PDE5 Inhibitors Beyond Erectile Dysfunction

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REVIEW PDE5 inhibitors beyond erectile dysfunction

P Sandner, J Hu¨ tter, H Tinel, K Ziegelbauer and E Bischoff

Product-Related Research, Bayer HealthCare, Wuppertal, Germany

The phosphodiesterase type-5 (PDE5) inhibitors sildenafil, vardenafil and tadalafil are widely used first-line therapy for erectile dysfunction (ED). Since the advent of sildenafil in 1998, more than 40 million men worldwide have been successfully treated with these compounds. The safety and high tolerability of PDE5 inhibitors make them an attractive tool to investigate further physiological functions of PDE5, for example the modulation of intracellular cyclic GMP (cGMP) pools. As cGMP is a key component of intracellular signaling this may provide novel therapeutic opportunities beyond ED even for indications in which chronic administration is necessary. The approval of sildenafil for the treatment of pulmonary hypertension in 2005 was a notable success in this area of research. A number of other potential new indications are currently in various phases of preclinical research and development. In recent years, extensive but very heterogeneous information has been published in this field. The aim of this review is to summarize existing preclinical and clinical knowledge and critically discuss the evidence to support potential future indications for PDE5 inhibitors. International Journal of Impotence Research (2007) 19, 533–543; doi:10.1038/sj.ijir.3901577; published online 12 July 2007

Keywords: lower urinary tract symptoms; benign prostate syndrome; premature ejaculation; Raynaud’s disease; Peyronie’s disease; heart failure

