sildenafil-citrate and Chronic-Disease

Protein-losing enteropathy (PLE) is a chronic condition involving multiple organ systems that may develop any time following Fontan completion. The pathogenesis of PLE is complex and multifactorial. Chronic venous hypertension, low cardiac output, and abnormal lymphatics may all play a role in the pathogenesis of PLE. Common signs and symptoms include chronic diarrhea, abdominal pain, and ascites. Diagnosis is based on the presence of signs and symptoms in addition to hypoalbuminemia and elevated stool alpha 1 antitrypsin. Early identification and a comprehensive approach to evaluation and treatment are important, as they may affect survival. The initial evaluation should include cardiac catheterization for hemodynamic assessment. Although an evidence base for treatment is lacking, various medical, interventional, and surgical approaches have been described with variable degrees of success. Commonly used therapies include nutritional support, diuretics, subcutaneous unfractionated heparin, budesonide, and sildenafil. Limited data exist for Fontan conversion or takedown. Assessment for heart transplantation should be considered. PLE mortality is high-approximately 50%-but may be mitigated by aggressive investigation and management. The evolving understanding of the role of lymphatics in the pathophysiology of PLE and the emerging role of interventional lymphatic procedures may further improve outcomes in this patient population.

Topics: Abdominal Pain; Academic Medical Centers; Ascites; Budesonide; Chronic Disease; Combined Modality Therapy; Diagnosis, Differential; Diarrhea; Diuretics; Female; Fontan Procedure; Heart Defects, Congenital; Heparin; Humans; Male; Prognosis; Protein-Losing Enteropathies; Rare Diseases; Risk Assessment; Sildenafil Citrate; Treatment Outcome

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but debilitating and life-threatening complication of acute pulmonary embolism. CTEPH results from persistent obstruction of pulmonary arteries and progressive vascular remodelling. Not all patients presenting with CTEPH have a history of clinically overt pulmonary embolism. The diagnostic work-up to detect or rule out CTEPH should include ventilation-perfusion scintigraphy, which has high sensitivity and a negative predictive value of nearly 100%. CT angiography usually reveals typical features of CTEPH, including mosaic perfusion, part or complete occlusion of pulmonary arteries, and intraluminal bands and webs. Patients with suspected CTEPH should be referred to a specialist centre for right-heart catheterisation and pulmonary angiography. Surgical pulmonary endarterectomy remains the treatment of choice for CTEPH and is associated with excellent long-term results and a high probability of cure. For patients with inoperable CTEPH, various medical and interventional therapies are being developed.

Topics: Angioplasty, Balloon; Bosentan; Chronic Disease; Endarterectomy; Endothelin Receptor Antagonists; Enzyme Activators; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Embolism; Purines; Pyrazoles; Pyrimidines; Sildenafil Citrate; Sulfonamides; Thromboembolism

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition that historically has a poor outcome with supportive medical treatment. Pulmonary endarterectomy (PEA) is the treatment of choice and offers the only chance of cure. A significant proportion of patients is either not suitable due to the distal distribution of the disease or has persistent pulmonary hypertension (PH) after PEA. Despite the lack of licensed therapies for CTEPH, the similarities in pathobiology of pulmonary arterial hypertension (PAH) and CTEPH has led to the compassionate use of PAH therapies in CTEPH patients. This article reviews the pathobiology of CTEPH and summaries the available evidence for the use of PAH-targeted drugs in CTEPH.

Topics: Antihypertensive Agents; Bosentan; Chronic Disease; Compassionate Use Trials; Endarterectomy; Humans; Hypertension, Pulmonary; Piperazines; Pulmonary Embolism; Purines; Pyrazoles; Pyrimidines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

Endocrine abnormalities are common in patients with chronic kidney disease (CKD) and lead to sexual dysfunction, anemia, hyperparathyroidism, and altered mineral metabolism. Common clinical problems include disturbances in menstruation in women, erectile dysfunction in men, and decreased libido and infertility in both sexes. Organic factors tend to be prominent and are related to uremia and other comorbid illnesses. Psychological factors and depression may exacerbate the primary problem. Alterations in the hypothalamic-pituitary axis are seen early in CKD and tend to worsen after patients start dialysis. Hypogonadism plays a dominant role in male sexual function, whereas changes in hypothalamic-pituitary function predominate in female sexual dysfunction. In patients on dialysis, treatment strategies include optimizing dose of dialysis, correction of anemia with erythropoietin, and correction of hyperparathyroidism. Successful kidney transplantation may restore normal sexual function, especially in younger patients.

Topics: Androgens; Chronic Disease; Erythropoietin; Female; Hormone Replacement Therapy; Humans; Hypogonadism; Kidney Diseases; Kidney Transplantation; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Recombinant Proteins; Sexual Dysfunction, Physiological; Sildenafil Citrate; Sulfones; Testosterone

Disabling pansclerotic morphea of childhood (DPMC) is a rare and severe variant of scleroderma. This report presents 3 cases that presented to the authors and studies 25 patients from the literature (English language only) for the presence of chronic nonhealing ulcers of skin and skin cancer. The authors identified a total of 30 patients (9 male and 21 female) aged between 1 and 37 years at time of presentation. All cases were less than 14 years old when the disease started. The majority of patients had an aggressive course with deep sclerotic lesions leading to joint contractures and immobility. Five patients suffered from chronic nonhealing leg ulcers (17%), but ulcers were present on other parts of the body (upper limbs, trunk, head) as well (n = 6). Four patients died because of complications of the disease such as sepsis or gangrene. Two patients developed a squamous cell carcinoma at the age of 16 years and 19 years, respectively (6.7%). The available treatment of DMPC-associated ulcers is unsatisfying. Only temporary improvements have been seen in a minority of patients. We report on marked improvement of chronic leg ulcers by a combination of sildenafil 3 x 20 mg/day and repeated application of a porcine small intestinal submucosal acellular matrix.

Topics: Adolescent; Adult; Carcinoma, Squamous Cell; Chronic Disease; Collagen; Combined Modality Therapy; Contracture; Female; Humans; Male; Piperazines; Purines; Scleroderma, Localized; Sildenafil Citrate; Skin Neoplasms; Skin Ulcer; Skin, Artificial; Sulfones; Vasodilator Agents

More than 70% of elderly men (>or=65) remain sexually active, and more than 40%, according to one estimate, are dissatisfied with their sex lives. Declining sexual function and a reluctance to seek medical attention with advancing age are cross-cultural observations. Normal erection is largely dependent on intact function of the central and peripheral nervous systems and the penile vascular endothelium. Consequently, chronic conditions (e.g., cardiovascular disease, diabetes mellitus) and lifestyle factors (e.g., smoking) that have adverse effects on the vascular endothelium and central and peripheral nervous systems, as well as on endocrine function or connective tissues within the corpus cavernosum of the penis, can attenuate erectile function. Because of these associations, assessment of sexual function in elderly men often reveals not only erectile dysfunction (ED) but also other reversible conditions. An expanding array of noninvasive options is available to assist the clinician in individualizing ED therapy to the unique health and lifestyle needs of each elderly ED patient and his partner. These treatment alternatives include the phosphodiesterase type 5 inhibitors sildenafil, vardenafil, and tadalafil, as well as other oral medications, such as alpha-adrenoceptor antagonists and topical vasoactive or testosterone therapy.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aged; Aging; Chronic Disease; Erectile Dysfunction; Humans; Life Style; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Testosterone; Vasoconstrictor Agents

Neurologic erectile dysfunction presents a diagnostic and treatment challenge to the internist and urologist. Multiple chronic disease modalities and traumatic etiologies exist. Education regarding these conditions and a detailed and thorough history and office work-up are the best resources for the clinician. Treatment can follow the model of proceeding from the least to most invasive procedure (process of care), taking into account patient and partner satisfaction. Because the psychology of grief and loss may enter into treatment of some neurologic conditions (e.g., erectile dysfunction after radical retropubic prostatectomy, spinal cord injury, or chronic diseases), a whole-patient approach encompassing psychotherapy is warranted.

Topics: Chronic Disease; Diabetic Neuropathies; Erectile Dysfunction; Humans; Intervertebral Disc Displacement; Male; Multiple Sclerosis; Parkinson Disease; Penile Prosthesis; Phosphodiesterase Inhibitors; Piperazines; Prostatectomy; Purines; Sildenafil Citrate; Spinal Cord Injuries; Sulfones

Pulmonary hypertension is associated with poor outcome in patients with chronic heart failure (CHF) and may be a therapeutic target. Our aims were to develop a noninvasive model for studying pulmonary vasoreactivity in CHF and characterize sildenafil's acute cardiovascular effects.. In a crossover study, 18 patients with CHF participated 4 times [sildenafil (2 × 20 mg)/or placebo (double-blind) while breathing air or 15% oxygen] at rest and during exercise. Oxygen saturation (SaO2) and systemic vascular resistance were recorded. Left and right ventricular (RV) function and transtricuspid systolic pressure gradient (RVTG) were measured echocardiographically. At rest, hypoxia caused SaO2 (P = 0.001) to fall and RVTG to rise (5 ± 4 mm Hg; P = 0.001). Sildenafil reduced SaO2 (-1 ± 2%; P = 0.043), systemic vascular resistance (-87 ± 156 dyn·s·cm; P = 0.034), and RVTG (-2 ± 5 mm Hg; P = 0.05). Exercise caused cardiac output (2.1 ± 1.8 L/min; P < 0.001) and RVTG (19 ± 11 mm Hg; P < 0.0001) to rise. The reduction in RVTG with sildenafil was not attenuated by hypoxia. The rise in RVTG with exercise was not substantially reduced by sildenafil.. Sildenafil reduces SaO2 at rest while breathing air, this was not exacerbated by hypoxia, suggesting increased ventilation-perfusion mismatching due to pulmonary vasodilation in poorly ventilated lung regions. Sildenafil reduces RVTG at rest and prevents increases caused by hypoxia but not by exercise. This study shows the usefulness of this model to evaluate new therapeutics in pulmonary hypertension.

Topics: Chronic Disease; Cross-Over Studies; Double-Blind Method; Echocardiography, Doppler; Exercise; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Male; Middle Aged; Oxygen Consumption; Pulmonary Circulation; Sildenafil Citrate; Vasodilator Agents; Ventricular Function, Left; Ventricular Function, Right

Distal-type chronic thromboembolic pulmonary hypertension (CTEPH) is a fatal disease for which a new therapeutic strategy needs to be developed. We examined the effects of percutaneous transluminal pulmonary angioplasty (PTPA).. We prospectively enrolled 12 patients with distal-type CTEPH. After stabilizing their condition with pulmonary vasodilators, we then performed PTPA, which markedly improved pulmonary hemodynamics and pulmonary artery structure, as confirmed by angiography and optical coherence tomography, and also significantly improved their long-term prognosis compared with 39 historical controls.. PTPA is a promising therapeutic option for distal-type CTEPH.

