Efficacy of oral epostane administration to terminate pregnancy in mated laboratory bitches.

Epostane was administered orally for 7 days at doses of 10-300 mg/dog/day, starting at early oestrus, mid-oestrus, or metoestrus in 162 mated beagle bitches. With the exception of the early oestrus group receiving 10 mg epostane dog/day x 7 days, the incidence of dogs whelping in all other treatments was statistically lower than that of the placebo-treated control group (P less than 0.01). The ED50 and ED90 values were 19.5 and 43.2 mg/dog, respectively, for administration at early oestrus, and 8.6 and 24.0 mg/dog, respectively, for administration at metoestrus. Progesterone concentrations were significantly decreased after administration at oestrus or metoestrus in all epostane-treated groups compared to those given placebo. There were no adverse reactions or clinically significant changes in laboratory parameters or health of the bitches related to the use of epostane. There were no changes in the reproductive performance of epostane-treated bitches at the next oestrus after treatment compared to placebo controls, and there were no reproductive problems noted in the progeny of epostane-treated bitches. These results suggest that the minimally effective dose of epostane for application during metoestrus is approximately 2.5 mg/kg and the effective dose range is about 2.5-5.0 mg/kg body weight. Oral epostane is potentially a novel agent for the safe interception of unwanted pregnancy in dogs.

The use of epostane, a 3(beta)-hydroxysteroid dehydrogenase delta 4-5 isomerase enzyme inhibitor, in oil suspension as a mismating agent in the dog.

Administration of epostane as a single subcutaneous injection in sesame oil prevented or terminated pregnancy in bred beagle bitches (P = 0.002). Doses of 15 and 20 mg/kg prevented or terminated pregnancy in all of 14 bred beagle bitches studied but demonstrated a high rate of serious abscess formation at the injection site. A dose of 10 mg/kg was partially effective in 3 of 12 subjects whelping live pups, and a dose of 2.5 mg/kg was completely ineffective in 12 of 12 subjects whelping live pups. Plasma progesterone levels were lowered in dose-related fashion with respect to both depth of depression (P < 0.01) and length of time (P < 0.05). Subjects in which pregnancy was maintained had significant differences (P < 0.01) in progesterone patterns compared with nonpregnant subjects, as measured by area under the curve. No clinically significant differences were seen between treated and control females with respect to return to estrus, subsequent fertility, or in a battery of serum electrolytes, blood parameters and serum enzymes.

Effect of milrinone (Corotrope) on the contractility of isolated dog ventricular muscle.

The bipyridine milrinone (Corotrope) is a new positive inotropic agent for treatment of congestive heart failure. The dose-response curves on electrically paced isolated dog ventricular trabeculae on contractile force were determined with single as well as cumulative dosages of milrinone. These dose-response curves differed both quantitatively and qualitatively. The "single-dose, dose-response" curve shows a flattening out in the dosage range of 1-5 micrograms/ml, which was followed by a second "single-dose, dose-response" curve between 5-50 micrograms milrinone/ml bathing fluid. The maximal response obtained at 50 micrograms/ml with the single dose-response was 1.44 +/- 0.15 g (132 +/- 9%), while with the cumulative dose-response maximum contractile change attained at 1 microgram/ml was 0.58 g (40 +/- 7%). This difference is possibly due to the tachyphylaxis produced by the first dose of milrinone which reduced the effects of the second dose. The biphasic dose-response to milrinone was converted to a monophasic one by raising [Ca2+] from 1.8-4.5 mM. A statistical analysis of the single-dose, dose-response curve was conducted by applying a third-degree polynomial fitted by least squares; the curve gave a statistically significant fit with the experimentally obtained data. This suggests that the plateau observed is not due to random variation and that the single-dose, dose-response curve consists of at least two portions. This point was further substantiated by showing that the Ca2+ channel blockers had an effect on the low dosages of milrinone (less than 2.5 micrograms/ml) but had no significant effect on the dosages above 5 micrograms/ml. Milrinone increases the rate of relaxation and decreases the time for 50 and 90% relaxation. The data suggest that milrinone may act on two different types of calcium channels.