The effects of antiallergic and bronchodilator drugs on platelet-activating factor (PAF-acether) induced bronchospasm and platelet aggregation

Lewis, Alan J.; Dervinis, Alphonse; Chang, Joseph

doi:10.1007/bf01966785

Cited by 38 publications

(13 citation statements)

References 20 publications

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“…Disodium cromoglycate (DSCG) was completely inactive against the effects of Paf-acether in vitro, in accordance with in vivo results (Lewis et al, 1984), and in contrast to the inhibition described by Basran et al (1983) with very high concentrations applied with Pafacether to human skin. This indicates that the antiallergic activity of DSCG is not accounted for by inhibition of the effects of Paf-acether.…”

Section: Discussionsupporting

confidence: 87%

Histamine and leukotriene‐independent guinea‐pig anaphylactic shock unaccounted for by Paf‐acether

Detsouli

Lefort

Vargaftig

1985

British J Pharmacology

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1 Ovalbumin induced dose-dependent contractions of lung parenchyma strips from sensitized guinea-pigs, whereas Paf-acether (I -alkyl-2-acetyl-sn-glycero-3-phosphoryl choline), a potential mediator of immediate hypersensitivity, induced a single contraction, followed by specific desensitization to a second exposure. 2 Lung strips desensitized to Paf-acether contracted to ovalbumin as did non-desensitized controls, even in the presence of inhibitors of other mediators of anaphylaxis. 3 Contractions by Paf-acether and by ovalbumin were reduced by nordihydroguaiaretic acid (NDGA) and by the phospholipase A2 inhibitorp-bromophenacyl bromide (0.1 -0.3 mM). Three other anti-lipoxygenase agents (diethylcarbamazine, 5 mM; eicosatetraynoic acid and BW755c, 0.1 mM), reduced the contractions by ovalbumin but also those due to acetylcholine, indicating non-specific effects. Neither the anti-allergic compound sodium cromoglycate (3 mM) nor the anti-leukotriene agent, FPL 55712 (0.01 mM), inhibited the contractions by ovalbumin or by Paf-acether. 4 A sensitized strip stimulated with ovalbumin released substances which contracted a non-sensitized strip mounted in the same organ bath. The contractions of the non-sensitized strip were abolished by FPL 55712 (0.01 mM), by NDGA and BW755c, (0.1 mM), whereas those of the sensitized one were unaffected. Leukotrienes are formed by the lung strips during shock but alone, they do not explain the contractile activity.5 The intravenous administration of ovalbumin (1 mg kg-') led to bronchoconstriction and thrombocytopenia, which were not modified by the anti-leukotriene substance FPL 55712 nor by aspirin. Bronchoconstriction was suppressed if FPL 55712 was used in combination with aspirin (20 mg kg-'), mepyramine and methysergide (200 jg kg-of either). Pretreatment of the guinea-pigs with propranolol reduced this inhibition to approximately 60%. In no instance was thrombocytopenia prevented. 6 In vitro contractions of the actively sensitized lung strip are not fully accounted for by histamine, FPL 55712-inhibitable leukotrienes or Paf-acether, whereas in systemic anaphylaxis histamine and leukotrienes (inhibited respectively by mepyramine and by FPL 55712) have a significant role.

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Section: Discussionsupporting

confidence: 87%

Histamine and leukotriene‐independent guinea‐pig anaphylactic shock unaccounted for by Paf‐acether

Detsouli

Lefort

Vargaftig

1985

British J Pharmacology

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“…This may relate to the observation that while NDGA is a relatively selective inhibitor in vitro, its potency and effectiveness appear to be diminished in vivo [18]. The reasons for the disparity in the effects of aspirin, indomethacin, BW755C and NDGA on Paf-induced bronchoconstriction are not immediately obvious, but reflect the conflicting results of previous studies [19][20][21][22]. Both lipoxygenase and cyclooxygenase products have been implicated as mediators of Paf-induced bronchoconstriction.…”

Section: Discussionmentioning

confidence: 78%

“…Both lipoxygenase and cyclooxygenase products have been implicated as mediators of Paf-induced bronchoconstriction. LEWIS and co-workers [19] have reported that indomethacin at high doses, but not aspirin, attenuated and that BW 755C, NDGA and also the putative cysteinyl-containing leukotriene antagonist FPL 55712, at a high and probably non-selective dose, also reduced Paf-induced bronchoconstriction. In contrast, in separate studies FPL 55712, NDGA and eicosatetraynoic acid (ETYA), a false substrate inhibitor of the cyclooxygenase and lipoxygenase pathways, were reported not to influence bronchoconstriction induced by i.v.…”