Topics: Aged; Angioplasty; Antihypertensive Agents; Bosentan; Chronic Disease; Combined Modality Therapy; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Prognosis; Prospective Studies; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

To assess the ocular effects and safety profile of chronic sildenafil oral dosing in patients with pulmonary arterial hypertension.. 12 week, double masked, randomised, placebo controlled, phase III trial with open label extension.. 53 institutions worldwide.. 277 adults with idiopathic pulmonary arterial hypertension or pulmonary arterial hypertension associated with connective tissue disease or after congenital heart disease repair (mean pulmonary artery pressure ≥25 mm Hg; pulmonary capillary wedge pressure ≤15 mm Hg at rest).. During the double masked study, oral sildenafil 20 mg, 40 mg, or 80 mg or placebo (1:1:1:1) three times daily for 12 weeks was added to baseline drug treatment. In the extension study, the placebo, 20 mg and 40 mg groups received 40 mg three times daily titrated to 80 mg three times daily at week 6. After unmasking, the dose was titrated according to clinical need.. Ocular safety (ocular examinations, visual function tests, participants' reports of adverse events, and visual disturbance questionnaire completed by investigators) by treatment group at 12 weeks, 24 weeks, 18 months, and yearly.. Findings of the objective assessments-that is, intraocular pressure and visual function tests (visual acuity, colour vision, and visual field)-were similar across groups (20 mg, n=69; 40 mg, n=67; 80 mg, n=71; placebo, n=70). No clinically significant changes occurred between baseline and 12 weeks, except for an efficacy signal in contrast sensitivity for the sildenafil 40 mg three times daily group. In right eyes, changes in intraocular pressure from baseline to week 12 ranged from a mean of -0.5 (95% confidence interval -1.3 to 0.2) mm Hg with placebo, -0.2 (-0.9 to 0.5) mm Hg with sildenafil 40 mg, and -0.1 (-0.7 to 0.5) mm Hg with 80 mg to 0.3 (-0.4 to 0.9) mm Hg with sildenafil 20 mg (the approved dose for pulmonary arterial hypertension). Mean changes from baseline to week 12 in contrast sensitivity in right eyes were -0.02 (SD 0.12) in the sildenafil 20 mg three times daily group compared with -0.05 (0.18) in the placebo group (P=0.044). Percentages of participants with deterioration in visual acuity (Snellen) from baseline to week 12 ranged from 10% (n=7) in the placebo group to 3% (n=2) in the sildenafil 20 mg three times daily group; the same percentages had visual field changes from normal to abnormal during the period in these two groups. The investigators did not deem any findings on colour vision assessment to be clinically significant. Findings of the objective assessments in the 40 mg and 80 mg three times daily sildenafil treatment groups and in left eyes were not substantially different, nor were any measures different throughout the open label extension compared with week 12. However, objective data were limited after month 18, as most participants had missing data or visual parameters were no longer collected by investigators. Incidence of ocular adverse events reported on the case report forms and assessed by the investigator was low with all doses, but a modest, dose related incidence of chromatopsia, cyanopsia, photophobia, and visual disturbance was reported with 80 mg three times daily consistent with the indicated dosing for erectile dysfunction. Retinal haemorrhages, captured on funduscopy, occurred in 2% (4/207) of sildenafil treated participants and none in the placebo group during the double masked study and in 4% (10/259) during the open label extension.. Sildenafil dosing up to 80 mg three times daily is safe and well tolerated from an ocular perspective in patients with pulmonary arterial hypertension. Daily chronic dosing in this patient population was not associated with visual change and had no detrimental effect on best corrected visual acuity, contrast sensitivity, colour vision, or visual field, or on slit lamp examinations, funduscopy, or intraocular pressure during the duration of this study.. Clinical trials NCT00644605 and NCT00159887.

Topics: Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Eye; Eye Diseases; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Incidence; Intraocular Pressure; Male; Middle Aged; Piperazines; Pulmonary Wedge Pressure; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Surveys and Questionnaires; Time Factors; Treatment Outcome; Vasodilator Agents; Visual Acuity

Nitric oxide (NO) can temporally and spatially match microvascular oxygen (O(2)) delivery (Qo(2mv)) to O(2) uptake (Vo(2)) in the skeletal muscle, a crucial adjustment-to-exercise tolerance that is impaired in chronic heart failure (CHF). To investigate the effects of NO bioavailability induced by sildenafil intake on muscle Qo(2mv)-to-O(2) utilization matching and Vo(2) kinetics, 10 males with CHF (ejection fraction = 27 ± 6%) undertook constant work-rate exercise (70-80% peak). Breath-by-breath Vo(2), fractional O(2)extraction in the vastus lateralis {∼deoxygenated hemoglobin + myoglobin ([deoxy-Hb + Mb]) by near-infrared spectroscopy}, and cardiac output (CO) were evaluated after sildenafil (50 mg) or placebo. Sildenafil increased exercise tolerance compared with placebo by ∼20%, an effect that was related to faster on- and off-exercise Vo(2) kinetics (P < 0.05). Active treatment, however, failed to accelerate CO dynamics (P > 0.05). On-exercise [deoxy-Hb + Mb] kinetics were slowed by sildenafil (∼25%), and a subsequent response "overshoot" (n = 8) was significantly lessened or even abolished. In contrast, [deoxy-Hb + Mb] recovery was faster with sildenafil (∼15%). Improvements in muscle oxygenation with sildenafil were related to faster on-exercise Vo(2) kinetics, blunted oscillations in ventilation (n = 9), and greater exercise capacity (P < 0.05). Sildenafil intake enhanced intramuscular Qo(2mv)-to-Vo(2) matching with beneficial effects on Vo(2) kinetics and exercise tolerance in CHF. The lack of effect on CO suggests that improvement in blood flow to and within skeletal muscles underlies these effects.

Topics: Aged; Cardiac Output; Chronic Disease; Cyclic Nucleotide Phosphodiesterases, Type 5; Exercise; Exercise Tolerance; Heart Failure; Humans; Male; Microcirculation; Middle Aged; Muscle, Skeletal; Nitric Oxide; Oxygen; Oxygen Consumption; Piperazines; Prospective Studies; Purines; Regional Blood Flow; Signal Transduction; Sildenafil Citrate; Sulfones; Vasodilator Agents

Relative area change (RAC) of the proximal pulmonary artery is a measurement of pulmonary artery distensibility and has been shown to correlate with vasoreactivity studies in patients with idiopathic pulmonary arterial hypertension. We have previously noted a relationship between invasive hemodynamic vasoreactivity testing and long-term response to sildenafil in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). We therefore set out to determine whether RAC can provide useful correlatory non-invasive data.. Patients recruited to a randomized, controlled trial (RCT) of sildenafil at 40 mg 3 times daily underwent additional magnetic resonance imaging (MRI) at the baseline of the trial. Eighteen patients had an MRI that led to a diagnosis of inoperable distal CTEPH or significant residual CTEPH post-operatively. The primary end-point was improvement in 6-minute walk test (6MWT) with secondary end-points of right heart catheterization-based hemodynamics, N-terminal pro-brain natriuretic peptide (NT pro-BNP) and functional class. RAC assessed by MRI was correlated with trial end-points.. Fourteen subjects with baseline MRI completed the protocol. RAC was the only baseline variable that correlated at 1 year to the primary end-point of improvement in 6MWT (r = 0.7, p = 0.006), and also to a change in NT pro-BNP (r = 0.59, p = 0.03). Using a cut-off of RAC over 20% there was an 87.5% sensitivity (95% confidence interval [CI]: 45% to 100%) and a 66.7% specificity (95% CI: 22% to 96%) for an improvement in 6MWT of >40 meters.. RAC correlates with functional response to sildenafil, as measured by the 6MWT, and improved heart function, as measured by NT pro-BNP. RAC shows potential in understanding and possibly predicting treatment response.

Topics: Adult; Aged; Cardiac Catheterization; Chronic Disease; Female; Heart; Hemodynamics; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Piperazines; Pulmonary Artery; Purines; Recovery of Function; Sensitivity and Specificity; Sildenafil Citrate; Single-Blind Method; Sulfones; Thromboembolism; Time Factors; Treatment Outcome; Vasodilator Agents; Walking

Post-traumatic Stress Disorder (PTSD) symptoms cause dysfunction in broad areas of patients' lives and those of their families. Sexual dysfunction (SD) is common in these patients and aggravates their distress, affecting overall sexual activity, desire, arousal, orgasm, activity and satisfaction. PTSD clinic patients are frequently referred for consultation and treatment in the SD clinic. This prospective naturalistic follow-up study of a random group of patients was intended to evaluate response to pharmacologic and psychotherapeutic interventions for SD, in terms of both sexual functioning and overall symptomatology.. Ten patients fulfilling DSM-IV diagnostic criteria for PTSD (one woman and nine men) were recruited. Treatment for the sexual symptoms was tailored individually and was administered in addition to the continuing (stable) treatment in the PTSD clinic.. After two months of treatment for the sexual symptoms, statistically significant improvements in all domains of sexual functioning were observed. In parallel, statistically significant improvements in all domains of the Impact of Events Scale scores were observed, both on the avoidance and intrusive subscales. There were no significant differences in response to treatment in terms of time elapsed since the onset of PTSD, or the pattern or severity of sexual and PTSD symptoms.. The results of this modest study demonstrate the importance of relating to the SD of PTSD patients irrespective of the duration or severity of their disorder. In this mixed group of PTSD patients with varied duration of symptoms, both SD and PTSD core symptoms improved significantly in response to individually tailored adjunctive treatment of the SD.

Topics: Adult; Chronic Disease; Combined Modality Therapy; Complementary Therapies; Female; Humans; Male; Middle Aged; Piperazines; Prospective Studies; Psychotherapy; Purines; Sexual Dysfunction, Physiological; Sildenafil Citrate; Stress Disorders, Post-Traumatic; Sulfones; Surveys and Questionnaires; Vasodilator Agents

The effects of chronic inhibition of 5'-phosphodiesterase with sildenafil on functional capacity, ventilatory efficiency, oxygen uptake, pulmonary hypertension, and endothelial function in chronic heart failure (CHF) are unknown.. We conducted a randomized, double-blind, placebo-controlled trial to assess the acute (1 hour after 50 mg by mouth) and chronic (4 weeks after 50 mg 3 times per day by mouth) effects of sildenafil in outpatients with CHF. The outcomes were cardiopulmonary exercise test parameters (chronic effect), echocardiographic-derived pulmonary artery systolic pressure, and plethysmography-derived forearm blood flow (acute and chronic effects).. Nineteen patients with CHF (48 +/- 12 years) with an ejection fraction of 28% +/- 6% were studied. Patients who received sildenafil (n = 11) showed improved maximal oxygen uptake, ventilatory efficiency, and oxygen uptake kinetics. Sildenafil decreased pulmonary artery systolic pressure levels at 60 minutes and at 4 weeks compared with changes after placebo (P = .004 for group and time interaction). Improvement in ventilatory efficiency was positively associated with reductions in pulmonary artery systolic pressure. Patients allocated to placebo demonstrated a trend toward decreased forearm blood flow after reactive hyperemia, whereas this remained unchanged in patients allocated to sildenafil.. Sildenafil administration for 4 weeks in stable outpatients with CHF improves functional capacity, ventilatory efficiency, oxygen uptake kinetics, and pulmonary hypertension. These effects may be mediated in part by improvements in endothelial function.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Exercise Test; Female; Follow-Up Studies; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Multivariate Analysis; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Plethysmography; Probability; Purines; Reference Values; Risk Assessment; Severity of Illness Index; Sildenafil Citrate; Sulfones; Survival Rate; Time Factors; Treatment Outcome

Although surgery is the treatment of choice for CTEPH, it is not appropriate for patients with surgically inaccessible distal disease. These patients are traditionally managed supportively, but may benefit from newer, more specific vasoactive therapies. This study examines the acute haemodynamic responses to inhaled nitric oxide (iNO) and intravenous sildenafil in this patient population.. Nine patients with de novo distal CTEPH and nine with persistent pulmonary hypertension post-pulmonary endarterectomy (PEA) were enrolled. At right heart catheterisation, following baseline haemodynamic measurements, iNO was administered at 20 ppm for 10 min. Following repeat measurements, iNO was discontinued with a subsequent washout period of 10 min. Sildenafil was then administered intravenously at two doses, to achieve plasma levels equivalent to 25 mg and 50 mg orally, with further measurements obtained at the end of each infusion.. Significant reductions in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) were demonstrated following both iNO (-4.3 mm Hg or -10.3% p=0.001 and -101 dyn/s/cm(5) or -15.6% p<0.001) and sildenafil (-7.4 mm Hg or -16.9% p<0.001 and -188.8 dyn/s/cm(5) or -25.1% p<0.001). Individual mPAP and cardiac output (CO) responses to iNO and sildenafil correlated well, but haemodynamic changes following sildenafil were consistently more marked. There was, however, no difference in effect between the two doses of sildenafil. Although sildenafil caused significant reductions in systemic vascular resistance, the net haemodynamic effect of sildenafil remained pulmonary selective. Subgroup analysis suggested that post-PEA patients were more responsive to both iNO and sildenafil than de novo patients.. Although all but one patient failed to fulfil the formal haemodynamic response criteria typically used in idiopathic pulmonary arterial hypertension (IPAH), subjects displayed significant acute responses to both iNO and sildenafil suggesting that increased vascular tone forms an important component of distal CTEPH. It is possible that these acute haemodynamic responses may translate to improved clinical outcomes, and thus further long term trials of sildenafil in distal CTEPH are warranted.

