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CGP 51901 is a non-anaphylactogenic mouse/human chimeric anti-human IgE antibody that binds to free IgE and surface IgE of IgE-expressing B cells but not to IgE bound to high affinity IgE receptors (Fc epsilonR1) on mast cells and basophils or low affinity IgE receptors (Fc epsilonR2) on other cells. A phase 1 double-blind, placebo-controlled, single dose study with doses of 3, 10, 30, and 100 mg of CGP 51901 was conducted in 33 pollen-sensitive subjects who had raised levels of serum IgE and received either intravenous CGP 51901 or placebo. The administration of CGP 51901 was well tolerated and resulted in a decrease of serum free IgE levels in a dose-dependent manner, with suppression after 100 mg of CGP 51901 reaching > 96%. Time of recovery to 50% of baseline IgE correlated with the dose of administered antibody and ranged from a mean of 1.3 d for the 3 mg to 39 d for the 100 mg dose. Total IgE, comprised of free and complexed IgE, increased as stored and newly synthesized IgE bound to CGP 51901. Complexed IgE was eliminated at a rate comparable with the terminal half-life of free CGP 51901 (11-13 d at all doses). Only one subject showed a weak antibody response against CGP 51901. We conclude that the use of anti-human IgE antibody is safe and effective in reducing serum IgE levels in atopic individuals and provides a potential therapeutic approach to the treatment of atopic diseases.

Salmeterol and formoterol, two new long-acting beta 2-agonists were equipotent (values of negative log molar concentration eliciting half-maximal effect [pD2] 9.2 +/- 0.03 and 8.9 +/- 0.03, respectively) in relaxing maximally contracted guinea pig tracheal spirals (histamine, 100 microM). Both agonists were 10 times more potent than L-isoproterenol and fenoterol and 100 times more potent than albuterol. L-Isoproterenol and fenoterol induced > 90% relaxation (percentage of maximal aminophylline relaxation). Formoterol and albuterol were equally efficacious. Formoterol was more efficacious (86 +/- 5%) than salmeterol (62 +/- 3%) or soterenol (59 +/- 3%). In minimally contracted tissues (10 microM histamine), agonist potencies increased 10-fold and relaxation was complete. In [125I]iodocyanopindolol-labeled bronchial membranes, formoterol and salmeterol induced high-affinity states of the beta 2-receptor (pKh 9.6 +/- 0.4 and 10.4 +/- 0.7, respectively), the former inducing a higher percentage (57 +/- 6 versus 28 +/- 4, p < 0.05). Only low-affinity binding (pKI) was observed when guanine nucleotide was present. pD2 values were similar to pKh values and relative efficacies significantly correlated with percentage of pKI sites. Formoterol and salmeterol were highly selective for the beta 2 versus beta 1-subtype (pKI values were 8.2 +/- 0.09 and 6.25 +/- 0.06 and 8.3 +/- 0.04 and 5.7 +/- 0.04, respectively). Albuterol (5.83 +/- 0.06 and 4.71 +/- 0.16) and fenoterol (6.33 +/- 0.07 and 5.67 +/- 0.05) were less selective. These results can explain the potencies and efficacies of salmeterol and formoterol in humans.

Agonist binding to the beta 2-adrenoceptors and its mapping were studied using the newly developed radioligand [3H]formoterol. The results of [3H]formoterol saturation binding and formoterol inhibition of [3H]formoterol binding were consistent with binding to a single class of receptors (Kd = 1.34 +/- 0.15 nM, Bmax = 154.9 +/- 8.0 fmol/mg protein in guinea pig lung membranes, n = 8; Kd = 1.05 +/- 0.17 nM, Bmax = 67.8 +/- 8.1 fmol/mg protein in human lung membranes, n = 5) and competition assays with other agonists and antagonists disclosed only a single class of site. The nonhydrolyzable GTP analogue GTP gamma S caused a reduction in both Kd and Bmax, indicating that the receptors labelled by [3H]formoterol are coupled to a guanine nucleotide binding regulatory protein. Receptor mapping of [3H]formoterol binding sites shows that beta 2-adrenoceptors were widely distributed in both guinea pig and human lung, with dense labelling over airway epithelium and uniformly over alveolar walls, and sparse labelling of airway and vascular smooth muscle. In addition, submucosal glands were also sparsely labelled in human bronchus. The distribution of beta 2-adrenoceptors was similar to the pattern previously described with non-selective radiolabelled antagonists in the presence of selective beta 1-adrenoceptor antagonists.

