Abstract
We investigated the capacity of ketoprofen lysine salt (KLS) to counteract the pulmonary effects of some mediators of airway inflammation. The protective ffect of KLS and its R-isomer against bradykinin (BK) induced plasma extravasation in the airways and bronchoconstriction was evaluated in anaesthetized guinea-pigs, in parallel with the capacity of KLS to inhibit the production of thromboxane A2 (TXA2). Moreover, we studied the ability of KLS to modulate leukotriene C4 (LTC4) and acetylcholine (ACH) induced bronchoconstriction and the associated production of TXA2. Nimesulide (NIM) was used as the reference compound.
KLS dose-dependently inhibited the bronchoconstriction and the associated production of TXA2 induced by BK, with closely related ID50 values of 31.2 and 34.0μg/kg i.v., respectively. The protection was evident 10 min after KLS administration and, at 100 μg/kg i.v., lasted up to 2h, Moreover, KLS dose-dependently inhibited the increase in capillary permeability induced by BK, with a potency (ID50 23.4 μg/kgi.v.) slightly higher than that shown against the bronchoconstriction. KLS also prevented the bronchoconstriction and TXA2 production triggered by LTC4, but not ACH induced bronchoconstriction. In all the models studied, KLS was about 10 times more potent than NIM.
These data demonstrate the capacity of KLS to counteract the bronchoconstriction induced by BK and LTC4 and to a large extent the airway inflammation induced by BK. Blockade of prostanoid production is likely to account for this protective effect, since the R-isomer of KLS was devoid of significant activity.
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Hayball PJ, Nation RL, Bochner F. Enantioselective pharmacodynamics of the nonsteroidal antiinflammatory drug ketoprofen. Chirality 1993;4:484–7.
Veys EM. 20 year's experience with ketoprofen. Scan J Rheumatol 1991;Suppl90:3–44.
Regoli D, Barabé J. Pharmacology of bradykinin and related kinins. Pharmacol Rev 1980;32:1–46.
Trifillieff A, Da Silva A, Gies JP. Kinins and the respiratory tract diseases. Eur Respir J 1993;6:576–87.
Proud D, Kinins. In: Barnes PJ, Rodger IW, Thomson NC, editors. Asthma. Basic mechanism and clinical management. London: Academic Press Ltd., 1992:277–85.
Proud D, Togias A, Naclerio RM, Crush SA, Norman PS, Lichtenstein LM. Kinins are generated in vivo following nasal airway challenge of allergic individuals with allergen. J Clin Invest 1983;72:1678–85.
Proud D, Naclerio RM, Gwaltney JMJr, Hendley JO. Kinins are generated in nasal secretions during natural rhinovirus colds. J Infect Dis 1990;161:120–3.
Carter Barnett JK, Cruse LW, Pround D. Kinins are generated in nasal secretions during influenza A infections in ferrets. Am Rev Respir Dis 1990;142:162–6.
Proud D, Reynolds CJ, LaCapra S, Kagey-Sobotka A, Lichtenstein LM, Naclerio RM. Nasal provocation with bradykinin induced symptoms of rhinitis and a sore throat. Am Rev Respir Dis 1988;137:613–6.
Drazen JM. Cysteinil Leukotrienes. In: Barnes PJ, Rodger IW, Thomson NC, editors. Asthma. Basic mechanism and clinical management. London: Academic Press Ltd., 1992:235–47.
Rossoni G, Omini C, Viganò T, Mandelli V, Folco GC, Berti F. Bronchoconstriction by histamine and bradykinin in guinea-pigs: relationship to thromboxane A2 generation and effect of aspirin. Prostaglandins 1980;20:547–57.
Omini C, Folco GC, Viganò T, Rossoni G, Brunelli G, Berti F. Leukotriene-C4 induced generation of PGI2 and TXA2 in guinea-pig in vivo. Pharmacol Res Comm 1981;13:633–40.
