Emerging drugs to target lower urinary tract symptomatology (LUTS)/benign prostatic hyperplasia (BPH): focus on the prostate
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The benign prostatic syndrome, comprising lower urinary tract symptomatology secondary to benign prostatic hyperplasia/enlargement, represents a major health care issue in westernized countries. The pharmacological management involves alpha-adrenoceptor antagonists, intervention into the hormonal control of prostate growth using inhibitors of the enzyme 5-alpha-reductase, and stimulation of the nitric oxide/cyclic GMP pathway by tadalafil, an inhibitor of the phosphodiesterase type 5.
This review summarizes the achievements which have been made in the development of drug candidates assumed to offer opportunities as beneficial treatment options in the management of the benign prostatic syndrome.
A review of the literature has revealed that the line of development is focusing on drugs interfering with peripheral neuromuscular/neuronal mechanisms (nitric oxide donor drugs, agonists/antagonists of endogenous peptides, botulinum toxin, NX-1207), the steroidal axis (cetrorelix) or the metabolic turn-over (lonidamine), as well as the combination of drugs already established in the treatment of lower urinary tract symptomatology/benign prostatic hyperplasia (phosphodiesterase 5 inhibitor plus alpha-adrenoceptor antagonist).
Many research efforts have provided the basis for the development of new therapeutic modalities for the management of lower urinary tract dysfunctions, some of which might be offered to the patients in the near future.
KeywordsLower urinary tract symptoms (LUTS) Benign prostatic hyperplasia (BPH) Pharmacotherapy
SÜ: data collection, manuscript writing. GTK: data collection, manuscript writing. DT: data collection/analysis, manuscript editing. AS: data collection, manuscript writing. AB: data collection/analysis. MAK: manuscript editing.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest and have received no payment for the preparation of the manuscript.
- 1.Guess HA (1995) Epidemiology and natural history of benign prostatic hyperplasia. Urol Clin North Am 22:247–261Google Scholar
- 8.van Kerrebroeck P, Chapple C, Drogendijk T, Klaver M, Sokol R, Speakman M, Traudtner K, Drake MJ (for the NEPTUNE Study Group) (2013) Combination therapy with solifenacin and tamsulosin oral controlled absorption system in a single tablet for lower urinary tract symptoms in men: efficacy and safety results from the randomised controlled NEPTUNE trial. Eur Urol 64:1003–1012CrossRefGoogle Scholar
- 9.Drake MJ, Oelke M, Snijder R, Klaver M, Traudtner K, van Charldorp K, Bongaerts D, van Kerrebroeck P (2017) Incidence of urinary retention during treatment with singe tablet combinations of solifenacin + tamsulosin OCAS™ for up to 1 year in adult men with both storage and voiding LUTS: a subanalysis of the NEPTUNE/NEPTUNE II randomized controlled studies. PLoS One 12:e0170726CrossRefGoogle Scholar
- 12.Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, Palacios JM, Vasylyev A, Manyak MJ (2015) Efficacy and safety of a fixed-dose combination of dutasteride and tamsulosin treatment (DUODART) compared with watchful waiting with initiation of tamsulosin therapy if symptoms do not improve, both provided with lifestyle advice, in the management of treatment-naïve men with moderately symptomatic benign prostatic hyperplasia: 2-year CONDUCT study results. BJU Int 16:450–459CrossRefGoogle Scholar
- 15.Porst H, Kim ED, CasabE AR et al (2011) Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial. Eur Urol 60:1105–1113CrossRefGoogle Scholar
- 16.Porst H, Oelke M, Goldfischer ER, Cox D, Watts S, Dey D, Viktrup L (2013) Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multi-national, randomized, placebo-controlled clinical studies. Urology 82:667–673CrossRefGoogle Scholar
