The range of therapies for treating erectile dysfunction

Transcription

1 REVIEW CME ARTICLE ORAL PHARMACOTHERAPY FOR ERECTILE DYSFUNCTION: CURRENT PERSPECTIVES ARTHUR L. BURNETT Dr. Burnett is on the Speakers Bureau for Pfizer. From the Department of Urology, Johns Hopkins University School of Medicine and James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, Maryland Reprint requests: Arthur L. Burnett, M.D., Department of Urology, Marburg 407, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD Submitted: March 4, 1999, accepted: April 12, 1999 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. 1,2 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. 3 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. 4,5 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. 6 Basic 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. 1999, ELSEVIER SCIENCE INC. UROLOGY 54: , /99/$ ALL RIGHTS RESERVED PII S (99)

2 BIOLOGY OF PENILE ERECTION Penile 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 In broad conceptual terms, control is provided by extracellular mechanisms (ie, autonomic nervous system and nonneurogenic 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. 10,15 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 endothelialderived 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. 12,13 Intracellular signal transduction affords control on the basis of second messenger molecules that stimulate specific pro- UROLOGY 54 (3),

3 tein 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 E 1, 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. 16,17 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. 12,13 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 crossbridging of myosin heads with actin filaments. Decreases in the cytoplasmic concentration of calcium ions induce the dissociation of the calciumcalmodulin-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. Membranebound 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 ATPase 18 and modulation of a potassium conductance pathway 19 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. 11,14 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 STRATEGIES The 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 path- 394 UROLOGY 54 (3), 1999

4 ways (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, alpha 1 -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. 20 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 DYSFUNCTION This 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-ARGININE The 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. 21 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. UROLOGY 54 (3),

5 SILDENAFIL CITRATE The 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, 22 serves as an inhibitor of phosphodiesterase type 5 that specifically inactivates cgmp 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. 17,26,28 In an initial double-blind, randomized, placebocontrolled 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. 29 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. 30 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, 31 an equivalent percentage of elderly patients as younger men reporting improved erections, 32 56% of diabetics reporting improved erections, 33 84% of patients with a psychogenic etiology for their erectile dysfunction reporting improved erections, 34 and 43% of patients after radical prostatectomy reporting improved erections, 34 although 80% of the patients who had undergone bilateral nerve-sparing procedures reported successful sexual intercourse. 35 In a meta-analysis of 10 studies consisting of 2085 men categorized as having severe erectile dysfunction, there was a 46% rate of reported successful sexual intercourse among patients using the medication compared with 8% for those using placebo. 36 These reports that sildenafil produces erectile responses among patients with erectile dysfunction from a broad range of etiologies and of major severity and meets efficacy criteria such as a well-determined threshhold of erectile response provide important support for the role of this oral therapy in the treatment of erectile dysfunction. A comprehensive analysis has also been performed to examine the safety and tolerability data accumulated from 10 studies consisting of 4274 patients receiving double-blind, placebocontrolled treatment for up to 1 year. 37 The most commonly reported adverse events were headache (16% sildenafil, 4% placebo), facial flushing (10% sildenafil, 1% placebo), and dyspepsia (7% sildenafil, 2% placebo), and they were mostly transient and mild or moderate. No cases of priapism were reported in this analysis. The adverse events were viewed as being consistent with the pharmacology of sildenafil as an inhibitor of type 5 phosphodiesterase, which may also be expressed in extrapenile vascular tissues. A 2.5% rate of discontinuation because of adverse events was reported with sildenafil compared with a 2.3% rate with placebo. These data suggesting that sildenafil is a welltolerated oral treatment for erectile dysfunction further support the clinical place afforded this medication in the contemporary treatment of erectile dysfunction. However, despite these favorable indications, several concerns remain. Among the guidelines for its use, 22,34 an absolute contraindication to the use of sildenafil is the concomitant use of nitrate drugs, which may result in severe and possibly fatal consequences, owing to a profound systemic vasodilatory effect of the drugs acting synergistically. 34 Caution may also be advised in administering the medication to patients with retinal disorders such as the rare congenital eye disease, retinitis pigmentosa, in view of the unknown long-term risk of retinal damage associated with effects of the drug on type 6 phosphodiesterase expressed in the retina. 22 These concerns emphasize the need for responsibility in the administration of the medication, as well as continued diligence to chart the long-term clinical experience with the medication and carry out additional objective evaluations of potential toxicities that have not yet been identified. APOMORPHINE Observations that the parenteral administration of apomorphine, a dopaminergic agonist, produces erectile responses in humans and animals provided the impetus for the development of an orally administered form of this agent. 38 Furthermore, basic scientific work in animals that elucidated dopami- 396 UROLOGY 54 (3), 1999

