Oral pharmacotherapy for erectile dysfunction: current perspectives

Abstract

The range of therapies for treating erectile dysfunction has expanded rapidly in recent years, with a trend toward understanding the scientific basis of erectile function and implementing therapies that are strategically based on this new knowledge. Treatment options in the field have evolved from penile prostheses that unnaturally provide a rigid erectile organ for sexual intercourse to various pharmacotherapies that are designed to restore or promote the biochemical mechanisms required for natural erectile function. As pharmacotherapies have evolved, their routes of administration have also been advanced ranging from local (eg, intracavernosal, intraurethral, and topical) to systemic (eg, subcutaneous and oral) forms. Among these, the oral route has consistently been highly attractive, particularly since this form offers a noninvasive route of delivery. The patient preference for oral forms of therapy for erectile dysfunction has been well demonstrated, with recent treatment outcome analyses revealing that patients persist in their preferences for some traditional oral therapies despite the poor efficacies and hence cause for significant dissatisfaction.1Jarow J.P Nana-Sinkam P Sabbagh M et al.Outcome analysis of goal directed therapy for impotence.J Urol. 1996; 155: 1609-1612Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 2Hanash K.A Comparative results of goal oriented therapy for erectile dysfunction.J Urol. 1997; 157: 2135-2138Abstract Full Text Full Text PDF PubMed Google Scholar This dilemma highlights the difficulty confronting specialists in this field who recognize that patients seek therapies that are convenient to deliver, cause minimal or no side effects, and are affordable while they expect them also to be consistently and immediately effective.3Morales A Heaton J.P.W Johnston B et al.Oral and topical treatment of erectile dysfunction present and future.Urol Clin North Am. 1995; 22: 879-886PubMed Google Scholar Although erectile dysfunction specialists have been charged with providing treatments that fulfill all the prerequisites for ideal treatment, the new science of penile erection is indeed evolving to provide therapeutic options that are increasingly good prospects in this regard.The rapidly evolving pharmacotherapy of erectile dysfunction by any route of administration is grounded in an improved knowledge of the mechanisms required for erectile function. The scientific basis of penile erection has become increasingly understood as a result of efforts to investigate the pathophysiology of erectile dysfunction and explore the physiology and molecular biology of the erectile process. The recognition that certain disease states and injury pertaining to the innervation, vascular supply, or structural integrity of the penis commonly result in erectile dysfunction has resulted in the identification of functional components required for penile erection.4NIH Consensus Development Panel on ImpotenceImpotence.JAMA. 1993; 270: 83-89Crossref PubMed Scopus (1107) Google Scholar, 5Benet A.E Melman A The epidemiology of erectile dysfunction.Urol Clin North Am. 1995; 22: 699-709PubMed Google Scholar Similarly, observations of the effects of various recreational and prescription medications on spinal and supraspinal neurotransmission, on the systemic and local pelvic blood circulation, and even on the hormonal axis have contributed to defining the basic mechanisms involved in erectile function.6Shabsigh R Is a drug effect part of your patient’s complaint of impotence?.Contemp Urol. 1993; 5: 51-61Google ScholarBasic scientific and clinical research work in the field has profoundly advanced concepts regarding the cellular and molecular mechanisms that are fundamental to erectile function. Although the process of erection can be viewed simply as a series of vascular events carried out principally under neural control, it is also a complex physiologic function involving the coordination of a host of biochemical factors and effector systems that operate locally in the penis and at extrapenile regulatory sites. Accordingly, modern pharmacologic interests in treating erectile dysfunction, both orally and by alternative routes, have taken into consideration that multiple opportunities exist to intervene by diverse mechanistic approaches. Given this background, this review is written to describe currently available and imminently emerging oral pharmacotherapies for the treatment of erectile dysfunction. Although the clinical roles and issues regarding their practical use serve as the main focus of this report, an initial overview of the physiologic and pharmacologic principles of penile erection is presented to appreciate the evolution and mechanisms of action of these agents.Biology of penile erectionPenile erection is essentially a vascular biologic process that involves blood