Novel glucocorticoid antedrugs possessing a 17beta-(gamma-lactone) ring.

The chemical synthesis and structure-activity relationships of a novel series of 17beta-glucocorticoid butyrolactones possessing either a 16alpha,17alpha-isopropylidene or -butylidene group are described. The sulfur-linked gamma-lactone group was incorporated onto the 17beta-position of the androstane nucleus via Barton ester decarboxylation and trapping the generated 17-radical with butyrolactone disulfides. The glucocorticoid butyrolactones were hydrolyzed in human plasma by the enzyme paraoxonase to the respective hydroxy acids, which were very weak glucocorticoid agonists. The rate of hydrolysis in plasma was very rapid (t1/2 = 4-5 min) in the case of lactones possessing a sulfur atom in the alpha-position of the butyrolactone group, whereas carbon-linked lactones were stable in plasma. 16alpha,17alpha-Butylidenes were more potent glucocorticoid agonists than the corresponding isopropylidene derivatives. Similarly, 1,4-dien-3-ones were more potent than the corresponding 4-en-3-ones. The butyrolactones linked to the steroidal nucleus via the beta-position were more potent glucocorticoid agonists than those linked through the alpha-position of the lactone. The most potent compounds were also shown to be stable in human lung S9 fraction, showed much lower systemic effects than budesonide in the thymus involution test, and possessed topical antiinflammatory activity in the rat ear edema model.

Social inequality of stroke mortality among US black populations, 1968 to 1987.

Though the rate of stroke mortality in the United States has been declining for all race-sex-specific groups, rates for blacks are among the highest in the world. Studies of the geographic and social variation of stroke mortality between populations have focused solely on either trends or social determinants, but not on both. In addition, conclusions have concentrated on the comparison of whites to nonwhites. The purpose of this study was to investigate the variation in stroke mortality trends, from 1968 to 1987, between US black populations categorized by the socioeconomic structure of the state economic area. The educational achievement profile of the population (percentage of the state economic area that had not completed high school) was used as an indicator of socioeconomic development. This aggregate study assessed whether (1) an inverse relationship existed between stroke mortality and educational achievement category, and (2) levels and trends of stroke mortality by educational achievement category varied from 1968 to 1987, for each age-gender-specific group (35 to 64, 65 to 74, and 75 to 84 years). Results showed an inverse relationship between educational achievement level of communities and stroke mortality, as well as a rank-ordering in level of educational achievement for all age-gender-specific groups. The absolute difference in rates among educational achievement levels clearly converged over time, with greater convergence in the period 1968 to 1978 than 1979 to 1987. The percent declines were similar across education categories. Results suggest that geographic inequalities in stroke mortality, in relation to socioeconomic structure, have converged over time.(ABSTRACT TRUNCATED AT 250 WORDS)