Arruzazabala M L, Más R, Molina V, Noa M, Carbajal D, Mendoza N
Center of Natural Products, National Center for Scientific Research, Havana City, Cuba.
Drugs R D. 2006;7(4):233-41. doi: 10.2165/00126839-200607040-00003.
Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate that results in obstructive lower urinary tract symptoms. Saw palmetto (Serenoa repens), the dwarf American palm (Arecaceae family), is commonly used to treat BPH. The Cuban royal palm (Roystonea regia) also belongs to the Arecaceae family, and 200-400mg of D-004, a lipid extract from its fruits, administered orally for 14 days has been shown to prevent testosterone- but not dihydrotestosterone-induced prostatic hyperplasia in rats. D-004 (125-250 microg/mL) added to preparations of rat vas deferens caused a marked, dose-dependent and significant inhibition of noradrenaline-induced smooth muscle contraction, a response mediated through alpha(1)-adrenoceptors, and was more effective in these respects than Saw palmetto. However, the in vivo effects of D-004 and Saw palmetto on the hypertensive response induced by noradrenaline were modest (albeit significant), and neither treatment affected resting blood pressure or heart rate in rats. The differential effects of D-004 in in vitro and in vivo models could be related to a differential affinity for adrenoceptor subtypes or to different bioavailabilities in vascular and urogenital targets. Phenylephrine injected into rodents induces prostatic hyperplasia with all the characteristic morphological changes of the condition but does not result in enlargement of the prostate. Therefore, this phenylephrine-induced change in rat prostate tissue is called atypical prostatic hyperplasia. It serves as an in vivo model of prostatic hyperplasia induced by stimulation of alpha(1)-adrenoceptors. The objective of this study was to determine whether D-004 can inhibit induction of atypical prostatic hyperplasia by phenylephrine in rats.
Rats were randomly distributed into five groups (ten rats/group). One group was a negative control and received oral vehicle only. The other four groups were injected subcutaneously with phenylephrine (2 mg/kg): of these groups, one was a positive control receiving the vehicle, and the other three groups were treated with D-004 or Saw palmetto (both 400 mg/kg) or tamsulosin 0.4 mg/kg. All active treatments were given orally for 28 days. After completion of treatment, rats were placed unrestrained in metabolic cages and micturition studies were performed. The rats were later killed and their prostates removed and weighed. Prostate samples were processed for histological study, with histological changes being assessed according to a scoring system. Bodyweight was measured at baseline and at weekly intervals.
Histological examination of positive control rats revealed features of atypical prostatic hyperplasia, with piling-up, papillary and cribiform patterns and budding-out of epithelial cells. Micturition assessment revealed that phenylephrine significantly lowered both the total volume of urine in 1 hour and the volume per micturition; the latter was considered the main efficacy variable. D-004 and Saw palmetto extracts significantly prevented this reduction in volume per micturition by 70.5% and 68.6%, respectively, while tamsulosin totally abolished the reduction in micturition induced by phenylephrine (100% inhibition). Tamsulosin, D-004 and Saw palmetto significantly reduced the histological changes of atypical prostatic hyperplasia induced by phenylephrine by 73.1%, 61.2% and 50.0%, respectively.
Administration of D-004 resulted in marked and significant prevention of phenylephrine-induced impairment of micturition and histological changes in rat prostate. These findings indicate that, in vivo, D-004 effectively opposes these responses to phenylephrine, which are mediated through urogenital alpha(1)-adrenoceptors. In this respect, D-004 was moderately more effective than Saw palmetto, a phytotherapeutic standard used to treat BPH, but less effective than tamsulosin, a selective alpha(1A)-adrenoceptor antagonist.
良性前列腺增生（BPH）是前列腺的一种非恶性肿大，可导致下尿路梗阻症状。锯叶棕（Serenoa repens），即矮生美洲棕榈（棕榈科），常用于治疗BPH。古巴王棕（Roystonea regia）也属于棕榈科，其果实的脂质提取物D - 004，口服200 - 400mg，持续14天，已显示可预防睾酮诱导而非二氢睾酮诱导的大鼠前列腺增生。将D - 004（125 - 250μg/mL）添加到大鼠输精管制剂中，可引起去甲肾上腺素诱导的平滑肌收缩的显著、剂量依赖性和明显抑制，该反应通过α(1) - 肾上腺素能受体介导，在这些方面比锯叶棕更有效。然而，D - 004和锯叶棕对去甲肾上腺素诱导的高血压反应的体内作用适度（尽管显著），且两种治疗均未影响大鼠的静息血压或心率。D - 004在体外和体内模型中的不同作用可能与对肾上腺素能受体亚型的不同亲和力或血管和泌尿生殖靶标的不同生物利用度有关。向啮齿动物注射去氧肾上腺素可诱导前列腺增生，并伴有该病症所有特征性的形态学变化，但不会导致前列腺肿大。因此，这种去氧肾上腺素诱导的大鼠前列腺组织变化称为非典型前列腺增生。它作为α(1) - 肾上腺素能受体刺激诱导的前列腺增生的体内模型。本研究的目的是确定D - 004是否能抑制去氧肾上腺素诱导的大鼠非典型前列腺增生。
将大鼠随机分为五组（每组10只）。一组为阴性对照，仅接受口服赋形剂。其他四组皮下注射去氧肾上腺素（2mg/kg）：在这些组中，一组为接受赋形剂的阳性对照，其他三组分别用D - 004或锯叶棕（均为400mg/kg）或坦索罗辛0.4mg/kg治疗。所有活性治疗均口服给药28天。治疗结束后，将大鼠无约束地置于代谢笼中进行排尿研究。随后处死大鼠，取出前列腺并称重。对前列腺样本进行组织学研究，根据评分系统评估组织学变化。在基线和每周间隔测量体重。
阳性对照大鼠的组织学检查显示非典型前列腺增生的特征，包括上皮细胞堆积、乳头状和筛状模式以及出芽。排尿评估显示，去氧肾上腺素显著降低了1小时内的总尿量和每次排尿量；后者被视为主要疗效变量。D - 004和锯叶棕提取物分别显著预防了每次排尿量的减少，预防率分别为70.5%和68.6%，而坦索罗辛完全消除了去氧肾上腺素诱导的排尿减少（100%抑制）。坦索罗辛、D - 004和锯叶棕分别显著降低了去氧肾上腺素诱导的非典型前列腺增生的组织学变化，降低率分别为73.1%、61.2%和50.0%。
给予D - 004可显著预防去氧肾上腺素诱导的大鼠排尿障碍和前列腺组织学变化。这些发现表明，在体内，D - 004有效地对抗了通过泌尿生殖α(1) - 肾上腺素能受体介导的对去氧肾上腺素的这些反应。在这方面，D - 004比用于治疗BPH的植物治疗标准锯叶棕略有效，但比选择性α(1A) - 肾上腺素能受体拮抗剂坦索罗辛效果差。
