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Analogs of (4aRS,5SR,9bRS)-2-ethyl-2,3,4,4a,5,9b-hexahydro-7-meth yl-5-p- tolyl-1H-indeno[1,2-c]pyridine (Sandoz 20-438, 10a; R1 = ethyl, R2 = R3 = methyl, R4 = H) have been synthesized and tested in mice for their ability to reduce testes weight and disrupt spermatogenesis. The activity was strongly dependent on stereoisomerism and chirality, consistent with a mechanism of action involving interaction with a specific macromolecule. It was affected by changes in the nitrogen substituent and most strikingly by changes in the p-substituent of the 5-aryl ring. A hydrogen, fluorine, hydroxy, or methoxy substituent led to loss of activity, whereas methyl (Sandoz 20-438, 10a), carboxylate (RTI-4587-054, 10k; R1 = ethyl, R2 = methyl, R3 = COOH, R4 = H), ester (RTI-4587-056, 12b; R1 = ethyl, R2 = methyl, R3 = COOMe, R4 = H), formyl (RTI-4587-030, 12i; R1 = ethyl, R2 = methyl, R3 = CHO, R4 = H), or hydroxymethyl (RTI-4587-055, 12g; R1 = ethyl, R2 = methyl, R3 = CH2OH, R4 = H) groups resulted in antispermatogenic compounds. Methyl ester 12b was an effective antifertility agent, without apparent effects on mating, when given orally to male mice at 7-15 mg/kg daily for 35 days. Further evaluation of these compounds as male contraceptive agents and probes for study of spermatogenesis appears warranted.

The discovery of antiprogestational steroids by the Roussel-Uclaf group not only was a major scientific advance but also opened the way to new methods of fertility control and new therapies for such conditions as cancer. RU486, the prototype of the series, is distinguished by a p-(N,N-dimethylaminophenyl) substituent at the 11 beta- position of the steroid framework, a 4,9-dien-3-one system and 17 beta-hydroxy-17 alpha-propynyl substituents. We examined the effect of varying the 17 alpha- substituent in 17 beta-hydroxy compounds analogous to RU486, the effect of introducing a progesterone side chain at C-17, and the effects of further substitution at C-17 alpha and C-16 alpha on the activity of these latter compounds. These studies indicate an important role for D-ring substituents in determining the balance of agonist/antagonist activity in this series. For example, 17 alpha-acetoxy-17 beta-acetyl substitution gave a potent antagonist, whereas 16 alpha-ethyl-17 beta-acetyl substitution resulted in a compound with potent progestational (agonist) activity. The compounds present opportunities for further interesting and useful biological investigations.

As newer interventional devices continue to enter the marketplace, balloon angioplasty remains the standard by which all devices are judged with regard to both safety and efficacy. It has been observed that predilating a stenosis with a small balloon followed by dilatation with an optimally sized larger balloon creates a more controlled arterial injury, reduces complications, and thus improves success rates. Exchanging two balloons for each lesion, however, increases the complexity and cost of the procedure in addition to increasing the amount of time required and the amount of radiation exposure. Therefore an "over-the-wire" dual-balloon catheter was developed with a small distal balloon and a larger proximal balloon on a 2.9F shaft to allow progressive coronary dilatation with a single device, without necessitating a balloon catheter exchange. The device was used successfully in 45 of 47 patients (78 lesions). The two failures were related to an inability to cross the lesion in one and failure of the device in the other. Twenty-one patients (47%) underwent a multivessel procedure. There were 29 left anterior descending/diagonal, 17 circumflex/marginal, 20 right coronary artery/posterior descending artery, and 10 vein graft lesions. The device was successfully delivered in the native anatomy to 12 distal, 27 mid, and 27, proximal lesions of which nine were osteal, for a procedural success rate of 97%. The mean stenosis was reduced from 80.7 +/- 11.5% to 15.2 +/- 11.9%. There were no major dissections, only 9 (11.2%) minor dissections, and no myocardial infarctions.(ABSTRACT TRUNCATED AT 250 WORDS)