Introduction cGMP-driven cascade of reactions. Ultimately, these pathways decrease intracellular calcium levels, It is well established that nitric oxide (NO) and thereby promoting relaxation of smooth muscle cells natriuretic peptides increase intracellular cGMP and a variety of other calcium-dependent pro- levels by stimulation of the soluble and membrane- cesses.3 Since inhibitors of PDE5 raise intracellular bound guanylate cyclase, respectively. This cGMP cGMP levels, the effects will be much more formation is the initial step of a ubiquitous bio- pronounced under conditions when cGMP forma- chemical pathway, regulating the cardiovascular, tion is already increased. Strong evidence to support central and peripheral nervous system.1 Phospho- this concept is the highly efficacious treatment of diesterases (PDEs) are intracellular enzymes that erectile dysfunction (ED) with PDE5 inhibitors.4 specifically catalyze the hydrolysis of the second Sexual stimulation induces a selective vasorelaxa- messengers cAMP and cGMP to the inactive meta- tion in penile tissue, which is predominantly bolites AMP and GMP. Among the 11 families of mediated by the release of NO in the cavernous PDEs a number are able to hydrolyze cGMP, but only nerve endings, the endothelium of penile arteries PDE5 exclusively catalyses the breakdown of and the corpora cavernosa. Relaxation is induced by cGMP.2 By counterbalancing cGMP production by the subsequent formation of cGMP. By preventing guanylate cyclases, PDE5 is able to decrease cGMP degradation of cGMP, PDE5 inhibitors reinforce this levels very effectively. Thus PDE5 inhibition in- physiological mechanism very efficaciously and creases intracellular cGMP levels and initiates a induce the appropriate vasorelaxation necessary to obtain an erection. It is the regulatory mechanism that forms the basis for the triumphal success of PDE5 inhibitors in the treatment of ED. Correspondence: Dr E Bischoff, Product-Related Research, Bayer HealthCare, Aprather Weg 18a, Wuppertal 42096, Three compounds are available worldwide, three Germany. others may enter into the market during the next E-mail: [email protected] years (Table 1). The wide, safe use of PDE5 Received 13 February 2007; revised 10 May 2007; inhibitors, together with an increasing understand- accepted 25 May 2007; published online 12 July 2007 ing of cGMP-regulated mechanisms, have triggered a PDE5 inhibitors beyond erectile dysfunction P Sandner et al 534 Table 1 Approved and emerging PDE5 inhibitors inhibitors. There is a large body of preclinical and clinical evidence showing that PDE5 inhibitors Compound Company Status reduce vascular resistance in the pulmonary circulation and pressure in the pulmonary arteries. The Sildenafil Pfizer Approved for ED and PAH rationale is based on the hypothesis that oxygena- Vardenafil Bayer AG Approved for ED Tadalafil Eli Lilly Approved for ED tion of the alveoli stimulates release of NO, which Udenafil5 Dong Pharmaceutical Approved for ED in causes a local relaxation of pulmonary resistance Co Ltd Korea, Phase 3 in US vessels. Inhibition of cGMP cleavage results in 6 Avanafil Tanabe Seiyaku, Phase 2 amplification of this regulatory pathway, causing licensed by Vivus SLX-21017 Surface Logics Phase 1 increased vasodilation without inducing a ventila- tion–perfusion mismatch. Abbreviations: ED, erectile dysfunction; PAH, pulmonary hyper- In animal models, such as the monocrotaline- tension; PDE5, phosphodiesterase type-5. induced pulmonary hypertension (PAH) in rats, it has been demonstrated that the PDE5 inhibitor sildenafil reduces pulmonary arterial pressure and number of attempts to find new applications for right heart hypertrophy.19 Moreover, it has been these agents. It has been shown that besides corpus shown that inhibition of cGMP cleavage by sildena- cavernosum, PDE5 is also expressed in smooth fil reduces the hypoxia induced rise in pulmonary muscles of the systemic vasculature,8 prostate,9 pressure and partially reverses pulmonary artery bladder,10 cardiac tissues,11,12 brain and plate- muscularization.20 lets,13,14 which imply additional target tissues for In clinical studies sildenafil also has been shown PDE inhibitors. The aim of this paper was to to be a safe and effective drug for patients with PAH. critically review and discuss recent findings in this A small crossover study showed that sildenafil field, and highlight possible future therapeutic uses improved exercise time and cardiac output signifi- of PDE5 inhibitors beyond ED. cantly, whereas pulmonary arterial pressure was only slightly decreased.21 In the SUPER-1 (Sildena- fil Use in Pulmonary Hypertension) study (a large, PDE5 inhibitors to treat cardiovascular randomized, controlled, multinational trial) sildenafil significantly improved exercise capacity, func- diseases and endothelial dysfunction tional class and hemodynamic parameters and was well-tolerated.22 On the basis of these data, sildena- PDE5 inhibitors may be optimally suited for the fil was approved in 2005 by the United States Food treatment of cardiovascular diseases, due to their and Drug Administration and the European Agency mechanism of action. Increases in intracellular for the Evaluation of Medicinal Products for the cGMP levels cause a relaxation of vascular smooth treatment of patients with PAH. muscles. This is not only a generalized vasodilation, since its extent depends on the physiological stimulus NO. In regions, where a relatively large NO production signals a high need for local Heart failure perfusion, the chosen PDE5 inhibitor should be Congestive heart failure (CHF) is a chronic debilitat- more efficacious than in areas with lower perfusion ing disease, which leads to infirmity and death demand. In contrast to unspecific vasodilators, within few years. Coronary artery disease, past PDE5 inhibitors trigger a demand-driven increase myocardial infarctions and hypertension are the in flow, which may offer the opportunity for a very major causes of heart failure. specific redistribution of blood flow into areas with There are numerous potential mechanisms by the highest perfusion needs. This may prevent which PDE5 inhibitors could exert positive effects luxury perfusion and steal phenomenon and a on the course and symptoms of this disease. The dramatic decrease in blood pressure. most prominent mechanism is a cGMP-mediated Other effects beyond vascular dilatation have relaxation of smooth muscle cells, which elicits a been described for PDE5 inhibitors, which may also direct vasodilation. Since this is observed primarily have a positive impact on cardiovascular diseases. in the pulmonary vasculature, it may particularly There are numerous reports that describe protective unload the right ventricle. In patients suffering from effects in ischemia/reperfusion in the heart.15 Other CHF, sildenafil decreased pulmonary resistance and authors have reported antihypertrophic,16 antiproli- improved peak oxygen uptake during exercise, ferative,17 and antifibrotic18 efficacy. whereas it did not influence these parameters in healthy volunteers.23 The positive effect of direct vascular dilation may be important in large blood Pulmonary hypertension vessels, since an improved compliance of the large The treatment of pulmonary arterial hypertension is arteries reduces peak ventricular pressure and the most established cardiovascular use of PDE5 improves peripheral perfusion during the diastole

