Exploration of therapeutic targets for sexual dysfunctions: lessons learned from the failed stories

Bibliography

• Zheng CJ, Han LY, Yap CW, Therapeutic targets: progress of their exploration and investigation of their characteristics. Pharmacol Rev 2006;58:259-79
   PubMed Web of Science ®Google Scholar
• Zheng C, Han L, Yap CW, Progress and problems in the exploration of therapeutic targets. Drug Discov Today 2006;11:412-20
   PubMed Web of Science ®Google Scholar
• Rajfer J. Discovery of NO in the penis. Int J Impot Res 2008;20:431-6
   PubMedGoogle Scholar
• Schmid EF, Smith DA. Keynote review: is declining innovation in the pharmaceutical industry a myth? Drug Discov Today 2005;10:1031-9
   PubMed Web of Science ®Google Scholar
• Verkman AS. Drug discovery in academia. Am J Physiol Cell Physiol 2004;286:C465-74
   PubMed Web of Science ®Google Scholar
• Imming P, Sinning C, Meyer A. Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov 2006;5:821-34
   PubMed Web of Science ®Google Scholar
• Hopkins AL, Groom CR. The druggable genome. Nat Rev Drug Discov 2002;1:727-30
   PubMed Web of Science ®Google Scholar
• Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001;46:3-26
   PubMed Web of Science ®Google Scholar
• Hardy LW, Peet NP. The multiple orthogonal tools approach to define molecular causation in the validation of druggable targets. Drug Discov Today 2004;9:117-16
   PubMedGoogle Scholar
• Walke DW, Han C, Shaw J, In vivo drug target discovery: identifying the best targets from the genome. Curr Opin Biotechnol 2001;12:626-31
   PubMedGoogle Scholar
• Shaikh SA, Jain T, Sandhu G, From drug target to leads--sketching a physicochemical pathway for lead molecule design in silico. Curr Pharm Des 2007;13:3454-70
   PubMedGoogle Scholar
• Smith C. Drug target validation: hitting the target. Nature 2003;422(6929):341, 343, 345
   Google Scholar
• Andersson K-E, Wagner G. Physiology of penile erection. Physiol Rev 1995;75:191-236
   PubMed Web of Science ®Google Scholar
• Traish AM, Netsuwan N, Daley J, A heterogeneous population of alpha 1 adrenergic receptors mediates contraction of human corpus cavernosum smooth muscle to norepinephrine. J Urol 1995;153:222-7
   PubMedGoogle Scholar
• Traish AM, Gupta S, Toselli P, Identification of alpha 1-adrenergic receptor subtypes in human corpus cavernosum tissue and in cultured trabecular smooth muscle cells. Receptor 1995;5:145-57
   PubMedGoogle Scholar
• Traish AM, Moreland RB, Huang YH, Goldstein I. Expression of functional alpha2-adrenergic receptor subtypes in human corpus cavernosum and in cultured trabecular smooth muscle cells. Recept Signal Transduct 1997;7:55-67
   PubMedGoogle Scholar
• Goepel M, Krege S, Price DT, Characterization of alpha-adrenoceptor subtypes in the corpus cavernosum of patients undergoing sex change surgery. J Urol 1999;162:1793-9
   PubMedGoogle Scholar
• Krege S, Goepel M, Sperling H, Michel MC. Affinity of trazodone for human penile a1- and a2-adrenoceptors. BJU Int 2000; 85:959-61
   PubMedGoogle Scholar
• Sperling H, Lorenz A, Krege S, An extract from the bark of Aspidosperma quebracho blanco binds to human penile alpha-adrenoceptors. J Urol 2002;168:160-3
   PubMedGoogle Scholar
• Davis B, Chapple C, Chess-Williams R. The alpha1L-adrenoceptor mediates contraction in human erectile tissue (Abstract 406). Eur Urol 1999;35(Suppl 2):102
   PubMedGoogle Scholar
• Rees RW, Ralph DJ, Royle M, Y-27632, an inhibitor of Rho-kinase, antagonizes noradrenergic contractions in the rabbit and human penile corpus cavernosum. Br J Pharmacol 2001;133:455-8
   PubMed Web of Science ®Google Scholar
