Arthur L. Beyler

Pituitary Gonadotropin Inhibitory Activity of Danazol

A steroid danazol (17-alpha-Pregn-4-en-20-yno(23-d)-isoxazol-17-ol) possesses a marked separation of pituitary gonadotropin inhibitory activity from overt sex hormonal activities. The effect of danazol on fertility in the rat was determined. Danazol produced a dose-related decrease in the weights of ventral prostate seminal vesicles and testes of mature male rats when given orally at 80 mg/kg daily for 6 months - 1 year. It also produced highly significant decreases in the weights of sex accessory organs and testes. Mature female rats showed a similar dose-related effect on ovaries adrenals and thymus. Body weight and ovaries increased during treatment. Danazol was not progestational in the Clauberg assay when adminsitered orally at doses as high as 80Omg/kg. A dose of 20Omg/kg for 6 days following insemination was completely effective in preventing pregnancy.

The biologic actions of a new series of bis(dichloroacetyl) diamines

Abstract Three members (Win 13,099, Win 17,416, Win 18,446) of a new series of bis(dichloroacetyl) diamines have been studied orally in rats, dogs, and/or monkeys. These data indicate the following points: 1. 1. These compounds proved to be relatively nontoxic substances which exert a specific effect upon the testes of the species studied. 2. 2. This biologic effect on the testes is characterized by arrest of spermatogenesis which is completely reversible within a few weeks after withdrawal of the drug. The Leydig, Sertoli, and spermatogonial cells appear to be normal even under the full influence of these drugs. 3. 3. The mechanism of the action of this phenomenon is not understood at present but should provide a fine tool in the study of the specific biochemical requirements for spermatogenesis.

The results of animal studies with ciprofibrate, a new orally effective hypolipidemic drug.

Findings are given to show that ciprofibrate, a new orally active phenoxyisobutyrate, is significantly more hypolipidemic than is the reference clofibrate. In hyperlipidemic rats ciprofibrate suppresses the increase in blood lipids 33% at a daily dosage of 0.6--3 mg/kg. The corresponding dosage for clofibrate is 125--460 mg/kg. Based on studies with cholesterol pools pre-labeled with [14C]mevalonate or with cholesterol-labeled pools in ciprofibrate-treated normolipidemic rats, ciprofibrate was shown to inhibit cholesterol biosynthesis. No evidence of the presence of 7- or 24-dehydrocholesterol was obtained in the sera of ciprofibrate-treated rats as shown by gas chromatography examination. The order of hypolipidemic effectiveness of ciprofibrate in hyperlipidemic rats provides a basis for anticipating that ciprofibrate will be hypolipidemic in hyperlipoproteinemic subjects who are considered at high risk of acquiring coronary artery disease.

Andro-stanazole, a new orally active anabolic steroid.

Summary Andro-stanazole (17β-hydroxy-17α-methylandrostano[3,2-c] pyrazole) has been evaluated for its nitrogen-retaining and androgenic activities in castrated male rats. Orally, it appears to be 30 times more anabolic and 1/4 as androgenic as methyl-testosterone. Parenterally, it appears to be 1/20 as anabolic and 1/40 as androgenic as testosterone propionate. Andro-stanazole is clearly an agent which merits further investigation for oral administration to patients under conditions where maximum anabolic action with minimum androgenic side effects is desired.

Myotrophic and Androgenic Activities of Androstanazole. A New Heterocyclic Steroid

Summary Myotrophic and androgenic activities of androstanazole have been evaluated using immature castrated male rats. The data indicate that androstanazole is 1/7 as myotrophic and 1/33 as androgenic as testosterone propionate when both agents are administered subcutaneously, whereas it is 2 times more myotrophic than. and 1/3 as androgenic as, methyltestosterone when the 2 agents are given orally. The data show that androstanazole is relatively more anabolic than androgenic regardless of route of administration. The results are discussed in light of nitrogen retention data previously reported for this compound.

Metabolic effects of a new hypolipidemic agent, ciprofibrate

Ciprofibrate, a new orally effective hypolipidemic agent like clofibrate, suppressed tyloxapol-induced hypercholesterolemia in rats. Ciprofibrate at 10 mg/kg was effective. Clofibrate required a dosage of 180 mg/kg to suppress the tyloxapol effect. Norepinephrine-induced free fatty acid release was inhibited by clofibrate in rats in accordance with earlier findings. Ciprofibrate and lifibrate differed from clofibrate in that, at hypocholesterolemically effective doses, neither inhibited the hormone sensitive lipase in vivo.