Topics: Administration, Inhalation; Adult; Antihypertensive Agents; Blood Pressure; Cardiac Output; Chronic Disease; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Injections, Intravenous; Male; Middle Aged; Nitric Oxide; Piperazines; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Thromboembolism; Treatment Outcome; Vascular Resistance; Vasodilation; Vasodilator Agents

This study sought to test the functional exercise capacity and endothelial function in a cohort of chronic heart failure (CHF) patients treated with chronic type 5 phosphodiesterase (PDE5) inhibitor.. In CHF, endothelial dysfunction is involved in muscle underperfusion, ergoreflex oversignaling, and exercise ventilation inefficiency. Inhibition of PDE5 by improving endothelial dysfunction might be beneficial.. Stable CHF patients were randomly assigned to placebo (23 patients) or sildenafil at the dose of 50 mg twice per day (23 patients) in addition to their current drug treatment for 6 months, with assessments (at 3 and 6 months) of endothelial function by brachial artery flow-mediated dilatation (FMD), cardiopulmonary exercise testing, and ergoreflex response.. In the sildenafil group only, at 3 and 6 months we observed reduction of systolic pulmonary artery pressure (from 33.7 to 25.2 mm Hg and 23.9 mm Hg), ergoreflex effect on ventilation (from 6.9 to 2.3 l x min(-1) and 1.9 l x min(-1)), ventilation to CO2 production slope (V(E)/VCO2, from 35.5 to 32.1 and 29.8), and breathlessness (score) (from 23.6 to 16.6 and 17.2), and an increase of FMD (from 8.5% to 13.4% and 14.2%), peak VO2 (from 14.8 to 18.5 ml x min(-1) x kg(-1) and 18.7 ml x min(-1) x kg(-1)), and ratio of VO2 to work rate changes (from 7.7 to 9.3 and 10.1). All changes were significant at p < 0.01. In the sildenafil group, a significant correlation was found at 3 and 6 months between changes in FMD and those in ergoreflex. Changes in ergoreflex correlated with those in peak VO2 and V(E)/VCO2 slope. No adverse effects were noted except for flushing in 3 patients.. In CHF, improvement in exercise ventilation and aerobic efficiency with sildenafil is sustained and is significantly related with an endothelium-mediated attenuation of exercising muscle oversignaling. Chronic sildenafil seems to be a remedy based on CHF pathophysiology and devoid of remarkable adverse effects.

Topics: Aged; Brachial Artery; Chronic Disease; Endothelium, Vascular; Exercise Test; Heart Failure; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Regional Blood Flow; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilation

Sildenafil is a selective Phosphodiesterase-5 inhibitor that has been reported to be a potent pulmonary vasodilator. We evaluated the safety, efficacy and pharmacokinetics of oral Sildenafil in a case series of children with pulmonary hypertension.. Three children, 1 with primary pulmonary hypertension (patient 1) and 2 with pulmonary hypertension associated with congenital heart disease (patients 2 and 3) were enrolled. Sildenafil was started at 0.5 mg/kg 4-hourly and the dose increased to 1.0 and then to 2.0 mg/kg/dose. Patients were assessed at baseline and then monthly for a total of 6 visits.. All patients reported increased exercise capacity with improvement in New York Heart Association functional class. The distance walked during the 6-min test increased by 74% (patient 1), 75% (patient 2) and 25% (patient 3) and oxyhaemoglobin saturations increased from 79%, 97% and 80% to 93%, 100% and 93%, respectively. There were no side effects and no fall in systemic blood pressure. Sildenafil plasma levels 1 h after a 0.5, 1.0 and 2 mg/kg dose of Sildenafil were 109+/-87, 150+/-62 and 368+/-200 ng/ml, respectively. They fell to 211+/-106 ng/ml 3 h after the 2.0 mg/kg dose.. Medium term Sildenafil therapy improves oxyhaemoglobin saturations and exercise tolerance in children with pulmonary hypertension without any side effects. Mean plasma levels 1 h after doses of 0.5-2.0 mg/kg are similar to the maximum plasma concentrations reported in adults receiving doses within the therapeutic range. Sildenafil use in children appears to be safe and may be beneficial in the management of pulmonary arterial hypertension.

Topics: Administration, Oral; Adolescent; Child; Chronic Disease; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Safety; Sildenafil Citrate; Sulfones

Topical therapies for anal fissure have largely focused on nitric-oxide donors (e.g., nitroglycerin), sometimes with undesirable side effects or inconsistent benefits. Topical phosphodiesterase inhibitors have theoretical merit but have never been reported in treatment of anal fissure. This article describes manometric analysis of the effects of a phosphodiesterase-5 inhibitor, topical sildenafil (Viagra) in 19 consecutive patients with chronic anal fissure with no previous treatment history.. Station pullthrough manometry was performed with patients in the left-lateral position. Maximum resting pressure (MRP1) was recorded, and 0.75 ml of 10 percent sildenafil was then instilled in the anal canal. Maximum resting pressure was repeated at the same distance from the anal verge. Thereafter, pressure was measured continuously. Time for initial relaxation (T1) and time to maximal relaxation (T2) were recorded. Average resting pressure (MRP2) was calculated. Results were analyzed by Student's t-test.. Topical administration of 10 percent sildenafil was accompanied by significant reduction in anal sphincter pressure (18 percent; P < 0.01). Only one patient failed to respond. Average onset of action was less than three minutes, with maximum effect one minute later. MRP1: 119.3 +/- 18.7 cmH(2)O. MRP2: 97.8 +/- 21.3 cmH(2)O. MRP2 < MRP1, P < 0.01. MRP M vs. F, ns. T1: 168 +/- 67 seconds (M = 210 +/- 72, F = 130 +/- 53, P < 0.02). T2: 230 +/- 78 seconds (M = 271 +/- 63, F = 183 +/- 75, P < 0.02). Mild-to-moderate anal discomfort was reported by 26 percent of patients. No headaches or other side effects were reported.. Topical administration of a phosphodiesterase-5 inhibitor (sildenafil, Viagra) significantly reduces anal sphincter pressure in patients with chronic anal fissure. A beneficial effect of nitric oxide on the spastic anal sphincter has been demonstrated previously. This study confirms that this effect need not be derived solely from nitric oxide donors. New therapeutic avenues for treatment of anal fissure through indirect enhancement of nitric oxide activity are suggested.

Topics: Administration, Topical; Adult; Aged; Anal Canal; Chronic Disease; Female; Fissure in Ano; Humans; Male; Manometry; Middle Aged; Muscle Hypertonia; Phosphodiesterase Inhibitors; Piperazines; Purines; Rest; Sildenafil Citrate; Sulfones

We sought to investigate the effects of sildenafil, a phosphodiesterase-5 (PDE(5)) inhibitor, on lung function and exercise performance in chronic heart failure (CHF).. In CHF, nitric oxide-mediated regulation of lung vascular tone and alveolar-capillary membrane conductance is impaired and contributes to exercise intolerance. The potential for benefits due to increased nitric-oxide availability is unexplored.. In 16 patients with CHF and 8 normal subjects, we measured-before and 60 min after sildenafil (50 mg) or placebo-ejection fraction, pulmonary hemodynamics, carbon monoxide diffusion capacity (DLco), with its membrane (D(M)) and capillary blood volume (V(c)) subcomponents, endothelial function (brachial reactive hyperemia) at rest, peak oxygen uptake (VO(2)), increments in VO(2) versus work rate (DeltaVO(2)/DeltaWR), changes in ventilation versus CO(2) production (VE/VCO(2)) slope, and recovery VO(2) time constant (tau) on exertion.. In CHF, sildenafil did not affect cardiac index, wedge pulmonary pressure, or ejection fraction; it significantly (p < 0.01) decreased pulmonary mean artery pressure (-20.4%) and arteriolar resistance (-45.1%), VE/VCO(2) slope (-9.0%) and recovery tau (-25.8%), and increased (p < 0.01) DLco (+11.1%), D(M) (+9.9%) peak VO(2) (+19.7%), DeltaVO(2)/DeltaWR (+11.0%), and brachial reactive hyperemia (+33.3%). No variations occurred in normal subjects and after placebo. Changes in DLco were related to those in VE/VCO(2) slope (r = -0.71; p = 0.002), and changes in brachial hyperemia correlated with those in DeltaVO(2)/DeltaWR (r = 0.80; p = 0.0002).. This study shows that in CHF PDE(5) inhibition modulates pulmonary pressure and vascular tone, and improves DLco, exercise peak VO(2), aerobic (DeltaVO(2)/DeltaWR) and ventilatory (VE/VCO(2) slope) efficiencies, and oxygen debt (recovery tau). Endothelial mechanisms may underlie these effects.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Cardiac Output, Low; Chronic Disease; Cyclic Nucleotide Phosphodiesterases, Type 5; Exercise; Exercise Tolerance; Female; Hemodynamics; Humans; Kinetics; Male; Middle Aged; Oxygen Consumption; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Pulmonary Circulation; Pulmonary Diffusing Capacity; Purines; Respiration; Sildenafil Citrate; Sulfones

The aim of this study was to evaluate whether sildenafil, used for treatment of erectile dysfunction (ED), affects the exercise tolerance and ischaemic threshold in men with exercise-induced angina not taking nitrates.. This was a double-blind placebo-controlled study in men with ED and chronic stable angina, assessing the effect of sildenafil on time to limiting angina during incremental treadmill exercise. Patients remained on their antianginal therapy and received a 100-mg dose of sildenafil or placebo 1h prior to treadmill exercise. Other measurements included times to onset of angina, 1-mm ST-segment depression, and total exercise time.. Adjusted treatment differences for the time to limiting angina, time to onset of angina, total exercise time, and time to 1-mm ST-segment depression were (mean+/-SE) 20+/-10s (95% CI, 1-39; P=0.040), 32+/-11s (95% CI, 11-53; P=0.004), 20+/-10s (95% CI, 0-39; P=0.049), and 12+/-17s (95% CI, -21 to 45, P=0.48), respectively, in favour of sildenafil. There were no serious treatment-related adverse events.. Sildenafil was well tolerated and did not adversely affect any exercise parameter in men with coronary artery disease and ED. Favourable trends in total exercise duration and times to onset of angina and limiting angina were recorded with sildenafil use.