- 17.Dmochowski R, Roehrborn C, Klise S, Xu L, Kaminetsky J, Kraus S (2013) Urodynamic effects of once daily tadalafil in men with lower urinary tract symptoms secondary to clinical benign prostatic hyperplasia: a randomized, placebo controlled 12-week clinical trial. J Urol 189(Suppl 1):S135–S140Google Scholar
- 19.Sharma M, Chadha R, Dhingra N (2017) Phytotherapeutic agents for benign prostatic hyperplasia: an overview. Mini Rev Med Chem 17:1346–1363Google Scholar
- 23.Tsuritani S, Nozaki T, Okumura A, Kimura H, Kazama T (2010) A prospective, randomized, controlled, multicenter study of naftopidil for treatment of male lower urinary tract symptoms associated with benign prostatic hyperplasia: 75 mg once daily in the evening compared to 25 mg thrice daily. Urol Int 85:80–87CrossRefGoogle Scholar
- 27.Chang RS, Chen TB, O’Malley SS, Pettibone DJ, DiSalvo J, Francis B, Bock MG, Freidinger R, Nagarathnam D, Miao SW, Shen Q, Lagu B, Murali Dhar TG, Tyagarajan S, Marzabadi MR, Wong WC, Gluchowski C, Forray C (2000) In vitro studies on L-771.688 (SNAP 6383), a new potent and selective alpha1A-adrenoceptor antagonist. Eur J Pharmacol 409:301–312CrossRefGoogle Scholar
- 28.Ford AP, Arredondo NF, Blue DR Jr, Bonhaus DW, Jasper J, Kava MS, Lesnick J, Pfister JR, Shieh IA, Vimont RL, Williams TJ, McNeal JE, Stamey TA, Clarke DE (1996) RS-17053 (N-[2-(2-cyclopropyl-methoxyphenoxy)ethyl]-5-chloro-alpha, alpha-dimethyl-1H-indole-3-ethanamine hydrochloride), a selective alpha1A-adrenoceptor antagonist, displays low affinity for functional alpha1-adrenoceptors in human prostate: implications for adrenoceptor classification. Mol Pharmacol 49:209–215Google Scholar
- 34.Hennenberg M, Schott M, Kan A, Keller P, Tamalunas A, Ciotkowska A, Rutz B, Wang Y, Strittmatter F, Herlemann A, Yu Q, Stief CG, Gratzke C (2016) Inhibition of adrenergic and non-adrenergic smooth muscle contraction in the human prostate by the phosphodiesterase 10-selective inhibitor TC-E 5005. Prostate 76:1364–1374CrossRefGoogle Scholar
- 36.Kim SW, Park NC, Lee SW, Yang DY, Park JK, Moon DG, Yang SK, Lee SW, Moon KH, Ahn TY, Kim SW, Park K, Min KS, Ryu JK, Son H, Jung J, Hyun JS (2017) Efficacy and safety of a fixed-dose combination therapy of tamsulosin and tadalafil for patients with lower urinary tract symptoms and erectile dysfunction: results of a randomized, double-blinded, active-controlled trial. J Sex Med 14:1018–1027CrossRefGoogle Scholar
- 38.Fawzi A, Kamel M, Salem E, Desoky E, Omran M, Elgalaly H, Sakr A, Maarouf A, Khalil S (2016) Sildenafil citrate in combination with tamsulosin versus tamsulosin monotherapy for management of male lower urinary tract symptoms due to benign prostatic hyperplasia: a randomised, double-blind, placebo-controlled trial. Arab J Urol 15:53–59CrossRefGoogle Scholar
- 39.Gacci M, Vittori G, Tosi N, Siena G, Rossetti MA, Lapini A, Vignozzi L, Serni S, Maggi M, Carini M (2012) A randomized, placebo-controlled study to assess safety and efficacy of vardenafil 10 mg and tamsulosin 0.4 mg vs. tamsulosin 0.4 mg alone in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Sex Med 9:1624–1633CrossRefGoogle Scholar
- 43.Kedia GT, Ückert S, Kedia M, Truss MC, Chigogidze T, Jonas U, Managadze LG (2006) In vitro effects of cyclic AMP- and cyclic GMP-stimulating drugs on the relaxation of the prostate smooth muscle tissue contraction induced by endothelin-1. Georgian Med News 131:7–13Google Scholar
- 45.Heuer O, Ückert S, Dobler G, Klocker H, Stief CG, Truss MC, Bartsch G, Jonas U (2004) Effects of phosphodiesterase inhibitors and nitric oxide donors on cultured human prostatic smooth muscle cells. Eur Urol 3(Suppl 2):19 (Abstract, presented at the 19th Congress of the European Association of Urology (EAU), Vienna, Austria, 24-March to 27-March 2004) CrossRefGoogle Scholar
- 48.Fernandes VS, Martínez-Sáenz A, Recio P, Ribeiro AS, Sánchez A, Martínez MP, Martínez AC, García-Sacristán A, Orensanz LM, Prieto D, Hernández M (2011) Mechanisms involved in nitric oxide-induced vasorelaxation in porcine prostatic arteries. Naunyn Schmiedebergs Arch Pharmacol 384:245–253CrossRefGoogle Scholar