International Journal of Impotence Research PDE5 inhibitors beyond erectile dysfunction P Sandner et al 535 by lowering pulse pressure. Such an effect could be stress and smoking. Pharmacological treatments, demonstrated by Hirata et al.24 In patients with however, are often disappointing and inefficient. controlled LV failure and ejection fractions lower Although there are numerous hypotheses, the than 35%; a single dose of 50 mg sildenafil im- mechanism of local vasoconstriction is not well proved cardiac performance by decreasing periph- understood.29 Nevertheless, there is increasing eral resistance, aortic and large artery stiffness and evidence that the NO/cGMP system plays a major wave reflection from peripheral sites. role. In scleroderma patients intra-arterial infusions Another potential benefit of PDE5 inhibitors may of L-arginine (the substrate for NO) and sodium be an improvement of endothelial function.25 A nitroprusside (a direct donor of NO) significantly placebo-controlled study showed that acute PDE5 decreased the occurrence of laboratory-induced inhibition with sildenafil-increased endothelium- Raynaud’s phenomenon.30 Rosenkranz et al.31 pub- dependent, flow-mediated vasodilation in patients lished a case report of a 65-year-old woman with with chronic heart failure.26 These findings were severe Raynaud phenomenon related to systemic confirmed by Hryniewicz et al.,27 who compared scleroderma. Treatment with sildenafil improved sildenafil with the angiotensin-converting enzyme severity and frequency of acrocyanosis, and laser- inhibitor ramipril, showing that both compounds Doppler flowmetry demonstrated improved perfu- improved flow-mediated dilation to a similar extent sion of the fingertips. in patients with heart failure. In an open-label pilot study, Caglayan et al.32 It is not clear to what extent the vascular effects of investigated the effects of the PDE5 inhibitor PDE5 inhibitors affect coronary and left ventricular Vardenafil on clinical symptoms and peripheral hemodynamics. In an experimental model of pa- blood flow in 40 patients with Raynaud’s phenom- cing-induced heart failure, Chen et al.28 observed enon. Laser-Doppler flowmetry revealed improved that sildenafil only caused a slight decrease of aortic peripheral blood flow in 75% of all patients, pressure, without any change in heart rate, left whereas 25% of the patients did not respond. These ventricular systolic pressure and contractility, cor- findings suggest that vardenafil can improve per- onary flow or myocardial oxygen consumption, ipheral blood flow and clinical symptoms in some either at rest or during exercise. In contrast to patients with Raynaud’s disease. findings in normal animals, sildenafil did not In 2005, Fries33 published results of a double- augment endothelium-dependent coronary vasodi- blind, placebo-controlled, fixed dose, crossover study latation in response to acetylcholine in animals in 16 patients with symptomatic secondary Ray- with CHF. naud’s phenomenon resistant to vasodilatory therapy. In 2005, Takimoto et al.16 presented an intriguing Treatment with sildenafil significantly reduced both study showing that the sildenafil completely sup- the frequency of Raynaud attacks and the cumulative presses cardiac hypertrophy in mice exposed to attack duration. Further, capillary blood flow velocity chronic pressure overload by an aortic banding increased in each individual patient. protocol. They also demonstrated that the drug even reversed a pre-established hypertrophy. A suggested mechanism of action was deactivation of multiple hypertrophy signaling pathways such as calcineurin/ PDE5 inhibitors to treat central nervous NFAT, phosphoinositide-3 kinase/Akt and ERK1/2. system disorders However, such a dramatic effect is difficult to understand and requires further investigation. PDEs are abundantly expressed in central nervous In summary, there is substantial evidence that system (CNS) tissue34 and there are an increasing PDE5 inhibitors may have positive effects in heart number of reports on the effects of PDE5 inhibitors failure and cardiac hypertrophy. However, the on the CNS.35 Studies have shown that both PDE5 potential mechanisms of action are not fully under- mRNA and PDE5 enzyme was detected in many stood and the clinical benefit remains to be demon- parts of the brain (for example, cortex, cerebellum strated. and hippocampus)36–38 and also in blood vessels within the brain (for example, cerebral, basilar and mesenteric artery).39 This suggests that the NO/ Raynaud’s disease cGMP pathway may be involved in a multitude of Raynaud’s disease is characterized by temperature- cerebral functions and may play a central role in sensitive, digital vasospasms leading to pale, cya- brain metabolism. A number of in vitro and in vivo notic skin mostly limited to the digits. Unlike the studies have investigated the effects of selective uncomplicated, primary idiopathic Raynaud’s phe- PDE5 inhibitors on cognitive functions and their nomenon, the secondary form is linked to connec- neuroprotective effects in stroke models. The pre- tive tissue diseases. This form presents more sence of PDE5 in the CNS might explain why PDE5 severely, with potentially disabling ulceration or inhibitor treatment may result in some degree of tissue necrosis. Non-pharmacological therapy in- back pain and myalgia as side effects of therapy. cludes avoidance of cold temperatures, emotional Data obtained from a rat model using sildenafil

