Current Perspectives on Intracavernosal Pharmacotherapy for Erectile Dysfunction

Home , Moxisylyte, Phentolamine, Trimix (breathing gas), Trimix (drug)

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in France as Icavex1 and Erecnos1 and tion-including properties of papaverine.1 Further the latter has since been withdrawn due to important early publications in this ®eld described unpro®table sales rates.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 noradrenaline-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 1.6% of patients, evidence of hepatotoxic potential.27 In animal studies, papaverine resulted in the 1 1 Alprostadil syn. PGE1 (Caverject and Edex or highest ®brosis-rate among all the investigated Viridal1) vasoactive drugs. For this reason, monotherapy with papaverine has been discontinued in most indus- trialized countries.34,35 However, due to its con- The pharmacologic pro®le of alprostadil is sum- siderably low cost, self-injection monotherapy with marized in Table 6. Intracavernously (i.c.)-injected papaverine still continues in many developing alprostadil may be partially metabolized by the countries. enzymes of the cavernous tissue and although considerable amounts reach the systemic circulation, it is metabolized during the passage through the lung.41,42 It is therefore not surprising that the Papaverine=phentolamine (Androskat1) half-life of i.c.-injected PGE1 is only 30 ± 60 sec. In contrast to papaverine or to the papaverine= phentolamine combination, large world-wide pro- The combination of papaverine=phentolamine spective studies have been conducted in accordance gained world-wide popularity with the publication with good clinical practice guidelines for both of Zorgniotti and Le¯eur in 1986.3 The pH values of alprostadil preparations (alprostadil sterile pow- marketed Androskat1 solution varies between 3.1 der ± Caverject1 and alprostadil alfadex ± Viridal1 and 3.5 and is stabile for 2 ± 3 y. The current cost or Edex1) and long-term follow-up of 4 ± 5 y is in Europe for 5Â2 ml ampoules containing 15 mg available.43 ± 46 A review of these large studies shows papaverine and 0.5 mg phentolamine per ml is that the ef®cacy-rate of alprostadil during in-of®ce approximately 60 US dollars. titration varied between 70 and 75% in more than Combining the 3050cAMP=cGMP accumulating 10 000 patients.27 Meanwhile, the author's experi- effects of papaverine and the alpha-adrenoceptor ence in more than 12 000 patients with ED under- blocking properties of phentolamine results in an going a 20 mg intracavernosal PGE injection test increased average response-rate up to 60 ± 70% 1 resulted in an in-of®ce ef®cacy rate of 72%, observed during in-of®ce testing.36 With home use, con®rming the data from the literature. response rates as high as 90% have been reported.37 In a variety of prospective self-injection trials, Prospective long-term comparison studies of papa- the success-rates (de®ned as successful coitus per injection) varied between 89 and 96%; this is higher Table 2 Side-effects of vasoactive drugs in retrospective than any reported ef®cacy rate among all the 27 studies available marketed vasoactive drugs (Table 3).43,46 No. patients Liver Typical side-effects with alprostadil self-injection (No. of Priapism Fibrosis Pain enzymes: therapy are the occurrence of penile pain in 8 ± 52%, Drug publications) (%) (%) (%) (%) however, with long-term follow-up and individual Papaverine 1527 7.1 5.7 4 1.6 dose adjustment, pain-rates decreased to 1 ± (15) 11%.45,46 Priapisms were almost exclusively ob- Pap.=Phentol. 2263 7.8 12.4 11.6 5.4 served in the titration-phase and varied between (22) 0.25 and 1% (Table 2).27,43,46 In the two major trials PGE1 2745 0.36 0.8 7.2 0 (Alprostadil) (10) with both alprostadil-preparations, penile ®brotic alterations were encountered in 7.5 ± 11.7% of

International Journal of Impotence Research Current perspectives on intracavernosal pharmacotherapy H Porst S94 Table 3 Success-rates of self-injection therapy with alprostadil Table 5 Impact of alprostadil (Viridal1) self-injection therapy (Viridal1=EDEX1) in the European prospective 4 year trial on self-esteem and partnership: results of a prospective, multicenter, 4 year trial in 162 patients46 Year follow-up No. injections No. successful coitus Percent Completers no. Positive impact Positive impact 1st year 6935 6293 91 Year of patients on self-esteem (%) on partnership (%) 2nd year 3937 3691 94 3rd year 3233 3050 94 1 116 78 81 4th year 2781 2679 96 2748789 Total 16886 15713 93 3638689 4548787

