Drug combinations for selfinjection therapy

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General considerations

PGE1 is still the first line option for patients who either do not respond or show contraindications for oral phosphodiesterase-5 inhibitors. Besides PGE1 mono therapy, several potentially useful combinations have been used for self-injection therapy as second line options. The vasoactive agents most commonly used in combination therapy, were phen-tolamine, papaverine, PGE1, and VIP. Potential advantages of the use of combination therapies over mono therapy may depend on the number of drugs/strength of the mixtures used, an increase of efficacy by targeting different sites of action in the erection process, reduction of side effects such as priapism or fibrosis, and reduction of costs per application.

For instance, in vitro studies on human and rabbit cavernosal strips demonstrated that phentolamine significantly potentiated relaxation induced by sildenafil, VIP and PGE1. These vasodilators also significantly enhanced relaxation induced by phen-tolamine in the cavernosal tissue strips. The enhancement of VIP and PGE1-induced relaxation (cAMP-mediated) by phentolamine suggests a syn-ergistic interaction, while the interaction between phentolamine and sildenafil (cGMP-mediated) appears to be additive [47]. The same investigators were also able to show that sildenafil and PGE1 has additive and synergistic effects, respectively, with phentolamine-induced relaxation. Therefore, in combination therapy using phentolamine as an adjunct, the efficacy of vasodilators that initiate erection via independent relaxant pathways is increased due to a reduction in adrenergic tone, through the a-adrenoceptor blockade.

Combination of papaverine and phentolamine (Androskat®)

The combination of papaverine/phentolamine has become popular since the publication of Adrian

Zorgniotti 1985, and has competed with alprostadil mono therapy for a long time [34]. The mixture of papaverine/phentolamine is commercially available and approved as Androskat® in several countries worldwide, especially in Europe. Androskat® is marketed in 2 ml ampoules containing 15mg papaverine and 0.5 mg phentolamine per 1ml, i.e. a total content of 30 mg papaverine +1mg phento-lamine per ampoule. As a rule of thumb, the efficacy of one ampoule Androskat® is comparable to 10 |g alprostadil, and two ampoules Androskat® to 20 |g alprostadil [15] (Table 8.1). The major disadvantages of papaverine/phentolamine is its relatively high risk of priapism >6 hours ranging between 2 and >10% (mean 7.8%) depending on the concentration of the first dose used [15], (Table 8.2).

The main indication for using the mixture of papaverine/phentolamine are patients with ED in whom PGE1-induced erections were felt intolerably painful, which is relatively often the case after major pelvic surgery (RRP, cystectomy, rectum amputation), or this minority of patients in whom PGE1 mono therapy turned out to be inferior to papaverine/phentolamine. Long-term use of the mixture of papaverine/phentolamine was marked with a considerably higher risk of cavernous fibrosis compared to alprostadil monotherapy [15].

Combination of papaverine/phentolamine/PGE1 (Triple drug, syn. Trimix)

The use of the triple drug combination of papaver-ine/phentolamine/PGE1 was reported for the first time in 1990 by Goldstein [48]. Since this publication a variety of reports on the usefulness of this drug combination was published in the literature, with wide range of dose recommendations (see Table 8.3). A direct comparative study investigated the equivalent doses of alprostadil monotherapy to the triple-drug combination in terms of efficacy [56] (Tables 8.4 and 8.5).

Table 8.3 Triple drug compositions: intracavernous injection of Trimix, a mixture of papaverine, phentolamine and PGEj, is indicated for patients unsuitable for PGEj injection due to poor response, pain or cost. Various dose combinations have been reported with the range of ratio (based on mass) for papaverine [12-30]: PGEj (0.006-0.02): phentolamine (taken as 1).