International Journal of Impotence Research PDE5 inhibitors beyond erectile dysfunction P Sandner et al 536 suggest a modulation of nociception by centrally evidence that the NO/cGMP pathway is implicated mediated effects.40 However, only limited informa- in repair mechanisms in rodent models of stroke. tion is available on the extent to which these drugs Oral treatment of rats with sildenafil (2 or 5 mg/ penetrate the blood–brain barrier.41 kg) 24 h after embolic stroke improved recovery of neurological outcome. Although there was no difference in infarct volume between the treated and untreated groups, sildenafil stimulated cell Effects of PDE5 inhibitors on learning and memory proliferation in the subventricular zone and stria- In vitro experiments have demonstrated that silde- tum, as indicated by an enhanced number of nafil and vardenafil both increase NO-mediated immature neurones.42,50,51 The potential of PDE5 cGMP accumulation in slices of rat hippocampus.36 inhibitors to augment neurogenesis was demon- Increased cortical levels of cGMP have also strated in a model using aged rats. These animals been demonstrated in vivo in rats treated with exhibit a greater impairment of neurological recov- sildenafil.42 ery after focal ischemia, compared with young rats. The functional role of cGMP was first demon- However, treatment with sildenafil (10 mg/kg), even strated in behavioral studies in rats. Injections of 8- 7 days after ischemia, significantly improved func- bromo-cGMP into hippocampus improved memory tional recovery, vascular density, endothelial cell performance in tasks of object recognition and proliferation and synaptogenesis, compared with passive avoidance retention.43 Subsequent animal untreated rats. These effects were also observed in studies with sildenafil have demonstrated the long- younger rats at lower doses (2 mg/kg).52 All of these term retention of an inhibitory avoidance response effects may contribute to the significantly improved in mice.44 Moreover, oral administration of the PDE5 functional recovery observed in sildenafil-treated, inhibitors sildenafil and vardenafil (1–10 mg/kg) compared with saline-treated rats. Studies carried immediately after training effectively improved the out by the same research group showed that memory performance of rats in object recognition increased cGMP levels induced neurogenesis in tasks.36,45 Thus, it may be argued that inhibition of adult progenitor cells derived from the subventri- PDE5 in the dorsal hippocampus improves object cular zone through activation of the phosphoinosi- recognition memory, which may result from in- tol-3-kinase/Akt glycogen synthase kinase-3 creased levels of cGMP. This hypothesis is sup- pathway.53 ported by the finding that learning impairment in Few studies have been published on the effects of rats can be induced by administration of the NO- sildenafil on cerebral blood flow (CBF) and oxyge- synthase inhibitor L-NAME which, in turn, can be nation, and results are controversial.54–57 Studies in attenuated by intraperitoneal administration of healthy subjects found no effect on CBF after sildenafil.46,47 treatment with oral sildenafil.55 However, results The effects of PDE5 inhibitors on memory pro- in stroke models in rats are extremely encouraging. cesses in humans have only been studied sporadi- Nevertheless, one has to keep in mind that due to cally. So far, no clear effects on behavioral measures the lack of clinical data the use of PDE5 inhibitors is of attention and verbal recognition memory have not indicated in stroke patients 6 months after acute been reported.48 However, one study found that stroke. Therefore, a proof of concept study in attention- and event-related brain potential mea- humans with acute stroke have to be conducted sures were improved by sildenafil. In another study, very carefully, but would be desirable to assess the the simple choice reaction time was reported to be potential of these drugs for this indication. faster in sildenafil-treated subjects.49 In conclusion, there is a clear body of evidence that these drugs have the potential to improve memory performance in animals, particularly in PDE5 inhibitors to treat urological disease the early consolidation process of long-term memory. This memory improvement might be mediated Female sexual dysfunction by elevations in central cGMP levels. Studies in The physiology of female sexual response is poorly humans suggest that information processing may be understood. Only a small number of experimental improved by sildenafil treatment. However, further studies have investigated the possible role of PDE5 studies designed to test memory-enhancing effects in the physiology of female genital organs. The of PDE5 inhibitors are needed to demonstrate a occurrence and hydrolytic activity of PDE5 in proof of principle for this class of drugs as a possible human clitoral corpus cavernosum and human tool for improving memory. vagina has been shown.58–60 Organ bath experiments have demonstrated the ability of PDE5 inhibitors to relax vaginal and clitoral muscles.61,62 Stroke Thus, it is logical to expect that PDE5 inhibitors may A number of publications from one particular improve vaginal and clitoral blood flow and facil- research group deliver growing experimental itate arousal and orgasm in women. To date, only

