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.
Publication types
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Clinical Trial, Phase I
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Multicenter Study
MeSH terms
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Administration, Oral
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Adult
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Antihypertensive Agents / administration & dosage
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Antihypertensive Agents / adverse effects
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Antihypertensive Agents / therapeutic use*
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Biomarkers / blood
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Biopterins / administration & dosage
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Biopterins / adverse effects
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Biopterins / analogs & derivatives*
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Biopterins / therapeutic use
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Chemokine CCL2 / blood
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Drug Therapy, Combination
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Endothelin Receptor Antagonists
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Exercise Test
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Exercise Tolerance / drug effects
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Female
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Humans
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Hypertension, Pulmonary / drug therapy*
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Hypertension, Pulmonary / metabolism
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Hypertension, Pulmonary / physiopathology
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London
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Male
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Middle Aged
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Natriuretic Peptide, Brain / blood
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Nitric Oxide / metabolism
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Oxidative Stress / drug effects
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Peptide Fragments / blood
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Phosphodiesterase 5 Inhibitors / therapeutic use
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Piperazines / therapeutic use
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Purines / therapeutic use
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Recovery of Function
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Sildenafil Citrate
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Sulfones / therapeutic use
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Tennessee
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Time Factors
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Treatment Outcome
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Walking
Substances
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Antihypertensive Agents
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Biomarkers
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CCL2 protein, human
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Chemokine CCL2
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Endothelin Receptor Antagonists
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Peptide Fragments
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Phosphodiesterase 5 Inhibitors
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Piperazines
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Purines
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Sulfones
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pro-brain natriuretic peptide (1-76)
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Natriuretic Peptide, Brain
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Biopterins
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Nitric Oxide
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Sildenafil Citrate
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sapropterin