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Current Perspectives on Intracavernosal Pharmacotherapy for Erectile Dysfunction

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International Journal of Impotence Research (2000) 12, Suppl 4, S91±S100 ß 2000 Macmillan Publishers Ltd All rights reserved 0955-9930/00 $15.00 www.nature.com/ijir Current perspectives on intracavernosal pharmacotherapy for erectile dysfunction H Porst1* 1Neuer Jungfernstieg 6a, 20354 Hamburg, Germany Thirty percent of males af¯icted with erectile dysfunction (ED) do not respond to oral drugs, another 15% reveal contraindications to currently available therapy, and a subset of patients actually prefer injection therapy due to its predictable short time-to-onset of erection and reliable rigidity compared to oral drugs. This paper provides both a historical and current perspective on intracavernosal therapy and reviews the popular injectable therapeutic agents that are currently used for the treatment of ED. Emphasis is placed on the ef®cacy, mechanism of action and side effect pro®les of approved and experimental injectable pharmacotherapy for ED. International Journal of Impotence Research (2000) 12, Suppl 4, S91±S100. Keywords: erectile dysfunction; penis, injectable pharmacotherapy History of intracavernosal pharmacotherapy acceptance following the publication of Goldstein in 1990, especially in the USA.8 In 1989, the relatively selective alpha1-adreno- It is generally acknowledged that the onset of ceptor blocker moxisylyte (thymoxamine) was in- intracavernosal pharmacotherapy began with the troduced by Buvat et al.9 Moxisylyte was ®rst publication by Virag in 1982 concerning the erec- marketed in France as Icavex1 and Erecnos1 and tion-including properties of papaverine.1 Further the latter has since been withdrawn due to important early publications in this ®eld described unpro®table sales rates. The erectile potential of the erectile potency of the alpha-adrenoceptor other vasoactive drugs, eg, calcitonin-gene-related- blockers phenoxybenzamine and phentolamine2 peptide (CGRP), linsidomine (syn. SIN-1), vaso- and the combination of papaverine=phentolamine active intestinal polypeptide (VIP) or sodium for autoinjection of the cavernous bodies.3 In fact, nitroprusside, was temporarily publicised but none the work of Zorgniotti and Le¯eur3 marked the of the cited compounds gained market appr- breakthrough of self-injection therapy as a comple- oval status.10 ± 15 In this context, two exceptions tely new tool in the management of male impotence. deserve mention. Firstly, the combination of papa- One year later, at the Second World Meeting on verine=phentol-zamine (Androskat1) was of®cially Impotence in Prague, PGE1 (alprostadil) was intro- approved by the local health authorities of several duced for self-injection therapy, by both Adaikan4 countries and is marketed in the Benelux and and Ishii.5 Two years later, these favorable pre- German-speaking countries of Europe. Secondly, liminary reports on alprostadil were con®rmed in the combination of VIP=Phentolamine (Invicorp1), larger clinical trials by Porst and Stackl, respec- originally studied by Gerstenberg et al in 1992, was tively.6,7 Alprostadil has since become the global of®cially approved in Denmark but not marketed leader in intracavernosal pharmacotherapy. It is and can be prescribed on an individual `named' marketed by two different companies as alprostadil basis in UK.16 sterile powder (Caverject1, Pharmacia & Upjohn) and alprostadil alfadex (Edex1, Viridal1, Schwarz Pharma AG); both agents exhibit an identical Pharmacological considerations of marketed ef®cacy- and side-effect spectrum. intracavernosal vasoactive drugs (Table 1) Parallel to the development of monotherapy with alprostadil, the trimix combination of PGE1= papaverine=phentolamine began to gain broad Papaverine *Correspondence: H Porst, Neuer Jungfernstieg 6a, 20354 Papaverine belongs to the family of non-selective Hamburg, Germany. phosphodiesterase inhibitors. Depending on the E-mail: [email protected] target-tissue-related dominance of the respective Current perspectives on intracavernosal pharmacotherapy H Porst S92 Table 1 Biological effects of marketed vasoactive drugs for self-injection therapy in erectile dysfunction Compound Site of action Effect on cavernous tissue Papaverine Phosphodiesterases (non-selective) 3050-cAMP=cGMP: L-type Ca2 channels (inhibition) Intracellular Ca2; Angiotensin II secretion (inhibition) Smooth muscle tone; Phentolamine a1 ± 2 adrenoceptors (blockade) Noradrenaline effects; Maxi K channels (stimulation) Hyperpolarization NO-synthase (stimulation) Intracellular NO: 0 0 Alprostadil (PGE1) Adenylate cyclase 3 5 -cAMP: Presynaptic a1 receptors (inhibition) Noradrenaline release; Angiotensin II secretion (inhibition) Smooth muscle tone; Maxi-K channels (stimulation) Hyperpolarization