Effects of pentoxifylline on sputum neutrophil elastase and pulmonary function in patients with cystic fibrosis: Preliminary observations,☆☆,,★★

Presented in part at the Sixth North American Cystic Fibrosis Conference, Washington, D.C., October 15-18, 1992.
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Abstract

High concentrations of free human neutrophil elastase in bronchial epithelial fluid are believed to be a major factor in the evolution of pulmonary injury in cystic fibrosis (CF). To test this hypothesis, we studied pentoxifylline, a compound that inhibits tumor necrosis factor alpha transcription and its stimulatory effect on polymorphonuclear neutrophils, in patients with CF who had chronic Pseudomonas bronchitis. Subjects older than 11 years of age randomly received placebo or pentoxifylline (1600 mg/day) orally, in a double-blind fashion, for 6 months. Pulmonary function and sputum elastase concentrations were determined before therapy and bimonthly during therapy; compliance was determined by measuring serum drug concentrations. Of the 16 patients who completed the study, 9 received pentoxifylline. The sputum elastase concentrations among placebo recipients were significantly increased from baseline at 4 and 6 months (F = 3.44; p < 0.05); the values remained unchanged in the treatment group. The mean forced vital capacity for the placebo group decreased from 59.2% ± 15.4% predicted at baseline to 52.0% ± 12.9% predicted at 6 months; the values in the treatment group remained largely unchanged. The forced vital capacity improved between baseline and 6 months for four of nine pentoxifylline recipients and none of the seven control patients (p = 0.09). During the study, four of seven placebo recipients experienced a significant pulmonary exacerbation compared with one of nine treated patients (p = 0.077). These findings support the hypothesis that polymorphonuclear neutrophil elastase is a factor in the evolution of CF lung disease; further studies are needed to define the role of pentoxifylline in the treatment of CF. (J PEDIATR 1994;125:992-7)

Section snippets

Patients

This study was approved by the West Virginia University Institutional Review Board for the Protection of Human Subjects; written, informed consent was ob tained from all subjects or their parents before study enrollment. All of the patients enrolled in this study had a sweat chloride concentration >60 mmol/L, either a family history or medical history compatible with CF, and documented respiratory colonization with P. aeruginosa antedating enrollment by at least 1 year. Patients who were

RESULTS

Twenty-two patients from the Mountain State Cystic Fibrosis Center fulfilled entry criteria. Two patients declined enrollment. Of the 20 patients who gave signed informed consent, 4 were dropped from the study: 2 patients failed to return as scheduled for the second pretherapy visit and 2 patients were noncompliant with drug therapy and follow-up visits. Of the remaining 16 patients, 7 were assigned to the control group and 9 to the treatment group (Table I). The two groups were similar in

DISCUSSION

Chronic pseudomonal endobronchitis leading to progressive pulmonary deterioration and ultimately to respiratory failure is the principal cause of morbidity and death in patients with CF.1 Baltimore et al.21 demonstrated that in lungs affected by CF, P. aeruginosa was found almost exclusively in the endobronchium, along with profound inflammation. Neutrophils are the predominant cell type found in CF sputa.22, 23, 24 Suter et al.4 demonstrated that sputum from Pseudomonas-infected patients with

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    From the Department of Pediatrics, West Virginia University School of Medicine, Morgantown, and Hoechst-Roussel Pharmaceuticals, Inc., Somerville, New Jersey.

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    Supported by grants from Hoechst-Roussel Pharmaceuticals, Inc., and the Cystic Fibrosis Foundation.

    Reprint requests: Stephen C. Aronoff, MD, Department of Pediatrics, West Virginia University School of Medicine, Health Science Center, Morgantown, WV 26506.

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