Developmental Status of Topical Therapies for Erectile and Ejaculatory Dysfunction
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International Journal of Impotence Research (2000) 12, Suppl 4, S80±S85 ß 2000 Macmillan Publishers Ltd All rights reserved 0955-9930/00 $15.00 www.nature.com/ijir Developmental status of topical therapies for erectile and ejaculatory dysfunction A Morales1* 1Queen's University, Department of Urology, Kingston General Hospital, Kingston, Ontario, Canada The most common of the sexual dysfunctions in men are premature ejaculation and impotence. Large strides have been made in the treatment of erectile disturbances but only limited and temporary successes have been achieved in the therapy of ejaculatory abnormalities. This manuscript examines the realm of topical therapy, its current limitations and the challenges that must be addressed if topical therapy is ever to have a niche in the urologist's treatment armamentarium. Topical agents for the treatment of premature ejaculation include anesthetics and herbal medications. The limited nature of the studies reported to date does not yet permit a reliable assessment of their ef®cacy. For the treatment of erectile dysfunction, some of the drugs administered by various other systemic routes appear to have some ef®cacy when delivered transdermally. Again, the studies and results are too limited for the urologist to develop a clear opinion about their ef®cacy. Further investigation of these drugs with the use of absorption enhancers is needed. International Journal of Impotence Research (2000) 12, Suppl 4, S80±S85. Keywords: erectile dysfunction; premature ejaculation; topical therapy; review Introduction Oral,1 intraurethral2 and sublingual3 administration of drugs have opened new and more acceptable avenues of therapy for ED. In the case of PE, the The most common sexual complaints in men are picture is different. Oral medications have produced premature ejaculation (PE) and erectile dysfunction only limited and temporary success and topical (ED). Both problems create signi®cant dif®culties for agents, usually anesthetics, have enjoyed waxing the sufferer and his partner, but the causal mechan- and waning interest because they have proven to be isms and therapeutic management of these condi- too cumbersome, ineffective, or tend to cause diffuse tions are dissimilar. This review will present, genital anesthesia which is not conducive to a separately, the current knowledge about topical satisfying experience. agents used to treat these two conditions. Topical (from the Greek, topicos: relative or related to a speci®c site, in this case, the penis) agents have not fared well in either the treatment Premature ejaculation of ED or PE. New compounds have offered initial promising initial results but demand further study to establish their effectiveness. Premature ejaculation or premature orgasm is The search for effective, non-invasive pharmaco- de®ned as the persistent or recurrent ejaculation of logical therapy for ED led to the exploration of semen with minimal sexual stimulation before, various routes of administration for compounds that upon or shortly after vaginal penetration and before are capable, by a number of mechanisms, of the person or his partner desires it.4 It is the most inducing or enhancing smooth muscle relaxation widespread form of male sexual dysfunction with an in the corporal bodies. Ultimately, the relaxant estimated prevalence in `normal' men of between 30 effect on smooth muscle should result in a satisfac- and 40%.5 It is commonly accepted that the normal tory penile erection. Although the search has been intravaginal ejaculatory latency time (IVELT) should enthusiastic, effective and safe medications have be no less than 2 min. The cause(s) of the dysfunc- only recently been evaluated and only a few of them tion are not thoroughly understood but it is have become part of the clinician's armamentarium. recognized that the neurological aspects of ejacula- tion involve two re¯ex mechanisms. The ®rst *Correspondence: A Morales Queen's University, Kingston (afferent) re¯ex is initiated by stimulation of the General Hospital, Kingston, Ontario, Canada. genital receptors, then travels through the pudendal E-mail: [email protected] nerves to the sacral cord with a ®nal destination at Topical therapies for erectile and ejaculatory dysfunction A Morales S81 the limbic lobe and the hypothalamus. The second Encouraging results utilizing this product were also re¯ex is transmitted from the urethra to the reported recently by Porst.15 Uncontrolled studies, ejaculatory center (segments S2 ± 4). Efferent ®bers however, offer little information about the ef®cacy of of pudendal parasympathetic nerves broadcast sig- a medication used to treat this condition in which nals to the ganglia; these