Studies on histaminergic compounds, III. Synthesis and histamine H2-activity of a series of corresponding histamine and dimaprit analogues

Structure-activity relationships of a series of histamine analogues were found to be identical, except for one minor discrepancy, to those of a series of corresponding dimaprit analogues. It was concluded that histamine and dimaprit most probably interact with the same binding sites of the histamine H₂-receptor.     

Bronchial hyperresponsiveness: the need for a distinction between hypersensitivity and excessive airway narrowing

Bronchial hyperresponsiveness is currently defined as an increase in sensitivity to a wide variety of airway narrowing stimuli. Most patients with asthma and chronic obstructive pulmonary disease (COPD) exhibit such an enhanced sensitivity. In asthma, in particular, this hypersensitivity is accompanied by excessive degrees of airway narrowing. This raises the question as to whether measures of sensitivity, e.g. the provocative concentration or dose producing 20% fall in FEV1 (PC20 or PD20), comprise all the relevant information in bronchial hyperresponsiveness. In adjunct to model studies, there is experimental evidence in man that the potential mechanisms of bronchial hyperresponsiveness can be divided into those causing hypersensitivity and those responsible for the increase in the maximal attainable degree of airway narrowing. The recognition and distinction of these components of hyperresponsiveness have clinical implications in the diagnosis and therapy of asthma and COPD. Bronchial hyperresponsiveness is a composite functional disorder, which requires treatment of each of its components.     

Studies on histaminergic compounds, IV. Non-isosterism between the imidazole, guanidino and isothiourea moieties at the H2-receptor

S,S'-Alkylenediisothioureas were found to show only weak agonistic or antagonistic H₂-activity, depending on the length of the alkylene chain. Introduction of a substituent in the amidino parts of both isothiourea groups resulted in a complete loss of the agonistic activity; only inactive compounds or weakly active H₂-antagonists were obtained. Replacing one of the isothiourea groups of the alkylenediisothioureas with n = 2, 3 or 4 by a guanidino group has hardly any or no effect at all on the histamine H₂-activity on the guinea-pig right atrium. However, extending the alkylene chain of these guanidylalkylisothioureas to n = 5 and 6 results in a strong increase in the H₂-agonistic activity.     

The combined effects of histamine and methacholine on the maximal degree of airway narrowing in normal humans in vivo

In normal subjects in vivo the dose-response curve to inhaled nonsensitizing stimuli reaches a plateau at mild degrees of airway narrowing. We investigated whether the limitation of the response is due to non-optimal smooth muscle activation, by administering high doses of histamine and methacholine together. In fifteen normal subjects a complete dose-response curve to methacholine was recorded by a tidal breathing method on three randomized days. On a separate day a complete histamine inhalation test was carried out. Each methacholine test was directly followed by double blind inhalation of the highest dose of either histamine or methacholine, or a dose of saline. The response was measured by flows from partial flow-volume curves (V 40p), and was expressed in % fall from baseline. Twelve subjects reached a maximal response plateau to methacholine which was reproducible. The addition of saline or extra methacholine did not change the response from its methacholine plateau value. Histamine caused a small increase in the response on top of the methacholine plateau (+ 9.0% fall; p less than 0.001). However, the response to the combined histamine and methacholine was not significantly larger than the maximal response to histamine alone. We conclude that there is no interaction between histamine and methacholine on the maximal degree of airway narrowing. This suggests that the plateau of the dose-response curve in normal subjects in vivo is due to other factors than limited smooth muscle activation.     

Hamartom des Duodenums

We report on a 34-year-old man who was admitted to our hospital with melena and hematemesis. Endoscopy showed a giant pedunculated polyp of the duodenum as the source of bleeding. The 10 cm long tumor was resected transduodenally by open surgery and the histological examination revealed it to be a hamartoma. This case demonstrates a very rare benign tumor of the duodenum, its possible clinical manifestation and treatment options.     

