Alpha-adrenoceptor antagonists have been used for the treatment of male erectile dysfunction (MED). Ro70-0004/003 (Ro70-0004) is a selective and orally active alpha1A-adrenoceptor antagonist. The objective of this study was to: (1) pharmacologically elucidate the alpha1-adrenoceptor subtype mediating norepinephrine-induced contraction of human isolated corpus cavernosal tissue and (2) conduct a clinical proof-of-concept study with Ro70-0004 to test the hypothesis that selective alpha1A-adrenoceptor blockade would improve erectile function in patients with MED. In vitro organ bath studies were conducted with strips of human isolated corpus cavernosal tissue obtained from patients undergoing penile prosthesis implantation. Prazosin, cyclazosin, RS-100329 and Ro70-0004/003 antagonized norepinephrine-induced contractile responses with affinity estimates (pK(B) or pA2) of 8.4, 7.3, 9.2 and 8.8, respectively, consistent with the singular involvement of alpha1A-adrenoceptor subtype. A clinical study (single center, observer-blind, randomized, placebo-controlled, extended period Latin-Square crossover design) was conducted in 24 male patients (mean age 44 y) with MED of no established organic cause to evaluate the efficacy of a 5-mg oral dose of Ro70-0004. The primary efficacy endpoint was the duration of rigidity > 60% at the base of the penis measured between 0.5 and 2.5 h post-dose. Rigidity was assessed by penile plethysmography using the RigiScan Plus device during visual sexual stimulation. The safety and efficacy of Ro70-0004 was also assessed. A 50-mg dose of sildenafil was included as a positive control. For the primary efficacy endpoint, the mean duration of erection was 9.69 min following administration of placebo, 8.28 min following Ro70-0004, and 22.64 min following sildenafil. Only the difference between sildenafil and placebo reached statistical significance (P < 0.05). A similar pattern was observed when measuring a duration of rigidity > 80% at the base of the penis (secondary endpoint). Ro70-0004 was safe and generally well tolerated (only two out of 20 patients reported at least one adverse event). The highly selective alpha1A-adrenoceptor antagonist, Ro70-0004, given at a single dose of 5 mg, did not improve erectile function when compared to placebo.

中文翻译：

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评价口服ro70-0004 / 003（α1A肾上腺素受体拮抗剂）在治疗男性勃起功能障碍中的作用。

α-肾上腺素能受体拮抗剂已用于治疗男性勃起功能障碍（MED）。Ro70-0004 / 003（Ro70-0004）是一种选择性的口服活性α1A-肾上腺素受体拮抗剂。这项研究的目的是：（1）药理学阐明介导去甲肾上腺素诱导的人离体海绵体组织收缩的α1-肾上腺素受体亚型，以及（2）用Ro70-0004进行临床概念验证研究以检验该假设选择性α1A-肾上腺素受体阻滞剂可改善MED患者的勃起功能。用从阴茎假体植入患者获得的人类分离的海绵体组织条带进行体外器官浴研究。哌唑嗪，环唑嗪，RS-100329和Ro70-0004 / 003拮抗去甲肾上腺素诱导的收缩反应，其亲和力估计值（pK（B）或pA2）分别为8.4、7.3、9.2和8.8，这与alpha1A-肾上腺素受体亚型的单一参与相一致。一项针对24名男性（平均年龄为44岁），没有确定的器质性原因的MED患者进行了一项临床研究（单中心，观察者盲，随机，安慰剂对照，延长的拉丁-方形交叉设计），以评估一种药物的疗效Ro70-0004的5毫克口服剂量。主要功效终点是给药后0.5至2.5小时之间在阴茎根部进行的僵硬持续时间> 60％。在视觉性刺激期间，使用RigiScan Plus设备通过阴茎体积描记法评估刚度。还评估了Ro70-0004的安全性和有效性。包含50 mg西地那非的剂量作为阳性对照。对于主要功效终点，安慰剂给药后的平均勃起持续时间为9.69分钟，Ro70-0004后为8.28分钟，而西地那非则为22.64分钟。仅西地那非和安慰剂之间的差异达到统计学显着性（P <0.05）。当测量阴茎根部（第二端点）的刚度持续时间> 80％时，观察到类似的模式。Ro70-0004是安全的，且一般耐受良好（20名患者中只有2名报告了至少一项不良事件）。与安慰剂相比，单剂量5 mg的高选择性α1A-肾上腺素受体拮抗剂Ro70-0004不能改善勃起功能。服用安慰剂后69分钟，Ro70-0004后8.28分钟，西地那非后22.64分钟。仅西地那非和安慰剂之间的差异达到统计学显着性（P <0.05）。当测量阴茎根部（第二端点）的刚度持续时间> 80％时，观察到类似的模式。Ro70-0004是安全的，且一般耐受良好（20名患者中只有2名报告了至少一项不良事件）。与安慰剂相比，单剂量5 mg的高选择性α1A-肾上腺素受体拮抗剂Ro70-0004不能改善勃起功能。服用安慰剂后69分钟，Ro70-0004后8.28分钟，西地那非后22.64分钟。仅西地那非和安慰剂之间的差异达到统计学显着性（P <0.05）。当测量阴茎根部（第二端点）的刚度持续时间> 80％时，观察到类似的模式。Ro70-0004是安全的，且一般耐受良好（20名患者中只有2名报告了至少一项不良事件）。与安慰剂相比，单剂量5 mg的高选择性α1A-肾上腺素受体拮抗剂Ro70-0004不能改善勃起功能。当测量阴茎根部（第二端点）的刚度持续时间> 80％时，观察到类似的模式。Ro70-0004是安全的，并且总体耐受性良好（20名患者中只有2名报告了至少一项不良事件）。与安慰剂相比，单次剂量为5 mg的高选择性alpha1A-肾上腺素受体拮抗剂Ro70-0004不能改善勃起功能。当测量阴茎根部（第二端点）的刚度持续时间> 80％时，观察到类似的模式。Ro70-0004是安全的，且一般耐受良好（20名患者中只有2名报告了至少一项不良事件）。与安慰剂相比，单剂量5 mg的高选择性α1A-肾上腺素受体拮抗剂Ro70-0004不能改善勃起功能。