Choi Bo Ram, Kim Hye Kyung, Soni Kiran Kumar, Karna Keshab Kumar, Lee Sung Won, So Insuk, Park Jong Kwan
Department of Urology, Chonbuk National University, Jeonju, Republic of Korea.
Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea.
Drug Des Devel Ther. 2018 Jun 22;12:1855-1863. doi: 10.2147/DDDT.S164049. eCollection 2018.
We investigated the benefits of the BK agonist 4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (LDD175) combined with tamsulosin and finasteride, in a benign prostatic hyperplasia (BPH) rat model.
Castration was performed by bilateral orchiectomy under ketamine anesthesia. A rat model of BPH was established by daily intramuscular administration of testosterone propionate plus 17β-estradiol for 8 weeks. Model rats were administered combinations of 20 mg/kg LDD175, 0.01 mg/kg tamsulosin and 1 mg/kg finasteride once daily by oral gavage for 4 weeks from week 6 to 9 post-surgery. Intraurethral pressure induced by electrostimulation of the hypogastric nerve was measured at the end of administration. Body and genitourinary organ weights were recorded, serums were assayed for hormone concentrations, and tissues were subjected to histopathology, and analyses of α1-adrenoceptor mRNA and protein expression levels after treatment.
Combined LDD175, tamsulosin, and finasteride significantly decreased prostatic index, serum hormone levels, epithelial thickness, and prostate expression of α1-adrenoceptors in BPH model rats. The 3-drug combination was more effective than any other combination or LDD175 alone.
These results suggest that LDD175 addition to tamsulosin and finasteride may be beneficial for the treatment of BPH patients who do not respond to tamsulosin plus finasteride.
我们在良性前列腺增生（BPH）大鼠模型中研究了BK激动剂4-氯-7-三氟甲基-10H-苯并[4,5]呋喃并[3,2-b]吲哚-1-羧酸（LDD175）联合坦索罗辛和非那雄胺的益处。
在氯胺酮麻醉下通过双侧睾丸切除术进行去势。通过每日肌肉注射丙酸睾酮加17β-雌二醇8周建立BPH大鼠模型。从术后第6周开始至第9周，模型大鼠通过口服灌胃每日给予20 mg/kg LDD175、0.01 mg/kg坦索罗辛和1 mg/kg非那雄胺的组合，持续4周。给药结束时测量由电刺激腹下神经引起的尿道内压。记录体重和生殖泌尿器官重量，检测血清激素浓度，对组织进行组织病理学检查，并分析治疗后α1-肾上腺素能受体mRNA和蛋白表达水平。
联合使用LDD175、坦索罗辛和非那雄胺可显著降低BPH模型大鼠的前列腺指数、血清激素水平、上皮厚度以及前列腺α1-肾上腺素能受体的表达。三联药物组合比任何其他组合或单独使用LDD175更有效。
这些结果表明，在坦索罗辛和非那雄胺基础上加用LDD175可能对坦索罗辛加非那雄胺治疗无效的BPH患者有益。
