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.

Safety of nifedipine in subjects with bronchial asthma and COPD.

This prospective study was undertaken to evaluate the safety of nifedipine, a calcium channel blocking agent, on 60 subjects with asthma, chronic obstructive pulmonary disease (COPD), angina, and normal subjects. All subjects received nifedipine, 20 mg, sublingually. Spirometry was done pre-drug administration and every 20 minutes after for two hours. Parameters measured were forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and forced expiratory flow at 25 percent to 75 percent of total volume (FEF25-75%). Subjects with asthma and COPD were also given nifedipine 20 mg three times daily, orally for two weeks, and tested biweekly during this period. All bronchodilators, beta-blockers, and long acting nitrates were withheld for five half-lives of the drug prior to test day. There was no adverse effect on the pulmonary function. We found a statistically significant improvement (p less than 0.05) in FEV1 after nifedipine. There was no tachyphylaxis at the end of two weeks. Nifedipine is safe in patients with asthma and/or chronic bronchitis.

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.

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.

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 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.

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.

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 development of a sensitive and specific radioreceptor assay for leukotriene B4.

To establish a simple and sensitive quantitation of leukotriene B4 (LTB4), we developed a radioreceptor assay (RRA) using a highly specific [3H]leukotriene B4[( 3H]LTB4) binding to a guinea pig spleen homogenate. The assay detected LTB4 levels as low as 0.12 pmol per tube. Fifty percent inhibition of bound [3H]LTB4 was obtained by 2.5 nM of unlabeled LTB4. [3H]LTB4 competition studies indicated that 20-hydroxy-LTB4 was 8 times, 6-trans-LTB4 was 640 times and 20-carboxy-LTB4 was 1000 times less effective than LTB4. The peptide leukotrienes C4, D4 and E4 showed no effect on [3H]LTB4 binding. Recovery rates averaged 97% after ethanol extraction and evaporation of known amounts of LTB4. The intra-assay coefficients of variation for three samples were 2.4%, 7.2% and 8.4%, respectively. This assay was validated by measuring LTB4 released from human granulocytes stimulated with calcium ionophore A23187. The LTB4 level was maximal at 10 min (156.8 +/- 36.2 pmol/3 x 10(6) cells) and decreased rapidly after 15 min. This radioreceptor assay for leukotriene B4 is highly sensitive and is comparable to the reported sensitivity by radioimmunoassay. The method is simpler and less expensive than other methods such as high pressure liquid chromatography and is suitable for routine measurement of leukotriene B4.

IL-1 receptor-type expression in relation to atopy.

BACKGROUND: IL-1 has 2 receptors, type I (IL-1RI) and type II (IL-1RII), which have 2 forms each, membrane (m) and soluble (s). When IL-1 binds to mIL-1RI, the active receptor, an inflammatory response is initiated, which does not occur when IL-1 binds to mIL-1RII, the decoy receptor. Both sIL-1RI and sIL-1RII function as IL-1-mopping mechanisms. We hypothesized that the ratio of active (mIL-1RI) to inactive (mIL-1RII, sIL-1RI, and sIL-1RII) receptors is important in determining the amount of inflammation produced in allergic reactions. OBJECTIVE: Our aim was to compare the concentrations of mIL-1RI and mIL-1RII on cultured PBLs and sIL-1RI, sIL-1RII, and IL-1beta in sera and supernatants of cultured PBMCs from atopic and nonatopic subjects. METHODS: The membrane receptors, soluble receptors, and IL-1beta concentrations were measured by ELISA with specific mAbs. RESULTS: Although there was no difference in the level of serum IL-1beta between the 2 groups, PBMCs from atopic persons spontaneously secreted higher levels of IL-1beta than those from nonatopic donors (P < .05). PBLs from atopic subjects compared with those from nonatopic individuals expressed higher mIL-1RI (P < .0001) and mIL-1RII (P < .05). Levels of both the soluble receptors from both serum (P < .0001) and PBMCs (P < .05) of nonatopic donors were higher than those found in atopic donors. CONCLUSION: This augmentation of mIL-1RI concomitant with a reduction in soluble receptors may be an important contributory factor to the inflammation that occurs with allergen exposure.

Comparison of the effects of verapamil and nifedipine on airway muscarinic reactivity and receptors.

Previous studies have shown inconsistent results of the effect of verapamil and nifedipine on airway reactivity. This study was undertaken to determine and compare their effects on the activity of airway muscarinic receptors by contraction experiments and by radioligand receptor binding assays. We found that verapamil (10(-5)-10(-4) M) reduced contraction at rat tracheal muscle to methacholine, a finding consistent with its inhibition on binding of (3H)QNB to bovine tracheal muscle membranes. Unlike verapamil, nifedipine (10(-5)-3 X 10(-5) M) inhibited neither methacholine response nor (3H)QNB binding. Verapamil but not nifedipine decreased the affinity of binding sites. Neither of them affected the concentration of (3H)QNB binding sites. We conclude that the effect of verapamil on airway muscarinic receptor binding sites differs qualitatively from that of nifedipine, and suggests that its effect on the binding sites could account for the inhibitory action of verapamil on airway muscarinic response.

Identification of calcium antagonist receptor binding sites using (3H)nitrendipine in bovine tracheal smooth muscle membranes.

(3H)Nitrendipine binding to the bovine tracheal muscle membrane at 25 degrees C was rapid, saturable (Bmax = 14.8 +/- 3.9 fmol/mg protein) and of high affinity (Kd = 0.15 +/- 0.04 nM). The rank order of Ca2+ antagonists competing for airway (3H)nitrendipine binding was nitrendipine not equal to nisoldipine not equal to nifedipine much greater than verapamil. Cromolyn, however, neither inhibited nor increased the binding.

The effect of beta adrenergic blockade on bronchial sensitivity to acetyl-beta-methacholine in normal and allergic rhinitis subjects.

The effect of propranolol inhalation on sensitivity to methacholine inhalation was studied in normal and allergic rhinitis subjects to determine whether beta adrenergic blockade alters sensitivity to mediators in nonasthmatic atopic individuals. A partial beta adrenergic blockade is suggested as being instrumental in asthma. Hay fever patients studied showed similar effects and also developed asthma for the first time.

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.

Effect of terfenadine on the bronchoconstriction induced by ultrasonically nebulized distilled water.

Ultrasonically nebulized distilled water (UNDW) has been shown to induce bronchoconstriction in asthmatics. The proposed mechanism is through changes in osmolarity of the airway fluids and subsequent release of mediators from airway mast cells. We investigated whether terfenadine has a protective effect on UNDW challenges. Twelve mild-to-moderate asthmatics responded to screening a methacholine and UNDW challenge. For four hours after the ingestion of 0, 120, and 240 mg of terfenadine pulmonary responses were performed, followed by a UNDW challenge. Nine of 12 subjects dropped 20% after 120 mg and after 240 mg. There was a suggestion of a protective effect at 120 mg (P = .054), which was significant at 240 mg (P = .012) when the areas under the dose-response curves were compared. Bronchoconstriction induced by UNDW may in part be caused by histamine release and was attenuated by an oral antihistamine.

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.