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
Twenty-seven adverse events were recorded for ten subjects. All adverse events were mild (n = 16) or moderate (n = 11); the most common events were headache (n = 6), rhinitis (n = 4), and cough (n = 3). No serious or unexpected adverse events were attributed to ICI 204,219.
Clinical laboratory tests showed a significant (p = 0.02) treatment difference in white blood cell count, with subjects taking formulation 1 having a significantly lower count than subjects taking formulation 2 (p = 0.006, 5.71 vs 6.35 x 103/L). This difference was not deemed to be clinically significant. Findings from physical examinations, electrocardiograms, and vital signs measurements were not statistically significantly different from baseline after treatment with ICI 204,219.
Our results indicate that inhalation formulations of ICI 204,219 successfully inhibited bronchoconstriction in subjects with reproducible sensitivity to ragweed challenges. Inhaled ICI 204,219, given 30 min before ragweed challenge, produced total inhibition of ragweed-induced bronchoconstriction in 31 of 39 challenges in 13 subjects with mild asthma who were tested in the absence of environmental exposure to ragweed. There were no differences in the results of antigen bronchoprovocation when patients were tested either 3 days or 4 weeks apart. Antigen-induced bronchoprovocation, therefore, appears to be a useful model to evaluate the efficacy of leukotriene receptor antagonists for the treatment of asthma, provided appropriate steps are taken to ensure the accuracy of the bronchoprovocation test results. In this study, in contrast to a previous study, we required subjects to have two reproducible screening provocations with ragweed before they underwent bronchoprovocation. canadian neightbor pharmacy
Fifteen subjects were given medications for allergic rhinitis and asthma during the intervals between allergen challenges, and five subjects received medications for other indications. None of the subjects received steroids or cromolyn in any form.
All 13 subjects had at least a 20 percent decrease in FEV, at both screening challenges, with responses provoked at allergen concentrations ranging from 0.05 to 6.25 |xg/ml.
Figure 1 shows allergen-induced changes in FEV, for subjects after both screening challenges and challenges after administration of ICI 204,219. Table 2 summarizes bronchial challenge test results by formulation; Table 3 presents bronchial challenge test results for each of the 13 subjects. canadian health&care mall
The majority of subjects tolerated bronchoprovocation testing without a 20 percent decrease in FEV, (31 of 39 challenges). The mean (SE) log shift was 1.6 (0.23), with a 95 percent confidence interval of a 1.0 to 2.2 log shift (10- to 158-fold shift). This was a significant (p = 0.0001) shift from the screening values. No statistically significant differences were observed between formulations. Six subjects had a 20 percent decrease in FEV, at end point allergen concentrations greater than fourfold of the screen concentrations. Only two subjects had a 20 percent decrease in FEV, at end point allergen concentrations within two dilutions of their maximum screen concentrations; one of the subjects received formulation 2 (four puffs), and the other subject received formulation 3 (one puff).
Power calculations included information from ten subjects with reproducible baseline data from a previous allergen-chal-lenge study. A sample size of 24 subjects in a three-period crossover design and the reproducibility criterion for baseline eligibility allowed detection of shifts greater than two allergen dilutions in the mean response to the ICI 204,219 formulations at an a level of 0.10 with a power of 80 percent. These levels were chosen to allow a reasonable estimate of equivalence for the protective effects of the aerosol formulations, given the limited number of subjects expected to meet entrance criteria.
Analysis of variance in a three-period crossover design was used to analyze safety data (vital signs measurements, pulmonary function test results, and laboratory test results). Changes in laboratory data within treatments were assessed by paired t tests. cialis professional
The efficacy of ICI 204,219 was assessed by measuring pulmonary function before and after bronchoprovocation during each treatment period. Following administration of ICI 204,219, subjects inhaled five breaths of control aerosol consisting of saline solution solvent. Baseline FEV, and forced vital capacity (FVC) were measured 10 min later. A dose-response curve was then derived for each subject after administering five inhalations of antigen at each of a series of increasing concentrations, with 10- to 15-min intervals between successive concentrations. sildenafil citrate pink
Subjects could not use inhaled or oral steroids, cromolyn sodium, or long-acting theophylline for the treatment of asthma. Acetaminophen was the sole nonprescription medication permitted for analgesia. Subjects were not permitted to receive prescription medications for acute exacerbation of asthma within 12 h of each trial period. Prescription medication was permitted during the study only after mutual consent of the investigator and the sponsor. All subjects were prohibited from consuming alcohol, caffeine, or any medication (other than those permitted above) that could theoretically interact with the trial medication. Written informed consent was obtained from each subject, and the study was approved by the appropriate Institutional Review Board (Western Institutional Review Board, Olympia, Wash).
During the 2 weeks before the trial, each subject provided a medical history and underwent a complete physical examination, 12-lead electrocardiography, routine clinical laboratory tests, a urine screen for drug abuse, pulmonary function tests, measurements of vital signs, and a determination of subjective symptoms. Subjects stopped taking all asthma and allergy medications at least 12 h before entering the study. canadian neightbor pharmacy
The sulfidopeptide leukotrienes (LTC4, LTD4, and LTE4), 5-lypoxygenase products of arachidonic acid metabolism, are believed to play a role in the pathogenesis of asthma. The sulfidopeptide leukotrienes constrict human airway smooth muscle, increase secretion of bronchial mucus,2 and increase vascular permeability, resulting in mucosal edema. Because leukotrienes are generated in response to antigen challenges, it has been hypothesized that leukotriene receptor antagonists could modify the airway response to antigen broncho-provocation. One approach to validating this hypothesis is to examine the effects of leukotriene receptor antagonists in subjects with asthma who are challenged in a controlled setting.