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Biomedical subjects

J R Brooks

Publications and source records attributed to J R Brooks.

At least 37 records · Page 2Linked to original sources
PubMed1986

Prostatic effects induced in dogs by chronic or acute oral administration of 5 alpha-reductase inhibitors.

A series of 4-azasteroidal 5 alpha-reductase inhibitors was tested in dogs to determine the effect of chronic (35-44 day) oral administration on prostate size and histology and acute oral administration on prostatic concentrations of testosterone (T) and dihydrotestosterone (DHT). The extent to which the results of the two tests were correlated was also studied in order to see whether the acute test could be used to predict activity in the chronic test. Six delta 1 analogs of the potent 5 alpha-reductase inhibitor, 4-MA (17 beta-N,N-diethylcarbamoyl-4-aza-4-methyl-5 alpha-androstan-3-one) were uniformly active at low dosage levels (less than or equal to 3 mg/kg) in both types of assay whereas several C1-C2 saturated analogs exhibited little activity in the chronic test. The nature of the side chain and whether there was a methyl or a proton at 4-N did not dramatically influence the activity of delta 1 compounds. There was a broad general agreement between the results of the two kinds of test in that if a compound acutely decreased the prostatic concentration of DHT it was likely to reduce prostate size and alter prostatic histology when given on a chronic basis.

5-alpha Reductase Inhibitors↗
PubMed1986

5 Alpha-reductase inhibitory and anti-androgenic activities of some 4-azasteroids in the rat.

Inhibition of 5 alpha-reductase and anti-androgenicity were studied in rats treated with various 4-azasteroids. The known inhibitor, N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA) served as a reference compound, and analogs of this basic molecule were assayed. Enhancement of enzyme inhibitory potency was usually seen with delta 1 analogs, whereas reduction in activity was noted with substitutuents such as delta 5, a spirotetrahydrofuran ring at C-17 or 4-deaza groups. Many of the 4-azasteroids had a much greater oral anti-androgenic effect against testosterone propionate (TP) than dihydrotestosterone propionate (DHTP). This difference in activity versus the two androgens is believed to reflect the necessity for TP to undergo reduction to DHT before becoming capable of stimulating prostatic growth. Inhibition of 5 alpha-reductase by active compounds prevented the conversion, thereby producing an anti-androgenic effect. In this regard, certain delta 1 analogs of 4-MA, particularly those bearing a 17 beta-(N-tert butylcarbamoyl) group, proved very effective against TP but were relatively inactive versus DHTP.

Androgen Antagonists↗
PubMed1986

Treatment of hirsutism with 5 alpha-reductase inhibitors.

Much os the evidence gathered from studies of 5 alpha-reductase activity levels and androgen metabolism in the skin of hirsute women and the excretion of androgen metabolites by hirsute women indicates that 5 alpha-reduced androgens are probably of primary importance in hirsutism. Unfortunately, until very recently, the lack of a suitable 5 alpha-reductase inhibitor made it very difficult to adequately test the hypothesis that such an inhibitor might be useful in the treatment of hirsutism and certain other androgen-related diseases. No substance was available which had good, unambiguous activity in vivo as a 5 alpha-reductase inhibitor. A number of 4-azasteroids have now been found to possess excellent 5 alpha-reductase inhibitory activity both in vitro and in vivo. Among other properties, several of these compounds show little or no affinity for the androgen receptor of rat prostate cytosol, they attenuate the growth promoting effect of T, but not DHT, on the ventral prostate of castrated male rats, they cause a marked reduction in prostatic DHT concentration in acutely treated rats and dogs and they bring about a significant decline in prostate size in chronically treated rats and dogs. It is expected that, in the near future, one or more of these highly active 5 alpha-reductase inhibitors will be tested in the clinic as a treatment for hirsutism. The results of those studies will be awaited with a great deal of interest since they should considerably advance our understanding of this disease and possibly contribute to its control.

5-alpha Reductase Inhibitors↗
PubMed1986

Azasteroids: structure-activity relationships for inhibition of 5 alpha-reductase and of androgen receptor binding.

