Abstract
LG 30435 is a quaternary phenothiazinic antihistamine, endowed with bronchodilator and antiallergic activity. Since PAF-acether (PAF) is a potential mediator of asthma, LG 30435 was assayed for its ability to counteract PAF-induced platelet aggregation (PA) in rabbit platelet rich plasma and bronchoconstriction (BC) in anaesthetized guinea-pigs, in comparison with other antihistamines. LG 30435 was the most potent and selective inhibitor of PAF-induced PA (IC50∶66 μM), concentrations three and more than fifteen fold higher being needed to inhibit PA induced by collagen and arachidonic acid respectively. The other antihistamines, namely mepyramine, promethazine, mequitazine, thiazinamium methyl sulfate and ketotifen were less potent inhibitors of PAF-induced PA, while interfered at lower concentrations with collagen-induced PA. LG 30435 and thiazinamium, administered intravenously, inhibited dose-dependently PAF-induced BC, starting from the dose of 0.1 μmol/kg. The travenously, inhibited dose-dependently PAF-induced BC, starting from the dose of 0.1 μmol/kg. The ED50 of LG 30435 was 0.28 μmol/kg, while the inhibition obtained with thiazinamium did not reach 50% even at 3 μmol/kg. Ketotifen and promethazine were partially active only at 3 μmol/kg, while mequitazine and mepyramine were inactive up to this dose. These results show that LG 30435 is endowed with a peculiar anti-PAF action, which may be advantageous in the treatment of asthma.
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References
M. C. Venuti,Platelet-activating factor: multifaceted biochemical and physiological mediator. Ann. Rep. Med. Chem.20, 193–202 (1985).
J. M. Lynch, G. S. Worthen and P. M. Henson, Platelet-activating factor. InDevelopment of Antiasthma Drugs. pp. 73–88 (Eds. D. R. Buckle and H. Smith). Butterworths, London 1984.
J. Morley, S. Sanjar and C. P. Page,The platelet in asthma. The Lancetii, 1142–1144 (1984).
B. B. Vargaftig, J. Lefort, M. Chignard and J. Benveniste,Platelet-activating factor induces a platelet-dependent bronchoconstriction unrelated to the formation of prostaglandin derivatives. Eur. J. Pharmac.65, 185–192 (1980).
B. B. Vargaftig, J. Lefort, F. Wal, M. Chignard and M. C. Medeiros,Non-steroidal anti-inflammatory drugs if combined with anti-histamine and anti-serotonin agents interfere with the bronchial and platelet effects of ‘platelet aggregating factor’ (PAF-acether). Eur. J. Pharmac.82, 121–130 (1982).
J. Bonnet, D. Thibaudeau and P. Bessin,Dependency of the PAF-acether induced bronchospasm on the lipoxygenase pathway in the guinea-pig. Prostaglandins26, 457–466 (1983).
A. J. Lewis, A. Dervinis and J. Chang,The effects of antiallergic and bronchodilator drugs on platelet activating factor (PAF-acether) induced bronchospasm and platelet aggregation. Agents and Actions15, 636–642 (1984).
A. Subissi, M. Criscuoli and A. R. Renzetti,LG 30435 is a new bronchodilator agent with multiple sites of action. Eur J. Pharmac.126, 81–89 (1986).
G. V. R. Born,Aggregation of blood platelets b adenosine diphosphate and its reversal. Nature194, 927–929 (1962).
S. N. Khan, P. A. Lane and A. D. Smith,Desaggregation of PAF-acether-aggregated platelets by verapamil and TMB-8 with reversal of phosphorylation of 40K and 20K proteins. Eur. J. Pharmac.107, 189–198 (1985).
U. Martin, C. Greenwood, L. P. Craps and M. Baggiolini,Ketotifen. Pharmacol. Biochem. Prop. Drug Subst.3, 424–460 (1981).
M. K. Church and C. F. Gradidge,Inhibition of histamine release from human lung in vitro by antihistamines and related drugs. Br. J. Pharmac.69, 663–667 (1980).
G. P. Lewis and I. S. Watts,Prostaglandin endoperoxides, thromboxane A 2 and adenosine diphosphate in collagen-induced aggregation of rabbit platelets. Br. J. Pharmac.75, 623–631 (1982).
W. C. Prozialeck,Interaction of quaternary phenothiazine salts with calmodulin. J. Pharmacol. Exp. Ther.231, 473–479 (1984).
T. J. Hallam, A. Sanchez and T. J. Rink,Stimulus-response coupling in human platelets. Biochem. J.218, 819–827 (1984).
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Criscuoli, M., Subissi, A., Daffonchio, L. et al. LG 30435, a new bronchodilator/antiallergic agent, inhibits PAF-acether induced platelet aggregation and bronchoconstriction. Agents and Actions 19, 246–250 (1986). https://doi.org/10.1007/BF01966213
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DOI: https://doi.org/10.1007/BF01966213