Inhibition of Immediate Hypersensitivity Reactions in Laboratory Animals by a Phenanthroline Salt (Ici 74,917)

Abstract

1 The activity of a new anti-allergic compound, I.C.I. 74,917, has been studied in the rat, mouse and guinea-pig.2 Following intravenous administration, I.C.I. 74,917 inhibits in a dose-dependent manner passive cutaneous anaphylaxis induced in rats and mice by heat-labile homocytotropic antibody. In rats, its potency is approximately 300 times that of disodium cromoglycate. 3 To achieve maximal inhibition, it is necessary to administer I.C.I. 74,917 at the same time as antigenic challenge; dosing before or after challenge has much less effect. 4 Liberation of histamine, provoked by the antigenic challenge of mast cells passively sensitized in vitro by IgE-like antibody, is reduced in the presence of I.C.I. 74,917. 5Intravenous administration of the compound has no significant effect upon local blueing reactions provoked in the rat by intradermal injection of histamine, 5-hydroxytryptamine or Compound 48/80. It has only a slight effect at high doses upon passive cutaneous anaphylaxis induced in the rat by heat-stable homocytotropic or heterologous (guinea-pig) antibodies. 6 Although not a bronchodilator in the guinea-pig, I.C.I. 74,917 partially inhibits systemic anaphylaxis. A consistent reduction in the severity of antigen-induced bronchospasm was demonstrated in the Konzett-R6ssler preparation at doses comparable to those inhibiting passive cutaneous anaphylaxis in the rat. However, there was only slight inhibition of passive cutaneous anaphylaxis in the guinea-pig. 7 I.C.I. 74,917 itself induces bronchospasm when administered to anaesthetized guinea-pigs or to a guinea-pig isolated lung preparation. This effect is reversed by salbutamol, but is not prevented by the prior administration of mepyramine, atropine or methysergide. 8 These results indicate that in the rat, mouse and guinea-pig, I.C.I. 74,917 is a potent inhibitor of certain types of immediate hypersensitivity reactions.

Antigen‐induced Bronchial Anaphylaxis in Actively Sensitized Guinea‐pigs: Anti‐anaphylactic Effects of Sodium Cromoglycate and Aminophylline

“…Martin showed that the failure of SCG to inhibit guinea-pig PCA is not only limited to reactions mediated by the non-reaginic IgG, antibody, but also occurs with the newly-recognized guinea-pig reaginlike antibody. The failure of SCG to inhibit PCA reactions mediated by IgGl-antibodies was also reported by Lopez & Bloch (1969), Evans & Thomson (1975), and Taylor & Roitt (1973). Assem & Richter (1971) found that SCG inhibited both IgG1 and reagin-mediated histamine release from guinea-pig lung.…”

“…Assem & Richter (1971) found that SCG inhibited both IgG1 and reagin-mediated histamine release from guinea-pig lung. Experiments with chopped lung produced variable results (Cox, 1967;Evans & Thomson 1975). Taylor & Roitt (1973), Carney (1976), andCatty &Fraser (1972), in experiments with guinea-pigs actively or passively sensitized, showed that suppression of IgE-mediated responses, either with SCG or by previous heat treatment of the antibody, potentiates cutaneous and pulmonary responses to antigen.…”

Effects of Cyclic Amp‐ and Cyclic Gmp‐phosphodiesterase Inhibitors on Immunological Release of Histamine and on Lung Contraction

“…M&B 22948 was indeed introduced as an inhibitor of reagin-mediated anaphylaxis (Broughton, Chaplen, Knowles, Lunt, Pain, Wooldridge, Ford, Marshall, Walker & Maxwell, 1974). Similarly ICI 74917 inhibits immediate hypersensitivity reactions (Evans & Thomson, 1975), and selectively inhibits cyclic GMP hydrolysis (Coulson et al, 1977;Ruckstuhl & Landry, 1981). It must also be noted that DSCG is a highly selective inhibitor of cyclic GMP hydrolysis (Bergstrand, Kristofferson, Lundquist & Schurmann 1977;and Table 1) and has been previously shown to inhibit histamine release from mast cells but not from basophils (Assem & Mongar, 1970).…”

The absorption and elimination of ICI 74,917 in man.

“…Subsequently other compounds have been shown to possess similar inhibitory effects on immediate hypersensitivity responses. Of these,4,7,917) as the disodium salt (Figure 1) has been shown to be 300 times more potent than DSCG in inhibiting dermal blueing reactions provoked by Compound 48/80 in rats (Evans & Thomson, 1975). This novel compound also inhibits allergic bronchospasm in the guinea-pig in a dose dependent manner.…”