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Phosphodiesterase Type 5 Inhibitors for the Treatment of Erectile Dysfunction in Patients with Diabetes Mellitus

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Phosphodiesterase Type 5 Inhibitors for the Treatment of Erectile Dysfunction in Patients with Diabetes Mellitus International Journal of Impotence Research (2002) 14, 466–471 ß 2002 Nature Publishing Group All rights reserved 0955-9930/02 $25.00 www.nature.com/ijir Phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction in patients with diabetes mellitus MA Vickers1,2* and R Satyanarayana1 1Department of Surgery, Togus VA Medical Center, Togus, Maine, USA; and 2Department of Surgery, Division of Urology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has become a first-line therapy for diabetic patients with erectile dysfunction (ED). The efficacy in this subgroup, based on the Global Efficacy Question, is 56% vs 84% in a selected group of non-diabetic men with ED. Two novel PDE5 inhibitors, tadalafil (Lilly ICOS) and vardenafil (Bayer), have recently completed efficacy and safety clinical trials in ‘general’ and diabetic study populations and are now candidates for US FDA approval. A summary analysis of the phase three clinical trials of sildenafil, tadalafil and vardenafil in both study populations is presented to provide a foundation on which the evaluation of the role of the individual PDE5 inhibitors for the treatment of patients with ED and DM can be built. International Journal of Impotence Research (2002) 14, 466–471. doi:10.1038=sj.ijir.3900910 Keywords: phosphodiesterase inhibitor; erectile dysfunction; diabetes mellitus; sildenafil; tadalafil; vardenafil Introduction (NO), vasointestinal peptide and prostacyclin, de- creases. Additionally, the endothelial cells that line the cavernosal arteries and sinusoids have a Pathophysiology of ED in diabetes decreased response to nitric oxide due to increased production of advanced glycation end-products and changes associated with insulin resistance.5,6 The Diabetes mellitus is a risk factor for erectile diabetic also experiences a decreased level of dysfunction (ED). ED is present in 32% of insulin- glutathione, a reducing agent that protects against dependent diabetics and 46% of non-insulin de- oxidative stress.7 This results in the premature pendent diabetics. ED is the result of both structural death of the non-adenergic, non-cholinergic nerve and molecular abnormalities. Atrophy or apoptosis, endings in the penis, thus lowering levels of second owing to loss of Bcl-2 expression in smooth muscle, messenger nitric oxide. The end result of decreased and increased connective tissue synthesis, due to production or decreased response to nitric oxide is a TGF beta, result in decreased compliance of caver- decrease in the stimulation of guanylate cyclase. nosal tissue.1,2 Both these changes reduce or inter- This enzyme cleaves GTP with resultant production fere with the gap junctions and K channels in of cyclic guanosine monophosphate (cGMP), the cavernosal smooth muscle that are necessary for power source for the relaxation of cavernosal coordinated relaxation of cavernosal tissue.3 The smooth muscle. In situations in which sexual chemical changes involve a shift in the balance stimulation does not induce critical amounts of between molecules that induce cavernosal smooth cGMP, calcium remains in its intracellular location, muscle contraction and those that induce smooth cavernosal muscle remains contracted and caverno- muscle relaxation.4 The concentration of constric- sal blood vessels do not dilate. Blood flow into the tors, including endothelin, prostanoids, and possi- penis is inadequate to engorge the sinusoids and bly angiotensin, increases with aging as the compress the venules. Functional penile rigidity is production of the relaxants, including nitric oxide not achieved. The oral treatment of ED in the diabetic is based on amplification of the response to NO stimulation. Sub-erectile levels of cGMP are increased to critical *Correspondence: MA Vickers, Department of Surgery, VA Medical Center, Togus, ME 04330, USA. erectile levels by delaying the degradation of this E-mail: [email protected] molecule. This is achieved through the inhibition of Received 19 March 2002; accepted 1 May 2002 the enzyme phosphodiesterase 5. Phosphodiesterase type 5 inhibitors MA Vickers et al 467 PDE5 inhibitors in ED taken. Sixteen men with ED received sildenafilona 25 mg, three times daily, outpatient basis. The study The final chapter of discovery of an oral drug that patients kept diaries in which they recorded when would dependably increase cGMP to levels that they had erections, whether the erections resulted could promote cavernosal smooth muscle relaxation from sexual stimulation, and how firm the erections began in the vascular laboratory. Phosphodiesterase were. The patients were also studied with the type 