Hormonal effects of turosteride, a 5α-reductase inhibitor, in the rat

Salle, E. Di; Guidici, Dorothy L.; Briatico, G.; Ornati, G.; Panzeri, A.

doi:10.1016/0960-0760(93)90181-u

Cited by 40 publications

(16 citation statements)

References 17 publications

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“…For example, prostatic growth induced by testosterone in castrated rats is inhibited by turosteride at doses of 1 -10 mg/kg (20) and by CGP53153 at doses of 0.01 -3 mg/ kg (21). On the other hand, the prostatic weights of normal rats are reduced by turosteride at doses of 3 -30 mg/kg (22) and by CGP53153 at doses of 1 -10 mg/ kg (21). This indicates that the doses of these compounds required to reduce prostatic weight in normal rats are over three times higher than those required to inhibit prostatic growth induced by testosterone in castrated rats.…”

Section: Discussionmentioning

confidence: 83%

“…Z-350 reduced prostatic content of dihydrotestosterone but slightly increased that of testosterone. It has previously been reported that the reduction in prostatic dihydrotestosterone levels caused by finasteride, a competitive inhibitor of 5a-R (25), is accompanied by an apparent increase in prostatic testosterone levels (26), and it has been suggested that the inhibitory effect of finasteride may gradually diminish because of these increased testosterone levels (22). The increased testosterone level would not be expected to interfere with the inhibitory action of Z-350, since Z-350 inhibits prostatic 5a-R non-competitively (16).…”

Section: Discussionmentioning

confidence: 99%

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Hormonal Effects of Z-350, Possessing Steroid 5 a-Reductase Inhibitory and a ι-Adrenoceptor Antagonistic Actions, in the Rat

Fukuda

Fukuta

Higashino

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-We examined the hormonal effects of Z-350, (S)-4-[3-(4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]propoxy}benzoyl)indole-1-yl]butyric acid hydrochloride, which has both a1-adrenoceptor blocking activity and steroid 5a-reductase inhibitory activity, in male and female rats. Z-350 administered orally for 14 days at a dose of 30 mg/ kg to normal male rats significantly reduced the weight of the prostate and seminal vesicles without affecting the weight of the testis, epididymis, adrenals, kidney or liver. Prostatic levels of dihydrotestosterone decreased dose-dependently, with a slight increase in the level of testosterone at a Z-350 dose of 100 mg/ kg. We observed no effects on the weight of the prostate in castrated rats or on the weight of the uterus in normal or 17b-estradiol-treated female rats. These results suggest that Z-350 inhibits prostatic growth via inhibition of steroid 5-reductase without other hormonal effects.Keywords: Z-350, Steroid 5a-reductase, Benign prostatic hyperplasia, Testosterone, Dihydrotestosterone Benign prostatic hyperplasia (BPH), which is a common disorder in aging men, is associated with growth of prostatic glandular and stromal elements. BPH causes symptoms in the lower urinary tract and reduces quality of life.The lower urinary tract symptoms caused by BPH are attributed to two main components: a dynamic component involving excessive contraction of prostatic smooth muscle mediated by a 1-adrenoceptors (1 -4) and a static component involving obstruction of the urethra by the enlarged prostate (5). a1-Adrenoceptor blockers (6 -10) represent a palliative approach to therapy for lower urinary tract symptoms caused by BPH and are effective in alleviating dynamic obstruction. On the other hand, anti-androgens can improve static obstruction by reducing prostatic mass, although they have adverse effects on sexual function, including impotence and decreased libido, which is caused by plasma testosterone deprivation (5).Steroid 5a-reductase (EC 1.3.1.22; 5a-R), a rate-limiting enzyme that converts testosterone to the potent androgen dihydrotestosterone, plays a critical role in prostatic growth (11). Finasteride is a specific 5a-R inhibitor that can reduce prostate volume with fewer adverse effects on sexual function than anti-androgens (12 -15), and it has already been approved for clinical use in the US and Europe.On the basis of the concept that combined activity (i.e., a 1-adrenoceptor blocking and 5a-R inhibition) may be more beneficial for the treatment of BPH than each activity alone, we recently reported the pharmacological profile of Z-350, which possesses a1-adrenoceptor blocking and 5a-R inhibitory activity, in vitro (16) and in vivo (17). Z-350 inhibited rat prostatic 5a-R in a non-competitive manner and prevented testosterone-induced re-growth of the prostate in castrated rats.In the present study, we investigated the effects of Z-350 on the weight of the testis, epididymis, adrenal gland and other organs in normal male rats to evaluate the hormonal eff...

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Hormonal Effects of Z-350, Possessing Steroid 5 a-Reductase Inhibitory and a ι-Adrenoceptor Antagonistic Actions, in the Rat

Fukuda

Fukuta

Higashino

et al. 2001

Japanese Journal of Pharmacology

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“…When tested on rat and human prostatic 5␣-reductases, the compound showed a similar degree of potency with IC 50 values of 53 and 55 nM, respectively [3,4]. Twenty-day oral administration of turosteride to adult male rats at doses of 3, 10, or 30 mg/ kg/day was found to cause a reduction in prostate weight associated with a reduction of prostatic DHT content by 61, 74, and 78%, respectively, without any relevant increase in prostatic T content [5].In this study we have investigated the effect of turosteride on the Dunning R3327 rat prostatic tumor growth in comparison with the effect of other androgen withdrawal therapies, i.e., the androgen receptor antagonist flutamide, the luteinizing hormone-releasing hormone (LH-RH) agonist leuprolide, or castration. In addition, the effect of these compounds on endocrine organ weights and serum hormone levels was also investigated.…”

mentioning

confidence: 69%

“…Furthermore, the role of T, in addition to that of DHT, in supporting prostatic cancer growth has not been completely clarified and it has been hypothesized that androgenic stimulus to prostatic can- cer could be provided by either DHT or T [11]. In this respect the observation that in rats turosteride is able to inhibit prostatic DHT levels without causing a secondary increase in tissue T concentration [5] could explain its antitumor activity observed in the Dunning model not sensitive to finasteride. In the present study when turosteride was administered at the lower oral dose of 50 mg/kg/day, no effect on tumor growth was observed, whereas prostate weight was inhibited by 53%.…”

Section: Discussionmentioning

confidence: 92%

Effect of turosteride, a 5α-reductase inhibitor, on the Dunning R3327 rat prostatic carcinoma

Zaccheo¹,

Giudici²,

Salle³

1997

Prostate

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“…When tested on human and rat prostatic 5␣-reductases, the compound showed a similar degree of potency, with IC50 values of 55 and 53 nM, respectively [6]. Turosteride was found to be more effective on the type 2 than type 1 isoform of the human re-combinant enzyme [7].…”

Section: Introductionmentioning

confidence: 94%

Effect of early treatment of prostate cancer with the 5α-reductase inhibitor turosteride in Dunning R3327 prostatic carcinoma in rats

1998

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Hormonal effects of turosteride, a 5α-reductase inhibitor, in the rat

Cited by 40 publications

References 17 publications

Hormonal Effects of Z-350, Possessing Steroid 5 a-Reductase Inhibitory and a ι-Adrenoceptor Antagonistic Actions, in the Rat

Hormonal Effects of Z-350, Possessing Steroid 5 a-Reductase Inhibitory and a ι-Adrenoceptor Antagonistic Actions, in the Rat

Effect of turosteride, a 5α-reductase inhibitor, on the Dunning R3327 rat prostatic carcinoma

Effect of early treatment of prostate cancer with the 5α-reductase inhibitor turosteride in Dunning R3327 prostatic carcinoma in rats

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