• Morton JS, Daly CJ, Jackson VM, McGrath GC. alpha1A-Adrenoceptors mediate contractions to phenylephrine in rabbit penile arteries. Br J Pharmacol 2007;150:112-20
   PubMed Web of Science ®Google Scholar
• Traish AM, Kim NN, Goldstein I, Moreland RB. Alpha-adrenergic receptors in the penis: identification, characterization, and physiological function. J Androl 1999;20:671-82
   PubMedGoogle Scholar
• Gupta S, Moreland RB, Daley JT, Corpus cavernosum smooth muscle expresses functional postsynaptic alpha-2-adrenergic receptors. Br J Phannacol 1998:123:1237-45
   Google Scholar
• Molderings GJ, Göthert M,van Ahlen H, Porst H. Noradrenaline release in human corpus cavernosum and its modulation via presynaptic alpha 2-adrenoceptors. Fundam Clin Pharmacol 1989;3:497-504
   PubMedGoogle Scholar
• de Tejada IS, Kim NN, Goldstein I, Traish AM. (2000) Regulation of pre-synaptic alpha adrenergic activity in the corpus cavernosum. Int J Impot Res 2000;12(Suppl 1):S20-5
   Google Scholar
• Morton JS, Daly CJ, Jackson VM, McGrath JC. Alpha(1A)-adrenoceptors mediate contractions to phenylephrine in rabbit penile arteries. Br J Pharmacol 2007;150:112-20
   PubMed Web of Science ®Google Scholar
• Cirino G, Sorrentino R, di Villa Bianca, Involvement of beta3-adrenergic receptor activation via cyclic GMP-but not NO-dependent mechanisms in humancorpus cavernosum function. Proc Natl Acad Sci USA 2003;100:5531-6
   PubMed Web of Science ®Google Scholar
• Levin RM, Wein AJ. Adrenergic alpha-receptors outnumber beta-receptors in human penile corpus cavernosum. Invest Urol 1980;18:225-6
   PubMedGoogle Scholar
• Adaikan PG, Karim SMM. Adrenoreceptors in the human penis. J Auton Pharmacol 1981;1:199-203
   PubMedGoogle Scholar
• Teixeira CE, Baracat JS, Zanesco A, Atypical beta-adrenoceptor subtypes mediate relaxations of Rabbit Corpus Cavernosum. J Pharmacol Exp Ther 2004;309:587-93
   PubMedGoogle Scholar
• Recio P, López PG, Fernández JL, Garcia-Sacristán A. Pharmacological characterization of adrenoceptors in horse corpus cavernosum penis. J Auton Pharmacol 1997;17:191-8
   PubMedGoogle Scholar
• Brock G. Oral phentolamine (Vasomax). Drugs Today (Barc) 2000;36:121-4
   PubMed Web of Science ®Google Scholar
• Goldstein I. Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction. Int J Impot Res 2000;12(Suppl 1):S75-80
   Google Scholar
• Goldstein I, Carson C, Rosen R, Islam A. Vasomax for the treatment of male erectile dysfunction. World J Urol 2001;19:51-6
   PubMedGoogle Scholar
• Padma-Nathan H, Goldstein I, Klimberg I, Long-term safety and efficacy of oral phentolamine mesylate (Vasomax) in men with mild to moderate erectile dysfunction. Int J Impot Res 2002;14:266-70
   PubMed Web of Science ®Google Scholar
• Poulet FM, Berardi MR, Halliwell W, Development of hibernomas in rats dosed with phentolamine mesylate during the 24-month carcinogenicity study. Toxicol Pathol 2004;32:558-66
   PubMedGoogle Scholar
• Zorgniotti AW, Lefleur RS. Auto-injection of the corpus cavernosum with a vasoactive drug combination for vasculogenic impotence. J Urol 1985;133:39-41
   PubMed Web of Science ®Google Scholar
• Robinette M, Moffat MJ. Intracorporeal injection of papaverine and phentolamine in the management of impotence. Br J Urol 1986;58:692-5
   PubMedGoogle Scholar
• Keogh EJ, Watters GR, Earle CM, Treatment of impotence by intracavernosal injections. A comparison of papaverine and papaverine and phentolamine: a double-blind crossover trial. J Urol 1989;142:726-8
   PubMed Web of Science ®Google Scholar
• Bechara A, Casabe A, Cheliz G, Comparative study of papaverine plus phentolamine versus prostaglandin E1 in erectile dysfunction. J Urol 1997:157:2132-34
   PubMed Web of Science ®Google Scholar
