sildenafil-citrate and Priapism

Ischemic priapism is a common but underrecognized morbidity affecting about 33% of adult men with sickle cell disease (SCD). The onset of priapism occurs in the prepubertal period and tends to be recurrent with increasing age. Significantly, priapism is associated with an unrecognized high burden of mental duress and sexual dysfunctions. The diagnosis of priapism is clinical. Many episodes of priapism will resolve spontaneously, but when an episode lasts longer than 4 hours, the episode is considered a urologic emergency requiring quick intervention with either corporal aspiration or shunt surgery. Only 3 randomized clinical trials (stilbesterol, ephedrine or etilefrine, and sildenafil) have been conducted for secondary priapism prevention in SCD. All 3 trials were limited with small sample sizes, selection biases, and inconclusive results after completion. The current molecular understanding of the pathobiology of priapism suggests a relative nitric oxide (NO) deficiency secondary to chronic hemolysis in SCD and associated phosphodiesterase type 5 dysregulation. We posit an increase in NO levels will restore the normal homeostatic relationship between voluntary erection and detumescence. Currently, 2 randomized phase 2 trials (1 double-blind, placebo-controlled trial and 1 open-label, single-arm intervention) are being conducted for secondary priapism prevention in men at high risk for recurrent priapism (NCT03938454 and NCT05142254). We review the epidemiology and pathobiology of priapism, along with mechanistic therapeutic approaches for secondary prevention of priapism in SCD.

Topics: Adult; Anemia, Sickle Cell; Clinical Trials, Phase II as Topic; Etilefrine; Hemolysis; Humans; Male; Priapism; Randomized Controlled Trials as Topic; Sildenafil Citrate

Sickle cell disease comprises a group of genetic haemoglobin disorders. The predominant symptom associated with sickle cell disease is pain resulting from the occlusion of small blood vessels by abnormally 'sickle-shaped' red blood cells. There are other complications, including chronic organ damage and prolonged painful erection of the penis, known as priapism. Severity of sickle cell disease is variable, and treatment is usually symptomatic. Priapism affects up to half of all men with sickle cell disease, however, there is no consistency in treatment. We therefore need to know the best way of treating this complication in order to offer an effective interventional approach to all affected individuals. This is an update of a previously published review.. To assess the benefits and risks of different treatments for stuttering (repeated short episodes) and fulminant (lasting for six hours or more) priapism in sickle cell disease.. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries. Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 09 September 2019. Date of most recent search of trial registries and of Embase: 01 October 2019.. All randomised or quasi-randomised controlled trials comparing non-surgical or surgical treatment with placebo or no treatment, or with another intervention for stuttering or fulminant priapism.. The authors independently extracted data and assessed the risk of bias of the trials.. Three trials with 102 participants were identified and met the criteria for inclusion in this review. These trials compared stilboestrol to placebo, sildenafil to placebo and a four-arm trial which compared ephedrine or etilefrine to placebo and ranged in duration from two weeks to six months. All of the trials were conducted in an outpatient setting in Jamaica, Nigeria and the UK. None of the trials measured our first primary outcome, detumescence. However, all three trials reported on the reduction in frequency of stuttering priapism, our second primary outcome; and from the evidence included in this review, we are uncertain whether stilboestrol, etilefrine or ephedrine reduce the frequency of stuttering priapism as the certainty of the evidence has been assessed as very low. Additionally, we conclude that sildenafil may make little or no difference (low-certainty evidence). Two trials reported on immediate side effects and we are uncertain whether etilefrine or ephedrine reduce the occurrence of these (very low-certainty of evidence) and also conclude that sildenafil may make little or no difference in side effects (low-quality evidence). Given that all of the trials were at risk of bias and all had low participant numbers, we considered the certainty of the evidence to be low to very low.. There is a lack of evidence for the benefits or risks of the different treatments for both stuttering and fulminant priapism in sickle cell disease. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions for priapism in sickle cell disease.

Topics: Adrenergic Agents; Anemia, Sickle Cell; Diethylstilbestrol; Ephedrine; Estrogens, Non-Steroidal; Etilefrine; Humans; Male; Priapism; Randomized Controlled Trials as Topic; Sildenafil Citrate; Tachycardia; Vasoconstrictor Agents; Young Adult

Priapism is an adverse drug reaction (ADR) associated with phosphodiesterase type 5 inhibitors (PDE5is) in the treatment of erectile dysfunction.. The purpose of this study was to identify the true data about PDE5i-associated priapism to properly counsel patients.. We queried the U.S. Food and Drug Administration (FDA) Adverse Reporting System Public Dashboard to identify cases of drug-induced priapism among medications commonly associated with priapism. Next, a systematic review and analysis of publications describing cases of drug-induced priapism were carried out.. The main outome of this study is incidence of PDE5i-induced priapism.. We found 411 cases of drug-induced priapism secondary to Viagra, Cialis, or Levitra reported to the Food and Drug Administration since 1998. Compared with PDE5is, drug-induced priapism was 2.6 (n = 1,065) and 2.0 times (n = 817) more commonly reported for second-generation antipsychotics and the antidepressant/sleep aid trazodone, respectively. A total of 240 manuscripts describing cases of drug-induced priapism in patients with non-sickle cell disease were identified. PDE5i-induced priapism accounted for only 2.9% (n = 7) of drug-induced priapism cases. Second-generation antipsychotics (33.8%), a group of "other" medications (11.3%), and alpha-adrenergic antagonists (8.8%) accounted for the greatest percentage of published drug-induced priapism cases.. Extensive counseling about priapism as an ADR for PDE5i for the routine treatment of erectile dysfunction is likely unnecessary.. The study used national-level data to identify drug-induced priapism cases. Reported and published cases of drug-induced priapism may reflect more severe and atypical cases of this ADR, which may have underestimated our results.. PDE5i-induced priapism is a rare event. Drug-induced priapism should be attributed to a wider spectrum of medications that can cause this condition. Rezaee ME, Gross MS. Are We Overstating the Risk of Priapism With Oral Phosphodiesterase Type 5 Inhibitors? J Sex Med 2020;17:1579-1582.

