1 The Search for Antiallergic Drugs for the Treatment of Asthma - Problems in Finding a Successor to Sodium Cromoglycate

Activity of Nedocromil Sodium in Mast-Cell-Dependent Reactions in the Rat

“…It has been shown to have therapeutic activity in a double-blind study in asthmatics on maintenance therapy with inhaled cor ticosteroids [4]. We report in this communication the evidence for the pharmacological effects of nedocro mil sodium in classical in vivo models of anaphylaxis in the rat.The passive cutaneous anaphylaxis (PCA) test in rats is an established screen for evaluating anti-aller gy compounds, using rats passively sensitised intradermally with serum containing IgE antibodies to an tigens such as ovalbumin (OA) [3,5,6]. Nedocromil sodium administered intravenously at the same time as antigen challenge inhibited the PCA reaction in a dose-related manner (0.5-8.0 mg/kg) and produced 50% inhibition (ED50 value) at 2.2 mg/kg (95% confi dence limits 1.8-2.6 mg/kg), an ED50 value similar to that found for sodium cromoglycate, 1.3 mg/kg (95% confidence limits 1.0-1.6 mg/kg).…”

“…In this programme, a new series of pyranoquinoline dicarboxylic acids was studied, from which nedocromil sodium [3] was identified. This compound is currently under development for the treatment of airway disease.…”

Alternative modes of action of sodium cromoglycate

“…Although the cardiovascular effects of SCG in the dog appear to be species-specific and are unlikely to be directly related to the clinical use of the drug, the sensory receptors responsible do provide a common site for studying the actions of novel cromoglycate-like compounds. Prior intravenous infusion of SCG into the dog blocks the effects of subsequent doses of SCG, and the ability of novel compounds to block the hypotensive effects of SCG has been used as a screen for cromoglycate-like activity [47] which has met with some success [1].…”

“…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 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.…”