Proyecciones y estrategias actuales en la búsqueda y desarrollo de nuevos medicamentos antiasmáticos y antialérgicos profilácticos / Current strategies and projections in the search for and development of new prophylactic antiasthmatic and antiallergic drugs

Se analizan las nuevas estrategias a seguir para el descubrimiento y desarrollo de nuevos y mejores medicamentos antiasmáticos. Los resultados obtenidos han conllevado a una reevaluación crítica de los métodos farmacológicos que se han utilizado hasta el presente en este campo. Los antagonistas del factor activador plaquetario y los leucotrienos al igual que los inmunomoduladores que ejercen efecto inhibitorio en la producción de la inmunoglobulina E (IgE), constituyen los principales avances para el logro de este objetivo

Inhibition of IgE-mediated N-acetylglucosaminidase and serotonin release from rat basophilic leukemia cells (RBL-2H3) by tenidap: a novel anti-inflammatory agent.

Tenidap [(Z)-5-chloro-2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1H- indole-1-carboxamide] is a novel anti-inflammatory compound of the oxindole class that currently is undergoing clinical evaluation in man. Here we demonstrate that tenidap inhibits (IC50 = approximately 10 microM) IgE-mediated secretion of granule constituents from the rat mast cell tumor line RBL-2H3. The inhibitory effect is rapid in onset, readily reversible, and appears to be unique when compared to a representative selection of other acidic (carboxylic acids, pyrazoles and oxicams) nonsteroidal anti-inflammatory compounds.

Modulation of mediator release from human basophils and pulmonary mast cells and macrophages by auranofin.

Auranofin, a new orally absorbable gold compound, inhibits IgE-(anti-IgE) and non-IgE-mediated (f-met-peptide and the Ca2+ ionophore A23187) histamine release from human basophils. Auranofin inhibits the release of histamine induced by phorbol myristate (TPA) and bryostatin 1 both in the presence and absence of extracellular Ca2+. Increasing the Ca2+ concentrations in the extracellular medium does not reduce the inhibitory effect of auranofin on anti-IgE- or A23187-induced secretion. Auranofin inhibits the de novo synthesis of sulfidopeptide leukotriene C4 (LTC4) induced by anti-IgE from basophils and mast cells purified from human lung. However, in both systems auranofin has a significantly greater inhibitory effect on LTC4 release than on histamine secretion. Finally, auranofin induces a concentration-dependent inhibition of A23187-induced leukotrine B4 (LTB4) release from purified human lung macrophages. These data suggest that auranofin modulates the release of preformed (histamine) and de novo synthesized (LTC4 and LTB4) chemical mediators from human inflammatory cells isolated from peripheral blood and human lung tissues.

Inhibition of IgE binding to tissue culture cells and leucocytes by pentapeptide.

The specific binding of radiolabelled IgE to a tissue culture lymphoblastoid cell line (Wil-2WT) was confirmed. The binding of IgE and Hamburger's IgE-derived pentapeptide Asp-Ser-Asp-Pro-Arg (HEPP) to Wil-2WT cells and to human leucocytes was compared. HEPP inhibition of IgE binding to leucocytes averaged 24% but with Wil-2WT cells only 12% inhibition was observed with double the amount of HEPP. Using myeloma IgE to inhibit the binding of tritiated HEPP to leucocytes and Wil-2WT cells confirmed the specificity of the peptide binding as well as the greater affinity of HEPP for leucocytes (basophils) compared to Wil-2WT lymphoblastoid cells. Based upon the extent of binding and the maximum inhibition attainable with HEPP it is suggested that the receptors for IgE on Wil-2WT cells, basophilic leucocytes and mast cells are not identical but that they share specificities in common. A new hypothesis for the mechanism of action of HEPP is proposed.

Ammonium and sulfate ion release of histamine from lung fragments.

In vitro studies with guinea pig lung fragments incubated with 10- to 200-mM concentrations of ammonium ion demonstrated the release of substanial quantities of histamine. Of the anions tested with ammonium ion, sulfate was the most potent, while nitrate and acetate ions were of intermediate potency and chloride was less potent. An osmotic effect is unlikely since equal concentrations of sodium chloride failed to release histamine. Isoproterenol, known to decrease anaphylactic histamine release, and acetycholine, known to increase histamine release, had no effect on the ammonium sulfate-mediated release of histamine. N-6 2'-O-Dibutyryladenosine 3',5' monophosphate (dibutyryl c-AMP) was also ineffective. These studies suggest that the inhalation irritation associated with certain sulfate and other salts, may be a function of their ability to release histamine in the presence of amonium ion.

Histamine release from human leukocytes: modulation by a cytochalasin B-sensitive barrier.

Cytochalasin B, a metabolic product of several fungi, enhances up to 10-fold the sensitivity and reactivity of human leukocytes to antigen E or anti-IgE-mediated histamine release. The effect of cytochalasin B is a result of its action on the second, antigen-independent, stage of histamine release. These data suggest that normally, antigen-triggered histamine release is modulated by a cytochalasin-sensitive barrier (CSB). This CSB modulation of histamine release can be separated from the modulating effect of cyclic adenosine monophosphate (AMP).

Naturally occurring human antiglobulins with specificity for E.

Human sera have been examined for antibodies with specific reactivity for gammaE using the tanned cell hemagglutination test. Cells tanned with three different gammaE myeloma proteins provided a reproducible test system. Inhibition of agglutination reactions by gammaE proteins, but not by gammaG, gammaA, gammaM, or gammaD confirmed the specificity of these reactions. 8.5% of 304 serial serum samples obtained from miscellaneous hospitalized patients showed clear-cut anti-gamma-globulins with specificity for gammaE. In most of these instances no definite clinical history of concomitant allergic disorders could be obtained. 53% of 73 patients with well-established allergic disorders (hay fever, extrinsic asthma) showed serum anti-gamma-globulins with reactivity for gammaE. Some patients studied before and after desensitization to Bermuda grass allergen showed an increase in titer or a conversion from negative to positive reactions for anti-gammaE antibodies following several month courses of progressive desensitization. Gradient and gel filtration studies indicated that anti-gammaE globulins were 19S gammaM in all instances. No clear correlation was noted between quantitative serum gammaE levels and titer of anti-gammaE antibodies.19S serum fractions with anti-gammaE antibody activity did not release histamine from normal human peripheral blood leukocytes, whereas specific rabbit anti-gammaE antisera consistently induced leukocytic histamine release. Moreover, macroglobulin fractions with anti-gammaE activity did not block allergen-specific leukocyte histamine release induced by in vitro leukocyte challenge with allergens such as Bermuda grass and leukocytes from allergic donors. In some instances 19S human serum fractions with anti-gammaE activity appeared to potentiate histamine release when incubated concomitantly with specific allergen and leukocytes from allergic individuals.

Mast cells from human respiratory tissue and their in vitro reactivity.

Human respiratory mast cells, which were obtained coincidentally with diagnostic bronchial brush biopsy, were maintained under conditions for short-term tissue culture. Most mast cells were viable and degranulated on exposure to antibody to immunoglobulin E or to the mast cell degranulating agent compound 48-80. The degranulation of human mast cells is characteristically an intracellular process with no extracellular extrusion of granules.