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Biomedical subjects

D W Cockcroft

Publications and source records attributed to D W Cockcroft.

At least 37 records · Page 2Linked to original sources
PubMed1999

Effect of aerosolized anti-IgE (E25) on airway responses to inhaled allergen in asthmatic subjects.

Intravenous administration of a humanized monoclonal antibody of IgE (E25) attenuates the early and late phase response to inhaled allergen in allergic asthmatic subjects. To test whether direct delivery of E25 to the airway might have the same effect, we conducted a randomized, double-blind, three group study in 33 subjects with mild allergic asthma (20 to 46 yr of age, 21 men, FEV(1) > 70% predicted). The airway responses to aerosolized allergen were determined at baseline, after 2 and 8 wk of once daily treatment with aerosolized placebo (n = 11), aerosolized E25 1 mg (n = 12), or aerosolized E25 10 mg (n = 10), and after 4 wk of treatment withdrawal. We found that E25 was detectable in the serum during aerosol treatment, although serum IgE did not change significantly in any of the three groups during treatment. In addition, both doses of E25 were no more effective than placebo in attenuating the early phase responses to allergen at both times during treatment. Although aerosolized E25 was generally well tolerated, one subject receiving aerosolized E25 10 mg daily was found to have serum IgG and IgA antibodies to E25. We conclude that aerosol administration of an anti-IgE monoclonal antibody does not inhibit the airway responses to inhaled allergen in allergic asthmatic subjects. We speculate that the observed lack of efficacy may be due to the inability of aerosol route of delivery to result in high enough concentrations of E25 in the tissue compartments surrounding IgE effector cells to neutralize IgE arising from local airway and pulmonary sources and IgE arising from the vascular space. Additionally, the aerosol route of delivery of monoclonal antibodies may be more immunogenic than the parenteral route.

Administration, Inhalation↗
PubMed1999

Pharmacologic therapy for asthma: overview and historical perspective.

For the 30 years between 1967 and 1997, pharmacologic therapy of asthma has consisted primarily of five classes of drugs, beta 2-agonists, anticholinergics, theophyllines, cromones, and corticosteroids. The first four of these classes of drugs have origins in herbal treatments going back 5000 or 6000 years. This article briefly reviews the history of asthma pharmacotherapy up to the late 1990s and outlines a current approach to the pharmacotherapy of asthma, which is but one component of an integrated overall approach to asthma treatment involving patient education and environmental control as well.

Adrenal Cortex Hormones↗
PubMed1998

Inhaled beta2-agonists and airway responses to allergen.

A series of investigations show that the regular use of inhaled beta2-agonists will increase all aspects of the airway response to allergen. The mechanism of this effect is uncertain; however, it appears to be different from the mechanism that produces tolerance to beta2-agonist effects. One possibility is that the regular use of beta2-agonists might induce a mast cell beta-receptor dysfunction that might make mast cells more prone to release mediators. As a result beta2-agonist use plus allergen exposure might cause more mediator release than does allergen exposure alone. The corollary of this is that beta2-agonist use plus allergen exposure might cause more airway inflammation than does allergen exposure alone. These hypotheses are both testable. I believe that this is a clinically important phenomenon and may well be a major reason for beta2-agonist-induced worsened asthma control. Further investigations are indicated to identify the mechanism and the clinical relevance of the phenomenon.

Adenosine Monophosphate↗
PubMed1998

Comparison of 3 different doses of budesonide and placebo on the early asthmatic response to inhaled allergen.

BACKGROUND: A simple laboratory method to evaluate relative potency of inhaled corticosteroids in asthma would be valuable. Single-dose studies with the allergen-induced late asthmatic response have failed to show a useful dose-response relationship. Treatment for several days with inhaled corticosteroids will also inhibit the allergen-induced early asthmatic response. METHODS: Twelve atopic asthmatic subjects were studied during a season when no medications were required except ipratropium bromide as needed. These subjects had positive allergen and methacholine inhalation tests and FEV1 greater than 70% of predicted value. A double-blind, randomized, cross-over study compared placebo and budesonide 100, 200, and 400 microg administered by means of Turbuhaler twice daily for 7 days with 6-day washout periods. Methacholine PC20 was measured before and after 6 days of treatment, and allergen PC15 was measured after 7 days of treatment. RESULTS: The allergen PC15 (n = 11) was significantly larger (P = .0001) for all doses of budesonide compared with placebo, but there was no significant difference between the 3 doses of budesonide, and no dose response was demonstrated. The methacholine PC20 was significantly larger after all budesonide treatments compared with placebo (P = .024), but there was no difference between the 3 doses. There was a progressive increase in the allergen PC15 chronologically (sequence effect) that was not explained by improvement in FEV1 or airway responsiveness; sequence effects were not seen for FEV1 or for pretreatment or posttreatment methacholine PC20. Statistical adjustment for sequence effect did not alter allergen PC15 statistics. CONCLUSION: A 7-day course of budesonide administered by means of Turbuhaler at 200, 400, or 800 microg per day provided marked and significant inhibition of the allergen-induced early asthmatic response compared with placebo. There was, however, no difference between the 3 doses. Therefore this method with these doses is not useful for providing assessment of relative potency.

Administration, Inhalation↗
PubMed1998

Tolerance to the bronchoprotective effect of salmeterol 12 hours after starting twice daily treatment.

BACKGROUND: Regular use of salmeterol has been associated with reduced bronchoprotective effect against methacholine as early as 24 hours after initiating treatment. OBJECTIVE: To determine whether loss of the bronchoprotective effect measured one hour after salmeterol could be demonstrated 12 hours following one previous dose. METHODS: Ten subjects with stable, mild asthma were enrolled in a randomized, placebo-controlled, double-blind, crossover study comparing two 2-dose treatment periods: (1) blinded salmeterol 50 microg inhaled at bedtime, followed by unblinded salmeterol 50 microg inhaled 12 hours later and (2) blinded placebo inhaled at bedtime, followed by unblinded salmeterol 50 microg inhaled 12 hours later. The methacholine PC20 was measured one hour after the morning salmeterol; FEV1 was measured just prior to the morning salmeterol dose and at the start of the methacholine inhalation test. RESULTS: The mean log methacholine PC20 recorded one hour after a single dose of salmeterol (1.20 +/- 0.17 SE) was significantly higher than the mean log methacholine PC20 recorded after two doses of salmeterol at 12-hour intervals (1.00 +/- 0.16 SE; P = .024). The mean FEV1 12 hours after salmeterol was significantly higher than the mean FEV1 recorded 12 hours after placebo (P = .0017), however, there was no significant difference between the FEV1 recordings one hour after the two unblinded doses of salmeterol. CONCLUSIONS: Tolerance to the bronchoprotective effect of salmeterol against methacholine induced bronchoconstriction occurs extremely quickly as it is evident 12 hours after starting twice daily treatment.

Administration, Inhalation↗
PubMed1997

Evaluation of single-dose inhaled corticosteroid activity with an allergen challenge model.

BACKGROUND: Inhaled corticosteroids are the most commonly used antiinflammatory agents for asthma. There is no simple way to compare objectively the relative potency of inhaled corticosteroids. The allergen-induced late asthmatic response (LAR) can be suppressed by a single dose of inhaled corticosteroid. OBJECTIVE: This study was undertaken to evaluate LAR as a model for the determination of the relative potency of single doses of inhaled corticosteroids. METHODS: We compared doses of 200 and 800 microg of a highly active inhaled corticosteroid (budesonide) with placebo and a marginally active investigational inhaled corticosteroid (D5159). Ten atopic patients with asthma completed a randomized, double-blind, double-dummy, multicenter, four-way, crossover trial. A standardized allergen challenge with the identical dose of allergen was performed 10 minutes after each of four blinded, single-dose treatments: 200 microg of budesonide, 800 microg of budesonide, 8 mg of D5159, and placebo, all administered from Turbuhaler. The LAR was recorded as the maximum percent fall in FEV1 between 4 and 7 hours, and the allergen-induced increase in methacholine airway responsiveness at 24 hours was recorded as the A log PC20 from the day before to the day after allergen challenge. RESULTS: There were no significant differences in the early asthmatic responses during the 4 days; the mean maximum percent in FEV1 fall ranged between 19.5% and 22%. D5159 produced a slight inhibition of the LAR with maximum percent fall in FEV1 recorded as 28.8% +/- 5.0% for D5159 versus 34.1% +/- 4.8% for placebo (p < 0.05). There was a greater reduction recorded after administration of the two doses of budesonide. The mean LAR was 15.1% +/- 3.8% for 200 microg of budesonide and 11.2% +/- 2.3% for 800 microg of budesonide (p < 0.01 compared with placebo and D5159). The two doses of budesonide were not statistically different. Airway responsiveness to methacholine increased by 1.07 doubling doses 24 hours after allergen challenge. This increased airway responsiveness was slightly, but not significantly, reduced by the three active treatments (0.6 to 0.91 doubling doses). CONCLUSION: The allergen-induced LAR model was able to differentiate a single dose of an active inhaled corticosteroid from placebo and a highly potent inhaled corticosteroid from a weak inhaled corticosteroid. The model did not differentiate between 2 fourfold doses of the highly active inhaled corticosteroid (at the doses used in this study), neither for the fall in FEV1 nor for the increase in airway hyperresponsiveness.

Administration, Inhalation↗
PubMed1997

The current dilemma with spirometric inclusion criteria for asthma drug trials.

BACKGROUND: Spirometric inclusion criteria for asthma drug studies often require resting airflow obstruction and resting bronchoconstriction. By current standards, these criteria define suboptimal to poor asthma control. OBJECTIVE: To determine what proportion of asthmatic patients attending a tertiary University-based respiratory clinic meet typical drug study spirometric criteria of a baseline FEV1 of 50% to 80% predicted and > or = 15% delta FEV1 improvement following 200 micrograms inhaled albuterol. METHODS: A retrospective review was performed on charts of white caucasian asthmatic patients attending three respiratory physician outpatient clinics at a University-based tertiary referral center. We reviewed charts of all patients with chronic asthma under current therapy. We excluded subjects with additional lung diseases that might affect lung function. Spirometric data were extracted from the most recent scheduled outpatient visit. RESULTS: We reviewed 590 charts of patients with mean age 35.3 +/- 18.3 years (range 6 to 94), 43% male, and 50% atopic. There was objective evidence of variable airflow obstruction or airway hyperresponsiveness in 70.2%; the diagnosis of asthma was based on historical data alone in 29.8%. The majority of patients (87.5%) required inhaled corticosteroids with more than 50% using medium to high doses. Baseline FEV1 was > 80% in 84.6% of subjects, 50% to 80% in 14.4%, and < 50% in 1.0%. FEV1 improved by > or = 15% 10 to 15 minutes after 200 micrograms inhaled albuterol in 13.6%. Only 9.0% of the 590 asthmatic patients fulfilled both criteria (FEV1 50% to 80% and delta FEV1 > or = 15%). CONCLUSION: Less than 10% of asthmatic patients attending a tertiary referral respiratory clinic fulfilled typical spirometry inclusion criteria for asthma drug trials. We suggest this approach to enrollment in asthma drug studies be reevaluated.

Administration, Inhalation↗
PubMed1997

Effect of single doses of S-salbutamol, R-salbutamol, racemic salbutamol, and placebo on the airway response to methacholine.

BACKGROUND: Commercially available salbutamol is a racemic mixture consisting of equal amounts of the two enantiomers, R-salbutamol and S-salbutamol, felt to be active and inert, respectively. METHODS: A double blind, randomised, four way, crossover study was performed in 12 well controlled asthmatic subjects (forced expiratory volume in one second (FEV1) > 70% predicted, no beta 2 agonists for > or = 4 weeks). Subjects were studied on four days at intervals of 48 hours to seven days. FEV1 was assessed before and both FEV1 and methacholine PC20 were measured 20 and 180 minutes after a single dose of nebulised racemic salbutamol 2.5 mg, R-salbutamol 1.25 mg, S-salbutamol 1.25 mg, and placebo. RESULTS: Equivalent bronchodilation was seen for both R-salbutamol and racemic salbutamol (mean (SE) 12.4 (3.1)% and 12.0 (3.0)%, respectively, at 20 minutes and 5.9 (2.9)% and 5.2 (2.2)% at 180 minutes). The increase in FEV1 of 5.2 (0.9)% at 20 minutes and the decline in FEV1 of 2.9 (2.1)% at 180 minutes after S-salbutamol were not significantly different from the placebo response. Compared with placebo the methacholine PC20 after R-salbutamol and racemic salbutamol improved by 3.3 (95% CI 2.5 to 4.1) and 3.4 (95% CI 2.6 to 4.2) doubling doses, respectively, at 20 minutes and 1.2 (95% CI 0.6 to 1.8) and 1.0 (95% CI 0.2 to 1.8) doubling doses at 180 minutes. S-salbutamol resulted in an improvement of 0.9 (95% CI 0.3 to 1.5) doubling doses at 20 minutes and no change at 180 minutes. Restlessness (n = 11) and increased pulse were seen 20 minutes after racemic and R-salbutamol but not S-salbutamol or placebo, and not at 180 minutes. There were no other adverse events. CONCLUSION: A single dose of 1.25 mg nebulised R-salbutamol produced equivalent bronchoprotection, bronchodilation, restlessness, and tachycardia as did 2.5 mg of racemic salbutamol. S-salbutamol 1.25 mg had a weak bronchoprotective effect; this could be because of a small amount of contamination with R-salbutamol or because S-salbutamol is an intrinsically weak beta 2 receptor stimulant.

Adult↗
PubMed1997

Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response.

Inhaled allergens, acting through IgE-dependent mechanisms, are important triggers of asthma symptoms and inducers of airway hyperresponsiveness and airway inflammation. The effect of anti-IgE recombinant humanized monoclonal antibody-E25 (rhuMAb-E25) on the provocation concentration of allergen causing a 15% fall in FEV1 (allergen PC15) during the allergen-induced early asthmatic response (EAR) was assessed in a multicenter, randomized, double-blind, parallel group study. Ten of 11 allergic asthmatic subjects randomized to receive intravenous rhuMAb-E25, 2 mg/kg on study day 0 and 1 mg/kg on Days 7, 14, 28, 42, 56, and 70 completed the study; nine received intravenous placebo. The allergen PC15 was measured on Days -1, 27, 55, and 77 and methacholine PC20 on Days -2, 42, and 76. rhuMAb-25 was well tolerated and only one patient (active group) was withdrawn because of a generalized urticarial rash after the first dose. Compared with baseline values (Day -1), the median allergen PC15 on Days 27, 55, and 77 were increased by 2.3, 2.2, and 2.7 doubling doses (delta log PC15/0.3) respectively with rhuMAb-E25 and -0.3, +0.1, and -0.8 doubling doses with placebo (p < or = 0.002). Methacholine PC20 improved slightly after rhuMAb-E25, this change becoming statistically significant on Day 76 (p < 0.05); no change was observed in the placebo group. Mean serum-free IgE fell by 89% after rhuMAb-E25 while there was no significant change after placebo. The inhibitory effects of rhuMAb-E25 on allergen-induced EAR suggest that it may be an effective, novel antiallergic treatment for asthma.

Adult↗
PubMed1996

Outpatient asthma management.

Asthma is an inflammatory disease. Educated asthmatics can be involved in self-managements strategies that focus on prevention and treatment of airway inflammation using environmental control and inhaled corticosteroids as the cornerstones of therapy. It is hoped that such an approach will reduce asthma morbidity and mortality rates.

Ambulatory Care↗
PubMed1996

The beta-agonist controversy.

After many years of increasing morbidity and mortality, several avenues of scientific investigation now appear to be converging to offer an explanation for the asthma paradox and indicate that regular or long-term use of short-acting inhaled beta-agonist drugs is inappropriate. Pharmacoepidemiologic studies indicate a strong association between increased beta-agonist use and asthma deaths, which does not appear entirely related to confounding by severity. Clinical data, although still limited, show little evidence for symptomatic or functional improvement during long-term beta-agonist therapy and, in many instances, reveal significant adverse effects. Related investigations offer evidence of potential plausible mechanisms, notably increased bronchial responsiveness to inhaled allergen, to explain these findings. A radical revision of the therapeutic use of these drugs in asthma has been prompted by these findings. Beta-agonist drugs remain essential for the management of acute severe attacks. They are also useful on demand for the relief of breakthrough symptoms and for prophylaxis of exercise-induced symptoms. In chronic asthma, however, adequate anti-inflammatory therapy is the treatment of choice. Long-term treatment with short-acting beta-agonist, even in the presence of seemingly adequate anti-inflammatory therapy, may be associated with deterioration of asthma over the long-term. The effects of long-acting beta-agonists remain under review. To date, there are no data that clearly indicate a deleterious effect, and many clinical trials show benefits in symptom control and improved lung function associated with their regular use. The significance of tachyphylaxis remains to be defined. Their current role is still somewhat unclear, but they have been successfully used in subjects in whom, despite the use of moderate doses of inhaled corticosteroid, short-acting bronchodilator is still frequently required. The use of twice-daily long-acting beta-agonist appears preferable to frequent use of short-acting beta-agonists.

Adrenergic beta-Agonists↗
PubMed1996

Salbutamol-induced increased airway responsiveness to allergen and reduced protection versus methacholine: dose response.

BACKGROUND: Two adverse effects of inhaled beta 2-agonists are increased airway responsiveness to allergen and tolerance to the bronchoprotective effect of beta 2-agonists versus bronchoconstrictors (e.g., methacholine). OBJECTIVE: We studied three doses of inhaled salbutamol, 200, 400, and 800 micrograms/day, to determine dose-response curves for these two adverse effects. METHODS: Ten atopic patients with mild, stable asthma free of all asthma medications, allergen exposure, and respiratory tract infection for at least 4 weeks participated in a double-blind, random-order, crossover study. There were four 1-week treatment periods with a 1-week washout period: placebo, salbutamol 200 micrograms, 400 micrograms and 800 micrograms per day. After each treatment, we assessed FEV1, bronchodilation 10 minutes after administration of 200 micrograms of salbutamol, methacholine PC20, methacholine dose-shift after administration of 200 micrograms of salbutamol, and allergen PC20. RESULTS: There was no significant difference in baseline FEV1, bronchodilation, or methacholine PC20. The methacholine dose shift was maximum after the placebo (3.4 +/- 0.22 doubling doses) and was significantly greater (p < 0.01) than all salbutamol regimens (2.2 to 2.6), which were not significantly different from each other (p > 0.05). Allergen PC20 was significantly lower (p < 0.02) after salbutamol 800 micrograms/day (geometric mean = 288 protein nitrogen units [PNU]/ml) than each of the other treatments (447 to 550 PNU/ml), which were not significantly different from each other (p > 0.05). CONCLUSION: Significant increase in airway responsiveness to allergen occurred only with the largest dose of inhaled salbutamol (800 micrograms/d); however, tolerance to the acute bronchoprotective effect of salbutamol was observed with all the three salbutamol regimens, even 200 micrograms/day. This suggests different mechanisms may be operative in producing these two effects.

Adolescent↗