Abstract
Lower urinary tract disorders include disorders affecting continence (stress urinary incontinence, urge urinary incontinence, and benign prostatic hyperplasia) and male erectile dysfunction. Although none of these conditions are fatal, they affect overall quality of life. Throughout modern medicine the treatment of these conditions was limited to psychological counseling or surgical intervention. In recent years, research defining the physiological mechanisms of continence and male sexual function has aided in the pharmacologic design of approaches to these conditions. These agents can act both centrally or on the peripheral genitourinary smooth muscle to alleviate disease symptoms. Incontinence is primarily treated with agents that act directly on the bladder smooth muscle such as muscarinic antagonists. However, afferent blockade to attenuate the spinalbulbospinal reflex pathway including mixed norepinephrine/serotonin reuptake inhibitors may provide a key breakthrough. Erectile dysfunction treatment has been revolutionized via the discovery of the nitric oxide pathway and phosphodiesterase 5 inhibitors. New peripheral targets as well as centrally acting agents represent potential emerging therapies. In this review, the pharmacologic basis of treatment of these disorders is discussed with special emphasis on emerging new therapeutics.
Footnotes
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ABBREVIATIONS. LUTD, lower urinary tract disorder; BPH, benign prostatic hyperplasia; CGRP, calcitonin gene-related peptide; CNS, central nervous system; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; 5-HT, 5-hydroxytryptamine; ET, endothelin; FDA, U.S. Food and Drug Administration; LUTS, lower urinary tract symptoms; MED, male erectile dysfunction; mAChR, muscarinic acetylcholine receptors; α-MSH, α-melanocyte-stimulating hormone; NO, nitric oxide; PACAP, pituitary adenylate cyclase-activating polypeptide; PDE, phosphodiesterase; PGE, prostaglandin E; sGC, soluble guanylate cyclase; SUI, stress urinary incontinence; UUI, urge urinary incontinence; VIP, vasoactive intestinal peptide; A-278637, (–)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide; A-350619, 3-[2-(4-chlorophenylsulfanyl)phenyl]-N-(4-dimethylaminobutyl)acrylamide]; ABT-866, N-[3-(1H-imidazol-4-ylmethyl)phenyl] ethanesulfonamide; BAY41-2272, 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4-ylamine; BMS-193884, 3-(N-(3,4-dimethyl-5-isoxazolyl)-4′-(2-oxazolyl)[1,1′-biphenyl]-2-sulfonamide; NAD-299, (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate; SR48968, (S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenylbutyl] benzamide; TAK-637, (aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g] [1,7]naphthyridine-6,13-dione; THIQ, N-[(3R)-1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl]-2-oxoethylamine; WAY100635, N-(2-(1-(4-(2-methoxyphenyl)piperazin-yl))ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride; WAY133537, 1,2-diaminocyclobutene-3,4-dione((R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile; Y-27632, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide; ZD6169, N-(4-benzoylphenyl)-3,3,3-trifluro-2-hydroxy-2-methylpropionamine.
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DOI: 10.1124/jpet.102.034991.
- Received August 22, 2003.
- Accepted December 16, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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