Covalently linking a peptidyl carbamate elastase inhibitor to a hydrophilic polymer increases its effectiveness in preventing emphysema and secretory cell metaplasia in the hamster.
A peptidyl carbamate, p-nitrophenyl N-(succinyl-L-alanyl-L-alanyl-L-prolyl-methyl)-N-isopropylcarbamate++ + (PCI) was tested for its ability to inhibit the elastolytic activity of human neutrophil elastase (HNE) and to prevent HNE-induced emphysema and secretory cell metaplasia in the hamster. In vitro, 50% of the elastolytic activity of 10 micrograms of HNE was inhibited by 0.9 micrograms of PCI, a molar ratio of PCI to HNE of 4.5. Bronchoalveolar lavage of hamsters receiving PCI intratracheally showed a rapid decrease in HNE inhibitory activity (4 min for 50% decrease), suggesting rapid clearance, binding, or inactivation of the PCI. Instillation of 300 micrograms of HNE combined with 100, 500, or 3,000 micrograms PCI, a 16-, 83-, and 503-fold molar excess of PCI, respectively (molar ratios of 17, 84, and 504), suppressed HNE-induced lung hemorrhage, but it did not moderate HNE-induced emphysema despite the large molar excess of inhibitor. When PCI was covalently bound to a linear hydrophilic polymer of alpha,beta-poly[N(2-hydroxyethyl)-D,L-aspartamide], producing a polymer-bound carbamate inhibitor (PPCI) of HNE, the time for a 50% decrease of PPCI functional activity from the hamster lung lavage was 421 min. Instillation of 100 micrograms of PPCI 1 h before instillation of 300 micrograms HNE resulted in significant amelioration of emphysema; 900 micrograms of PPCI was required to obtain amelioration of bronchial secretory cell metaplasia. The larger dose of PPCI also provided significant amelioration of emphysema when the interval between PPCI and HNE administration was 8 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Stone
P J
PJ
Department of Biochemistry, Boston University School of Medicine, MA 02118.
Lucey
E C
EC
Noskova
D
D
Digenis
G A
GA
Snider
G L
GL
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006224:Cricetinae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D007322:Instillation, Drug; D019272:Leukocyte Elastase; D008297:Male; D008647:Mesocricetus; D008679:Metaplasia; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000737:chemistry; D011102:Polyhydroxyethyl Methacrylate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011656:Pulmonary Emphysema / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D014132:Trachea
D002219:Carbamates; D004338:Drug Combinations; D009842:Oligopeptides; C079381:4-nitrophenyl N-(succinyl-alanyl-alanyl-prolylmethyl)-N-isopropylcarbamate; D011102:Polyhydroxyethyl Methacrylate; C023037:poly(2-hydroxyethyl acrylate); D010196:Pancreatic Elastase; D019272:Leukocyte Elastase