Prospects for an oral intal

Stokes, T.C.; Morley, John E.

doi:10.1016/s0007-0971(81)80002-2

Cited by 66 publications

(16 citation statements)

References 54 publications

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“…This study has demonstrated that expression of an acute allergic reaction was insufficient to account for air way hyperreactivity in the guinea pig, which is consistent with the clinical finding that suppression of acute manifestations of the allergic response is not necessarily accompanied by diminished hyperreactivity (18,19) and the lack of clinical efficacy of compounds selected as anti asthma drugs by reference to acute allergic reactions (20). Observation of changed responsivity to inhaled spasmo gens following inhalation of allergen is a widely used tech nique for studying the airway hyperreactivity in clinical asthma.…”

Section: Discussionsupporting

confidence: 85%

Allergic Bronchospasm and Airway Hyperreactivity in the Guinea Pig

Hoshiko

Morley

1993

Japanese Journal of Pharmacology

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ABSTRACT-In passively sensitized guinea pigs, slow infusion of an amount of ovalbumin insufficient to evoke airway obstruction induces hyperreactivity of the airways. A wide range of changed responsivity was observed for different test spasmogens, with leukotriene C4 > histamine > prostaglandin Fl, > bradykinin > leukotriene E4> serotonin > acetylcholine. Injection of ovalbumin as a bolus produced pronounced airway obstruction without hyperreactivity. Airway obstruction due to vascular engorgement (dextran infusion) or edema (histamine infusion) did not result in hyperreactivity. Infusion of PAF induced pronounced airway obstruction together with hyperreactivity, but with a rank order of histamine>leukotriene C4> serotonin > bradykinin > leukotriene E4 > acetylcholine. It can be concluded that allergic airway hyper reactivity in the guinea pig is spasmogen-selective and largely independent of airway obstruction. These observations question the presumption of non-selective hyperreactivity in allergic asthma and cast doubt upon the proposal that airway hyperreactivity is secondary to airway obstruction.

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Section: Discussionsupporting

confidence: 85%

Allergic Bronchospasm and Airway Hyperreactivity in the Guinea Pig

Hoshiko

Morley

1993

Japanese Journal of Pharmacology

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“…SCG was originally introduced as a mast cell-stabilizing drug and the first of a novel class of therapeutic agents for the treatment of allergic diseases [8]. However, its mast cell-stabilizing property is unlikely to explain the therapeutic efficacy of SCG in the treatment of asthma, because many compounds that are far more potent in stabilizing mast cells have failed to show therapeutic usefulness [30]. More recently, SCG has been shown to inhibit bronchoconstrictor responses evoked by irritants including bradykinin [31] and sulphur dioxide [32].…”

Section: Discussionmentioning

confidence: 99%

Effect of cromolyn on adenosine-induced airway microvascular leakage in sensitized rats

