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Erectile dysfunction and cardiovascular disease.

Patients with cardiovascular disease are at increased risk of developing erectile dysfunction (ED). This may be a consequence of atherosclerosis of the penile arteries, a reduced cardiac output, or a side-effect of drugs used to reduce cardiovascular risk factors (particularly beta-blockers, thiazide diuretics and, occasionally, lipid-lowering drugs). ED is a distressing condition, which often diminishes the patient's self-esteem, with the potential for damage to his psychological health and his relationship with his partner and family. When treating ED, the underlying aetiology should be established by careful examination and consideration of medical history and concurrent medication. Until recently, pharmacological treatment options involved intracavernous injections (alprostadil or moxisylyte) or intraurethral alprostadil. These treatments are often inconvenient and not well accepted by the patient. The recent introduction of oral sildenafil promises to revolutionise the treatment of ED. In double-blind, placebo-controlled trials in patients with ED, sildenafil improved erectile function and quality of life and was well tolerated. ED is a clinically important complication of cardiovascular disease and should be asked about and treated accordingly. It is important that effective treatments, including sildenafil, should be available for treating patients with cardiovascular disease and ED.

Coronary Disease↗

Percutaneous lumbar sympathectomy in the treatment of erectile dysfunction secondary to cavernous adrenergic hypertone: initial results of an original technique.

Corporeal smooth muscle tone is regulated by a delicate balance between contraction and erectile smooth muscle. An abnormal balance in basal conditions, due to an augmented contraction of erectile smooth muscle, defined "dysfunctional antagonism", may be responsible of a particular condition of erectile dysfunction (ED), secondary to cavernous adrenergic hypertone (CAY). In order to investigate the possibility to treat CAY with a definitive inhibition of adrenergic innervation to corpora cavernosa, we evaluated the results of an original technique of percutaneous lumbar sympathectomy (PLS) in a group of patients with clinical signs and symptoms of CAY In our study, 14 patients were selected and treated with PLS. Pre-treatment evaluation was designed to identify patients with ED caused by CAY, eligible for surgical treatment, and consisted of medical history, the self administered International Index of Erectile Function and Doppler sonography evaluation of cavernous arteries. Were considered eligible to the surgical treatment the patients with normal PSV values and abnormal EDV values after first injection of alprostadil, but reduced to zero after redosing with alprostadil and phentolamine. All these patients were treated with percutaneous bilateral lumbar ganglionic block with mepivacaine and, at a successive time, phenol 4% and evaluated after I and 4 months. Each evaluation consisted of a self-administered IIEF questionnaire, physical examination and Doppler sonography evaluation. Among the 14 patients selected and treated with temporary block with mepivacaine, 3 reported significant adverse events, consisting of loss of ejaculation (2 patients) and severe lumbar pain (1 patient). In all the other patients treated, only mild to moderate lumbar pain was reported. 10 patients out of the 14 treated with mepivacaine accepted to undergo the successive step of ganglionic block with phenol. Nine patients reported improved erections at both visits, as assessed by the GEQ. Moreover, the analysis of responses to IIEF questions 2-3 showed a highly significant improvement in erectile function compared to scores at baseline. Doppler sonography showed normal flow parameters at both visits in 8 patients. No significant adverse events were recorded after the procedures, except for mild to moderate lumbar pain. Clinical data collected in this study seem to confirm chemical sympathesctomy as a reliable, effective and safe therapeutic option in ED secondary to CAY.

Adult↗

[An overview of the management of erectile disorders].

The large successive studies on the treatment of erectile disorders started with local injections of papaverine in 1982, followed by the marketing of intracavernous injections of alprostadil in 1994 and, in 1998, sildenafil, the first type 5 phosphodiesterase inhibitor. An efficient alternative to improve the quality and duration of an erection is presently represented by intra-cavernous injections of alprostadil alfadex when oral treatments are insufficient, inefficient or contraindicated.

Drug Administration Routes↗

Advances in the Management of Post-Radical Prostatectomy Erectile Dysfunction: Treatment Strategies When PDE-5 Inhibitors Don't Work.