Experimental rhinovirus 16 infection increases intercellular adhesion molecule-1 expression in bronchial epithelium of asthmatics regardless of inhaled steroid treatment

BACKGROUND: Rhinovirus infections in airway epithelial cells in vitro have been shown to upregulate intercellular adhesion molecule-1 (ICAM-1) expression. Epithelial ICAM-1, in its dual role as the major rhinovirus receptor and as adhesion molecule for inflammatory cells may be involved in the pathogenesis of rhinovirus-induced exacerbations of asthma. OBJECTIVE: We aimed to investigate the effect of experimental rhinovirus 16 (RV16) infection on ICAM-1 expression in bronchial mucosal biopsies in asthma. In addition, the effect of 2 weeks pretreatment with inhaled budesonide (800 microg b.d.) on RV16-associated changes in ICAM-1 expression was studied. METHODS: The study had a parallel, placebo-controlled design in 25 steroid-naive nonsmoking atopic asthmatic subjects. After 2 weeks budesonide (BUD) or placebo (PLAC) pretreatment bronchoscopy was performed 2 days before (day -2) and 6 days after (day 6) RV16 inoculation (on days 0 and 1). Immunohistochemical staining for ICAM-1 was performed on snap-frozen bronchial biopsies. ICAM-1 staining intensity on the basal epithelial cells was scored semiquantitatively from 1 (weak) to 3 (intense). Similarly, epithelial intactness was noted (1 = basal cells only, 2 = basal and parabasal cells, 3 = intact epithelium). RESULTS: ICAM-1 scores were not significantly different between the groups at day -2 (P > or = 0.08). Subsequent RV16 infection was associated with a trend towards an increase in ICAM-1 expression in the BUD-group (P = 0.07), whereas the increase was significant in the PLAC-group (P = 0.03). However, the increase was not significantly different between the groups (P = 0.74). Epithelial intactness score was not different between the groups before RV16 infection (P > or = 0.07), and no significant changes were observed in either group (P > or = 0.59). Moreover, ICAM-1 score did not correlate significantly with epithelium score in either group, at any time-point (P > or = 0.27). CONCLUSION: We conclude that an RV16 common cold in atopic asthmatic subjects is associated with increased ICAM-1 expression in the bronchial epithelium, which is not related to epithelial intactness. Glucocorticoid treatment does not appear to prevent the RV16-associated increased ICAM-1 expression. This suggests that other treatment modalities are required to protect against the spreading of infection during rhinovirus-induced exacerbations in asthma.     

Small airways function and molecular markers in exhaled air in mild asthma

BACKGROUND: Several studies suggest that the periphery of the lung is the major site of inflammation in asthma. Fractional exhaled nitric oxide (Feno) and 8-isoprostane have been proposed as biomarkers of inflammation and oxidative stress. We therefore hypothesised that small airway dysfunction in asthma is of inflammatory origin that can be detected by molecular markers in exhaled air. To test this hypothesis, we examined the relationship of Feno and 8-isoprostane in exhaled air with small airways function as assessed by the single breath nitrogen test. METHODS: Sixteen patients (14 women) with mild atopic asthma (forced expiratory volume in 1 second >80% predicted) of mean (SD) age 23.0 (5.5) years participated in a cross sectional study. Feno was recorded by chemiluminescence and 8-isoprostane was measured by ELISA in concentrated exhaled breath condensate. The slope of phase III (deltaN2) and the closing volume (CV) were assessed from the single breath washout curve. RESULTS: The median Feno level was 30.4 ppb (range 10.1-82.8), the median 8-isoprostane concentration in exhaled breath condensate was 2.2 pg/ml (range 1.6-2.7), and the mean (SD) deltaN2 value was 1.1 (0.4)% N2/l. Feno was positively associated with deltaN2 (r(s) = 0.54, p = 0.032) while 8-isoprostane was inversely correlated with FEV1% predicted (rs= -0.58; p = 0.017) and CV as a percentage of vital capacity (rs= 0.58; p = 0.019). CONCLUSIONS: Feno and 8-isoprostane in exhaled air are associated with small airways function in mild asthma. This suggests that these markers reflect small airway inflammation and favours a role for them as disease markers that is complementary to spirometry in the monitoring of patients with asthma.