Topics: Erectile Dysfunction; Humans; Male; Phosphodiesterase 5 Inhibitors; Priapism; Sildenafil Citrate; Tadalafil

With only 34 prior cases in world literature, partial priapism (PP), also called partial segmental thrombosis of the corpus cavernosum, is a rare urological condition. The aetiology and treatment of PP is still unclear, but bicycle riding, trauma, drug usage, sexual intercourse, haematological diseases and α-blockers have been associated with PP. In this case report and world literature review, we describe the case of a 50-year-old man suffering from PP after ingesting 100 mg of sildenafil. The patient was treated with a surgical incision for corpus cavernosum and clot evacuation, as a conservative treatment of PP was not feasible due to severe pain and unresponsiveness to analgesics.

Topics: Humans; Male; Middle Aged; Penile Diseases; Phosphodiesterase 5 Inhibitors; Piperazines; Priapism; Purines; Sildenafil Citrate; Sulfones; Thrombosis

Ischemic priapism is a rare occurrence which can cause severe erectile dysfunction (ED) without timely treatment. This retrospective study reports our experience in treating prolonged ischemic priapism and proposes our further considerations. In this paper, a total of nine patients with prolonged ischemic priapism underwent one to three types of surgical shunts, including nine Winter shunts, two Al-Ghorab shunts and one Grayhack shunt. During the follow-up visit (after a mean of 21.11 months), all patients' postoperative characters were recorded, except one patient lost for death. Six postoperative patients accepted a 25-mg oral administration of sildenafil citrate. The erectile function of the patients was evaluated by their postoperative 5-item version of International Index of Erectile Function Questionnaire (IIEF-5), which were later compared with their premorbid scores. All patients had complete resolutions, and none relapsed. The resolution rate was 100%. Seven patients were resolved with Winter shunts, one with an Al-Ghorab shunt and one with a Grayhack shunt. The mean hospital stay was 8.22 days. There was only one urethral fistula, and the incidence of postoperative ED was 66.67%. Four patients with more than a 72-h duration of priapism had no response to the long-term phosphodiesterase type 5 (PDE-5) inhibitor treatment. These results suggest that surgical shunts are an efficient approach to make the penis flaccid after prolonged priapism. However, the severe ED caused by prolonged duration is irreversible, and long-term PDE-5 inhibitor treatments are ineffective. Thus, we recommend early penile prosthesis surgeries for these patients.

Topics: Adult; Aged; Erectile Dysfunction; Humans; Ischemia; Male; Middle Aged; Penile Prosthesis; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Priapism; Purines; Sildenafil Citrate; Sulfones; Ultrasonography; Vascular Surgical Procedures

To review special safety topics associated with sildenafil and to document the tolerability of 50- and 100-mg doses, overall and by age, in men with erectile dysfunction (ED).. Data were collated from 67 double-blind placebo-controlled (DBPC) trials (> 14,000 men) conducted by the manufacturer and from the manufacturer's postmarketing safety database (39,277 patients). The DBPC data were stratified by dose, starting dose and age (> or = 65 and > or = 75 years). Special safety topics included cardiovascular risk, priapism, non-arteritic anterior ischaemic optic neuropathy (NAION), impaired renal and hepatic function, drug interactions (i.e. nitrates, cytochrome P3A4 inhibitors, other ED therapies and alpha-blockers) and incorrect use.. Sildenafil was well tolerated at a dose of 50 or 100 mg in men with ED, overall, in those aged > or = 65 years, and in those aged > or = 75 years. Analyses of the databases did not reveal any causal link between sildenafil and cardiovascular events, or any new safety risks relating to cardiovascular events, priapism, NAION, hearing loss or drug interactions. In the small number of men with moderate impairment of renal function or hepatic function who were treated with sildenafil in DBPC trials, the safety profile was similar to that in men with no impairment of renal or hepatic function. Overdose with sildenafil was rare in the ED population. No new safety issues, emerging trends or adverse reactions were identified in conjunction with overdose, dependence, abuse or misuse.. This collated review confirms generally the good tolerability and established safety profile of sildenafil 50 and 100 mg in men with ED and reveals no new safety issues.

Topics: Aged; Cardiovascular Diseases; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Drug Overdose; Erectile Dysfunction; Hearing Disorders; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Priapism; Product Surveillance, Postmarketing; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Treatment Outcome

