Beneficial effect of JTV-803, a new synthetic inhibitor of activated factor X, against both lipopolysaccharide-induced and tissue factor-induced disseminated intravascular coagulation in rat models.

We examined whether JTV-803, a specific activated factor X inhibitor independent of antithrombin III (ATIII), is effective against disseminated intravascular coagulation (DIC) in rat models induced by tissue factor (TF) or lipopolysaccharides (LPS). In male Wistar rats, DIC was induced by a 4 h infusion of thromboplastin (3.75 U/kg) or LPS (50 mg/kg). The rats were given JTV-803 (0.3 or 3 mg/kg, bolus intravenously) (JTV-803 groups) or low molecular weight heparin (LMWH groups) (200 U/kg, bolus intravenously) prior to an injection of TF or LPS. The results showed that JTV-803 was dose-dependently effective against DIC in both TF-induced and LPS-induced rat models. This anti-DIC effect of JTV-803 at higher doses was almost equivalent to that of LMWH in both types of DIC. Plasma ATIII activity was more prominent in the group treated with JTV-803 than in that treated with LMWH. None of rats died in the TF-induced DIC model with or without drug administration. On the contrary, seven of 22 rats died (mortality rate, 31.8%) in the LPS-induced DIC model without drug administration. Although the mortality rate of rats induced with LPS and treated with LMWH was quite high (6/16, 37.5%), none of the LPS-induced rats treated with JTV-803 died. These findings suggested that JTV-803 can treat both TF-induced and LPS-induced DIC models, and that this drug has greater potential in preserving ATIII and in improving the prognosis of DIC.

Fetal circulatory responses to maternal blood loss.

We examined the fetal circulatory responses to maternal blood loss in pregnant women during the third trimester. Seven healthy women with placenta previa and singleton pregnancies underwent phlebotomies in an autologous donation program. Four hundred milliliters of blood was collected within 15 min at 34 and 35 weeks of gestation. Continuous electric recordings of fetal heart rate were performed during the first blood collection, and the maternal uterine artery (UtA), umbilical artery (UmA) and fetal middle cerebral artery (MCA) Doppler velocity waveforms were recorded before, immediately after and 24 h after the second collection in each patient. The average fetal heart rate, maternal UtA and UmA pulsatility indices did not change measurably during or after maternal blood collections. However, the average fetal MCA pulsatility index decreased significantly 24 h after maternal blood loss. The observation of a decrease in fetal MCA pulsatility index may indicate delayed fetal asphyxia following mild maternal hemorrhage.

The striking effect of hyperbaric oxygenation therapy in the management of chronic idiopathic intestinal pseudo-obstruction.

Chronic idiopathic intestinal pseudo-obstruction is one of the disorders that is most refractory to medical and surgical treatment. Even when patients are given nutritional support, including total parenteral nutrition, obstructive symptoms seldom disappear. We report a case of chronic idiopathic intestinal pseudo-obstruction, due to myopathy, in which hyperbaric oxygenation therapy was strikingly effective. The presence of myopathy was histologically confirmed on the surgically resected jejunal specimen. Hyperbaric oxygenation resulted not only in relief of the patient's obstructive symptoms but also in a rapid decrease of abnormally accumulated intestinal gas. At last, he could resume oral intake without any critical adverse effects. These observations strongly suggest that hyperbaric oxygenation can be an effective therapy in the management of chronic idiopathic intestinal pseudo-obstruction.

Pancreatitis in ulcerative colitis: a case report of improved stricture of the main pancreatic duct.

We present one case with pancreatitis that synchronized with manifestations of ulcerative colitis, in which an improvement of stricture of the main pancreatic duct was observed. A 27-year-old man, having a history of nonalcoholic acute pancreatitis, complained of anal bleeding and pain in the epigastric region. The treatment for pancreatitis relieved the pain and decreased the serum levels of pancreatic enzymes to within normal ranges. Colonoscopy and histopathologic examination revealed ulcerative colitis in the rectum, and treatment with steroid enema made proctitis quiescent. Endoscopic retrograde pancreatography demonstrated a remarkable and short stricture of the main pancreatic duct, which improved at follow-up pancreatography. In a 20-month follow-up period, active proctitis relapsed with a episode of recurrent pancreatitis once, and without pancreatitis once.

