Lenalidomide treatment of Japanese patients with myelodysplastic syndromes with 5q deletion: a post-marketing surveillance study.

Lenalidomide was approved in Japan for the treatment of patients with myelodysplastic syndromes associated with a 5q deletion (del 5q-MDS) in August 2010. A post-marketing surveillance (PMS) study enrolled 173 patients with del 5q-MDS who started lenalidomide treatment between August 2010 and September 2011 (mean ± standard deviation [SD] age 72.4 ± 9.0 years) and observed for up to 6 cycles or 6 months. Adverse drug reactions (ADRs) and serious ADRs were reported in 78.0% and 50.9% of patients. The most commonly observed ADRs were thrombocytopenia or platelet count decreased (46.2%), neutropenia or neutrophil count decreased (42.2%), and rash (23.1%). Of 114 patients who were red blood cell transfusion-dependent at baseline, 39 (34.2%) achieved transfusion independence during lenalidomide treatment. Of 173 patients, 19 (11.0%) had confirmed acute myeloid leukemia (AML) progression during the study. Moreover, long-term follow-up (3 years) was available for 68 of the 173 patients, of whom 12 (17.6%) progressed to AML during the additional period. This PMS study investigated the safety and effectiveness of lenalidomide in patients with del 5q-MDS. No new safety concerns were noted in routine clinical use in Japan and no evidence was found for an increased risk of AML progression following lenalidomide treatment.

[A case of successful control for primary duodenal cancer with combined CPT-11, CDDP and DOC chemotherapy].

We have experienced a rare case of primary duodenal carcinoma with perforation of the duodenum. Combined CPT- 11, CDDP and DOC chemotherapy achieved a partial response. A 54-year-old man with serious abdominal pain visited our hospital with a diagnosis of acute peritonitis due to perforation of digestive tract on CT scan. An emergency operation was performed with patch for perforation of the duodenum. Endoscopic examination and biopsy after surgery showed duodenal adenocarcinoma. Abdominal CT scan revealed metastasis to the periaortic lymph nodes. Therefore, we diagnosed primary duodenal carcinoma with metastasis to the periaortic lymph nodes. Combined CPT-11, CDDP and DOC chemotherapy were performed. After two courses, endoscopic examination and biopsy showed primary lesion of the duodenum had disappeared. Metastatic lymph nodes were reduced from CT scan after three courses, and successfully controlled until nine courses. Then regimen was changed to S-1 alone and S-1/CPT-11. The patient remained alive for two years after the operation without tumor progression.

An autopsy case of poisoning with ethanol and psychotropic drugs.

A case of fatal poisoning involving ethanol with psychotropic drugs is presented. Quantitative toxicological analysis showed that the concentrations of ethanol, amoxapine and phenobarbital in the femoral blood were 2.86 mg/ml, 0.41 microg/ml and 6.80 microg/ml, respectively. We concluded that the cause of death was due to the combination use of ethanol, amoxapine and phenobarbital.

[A case of long survival of unresected gastric cancer with excellent QOL administered by S-1 alone].

We report a case of unresectable gastric cancer, who had been treated with S-1 alone for 3 years without cancerous symptoms. The patient was a 66-year-old male. His diagnosis was advanced gastric cancer based on gastrofiberscopy. He underwent surgery on April 15, 2003. The tumor proved to be unresectable due to direct invasion of the pancreatic head, so only gastrojejunostomy was performed. On day 14 after surgery, the administration of S-1 alone was commenced at a dose of 100 mg per day in a 4-week course of medication at 2-week intervals. No side effects were noted. Moreover, his quality of life (QOL) was not disturbed, and he led an active social life throughout the course. Long survival was achieved by S-1 alone.

[A case of non-curatively resected scirrhous gastric cancer successfully treated over 2 years with weekly administration of paclitaxel].

We report a patient with far-advanced gastric cancer treated by weekly administration of paclitaxel (TXL) over 2 years. The patient was a 66-year-old female with peritoneal metastasis and remarkable lymph node metastasis of scirrhous gastric cancer. She underwent a non-curative resection with total gastrectomy and splenectomy in May 2002. Postoperative chemotherapy with TS-1 (80 mg/body) was performed. Due to grade 4 neutropenia and grade 2 anorexia, this treatment could not be continued. Three months after surgery, the tumor marker (CA19-9) had elevated to an abnormal level. Alternatively, TXL was administered at a weekly dose of 70 mg/m2 for 3 weeks followed by 6 weeks rest from September 2002. The tumor marker (CA19-9) gradually decreased to the normal level. Because of the long rest interval, 10 courses of treatment could be continued, and the patient has been alive over 2 years with the cancer controlled. There have been few effective chemotherapies for gastric cancer with peritoneal metastasis. Weekly paclitaxel therapy is considered to be effective for the treatment of advanced scirrhous gastric cancer with peritoneal metastasis.

