Stanley C. Lyster

Antifertility Activities of Two Diphenyl-Dihydronaphthalene Derivatives

Summary U-10520A and U-11100A, derivatives of 1,2-diphenyl-3,4-dihydronaphthalene, possess oral antifertility activity in rats, guinea pigs, and rabbits. Efficacy, following daily doses as low as 5 μg, is restricted to first 4 days of pregnancy. Antifertility activity has not been observed in hamsters. These compounds cause minimal uterotropic stimulation and also inhibit estradiol-induced uterine weight increases. Gonadotropin inhibiting activity is not observed at therapeutic doses. In contrast to many compounds reported to effectively inhibit pregnancy, both U-10520A and U-11100A possess very favorable therapeutic ratios.

An Orally Effective Mammalian Antifertility Agent

Summary U-11555A, a derivative of 2,3-diphenylindene, is an orally active antifertility agent in laboratory mammals. In rats, its efficacy is limited to the period of tubal transport of the zygote. Single oral doses, administered any time within 4 days of breeding, effectively inhibit pregnancy. After the zygote has reached the uterus U-11555A is ineffective as a pregnancy inhibitor. At effective antifertility dosages, U-11555A does not exhibit significant progestational, antiprogestational, antigonadotropic, androgenic, or estrogenic activities. U-11555A inhibits the uterine and vaginal response to endogenous and exogenous estrogens.

The pharmacology of 2-(2-fluoro-4-biphenylyl)Propionic acid (Flurbiprofen) A potent non-steroidal anti-inflammatory drug

Flurbiprofen is a potent, orally active, nonsteroidal anti-inflammatory drug in experimental animals. It is less toxic and more potent than indomethacin in certain types of acute and chronic inflammation in the rat. Like indomethacin, flurbiprofen has a prolonged duration of antiinflammatory action. It is effective in all in vitro assay systems used currently for the assessment of other nonsteroidal anti-inflammatory drugs. It is more potent than indomethacin in only one of these in vitro systems, red cell aggregation and sedimentation caused by the addition of dextran. Flurbiprofen may prove to be a useful adjunct for the treatment of various inflammatory diseases in man.

Reproductive Mechanisms Influenced by a Diazocine

Summary 2,8-Dichloro-6,12-diphenyl-dibenzo[b,f][l,5] diazocine completely inhibited pregnancy when administered either orally or subcutaneously to female rats at doses as low as 0.5 mg daily for 7 days at time of mating. At higher doses, single treatments prior to completion of implantation were equally effective. Systemic or fetal toxicity did not occur at therapeutic doses. This compound also induced uterine growth, vaginal cornification, blastocyst implantation and inhibited gonadotropin activity. Each of these latter effects are indicative of estrogenic properties, and are probably involved with antifertility efficacy. This non-steroidal compound is a structurally unique addition to those agents with these biological activities.

Aggregation of red cells and effects of nonsteroidal anti-inflammatory drugs.

Summary and Discussion Carrageenan, dextran, phytohemagglutinin-P, alpha-amylase, acid phosphatase, polycytidylic acid, polyadenylic acid, polygalacturonic acid, poly-L-proline, poly-L-glutamic acid and others promote red cell sedimentation rates (ESR) when added to washed red cells. Rabbit antisera to red cells and serum promote the ESR when added to either whole blood or washed red cells. All of these various acceleratory responses, with the exception of those induced by enzymes, are inhibited by nonsteroidal anti-inflammatory drugs (NAIFD). Many other pharmacologic classes, with the exception of ethacrynic acid, probenecid, sodium cromoglycate and chlorothiazide, fail to display similar inhibitory effects. The elevated ESR is inhibited when drugs are added before, during, or after the addition of dextran. The ESR is inhibited by 2, 4-dinitrophenol, but not other metabolic inhibitors. Heavy metal ions and anerobiosis have no effect on dextran-induced ESR. Agents accelerating the ESR induce acute inflammatory responses when inoculated locally into the hindpaws of rats. Drugs whose inhibitory effects are less readily removed from dextran-treated red cells by repeated saline washings, e.g., indomethacin, have longer durations of action when tested in acute inflammatory reactions of intact animals against salicylic acid whose effects are removed more rapidly. Mechanisms of action of accelerators or inhibitors of the ESR are unknown. The NAIFD are, for the most part, acidic. They may adhere to available positive charges on damaged or altered cell membranes and prevent their tendency to “stick,” adhere, aggregate, clump or pull together. Although red cell aggregation is among the many convenient models for the assessment in vitro of well-known NAIFD, it fails, like many other isolated methods (3-5), to have predictive value for unknown agents. Many undisclosed chemical agents have been discovered to be extremely potent in the isolated ESR system. When given subsequently at varying dosages and routes of administration to animals, however, they fail (in our hands, at least) to display “anti-inflammatory” activity. The dextran- and carrageenan-induced ESR appears to be a rather specific method for screening NAIFD discovered by other methods and for the study of their probable mechanisms of action.