Effects of DX-9065a, an orally active, newly synthesized and specific inhibitor of factor Xa, against experimental disseminated intravascular coagulation in rats.

We investigated the protective effects of DX-9065a, an orally active, newly synthesized and specific inhibitor of factor Xa, against two kinds of experimental disseminated intravascular coagulation (DIC) in rats. Endotoxin-induced experimental DIC was induced by a 4-h sustained infusion of endotoxin at a dose of 100 mg/kg. Thromboplastin-induced experimental DIC was induced by a bolus injection of thromboplastin at a dose of 150 mg/kg. The rats were orally administered DX-9065a at 10, 30 or 100 mg/kg 30 min before endotoxin or thromboplastin injection. In both DIC models, DX-9065a showed a protective effect against DIC, at all doses and in all parameters, including fibrin/fibrinogen degradation products (FDP), fibrinogen level, prothrombin time, activated partial thromboplastin time, platelet count and the number of renal glomeruli with fibrin thrombi. When DX-9065a was orally administrated at 100 mg/kg without endotoxin or thromboplastin, no significant changes were seen in hemostatic parameters except PT and APTT, and no fibrin thrombi or abnormal bleeding were seen in renal specimens. These findings suggest that the new oral anti-Xa drug, DX-9065a, has an effect in reducing the severity of DIC. However, further dose-finding and safety studies of this drug have still to be assessed.

Therapeutic effect of a CDDP-epirubicin-Lipiodol emulsion on advanced hepatocellular carcinoma.

Prior injection of an anticancer agent and Lipiodol mixture is a key point for the treatment of hepatocellular carcinoma (HCC). We therefore prepared a new, improved emulsion of Lipiodol containing a high dose of cis-diamminedichloroplatinum (CDDP) and epirubicin by replacing the ionic contrast medium (Urografin 67) with a nonionic contrast medium (Iopamidol; Iopamiron 300) and adding phosphatidyl choline. This CDDP-epirubicin-Lipiodol emulsion (CELE) was examined pharmacologically and chemically with the following results. The size of these particles is less than 10 microns (diameter) for up to 24 h; the release of 28%-34% of the CDDP and 80%-90% of the epirubicin was estimated in the dissolution test, and 85% of the CDDP and 35% of the epirubicin was retained in the organs in the moment calculation. CELE was injected into 58 HCC patients via a celiac angiographic catheter. In 36 of these patients, the CELE injection was followed by transcatheter arterial embolization (TAE) therapy. Following the administration of CELE as one-shot injection therapy for stage IV HCC, the 1-year survival rate was 59% and the 2-year survival rate was 27%. Moreover, in patients (stage II, 12; stage III, 8; stage IV, 16) who received CELE and subsequently underwent TAE therapy, the 1-year survival rate was 90% and the 2-year survival rate was 67%. The nonionic contrast medium with Lipiodol forms finer emulsified particles, and these particles are more capable of penetrating into the tumor. In addition, the greater pharmacological stability of these particles provides a slow-release effect and prolonged stability of their shape. Finally, theoretically, the use of two major anticancer agents such as CDDP and epirubicin showed a greater clinical effect in the treatment of HCC than either our earlier suspension or a single anticancer agent.

Treatment of hepatocellular carcinoma with a CDDP-epirubicin-lipiodol suspension: a pilot clinico-pharmacological study.