6 nergic mechanisms for the central mediation of penile erection suggested its particular relevance in the treatment of men with psychogenic impotence. 9 Such investigation began after the development of a novel buccal formulation that exploits its mucosal absorption and overcomes its poor bioavailability when ingested. 39 In an initial placebocontrolled clinical trial among men in whom no organic etiology was specified for their erectile dysfunction, the formulation was found to be significantly more effective than placebo according to objective rigidity testing. 39 Subsequent evaluation consisting of patient-reported successful sexual intercourse for up to 7 months indicated a response rate in 7 (64%) of 11 patients. 39 The investigators recognized that the nausea, vomiting, drowsiness, hypotension, and yawning side effects of the medication might limit its toleration but also suggested that a low dosage range might overcome this limitation. A recent report has described the results of this formulation in a multicenter, double-blind, placebo-controlled study of 457 men with erectile dysfunction without a major organic component. 40 Using the percentage of attempts resulting in successful sexual intercourse as an end point, the study showed a 45.8% success rate for the 2-mg dosage compared with 32.2% for placebo, a 52% success rate for the 4-mg dosage compared with 35% for placebo, and a 59.6% success rate for the 6-mg dosage compared with 34.2% for placebo. The most commonly observed adverse event was nausea in 39%, 19.5%, and 2.1% of patients for the 6, 4, and 2-mg dosages, respectively. The results of these studies provide some support for the idea that a centrally acting initiator of erectile responses may serve as a useful buccal pharmacologic option for treating erectile dysfunction. However, the selection of an optimal dosage remains confounded by the substantial adverse effects that offset the usefulness of the most highly efficacious dosages. At present, the medication remains available in investigational protocols only. LEVODOPA Another dopaminergic agonist, levodopa, a precursor of dopamine used in the treatment of Parkinson s disease, was recently evaluated in a clinical trial consisting of 21 men without complaints of erectile dysfunction who used the medication at an 800-mg daily oral dosage for 7 days and were studied by sleep-related penile tumescence monitoring. 41 Accordingly, all 21 men met objective criteria of erectile responses that were significantly better than baseline responses. No adverse effects were reported. The results provide further support for a central dopaminergic erection mediation pathway and would support the development of pharmacologic agents with dopaminergic action for the treatment of erectile dysfunction. However, further investigation is necessary to examine the role of levodopa in men established to have erectile dysfunction and in the context of a coital situation. PHENTOLAMINE The erectogenic potential for agents that inhibit the sympathetically mediated adrenergic effector system responsible for penile detumescence and flaccidity has been well demonstrated with the intracavernous pharmacotherapeutic use of phentolamine, an alpha 1 -selective adrenergic receptor antagonist. In early clinical investigation, phentolamine used at a 50-mg oral dosage produced erections that enabled successful sexual intercourse in 11 (68.8%) of 16 patients in one trial 42 and in 36 (42.3%) of 85 patients in another. 43 In another investigation conducted according to a prospective, double-blind, placebo-controlled protocol that excluded patients with a primary psychogenic etiology for their erectile dysfunction, successful intercourse rates were reported to be 3 (30%) of 10, 5 (50%) of 10, and 4 (40%) of 10 among patients using 20, 40, and 60-mg dosages of oral phentolamine, respectively, compared with a 2 (20%) of 10 rate reported among patients using placebo. 44 Large multicenter trials involving patients considered to have minimal erectile dysfunction with a broad-spectrum etiology evaluated by a placebocontrolled, parallel group, double-blind study design with randomization to two oral phentolamine dosages or placebo and by a placebo-controlled, crossover design with a fixed dosage of 40 mg oral phentolamine or placebo were recently reported. 45 In the former study, erectile function improvement was shown in 37% and 45% of men using the 40 and 80-mg dosages, respectively, and in 16% of men on placebo. In the latter study, erectile function improvement was shown in 34% of men using 40 mg of oral phentolamine and in 21% of men taking placebo. These studies have uniformly shown that the medication is virtually devoid of serious adverse effects, with less than 10% of patients taking the 40-mg dosage in the most recent report experiencing headaches, facial flushing, or nasal congestion. 45 However, the efficacy of this medication for men with more severe forms of erectile dysfunction who may evaluate their success in performing sexual intercourse as a satisfactory end point remains uncertain. Although the medication has received commercial support for development, the formulations evaluated thus far appear limited to use in investigational trials. YOHIMBINE An indole alkaloid derived from the bark of the yohimbe tree that has long been available and be- UROLOGY 54 (3),

