Safety and efficacy of Sildenafil therapy in children with pulmonary hypertension

https://doi.org/10.1016/j.ijcard.2004.09.002Get rights and content

Abstract

Objective

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.

Methods

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.

Results

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.

Conclusions

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.

Introduction

Sildenafil citrate (Viagra, Pfizer Pharmaceuticals) is a selective orally active Phosphodiesterase-5 (PDE-5) inhibitor that has been used extensively for the treatment of erectile dysfunction [1]. A number of serious cardiovascular adverse events have been associated with its use, including myocardial infarction and sudden cardiac death in adults with coronary artery disease [2]. These adverse events were attributed to the systemic vasodilating effect of Sildenafil resulting in systemic hypotension in patients receiving nitrates.

Sildenafil is rapidly absorbed by the gastrointestinal tract and is metabolised by the CYP3A4 and CYP2C9 hepatic microsomal enzymes. Its major active metabolite (UK-103, 320) is the product of N-desmethylation of Sildenafil and has 50% of the potency of the parent compound [3]. The maximum observed concentrations of both substances occur within 1 h of oral dosage in adult male volunteers and increase proportionaly to the dose administered. The mean terminal half-lives of Sildenafil and UK-103, 320 are similar, between 3 and 5 h [4].

PDE-3 and 5 are the main PDE isoforms found in the pulmonary vasculature [5]. PDE-5 is specific for the breakdown of cyclic guanosine 3,5′-monophosphate (cGMP), the second messenger through which nitric oxide modulates pulmonary vascular tone [6]. There are few reports in the literature describing the selective pulmonary vasodilative action of Sildenafil in adults with pulmonary arterial hypertension [7], [8]. Sildenafil ameliorates the effects of nitric oxide withdrawal in infants with acute pulmonary hypertension after reparative surgery for congenital heart disease [9]. We have also reported the beneficial effects of Sildenafil therapy in a child with pulmonary arterial hypertension [10].

The purpose of the present study was to evaluate the safety and efficacy of medium term Sildenafil therapy in chronic pulmonary hypertension and assess its pharmacokinetics during oral administration in children.

Section snippets

Materials and methods

The study was approved by the Royal Brompton and Harefield and the National Heart and Lung Institute Ethics Committee and a written informed consent was obtained by the patients and their parents. Paediatric patients with a diagnosis of pulmonary arterial hypertension, either primary or associated with congenital heart disease were included [11]. Patients were excluded if they were taking nitric donors such as glyceryl trinitrate, had known allergy or hypersensitivity to phosphodiesterase

Results

All patients reported a subjective improvement in their clinical status after Sildenafil therapy with a change in NYHA functional class (Table 2). This effect did not seem to be dose-dependent, as increasing Sildenafil doses beyond 0.5 mg/kg were not associated with further improvement in the physical well-being described by the children or their guardians. Cycle ergometry was attempted at baseline in patients 1 and 3, but the test was terminated within the first 11/2 and 3 min, respectively,

Discussion

Pulmonary arterial hypertension may occur in childhood in association with congenital heart defects or as a primary disease process. Conventional therapy includes nocturnal oxygen, vasodilators, usually calcium channel antagonists and anticoagulation [16], [17]. There are currently newer forms of therapy available for patients with pulmonary arterial hypertension. These include prostacyclin and its analogues (Epoprostenol used as a continuous infusion, inhaled and intravenous Iloprost,

Acknowledgements

AAK was funded by the Royal Brompton Clinical Research Committee.

Sildenafil citrate was supplied by Pfizer Pharmaceuticals, Sandwich, Kent, UK.

Sildenafil plasma assays were performed by Sandwich Laboratories, Pfizer Ltd., Sandwich, Kent, UK.

Mrs. Sukeshi Makhecha (Specialist Pharmacist, Paediatrics) and Mrs. Vibha Teli (Principal pharmacy technician, drug information and clinical trials) at the Royal Brompton Pharmacy for their great help and advice.

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