patients during the course of the 4 ± 5 y of long-term ling-test and 61% (37=61) for the self-injection follow-up.45,46 The prevailing majority of ®brotic group. Claimed advantages of moxisylyte in other alterations were small nodules which did not studies were the low risk of priapism (< 1%) and interfere with erectile function or vaginal penetra- ®broses (< 2%) but these low side-effect rates tion (Table 4). Between 33 and 47% of these penile were put into perspective by low ef®cacy rates if ®broses healed spontaneously, suggesting that the compared to alprostadil or papaverine=phentola- incidence of persistent penile ®broses in patients on mine.47 ± 49 In addition, in all published moxisylyte long-term self-injection therapy is between 5 and trials, clinically relevant drops in blood pressure 7%.43,44,46 Similar to self-injection trials with all accompanied by orthostatic symptoms and dizzi- vasoactive drugs, the drop-out rates in the alpros- ness were described in 5 ± 8% of patients.48,49 tadil trials were relatively high, eg, 55% after 18 Moxisylyte was originally marketed under two months in the alprostadil-sterile powder (Caver- different trade names ± Icavex1 and Erecnos1, but ject1) study and 54% after 24 months in the due to its low market acceptance, the latter one was alprostadil-alfadex (Viridal1) trial.44 ± 46 After 4 y of withdrawn some time ago. follow-up, 33% of patients continued therapy with alprostadil alfadex and 22% continued regular therapy with alprostadil sterile powder after 5 y of VIP=phentolamine combination (Invicorp1) follow-up.45,46 The satisfaction-rates of both male and female partners in the group who continued were high and ranged between 91 and 95%.46 In As VIP alone injected i.c. in volunteers did not addition, between 78 and 89% of patients and their result in rigid erections, a combination of VIP and female sexual partners stated that the self-injection phentolamine was developed for self-injection ther- therapy markedly improved both the self-esteem of apy (Table 8).13,50 In an early prospective 6 month the af¯icted males and the partner-relationships trial with 30 mg VIP and 0.5 ± 2 mg phentolamine in (Table 5).46 52 patients who underwent a total of 1380 sched- uled injections, no priapisms, pain or ®broses were reported.16 In a larger prospective trial with 289 patients (mean age 58.5 y), 77% responded with Moxisylyte (Icavex1) grade 3 erections, considered by the investigators to be suf®cient for intercourse.51 In this study, two priapisms (0.6%) were observed. Final results of the Moxisylyte (Table 7), an alpha-adrenergic blocking UK multicenter placebo-controlled Invicorp1-trial compound with preference of alpha1-adrenoceptors were published by Sandhu in 1999 and are summar- was investigated in comparison to alprostadil ized in Table 9.52 In this prospective trial, the total alfadex in a prospective trial.47 The ef®cacy rates drop-out rate (calculated from the date of ®rst- for 20 mg alprostadil were 75% (56=75) con®rmed patient-in and last-patient-out after 6 months was with a positive Buckling-test and increased to 85% 65.5% (199=304) and was thus considerably higher when the same patients performed self-injection than in all other alprostadil injection trials.43,46,52 therapy at home. The comparable ef®cacy rates after There were no comments about the reasons for this 20 mg moxisylyte were 40% (32=81) for the Buck- high drop-out rate.

Table 4 Penile ®brosis in prospective self-injection trials with alprostadil preparations43 ± 45

No. Follow-up Fibrosis Outcome Nodules= Cavernous Brand name patients (months) (all) (spontaneaus healing) plaques Deviations ®brosis

Viridal1=Edex1 162 48 11.7% (19) 47%. (19) 10 6 3 Caverject1= 848 6 4%. (34) NA NA NA NA Europe 511 18 5.1% (26) NA NA NA NA Caverject1=US 683 18 7.5% (51) 33%22821.

