Effects of C5a on guinea pig lung: histamine release and mechanism of contraction.

C5a, a product of complement system activation, causes a significant contraction of the isolated guinea pig trachea, and the antihistamine diphenhydramine does not alter the rate, amplitude, or duration of the contraction (Regal et al., 1980). The present study demonstrates that over the range of C5a concentrations investigated, the C5a-induced contractile response of the trachea maximized, whereas the contraction of lung parenchymal strips and the release of histamine from chopped lung did not.

Ultrastructural and histochemical observations of respiratory epithelium and gland.

Secretory products of epithelial cells of the human respiratory tract have been studied biochemically and by a variety of histochemical methods for differentiating and characterizing complex carbohydrates at the light and electron microscopic level. By light microscopy a majority of mucous secretory cells of the surface epithelium secret glycoprotein with terminal sialic acid, penultimate galactose residues, and variable sulfate esters. Ultrastructurally the mucous cells of the surface epithelium vary within and between regions of the respiratory tree and comprise a heterogeneous population of cells differing in the fine structure and cytochemistry of their secretory granules.

C5a-induced histamine release. Species specificity.

C5a has long been known to cause histamine release from isolated perfused guinea pig lung, isolated human basophils, rat and guinea pig mast cells, and guinea pig skin. The purpose of the present study was to compare the ability of guinea pig C5a to cause histamine release from lung fragments of dog, rabbit and rat with that released from guinea pig lung fragments. In addition, C5a-induced histamine release from the skin of the guinea pig, rabbit, and rat was investigated by examining antihistamine inhibition of C5a-induced vascular permeability changes.

Effect of extracts of Angelica polymorpha on reaginic antibody production.

An aqueous extract of Angelica polymorpha was examined for its immunoregulating properties. Its effect on the production of antibodies was tested in (C57BL/6 X DBA/2)F1 mice. When the animals were treated daily with the extract, the serum titers of reaginic antibodies normally observed after a single injection dinitrophenylovalbumin (DNP3-OA) were significantly lower, and the higher and more sustained reaginic titers induced by booster injections of DNP3-OA were also inhibited.

Effect of histamine agonists and antagonists on the production of murine reaginic antibodies.

At least wo histamine receptors have been pharmacologically defined. Using the appropriate agonists and antagonists, the possible involvement of these receptor types in the production of reaginic antibodies in the rodent was investigated. After injecting mice with dinitrophenyl-ovalbumin (DNP-OA), maximal serum reaginic titers occurred on day 11 as measured by heterologous passive cutaneous anaphylaxis.

Immunologic histamine release in vitro from the heart and lung of the cynomolgus monkey.

Immunologic histamine release was evoked from the sensitized fragmented cardiac and pulmonary tissue of the cynomolgus monkey by a reverse anaphylactic reaction. Ventricular and pulmonary tissue released a similar fraction (approximately 6%) of the total tissue histamine when challenged with antihuman IgE, presumably reflecting the 'active' sensitization of the monkey in vivo. Passive sensitization of these tissues in vitro resulted in significantly greater immunologic histamine release in 6 of the 14 ventricles and d a similar fraction (approximately 6%) of the total tissue histamine when challenged with antihuman IgE, presumably reflecting the 'active' sensitization of the monkey in vivo.

Histamine release from rat lung sensitized in vitro with mouse serum--an alternative pharmacologic method.

The ability of mouse anti-dinitropheny ovalbumin (anti-DNP-OA) serum to sensitize rat lung fragments can be demonstrated by the release of histamine from the tissue after antigenic challenge. This method can be utilized to evaluate anti-allergic agents, e.g.

Preclinical evaluation of Antiallergic agents.

This paper examines the advantages and disadvantages of many in vivo and in vitro experimental model systems employed in the preclinical testing of antiallergic drugs.

Application of quantitative structure-activity relationships in the development of the antiallergic pyranenamines.

QSAR techniques played a major role in development of the antiallergic pyranenamines (I). Graphical analysis of data resulting from an unsuccessful Topliss approach suggested that increased substituent hydrophilicity might enhance potency. The 3-NHAc-4-OH derivative which first resulted was an order of magnitude more potent than any preceding series member, and its deacylated congenar is clinical candidate SK&F 78729 (R1 = -NH2, R2 - OH, R3 = H).

Pyranenamines: a new series of antiallergic compounds.

Condensation of 3,5-diacylpyrantriones with various aromatic amines gave a new class of potent, orally active, antiallergic compounds, the 3-[(arylamino)ethylidene]-5-acylpyrantriones, hereafter referred to as pyranenamines, as evaluated not only in the traditional rat passive cutaneous anaphylaxis (PCA) assay but also in the in vitro fragmented rat and primate lung assay. Potencies in the PCA system, when measured intravenously, reached a maximum ID50 of 0.9 mu/kg (1000 times more potent than disodium chromoglycate) with 5-acetyl-4-hydroxy-3-[1-[(3,5-bis-glyceramoylphenyl)amino]ethylidene]-2H-pyran-2,6(3H)-dione (100), as predicted by structure-activity relationship (SAR) analysis.

