Molecular mechanisms and pharmacokinetics of phosphodiesterase-5 antagonists

The prominence of phosphodiesterase-5 (PDE-5) inhibitors in the treatment of male erectile dysfunction and other diseases related to vascular dysfunction mandates a comprehensive understanding of the properties and effects of these compounds. Three potent and selective PDE-5 inhibitors (sildenafil, tadalafil, and vardenafil) have been approved for clinical use. The clinical efficacy and safety profiles of these medications are related to their molecular mode of action, the selectivity for PDE-5, and the pharmacokinetic properties (absorption, bioavailability, time to onset of action, distribution, metabolism, and elimination). These PDE-5 inhibitors share some common properties with regard to mechanisms of action and selectivities for PDE-5. They also have distinctive characteristics that may impact their clinical use. This article focuses on the basic biochemistry of cyclic guanosine monophosphate signaling and the pharmacokinetic parameters that describe characteristics of drug action of these PDE-5 inhibitors in facilitating smooth muscle relaxation, leading to improved penile erectile response or causing side effects.     

Sildenafil: A 4-year update in the treatment of 20 million erectile dysfunction patients

Sildenafil citrate, the first internationally approved and widely used oral agent for the treatment of erectile dysfunction (ED), has revolutionized the treatment of ED throughout the past 5 years. This phosphodiesterase type-5 (PDE-5) inhibitor is selective for corpus cavernosum smooth muscle tissue and produces excellent erectile function. Its efficacy and safety over a wide variety of etiologies of ED and severities of ED demonstrates its usefulness in the clinical treatment of these patients. More than 20 million men have been treated worldwide with sildenafil with excellent results. ED caused by difficult-to-treat etiologies such as radical prostatectomy, severe diabetes, and spinal cord injury have demonstrated efficacy. Although sildenafil citrate, like all PDE-5 inhibitors, is contraindicated in patients taking nitrate medications for cardiac disease, it is effective and safe for those cardiovascular patients who are not taking nitrate medications. The incidence of adverse cardiovascular events in patients taking sildenafil does not differ from those of the general population. Investigations into the pharmacologic effect of sildenafil on coronary myocardial tissue further supports the safety of this medication. Sildenafil has been safe and effective in patients taking various medications including multiple antihypertensive drugs, selective serotonin reuptake inhibitors, cardiac, and diabetic medications.     

Transient global amnesia after intake of tadalafil, a PDE-5 inhibitor: a possible association?

Inhibitors of phosphodiesterase type 5 (PDE-5) are well established as an oral treatment for the majority of patients with erectile dysfunction (ED). PDE-5 is found in high concentration in smooth muscle cells of the corpora cavernosa. However, enzymes of the PDE family are also expressed in various other tissues, including the brain. Little is known about its effects on the central nervous system (CNS), although it has been suggested that PDE-5 inhibitors might cross the blood-brain barrier. Side effects, such as headache, nasal congestion, flushing, nausea, are much more common. We describe a patient who had a transient global amnesia (TGA) after his first-ever use of tadalafil, a potent PDE-5 inhibitor. Despite the fact that the aetiology of TGA has not entirely been clarified at present, we consider the hypothesis of a causal relationship as tempting with respect to the current hypotheses of TGA pathophysiology. This case, together with others, suggests that PDE-5 inhibitors might be capable of exerting adverse effects in the CNS. Physicians should be aware of the possibility of neurological disturbances when prescribing PDE-5 inhibitors for ED.     

Erectile dysfunction secondary to nerve-sparing radical retropubic prostatectomy: Comparative phosphodiesterase-5 inhibitor efficacy for therapy and novel prevention strategies

Postprostatectomy erectile dysfunction appears to be initiated by neuropraxia and perpetuated by cavernosal smooth muscle apoptosis. Phosphodiesterase-5 (PDE-5) inhibitor therapy is the current cornerstone of erectile dysfunction (ED) therapy in this population. Although no head-to-head trials have been performed with sildenafil, vardenafil, and tadalafil in this population, there are numerous studies in the general ED population. The results of these studies demonstrate that neither of the new PDE-5 inhibitors met statistical noninferiority to sildenafil. Sildenafil has been studied in a novel primary prevention modality using nightly administration after a bilateral nerve-sparing prostatectomy. In this novel approach, it effected a sevenfold improvement in return of spontaneous, normal erectile function 2 months after drug discontinuation. This effect appears to be mediated by properties unique to sildenafil that include improved endothelial function and neuronal regeneration and neuroprotection. In primary prevention, unlike ED therapy, one has only “one shot” by definition. Therefore, it is even more critical to apply evidence-based medicine.     

