We had concerns that patients would spontaneously cough or show bronchoconstriction, so we cannot explain our results other than as a valid reflection of protection from allergen-induced bronchoconstriction. Neither patient suggestibility nor clinician bias should allow patients to inhale 10 to 158 times more ragweed.
ICI 204,219 is one of several aerosol formulations of leukotriene receptor antagonists to be investigated in humans. FPL 55712, the first available inhaled leukotriene receptor antagonist, produced mild bronchodilation in two of four subjects with asthma, but further application of the drug was limited by its associated throat discomfort. Aerosol formulations of SKF 104,353, a potent antagonist of LTD4 and LTE4, and L-648,051, a selective competitor of LTC4 and of LTD4, are currently being evaluated in clinical studies. Bel et al evaluated the effects of inhaled L-648,051 on the airway response to inhaled antigen in 10 subjects with asthma who inhaled doses of 12 mg of L-648,051 before and 3 h after the allergen challenge. In contrast to the results with ICI 204,219, there was no consistent effect on antigen-induced airway responsiveness. The relative lack of effect with L-648.051 suggested that either the potency or duration of activity of L-648,051 is limited or that LTC4 and LTD4 do not play an important role in human allergic asthma. A subsequent study was conducted with 800 jig of inhaled L-648,051 to determine its ability to prevent and reverse antigen-induced asthma. L-648,051, when given prophylactically, had a slight but significant effect on airway resistance during the early phase but not during the late phase. Some improvement in FEV, and FVC was observed during the early phase; however, the changes were not statistically significant. When given after the antigen challenge, L-648.051 was not effective in reversing antigen-induced asthma. From these results, the investigators concluded that LTD4 does play a role in the immediate phase of antigen-induced asthma, but that higher doses of L-648,051 should be tested in humans. canadian health mall
ICI 204,219 is the only leukotriene receptor antagonist that has been shown to be effective in blocking bronchoprovocation when given both by the oral and inhaled routes. An oral dose of 40 mg was given 2 h before the cat-dander challenge, whereas only 0.2 mg of inhaled ICI 204,219 was required 30 min before ragweed challenge. In the former study, which used a comparable challenge protocol, oral ICI 204,219 shifted the PC20 significantly, approximately tenfold on average. Two of 13 subjects (15 percent) had censored responses. In contrast, the lower doses of inhaled ICI 204,219 used in this study shifted the PC20 significantly, approximately 46-fold on average. Thirty-one of 39 subjects (79 percent) showed a censored response. These data suggest that the inhaled route of administration may have provided higher local concentrations of active drug in the airway than the oral formulation. Generally, inhaled formulations for existing respiratory therapies have achieved broad acceptance because of their rapid onset of action and improved therapeutic-to-toxic ratio. In addition, inhaled premedications can be given in a more timely or spontaneous fashion than oral medications when a known bronchoconstrictive exposure is occurring.
In conclusion, we have demonstrated that inhalation formulations of ICI 204,219 successfully inhibited bronchoconstriction in subjects with reproducible sensitivity to ragweed challenges.