• Keijzers GB. Aviptadil (Senatek). Curr Opin Investig Drugs 2001;2(4):545-9
   PubMedGoogle Scholar
• Shah PJ, Dinsmore W, Oakes RA, Hackett G. Injection therapy for the treatment of erectile dysfunction: a comparison between alprostadil and a combination of vasoactive intestinal polypeptide and phentolamine mesilate. Curr Med Res Opin 2007;23:2577-83
   PubMed Web of Science ®Google Scholar
• Choppin A, Blue DR, Hegde SS, Evaluation of oral RO70-0004/003, an alpha 1 Aadrenoceptor antagonist, in the treatment of male erectile dysfunction. Int J Impot Res 2001;13:157-61
   PubMedGoogle Scholar
• Morales A. Yohimbine in erectile dysfunction: the facts. Int J Impot Res 2000;12(Suppl 1):S70-4
   Google Scholar
• Andersson KE. Pharmacology of penile erection. Pharmacol Rev 2001;53:417-50
   PubMed Web of Science ®Google Scholar
• Krege S, Goepel M, Sperling H, Michel MC. Affinity of trazodone for human penile alpha1- and alpha2-adrenoceptors. BJU Int 2000;85:959-61
   PubMedGoogle Scholar
• Fink HA, MacDonald R, Rutks IR, Wilt TJ. Trazodone for erectile dysfunction: a systematic review and meta-analysis. BJU Int 2003;92:441-6
   PubMed Web of Science ®Google Scholar
• van Dijk MM, de la Rosette JJ, Michel MC. Effects of alpha(1)-adrenoceptor antagonists on male sexual function. Drugs 2006;66:287-301
   PubMed Web of Science ®Google Scholar
• Hosoda C, Tanoue A, Shibano M, Correlation between vasoconstrictor roles and mRNA expression of alpha1-adrenoceptor subtypes in blood vessels of genetically engineered mice. Br J Pharmacol 2005;146:456-66
   PubMedGoogle Scholar
• Sanbe A, Tanaka Y, Fujiwara Y, Alpha1-adrenoceptors are required for normal male sexual function. Br J Pharmacol 2007;152:332-40
   PubMed Web of Science ®Google Scholar
• Methven L, Simpson PC, McGrath JC. Alpha1A/B-knockout mice explain the native alpha1D-adrenoceptor's role in vasoconstriction and show that its location is independent of the other alpha1-subtypes. Br J Pharmacol 2009;158:1663-75
   PubMedGoogle Scholar
• Chaudhry A, Granneman JG. Differential regulation of functional responses by beta-adrenergic receptor subtypes in brown adipocytes. Am J Physiol 1999;277:R147-53
   Google Scholar
• Lindquist JM, Fredriksson JM, Rehnmark S, Beta 3- and alpha1-adrenergic Erk1/2 activation is Src- but not Gi-mediated in Brown adipocytes. J Biol Chem 2000;275:22670-7
   PubMed Web of Science ®Google Scholar
• Zahir M, Gould L. Phentolamine and beta-adrenergic receptors. J Clin Pharmacol New Drugs 1971;11:197-203
   PubMedGoogle Scholar
• Hong SS, Bavadekar SA, Lee SI, Bioisosteric phentolamine analogs as potent alpha-adrenergic antagonists. Bioorg Med Chem Lett 2005;15:4691-5
   PubMedGoogle Scholar
• Bavadekar SA, Hong SS, Lee SI, Bioisosteric phentolamine analogs as selective human alpha(2)- versus alpha(1)-adrenoceptor ligands. Eur J Pharmacol 2008;590:53-60
   PubMedGoogle Scholar
• Meador-Woodruff JH. Update on dopamine receptors. Ann Clin Psychiatry 1994;6:79-90
   PubMedGoogle Scholar
• Björklund A, Dunnett SB. Dopamine neuron systems in the brain: an update. Trends Neurosci 2007;30:194-202
   PubMed Web of Science ®Google Scholar
• Hull EM, Du J, Lorrain DS, Matuszewich L. Extracellular dopamine in the medial preoptic area: implications for sexual motivation and hormonal control of copulation. J Neurosci 1995;15:7465-71
   PubMed Web of Science ®Google Scholar
• Melis MR, Succu S, Mascia MS, Extra-cellular dopamine increases in the paraventricular nucleus of male rats during sexual activity. Eur J Neurosci 2003;17:1266-72
   PubMed Web of Science ®Google Scholar
• Melis MR, Argiolas A. Dopamine and sexual behaviour. Neurosci Biobehav Rev 1995;19:19-38
   PubMed Web of Science ®Google Scholar
