Emerging drugs to target lower urinary tract symptomatology (LUTS)/benign prostatic hyperplasia (BPH): focus on the prostate

Abstract

Objectives

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.

Methods

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.

Results

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).

Conclusion

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.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Guess HA (1995) Epidemiology and natural history of benign prostatic hyperplasia. Urol Clin North Am 22:247–261

    CAS  PubMed  Google Scholar 

  2. 2.

    Paolone DR (2010) Benign prostatic hyperplasia. Clin Geriatr Med 26:223–239

    PubMed  Article  Google Scholar 

  3. 3.

    Chughtai B, Forde JC, Thomas DD, Laor L, Hossack T, Woo HH, Te AE, Kaplan SA (2016) Benign prostatic hyperplasia. Nat Rev Dis Primers 2:16031

    PubMed  Article  Google Scholar 

  4. 4.

    Andersson KE (2002) Alpha-adrenoceptors and benign prostatic hyperplasia: basic principles for treatment with alpha-adrenoceptor antagonists. World J Urol 19:390–396

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Djavan B, Chapple C, Milani S, Marberger M (2004) State of the art on the efficacy and tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Urology 64:1081–1088

    PubMed  Article  Google Scholar 

  6. 6.

    Lepor H (2016) Alpha-blockers for the treatment of benign prostatic hyperplasia. Urol Clin North Am 43:311–323

    PubMed  Article  Google Scholar 

  7. 7.

    Roehrborn CG, Schwinn DA (2004) Alpha1-adrenergic receptor and their inhibitors in lower urinary tract symptoms an benign prostatic hyperplasia. J Urol 171:1029–1035

    CAS  PubMed  Article  Google Scholar 

  8. 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 64:1003–1012

    Article  CAS  Google Scholar 

  9. 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:e0170726

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. 10.

    Naslund MJ, Miner M (2007) A review of the clinical efficacy and safety of 5-alpha-reductase inhibitors for the enlarged prostate. Clin Ther 29:17–25

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Nickel JC, Gilling P, Tammela TL, Morrill B, Wilson TH, Rittmaster RS (2011) Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS). BJU Int 108:388–394

    CAS  PubMed  Article  Google Scholar 

  12. 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 16:450–459

    Article  CAS  Google Scholar 

  13. 13.

    de Nunzio C, Presicce F, Tubaro A (2016) Combination therapies for improved management of lower urinary tract symptoms/benign prostatic hyperplasia. Drugs Today (Barcelona) 52:501–517

    Article  Google Scholar 

  14. 14.

    Ozdemir I, Bozkurt O, Demir O, Aslan G, Esen AA (2009) Combination therapy with doxazosin and tenoxicam for the management of lower urinary tract symptoms. Urology 74:431–435

    PubMed  Article  Google Scholar 

  15. 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 60:1105–1113

    CAS  PubMed  Article  Google Scholar 

  16. 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 82:667–673

    PubMed  Article  Google Scholar 

  17. 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–S140

    CAS  PubMed  Google Scholar 

  18. 18.

    Dedhia RC, McVary KT (2008) Phytotherapy for lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol 179:2119–2125

    PubMed  Article  Google Scholar 

  19. 19.

    Sharma M, Chadha R, Dhingra N (2017) Phytotherapeutic agents for benign prostatic hyperplasia: an overview. Mini Rev Med Chem 17:1346–1363

    CAS  PubMed  Google Scholar 

  20. 20.

    de Mey C (1998) Cardiovascular effects of alpha-blockers used for the treatment of symptomatic BPH: impact on safety and well-being. Eur Urol 34(Suppl 2):18–28 (Erratum in: Eur Urol (1998) 34:527)

    PubMed  Article  Google Scholar 

  21. 21.

    Castiglione F, Benigni F, Briganti A, Salonia A, Villa L, Nini A, Di Trapani E, Capitanio U, Hedlund P, Montorsi F (2014) Naftopidil for the treatment of benign prostate hyperplasia: a systematic review. Curr Med Res Opin 30:719–732

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Perumal C, Chowdhury PS, Ananthakrishnan N, Nayak P, Gurumurthy S (2015) A comparison of the efficacy of naftopidil and tamsulosin hydrochloride in medical treatment of benign prostatic enlargement. Urol Ann 7:74–78

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. 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 85:80–87

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Yokoyama T, Kumon H, Nasu Y, Takamoto H, Watanabe T (2006) Comparison of 25 and 75 mg/day naftopidil for lower urinary tract symptoms associated with benign prostatic hyperplasia: a prospective, randomized controlled study. Int J Urol 13:932–938

