近藤 一直

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 moro potent antihyperplastic action than does tranilast. Antiallergic agents may be effective in preventing restenosis after coronary angioplasty.

YM90K is a novel, selective and competitive α-amino-3-hydroxy-5- methylisoxazole-4-propionate receptor antagonist with neuroprotective properties, and it is currently under development for the intravenous treatment of stroke and other conditions of acute neuronal degeneration. The safety and pharmacokinetics of YM90K in healthy men was investigated after single doses up to 36 mg and repeated doses of 24 mg given by intravenous infusion over 3 hours. YM90K was well tolerated in healthy men and induced only mild changes in kidney function markers. Unchanged plasma drug concentration reached a near steady state during 3-hour infusion and rapidly decreased in a biphasic manner after the completion of infusion. YM90K showed linear pharmacokinetics. In the repeated-dose study, no significant differences were observed in pharmacokinetics of YM90K between the first and fifth dose. Unchanged urinary drug excretion was as high as 63.2% to 78.3% of the dose, most of which was excreted within 1 hour after the completion of infusion. YM90K is thought to be excreted mainly by renal tubular secretion. YM90K showed neither significant adverse reactions nor severe abnormalities in physical and laboratory examinations of the study participants and demonstrated safety and pharmacokinetic profiles compatible with clinical use.

Intimal thickening in the femoral artery of spontaneously hypertensive rats (SHR) was initiated by endothelial damage induced by the photochemical reaction between green light and systemic rose bengal. This model represents a non-mechanical method of producing vessel wall denudation. Neointima formation was assessed by calculating the cross-sectional area of intima, media and lumen, using computer analysis. Tranilast (30, 100 and 300 mg/kg, p.o.), administered 2 days prior to endothelial injury, reduced intimal area by 29, 62 and 87%, respectively, compared to that of vehicle-treated controls. In cultured SHR-derived vascular smooth muscle cells, tranilast produced concentration-dependent inhibition of mitogenesis, whether stimulated by platelet-derived growth factor, basic fibroblast growth factor, insulin-like growth factor or fetal bovine serum. These results suggest that tranilast may be effective in preventing coronary restenosis.