- 49.Roshani A, Khosropanah I, Salehi M, Kamran AN (2010) Effects of isosorbide dinitrate on the urinary flow rate in patients with benign prostatic hyperplasia. Urol J 7:183–187Google Scholar
- 55.Rozsa B, Nadji M, Schally AV, Dezso B, Flasko T, Toth G, Mile M, Block NL, Halmos G (2011) Receptors for luteinizing hormone-releasing hormone (LHRH) in benign prostatic hyperplasia (BPH) as potential molecular targets for therapy with LHRH antagonist cetrorelix. Prostate 71:445–452CrossRefGoogle Scholar
- 56.Rick FG, Schally AV, Block NL, Halmos G, Perez R, Fernandez JB, Vidaurre I, Szalontay L (2001) LHRH antagonist Cetrorelix reduces prostate size and gene expression of proinflammatory cytokines and growth factors in a rat model of benign prostatic hyperplasia. Prostate 71:736–747CrossRefGoogle Scholar
- 63.Sacco E, Bientinesi R, Marangi F, Totaro A, D’Addessi A, Racioppi M, Pinto F, Vittori M, Bassi P (2012) Patient-reported outcomes in men with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) treated with intraprostatic onabotulinumtoxin A: 3 month results of a prospective single-armed cohort study. BJU Int 110(11):E837–E844CrossRefGoogle Scholar
- 67.Morelli A, Vignozzi L, Filippi S, Vannelli GB, Ambrosini S, Mancina R, Crescioli C, Donati S, Fibbi B, Colli E, Adorini L, Maggi M (2007) BXL-628, a vitamin D receptor agonist effective in benign prostatic hyperplasia treatment, prevents RhoA activation and inhibits RhoA/Rho kinase signaling in rat and human bladder. Prostate 67:234–247CrossRefGoogle Scholar
- 68.Penna G, Fibbi B, Amuchastegui S, Corsiero E, Laverny G, Silvestrini E, Chavalmane A, Morelli A, Sarchielli E, Vannelli GB, Gacci M, Colli E, Maggi M, Adorini L (2009) The vitamin D receptor agonist elocalcitol inhibits IL-8-dependent benign prostatic hyperplasia stromal cell proliferation and inflammatory response by targeting the RhoA/Rho kinase and NF-kappa B pathways. Prostate 69:480–493CrossRefGoogle Scholar
- 70.Colli E, Rigatti P, Montorsi F, Artibani W, Petta S, Mondaini N, Scarpa R, Usai P, Olivieri L, Maggi M (for the BPH Italian Study Group) (2006) BXL-628, a novel vitamin D3 analog arrests prostate growth in patients with benign prostatic hyperplasia: a randomized clinical trial. Eur Urol 49:82–86CrossRefGoogle Scholar
- 72.van Kerrebroeck P (2011) Nocturia: current status and future perspectives. Curr Opin Obstet Gynecol 23:376–385Google Scholar
- 80.Palea S, Corsi M, Artibani W, Ostardo E, Pietra C (1996) Pharmacological characterization of tachykinin NK2 receptors on isolated human urinary bladder, prostatic urethra and prostate. J Pharmacol Exp Ther 277:700–705Google Scholar
- 88.Kunit T, Lusuardi L (2014) An evidence-based review of NX1207 and its potential in the treatment of benign prostatic hyperplasia. Res Rep Urol 6:67–70Google Scholar
- 89.Shore N, Tutrone R, Efros M, Bidair M, Wachs B, Kalota S, Freedman S, Bailen J, Levin R, Richardson S, Kaminetsky J, Snyder J, Shepard B, Goldberg K, Hay A, Gange S, Grunberger I (2018) Fexapotide triflutate: results of long-term safety and efficacy trials of a novel injectable therapy for symptomatic prostate enlargement. World J Urol 36:801–809CrossRefGoogle Scholar
- 90.Brawer MK (2005) Lonidamine: basic science and rationale for treatment of prostatic proliferative disorders. Rev Urol 7(Suppl 7):S21–S526Google Scholar
- 91.Nath K, Guo L, Nancolas B, Nelson DS, Shestov AA, Lee SC, Roman J, Zhou R, Leeper DB, Halestrap AP, Blair IA, Glickson JD (2016) Mechanism of anti-neoplastic activity of lonidamine. Biochim Biophys Acta 1866:151–162Google Scholar
- 92.Roehrborn CG (2005) The development of lonidamine for benign prostatic hyperplasia and other indications. Rev Urol 7(Suppl 7):S12–S620Google Scholar
- 93.Ditonno P, Battaglia M, Selvaggio O, Garofalo L, Lorusso V, Selvaggi FP (2005) Clinical evidence supporting the role of lonidamine for the treatment of BPH. Rev Urol 7(Suppl 7):S27–S533Google Scholar