Abstract
Studies were conducted to assess the efficacy and safety of a synthetic peptide-containing surfactant in the treatment of respiratory distress syndrome (RDS) in preterm (approximately 80% of normal gestation) infant rhesus monkeys. Surfactant was prepared consisting of the phospholipids dipalmitoylphosphatidyl choline and palmitoyl-oleoyl phosphatidyl glycerol and a synthetic peptide modeled after surfactant protein B (SP-B),“KL4-Surfactant” contained a peptide having the sequence KLLLLKLLLLKLLLLKLLLLK, where “K” is lysine and “L” is leucine. The peptide was selected because it mimics the repeating stretches of hydrophobic residues with intermittent basic hydrophilic residues seen in SP-B. KL4-Surfactant was shown to have biophysical activity assessed as the ability to lower surface tension at an air-liquid interface in a pulsating bubble surfactometer. Thirty premature rhesus monkeys were treated shortly after birth with one dose of KL4-Surfactant. The arterial to alveolar oxygen partial pressure ratio (a/A) was found to rise from a pretreatment level of 0.11 ± 0.01 (mean ± SEM), indicative of severe RDS, to 0.40 ± 0.02 at 12-13 h post-treatment. The improvement in oxygenation persisted throughout the study period, with a mean a/A at 22-23 h of 0.45± 0.07. Chest radiographs and gross and microscopic examination of the lungs all confirmed the reversal of the atelectasis seen before treatment. Animals treated with a dose of 200 mg/kg showed a faster, more consistent, and greater response than did a group treated with an average dose of 127 mg/kg. There was no evidence of toxicity after treatment with the higher dose as demonstrated by physiologic, hematologic, biochemical, and pathologic data. The importance of the peptide in the synthetic surfactant was apparent from the results obtained with a control group of nine premature monkeys treated with a non-peptide-containing surfactant; the a/A of this group was 0.15± 0.03 at nine hours of age as compared with a value of 0.38 ± 0.02 for 30 comparable animals receiving KL4-Surfactant.
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Abbreviations
- a/A:
-
ratio of arterial to alveolar oxygen tension
- DPPC:
-
dipalmitoyl-sn-glycero-3-phosphocholine
- Fio2:
-
fraction of inspired oxygen
- MAP:
-
mean airway pressure
- PG:
-
phosphatidyl glycerol
- POPG:
-
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol
- RDS:
-
respiratory distress syndrome
- SP:
-
surfactant protein
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Acknowledgements
The authors are grateful to Kenway Hoey, Tom Madden, and Pete Glavinos for preparation of synthetic peptides and many of the batches of peptide containing surfactant. We thank Dr. Colin Bloor for the morphometric analyses of lung histologic sections. We also thank Sarah Davis and the staff of the California Regional Primate Research Center in Davis, CA, without whose expert assistance these studies could not have been performed.
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Supported by Grant HL-23584 from the Public Health Service, Grant N00014 from the Office of Naval Research, Primate Research Center Grant National Institutes of Health RR00169, and by the R. W. Johnson Pharmaceutical Research Institute.This is publication number 9057-IMM from the Department of Immunology, The Scripps Research Institute.
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Revak, S., Merritt, T., Cochrane, C. et al. Efficacy of Synthetic Peptide-Containing Surfactant in the Treatment of Respiratory Distress Syndrome in Preterm Infant Rhesus Monkeys. Pediatr Res 39, 715–724 (1996). https://doi.org/10.1203/00006450-199604000-00025
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DOI: https://doi.org/10.1203/00006450-199604000-00025
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