Epristeride is a selective and specific uncompetitive inhibitor of human steroid 5 alpha-reductase isoform 2.

Specificity of an enzyme inhibitor can have profound implications upon the compound's therapeutic potential, utility and safety profile. As potent inhibitors of human steroid 5 alpha-reductase (SR) the 3-androstene-3-carboxylic acids, or steroidal acrylates, may be useful in treatment of diseases such as benign prostatic hyperplasia for which 5 alpha-dihydrotestosterone (DHT) appears to be a causative agent. To determine its specificity profile, the interactions of a representative compound from this class, N-(t-butyl)androst-3,5-diene-17 beta-carboxamide-3-carboxylic acid (epristeride, SK&F 105657), have been studied with 7 other steroid processing enzymes and 5 steroid hormone receptors. The affinity of epristeride for each of these 12 potential targets was found to be at least 1000-fold weaker than that for SR, the intended target. In addition, using samples of the individually expressed two known forms of human SRs, epristeride has been shown to be a selective inhibitor of the recombinant human SR type 2, the predominant activity found in the prostate of man. Nonetheless, the mechanisms of SR inhibition for both isoenzymes involve formation of a ternary complex with epristeride, NADP+, and enzyme. Epristeride, consequently, has been shown to be an uncompetitive inhibitor versus steroid substrate of both human SR isoenzymes. These results suggest that this 3-androstene-3-carboxylic acid is a specific and selective inhibitor of the human type 2 SR, and that epristeride is an attractive compound for further investigation as a safe and effective therapeutic agent in the potential treatment of disease states associated with DHT-induced tissue growth.

Cloning, expression and functional characterization of type 1 and type 2 steroid 5 alpha-reductases from Cynomolgus monkey: comparisons with human and rat isoenzymes.

The Cynomolgus monkey may provide an alternative pharmacological model in which to evaluate the efficacy of novel inhibitors of the two known human steroid 5 alpha-reductase (SR) isoenzymes. To evaluate the suitability of this species at the level of the molecular targets, a Cynomolgus monkey prostate cDNA library was prepared and screened using human SR type 1 and 2 cDNAs as hybridization probes. Two distinct cDNA sequences were isolated encoding the monkey type 1 and 2 SR isoenzymes. These sequences share 93 and 95% amino acid sequence identity with their human enzyme counterparts, respectively. Difference in monkey type 1 SR, however, was found within the contiguous four amino acids corresponding to the regions in the human and rat sequences that have been proposed previously to influence steroid and inhibitor affinities. Subsequently, both monkey cDNAs were individually expressed in a mammalian cell (CHO) line. Enzyme activities of both monkey SRs were localized to the membrane fractions of CHO cell extracts. Like the human and rat enzymes, the monkey type 1 and type 2 SRs were most active at neutral and low pH, respectively. The results of inhibition studies with over 30 known SR inhibitors, including epristeride, 4MA, and finasteride, indicate that the monkey SR isoenzymes are functionally more similar to the human than the rat homologues. The results from initial velocity and inhibition studies as functions of pH with the human and monkey type 2 SRs also compare favorably. These results, together, suggest that the monkey SR isoenzymes are structurally and functionally comparable on a molecular level to their respective human counterparts, supporting the relevance and use of the Cynomolgus monkey as a pharmacological model for in vivo evaluation of SR inhibitors.

Parental perceptions surrounding risks and benefits of immunization.

In recent years, parental concerns about vaccine safety have increased as the threat of disease has decreased. A national survey showed that, in general, parents agree that vaccines benefit their children and that their children may be at risk for contracting a disease if unvaccinated. When asked about understanding the benefits and risks of vaccines, most parents (57%) found numbers and statistics most helpful. A substantial minority (17%) of parents were somewhat or not confident in vaccine safety. Parents less confident in vaccine safety agreed less with the statement that they usually followed the advice of their child's doctor. Incomes and education levels affected responses. This positive relationship between confidence in vaccine safety and reliance on doctors for advice may indicate the need for healthcare providers to identify opportunities to (1) solicit questions about vaccine safety, (2) address vaccine safety-related questions in a way meaningful to parents, and (3) strengthen doctor-patient relationships. A parent communication tool is proposed.

Determinism and mass-media portrayals of genetics.

Scholars have expressed concern that the introduction of substantial coverage of "medical genetics" in the mass media during the past 2 decades represents an increase in biological determinism in public discourse. To test this contention, we analyzed the contents of a randomly selected, structured sample of American public newspapers (n=250) and magazines (n=722) published during 1919-95. Three coders, using three measures, all with intercoder reliability >85%, were employed. Results indicate that the introduction of the discourse of medical genetics is correlated with both a statistically significant decrease in the degree to which articles attribute human characteristics to genetic causes (P<.001) and a statistically significant increase in the differentiation of attributions to genetic and other causes among various conditions or outcomes (P<. 016). There has been no statistically significant change in the relative proportions of physical phenomena attributed to genetic causes, but there has been a statistically significant decrease in the number of articles assigning genetic causes to mental (P<.002) and behavioral (P<.000) characteristics. These results suggest that the current discourse of medical genetics is not accurately described as more biologically deterministic than its antecedents.

Public attitudes regarding the donation and storage of blood specimens for genetic research.

OBJECTIVE: As sequencing of the human genome is completed, there is a need for population-based research to assess frequencies of genetic variants and their associations with human diseases. The authors therefore assessed the current climate regarding the donation and storage of blood for genetic research. METHODS: Data from the American Healthstyles Survey fo health attitudes and behavior were examined. In the 1998 survey, four questions regarding blood donation and storage for genetic research were posed to the participants. RESULTS: Of 3,130 participants, 2,621 (84%) completed these questions. Of the respondents, 42% were in favor of both blood donation and long-term storage for genetic research, 37% were in favor of either blood donation or storage but not both and 21% were not willing to donate blood or have it stored for genetic research under any circumstances. Loglinear analysis demonstrated that the characteristics of respondents who favored blood donation and long-term storage for genetic research were attitudinal; specifically, those believing that genetic research will prevent disease [odds ratio (OR) 2.9; p<0.001]; those believing in genetic determinism (OR 1.5; p=0.004) and those agreeing they would participate in government research (OR 2.9; p<0.001). The model also demonstrated that characteristics indirectly associated with attitudes toward blood donation/storage for genetic research were demographic and included higher education, white race, living in the Mountain/Pacific or mid-Atlantic regions of the United States and positive family history of a genetic disorder (p<0.05). CONCLUSION: Understanding the various factors contributing to knowledge, attitudes and behavior regarding the donation and storage of blood specimens for genetic research will contribute to future actions in communication genetic research goals to the public and recruitment for population-based genetic studies.