RU 58841, a new specific topical antiandrogen: A candidate of choice for the treatment of acne, androgenetic alopecia and hirsutism

Battmann, T.; Bonfils, A.; Branche, C.; Humbert, Jean-Paul; Goubet, F.; Teutsch, G.; Philibert, D.

doi:10.1016/0960-0760(94)90250-x

Cited by 57 publications

(33 citation statements)

References 24 publications

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“…Nevertheless, 'tissue selectivity,' particularly for the prostate tumor, has become one of the major pharmacological features to achieve in the development of novel nonsteroidal antiandrogens. (Tables I and II) was developed in Europe for topical treatment of acne and alopecia (42,43), due to its short half life in vivo (less than one hour). Topical application not only avoids extensive hepatic metabolism (N-dealkylation) but also provides for effective regional treatment without systemic antiandrogen activity due to the formation of active metabolite (43,44).…”

Section: Nonsteroidal Androgen Receptor Antagonistsmentioning

confidence: 99%

“…(Tables I and II) was developed in Europe for topical treatment of acne and alopecia (42,43), due to its short half life in vivo (less than one hour). Topical application not only avoids extensive hepatic metabolism (N-dealkylation) but also provides for effective regional treatment without systemic antiandrogen activity due to the formation of active metabolite (43,44). In comparison, structural analog RU58642 was shown to be orally active (35), and could significantly reduce prostate and seminal vesicle weights in intact male rats at dose rates from 1 to 30 mg/kg/day.…”

Section: Nonsteroidal Androgen Receptor Antagonistsmentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

2006

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Testosterone and structurally related anabolic steroids have been used to treat hypogonadism, muscle wasting, osteoporosis, male contraception, cancer cachexia, anemia, and hormone replacement therapy in aging men or age-related frailty; while antiandrogens may be useful for treatment of conditions like acne, alopecia (male-pattern baldness), hirsutism, benign prostatic hyperplasia (BPH) and prostate cancer. However, the undesirable physicochemical and pharmacokinetic properties of steroidal androgen receptor (AR) ligands limited their clinical use. Nonsteroidal AR ligands with improved pharmacological and pharmacokinetic properties have been developed to overcome these problems. This review focuses on the pharmacokinetics, metabolism, and pharmacology of clinically used and emerging nonsteroidal AR ligands, including antagonists, agonists, and selective androgen receptor modulators.

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Section: Nonsteroidal Androgen Receptor Antagonistsmentioning

confidence: 99%

Section: Nonsteroidal Androgen Receptor Antagonistsmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

2006

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“…RU58841 is a new nonsteroidal antiandrogen with high affinity for the ARs from hamster prostate and flank organ. Animal studies suggest that RU58841 is a candidate for the treatment of androgen-dependent skin diseases (24).…”

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confidence: 99%

Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells

Miyamoto

Yeh

Wilding

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

183

120

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Although hormone therapy with antiandrogens has been widely used for the treatment of prostate cancer, some antiandrogens may act as androgen receptor (AR) agonists that may result in antiandrogen withdrawal syndrome. The molecular mechanism of this agonist response, however, remains unclear. Using mammalian two-hybrid assay, we report that antiandrogens, hydroxyf lutamide, bicalutamide (casodex), cyproterone acetate, and RU58841, and other compounds such as genistein and RU486, can promote the interaction between AR and its coactivator, ARA70, in a dose-dependent manner. The chloramphenicol acetyltransferase assay further demonstrates that these antiandrogens and related compounds significantly enhance the AR transcriptional activity by cotransfection of AR and ARA70 in a 1:3 ratio into human prostate cancer DU145 cells. Our results suggest that the agonist activity of antiandrogens might occur with the proper interaction of AR and ARA70 in DU145 cells. These findings may provide a good model to develop better antiandrogens without agonist activity.

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“…RU58841 is a nonsteroidal blocker of andro gen receptor and is known to bind with the receptor higher than testosterone. Also, topi cal application of RU58841 reduced the size of hamster flank organs [18].…”

Section: Introductionmentioning

confidence: 99%

Effects of Topical Antiandrogen and 5-Alpha-Reductase Inhibitors on Sebaceous Glands in Male Fuzzy Rats

Ye¹,

Imamura²,

Imanishi³

et al. 1997

Skin Pharmacol Physiol

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The fuzzy rat, a genetic mutant between hairless and hairy albino rats, expresses androgen-dependent hypersecretion of sebum and hyperplastic sebaceous glands. Using this model for human acne, we examined the effects of inhibitors of human steroid 5α-reductase isozymes, type I (MK386) and type II (finasteride), and an androgen receptor blocker (RU58841) on regression of glandular and ductal hyperplasia. The above three agents, 1 % weight volume, were dissolved into the vehicle (propy-lene glycol, alcohol and water) and applied on the backs of peripubertal male rats for 2 months. Control and castrate groups received vehicle alone. At 8 weeks, we examined the size of the sebaceous glandular lobules and ducts in split epidermal preparations as well as in frozen sections of skin stained with osmium-potassium dichromate solution. The number of bro-modeoxyuridine (BrdU)-positive cells was counted in the glandular lobes in split-skin tissues stained with BrdU immunochemistry. The results revealed that the sizes of both lobes and ducts in castrates were 40-60% smaller than in controls. RU58841 induced glandular and ductal regression equivalent to that in castrates. Finasteride induced a moderate degree of lobular and ductal reduction, whereas MK386 caused only ductal regression. Reduction of BrdU-positive cells in the sebaceous lobes was found in the skin treated with finasteride and RU58841. Serum concentrations of testosterone and dihydrotestosterone showed no significant changes in all drug-treated rats. The weight of the prostatic lobes was reduced significantly in rats treated with finasteride but not by the other two agents. RU58841 effectively counteracted endogenous androgens resulting in a suppression of growth of the sebaceous glands but not the prostate. This rodent model for androgen-dependent hyperplasia of the sebaceous glands is useful for the study of many pharmacological aspects comprising the rate of percutaneous absorption, stability and affinity to target organs of the testing compounds, and selection of adequate vehicles for topical application.

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RU 58841, a new specific topical antiandrogen: A candidate of choice for the treatment of acne, androgenetic alopecia and hirsutism

Cited by 57 publications

References 24 publications

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells

Effects of Topical Antiandrogen and 5-Alpha-Reductase Inhibitors on Sebaceous Glands in Male Fuzzy Rats

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