filling and maintenance within the organ, resulting in rigidity for a duration that sufficiently enables vaginal penetration. The key feature of this process is corporal smooth muscle relaxation, a function of the inflow arteries that dilate and thereby permit increased blood entry into the penis, and of the cavernous tissue trabeculae that engorge with blood and contribute to the veno-occlusive mechanism that restricts egress of blood from the penis. This function contrasts with that of the flaccid state of the penis, in which the trabecular smooth musculature is tonically contracted and limited blood flow circulates within the relatively constricted vasculature of the organ. Thus, the regulation of vascular and trabecular smooth muscle relaxation or contraction in the penis, which refers to the physiology of corporal smooth muscle tone, determines its erect or flaccid state, respectively.Corporal smooth muscle tone is controlled by an elaborate, integrative regulatory system, involving cellular and molecular mechanisms that serve to initiate and propagate the erectile stimulus required for penile erection.7Saenz de Tejada I Mechanisms for the regulation of penile smooth muscle contractility.in: Lue T.F World Book of Impotence. Smith-Gordon, London1992: 39-48Google Scholar, 8Andersson K.-E Wagner G Physiology of penile erection.Physiol Rev. 1995; 75: 191-236Crossref PubMed Scopus (1019) Google Scholar, 9Argiolas A Melis M.R Neuromodulation of penile erection an overview of the role of neurotransmitters and neuropeptides.Prog Neurobiol. 1995; 47: 235-255Crossref PubMed Scopus (146) Google Scholar, 10Giuliano F.A Rampin O Benoit G et al.Neural control of penile erection.Urol Clin North Am. 1995; 22: 747-766PubMed Google Scholar, 11Christ G.J The penis as a vascular organ the importance of corporal smooth muscle tone in the control of erection.Urol Clin North Am. 1995; 22: 727-745PubMed Google Scholar, 12Lue T.F Iriye C.A Medical management of erectile dysfunction.in: Walsh P.C Retik A.B Stamey T.A Campbell’s Urology Update 22. WB Saunders, Philadelphia1997: 1-9Google Scholar, 13Stief C.G Noack T Andersson K.-E Signal transduction in cavernous smooth muscle.World J Urol. 1997; 15: 27-31Crossref PubMed Scopus (46) Google Scholar, 14Christ G.J The “syncytial tissue triad” a model for understanding how gap junctions participate in the local control of penile erection.World J Urol. 1997; 15: 36-44Crossref PubMed Scopus (32) Google Scholar In broad conceptual terms, control is provided by extracellular mechanisms (ie, autonomic nervous system and non-neurogenic modulatory factors), intracellular mechanisms (ie, signal transduction pathways within corporal smooth muscle cells), and intercellular mechanisms (ie, cell-to-cell communication processing within corporal tissue). Various neurotransmitters are the principal agents in the origination and mediation of the erectile response, although hormones, and even autocrine and paracrine substances locally released from the endothelium or smooth muscle components of the erectile tissue, exert roles as erectile effectors. Second messenger molecules and ions transmit and amplify the extracellularly generated chemical signal after activation of membrane receptor proteins or intracellular enzyme pathways. Ion channels and gap junctions facilitate the coordination of corporal smooth muscle tone by permitting the intracellular and intercellular passage of physiologically relevant ions and second messenger molecules.The neurologic system represents the primary regulator of penile erections, exerting both proerectile and antierectile roles at peripheral and central nervous system levels.10Giuliano F.A Rampin O Benoit G et al.Neural control of penile erection.Urol Clin North Am. 1995; 22: 747-766PubMed Google Scholar, 15Burnett A.L Neurophysiology of erectile function and dysfunction.in: Hellstrom W.J.G The Handbook of Sexual Dysfunction. The American Society of Andrology, San Francisco1999: 12-17Google Scholar Peripherally, autonomic nervous system control consists of the sympathetic division, which is primarily associated with corporal smooth muscle contraction, and the parasympathetic division, which is associated with corporal smooth muscle relaxation. The primary antierectile neuroeffector in the penis has been confirmed to be the classic sympathetic neurotransmitter norepinephrine, released from local adrenergic nerve terminals. The proerectile neuroeffector does not appear to be exclusively the classic parasympathetic neurotransmitter acetylcholine released from cholinergic dilator nerves. Rather, a nonadrenergic, noncholinergic inhibitory neuroeffector system is perceived to exert this control. This system releases proerectile chemical mediators that have vasorelaxant effects and oppose the effects of contractile factors. Various neuronal and paracrine mediators representing this alternative system have been identified