Highly selective inhibitors of phosphodiesterase type 5 (PDE5I) have been commercially available for over a decade. Our knowledge of these drugs continues to expand.. To review developments within the past 18 months on the utilization of PDE5I in preclinical studies and clinical practice. The focus of this article is on updates on regular dosing regimens of PDE5I other than the newly approved daily dose tadalafil.. PubMed search utilizing the terms "phosphodiesterase type 5 inhibitor," PDE5 inhibitor,""sildenafil,""vardenafil," and "tadalafil." Articles were screened based on whether or not they addressed issues of routine dosing of PDE5I. Manuscripts on the newly approved daily dose tadalafil for erectile dysfunction (ED) were deferred for analysis in a separate manuscript in this series.. Peer reviewed publications on routine dosing of PDE5I published in the medical literature since 2007.. There have been numerous publications in the past 2 years regarding routine dosing of PDE5I for three major urological indications; penile rehabilitation, stuttering priapism, and management of lower urinary tract symptoms (LUTS). Evidence from basic science investigations has indicated that daily dose PDE5I may improve erectile function and exert a number of beneficial tissue effects on the penis. Unfortunately, data from human series of routine dose PDE5I for penile rehabilitation after radical prostatectomy are conflicting, with the two largest studies showing no benefit to daily dose therapy in the post-radical prostatectomy and the general ED populations. PDE5I are generally helpful at reducing symptoms of LUTS, particularly when given in conjunction with alpha blockers. Routine dosing of PDE5I has also been utilized successfully for management of stuttering ischemic priapism and several other medical indications.. PDE5I given as routine doses have clinical promise. Further research is required to clarify their safety and efficacy for various indications.

Topics: Humans; Imidazoles; Impotence, Vasculogenic; Male; Penis; Phosphodiesterase Inhibitors; Piperazines; Priapism; Prostatectomy; Purines; Secondary Prevention; Sildenafil Citrate; Sulfones; Triazines; Urologic Diseases; Vardenafil Dihydrochloride; Vasodilator Agents

We identify whether tachyphylaxis and priapism effects of sildenafil are related to regulation of phosphodiesterase-5 (PDE-5) expression.. Cavernous smooth muscle cells (CSMCs) were isolated from young rats and treated with 0, 1, 10 and 25 microM sildenafil with or without 100 microM of sodium nitroprusside for 3 and 7 days. The cells were subjected to reverse transcriptase-polymerase chain reaction and Western blot analysis for PDE-5 expression. Plasmid constructs carrying PDE-5A1 and PDE-5A2 promoters were transfected into COS-7 cells, treated with 25 microM sildenafil and analyzed for promoter activities. To simulate priapism, CSMCs were cultured under anoxia or hypoxia and then analyzed for PDE-5 expression. Furthermore, rats underwent bilateral pudendal arterial ligation for 1 day to 14 weeks, and corpus cavernous tissues were subjected to reverse transcriptase-polymerase chain reaction analysis for PDE-5 expression.. Up-regulation of PDE-5 was noted in CSMCs treated with 25 microM sildenafil for 7 days. PDE-5 messenger RNA and protein levels were significantly increased in the 7-day sildenafil treated cultures. Sodium nitroprusside appeared to down-regulate PDE-5 expression. Sildenafil significantly increased the activities of PDE-5A1 promoter. PDE-5 expression was significantly reduced under anoxia and hypoxia. The corpus cavernous tissue showed a gradual decrease in PDE-5 expression under ischemia.. Repeated treatment with sildenafil at high concentrations was needed to simulate tachyphylaxis in our cell culture system. Adequate oxygenation was important for PDE-5 expression. Thus, sicklemic patients may express PDE-5 at abnormally low levels, predisposing them at risk of stuttering priapism.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cells, Cultured; Cyclic Nucleotide Phosphodiesterases, Type 5; Down-Regulation; Male; Penile Erection; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Priapism; Purines; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Sildenafil Citrate; Sulfones; Tachyphylaxis; Up-Regulation

In this period we observed seven patients of whom four presented with low flow and three with high flow priapism. In two of the patients with ischemic priapism, simple blood aspiration from the corpora allowed for a quick detumescence, while in the other two cases a derivative intervention (one spongio cavernous and one glans cavernous) had to be performed. In all the three patients with high flow priapism we performed a superselective arteriography that obtained the visualisation of the arteriovenous fistula. These patients restarted their sexual activity after about three months. A six months a patient with low flow priapism restored sexual activity due to sildenafil 50 mg.

Topics: Adult; Aged; Algorithms; Erectile Dysfunction; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Priapism; Purines; Sildenafil Citrate; Sulfones

Successful preventive therapy for ischemic priapism, a disorder of penile erection with major physical and psychologic consequences, is limited. We conducted a randomized, double-blind, placebo-controlled clinical trial to assess the efficacy and safety of sildenafil by a systematic dosing protocol to prevent recurrent ischemic priapism associated with sickle cell disease.. Thirteen patients with sickle cell disease reporting priapism recurrences at least twice weekly were randomized to receive sildenafil 50 mg or placebo daily, unassociated with sleep or sexual activity, for 8 weeks, followed by open-label use of this sildenafil regimen for an additional 8 weeks.. Priapism frequency reduction by 50% did not differ between sildenafil and placebo groups by intention-to-treat or per protocol analyses (P = 1.0). However, during open-label assessment, 5 of 8 patients (62.5%) by intention-to-treat analysis and 2 of 3 patients (66.7%) by per protocol analysis met this primary efficacy outcome. No significant differences were found between study groups in rates of adverse effects, although major priapism episodes were decreased 4-fold in patients monitored "on-treatment.". Sildenafil use by systematic dosing may offer a strategy to prevent recurrent ischemic priapism in patients with sickle cell disease.

