1 Intravenous injection of ioxaglate (4 g iodine kg 71), an iodinated radiographic contrast medium, caused a marked protein extravasation, pulmonary oedema and a decrease in the arterial partial oxygen pressure in rats. 2 All of these reactions to ioxaglate were reversed by the pretreatment with gabexate mesilate (10 and 50 mg kg 71, 5 min prior to injection) or nafamostat mesilate (3 and 10 mg kg 71 ), in which the inhibition was complete after injection of nafamostat mesilate (10 mg kg 71 ). 3 Both gabexate mesilate and nafamostat mesilate inhibited the activity of puri®ed human lung tryptase, although the latter compound was far more potent than the former. 4 Ioxaglate enhanced the nafamostat-sensitive protease activity in the extracellular¯uid of rat peritoneal mast cell suspensions. 5 Tryptase enhanced the permeability of protein through the monolayer of cultured human pulmonary arterial endothelial cells. Ioxaglate, when applied in combination with rat peritoneal mast cells, also produced the endothelial barrier dysfunction. These eects of tryptase and ioxaglate were reversed by nafamostat mesilate. 6 Consistent with these ®ndings, immuno¯uorescence morphological analysis revealed that tryptase or ioxaglate in combination with mast cells increased actin stress ®bre formation while decreasing VE-cadherin immunoreactivity. Both of these actions of tryptase and ioxaglate were reversed by nafamostat mesilate. 7 These ®ndings suggest that tryptase liberated from mast cells plays a crucial role in the ioxaglateinduced pulmonary dysfunction. In this respect, nafamostat mesilate may become a useful agent for the cure or prevention of severe adverse reactions to radiographic contrast media. British Journal of Pharmacology (2003) 138, 959 ± 967. doi:10.1038/sj.bjp.0705121 Keywords: Radiographic contrast media; vascular hyperactivity; pulmonary edema; endothelial barrier function; tryptase; actin stress ®bre; VE-cadherin Abbreviations: BSA, bovine serum albumin; HBSS, Hank's balanced salt solution; HPAECs, human pulmonary arterial endothelial cells; PAR-2, proteinase-activated receptor-2; PBS, phosphate buered saline; RCM, radiographic contrast media; t-Boc-Phe-Ser-Arg- IntroductionIn spite of increasing use of radiographic contrast media (RCM), no eective prevention or therapy for the anaphylactoid reactions, including bronchospasm, dyspnea, laryngeal oedema and pulmonary oedema accompanying respiratory distress, induced by the intravascular injection of RCM has yet been established. The pulmonary oedema is a serious lifethreatening adverse event, although the incidence is rare. The RCM-induced pulmonary oedema is a non-cardiogenic type and appears to be related to the increase in pulmonary vascular permeability subsequent to the activation of in¯ammatory cascade or the release of a variety of chemical mediators (Bouachour et al., 1991). Although the precise mechanisms underlying the RCM-induced vascular hyperpermeability or pulmonary dysfunction remain to be clari®ed, several lines of evidence have suggested that ...

Mast cell histamine release is considered to be associated with the etiology of anaphylactoid reactions to iodinated radiographic contrast media (RCM). In the present study, the effects of various ionic and non-ionic RCM on histamine release from mast cells were compared, and the possible mechanisms of the histamine release were subsequently determined. Both ionic (ioxaglate and amidotrizoate) and non-ionic (iohexol, ioversol, iomeprol, iopamidol and iotrolan) RCM increased histamine release from the dissociated rat pulmonary cells, whereby ionic materials were more potent than non-ionic agents. There was no significant correlation between the extent of histamine release and the osmolarity of each RCM solution. In addition, hyperosmotic mannitol solution (1000 mOsm/kg) caused no marked histamine release. Thus, it is unlikely that the hyperosmolarity of RCM solutions contributes to the histamine release. RCM also stimulated, but to a lesser extent, the histamine release from rat peritoneal cells. The RCM-induced histamine release from both types of cells was inhibited by dibutyl cyclic AMP or combined treatment with forskolin and 3-isobutyl-1-methylxanthine. Corresponding to these results, RCM markedly reduced the cellular cyclic AMP content. On the other hand, the removal of intracellular but not the extracellular Ca2+ attenuated the RCM-induced mast cell histamine release. From these findings, it is suggested that the decrease in cellular cyclic AMP content and an increase in intracellular Ca2+ contribute at least in part to the RCM-induced mast cell histamine release.