Phosphodiesterase type-5 (PDE-5) inhibitors have revolutionized the treatment of post-radical prostatectomy erectile dysfunction. For those patients who undergo a non-nerve-sparing radical prostatectomy or whose condition fails to respond to PDE-5 inhibitors, alternative treatment with intracavernous injection therapy, transurethral alprostadil, vacuum erection devices, and recently described combination therapy is available. The goals of therapy are to provide the patient with a means of obtaining an erection so that the patient and his partner may resume sexual relations as soon as possible following radical prostatectomy. There is evidence that early institution of treatment may promote improvement in the return of spontaneous erections in patients who have undergone nerve preservation. In patients who undergo non-nerve-sparing procedures, therapy may improve penile rigidity. Intracavernous injection therapy, transurethral alprostadil, and vacuum devices are highly effective in the management of post-prostatectomy erectile dysfunction. High dropout rates, which are not related to adverse effects, have been described with all 3 modalities. Pre- and postoperative counseling may improve patient and partner satisfaction.

Journal Article↗

The role of colour Doppler imaging in the management of Peyronie's disease.

OBJECTIVE: To determine the role of colour Doppler imaging (CDI) in the investigation of erectile dysfunction in patients with Peyronie's disease. PATIENTS AND METHODS: Fifty consecutive patients (age 35-75 years) with Peyronie's disease who were considered suitable for surgical treatment were investigated using CDI to determine the haemodynamic variables of penile vasculature after an intracorporeal injection of 20 microg of alprostadil (with manual self-stimulation). A clinician independently recorded the quality of erection and the deformity. RESULTS: Twenty of 50 patients (40%) considered they had normal erectile function despite their penile deformity and all had normal responses, although they tended to exaggerate the degree of penile deformity. Of the 30 remaining patients, 21 who considered themselves to have erectile dysfunction had normal clinical and CDI haemodynamic responses to alprostadil. The remaining nine patients had a variety of erectile problems and whilst CDI showed altered haemodynamic values, in no case did CDI alter the proposed treatment based on the clinically apparent features of those patients. CONCLUSION: Colour Doppler imaging of the penis after pharmacologically induced erection gives anatomical and functional information in patients with Peyronie's disease but does not provide useful additional information to aid the selection of surgical treatment for the disease.

Adult↗

[Ambulatory treatment of erectile dysfunction].

Intracavernous injection of vasodilating agents and vacuum constriction devices are the therapeutic alternatives in outpatients with secondary erectile dysfunction in Europe. The agents commonly used include papaverine, alprostadil and phentolamine, singly or in combination. Quality of erectile response has agent related characteristics and is dose-dependent. Optimal clinical response ranges from full response for adequate sexual performance to a duration exceeding patient's and partner's wishes. Therefore, the adequate response must be titrated for every patient individually. Vacuum erection devices are efficacious and well accepted from patients and their partners if they can accept the artificial aspect of this approach. Vacuum erection devices are not suitable for men in unstable relations. Injection therapy and vacuum device interfere with spontaneity. The medicated urethral system for erection (MUSE) is a new approach to deliver alprostadil to the corpus cavernosum. The application is more user-friendly than with injections but response rates for adequate satisfactory sexual performance are lower than with intracavernous injections. Therefore indications may be limited to specific etiologies such as neurogenic erectile dysfunction. There is currently no efficient pill on the market although a wide range of therapies are used. Approval and introduction of new oral treatments like Sildenafil and others are awaited by patients and physicians. The availability of new and highly efficient treatment options does not simplify evaluation and treatment of patients with ED. In the contrary they request refinements in the diagnostic process for etiologic diagnosis with subsequently least invasive treatment and minimal side effects.

Ambulatory Care↗

Congenital heart disease and respiratory distress syndrome. Reversal of indomethacin closure of patent ductus arteriosus by prostaglandin therapy in a preterm infant.

Two relatively large premature newborn infants with respiratory distress syndrome and ductus-dependent congenital heart disease were treated. In one, pharmacologic closure of the ductus arteriosus resulted in severe hypoxemia. The patency of the ductus as reestablished with the infusion of alprostadil (PGE1), until palliative surgery was performed. In the second case, persistent pulmonary hypertension was clinically suspected, and pharmacologic therapy was initiated without adequate cardiac evaluation. In large premature infants with respiratory distress syndrome, closure of the ductus arteriosus should not be attempted before ruling out the presence of ductus-dependent congenital heart disease. Furthermore, pharmacologic closure of ductus arteriosus can be reversed by the infusion of prostaglandin.