Testosterone and erectile dysfunction

The role of testosterone on sexual desire, interest and motivation is well established, but its effects on erectile function remain controversial. Animal data show that experimental or medical castration results in loss of the intracavernosal pressure, smooth muscle/connective tissue balance, and penile tissue concentration of nitric oxide synthase-containing nerves, which alter the fibroelastic properties of penile tissue compliance, leading to veno-occlusive dysfunction and therefore erectile dysfunction. Castration also induces apoptosis of penile erectile tissue, and new DNA synthesis is induced by treatment with testosterone. In an animal model of venogenic erectile dysfunction, intracavernous vascular endothelial growth factor (VEGF), in addition to testosterone, restores the smooth muscle/connective tissue balance, endothelial cell hypertrophy and hyperplasia and normalizes the diameter of the dorsal nerve fibres, thereby preventing veno-occlusive dysfunction. There is some evidence that treatment with testosterone may be beneficial to men with erectile dysfunction who have low baseline testosterone levels. Androgens may also control the expression and activity of phosphodiesterase type-5 (PDE-5) in the penile corpus cavernosum. Oral drug therapy with PDE-5 inhibitors fails in some patients with erectile dysfunction. However, when testosterone is used together with a PDE-5 inhibitor, sexual function is restored in these patients, creating the potential for pharmacological combination therapy with testosterone for the treatment of erectile dysfunction.     

Phosphodiesterase-5 inhibition: the molecular biology of erectile function and dysfunction

This article discusses the role of phosphodiesterase-5 (PDE-5) inhibition in the molecular biology of erectile function and dysfunction. Commercially marketed PDE-5 inhibitors are highly specific for PDE-5, and in the face of continuing cyclic GMP (cGMP) synthesis,elevate cellular cGMP. This elevation results from direct competitive inhibition of PDE-5 and from blocking the negative feedback regulation of the enzyme. Elevation of cGMP activates cGMP-dependent protein kinase, which mediates the effects of the cGMP-signaling pathway to decrease smooth muscle tone and dilate penile vascular smooth muscle. By exploiting features of PDE-5 regulatory mechanisms that modulate PDE-5 function, the inhibitors enhance their own potencies.     

Erectile dysfunction and treatment of carcinoma of the prostate

Prostate cancer is the leading malignancy in men in the United States and causes more than 60,000 deaths annually. Treatment of prostate cancer, whether it be with surgery, radiation therapy, cryotherapy, or medical treatment, is associated with significant life-altering morbidity. Incontinence and erectile dysfunction (ED) too often are sequelae of these treatment alternatives. ED can be a significant complication and can alter the life of the patient with prostate cancer and his partner. Newer modifications of the radical prostatectomy with nerve-sparing techniques are the cornerstone of erection preservation. Time following radical prostatectomy has been shown to increase erectile function such that more patients have functional erections at 3 years than 1 year after surgery. With the advent of phosphodiesterase-5 (PDE-5) inhibitors, many men can have improved functional erections and return to active coitus. Prevention of ED also is an important management technique. Evidence is gathering that prophylaxis with regular vasoactive injection or daily PDE-5 agents may be an integral part of preservation of corpus cavernosum smooth muscle function. Combination medical therapy and surgical penile prosthesis implantation also are options for patients who do not respond to oral PDE-5 inhibitors.     