Abrupt closure of a coronary artery after successful angioplasty remains a problem for the interventionalist. Many laboratories continue to administer heparin intravenously for 12 to 24 hours in an attempt to alleviate this problem. But prolonged heparin therapy delays sheath removal and may lead to groin and vascular complications, and so prolong the hospital stay. To test the hypothesis that subcutaneous heparin was as efficacious as intravenous heparin in preventing acute closure while reducing the vascular complications associated with extended sheath placement, we prospectively randomized 151 patients to two groups. The intravenous group, 77 patients, received continuous intravenous heparin at 1000 units/hour for 12 to 18 hours; the subcutaneous group, 74 patients, received 12,500 units subcutaneously every 12 hours for three doses after sheath removal 2 to 3 hours after the angioplasty. The activated clotting time immediately after the angioplasty was 401 +/- 108 seconds in subcutaneous group, as compared with 368 +/- 67 seconds in the intravenous group (p = 0.028). Patients receiving subcutaneous heparin continued to show adequate anticoagulation, with a PTT of 85 +/- 21 seconds obtained approximately 12 hours after the procedure. The PTT at discharge was statistically greater in the subcutaneous group, at 49.2 +/- 21 seconds, versus 35.6 +/- 13 seconds in the intravenous group (p < 0.001). Abrupt occlusion was similar in both groups, but the hematomas and bleeding/oozing in the intravenous group was significantly higher when compared with that of the subcutaneous group, 16 versus 6 (p = 0.026) and 26 versus 7 (p < or = 0.002), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

16 alpha-Ethyl-17 beta-acetyl substitution in the D-ring of steroids having an 11 beta-aryl-4,9-dien-3-one structure resulted in compounds with strong progestational activity. These compounds caused endometrial proliferation in the uterus of estrogen-primed rabbits with a potency greater than that of progesterone and had no detectable antiprogestational activity in this model. This is in stark contrast with the marked antiprogestational activity in rabbits, rats and humans reported for most 11 beta-aryl-4,9-diene-3-keto steroids such as RU 486 and its 17 beta-acetyl-17 alpha-acetoxy analog, 17 alpha-acetoxy-11 beta-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene- 3,20-dione. Examination of structure activity relationships in combination with computer aided molecular modelling suggests that a binding interaction of the 16 alpha-ethyl group with the progesterone receptor (PR) or the PR-progestin response element complex may play the major role in this reversal of activity profile.

Four experiments were designed to investigate the influence of photoperiod and other environmental factors on androgen production and reproductive maturation in deer mice. Male prairie deer mice (Peromyscus maniculatus), born in a light/dark cycle of 6L:18D, either remained in this short photoperiod or were switched to a long day regimen of 16L:8D at weaning. In a cross-sectional experiment, the deer mice were killed between 3 and 8 weeks of age for measurement of serum testosterone concentration and reproductive organ weights. In a second experiment, blood was collected from each mouse at weekly intervals between 3 and 9 weeks of age. This repeated measures design was used to reduce the high variability in testosterone values observed in the first experiment. Reproductive organs were weighed at the termination of the experiment. Testosterone concentrations and reproductive organ weights were greater in males reared in the long photoperiod in both experiments. In a third experiment, the animals were housed under five different conditions to test the influence of high ambient temperature and melatonin as well as photoperiod. At 7 weeks of age, they received an injection of hCG or saline. More testosterone was released in deer mice reared in 16L:8D and 27 C than in those reared in short days (6L:18D) or those reared in high ambient temperature (35 C) or those treated with exogenous melatonin. One week later, animals were sacrificed. The single hCG treatment caused significant reversal of the suppression of accessory sex organ weights following melatonin, short days or 35 C temperature. In a fourth experiment, the additive influence of melatonin and 35 C temperature was tested. Animals treated with 35 C or both melatonin and 35 C had lower serum testosterone at 7 weeks of age, released less testosterone after hCG, and had smaller organ weights with or without hCG than long day controls. The influence of melatonin treatment and 35 C temperature appears to be additive for testicular weight and testosterone release after hCG. Thus, the attenuation of reproductive development that accompanied short days, melatonin treatment and high ambient temperature occurred via diminished testosterone secretion, which can be overcome at least in part by gonadotropin treatment.