TGF-b1 (inhibition) Collagen-production; Moxisylyte a1-adrenoceptors Noradrenaline effects; VIP Adenylate cyclase 3050-cAMP: phosphodiesterases (PDE1 to PDE10), administration receptor activity with LDL degradation, positive of papaverine results in cAMP or cGMP accumula- effects on rheologic properties and blood viscosity, tion. Papaverine also appears to exert inhibitory decrease of cholesterol deposition into the arterial effects on L-type voltage-dependent Ca2 channels wall and inhibition of platelet aggregation resulting and on angiotensin II secretion.17,18 in atherosclerosis prevention, inhibition of noradre- naline-induced lipolysis, and positive effects on cellular nutritive metabolism of ischemic tissue due Phentolamine to decrease of the lactate to pyruvate ratio. Phentolamine represents a non-selective alpha1±2- Moxisylyte (thymoxamine) adrenoceptor blocker with impact both on pre- and post-synaptic alpha-adrenoceptors. In the canine- model, phentolamine administration resulted in a Moxisylyte has alpha1±2-receptor blocking proper- 9,28 50 ± 100% increase of penile arterial blood ¯ow ties with preference for alpha1-adrenoceptors. without an additional in¯uence on the veno- Moxisylyte is a pro-drug that is immediately con- occlusive mechanism.19 Beyond this dominant verted to ®ve metabolites, four of which exhibit pharmacological action, it was shown that phento- biological activities.28 lamine has potassium channel opening, endothelin antagonist and direct nitric oxide (NO)-synthase activating properties.20,21 Vasoactive intestinal polypeptide Vasoactive intestinal polypeptide (VIP) is a natu- Alprostadil (PGE1) rally occurring neurotransmitter which is co-loca- lized with NO at the nonadrenergic, noncholinergic Proven pharmacological and biological effects of (NANC) nerve-terminals in cavernous tissue.29 VIP alprostadil in the context of ED are: stimulates adenylate cyclase and results in the 0 0 (1) Stimulation of adenylate cyclase with generation generation of 3 5 -cAMP. In animal studies, intra- of 3050-cAMP.22 cavernosal VIP induced tumescence and partial erection, which was primarily due to decreased (2) Inhibition of noradrenaline release at alpha1- adrenoceptors via presynaptic prostaglandin penile venous out¯ow and to a minor extent, 30 receptors.23 increased arterial in¯ow. (3) Inhibition of angiotensin II secretion.18 (4) Stimulation of maxi-K ion channels resulting in membrane hyperpolarization.24 Clinical results of self-injection therapy with (5) Neuromodulatory activities on the medial pre- marketed vasoactive drugs optic area.25 (6) Inhibition of the transforming growth factor b1 (TGF-b1) resulting in anticollagen and therefore Papaverine anti®brotic effects.26 In addition, prostaglandins and especially PGE1 Papaverine is extremely stable in solution and loses have demonstrated other biological effects includ- only 10% of its potency over a 4 y period. Commer- ing:27 decrease of low density lipoprotein (LDL) cial papaverine solutions have a low pH between 3 International Journal of Impotence Research Current perspectives on intracavernosal pharmacotherapy H Porst S93 and 3.7; at pH values above 5, the compound verine alone to the mixture of papaverine= precipitates. After intracavernosal application, max- phentolamine conducted under good clinical prac- imal plasma levels are reached within 10 to 30 min tice guidelines are not available. In valuable retro- and the half-life is approximately 1 to 2 h.31 spective studies that have considered important Papaverine is extensively metabolised in the liver. issues related to self-injection therapy, ie, success-, Reported ef®cacy rates with dosages between 30 and side-effect- and drop-out rates, global ef®cacy rates 110 mg varied between 27 and 78% and were were 68.5% in diagnostic use in 3016 assessed dependent on dosage and the patient population patients.27 Frequent side-effects were similar to investigated.27,32,33 A literature analysis of 19 pub- those of papaverine. Priapisms were reported in lications that included 2181 patients overall demon- 6 ± 15% and ®brotic alterations occurred in an strated that papaverine produced an average average of 12.4% of patients treated (see Table 2), response rate of 61% in in-of®ce testing.27 The most although in some studies, ®brotic complications important side-effects were priapisms in 3 ± 18.5%, occurred in considerably higher percentages of 18 ± which mostly occurred during the titration phase. 57%.27,37 ± 40 Hepatotoxic effects with elevation of Fibrotic alterations were seen in 5 ± 30% of patients liver enzymes were reported in an average of 5.4% with an average of 5.7% in 15 retrospective studies (43=799) of patients in one review of varied (Table 2).27,32,33 In long-term self-injection trials, publications.27 papaverine produced liver enzyme elevations in
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