Alternative modes of action of sodium cromoglycate

Abstract

Alternative modes of action of sodium cromoglycateSodium cromoglycate (SCG) remains a unique drug in the management of asthma. Despite the intensive efforts of many pharmaceutical companies [1] to replace SCG with a more potent, more efficacious, orally active or longer acting agent, SCG is the only drug of its type which has been accepted into clinical practice since the demonstration of its prophylactic activity by ALTOUNYAN [2]. The attempts to develop new 'anti-allergic' drugs have been extensively reviewed by others in this journal and elsewhere [1,3].Despite the general acceptance that the primary mode of action of cromoglycate is to stabilize the mast cell membrane and thus prevent the release of bronchoactive or inflammatory mediators, two major anomalies have emerged which contradict this view. The first is the demonstration of activity with sodium cromoglycate in man in some forms of asthmatic bronchoconstriction in which mast cells or allergic mechanisms may not be involved. Secondly, many novel compounds, far more potent than SCG in mast cell-mediated animal models, have demonstrated little or no efficacy when tested in the clinic. These anomalies will be discussed later but it may be relevant to point out here that much of the initial pioneering, experimental work with SCG was carried out in man [2] and the animal models followed! In this paper two parallel lines of research are reviewed in which we attempted to demonstrate activity with SCG in animal models of immediate, airway hypersensitivity or we investigated the effects of SCG on vagally-mediated reflex bronchoconstriction.The passive cutaneous anaphylaxis (PCA) test in rats was one of the first in vivo animal models in which cromoglycate was shown to be effective [4] and has since been used extensively in screening this type of compound. Our early attempts to develop a clinically relevant test in the airways for SCG-like activity included studies with passive lung anaphylaxis (PLA) in the rat [5,6]. Rats were sensitized by the intravenous injection of high titre reaginic antiserum prepared in rats [7] and twenty-four hours later the rats were anaesthetized and SCG and other anti-anaphylactic compounds were given 1 minute before challenge with antigen. Bronchoconstriction was measured by a modification of the method of KONZETT and ROSSLER [8]. The IDs0 for SCG as an inhibitor of PLA was found to be 1.3 mg/kg compared with 1.0 mg/kg in the PCA test. Comparison of the activity of 13 novel anti-anaphylactic compounds in the PCA tests and PLA tests resulted in a highly significant correlation (p < 0.001) when the dose-ratios of compounds relative to SCG were compared in both tests [5].In parallel with the investigation of the effects ofcromoglycate on anaphylactic bronchoconstriction in the rat, in vivo we were able to look at the drug's effects on the release of the ~ediators of anaphylactic bronchoconstriction in vitro. We did this using the technique of cascade superfusion of isolated tissues [9]. Using suitable assay tissues and appropriate ant...

Pulmonary Vascular Response to Aerosolized Cromolyn Sodium and Repeated Epochs of Isocapneic Alveolar Hypoxia in Lambs

“…Because the residence time of the drug in the peribronchial/perivascular tissues after inhalation would be increased over that expected after intravenous administration, aerosol delivery of CS would place the drug at its primary site of action and result in prolonged residence at that site because of its slow distribution. CS may have pharmacologic effects other than stabilization of mast cell membranes as it has been shown to exert direct effects on bronchial smooth muscle (23) and to inhibit reflex-induced bronchoconstriction in dogs, most likely by suppressing lung irritant receptors (24). It has also been shown to inhibit the inflammatory effects of platelet-activating factor, a known bronchoconstrictor and vasoconstrictor, by a mechanism independent of mast cell activity (25).…”

The effects of topical sodium cromoglicate on itch and flare in human skin induced by intradermal histamine: a randomised double-blind vehicle controlled intra-subject design trial

“…The techniques used for this study were similar to those described in the original study with nedocromil sodium [13]. …”

“…The most likely mechanism of action is to prevent the activation of sensory nerves. This was initially proposed from airway studies in humans [11,12] and experimental animals [13]. This proposal is supported by a study with the related chromone, nedocromil sodium, which, when introduced into the skin by iontophoresis, causes inhibition of histamine-induced itch and flare but has no effect on the wheal [14].…”