and studied as possible vasorelaxants in the penis, including gaseous molecules (eg, nitric oxide), neuropeptides (eg, vasoactive intestinal peptide, calcitonin gene-related peptide, substance P), purines (eg, adenosine triphosphate), decarboxylated amino acids, prostaglandins, bradykinin, and endothelial-derived factors. Antierectile effectors besides norepinephrine include neuropeptide Y and paracrine factors such as thromboxane, histamine, endothelin, and angiotensin II.At the central level, the roles of monoamines (eg, dopamine, norepinephrine, and 5-hydroxytryptamine [5-HT]), amino acids, neuropeptides (eg, oxytocin, prolactin, adrenocorticotropin [ACTH], opioids), and, recently, nitric oxide have been explored as erectile neuroeffectors. In the spinal pharmacology of penile erections, 5-HT (serotonin) has been most strongly implicated and may exert a role in both sympathetic and parasympathetic outflows. Depending on the action of the chemical at different 5-HT receptors, it may be associated with inhibitory (antierectile) or facilitatory (proerectile) effects on erectile responses. The supraspinal pharmacology of penile erection appears to involve several key neurotransmitters involving particular regulatory brain sites. A prevailing current thesis regarding central neurotransmission is that various neurotransmitter interactions converge on proerectile oxytocinergic neurotransmission in the paraventricular nucleus of the hypothalamus. Nitric oxide, dopamine, excitatory amino acids (eg, glutamic acid, aspartic acid), and even oxytocin itself have been proposed as activators of oxytocinergic pathways; opioid peptides are inhibitory in this regard. ACTH-like peptides appear to produce erections through an associated, although incompletely defined, pathway likely operating at the hypothalamic level.Additional regulation occurs at the level of the corporal smooth muscle cell involving intracellular signal transduction and intercellular communication mechanisms.12Lue T.F Iriye C.A Medical management of erectile dysfunction.in: Walsh P.C Retik A.B Stamey T.A Campbell’s Urology Update 22. WB Saunders, Philadelphia1997: 1-9Google Scholar, 13Stief C.G Noack T Andersson K.-E Signal transduction in cavernous smooth muscle.World J Urol. 1997; 15: 27-31Crossref PubMed Scopus (46) Google Scholar Intracellular signal transduction affords control on the basis of second messenger molecules that stimulate specific protein kinase-dependent biochemical cascades or ionic fluxes that alter the contractility of corporal smooth muscle. The cyclic nucleotide second messenger system involves the activation of membrane-bound or soluble guanylate and adenylate cyclases, which catalyze the production of 3′,5′-cyclic guanosine monophosphate (cGMP) and 3′,5′-cyclic adenosine monophosphate (cAMP), respectively, from their corresponding nucleotide triphosphates; these second messengers then proceed to activate various protein kinase interactions that induce corporal smooth muscle relaxation. This system explains the mechanism of action involving the principal proerectile mediator nitric oxide. With its diffusion from nerve endings and endothelium into corporal smooth muscle cells, this gaseous chemical binds with the soluble form of guanylate cyclase, which then induces cGMP production. Examples of adenylate cyclase activators are beta-adrenergic agonists and prostaglandin E1, which interact with the enzyme by way of specific membrane-bound receptors. The biochemical degradation of these cyclic nucleotides into inactive forms by phosphodiesterase hydrolysis also has implications with regard to regulating corporal smooth muscle tone.16Rall T.W Formation and degradation of cyclic nucleotides an overview.in: Nathanson J.A Kebabian C.N Handbook of Experimental Pharmacology. Springer-Verlag, New York1982: 3-16Google Scholar, 17Stief C.G Uckert S Becker A.J et al.The effect of the specific phosphodiesterase (PDE) inhibitors on human and rabbit cavernous tissue in vitro and in vivo.J Urol. 1998; 159: 1390-1393Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar The phosphoinositide system describes a pharmacomechanical coupling cascade involving inositol polyphosphates that stimulate the release of calcium from intracellular sarcoplasmic reticulum, resulting in tissue contraction. Norepinephrine, endothelin, angiotensin, vasopressin, and acetylcholine represent agonists of this system and operate by interacting with specific phosphoinositide system-associated membrane-bound receptors.Mechanisms involved in intracellular ion homeostasis also play a significant role in the regulation of corporal smooth muscle tone.12Lue T.F Iriye C.A Medical management of erectile dysfunction.in: Walsh P.C Retik A.B Stamey T.A Campbell’s Urology Update 22. WB Saunders, Philadelphia1997: 1-9Google Scholar, 13Stief C.G Noack T Andersson K.