Alprostadil↗

A retrospective, study of prescribing for erectile dysfunction in a UK population during 1997-2000: demand was neither excessive nor continuing to rise.

PURPOSE: The UK NHS restricted the prescription of sildenafil to a range of clearly defined clinical situations. We describe the pattern of pharmaceutical management of erectile dysfunction (ED) during the period when the new drug was introduced and then regulated. METHODS: We studied the population of males aged over 16 (n = 121,783) who were continuously registered with 60 practices in Tayside between 1 October 1997 and 30 June 2000 using record linkage and case-note verification. The patients' GPs allowed a research nurse to examine the records of these patients for demographic details, comorbidities and resource use. RESULTS: Five hundred and fifty five patients received 2493 prescriptions for alprostadil or sildenafil. The addition of an oral agent to the available therapies in 1998 did lead to a more rapid rise in prescribed treatments but this reached a plateau 3.47 per 1000 adult males per quarter after 12-15 months. Fifty eight per cent of the men had a comorbidity associated with ED. More comorbidities were found in men aged 50-69 and those living in areas of greater deprivation. Depression was a more common comorbidity in younger patients and more men from affluent areas were prescribed sildenafil following prostatectomy. CONCLUSIONS: In the Tayside region of the UK, the introduction of an effective, acceptable oral therapy for erectile dysfunction led to a rise in prescriptions issued for ED. This rise appeared to stop after 12-15 months, perhaps partly because of the governmental restrictions imposed.

Adult↗

Study of the cremasteric muscle during erection.

BACKGROUND: Mechanism of testicular elevation during erection is not known. We investigated the hypothesis that erection evokes reflex cremasteric muscle (CM) contraction which effects testicular elevation. METHODS: Electromyographic (EMG) response of CM to erection was recorded in 26 healthy volunteers (age 36.7 +/- 6.8 SD years). Erection was induced by intracavernosal injection of alprostadil. CM response was tested before and after individual glans penis (GP) and CM anesthetization. RESULTS: The CM exhibited resting electric activity of mean amplitude of 74.8 +/- 6.3 microV which, on erection, increased to 486.6 +/- 36.8 microV (P < 0.001). Response was momentary. Anesthetization of erect GP did not effect increase of CM EMG activity, while bland gel did. Anesthetized CM did not respond to GC erection while saline infiltrated did. CONCLUSIONS: The CM appears to contract during erection through a reflex which we call 'peno-cremasteric reflex'. CM contraction assumingly elevates testicle and support cord veins; it may effect testicular compression, thus expressing its secretions into vas deferens.

Action Potentials↗

Prostacyclin inhibits adhesion of polymorphonuclear leukocytes to human vascular endothelial cells due to adhesion molecule independent regulatory mechanisms.

Prostacyclin is an important endothelial mediator involved in the interaction of neutrophils (PMN) with the vessel wall. Many studies have shown the beneficial effects of prostacyclin in ischemia and reperfusion. However, no previous study has investigated the direct effects of the prostacyclin analogs iloprost (ILO) and alprostadil (PGE(1)) on the endothelial part of the adhesion process. Human umbilical vein endothelial cells (HUVECs) were grown to confluence, stimulated with 300 U/ml TNF-alpha and treated with increasing concentrations of ILO and PGE(1). The cells were washed to remove TNF and the inhibitors and adhesion of fluorescence-green labeled PMN was determined microscopically. ICAM-1, VCAM-1 and E-selectin expression were measured by a cell-surface ELISA. The chemoattractant activity of the endothelial cell releasate was tested in a Boyden chamber.ILO and PGE(1) reduced PMN-adhesion in a concentration-dependent manner (ILO: -54 +/- 9 % at 0.5 microM, PGE1: -46 +/- 10 % at 10 microM). However, the surface expression of ICAM-1, VCAM-1 and E-selectin remained unaltered. When the supernatant of iloprost/PGE(1)-treated cells was transferred onto cells that were activated, but not treated with ILO or PGE(1), the reduction of PMN adhesion remains sustained. These data indicate that the inhibitory effect of ILO/ PGE(1) treatment is achieved by a reduced chemoattractant potential. PAF-antagonists were able to block neutrophil adhesion and mimicked the effect of ILO, while exogenous PAF diminished the inhibitory effect of ILO concentration-dependently. This study demonstrates the beneficial effects of ILO and PGE(1) on inflammatorily activated endothelial cells. These prostacyclin analogs inhibit PMN-adhesion despite maximal adhesion molecule expression by regulating the balance of - yet to be determined - endothelial-derived mediators.

