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Clin Exp Pharmacol Physiol. 2008 Jan;35(1):17-22.

Effects of direct haemoperfusion through fibres immobilizing polymyxin B and nafamostat mesilate on endotoxaemia in conscious Guinea-pigs.

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  • 1Emergency and Critical Care Medicine, Nippon Medical School, Tokyo, Japan. nakanow@nms.ac.jp

Abstract

1. Direct haemoperfusion through a network of fibres immobilizing polymyxin B (PMX-B) is used for the treatment of septic shock, but the mechanism underlying its clinical benefits remains unclear. The aims of the present study were to assess the actions of direct haemoperfusion through fibres immobilizing PMX-B (PMX-DHP) on the effects of exogenously administered endotoxin in conscious guinea-pigs and to examine the difference in the effects of heparin compared with nafamostat mesilate (NM) used as an anticoagulant. Although nafamostat is widely used in Japan, the agent cannot necessarily be used elsewhere in the world. Therefore, the study aimed to investigate and elucidate the effectiveness of NM compared with heparin. 2. Colonic motion was monitored continuously via telemetry using a force transducer attached to the taenia caecum, whereas blood pressure was monitored using a carotid artery catheter. To establish a haemoperfusion circuit in each freely moving and conscious guinea-pig, catheters were implanted in the carotid artery and the jugular vein, tunnelled subcutaneously, exteriorized at the back of the neck in contact with a lightweight tethering spring and attached to a swivel device at the top of the cage. On the day after the operation, lipopolysaccharide (LPS; Escherichia coli, O111:B4; 1 mg/kg) was administered i.v. and PMX-DHP was conducted for 2 h. Heparin (50 IU/h) or NM (0.4 mg/h) was used as the anticoagulant. Furthermore, guinea-pigs were administered a lethal dose of LPS (10 mg/kg) and the survival rate was examined for animals undergoing PMX-DHP compared with control animals. 3. In guinea-pigs treated with PMX-DHP, relaxation of colonic longitudinal muscle caused by LPS was significantly suppressed, as were decreases in blood pressure. Of the two anticoagulants used, NM was more effective than heparin. In addition, PMX-DHP significantly increased the survival rate of guinea-pigs that received potentially lethal doses of LPS. 4. In conscious and unrestrained guinea-pig endotoxaemia model, PMX-DHP significantly improved intestinal paralysis and decreases in blood pressure. These effects were augmented more by NM than by heparin when an anticoagulant was used in the perfusion process. These findings suggest that haemoperfusion using PMX and NM performed in the early stage of endotoxaemia is an effective treatment.

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