sildenafil-citrate and Pulmonary-Veno-Occlusive-Disease

Pulmonary arterial hypertension (PAH) is a rare disease characterized by vascular proliferation and remodeling, resulting in a progressive increase in pulmonary arterial resistance, right heart failure, and death. The pathogenesis of PAH is multifactorial, with endothelial cell dysfunction playing an integral role. This endothelial dysfunction is characterized by an overproduction of vasoconstrictors and proliferative factors, such as endothelin-1, and a reduction of vasodilators and antiproliferative factors, such prostacyclin and nitric oxide. Phosphodiesterase type 5 (PDE-5) is implicated in this process by inactivating cyclic guanosine monophosphate, the nitric oxide pathway second messenger. PDE-5 is abundantly expressed in lung tissue, and appears to be upregulated in PAH. Three oral PDE-5 inhibitors are available (sildenafil, tadalafil, and vardenafil) and are the recommended first-line treatment for erectile dysfunction. Experimental studies have shown the beneficial effects of PDE-5 inhibitors on pulmonary vascular remodeling and vasodilatation, justifying their investigation in PAH. Randomized clinical trials in monotherapy or combination therapy have been conducted in PAH with sildenafil and tadalafil, which are therefore currently the approved PDE-5 inhibitors in PAH treatment. Sildenafil and tadalafil significantly improve clinical status, exercise capacity, and hemodynamics of PAH patients. Combination therapy of PDE-5 inhibitors with prostacyclin analogs and endothelin receptor antagonists may be helpful in the management of PAH although further studies are needed in this area. The third PDE-5 inhibitor, vardenafil, is currently being investigated in PAH. Side effects are usually mild and transient and include headache, flushing, nasal congestion, digestive disorders, and myalgia. Mild and moderate renal or hepatic failure does not significantly affect the metabolism of PDE-5 inhibitors, whereas coadministration of bosentan decreases sildenafil and tadalafil plasma levels. Due to their clinical effectiveness, tolerance profile, and their oral administration, sildenafil and tadalafil are two of the recommended first-line therapies for PAH patients in World Health Organization functional classes II or III.

Topics: Algorithms; Carbolines; Humans; Hypertension, Pulmonary; Imidazoles; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Veno-Occlusive Disease; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride

A 24-year-old woman, a baby-sitter with no known comorbidities, presented to the outpatient department with complaints of modified Medical Research Council grade IV breathlessness for 3 months, chest pain, and dry cough for 2 weeks. There was no known disease history, including respiratory, flu-like illness, or connective tissue disorder. There was no use of chemotherapeutic, oral contraceptive drugs, exposure to toxic substances, or smoking. A review of systems was negative for fever, arthralgia, myalgia, Raynaud phenomenon, skin thickening, rash, or leg swelling. The patient had no family history suggestive of a genetic syndrome.

Topics: Chest Pain; Computed Tomography Angiography; Cough; Diagnosis, Differential; Dyspnea; Echocardiography; Endothelin A Receptor Antagonists; Female; Hemangioma, Capillary; Humans; Hypertension, Pulmonary; Lung Neoplasms; Lung Transplantation; Mutation; Oxygen Inhalation Therapy; Phosphodiesterase 5 Inhibitors; Protein Serine-Threonine Kinases; Pulmonary Veno-Occlusive Disease; Pyrimidines; Respiratory Function Tests; Sildenafil Citrate; Sulfonamides; Young Adult

Topics: Aged; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Female; Humans; Pulmonary Veno-Occlusive Disease; Pyrimidines; Sildenafil Citrate; Sulfonamides; Tomography, X-Ray Computed; Vasodilator Agents

Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension (PH). Misdiagnosis of the disease is common since PVOD presents with clinical and radiographic features mimicking idiopathic pulmonary arterial hypertension or even PH due to interstitial lung disease. Vasodilators may not be efficacious in PVOD and may in fact worsen hemodynamic status with the development of pulmonary edema. Lung transplantation represents the best treatment option. In the present report we describe the challenging diagnosis of PVOD in a patient with PH referred to our department. Final diagnosis was established by surgical lung biopsy. The patient was offered sequential combination therapy under close monitoring and maintained remarkable clinical stabilization while being on the waiting list for lung transplantation.

