Safety of sapropterin dihydrochloride (6r–bh4) in patients with pulmonary hypertension

Abstract

The authors investigated the safety of oral tetrahydrobiopterin (BH4), a cofactor for nitric oxide synthesis, as a novel treatment for pulmonary hypertension (PH). Eighteen patients with pulmonary arterial hypertension or inoperable chronic thromboembolic PH received sapropterin dihydrochloride (6R-BH4), the optically active form of BH4, in addition to treatment with sildenafil and/or endothelin receptor antagonists in an open-label, dose-escalation study. 6R-BH4 was administered starting at a dose of 2.5 mg/kg and increasing to 20 mg/kg over 8 weeks. Changes in markers of nitric oxide synthesis, inflammation and oxidant stress, as well as exercise capacity and cardiac function were measured. 6R-BH4 was well tolerated at all doses without systemic hypotension, even when given in combination with sildenafil. There was a small but significant reduction in plasma monocyte chemoattractant protein (MCP)-1 levels on 5 mg/kg. No significant changes in measures of nitric oxide synthesis or oxidant stress were observed. There was improvement in 6-minute walk distance, most significant at a dose of 5 mg/kg, from 379 ± 61 to 413 ± 57 m 414 ± 57 m (P = .002). Oral 6R-BH4 can be administered safely in doses up to 20 mg/kg daily to patients with PH. Further studies are needed to explore its therapeutic potential.

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

“…Redox Signal. 20,[164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179][180][181][182] …”

“…Clinical studies examining the effects of xanthine oxidase inhibitors (70,204), tetrahydrobiopterin (sapropterin dihydrochloride [6r-bh4]) (167), and N-acetylcysteine (165) have demonstrated improved vascular function and blood pressure lowering in patients with hypertension, chronic kidney disease, and pulmonary hypertension. However, a recent clinical trial demonstrated that in patients with CAD, oral tetrahydrobiopterin treatment failed to improve endothelial function or cardiovascular outcomes, possibly due to autooxidation of the compound (47).…”

Effects of Tetrahydrobiopterin Oral Treatment in Hypoxia‐Induced Pulmonary Hypertension in Rat

“…Encouraging results also come from our recent clinical safety study of BH 4 in patients with pulmonary arterial hypertension, where BH 4 treatment at a dosage of 5 mg/kg/day was associated with a positive signal, an increase in 6-minute walk distance, and reduced plasma levels of monocyte chemoattractant protein 1. 42 Collectively, these data suggest that BH 4 supplementation has therapeutic potential for pulmonary hypertension.…”

New horizons in pulmonary arterial hypertension therapies

“…The efficacy of the eNOS coupling molecule, the eNOS co-factor sapropterin dihydrochloride, with PH has been assessed in the treatment of patients [60]. The small study of 18 patients monitored markers of NO synthesis, inflammation, exercise capacity and cardiac function [60].…”