International Journal of Impotence Research Current perspectives on intracavernosal pharmacotherapy H Porst S95 The greatest advantage of the Invicorp1 prepara- was compared against Alprostadil 20 mg (Caver- tion is its availability in a ready-for-use automatic ject1). In this small series, the response rates for single injection device equipped with a 29 gauge Invicorp1 were 60% (15=25) compared to 72% needle (Figure 1). This device may be preferred by (18=25) for Caverject1. The automatic injection many patients because the necessity to reconstitute device for the Invicorp1 -combination represents alprostadil preparations and the requirement for a very convenient and user-friendly solution for manual injections is avoided. intracavernosal injections. As mentioned above, The author's personal experiences with the Invicorp1 is approved but not marketed in Denmark VIP=phentolamine combination are limited to 25 and can be prescribed on an individual named- patients in whom the Invicorp1 1=2-combination patient basis in the UK. The dosages for Invicorp1 1 are 25 mgVIP=1 mg phentolamine or 2 mg phentolamine for Invicorp1 2, respectively. Table 6 Pharmacological pro®le of alprostadil (Caverject1 or Virdal1=Edex1) Sites of action Adenylate cyclase?3050-cAMP: Clinical experiences with experimental Presynaptic on alpha1 adrenoceptors? noradrenaline; vasoactive drugs (Table 10) Angiotensin secretion;?muscle tone; Stimulation Maxi-K-channels?Hyper- polarization Linsidomine (SIN 1) Neuromodulation preoptic area Inhibition TGF b1?Collagen; Dosages 2.5 ± 40 mg Linsidomine belongs to the family of NO-donors and Pharmacokinetics Metabolism intracavernosal and during lung- passage generates NO non-enzymatically, subsequently Half-life 30 ± 60 sec resulting in stimulation of guanylate cyclase and 0 0 PGE0 active metabolite ultimately, 3 5 -cGMP accumulation. Very promising Ef®cacy 70 ± 80% Side-effects Pain 10 ± 20%, priapism < 1%, ®brosis 5 ± 11% Target-group Non-responders to or contraindications for Table 9 Ef®cacy-rates of VIP=phentolamine (Invicorp1 after oral (Sildena®l, Apomorphine) therapy, in-of®ce testing plus visual sexual stimulation. Number of In combination with oral drug therapy for patients 289, mean age 58.5 years (range 27 ± 79)52 severe ED-patients (salvage therapy) No. of Responders Responders ED-etiology patients to Invicorp 1 to Invicorp 2

Arteriogenic 72 59.7% 80.6% Diabetes 62 64.5% 85.5% Table 7 Pharmacologic pro®le of moxisylyte (thymoxamine) Neurogenic 3 100%±. (Icavex1) Mixed 152 63.8% 82.9% Total 289 63.3% 83.1% Site of action Alpha1-adrenoceptors (blockade) Impact on erection Sympathetic tone; Smooth muscle tone; Dosages 10=20 mg Pharmacokinetics Four active metabolites Excretion with urine Ef®cacy Low (20 ± 40%) Side effects Priapism < 1%, ®brosis < 2% Hypotonic reactiondizziness 5 ± 8% Target group Patients with contraindications to sildena®l and inconvenient painful erections to PGE1

Table 8 Pharmacological pro®le of VIP=phentolamine (Invicorp1)

Site of Action VIP: Adenylcyclase? 3050-cAMP: Phentol: alpha1=alpha2 receptors (blockade) Maxi-K-channels (activation) Endothelin-antagonism, blockade 5-HT-rec. Dosage 25 mg VIP=1 mg or 2 mg Phentolamine Ef®cacy 60 ± 70% mixed ED-patients partially non- responders to PGE1 Side effects Flush 70 ± 80%, Priapism < 1%, Fibrosis? Target group Non-responders or contraindications to Apomporphine=Sildena®l Principally all ED-patients Figure 1 Automatic single injection device for use with Invicorp1.

International Journal of Impotence Research Current perspectives on intracavernosal pharmacotherapy H Porst S96 Table 10 Non-marketed vasoactive drugs with potential for self-injection therapy

Compounds Dosage Results (ef®cacy) Conclusion

PGE1=CGRP 20 mg=5 mg 30% of non-responders to 40 mg PGE1 Salvage-therapy potential Linsidomine (SIN-1) 1 mg 35 ± 74% Inferior to PGE1 Sodium nitroprusside 300 ± 600 mg 64 ± 84% More side-effects than PGE1 Triple-drug (trimix) Up to 80 ± 90% Salvage therapy Pap=Phentol=PGE1 30 mg=1mg=20 mg

