pyrimidinones and tranilast

We established a new and facile model to investigate allergic mechanism and assess the effect of antiallergic compounds. Male Wistar rats were actively or passively sensitized. Active sensitization was performed by injection of both dinitrophenylated-ovalbumin (DNP-OA) and Bordetella pertussis. Nine days later, DNP-OA was injected into the right hind footpad. This antigen challenge induced a biphasic footpad swelling that consisted of an early-phase (EPR) and a late-phase response (LPR). In rats passively sensitized with rat anti-DNP-OA serum, DNP-OA induced only EPR. The EPR was suppressed by disodium cromoglycate, a mast cell stabilizer, but not by cyclosporin A, an immunosuppressant, while the LPR was suppressed by cyclosporin A. Furthermore, to investigate these two allergic responses determined by the interactions between the hapten and the carrier proteins, two distinct haptenated antigens were created. DNP-Ascaris (DNP-As) induced a marked EPR and LPR in DNP-As-sensitized rats. However, DNP-As induced only EPR in DNP-OA-sensitized rats, indicating that the usage of the same carrier protein in both sensitization and challenge was necessary for induction of LPR. These data suggest that this actively sensitization model in which EPR and LPR are functionally distinguishable should be useful for evaluating the efficacy of antiallergic compounds.

Topics: Aminopyridines; Animals; Anti-Allergic Agents; Antigens; Cromolyn Sodium; Cyclosporine; Dinitrobenzenes; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Edema; Haptens; Hindlimb; Hypersensitivity, Delayed; Male; ortho-Aminobenzoates; Ovalbumin; Passive Cutaneous Anaphylaxis; Promethazine; Pyridines; Pyrimidinones; Quinolones; Rats; Rats, Wistar

N-(3',4'-dimethoxycinnamoyl) anthranilic acid (tranilast), an effective anti-allergic drug, has successfully prevented restenosis in patients who have undergone percutaneous transluminal coronary angioplasty. To elucidate the mechanism of tranilast, we investigated its antagonistic effect to angiotensin II, which plays a pivotal role in the proliferation of vascular smooth muscle cells, using angiotensin II-induced contractions in human gastroepiploic artery and rabbit aorta. The possible antagonistic effects of other anti-allergic agents such as 4-( p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)-phthal azinone hydrochloride (azelastine), 9-methyl-3-( 1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyramidin-4-one potassium salt (pemirolast) and disodium cromoglycate were also compared. Tranilast dose-dependently inhibited the angiotensin II-induced contractions in human and rabbit arteries (IC50 = 3.6x10(-5) M and pD'2 = 3.69, respectively). Pemirolast showed a weak antagonistic effect to angiotensin II, but the effective concentration cannot be administered in clinical dosage. Tranilast and pemirolast had no effect on the concentration-contractile response curves for KCI and norepinephrine. Azelastine inhibited angiotensin II-, KCl- and norepinephrine-induced contractions non-specifically, while disodium cromoglycate did not affect these contractile responses. Tranilast but not azelastine showed synergistic action with 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimi dazole-7-carboxylic acid (CV- 11974) in antagonizing angiotensin II-induced contraction and the inhibitory pattern was similar to that of the non-peptide angiotensin II AT1 receptor antagonist CV-11974. These findings indicate that only tranilast possesses the unique ability to antagonize angiotensin II in clinical dosage, which may contribute at least in part to prevention of restenosis after percutaneous transluminal coronary angioplasty.

Topics: Adrenergic alpha-Agonists; Adult; Aged; Aged, 80 and over; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Aorta; Arteries; Cromolyn Sodium; Dose-Response Relationship, Drug; Histamine Antagonists; Humans; In Vitro Techniques; Male; Middle Aged; Muscle, Smooth, Vascular; Norepinephrine; ortho-Aminobenzoates; Potassium Chloride; Pyridines; Pyrimidinones; Rabbits; Vasoconstriction

We previously reported that tranilast, an antiallergic agent, reduced intimal thickening after endothelial injury in rats. In this study, to verify whether or not antiallergic agents inhibit intimal thickening, we investigated the effect of pemirolast on intimal thickening after endothelial injury and compared its effect with that of tranilast. Administration of two antiallergic agents, pemirolast (0.1, 1, and 10 mg/kg, p.o.) and tranilast (300 mg/kg, p.o., daily), was begun 2 days before endothelial injury and continued until the animals were killed. Endothelial injury in the rat femoral artery was induced by a photochemical reaction between localized irradiation by green light and intravenously administered rose bengal. To evaluate intimal hyperplasia, we measured the cross-sectional area of the intima 21 days after endothelial damage. Pemirolast at doses of 0.1, 1, and 10 mg/kg reduced the intimal area to 2.10 +/- 0.33, 1.36 +/- 0.19, and 1.35 +/- 0.18 (x0.01 mm2), respectively, and tranilast showed a tendency to reduce the intimal area, which was 1.86 +/- 0.35 x 0.01 mm2, compared with findings for controls (2.83 +/- 0.49 x 0.01 mm2). In rat A10 vascular smooth-muscle cells, we investigated the effects of antiallergic agents on migration by using a modified Boyden chamber assay and on proliferation by using the bromodeoxyuridine-incorporation assay. Two antiallergic agents inhibited in a concentration-dependent manner both migration and proliferation of smooth muscle cells stimulated by platelet-derived growth factor. These results suggest that antiallergic agents directly inhibit migration of smooth-muscle cells to the intima from the media and proliferation in the intima, and that pemirolast has more potent antihyperplastic action than does tranilast. Antiallergic agents may be effective in preventing restenosis after coronary angioplasty.

Topics: Animals; Antimetabolites; Arteries; Bromodeoxyuridine; Cell Division; Cell Movement; Cells, Cultured; Endothelium, Vascular; Histamine Antagonists; Histamine H1 Antagonists; ortho-Aminobenzoates; Pyridines; Pyrimidinones; Rats; Tunica Intima

The effects of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX), a new antiallergic drug, on passive cutaneous anaphylaxis (PCA) mediated by homologous IgE or IgG antibody were investigated in rats and guinea pigs. TBX (i.v. and p.o.) clearly inhibited IgE- and IgGa-mediated homologous PCAs in rats, without showing any inhibition of the skin reactions caused by histamine, serotonin and bradykinin in contrast to the inhibition of prostaglandin E1-induced skin reaction. Neither adrenalectomy nor propranolol treatment modified TBX's inhibition of the former PCA. With regard to tachyphylaxis to TBX, it was demonstrable in IgE-mediated homologous PCA in rats when they were pretreated with TBX (0.5 mg/kg, i.v.), followed 60 min later by a second dose of the drug (0.05 mg/kg, i.v.). There was no cross-tachyphylaxis between disodium cromoglycate (DSCG) and TBX. Homologous PCA caused by guinea pig IgE was also inhibited in a dose-dependent fashion by i.v. and p.o. administrations of TBX, although higher doses of TBX were needed to inhibit guinea pig PCA than the rat one. Interestingly, TBX showed more potent inhibition of both rat and guinea pig homologous PCAs than DSCG or tranilast. The results obtained indicate that TBX is an orally effective antiallergic agent displaying no antagonistic actions on the chemical mediators released.

Topics: Animals; Cromolyn Sodium; Guinea Pigs; Immunoglobulin E; Immunoglobulin G; Male; ortho-Aminobenzoates; Passive Cutaneous Anaphylaxis; Pyridines; Pyrimidinones; Rats; Rats, Inbred Strains