Topics: Adolescent; Adult; Anemia, Sickle Cell; Double-Blind Method; Humans; Ischemia; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Priapism; Prospective Studies; Purines; Recurrence; Sildenafil Citrate; Sulfones; Young Adult

Despite their efficacy and general safety, rare but devastating adverse drug reactions have been associated with phosphodiesterase type 5 inhibitors.. To determine the safety profile of oral phosphodiesterase type 5 inhibitors with a particular focus on priapism and malignant melanoma.. In this case-non-case study, we queried the individual case safety reports for phosphodiesterase type 5 inhibitors within the World Health Organization global database of individual case safety reports (VigiBase) between 1983 and 2021. We included all individual case safety reports for sildenafil, tadalafil, vardenafil, and avanafil in men. For comparison, we also extracted the safety data from the Food and Drug Administration trials for these drugs. We assessed the safety profile of phosphodiesterase type 5 inhibitors by disproportionality analysis by measuring reporting odds ratio for their most commonly reported adverse drug reactions, once for all phosphodiesterase type 5 inhibitor reports and once for reports of oral phosphodiesterase type 5 inhibitor use in adult men (≥18 years old) with sexual dysfunction.. A total of 94,713 individual case safety reports for phosphodiesterase type 5 inhibitors were extracted. A total of 31,827 individual case safety reports were identified relating to adult men taking oral sildenafil, tadalafil, vardenafil, or avanafil for sexual dysfunction. The most common adverse drug reactions included poor drug efficacy (42.5%), headache (10.4% vs. 8.5%-27.6% [Food and Drug Administration]), abnormal vision (8.4% vs. ≤4.6% [Food and Drug Administration]), flushing (5.2% vs. 5.1%-16.5% [Food and Drug Administration]), and dyspepsia (4.2% vs. 3.4%-11.1% [Food and Drug Administration]). Priapism showed significant signals for sildenafil (reporting odds ratio = 13.81, 95% confidence interval: 11.75-16.24), tadalafil (reporting odds ratio = 14.54, 95% confidence interval: 11.56-18.06), and vardenafil (reporting odds ratio = 14.12, 95% confidence interval: 8.36-22.35). Comparing with other medications in VigiBase, sildenafil (reporting odds ratio = 8.73, 95% confidence interval: 7.63-9.99) and tadalafil (reporting odds ratio = 4.25, 95% confidence interval: 3.19-5.55) had significantly higher reporting odds ratios for malignant melanoma.. Phosphodiesterase type 5 inhibitors show significant signals correlating with priapism among a large international cohort. Further clinical study is needed to elucidate whether this is from proper or inappropriate use or other confounding conditions, as analysis of pharmacovigilance data does not allow for quantifying the clinical risk. Also, there appears to be a relationship between phosphodiesterase type 5 inhibitor use and malignant melanoma, which warrants additional study to better understand causation.

Topics: Adolescent; Adult; Erectile Dysfunction; Humans; Male; Melanoma; Melanoma, Cutaneous Malignant; Pharmacovigilance; Phosphodiesterase 5 Inhibitors; Priapism; Sildenafil Citrate; Tadalafil; Vardenafil Dihydrochloride; World Health Organization

Topics: Adult; Humans; Male; Penis; Phosphodiesterase 5 Inhibitors; Priapism; Sildenafil Citrate

We present a case of priapism in a homeless patient with a psychiatric history of major depression, PTSD, polysubstance abuse (alcohol and cocaine) and past psychotropic medication use who was admitted to a local hospital for suicidal ideation. Priapism is a serious urological and a medical emergency which has often been associated with psychotropic medications (including the antidepressant trazodone), use of marijuana and alcohol, and other factors. This clinical case highlights the additive risks of medications and comorbid conditions in contributing to onset of priapism, emphasizing the importance of any pre-existing medical illness, diagnoses, and comorbid mental illnesses. Moreover, clinicians should consider potential side effects of all medications used and their drug interactions as they manage patients who develop this condition.

Topics: Adrenergic alpha-1 Receptor Antagonists; Depressive Disorder, Major; Hepatitis C; Humans; Male; Middle Aged; Phenylephrine; Phosphodiesterase 5 Inhibitors; Priapism; Prostatic Hyperplasia; Selective Serotonin Reuptake Inhibitors; Sildenafil Citrate; Sleep Initiation and Maintenance Disorders; Substance-Related Disorders; Sulfonamides; Tamsulosin; Trazodone; Vasoconstrictor Agents

Recent research suggests that priapism in sickle cell disease (SCD) is due to dysregulation of penile erection homeostasis including alteration of nitric oxide synthase (NOS) and phosphodiesterase type 5 (PDE5) activities by excessive levels of reactive oxygen species (ROS) released during hemolysis. It is unknown if subacute exposure to hemolysis is sufficient or if chronic reconditioning of erectile tissues is required for perturbation of homeostatic pathways and whether PDE5 inhibitor (PDE5I) treatment can restore erectile homeostasis in the subacute setting.. The aim of this study was to investigate the effects of subacute hemolysis (3-month exposure) on priapism and NO pathway regulation.. Mice underwent bone marrow transplantation with either SCD (BM-SS) or wild-type (WT) bone marrow. BM-SS mice were treated with sildenafil 100 mg/kg/day. We measured intracavernous pressure (ICP) measurements with or without cavernous nerve stimulation following bone marrow transplantation to assess for priapism.. ICP and frequency of erections were assessed. Penile tissues were analyzed for NOS, protein kinase G (PKG), PDE5, and ROS activities.. BM-SS mice demonstrated a priapism phenotype. PDE5I treatment reduced the frequency of erections in BM-SS mice (1.7 ± 1.1 vs. 5.5 ± 2.8 erections per hour, P < 0.05). Penile tissues from BM-SS mice demonstrated decreased NOS, PKG, PDE5 and elevated ROS activities compared with that of control mice. PDE5I treatment increased NOS (11.6 ± 1.3% vs. 7.8 ± 2.3%, P < 0.05) and PDE5 (76.3 ± 9.8% vs. 52.3 ± 11.1%, P < 0.05) activities and decreased ROS activity (137.8 ± 12.1% vs. 199.1 ± 11.3%, P < 0.05) compared with non-PDE5I treated BM-SS mice. PKG activity was increased beyond control levels with PDE5I treatment (158.4 ± 10.3%, P < 0.05).. Short-term hemolysis is sufficient to establish a priapism phenotype and results in loss of erectile function. PDE5I treatment ameliorates priapism, in part, because of restored NO balance with decreased ROS generation and increased PDE5 activity.