results with success-rates of up to 69% (78=113) From this we can surmise that no pharmaceutical were reported by authors of one study group,11,53 but company opted to bring this combination product could not be con®rmed by others.12,54 In a small through the rigorous path toward market approval. comparative trial conducted by the author in 40 patients, the ef®cacy-rates (partial or full rigidity) after 1 mg SIN-1 were 35% compared to 82.5% after alprostadil 20 mg.12 Due to these signi®cantly lower ef®cacy-rates with admittedly low side effect rates, the compound was not pursued further and did not Triple-drug (trimix) ± papaverine=phentolamine= enter a full clinical trial program toward market PGE1 development. Combining the three vasoactive drugs: papaverine, phentolamine and PGE1 allows one to reduce the Sodium nitroprusside dosages of the individual compounds and therefore to lower the risks of side-effects attributed to the respective single drugs while increasing ef®cacy Sodium nitroprusside, a NO-donor similar to SIN-1 rates. Reported dosages of single compounds in was evaluated in a comparative trial with alprosta- several publications varied between 4.4 and 15 mg dil.15 In a total of 95 patients, 49% responded with papaverine, 0.15 and 0.5 mg phentolamine, and 1.5 partial and 15% with complete rigidity to 300 ± 8,57,58 and 20 mg PGE1 per ml. Response rates with 400 mg doses of nitroprusside compared to 54% and the trimix combination in non-selected patients 20%, respectively, after 20 mg alprostadil. With with ED approached 80 ± 90% and were thus 10 ± nitroprusside doses of 600 mg, global response rates 15% higher than after 20 mg alprostadil monother- of 84% were achieved. Because alprostadil pro- apy.57,59 Because rigid erections following trimix duced better response rates and sodium nitroprus- administration were achieved in 50 ± 62% of so- side was incriminated with hypotonic blood called non-responders, some authors suggested that pressure reactions in up to 15% of patients, this trimix would be useful rescue therapy for non- compound did not enter the phase of multicenter responders to monotherapy with alprostadil or the trials. combination of papaverine=phentolamine.8,58 In two prospective trials the trimix combination was preferred by 46 ± 67% of patients compared to 19 ± Calcitonin gene related peptide combined with PGE 23% for the approved alprostadil sterile powder 1 (Table 11).60,61 In the author's hands, the trimix combination Calcitonin gene related peptide (CGRP) a potent produces a response in 30 ± 40% of non-responders vasodilator, increased penile blood ¯ow and re- to 40 mg alprostadil. It can easily be easily be sulted in tumescence but not rigidity when given prepared by mixing one ampule of Androskat1 intracavernously in dosages of 500 mg.10 In a popula- (30 mg papaverine=1 mg phentolamine) with 10 ± tion of 65 patients, of whom 91% were non- 20 mg Caverject1. Within the context of this extem- responders to the papaverine (30 mg)=phentolamine poraneous reconstitution, it must be considered that (1 mg) combination, CGRP (5 mg) combined with the stability of the three drug combination varies 55 PGE1 (10 mg) produced rigid erections in 55%. In with a 30% degradation of the PGE1-concentration another study performed by Schwarzer et al, 30% of within 60 days.62 patients who failed 40 mg PGE1 or 80 mg papaverine The trimix self-injection therapy should be or the combination of 60 mg papaverine plus 2 mg reserved for patients who do not respond to phentolamine obtained rigid erections following alprostadil or for those who experience painful 56 treatment with 5 mg CGRP plus 20 mg PGE1. Since erections after alprostadil alone. Trimix is princi- these reports which appeared nearly a decade ago, pally associated with the same side-effect and risk- no further reports on the validity and safety of the pro®le of papaverine and phentolamine, especially CGRP=PGE1 combination have been published. in terms of priapism and ®brosis.

International Journal of Impotence Research Current perspectives on intracavernosal pharmacotherapy H Porst S97 1 Table 11 Intra-individual comparison between alprostadil (Caverject ) and trimix (Pap=Phentol=PGE1) Alprostadil study Trimix study No. preference study No. patients study 1a 2b 1a 2b 1a 2b 1a 2b

Better ef®cacy 22% 14% 37% 62% 41% 24% 68 21 General preference 23% 19% 46% 67% 31% 14% aRef. 60; bref. 61.