-E Signal transduction in cavernous smooth muscle.World J Urol. 1997; 15: 27-31Crossref PubMed Scopus (46) Google Scholar Cytoplasmic calcium ion concentration is a particularly important regulator of corporal smooth muscle contraction and relaxation. Increases in the cytoplasmic concentration of calcium ions lead to its binding with calmodulin and activation of myosin light-chain kinase, which then catalyzes the phosphorylation of myosin light-chain subunits as a fundamental step for the actin-myosin myofilament interaction that contracts smooth muscle. Phosphorylated myosin light-chain subunits also activate myosin adenosine triphosphatase (ATPase), which hydrolyzes adenosine triphosphate to provide energy for the cross-bridging of myosin heads with actin filaments. Decreases in the cytoplasmic concentration of calcium ions induce the dissociation of the calcium-calmodulin-myosin light-chain kinase complex, resulting in dephosphorylation of the myosin light-chain subunits by myosin light-chain phosphatase, that relaxes smooth muscle.Neuronal or hormonal stimulation can regulate calcium ion influx by cell-surface membrane channels, that leads to smooth muscle contraction. However, adrenergic agonists can induce contractile effects independent of calcium influx apparently by a “calcium-sensitizing” effect. Membrane-bound guanosine triphosphate-binding protein interactions may explain calcium ion-independent tissue tone effects that occur without changes in membrane potential. On the other hand, regulation of membrane potential may nonetheless occur in the absence of direct calcium ion channel activation. Beta-adrenergic agents, atrial natriuretic factor, and nitric oxide can operate in this fashion to induce smooth muscle relaxation by cGMP/protein kinase-associated potassium channel activation that hyperpolarizes the cell membrane. Additional biochemical mechanisms of action for nitric oxide such as the activation of sodium-potassium ATPase18Gupta S Moreland R.B Munarriz R et al.Possible role of Na+-K+-ATPase in the regulation of human corpus cavernosum smooth muscle contractility by nitric oxide.Br J Pharmacol. 1995; 116: 2201-2206Crossref PubMed Scopus (86) Google Scholar and modulation of a potassium conductance pathway19Seftel A.D Viola D.A Kasner S.E et al.Nitric oxide relaxes rabbit corpus cavernosum smooth muscle via a potassium-conductive pathway.Biochem Biophys Res Commun. 1996; 219: 382-387Crossref PubMed Scopus (25) Google Scholar provide alternative modes to alter the membrane potential that favors smooth muscle relaxation.In addition to these controls, gap junctions provide a mechanistic basis for the strong electrical coupling between corporal smooth muscle cells that accounts for the rapid and syncytial erectile tissue responsiveness to effector stimulation.11Christ G.J The penis as a vascular organ the importance of corporal smooth muscle tone in the control of erection.Urol Clin North Am. 1995; 22: 727-745PubMed Google Scholar, 14Christ G.J The “syncytial tissue triad” a model for understanding how gap junctions participate in the local control of penile erection.World J Urol. 1997; 15: 36-44Crossref PubMed Scopus (32) Google Scholar These represent cell membrane protein junctions (connexins) that function as channels between cells for the rapid passage of second messenger molecules and ions. Connexin 43 appears to be the predominant gap junction protein expressed in human corporal smooth muscle serving this purpose.Developing oral pharmacotherapeutic strategiesThe conceptual framework for understanding the physiology of penile erection and its regulatory mechanisms provides a foundation for considering pharmacotherapeutic approaches for treating erectile dysfunction. As stated earlier, the erectile state can be viewed simply as a finely controlled physiologic equilibrium between antierectile and proerectile mechanisms that influence corporal smooth muscle tone. Thus, the objective to stimulate erections pharmacotherapeutically might reasonably be based on strategies that suppress antierectile mechanisms or promote proerectile mechanisms, or achieve both.At the local or peripheral level, basic strategies are to (a) increase vascular and trabecular smooth muscle relaxation and (b) decrease vascular and trabecular smooth muscle contraction. Possible approaches to increase corporal smooth muscle relaxation include the application of receptor agonists or direct activators of tissue relaxant pathways (eg, effectors of cGMP and cAMP synthesis) and the application of agents that potentiate the effects of these relaxant pathways (eg, phosphodiesterase inhibitors). One approach to decrease corporal smooth muscle contraction is to apply receptor antagonists of tissue contractile pathways (eg, alpha1-adrenergic antagonists).At the central level, a similar strategic adjustment of proerectile and antierectile mechanisms can be considered for therapeutic purposes. However, such strategies must take into consideration