Effects of a 7-day infusion of glucose on insulin secretion in vivo and in vitro in ventromedial hypothalamic-lesioned obese rats.

Excessive stimulation of insulin secretion may be one cause of the beta-cell dysfunction induced by hyperglycemia. We investigated a possible link between the prior endogenous hypersecretion of insulin and this dysfunction by performing a 7-day glucose infusion (50% wt/vol, 1.2 ml/h) on ventromedial hypothalamic VMH-lesioned hyperinsulinemic rats. Intravenous glucose tolerance tests (i.v.GTT 1.0 g/kg) revealed that a 3-day glucose infusion enhanced the insulin responses in both the sham- and VMH-lesioned rats compared with saline infusions. A similar 7-day glucose infusion enhanced the insulin response to glucose in sham-lesioned rats but not in VMH-lesioned rats. Batch-incubation of islets isolated from sham-lesioned rats showed an enhanced insulin response to glucose after 7 days of glucose treatment compared with the saline infusions. Conversely, the glucose infusion in VMH-lesioned rats markedly suppressed the in vitro insulin response. In sham- and VMH-lesioned rats, similar islet insulin contents were produced by saline and glucose treatments. Electron microscopy revealed that glucose infusions impaired the granule-releasing function of the beta-cells in VMH-lesioned rats, while insulin synthesis was accelerated in either group. These findings support the notion that excessive secretion is partly responsible for the beta-cell dysfunction induced by hyperglycemia without signs of exhaustion.

[Two cases of pseudomyxoma peritonei that responded to intraperitoneal administrations of a combined CDDP, 5-FU and MMC therapy].

Pseudomyxoma peritonei, which is the seeding of the peritoneum by mucin-secreting metastatic deposits and the filling of the peritoneal cavity by these secretions, is a malignancy that even after excision of the metastatic areas has a poor prognosis, since no effective therapy has yet been established. Herein, we report two cases of pseudomyxoma peritonei that responded to a combined postsurgical therapy consisting of CDDP, 5-FU and MMC. Case 1 involved a 56-year-old woman who underwent an appendectomy, a bilateral ovariectomy, and an omentectomy, due to pseudomyxoma peritonei. Further, a subcutaneous implant-type reservoir was sited intraperitoneally for postoperative chemotherapy. At 30 days after surgery, therapy commenced, consisting of 100 mg of CDDP and 20 mg of MMC administered intraperitoneally and 1,000 mg of 5-FU continuously infused by intravenous drip. This combined therapy was given for 5 days and repeated 8 times. As a result, the serum CEA value, which had elevated postoperatively, fell within the respective normal range, and at 4 years postoperatively, this patient remains alive. Case 2 concerns a 59-year-old woman who underwent an appendectomy, a right ovariectomy, and an omentectomy due to pseudomyxoma peritonei, and was postoperatively given 50 mg intraperitoneal administration of CDDP. She received 2 courses of postoperative chemotherapy similar to that given case 1 but with the addition of a 500 mg 5-FU intraperitoneally. At 8 months postoperatively, she is alive and disease-free. Given the above results, intraperitoneal administrations of this combined CDDP-5-FU-MMC therapy may be effective for patients with pseudomyxoma peritonei.

[Changes of cytokine levels in ascitic fluid after intraperitoneal administration of OK-432 or CDDP].

In order to evaluate the biological response after intraperitoneal administration of OK-432 and CDDP, we studied the changes of cytokine levels in ascitic fluid. A total of 53 gastric cancer patients were included in this study. OK-432 20KE was administered in 7 patients and CDDP was administered in 4 patients intraperitoneally during operation. The IL-6, IL-8, TNF-alpha and sTNF RI levels in ascitic fluid were measured from 0 to 5 postoperative day. These results were compared with those obtained from the control groups (42 patients). The ascitic level of IL-6 increased immediately after operation, then gradually decreased. The elevations of IL-6 from 0 to 5 postoperative day were remarkably higher in the OK-432 treated group, and those on 0 and 1 postoperative days were remarkably lower in CDDP treated group than in the control group. Similarly, the ascitic level of IL-8 elevated soon after operation and then decreased gradually. In the OK-432 treated group, the ascitic level of IL-8 was significantly higher than in the control group from 0 to 2 postoperative day. Ascitic TNF-alpha was detectable only in the ascites soon after operation in the OK-432 treated group. The ascitic level of sTNF RI peaked on 2 postoperative day in the control and the OK-432 treated group and 1 postoperative day in the CDDP treated group. There were no significant differences between these groups.

[Changes in cytokine levels in ascitic fluid after intraperitoneal administration of OK-432].

In order to evaluate the biological response after intraperitoneal administration of OK-432, we studied the changes of cytokine levels in ascitic fluid. In 6 advanced gastric cancer patients with peritoneal dissemination or extensive lymph node metastases, OK-432 20 KE was administered intraperitoneally during operation and the IL-6, IL-8 and IFN-gamma levels in ascitic fluid were measured from 0 to 5 postoperative days. These results were compared with those obtained from non-OK-432 administered control groups (17 cases). The ascitic level of IL-8 increased immediately after operation and gradually decreased. In the OK-432 treated group, the elevation of IL-8 on 0 and 1 postoperative days was remarkable, and there were statistically significant differences with the control group. Similarly, the ascitic level of IL-6 elevated soon after operation and then decreased gradually. In the OK-432 treated group, the ascitic level of IL-6 was significantly higher than in the control group after 3 postoperative days. There were no differences in changes of ascitic IFN-gamma levels between the groups. From these results, IL-6 and IL-8 appeared to be induced in ascitic fluid by intraperitoneal administration of OK-432.