Home 
Erectile Dysfunction (ED) European Urology - The Evolution of ED Therapy in the 21st Century
Erectile Dysfunction (ED) European Urology - The Evolution of ED Therapy in the 21st Century | European Urology - The Evolution of ED Therapy in the 21st Century |
|
|
|
|
|
| Monday, 25 December 2006 | ||
|
Volume 50, Issue 6, Pages 1157-1159 (December 2006) Article Outline: Great strides have been achieved in our understanding of the physiology of erectile dysfunction (ED) and the potential for therapeutics over the past two decades [1], [2]. Whereas just 10 yr ago, intracavernous vasoactive injection therapy was commonly administered to those few individuals who sought medical help for their sexual concerns, today the use of oral pills, shown to be safe and effective in >75% of those affected, represents the chosen therapeutic approach in >90% of cases. Media outlets targeted at the lay public frequently address the relationship of neurovascular dysfunction and the development of ED as an important medical issue. The identification of ED as a potential marker or early warning sign of impending cardiovascular events has received much media attention recently and heightens the importance of those affected discussing the topic with their physician. Despite the enhanced attention to the condition and the availability of effective therapy, only a minority of men with ED seek medical care [3]. Exciting novel research into the impact of phosphodiesterase inhibitors on endothelial function, coexisting voiding dysfunction, and the potential for positively affecting cardiovascular health with a reduction in cardiovascular adverse events have been reported. Understanding where clinicians are at present in the management of ED is essential in assessing the value of evolving approaches and research in this field. Oral management of ED has become the treatment of choice for most patients and physicians owing to a number of factors. Key among the advantages of oral therapy are ease of use, safety, efficacy, reliability, extensive clinical experience with these agents, and their ability to enhance erectile function across a wide spectrum of ED etiologies. The commonly reported weaknesses of oral therapy are cost, the need for a medical consultation, side-effects, and lack of efficacy in roughly 25% of men. With this balance of positive and negative attributes of oral therapy in mind, let us explore whether novel gene-based approaches are needed for the treatment of ED. In my mind, the clear need for alternative approaches to the management of ED is without doubt. At present, >66% of men suffering from erectile concerns have not received effective treatment because of a wide variety of issues ranging from embarrassment, denial, lack of information about treatment options, lack of efficacy, side-effects, and financial reasons. The ability for novel approaches to address these weaknesses would represent an important advance in the field. Additionally, phosphodiesterase type 5 inhibitors (PDE5-Is) compensate rather than reverse the perceived cause of the ED, a consideration for some. In their article, Kendirci et al. [4] have summarised the exciting developments in the world of gene-based research, exploring the potential use of multiple agents for erectile enhancement delivered through a variety of vectors and routes. They have clearly articulated the argument in favour of universal acceptance and excitement over the role of these therapies for ED as we all search for the solution for those individuals affected. Although it is clear to me that gene-based research in animal models has been performed and published, exploring a wide range of physiologic conditions attempting to replicate human disease, at present few actual human data exist. Currently, only a single published report describing very preliminary human results exists [5]. The authors have eloquently described both the essential elements necessary to raise gene therapy for the management of ED into the clinical meaningful arena and the gaps in our current knowledge. I believe we all need to be aware of what those specific targets are before we can view gene therapy as a truly viable option for patients: efficacy, safety, ease of application/availability, and cost. Specifically, a large variety of putative targets exists, with an equally large group of gene-based therapeutic agents, delivered through several vectors [6], [7], [8], [9], [10]. Before any statements relating to clinical importance or utility are made, several research questions in humans need to be addressed. Among the most appealing aspects of gene therapy for ED is the concept of treating the problem rather than simply compensating for a dysfunction. If shown to be accurate, that specific cellular-based defects exist in men, then this therapeutic approach would be further strengthened. At present this sophisticated