Topics: Adolescent; Adult; Aged; Angina Pectoris; Chronic Disease; Double-Blind Method; Erectile Dysfunction; Exercise Test; Exercise Tolerance; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

To assess the acute effects of sildenafil citrate (VIAGRA) on the intraocular pressure (IOP) of patients with chronic open-angle glaucoma.. This was a double-blind, randomized, placebo-controlled, crossover study, in which 15 patients received a single oral dose of sildenafil 100 mg or matching placebo on two separate occasions.. Fifteen subjects aged 63 +/- 14 years (mean +/- SD) with bilateral chronic open-angle glaucoma were administered a single oral dose of sildenafil 100 mg or matching placebo on two separate occasions at least 3 days apart. IOP was measured in both eyes by Goldmann ap-planation tonometry at baseline and then at 1-5 hours after dosing. Brachial artery systolic and diastolic blood pressures were determined by sphygmomanometry, and heart rate was also monitored at baseline and 1-5 hours after dosing.. Compared with placebo, no statistically or clinically significant change in IOP was detected after a single dose of sildenafil 100 mg (P =.20). Moreover, no significant change in mean systemic blood pressure (P =.12) or heart rate (P =.72) was detected after treatment with sildenafil.. At the maximum therapeutic dose of 100 mg, sildenafil did not produce any significant acute change in IOP in men with chronic open-angle glaucoma. This information is of importance for patients with glaucoma receiving sildenafil for treatment of erectile dysfunction.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Blood Pressure; Chronic Disease; Cross-Over Studies; Double-Blind Method; Erectile Dysfunction; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tonometry, Ocular

It has been suggested that phosphodiesterase 5 (PDE5) inhibition is potentially hazardous and that it increases the risk of cardiac events in patients with coronary artery disease. This study sought to evaluate whether PDE5 inhibition with sildenafil exerts any effect on exercise-induced myocardial ischemia in patients on beta-blockers.. Fourteen patients underwent a baseline exercise test off-therapy and were then started on atenolol (100 mg once daily). After a run-in phase of 1 week, patients underwent a second exercise test and were randomized to receive either sildenafil (50 mg) or placebo given in a random order on two different occasions, 2 days apart. Exercise test was repeated 2 hours after the administration of sildenafil or placebo.. All patients had a > 1 mm ST-segment depression while off-therapy. Eight patients had a negative exercise test response after atenolol, which was unaltered by the adjunct of either sildenafil or placebo. In the remaining subjects, atenolol significantly prolonged the time to 1 mm ST-segment depression and the exercise time. Sildenafil and placebo did not reverse the beneficial effect of atenolol upon exercise-induced myocardial ischemia.. PDE5 inhibition does not worsen exercise capacity and exercise-induced myocardial ischemia in patients with chronic stable angina whose symptoms and exercise test response are well controlled by beta-blocker therapy.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Angina Pectoris; Atenolol; Blood Pressure; Chronic Disease; Contraindications; Drug Interactions; Exercise Test; Heart Rate; Humans; Male; Middle Aged; Myocardial Ischemia; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

To determine the acute effects of type 5 phosphodiesterase inhibition with sildenafil on flow-mediated vasodilation in the brachial artery of patients with chronic heart failure.. Impaired endothelium-dependent, flow-mediated vasodilation in patients with heart failure is partly attributable to hyporesponsiveness of cyclic guanosine monophosphate (cGMP) mediated vasorelaxation effector mechanisms in vascular smooth muscle. The effect of inhibition of cGMP degradation with sildenafil, a specific type 5 cGMP phosphodiesterase inhibitor, on flow-mediated dilation in heart failure is unknown.. Flow-mediated vasodilation after release of 1, 3 and 5 min of transient arterial occlusion was measured in the brachial artery with high resolution two-dimensional ultrasound imaging in 48 patients with chronic heart failure before and 1 h after randomized, double-blind assignment to a single oral dose of sildenafil 12.5, 25 or 50 mg or matching placebo.. In response to oral administration of a single dose of study drug, the change in flow-mediated vasodilation after release of 1, 3 and 5 min of arterial occlusion was significantly greater in patients receiving sildenafil 25 mg (3.3 +/- 1.9, 3.8 +/- 1.8 and 4.0 +/- 1.8%, respectively, p < 0.05) and patients receiving sildenafil 50 mg (3.7 +/- 1.3, 4.1 +/- 1.1, 3.9 +/- 1.3%, respectively, p < 0.05) than that of patients receiving placebo (0.7 +/- 1.1, 0.2 +/- 1.2, 0.6 +/- 0.8%, respectively).. Acute type 5 phosphodiesterase inhibition with sildenafil 25 and 50 mg increases endothelium-dependent, flow-mediated vasodilation in patients with chronic heart failure when compared with placebo.

Topics: Blood Circulation; Blood Flow Velocity; Cardiac Output, Low; Chronic Disease; Double-Blind Method; Female; Humans; Isoenzymes; Male; Middle Aged; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Reference Values; Sildenafil Citrate; Sulfones; Vasodilation

Topics: Adult; Central Serous Chorioretinopathy; Chronic Disease; Fluorescein Angiography; Follow-Up Studies; Fundus Oculi; Humans; Male; Phosphodiesterase 5 Inhibitors; Prospective Studies; Retinal Pigment Epithelium; Sildenafil Citrate; Tomography, Optical Coherence

Research comparing bosentan and macitentan in chronic thromboembolic pulmonary hypertension (CTEPH) is scarce, although macitentan might have superior pharmacologic properties. We present the first real-world, 2-year follow-up results and compare clinical outcomes of both drugs in CTEPH.. All consecutive, technical inoperable or residual CTEPH patients receiving bosentan or macitentan, diagnosed in our multidisciplinary team between January 2003 and January 2019, were included. We report and compare survival, clinical worsening (CW), adverse events, WHO FC, NT-proBNP and 6-min walking test (6MWT) until 2 years after medication initiation.. In total, 112 patients receiving bosentan or macitentan (58% female, mean age 62 ± 14 years, 68% WHO FC III/IV, 51% bosentan) could be included. Mean treatment duration was 1.9 ± 0.4 years for bosentan and 1.2 ± 0.6 years for macitentan. Two-year survival rate was 91% for bosentan and 80% for macitentan (HR mortality macitentan 1.85 [0.56-6.10], p = 0.31). Two-year CW-free survival was 81% and 58%, respectively (HR CW macitentan 2.16 [0.962-4.87], p = 0.06). Right atrial pressure, cardiac output (for mortality alone) and 6MWT lowest saturation were multivariate predictors at baseline. Overall adverse event rates were comparable and WHO FC, NT-proBNP and 6MWT distance improved similar for both drugs till 2-year follow-up.. CTEPH patients receiving bosentan or macitentan have improved clinical outcomes till 2-year follow-up, without significant differences in outcomes between both therapies.

Topics: Aged; Bosentan; Chronic Disease; Drug Therapy, Combination; Endarterectomy; Endothelin Receptor Antagonists; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Pulmonary Embolism; Pyrazoles; Pyrimidines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Survival Rate; Walk Test

A proportion of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) do not achieve treatment goals or experience side effects on their current therapy. In such cases, switching patients to a new drug while discontinuing the first may be a viable and appropriate treatment option. CAPTURE was designed to investigate how physicians manage the switching of patients to riociguat in real-world clinical practice. Observations from the study were used to assess whether recommendations in the riociguat prescribing information are reflected in clinical practice.. CAPTURE was an international, multicenter, uncontrolled, retrospective chart review that collected data from patients with PAH or inoperable or persistent/recurrent CTEPH who switched to riociguat from another pulmonary hypertension (PH)-targeted medical therapy. The primary objective of the study was to understand the procedure undertaken in real-world clinical practice for patients switching to riociguat.. Of 127 patients screened, 125 were enrolled in CAPTURE. The majority of patients switched from a phosphodiesterase type 5 inhibitor (PDE5i) to riociguat and the most common reason for switching was lack of efficacy. Physicians were already using the recommended treatment-free period when switching patients to riociguat from sildenafil, but a slightly longer period than recommended for tadalafil. In line with the contraindication, the majority of patients did not receive riociguat and PDE5i therapy concomitantly. Physicians also followed the recommended dose-adjustment procedure for riociguat.. Switching to riociguat from another PH-targeted therapy may be feasible in real-world clinical practice in the context of the current recommendations.

Topics: Aged; Aged, 80 and over; Chronic Disease; Drug Substitution; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pulmonary Embolism; Pyrazoles; Pyrimidines; Retrospective Studies; Sildenafil Citrate; Tadalafil

This study evaluated the incremental effect of riociguat on pulmonary hemodynamics in patients with inoperative or persistent chronic thromboembolic pulmonary hypertension (CTEPH) treated previously with sildenafil.. The retrospective study included 28 patients diagnosed with CTEPH who were ineligible for surgical treatment due to distal thrombi location or who suffered from persistent CTEPH after pulmonary endarterectomy and who were treated with sildenafil at a dose of 25 mg TID for a minimum of 3 months. Sildenafil was subsequently discontinued, and riociguat therapy was started with gradually increasing doses. Right heart catheterization was performed and WHO functional class (FC) was assessed in each patient at three time points: before starting sildenafil therapy (baseline), before the transition to riociguat, and after 3 to 6 months of therapy with riociguat.. Compared to baseline, the use of sildenafil and riociguat significantly decreased pulmonary vascular resistance (PVR) (10.47 ± 3.56 vs. 7.81 ± 3.58 Wood units, p < 0.001) and mean pulmonary arterial pressure (PAP) (54.1 ± 11.6 vs. 46.1 ± 13.2 mm Hg; p < 0.001) while increasing cardiac output (CO) (4.31 ± 0.88 vs. 4.85 ± 0.87 L/min; p = 0.007). Switching from sildenafil to riociguat reduced PVR by 14% (p = 0.005) and the mean PAP by 6% (p = 0.03) while increasing CO by 11% (p = 0,002). The number of patients with WHO FC III and IV symptoms decreased from 71,4% to 57,1% (p = 0,02) after the change from sildenafil to riociguat.. Replacing sildenafil with riociguat in patients with inoperable or persistent CTEPH may improve pulmonary hemodynamics and FC.

Topics: Aged; Aged, 80 and over; Chronic Disease; Drug Substitution; Enzyme Activators; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyrimidines; Retrospective Studies; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Topics: Adult; Age Distribution; Aged; Anticoagulants; Bosentan; Chronic Disease; Female; Humans; Hypertension, Pulmonary; Incidence; Latvia; Male; Middle Aged; Phenylpropionates; Prevalence; Pulmonary Embolism; Pyrazoles; Pyridazines; Pyridones; Registries; Rivaroxaban; Sex Distribution; Sildenafil Citrate; Sulfonamides; Vasodilator Agents; Warfarin; Young Adult

Persistent pulmonary hypertension of the newborn (PPHN) is the most common neonatal form and mostly reversible after a few days with improvement of the underlying pulmonary condition. When pulmonary hypertension (PH) persists despite adequate treatment, the severity of parenchymal lung disease should be assessed by chest CT. Pulmonary vein stenosis may need to be ruled out by cardiac catheterisation and lung biopsy, and genetic workup is necessary when alveolar capillary dysplasia is suspected. In PPHN, optimisation of the cardiopulmonary situation including surfactant therapy should aim for preductal SpO2between 91% and 95% and severe cases without post-tricuspid-unrestrictive shunt may receive prostaglandin E1 to maintain ductal patency in right heart failure. Inhaled nitric oxide is indicated in mechanically ventilated infants to reduce the need for extracorporal membrane oxygenation (ECMO), and sildenafil can be considered when this therapy is not available. ECMO may be indicated according to the ELSO guidelines. In older preterm infant, where PH is mainly associated with bronchopulmonary dysplasia (BPD) or in term infants with developmental lung anomalies such as congenital diaphragmatic hernia or cardiac anomalies, left ventricular diastolic dysfunction/left atrial hypertension or pulmonary vein stenosis, can add to the complexity of the disease. Here, oral or intravenous sildenafil should be considered for PH treatment in BPD, the latter for critically ill patients. Furthermore, prostanoids, mineralcorticoid receptor antagonists, and diuretics can be beneficial. Infants with proven or suspected PH should receive close follow-up, including preductal/postductal SpO2measurements, echocardiography and laboratory work-up including NT-proBNP, guided by clinical improvement or lack thereof.

Topics: Acute Disease; Administration, Inhalation; Bronchopulmonary Dysplasia; Cardiac Catheterization; Chronic Disease; Consensus; Constriction, Pathologic; Endothelium-Dependent Relaxing Factors; Extracorporeal Membrane Oxygenation; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Lung Diseases; Nitric Oxide; Persistent Fetal Circulation Syndrome; Phosphodiesterase 5 Inhibitors; Pulmonary Veins; Sildenafil Citrate; Tomography, X-Ray Computed

Symptoms in patients with chronic thromboembolic pulmonary hypertension (CTEPH) predominantly occur during exercise, while haemodynamic assessment is generally performed at rest. We hypothesised that exercise imaging of RV function would better explain exercise limitation and the acute effects of pulmonary vasodilator administration than resting measurements.. Fourteen patients with CTEPH and seven healthy control subjects underwent cardiopulmonary testing to determine peak exercise oxygen consumption (VO2peak) and ventilatory equivalent for carbon dioxide (VE/VCO2) at the anaerobic threshold. Subsequently, cardiac MRI was performed at rest and during supine bicycle exercise with simultaneous invasive measurement of mean pulmonary arterial pressure (mPAP) before and after sildenafil.. During exercise, patients with CTEPH had a greater increase in the ratio of mPAP relative to cardiac output (CO) than controls (6.7 (5.1-8.7) vs 0.94 (0.86-1.8) mm Hg/L/min; p < 0.001). Stroke volume index (SVi) and RVEF increased during exercise in controls, but not in patients with CTEPH (interaction p < 0.001). Sildenafil decreased the mPAP/CO slope and increased SVi and RVEF in patients with CTEPH (p < 0.05) but not in controls. In patients with CTEPH, RVEF reserve correlated moderately with VO2peak (r = 0.60; p = 0.030) and VE/VCO2 (r = -0.67; p = 0.012). By contrast, neither VO2peak nor VE/VCO2 correlated with resting RVEF.. Exercise measures of RV function explain much of the variance in the exercise capacity of patients with CTEPH while resting measures do not. Sildenafil increases SVi during exercise in patients with CTEPH, but not in healthy subjects.