• Lal S, Tesfaye Y, Thavundayil JX, Apomorphine: clinical studies on erectile impotence and yawning. Prog Neuropsychopharmacol Biol Psychiatry 1989;13:329-39
   PubMed Web of Science ®Google Scholar
• Andersson KE, Argiolas A, Burnett A, Future treatment targets. Sexual medicine: sexual dysfunction in men and women. In: Lue TF, Basson R, Rosen R, Giuliano F, Khoury S, Montorsi F, editors, Distributor editions 21. Health Publications Ltd., Paris; 2004. p. 567-603
   Google Scholar
• Argiolas A, Melis MR. Central control of penile erection: role of the paraventricular nucleus of the hypothalamus. Prog Neurobiol 2005;76:1-21
   PubMed Web of Science ®Google Scholar
• Melis MR, Succu S, Sanna F, PIP3EA and PD-168077, two selective dopamine D4 receptor agonists, induce penile erection in male rats: site and mechanism of action in the brain. Eur J Neurosci 2006;24:2021-30
   PubMed Web of Science ®Google Scholar
• Succu S, Sanna F, Melis T, Stimulation of dopamine receptors in the paraventricular nucleus of the hypothalamus of male rats induces penile erection and increases extra-cellular dopamine in the nucleus accumbens: involvement of central oxytocin. Neuropharmacology 2007;52:1034-43
   PubMed Web of Science ®Google Scholar
• Melis MR, Succu S, Argiolas A. Dopamine agonists increase nitric oxide production in the paraventricular nucleus of the hypothalamus: correlation with penile erection and yawning. Eur J Neurosci 1996;8:2056-63
   PubMed Web of Science ®Google Scholar
• Matsumoto K, Yoshida M, Andersson KE, Hedlund P. Effects in vitro and in vivo by apomorphine in the rat corpus cavernosum. Br J Pharmacol 2005;146:259-67
   PubMedGoogle Scholar
• d'Emmanuele di Villa Bianca R, Sorrentino R, Peripheral relaxant activity of apomorphine and of a D1 selective receptor agonist on human corpus cavernosum strips. Int J Impot Res 2005;17:127-33
   PubMedGoogle Scholar
• Stief C, Padley RJ, Perdok RJ, Sleep DJ. Cross-study review of the clinical efficacy of apomorphine SL 2 and 3 mg: pooled data from three placebo-controlled, fixed-dose cross-over studies. Eur Urol 2002;(Suppl 1):12-36
   PubMedGoogle Scholar
• Heaton J, Sleep D, Perdok R, Efficacy and safety of Uprima (apomorphine SL) in patients with documented comorbidities of hypertension, coronary artery disease (CAD) or diabetes. Int J Impotence Res 2001;13(Suppl 4):S32, Abstr.87
   Google Scholar
• Gontero P, D'Antonio R, Pretti G, Clinical efficacy of Apomorphine SL in erectile dysfunction of diabetic men. Int J Impot Res 2005;17:80-5
   PubMed Web of Science ®Google Scholar
• Perimenis P, Gyftopoulos K, Giannitsas K, A comparative, crossover study of the efficacy and safety of sildenafil and apomorphine in men with evidence of arteriogenic erectile dysfunction. Int J Impot Res 2004;16:2-7
   PubMed Web of Science ®Google Scholar
• Strebel RT, Reitz A, Tenti G, Apomorphine sublingual as primary or secondary treatment for erectile dysfunction in patients with spinal cord injury. BJU Int 2004;93:100-4
   PubMed Web of Science ®Google Scholar
• Giammusso B, Colpi GM, Cormio L, An open-label, randomized, flexible-dose, crossover study to assess the comparative efficacy and safety of sildenafil citrate and apomorphine hydrochloride in men with erectile dysfunction. Urol Int 2008;81:409-15
   PubMedGoogle Scholar
• Afif-Abdo J, Teloken C, Damião R, Comparative cross-over study of sildenafil and apomorphine for treating erectile dysfunction. BJU Int 2008;102:829-34
   PubMedGoogle Scholar
• Strebel RT, Reitz A, Tenti G, Apomorphine sublingual as primary or secondary treatment for erectile dysfunction in patients with spinal cord injury. BJU Int 2004;93:100-4