Alprostadil↗

Pseudo-Bartter syndrome in a neonate on prostaglandin infusion.

UNLABELLED: We describe a case of iatrogenic pseudo-Bartter syndrome caused by administration of prostaglandin E1 (PGE1 alprostadil). Although the use of i.v. PGE1 is a well-established pharmacological therapy in neonates with a ductus-dependent congenital cardiopathy to ensure ductus-dependent flow, we could only find one other report on pseudo-Bartter syndrome related to PGE1 infusion. CONCLUSION: Primary Bartter syndrome is associated with endogenous increased levels of prostaglandins. Therefore, we postulate that the dose of prostaglandin E1 administered, immaturity and the genetic background are all relevant factors involved in the phenotypic presentation of iatrogenic pseudo-Bartter syndrome in this preterm infant.

Abnormalities, Multiple↗

Experience with intracavernosal tri-mixture for the management of neurogenic erectile dysfunction.

Using papaverine, papaverine/phentolamine, or prostaglandin E1 (PGE1), intracavernosal pharmacotherapy has been successful in treating erectile dysfunction. The limiting factor of using these medicines is intracorporeal fibrosis with the first two and a high cost with PGE1. Our experience with intracavernosal therapy in patients with impotence secondary to neurogenic disease has included 35 men, 30 of whom are spinal cord injured, 3 after radical prostatectomy, 1 with multiple sclerosis, and 1 with lower extremity weakness after surgery. Patients ranged in age from 22 to 59 years, with an average of 36.3 years; mean follow-up was 13.8 months. Intracavernosal therapy has been performed with a tri-mixture of papaverine hydrochloride (smooth muscle relaxant), phentolamine mesylate (alpha-adrenergic blocking agent) and alprostadil (PGE1- a vasodilator and smooth muscle relaxant). Of the patient population, all 35 patients were able to have adequate erections for sexual relations with minimal complications. Acting synergistically, the ingredients promote erectile activity using small doses and without a significant incidence of priapism or fibrosis. Techniques of injection, dosing and followup are discussed.

Adult↗

The use of prostaglandins in the immediate postsurgical liver transplant period.

INTRODUCTION: Experimental evidence has suggested that prostaglandins have positive effects on hepatic perfusion after transplantation. However, randomized clinical trials have failed to show their usefulness to decrease the incidence of primary nonfunction. In order to demonstrate its therapeutic role, we performed a clinical study in which PGE1 was administered only after the appearance of posttransplant liver dysfunction. MATERIALS AND METHODS: Forty patients with macroscopic signs of hypoperfusion or lacking bile production at the end of the operation (n = 24) or with an increase in transaminases and fall in biliary production in the first 24 hours postsurgery (n = 16) were administered alprostadil (PGE1; 0.01 mug/kg/min to the maximum plateau of 0.06 mug/kg/min). We measured the mean values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), activated thromboplastin time-ratio (aPTT-r), international normalized ratio (INR), bilirubin, creatinine and plasma nitrogen, PaO(2)/FiO(2) at the start of the treatment and every 6 hours for 48 hours, and daily diuresis. RESULTS: There appeared to be a significant decrease in AST, INR, aPTT-r, and creatinine clearance (P < .05), while there was a significant rise in the blood urea nitrogen (P < .001). ALT and bilirubin did not show significant variations. The PaO(2)/FiO(2) ratio showed a significant decrease (P < .001) in pulmonary vasodilatation. CONCLUSIONS: Prostaglandins used in the manner in our study showed a significant efficiency to improve liver dysfunction after transplantation.

Alprostadil↗

A new era in the treatment of erectile dysfunction.

