title: 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.
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. Ivan.Robbins@vanderbilt.edu
authors.forename: Ivan M
authors.initials: IM
authors.lastname: Robbins
authors.forename: Anna R
authors.initials: AR
authors.lastname: Hemnes
authors.forename: J Simon
authors.initials: JS
authors.lastname: Gibbs
authors.forename: Brian W
authors.initials: BW
authors.lastname: Christman
authors.forename: Luke
authors.initials: L
authors.lastname: Howard
authors.forename: Sharon
authors.initials: S
authors.lastname: Meehan
authors.forename: Ines
authors.initials: I
authors.lastname: Cabrita
authors.forename: Rochelle
authors.initials: R
authors.lastname: Gonzalez
authors.forename: Tracy
authors.initials: T
authors.lastname: Oyler
authors.forename: Lan
authors.initials: L
authors.lastname: Zhao
authors.forename: Rui-Hong
authors.initials: RH
authors.lastname: Du
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Mendes
authors.forename: Martin R
authors.initials: MR
authors.lastname: Wilkins
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001708:Biopterins / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018932:Chemokine CCL2 / Q000097:blood; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D005080:Exercise Test; D017079:Exercise Tolerance / Q000187:drug effects; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008131:London; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000097:blood; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D011687:Purines / Q000627:therapeutic use; D020127:Recovery of Function; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000627:therapeutic use; D013714:Tennessee; D013997:Time Factors; D016896:Treatment Outcome; D016138:Walking
chemical_list: D000959:Antihypertensive Agents; D015415:Biomarkers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D065128:Endothelin Receptor Antagonists; D010446:Peptide Fragments; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D001708:Biopterins; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; C003402:sapropterin