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1.
J Pharmacol Exp Ther ; 293(1): 281-8, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10734180

ABSTRACT

The anti-inflammatory/antiallergic activity of a novel second-generation p38 mitogen-activated protein kinase inhibitor, SB 239063[trans-1-(4-hydroxycyclohexyl) -4-(4-fluorophenyl)-5-(2-methoxypyridimidin-4-yl)imidazole], was investigated in vivo and in vitro. SB 239063 had an IC(50) of 44 nM for inhibition of recombinant purified human p38alpha. In lipopolysaccharide-stimulated human peripheral blood monocytes, SB 239063 inhibited interleukin-1 and tumor necrosis factor-alpha production (IC(50) values = 0.12 and 0.35 microM, respectively). A role for p38 kinase in cytokine-associated inflammation in the mouse was shown by p38 activation in the lung and inhibition of lipopolysaccharide-induced tumor necrosis factor-alpha production by SB 239063 (ED(50) = 5.8 mg/kg p.o.). Antiallergic activity was demonstrated by essential abolition (approximately 93% inhibition) of inhaled ovalbumin (OA)-induced airway eosinophilia by SB 239063 (12 mg/kg p.o.), measured by bronchoalveolar lavage (BAL) in OA-sensitized mice. In addition, p38 kinase was found by Western analysis to be activated in guinea pig lung. Administration of SB 239063 (10 or 30 mg/kg p.o.) in conscious guinea pigs markedly reduced ( approximately 50% inhibition) OA-induced pulmonary eosinophil influx, measured by BAL 24 h after antigen. SB 239063 (10 mg/kg b.i.d. p.o.) administered after leukotriene D(4) inhalation, reduced by 60% the persistent airway eosinophilia seen at 4 days. Apoptosis of cultured eosinophils isolated from guinea pig BAL was increased by SB 239063 (1-10 microM) in the presence of interleukin-5. These results indicate that SB 239063 is a potent inhibitor of inflammatory cytokine production, inhibits eosinophil recruitment, in addition to enhancing apoptosis of these cells. Collectively, the results support the potential utility of p38 kinase inhibitors, such as SB 239063, for the treatment of asthma and other inflammatory disorders.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors , Cytokines/biosynthesis , Enzyme Inhibitors/pharmacology , Eosinophilia/chemically induced , Imidazoles/pharmacology , Mitogen-Activated Protein Kinases , Pyrimidines/pharmacology , Respiratory System/pathology , Administration, Inhalation , Animals , Apoptosis/drug effects , Blotting, Western , Bronchoalveolar Lavage Fluid/cytology , Bronchoconstriction/drug effects , Eosinophilia/pathology , Guinea Pigs , Humans , Leukotriene D4/administration & dosage , Leukotriene D4/pharmacology , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred BALB C , Monocytes/drug effects , Monocytes/metabolism , Phagocytosis/drug effects , Plethysmography, Whole Body , Respiratory System/drug effects , Tumor Necrosis Factor-alpha/biosynthesis , p38 Mitogen-Activated Protein Kinases
2.
J Pharmacol Exp Ther ; 292(2): 803-9, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10640321

ABSTRACT

In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor.


Subject(s)
Cough/prevention & control , Levallorphan/analogs & derivatives , Narcotic Antagonists/pharmacology , Pyrroles/therapeutic use , Receptors, Opioid, delta/drug effects , Receptors, Opioid, delta/physiology , Animals , CHO Cells , Carbazoles/pharmacology , Cell Line , Cloning, Organism , Codeine/pharmacology , Cricetinae , Dextromethorphan/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Guinea Pigs , Humans , Hydrocodone/pharmacology , Levallorphan/therapeutic use , Male , Naloxone/pharmacology , Protein Binding , Pyridines/pharmacology , Pyrrolidines/pharmacology , Receptors, Opioid, delta/agonists , Receptors, Opioid, kappa/agonists , Receptors, Opioid, kappa/drug effects , Receptors, Opioid, kappa/physiology , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/drug effects , Receptors, Opioid, mu/physiology
3.
J Pharmacol Exp Ther ; 287(3): 988-95, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9864284

ABSTRACT

We evaluated the airway activity of the novel phosphodiesterase type 4 inhibitor SB 207499 [Ariflo; c-4-cyano-4-(3-cyclopentyloxy-4-methoxyp henyl-r-1-cyclohexane carboxylic acid)], in the guinea pig. Ovalbumin (OA)-induced contractions of guinea pig isolated tracheal strips were inhibited by SB 207499 with an EC50 of 1 microM but had little or no effect on exogenous agonist-induced contraction, which suggests that its effect on OA-induced contraction in vitro is primarily due to inhibition of mediator release from mast cells. In anesthetized guinea pigs, SB 207499 inhibited OA-induced bronchoconstriction with i.v. and p.o. ID50 values of 1.7 and 17 mg/kg, respectively. At 1, 3 and 6 hr after SB 207499 (30 mg/kg p.o.), OA-induced bronchospasm was inhibited by 92%, 70% and 58%, respectively, corresponding to elevated plasma concentrations of 1.62 +/- 0.19, 1.65 +/- 0.29 and 0. 93 +/- 0.24 microg/ml, respectively, of SB 207499. SB 207499 also inhibited house dust mite-induced bronchoconstriction (ID50 = 0.9 mg/kg i.v. and 8.9 mg/kg p.o.). In contrast to its lack of bronchorelaxant activity in vitro, SB 207499 inhibited bronchospasm induced by i.v. leukotriene D4 (LTD4) [ID50 = 3 mg/kg i.v.]. The bronchorelaxant effect of i.v.-administered SB 207499 was at least additive with that of salbutamol in reversing infused histamine-enhanced airway tone, but it did not alter base line or enhance salbutamol-induced cardiovascular effects. In conscious guinea pigs, SB 207499 (10 or 30 mg/kg p.o.), 1 hr before antigen or LTD4 challenge, markedly reduced bronchospasm and subsequent eosinophil influx as measured by bronchoalveolar lavage 24 hr after provocation. SB 207499 administered after OA or LTD4 challenge also reduced airway eosinophilia measured at 24 hr after OA challenge or 96 hr after LTD4 challenge. These results, coupled with the broad anti-inflammatory activity of SB 207499 previously described (Barnett et al., 1998), suggest that SB 207499 will be useful in the treatment of asthma and other inflammatory disorders.