7 lieved to have potent erectogenic if not aphrodisiac properties, yohimbine has only recently been seriously investigated as a treatment for erectile dysfunction. The compound has been characterized as an alpha 2 -adrenergic receptor antagonist with likely significant central effects on the mediation of penile erection. 46 In an early investigation of the role of this medication at a 6-mg oral dosage used three times daily, men with erectile dysfunction of a primary organic etiology were noted to report a 42% response rate compared with a 62% response rate reported among men having a primary psychogenic etiology and a 16% response rate reported in the placebo group. 47 A meta-analysis of all randomized, placebo-controlled trials involving yohimbine suggested a superior effect for the medication compared with placebo. 48 A recent study examining the role of this medication at a 100-mg daily oral dosage for 30 days in men with organic erectile dysfunction reported a response that enabled sexual intercourse in only 3 (13.6%) of 22 men, which did not differ statistically from the placebo response. 49 Adverse effects appear to be relatively infrequent, although they occur more commonly with increasing dosages. These include hypertension, anxiety, tachycardia, and headache. 48,49 A stance taken by the American Urological Association Guidelines Committee on Erectile Dysfunction is that this medication offers no efficacy for organic erectile dysfunction. 50 TRAZODONE Early reports that the antidepressant medication trazodone caused priapism 51 led to intense scientific investigation into its possible role for the treatment of erectile dysfunction. According to described mechanisms at the spinal cord level, the active metabolite of trazodone acts as an agonist of the proerectile 5-HT 1c receptor through reuptake inhibition and may also exert effects as an antagonist of antierectile 5-HT 1a and 5-HT 2 receptors. 10,15 Support also exists for the role of trazodone as an alpha-adrenergic antagonist at the corporal tissue level. 52 In clinical use at dosages typically ranging from 100 to 200 mg orally at bedtime, initial efficacy rates for erectile improvement ranged between 60% and 78% In a double-blind, placebo-controlled multicenter trial in which the medication at a 150-mg oral daily dosage was administered by randomization with placebo for 4 weeks to men with diverse etiologies for their erectile dysfunction, subjective response rates were 4 (15%) of 26 using the medication compared with 5 (16%) of 32 using placebo. 56 In a randomized, double-blind, placebo-controlled trial involving men indicating at least a 3-month duration of erectile dysfunction of any form, patients using trazodone at a 50-mg daily dosage for 3 months reported a 19% erection improvement rate compared with a 24% rate reported among those on placebo. 57 The medication appears to be reasonably well tolerated and safe, with minimal side effects of drowsiness (31%), fatigue (19%), and dry mouth (1%). 56,57 Unfortunately, the sum of the recent data suggests no clinical efficacy for this medication, particularly for severe forms of erectile dysfunction. LIMAPROST The enthusiasm for prostaglandin E 1 as a peripherally active vasodilator that has been effectively applied in intracavernous pharmacotherapy regimens prompted consideration for this medication as an oral agent. The administration of limaprost at a 30- g oral dosage three times daily for 8 weeks to patients categorized as having mild erectile dysfunction resulted in 11 (45.8%) of 24 reporting successful sexual intercourse compared with 4 (16.7%) of 24 reporting this outcome taking the Chinese herbal drug, gosyajinki-gan, over the same period. 58 Objective rigidity measurements were also significantly higher with limaprost treatment. Adverse effects were reportedly negligible, as only 1 patient using limaprost treatment developed facial flushing. Despite these favorable early results, further systematic study of this medication is required to corroborate these findings. NALTREXONE The opioid inhibitory effect on erectile function in both animals and humans is consistent with hypothesized central pathways that mediate erectile function. 9 In a randomized, double-blind, placebocontrolled pilot study involving 20 patients without a documented organic etiology for their erectile dysfunction, use of naltrexone, an opiate antagonist, at a dosage of as much as 25 mg orally twice daily during an 8-week period resulted in a statistically significant improvement in erections but no apparent increased frequency in sexual intercourse in the treatment group compared with controls. 59 No apparent side effects were identified. Although these findings represent a limited investigation of the role of opiate antagonist therapy, further support from systematic study of these agents must be obtained before considering them to have any substantial efficacy in the treatment of erectile dysfunction. CONCLUSIONS The introduction of oral options for treating erectile dysfunction is welcomed and promises to revolutionize management of this disorder. The development of new oral agents has coincided with an improved understanding of the physiology and 398 UROLOGY 54 (3), 1999