   PubMed Web of Science ®Google Scholar
• Pavone C, Curto F, Anello G, Prospective, randomized, crossover comparison of sublingual apomorphine (3 mg) with oral sildenafil (50 mg) for male erectile dysfunction. J Urol 2008;179(5 Suppl):S92-4
   Google Scholar
• Porst H, Behre HM, Jungwirth A, Burkart M. Comparative trial of treatment satisfaction, efficacy and tolerability of sildenafil versus apomorphine in erectile dysfunction--an open, randomized cross-over study with flexible dosing. Eur J Med Res 2007;12:61-7
   PubMed Web of Science ®Google Scholar
• Perimenis P, Markou S, Gyftopoulos K, Efficacy of apomorphine and sildenafil in men with nonarteriogenic erectile dysfunction. A comparative crossover study. Andrologia 2004;36:106-10
   PubMed Web of Science ®Google Scholar
• Maclennan KM, Boshier A, Wilton LV, Shakir SA. Examination of the safety and use of apomorphine prescribed in general practice in England as a treatment for erectile dysfunction. BJU Int 2006;98:125-31
   PubMed Web of Science ®Google Scholar
• Porst H. Oral Pharmacotherapy of Erectile Dysfunction in “Standard Practice in Sexual Medicine”, Porst H, Buvat J, editors, 1st edition, 2006 International Society for Sexual Medicine Blackwell Publishing, Oxoford, 2006; p. 75-93
   Google Scholar
• Tsai MJ, Huang YB, Wu PC, Oral apomorphine delivery from solid lipid nanoparticleswith different monostearate emulsifiers: pharmacokinetic and behavioral evaluations. J Pharm Sci 2010;100:547-57
   Google Scholar
• Andersson KE. Pharmacology of penile erection. Pharmacol Rev 2001;53:417-50
   PubMed Web of Science ®Google Scholar
• Riley A, Main M, Morgan F. Inhalation device allows novel administration of apomorphine in men with erectile dysfunction—efficacy and safety findings. J Sex Med 2010;7:1508-17
   PubMed Web of Science ®Google Scholar
• Carson CC, Dean JD. Management of erectile dysfunction in clinical practice. 1st edition. Springer-Verlag Limited, London; 2007. p. 66-70
   Google Scholar
• Patel MV, Kolasa T, Mortell K, Discovery of 3-methyl-N-(1-oxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′-bipyridine]-1′-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction. J Med Chem 2006;49:7450-65
   PubMed Web of Science ®Google Scholar
• Melis MR, Succu S, Sanna F, PIP3EA and PD-168077, two selective dopamine D4 receptor agonists, induce penile erection in male rats: site and mechanism of action in the brain. Eur J Neurosci 2006;24:2021-30
   PubMed Web of Science ®Google Scholar
• Brioni JD, Moreland RB, Cowart M, “Activation of dopamine D4 receptors by ABT-724 induces penile erection in rats”. Proc Natl Acad Sci USA 2004;101:6758-63
   PubMed Web of Science ®Google Scholar
• Bitner RS, Nikkel AL, Otte S, Dopamine D4 receptor signaling in the rat paraventricular hypothalamic nucleus: evidence of natural coupling involving immediate early gene induction and mitogen activated protein kinase phosphorylation. Neuropharmacology 2006;50:521-31
   PubMedGoogle Scholar
• Giuliano F, Clement P. Neuroanatomy and physiology of ejaculation. Annu Rev Sex Res 2005;16:190-216
   PubMedGoogle Scholar
• Coolen LM, Allard J, Truitt WA, McKenna KE. Central regulation of ejaculation. Physiol Behav 2004;83:203-15
   PubMed Web of Science ®Google Scholar
• Krüger TH, Hartmann U, Schedlowski M. Prolactinergic and dopaminergic mechanisms underlying sexual arousal and orgasm in humans. World J Urol 2005;23:130-8
   PubMed Web of Science ®Google Scholar
• Hull EM, Muschamp JW, Sato S. Dopamine and serotonin: influences on male sexual behavior. Physiol Behav 2004;83:291-307
   PubMed Web of Science ®Google Scholar
• de Jong TR, Veening JG, Waldinger MD, Serotonin and the neurobiology of the ejaculatory threshold. Neurosci Biobehav Rev 2006;30:893-907