The recent introduction of sildenafil has revolutionized the treatment of erectile dysfunction (ED). The availability of sildenafil, the first effective oral agent for ED, has also expanded the field of sexual healthcare to include general and primary care practitioners and other nonurology specialists. A new process-of-care algorithm has been developed to facilitate the evaluation and treatment of ED in these nonurology settings. Sildenafil has been demonstrated to be safe and effective in randomized, double-blind, placebo-controlled trials involving >3,000 men ages 19-87 years. Sildenafil is effective across a broad range of etiologies including diabetes. For patients in whom first-line treatment with sildenafil fails or ceases to be effective, second-line interventions with intracavernosal self-injection therapy or transurethral alprostadil may be indicated. In addition to sildenafil, other oral agents such as oral phentolamine and sublingual apomorphine are now in clinical trials. Drugs under development include second-generation phosphodiesterase type 5 (PDE5) inhibitors, endothelin antagonists, and agents that offer specific molecular targeting. Clinical studies are also being planned to examine the efficacy of combination oral drug regimens for ED.

3',5'-Cyclic-GMP Phosphodiesterases↗

L-arginine, prostaglandin, and white cell filtration equally improve myocardial protection in stressed neonatal hearts.

OBJECTIVES: L-Arginine may improve cardioplegic protection by increasing nitric oxide production. However, L-arginine may also be detrimental because it generates the free radical peroxynitrite. It would, therefore, be advantageous if the benefits of L-arginine could be achieved by another means. METHODS: Twenty neonatal piglets underwent 60 minutes of ventilator hypoxia (inspired oxygen fraction 8%-10%) followed by 20 minutes of ischemia on cardiopulmonary bypass (stress) and were then protected for 70 minutes with multiple doses of blood cardioplegic solution. In 5 piglets (group 1), the cardioplegic solution was not modified; in 5 (group 2), low-dose L-arginine (4 mmol/L) was added; in 5 (group 3), prostaglandin E(1) (alprostadil, 4 microgram/L) was added; and in 5 (group 4), the cardioplegic solution was passed through a leukodepleting filter. Myocardial function was assessed by pressure volume loops and expressed as percentage of control, and coronary vascular resistance was measured with each cardioplegic infusion. RESULTS: Unmodified blood cardioplegic solution (group 1) was unable to protect the severely stressed myocardium, resulting in depressed systolic function (39% +/- 1%) and preload recruitable stroke work (40% +/- 1%), increased diastolic stiffness (239% +/- 3%), and high conjugated diene production, myeloperoxidase activity, and coronary vascular resistance. In contrast, cardioplegic solutions modified with L-arginine, prostaglandin E(1), or leukodepletion, resuscitated the stressed myocardium, resulting in complete return of systolic function (100% vs 101% vs 101%; P <.001 vs group 1) and preload recruitable stroke work (100% vs 101% vs 101%; P <.001 vs group 1), minimal increase in diastolic stiffness (160% vs 162% vs 160%; P <. 001 vs group 1), and lowered conjugated diene production, myeloperoxidase activity, and coronary vascular resistance (P <.001 vs group 1 for each). CONCLUSIONS: (1) Unmodified blood cardioplegic solution is unable to protect the severely stressed myocardium. (2) L-Arginine, prostaglandin E(1), and leukocyte filtration all improve myocardial protection equally and appear to work by limiting a white blood cell-mediated injury. This reduces oxygen-derived free radical formation, maintains vascular function, and restores functional recovery. Since L-arginine may be detrimental, surgeons should consider using prostaglandin E(1) and/or a leukocyte filter instead.

Alprostadil↗

Preimplantation retrograde pneumoplegia in clinical lung transplantation.

OBJECTIVE: Retrograde pneumoplegia seems to improve early graft function in experimental and clinical lung transplantation. We evaluated the role of retrograde flushing in addition to antegrade pneumoplegia in clinical lung transplantation. METHODS: Fourteen patients undergoing lung transplantation were randomized into 2 groups: in group I we performed antegrade pulmonary artery flushing with alprostadil (prostaglandin E1) and modified Euro-Collins solution at the time of retrieval. In group II additional retrograde flushing through the pulmonary veins was performed at the back table, before reimplantation. Hemodynamic variables, mean airway pressure, and blood gas analysis were monitored at different time points. Postoperative volumetric monitoring was performed to assess extravascular lung water. The reimplantation response was assessed by a radiographic score; extubation time and intensive care unit stay were recorded. RESULTS: During retrograde flushing, blood and clots coming out from the pulmonary artery were observed; 2 lungs harvested from a donor with multiple bone fractures had fat emboli in the retrograde perfusate. Hemodynamic monitoring did not demonstrate any difference between the 2 groups. The ratio of arterial oxygen tension to inspired oxygen fraction, extravascular lung water, duration of intubation, and length of stay in the intensive care unit were improved in group II, but the differences did not reach statistical significance. Intrapulmonary shunt fraction was significantly improved in group II at each time point ( P =.02), as well as indexed alveolar-arterial oxygen tension gradient (P =.04), mean airway pressure (P =.04), and chest x-ray score ( P =.03). CONCLUSIONS: Preimplantation retrograde flushing is not detrimental and helps to improve early graft function.