Topics: Chronic Disease; Exercise; Exercise Test; Female; Heart Ventricles; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Oxygen Consumption; Piperazines; Pulmonary Embolism; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Vasodilator Agents; Ventricular Function, Right

Patients with normalized mean pulmonary artery pressure (mPAP) after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) do not always regain normal exercise capacity. We evaluated right ventricular function, its interaction with both pulsatile and resistive afterload, and the effect of sildenafil during exercise in these patients.. Fourteen healthy controls, 15 CTEPH patients, and 7 patients with normalized resting mPAP (≤25 mm Hg) post-PEA underwent cardiopulmonary exercise testing, followed by cardiac magnetic resonance imaging with simultaneous invasive mPAP measurement during incremental supine cycling exercise. Peak oxygen consumption and peak heart rate were significantly reduced in post-PEA and CTEPH patients compared to controls. The mPAP-cardiac output slope was steeper in post-PEA patients than in controls and similar to CTEPH. Relative to controls, resting right ventricular ejection fraction was reduced in CTEPH, but not in post-PEA patients. In contrast, peak exercise right ventricular ejection fraction was reduced both in post-PEA and CTEPH patients. Exercise led to reduction of pulmonary arterial compliance in all groups. Nevertheless, resting pulmonary arterial compliance values in CTEPH and post-PEA patients were even lower than those in controls at peak exercise. In post-PEA patients, sildenafil did not affect resting hemodynamics nor right ventricular function, but decreased the mPAP/cardiac output slope and increased peak exercise right ventricular ejection fraction.. Exercise intolerance in post-PEA patients is explained by abnormal pulmonary vascular reserve and chronotropic incompetence. The mPAP/cardiac output slope and pulmonary arterial compliance are sensitive measures demonstrating abnormal resistive and pulsatile pulmonary vascular function in post-PEA patients. These abnormalities are partially attenuated with sildenafil.

Topics: Adult; Aged; Arterial Pressure; Bicycling; Case-Control Studies; Catheterization, Swan-Ganz; Chronic Disease; Compliance; Endarterectomy; Exercise Test; Exercise Tolerance; Female; Heart Rate; Hemodynamics; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging; Male; Middle Aged; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Predictive Value of Tests; Pulmonary Artery; Pulmonary Embolism; Recovery of Function; Risk Factors; Sildenafil Citrate; Stroke Volume; Treatment Outcome; Ventricular Function, Right; Young Adult

Inhaled nitric oxide (NO) and other cGMP- or cAMP-dependent pulmonary vasodilators are often used in combination for the treatment of the persistent pulmonary hypertension of the newborn syndrome. There is in vitro evidence to indicate that NO downregulate the pulmonary vascular response to cGMP-dependent agonists raising concern as to whether a synergistic effect is observed when employing a combined strategy in newborns. Hypothesizing that a synergistic effect is absent, we evaluated newborn and juvenile rat pulmonary arteries to determine the individual and combined vasodilatory effect of cGMP- and cAMP-dependent agonists. In precontracted near-resistance pulmonary arteries, the addition of sildenafil reduced vasorelaxation response to NO donor S-nitroso-N-acetyl penicillamine (SNAP). A similar decrease in SNAP-induced vasodilation was observed in arteries pretreated with BAY 41-2272 (10(-9) M), a soluble guanylate cyclase stimulator cGMP, and its downstream protein kinase activator. cGMP also reduced the vasorelaxant response to the cAMP-dependent forskolin. Inhibition of endogenous vascular NO generation enhanced SNAP-induced relaxation. The present data suggest that the mechanism involved in the cGMP desensitization to other relaxant agonists involves downregulation of the small heat shock protein HSP20 and is evident in rat pulmonary and systemic vascular smooth muscle cells. In newborn rats with chronic hypoxia-induced pulmonary hypertension, the combination of sildenafil and inhaled NO resulted in a lesser reduction in pulmonary vascular resistance compared with their individual effect. These data suggest that clinical exposure to one cGMP-dependent pulmonary vasodilator may affect the response to other cGMP- or cAMP-mediated agonists.

Topics: Animals; Animals, Newborn; Chronic Disease; Cyclic GMP; Female; HSP20 Heat-Shock Proteins; HSP27 Heat-Shock Proteins; Hypoxia; Male; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Donors; Phosphorylation; Piperazines; Primary Cell Culture; Protein Kinase Inhibitors; Pulmonary Circulation; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

We aimed to study whether pulmonary arterial distensibility (PAD) correlates with hemodynamic parameters in chronic thromboembolic pulmonary hypertension (CTEPH) using electrocardiogram (ECG)-gated 320-slice multidetector computed tomography (MDCT).. ECG-gated 320-slice MDCT and right heart catheterization (RHC) was performed in 53 subjects (60.6±11.4 years old; 37 females) with CTEPH. We retrospectively measured the minimum and maximum values of the cross sectional area (CSA) of the main pulmonary artery (mainPA), right pulmonary artery (rtPA), and left pulmonary artery (ltPA) during one heartbeat. PAD was calculated using the following formula: PAD = [(CSAmaximum-CSAminimum)/CSAmaximum]×100(%). The correlation between hemodynamic parameters and PAD was assessed. Mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were 40.8±8.7 mmHg and 8.3±3.0 wood units, respectively. PAD values were as follows: mainPA (14.0±5.0%), rtPA (12.8±5.6%), and ltPA (9.7±4.6%). Good correlations existed between mainPAD, with mPAP (r = -0.594, p<0.001) and PVR (r = -0.659, p<0.001). The correlation coefficients between rtPAD and ltPAD with pulmonary hemodynamics were all lower or equal than for mainPAD.. PAD measured using ECG-gated 320-slice MDCT correlates with pulmonary hemodynamics in subjects with CTEPH. The mainPA is suitable for PAD measurement.

Topics: Aged; Chronic Disease; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Multidetector Computed Tomography; Oxygen Inhalation Therapy; Piperazines; Pulmonary Artery; Pulmonary Embolism; Purines; Risk Factors; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Vascular Capacitance; Vasodilator Agents

We evaluated the effectiveness of tamsulosin monotherapy versus tamsulosin plus sildenafil combination therapy on erectile dysfunction (ED) in young patients with type III chronic prostatitis and ED by using symptom score scales.. 44 male patients were divided into 2 groups: the first group (20 patients) was treated with tamsulosin 0,4 mg monotherapy and the second one 24 patients) was treated with tamsulosin 0,4 mg plus sildenafil 50 mg combination therapy. “International Prostate Symptom Score, “National Institute of Health Chronic Prostatitis Symptom Index" (NIH-CPSI) and “International Index of Erectile Function" (IIEF-5) were investigated in each group of patients, and scores calculated during the first medical examination. Both groups were treated with tamsulosin once daily for 60 days, while sildenafil 50 mg was given on demand (at least 2 times per week) for 60 days. During the second medical examination IPSS, NIH-CPSI and IIEF-5 scores were analyzed once more. Afterwards, the alterations of scores among medical examinations in each group and between both groups were statistically compared.. The age average of the 44 cases included was 32.04 3.15 years. Both groups present a statistically significant decrease, between the first and the second medical examination, in IPSS, NIH-CPSI scores and statistically significant increase in IIEF-5 score. In addition, there is no statistically significant difference, in all scores, between mono and combination therapy.. tamsulosin monotherapy, as well as a combination therapy (tamsulosin plus sildenafil) has an improving effect on symptoms and on ED in patients with type III prostatitis. In the near future alpha-blockers monotherapy could be used in the treatment of chronic prostatitis and ED cases instead of phosphodiesterase type 5 (PDE-5) inhibitors combination therapy.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adult; Chronic Disease; Drug Therapy, Combination; Erectile Dysfunction; Humans; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Prostatitis; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Tamsulosin; Young Adult

Patients with inoperable chronic thromboembolic pulmonary hypertension (Inop-CTEPH) treated with conventional therapy have a poor survival. We compare the 3-year survival between those treated with conventional therapy and those treated with conventional therapy and a combination of novel drugs. We also evaluate the clinical course. A total of 34 Inop-CTEPH consecutive patients were evaluated from 1991 to 2009 including right heart catheterization (RHC) and perfusion lung scan (PLS): 7 underwent surgical treatment while 27 were confirmed inoperable. Of these 27 patients, 12 evaluated from 1991 to 2003 (Group 1) were treated with conventional therapy and 15 evaluated from 2004 to 2009 (Group 2) were treated with conventional and novel therapies. At baseline, no group difference emerged at RHC. Based on clinical course, novel drugs and oxygen supplementation were given to patients of Group 2. Seven of these who had worse clinical course repeated RHC and four of them also PLS during therapy. Those without repeat RHC had baseline pulmonary artery mean pressure and brain natriuretic peptide (NT-proBNP) lower and mixed venous saturation (SvO2) and exercise test higher (p = 0.022, 0.015, 0.044 and 0.003, respectively). During therapy, those with repeat RHC had total pulmonary vascular resistance reduced (p = 0.012), base excess increased (p = 0.002) and significant redistribution of pulmonary blood flow at PLS. At the 3-year follow-up, survival was 86% in Group 2 and 31% in Group 1 (p = 0.031). In Inop-CTEPH patients, the clinical course may help to select drugs and the level of oxygen supply that can improve hemodynamics, gas exchange and long-term survival.

Topics: Acid-Base Equilibrium; Aged; Antihypertensive Agents; Blood Gas Analysis; Bosentan; Cardiac Output; Chronic Disease; Drug Therapy, Combination; Exercise Test; Female; Humans; Hypertension, Pulmonary; Isoxazoles; Male; Middle Aged; Oxygen Consumption; Oxygen Inhalation Therapy; Piperazines; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Rate; Thiophenes; Thromboembolism; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Topics: Adult; Aged; Aged, 80 and over; Chronic Disease; Female; Humans; Leg Ulcer; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Thrombophilia

Topics: Bronchopulmonary Dysplasia; Chronic Disease; Humans; Infant, Newborn; Infant, Premature; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Chronic kidney disease, or renal impairment (RI) can increase plasma levels for drugs that are primarily renally cleared and for some drugs whose renal elimination is not a major pathway. We constructed physiologically based pharmacokinetic (PBPK) models for 3 nonrenally eliminated drugs (sildenafil, repaglinide, and telithromycin). These models integrate drug-dependent parameters derived from in vitro, in silico, and in vivo data, and system-dependent parameters that are independent of the test drugs. Plasma pharmacokinetic profiles of test drugs were simulated in subjects with severe RI and normal renal function, respectively. The simulated versus observed areas under the concentration versus time curve changes (AUCR, severe RI/normal) were comparable for sildenafil (2.2 vs 2.0) and telithromycin (1.6 vs 1.9). For repaglinide, the initial, simulated AUCR was lower than that observed (1.2 vs 3.0). The underestimation was corrected once the estimated changes in transporter activity were incorporated into the model. The simulated AUCR values were confirmed using a static, clearance concept model. The PBPK models were further used to evaluate the changes in pharmacokinetic profiles of sildenafil metabolite by RI and of telithromycin by RI and co-administration with ketoconazole. The simulations demonstrate the utility and challenges of the PBPK approach in evaluating the pharmacokinetics of nonrenally cleared drugs in subjects with RI.