   PubMedGoogle Scholar
• Gravitt K, Marson L. Effect of the destruction of cells containing the serotonin reuptake transporter on urethrogenital Reflexes. J Sex Med 2007;4:322-31
   PubMedGoogle Scholar
• Montejo-González AL, Llorca G, Izquierdo JA, SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther 1997;23:176-94
   PubMed Web of Science ®Google Scholar
• Waldinger MD. Premature ejaculation: state of the art. Urol Clin N Am 2007;34:591-9
   PubMed Web of Science ®Google Scholar
• Waldinger MD, Zwinderman AH, Schweitzer DH, Olivier B. Relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and meta-analysis. Int J Impot Res 2004;16:369-81
   PubMed Web of Science ®Google Scholar
• Ahlenius S Larsson K. Synergistic actions of the 5-HT1A antagonist WAY-100635 and citalopram on male rat ejaculatory behavior. Eur J Pharmacol 1999;379:1-6
   PubMedGoogle Scholar
• Abdel-Hamid IA, Jannini EA, Andersson KE. Premature ejaculation: focus on therapeutic targets. Expert Opin Ther Targets 2009;13:175-93
   PubMed Web of Science ®Google Scholar
• Black K, Shea C, Dursun S, Kutcher S. Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria. J Psychiatry Neurosci 2000;25:255-61
   PubMed Web of Science ®Google Scholar
• Waldinger MD. Emerging drugs for premature ejaculation. Expert Opin Emerg Drugs 2006;11:99-109
   PubMedGoogle Scholar
• Waldinger MD, Schweitzer DH. Premature ejaculation and pharmaceutical company-based medicine: the dapoxetine case. J Sex Med 2008;5(4):966-97
   PubMedGoogle Scholar
• McMahon CG, Althof SE, Kaufman JM, Efficacy and safety of dapoxetine for the treatment of premature ejaculation: Integrated analysis of results from five phase 3 trials. J Sex Med 2010; doi: 10.1111/j.1743-6109.2010.02097.x
   Google Scholar
• Waldinger MD, Zwinderman AH, Olivier B, Schweitzer DH. The majority of men with lifelong premature ejaculation prefer daily drug treatment: an observation study in a consecutive group of Dutch men. J Sex Med 2007;4(1):1028-37
   PubMedGoogle Scholar
• Salonia A, Rocchini L, Sacca A, Acceptance of and discontinuation rate from paroxetine treatment in patients with lifelong premature ejaculation. J Sex Med 2009;6:2868-77
   PubMed Web of Science ®Google Scholar
• McMahon CG. Long term results of treatment of premature ejaculation with selective serotonin re-uptake inhibitors. Int J Impot Res 2002;14(3 Suppl):S19
   Google Scholar
• Waldinger MD. Premature ejaculation: definition and drug treatment. Drugs 2007;67:547-68
   PubMed Web of Science ®Google Scholar
• Bradley D. Why big pharma needs to learn the three 'R's. Nat Rev Drug Discov 2005;4:446
   PubMedGoogle Scholar
• Taber MT, Wright RN, Molski TF, Neurochemical, pharmacokinetic, and behavioral effects of the novel selective serotonin reuptake inhibitor BMS-505130. Pharmacol Biochem Behav 2005;80:521-8
   PubMedGoogle Scholar
• Giuliano F. 5-HT in premature ejaculation: opportunities for therapeutic intervention. Trends Neurosci 2007;30:79-84
   PubMed Web of Science ®Google Scholar
• Azam U. Late-stage clinical development in lower urogenital targets: sexual dysfunction. Br J Pharmacol 2006;147(S2):S153-9
   Google Scholar
• Hoyle CH, Stones RW, Robson T, Innervation of vasculature and microvasculature of the human vagina by NOS and neuropeptide-containing nerves. J Anat 1996;188:633-44
   PubMed Web of Science ®Google Scholar
• Martin-Alguacil N, Pfaff DW, Shelley DN, Schober JM. Clitoral sexual arousal: an immunocytochemical and innervations study of the clitoris. BJU Int 2008;101:1407-13
   PubMedGoogle Scholar