International Journal of Impotence Research PDE5 inhibitors beyond erectile dysfunction P Sandner et al 537 sildenafil has been investigated clinically for effects expressed in the prostate.9,79 Various PDE inhibi- on female sexual function. However, the results of tors, including zaprinast (used for PDE5 inhibition), these clinical trials were not very encouraging. are able to relax human prostate tissue in vitro.9,80 Sildenafil showed only moderate effects to most There is also recent evidence that the PDE5 women with female sexual dysfunction (FSD).63–66 inhibitors vardenafil, sildenafil and tadalafil are Studies showed that PDE5 inhibition may benefit able to relax prostate, bladder and urethral tissues in individuals with female sexual arousal disorder vitro.17 Moreover, preclinical research has demon- (FSAD), but not with hypoactive sexual desire strated a reduction of non-voiding contractions disorder (HSDD). This finding might be especially in vivo in rats treated with vardenafil or sildenafil.17,81 important for women with diabetes as FSAD is the Even more striking are the recent observations from most commonly reported sexual problem in this clinical studies, where a reduction of LUTS was group of patients.67 Indeed, it has recently been reported in patients with BPH treated with sildenafil shown that sildenafil improved sexual function in and tadalafil.82–84 The International Prostate Symp- premenopausal women with diabetes.68 Thus it tom Score (IPSS), which includes obstructive and appears that certain patient groups may benefit from irritative scoring, was significantly reduced in treatment with PDE5 inhibitors, but further studies patients with BPS treated with 100 mg sildenafil or are required to confirm this. 20 mg tadalafil, once daily, for 12 weeks. In both When planning future studies, new findings studies, there were no changes in urodynamic concerning female sexuality should be taken into parameters and positive effects were related to consideration. The linear model of sexual response, improvement of symptoms. There is therefore which is true for men, disregards the relative evidence that PDE5 inhibitors may be an additional independence between subjective and objective treatment option for patients suffering from LUTS. aspects of women’s sexual response.69 This can explain the lack of correlation between the improvement of objective arousal (for example, increase of clitoral blood flow) and the subjective sexual Overactive bladder and incontinence feelings. Moreover, the frequency of sexual fantasies Overactive bladder (OAB) is a term, defined by the or sexual thought has little correlation with sexual International Continence Society, and is usually satisfaction in women.70,71 Thus daily diary mea- described as urgency with or without incontinence, sures, event logs or number of successful or frequency and nocturia.85 Urgency urinary incon- satisfactory sexual events might not be the most tinence (UUI) is a sudden and compelling desire to sensitive and reliable measures of outcome in FSD pass urine, which can be accompanied by the clinical trials.72 involuntary leakage of urine. In addition, OAB Therefore, in light of these findings, any clinical patients display higher voiding frequency, with 48 studies to evaluate the benefits of PDE5 treatment episodes of voiding during daytime and nocturia, for women with FSD may require a modified design. with more then 1 voiding during sleeping time. Urge urinary incontinence (UUI) is the most bothersome symptom of OAB and is associated with a significantly reduced quality of life of the patients.86 The Benign prostate syndrome and lower urinary tract pathophysiology of this disease is not fully under- symptoms (BPS/LUTS) stood and seemed to be multifactorial. The voiding Benign prostate syndrome (BPS) comprises lower process is normally tightly regulated by neural urinary tract symptoms (LUTS) and benign prostate circuits within the brain and the spinal cord, which hyperplasia (BPH), which can cause bladder outlet co-ordinate smooth muscle activity in bladder and obstruction (BOO). LUTS may also be present in urethra. Direct contraction and relaxation of the patients without benign prostate enlargement (BPE). bladder smooth muscle plays a critical role in this LUTS comprises obstructive symptoms and irrita- disease.87 In addition to local application of botuli- tive symptoms: obstructive symptoms are induced num toxin or resiniferatoxin,88,89 the main treatment by compression of the urethra caused by BPE; option is based on muscarinic receptor antagonists irritative symptoms occur during the filling phase (antimuscarinics). These prevent acetylcholine-in- of the bladder and are characterized by non-voiding duced contraction of the detrusor muscle by block- contractions of the bladder detrusor muscle.73–75 ing post-synaptic M3 receptors during the filling LUTS considerably decreases the quality of life of phase.90,91 Evidence that PDE inhibitors may be affected patients and is a major healthcare problem used for the treatment of OAB and UUI is rare and is in developed countries. The main treatment options only indirect. It has been shown that different PDE – besides prostatic surgery – are a-blockers and 5-a isogenes, including PDE5, are expressed in the reductase inhibitors.76,77 detrusor muscle.10 Further, PDE inhibitors, includ- PDE activity in human prostate tissues was first ing PDE5, reduced the tonus of bladder muscle in reported in 1970.78 Later studies demonstrated that vitro.92–95 As these effects are relatively weak, there various PDE isoenzymes, including PDE5, are is increasing evidence that the effects of PDE5

