Efficacy of Ibuprofen and Pentoxifylline in the Treatment of Phosgene-induced Acute Lung Injury

Abstract

Phosgene, a highly reactive former warfare gas, is a deep lung irritant which produces adult respiratory distress syndrome (ARDS)‐like symptoms following inhalation. Death caused by phosgene involves a latent, 6–24‐h, fulminating non‐cardiogenic pulmonary edema. The following dose‐ranging study was designed to determine the efficacy of a non‐steroidal anti‐inflammatory drug, ibuprofen (IBU), and a methylxanthine, pentoxifylline (PTX). These drugs were tested singly and in combination to treat phosgene‐induced acute lung injury in rats. Ibuprofen, in concentrations of 15–300 mg kg−1 (i.p.), was administered to rats 30 min before and 1 h after the start of whole‐body exposure to phosgene (80 mg m−3 for 20 min). Pentoxifylline, 10–120 mg kg−1 (i.p.), was first administered 15 min prior to phosgene exposure and twice more at 45 and 105 min after the start of exposure. Five hours after phosgene inhalation, rats were euthanized, the lungs were removed and wet weight values were determined gravimetrically. Ibuprofen administered alone significantly decreased lung wet weight to body weight ratios compared with controls (P ⩽ 0.01) whereas PTX, at all doses tested alone, did not. In addition, the decrease in lung wet weight to body weight ratio observed with IBU+PTX could be attributed entirely to the dose of IBU employed. This is the first study to show that pre‐ and post‐treatment with IBU can significantly reduce lung edema in rats exposed to phosgene.

Temporal Changes in Respiratory Dynamics in Mice Exposed to Phosgene

“…We have shown that as time increases there is a significant reduction in macrophages and increase in neutrophils in the lavage fluid of mice (Duniho et al, 2001). We have investigated the use of ibuprofen in three different animal models and found that ibuprofen not only reduced the lung wet/dry weight ratio, but also increased survival rates in mice when treatment occurred after exposure (Kennedy et al, 1990;Sciuto et al, 1996b;Sciuto, 1997). The delivery of these agents to exposed individuals should be through inhalation.…”

Clinical Drug Treatment of Edemagenic Gas-Induced Lung Injury

“…Dosing times were determined based on the t'/a of IBU, which is about 2-4 h, and on previous work done in this laboratory using rats (37). ffiU was mixed in saline 42 mg/ml and pH was adjusted to 7.5 with 300 nl of 0.25 M HCl; the BU was then sterile filtered using a 0.45^ filter cup.…”

“…Earlier studies, one an isolated perfused rabbit lung and the other, pre/post-treatment administration in rats, focused on the amelioration of phosgene-induced pulmonary edema (37,70). This study focused solely on the survival of mice treated with IBU following a lethal dose of phosgene.…”

Ibuprofen Treatment Enhances the Survival of Mice Following Exposure to Phosgene

“…Dosing times were determined based on the t ½ of IBU, which is about 2-4 h, and on previous work done in this laboratory using rats (Sciuto et al, 1996b). Drug concentrations were determined by the method of Chan, which involved calculations based on the LD50 (Chan et al, 1973).…”

“…IBU, a cyclooxygenase inhibitor, has been shown to be efficacious in several acute lung injury models such as smoke inhalation (Stewart et al, 1990;Shinoza et al, 1986), paraquat (Lindenschmidt et al, 1983), and acid aspiration (Utsunomiya et al, 1982). IBU has also been examined successfully in previous phosgene inhalation models Sciuto et al, 1996b).…”