Additive effect of oral LDD175 to tamsulosin and finasteride in a benign prostate hyperplasia rat model

• Published in: Drug design, development and therapy Vol. 12; pp. 1855 - 1863
• Main Authors: Choi, Bo Ram, Kim, Hye Kyung, Soni, Kiran Kumar, Karna, Keshab Kumar, Lee, Sung Won, So, Insuk, Park, Jong Kwan
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 2018; Taylor & Francis Ltd; Dove Medical Press
• Subjects: 17β-Estradiol; 5α-reductase inhibitors; Abdomen; Administration, Oral; Adrenergic receptors; Anesthesia; Animals; Aprotinin; Benign; Benzofurans - administration & dosage; benzofuroindole; Biomedical research; Bladder; Carboxylic acids; Castration; Combination drug therapy; Disease Models, Animal; Drug Therapy, Combination; EDTA; Estradiol; Estrogens; Finasteride; Finasteride - administration & dosage; Gene expression; Histochemistry; Histopathology; Hormones; Hyperplasia; Indoles; Indoles - administration & dosage; intraurethral pressure; Ketamine; Laboratory animals; Male; Messenger RNA; mRNA; Original Research; Phenols (Class of compounds); Physiology; Polyethylene; Pressure transducers; Propionic acid; Prostate; Prostatic hyperplasia; Prostatic Hyperplasia - blood; Prostatic Hyperplasia - drug therapy; Rats; Rats, Sprague-Dawley; Receptors (physiology); Receptors, Adrenergic, alpha-1 - analysis; Receptors, Adrenergic, alpha-1 - genetics; Retirement benefits; RNA; Rodents; Serum; Sex hormones; Smooth muscle; Sulfonamides - administration & dosage; Surgery; Tamsulosin; Testosterone; Testosterone - blood; Testosterone propionate; Urogenital system; Urology; α1-adrenergic receptor antagonists; α1-adrenoceptors; United States > US; South Korea; Japan; 5α-reductase inhibitors; α1-adrenergic receptor antagonists; intraurethral pressure; benzofuroindole; α1-adrenoceptors
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S164049

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.