Topics: Area Under Curve; Carbamates; Chronic Disease; Computer Simulation; Drug Interactions; Humans; Ketolides; Kidney Diseases; Models, Biological; Piperazines; Piperidines; Purines; Sildenafil Citrate; Sulfones

We tested the hypothesis that chronic treatment with sildenafil attenuates left ventricular (LV) remodeling and prevents exercise intolerance in chronic mitral regurgitation (MR).. MR was created in Sprague-Dawley rats by making a hole on the mitral leaflet. Two weeks after MR creation, MR and LV dilatation were confirmed by echocardiography, and rats were randomly assigned to sildenafil treatment (MR+sildenafil group; 50 mg/kg PO twice a day; n=16) or normal saline only (MR group; n=16) and continued for 4 months. Sixteen sham rats were compared with MR rats. After 4 months, LV size was smaller in the MR+sildenafil compared with the MR group (LV end-systolic dimension, 4.7±0.3 for sham versus 5.9±0.3 for MR+sildenafil versus 7.4±0.5 mm for MR; P<0.05; LV end-diastolic dimension, 8.3±0.4 versus 10.5±0.2 versus 11.7±0.61 mm, respectively; P<0.05). LV ejection fraction was greater in the MR+sildenafil group than in the MR group (70.2±2.2 for sham versus 67.0±4.2 for MR+sildenafil versus 58.9±2.5 for MR; P=0.01). Serial treadmill test revealed that exercise capacity was reduced in the MR but not in the MR+sildenafil group. Transcriptional profiling of cardiac apical tissues revealed that gene sets related to inflammatory response, DNA damage response, cell cycle checkpoint, and cellular signaling pathways were significantly enriched by genes with reciprocal changes. Pathological analysis showed that perivascular fibrosis was more prominent in the MR than in the MR+sildenafil group and that the percentage of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells was 2-fold greater in the MR compared with the MR+sildenafil group.. Sildenafil significantly attenuates LV remodeling and prevents exercise intolerance in a rat model of chronic MR. This benefit may be associated with the antiapoptotic, anti-inflammatory effects of sildenafil.

Topics: Animals; Chronic Disease; Disease Models, Animal; Male; Mitral Valve Insufficiency; Physical Conditioning, Animal; Physical Endurance; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Survival Analysis; Time Factors; Ventricular Remodeling

The present study evaluated the effects of sildenafil using the 4-vessel occlusion (VO)/internal carotid artery (ICA) model of chronic cerebral hypoperfusion (HCC). We previously found that permanent, three-stage occlusion of the vertebral arteries (VA) and ICA, four-VO/ICA, with an interstage interval (ISI) of 7 days was innocuous and caused no structural or functional outcomes in rats. Therefore, before testing sildenafil, we evaluated how a reduction in the number of occlusion stages (from three stages to two) and a shortening of the ISI might impact the survival rate, capacity for learning and memory, and histomorphological integrity of the hippocampus. Survival decreased from 100% to 70%, 62%, and 0% as the ISI was shortened from 7 to 5, 4, or 3 days, respectively. Using the two shortest ISIs, sildenafil (0.75-3.0 mg/kg, p.o.) abolished the mortality rate by approximately 95%. Profound neurodegeneration occurred in the CA1, CA2, CA3, and CA4 hippocampal subfields after an ISI of 4 days. Despite this, however, memory performance was unaffected. Subsequently, sildenafil treatment reduced 4-VO/ICA-induced hippocampal damage. The present results suggest that sildenafil may be potentially beneficial in the treatment of chronic cerebral hypoperfusion. Further studies should examine the manner by which the chronic 4-VO/ICA model may effectively cause cognitive impairment, thus improving its applicability in testing the effects of drugs against structural and/or functional outcomes of chronic cerebral hypoperfusion.

Topics: Animals; Carotid Artery Diseases; Cell Death; Cerebrovascular Disorders; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Hippocampus; Male; Maze Learning; Memory; Piperazines; Purines; Pyramidal Cells; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents; Vertebrobasilar Insufficiency

There are only a few reports of pulmonary hypertension (PH) in hypersensitivity pneumonitis (HP) and an approved vasomodulatory therapy for PH does not exist at all for interstitial lung disease (ILD), particularly for HP.. The case of a 53-year-old woman with chronic HP and severe life-threatening PH treated with a combined specific vasomodulatory therapy is reported. Sustained clinical and hemodynamic improvement was achieved.. Further investigation of PH in HP and specific vasomodulatory therapy is necessary.

Topics: Alveolitis, Extrinsic Allergic; Chronic Disease; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Phenylpropionates; Piperazines; Purines; Pyridazines; Sildenafil Citrate; Sulfones; Vasodilator Agents

The objective of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of the static allodynia response to pregabalin with and without sildenafil in a chronic constriction injury model of neuropathic pain. Six treatment groups were evaluated every 30 min for 6 h. Rats were treated with either 1) a saline infusion; 2) a 2-h pregabalin infusion at 4 mgxkg(-1)xh(-1); 3) a 2-h pregabalin infusion at 10 mgxkg(-1)xh(-1); 4) a 2.2-mg loading dose + 12 mgxkg(-1)xmin(-1) infusion of sildenafil; 5) a 2-h pregabalin infusion at 1.6 mgxkg(-1)xh(-1) with sildenafil; and 6) a 2-h infusion of pregabalin at 4 mgxkg(-1)xh with sildenafil. The static allodynia endpoint was modeled by using three population PD approaches: 1) the behavior of the injured paw using a three-category ordinal logistic regression model; 2) paw withdrawal threshold (PWT) (g) between the injured and uninjured paw using the Hill equation with a baseline function; and 3) the baseline normalized difference in PWT between the injured and uninjured paw. The categorical model showed a significant shift in the concentration-response relationship of pregabalin to lower concentrations with concomitant sildenafil. Likewise, the continuous PK-PD models demonstrated a reduction in the EC(50) of pregabalin necessary for PD response in the presence of sildenafil. The difference-transformed PD model resulted in a 54.4% (42.3-66.9%) decrease in EC(50), whereas the percentage-transformed PD model demonstrated a 53.5% (42.7-64.3%) shift. It is concluded from these studies that there is a synergistic PD interaction between pregabalin and sildenafil.

Topics: Analgesics; Animals; Calcium Channels; Chronic Disease; Drug Interactions; gamma-Aminobutyric Acid; Hyperalgesia; Ion Channel Gating; Ligands; Male; Models, Biological; Pain; Pain Threshold; Phosphodiesterase 5 Inhibitors; Piperazines; Pregabalin; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones

To explore the efficacy of sildenafil on erectile dysfunction (ED) of newlyweds, the author studied 60 outpatients within a month of marriage, who suffered from sexual intercourse (SI) failure caused by ED and showed no improvement after receiving sex education and psychological consultation. The patients were given oral sildenafil, 100 mg for the first and second times, 50 mg for the third and fourth times, no more than once every day, with a 1- to 3-day break between every two times. Four times of sildenafil administration formed one course of treatment. Sildenafil was taken 1 h before SI and was aided with adequate sexual stimulation. The rates of successful SI due to improved erection during and after a course of sildenafil treatment were 93.3% (56/60) and 85% (51/60), both P > 0.05. In the groups with one and more than one SI failure the successful SI rates after a sildenafil treatment course were 93.1% (27/29) and 77.4% (24/31), both P > 0.05. Oral sildenafil with psychological therapy in the treatment of ED of newlyweds proves to be effective in restoring the patients' sexual function and relieving their mental pressure or stress.

Topics: Adult; Chronic Disease; Erectile Dysfunction; Humans; Male; Marriage; Phosphodiesterase Inhibitors; Piperazines; Prostatitis; Purines; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Young Adult

Chronic lung disease (CLD) is often complicated by chronic pulmonary vascular changes and pulmonary hypertension (PH) in young children. Current therapies for severe PH in such patients, including oxygen, inhaled nitric oxide, and parenteral prostacyclin, are often suboptimal, cumbersome, and expensive. Recently, oral endothelin receptor blockers and phosphodiesterase-5 inhibitors have been used successfully to control and reverse pulmonary vascular disease in idiopathic PH, but the use and efficacy of these agents in pediatric CLD have not been previously reported. We report a series of six children with CLD and severe PH treated with bosentan (six of six) and sildenafil (four of six). Vascular reactivity was assessed by cardiac catheterization prior to and after 6 months of therapy. Serial echocardiography was also used to assess response. Patients have been treated for 2.1-2.9 years (mean, 2.53 years). Response to therapy has included improvement in oxygenation, symptoms, echocardiographic parameters, and hemodynamics by cardiac catheterization. Transiently elevated liver enzymes were noted associated with viral respiratory infections in two subjects; no other adverse effects were noted. Three patients with large cardiac right-to-left shunts prior to therapy had subsequent shunt reversal, two of whom underwent shunt closure later. Oral therapy with bosentan alone or in combination with sildenafil improves PH in patients with CLD over a period of 3-4 years.

Topics: Administration, Oral; Antihypertensive Agents; Bosentan; Bronchopulmonary Dysplasia; Cardiac Catheterization; Child; Child, Preschool; Chronic Disease; Female; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Topics: Chronic Disease; Endarterectomy; Humans; Hypertension, Pulmonary; Piperazines; Pulmonary Embolism; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil has been shown to be effective in the treatment of pulmonary hypertension, and has favourable effects on endothelial function. Our hypothesis is that a part of the beneficial effects of sildenafil in patients with pulmonary hypertension is due to the improvement of the endothelial function.. Nine patients (seven females, age 67+/-9 years) with thromboembolic pulmonary hypertension were treated with sildenafil, at a mean dose of 150+/-75 mg/die. At baseline and after 6 months all patients underwent: right-heart catheterization, 6-min walking distance, and a study of endothelial function, including the measure of the flow-mediated vasodilation of the brachial artery, and the dosage of plasma levels of endothelin-1 and von Willebrand factor.. During follow-up we found a significant reduction of mean pulmonary artery pressure and arteriolar resistances. Accordingly, the functional capacity improved (an average of+37 m). Sildenafil improved endothelial-dependent vasodilation and reduced plasma concentrations of endothelin-1 (from 4.5+/-0.6 to 3.1+/-0.7 pg/mL; p<0.0001) and von Willebrand factor (from 183.1+/-10.1 to 149.1+/-17.6 mU/mL; p<0.0001).. Improvement of the endothelial function may represents one of the mechanisms able to explain the favourable effects sildenafil has shown in patients with pulmonary hypertension.

Topics: Aged; Brachial Artery; Chronic Disease; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilation

Acquired or hereditary prothrombotic risk factors may lead to cerebral venous sinus thrombosis (CVST), particularly when other predisposing factors coexist. A 57-year-old man experienced right leg deep venous thrombosis, severe thrombosis of the haemorrhoid plexus and CVST over a 12-month period during which he was taking sildenafil regularly twice a week. Sildenafil is a phosphodiesterase 5 (PDE5)-inhibitor used for erectile dysfunction (ED). A slight reduction in antithrombin III and free protein S levels was demonstrated. After suspension of sildenafil and six months on oral anticoagulants, clinical improvement was obtained. Recurrent venous thrombosis, including CVST, may complicate prolonged treatment with PDE5-inhibitors in subjects at risk. Periodic monitoring of clotting factors is recommended in these subjects.

