Each value represents the mean ± S.E.M from at least three tests. Modified with permission from ref. 18.

Transcription

1

2 Fig. 1 Chemical structure of naftopidil. Table 1 Affinity of naftopidil at the cloned human a 1-adrenoceptors. Each value represents the mean ± S.E.M from at least three tests. Modified with permission from ref. 18.

3 Table 2 Effects of naftopidil on phenylephrine-induced increases in prostatic pressure and mean blood pressure in anesthetized dogs. Phenylephrine (3,u g, kg) was injected before and 40 min after the administration of each test compound. Each value represents the mean ± S.E.M from 6 dogs. Asterisks denote significant difference vs. vehicle by Dunnett test. *P < 0.05, * *P < Modified with per mission from ref. 18. Table 3 Comparative antagonist potencies for a 1 adrenoceptor antagonists as inhibitors of phenylephrine-induced increases in prostatic pressure and mean blood pressure in anesthetized dogs. Data represent the doses (expressed in u g,,"kg) inhibiting by 50% the prostatic pressure (PP) and mean blood pressure (BP) induced by phenylephrine and the ratio between the doses (BP,,,"PP: selectivity index). Reproduced with permission from ref. 18.

4 Fig. 2 Effects of naftopidil, tamsulosin and prazosin on orthostatic hypotension (A) and mean blood pressure (B) in conscious rabbits. Or thostatic hypotension was defined as the change in mean blood pressure to upright tilt for 1 min. Each point represents the mean ± S.E.M. of 5 animals. Asterisks denote significant differense vs. vehicle by Dunnett test. *P <0.05, * *P <0.01. Modified with permission from ref. 27.

5

6 1) Caine M and Perlberg S: Dynamics of acute reten tion in prostatic patients and role of adrenergic re ceptors. Urology 9, (1977) 2) Barry MJ: Epidemiology and natural history of be nign prostatic hyperplasia. Urol Clin North Am 17, (1990) 4) Gosling JA and Thompson SA: A neurohistochemi cal and histological study of peripheral autonomic neurons of the human bladder neck and prostate. Urol Int 32, (1977) 5) Vaalasti A and Heronen A: Autonomic innervation of the human prostate. Invest Urol 17, (1980) 6) Furuya S, Kumamoto E, Yokoyama T, Tsukamoto T, Izumi T and Abiko Y: Alpha-adrenergic activity and urethral pressure in prostatic zone in benign prostatic hypertrophy. J Urol 128, (1982) 7) Hieble JP, Caine M and Zalaznik E: In vitro char acterization of the a-adrenoceptors in human pros tate. Eur J Pharmacol 107, (1985) 8) Kunusawa Y, Kawabe K, Niijima T, Honda K and Takenaka T: A pharmacological study on a adren ergic receptor subtypes in smooth muscle of human urinary bladder base and prostatic urethra. J Urol 134, (1985) 9) Muramatsu I, Yamanaka K and Kigoshi S: Phar macological profile of the novel a -adrenoceptor an tagonist KT-611 (Naftopidil). Jpn J Pharmacol 55, (1991) 10) Yamada S, Suzuki M, Kato Y, Kimura R, Mori R, Matsumoto K, Maruyama M and Kawabe K: Bind ing characteristics of naftopidil and a 1-adreno ceptor antagonists to prostatic a -adrenoceptors in benign prostatic hypertrophy. Life Sci 50, (1992) 11) Hieble JP, Byllund DB, Clarke DE, Eikenburg DC, Langer SZ, Lefkowitz RJ, Minneman KP and Ruffolo RJ: International Union of Pharmacology. X. Recommendation for nomenclature of alpha 1 adrenoceptors: consensus update. Pharmacol Rev 47, (1995) 12) Cotecchia S, Schwinn DA, Randall RR, Lefkowitz RJ, Caron MG and Kobilka BK: Molecular cloning and expression of the cdna for the hamster alpha 1-adrenergic receptor. Proc Natl Acad Sci USA 85, (1988) 13) Perez DM, Piascik MT and Graham RM: Solution phase library screening for the identification of rare clones: isolation of an a 1-D-adrenergic recep tor cdna. Mol Pharmacol 40, (1991) 14) Hirasawa A, Horie K, Tanaka T, Takagaki K, Murai M, Yano J and Tsujimoto G: Cloning, func tional expression and tissue distribution of human cdna for the a lc-adrenergic receptor. Biochem Biophys Res Commun 195, (1993) 15) Hirasawa A, Horie K, Tanaka T, Takagaki K, Murai M, Yano J and Tsujimoto G: Cloning, func tional expression and tissure distribution of hu man a 1C-adrenoceptor splice variants. FEBS Lett 363, (1995) 16) Moriyama N, Kurimoto S, Horie S, Nasu K, Tanaka T, Yano K, Hirano H, Tsujimoto G and Kawabe K: Detection of a 1-adrenoceptor subtypes in human hypertrophied prostate by in situ hy bridization. Histochem J 28, (1996) 17) Cavalli A, Lattion A-L, Hummler E, Nenniger M, Pedrazzini T, Aubert J-F, Michel MC, Yang M, Lembo G, Vecchione C, et al : Decreased blood pressure response in mice deficient of the a lb adrenergic receptor. Proc Natl Acad Sci USA 94, (1997) 18) Takei R, Ikegaki I, Shibata K, Tsujimoto G and Asano T: Naftopidil, a novel a 1-adrenoceptor an tagonist, displays selective inhibition of canine prostatic pressure and high affinity binding to cloned human a 1-adrenoceptors. Jpn J Pharmacol 79, (1999) 19) Foglar R, Shibata K, Horie K, Hirasawa A and Tsujimoto G: Use of recombinant a 1-adrenoceptors to characterize subtype selectivity of drugs for the treatment of prostatic hypertrophy. Eur J Pharma col 288, (1995) 20) Blue D, Zhu QM, Isom P, Young S, Larson M and Clarke DE: Effect of a 1-adrenoceptor antagonists in dog prostate blood pressure models. FASEB J 10, A425 (1996) 21) Kenny BA, Miller AM, Williamson IJR, O'Connell J, Chalmers DH and Naylor AM: Evaluation of the pharmacological selectivity profile of a 1 adrenocep tor antagonists at prostatic a 1 adrenoceptors: binding, functional and in vivo studies. Br J Phar macol 118, (1996) 22) Brune ME, Katwala SP, Milicic I, Buckner SA, Ireland LM, Kerwin JF Jr and Hancock AA: Ef fects of selective and nonselective alpha-l adreno ceptor antagonists on intraurethral and arterial pressures in intact conscious dogs. Pharmacology 53, (1995) 23) Forray C, Bard JA, Wetzel JM, Chiu G, Shapiro E, Tang R, Lepor H, Hartig PR, Weinshank RL, Branchek TA, et al: The a 1-adrenergic receptor that mediates smooth muscle contraction in hu man prostate has the pharmacological properties of the cloned human a lc subtype. Mol Pharmacol 45, (1994) 24) Langer SZ: Nomenclature and state of the art on alpha I -adrenoceptors. Eur Urol 33, suppl 2, 2-6 (1998) 25) Take H, Shibata K, Awaji T, Hirasawa A, Ikegai I, Asano T, Takada T and Tsujimoto G: Vascular a 1 adrenoceptor subtype selectivity and a 1-blocker induced orthostatic hypotension. Jpn J Pharmacol 77, (1998) 26) Arai K, Tanoue A, Goda N, Takeda M, Takahashi K and Tsujimoto G: Characterization of the mouse