Topics: Acute Disease; Anemia, Sickle Cell; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Hemolysis; Male; Mice; Mice, Transgenic; Nitric Oxide Synthase; Penile Erection; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Priapism; Signal Transduction; Sildenafil Citrate

Patients with recurrent ischemic priapism have historically been treated with anti-androgen therapy due to the limited available evidence for more targeted therapies to treat the underlying pathophysiologic mechanisms of this condition. We report a case in which anti-androgen therapy caused significant adverse side effects and likely masked this patient's elevated prostate-specific antigen (PSA) levels, which adversely impacted the timely diagnosis and treatment of his prostate cancer.. A 69-year-old man treated with anti-androgens for priapism initially developed unwanted anti-androgenic side effects such as gynecomastia, erectile dysfunction, and decreased libido. After decreasing his anti-androgen dosage and starting a specified regimen of phosphodiesterase type 5 inhibitor therapy, his serum PSA levels were found to be elevated. He was subsequently diagnosed with adenocarcinoma of the prostate and underwent a radical prostatectomy with the pathologic finding of high-grade, locally progressive disease.. Anti-androgen therapy carries significant complication risks, including the potential to alter the diagnosis and treatment of prostate cancer. Clinicians administering this therapy for priapism management should be aware of these possible risks.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Anilides; Delayed Diagnosis; Humans; Male; Nitriles; Phosphodiesterase 5 Inhibitors; Piperazines; Priapism; Prostate-Specific Antigen; Prostatic Neoplasms; Purines; Secondary Prevention; Sildenafil Citrate; Sulfones; Tosyl Compounds

Sickle cell disease (SCD)-associated vasculopathy in the penis is characterized by aberrant nitric oxide and phosphodiesterase (PDE) 5 signaling, and by increased oxidative stress. Preliminary clinical trials show that continuous treatment with PDE5 inhibitor sildenafil unassociated with sexual activity decreases priapic activity in patients with SCD. However, the mechanism of its vasculoprotective effect in the penis remains unclear.. We evaluated whether continuous administration of PDE5 inhibitor sildenafil promotes eNOS function at posttranslational levels and decreases superoxide-producing enzyme NADPH oxidase activity in the sickle cell mouse penis.. SCD transgenic mice were used as an animal model of SCD. WT mice served as controls. Mice received treatment with the PDE5 inhibitor sildenafil (100 mg/kg/day) or vehicle for 3 weeks. eNOS phosphorylation on Ser-1177 (positive regulatory site), eNOS interactions with heat-shock protein 90 (HSP90) (positive regulator), phosphorylated AKT (upstream mediator of eNOS phosphorylation on Ser-1177), an NADPH oxidase catalytic subunit gp91(phox), and a marker of oxidative stress (4-hydroxy-2-nonenal [HNE]) were measured by Western blot.. Effect of continuous sildenafil treatment on eNOS posttranslational activation, NADPH oxidase catalytic subunit, and oxidative stress in the penis of the sickle cell mouse.. Continuous treatment with sildenafil reversed (P < 0.05) the abnormalities in protein expressions of P-eNOS (Ser-1177), eNOS/HSP90 interaction, P-AKT, protein expression of gp91(phox), and 4-HNE, in the sickle cell mouse penis. Sildenafil treatment of WT mice did not affect any of these parameters.. Our findings that sildenafil enhances eNOS activation and inhibits NADPH oxidase function in the sickle cell mouse penis offers a vasculoprotective molecular basis for the therapeutic effect of sildenafil in the penis in association with SCD.

Topics: Aldehydes; Anemia, Sickle Cell; Animals; Male; Mice; Mice, Transgenic; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidation-Reduction; Oxidative Stress; Penis; Phosphodiesterase 5 Inhibitors; Phosphorylation; Piperazines; Priapism; Purines; Sildenafil Citrate; Sulfones; Superoxides

Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders.

Topics: Anemia, Sickle Cell; Animals; Blotting, Western; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Male; Mice; Mice, Knockout; Mice, Transgenic; Nitric Oxide; Nitric Oxide Synthase Type III; Nitrosation; Oxidative Stress; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Priapism; Purines; Reactive Oxygen Species; Signal Transduction; Sildenafil Citrate; Sulfones

Topics: Anti-Retroviral Agents; Central Nervous System Stimulants; Combined Modality Therapy; Dietary Supplements; Drug Interactions; Drug Therapy, Combination; Emergency Service, Hospital; Food Contamination; HIV Infections; Humans; Male; Methamphetamine; Middle Aged; Piperazines; Plant Preparations; Priapism; Purines; San Francisco; Secondary Prevention; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

We report a case of priapism in a 6-month-old boy of African descent who had been receiving intravenous sildenafil, a phosphodiesterase-5 inhibitor. An orthotopic cardiac transplantation had been performed at 6 months of age, 2 months after he had received a Berlin heart. The pre-, peri-, and postoperative care required multiple transfusions, and postoperative pulmonary hypertension required treatment with intravenous sildenafil. He developed a series of prolonged, semitumescent erections (30-180 minutes) that resolved spontaneously without the need for urologic intervention. Subsequent investigations revealed he was a carrier of a sickle cell gene. Although the precise etiology of the prolonged penile erection is unclear, it was likely secondary to the use of sildenafil and the sickle cell trait.