Adult↗

Treatment of intracorporeal injection nonresponse with sildenafil alone or in combination with triple agent intracorporeal injection therapy.

PURPOSE: We assess the efficacy of sildenafil as salvage therapy for intracorporeal injection therapy nonresponse. MATERIALS AND METHODS: The study group comprised 93 patients with a mean age of 53.6 years (range 24 to 77) with chronic erectile dysfunction. In all cases a home trial of intracavernosal injection of high dose alprostadil and triple agent intracavernosal injection therapy had failed. Patients were treated with sildenafil citrate alone or in combination with intracavernosal injection therapy. RESULTS: The etiology of erectile dysfunction was arteriogenic in 29 cases, cavernosal venous leakage in 36, mixed vasculogenic in 24, psychogenic in 3 and post-priapism intracavernous fibrosis in 1. Of the 32 sildenafil responders (34% of the study group) 30 required 100 and 2 required 50 mg. The 29 sildenafil intracavernosal injection (combined therapy) responders (31% of the study group) required 100 mg. sildenafil. There were 32 nonresponders (34% of the study group). Mean International Index of Erectile Function questions 3 and 4 scores were 1.7 and 1.5 at baseline, 2.3 and 1.9 with intracavernosal injection, 4.6 and 42.2 with sildenafil, and 4.1 and 4.10 with combined therapy, respectively. Of the 93 patients 29 (31%) treated with intracavernosal injection reported adverse effects, including penile pain in 27, dizziness in 5 and headache in 2. Of the patients treated with sildenafil 34 (37%) reported side effects, including headache in 30, facial flushing in 25, dyspepsia in 12, nasal congestion in 9, dizziness in 5 and visual disturbances in 1. Of the 41 patients given combined therapy 20 (49%) reported adverse effects, including penile pain in 15, headache in 15, facial flushing in 12, dyspepsia in 7, nasal congestion in 3, dizziness in 12 and syncope in 1. CONCLUSIONS: Sildenafil alone or sildenafil plus intracavernosal injection is effective salvage therapy for intracavernosal injection nonresponse. Sildenafil in combination with intracavernosal injection is associated with a 33% incidence of adverse effects, including a 20% incidence of dizziness.

Adult↗

MUSE therapy: preliminary clinical observations.

OBJECTIVES: Intracavernosal injection of vasodilating agents has been a mainstay in the treatment of erectile dysfunction. Recently, a transurethral delivery system (MUSE) for alprostadil (prostaglandin E1) was introduced as an alternative form of pharmacotherapy. METHODS: One hundred consecutive patients with erectile dysfunction were treated with MUSE in doses ranging from 125 to 1000 micrograms and their erections were observed in the clinical setting. All patients had previous intracavernosal injections of combination pharmacotherapy (papavarine, Regitine, and/or prostaglandin E1). RESULTS: Of these 100 patients that used MUSE, only 7% had well-sustained, rigid erections while 30% had full erections but with partial rigidity. The remaining 63% of patients did not achieve erections that they thought were adequate for penetration. Penile and/or perineal pain occurred in 24% of patients, 3% had a syncopal episode, and 3% experienced urethral bleeding. One patient had priapism that required drainage. Using intracavernosal injections, 49% had sustained rigid erections, 40% had full erections with partial rigidity, and 11% did not have a response satisfactory for penetration. CONCLUSIONS: These data suggest that intracavernosal injections appear to be more effective than MUSE in achieving a rigid erection in men with erectile dysfunction.

Adult↗