A series of steroids, primarily 4-azasteroids, were prepared and tested in vitro as inhibitors of human and rat prostatic 5 alpha-reductase and of binding of dihydrotestosterone to the rat androgen receptor. The primary structural modifications were changes of the A ring and of moieties attached at the C-17 position of the steroid nucleus. New A-ring modifications included the 4-cyano-3-oxo-delta 4 system in the carbocyclic series and 1 alpha-CN, 1 alpha-CH3, 1 alpha,2 alpha-CH2, 2 beta-F, 2-aza, 2-oxa, and A-homo changes in the 3-oxo-4-aza series. In addition, 4-azasteroids with a D-homo ring or methyl substitution at C-7 (alpha and beta) or C-16 (alpha and beta) were prepared. The majority of the C-17 substituents were prepared from reactive intermediates derived from the 17 beta-COOH. Enhanced 5 alpha-reductase inhibition in both the human and rat enzyme assays is seen with 4-CN substitution on 3-oxo-delta 4 steroids and with a C-17 side chain incorporating a lipophilically substituted semipolar group on the 4-aza-3-oxo-5 alpha-androstane nucleus. Fewer highly active compounds were found in the human enzyme assay than in the rat assay. Structural requirements for inhibition of the rat androgen receptor are much different from those for inhibition of the enzyme. The 17 beta-OH moiety enhances potency more than any other feature while introduction of double bonds at C-1 or C-5 in the azasteroid gives a small improvement. Azasteroids unsubstituted at the 4-position show greatly diminished receptor activity.

5-alpha Reductase Inhibitors↗
PubMed1985

Surgery for thyroid carcinoma.

The cases of thyroid carcinoma treated at this hospital during the period 1948 to 1981 were reviewed retrospectively. Nine hundred eighty-six patients with thyroid nodules were operated on. One hundred fifty-two were thyroid carcinoma (59 papillary, 36 mixed papillary-follicular, 30 follicular, 20 anaplastic, 5 medullary, and 2 Hurthle cell tumors). There was a 92% follow-up for a mean of 10 years. In the last decade, patients presented at a younger age, the female predominance was diminished, and 15% had had previous neck irradiation. Surgery consisted of total (27) or subtotal thyroidectomy (89), lobectomy or nodulectomy (24), and biopsy (12). Total thyroidectomy had an incidence of postoperative complications that was 20 times higher than that with partial thyroidectomy (P less than 0.001). Disease-related death, recurrence, and survivor status were discussed. There was no significant difference between total versus subtotal thyroidectomy. This study reaffirms the usefulness of subtotal resection and the avoidance of morbidity of more radical total thyroidectomy surgery.

Adenocarcinoma↗
PubMed1985

Surgical management of gastric adenocarcinoma.

This paper has analyzed the results of surgical management of 196 patients with gastric carcinoma treated from 1958 through 1982 at the Brigham and Women's Hospital in Boston and compares the experience during this time period with that of the previous 45 years. Surgical technique, operative mortality and complications, and 5 year survival were recorded. The resectability rate of the tumor in patients explored was 78.1 percent, and the 5 year survival rate for all 153 gastrectomies was 24.9 percent (36.2 percent for curative gastrectomy and 8.6 percent for palliative gastrectomy). Chronologic comparison over the years showed a decrease in the incidence of cancer of the stomach over the past 65 years, a steady increase in the 5 year absolute survival of patients with gastric carcinoma, and a significant decrease in the operative mortality and an increase in the 5 year survival after subtotal gastrectomy.

Adenocarcinoma↗
PubMed1984

13C-NMR spectral study of reductively [13C]methylated glycophorin B.

Glycophorin BN was reductively [13C]methylated and the 13C chemical shift of the N-terminal [13C]dimethyl-leucine residue was monitored as a function of pH. These results were compared to the pH-dependent chemical shift studies of the N-terminal [13C]dimethylleucine residues of intact glycophorin AN and N-terminal glyco-octapeptide AN. The results indicate that the titration data for [13C]dimethylleucine of glycophorin BN more closely resembles the titration data observed for the [13C]dimethylleucine residue of the N-terminal glyco-octapeptide AN rather than for the [13C]dimethylleucine residue of intact glycophorin AN. Integration of the 13C resonances indicated that glycophorin BN contains 3-4 lysine residues.

Glycophorins↗
PubMed1984

Azasteroids as inhibitors of rat prostatic 5 alpha-reductase.

