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文献概要
要旨 α1遮断薬は前立腺肥大症に対する第一選択薬である。しかし，下部尿路症状に対する新薬の開発とともに，前立腺肥大症に対する薬物治療の概念は変化しつつある。前立腺肥大症はQOL疾患であり，効率的なα1遮断薬の投与やα1遮断薬を中心とした併用療法が，オーダーメードに行われることが望まれる。また，症状に対する対処療法のみならず，病態を理解することによって疾患そのものへの新しい創薬開発が進められることが期待されている。本稿では，前立腺肥大症に対する薬物治療の現況と，高齢者QOL向上に向けたα1遮断薬を中心とした新たな治療のアルゴリズムの構築および創薬開発に向けた私たちの取り組みについて概説した。
参考文献
1）Hieble JP, Bylund DB, Clarke DE, et al：International Union of Pharmacology. X. Recommendation for nomenclature of alpha 1-adrenoceptors：consensus update. Pharmacol Rev 47：267-270, 1995
2）Price DT, Lefkowitz RJ, Caron MG, et al：Localization of mRNA for three distinct alpha 1-adrenergic receptor subtypes in human tissues：implications for human alpha-adrenergic physiology. Mol Pharmacol 45：171-175, 1994
3）Price DT, Schwinn DA, Lomasney JW, et al：Identification, quantification, and localization of mRNA for three distinct alpha 1 adrenergic receptor subtypes in human prostate. J Urol 150：546-551, 1993
4）Nasu K, Moriyama N, Kawabe K, et al：Quantification and distribution of alpha 1-adrenoceptor subtype mRNAs in human prostate：comparison of benign hypertrophied tissue and non-hypertrophied tissue. Br J Pharmacol 119：797-803, 1996
5）Kojima Y, Sasaki S, Shinoura H, et al：Quantification of alpha1-adrenoceptor subtypes by real-time RT-PCR and correlation with age and prostate volume in benign prostatic hyperplasia patients. Prostate 66：761-767, 2006
6）Kojima Y, Sasaki S, Imura M, et al：Correlation between expression of alpha1-adrenoceptor subtype mRNA and severity of lower urinary tract symptoms or bladder outlet obstruction in benign prostatic hyperplasia patients. BJU int 107：438-442, 2011
7）Hayase M, Hashitani H, Yanai Y, et al：Mechanisms of human prostate smooth muscle spontaneous contraction. J Urol 179（Suppl）：454-455, 2008
8）Lepor H, Zhang W, Kobayashi S, et al：A comparison of the binding and functional properties of alpha-1 adrenoceptors and area density of smooth muscle in the human, canine and rat prostates. J Pharmacol Exp Ther 270：722-727, 1994
9）Malloy BJ, Price DT, Price RR, et al：Alpha1-adrenergic receptor subtypes in human detrusor. J Urol 160：937-943, 1998
10）Kojima Y, Sasaki S, Oda N, et al：Prostate growth inhibition by subtype-selective alpha1-adrenoceptor antagonist naftopidil in benign prostatic hyperplasia. Prostate 69：1521-1528, 2009
11）Hampel C, Dolber PC, Smith MP, et al：Modulation of bladder alpha1-adrenergic receptor subtype expression by bladder outlet obstruction. J Urol 167：1513-1521, 2002
12）Takahashi S, Tajima A, Matsushima H, et al：Clinical efficacy of an alpha1A/D-adrenoceptor blocker（naftopidil）on overactive bladder symptoms in patients with benign prostatic hyperplasia. Int J Urol 13：15-20, 2006
13）Chen Q, Takahashi S, Zhong S, et al：Function of the lower urinary tract in mice lacking alpha1d-adrenoceptor. J Urol 174：370-374, 2005
14）Ishihama H, Momota Y, Yanase H, et al：Activation of alpha1D adrenergic receptors in the rat urothelium facilitates the micturition reflex. J Urol 175：358-364, 2006
15）Yanase H, Wang X, Momota Y, et al：The involvement of urothelial alpha1A adrenergic receptor in controlling the micturition reflex. Biomed Res 29：239-244, 2008
16）Domyancic AV and Morilak DA：Distribution of alpha1A adrenergic receptor mRNA in the rat brain visualized by in situ hybridization. J Comp Neurol 386：358-378, 1997