Steroids and experimental mammary cancer.

This paper describes experimentation with laboratory animals to discover the effects of steroids on mammary cancer. Methods for experiments on rat mammary fibroadenoma responsive tumor; rat mammary fibroadenoma testosterone propionate (TP)-resistant tumor; and C3H mammary adenocarcinoma are detailed. Some results are: 1) TP-responsive tumor--tumors grow slowly during the 1st 20 days after implantation and the administration of 1 mg/day of TP caused tumor inhibition in the range of 95-99% withdrawal of TP caused the tumor to continue to grow but TP did not kill the tumor cells; 2) hydrocortisone had little effect on tumor growth; 3) estradiol at low doses stimulates and at high doses inhibits tumor growth; 4) 6alpha-methyl-17alpha-acetoxyprogesterone (Provera) or 6alpha-methyl-17-hydroxyprogesterone acetate (6-MAP) inhibits tumor growth and is a pituitary inhibitor in male and female weanling rats; 5) TP at dose levels which inhibit tumors causes androgenic effects in both sexes 6) 11alpha-hydroxy-17-methyltestosterone and 9beta11beta-epoxy-17-methyltestosterone are as effective as TP in inhibiting tumors yet exert different effects on the uterus and preputial glands; 7) only 2-methyl-19-nortestosterone inhibits testicular development in the male rat and is less than 1% effective as TP as an androgen yet is an effective antitumor agent; 8) 9alpha-fluro-11beta-hydroxy-17-methyltestosterone (Halotestin) is an antitumor agent and produces less androgenic activity than TP; 9) although mammary fibroadenoma is resistant to increasing amounts of TP is is not resistant to Halotestin which they are not able to metabolize 10) ACTH administration causes retardation of C3H mammary tumor growth but luteotropin estradiol testosterone and progesterone have little influence; 11) prednisolone retards tumor growth but does not kill cells; and 12) the assessment of antitumor activity in C3H mice was merely a reflection of other metabolic effects of C21 steroids. The authors emphasize that steroids and their derivatives of different glandular origins have the ability to inhibit mammary tumor development in 2 different species of animals bearing 2 and 3 different types of mammary cancer; steroids effective against the TP-responsive cancer are not active against the C3H type and vice versa. Thus it would be ideal to discover a steroid that inhibits both tumors and especially one that would kill the cancer cells instead of just inhibiting growth. More knowledge is dependent on research in endocrinology.

Antiarthritic Effects of the Antispermatogenic Agent 2,3-Dihydro-(1-naphthyl)-4-(1H)-quinazolinone (U-29,409)

Summary and Discussion U-29,409 (2,3-dihydro- (1-naphthyl)-4-(1H)-quinazolinone), a male antispermatogenic drug, exerts anti-arthritic effects in rats similar to those elicited by Cytoxan. However, it is less effective than the latter. Laboratory screening tests fail to show that U-29,409 has acute anti-inflammatory effects when given as a single dose or for 1 week prior to performing acute inflammatory reactions. In combination with Cytoxan, U-29,409 appears to exert a synergistic inhibitory effect on developing arthritis. Neither Cytoxan nor U-29,409 appears to exert significant inhibitory effects in rats with established disease. Both drugs, unlike nonsteroidal anti-inflammatory drugs, fail to display inhibitory effects in yeast-induced fever of rats.

Induction of Inflammation, Fever, and Acceleration of Adjuvant-Disease by Surfactants

Summary and Discussion Saponin, Filipin, and digitonin produce acute inflammation and fever when injected into the hindpaw or subcutaneously. Digitonin-induced inflammation and fever are inhibited by anti-inflammatory drugs. Digitonin is at least 20 times more potent than carrageenin on a weight basis when injected into the hindpaw of rats.

Effect of 7α-Methylation on Biological Activities of Norethindrone

Summary A very substantial increase of oral gonadotropin inhibiting (34 X), pregnancy inhibiting (10 X) and uterotropic (24 X) potencies was observed for 7α-meth-y1-17 α-ethynyl-19-nortestosterone (U-13851) compared to 17-ethynyl-19-nortestosterone (norethindrone) even though progestational potency was not enhanced. Although anabolic and androgenic properties are greatly increased in some 7α-methyl derivatives of testosterone and 19-nortestosterone, U-13851 did not appear to produce a typical androgenic response in laboratory tests. The authors wish to express their appreciation to J. I. Northam for statistical analysis of data and to J. C. Cornette and A. D. Forbes for technical assistance.