diagnostic testing, to my knowledge, does not exist to determine in an individual clinical patient whether his ED is related to enhanced nitric oxide breakdown from excessive free oxygen radicals or reduced production secondary to diabetes or inadequate smooth muscle relaxation as a consequence of impaired ion channel opening. In fact, I would argue that if proven to be safe and clinically effective over a significant length of time in humans, the concept of reversing a specific dysfunction with gene therapy would represent the exception rather than the rule. In my consultations, most men with ED have a multitude of coexisting risk factors contributing to multisystem causes for their erectile malfunction. The man with diabetes usually has impaired vasculature with both small and large vessel disease in addition to his sensory loss from dorsal nerve dysfunction and impaired cavernous nerve function. If true, then is delivery of increased nitric oxide synthase through an adenoassociated viral vector really reversing the problem any more than a PDE5-I? The goal of this editorial is to put into perspective the concept of gene-based therapies for the management of ED in large populations of affected individuals. What are the societal benefits, risks, and ultimately costs of such a treatment strategy? Is it a practical approach that we can realistically expect to be clinically available to large groups of men, worldwide in our lifetime? If not, does that in any way reduce the scientific validity of this type of research? Although I understand the science and believe many of the tenets that form the foundation of its rationale, I honestly believe oral therapy for ED, whether it is based on PDE5-I usage or derived from other evolving targeted therapies, will remain the cornerstone of ED management long into the 21st century. The concept of developing dysfunction-based targeted therapy delivered through vectors that prove to be safe in humans, providing reversal of the pathology that is responsible for the ED, is both intellectually stimulating and clinically intriguing. The accessible position of the penis, the requirement for a modest incorporation rate, and the need for only slight alterations in the balance of vasoconstriction to vasodilation all speak to the clinical potential of this approach. Like many areas of medicine and research, a gene therapy-based approach to treat ED is an exciting area of research that has huge clinical potential; whether it ever is realised will be determined based on how its safety, efficacy, and cost compare to existing therapy. In the case of ED, this may be a very tough competitor to beat. References 1. Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, Snyder SH. Nitric oxide: a physiologic mediator of penile erection. Science. 1992;257:401–403. 2. Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ. Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N Engl J Med. 1992;326:90–94. 3. Nicolosi A, Laumann EO, Glasser DB, Brock GB, King R, Gingell C. Sexual activity, sexual disorders and associated help-seeking behavior among mature adults in five Anglophone countries from the Global Survey of Sexual Attitudes and Behaviors (GSSAB). J Sex Marital Ther. 2006;32:331–342. MEDLINE | CrossRef 4. Kendirci M, Teloken PE, Champion HC, Hellstrom WJG, Bivalacqua TJ. Gene therapy for erectile dysfunction: fact or fiction?. Eur Urol. 2006;50:1208–1222. 5. Melman A, Bar-Chama N, McCullough A, Davies K, Christ G. The first human trial for gene transfer therapy for the treatment of erectile dysfunction: preliminary results. Eur Urol. 2005;48:314–318. 6. Bivalacqua TJ, Hellstrom WJ. Potential application of gene therapy for the treatment of erectile dysfunction. J Androl. 2001;22:183–190. 7. Christ GJ. Frontiers in gene therapy for erectile dysfunction. Int J Impot Res. 2003;15:S33–S40. 8. Gonzalez-Cadavid NF, Burnett AL, Magee TR, et al.. Expression of penile neuronal nitric oxide synthase variants in the rat and mouse penile nerves. Biol Reprod. 2000;63:704–714. 9. Hsieh PS, Bochinski DJ, Lin GT, Nunes L, Lin CS, Lue TF. The effect of vascular endothelial growth factor and brain-derived neurotrophic factor on cavernosal nerve regeneration in a nerve-crush rat model. BJU Int. 2003;92:470–475. 10. Bivalacqua TJ, Armstrong JS, Biggerstaff J, et al.. Gene transfer of extracellular SOD to the penis reduces O2− and improves erectile function in aged rats. Am J Physiol Heart Circ Physiol. 2003;284:H1408–H1421. Gerald Brock Department of Surgery, University of Western Ontario, London, Ontario, Canada N6A 4V2 published online 6 September 2006.
Please log-in or register in order to submit comments. Powered by AkoComment! |
||
| < Prev | Next > |
|---|
|
UroToday, 1802 Fifth Street, Berkeley CA 94710 510.540.0930 (fax), info@urotoday.com ISSN 1939-4810
Privacy Policy | © 2009 UroToday ® All Rights Reserved |