Topics: Heart Transplantation; Humans; Hypertension, Pulmonary; Infant; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Priapism; Purines; Sickle Cell Trait; Sildenafil Citrate; Sulfones

Priapism is a common concern in sickle cell disease. With a high frequency of recurrences and serious long-term sequela, a preventative, rather than traditionally reactive approach, needs to be taken in these patients. Reports have shown successful use of sildenafil as a prophylactic treatment but have failed to address adverse outcomes, including vasoocclusive pain crises, of chronic sildenafil therapy in sickle cell patients.. We wish to draw attention to the potential adverse outcomes of this therapy on the overall state of the patient's disease for consideration in future studies.. We used sildenafil in a patient suffering from almost daily attacks of priapism.. Sildenafil was successful in decreasing the frequency of priapism; however, our patient experienced an increased frequency of vasoocclusive crises, something not previously addressed.. Future studies of sildenafil use in sickle cell disease need to assess the global state of the disease, not just the frequency of priapism.

Topics: Adult; Anemia, Sickle Cell; Humans; Male; Penile Erection; Phosphodiesterase 5 Inhibitors; Piperazines; Priapism; Purines; Sildenafil Citrate; Sulfones

Priapism is associated with sickle cell disease (SSD); however, few men receive education about this condition, which contributes to attenuated return of functional erections.. To define the demographics, SSD status, and treatment outcomes of African-American men presenting with priapism.. Demographics, medical history, self-report of sickle cell status, and outcome assessment using International Inventory of Erectile Function (IIEF) of men with priapism were retrospectively reviewed.. A review of 39 cases of venocclusive priapism in African-American men was conducted. Charts were reviewed for demographics, medical history including SSD status by patient self-report, serum hemoglobin electrophoresis results, and priapism treatment and outcome.. Mean duration of presenting priapism episode was 22 +/- 12 hours (6-70 hours). Eight percent of men had priapism for <12 hours, 59% 12-24 hours, 22% 24-36 hours, and 11% >36 hours. All patients with priapism events of >12 hours complained of reduction in erectile rigidity. No patients with priapism >36 hours duration had return of spontaneous functional erections, but 44% (24-36 hours), 78% (12-24 hours) and 100% (<12 hours) were able to generate functional erections with or without the use of sildenafil. Follow-up IIEF erectile function domain scores paralleled incidence of functional erections. Penile shunt surgery was required in 28%. Only 5% of men recalled learning that priapism was a complication of SSD. Six men denied a history of SSD; however, hemoglobin electrophoresis revealed abnormal hemoglobin S and elevated hemoglobin F levels in four of these men.. The association of SSD and venocclusive priapism is well known in the medical community, yet few patients ever receive education regarding the emergency nature of the condition. The majority of men presents in a delayed fashion, and a significant proportion requires shunt surgery leading to long-term erectile dysfunction. Of those who denied having SSD, two-thirds had SSD by hemoglobin electrophoresis.

Topics: Adrenergic alpha-Agonists; Adult; Anemia, Sickle Cell; Black People; Emergency Service, Hospital; Erectile Dysfunction; Humans; Injections; Male; Phenylephrine; Phosphodiesterase Inhibitors; Piperazines; Priapism; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Time Factors; Urologic Surgical Procedures, Male

Nitrergic neurons are important for erectile responses in the corpus cavernosum and impaired signalling results in erectile dysfunction, today treated successfully by oral administration of the selective phosphodiesterase 5 (PDE 5) inhibitors sildenafil, tadalafil and vardenafil. Although the importance of nitrergic neurons in urogenital function has become evident, it has not been investigated if the PDE 5 inhibitors affect the nerve-induced release of nitric oxide (NO). In a previous study we found that the soluble guanylate cyclase (sGC)/cyclic guanosine 3',5'-monophosphate (cGMP) pathway might modulate nerve-induced release of NO in isolated cavernous tissue.. Electrical field stimulation (EFS 5 Hz, 40 V, 0.3 ms pulse duration, 25 pulses at intervals of 2 min) of rabbit isolated cavernous tissue elicited reproducible, nerve-mediated relaxations in the presence of scopolamine (10(-5) M), guanethidine (10(-5) M) and phenylephrine (3 x 10(-6) M). In superfusion experiments, nerve stimulation (20 Hz, 40 V, 1 ms) of the cavernous tissue evoked release of NO/NO2-, measured by chemiluminescence.. Sildenafil, tadalafil and vardenafil decreased the muscular tone and prolonged the relaxations to nerve stimulation. The evoked release of NO decreased to 72+/-11%, 55+/-16% and 61+/-14% of control, respectively after addition of sildenafil, tadalafil or vardenafil (all 10(-4) M, n=6-8, p<0.05).. Selective PDE 5 inhibitors influence the nerve-induced release of NO, probably via cGMP-mediated negative feedback. This negative feedback might explain why priapism is not seen during monotherapy with the PDE inhibitors.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Carbolines; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Imidazoles; In Vitro Techniques; Male; Muscle, Smooth; Nitrergic Neurons; Nitric Oxide; Penis; Phosphodiesterase Inhibitors; Piperazines; Priapism; Purines; Rabbits; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride

Recent evidence suggests that blocking inducible nitric oxide (NO) synthase in the penis may exacerbate fibrotic processes and that application of medications known to increase NO in tissues may prevent fibrosis.. To report the use of an antifibrotic regimen consisting of medications known to upregulate NO production in two patients with refractory priapism.. Two patients presented with priapism of greater than 48-hour duration. After corporal aspiration/irrigation and shunting procedures failed, both were prescribed a daily antifibrotic regimen comprising the phosphodiesterase inhibitors pentoxifylline and sildenafil, and the NO precursor, L-arginine.. At 1 year, both patients were found to have supple corpora without evidence of corporal fibrosis.. An antifibrotic regimen consisting of upregulators of NO production may ameliorate the corporal fibrosis associated with recalcitrant priapism.