全面康复:勃起功能障碍治疗的新目标

5型磷酸二酯酶(PDE5)抑制剂有效改善勃起功能障碍(ED)患者的勃起功能。枸橼酸西地那非的应用范围不断扩展,肺动脉高压已成为新的适应证。临床研究发现,西地那非能改善多种血管性疾病患者的内皮功能。在ED领域的研究进展包括:动物实验发现,西地那非可以改善海绵体内皮功能,增强磷酸化内皮型一氧化氮合酶(eNOS)蛋白表达,逆转缺血或缺氧导致的海绵体内压(ICP)降低。临床研究证实,西地那非可以使50%以上ED患者阴茎勃起恢复到最充分的硬度(4级勃起);使50%以上保留神经的根治性前列腺切除术后患者勃起功能康复,自发产生足以性交的勃起;使ED患者的自尊心、自信心和性关系满意度等社会心理功能恢复正常。从勃起功能到社会心理功能的全面恢复可能成为今后ED治疗的新目标。     

磷酸二酯酶5抑制剂治疗勃起功能障碍的疗效和安全性比较

磷酸二酯酶 5 (PDE 5 )抑制剂西地那非的问世使男性勃起功能障碍 (ED)的治疗手段发生了根本性的改变。1998年以来有 10 0多个国家的 2 0 0 0多万患者使用了西地那非 ,患者的死亡率与总体人群的死亡率差异无显著性。西地那非治疗ED平均有效率达 80 %以上 ,成为治疗ED的首选手段。随着新的PDE 5抑制剂伐地那非和泰地那非在国外先后进入临床使用 ,药物治疗ED有了更多的选择。本文通过比较 3种PDE 5抑制剂的药效学、药动学及不良反应以评价其疗效和安全性。     

同期内使用3种PDE5抑制剂治疗ED的经验

目的:观察与比较同期内使用3种PDE5抑制剂治疗ED患者的疗效,满意情况和不良反应。分析影响患者疗效、接受度、倾向性的因素。方法:11个月在门诊应用3种PDE5抑制剂治疗ED患者331例。使用西地那非134例,他达拉非88例,及伐地那非109例。医师详细指导药物的应用,注意事项,观察的内容等,并互留电话,列表登记、随访。结果:复诊或电话随访时间,结果为:①获得良好的疗效及满意率为西地那非72例(79.12%),他达拉非52例(78.78%),伐地那非63例(81.81%)。②PDE5抑制剂单纯或交叉应用的资料分析显示:青年患者或新婚者,偏好伐地那非;③中青年患者倾向于他达拉非;中老年及较长期应用PDE5抑制剂的患者多选用西地那非。3种PDE5抑制剂用于早泄均有一定疗效。④对不能继续用此类药治疗ED的原因进行了分析,分别为:价高,不治本,效果差,耽心不良反应。结论:①同期3种PDE5抑制剂治疗ED的疗效基本相近。亦各有一些优势和特点。②3种PDE5抑制剂的安全性均好,一般、轻度不良反应相近,中度、特殊的不良反应少,严重不良反应均无发生。③PDE5抑制剂的疗效观察,目前众多的问卷、量表实际均仍以主观的感受为主。对同一个人以相同形式、相同问题、繁简一致阐述,获得的有关疗效满意情况、感受等简易回答是有可比性、可信度和实用性的。     

Erectile dysfunction in the cardiac patient

Erectile dysfunction (ED) often is caused by endothelial dysfunction and may be a sign that a patient has vascular disease elsewhere in the body. Risk factors for coronary artery disease such as lipid abnormalities, smoking, diabetes, and hypertension also are risk factors for ED. Oral therapy for ED, such as sildenafil, inhibits phosphodiesterase-5 (PDE-5) and the breakdown of cyclic guanosine monophosphate. PDE-5 inhibitors have been shown to be safe and effective for the therapy for ED, but remain contraindicated in patients receiving organic nitrates. These agents are mild vasodilators and are being investigated for their treatment potential for patients with pulmonary hypertension, heart failure, and endothelial dysfunction.     