5 (PDE5) had been identified as the enzyme that Rigiscan. The results were encouraging and showed degraded cGMP.8 It resides in vascular smooth a clear difference between the treatment and place- muscle cells and platelets. Researchers theorized bo. Subsequent studies confirmed the efficacy and that inhibition of this enzyme offered potential safety of sildenafil in the treatment of ED with a benefits for patients with hypertension or angina. variety of etiologies, including vascular, psycho- In 1986, Pfizer researchers began their search for a genic, and neurological. In 1998, the US FDA PDE5 inhibitor. In 1989, they synthesized sildenafil, approved sildenafil for the treatment of ED. It soon a chemical that selectively targeted and powerfully became the first-line therapy. Soon, a search for inhibited PDE5. Clinical studies on sildenafilasa novel, superior PDE5 inhibitors was initiated. Var- drug for angina began in 1991. The initial study, denafil (Bayer) and tadalafil (Lilly ICOS) are the designed to assess the drug’s safety, revealed no products of these efforts and are presently candi- unusual findings. In 1992, a multiple-dose phase 1 dates for US FDA approval. All three PDE5 inhibitors trial was initiated. A few of the study patients are similar in structure to cyclic guanosine mono- reported an ‘adverse event’—an increased tendency phosphate (Figure 1). to get erections. Later that year the drug was tested The phase three trials (efficacy and safety) for in men with angina. The hemodynamic effects were sildenafil, tadalafil and vardenafil in the general ‘fairly mild’. population (organic, psychogenic and mixed ED) In 1992, Rajfer and Ignarro published their work and the phase three trial of sildenafil in the diabetic showing that nitric oxide (NO) caused smooth population have been published in peer reviewed muscle relaxation in human cavernosal tissue. The journals.9 – 12 Additionally, the phase three trials of basic mechanism involved sexual stimulation that tadalafil and vardenafil in the diabetic population triggered the release of NO from nerve endings in the have been published in abstract=poster form.13,14 penis. This NO in turn stimulated the production of These publications have prompted speculation cGMP, which dilated penile blood vessels and concerning the role of the various PDE5 inhibitors relaxed the smooth muscle in the walls of the in the treatment of ED. The temptation to draw cavernosal sinusoids. These two effects promote conclusions based on simple comparison of these engorgement of the penis and penile rigidity. studies must be rejected for several reasons. On Several basic and clinical researchers at Pfizer review of these studies, it is apparent that inclusion lobbied for further study of the PDE5 inhibitor in and exclusion criteria vary. The criteria for the treatment of ED based on its ability to relax vascular classification of ED, the percentage of patients with smooth muscle, its ‘adverse event — tendency to get psychogenic ED, the dosing methodology (fixed vs an erection in the angina trials’, and the UCLA NO dose escalation), and the duration of the studies also research. Even before Pfizer scientists isolated PDE5 vary. These differences likely impacted treatment from human corpus cavernosal tissue (1994), the first outcomes. No head-to-head comparative trials with study (1993) of sildenafil for treating ED was under- the PDE5 inhibitors have been published. Figure 1 The structures of three PDE5 inhibitors have components which are similar to cyclic GMP. International Journal of Impotence Research Phosphodiesterase type 5 inhibitors MA Vickers et al 468 Although no definite conclusion concerning drug diabetes mellitus, cancer chemotherapy agents, superiority can be made from these studies, a systemic corticosteroids, warfarin or antiandrogen comparative summary helps demonstrate the effi- therapy. Potential candidates in the vardenafil study cacy and safety of the class of PDE5 inhibitors and were excluded if they had not responded to the potential advantages of individual PDE5 inhibi- sildenafil. In addition, patients were excluded from tors. The general population trials are included to the study based on half (five of 10) of the provide an overall perspective for the use of exclusionary criteria of the sildenafil study. Patients individual PDE5 inhibitors in ED and to provide a with hypogonadal testosterone levels, TSH levels of background for the evaluation of the role of PDE5 < 0.28 mU=l, or with a previous radical prostatect- inhibitors in diabetic patients. The summary analy- omy were excluded. The percentage of patients with sis includes methodology, efficacy, and safety. organic, psychogenic, or mixed ED was not provided in the tadalafil study. The tadalafil 2 mg dose results are not included in this analysis because there was Methodology no significant difference from placebo
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