that a particular drug may possess both proerectile and antierectile properties and its actual physiologic effect may depend on its combined interactions at possibly multiple brain or spinal cord regulatory sites, its dose-response relationships, and its receptor specificities.20Steers W.D Current perspectives in the neural control of penile erection.in: Lue T.F World Book of Impotence. Smith-Gordon, London1992: 23-32Google Scholar These considerations suggest that pharmacologic agents intended to exert effects centrally on penile erection must be particularly well evaluated before deciding whether they would offer a therapeutic benefit.Although the aforementioned scheme suggests the feasibility of multiple pharmacotherapeutic strategies for erectile dysfunction, several constraints are worth mentioning for the effective implementation of therapies whether the drug is to be delivered orally or by another route. First, potential therapies must be carefully evaluated to ensure that they are pharmacologically advantageous and clinically relevant. Thus, some rational mechanism of action should be discernible for the drug of interest in line with its presumed erectogenic potential, although it is also recognized that a complete definition of a particular drug’s mechanism may not be fully known at present. Related clinical pharmacokinetic concerns pertain to how completely and efficiently the drug is absorbed, what treatment schedule is required for it to be effective, whether it is metabolized to active or inactive forms, and whether it produces intolerable side effects.Second, the basis for assessing the efficacy of a potential drug treatment hinges on the quality of its clinical evaluation. The implication is that any presumably erectogenic drug should be subjected to an appropriately designed clinical trial. Accordingly, the type and severity of the erectile dysfunction should be characterized among study participants. Other issues to consider in evaluating the clinical role of a particular drug include whether the study was conducted prospectively, enrolled and randomized a sufficient number of patients, employed a multiple drug dose protocol to ascertain a meaningful dose-response relationship, and used placebo controls.Third, attention to outcome measures is particularly germane in this field of research. It is noteworthy that monitoring the erectogenic efficacy of any drug can be accomplished both objectively using clinical criteria of organ rigidity and subjectively using patient and partner questionnaires that report the degree of success with sexual intercourse. Recent trends to establish the roles of therapies in the field have reflected an increasing awareness that erectile performance significantly relates to quality-of-life issues, and thus subjective reporting is valuable. However, irrespective of the assessment tool used, results should be quantified in a standard manner to be able to discern the efficacy of the therapy and rate it meaningfully against another.Oral therapies for erectile dysfunctionThis section presents several options for the oral pharmacotherapeutic management of erectile dysfunction that are currently available for clinical use or are under scientific investigation in clinical trials. Discussion of widely touted, easily accessible therapies is limited to those that offer likely mechanisms of action for erection induction or have been subjected to a methodologically sound clinical evaluation, as suggested in the previous section, that allows some reasonable judgment to be made regarding their plausible roles. Brief presentations are made of a few interesting therapies that were discovered during their initial use in other clinical applications to have erectogenic potential and have been further examined for medical treatment of erectile dysfunction. Promising therapies that are under scientific investigation in clinical trials but are not yet approved for clinical distribution are presented based on their preliminary reports. The discussion is restricted to nonhormonal pharmacotherapeutic options, acknowledging that other specific indications typically invoke the administration of hormonal therapies (eg, testosterone for hypogonadism and bromocriptine for hyperprolactinemia).l-arginineThe discovery that nitric oxide is the principal mediator of penile erection prompted considerations that the precursor of this chemical may be used for the treatment of erectile dysfunction. In a small study involving 15 men using 2800-mg oral dosages of the amino acid for 2 weeks, 6 (40%) reported improvement in the quality of their erections.21Zorgniotti A.W Lizza E.F Effect of large doses of the nitric oxide precursor, l-arginine, on erectile dysfunction.Int J Impot Res. 1994; 6: 33-35PubMed Google Scholar There was no apparent toxicity or side effects associated with the treatment. Further systematic study is required before accepting l-arginine