7 alphald-adrenergic receptor gene. Jpn J Pharma col 81, (1999) Abstract Pharmacological properties of naftopidil, a drug for treatment of the bladder outlet obstruction for patients with benign prostatic hyperplasia. Ichiro IKEGAKI (Laboratory for Pharmacology, Institute for Life Science Research, Asahi Chemical Industry Co., Ltd., Mifuku, Tagata-gun, Shizuoka , Japan). Folia Pharmacol. Jpn. (Nippon Yakurigaku Zasshi) 116, (2000) Naftopidil, a phenylpiperazine derivative, is a novel a 1-adrenoceptor antagonist and is new drug for the bladder outlet obstruction in patients with benign prostatic hyperplasia (BPH). Naftopidil competitively inhibited specific [3H] prazosin binding in prostatic membranes of humans, and its Ki value was 11.6 nm. Using cloned human a 1-adrenoceptor subtypes (a la, a lb and a 1d), naftopidil was selective for the a ld adrenoceptor with approximately 3 and 17-fold higher affinity than for the a la and a lb-adrenoceptor subtypes, respectively. In anesthetized dogs, naftopidil selectively inhibited the phenylephrine-induced in crease in prostatic pressure compared with mean blood pressure. The selectivity of naftopidil for prostatic pressure was more potent than those of tamsulosin and prazosin. In conscious rabbits, the effect of naftopidil on the blood pressure reactions following the tilting was less potent than those of tamsulosin and prazosin. In clinical studies, naftopidil has been demonstrated to be effective in the treatment of blad der outlet obstruction in patients with BPH. In Japan, naftopidil has been already approved for clinical use as a drug for BPH. Keywords: Naftopidil; a 1-Adrenoceptor antagonist; prostate pressure; benign prostatic hyperplasia; or thostatic hypotension