Special topics on self-injection therapy months and an average injection frequency of (Table 12) three per month, focal ®brotic alterations were more frequently observed in the diabetic cohort (25%) compared to 3% in the control-group.65 This Patients treated concurrently with anticoagulants series supports the author's impressions that insulin-dependent diabetics are more prone to the occurrence of ®brosis than other patient subsets. The safety of vacuum-therapy and self-injection therapy was compared in a cross-over study of 33 patients being treated with warfarin.63 In only 11 (1.6%) of 706 documented vacuum applications and Managing complications of self-injection three (0.5%) of 605 self-injections, ecchymoses of therapy the penile skin were recorded in patient diaries, indicating that the risk of bleeding, both in vacuum therapy and self-injection therapy, is not higher in Priapism the group receiving anticoagulants than it would be in a normal patient population. In the author's clinical practice, following 10 patients treated with It is generally accepted that priapisms lasting > 6h the anticoagulant marcoumar for a number of years, should be interrupted to prevent tissue damage. no severe bleeding complications have been Electromicroscopical investigations by Spycher observed. Therefore, patients treated with antico- (1986) suggested that irreversible tissue impairment agulants (either platelet aggregation inhibitors or may be occurring after 12 ± 18 h.66 According to the warfarin=marcoumar) do not represent contraindi- author's personal observation of more than 150 cations for self-injection therapy provided they are patients with drug-induced priapisms, direct injec- carefully instructed in self-injection techniques and tion of a sympathomimetic antidote is suf®cient use thin (27 ± 30 gauge) needles. if the priapism did not last longer than 12 h. In priapisms longer than 12 ± 18 h duration, it is reasonable to evacuate the entrapped hypoxemic Transplant recipients blood with i.c. insertion of a butter¯y cannula, wait 10 ± 15 min until reoxygenation has established, then inject the adrenergic antidote if it is still A study conducted with 26 renal transplant patients deemed necessary. Among all the available adrener- did not reveal any increased risk for self-injection gic drugs, etilefrine and phenylephrine have the therapy,64 corroborating the author's own experi- least impact on cardiac b-receptors and are therefore ences with three transplanted patients (two kidneys, probably the safest choice.67 The recommended one heart). dosages are 5 ± 20 mg for etilefrine or 0.1 ± 0.5 mg for phenylephrine. It is reasonable to start with a low dosage and massage the penis between the Patients with diabetes mellitus ®ngers after removal of the needle to promote circulation of the injected antidote within the entrapped blood in the cavernous bodies. If the In a comparative trial among 16 diabetic and 29 non- erection persists after 15 min, a repeat dosage should diabetic patients with a mean follow-up of 9.4 be injected in to the opposite cavernous body. If this

Table 12 Self-injection therapy in special risk-groups

Risk-group No. of patients Ref. Conclusion

Antikoagulants (Warfarin) 33 63 No increased risk of bruising Kidney transplant 26 64 No increased risk of infection or ®brosis Diabetes mellitus 16 65 Considerable increased risk of pain Non-diabetes 29 (19% vs 3%), cavernitis (19% vs 0%) and ®brosis (25% vs 3%)

International Journal of Impotence Research Current perspectives on intracavernosal pharmacotherapy H Porst S98 injection also fails, evacuation is advisable. After the those with severe cardiac disease or those antidote injection, blood pressure readings must be treated with antihypertensive polypharmaco- taken to detect blood pressure increases, which are therapy. successfully treated by oral or fast-acting sublingual (2) According to the author's personal experiences, nifedipine. about 15% of alprostadil responders are sildena®l non-responders. In particular, this observation will be true in patients who are likely Fibrosis to have cavernous nerve impairment (pelvic surgery or trauma, insulin dependent diabetes). (3) According to the author's personal experiences As described earlier, most ®brotic alterations that and recent reports, 30 ± 40% of patients satis®ed develop during the course of self-injection therapy with long-term self-injection therapy will stay are mild or moderate and concern small nodules in on this therapy despite sildena®l (Table 13).68 the tunica albuginea or in the penile septum (Table (4) In a considerable number of patients ( 50%) 4). In this case, the patient should be re-instructed in who do not respond to either sildena®l or the correct injection technique and taught to avoid injection-therapy, the combination of both meth- the affected area when performing future injections. ods has the potential to rescue these patients In the event real ®brotic plaques with or without and preserve them from vacuum therapy or penile curvature develop, self-injections should penile implants.70,71 temporarily be discontinued for 3 ± 4 months. Following reassessment by an in-of®ce intracavernosal injection test, the option of surgical interven- tions (corporoplasty or penile implant) versus continuation of injection therapy should become References evident. If corporoplasty seems unavoidable, sexual intercourse may be resumed after 3 ± 4 months, supplemented again with self-injection or trans- 1 Virag R. Intracavernous injection of papaverine for erectile failure. Lancet 1982; 2: 938. urethral therapy. Alternatively, and preferably, 2 Brindley GS. Cavernosal alpha-blockade: a new treatment for oral sildena®l (Viagra1) or apomorphine SL, may investigating and treating erectile impotence. Br J Psychiatry be used, provided that these novel oral compounds 1983; 143: 332 ± 337. prove to be effective in these patients. 3 Zorgniotti, AW, Le¯eur RS. Autoinjection of the corupus cavernosum with a vasoactive drug combination for vasculo- genic impotence. J Urol 1985; 133: 39 ± 41. 4 Adaikan PG, Kottegoda SR, Ratnam SS. A possible role for Future role of self-injection therapy versus oral prostaglandin E1 in human penile erection. In: Abstract Book Second World Meeting on Impotence, Prague, 1986, Abstr.2.6. drug therapy 5 Ishii N et al. Therapeutic trial with prostaglandin E1 for organic impotence. In: Abstract Book Second World Meeting on Impotence, Prague, 1986, Abstr.11.2. There is no question that, since ef®cacious oral drug 6 Porst H. Comparative usefulness of prostaglandin E1, papa- therapy like sildena®l has become available, man- verine and papaverine=phentolamine for the diagnosis of erectile dysfunction in 61 patients. Urolog 1988; 27: 22 ± 26. agement of male impotence has dramatically im- 7 Stack W, Hasun R, Marberger M. Intracavernous injection of proved. Notwithstanding the observation that most prostaglandin E1 in impotent men. J Urol 1998; 140: 66. ED patients can be managed by oral drug therapy, 8 Goldstein I et al. Rescuing the failed papaverine= there will be a considerable number of candidates phentolamine erection: a proposed synergistic action of for self-injection therapy. These candidates will papaverine, phentolamine and prostaglandin E1. J Urol 1990; 143: 304A. likely be represented in the following categories: 9 Buvat J et al. Safety of intracavernous injections using an alpha-blocking agent. J Urol 1989; 141: 1364 ± 1367. (1) About 15 ± 20% of all patients with erectile 10 Stief CG et al. Calcitonin gene related peptide: a possible role dysfunction show contraindications to sildena- in human penile erection and its therapeutic application in ®l-like nitrate or NO-donor medications, ie, impotent patients. J Urol 1991; 146: 1010 ± 1014.