signals result in the release emotional factors play such a signi®cant role. of neurotransmitters which, by depolarizing peri- Furthermore, without bene®t of further assessment neal muscles, translate into rhythmic contractions or follow-up, the promising results of these limited and seminal emission.6 studies are called into question, leaving the true Behavioral therapy has been commonly used to ef®cacy of the compound uncon®rmed. Research treat PE. Treatment paradigms have generally been methods are also in need of improvement. For empirical and the proposed underlying emotional example, although the IVELT may indeed improve abnormalities have not been reliably documented. following treatment, this approach to evaluating Successes of behavioral therapy are limited and drug ef®cacy carries some signi®cant drawbacks: it almost invariably have been temporary; most of the requires a 30 min application, the use of a condom, post-therapy bene®ts are lost within 3 y of treat- the cost is relatively high, and the patient must ment.7 This monumental failure of behavioral endure numbness of the entire penis. therapy, not surprisingly, has led to an increasing We have recently embarked upon a study of a `medicalization' of the treatment of PE. proprietary metered-dose aerosol formulation of the Systemic pharmacotherapy is another pillar of the same agents (prilocaine lidocaine) in a formula- treatment for PE. Adrenergic antagonists have tion known as a `eutectic mixture' that causes both demonstrated ef®cacy in a few small studies.8 drugs to remain in liquid form at room temperature. Similar remarks can be applied to the use of Since penetration of most drugs is inversely propor- gamma-amino butyric acid (GABA), a neurohor- tional to the percentage of drug in ionized or mone that inhibits neural pathways. The lack of charged form, the delivery of pure base drug will follow-up studies suggests that their ef®cacy theoretically provide the best penetration of the (although not their cost) is comparable to that of compound. The main advantage is that the agent can behavioral therapy. Serotonin reuptake inhibitors be delivered to a speci®c, limited area (in this currently enjoy much popularity. The non-selective situation, to the glans penis). Furthermore, the blocker clomipramide,9 and the selective blockers, slightly oily nature of the drug combination ensures ¯uoxetine10 and paroxetine11 are reported to in- that it stays at the site (residency). Its effect is crease the IVELT for up to 10 min. All of these prompt (10 ± 15 min) and once the glans is anesthe- compounds required continuous dosing and are, not tized, the thin ®lm can be wiped off with a damp surprisingly, associated with side effects (dizziness, cloth, avoiding the need for a condom to prevent dry mouth, fatigue, diarrhea). partner contamination. The initial results are Men with PE exhibit abnormal autonomic re¯ex encouraging16 but further experience is needed. pathways for the ejaculatory process. The reported abnormalities are, most commonly: lower vibratory threshold to ejaculation; shorter bulbocavernous Herbal extracts latency time, and higher bulbocavernosus evoked potentials.12,13 Such ®ndings provide the rational The SS cream (Cheil Jedang Corporation, Seoul, background for dampening the sensory input from Korea) is a proprietary preparation consisting of the glans that could return these men to a baseline extracts of nine herbal medicines: Bufonis venenum, circuitry and increase the IVELT. Therapeutic Angelicae gigantis radix, Cistanchis caulis, Torilis intervention with topical agents, believed to be semen, Ginseng radix alba, Zanthoxylli fructus, capable of correcting the heightened genital sensi- Asiasari radix, Caryophylli ¯os and Cinnamoni tivity, is presently limited to the agents described cortex.17 It is applied to the glans about 1 h prior below. to intercourse and then removed with a wet towel shortly before foreplay and vaginal penetration. Initial claims of ef®cacy were positive and, more Topical anesthetics (TA) recently, a controlled study has supported these claims. In a double-blind, randomized, multicenter trial of 106 patients, Choi et al18 reported that `the The rationale mentioned above makes the use of TA mean ejaculatory latency was signi®cantly an appealing possibility for treating patients with prolonged after the application of SS-creams PE. Unfortunately, TAs have been used indiscrimi- (10.92 Æ 9.83 min) (placebo: 2.45 Æ 2.95). Prolonga- nately and the literature offers very few credible tion of ejaculatory latency more than 2 minutes than studies. Berkovitch et al14 reported a marked im- that of the screening period were 82.2% after the provement in IVELT with the use of a prilocaine application of SS-cream (10.3% in placebo)'. The lidocaine cream (EMLATM, Astra Pharmaceuticals, adverse