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Plasma exudation has been suggested to be an important component of the inflammatory response in asthma. Bradykinin elicits many of the features of asthma, including bronchoconstriction, cough, plasma exudation and mucus secretion. In an attempt to quantify local plasma exudation, we have employed a novel low-trauma technique with the aim of challenging and lavaging a central part of the bronchial tree, by selecting a medium sized bronchus. A fibreoptic bronchoscopy was performed in non-smoking healthy volunteers. The instrument was placed proximally in the right upper lobe bronchus. A plastic catheter, equipped with an inflatable latex balloon, was inflated with air (2–4 cmH₂O). A solution (100 μ l of either two different concentrations of bradykinin: 0·09 and 0·9 mg ml⁻¹; or normal saline) was instilled through the catheter and distal to the balloon. Eight minutes later a lavage procedure with 10 ml of saline was performed through the catheter. The procedure was then repeated twice, with the other solutions, but from the lingular and middle lobe bronchi. All solutions were given in a blinded fashion, and two different studies were performed. Lavage concentrations of albumin and IgG were quantified as measurements of plasma exudation. In our first study we found that bradykinin challenge significantly increased concentrations of albumin and IgG. In study two, there was no numeric increase in plasma proteins after local bradykinin challenge, but the concentration of thromboxane was significantly increased in lavages from bradykinin-challenged bronchi. Thus, local bronchial administration of bradykinin has the capacity to induce exudation of large plasma macromolecules into the bronchial lumen, as well as local thromboxane production. Copyright 2001 HARCOURT PUBLISHERS LTD.

Inhalation of drugs has made a great difference in terms of optimizing asthma therapy. The challenge for the next generation of inhalers will be to provide still greater benefits to patients in terms of efficacy, safety, and convenience. Dry powder inhalers (DPIs) are innovative new inhalation devices and comparisons with pressurized metered dose inhalers (pMDIs) show that DPIs are at least as efficient at delivering drugs, and may be a superior delivery device for some drugs. To compare different inhaler devices, drug dose comparisons that lie on the slope of the dose-response curve should be selected, and it is important to analyze the risk:benefit ratio (therapeutic ratio). Some of the new devices contain aerosols with a smaller particle size than current designs. Monodispersed aerosols with a very narrow range of particle sizes may target drug delivery to specific areas of the lung where it is most effective. However, as smaller particles are more easily absorbed into the pulmonary circulation via the alveoli, these formulations may be associated with a higher incidence of systemic side effects. The optimal particle size required to maximize the therapeutic ratio of a molecule may be different for a β2-agonist than for an inhaled corticosteroid. A greater understanding of this relationship will be required if we are to achieve better drug targeting with future inhalers.

Inhalation of drugs has made a great difference in terms of optimizing asthma therapy. The challenge for the next generation of inhalers will be to provide still greater benefits to patients in terms of efficacy, safety, and convenience. Dry powder inhalers (DPIs) are innovative new inhalation devices and comparisons with pressurized metered dose inhalers (pMDIs) show that DPIs are at least as efficient at delivering drugs, and may be a superior delivery device for some drugs. To compare different inhaler devices, drug dose comparisons that lie on the slope of the dose-response curve should be selected, and it is important to analyze the risk:benefit ratio (therapeutic ratio). Some of the new devices contain aerosols with a smaller particle size than current designs. Monodispersed aerosols with a very narrow range of particle sizes may target drug delivery to specific areas of the lung where it is most effective. However, as smaller particles are more easily absorbed into the pulmonary circulation via the alveoli, these formulations may be associated with a higher incidence of systemic side effects. The optimal particle size required to maximize the therapeutic ratio of a molecule may be different for a β2-agonist than for an inhaled corticosteroid. A greater understanding of this relationship will be required if we are to achieve better drug targeting with future inhalers.

Some inhalers have been claimed to give better deposition, resulting in higher efficacy. In a previous study we did not find any evidence of different potency of salbutamol given either via pMDI or Turbuhaler®. The aim of the present study was to compare the efficacy and safety of salbutamol given via Diskus™or Turbuhaler. Twenty-five asthmatics with step-wise reversible airflow obstruction (total reversibility of at least 15%) were included in a randomized, double-dummy, placebo-controlled cross-over study. On each study day, the patients were given placebo repeatedly, or cumulative doses of 200, 400, 800, 1600 and 3200 μg salbutamol given via either device (double-blind, placebo-controlled). Salbutamol caused a dose-related increase in FEV1when given by Diskus or Turbuhaler. The improvement in FEV1was similar regardless of whether salbutamol was given via Diskus or Turbuhaler, at equivalent microgram doses. After a total cumulative dose of 3200 μg, mean FEV1for Diskus was 2·46 l (change from baseline of 20·5%), for Turbuhaler 2·50 l (change from baseline 24·6%) and for placebo 2·11 l (3% change from baseline). After correcting for different baseline differences, the percentage difference between Diskus and Turbuhaler was −1·8% (P=0·2). Systemic effects (potassium and heart rate) did not differ between Diskus or Turbuhaler. We conclude that the efficacy of salbutamol given at equivalent microgram doses, as well as side-effects, are comparable when the drug is given via Diskus or Turbuhaler. The present data shows that salbutamol given by these devices have similar therapeutic ratios.