The objective of this study was to evaluate the potency and efficacy (intrinsic activity) of formoterol and salmeterol and their duration of action in comparison with other beta-adrenoceptor agonists in isolated human bronchi. Human bronchi were obtained at thoracotomy from patients with lung cancer. Potency (-log of the concentration of drug inducing 50% of maximal relaxation (-log EC50)) and efficacy (maximal effect (Emax), % of response to theophylline 3 x 10(-3) mol.l-1) were determined by analysis of cumulative isometric concentration-response curves to beta 2-adrenoceptor agonists in bronchial rings at resting tone or contracted maximally with acetylcholine 10(-3) mol.l-1 to induce functional antagonism. The onset and duration of action of beta-adrenoceptor agonists were measured by assessing the relaxant activity of drugs on the basal tone of isolated bronchi. In terms of potency, the rank order of the substances studied was formoterol > fenoterol > or = salmeterol > or = isoprenaline > or = salbutamol > or = adrenaline > or = terbutaline. Formoterol was 150-200 times more potent than isoprenaline. On preparations contracted with acetylcholine 10(-3) mol.l-1 the intrinsic activity (IA) of salbutamol, terbutaline and salmeterol compared with that of isoprenaline ranged 0.62-0.66. Intrinsic activity was higher with formoterol (0.84) and fenoterol (0.75). The onset of action of formoterol (2.14 +/- 0.55 min, n = 11) was not significantly different from that of salbutamol (1.90 +/- 0.24 min, n = 8) but shorter than that of salmeterol (6.40 +/- 1.40 min, n = 10).(ABSTRACT TRUNCATED AT 250 WORDS)

The air we breathe contains certain gases and particles, some of which may be a threat to man. The respiratory tract is their first target because it comes into direct contact with them, and to protect the body itself it mobilizes defense mechanisms of high complexity. To understand these it is necessary to analyze the toxic modalities of these air contaminants: composition, deposition and transit through the respiratory tract. As far as the particles are concerned, the aerodynamic diameter is an important factor in determining the manner of deposition. Also of importance are shape, density, degree of humidity and radioactivity. Some particles are infectious, some are antigenic, and some are toxic due to their physical structure or chemical composition. Emphasis is placed on the role of aerosols, particularly tobacco smoke, as pollution factors or co-factors with other pollutants. The characteristics of the exposed subject capable of defining a risk profile varying from person to person are dwelt on. This approach presupposes a separation, within the cleaning and defense mechanisms, of the mechanical means which bring physical phenomena into play on the basis of fixed structures in the respiratory tract (cilium, mucous cells, surfactant). This is followed by study of the immunologic means of defense essentially involving cellular elements residing temporarily in the lung (T or B lymphocytes, plurinuclears, alveolar histiocytes in particular). Many enzyme systems are also involved in this pulmonary defense and in keeping homeostasis working. Particular attention is focused on some of them, such as the antiproteases and cytochrome P450.(ABSTRACT TRUNCATED AT 250 WORDS)