• Burnett AL, Calvin DC, Silver RI, Immunohistochemical description of nitric oxide synthase isoforms in human clitoris. J Urol 1997;158:75-8
   PubMed Web of Science ®Google Scholar
• Cellek S, Moncada S. Nitrergic neurotransmission mediates the non-adrenergic non-cholinergic responses in the clitoral corpus cavernosum of the rabbit. Br J Pharmacol 1998;125:1627-9
   PubMedGoogle Scholar
• Park JK, Kim JU, Lee SO, Nitric oxide-cyclic GMP signaling pathway in the regulation of rabbit clitoral cavernosum tone. Exp Biol Med 2002;227:1022-30
   Google Scholar
• Creighton SM, Crouch NS, Foxwell NA, Cellek S. Functional evidence for nitrergic neurotransmission in a human clitoral corpus cavernosum: a case study. Int J Impot Res 2004;16:319-24
   PubMedGoogle Scholar
• Kim SW, Jeong SJ, Munarriz R, Role of the nitric oxide-cyclic GMP pathway in regulation of vaginal blood flow. Int J Impot Res 2003;15:355-61
   PubMed Web of Science ®Google Scholar
• Traish AM, Botchevar E, Kim NN. Biochemical factors modulating female genital sexual arousal physiology. J Sex Med 2010;7:2925-46
   PubMed Web of Science ®Google Scholar
• D'Amati G, di Gioia CR, Bologna M, Type 5 phosphodiesterase expression in the human vagina. Urology 2002;60:191-5
   PubMed Web of Science ®Google Scholar
• Uckert S, Oelke M, Waldkirch E, Cyclic adenosine monophosphate and cyclic guanosine monophosphate-phosphodiesterase isoenzymes in human vagina: relation to nitric oxide synthase isoforms and vasoactive intestinal polypeptide-containing nerves. Urology 2005;65:604-10
   PubMedGoogle Scholar
• Oelke M, Hedlund P, Albrecht K, Expression of cAMP and cGMP-phosphodiesterase isoenzymes 3, 4, and 5 in the human clitoris: immunohistochemical and molecular biology study. Urology 2006;67:1111-16
   PubMedGoogle Scholar
• Uckert S, Oelke M, Albrecht K, Immunohistochemical description of cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human labia minora. J Sex Med 2007;4:602-8
   PubMedGoogle Scholar
• Traish A, Moreland RB, Huang YH, Development of human and rabbit vaginal smooth muscle cell cultures: Effects of vasoactive agents on intracellular levels of cyclic nucleotides. Mol Cell Biol Res Commun 1999;2:131-7
   PubMedGoogle Scholar
• Park K, Moreland RB, Goldstein I, Sildenafil inhibits hosphodiesterase type 5 in human clitoral corpus cavernosum smooth muscle. Biochem Biophys Res Commun 1998;249:612-17
   PubMed Web of Science ®Google Scholar
• Vemulapalli S, Kurowski S. Sildenafil relaxes rabbit clitoral corpus cavernosum. Life Sci 2000;67:23-9
   PubMedGoogle Scholar
• Park K, Moreland RB, Goldstein I, Sildenafil inhibits phosphodiesterase type 5 in human clitoral corpus cavernosum smooth muscle. Biochem Biophys Res Commun 1998;249:612-17
   PubMed Web of Science ®Google Scholar
• Angulo J, Cuevas P, Cuevas B, Vardenafil enhances clitoral and vaginal blood flow responses to pelvic nerve stimulation in female dogs. Int J Impot Res 2003;15:137-41
   PubMedGoogle Scholar
• Caruso S, Intelisano G, Lupo L, Agnello C. Premenopausal women affected by sexual arousal disorder treated with sildenafil: a double-blind, cross-over, placebo-controlled study. BJOG 2001;108:623-8
   PubMed Web of Science ®Google Scholar
• Berman JR, Berman LA, Lin H, Effect of sildenafil on subjective and physiologic parameters of the female sexual response in women with sexual arousal disorder. J Sex Marital Ther 2001;27:411-20
   PubMed Web of Science ®Google Scholar
• Berman JR, Berman LA, Toler SM, Safety and efficacy of sildenafil citrate for the treatment of female sexual arousal disorder: a double-blind, placebo controlled study. J Urol 2003;170:2333-8
   PubMed Web of Science ®Google Scholar