Effects of testosterone on erectile function: implications for the therapy of erectile dysfunction

Sexual potency declines with age, as does the efficiency of erection. Many studies show that different patterns of erectile dysfunction (ED), varying from occasional inability to obtain a full erection, impairment throughout intercourse and total absence of erectile response, might not be triggered by psychological factors only. Recent research indicates that ED relies on organic causes, and has challenged the development of new therapies. One therapeutic approach in patients who have testosterone deficiency is based on androgen therapy. Thus, we reviewed data on testosterone-induced effects relative to erectile function, summarizing the results from studies reported in 1991-2006 on testosterone therapy in patients with ED and hypogonadism, with a special focus on men not responding to phosphodiesterase-5 (PDE-5) inhibitors. We searched several computerized databases parallel with printed bibliographic references. Many studies have established animal models, which confirm that testosterone is important in modulating the central and peripheral regulation of ED. Testosterone deprivation has a strong negative impact on the structure of penile tissues and erectile nerves, which can be prevented by androgen administration. Combined therapy regimens with PDE-5 inhibitors and testosterone might improve ED in patients with hypogonadism of different causes. Thus, androgen treatment in hypogonadic patients, including those unresponsive to PDE-5 inhibitors, often results in an improvement of ED. Testosterone therapy is safe and convenient, while rapidly correcting low testosterone levels.     

Endothelial rehabilitation: the impact of chronic PDE5 inhibitors on erectile function and protein alterations in cavernous tissue of diabetic rats

BACKGROUND: Diabetic men generally have reduced efficacy with PDE-5 inhibitors (PDE5i) for the treatment of erectile dysfunction (ED). OBJECTIVE: To determine whether chronic vardenafil exposure alters cavernous protein expression predicting improved erectile function in diabetes. DESIGN: Forty-two adult male Sprague Dawley rats with streptozotocin-induced (50mg/kg IP) diabetes for 4 wk, were exposed to either vehicle or vardenafil for 6 wk. Assessments compared the impact of vardenafil given at 1h and 20 h to erectile function and cellular alterations and downstream translation of cavernous protein profiles were aimed. INTERVENTION: Vehicle or vardenafil 0.5mg/kg/day by oral gavage for 6 wk. MEASUREMENTS: Erectile function, penile tissue morphology, protein expression and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI) protein profiling were determined. RESULTS AND LIMITATIONS: A significant increase of intracavernous pressure was seen in both treatment arms compared to diabetic rats not receiving vardenafil. Immunohistochemical staining showed improved endothelial and smooth muscle cell staining with chronic vardenafil use. Western blot analysis demonstrated increased endothelial cell eNOS and smooth muscle alpha-actin protein content. SELDI protein profiling showed enhanced proteins expression at molecular weights of 14.7, 20, 41.9, 66.2, and 83.9 kDa in the chronically treated vardenafil group. CONCLUSIONS: Vardenafil was effective in treating diabetic-induced ED with the greatest effect achieved through chronic dosing, with no additive effect measured with the final acute dose. Changes noted in the histology and protein expression indicate that vardenafil may have a protective effect in this disease state. This finding may serve as a basis for further work evaluating the utility of chronic vardenafil dosing in diabetic men.     

Effect of PDE5 inhibition combined with free oxygen radical scavenger therapy on erectile function in a diabetic animal model

