Additive effect of oral LDD175 to tamsulosin and finasteride in a benign prostate hyperplasia rat model
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 anesthesi...
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Published in | Drug design, development and therapy Vol. 12; pp. 1855 - 1863 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
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Dove Medical Press Limited
2018
Taylor & Francis Ltd Dove Medical Press |
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Abstract | 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. |
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AbstractList | Objective: We investigated the benefits of the BKCa 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. Materials and methods: 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. Results: 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. Conclusion: 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. Objective: We investigated the benefits of the B[K.sub.Ca] 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. Materials and methods: Castration was performed by bilateral orchiectomy under ketamine anesthesia. A rat model of BPH was established by daily intramuscular administration of testosterone propionate plus 17[beta]-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 [alpha]1-adrenoceptor mRNA and protein expression levels after treatment. Results: Combined LDD175, tamsulosin, and finasteride significantly decreased prostatic index, serum hormone levels, epithelial thickness, and prostate expression of [alpha]1-adrenoceptors in BPH model rats. The 3-drug combination was more effective than any other combination or LDD175 alone. Conclusion: 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. Keywords: [alpha]1-adrenoceptors, [alpha]1-adrenergic receptor antagonists, benzofuroindole, intraurethral pressure, 5[alpha]-reductase inhibitors Bo Ram Choi,1-3 Hye Kyung Kim,4,* Kiran Kumar Soni,1-3 Keshab Kumar Karna,1-3 Sung Won Lee,5 Insuk So,6 Jong Kwan Park1-3,* 1Department of Urology, Chonbuk National University, Jeonju, Republic of Korea; 2Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea; 3Clinical Trial Center of Medical Device of Chonbuk National University, Jeonju, Republic of Korea; 4College of Pharmacy, Kyungsung University, Busan, Republic of Korea; 5Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 6Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea *These authors contributed equally to this work Objective: We investigated the benefits of the BKCa 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.Materials and methods: 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.Results: 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.Conclusion: 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. Keywords: α1-adrenoceptors, α1-adrenergic receptor antagonists, benzofuroindole, intraurethral pressure, 5α-reductase inhibitors 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. OBJECTIVEWe investigated the benefits of the BKCa 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. MATERIALS AND METHODSCastration 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. RESULTSCombined 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. CONCLUSIONThese 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. |
Audience | Academic |
Author | Choi, Bo Ram Karna, Keshab Kumar Soni, Kiran Kumar So, Insuk Kim, Hye Kyung Lee, Sung Won Park, Jong Kwan |
AuthorAffiliation | 1 Department of Urology, Chonbuk National University, Jeonju, Republic of Korea 3 Clinical Trial Center of Medical Device of Chonbuk National University, Jeonju, Republic of Korea 4 College of Pharmacy, Kyungsung University, Busan, Republic of Korea 2 Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea 5 Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 6 Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea |
AuthorAffiliation_xml | – name: 2 Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea – name: 1 Department of Urology, Chonbuk National University, Jeonju, Republic of Korea – name: 6 Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea – name: 3 Clinical Trial Center of Medical Device of Chonbuk National University, Jeonju, Republic of Korea – name: 4 College of Pharmacy, Kyungsung University, Busan, Republic of Korea – name: 5 Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea |
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CitedBy_id | crossref_primary_10_3390_nu11010101 crossref_primary_10_1038_s41391_020_00277_1 crossref_primary_10_3390_antiox11061149 crossref_primary_10_1016_j_biomaterials_2021_120857 crossref_primary_10_1096_fj_202000737RRR |
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Keywords | 5α-reductase inhibitors α1-adrenergic receptor antagonists intraurethral pressure benzofuroindole α1-adrenoceptors |
Language | English |
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Snippet | 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... Objective: We investigated the benefits of the B[K.sub.Ca] agonist 4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (LDD175)... Objective: We investigated the benefits of the BKCa agonist 4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (LDD175) combined with... OBJECTIVEWe investigated the benefits of the BKCa agonist 4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (LDD175) combined with... Bo Ram Choi,1-3 Hye Kyung Kim,4,* Kiran Kumar Soni,1-3 Keshab Kumar Karna,1-3 Sung Won Lee,5 Insuk So,6 Jong Kwan Park1-3,* 1Department of Urology, Chonbuk... |
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SubjectTerms | 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 |
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Title | Additive effect of oral LDD175 to tamsulosin and finasteride in a benign prostate hyperplasia rat model |
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