Nafamostat mesilate, a noncalcium compound, as an anticoagulant, induces calcium-dependent haemolysis when infused with packed erythrocytes.

BACKGROUND: Nafamostat mesilate (NM), a protease inhibitor, is available for acute pancreatitis and disseminated intravascular coagulopathy and is used as an anticoagulant for haemodialysis in Japan. Co-infusion of red cell concentrates (RCC) and intravenous drugs is usually contraindicated. Because of limited venous access, adherence to the guidelines may be compromised in some clinical settings. Therefore, we investigated the influence of co-infusion of RCC and various anticoagulants on haemolysis in vitro. METHODS: We investigated the effect of co-incubation of RCC and various anticoagulant drugs [NM, gabexate mesilate (GM), heparin] in packed erythrocytes. We evaluated haemolysis using lactate dehydrogenase and free haemoglobin. In addition, we also evaluated the influence of co-incubation on phosphatidylserine (PS) expression on the erythrocyte membrane. RESULTS: GM and NM induced haemolysis in a dose-dependent manner, which was inhibited by removal of citrate and pretreatment with the calcium chelator, ethylenediaminetetraacetic acid. In a dynamic experiment using an infusion pump, NM not only induced haemolysis during co-infusion with RCC but also elevated PS expression dependent on extracellular calcium. CONCLUSION: NM and GM induce haemolysis in packed erythrocytes in the presence of citrate that is dependent on extracellular calcium.

Carcinogenicity of dextran sulfate sodium in relation to its molecular weight.

The carcinogenicity of dextran and 3 kinds of dextran sulfate sodium with different molecular weights and almost the same sulfur content were compared in ACI rats. Dextran sulfate sodium of molecular weight 54,000 showed a strong carcinogenic activity when it was given orally as 2.5% diet, whereas dextran sulfate sodium of molecular weight 520,000 and 9500 and dextran showed no significant carcinogenicity, i.e. the peak of carcinogenic activity of dextran sulfate sodium appeared at molecular weight 54,000, and dextran sulfates with larger or smaller molecular weights had no carcinogenic activity.

Enhancement by bracken of induction of tumours of the upper alimentary tract by N-propyl-N-nitrosourethan.

The effect of bracken on the induction of tumours of the upper alimentary tract by N-propyl-N-nitrosourethan (PNU) was studied in 7-week-old ACI rats. Group I received a solution of 400 pts/10(6) of PNU in their drinking water for 6 weeks; Groups II and III were given PNU as in Group I, and then from 1 week later were fed on diets containing 5 and 30% bracken, respectively, for 33 weeks; Groups IV and V were fed on diets containing 5 and 30% bracken, respectively, for 33 weeks, from 14 weeks after birth. A control group was given basal diet and water only. The experiment was terminated after 40 weeks. The induction of tumours of the upper alimentary tract by PNU was enhanced by bracken diet; i.e. the incidence of pharyngeal tumours in male rats was significantly higher (P less than 0.025) in Group II (10/13) than in Group I (3/13). The incidence and multiplicity of oesophageal tumours in female rats were also higher in Group III than in Group I (P less than 0.025 for incidence; P less than 0.05 for multiplicity). Histologically, the oesophageal tumours in female rats in Groups II and III were not only papillomas but also squamous-cell carcinomas, whereas those in females of Group I were all papillomas. Furthermore, the incidence of tumours of the forestomach in female rats was also higher (P less than 0.05) in Group II (11/13) than in Group I (4/12).

Effect of degraded carrageenan on the intestine in germfree rats.

The role of intestinal bacterial flora in display of the effect of degraded carrageenan was investigated by feeding 9 germfree and 12 conventional female Wistar rats on diet containing 10% carrageenan for 63 days. Animals were sacrificed 7, 20, 35, and 63 days after the start of feeding and histological changes induced by carrageenan were studied. The germfree rats showed mucosal lesions, such as macrophage aggregates, erosion, and squamous metaplasia of the large intestine, and these lesions were more extensive than those in the conventional rats. Therefore, it was concluded that bacterial flora are not essential for display of the biological effects of degraded carrageenan.

Induction of intestinal tumors in rats by dextran sulfate sodium.

The carcinogenicity of dextran sulfate sodium was studied in inbred ACI rats. In group 1, 10 male rats were fed a 10% dextran sulfate sodium diet; in group 2, 14 male and 12 female rats were fed a 5% dextran sulfate sodium diet; and in the control group, 9 male and 9 female rats were given the basal diet without dextran sulfate sodium. After the start of the feeding regimen, all rats given the 10% dextran sulfate sodium diet died of severe diarrhea and anemia within 14 days and 15 of 23 surviving rats fed a 5% dextran sulfate sodium diet developed intestinal tumors between 134 and 215 days. These tumors were induced in the colon and cecum and consisted of adenomas, adenocarcinomas, and papillomas.

CArcinogenic activity of clivorine, a pyrrolizidine alkaloid isolated from Ligularia dentata.

The carcinogenic activity of clivorine, a pyrrolizidine alkaloid isolated from Ligularia dentata, was studied in inbred ACI rats. Twelve animals in the experimental group received a 0.005% solution of clivorine in drinking water for 340 days and survived beyond 440 days after the beginning of the experiment. Of this group, 8 developed tumors in the liver; 2 developed hemangioendothelial sarcomas, and 6 developed neoplastic nodules. The hemangioendothelial sarcoma showed metastasis in the lung of one rat. No tumors were observed in the liver of the control animals.

Effect of "drugs for liver disease" on hepatotoxic action of carbon tetrachloride. II. Effect of protoporphyrin and phosphorylcholine on microsomal drug-metabolizing enzyme activities and the components in injuried liver.

The effect of "drugs for liver disease", protoporphyrin (PP) and phosphorylcholine (PC), on CCl4-induced liver injury was studied. Attention was given to the levels of microsomal drug-metabolizing enzyme and lipolytic enzyme activities and of some microsomal components such as phospholipid and peroxides. Administration of PP to CCl4-poisoned rats was found to increase the decreased microsomal drug-metabolizing enzyme activities, aminopyrine N-demethylase, aniline p-hydroxylase, cytochrome P-450 and b5 and lipolytic enzyme activity in CCl4-poisoned liver (12-20% increase as compared with those of the poisoned rats), and returned to control levels earlier than in CCl4-poisoned rats. Furthermore, administration of PP to CCl4-poisoned rats caused a decrease in the lipid peroxidation. A single dose of PP to normal rats was shown to increase these parameters, to a small extent. One of the mechanisms may be attributed to the fact that PP increases the biosynthesis of the hemoproteins by means of the incorporation of PP into the pigments and protects the membranes from lipid peroxides and the free radicals. On the other hand, administration of PC to the poisoned rats did not enhance the levels of the drug-metabolizing enzyme activities except for aminopyrine N-demethylase. Phospholipid phosphorous content, however, increased by 13-14% when PC was given. Thus, it is considered that PC may enhance the reconstitution of phospholipids in the injured membrane.