Henry Gong

Effect of cetirizine, a new histamine H1 antagonist, on airway dynamics and responsiveness to inhaled histamine in mild asthma

Cetirizine, a major human metabolite of hydroxyzine, preserves the histamine H1-antagonist activity of the parent compound but poorly penetrates the blood-brain barrier, thus minimizing sedative and anticholinergic effects. In 10 young (mean age 27.7 years) subjects with mild asthma (FEV1 greater than 70% predicted), we evaluated the bronchodilator and protective efficacy of 5, 10, and 20 mg of cetirizine against bronchospasm induced by histamine inhalation (0.03 to 20 mg/ml) in comparison with placebo and hydroxyzine, 25 mg, using a random, double-blind crossover design. The provocative concentration of histamine causing a 20% decline in FEV1 for all 10 subjects from the postdiluent control value was more than fourfold greater after each active drug than after placebo. Cetirizine, 5 to 20 mg, provided significantly greater protection against histamine-induced bronchospasm than hydroxyzine (p less than 0.001); moreover, a dose-dependent protective effect was noted with cetirizine. Significant bronchodilation was also found: at 60 minutes, FEV1 increased significantly after all active antihistamines compared to placebo and after 20 mg of cetirizine compared to hydroxyzine (p less than 0.05). FEV1 increased significantly at 120 minutes after hydroxyzine and after cetirizine in both the 20 and 10 mg doses compared to placebo (p less than 0.05). We conclude that in subjects with mild asthma, orally administered cetirizine provides significant dose-dependent protection against histamine-induced bronchoconstriction, which in the doses studied is superior to that produced by the parent compound, hydroxyzine. In addition, cetirizine in 5 to 20 mg doses causes acute bronchodilation. These results suggest a possible role of cetirizine in asthma therapy.

Metered-dose inhaler usage in subjects with asthma: Comparison of Nebulizer Chronolog and daily diary recordings

The Nebulizer Chronolog (NC) is a portable electronic device that attaches to standard metered-dose inhalers (MDIs) and records and stores the date and time of each MDI actuation. We evaluated the long-term performance of the NC and compared its data to concurrent recordings of self-administered MDI usage in daily diaries. Eighty-three subjects with asthma were evaluated during a 7 1/2-month panel study of air pollution effects. Although 44 (53%) of the NCs developed a malfunction during the study, the average total (+/- SD) percentage of useful days with functioning NCs was still 86 +/- 18% (median 93%). The agreement between the daily diary and NC recordings was very high, that is, 50 (67%) of 75 subjects had perfect agreement. Eighteen subjects with over or under diary reporting were detected. We conclude that the NC is an effective, objective, accurate, and continuous monitor of daily MDI usage despite some remediable technical problems. The NC can facilitate the evaluation of short- and long-term medication usage patterns and compliance issues in MDI-related research and clinical settings.

Human and Rabbit Newborn Lung Macrophages Have Reduced Anti-Candida Activity

ABSTRACT: Bronchoalveolar macrophages (BAM) protect the adult lung from low level microbial contamination. The antimicrobial activity of human newborn RAM is unknown. BAM were isolated from effluents of suctioned, intubated newborns and from bronchoalveolar lavage of healthy, nonsmoking adult volunteers. An in vitro cytologic slide assay was developed and used to ascertain: 1) inhibition of intracellular filamentation of Candida albicans (active yeast growth) and 2) killing + digestion of ingested C. albicans. The ability to restrict intracellular yeast filamentation was markedly different for human newborn versus adult BAM. Adult BAM were five times more effective in restricting intracellular filamentation of Candida compared to newborn cells (p < 0.01). Nonfilamented ingested yeast were also handled differently by newborn and adult macrophages. Nonfilamented yeast were killed and digested by adult BAM at a rate that was 2.5 times above that noted in neonatal lung macrophages (p < 0.005). However, no differences were found in the total number of killed + digested Candida within human newborn and adult BAM [adult = 32A ± 10.5% (n = 5), newborn <1200 g = 39.6 ± 16.8% (n = 8), and newborn >1200 g = 30.2 ± 11.1 % (n = 16), mean ± S.D.]. Neonatal BAM were able to destroy C. albicans at a level equivalent to adult cells because there newborn phagocytes allowed intracellular Candida to enter a state of active growth, thereby rendering the yeast more susceptible to killing and digestion. The anti-Candida activity noted in lung macrophages recovered from normal 1-day-old and adult rabbits was similar to that seen in human BAM. Kinetic studies of intra- and extracellular yeast filamentation with time revealed that extracellular yeast were unrestricted in their ability to grow (filamentation = 98 ± 0.5% by 2 h). Bonchoalveolar macrophages recovered from rabbits exposed to 95 + % O2 for 96 h after birth had a 2-fold higher rate of intracellular Candida filamentation when compared to BAM lavaged from newborn rabbits raised in room air [66.3 ± 5.9% versus 33 ± 13.5% (mean ± SD, p < 0.025)]. Oxygen exposure did not alter macrophage phagocytosis. We conclude that oxygen therapy may be an important factor underlying the fungistatic limitations of BAM from newborns undergoing intensive care.

Antibody-dependent cellular cytotoxicity mediated by lung macrophages: a comparison of two target cells.

Mononuclear cell-mediated cytotoxicity may be an important cellular immune function in host lung defense. Prior investigators have shown that lung macrophages participate in cell cytotoxicity which is antibody-dependent (ADCC). We tested the hypothesis that alveolar macrophages share some cell surface receptors for the Fc portion of IgG, i.e., Fc receptors, similar to those found on circulating monocytes in order to function in ADCC. Hence, ADCC mediated by autologous human blood monocytes and lung macrophages was studied by measuring the release of chromium-51 from prelabeled target erythrocytes coated with IgG. Alveolar macrophages were obtained from healthy adult subjects by bronchoalveolar lavage and tested against two different erythrocyte target cells to measure ADCC activity. Our results show significant activity by alveolar macrophages demonstrated against chicken erythrocytes at a target to effector cell ratio of 2:1 or 10:1 and with an antibody concentration of 1:100 or 1:400 (volume per volume, p less than 0.05, Students test). However, when a peripheral blood monocyte specific target cell (human type B erythrocyte) was utilized, alveolar macrophages were not as capable of significant ADCC activity against these monocyte-specific target cells. The inability of lung macrophages to function in ADCC against other target cells (i.e., human type B erythrocytes) unlike the peripheral blood monocytes suggests that some Fc receptors are not shared. In other words, these different cell types share IgG receptors but differences in activity may be due to some changes in the Fc portions of IgG due to cellular differentiation. The use of these target cells may potentially be useful in functionally discriminating between two types of adherent autologous mononuclear cells (lung macrophages vs. blood monocytes).