Muco-ciliary transport is only effective because of the coordination of the ciliary beats (metachronous) and the harmony between mucus and cilia. The tip of the cilia is in contact with a jellyform layer of mucus propelled to the oropharynx. This jellyform layer has a complex rheological behaviour: it flows like a liquid and shapes like solid elastic. When the rheological properties of bronchial secretion are abnormal, mucociliary transport becomes inefficient. However, the most fluid secretions are not necessarily best transported, because the elasticity and viscosity to guarantee efficient muco-ciliary transport can only vary within defined limits. The mechanism regulating the ciliary beats is poorly understood; the bronchial secretions conduct impulses through the autonomic nervous system as well as mediators such as histamine and the metabolites of arachidonic acid. Mucociliary function may be studied either, directly through mucociliary transport or through mucociliary clearance. A fall in mucociliary activity can be produced by a primary ciliary disorder, by bronchial disease or the consequences of respiratory infection. General anaesthetics and Atropine slow mucociliary transport but Ipratropium bromide does not; Theophylline and sympathomimetics speed it up. The expectorants are mucolytics (proteolytic enzymes, N-acetyl-cysteine), there are agents to correct hydration anomalies of the bronchial secretion (water, hypertonic sodium chloride) iodides, antifibrins by substitution, anti-inflammatory agents and mucoregulatory agents (S-carboxymethylcysteine, bromhexine). The efficacy of the greater part of these expectorants has not been established in vivo by controlled therapeutic trials.

Twelve patients with chronic severe asthma, having previously shown an FEV1 increase of less than 20% of the predicted value with prednisolone treatment (20-60 mg daily for 10 days), took part in a double blind crossover comparison of equipotent anti-inflammatory doses of betamethasone and prednisolone. Betamethasone (8 mg) and prednisolone (40 mg) were administered daily for 10 days with a washout period of 10 days between. In this first part of the study betamethasone was administered intramuscularly and prednisolone orally. Placebo injections and tablets were used. Mean FEV1 was not significantly different before each period. There was a significant increase in FEV1 while they were taking betamethasone but not prednisolone. Individual analysis of the data showed that FEV1 increased with betamethasone in nine patients and remained stable or decreased in three. During treatment with prednisolone baseline FEV1 increased moderately in three patients (FEV1 0.3, 0.5 and 0.6 l) and remained stable or decreased in nine. There was no significant difference between the bronchodilator responses to cumulative doses of inhaled salbutamol when they were measured immediately before, on the last day of treatment with each steroid, and between steroid treatment periods. The same protocol was followed four months later in five of the 12 patients but both drugs were administered orally on this occasion. Similar results were obtained. The greater effect of betamethasone on bronchial obstruction may be due to its longer biological half life or to some unidentified property of its metabolites. The bronchial response to inhaled beta 2 agonist appears not to be influenced by either steroid in these patients.

Platelet-activating factor (PAF) administered i.v. or by aerosol to guinea pigs elicited an increase in airway responsiveness to both acetylcholine and histamine when compared with guinea pigs exposed to the vehicle bovine serum albumin (BSA). After i.v. PAF, the ED100 for acetylcholine and histamine was 5.4 and 3.4 micrograms/kg, respectively, in comparison with 17 and 6 micrograms/kg, respectively, before PAF, representing approximately a 3- and 2-fold increase in responsiveness, respectively. After aerosol PAF (500 micrograms), the ED100 for acetylcholine and histamine was 13 and 7 micrograms/kg, respectively, whereas after aerosolized BSA, the ED100 for acetylcholine and histamine was 23 and 12 micrograms/kg, respectively, representing approximately a 2-fold increase in responsiveness. However, airway smooth muscle obtained from these PAF- or BSA-treated animals did not exhibit any differences in contractile response to histamine or acetylcholine in vitro. Likewise, there were not significant differences in the binding affinity or receptor density between PAF- and BSA-treated tissues with [3H]quinuclidinylbenzilate or [3H]pyrilamine binding, which were used to identify muscarinic and H1-histamine receptors, respectively. Furthermore, histamine and carbachol-induced phosphoinositide hydrolysis was similar in PAF- and BSA-treated tracheal smooth muscle preparations. Thus, PAF induces airway hyperresponsiveness in the guinea pig that is not related to changes in airway smooth muscle or to changes in muscarinic and histamine (H1) receptor density or function.