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

Robbins IM, Hemnes AR, Gibbs JS, Christman BW, Howard L, Meehan S, Cabrita I, Gonzalez R, Oyler T, Zhao L, Du RH, Mendes LA, Wilkins MR
Exp Lung Res. 2011 37 (1): 26-34

PMID: 21077779 · DOI:10.3109/01902148.2010.512972

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.

MeSH Terms (30)

Administration, Oral Adult Antihypertensive Agents Biomarkers Biopterin Chemokine CCL2 Drug Therapy, Combination Endothelin Receptor Antagonists Exercise Test Exercise Tolerance Female Humans Hypertension, Pulmonary London Male Middle Aged Natriuretic Peptide, Brain Nitric Oxide Oxidative Stress Peptide Fragments Phosphodiesterase 5 Inhibitors Piperazines Purines Recovery of Function Sildenafil Citrate Sulfones Tennessee Time Factors Treatment Outcome Walking

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