sildenafil-citrate and Anemia--Sickle-Cell

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

The sickle hemoglobin is an abnormal hemoglobin due to point mutation (GAG → GTG) in exon 1 of the β globin gene resulting in the substitution of glutamic acid by valine at position 6 of the β globin polypeptide chain. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of sickle cell disease in general and sickle cell anemia in particular. The disease itself is chronic in nature but many of its complications are acute such as the recurrent acute painful crises (its hallmark), acute chest syndrome, and priapism. These complications vary considerably among patients, in the same patient with time, among countries and with age and sex. To date, there is no well-established consensus among providers on the management of the complications of sickle cell disease due in part to lack of evidence and in part to differences in the experience of providers. It is the aim of this paper to review available current approaches to manage the major complications of sickle cell disease. We hope that this will establish another preliminary forum among providers that may eventually lead the way to better outcomes.

Topics: Anemia, Sickle Cell; Blood Transfusion; Clinical Trials as Topic; Disease Management; Gastrointestinal Diseases; Humans; Hydroxyurea; Hypertension, Pulmonary; Muscular Diseases; Nervous System Diseases; Pain; Phenotype; Piperazines; Purines; Retinal Diseases; Sildenafil Citrate; Sulfones; Treatment Outcome

The long-term prognosis for patients with pulmonary arterial hypertension (PAH) remains poor, despite advances in treatment options that have been made in the past few decades. Recent evidence suggests that World Health Organization functional class I or II patients have significantly better long-term survival rates than patients in higher functional classes, thus providing a rationale for earlier diagnosis and treatment of PAH. However, early diagnosis is challenging and there is frequently a delay between symptom onset and diagnosis. Screening programmes play an important role in PAH detection and expert opinion favours echocardiographic screening of asymptomatic patients who may be predisposed to the development of PAH (i.e. those with systemic sclerosis or sickle cell disease), although current guidelines only recommend annual echocardiographic screening in symptomatic patients. This article reviews the currently available screening programmes, including their limitations, and describes alternative screening approaches that may identify more effectively those patients who require right heart catheterisation for a definitive PAH diagnosis.

Topics: Anemia, Sickle Cell; Antihypertensive Agents; Bosentan; Early Diagnosis; Echocardiography, Doppler; Exercise Test; Humans; Hypertension, Pulmonary; Mass Screening; Natriuretic Peptide, Brain; Peptide Fragments; Piperazines; Practice Guidelines as Topic; Purines; Respiratory Function Tests; Risk Factors; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Modern health care has greatly increased longevity for patients with congenital hemolytic anemias (such as sickle cell disease and thalassemia) and human immunodeficiency virus (HIV) infection. It is estimated that 10% of patients with hemoglobinopathies and 0.5% of patients with HIV infection develop moderate to severe pulmonary hypertension. Pulmonary hypertension is a relentlessly progressive disease leading to right heart failure and death. Worldwide, there are an estimated 30 million patients with sickle cell disease or thalassemia and 40 million patients with HIV disease. Considering the prevalence of pulmonary vascular disease in these populations, sickle cell disease and HIV disease may be the most common causes of pulmonary hypertension worldwide. In this review, the available data on epidemiology, hemodynamics, mechanisms, and therapeutic strategies for these diseases are summarized. Because therapy is likely to reduce morbidity and prolong survival, efforts to screen, diagnose, and treat these patients represent a global health opportunity.

Topics: Anemia, Hemolytic, Congenital; Anemia, Sickle Cell; Antiretroviral Therapy, Highly Active; Blood Transfusion; Echocardiography, Doppler, Color; Heart Failure; HIV Infections; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

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

In adults with sickle cell disease (SCD), an increased tricuspid regurgitation velocity (TRV) by Doppler echocardiography is associated with increased morbidity and mortality. Although sildenafil has been shown to improve exercise capacity in patients with pulmonary arterial hypertension, it has not been evaluated in SCD. We therefore sought to determine whether sildenafil could improve exercise capacity in SCD patients with increased TRV and a low exercise capacity. A TRV ≥ 2.7 m/s and a 6-minute walk distance (6MWD) between 150 and 500 m were required for enrollment in this 16-week, double-blind, placebo-controlled sildenafil trial. After 74 of the screened subjects were randomized, the study was stopped early due to a higher percentage of subjects experiencing serious adverse events in the sildenafil arm (45% of sildenafil, 22% of placebo, P = .022). Subject hospitalization for pain was the predominant cause for this difference: 35% with sildenafil compared with 14% with placebo (P = .029). There was no evidence of a treatment effect on 6MWD (placebo-corrected effect -9 m; 95% confidence interval [95% CI] -56-38; P = .703), TRV (P = .503), or N-terminal pro-brain natriuretic peptide (P = .410). Sildenafil appeared to increase hospitalization rates for pain in patients with SCD. This study is registered at www.clinicaltrials.gov as NCT00492531.

