High affinity [3H]formoterol binding sites in lung: Characterization and autoradiographic mapping

Agonist binding to the β2-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 (K(d) = 1.34 ± 0.15 nM, B(max) = 154.9 ± 8.0 fmol/mg protein in guinea pig lung membranes, n = 8; K(d) = 1.05 ± 0.17 nM, B(max) = 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 GTPγS caused a reduction in both K(d) and B(max), 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 β2-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 β2-adrenoceptors was similar to the pattern previously described with non-selective radiolabelled antagonists in the presence of selective β1-adrenoceptor antagonists.link_to_subscribed_fulltex

The effect of intravenous administration of a chimeric anti-IgE antibody on serum IgE levels in atopic subjects: efficacy, safety, and pharmacokinetics.

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