17）Sugaya K, Nishijima S, Miyazato M, et al：Effects of intrathecal injection of tamsulosin and naftopidil, alpha-1A and-1D adrenergic receptor antagonists, on bladder activity in rats. Neurosci Lett 328：74-76, 2002
18）Guimarães S and Moura D：Vascular adrenoceptors：an update. Pharmacol Rev 53：319-356, 2001
19）Rudner XL, Berkowitz DE, Booth JV, et al：Subtype specific regulation of human vascular alpha（1）-adrenergic receptors by vessel bed and age. Circulation 100：2336-2343, 1999
20）Michel MC：Alpha1-adrenoceptors and ejaculatory function. Br J Pharmacol 152：289-290, 2007
21）Hisasue S, Furuya R, Itoh N, et al：Ejaculatory disorder caused by alpha-1 adrenoceptor antagonists is not retrograde ejaculation but a loss of seminal emission. Int J Urol 13：1311-1316, 2006
22）Schwinn DA and Afshari NA：alpha（1）-Adrenergic receptor antagonists and the iris：new mechanistic insights into floppy iris syndrome. Surv Ophthalmol 51：501-512, 2006
23）Nakamura S, Taniguchi T, Suzuki F, et al：Evaluation of alpha1-adrenoceptors in the rabbit iris：pharmacological characterization and expression of mRNA. Br J Pharmacol 127：1367-1374, 1999
24）Bell CM, Hatch WV, Fischer HD, et al：Association between tamsulosin and serious ophthalmic adverse events in older men following cataract surgery. JAMA 301：1991-1996, 2009
25）Yamanishi T, Yasuda K, Kamai T, et al：Single-blind, randomized controlled study of the clinical and urodynamic effects of an a-blocker（naftopidil）and phytotherapy（eviprostat）in the treatment of benign prostatic hyperplasia. Int J Urol 11：501-509, 2004
26）Ikemoto I, Kiyota H, Ohishi Y, et al：Usefulness of tamsulosin hydrochloride and naftopidil in patients with urinary disturbances caused by benign prostatic hyperplasia：a comparative, randomized, two-drug crossover study. Int J Urol 10：587-594, 2003
27）Lepor H, Auerbach S, Puras-Baez A, et al：A randomized, placebo-controlled multicenter study of the efficacy and safety of terazosin in the treatment of benign prostatic hyperplasia. J Urol 148：1467-1474, 1992
28）Fawzy A, Braun K, Lewis GP, et al：Doxazosin in the treatment of benign prostatic hyperplasia in normotensive patients：a multicenter study. J Urol 154：105-109, 1995
29）Gillenwater JY, Conn RL, Chrysant SG, et al：Doxazosin for the treatment of benign prostatic hyperplasia in patients with mild to moderate essential hypertension：a double-blind, placebo-controlled, dose-response multicenter study. J Urol 154：110-115, 1995
30）Chapple CR, Wyndaele JJ, Nordling J, et al：Tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist：a meta-analysis of two randomized, placebo-controlled, multicentre studies in patients with benign prostatic obstruction（symptomatic BPH）. European Tamsulosin Study Group. Eur Urol 29：155-167, 1996
31）Lepor H：Phase Ⅲ multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin Investigator Group. Urology 51：892-900, 1998
32）Yasuda K, Yamanishi T, Tojo M, et al：Effect of naftopidil on urethral obstruction in benign prostatic hyperplasia：assessment by urodynamic studies. Prostate 25：46-52, 1994
33）Lepor H：Long-term efficacy and safety of terazosin in patients with benign prostatic hyperplasia. Terazosin Research Group. Urology 45：406-413, 1995
34）Narayan P, Evans CP and Moon T：Long-term safety and efficacy of tamsulosin for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia. J Urol 170：498-502, 2003
35）Kawabe K, Yoshida M and Homma Y；Silodosin Clinical Study Group：Silodosin, a new alpha1A-adrenoceptor-selective antagonist for treating benign prostatic hyperplasia：results of a phase Ⅲ randomized, placebo-controlled, double-blind study in Japanese men. BJU Int 98：1019-1024, 2006