Topics: Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Chronic Disease; Cranial Sinuses; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Secondary Prevention; Sildenafil Citrate; Sinus Thrombosis, Intracranial; Sulfones; Treatment Outcome; Venous Thrombosis

Persistent stimulation of nociceptors and C-fibers by tissue injury causes hyperalgesia and allodynia by sensitization of nociceptors and facilitation of synaptic transmission in the spinal cord. The important participant in the inflammatory response of injured peripheral nerve may be nitric oxide (NO). The aim of the present study was to test the sensitivity of PDE5 inhibitor sildenafil in chronic constriction injury (CCI) model a rat model of neuropathic pain. Sciatic nerve injury is associated with development of hyperalgesia 14 days after the nerve ligation. Sildenafil (100 and 200 microg/rat, i.t.) produced a significant decrease in pain threshold, which in lower dose did not alter the nociceptive threshold. The hyperalgesic effect of sildenafil was blocked by L-NAME and methylene blue (MB), which on per se treatment showed antinociceptive effect in nerve ligated rats. The results from the present study indicated that the major activation of NO-cGMP pathway in the chronic constriction injury model of neuropathic pain. The aggravation of hyperalgesic response might be due to the increased cGMP levels resulting in PKG-I activation and its upregulation.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Chronic Disease; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hyperalgesia; Injections, Spinal; Male; Methylene Blue; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pain; Pain Threshold; Piperazines; Purines; Rats; Rats, Wistar; Sciatic Neuropathy; Signal Transduction; Sildenafil Citrate; Sulfones

Type V phosphodiesterase (PDE V) metabolizes cyclic guanosine monophosphate (cGMP) and is abundant in the kidney and vasculature and was found recently in the heart. Sildenafil is a PDE V inhibitor that is used clinically for erectile dysfunction. Brain natriuretic peptide (BNP) is a cardiac peptide with vasodilating, lusitropic, and natriuretic properties that are mediated via cGMP. It was hypothesized that chronic inhibition of PDE V (PDE VI) will enhance the renal actions of exogenous BNP by potentiating the renal cGMP. The cardiorenal and humoral function was determined at baseline in two groups of dogs with pacing-induced overt chronic heart failure (CHF; 240 bpm for 10 d): Group 1 (n = 6) received Sildenafil 50 mg orally three times daily during the 10 d of pacing, and group 2 (n = 5) received no PDE V inhibitor. The response to acute subcutaneous BNP (5 microg/kg) administration also was compared in both groups on day 11. The GFR was assessed by inulin clearance (P < 0.05). There was no improvement of renal function in group 1 after 10 d of PDE VI as compared with group 2, despite having higher cardiac output (P < 0.05). Group 1 had significantly higher plasma (44 +/- 2 versus 21 +/- 3 pmol/ml; P < 0.05) and urinary cGMP (4219 +/- 900 versus 1954 +/- 300 pmol/min; P < 0.05) as compared with group 2. With acute subcutaneous BNP administration, group 1 had a natriuretic and diuretic response that was associated with an increase in GFR (30 +/- 6 to 45 +/- 6 ml/min; P < 0.05) and that was not observed in group 2 (25 +/- 6 to 29 +/- 4 ml/min). Plasma BNP increased to a similar extent in both groups with subcutaneous BNP. In contrast, group 1 had a much greater urinary cGMP excretion (4219 +/- 900 to 8600 +/- 1600 pmol/min; P < 0.05) as compared with group 2 (1954 +/- 300 to 3580 +/- 351 pmol/min; P < 0.05). In experimental overt CHF, chronic administration of PDE V inhibitor did not enhance renal function despite an improvement in cardiac output. However, chronic PDE VI significantly enhanced the renal hemodynamic and excretory responses to exogenous BNP. This study supports a role for PDE V as contributing to renal maladaptation in a model of experimental overt CHF and the strategy of maximizing the renal cGMP system by combined PDE VI and natriuretic peptides in CHF to improve renal function.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Chronic Disease; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Heart Failure; Kidney; Male; Natriuretic Peptide, Brain; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Persistent pulmonary hypertension of the newborn (PPHN) was described in 1969 by Gersomy and co-workers as persistent foetal circulation. Supra - systemic pulmonary artery pressures result in right to left shunting of blood through the ductus arteriosus and/or foramen ovale. This results from failure of the normal adaptation to extra uterine life of the foetal heart/lung system. The incidence is estimated at about 0.1-0.2% of live born infants, majority being term or post term. There is no race or gender related predisposition. Management was always difficult before the advent of nitric oxide (and now sildenafil). We report two newborn infants born at The Mater Hospital with perinatal asphyxia resulting inpersistent pulmonary hypertension that were successfully managed with sildenafil.

Topics: Asphyxia Neonatorum; Chronic Disease; Female; Humans; Hypertension, Pulmonary; Hypoxia; Infant, Newborn; Pharmacy Service, Hospital; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

We describe four cases of chronic pulmonary hypertension in infants and children with chronic lung disease and pulmonary hypoplasia due to severe congenital diaphragmatic hernia (CDH) or congenital cystic adenomatoid malformation (CCAM). We report data from cardiac catheterization under various conditions: baseline respiratory support and room air, hyperoxic and inhaled nitric oxide challenge. We further report cardiac catheterization measures after chronic pulmonary vasodilator therapy with sildenafil alone or a combination of sildenafil and inhaled nitric oxide (three patients).. Case series.. Tertiary academic center.. Infants and children ages 0-11 yrs with CDH (n = 3) or CCAM (n = 1) with evidence of chronic pulmonary hypertension by echocardiogram and cor pulmonale (n = 3).. Catheterization and pulmonary vasodilator therapy.. Pulmonary vascular resistance, pulmonary arterial pressure, and changes in these measures were assessed. A 20% change in pulmonary vascular resistance was considered a clinically significant response. Ten catheterizations were performed in four patients. All patients had elevated pulmonary vascular resistance and pulmonary arterial pressures at initial catheterizations and significant vasodilation during inhaled nitric oxide.. Chronic lung disease following pulmonary hypoplasia from CDH and CCAM is associated with abnormal pulmonary vascular tone in infants and children with evidence of chronic pulmonary hypertension. Chronic pulmonary vasodilator therapy may improve pulmonary vascular function and enhance lung growth in infants and children who are treated during their period of potential for rapid lung growth.

Topics: Cardiac Catheterization; Child; Child, Preschool; Chronic Disease; Cystic Adenomatoid Malformation of Lung, Congenital; Female; Free Radical Scavengers; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Lung; Lung Diseases; Male; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

We investigated the pulmonary vascular effects of prophylactic use of sildenafil, a specific phosphodiesterase-5 inhibitor, in late-gestation fetal lambs with chronic pulmonary hypertension. Fetal lambs were operated on at 129 +/- 1 days gestation (term = 147 days). Ductus arteriosus (DA) was compressed for 8 days to cause chronic pulmonary hypertension. Fetuses were treated with sildenafil (24 mg/day) or saline. Pulmonary vascular responses to increase in shear stress and in fetal PaO2 were studied at, respectively, day 4 and 6. Percent wall thickness of small pulmonary arteries (%WT) and the right ventricle-to-left ventricle plus septum ratio (RVH) were measured after completion of the study. In the control group, DA compression increased PA pressure (48 +/- 5 to 72 +/- 8 mmHg, P < 0.01) and pulmonary vascular resistance (PVR) (0.62 +/- 0.08 to 1.15 +/- 0.11 mmHg x ml(-1) x min(-1), P < 0.05). Similar increase in PAP was observed in the sildenafil group, but PVR did not change significantly (0.54 +/- 0.06 to 0.64 +/- 0.09 mmHg x ml(-1) x min(-1)). Acute DA compression, after brief decompression, elevated PVR 25% in controls and decreased PVR 35% in the sildenafil group. Increased fetal PaO2 did not change PVR in controls but decreased PVR 60% in the sildenafil group. %WT and RVH were not different between groups. Prophylactic sildenafil treatment prevents the rise in pulmonary vascular tone and altered vasoreactivity caused by DA compression in fetal lambs. These results support the hypothesis that elevated PDE5 activity is involved in the consequences of chronic pulmonary hypertension in the perinatal lung.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Chronic Disease; Ductus Arteriosus; Fetus; Hemodynamics; Hypertension, Pulmonary; Lung; Oxygen; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Pulmonary Circulation; Purines; Sheep; Sildenafil Citrate; Stress, Mechanical; Sulfones; Vascular Resistance; Vasodilation

Sildenafil, a phosphodiesterase-5 inhibitor, induces cardioprotection against ischemia/reperfusion injury via opening of mitochondrial K(ATP) channels. It is unclear whether sildenafil would provide similar protection from doxorubicin-induced cardiotoxicity.. Male ICR mice were randomized to 1 of 4 treatments: saline, sildenafil, doxorubicin (5 mg/kg IP), and sildenafil (0.7 mg/kg IP) plus doxorubicin (n=6 per group). Apoptosis was assessed with the use of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and in situ oligo ligation methods. Desmin distribution was determined via immunofluorescence. Bcl-2 expression was analyzed by Western blot. Left ventricular function was assessed by measuring developed pressure and rate pressure product in Langendorff mode. ECG changes indicative of doxorubicin cardiotoxicity were also measured. For in vitro studies, adult ventricular cardiomyocytes were exposed to doxorubicin (1 micromol/L), sildenafil (1 micromol/L) with or without N(G)-nitro-L-arginine methyl ester (L-NAME) (100 micromol/L), or 5-hydroxydecanoate (100 micromol/L) 1 hour before doxorubicin and incubated for 18 hours. Doxorubicin-treated mice demonstrated increased apoptosis and desmin disruption, which was attenuated in the sildenafil+doxorubicin group. Bcl-2 was decreased in the doxorubicin group but was maintained at basal levels in the sildenafil+doxorubicin group. Left ventricular developed pressure and rate pressure product were significantly depressed in the doxorubicin group but were attenuated in the sildenafil+doxorubicin group. ST interval was significantly increased in the doxorubicin group over 8 weeks. In the sildenafil+doxorubicin group, ST interval remained unchanged from baseline. Doxorubicin caused a significant increase in apoptosis, caspase-3 activation, and disruption of mitochondrial membrane potential in vitro. In contrast, sildenafil significantly protected against doxorubicin cardiotoxicity; however, this protection was abolished by both L-NAME and 5-hydroxydecanoate.. Prophylactic treatment with sildenafil prevented apoptosis and left ventricular dysfunction in a chronic model of doxorubicin-induced cardiomyopathy.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Apoptosis; Cardiomyopathies; Chronic Disease; Cyclic Nucleotide Phosphodiesterases, Type 5; Doxorubicin; Drug Therapy, Combination; Heart Failure; Male; Mice; Mice, Inbred ICR; Myocytes, Cardiac; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Premedication; Purines; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Left

Devising therapies that might prevent the onset or progression of pulmonary hypertension in newborns has received little attention. Our major objective was to determine whether sildenafil, a selective phosphodiesterase inhibitor, prevents the development of an early stage of chronic hypoxia-induced pulmonary hypertension in newborn pigs. Another objective was to determine whether sildenafil causes pulmonary vasodilation without systemic vasodilation in piglets with chronic pulmonary hypertension. Piglets were raised in room air (control, n = 5) or 10-11% O(2) (hypoxic, n = 17) for 3 days. Some piglets (n = 4) received oral sildenafil, 12 mg/kg/day, throughout exposure to hypoxia. All piglets were anesthetized and catheterized, and pulmonary arterial pressure (Ppa), pulmonary wedge pressure (Pw), aortic pressure (Ao), and cardiac output (CO) were measured. Then for some piglets raised in hypoxia for 3 days, a single oral sildenafil dose (3 mg/kg, n = 6) or placebo (n = 5) was given, and hemodynamic measurements were repeated. For piglets raised in hypoxia for 3 days, mean Ppa and calculated PVR were elevated above respective values in control piglets. Mean Ppa and PVR did not differ between piglets that received sildenafil throughout exposure to hypoxia and those that did not. For piglets with chronic hypoxia-induced pulmonary hypertension that received a single oral dose of sildenafil, mean Ppa and PVR decreased, while mean Pw, CO, mean Ao, and systemic vascular resistance remained the same. All hemodynamic measurements were unchanged after placebo. Oral sildenafil did not influence the early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. However, a single oral dose of sildenafil caused pulmonary vasodilation, without systemic vasodilation, in piglets with chronic hypoxia-induced pulmonary hypertension, which may have therapeutic implications.