as an effective treatment for erectile dysfunction.Sildenafil citrateThe recently described roles of cyclic nucleotides as important second messenger molecules in the signal transduction mechanisms required for corporal smooth muscle relaxation has advanced pharmacologic strategies designed to promote their action. On the basis that phosphodiesterases hydrolyze cyclic nucleotides to their inactive forms, agents that inhibit the activities of these enzymes have represented an attractive approach to prevent cyclic nucleotide degradation and thus potentiate the mechanisms leading to erection. Furthermore, the demonstration that different phosphodiesterase isoenzymes predominate in various tissues of the body has afforded the development of inhibitors with expected tissue-specific relaxant effects. Sildenafil citrate (Viagra), approved by the Food and Drug Administration for clinical distribution in March 1998,22FDA resources page. Food and Drug Administration web site. Available at http://www.fda.gov/cder/consumerinfo/viagra/default.htm. Accessed December 1998.Google Scholar serves as an inhibitor of phosphodiesterase type 5 that specifically inactivates cGMP.23Boolell M Allen M.J Ballard S.A et al.Sildenafil an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction.Int J Impot Res. 1996; 8: 47-52PubMed Google Scholar, 24Jeremy J.Y Ballard S.A Naylor A.M et al.Effects of sildenafil, a type-5 cGMP phosphodiesterase inhibitor, and papaverine on cyclic GMP and cyclic AMP levels in the rabbit corpus cavernosum in vitro.Br J Urol. 1997; 79: 958-963Crossref PubMed Google Scholar, 25Moreland R.B Goldstein I Traish A Sildenafil, a novel inhibitor of phosphodiesterase type 5 in human corpus cavernosum smooth muscle cells.Life Sci. 1998; 62: 309-318Crossref PubMed Google Scholar, 26Ballard S.A Gingell C.J Tang K et al.Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes.J Urol. 1998; 159: 2164-2171Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar, 27Chuang A.T Strauss J.D Murphy R.A et al.Sildenafil, a type-5 cGMP phosphodiesterase inhibitor, specifically amplifies endogenous cGMP-dependent relaxation in rabbit corpus cavernosum smooth muscle in vitro.J Urol. 1998; 160: 257-261Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar Its role in the treatment of erectile dysfunction has evolved from the confirmation of phosphodiesterase type 5 in human cavernous tissue and the potent relaxant effect of its inhibition on precontracted human cavernous tissue in vitro.17Stief C.G Uckert S Becker A.J et al.The effect of the specific phosphodiesterase (PDE) inhibitors on human and rabbit cavernous tissue in vitro and in vivo.J Urol. 1998; 159: 1390-1393Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 26Ballard S.A Gingell C.J Tang K et al.Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes.J Urol. 1998; 159: 2164-2171Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar, 28Taher A Meyer M Stief C.G et al.Cyclic nucleotide phosphodiesterase in human cavernous smooth muscle.World J Urol. 1997; 15: 32-35Crossref PubMed Scopus (63) Google ScholarIn an initial double-blind, randomized, placebo-controlled crossover study in which the agent was used in patients with no discernible major organic component associated with their erectile dysfunction, 10 (83.3%) of 12 patients reported improved erectile activity while receiving sildenafil compared with 2 (16.7%) of 12 patients taking placebo.29Boolell M Gepi-Atee S Gingell J.C et al.Sildenafil, a novel effective oral therapy for male erectile dysfunction.Br J Urol. 1996; 78: 257-261Crossref PubMed Scopus (522) Google Scholar Subsequent evaluation of the efficacy of this agent conducted in similarly designed trials that also permitted dose escalation (25, 50, or 100-mg dosages) in patients with erectile dysfunction from a broad spectrum of etiologies demonstrated a 69% successful sexual intercourse rate reported by men receiving sildenafil compared with 22% for those receiving placebo.30Goldstein I Lue T.F Padma-Nathan H et al.Oral sildenafil in the treatment of erectile dysfunction.N Engl J Med. 1998; 338: 1397-1404Crossref PubMed Scopus (2026) Google Scholar Erectile function responses have been demonstrated in various select patient populations studied systematically using the medication, including 75% of spinal cord-injured patients reporting improved erections,31Derry F Glass C Dinsmore W et al.Sildenafil (Viagra™) an oral treatment for men with erectile dysfunction caused by traumatic spinal cord injury—a 28 day, double-blind, placebo-controlled, parallel-group, dose-response study.Neurology. 1997; 48: A215Google Scholar an equivalent percentage of elderly patients as younger men reporting improved erections,32Wagner G Mayton M Smith M.D Analysis of the efficacy of sildenafil (Viagra™) in the treatment of male erectile dysfunction in elderly patients.J Urol. 1998; 159 (abstract): 239Abstract Full Text Fu