• Caruso S, Intelisano G, Farina M, Thefunction of sildenafil on female sexual pathways: a doubleblind, cross-over, placebo-controlled study. Eur J ObstetGynecol Reprod Biol 2003;110:201-6
   PubMed Web of Science ®Google Scholar
• Basson R, Brotto LA. Sexual psychophysiology and effects of sildenafil citrate in oestrogenised women with acquired genital arousal disorder and impaired orgasm: a randomised controlled trial. BJOG 2003;110:1014-24
   PubMed Web of Science ®Google Scholar
• Basson R, McInnes R, Smith MD, Efficacy and safety of sildenafil citrate in women with sexual dysfunction associated with female sexual arousal disorder. J Womens Health Gend Based Med 2002;11:367-77
   PubMedGoogle Scholar
• Kaplan SA, Reis RB, Kohn IJ, Safety and efficacy of sildenafil in postmenopausal women with sexual dysfunction. Urology 1999;53:481-6
   PubMed Web of Science ®Google Scholar
• Dasgupta R, Wiseman OJ, Kanabar G, Efficacy of sildenafil in the treatment of female sexual dysfunction due to multiple sclerosis. J Urol 2004;171:1189-93
   PubMed Web of Science ®Google Scholar
• Shields KM, Hrometz SL. Use of sildenafil for female sexual dysfunction. Ann Pharmacother 2006;40:931-4
   PubMedGoogle Scholar
• Mayor S. Pfizer will not apply for a licence for sildenafil for women. BMJ 2004;328(7439):542
   PubMedGoogle Scholar
• Leiblum SR, Chivers ML. Normal and persistent genital arousal in women: new perspectives. J Sex Marital Ther 2007;33:357-73
   PubMed Web of Science ®Google Scholar
• Brotto LA, Gehring D, Klein C, Psychophysiological and subjective sexual arousal to visual sexual stimuli in new women. J Psychosom Obstet Gynaecol 2005;26:237-44
   PubMed Web of Science ®Google Scholar
• Suschinsky KD, Lalumiere ML, Chivers ML. Sex differences in patterns of genital sexual arousal: measurement artifacts or true phenomena? Arch Sex Behav 2009;38:559-73
   PubMed Web of Science ®Google Scholar
• Laan E, Everaerd W. Determinants of female sexual arousal: Psychophysiological theory and data. Annu Rev Sex Res 1995;6:32-76
   Google Scholar
• Brown AD, Blagg J, Reynolds DS. Designing drugs for the treatment of female sexual dysfunction. Drug Discov Today. 2007;12(17-18):757-66
   PubMedGoogle Scholar
• Chivers M, Rosen RC. PDE5 inhibitors and female sexual response: faulty protocols or paradigms? J Sex Med 2010;7:858-72
   PubMed Web of Science ®Google Scholar
• Wagner G, Ottesen B. Vaginal blood flow during sexual stimulation. Obstetrics & Gynecology 1980;56:621-4
   PubMed Web of Science ®Google Scholar
• Ottesen B, Pedersen B, Nielsen J, Vasoactive intestinal polypeptide (VIP) provokes vaginal lubrication in normal women. Peptides 1987;8:797-800
   PubMed Web of Science ®Google Scholar
• Laan E, van Lunsen RH, Everaerd W. The effects of tibolone on vaginal blood flow, sexual desire and arousability in postmenopausal women. Climacteric 2001;4:28-41
   PubMedGoogle Scholar
• Levin RJ. Sex and the human female reproductive tract—what really happens during and after coitus. Int J Impot Res 1998;10(Suppl 1):S14-21
   Google Scholar
• Min K, Munarriz R, Yerxa BR, Selective P2Y2 receptor agonists stimulate vaginal moisture in ovariectomized rabbits. Fertil Steril 2003;79:393-8
   PubMedGoogle Scholar
• Park K, Han HJ, Kim SW, Expression of aquaporin water channels in rat vagina: potential role in vaginal lubrication. J Sex Med 2008;5:77-82
   PubMedGoogle Scholar
• Salonia A, Giraldi A, Chivers ML, Physiology of women's sexual function: basic knowledge and new findings. J Sex Med 2010;7:2637-60
   PubMed Web of Science ®Google Scholar
• Giuliano F, Pfaus J, Balasubramanian S, Experimental models for the study of female and male sexual function. J Sex Med 2010;7:2970-95
   PubMed Web of Science ®Google Scholar