Table 13 Self-injection therapy vs oral sildena®l: preference of patients previously familiarized with self-injection technique

Ref. No. of patients Drug used Preference of injection therapy Both methods alternating Combination of both methods

68 110 Alprostadil 28% 13% ? or trimix (31) (14) 69 66 Trimix 48% ? ? (32) Porst 173 Alprostadil 39% 6% 4% Unpublished (57) (10) (6)

International Journal of Impotence Research Current perspectives on intracavernosal pharmacotherapy H Porst S99 11 Stief CG et al. Preliminary report on the effect of the nitric 34 Aboseif SR et al. Local and systemic effects of chronic oxide donor SIN-1 on human cavernous tissue in vivo. World intracavernous injection of papaverine, prostaglandin E1 and J Urol 1991; 9: 237 ± 240. saline in primates. J Urol 1989; 142: 403. 12 Porst H. Prostaglandin E1 and the nitric oxide donor 35 Stackl W, Loupal G, Holzmann A. Intracavernous injection of linsidomine for erectile failure: a diagnostic comparative vasoactive drugs in the rabbit. Urol Res 1988; 16: 455 ± 458. study of 40 patients. J Urol 1993; 149: 1280 ± 1283. 36 Juenemann KP et al. Offene Multicenterstudie zur Differen- 13 Wagner G, Gerstenberg T. Intracavernosal injection of vaso- tialdiagnostik der erektilen Dysfunktion mit einer Papaverin= active intestinal polypeptide (VIP) does not induce erection Phentolamin-Kombination (By 023). Urologe A 1988; 27: in man per se. World J Urol 1987; 5: 171 ± 177. 2±7. 14 Brock G, Breza J, Lue TF. Intracavernous sodium nitroprus- 37 Witjes WPJ et al. The ef®cacy and acceptance of intracaver- side: inappropriate impotence treatment. J Urol 1993; 150: nous autoinjection therapy with the combination of papaver- 864 ± 867. ine=phentolamine. A prospective multicenter trial in 60 15 Martinez-Pineiro L et al. Preliminary results of a comparative patients. Int J Impot Res 1992; 4: 65 ± 72. study with intracavernous sodium nitroprusside and prosta- 38 Girdley FM et al. Intracavernous self-injection for impotence: glandin E1 in patients with erectile dysfunction. J Urol 1995; a long-term therapeutic option? Experience in 78 patients. 153: 1487 ± 1490. J Urol 1988; 140: 972. 16 Gerstenberg TC et al. Intracavernous self-injection with 39 Lakin MM et al. Intracavernous injection therapy: analysis of vasoactive intestinal polypeptide and phentolamine in the results and complications. J Urol 1990; 143: 1138. management of erectile failure. J Urol 1992; 147: 1277 ± 1279. 40 Levine SB et al. Side effects of self-administration of 17 Iguchi M et al. On the mechanism of papaverine inhibition of intracavernous papaverine and phentolamine for the treatment the voltage-dependent Ca current in isolated smooth muscle of impotence. J Urol 1989; 141: 54. cells from the guinea pig trachea. J Pharmacol Exp Ther 1992; 41 Roy AC et al. Prostaglandin 15-hydroxydehydrogenase activ- 263: 194. ity in human penile corpora cavernosa and its signi®cance in 18 Kifor J et al. Tissue Angiotensin II as a modulator of erectile prostaglandin mediated penile erection. Br J Urol 1989; 64: function. I Angiotensin peptide content, secretion and effects 180 ± 182. in the corpus cavernosum. J Urol 1997; 157: 1920 ± 1925. 42 Cawello W et al. Pharmacokinetics of prostaglandin E1 and its 19 Juenemann KP et al. Hemodynamics of papaverine- main metabolites after intracavernous injection and short-term and phentolamine-induced penile erection. J Urol 1986; 136: infusion of prostaglandin E1 in patients with erectile dysfunc- 158 ± 161. tion. J Urol 1997; 158: 1403 ± 1407. 20 Gupta S et al. Relaxation of corpus cavernosum smooth 43 Linet OI, Ogrinc FG, and Alprostadil Study Group. Ef®cacy muscle by phentolamine via a non-adrenergic mechanism. Int and safety of intracavernosal Alprostadil in men with erectile J Impot Res 1998; 10(Suppl 1): S27. dysfunction. New Engl J Med 1996; 334: 873 ± 877. 21 Traish A et al. Phentolamine mesylate relaxes penile corpus 44 Linet OI, Ogrinc FG. Penile ®brosis during 18 months of cavernosum by adrenergic and non-adrenergic mechanisms. intracavernosal therapy with Alprostadil (Caverject1). Int J Int J Impot Res 1998; 10: 215 ± 223. Impot Res 1996; 8: D85. 22 Paoletti R. Biochemistry and pharmacology of prostaglandin 45 Linet OJ. Long-term safety of CaverjectTM (Alprostadil S.PO, E1: Introductory remarks. In: Sinzinger H, Rogatti W, (eds). PGE1) in erectile dysfunction (ED). Int J Impot Res 1998; 10: Prostaglandin E1 in Atherosclerosis. Springer-Verlag: New S37. York 1986, pp 3 ± 7. 