When human cytotrophoblastic cells in the early stage of pregnancy were cultured in a serum-free medium in the presence of human macrophage colony-stimulating factor (M-CSF), the cytotrophoblastic cells fused and formed a typical syncytiotrophoblast which had a dense distribution of microvilli revealed under an electron microscope. On the other hand, cytotrophoblasts incubated with anti-M-CSF antibody showed hardly any syncytiotrophoblast formation. Following this finding, we studied the differentiation of chorionic cells from the viewpoint of hormone secretion. When cytotrophoblasts were incubated in the presence of M-CSF, the supernatant of the culture showed an increase in human chorionic gonadotropin and human placental lactogen levels in proportion to the concentration of M-CSF added. When cytotrophoblasts were incubated in the presence of anti-M-CSF antibody or anti-fms antibody, human chorionic gonadotropin and human placental lactogen secretion were suppressed. Thus, M-CSF was morphologically and endocrinologically found to induce the differentiation of chorionic cells.

We have previously shown that sensory nerve peptides contribute to the pathogenesis of pulmonary hypersensitivity reactions (HSRs) to paclitaxel in rats. Moreover, pemirolast, an antiallergic agent, reverses the HSRs to paclitaxel, although the mechanism is considered to result from the blockade of paclitaxel-induced release of sensory peptides, rather than the inhibition of histamine release. In the present study, we investigated the preventive effect of pemirolast against acute HSRs in a total of 84 patients who undertook postoperative paclitaxel plus carboplatin chemotherapy every 4 weeks for ovarian cancer. Patients were assigned to receive oral lactose (placebo) or pemirolast (10 mg), 2 hr before paclitaxel infusion. All patients received conventional premedication, including oral diphenhydramine, intravenous ranitidine and intravenous dexamethasone, 30 min before paclitaxel infusion. The HSRs that led to the discontinuance of paclitaxel infusion (grade 2) occurred in 5 of 42 patients in placebo group, whereas none of pemirolast-treated 42 patients showed any signs of HSRs. Plasma histamine concentrations were not changed after paclitaxel infusion in either group. Our present findings suggest that pemirolast is potentially useful for prophylaxis of paclitaxelinduced HSRs. In this respect, the use of pemirolast as premedication is expected to be beneficial to the safety management in patients who undergo chemotherapy containing paclitaxel. ' 2005 Wiley-Liss, Inc.Key words: paclitaxel; hypersensitivity reactions; pemirolast; histamine; ovarian cancer Paclitaxel (Taxol) is a widely used chemotherapeutic agent for several malignancies, including ovarian cancer, breast cancer, endometrial cancer, nonsmall-cell lung cancer and stomach cancer. However, the use of paclitaxel is sometimes limited due to the incidence of severe hypersensitivity reactions (HSRs). The HSRs to paclitaxel are characterized by flushing, chest discomfort, respiratory distress and pulmonary edema, 1-4 and the incidence is particularly high in patients with ovarian cancer who undertook postoperative chemotherapy containing paclitaxel. 5 To avoid the HSRs, premedication containing histamine H 1 and H 2 antagonists in combination with glucocorticoids is always prescribed, [6][7][8][9][10] although the preventive effect is by no means complete. However, there has been no direct evidence suggesting that the HSRs to paclitaxel are mediated by the release of histamine from mast cells or basophils. We have recently shown that paclitaxel causes pulmonary vascular hyperpermeability and edema and the decrease in arterial partial oxygen pressure in rats.11 The toxic effects of paclitaxel in rat lungs are attenuated by neurokinin NK 1 and NK 2 receptor antagonists, or chemical sensory denervation with repeated capsaicin treatment, but not by histamine H 1 or H 2 antagonists, thereby suggesting that the pulmonary adverse reactions induced by paclitaxel are mediated by sensory nerve peptides such as substance P and neurokinin A, but not by mast cell hista...

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