8 molecular basis of penile erection. Further experimental and clinical progress in the field is eagerly anticipated. However, conclusions regarding the eventual roles of these therapies should only follow close scrutiny of their treatment efficacies and safety profiles. REFERENCES 1. Jarow JP, Nana-Sinkam P, Sabbagh M, et al: Outcome analysis of goal directed therapy for impotence. J Urol 155: , Hanash KA: Comparative results of goal oriented therapy for erectile dysfunction. J Urol 157: , Morales A, Heaton JPW, Johnston B, et al: Oral and topical treatment of erectile dysfunction: present and future. Urol Clin North Am 22: , NIH Consensus Development Panel on Impotence: Impotence. JAMA 270: 83 89, Benet AE, and Melman A: The epidemiology of erectile dysfunction. Urol Clin North Am 22: , Shabsigh R: Is a drug effect part of your patient s complaint of impotence? Contemp Urol 5: 51 61, Saenz de Tejada I: Mechanisms for the regulation of penile smooth muscle contractility, in Lue TF (Ed): World Book of Impotence. London, Smith-Gordon, 1992, pp Andersson K-E, and Wagner G: Physiology of penile erection. Physiol Rev 75: , Argiolas A, and Melis MR: Neuromodulation of penile erection: an overview of the role of neurotransmitters and neuropeptides. Prog Neurobiol 47: , Giuliano FA, Rampin O, Benoit G, et al: Neural control of penile erection. Urol Clin North Am 22: , Christ GJ: The penis as a vascular organ: the importance of corporal smooth muscle tone in the control of erection. Urol Clin North Am 22: , Lue TF, and Iriye CA: Medical management of erectile dysfunction, in Walsh PC, Retik AB, Stamey TA, et al (Eds): Campbell s Urology: Update 22. Philadelphia, WB Saunders, 1997, pp Stief CG, Noack T, and Andersson K-E: Signal transduction in cavernous smooth muscle. World J Urol 15: 27 31, Christ GJ: The syncytial tissue triad : a model for understanding how gap junctions participate in the local control of penile erection. World J Urol 15: 36 44, Burnett AL: Neurophysiology of erectile function and dysfunction, in Hellstrom WJG (Ed): The Handbook of Sexual Dysfunction. San Francisco, The American Society of Andrology, 1999, pp Rall TW: Formation and degradation of cyclic nucleotides: an overview, in Nathanson JA, and Kebabian CN (Eds): Handbook of Experimental Pharmacology. New York, Springer- Verlag, 1982, pp Stief CG, Uckert S, Becker AJ, et al: The effect of the specific phosphodiesterase (PDE) inhibitors on human and rabbit cavernous tissue in vitro and in vivo. J Urol 159: , Gupta S, Moreland RB, 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 116: , Seftel AD, Viola DA, Kasner SE, et al: Nitric oxide relaxes rabbit corpus cavernosum smooth muscle via a potassium-conductive pathway. Biochem Biophys Res Commun 219: , Steers WD: Current perspectives in the neural control of penile erection, in Lue TF (Ed): World Book of Impotence. London, Smith-Gordon, 1992, pp Zorgniotti AW, and Lizza EF: Effect of large doses of the nitric oxide precursor, L-arginine, on erectile dysfunction. Int J Impot Res 6: 33 35, FDA resources page. Food and Drug Administration web site. Available at viagra/default.htm. Accessed December Boolell M, Allen MJ, Ballard SA, et al: Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 8: 47 52, Jeremy JY, Ballard SA, Naylor AM, 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 79: , Moreland RB, Goldstein I, and Traish A: Sildenafil, a novel inhibitor of phosphodiesterase type 5 in human corpus cavernosum smooth muscle cells. Life Sci 62: , Ballard SA, Gingell CJ, 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 159: , Chuang AT, Strauss JD, Murphy RA, 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 160: , Taher A, Meyer M, Stief CG, et al: Cyclic nucleotide phosphodiesterase in human cavernous smooth muscle. World J Urol 15: 32 35, Boolell M, Gepi-Atee S, Gingell JC, et al: Sildenafil, a novel effective oral therapy for male erectile dysfunction. Br J Urol 78: , Goldstein I, Lue TF, Padma-Nathan H, et al: Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 338: , Derry 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 48: A215, Wagner G, Mayton M, and Smith MD: Analysis of the efficacy of sildenafil (Viagra ) in the treatment of male erectile dysfunction in elderly patients (abstract). J Urol 159: 239, Rendell MS, Rajfer J, Wicker PA, et al: Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. JAMA 281: , Pfizer, Viagra (sildenafil citrate) Package Insert. Revised November Zippe CD, Kedia AW, Kedia K, et al: Treatment of erectile dysfunction after radical prostatectomy with sildenafil citrate (Viagra). Urology 52: , Steers WD: Meta-analysis of the efficacy of sildenafil (Viagra ) in the treatment of severe erectile dysfunction (abstract). J Urol 159: 238, Morales A, Gingell C, Collins M, et al: Clinical safety of oral sildenafil citrate (Viagra) in the treatment of erectile dysfunction. Int J Impot Res 10: 69 73, Lal S, Laryea E, Thavundayil JX, et al: Apomorphineinduced penile tumescence in impotent patients preliminary findings. Prog Neuropsychopharmacol Biol Psychiatry 11: , Heaton JPW, Morales A, Adams MA, et al: Recovery of erectile function by the oral administration of apomorphine. Urology 45: , Padma-Nathan H, Fromm-Freeck S, Ruff DD, et al: Efficacy and safety of apomorphine sl vs placebo for male erectile dysfunction (MED) (abstract). J Urol 159: 241, UROLOGY 54 (3),