46 Porst H et al. Intracavernous Alprostadil Alfadex Ð an 23 Molderings GJ et al. Modulation of noradrenaline release in effective and well tolerated treatment for erectile dysfunction. human corpus cavernosum by presynaptic prostaglandin Results of a long-term European study. Int J Impot Res 1998; receptors. Int J Impot Res 1992; 4: 19. 10: 225 ± 231. 24 Zhang P et al. PGE1-induced alterations in Maxi-K -channel 47 Buvat J et al. Double-blind multicenter study comparing activity in cultured human corporal smooth muscle cells. Alprostadil alpha cyclodextrin with Moxisylyte chlorhydrate J Urol 1996; 155: 678 A. in patients with chronic erectile dysfunction. J Urol 1998; 159: 25 Moltz H. E-series prostaglandins and arginine vasopressin in 116 ± 119. the modulation of male sexual behavior. Neurosci Biobehav 48 Buvat J et al. Reduced rate of ®brotic nodules in the cavernous Rev 1990; 14: 109. bodies following auto-intracavernous injection of moxisylyte 26 Moreland RB et al. PGE1 supresses the induction of new compared to papaverine. Int J Impot Res 1991; 3: 123 ± 128. collagen synthesis by transforming growth factor b1 in human 49 Costal P, Iacovella JA, Bouvet AA. Ef®cacy and tolerability of corpus cavernosum smooth muscle: mechanism of penile Moxisylyte and placebo injected intracavernously in patients ischemia associated ®brosis. J Urol 1994, 151(Part 2): 413 A. with erectile dysfunction (ED): a multicenter, double-blind 27 Porst H. Review article. The rationale for prostaglandin E1 in study. 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International Journal of Impotence Research Current perspectives on intracavernosal pharmacotherapy H Porst S100 56 Schwarzer UJ et al. Calcitonin-gene-related-peptide for therapy 65 Plekhanov AY, Zhivovo AV, Goryachew LA. Comparative of erectile importance. Int J Impot Res 1992; 4: 219 ± 222. complications rate after Alprostadil intracavernous pharma- 57 Bennett AH, Carpenter AJ, Barada JH. An improved vasoactive cotherapy for erectile dysfunction in diabetes mellitus vs non- drug combination for a pharmacological erection program. diabetic patients. Int J Impot Res 1998; 10(Suppl 1): S50. J Urol 1991; 146: 1564. 66 Spycher MA, Hauri D. The ultrastructure of the erectile tissue 58 Derouet H, Meeth M, Bewermeier H. Die Behandlung von in priapism. J Urol 1986; 135: 142. SKAT-Non-Respondern mit einem Papaverin=Phentolamin- 67 Lee M, Cannon B, Shari® R. Chart for preparation of dilutions Prostaglandin E1 ± Gemisch. Akt Urol 1996; 27: 271 ± 274. of alpha-adrenergic agonists for intracavernous use in treat- 59 Hamid S, Dhabuwala CB, Pontes EJ. Combination intracaver- ment of priapism. J Urol 1995; 153: 1182 ± 1183. nous pharmacotherapy in the management of male erectile 68 Apostolidis A et al. Sildena®l vs intracavernosal dysfunction. Int J Impot Res 1992; 4: 109 ± 112. injection (ICI): ef®cacy and preference in patients following 60 Kulaksizoglu H et al. Comparison of Alprostadil Sterile ICI for > 1y. 3rd Meeting of the European Society for Powder (Caverject1) with Trimix. Nomogram and patient Impotence Research, 30 Jan ± 2 Feb, 2000, Barcelona, Abstract satisfaction. J Urol 1997; 157: 180. book, p 8. 61 Mellinger BC, Abbatiello S, Tarnow SL. Tri-mix versus 69 Brannigan RE et al. Comparison of Sildena®l citrate (Viagra1) Caverject1. Effective doses and patient preferences. J Urol versus Trimix intracavernosal injection (ICI) as treatment for 1997; 157: 180. erectile dysfunction (ED). J Urol 1999; 161: 214. 62 Soli M et al. Chemical evaluation of the stability of vasoactive 70 McMahon CG, Samali R, Johnson H. Treatment of intracor- cocktails with PGE1, papaverine and phentolamine. Eur Urol poreal injection non-response with Sildena®l alone or in 1999; 35: 100. combination with triple agent intracorporeal injection therapy. 63 Limoge JP et al. Minimally invasive therapies in the treatment J Urol 1999; 162: 1992 ± 1997. of erectile dysfunction in anticoagulated cases: a study of 71 Porst H. Editorial Comment to McMahon CG, Samali R, satisfaction and safety. J Urol 1996; 155: 1277 ± 1279. Johnson H. Treatment of intracorporeal injection non-response 64 Mansi MF, Ackhudair WK, Huraib S. Treatment of erectile with Sildena®l alone or in combination with triple dysfunction after kidney transplantation with intracavernosal agent intracorporeal injection therapy. J Urol 1999; 162: self-injection of prostaglandin E1. JUrol1998; 159: 1927 ± 1930. 1997 ± 1998.