The aim of the present study was to characterize the airway effects of U46619, a stable thromboxane A2 mimetic, instilled into the trachea of guinea pigs in vivo, and to investigate the role of different mediators in these effects. The airflow obstruction was evaluated by measurement of airway insufflation pressure (P1) and plasma extravasation by quantification of Evans Blue dye (EBD) in airways. U46619, given as a single dose to each animal (1 pmol-10 nmol), caused a dose-dependent increase in P1 and extravasation of EBD. The threshold dose required to induce an increase in P1 was 30 times lower than the threshold dose necessary to evoke EBD extravasation. The role of inflammatory mediators was studied when 10 pmol (inducing only the increase in P1) or 10 nmol (inducing the increase in both P1 and EBD extravasation) of U46619 was administered. The effects of both doses of U46619 were abolished by ICI192,605, an antagonist of prostanoid receptor for thromboxane A2 (0.5 mg/kg i.v.). The airflow obstruction induced by 10 nmol of U46619 was potentiated by indomethacin, a cyclo-oxygenase inhibitor (10 mg/kg i.v.). EBD extravasation induced by 10 nmol U46619 was attenuated by BW70C (6 mg/kg i.v.), a selective 5-lipoxygenase inhibitor, by ICI198,615 (0.5 microgram/kg i.v.), a leukotriene D4/E4 receptor antagonist and by WEB2086 (1 mg/kg i.v.) a platelet-activating factor receptor antagonist. Pyrilamine (2 mg/kg i.v.), a histamine H1 receptor antagonist, did not have any influence on U46619-induced airway effects. We conclude that U46619 possesses a higher potency in the induction of airflow obstruction than in the induction of plasma extravasation and that U46619-induced plasma extravasation may be partly mediated via leukotrienes and platelet-activating factor.

Thromboxane A2(TXA2) is a potent constrictor of both airway and vascular smooth muscle. In addition, plasma exudation is induced in the airways by a thromboxane mimetic (U-46619). Because plasma exudation is associated with a local vasodilatation and increased local blood flow, we hypothesized that the general vasoconstrictor effect of U-46619 would be weaker in the airways than in other vascular beds, perhaps resulting in increased local airway blood flow. We studied the effects of i.v. U-46619 on blood pressure, lung resistance as well as blood flow, plasma exudation in airways and leg skeletal muscle in guinea pigs. We found (1) i.v. U-46619 increases the systemic blood pressure, blood flow in tracheal mucosa but decreases blood flow in leg skeletal muscle; (2) i.v. U-46619 induces plasma exudation in the airways, but not in the leg skeletal muscle; (3) a positive relationship between blood pressure and tracheal blood flow as well as airway plasma exudation, a negative relationship between blood pressure and blood flow in leg skeletal muscle; (4) i.v. U-46619 significantly increases lung resistance. We conclude that i.v. U-46619 induces plasma exudation in airways but not in skeletal muscle, and that this plasma exudation is associated with the increased local blood flow, which in turn is caused by increased inflow pressure and redistribution of the total body blood flow to the airways. © 1997 by Elsevier Science Inc.

The mechanisms producing long duration of action for formoterol and salmeterol are not fully understood. The aim of the current study was to examine how the concentration of long and short acting ß2-adrenoceptor agonists affects their relaxation kinetics in airway smooth muscle. Onset (time to peak relaxation) and offset of action (reassertion of reversible relaxation following repeated ß-adrenoceptor blockade and washout) were measured in the guinea pig trachea precontracted postjunctionally by carbachol 0.3 µM in vitro. At 10-1,000% (C1O-C1,000) of the maximally effective concentration (C100: 150 nM formoterol, 10 µM salbutamol, 30 µM salmeterol), salbutamol had a shorter time to peak relaxation than did salmeterol. Formoterol and salmeterol had a similar time to peak relaxation at C10, but, in contrast to salmeterol, formoterol's time to peak relaxation became markedly shorter and similar to that of salbutamol as the concentration was increased up to C1,000. Significant reversible reasserted relaxation was demonstrated for salmeterol alone at C10. At C30-C1,000, however, salmeterol produced irreversible relaxation only, in spite of repeated ß-adrenoceptor blockade by sotalol 10 µM followed by washout. In contrast, formoterol produced an increasing reversible reasserted relaxation at C30-C1,000. Salbutamol produced significant, reversible reasserted relaxation at C1,000 only. In conclusion, the concentration determines the onset and offset of action for formoterol and to a lesser extent for salbutamol, but not for salmeterol. To cause sustained action, a submaximally effective concentration is sufficient for salmeterol, whereas formoterol requires a maximally effective concentration. The rank order of concentration dependence for the relaxation kinetics is not paralleled by the rank order of lipophilicity for formoterol, salbutamol, and salmeterol. Therefore, factors other than lipophilicity may also play a role in determining the relationship between concentration and relaxation kinetics for the investigated ß2-agonists.

BACKGROUND: In many countries, two dry powder formulations of inhaled formoterol are available for clinical use; one uses a single-dose device (Foradil, Aerolizer), and the other uses a multiple-dose device (Oxis, Turbuhaler).OBJECTIVES: To study the bronchodilating effect of formoterol 12 μg when delivered via the Aerolizer and Turbuhaler devices over 12 h.STUDY DESIGN: Randomized, double-blind, placebo controlled crossover study. Forced expiratory volume in one second (FEV1) was monitored during a 12 h period.PATIENTS: Nineteen nonsmoking asthma patients were included in the trial on the basis of reversibility of symptoms in response to inhaled salbutamol (either 200 or 400 μg given cumulatively; minimum reversibility 15%).RESULTS: There were no significant differences between the two dry powder devices regarding the change from baseline of FEV1 over 12 h, the area under the curve of FEV1 over 12 h or the maximum value of FEV1. The improvement in FEV1 with formoterol 12 μg versus placebo was highly significant for both devices.CONCLUSIONS: Formoterol is similarly effective when used as a dry powder when given by either Aerolizer or the Turbuhaler.