Topics: Anemia, Sickle Cell; Double-Blind Method; Exercise Tolerance; Female; Hemodynamics; Hospitalization; Humans; Male; Middle Aged; Pain; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tricuspid Valve Insufficiency; Vasodilator Agents

Pulmonary hypertension is a frequent complication of sickle cell disease that is associated with haemolysis, impaired nitric oxide bioavailability and high mortality. We sought to evaluate the safety and efficacy of selective pulmonary vasodilators and antiproliferative agents in this at-risk population. After optimising sickle cell disease therapy to stabilise haemoglobin and fetal haemoglobin levels, we evaluated the safety and efficacy of sildenafil in 12 patients with sickle cell disease and pulmonary hypertension. Sildenafil therapy (mean duration 6 +/- 1 months) decreased the estimated pulmonary artery systolic pressure [50 +/- 4 to 41 +/- 3 mmHg; difference 9 mmHg, 95% confidence interval (CI): 0.3-17, P = 0.043] and increased the 6-min walk distance (384 +/- 30 to 462 +/- 28 m; difference 78 m, 95% CI: 40-117, P = 0.0012). Transient headaches occurred in two patients and transient eye-lid oedema in four patients. No episodes of priapism occurred in the three men in the study; two of them were on chronic exchange transfusions and one had erectile dysfunction.. (1) sickle cell disease patients with anaemia and pulmonary hypertension have significant exercise limitation; (2) the 6-min walk distance may be a valid endpoint in this population; (3) therapy with sildenafil appears safe and improves pulmonary hypertension and exercise capacity. Additional phase I studies in males with sickle cell disease followed by phase II/III placebo controlled trials evaluating the safety and efficacy of sildenafil therapy in sickle cell disease patients with pulmonary hypertension are warranted.

Topics: Adult; Anemia, Sickle Cell; Cardiac Catheterization; Echocardiography; Exercise Test; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pilot Projects; Piperazines; Purines; Reproducibility of Results; Sildenafil Citrate; Statistics, Nonparametric; Sulfones; Systole; Vascular Resistance; Vasodilator Agents

Sickle cell disease (SCD) is associated with intravascular hemolysis and oxidative inhibition of nitric oxide (NO) signaling. BAY 54-6544 is a small-molecule activator of oxidized soluble guanylate cyclase (sGC), which, unlike endogenous NO and the sGC stimulator, BAY 41-8543, preferentially binds and activates heme-free, NO-insensitive sGC to restore enzymatic cGMP production. We tested orally delivered sGC activator, BAY 54-6544 (17 mg/kg/d), sGC stimulator, BAY 41-8543, sildenafil, and placebo for 4-12 weeks in the Berkeley transgenic mouse model of SCD (BERK-SCD) and their hemizygous (Hemi) littermate controls (BERK-Hemi). Right ventricular (RV) maximum systolic pressure (RVmaxSP) was measured using micro right-heart catheterization. RV hypertrophy (RVH) was determined using Fulton's index and RV corrected weight (ratio of RV to tibia). Pulmonary artery vasoreactivity was tested for endothelium-dependent and -independent vessel relaxation. Right-heart catheterization revealed higher RVmaxSP and RVH in BERK-SCD versus BERK-Hemi, which worsened with age. Treatment with the sGC activator more effectively lowered RVmaxSP and RVH, with 90-day treatment delivering superior results, when compared with other treatments and placebo groups. In myography experiments, acetylcholine-induced (endothelium-dependent) and sodium-nitroprusside-induced (endothelium-independent NO donor) relaxation of the pulmonary artery harvested from placebo-treated BERK-SCD was impaired relative to BERK-Hemi but improved after therapy with sGC activator. By contrast, no significant effect for sGC stimulator or sildenafil was observed in BERK-SCD. These findings suggest that sGC is oxidized in the pulmonary arteries of transgenic SCD mice, leading to blunted responses to NO, and that the sGC activator, BAY 54-6544, may represent a novel therapy for SCD-associated pulmonary arterial hypertension and cardiac remodeling.