Appendix Dr Heaton: These are multi-dimensional problems and we're only providing a solution to one small part of them. We're happy to treat ED pharmaco- Open discussion following Dr Porst's presentation logically, but we're shying away from treating all the other multi-factoral things, so we lose a lot of Dr Pryor: One of the questions, not only with people. Chronic diseases are managed with chronic therapies and we haven't got into that mode yet. injection therapy, but also with oral therapy and penile implants is, why don't people continue with therapy? I predict the same thing will happen with oral therapies that happened with injection therapy; Dr Nehra: Did you say that patients who've had over half the patients will ultimately drop out implants that are not working don't want them? within 3 to 5 y.

Dr Porst: In the oral trials we have no long-term data. There are long-term trials, two, four and ®ve Dr Pryor: I've had some patients who get them and years with Caverject. With sildena®l or with apo- they want to know that they can get an erection and morphine, we have only 18 months. There are ®ve or that the prosthesis works. They have the opportu- six major reasons for drop-outs with any kind nity to use it and they just don't. of therapy in erectile dysfunction, including loss of partner, cancer, other diseases and unhappiness with injection therapy. Dr Nehra: Keep in mind that the mean age is 59. You have patient issues, concurrent medical pro- Dr Pryor: I agree, it's probably not going to be one blems, you may have partner problems, marital answer. In our study published in Urology a few discord, and all these things need to be in years ago, the patients liked injection therapy, but perspective. I discuss this with all my patients pre- even if they liked it, they still dropped out. operatively.

International Journal of Impotence Research