Tamaoki¹,

Yamawaki²,

Taira³

et al. 1999

Eur Respir J

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Inhalation of adenosine causes bronchoconstriction in asthmatic subjects, but the effect of this purine nucleotide on airway vascular permeability is unknown.In order to determine whether adenosine produces airway microvascular leakage and, if so, to examine the effect of cromolyn (sodium cromoglycate (SCG)) on this extravasation of Evans blue was measured in the airways of ovalbumin-sensitized Brown Norway rats.Inhaled adenosine caused microvascular leakage in sensitized but not in nonsensitized rats, and the response was abolished by capsaicin pretreatment or the tachykinin neurokinin-1 receptor antagonist FK888. Adenosine-induced vascular leakage became apparent in nonsensitized rats when treated with phosphoramidon, and airway neutral endopeptidase activity was lower in sensitized than in nonsensitized animals. The extravasation induced by adenosine in sensitized rats was dose dependently inhibited by SCG aerosols. SCG likewise inhibited microvascular responses to substance P, but had no effect on those to platelet-activating factor.These results suggest that: 1) adenosine induces airway microvascular leakage in sensitized rats through stimulation of neurokinin-1 receptors; 2) this effect is associated with a sensitization-induced decrease in neutral endopeptidase activity; and 3) sodium cromoglycate inhibits adenosine-induced extravasation, presumably via functional antagonism of tachykinins. Eur Respir J 1999; 14: 1082±1087. Adenosine is a naturally occurring purine nucleotide formed by the cleavage of adenosine 5'-monophosphate by 5'-nucleotidase or by the catabolism of S-adenosylhomocysteine. Based on the findings that adenosine can be released from mast cells in both early-and late-phase asthmatic responses via antigen/immunoglobulin E (IgE) interaction after allergen bronchoprovocation [1] and that inhaled adenosine causes bronchoconstriction in asthmatics but not in normal subjects [2], this purine nucleotide is thought to play a role in the pathophysiology of asthma. Increased microvascular permeability and plasma protein extravasation in the airways might contribute to mucosal oedema, inflammatory cell infiltration and epithelial cell desquamation, which are characteristic features of asthma [3]. Previous studies have shown that adenosine induces plasma extravasation in rat skin [4] and hamster cheek pouch [5], but its effect on airway microvascular permeability is unknown.Cromolyn (sodium cromoglycate (SCG)) is an antiallergic drug and has been widely used in the treatment of asthma [6,7]. Although SCG has long been recognized as a mast cell-stabilizing agent [8], its mechanism of action in asthma is still unclear. CROSSMAN et al. [9] showed that oedema formation in the human skin produced by substance P was reduced by SCG, suggesting that SCG may modify tachykinin actions. Therefore, the purposes of the present study were: 1) to determine whether adenosine produces airway vascular leakage; 2) to elucidate the possible involvement of tachykinins in the effect of adenosine; and 3) to deter...

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“…Taylor & Sheldon (1977) have suggested that there may be an essential co-factor in lung tissue that enables SCG to affect mast cell stabilisation. It has also been argued (Stokes & Morley, 1981) that the effectiveness of SCG in the treatment of asthma could be unrelated to mast cell stabilization and be dependent upon other properties such as effects on irritant receptors. This would provide a further explanation for its lack of inhibitory effect on the allergen induced skin weal.…”

Section: Discussionmentioning

confidence: 99%

A comparison of the in vivo effects of ketotifen, clemastine, chlorpheniramine and sodium cromoglycate on histamine and allergen induced weals in human skin.

Phillips¹,

Thomas²,

Moodley³

et al. 1983

Brit J Clinical Pharma

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1 The effect of ketotifen was compared with that of clemastine and chlorpheniramine, known antihistamines, and sodium cromoglycate, a drug considered to have mast cell 'stabilizing' properties on histamine and allergen wealing reactions in human skin, in random order, double-blind, placebo controlled studies. 2 Ketotifen was significantly more potent in the inhibition of both histamine (P < 0.001) and allergen (P < 0.001) skin wealing reactions than either clemastine or chlorpheniramine. Sodium cromoglycate had no significant effect on either histamine or allergen skin wealing reactions in any of the concentrations tested. 3 However ketotifen, like clemastine, had a significantly greater inhibitory effect on histamine than on allergen induced weals (P < 0.001) and both drugs were shown to act as competitive antagonists of histamine. 4 Ketotifen has been shown to be a potent anti-histamine but there is no evidence from these in vivo studies to suggest that it has any additional inhibitory activity on release of mediators from mast cells in human skin.

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Prospects for an oral intal

Cited by 66 publications

References 54 publications

Allergic Bronchospasm and Airway Hyperreactivity in the Guinea Pig

Allergic Bronchospasm and Airway Hyperreactivity in the Guinea Pig

Effect of cromolyn on adenosine-induced airway microvascular leakage in sensitized rats

A comparison of the in vivo effects of ketotifen, clemastine, chlorpheniramine and sodium cromoglycate on histamine and allergen induced weals in human skin.

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