cyproheptadine, epinephrine, phenylephrine, alpha-tocopherol, indomethacin, and bufexamac were inactive. It is suggested that the procedure employed may be useful in the screening and evaluation of topical anti-inflammatory agents.
Concurrent administration of 1alpha,25-dihydroxycholecalciferol [1alpha,25-(OH)2-CC] to intact and thyroparathyroidectomized rats treated with ethane-1-hydroxy-1,1-diphosphonate (EHDP) prevented or reversed the EHDP-induced inhibition of bone mineralization as measured by changes in epiphyseal plate width and ash content of bone. An analog, 1alpha-droxycholecalciferol, was also effective. Recovery of bone after EHDP treatment was also significantly improved by administration of 1alpha,25-(OH)2-CC as evidenced by enhanced uptake of 45Ca by epiphyseal plates and decreased plate widths. Cholecalciferol (CC), ergocalciferol, dihydrotachysterol2, 5,6-trans-CC, 25-OH-CC, 5,6-Trans-25-OH-CC, and 1alpha24R,25-(OH)3-CC also blocked EHDP-induced epiphyseal plate widening, but required high, pharmacological dose levels. 24R,25- (OH)2-CC was inactive at doses up to 10 microgram/day. Since EHDP-treated rats are not deficient in calcium or phosphate, these data suggest that 1alpha,25-dihydroxycholecalciferol promoted bone mineralization independently of effects upon the intestinal absorption of calcium and phosphate.
Treatment with dl-6-(N-\g=a\-pipecolinomethyl)-5-hydroxyindane maleate (PMHI) has been found to depress testicular weight and interfere with spermatogenesis and fertility in the male rat. At equal doses by weight, PMHI caused a greater reduction in testicular weight than WIN 18446, nitrofurazone, methallibure and diethylstilboestrol, but lesser reductions in seminal vesicle and ventral prostate weights than were obtained with the two antigonadotrophic compounds, methallibure and diethylstilboestrol. Doses of the compound which were effective in the male rat did not interfere with normal oestrous cycles or fertility when administered to female rats.
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