36）前立腺肥大症診療ガイドライン．日本泌尿器科学会，東京，2011
37）Kojima Y, Sasaki S, Imura M, et al：Tamsulosin reduces nighttime urine production in benign prostatic hyperplasia patients with nocturnal polyuria：a prospective open-label long-term study using frequency-volume chart. Neurourol Urodyn 31：80-85, 2012
38）McConnell JD, Roehrborn CG, Bautista OM, et al；Medical Therapy of Prostatic Symptoms（MTOPS）Research Group：The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 349：2387-2398, 2003
39）Kojima Y, Hayase M, Sasaki S, et al：New pharmacologic horizons in the treatment of benign prostatic hyperplasia. Curr Drug Ther 5：262-270, 2010
40）Takei R, Ikegaki I, Shibata K, et al：Naftopidil, a novel alpha1-adrenoceptor antagonist, displays selective inhibition of canine prostatic pressure and high affinity binding to cloned human alpha1-adrenoceptors. Jpn J Pharmacol 79：447-454, 1999
41）Kojima Y, Kubota Y, Sasaki S, et al：Translational pharmacology in aging men with benign prostatic hyperplasia：molecular and clinical approaches to alpha1-adrenoceptors. Curr Aging Sci 2：223-239, 2009
42）Kojima Y, Sasaki S, Kubota Y, et al：Up-regulation of α1a and α1d-adrenoceptors in the prostate by administration of subtype selective α1-adrenoceptor antagonist tamsulosin in patients with benign prostatic hyperplasia. J Urol 186：1530-1536, 2011
43）Kojima Y, Sasaki S, Kubota Y, et al：Expression of alpha1-adrenoceptor subtype mRNA as a predictor of the efficacy of subtype selective alpha1-adrenoceptor antagonists in the management of benign prostatic hyperplasia. J Urol 179：1040-1046, 2008
44）Roehrborn CG, Siami P, Barkin J, et al；CombAT Study Group：The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia：4-year results from the CombAT study. Eur Urol 57：123-131, 2011
45）Kojima Y, Sasaki S, Shinoura H, et al：Change of expression levels of alpha1-Adrenoceptor subtypes by administration of alpha1d-adrenoceptor-subtype-selective antagonist naftopidil in benign prostate hyperplasia patients. Prostate 67：1285-1292, 2007
46）Evans WE and McLeod HL：Pharmacogenomics-drug disposition, drug targets, and side effects. N Engl J Med 348：538-549, 2003
47）Meyer UA：Pharmacogenetics and adverse drug reactions. Lancet 356：1667-1671, 2000
48）Severino G and Del Zompo M：Adverse drug reactions：role of pharmacogenomics. Pharmacol Res 49：363-373, 2004
49）Nebert DW, Jorge-Nebert L and Vesell ES：Pharmacogenomics and“individualized drug therapy”：high expectations and disappointing achievements. Am J Pharmacogenomics 3：361-370, 2003
50）Kojima Y, Sasaki S, Hayashi Y, et al：Subtypes of alpha1-adrenoceptors in BPH：future prospects for personalized medicine. Nature Clin Pract Urol 6：44-53, 2009
51）Andriole GL, Bostwick DG, Brawley OW, et al；REDUCE Study Group：Effect of dutasteride on the risk of prostate cancer. N Engl J Med 362：1192-202, 2010
52）Kaplan SA, Roehrborn CG, Rovner ES, et al：Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder：a randomized controlled trial. JAMA 296：2319-2328, 2006
53）Yamaguchi O, Kakizaki H, Homma Y, et al；ASSIST Study Group：Solifenacin as add-on therapy for overactive bladder symptoms in men treated for lower urinary tract symptoms：ASSIST, randomized controlled study. Urology 78：126-133, 2011
54）Nishizawa O, Yamaguchi O, Takeda M, et al：Randomized controlled trial to treat benign prostatic hyperplasia with overactive bladder using an alpha-blocker combined with anticholinergics. LUTS 3：29-35, 2011