International Journal of Impotence Research PDE5 inhibitors beyond erectile dysfunction P Sandner et al 538 inhibitors are at least in part related to their and tadalafil have been used to treat PE/RE patients influence on the urothelium. It was shown in guinea in several clinical studies.113,114 In these studies an pigs that urothelial, suburothelial and intramural increased intravaginal ejaculatory latency time neurons contain considerable amounts of endothe- (IELT) was found after treatment with sildenafil,115 lial NO synthase (eNOS) and NO-inducible cGMP, vardenafil116 and tadalafil.117 However, these stu- which may be important for bladder sensations and dies were often performed in an open label manner, the micturition threshold.96,97 There is preliminary with poorly defined inclusion criteria and without evidence regarding the effects of the PDE-1 inhibitor, consistent objective physiological end points. vinopectine, in patients with OAB.98 However, as Therefore, despite these very promising clinical yet, clinical data to support the use of PDE5 results only one clinical trial conducted with inhibitors for the treatment of OAB are limited. sildenafil fulfilled the evidence-based medicine The symptoms of LUTS (urgency, frequency, noctur- criteria.113 In this placebo-controlled, double-blind ia) in patients with BPH are similar to those of UUI study within almost 160 patients, no significant in patients with OAB.75 Both LUTS and UUI increase in IELT was observed. However, patients symptoms originate within the bladder and are treated with sildenafil reported significantly in- characterized by detrusor overactivity.75 This may creased ejaculatory control, increased ejaculatory explain the finding that the M3 antagonist, tolter- confidence and had a decreased post-ejaculatory odine, which is normally used in patients with erectile refractory time.118 Thus, further preclinical OAB, significantly improved the symptoms of LUTS research on the role of PDE inhibitors in PE is when used in patients with BPH.99,100 Thus, it might required, together with clinical trials to evaluate the be assumed that if PDE5 inhibition reduces symp- potential benefits of PDE5 inhibitor treatment for toms of LUTS, it may also reduce UUI symptoms in patients with PE. patients with OAB.82,84,101 Both preclinical models and clinical studies are required to investigate the efficacy of marketed PDE5 inhibitors in the treat- Peyronie’s disease ment of OAB. Peyronie’s disease (PD) is a disorder characterized by fibrotic plaques of the tunica albuginea of the penis. The prevalence rate of PD is estimated to be Premature ejaculation between 0.4% and 9%, depending on the exact Premature or rapid ejaculation (PE/RE) is a common criteria used to define the condition.119,120 The male sexual disorder with prevalence rates of cause of fibrotic plaques in patients with PD is 5–30%.102–104 However, the pathophysiology and unknown, but it is hypothesized that trauma with underlying molecular mechanism are only poorly excessive wound healing, infections and autoim- understood. No approved pharmacotherapy is cur- mune disease may cause this local fibrosis within rently available, but tricyclic antidepressants, ser- the penis. The molecular mechanisms underlying otonin reuptake inhibitors and topical applications this condition are poorly understood. Pharmacother- of local anaesthetics are used in the treatment of this apy is still in an experimental stage, and therefore condition.105 Psychological counseling and beha- surgery is currently the predominant treatment vioral therapy, either alone or in combination with option.119 As the proliferation and accumulation of drug treatment, have also shown success.106 How- fibroblasts in the penis promote PD, one possible ever, current treatment options are limited both in therapeutic approach is the prevention of fibroblast their efficacy and also, partly, by their side effects. proliferation. It has been demonstrated that the Consequently, substantial efforts are underway both NOS/NO/cGMP system plays an important role in to increase understanding of the pathophysiology the progression of plaque development, since in- of PE, and to search for more effective therapies. hibition of inducible NO synthase (iNOS) results in Research has shown that relaxation of smooth exacerbated fibrosis.121 In primary cultures of hu- muscles within the vas deferens and seminal man PD-derived fibroblasts, sildenafil and the non- vesicles may attenuate ejaculation, a finding which specific PDE inhibitor, theophyllin, reduced col- may be useful in developing therapies for PE. The lagen I synthesis and myofibroblast differentiation role of the NO/cGMP pathway in PE has been and increased apoptosis in vitro.122 Very recently, an investigated and it was found that NO-donors107–110 in vivo rat model of PD was used to demonstrate that are able to relax the vas deferens and seminal vardenafil significantly decreased collagen I and III vesicles.111 Moreover, it was also reported that deposition and reduced the numbers of myofibro- eNOS knockout mice (lacking the gene for endothe- blasts in PD plaques.123 There is currently no lial NO synthase) have higher rates of ejaculation, clinical data to support the use of PDE5 inhibitors with less stimulation required to elicit ejaculation, for the treatment of PD. Therefore, a future goal compared to wild type mice.112 Despite the involve- should be to confirm the existing in vitro and in vivo ment of the NO/cGMP system in PE, preclinical preclinical evidence in clinical trials to evaluate in vivo results with PDE inhibitors are still missing. the potential of PDE5 inhibitors for the treatment However, the PDE5 inhibitors sildenafil, vardenafil of PD.