Pharmacologic characterization of the antiallergic activity of SK&F 78729-A.

SK&F 78729-A, one of a series of pyranenamine compounds, was studied in several laboratory models of immediate-type hypersensitivity reactions. In vivo, SK&F 78729-A, i.v.

Pharmacologic regulation of antigen-induced mediator release from canine lung.

The ascaris antigen-induced release of histamine and a slow-reacting substance of anaphylaxis (SRS-A) from passively sensitized fragmented canine lung is further characterized. Histamine and SRS-A were released within 30 sec of antigen challenge, reached a maximum at 7 and 10 min, respectively, and thereafter appeared to remain constant to 30 min. Contractions of guinea pig ileum produced by canine SRS-A were competitively antagonized by the SRS-A antagonist FPL-55712.

Characterization of the adrenergic activity of carbuterol (SK&F 40383-A).

Carbuterol is a beta-adrenergic bronchodilator with selectivity for bronchial smooth muscle relative to cardiac and vascular tissues of several species including man. The present studies were undertaken to further characterize its adrenergic profile. In vitro studies demonstrated that carbuterol was a direct acting beta-adrenergic agonist, not dependent on endogenous catecholamine release, and was devoid of alpha-adrenergic agonist activity.

The effect of metiamide in in vitro and in vivo canine models of type I hypersensitivity reactions.

The histamine H2-receptor antagonist metiamide was evaluated in in vitro and in vivo canine models of immediate-type hypersensitivity reactions. At concentrations of 2 and 4 X 10(-4) M, the antagonist significantly increased the amount of histamine present in the medium surrounding passively sensitized canine lung fragments which had been challenged with ascaris antigen. In contrast, the compound was without effect on the release of a slow reacting substance of anaphylaxis.

Further studies on the tachyphylaxis to DSCG. The effects of concentration and temperature.

The tachyphylaxis to DSCG's inhibition of anaphylactic histamine release has been demonstrated in passively sensitized rat lung fragments. The induction of tachyphylaxis appears to depend on the concentration of the drug and the length of pretreatment. Tachyphylaxis is relatively independent of the concentration of the second exposure to DSCG.

Studies on the mechanism of tachyphylaxis to disodium cromoglycate.

The tachyphylaxis to disodium cromoglycate's (DSCG) inhibition of antigen-induced histamine release is readily demonstrable utilizing passively sensitized rat lung fragments. This tachyphylaxis to DSCG is evident whether or not calcium is present during drug preincubation. An attempt to relate the mechanism of tachyphylaxis to the DSCG-induced release of an endogenous cellular inhibitory material was unsuccessful insofar as could be demonstrated by an effect on mediator release.

Canine airway responses to acetylcholine, prostaglandin F2alpha, histamine, and serotonin after chronic antigen exposure.

Dose-response curves were obtained for aerosols of acetylcholine (ACh), prostaglandin F2alpha (PGF2alpha), histamine (H), and 5-hydroxytryptamine (5-HT) on pulmonary resistance (Rp) and dynamic lung compliance (Cdyn) in Ascaris-hypersensitive dogs. Previously, these animals had been subjected to chronic biweekly "allergic asthmatic" episodes by aerosol administration of Ascaris antigen. When examined either one week before or after antigen provocation the airways were not hyperreactive to ACh, H, or 5-HT but did demonstrate a modest hyperreactivity to PGF2alpha.

The effect of cholinergic agents on a canine model of allergic asthma.

Pharmacologic agents capable of influencing the activity of the cholinergic nervous system were evaluated for possible effects on a canine model of allergic asthma. Dogs with an active cutaneous sensitivity to an antigen (Ag) prepared from Ascaris suum were subjected to repeated aerosol Ag provocations at 2-wk intervals. Ag-induced increases in pulmonary resistance (Rp) and decreases in dynamic lung compliance (Cdyn) were obtained in the presence and absence of drugs.

IgE-mediated histamine and SRS-A release from respiratory cells and peripheral blood leukocytes of rhesus monkeys.

Peripheral blood leukocytes (PBL) and free respiratory cells (RC) of the mast cell-basophil type were obtained from normal rhesus monkeys or rhesus monkeys with defined immediate-type hypersensitivity to ascaris antigen (AA). PBL or RC from the latter were exposed to AA and the former were exposed to anti-IgE. Histamine (H) release and release of a slow reacting substance of anaphylaxis (SRS-A) occurred following exposure of the appropriate cells to AA or anti-IgE.

Antiarthritic properties and unique pharmacologic profile of a potential chrysotherapeutic agent: S K & F D-30162.

SK&F D-39162, a potential chrysotherapeutic agent, on oral administration was effective in suppressing the development of inflammatory lesions and 7S anti-sheep red blood cell antibody formation in adjuvant arthritic rats. Oral absorption of SK&F D-39162 was indicated by the presence of serum gold levels. In contrast to orally administered SK&F D-39162, gold sodium thiomalate administered intramuscularly at equivalent gold doses, appeared to be less effective in suppressing the primary and secondary lesions of adjuvant arthritis, produced relatively higher levels of gold in both serum and kidneys and produced marked toxicity.