55）McNeal J：Pathology of benign prostatic hyperplasia：insight into etiology. Urol Clin North Am 17：477-486, 1990
56）Lee KL and Peehl DM：Molecular and cellular pathogenesis of benign prostatic hyperplasia. J Urol 172：1784-1791, 2004
57）Mori F, Oda N, Sakuragi M, et al：New histopathological experimental model for benign prostatic hyperplasia：stromal hyperplasia in rats. J Urol 181：890-898, 2009
58）Ropiquet F, Giri D, Lamb DJ, et al：FGF7 and FGF2 are increased in benign prostatic hyperplasia and are associated with increased proliferation. J Urol 162：595-599, 1999
59）Kyprianou N, Tu H and Jacobs SC：Apoptotic versus proliferative activities in human benign prostatic hyperplasia. Hum Pathol 27：668-675, 1996
60）Giri D and Ittmann M：Interleukin-1alpha is a paracrine inducer of FGF7, a key epithelial growth factor in benign prostatic hyperplasia. Am J Pathol 157：249-255, 2000
61）Levitt JM, Song W, Guariguata L, et al：Up-regulation of a family of interferon-inducible inflammatory chemokines in benign prostatic hyperplasia. J Urol 175：468, 2006
62）Kramer G, Steiner GE, Handisurya A, et al：Increased expression of lymphocyte-derived cytokines in benign hyperplastic prostate tissue, identification of the producing cell types, and effect of differentially expressed cytokines on stromal cell proliferation. Prostate 52：43-58, 2002
63）Kramer G and Marberger M：Could inflammation be a key component in the progression of benign prostatic hyperplasia. Curr Opin Urol 16：25-29, 2006
64）Fromont G, Chene L, Latil A, et al：Molecular profiling of benign prostatic hyperplasia using a large scale real-time reverse transcriptase-polymerase chain reaction approach. J Urol 172：1382-1385, 2004
65）Imura M, Kojima Y, Kubota Y, et al：Regulation of cell proliferation through a KIT-mediated mechanism in benign prostatic hyperplasia. Prostate 72：1506-1513, 2012
66）Kubota Y, Hashitani H, Shirasawa N, et al：Altered distribution of interstitial cells in the guinea pig bladder following bladder outlet obstruction. Neurourol Urodyn 27：330-340, 2008
67）Kubota Y, Kojima Y, Shibata Y, et al：Role of KIT-positive interstitial cells of Cajal in the urinary bladder and possible therapeutic target for overactive bladder. Adv Urol 2011：816342, 2011
68）Ohya S, Niwa S, Kojima Y, et al：Intermediate-conductance Ca2＋-activated K＋ channel, KCa3.1, as a novel therapeutic target for benign prostatic hyperplasia. J Pharmacol Exp Ther 338：528-536, 2011
69）Niwa S, Ohya S, Kojima Y, et al：Down-regulation of the large-conductance Ca（2＋）-activated K＋ channel, K（Ca）1.1 in the prostatic stromal cells of benign prostate hyperplasia. Biol Pharm Bull 35：737-744, 2012
70）Prakash K, Pirozzi G, Elashoff M, et al：Symptomatic and asymptomatic benign prostatic hyperplasia：molecular differentiation by using microarrays. Proc Natl Acad Sci USA 99：7598-7603, 2002
71）Cannon GW and Getzenberg RH：A serum-based assay for JM-27 can identifynmen with symptomatic benign prostatic hyperplasia. J Urol 175：436, 2006
72）Walden PD, Lefkowitz GK, Ficazzola M, et al：Identification of genes associated with stromal hyperplasia and glandular atrophy of the prostate by mRNA differential display. Exp Cell Res 245：19-26, 1998
73）Kojima Y, MizunoK, Sasaki S, et al：Gene expression profiling and functional network analysis of benign prostatic hyperplasia model rat. J Urol 187（Suppl）：636-637, 2012
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