International Journal of Impotence Research PDE5 inhibitors beyond erectile dysfunction P Sandner et al 539 Priapism dyspepsia and head ache, reported.82 However, Priapism is a rare disease within the general there is still lack of sufficient clinical data about population. However, in certain patient groups (for long-term chronic treatment with daily-dosed PDE5 example, patients with sickle cell disease) the inhibitors to assess completely the risk-benefit incidence of priapism may be as high as 40%. The potential for new indications. This finding is pathophysiology of priapism is still elusive, but it is important, as many of the proposed new indications thought that the persistent erections observed in for PDE5 inhibitors would require chronic daily patients with this condition may be due to dysfunc- dosing. Although many of the new research avenues tional penile blood flow.124,125 Data from several are still in their early stages, there is a strong small clinical trials suggest that PDE5 inhibitors possibility that some will move from bench to may be used successfully for the treatment of bedside (Table 2). priapism.126 It is hypothesized that long-term treat- Many of the new indications for PDE5 inhibitors ment with sildenafil may prevent downregulation of are characterized by regional deficiencies in blood PDE5 protein, and therefore prevent the chronic supply, which can be modulated via the NO-cGMP cGMP accumulation and excessive penile blood pathway. The use of PDE5 inhibitors may be flow seen in patients with priapism.127 This hypoth- beneficial due to their capacity to reverse endothe- esis must now be confirmed in clinical trials with lial dysfunction and to selectively improve NO- larger numbers of patients. modulated regional blood flow in areas of greatest need (for example, in Raynaud’s disease). Moreover NO/cGMP might also have antifibrotic effect, which is necessary for the treatment of fibrotic disorders Conclusions (for example, PD). The successful development of sildenafil for the treatment of PAH demonstrates PDE5 inhibitors are the gold standard for treatment that it is possible to take advantage of both of ED. The efficacy, wide availability, safety and hemodynamic and anti-remodelling mechanisms high tolerability of this class of drugs have made beyond ED. them the focus of extensive research by both, basic The rationale for the use of PDE5 inhibitors for the researchers and clinicians in recent years. Moreover, treatment of heart failure is similar to that for PAH. based on a variety of clinical studies with daily Inhibition of PDE5 induces a reduction in vascular dosing for the treatment of ED, and the use of resistance in the pulmonary circulation, which sildenafil for treatment of PAH chronic dosing of unloads the right ventricle. However, there are a PDE5 inhibitors has not raised serious safety number of other potential mechanisms by which problems up to now. From the studies in patients PDE5 inhibitors may have a positive influence on with ED- and LUTS-treated 12 weeks with Viagra heart failure, and the impact of these effects is, as yet, once daily, there were only little side effects, mainly unclear. Therefore, despite a variety of encouraging

