赛洛多辛为选择性a-1A-肾上腺能阻滞剂,临床前研究表明,其对尿道的选择性效应分别较哌唑嗪和坦索罗辛高12和7.5倍.本品2006年在日本上市,
商品名Urief
赛洛多辛(Silodosin，Rapaflo)胶囊用于治疗因良性前列腺增生（BPH）引起的排尿困难症状。
赛洛多辛为α-1受体阻滞剂，通过阻滞前列腺、膀胱和尿道中的肾上腺素-1受体起效。通过该对受体产生阻滞，放松组织平滑肌，从而缓解BPH的症状。该药每天服用一次，建议肝肾正常的患者日剂量服用8毫克，有中度肝肾损伤的患者服用4毫克的日剂量。同时，严重肝肾损伤内患者不建议服用，未批准儿童患者使用。
一项有932名男性受试者参加了两个12周的临床试验显示，与安慰剂组相比，赛洛多辛对于改善BPH症状和增加尿流量具有显著的统计学意义。
使用赛洛多辛最常见的副作用射精障碍,停药后该副作用也随之消失。其他的副作用还包括眩晕、头昏、腹泻、直立性低血压（站立时血压下降）、头痛、鼻咽炎（鼻腔和喉头的病毒性感染）以及鼻塞。
用于排尿障碍的新药SilodosinSilodosin(KMD-3213,kAD-3213)是一种α1-肾上腺素受体拮抗剂，对与良性前列腺增生有关的排尿障碍有疗效。本品由日本Kissei与Daiichi医药公司联合开发。在日本，这两家医药公司具有使用不同商标名称共同销售产品的权力，而Kissei保留国外的研发和营销权。
该药分子式为：
C25H33F3N3O4CSA:
160970-64-9CAS:
169107-04-4(其双氢溴化物）
良性前列腺增生（BPH）是老年男性常见病之一，以前列腺的非恶性增大为特征。在60岁或以上的老年人中有50%以上患有此症，而在85岁及以上的老年人中有90%以上者发病。其发病原因尚未阐明，一般认为与性激素和胆固醇等的分泌、代谢失调有关。有人认为，老年人因垂体－促性腺激素－睾丸的作用途径减弱或因内源性变化，使睾丸退化、性机能下降、睾酮值降低、前列腺因结缔组织增多，使腺上皮改变、前列腺增大。前列腺的增大会压迫尿道，导致膀胱尿流不畅，甚至堵塞膀胱出口。在人类前列腺中存在α1A-肾上腺素受体，该受体的激活会加重尿道梗阻和排尿困难症状。
因此，通过阻断α1A-肾上腺素受体的结合，可使梗阻的前列腺平滑肌松弛，从而改善症状。
与对所有α-受体亚型均有高亲和常数的（pKD＞9）哌唑嗪和坦索罗辛（tamsulosin,已上市用于前列腺增生引起的排尿障碍）比较，Silodosin（10-2000pmol/L）仅对α1A-肾上腺素受体有较高的亲和力（pKD＝10.5），而对α1B-及α1D-肾上腺素受体的亲和力不明显。竞争性结合试验也显示，[3H]－Silodosin对α1A-受体亚型具有高的缔合能力（pKi＝10.4）比对α1B（pKi＝8.1）和α1D（pKi＝8.6）高。[3H]-Silodosin对鼠颌下腺的α1A受体亚型表现出高亲和力，而对鼠肝的α1B受体亚型无亲和力。
有关裸鼠组织的结合实验研究表明：Silodosin在肝中（Ki=16 nmol/L）和颌下腺中(Ki=0.15 nmol/L)的抑制曲线符合单室模型，而在心肌膜上则即有低亲和、也有高亲和的结合位点。
对表达α1A受体亚型的CHO细胞，Silodosin能抑制去甲肾上腺素引起的细胞内Ca2+浓度增加，其IC50为(0.32±0.05）nmol/L；而对表达α1B和α1D的CHO细胞的作用较弱，即使高浓度的药物也不能起到完全抑制作用。此外，实验表明，与[3H]－哌唑嗪相比，[3H]－Silodosin对人的主要含α1A受体亚型的前列腺膜的亲和力更高；而且，Silodosin对人的前列腺的亲和力比对含α1B受体亚型的主动脉样本的亲和力高出200倍。
有人采用经脑干横切术消除大脑功能的实验犬为对象，比较了Silodosin、坦索罗辛和哌唑嗪对电刺激下腹神经引起的犬尿道压力增加的抑制作用。结果表明，静脉给药后，Silodosin对尿道的选择性作用分别比哌唑嗪高12倍，比坦索罗辛高7.5倍。Silodosin能明显抑制去甲肾上腺素引起的人前列腺收缩（K＝9.45±0.025），药效与坦索罗辛相当，而比哌唑嗪更强。Silodosin与人体前列腺的亲和力比其对人肠系膜动脉的亲和力高100倍。
Silodosin对BPH大鼠模型的膀胱活动亢进有剂量依赖性的抑制作用，并能提高膀胱收缩的压力阈。这表明本品除能改善膀胱功能外，对BPH的刺激症状也有改善作用。
在对药物与α1受体的结合程度进行评估时，采用了有关Silodosin与人和大鼠体内前列腺α1受体结合的有关参数。结果表明，口服用药0.5-6小时后，被药物结合的α1受体比率在60%-90%范围内，24小时后降为40%。
据有关资料透露，2002年上半年，Silodosin已在日本完成了Ⅱ期临床试验研究，正进行Ⅲ期临床试验，而同时也在美国进行Ⅱ期临床试验。
Manufacturer:
Watson Pharmaceuticals, Inc.
Pharmacological Class:
α1A blocker
Active Ingredient(s):
Silodosin 4mg, 8mg; caps.
Indication(s):
Benign prostatic hyperplasia (BPH).
Pharmacology:Alpha-1 receptors are located in the prostate, prostatic urethra, bladder base, and bladder neck. The blockade of these receptors causes the relaxation of smooth muscles, improving urinary flow and reducing the symptoms of BPH. Several subtypes of α1-blockers have been identified. Silodosin is an α-blocker that has been shown to be highly selective for the α1A subtype.