Phosphodiesterase (PDE) inhibitors represent an important advance in the treatment of erectile dysfunction (ED). In spite of widespread use and generally good efficacy, as a class they remain ineffective in 15-57% of men. Specific cohorts of patients with severe vascular or neurogenic basis to their ED, such as diabetic men or those who have undergone radical pelvic surgery, demonstrate lower response rates with PDE inhibition treatment. We believe that circulating levels of nitric oxide (NO) may be enhanced through delivery of adequate concentrations of free oxygen radical scavenger molecules such as vitamin E. Higher levels of NO, theoretically, should produce increased penile blood flow with the potential for a synergistic effect when combined with a PDE5 inhibitor. With this hypothesis in mind, 20 adult male Sprague-Dawley streptozotocin-induced (60 mg/kg i.p.) diabetic rats were divided into four therapeutic groups (n=5). Group I--control animals received peanut oil, group II--vitamin E 20 IU/day, group III--sildenafil 5 mg/kg/day and group IV--vitamin E 20 IU/day plus sildenafil 5 mg/kg/day, by oral gavage daily for 3 weeks. Erectile function was assessed as a rise in intracavernous pressure following cavernous nerve electrostimulation. Penile tissue was harvested to determine the changes in tissue morphology including neuronal nitric oxide synthase, smooth muscle alpha-actin and endothelial cell integrity. PDE5 protein content and activity were measured. Significant increases in intracavernous pressure were measured in the animals receiving combined vitamin E plus sildenafil treatment. Immunohistochemical staining showed increases of neuronal nitric oxide synthase, endothelial cell and smooth muscle cell staining. Western blot analysis did not show significant differences of PDE5 protein between the groups. However, higher PDE5 activity was measured in the sildenafil group and lower activity of PDE5 was recorded in the cohort receiving vitamin E with sildenafil. Vitamin E enhanced the therapeutic effect of the PDE5 inhibitor in a meaningful way in this animal model of diabetes. This study indicates a potential means of salvaging erectile function among patients who are refractory to sildenafil.     

Pre-clinical evidence for the use of phosphodiesterase-5 inhibitors for treating benign prostatic hyperplasia and lower urinary tract symptoms

OBJECTIVE: To evaluate the potential of sildenafil, vardenafil and tadalafil, all phosphodiesterase-5 (PDE-5) inhibitors used for treating erectile dysfunction, for treating benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). MATERIALS AND METHODS: The mRNA expression of the PDE-5 was determined in rat LUT tissues. The PDE-5 inhibitors were also tested in organ-bath experiments and in a partial bladder outlet obstruction (BOO) rat model in vivo. RESULTS: The highest PDE-5 mRNA expression was in the bladder, followed by the urethra and prostate. PDE-5 inhibitors dose-dependently reduced the contraction of the isolated bladder, urethral and prostate strips. The rank order of potency was vardenafil > sildenafil > tadalafil. In human prostate stromal cells vardenafil inhibited cell proliferation and was more effective than tadalafil and sildenafil. In the BOO model, there was a reduction in the non-voiding contractions after bolus intravenous administration of 3 mg/kg sildenafil and vardenafil. CONCLUSION: These results show that PDE-5 is expressed in LUT tissues. PDE-5 inhibitors induced significant relaxation of these tissues, inhibited the proliferation of human prostate stromal cells and reduced the irritative symptoms of BPH/LUTS in vivo. Therefore, PDE-5 inhibitors could be used as an effective treatment for BPH/LUTS.     

Gene therapy and erectile dysfunction： the current status

Current available treatment options for erectile dysfunction （ED） are effective but not without failure and/or side effects. Although the development of phosphodiesterase type 5 （PDE5） inhibitors （i.e. sildenafil, tadalafil and vardenafil） has revolutionized the treatment of ED, these oral medications require on-demand access and are not as effective in treating ED related to diabetic, post-prostatectomy and severe veno-occlusive disease states. Improvement in the treatment of ED is dependent on understanding the regulation of human corporal smooth muscle tone and on the identification of relevant molecular targets. Future ED therapies might consider the application of molecular technologies such as gene therapy. As a potential therapeutic tool, gene therapy might provide an effective and specific means for altering intracavernous pressure ＂on demand＂ without affecting resting penile function. However, the safety of gene therapy remains a major hurdle to overcome before being accepted as a mainstream treatment for ED. Gene therapy aims to cure the underlying conditions in ED, including fibrosis. Furthermore, gene therapy might help prolong the efficacy of the PDE5 inhibitors by improving penile nitric oxide bioactivity. It is feasible to apply gene therapy to the penis because of its location and accessibility, low penile circulatory flow in the flaccid state and the presence of endothelial lined （lacunar） spaces. This review provides a brief insight of the current role of gene therapy in the management of ED.     