9 41. Horita H, Sato Y, Adachi H, et al: Effects of levodopa on nocturnal penile tumescence: a preliminary study. J Androl 19: , Gwinup G: Oral phentolamine in non-specific erectile insufficiency. Ann Intern Med 109: , Zorgniotti AW: Experience with buccal phentolamine mesylate for impotence. Int J Impot Res 6: 37 41, Becker AJ, Stief CG, Machtens S, et al: Oral phentolamine as treatment for erectile dysfunction. J Urol 159: , Goldstein I: Efficacy and safety of oral phentolamine (Vasomax) for the treatment of minimal erectile dysfunction (abstract). J Urol 159: 240, Clark JT: Suppression of copulatory behaviour in male rats following central administration of clonidine. Neuropharmacology 30: , Morales A, Surridge DG, Marshall PG, et al: Non-hormonal pharmacological treatment of organic impotence. J Urol 128: 45 47, Ernst E, and Pittler MH: Yohimbine for erectile dysfunction: a systematic review and meta-analysis of randomized clinical trials. J Urol 159: , Telöken C, Rhoden EL, Sogari P, et al: Therapeutic effects of high dose yohimbine hydrochloride on organic erectile dysfunction. J Urol 159: , Montague DK, Barada JH, Belker AM, et al: Clinical guidelines panel on erectile dysfunction: summary report on the treatment of organic erectile dysfunction. J Urol 156: , Carson CC, and Mino RD: Priapism associated with trazodone therapy. J Urol 139: , Saenz de Tejada I, Ware JC, Blanco R, et al: Pathophysiology of prolonged penile erection associated with trazodone use. J Urol 165: 60 63, Abber JC, Lue TF, Luo JA, et al: Priapism induced by chlorpromazine and trazodone: mechanism of action. J Urol 137: , Kurt U, Ozkardes J, Altug U, et al: The efficacy of antiserotoninergic agents in the treatment of erectile dysfunction. J Urol 152: , Lance R, Albo M, Costabile RA, et al: Oral trazodone as empirical therapy for erectile dysfunction: a retrospective review. Urology 46: , Meinhardt W, Schmitz PIM, Kropman RF, et al: Trazodone, a double blind trial for treatment of erectile dysfunction. Int J Impot Res 9: , Costabile RA, and Spevak M: Trazodone is not effective therapy for erectile dysfunction: the results of a placebo controlled, double blind study (abstract). J Urol 159: 240, Sato Y, Horita H, Adachi H, et al: Effect of oral administration of prostaglandin E 1 on erectile dysfunction. Br J Urol 80: , van Ahlen H, Piechota HJ, Kias HJ, et al: Opiate antagonists in erectile dysfunction: a possible new treatment option? Eur Urol 28: , UROLOGY 54 (3), 1999