In order to reduce adverse effects, this drug should be taken with a meal. When taken with a moderate fat, moderate calorie meal, there were variable effects on drug absorption, including reductions in the maximum plasma concentration ranging from 18–43% and decreases in the extent of absorption from 4–49%.
Silodosin is metabolized by several pathways, including glucuronidation by UDP-glucuronosyltransferase 2B7 (UGT2B7) and oxidation by CYP3A4. Strong inhibitors of UGT2B7 (eg, valproate, fluconazole, probenecid) may increase exposure to silodosin.
Clinical Trials:
Two double-blind, 12-week studies were conductedtoevaluatetheefficacyofsilodosin 8mg/day in treating the symptoms of BPH. The primaryefficacyassessment was the International Prostate Symptom (IPS) score, whichexaminedirritativeandobstructive symptoms. A secondary endpoint was the maximum urine flow rate. In bothstudies, at week 12, the mean changes from baseline to last assessment in total IPS score was significantly greater for patients treated with silodosin than for those given placebo. Significant increases in maximum urinary flow rates from baseline to lastassessment were seen for the study drugcompared to placebo in both studies. Both parameters were improved compared to baseline at the first scheduled observation and continued throughout 12 weeks of treatment.
Legal Classification:
Rx
Adults:
Take with food once daily. Normal renal function:
8mg. Renal
impairment (CrCl 30–50mL/min):
4mg.
Children:
Not recommended.
Contraindication(s):
Severe renal impairment (CrCl <30mL/min). Severe hepatic impairment (Child-Pugh score ≥10). Concomitant potent CYP3A4 inhibitors (eg,
ketoconazole,
itraconazole, clarithromycin, ritonavir).Precaution(s):
Not for treating hypertension. Exclude prostate cancer. Anticipated cataract surgery (may causeintraoperativefloppyrissyndrome;adviseophthalmologist). Pregnancy (Cat.B), nursing mothers:
not
applicable (not indicated for use in women).Interaction(s):
See Contraindications. Concomitant other α-blockers, other strong P-glycoprotein inhibitors (eg, cyclosporine):not recommended. May be potentiated by moderate CYP3A4 inhibitor(eg,erythromycin, diltiazem, verapamil). Caution with other antihypertensives.
Adverse Reaction(s):
Retrograde ejaculation, dizziness, diarrhea, orthostatic hypotension, headache, nasopharyngitis, nasal congestion. How Supplied:Caps 4mg—30, 100 8mg—30, 90
Last Updated:
4/24/2009