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Anti-Asthmatic Agents/pharmacology , Cyclohexanecarboxylic Acids/pharmacology , Enzyme Inhibitors/pharmacology , Animals , Bronchial Spasm/etiology , Bronchial Spasm/prevention & control , Bronchoconstriction/drug effects , Bronchodilator Agents/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 4 , Cyclohexanecarboxylic Acids/administration & dosage , Guinea Pigs , Histamine , In Vitro Techniques , Leukotriene D4 , Muscle Contraction/drug effects , Nitriles , Ovalbumin , Trachea/drug effects
4.
J Pharmacol Exp Ther ; 270(1): 250-9, 1994 Jul.
Article in English | MEDLINE | ID: mdl-8035322

ABSTRACT

Selective inhibition of phosphodiesterase (PDE) isozymes has been shown to inhibit inflammatory cell function and relax airway smooth muscle and, thus, may be useful in the therapy of asthma. In guinea pigs sensitized to ovalbumin (OA), the effects of three PDE inhibitors were compared: siguazodan (PDE III selective, IC50 = 0.7 microM), rolipram (PDE IV selective, IC50 = 0.8 microM) and zardaverine (dual PDE III/IV, IC50S = 2.5 microM and 1.1 microM, respectively) against histamine-, leukotriene (LT) D4- and OA-induced bronchospasm in vitro and in vivo. Rolipram or zardaverine (0.1-10 microM), but not siguazodan, inhibited OA-induced contraction of the isolated trachea in a concentration-dependent manner. Rolipram or siguazodan alone (10 microM) were ineffective against histamine- or LTD4-induced contractions. Zardaverine alone (10 microM) or the combination of rolipram and siguazodan (10 microM each) markedly antagonized the contractions elicited by both spasmogens. In anesthesized, ventilated guinea pigs, the i.v. ID50S against OA-induced bronchospasm were: rolipram = 0.2 mg/kg, siguazodan > 10 mg/kg and zardaverine = 2.4 mg/kg. When administered at doses up to 7.5 mg/kg, i.v., rolipram or siguazodan were markedly less effective (i.e., < or = 50% inhibition) than zardaverine (ID50S = 2.4 and 1.7 mg/kg, respectively) at blocking exogenous histamine- or LTD4-induced bronchospasm. However, when administered in combination with siguazodan (5.4 mg/kg, i.v.), rolipram (0.4-5.4 mg/kg) abolished histamine- and LTD4-induced bronchoconstriction. In conscious guinea pigs, zardaverine (5 mg/kg, intragastrically (i.g.) or the combination of rolipram and siguazodan (5 mg/kg each) were substantially more effective than rolipram or siguazodan alone at inhibiting aerosol histamine- or LTD4-induced bronchospasm. In the same animals, rolipram or zardaverine (5 mg/kg, i.g.) but not siguazodan (5 mg/kg, i.g.) markedly inhibited aerosol OA-induced bronchoconstriction. The OA-induced pulmonary eosinophil infiltration in these animals was attenuated by all treatments with zardaverine producing the greatest degree of inhibition. These results indicate that 1) PDE IV inhibitors but not PDE III inhibitors are effective at blocking antigen-induced bronchospasm, 2) compounds that selectively inhibit either PDE III or PDE IV are poor inhibitors of bronchoconstriction elicited by exogenously administered spasmogens, and 3) the combined inhibition of both PDE III and PDE IV isozymes acts in an additive or synergistic manner to inhibit bronchospasm in the guinea pig.


Subject(s)
Bronchial Spasm/drug therapy , Eosinophils/drug effects , Isoenzymes/antagonists & inhibitors , Phosphodiesterase Inhibitors/pharmacology , Pulmonary Eosinophilia/drug therapy , Animals , Antigens/pharmacology , Bronchial Spasm/enzymology , Bronchoalveolar Lavage Fluid , Bronchoconstriction/drug effects , Drug Synergism , Eosinophils/cytology , Eosinophils/physiology , Guanidines/pharmacology , Guinea Pigs , Histamine Antagonists/pharmacology , In Vitro Techniques , Leukotriene D4/antagonists & inhibitors , Male , Plethysmography, Whole Body , Pulmonary Eosinophilia/enzymology , Pyridazines/pharmacology , Pyrrolidinones/pharmacology , Rolipram , Trachea/drug effects
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