A series of A-ring heterocyclic steroids has been prepared and tested for inhibition of rat prostatic steroid 5 alpha-reductase in vitro. Strikingly high inhibitory activity was found with a group of 17 beta-substituted 4-methyl-4-aza-5 alpha-androstan-3-ones. These compounds were prepared from 3-keto-delta 4-precursors by oxidative (O3 or NaIO4-KMnO4) A-ring cleavage followed, in turn, by ring closure with an amine and hydrogenation over platinum catalyst. Other A-ring azasteroids were made by Beckmann rearrangement of oximes of 2-oxo-A-nor, 3-oxo- and 4-oxo-5 alpha-androstanes. An A-nor-2-oxo-3-azasteroid was prepared by oxidative decarbonylation of a precursor 2,3-dioxo-4-azasteroid with m-chloroperbenzoic acid. A-ring modifications of the 4-azasteroids included delta 1-unsaturation, 2- and 4-substituents, and 3-carbonyl replacements. Side chains at the 17-position were varied with an emphasis on carboxylate derivatives (salts, esters, and amides).

5-alpha Reductase Inhibitors↗
PubMed1983

12. Androgens: Pharmacodynamics and antagonists. Biochemical and biological studies with 4-aza-steroidal 5 alpha-reductase inhibitors.

A series of 4-aza-3-oxosteroids were found to be good inhibitors of steroid 5 alpha-reductase. Two of these compounds. 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA) and 4-methyl-4-aza-5 alpha-pregnan-3-one-20(s)-carboxylate, inhibit 5 alpha-reductase competitively with testosterone (T) with Ki values of 5 and 1.7 nM, respectively. These 5 alpha-reductase inhibitors also have an affinity to the androgen receptor which is orders of magnitude lower than that of 5 alpha-dihydrotestosterone (DHT), spironolactone and cyproterone acetate. 4-MA decreases the prostatic concentration of DHT and increases that of T in intact male rats and in castrates given T or its propionate derivative. 4-MA is a better inhibitor of T-induced growth than of DHT-induced growth of the prostate and seminal vesicles in castrated rats. It decreases the weight of the prostate and seminal vesicles in intact rats and that of the prostate in dogs. It has no significant antifertility activity in rats. In pregnant rats, 4-MA reduces the ano-genital distance of male fetuses. 4-MA has no significant androgenic, estrogenic, progestational, antiprogestational or antigonadotrophic activity.

5-alpha Reductase Inhibitors↗
PubMed1982

Effect of a new 5 alpha-reductase inhibitor on size, histologic characteristics, and androgen concentrations of the canine prostate.

Mature male beagles were used in studies designed to determine the effect of the steroidal 5 alpha-reductase inhibitor 17 beta-N,N-diethylcarbamoyl-4-aza-4-methyl-5 alpha-androstan-3-one (4-MA) on size, histology, and androgen concentration of the prostate. Subcutaneous administration of 3 or 15 mg/kg/day for 43 days caused a sharp decline in prostate volume. flattening of prostatic epithelial cells, vacuolization of the cytoplasm and pycnosis of the nuclei. Whereas serum testosterone levels remained normal in dogs injected with 3 mg/kg/day, they were lower in those that received 15 mg/kg/day. Concentration of both testosterone and 5 alpha-dihydrotestosterone were reduced in the prostates of dogs that had received either 3 or 15 mg/kg/day of 4-MA. The 15 mg/kg/day level also appeared to adversely affect spermatogenesis. In a 43-day study, 4-MA given orally once each day at levels of 0.1, 0.3, or 1 mg/kg failed to cause a significant decrease in prostate volume. However, daily divided oral doses totaling 1 or 3 mg/kg were given in a 42-day test and both treatment levels produced significant reductions in prostate size.

5-alpha Reductase Inhibitors↗
PubMed1980

Bioactive conformation of luteinizing hormone-releasing hormone: evidence from a conformationally constrained analog.

An analog of luteinizing hormone-releasing hormone containing a gamma-lactam as a conformational constraint has been prepared with the use of a novel cyclization of a methionine sulfonium salt. The analog is more active as a luteinizing hormone-releasing hormone agonist that the parent hormone, and provides evidence for a bioactive conformation containing a beta-turn.

Amino Acid Sequence↗
PubMed1980

Presidential address. John Jeffries. Tory surgeon during the flowering of Boston medicine, 1750 to 1800.

Boston medicine in the period 1750 to 1800 is described, along with the life and contributions to Boston medicine and surgery of John Jeffries, a Tory surgeon. Jeffries received his medical degree in Scotland and then practiced in Boston until 1775, when he departed with the English. He eventually returned to Boston to complete an illustrious practice from 1789 to 1819. Among his other accomplishments, he and a Frenchman were the first to fly a hot air balloon across the English channel. His contributions to the development of Boston surgery and its medical societies were significant.

Boston↗