Topics: Arginine; Enzyme Inhibitors; Fibrosis; Humans; Male; Middle Aged; Nitric Oxide; Nitric Oxide Synthase; Penis; Pentoxifylline; Phosphodiesterase Inhibitors; Piperazines; Priapism; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

Recurrent ischemic priapism describes a disorder of repeated episodes of prolonged penile erection that frequently leads to devastating complications of erectile tissue damage and erectile dysfunction. A mechanistic role for dysregulated phosphodiesterase 5 (PDE5) in the deranged smooth muscle response of the corpus cavernosum of the penis offers new understanding about the pathogenesis of the disorder and suggests that PDE5 may serve as a molecular target for its treatment and prevention. We explored the use of PDE5 inhibitors to treat recurrent priapism, based on the hypothesis that the erection regulatory function of PDE5 would be regularized by this treatment and protect against further episodes.. We administered PDE5 inhibitors using a long-term therapeutic regimen to 3 men with sickle cell disease-associated priapism recurrences and 1 man with idiopathic priapism recurrences.. Long-term PDE5 inhibitor treatment alleviated priapism recurrences.. These observations support the hypothesis that PDE5 dysregulation exerts a pathogenic role for priapism associated with hematologic dyscrasias, as well as idiopathic priapism. Although these preliminary findings suggest that continuous, long-term PDE5 inhibitor therapy may be useful as a preventative strategy for priapism, additional evaluation in the form of a controlled clinical trial is needed.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Anemia, Sickle Cell; Carbolines; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Humans; Male; Nitric Oxide; Penile Erection; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Priapism; Purines; Recurrence; Signal Transduction; Sildenafil Citrate; Sulfones; Tadalafil

During the last decade new approaches to the treatment of pulmonary arterial hypertension (PH) have increased symptomatic relief and prolonged survival. PH is a common sequel of the hemoglobinopathies, thalassemia and sickle cell anemia, but the use of standard oral treatment options, such as calcium channel blockers, endothelin receptor antagonists, and long-term anticoagulation therapy, is limited because of toxicity and poor effectiveness. Sildenafil citrate is a selective and potent inhibitor of cGMP-specific phosphodiesterase-5 (PDE5) which promotes selective smooth muscle relaxation in lung vasculature and has been utilized successfully in the treatment of PH. The primary objective of this study was to evaluate the efficacy of sildenafil treatment in the control of PH in patients with hemoglobinopathies.. In this study patients with hemoglobinopathies (thalassemia intermedia n=4; thalassemia major n=2; sickle thalassemia n=1) suffering from severe PH were treated with sildenafil citrate (50 mg b.i.d.) for periods ranging from 4 to 48 months.. A significant decrease in pulmonary pressure and improvement in exercise capacity and functional class were observed in all patients. No significant adverse events were reported.. These data, in a small group of patients, indicate that sildenafil citrate is effective in the treatment of PH in hemoglobinopathies that cannot be treated with alternative oral drugs and is well tolerated long-term at a daily dose of 100 mg, though studies including more patients may uncover toxicities and limitations of efficacy.

Topics: Administration, Oral; Adult; Blood Transfusion; Clinical Trials as Topic; Dose-Response Relationship, Drug; Echocardiography, Doppler; Female; Hemoglobinopathies; Humans; Hypertension, Pulmonary; Male; Piperazines; Priapism; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Vasodilator Agents

To investigate the effects of a purified scorpion toxin (Ts3) on human corpus cavernosum (HCC) in vitro. Scorpion venoms cause a massive release of neurotransmitters that contribute to the clinical symptoms resulting from envenomation.. HCC strips were mounted in organ baths containing Krebs solution. After equilibration, the tissues were precontracted with phenylephrine (10 micromol/L). The relaxations caused by Ts3 (30 nmol/L) were compared with those induced by electrical field stimulation (1 to 20 Hz) and nitric oxide (NO, 1 to 100 micromol/L).. The addition of Ts3 evoked long-lasting relaxations of precontracted HCC strips, and exogenously applied NO and electrical field stimulation caused short-lived responses. The NO synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 100 micromol/L) reduced by 87% +/- 2% the Ts3-induced relaxations; this inhibition was reversed by pretreating the tissues with L-arginine (1 mmol/L). The relaxant responses mediated by Ts3 were blocked to a similar degree by the soluble guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3,-alquinoxalin-1-one] (10 micromol/L). In contrast, the addition of the phosphodiesterase type 5 inhibitor sildenafil (0.1 micromol/L) significantly enhanced Ts3-evoked relaxations by 78% +/- 4%. The sodium channel blocker tetrodotoxin (1 micromol/L) completely blocked the relaxant responses elicited by both Ts3 and electrical field stimulation, without significantly affecting those elicited by NO.. The results indicate that Ts3 relaxes the HCC through the release of NO from nitrergic nerves. The elucidation of this mechanism is useful for the development of new therapeutic strategies to treat priapism after scorpion envenomation or to modulate sodium channel activity in the case of penile dysfunction.