Clinical update on phosphodiesterase type-5 inhibitors for erectile dysfunction

Erectile dysfunction (ED) affects the sexual lives of millions of men. The first-line oral pharmacotherapy for most ED patients is phosphodiesterase type-5 (PDE-5) inhibitors, of which three are available. Sildenafil is the most widely prescribed oral agent for ED and has a very satisfactory efficacy–safety profile in all patient categories. Tadalafil and vardenafil were introduced in the European Union and in the United States in 2003 and 2004, respectively. The three PDE-5 inhibitors share many pharmacological and clinical characteristics, and each has unique features. This review, which is based on the contemporary literature on PDE-5 inhibitors, describes the chemical, pharmacological, and clinical features of sildenafil, vardenafil, and tadalafil. The first section reviews the pathophysiology of penile erection and PDE-5 inhibitor pharmacology. The second section summarizes data regarding efficacy and safety of the three drugs in treating ED in the general population as well as in selected patient categories.     

Sildenafil citrate, a selective phosphodiesterase type 5 inhibitor: urologic and cardiovascular implications

Erectile dysfunction (ED) occurs in varying degrees in an estimated 20 to 30 million American men and is associated with adverse effects on quality of life; particularly personal well-being, family and social interrelationships. Research into ED has focused primarily on the physiologic mechanisms of corpus cavernosum smooth muscle relaxation, and penile erection as the end result of smooth muscle relaxation. These processes are mediated by cholinergic, nonadrenergic, noncholinergic (NANC, e.g., nitric oxide), vasoactive intestinal peptide (VIP), and potentially calcitonin gene-related peptide (CGRP) containing nerves. Release of nitric oxide following sexual stimulation from non-adrenergic, non cholinergic nerves and vascular endothelium activates guanylyl cyclase and induces intracellular cGMP synthesis. In turn, cGMP results in lowering intracellular concentrations, inhibits contractility of the penile smooth muscle, and induces an erectile response. Phosphodiesterase type 5 (PDE 5) is the predominant enzyme responsible for cGMP hydrolysis in trabecular smooth muscle. Activation of PDE 5 terminates NO-induced, cGMP-mediated smooth muscle relaxation, and subsequent penile flaccidity. Sildenafil citrate is a potent PDE type 5 reversible and selective inhibitor which blocks cGMP hydrolysis effectively. FDA approval of sildenafil citrate as the first oral agent for ED in males has resulted in significant interest. We discuss the clinical and pharmacologic properties of sildenafil citrate as well as the urologic and cardiac implications.     

THE EFFECT OF THE SPECIFIC PHOSPHODIESTERASE (PDE) INHIBITORS ON HUMAN AND RABBIT CAVERNOUS TISSUE IN VITRO AND IN VIVO

Purpose

Phosphodiesterases (PDE) are key enzymes in the regulation of the smooth muscle tone. Experimental studies showed PDE III and V-isoenzymes to play an important role in the smooth muscle tone regulation of corpus cavernosum. Recently, a specific PDE III-inhibitor (milrinone) and a PDE V-inhibitor (sildenafil) were introduced in clinical studies. An experimental study was done to examine a potential role of PDE-inhibitors in the treatment of erectile dysfunction.

Materials and Methods

In the organ bath, strips from human and rabbit corpus cavernosum were precontracted and increasing doses of PDE inhibitors were added. In patients with erectile dysfunction as well as in rabbits, intracavernous injections of milrinone were done.

Results

PDE-inhibitors dose-dependently relaxed human and rabbit corpus cavernosum strips. In the precontracted human cavernous tissue, milrinone and sildenafil were equally potent and efficacious in vitro. In the rabbit, milrinone induced slight tumescence but dramatic circulatory side effects. In patients, penile tumescences as well as full erections were observed.

Conclusions

Milrinone strongly relaxes human cavernous smooth muscle cells but it exhibits low relaxant effects in the rabbit cavernous tissue. In human tissue, sildenafil was equieffective with milrinone in vitro. In vivo, milrinone induced a good erectile response in humans but a poor erectile effect in rabbits. Our results support a possible potential for selective PDE-III and -V inhibitors in the treatment of impotence and give further evidence that the rabbit is an animal model of limited value to study the effects of drugs on cavernous smooth muscle tone regulation in vivo.