ANABOLIC STEROID THERAPY IN THE MANAGEMENT OF CANCER: A SUMMARY.

According to statistical estimates (l), more than 800,000 patients are being treated for cancer in the United States and approximately 525,000 new cases will be diagnosed for the first time this year. About 16 per cent of all deaths are due to cancer-a cause second only to cardiovascular disease. However, an encouraging aspect is the real progress being made in regard to cure. Approximately one-third of all cancer patients are cured, and the frequency of this fortunate result is slowly but steadily increasing. Surgery produces many cures and is almost always at least palliative. In addition, for the two-thirds of the patients who ultimately succumb to cancer, there are numerous and varied chemotherapeutic and radiotherapeutic procedures which may induce a remission or slow the progress of the disease. As a result of these better therapeutic attacks on cancer, patients are living longer; thus there is greater need and opportunity for the use of agents which will control pain and maintain the nutritional state, physical vigor and mental equanimity of the patient for prolonged periods. Fortunately, pain can now be more readily controlled by the newer synthetic analgesics, and there is the promise of nonaddictive analgesics of still greater potency in the near future. For the physiotonic needs of the cancer patient there is a group of new anabolic compounds which have unique value in improving the physical state through specific anabolic actions. That is, they stimulate the build-up of tissue protein in increased amounts, and thus conserve the protein matrix of the vital tissues such as the parenchymatous organs, the bones and the skeletal muscles. This anabolic action is also associated with physiotonic actions such as a sense of well-being, and with anticatabolic effects, particularly against the destructive influences of excess corticosteroids. These new anabolic compounds are synthetic derivatives of testosterone, in which by modifications in the chemical structures the anabolic power has been increased and the androgenic activity decreased to the point where for the majority of patients the protein anabolic responses can be elicited to therapeutically useful degrees without provoking undesirable sex stimulation or androgenic side effects. The compound in which this crucial separation is most complete is known as stanosolol,1 and it is the main subject to be discussed in this article.

Uterine Growth Stimulating and Testicular Growth Suppressing Activities of 17α-Ethinylandrostane-3β,17β3-diol, Its Δ-Analog and Derivatives.

Summary and Conclusions (1) The biological activity of ethinylandrostanediol and its Δ 5 -analog has been found to be predominantly estrogenic rather than androgenic. The relative testicular growth suppressing (TGSp) activity effected by these ethinyl-diols was considerably greater than observed for equivalent estrogenic doses of estradiol-17β or ethinylestradiol. (2) Low molecular weight esters (less than 6 carbon atoms) of these non-phenolic steroids were more active than their parent alcohols, but the degree of estrogenicity (UGSt) diminished more abruptly than did TGSp activity as the size of the ester group was increased. Of the compounds tested, the 3a-ethylbutyrate of ethinyl-Δ 5 -androstenediol effected the greatest degree of testicular growth suppression (TGSp) per unit of estrogenicity (UGSt-ED50), when 35-40 gram immature in tacts rats were used.

Stimulatory Effect of Estrogen Pretreatment on 3β-Hydroxysteroid Dehydrogenase Activity of Rat Testicular Tissue

Summary 1. Pretreatment doses of estrogens, which brought about marked curtailment in testicular androgen production as evidenced by sex accessory organ atrophy, increased the 3β-ol-dehydrogenase content of rat testicular homogenates. Estradiol- 17β was approximately 50 times more active than diethylstilbestrol dipalmitate in this respect. 2. This evidence suggests that the reaction catalyzed by the 3β-ol-dehydrogenase system is not the limiting one with respect to disrupted androgen production induced by estrogen pretreatment.

REVERSAL BY ANDROSTANAZOLE OF CATABOLIC ACTIONS OF CORTISONE ACETATE

a 24 hour experimental period. Cortisone acetate was given subcutaneously as 5 uniformly spaced injections during the first 8 hours of this period. Increments over control values of body weight loss and urinary nitrogen excretion during the 24 hours were used to assess the catabolic actions of the glucocorticoid administered over a total dose range from 6.25 to 60 mg/kg. Under these experimental conditions, 60 mg/kg of cortisone acetate increased the body weight loss from 12 g/rat for the control group to 25 g/rat. Urinary nitrogen excretion rose concurrently from 71 mg/100 g of rat for the control group to 122 mg/100 g of rat. Lower doses of cortisone acetate produced correspondingly smaller catabolic effects. Invariably the body weight loss during fasting or cortisone administration was much greater than could be accounted for on the basis of amount of nitrogen excreted. It was considered of interest to determine to what extent anabolic steroids might reverse