Table 2 Status of new and emerging indications for PDE5 inhibitors

Indication Preclinical data Clinical trials

Pulmonary hypertension Monocrotaline model in rats,19 hypoxia induced SUPER-1 trial: improvement in exercise capacity PAH in mice20 in PAH patients22 Heart failure Aortic banding in mice,16 only minor effects in Improvement in flow-mediated vasodilatation in pacing induced heat failure in dogs28 CHF patients26,27 Raynaud’s disease None Significant reduction in frequency and duration of Raynaud attacks33 Cognitive dysfunction PDE5 expression profiling,36–39 in vitro None studies,36,42 behavioral models with rodents43–47 Stroke Various stroke models in rats42,50–53 None Female sexual dysfunction PDE5 expression and activity in vitro58–60; Moderate effects in pre- and post-menopausal isolated organ bath61,62 women,63–66 improved sexual function in premenopausal women with diabetes68 Benign prostate syndrome Expression profiling,79 isolated organ bath,9,17,80 LUTS in ED patients,82 LUTS in BPS patients84 and LUTS rodents in-vivo17,81 Overactive bladder and urge Expression profiling,10 isolated organ bath92–95 None urinary incontinence Premature ejaculation Isolated organ bath111 Clinical relevance not yet clear113 Peyronie’s disease In vitro and in vivo data121–123 None Priapism None Some efficacy, clinical relevance not yet clear126,127

Abbreviations: BPS, benign prostate syndrome; CHF, congestive heart failure; LUTS, lower urinary tract symptoms; PAH, pulmonary hypertension; PDE5, phosphodiesterase type-5.

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