Lipiodol injection is a useful method for detecting liver tumors, especially hepatocellular carcinoma (HCC). We therefore prepared and tested a new emulsion of lipiodol containing epirubicin and cis-diammine-dichloroplatinum (CDDP), drugs that are very effective against HCC. This CDDP-epirubicin-lipiodol suspension (CELS) was injected into 18 HCC patients via a celiac angiographic catheter. In 11 of these patients, CELS was followed by transcatheter arterial embolization (TAE) therapy. Clinical and pharmacological investigations were performed in all 18 patients, and the following results were obtained. CELS is pharmacologically and chemically stable, and both the results of the dissolution test and the serum levels of these two drugs indicate that slow release can be obtained. After the injection of CELS, serum levels of AFP and PIVKA-II decreased immediately, and no fatal clinical side effects were encountered. Although no statistically significant difference was observed, the survival (Kaplan-Meier method) of patients injected with CELS in the presence or absence of TAE therapy can be estimated to be much longer than that of patients receiving CDDP-lipiodol suspension injection in the presence (16 patients) or absence (6 patients) of TAE therapy. A combination of CELS injection and TAE therapy might be effective and useful for the treatment of HCC.

[A case of ankylosing spondylitis complicating Crohn's disease].

A 20-year-old man, who had suffered from ankylosing spondylitis for about 1 year, was admitted to our hospital due to melena and syncope. Physical examination revealed tenderness of abdomen and sacroiliac joint, and decreased spinal mobility. X-ray examination showed sacroiliitis and squaring of vertebral bodies. RA test and RAHA, negative; CRP, strongly positive; HLA-B 27 positive. Intestinal barium enema revealed skipping longitudinal fissure at terminal ileum, and a biopsy specimen of the colon revealed non-caseating granuloma. The association of ankylosing spondylitis and Crohn's disease has widely been known in Europe and United States; but this is the first case reported in detail in Japan, where incidences of both diseases were much lower than those found in Caucasians.

Increased lymphocyte transport by lipid absorption in rat mesenteric lymphatics.

The effect of olive oil administration on lymphocyte transport through mesenteric lymphatics was examined to see the possible involvement of nutritional absorption in lymphocyte traffic from the intestinal mucosa. After the olive oil administration to rats, remarkable increase in lymphocyte flux was observed within 2 h in lymph samples collected from rats with lymphatic fistula. The use of a high-speed microscopic video system made it possible to analyze accurately the lymphocyte transport in rapid movement that could not be detected by any of the ordinary video systems. The direct observation of mesenteric collecting lymphatics by this system showed an increment of lymphocyte transport from the intestinal mucosa by lipid absorption in 2 h. The contraction frequency of intestinal collecting lymphatics was also enhanced by olive oil administration. The densitometric analysis on video image was applied to estimate the extent of lipid absorption. The combination of a high-speed video system and the densitometric analysis revealed that the increase in lymphocyte flux occurred before lipid absorption reached its maximum and also demonstrated that the lymphocyte transport returned to control levels under the maximal absorptive condition. The results suggest that the fat absorption could be an important factor influencing the lymphocyte transport in the lymphatic system of intestine.

Abnormal fatty acid composition of plasma lipids in patients with protein-losing enteropathy.

This study was performed to clarify how disturbance of lipid metabolism occurred in patients with protein-losing enteropathy (PLE) as compared with that of control individuals and patients with malabsorption syndrome. Analysis of plasma lipids at fasting state showed a decreased proportion of essential fatty acid, especially linoleic and arachidonic acid fractions in patients with malabsorption syndrome as well as in patients with PLE group A, which was due to proven disorders of intestinal lymphatics. An increase in percentage of oleic acid fraction and a percentage increase in plasma triglyceride levels after an oral administration of olive oil was depressed in patients with malabsorption syndrome and PLE group A when compared with that of normal subjects. Patients with PLE group B, which was not due to major lymphatic disorders, were similar to normal in these parameters. These abnormalities were found to be marked when remarkable abnormalities of lymphatics were accompanied.

Radiographic and endoscopic features of colonic ulcers in systemic lupus erythematosus.

The radiographic and endoscopic features of the colonic ulcers during the course of a case of systemic lupus erythematosus are illustrated. Barium enema revealed the "collar button" type of penetrating ulcers in the left half of the colon and endoscopy demonstrated multiple round- or oval-shaped discrete ulcers, so-called "punched-out" ulcers with pale mucosa. These findings are compared with those of the reported cases of systemic lupus erythematosus and ulcerative colitis. Steroid and 6-mercaptopurine therapy was effective in this case.