Takenaka T, Fujikura T, Honda K, Asano M, Niigata K
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Yakugaku Zasshi. 1995 Oct;115(10):773-89. doi: 10.1248/yakushi1947.115.10_773.
Benign prostatic hyperplasia (BPH) is an age-related disorder characterized by urinary outlet obstruction. This obstruction is due to both mechanical compression of the urethra by the hypertrophied prostate and to functional contraction of the prostate and urethra by sympathetic stimulation. We invented a novel compound tamsulosin hydrochloride, a sulphamoylphenethylamine derivative which possesses potent and selective alpha a-antagonism, and showed that this compound selectively reduced the intra-urethral pressure in the prostatic segment of the urethra in vivo. We also found that the alpha 1-adrenoceptor plays an important functional role in the prostate and urethra. For clinical use, a control release formulation was developed. This formulation did not induce orthostatic hypotension and could be administered at a fixed dose. A placebo-controlled double-blind dose finding study resulted in 0.2 mg/d as the optimal dose. This formulation significantly improved urinary outlet obstruction without affecting blood pressure as compared with placebo in P-III study, and was approved in 1993 for use in the treatment of bladder outlet obstruction associated with BPH. Tamsulosin hydrochloride is the first alpha 1-antagonist which improves bladder outlet obstruction associated with BPH without affecting blood pressure, and the treatment can be initiated and maintained at a fixed dose. Recently, the alpha 1-adrenoceptor subtypes alpha 1A, alpha 1B and alpha 1C were identified. The alpha 1C subtype is predominant and plays an important role in the human prostate. Tamsulosin hydrochloride shows high selectivity for this subtype, further supporting the clinical findings that tamsulosin hydrochloride improves bladder outlet obstruction associated with BPH with no effect on the cardiovascular system.
良性前列腺增生（BPH）是一种与年龄相关的疾病，其特征为尿路梗阻。这种梗阻是由于前列腺肥大对尿道的机械性压迫以及交感神经刺激引起的前列腺和尿道功能性收缩所致。我们发明了一种新型化合物盐酸坦索罗辛，它是一种氨磺酰苯乙胺衍生物，具有强效且选择性的α1 - 拮抗剂作用，并表明该化合物在体内能选择性降低尿道前列腺段的尿道内压。我们还发现α1 - 肾上腺素能受体在前列腺和尿道中发挥重要的功能作用。为用于临床，开发了一种控释制剂。该制剂不会引起体位性低血压，且可固定剂量给药。一项安慰剂对照双盲剂量探索研究得出0.2mg/d为最佳剂量。在III期研究中，与安慰剂相比，该制剂显著改善了尿路梗阻且不影响血压，并于1993年被批准用于治疗与BPH相关的膀胱出口梗阻。盐酸坦索罗辛是首个不影响血压而改善与BPH相关的膀胱出口梗阻的α1 - 拮抗剂，且治疗可从固定剂量开始并维持。最近，已鉴定出α1 - 肾上腺素能受体亚型α1A、α1B和α1C。α1C亚型占主导地位且在人类前列腺中起重要作用。盐酸坦索罗辛对该亚型具有高度选择性，进一步支持了盐酸坦索罗辛改善与BPH相关的膀胱出口梗阻且对心血管系统无影响的临床研究结果。
