Pulmonary pharmacology最新文献

To assess the effects of azelastine in patients with cough-variant asthma, we measured the cough threshold for capsaicin (the concentration required to elicit more than five coughs) in 16 patients with cough-variant asthma before and after 4 weeks of treatment with azelastine (2 mg; b.i.d.) or placebo. After treatment, coughing decreased in all patients and the cough threshold for capsaicin increased significantly, from 0.67±0.30 μmto 4.76±1.55 μm(P<0.01) in the azelastine group. However, the cough threshold for capsaicin did not increase significantly, from 0.86±0.33 μmto 1.11±0.35 μm(P>0.10) in the placebo group. These results suggest that azelastine inhibits coughing in patients with cough-variant asthma.

We studied the effect of a new antiallergic compound, TYB-2285 (3,5-bis(acetoxyacetylamino)-4-chlorobenzonitrile), on antigen-induced early and late bronchoconstriction and airway responsiveness in conscious allergic sheep. The same general protocol was used for all studies, except that the dosage and time of TYB-2285 treatment was varied. The basic protocol consisted of determining airway responsiveness to inhaled carbachol, then measuring the airway responses toAscaris suumantigen challenge followed 1 day later by a post challenge assessment of airway responsiveness. Specific lung resistance (SR_L) was used to measure the airway responses to antigen and carbachol and the concentration of carbachol that caused a 400% increase in SR_L(PC₄₀₀) was used as a measure of airway responsiveness. All protocols were of crossover design, such that each sheep served as its own control and each protocol employed six to eight animals. In all instances, TYB-2285 or vehicle control (methylcellulose) was given orally. When TYB-2285 (100 mg/kg) was given at 16 and 2 h before the challenge, the early response, the late response and the post antigen-induced airway hyperresponsiveness (AHR) as indicated by a decrease in the PC₄₀₀was inhibited significantly. TYB-2285 (100 mg/kg), when given 1 h after challenge, inhibited the late response and AHR significantly. TYB-2285 (100 mg/kg), when given 8 h after the challenge, also inhibited the antigen-induced AHR. When animals were given TYB-2285 (100 mg/kg) at 32, 56 and 80 h after the challenge, the antigen-induced AHR that persisted (for 1 week) in the control trial was reversed to the normal level. TYB-2285 (30 mg/kg), when given at 1, 32, 56 and 80 h after the challenge, inhibited late response slightly and reversed the persistent AHR to the normal level. At lower doses (3 and 10 mg/kg) there was no protection of the early response, the late response or AHR. Pretreatment with TYB-2285 (100 mg/kg) also prevented the antigen-induced influx of eosinophils in bronchoalveolar lavage obtained 24 h after segmental antigen challenge. TYB-2285 did not inhibit histamine or LTD₄-induced bronchoconstriction nor did the active metabolites of TYB-2285, TC-286 and TC-326 inhibit acetylcholine-induced contraction of sheep tracheal smooth muscle. These results suggest that TYB-2285 has both antiallergic and antiinflammatory properties in the sheep model of allergic bronchoconstriction. The compound demonstrates both prophylactic and therapeutic activity and, therefore, may be potentially useful in the treatment of allergen-induced airway disease.

No abstract

No abstract

The long-acting β₂-agonist salmeterol has been shown in several in vitro studies to produce non-β-mediated relaxant effects. The aim of the present study was to investigate whether these effects have any relevance in humans in vivo. Thirteen healthy individuals were studied in a randomized, double-blind, cross-over study on five separate days. The subjects were pre-treated orally with either propranolol 400 mg in order to block β-adrenoceptor mediated effects or placebo. Two hours after drug intake, three increasing doses of salmeterol (25 + 50 + 100 μg), salbutamol (100 + 200 + 400 μg) or placebo were given from matched meter dose inhalers at 1-h intervals between doses. Specific airway conductance (sGAw) was measured in a body plethysmograph at the beginning of the experiment and 30 and 60 min after each inhaled dose of the β-agonists. Salmeterol and salbutamol produced the same maximal increase in sGAw and had the same area under the dose-response curves. Pre-treatment with propranolol totally inhibited the effect of both drugs. In conclusion, salmeterol at clinically used doses did not produce any non-β-mediated bronchodilating effect in normal individuals, measured as sGAw. Salmeterol and salbutamol showed the same efficacy but salmeterol was four times more potent than salbutamol.

Leukotrienes (LK) play an important role in the inflammatory response found in the asthmatic airway and it is therefore of interest to explore the clinical value of agents which can either block the effect or inhibit the synthesis of leukotrienes. If tachyphylaxis does not develop, repeated LTD₄ challenges can be used for dose ranging studies.

Tachyphylaxis has been observed when LTD₄ challenge intervals are kept below 1 h, but the effect of prolonging the interval is uncertain. The aim of this study was therefore to investigate the interval between LTD₄ challenges necessary to avoid development of tachyphylaxis.

Ten stable adult asthmatics with moderate asthma were challenged seven times: a screening day to secure responsiveness to LTD₄, two challenges on three separate days with an interval of 2, 4 and 6h, respectively. No significant differences between mean PC₂₀-LTD₄ Values (P>0.5) was found. It was concluded that tachyphylaxis to repeated LTD₄ challenges of asthmatics does not develop when challenge intervals are prolonged above 2 h.

Bronchodilator efficacy of salbutamol (200 μg), salmeterol (50 μg) and ipratropium bromide (40 μg) aerosols las been compared in 16 patients with stable chronic obstructive pulmonary disease (COPD) using a double-blind placebo controlled cross-over design. When absolute changes in FEV, were used as the response criterion, efficacy of the three drugs was significantly better than placebo (P<0.05). The onset of bronchodilatation after ipratropium bromide was slower than after salbutamol, but ipratropium induced more and longer-lasting bronchodilatation than the adrenergic drug. Salmeterol was slower but its duration was longer than salbutamol. The onset of the effect of salmeterol was slower than ipratropium bromide, but salmeterol showed, on average, superior bronchodilator efficacy compared with the anticholinergic agent, sustaining bronchodilation longer than ipratropium bromide (responses to salmeterol were significantly (P<0.05) greater than those to ipratropium bromide from 4–12 h time period, but from 15 min to 1 h time periods response to ipratropium bromide exceeded salmeterol). The mean FEV, area under the curve was significantly (P<0.05) larger after salmeterol when compared to ipratropium bromide and salbutamol. Moreover, the mean FEV, area under the curve after ipratropium bromide was significantly (P<0.05) higher than that after salbutamol. In any case, our data showed individual differences in patient response. We conclude that salmeterol compares favourably with ipratropium bromide in terms of effects on lung function at clinically recommended doses because it has a longer duration of action than ipratropium bromide. The longer dosing intervals, which may enhance compliance, encourage its administration in patients with COPD.

Using radioactive tracers, we measured blood volume, albumin exchanges and blood leukocyte sequestration within lungs, following an intravenous injection of lipopolysaccharide (0.1–1 mglkg). Neutrophil infiltration into the airways was followed in parallel experiments. Dexamethasone pretreatment (20 mg/kg, subcutaneous) failed to prevent early pulmonary changes induced by lipopolysaccharide as decreased blood volume, leukocyte sequestration, leukopenia or the increased trans-endothelial albumin exchanges. However, dexamethasone provided a significant protection against the later albumin leakage through the endothelial/epithelial barrier and the neutrophil accumulation in the airways observed in lipopolysaccharide-treated guinea-pigs. Our results indicate that the protective effect of dexamethasone in lipopolysaccharide-induced lung injury might derive from an initial reduction of leukocyte adhesion and a later decrease in alveolo-capillary permeability.