Topics: Anemia, Sickle Cell; Animals; Arterial Pressure; Disease Models, Animal; Enzyme Activation; Enzyme Activators; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Mice, Transgenic; Morpholines; Nitric Oxide; Pulmonary Artery; Pyrimidines; Sildenafil Citrate; Soluble Guanylyl Cyclase; Vasodilation; Ventricular Dysfunction, Right; Ventricular Function, Right; Ventricular Pressure; Ventricular Remodeling

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

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

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

One of the features of homozygous sickle cell disease (HbSS) is the impaired elasticity of the erythrocyte membrane that could impede microcirculatory blood flow and cause hypoxia and tissue damage. We investigated the effect of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor that inhibits the breakdown of cyclic guanosine monophosphate (cGMP) resulting in vasodilatation, on the elasticity of HbSS erythrocyte.. Blood samples from ten HbSS patients in steady state was exposed to different doses (5, 10, 20, and 40 μg/mL) of sildenafil and the elasticity of the erythrocytes measured at native hematocrit with the BioProfiler. An equal number of subjects with normal hemoglobin (HbAA) served as the control group.. There was a marginal increase in elasticity with 5 μg/mL of the drug and this became significant (P<0.05) with the 10 μg/mL dose. Thereafter, gradual nonsignificant decreases were observed with the 20 and 40 μg/mL doses. A similar trend was observed for the control group. The elasticity values for the HbSS subjects at native hematocrit were significantly (P<0.05) less when compared with the corresponding concentrations for the HbAA controls. This was reversed at a corrected hematocrit of 45%.. The result of this study shows that sildenafil caused an initial increase in erythrocyte membrane elasticity in both HbSS and HbAA subjects, and this later decreased with increasing concentration of the drug possibly due to the dual effect of cyclic adenosine monophosphate (cAMP).

Topics: Adult; Anemia, Sickle Cell; Elasticity; Erythrocytes; Female; Homozygote; Humans; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Young Adult

Fetal hemoglobin (HbF) induction involves NO-cGMP signaling pathways. L-arginine, an NO precursor, and the phosphodiesterase (PDE) 5 inhibitor sildenafil, which potentiates cGMP, were studied in adults with sickle cell disease (SCD) who were stably on HU.. Twenty four courses of L-arginine (0.1-0.2 g/kg divided TID) or sildenafil (25-100 mg TID), assigned based on gender due to concerns about sildenafil-related priapism, were successfully completed. Biochemical assays, pulmonary pressures, and cardiopulmonary exercise capacity are reported from patients in whom serial values are available. Hematologic responses are reported in 14 subjects with HbSS who had stable baseline HbF levels.. L-arginine increased plasma arginine and ornithine, but not citrulline, suggesting diversion by plasma arginase from NO, and citrulline, generation. Glutathione increased only in patients on L-arginine. Sildenafil increased plasma cGMP and citrulline, but not other amino acids. Pulmonary pressures and 6-min walk distances improved only in patients on sildenafil. In subjects with stable baseline HbF levels, HbF levels changed little from a normalized baseline on l-arginine, decreasing by 2.9 +/- 16.1%, n = 6; P = n.s., but increased on sildenafil, by 7.5 +/- 11.7%, n = 8, P < 0.05. Absolute reticulocyte counts initially decreased in patients on sildenafil.. L-arginine, at doses that increase plasma arginine levels, altered redox potential in red cells. The lack of clinically detectable efficacy of L-arginine may be due to increased arginine metabolism in SCD patients. In vivo augmentation of the cyclic nucleotide pathway by PDE inhibition may induce HbF slightly, but strikingly improves hemodynamic and functional status in SCD.

Topics: Adult; Anemia, Sickle Cell; Arginase; Arginine; beta-Globins; Citrulline; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Fetal Hemoglobin; Humans; Hydroxyurea; Male; Middle Aged; Ornithine; Phosphodiesterase Inhibitors; Piperazines; Purines; Reticulocyte Count; Sildenafil Citrate; Sulfones

The acute chest syndrome (ACS) of sickle cell disease (SCD) is a leading cause of death in SCD, with a high incidence following surgery, though only one case has been reported following cardiac surgery. We present a case of ACS in an adult undergoing aortic valve replacement (AVR) despite instituting established peri-operative optimization measures to prevent sickling. Early diagnosis of this condition in our patient as a distinct clinical entity facilitated appropriate, specific therapy and a good subsequent postoperative recovery. Greater recognition of this syndrome in the growing number of adult sickle cell patients presenting for cardiac surgery may help improve their outcome.