Topics: Administration, Oral; Animals; Animals, Newborn; Chronic Disease; Cyclic GMP; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Infant, Newborn; Infant, Newborn, Diseases; Lung; Piperazines; Pulmonary Artery; Purines; Reference Values; Sildenafil Citrate; Sulfones; Swine; Treatment Outcome; Vasodilator Agents

Inhibition of the type 5 phosphodiesterase and inhibition of Rho kinase are both effective in reducing pulmonary hypertension (PH). Here we investigate whether Rho kinase inhibition is involved in the beneficial effect of the type 5 phosphodiesterase inhibitor sildenafil on PH. Chronic hypoxia-induced PH in rats is associated with an increase in RhoA activity in pulmonary artery that was maximal after 2 days (10.7+/-0.9-fold increase, n=6, P<0.001). The activity of Rho kinase assessed by measuring the level of myosin phosphatase target subunit 1 (MYPT1) phosphorylation was also increased (5.7+/-0.8-fold over control, n=8). Chronic fasudil (30 mg kg(-1) day(-1); 14 days) and sildenafil (25 mg kg(-1) day(-1); 14 days) treatments reduced PH and pulmonary cardiovascular remodelling, and inhibited the MYPT1 phosphorylation in pulmonary artery from hypoxic rats by 82.3+/-3% (n=4) and by 76.6+/-2% (n=4), respectively. The inhibitory effect of sildenafil (10 microM) on MYPT1 phosphorylation was demonstrated by the loss of actin stress fibres in vascular smooth muscle cells. However, in vitro kinase assays indicated that sildenafil had no direct inhibitory action on Rho kinase activity. Sildenafil treatment induced increased RhoA phosphorylation and association to its cytosolic inhibitory protein, guanine dissociation inhibitor (GDI) in pulmonary artery.We propose that sildenafil inhibits RhoA/Rho kinase-dependent functions in pulmonary artery through enhanced RhoA phosphorylation and cytosolic sequestration by GDI. The inhibition of intracellular events downstream of RhoA thus participates in the beneficial effect of sildenafil on PH.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Actins; Animals; Carrier Proteins; Chronic Disease; Cytoskeleton; Guanine Nucleotide Dissociation Inhibitors; Hypertension, Pulmonary; Hypoxia; Male; Phosphodiesterase Inhibitors; Phosphoprotein Phosphatases; Phosphorylation; Piperazines; Protein Phosphatase 1; Purines; Rats; Rats, Wistar; rhoA GTP-Binding Protein; Sildenafil Citrate; Sulfones

Topics: Adult; Arginine; Chronic Disease; Citrulline; Cyclic GMP; Endothelium, Vascular; Erectile Dysfunction; Humans; Hypertension, Pulmonary; Infant; Male; Marketing; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

We describe a case of chronic pulmonary hypertension in a 7-wk-old infant with congenital diaphragmatic hernia and an oral teratoma. Our patient was dependent on low-dose inhaled nitric oxide and was still very unstable with systemic right ventricular pressures leading to frequent oxygen desaturations. We administered sildenafil therapy to stabilize the infant with discontinuation of inhaled nitric oxide. We describe successful discontinuation of the inhaled therapy as well as a period of stabilization and improvement with continued sildenafil administration.. Case report.. Intensive care nursery in tertiary academic center.. A 7-wk-old infant with congenital diaphragmatic hernia who was mechanically ventilated from birth.. Oral sildenafil 0.3 mg/kg/dose every 12 hrs.. Right ventricular pressure (from tricuspid valve regurgitant flow) to systemic systolic arterial pressure was measured by echocardiogram. Right ventricular to systemic pressure ratio was marginally improved with the initiation of sildenafil therapy. Inhaled nitric oxide was successfully discontinued, and the patient clinically stabilized temporarily, but he ultimately succumbed to his pulmonary hypertension.. Sildenafil may be a useful therapy for chronic pulmonary hypertension in congenital diaphragmatic hernia, but further studies of safety and efficacy need to be performed.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Chronic Disease; Cyclic Nucleotide Phosphodiesterases, Type 5; Echocardiography; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones

Sildenafil, a potent type 5 nucleotide-dependent phosphodiesterase (PDE) inhibitor, has been recently proposed as a therapeutic tool to treat or prevent pulmonary artery hypertension (PAHT). We thus studied the effect of sildenafil on both the calcium signaling of isolated pulmonary artery smooth muscle cells (PASMCs) and the reactivity of pulmonary artery (PA) obtained from chronic hypoxia (CH)-induced pulmonary hypertensive rats compared with control (normoxic) rats. CH rats were maintained in an hypobaric chamber (50.5 kPa) for 3 wk leading to full development of PAHT. Intracellular calcium concentration ([Ca2+]i) was measured in PASMCs loaded with the calcium fluorophore indo 1. Unlike in control rats, sildenafil (10-100 nM) decreased the resting [Ca2+]i value in PASMCs obtained from CH rats. In PASMCs from both control and CH rats, sildenafil concentration dependently inhibited the [Ca2+]i response induced by G-coupled membrane receptor agonists such as angiotensin II and phenylephrine but had no effect on the amplitude of the [Ca2+]i response induced by caffeine. Sildenafil (0.1 nM-1 microM) concentration dependently reduced basal PA tone that is present in CH rats and relaxed PA rings precontracted with phenylephrine in both control and CH rats. These data show that sildenafil is a potent pulmonary artery relaxant in CH rats and that it normalizes CH-induced increases in resting [Ca2+]i and basal tone. Consequently, pharmacological inhibition of sildenafil-sensitive PDE5 downregulates the Ca2+ signaling pathway involved in this model of pulmonary hypertension.

Topics: Angiotensin II; Animals; Caffeine; Calcium; Calcium Signaling; Chronic Disease; Disease Models, Animal; Hypertension, Pulmonary; Hypoxia; Male; Muscle, Smooth, Vascular; Phenylephrine; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Vasoconstriction; Vasoconstrictor Agents

The treatment of erectile dysfunction (ED) has been revolutionised by new agents to inhibit the enzyme PDE5. The scientific basis of this treatment of ED includes relaxation of the corpus cavernosum smooth muscle tissue by inhibition of PDE5 that breaks down cGMP, the key pathway for the production of erectile function in humans. Many clinical studies, both pre- and post-marketing, have demonstrated the clinical efficacy and safety of sildenafil (Viagra, Pfizer) - the first approved selective PDE inhibitor for the treatment of ED. Sildenafil is inhibitory of PDE5 at a rate tenfold higher than for the next PDE (PDE6), which produces visual changes through the retinal rods. Its clinical effectiveness has been well documented in the majority of men with ED irrespective of aetiology. The aetiology of ED, also, does not appear to effect the function of sildenafil in relaxing corpus cavernosum smooth muscle tissue. Adverse events are usually associated with the vascular changes from PDE5 inhibition. These include headache and flushing. Each of these adverse events, however, declines with medication use. With the use of sildenafil, it has been clearly, clinically demonstrated that the selective inhibition of PDE5 is an appropriate, effective, safe method for the treatment of ED of all aetiologies and severities.

Topics: Aged; Area Under Curve; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Chronic Disease; Erectile Dysfunction; Humans; Kidney Diseases; Male; Phosphodiesterase Inhibitors; Piperazines; Product Surveillance, Postmarketing; Purines; Sildenafil Citrate; Sulfones

After the acute phase, a patient who is diagnosed with cardiac or vascular disease becomes "chronically ill". This patient will then still spend many years without symptoms or impairments. One day, a percentage of such patients will be confronted with the problem of erectile dysfunction. Various studies have demonstrated that this problem occurs with a higher frequency in patients with cardiovascular diseases, in particular when they have to be treated for hypertension, diabetes mellitus or dyslipidemia. Very rarely are stenoses or occlusions found in the arteries responsible for penile circulation. More recent data indicates that a diffuse anomaly of the vascular endothelium is present, for which erectile dysfunction is a marker. Nowadays, medical care has achieved a better degree of standardization, not only thanks to knowledge about the effects of cardiovascular medication, but also because the physician can now prescribe drugs that treat erectile dysfunction.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Chronic Disease; Endothelium, Vascular; Erectile Dysfunction; Humans; Impotence, Vasculogenic; Male; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Vasodilator Agents

Erectile dysfunction is one of the factors influencing negatively the quality of life of patients in hemodialytic treatment. The international literature shows that erectile dysfunction is present in 30% of patients with chronic renal failure and in 50% of patients undergoing dialytic treatment. Fertility, libido and erectile dysfunction, suffer progressive worsening with time, in spite of hemodialysis. The availability of a drug like Sildenafil can improve the quality of life of the patient and give him a normal sexual activity.. Twenty patients between 29 and 51 years, were selected; 2 of these had been subjected to renal transplant, with a dialytic treatment time varying from 3 to 13 years. Before the treatment all the patients have been subjected to an andrological screening (testosterone, prolactin, penile color Doppler ultrasound) and proposed the IIEF test. Therapeutic strategy included the assumption of the drug in the days in which the patients were not subjected to dialysis, with an interval from 1 to 3 weeks between assumption and another. The dose was 25-50 mg. At the end of three months of therapy the patients were again subjected to the IIEF test.. All patients reported an improvement in sexual activity and sexual desire with very good repercussions on general and psychophysical conditions.. The results demonstrate at least that Sildenafil is also effective in uremic patients in dialytic treatment or after renal transplant and that it can therefore resolve one of the main problems for the normal development of the life of such patients.

Topics: Adult; Chronic Disease; Erectile Dysfunction; Humans; Kidney Failure, Chronic; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Uremia

We assessed the efficacy and safety of sildenafil citrate as treatment for erectile dysfunction.. A total of 433 completely evaluated men with chronic erectile dysfunction were treated with sildenafil citrate. Response was assessed prospectively by baseline and followup physician interviews, and by a patient self-administered 15-item questionnaire on the domains of patient treatment response and satisfaction, partner treatment satisfaction, comparative previous treatment satisfaction, adverse effects, and patient and partner quality of life.. Of the 304 men (70.2%) who completed the questionnaire 278 received sildenafil, including 186 who previously had undergone treatment for erectile dysfunction, principally involving intracavernous injection therapy. A response was elicited by a median dose of 100 mg. in 188 patients (67.6%) who achieved erection suitable for sexual intercourse. Those with psychogenic erectile dysfunction responded significantly better than those with organic dysfunction (p <0.001). Erection suitable for intercourse was attained by 30.8% of patients with erectile dysfunction after radical prostatectomy and 80% with cavernous veno-occlusive dysfunction. Of previous intracavernous injection responders 29.9% were refractory to sildenafil, while 33. 3% of previous intracavernous injection nonresponders responded to sildenafil. The sildenafil response was considered inferior to the intracavernous injection response by 43.6% of the men who previously responded to intracavernous injection, of whom 51.5% continued to receive intracavernous injection as the only treatment (19.5%) or as an alternative to sildenafil (32%). Adverse effects in 53.6% of cases were assessed as mild in 56.4%, moderate in 38.3% and severe in 5.3%. Multiple adverse effects were reported by 62.4% of patients, while 17 (6.1%) discontinued sildenafil as a direct result of intolerable adverse effects. The most common adverse effects were facial flushing in 33.5% of cases, headaches in 23.4%, nasal congestion in 12.6%, dyspepsia in 10.1% and dizziness in 10.8%. Baseline patient and partner quality of life scores significantly improved after sildenafil treatment (p <0.001), while significantly improved quality of life was noticed by 51.5% and 43.1%, respectively.. Sildenafil citrate is effective oral first line treatment for erectile dysfunction. Although more than 50% of men reported adverse effects, most were considered mild and rarely resulted in treatment cessation. There was a trend in those on intracavernous injection who responded to sildenafil to continue intracavernous injection as the only therapy or as an alternative to sildenafil. Also, we noted that some cases refractory to sildenafil responded to intracavernous injection. These findings imply that intracavernous injection remains an effective erectile dysfunction treatment option.

Topics: Adult; Aged; Aged, 80 and over; Chronic Disease; Erectile Dysfunction; Humans; Male; Middle Aged; Patient Satisfaction; Phosphodiesterase Inhibitors; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Treatment Outcome