Topics: Adolescent; Adult; Child; Cyclic GMP; Drug Evaluation, Preclinical; Electric Stimulation; Enzyme Inhibitors; Humans; In Vitro Techniques; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Neurotoxins; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxadiazoles; Penis; Phenylephrine; Piperazines; Priapism; Purines; Quinoxalines; Scorpion Venoms; Second Messenger Systems; Sildenafil Citrate; Sodium Channel Blockers; Sulfones; Tetrodotoxin

Sildenafil citrate is the first FDA-approved oral agent for male erectile dysfunction. Common adverse effects include flushing, headache, and dyspepsia, although more serious side effects have been reported. Because of its specific therapeutic indication, sildenafil toxicity has been limited almost exclusively to adults. We report a symptomatic case of pediatric sildenafil ingestion.. A 2-year-old male ingested 75 mg of sildenafil citrate (Viagra) 2 hours prior to arrival at an emergency room. Ipecac syrup had been given at home with one episode of vomiting. Activated charcoal was considered but withheld due to the delayed presentation to the hospital. The patient was observed in the hospital for 17.5 hours. Observed clinical effects included facial flushing, transient penile engorgement, bilateral rhonchi, and diarrhea. No significant cardiovascular effects were seen. A bronchodilator was given with resolution of rhonchi. No other specific interventions were required. One day after discharge, the patient had one additional bout of diarrhea and complained of pain in the penile region for one day. Two weeks after the exposure, the patient's mother denied any unusual symptoms.. Pediatric ingestion of sildenafil may result in mild symptoms including persistent flushing and penile engorgement with associated pain. Penile pain may persist even after resolution of the erection. It is questionable whether the respiratory symptoms and diarrhea were related since neither has been described following sildenafil exposure. Significant cardiovascular symptoms were not seen. Early administration of ipecac syrup did not prevent symptoms from developing.

Topics: Bronchodilator Agents; Child, Preschool; Diarrhea; Emetics; Flushing; Humans; Hypotension; Ipecac; Male; Piperazines; Poisoning; Priapism; Purines; Respiratory Sounds; Sildenafil Citrate; Sulfones

Topics: Antidepressive Agents; Drug Therapy, Combination; Erectile Dysfunction; Humans; Male; Phosphodiesterase Inhibitors; Piperazines; Priapism; Purines; Sildenafil Citrate; Sulfones; Trazodone

Topics: Adult; Alprostadil; Drug Therapy, Combination; Erectile Dysfunction; Humans; Male; Middle Aged; Papaverine; Phentolamine; Phosphodiesterase Inhibitors; Piperazines; Priapism; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Adult; Anemia, Sickle Cell; Follow-Up Studies; Humans; Male; Piperazines; Priapism; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Ultrasonography; Vasodilator Agents

Topics: Adult; Analgesics, Opioid; Codeine; Drug Interactions; Humans; Male; Middle Aged; Piperazines; Priapism; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Abscess; Humans; Injections; Male; Middle Aged; Penile Diseases; Phosphodiesterase Inhibitors; Piperazines; Priapism; Purines; Rupture, Spontaneous; Sildenafil Citrate; Sulfones

We report our experience in the management of priapism.. In a 2-year period we observed 7 patients of whom 4 presented with low flow and 3 with high flow priapism.. In 2 of the patients with ischemic priapism, simple blood aspiration from the corpora allowed for a quick detumescence, while in the other 2 cases a derivative intervention (1 spongio cavernous and 1 glans cavernous) had to be performed. In all the 3 patients with high flow priapism we performed a superselective arteriography that obtained the visualisation of the arteriovenous fistula. These patients restarted their sexual activity after about three months. At six months a patient with low flow priapism restored sexual activity due to sildenafil 50 mg.. The importance of distinguishing low and high flow priapism was confirmed.

Topics: Adult; Aged; Algorithms; Decision Trees; Erectile Dysfunction; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Priapism; Purines; Sildenafil Citrate; Sulfones

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Male; Muscle, Smooth, Vascular; Penis; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Priapism; Purines; Sickle Cell Trait; Sildenafil Citrate; Sulfones

We report the first case of priapism associated with the use of sildenafil citrate. The patient was a 28-year-old man with mild erectile dysfunction after penile trauma who self-treated with a 100-mg dose of sildenafil citrate, resulting in low-flow priapism. After aspiration and intracorporal injection of alpha-agonists, the priapism resolved. The patient's erectile function returned to his prepriapism baseline.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Erectile Dysfunction; Humans; Male; Penis; Phosphodiesterase Inhibitors; Piperazines; Priapism; Purines; Sildenafil Citrate; Sulfones

A 53 year-old Japanese man was referred to our hospital for persistent priapism, which had been induced by 200 mg (usual dose 25-50 mg) of sildenafil citrate (Viagra) three days earlier. He had a history of erectile dysfunction and had undergone penile injection therapy elsewhere; however, he had not used injection therapy this time. He obtained sildenafil personally without a doctor's prescription. He had not taken any other drugs that affect the metabolism of sildenafil, nor did he have any medical complications that might induce priapism. Since needle aspiration and irrigation were ineffective as first line therapy, surgical treatment was indicated to relieve the condition; a incision of tunica albuginea of both corpora cavernosa was made, and vigorous irrigation of saline washed out the blood clots. This is the first case report of priapism induced by sildenafil. Although this drug can be obtained through private commerce, it should be used under professional guidance as its abuse may lead to severe morbidity.

Topics: Humans; Male; Middle Aged; Nonprescription Drugs; Phosphodiesterase Inhibitors; Piperazines; Priapism; Purines; Sildenafil Citrate; Sulfones