Section: Discussionmentioning

confidence: 94%

“…In addition to its capacity to induce sustained lung inflammation [1] and selective eosinophil chemotaxis [2], Pafis a potent bronchoconstricting agent in experimental animals [3,7,8,19,21,22] and humans [4]. The identification of Paf in the perfusate of antigen challenged sensitized guinea-pig lungs [5], in the blood of allergic asthmatics following antigen challenge [6], and the efficacy of selective Paf receptor antagonists in animal models of allergic bronchospasm in vivo [7,8] are each strongly suggestive of a role for Paf in immediate hypersensitivity reactions.…”

Section: Introductionmentioning

confidence: 99%

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Increased airways responsiveness to histamine induced by platelet activating factor in the guinea-pig: possible role of lipoxygenase metabolites

1988

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In anaesthetized guinea-pigs pretreated with propranolol (1 mg/kg, i.v.), platelet activating factor (Paf, 0.02 micrograms/kg, i.v.) caused an acute increase in airways response to histamine (0.5-3.0 micrograms/kg, i.v.) measured as intratracheal pressure. Treatment with the cyclooxygenase inhibitors, aspirin (10 mg/kg, i.v.) or indomethacin (5 mg/kg, i.v.), enhanced the magnitude and duration of this effect but a combined lipoxygenase/cyclooxygenase inhibitor, BW 755C (20 mg/kg, i.v.), prevented the increase in responsiveness. In aspirin treated animals, a putative lipoxygenase inhibitor NDGA (10 mg/kg, i.v.). or atropine methyl nitrate (1 mg/kg, i.v.) or bilateral vagotomy reduced the magnitude of Paf-induced increased histamine responses but did not prevent the effect. Bronchoconstriction induced by Paf was variably influenced by the drug treatments. These data suggest that Paf causes an acute increase in airways responsiveness to histamine in the guinea-pig through a mechanism that may, in part, be dependant on the release of lipoxygenase metabolites.

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“…However, neither Wy-41,195 nor DSCG (both at 1-10 mg/kg, i.v.) influenced PAF-acether induced bronchospasm in anesthetized guinea pigs [16]. Furthermore, neither compound (at 10 .4 M) influenced PAF-acether induced rabbit platelet aggregation [16].…”

Section: Guinea Pig Skin and Airway Modelsmentioning

confidence: 97%

The development of Wy-41,195, an orally effective antiallergic drug in animal models

Lewis¹,

Carlson²,

Forster³

et al. 1986

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IntroductionDisodium cromoglycate (DSCG) administered by aerosol is well established as a prophylactic treatment for asthma. Since it is not effective orally and does not benefit all asthmatics, the search for a more potent and orally effective analog has attracted the attention of numerous pharmaceutical companies [1,2]. Unfortunately, a poor correlation exists between preclinical screening models and clinical activity [3]. The former are based on the premise that DSCG stabilizes mast cell membranes and prevents the release of allergic mediators induced by antigen-cell bound IgE interaction.This review is an account of the preclinical and clinical development of 195 (Fig. 1), an orally effective antiallergic compound. It was originally selected from a series of oxanilic acids [4] that were effective in rat passive cutaneous anaphylaxis (PCA), a screening test adopted for predicting DSCG-like antiallergic activity. However, in addition to its action on the mast cell, DSCG inhibits reflex bronchoconstriction in dogs [5] and bronchoconstriction induced in man by hyperventilation [6], cold air [7] and SO2 [8], events not associated with mast cell activation. Consequently, we have also examined the effects of 195 in preclinical models involving reflex bronchoconstriction and airways hyperresponsiveness.

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The effects of antiallergic and bronchodilator drugs on platelet-activating factor (PAF-acether) induced bronchospasm and platelet aggregation

Cited by 38 publications

References 20 publications

Histamine and leukotriene‐independent guinea‐pig anaphylactic shock unaccounted for by Paf‐acether

Histamine and leukotriene‐independent guinea‐pig anaphylactic shock unaccounted for by Paf‐acether

Increased airways responsiveness to histamine induced by platelet activating factor in the guinea-pig: possible role of lipoxygenase metabolites

The development of Wy-41,195, an orally effective antiallergic drug in animal models

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