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Yasuda K, Yamanishi T, Tojo M, Nagashima K, Akimoto S, Shimazaki J (1994) Effect of naftopidil on urethral obstruction in benign prostatic hyperplasia: assessment by urodynamic studies. Prostate 25:46–52

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Tanaka T, Kuratsukuri K, Yoshimura R, Adachi T, Yamaguchi T, Ohmachi T, Yamamoto S, Nakamura T, Tamada S, Nakatani T (2015) Efficacy of naftopidil for nocturia in male patients with lower urinary tract symptoms: comparison of morning and evening dosing. Int J Urol 22:317–321

    CAS  PubMed  Article  Google Scholar 

  27. 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 409:301–312

    CAS  PubMed  Article  Google Scholar 

  28. 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 49:209–215

    CAS  PubMed  Google Scholar 

  29. 29.

    Marshall I, Burt RP, Green GM, Hussain MB, Chapple CR (1996) Different subtypes of alpha1A-adrenoceptor mediating contraction of rat epididymal vas deferens, rat hepatic portal vein and human prostate distinguished by the antagonist RS-17053. Br J Pharmacol 119:407–415

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Hedlund P, Ekstrom P, Larsson B, Alm P, Andersson KE (1997) Heme oxygenase and NO-synthase in the human prostate—relation to adrenergic, cholinergic and peptide-containing nerves. J Auton Nerv Syst 63:115–126

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Hedlund P, Larsson B, Alm P, Andersson KE (1996) Nitric oxide synthase-containing nerves and ganglia in the dog prostate: a comparison with other transmitters. Histochem J 28:635–642

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Takeda M, Tang R, Shapiro E, Burnett AL, Lepor H (1995) Effects of nitric oxide on human and canine prostates. Urology 45:440–446

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Naibar-Kaszkiel AT, Di Iulio JL, Li CG, Rand MJ (1997) Characterisation of excitatory and inhibitory transmitter systems in prostate glands of rats, guinea pigs, rabbits and pigs. Eur J Pharmacol 337:251–258

    Article  Google Scholar 

  34. 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 76:1364–1374

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Bechara A, Romano S, Casabé A, Haime S, Dedola P, Hernández C, Rey H (2008) Comparative efficacy assessment of tamsulosin vs. tamsulosin plus tadalafil in the treatment of LUTS/BPH. Pilot study. J Sex Med 5:2170–2178

    CAS  PubMed  Article  Google Scholar 

  36. 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 14:1018–1027

    PubMed  Article  Google Scholar 

  37. 37.

    Kaplan SA, Gonzalez RR, Te AE (2007) Combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. Eur Urol 51:1717–1723

    CAS  PubMed  Article  Google Scholar 

  38. 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 15:53–59

    PubMed  PubMed Central  Article  Google Scholar 

  39. 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 9:1624–1633

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Mason RP, Cockcroft JR (2006) Targeting nitric oxide with drug therapy. J Clin Hypertens (Greenwich) 8(Suppl 4):40–52

    CAS  Article  Google Scholar 

  41. 41.

    Scatena R, Bottoni P, Martorana GE, Giardina B (2005) Nitric oxide donor drugs: an update on pathophysiology and therapeutic potential. Expert Opin Investig Drugs 14:835–846

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Oliveira-Paula GH, Tanus-Santos JE (2019) Nitrite-stimulated gastric formation of S-nitrosothiols as an antihypertensive therapeutic strategy. Curr Drug Targets 20:431–443

    CAS  PubMed  Article  Google Scholar 

  43. 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 131:7–13

    Google Scholar 

  44. 44.

    Kedia GT, Ückert S, Scheller F, Chigogidze T, Managadze L, Jonas U, Truss MC (2006) In vitro functional responses of isolated normal human prostatic tissue to compounds interacting with the cyclic guanosine monophosphate pathway. Urology 67:1292–1297

    PubMed  Article  Google Scholar 

  45. 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)

    Article  Google Scholar 

  46. 46.

    Berger AP, Deibl M, Leonhartsberger N, Bektic J, Horninger W, Fritsche G, Steiner H, Pelzer AE, Bartsch G, Frauscher F (2005) Vascular damage as a risk factor for benign prostatic hyperplasia and erectile dysfunction. BJU Int 96:1073–1078

    PubMed  Article  Google Scholar 

  47. 47.

    Saito M, Tsounapi P, Oikawa R, Shimizu S, Honda M, Sejima T, Kinoshita Y, Tomita S (2014) Prostatic ischemia induces ventral prostatic hyperplasia in the SHR: possible mechanism of development of BPH. Sci Rep 4:3822

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. 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 384:245–253

    CAS  PubMed  Article  Google Scholar 

  49. 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 7:183–187

    PubMed  Google Scholar 

  50. 50.