Injection volume

Reference Trimix Stock Solution Ratio (equimass basis) (ml)

Papaverine

PGEj

Phentolamine

Papaverine

PGEj

Phentolamine

Bennett et al [49]

17.6mg/ml

5.9 |xg/ml

0.59mg/ml

B0

0.01

1 0.25

Govier et al [50]

22.5mg/ml

S.B |ig/ml

O.SBmg/ml

27

0.01

1 0.B6

Israilov et al [51]

19.4mg

16.4

1.6

12.1

0.01

1 NA

Marshall et al [52]

12mg

9| g

1 mg

12

0.009

1 0.1-0.S

Shenfield et al [5B]

4.5mg/0.5ml

5 |ig/0.5 ml

O.25mg/O.5ml

1S

0.02

1 0.5

Mulhall et al [54]

B0mg

10 |ig

1 mg

B0

0.01

1 NA

B0mg

25 | g

2 mg

15

0.0125

1 NA

Montorsi et al [55]

150mg

B0 |ig

5 mg

B0

0.006

1 0.1S-0.21

BOOmg

100 |g

10mg

B0

0.01

1 0.1S-0.21

BOOmg

200 |g

20mg

15

0.01

1 0.1S-0.21

The Trimix stock solution of Montorsi et al. [55] is in B ml.

The Trimix stock solution of Montorsi et al. [55] is in B ml.

There is no question that at present the triple drug combination represents the most effective regimen in self-injection therapy, which was also preferred over alprostadil in the cited trial [56]. The major disadvantage of this powerful drug-combination is the fact that up to now, no commercially available preparation exists worldwide, i.e. the patients or the pharmacists have to reconstitute this combination individually, which is relatively complicated and cumbersome for many patients.

Combination of VIP and Phentolamine (Invicorp®)

The use of the combination of VIP and phentolamine in a larger series of patients with ED was published for the first time in 1992 [57]. After a couple of studies [58,59], the mixture of VIP/phentolamine in doses of 25 |g/1mg or 25 |g/

Table 8.4 Equivalent efficacy doses of alprostadil powder (Caverject®) and papaverine/phentolamine/PGE l combination (triple drug solution) in 68 patients. From Kulaksizoglu et al. [56].

Alprostadil Papaverine(mg)/

2 mg was introduced commercially as Invicorp®, available with a very user-friendly automatic injection device for single use (Senetek-CA, USA), and approved in some countries (Denmark, UK, New Zealand). Although the VIP/phentolamine combination was very promising, especially due to its self-injection device and relatively high efficacy, it was never marketed worldwide. This is presumably due to the considerable decrease of the market for injectables in ED. To the knowledge of the authors, at present the VIP/phentolamine combination is not officially available in any country.

Other drug combinations for self-injection therapy

There are a variety of other drug combinations, mostly with PGE1 (alprostadil), such as triple drug with PGE1/papaverine/chlorpromazine (0.5 mg/ml) instead of phentolamine, or triple drug + atropine, PGE1 + ketanserin, PGE1 + CGRP (calcitonin gene-related peptide), PGE1 + forskolin (activates the enzyme adenylate cyclase and increases intracel-lular cAMP), or triple drug and forskolin, but none of these combinations were able to achieve any market acceptance or official approval [60].

Combination of self-injection therapy and oral drug therapy

The successful conversion of non- responders either to high dose alprostadil mono-therapy (40 |g) or to the triple drug combination (40 |g PGE1/48mg papaverine/3.2mg phentolamine) by combining

Table 8.5 Intra-individual comparative study of alprostadil powder (Caverject®) and papaverine/phentolamine/PGEj (triple drug solution). From Kulaksizoglu etal. [56].

Alprostadil powder (PGE1 Caverject)

Papaverine/phentolamine/PGE1 (triple drug solution)

No preference (both the same)

Overall assessment better

23%

46%

31%

Improved rigidity

22%

37%

41%

Erection maintenance better

19%

37%

44%

Reproducibility better

15%

35%

50%

Orgasm/ejaculation better

0

0

100%

Potential of mal-injection in self-injection technique Correct intrasinusoidal injection

Alprostadil Self InjectionPenile Self Injections Demonstration

Potential of mal-injection in self-injection technique Correct intrasinusoidal injection

Caverject Tri Mix

Fig. 8.2 Technique of self-injection therapy. From Porst [60].

self-injection therapy with 100mg sildenafil, was reported in 34% [32] of 93 patients treated in this way [61]. In another prospective, placebo (against sildenafil) controlled study with 40 patients experiencing unsatisfactory erections at both the 50 and 100mg dose of sildenafil, the combined treatment with 20 |g IC-PGE1 resulted in a statistically significant improvement of the erectile response as assessed by the IIEF-EF in 65% of the patients [62].

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