Am. J. Respir. Crit. Care Med., Volume 157, Number 2, February 1998, 484-490

A Pilot Clinical Trial of Oral Sodium 4-Phenylbutyrate (Buphenyl) in F508-Homozygous Cystic Fibrosis Patients
Partial Restoration of Nasal Epithelial CFTR Function

RONALD C. RUBENSTEIN and PAMELA L. ZEITLIN

Eudowood Division of Pediatric Respiratory Sciences, The Johns Hopkins Medical Institutions, Baltimore, Maryland

Sodium 4-phenylbutyrate (Buphenyl, 4PBA) is a new FDA approved drug for management of urea cycle disorders. We have previously presented data suggesting that 4PBA, at clinically achievable concentrations, induces CFTR channel function on the plasma membrane of F508-expressing cystic fibrosis (CF) airway epithelial cells in vitro (Rubenstein, R. C., and P. L. Zeitlin, 1997. J. Clin. Invest. 100:2457- 2463). We hypothesized that 4PBA would induce epithelial CFTR function in vivo in individuals homozygous for F508-CFTR. A randomized, double-blind, placebo-controlled trial in 18 F508- homozygous patients with CF was performed with the maximum approved adult dose of 4PBA, 19 grams p.o. divided t.i.d., given for 1 wk. Nasal potential difference (NPD) response patterns and sweat chloride concentrations were determined before and after study drug treatment, and 4PBA and metabolites were assayed in plasma and urine at the end of study drug treatment. Subjects in the 4PBA group demonstrated small, but statistically significant improvements of the NPD response to perfusion of an isoproterenol/amiloride/chloride-free solution; this measure reflects epithelial CFTR function and is highly discriminatory between patients with and without CF. Subjects who had received 4PBA did not demonstrate significantly reduced sweat chloride concentrations or alterations in the amiloride-sensitive NPD. Side effects due to drug therapy were minimal and comparable in the two groups. These data are consistent with 4PBA therapy inducing CFTR function in the nasal epithelia of F508-homozygous CF patients.

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