    Tadayyon F, Izadpanahi M, Aali S, Mazdak H, Khorrami MH (2012) The effect of sublingual isosorbide dinitrate on acute urinary retention due to benign prostatic hyperplasia. Saudi J Kidney Dis Transpl 23:782–785

    PubMed  Article  Google Scholar 

  51. 51.

    Klotz T, Mathers MJ, Bloch W, Nayal W, Engelmann U (1999) Nitric oxide based influence of nitrates on micturition in patients with benign prostatic hyperplasia. Int Urol Nephrol 31:335–341

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Hedlund P (2005) Nitric oxide/cGMP-mediated effects in the outflow region of the lower urinary tract—is there a basis for pharmacological targeting of cGMP? World J Urol 23:362–367

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Kedia GT, Ückert S, Jonas U, Kuczyk MA, Burchardt M (2008) The nitric oxide pathway in the human prostate: clinical implications in men with lower urinary tract symptoms. World J Urol 26:603–609

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Siejka A, Schally AV, Block NL, Barabutis N (2010) Mechanisms of inhibition of human benign prostatic hyperplasia in vitro by the luteinizing hormone-releasing hormone antagonist cetrorelix. BJU Int 106:1382–1388

    CAS  PubMed  Article  Google Scholar 

  55. 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 71:445–452

    CAS  PubMed  Article  Google Scholar 

  56. 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 71:736–747

    Article  CAS  Google Scholar 

  57. 57.

    Debruyne F, Tzvetkov M, Altarac S, Geavlete PA (2010) Dose-ranging study of the luteinizing hormone-releasing hormone receptor antagonist cetrorelixpamoate in the treatment of patients with symptomatic benign prostatic hyperplasia. Urology 76:927–933

    PubMed  Article  Google Scholar 

  58. 58.

    Swaminathan S (2011) Molecular structures and functional relationships in clostridial neurotoxins. FEBS J 278:4467–4485

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Lam KH, Yao G, Jin R (2015) Diverse binding modes, same goal: the receptor recognition mechanism of botulinum neurotoxin. Prog Biophys Mol Biol 117:225–231

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Chartier-Kastler E, Mehnert U, Denys P, Giuliano F (2009) Perspective of Botox for treatment of male lower urinary tract symptoms. Curr Opin Urol 19:20–25

    Article  Google Scholar 

  61. 61.

    Brisinda G, Cadeddu F, Vanella S, Mazzeo P, Marniga G, Maria G (2009) Relief by botulinum toxin of lower urinary tract symptoms owing to benign prostatic hyperplasia: early and long-term results. Urology 73:90–94

    PubMed  Article  Google Scholar 

  62. 62.

    Chuang YC, Chiang PH, Yoshimura N, De Miguel F, Chancellor MB (2006) Sustained beneficial effects of intraprostatic botulinum toxin type A on lower urinary tract symptoms and quality of life in men with benign prostatic hyperplasia. BJU Int 98:1033–1037

    CAS  PubMed  Article  Google Scholar 

  63. 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–E844

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Marberger M, Chartier-Kastler E, Egerdie B, Lee KS, Grosse J, Bugarin D, Zhou J, Patel A, Haag-Molkenteller C (2013) A randomized double-blind, placebo-controlled phase 2 dose-ranging study of onabotulinumtoxin A in men with benign prostatic hyperplasia. Eur Urol 63:496–503

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Shim SR, Cho YJ, Shin IS, Kim JH (2016) Efficacy and safety of botulinum toxin injection for benign prostatic hyperplasia: a systematic review and meta-analysis. Int Urol Nephrol 48:19–30

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Comeglio P, Chavalmane AK, Fibbi B, Filippi S, Marchetta M, Marini M, Morelli A, Penna G, Vignozzi L, Vannelli GB, Adorini L, Maggi M (2010) Human prostatic urethra expresses vitamin D receptor and responds to vitamin D receptor ligation. J Endocrinol Invest 33:730–738

    CAS  PubMed  Article  Google Scholar 

  67. 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 67:234–247

    PubMed  Article  CAS  Google Scholar 

  68. 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 69:480–493

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Adorini L, Penna G, Amuchastegui S, Cossetti C, Aquilano F, Mariani R, Fibbi B, Morelli A, Uskokovic M, Colli E, Maggi M (2007) Inhibition of prostate growth and inflammation by the vitamin D receptor agonist BXL-628 (elocalcitol). J Steroid Biochem Mol Biol 103:689–693

    CAS  PubMed  Article  Google Scholar 

  70. 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 49:82–86

    Article  CAS  Google Scholar 

  71. 71.