Topics: Acute Chest Syndrome; Administration, Inhalation; Administration, Oral; Anemia, Sickle Cell; Aortic Valve Stenosis; Combined Modality Therapy; Critical Care; Early Diagnosis; Female; Heart Valve Prosthesis Implantation; Humans; Middle Aged; Nitric Oxide; Piperazines; Purines; Respiration, Artificial; Severity of Illness Index; Sildenafil Citrate; Sulfones; Tomography, X-Ray Computed; Tracheostomy; Treatment Outcome; Vasodilator Agents

Pulmonary Hypertension is a serious complication of sickle cell disease (SCD), with high morbidity and mortality. Endothelin (ET)-1, a potent vasoconstrictor elevated in SCD, acts through the ET receptors (ETR), ETR-A and ETR-B. Bosentan and ambrisentan are ETR blockers used in primary pulmonary hypertension. We report on the use of ETR blocking agents in a cohort of 14 high-risk SCD adult patients with pulmonary hypertension. Patients underwent right heart catheterization, 6-min walk test, echocardiogram, physical examination and blood work-up before starting ETR blockers. Eight patients received ETR blockers as initial therapy; six patients were already taking sildenafil. Over more than 6 months of therapy, sequential measurements of 6-min walk distance increased significantly (baseline 357 +/- 22 to 398 +/- 18 m at 5-6 months, P < 0.05). Downward trends were observed for amino-terminal brain natriuretic peptide and tricuspid regurgitant velocity. Pulmonary artery mean pressures decreased in three patients that had repeat right heart catheterization (44-38 mmHg). Adverse events were: increased serum alanine aminotransferase (2), peripheral oedema (4), rash (1), headache (3), decreased haemoglobin (2). Therapy was stopped in two patients who were switched then to the other ETR blocker agent. These data suggest preliminary evidence for the benefit of bosentan and ambrisentan in pulmonary hypertension in SCD.

Topics: Adult; Anemia, Sickle Cell; Antihypertensive Agents; Bosentan; Cardiac Catheterization; Drug Evaluation; Drug Therapy, Combination; Endothelin Receptor Antagonists; Exercise Test; Humans; Hypertension, Pulmonary; Middle Aged; Phenylpropionates; Piperazines; Purines; Pyridazines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

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

Increased platelet activation is recognized in patients with sickle cell disease (SCD), but its pathogenesis and clinical relevance remain uncertain. Pulmonary arterial hypertension (PAH), an important complication of SCD, is characterized by a proliferative pulmonary vasculopathy, in situ thrombosis, and vascular dysfunction related to scavenging of nitric oxide (NO) by hemoglobin released into blood plasma during intravascular hemolysis. We investigated links between platelet activation, PAH and NO scavenging in patients with SCD. Platelet activation marked by activated fibrinogen receptor correlated to the severity of PAH (r = 0.58, P < .001) and to laboratory markers of intravascular hemolysis, such as reticulocyte count (r = 0.44, P = .02). In vitro exposure of platelets to pathologically relevant concentrations of cell-free hemoglobin promoted basal- and agonist-stimulated activation and blocked the inhibitory effects on platelet activation by an NO donor. In patients with SCD, administration of sildenafil, a phosphodiesterase-5 inhibitor that potentiates NO-dependent signaling, reduced platelet activation (P = .01). These findings suggest a possible interaction between hemolysis, decreased NO bioavailability, and pathologic platelet activation that might contribute to thrombosis and pulmonary hypertension in SCD, and potentially other disorders of intravascular hemolysis. This supports a role for NO-based therapeutics for SCD vasculopathy. This trial was registered at www.clinicaltrials.gov as no. NCT00352430.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Anemia, Sickle Cell; Female; Flow Cytometry; Hemoglobins; Hemolysis; Humans; Hypertension, Pulmonary; Male; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Platelet Activation; Purines; Sildenafil Citrate; Sulfones; Thrombosis

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

Topics: Anemia, Sickle Cell; Drug Therapy, Combination; Ejaculation; Genital Diseases, Male; Humans; Male; Male Urogenital Diseases; Phosphodiesterase Inhibitors; Piperazines; Prostatectomy; Purines; Sildenafil Citrate; Sulfones; Urologic Diseases; Vasodilator Agents

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