Kawikova I, Arakawa H, Lofdahl CG, Skoogh BE, Lotvall J. Bradykinin-induced airflow obstruction and airway plasma exudation: effect of drugs that inhibit acetylcholine, thromboxane A2 or leukotriene. Br J Pharmacol 1993;110:657–64.
Ichinose M, Belvisi MG, Barnes PJ. Bradykinin-induced bronchoconstriction in guinea-pigs in vivo: role of neural mechanism. J Pharmacol Exp Ther 1990;253:594–9.
Saria A, Lundberg JM, Skofitsch G, Lemberk F. Vascular protein leakage in various tissues induced by substance P, capsaicin, bradykinin, serotonin, histamine and antigen challenge. Naunyn Schmied Arch Pharmacol 1983;324:212–8.
Bellussi L, Passali D. Treatment of upper airways inflammation with nimesulide. Drugs 1993;46 Suppl 1:107–10.
Sofia M, Molino A, Mormile M, Stanziola A, Scaricabarozzi I, Carratù L. Nimesulide in the treatment of chronic bronchitis. Drugs 1993;46 Suppl 1:111–4.
Berti F, Folco GC, Giachetti A, Malandrino S, Omini C, Viganò T. Atropine inhibits thromboxane A2 generation in isolated lungs of the guinea-pig. Br J Pharmacol 1980;68:467–72.
Berti F, Rossoni G, Bruschi A, Villa LM, Trento F, Della Bella D, et al. Influence of theophylline on both bronchoconstriction and plasma extravasation induced by acetaldehyde in guinea-pigs. Arzneim Forsch Drug Res 1994;44, 3:323–6.
Rogers DF, Dijk S. Barnes PJ. Bradykinin-induced plasma exudation in guinea-pigs airways: involvement of platelet activating factor. Br J Pharmacol 1990;101:739–45.
Maggi CA, Patacchini R, Santiccioli P, Geppetti P, Cecconi R, Giuliani S, et al. Multiple mechanism in the motor responses of guinea-pig isolated urinary bladder to bradykinin. Br J Pharmacol 1989;98:619–9.
MacLean DB, Hayes L. Bradykinin-evoked release of calcitonin gene-related peptide (CGRP) and substance P (SP) from cultured vagal sensory neurons: inhibition by indomethacin. Soc. Neurosci Abstr 1990;15:80–2.
Fuller RW, Dixon CM, Cuss FM, Barnes PJ. Bradykinin-induced brochoconstriction in humans: mode of action. Am Rev Respir Dis 1987;135:176–80.
Polosa R, Phillips GD, Lai CK, Holgate ST. Contribution of histamine and prostaglandins to bronchoconstriction provoked by inhalation of bradykinin in atopic asthma. Allergy 1990;45:174–82.
Churchill L, Pongracic JA, Reynolds CJ, Naclerio RM, Proud D. Pharmacology of nasal provocation with bradykinin: studies of tachyphylaxix, cyclooxygenase inhibition, alpha-adrenergic stimulation, and receptor subtype. Int Arch Allergy Appl Immunol 1991;95:322–31.
Baraniuk JN, Silver PB, Kaliner MA, Barnes PJ. Ibuprofen augments bradykinin-induced glycoconjugate secretion by human nasal mucosa in vivo. J Allergy Clin Immunol 1992;89:1032–9.
Mira E, Mevio E, Perotti M. Treatment of pharyngitis and pharyngolaringitis. Comparison of phenylprenazone and flurbiprofen (Froben RTM) adminstered orally and rectally. Clin Trials J 1984;21:100–8.
Olive G, Bertin L, Pons G, Lasfargues G, Duhamel JF, Maudelonde C, et al. Randomized, double-blind, multicenter controlled trial of ibuprofen for tonsillitis and pharyngitis in children. Eur J Pharmacol 1990;183:1042–3.
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Daffonchio, L., Rossoni, G., Clavenna, G. et al. Protective activity of ketoprofen lysine salt against the pulmonary effects induced by bradykinin in guinea-pigs. Inflamm Res 45, 259–264 (1996). https://doi.org/10.1007/BF02259613
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DOI: https://doi.org/10.1007/BF02259613