    Hanley MR, Benton HP, Lightman SL, Todd K, Bone EA, Fretten P, Palmer S, Kirk CJ, Michell RH (1984) A vasopressin-like peptide in the mammalian sympathetic nervous system. Nature (London) 309:258–261

    CAS  Article  Google Scholar 

  72. 72.

    van Kerrebroeck P (2011) Nocturia: current status and future perspectives. Curr Opin Obstet Gynecol 23:376–385

    PubMed  Google Scholar 

  73. 73.

    Oelke M, Adler E, Marschall-Kehrel D, Herrmann TR, Berges R (2014) Nocturia: state of the art and critical analysis of current assessment and treatment strategies. World J Urol 32:1109–1117

    PubMed  Article  Google Scholar 

  74. 74.

    Ali F, Guglin M, Vaitkevicius P, Ghali JK (2007) Therapeutic potential of vasopressin receptor antagonists. Drugs 67:847–858

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Lemmens-Gruber R, Kamyar M (2008) Pharmacology and clinical relevance of vasopressin antagonists. Der Internist (Berlin) 49:628–634

    CAS  Article  Google Scholar 

  76. 76.

    Yoshimura N, Kaiho Y, Miyazato M, Yunoki T, Tai C, Chancellor MB, Tyagi P (2008) Therapeutic receptor targets for lower urinary tract dysfunction. Naunyn Schmiedeberg’s Arch Pharmacol 377(4–6):437–448

    CAS  Article  Google Scholar 

  77. 77.

    Bodanszky M, Sharaf H, Roy JB, Said SI (1992) Contractile activity of vasotocin, oxytocin, and vasopressin on mammalian prostate. Eur J Pharmacol 216:311–313

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Crankshaw D (1989) [Arg8]vasopressin-induced contractions of rabbit urinary bladder smooth muscle. Eur J Pharmacol 173(2–3):183–188

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Gupta J, Russell R, Wayman C, Hurley D, Jackson V (2008) Oxytocin-induced contractions within rat and rabbit ejaculatory tissues are mediated by vasopressin V1A receptors and not oxytocin receptors. Br J Pharmacol 155:118–126

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 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 277:700–705

    CAS  PubMed  Google Scholar 

  81. 81.

    Malherbe P, Ballard TM, Ratni H (2011) Tachykinin neurokinin 3 receptor antagonists: a patent review (2005–2010). Expert Opin Ther Pat 21:637–655

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Bakali E, Elliott RA, Taylor AH, Willets J, Konje JC, Tincello DG (2013) Distribution and function of the endocannabinoid system in the rat and human bladder. Int Urogynecol J 24:855–863

    PubMed  Article  Google Scholar 

  83. 83.

    Hedlund P (2014) Cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction. Neurourol Urodyn 33:46–53

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Hedlund P, Gratzke C (2016) The endocannabinoid system—a target for the treatment of LUTS? Nat Rev Urol 13:463–470

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Gratzke C, Weinhold P, Reich O, Seitz M, Schlenker B, Stief CG, Andersson KE, Hedlund P (2010) Transient receptor potential A1 and cannabinoid receptor activity in human normal and hyperplastic prostate: relation to nerves and interstitial cells. Eur Urol 57:902–910

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Shore N (2010) NX-1207: a novel investigational drug for the treatment of benign prostatic hyperplasia. Expert Opin Investig Drugs 19:305–310

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Shore N, Cowan B (2011) The potential for NX-1207 in benign prostatic hyperplasia: an update for clinicians. Ther Adv Chronic Dis 2:283–377

    Article  CAS  Google Scholar 

  88. 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 6:67–70

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 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 36:801–809

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Brawer MK (2005) Lonidamine: basic science and rationale for treatment of prostatic proliferative disorders. Rev Urol 7(Suppl 7):S21–S526

    PubMed  PubMed Central  Google Scholar 

  91. 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 1866:151–162

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Roehrborn CG (2005) The development of lonidamine for benign prostatic hyperplasia and other indications. Rev Urol 7(Suppl 7):S12–S620

    PubMed  PubMed Central  Google Scholar 

  93. 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–S533

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Stefan Ückert.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest and have received no payment for the preparation of the manuscript.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ückert, S., Kedia, G.T., Tsikas, D. et al. Emerging drugs to target lower urinary tract symptomatology (LUTS)/benign prostatic hyperplasia (BPH): focus on the prostate. World J Urol 38, 1423–1435 (2020). https://doi.org/10.1007/s00345-019-02933-1

Download citation

Keywords

  • Lower urinary tract symptoms (LUTS)
  • Benign prostatic hyperplasia (BPH)
  • Pharmacotherapy