Topics: Adult; Bosentan; Diagnosis, Differential; Disease Progression; Drug Therapy, Combination; Endothelin Receptor Antagonists; Epoprostenol; Humans; Iloprost; Lung; Lung Transplantation; Male; Piperazines; Pulmonary Artery; Pulmonary Veno-Occlusive Disease; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Tomography, X-Ray Computed; Vasodilator Agents; Waiting Lists

A 33-year-old male with severe hereditary pulmonary arterial hypertension had a confirmed diagnosis of occlusive venopathy and microvasculopathy. He remained stable for three and a half years on oral sildenafil, 75 mg t.i.d. (six-minute walked distance of 375 m vs 105 m at baseline), but required addition of bosentan (125 mg b.i.d.), subsequently. Despite the fatal outcome at five years post-diagnosis, the observations suggest a potential usefulness of vasodilators as a bridge for lung transplant in selected cases with significant venous/capillary involvement. The occurrence of veno-occlusive and capillary lesions in the familial form of pulmonary arterial hypertension reinforces the difficulties with the current classification of the disease.

Topics: Adult; Biopsy; Familial Primary Pulmonary Hypertension; Fatal Outcome; Humans; Hypertension, Pulmonary; Lung; Male; Phenotype; Piperazines; Pulmonary Veno-Occlusive Disease; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Edema; Pulmonary Veno-Occlusive Disease; Purines; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Left

Topics: Bosentan; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Middle Aged; Piperazines; Pulmonary Edema; Pulmonary Medicine; Pulmonary Veno-Occlusive Disease; Purines; Risk; Sildenafil Citrate; Sulfonamides; Sulfones; Tomography, X-Ray Computed; Treatment Outcome

Pulmonary veno-occlusive disease (PVOD) is a disorder which causes progressive pulmonary hypertension, usually presenting with worsening dyspnoea and right heart failure. Pulmonary oedema induced by pulmonary vasodilator therapy to reduce pulmonary arterial pressure has been well described in PVOD, but here we describe a case of PVOD presenting with recurrent episodes of acute non-cardiogenic pulmonary oedema, in the absence of significant pulmonary hypertension. Concern over the risk of precipitating pulmonary oedema led us to use inhaled nitric oxide to predict the safety and efficacy of sildenafil.

Topics: Adult; Bronchodilator Agents; Dyspnea; Humans; Male; Nitric Oxide; Piperazines; Pulmonary Edema; Pulmonary Veno-Occlusive Disease; Purines; Recurrence; Sildenafil Citrate; Sulfones; Tomography, X-Ray Computed; Vasodilator Agents

Pulmonary veno-occlusive disease is refractory to medical treatment and is generally associated with a poor prognosis. Treatment with vasodilators, such as prostacyclin, of patients with PVOD is controversial because of concerns regarding hemodynamic deterioration. Although a preferential pulmonary vasodilatory effect of a specific phosphodiesterase-5 inhibitor, sildenafil, has recently been reported in patients with primary pulmonary hypertension, little information is available regarding the effect of sildenafil on patients with pulmonary veno-occlusive disease. In the present case, remarkable improvement of hemodynamics and of clinical course was produced by adjunctive use of oral sildenafil in association with intravenous high-dose epoprostenol. These findings suggest that sildenafil may be a therapeutic option in the medical treatment of pulmonary veno-occlusive disease.

Topics: Adult; Antihypertensive Agents; Drug Therapy, Combination; Dyspnea; Epoprostenol; Humans; Lung; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Veno-Occlusive Disease; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

We hypothesized that chronic oral administration of the phosphodiesterase-5 inhibitor sildenafil could improve the exercise capacity and pulmonary hemodynamics in patients with pulmonary arterial hypertension (PAH) on the basis of previous short-term studies. We tested this hypothesis in 14 subjects with PAH, including seven patients with the idiopathic form and seven patients with atrial septal defects, but no other congenital heart abnormalities. Patients were subjected to a 6-min walk test and dyspnea was graded according to the Borg scale. Pulmonary flow and pressures were measured by Doppler echocardiography. Patients were given sildenafil, 75 mg orally three times a day, and followed up for 1 year. Sildenafil therapy resulted in the following changes: increase in the 6-min walk distance from a median value of 387 m (range 0 to 484 m) to 462 m (range 408 to 588 m; P < 0.01), improvement of the Borg dyspnea score from 4.0 (median value) to 3.0 (P < 0.01), and increased pulmonary flow (velocity-time integral) from a median value of 0.12 (range 0.08 to 0.25) to 0.23 (range 0.11 to 0.40; P < 0.01) with no changes in pulmonary pressures. In one patient with pulmonary veno-occlusive disease diagnosed by a lung biopsy, sildenafil had a better effect on the pulmonary wedge pressure than inhaled nitric oxide (15 and 29 mmHg, respectively, acute test). He walked 112 m at baseline and 408 m at one year. One patient died at 11 months of treatment. No other relevant events occurred. Thus, chronic administration of sildenafil improves the physical capacity of PAH patients and may be beneficial in selected cases of veno-occlusive disease.

Topics: Adolescent; Adult; Echocardiography, Doppler; Exercise Tolerance; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Veno-Occlusive Disease; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome