C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks--final results of the I.M.P.A.C.T.2 study.

BACKGROUND: The placebo-controlled study International Multicentre Prospective Angioedema C1-INH Trial 1 (I.M.P.A.C.T.1) demonstrated that 20 U/kg C1 esterase inhibitor (C1-INH) concentrate (Berinert®; CSL Behring, Marburg, Germany) is effective in treating acute abdominal and facial Hereditary Angioedema (HAE) attacks. METHODS: I.M.P.A.C.T.2 was an open-label extension study of I.M.P.A.C.T.1 to evaluate the safety and efficacy of long-term treatment with 20 U/kg C1-INH for successive HAE attacks at any body location. Efficacy outcomes included patient-reported time to onset of symptom relief (primary) and time to complete resolution of all symptoms (secondary), analysed on a per-patient and per-attack basis. Safety assessments included adverse events, vital signs, viral safety and anti-C1-INH antibodies. RESULTS: During a median study duration of 24 months, 1085 attacks were treated in 57 patients (10-53 years of age). In the per-patient analysis, the median time to onset of symptom relief was 0.46 h and was similar for all types of attacks (0.39-0.48 h); the median time to complete resolution of symptoms was 15.5 h (shortest for laryngeal attacks: 5.8 h; 12.8-26.6 h for abdominal, peripheral and facial attacks). Demographic factors, type of HAE, intensity of attacks, time to treatment, use of androgens and presence of anti-C1-INH antibodies had no clinically relevant effect on the efficacy outcomes. There were no treatment-related safety concerns. No inhibitory anti-C1-INH antibodies were detected in any patient. CONCLUSIONS: A single dose of 20 U/kg C1-INH concentrate is safe and provides reliable efficacy in the long-term treatment of successive HAE attacks at any body location.

Terfenadine effect on the bronchoconstriction, dermal response, and leukopenia induced by platelet-activating factor.

We have investigated the protective effect of oral terfenadine, a H1 antagonist, on the dermal and pulmonary response, and changes of circulating WBCs to injected and inhaled platelet activating factor. Nine men with mild asthma participated in a double-blind, crossover study using terfenadine, 120 mg, or placebo. Three hours after administration of study drug, pulmonary function was measured, and a PAF challenge was performed. Skin test to histamine and PAF was performed prior to study drug, and 2.5 hours after drug. Circulating WBC count was determined prior to PAF inhalation and during the PAF challenge. There was a significant improvement in pulmonary function on terfenadine. Terfenadine significantly inhibited the wheal and flare response to histamine and the flare response to injected PAF. Terfenadine did not have an effect on the change in circulating WBC count or the change in pulmonary function to inhaled PAF. These results suggest a limited role for endogenous histamine for the effects of PAF.

Effect of inhaled amiloride on the bronchial response to methacholine and cold air hyperventilation challenges.

Inhaled amiloride has been recently demonstrated to have an effect on the decline of pulmonary function in patients with cystic fibrosis. Other diuretics have been demonstrated to provide protection against bronchoconstriction in asthmatic subjects. We report on the effect of inhaled amiloride on cold air hyperventilation challenge (CAHC) and methacholine challenge in asthmatics. We studied nine subjects with mild-moderate asthma in a double-blind, placebo-controlled, crossover study. Our results showed amiloride did not significantly protect against the bronchoconstriction induced by CAHC. Inhaled amiloride did not affect FEV1 in the hour after inhalation, and there was no significant difference between placebo or amiloride on the dose of methacholine causing a 20 percent fall in FEV1. Inhaled amiloride appears not to have a profile of action as previously seen with inhaled furosemide.

Comparison of ultrasonically nebulized distilled water and cold-air hyperventilation challenges in asthmatic patients.

Cold-air hyperventilation (CAHC) and ultrasonically nebulized distilled water (UNDW) challenges were compared in 11 asthmatic patients who were moderately sensitive to methacholine. The challenges were performed on two separate days within one week of each other. Baseline FEV1 on each test day was greater than 70 percent of predicted. Ten of 11 subjects' FEV1 decreased at least 15 percent, and nine of 11 decreased at least 20 percent during the UNDW. Ten of 11 subjects' FEV1 decreased at least 10 percent, and eight of 11 decreased at least 15 percent during the CAHC. Using a Spearman rank coefficient, the results of the CAHC and UNDW were compared; the best correlation between the various CAHC and UNDW measurements equaled only 0.51. The correlation between UNDW and CAHC suggests that the mechanism of action of each challenge may be different.

Effect of platelet-activating factor inhalation on nonspecific bronchial reactivity in man.

Bronchial hyperactivity is a recognized hallmark of asthma, characterized by an exaggerated bronchial response to numerous mediators, including histamine. It is also well recognized that bronchial hyperresponsiveness is increased following allergen exposure, although no particular mediator has been shown to induce this response. The recent observation that PAF can induce increased nonspecific bronchial reactivity in normal subjects emphasizes its importance as an inflammatory mediator. In this report we sought to further elucidate the role of PAF in airway hyperreactivity by comparing the effect of PAF on methacholine-induced airway responsiveness in six non-asthmatic subjects. Nonspecific airway responsiveness was not significantly increased following PAF inhalation at 6 hours nor was it increased at 1, 2, 7, or 14 days. Further elucidation of the potential role of PAF in explaining changes in airway reactivity is necessary.

Association of MS Pi phenotype with airway hyperresponsiveness.

Asthmatic families (AFs) and normal families (NFs) were studied to determine the relationship between bronchial hyperresponsiveness and alpha 1-antitrypsin protease inhibitor phenotype. We studied IgE levels, skin test scores, and methacholine sensitivity. In both the AF and NF groups, the subjects with the MS phenotype had significantly greater methacholine-induced bronchial hyperresponsiveness sensitivity than the MM and MZ subjects. These findings suggest that the S allele may be associated with bronchial hyperresponsiveness.

Effect of PAF-acether inhalation on nonspecific bronchial reactivity and adrenergic response in normal and asthmatic subjects.

Bronchial hyperreactivity, although recognized as a hallmark of asthma, is not totally understood. Mast cell-derived mediators, including histamine, have been shown to cause immediate bronchoconstriction, but until recently, no single mediator has been shown to induce prolonged changes in airway reactivity. Recent reports indicate PAF-acether (PAF) can induce increased nonspecific bronchial reactivity in normal subjects but not in asthmatics. We sought to elucidate the role of PAF in airway hyperreactivity by comparing the effect of inhaled PAF on methacholine and isoproterenol airway responsiveness in six nonasthmatic and six asthmatic subjects. Neither nonspecific airway reactivity nor isoproterenol responsiveness was changed following PAF inhalation in the nonasthmatic subjects in the six days following PAF. Asthmatics had increased airway responsiveness to methacholine at two hours post-PAF, which did not persist. Responsiveness to isoproterenol did not change in the asthmatic subjects. Additional evaluation of the role of PAF in causing changes in airway reactivity is warranted.

Longitudinal changes in bronchial hyperresponsiveness in asthmatic and previously asthmatic children.

To determine if nonspecific bronchial hyperresponsiveness is present to the same degree in previously asthmatic children compared with currently asthmatic children, a longitudinal study was conducted. On the basis of a standardized respiratory questionnaire, 139 children from asthmatic families, between the ages of 6 and 21 years, were identified. Subjects had skin tests, a serum IgE level, and a methacholine challenge test. IgE and skin tests demonstrated atopy in both the previously and currently asthmatic children, which persisted over time. Bronchial hyperresponsiveness within the asthmatic children was not significantly different between visits. Previously asthmatic children did have significantly decreased airway hyperresponsiveness over time. Age did not affect the results of the bronchial hyperresponsiveness in the currently asthmatic children. Currently asthmatic children, however, were significantly more atopic when compared with previously asthmatic children at their initial evaluation. Currently asthmatic children were also more bronchial responsive and remained so over time. Bronchial hyperresponsiveness is persistent in children with current asthma symptoms.

Probability of asthma based on methacholine challenge.

Methacholine inhalation challenge has become an accepted test to determine the presence of airway hyperresponsiveness, a hallmark of asthma. To help physicians interpret the results of a methacholine challenge test in a clinical setting, we analyzed the test data of 1,105 subjects, asthmatics and nonasthmatics. Applying Bayes' theorem, a nomogram was constructed incorporating the prechallenge clinical diagnosis with the response to methacholine to give a posttest probability of the diagnosis of asthma. The resulting curves represent different levels of cumulative breath units at which a methacholine challenge can be considered positive. The results of a methacholine challenge test, in association with a physician's clinical assessment, can be a valuable tool in the diagnosis of asthma in those patients with an atypical history and/or physical examination.

The effect of RP 59227, a platelet-activating factor antagonist, against antigen challenge and eosinophil and neutrophil chemotaxis in asthmatics.

STUDY OBJECTIVES: Platelet-activating factor (PAF), an inflammatory mediator, induces microvascular leak, eosinophil chemotaxis, and possibly increases non-specific bronchial hyperresponsiveness in humans. PAF antagonists may have clinical benefits in asthma. DESIGN: We determined the safety and efficacy of a 240 mg oral dose of RP-59227 in attenuating the early and late phase antigen challenge in eight asthmatics, using a double-blind, placebo-controlled, crossover design. Also determined was the effect of the ex vivo addition of PAF following placebo or drug and the level of neutrophil (NCA) and eosinophil chemotactic activity (ECA) in the serum immediately, and 4 h after antigen challenge with either drug or placebo. RESULTS: There was not a significant difference in the maximum percent fall in FEV1 during the early and late phase on screening or placebo days or drug RP-59227 days. There was a significant inhibitory effect (p < 0.05) in peak ECA and NCA in blood after RP-59227. The addition of PAF to ex vivo serum was less effective in inducing chemotaxis to eosinophils following RP-59227 (p < 0.05). CONCLUSIONS: RP-59227 attenuated the release of NCA and ECA after antigen challenge, and reduced the effect of exogenously added PAF in inducing eosinophil chemotaxis but did not protect against the antigen-induced early or late phase response.

Effect of loratadine on human eosinophil function in vitro.

We investigated the in vitro effect of loratadine, a new nonsedating H1 histamine antagonist, on the eosinophil functions of chemotaxis, superoxide anion (O2-) generation and eosinophil cationic protein (ECP) release, using purified eosinophils obtained from allergic patients. Loratadine significantly attenuated platelet-activating factor (PAF)-induced eosinophil chemotaxis and O2- generation at therapeutic concentrations (equivalent to serum concentrations after single oral administration of 20 mg or 40 mg). Loratadine, however, had no effect on PAF-induced ECP release. These findings suggest that loratadine has a direct inhibitory effect on eosinophil activation and may be beneficial in the therapy of allergic disorders with its anti-allergic properties.

Incorporation and analysis of ultrasonically nebulized distilled water challenges in an epidemiologic study of asthma and bronchial reactivity.

The usefulness of an ultrasonically nebulized distilled water (UNDW) challenge as a screening procedure was tested in an on-going epidemiologic study of asthma and bronchial reactivity. Sixty-six individuals underwent a methacholine challenge, an UNDW challenge, and were administered a standardized respiratory disease questionnaire. To perform the UNDW challenge, subjects inhaled increasing volumes of nebulized distilled water while breathing tidally. Thirty-eight asthmatics, two former asthmatics, 14 normal, and 12 allergic subjects, were included. Sixty-six percent of the asthmatics dropped 20% from their baseline FEV1 during the UNDW challenge. Only one allergic or normal subject had a similar drop. The Pearson's correlation coefficient between methacholine and UNDW challenges was 0.60. If positive, an UNDW seems to be highly specific in supporting a diagnosis of asthma, while methacholine challenges are more useful in verifying the presence of non-specific bronchial reactivity.

Correlation of methacholine-induced non-specific bronchial reactivity and cold air hyperventilation challenge.

The degree of bronchoconstriction seen with cold air hyperventilation challenge was determined in 48 adult subjects with known degrees of methacholine-induced bronchial reactivity. The degree of bronchial reactivity as determined by the cold air hyperventilation challenge significantly correlated with the non-specific bronchial reactivity determined by a methacholine inhalation challenge. Cold air hyperventilation challenge can accurately confirm the presence of reactive airway disease.

Effect of terfenadine on cold air-induced bronchospasm.

Cold air hyperventilation challenge (CAHC) has been shown to induce bronchoconstriction in asthmatics. We investigated whether terfenadine, a non-sedating H1 antihistamine, had a protective effect against CAHC. Twelve mild-moderate asthmatics, sensitive to both methacholine and CAHC, underwent a double-blind 3-way crossover study of terfenadine at doses of 0, 120, and 240 mg. For four hours after administration of the study drug, pulmonary responses were measured, followed by a CAHC. There was a significant improvement in pulmonary function on the 120-mg and 240-mg days. The percent drop in FEV1 to CAHC was determined by comparing the pre-challenge baseline to the challenge responses. There was a significant attenuation in the FEV1 fall immediately after challenge on active drug days, but it was not sustained. Terfenadine appears to have an attenuating effect against CAHC-induced bronchoconstriction.

Effect of terfenadine on pulmonary function, histamine release, and bronchial challenges with nebulized water and cold-air hyperventilation.

To assess the effectiveness of terfenadine on bronchoconstriction in asthmatics, 12 asthmatic patients between the ages of 19 and 43 were challenged with ultrasonically nebulized distilled water (UNDW) and treated with terfenadine, 120 or 240 mg, or placebo in a three-way crossover double-blind study. A similar study of 12 asthmatics (nine from the UNDW trial) was performed using cold-air hyperventilation challenge (CAHC). In vitro analyses were also made of samples from ten mild asthmatics to determine the effect of terfenadine on basophil histamine release. Terfenadine, 240 mg, showed significant (P = .012) benefit over placebo in improving pulmonary function after UNDW challenge. Modest but significant (P less than .05) bronchodilator benefits were also demonstrated by terfenadine, 240 and 120 mg, after CAHC. Finally, the in vitro study showed significant inhibition by terfenadine of anti-IgE-induced histamine release from human basophils.

The effect of formoterol on the late asthmatic phenomena in guinea pigs.

We investigated the effects of formoterol, a new, long-acting, selective beta 2-adrenoceptor agonist, on the antigen-induced late asthmatic response (LAR) and airway inflammation in guinea pigs. Animals were sensitized by exposure to aerosolized ovalbumin (2% in saline). After antigen challenge, preceded by administration of an H1-receptor antagonist, specific airway conductance was measured with a two-chambered whole-body plethysmograph. An aerosolized solution of formoterol, isoproterenol, or saline was inhaled 15 minutes before challenge. Bronchoalveolar lavage (BAL) was performed 24 hours after challenge. The provocative concentrations of histamine required to decrease specific airway conductance by 50% were obtained before challenge, at 24 hours, and at 72 hours after challenge. The LAR (52.7% +/- 7.7% of the baseline; p less than 0.02) was observed 6 to 8 hours after antigen challenge. An increased cellular influx in BAL (mainly eosinophils and macrophages) and an increased bronchial responsiveness to histamine occurred 24 hours after antigen challenge. Formoterol completely inhibited the LAR and the cellular increase in BAL; however, isoproterenol failed to prevent either the cellular infiltration or the LAR. Formoterol also decreased the antigen-induced increase in bronchial reactivity. These findings suggest that formoterol has inhibitory effects on the underlying inflammatory processes in antigen-induced asthma in addition to prolonged bronchodilation.

The effect of WEB 2086 on PAF-induced eosinophil chemotaxis and LTC4 production from eosinophils.

We investigated the effect of WEB 2086, a selective platelet-activating factor (PAF) receptor antagonist, on PAF-induced eosinophil chemotaxis and LTC4 production. WEB 2086 inhibited PAF-induced eosinophil chemotaxis in normals and asthmatics. To further determine if WEB 2086 is a selective PAF receptor antagonist, we examined the effect of WEB 2086 against formyl-methionyl-leucyl-phenylalanine (fMLP)-induced or eosinophil chemotactic factor of anaphylaxis (ECF-A)-induced eosinophil chemotaxis. WEB 2086 did not have a significant inhibition against fMLP or ECF-A-induced eosinophil chemotaxis. These results suggest that WEB 2086 is a selective and potent inhibitor of PAF-induced eosinophil chemotaxis and LTC4 production from eosinophils, due to its antagonism of PAF-receptors.

Importance of interleukin-3 on histamine release from human basophils.

We investigated the effects of interleukin-3 (IL-3) on histamine release (direct releasing and indirect enhancing effects) from basophils in allergic asthmatic subjects. Interleukin-3 caused direct histamine release (HR) in selected donors (IL-3 responders) and enhanced anti-IgE-induced HR in other IL-3 nonresponders, although both direct releasing and indirect enhancing activities of IL-3 on HR did not coexist with each other. There was a significant correlation between IL-3-induced HR and spontaneous histamine release (r = .8532, P < .0001).

Bronchial reactivity pattern in nonasthmatic parents of asthmatics.

Genetic mechanisms have been proposed to explain the presence of asthma in families. A methacholine challenge can identify individuals with bronchial reactivity (a hallmark of asthma). It may then be possible to determine whether the presence of non-specific bronchial reactivity, as detected by a methacholine response, has potential as a genetic marker. Thirty-one non-asthmatic parent pairs of asthmatic children were selected from asthma (AF) families enrolled in a Natural History of Asthma study. Parent pairs were chosen if both gave negative responses to a modified National Heart, Lung and Blood Institute questionnaire on asthma. The methacholine response of these parents of asthmatic children had a bimodal distribution. These results show that the methacholine response can mark bronchial reactivity without the presence of clinical asthma and that a familial component of bronchial reactivity exists which may be transmitted from one generation to the next.