Effect of TA-270, a novel quinolinone derivative, on antigen-induced nasal blockage in a guinea pig model of allergic rhinitis.

TA-270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone) is a novel quinolinone derivative that has been demonstrated to possess an anti-oxidative activity against peroxynitrite, a potent oxidant, that is generated by the reaction of nitric oxide with superoxide anions. The current study describes the inhibitory effect of TA-270 on the biphasic nasal blockage induced by repeated antigen challenge in an allergic rhinitis guinea pig model. In the present in vitro study, TA-270 potently inhibited the oxidative reaction induced by peroxynitrite (IC(50)=79 nM). In addition, TA-270 (0.3-30 mg/kg, p.o.) dose-dependently inhibited peroxynitrite (3 mM, 10 mul/nostril)-induced nasal blockage in guinea pigs. In the antigen-induced allergic rhinitis model, TA-270 (0.3, 3, and 30 mg/kg, p.o.) given 1 h before the antigen challenge suppressed early phase nasal blockage by 36%, 42%, and 63%, respectively. Furthermore, TA-270 (0.3, 3, and 30 mg/kg, p.o.) showed a relatively strong suppression of late phase nasal blockage (39%, 62%, and 72%, respectively). The late phase nasal blockage was significantly inhibited (61%) even when TA-270 (30 mg/kg, p.o.) was administered 18 h before the antigen challenge. In conclusion, TA-270 improved antigen-induced nasal blockage, probably through its peroxynitrite scavenging action, and the effect was sustained for at least 18 h. Thus, TA-270 would be expected to relieve nasal blockage in allergic rhinitis patients.

Application of energy dispersive X-ray fluorescent spectrometry (EDXRF) in drug-related cases.

We applied here energy dispersive X-ray fluorescent spectrometry (EDXRF) to two medico-legal autopsy cases of bromvalerylurea ingestion. Rapid elemental analysis using EDXRF identified bromide in blood, urine and stomach contents of victims during autopsy. The present cases indicate that screening with EDXRF, an instrument suitable for non-destructive, rapid elemental analysis, provides useful information for identification of drugs.

TA-270 [4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone], an anti-asthmatic agent, inhibits leukotriene production induced by IgE receptor stimulation in RBL-2H3 cells.

A novel quinolinone derivative, TA-270 [4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone], has been shown to inhibit antigen-induced asthmatic responses including the early-phase bronchoconstriction in actively sensitized guinea pigs. Here we characterized the action mechanisms of TA-270 in cellular level in vitro. In RBL-2H3 mast cells sensitized with dinitrophenol (DNP)-specific IgE, the antigen exhibited several mast cell functions, including hexosaminidase release as a marker of degranulation, production of tumor necrosis factor-alpha, and production of immunologically detective leukotrienes. These antigen-induced actions were associated with the activation of several early signaling events, including inositol phosphate production reflecting phospholipase C activation and extracellular signal-regulated kinase activation. When the cells were treated with TA-270, the antigen-induced leukotriene production was almost completely suppressed, but other antigen-induced actions listed above were hardly affected. This drug also failed to affect the antigen-induced phospholipase A2 activation as evaluated by the total release of arachidonic acid and its metabolites from the cells prelabeled with radioactive arachidonic acid. However, TA-270 clearly changed the arachidonic acid metabolic pathway. It suppressed the accumulation of 5-lipoxygenase products, including leukotrienes, but hardly affected the accumulation of cyclooxygenase products. The inhibitory action of TA-270 on leukotriene production was also observed in human neutrophils and eosinophils. We conclude that TA-270 inhibits 5-lipoxygenase activity and, thereby, suppresses the antigen-induced leukotriene production.

Effects of radical scavengers, TA248 and TA276, on stunned myocardium in dogs: involvement of K ATP channels.

TA248 (7-(beta-D-glucopyranosyloxy)-4-hydroxy-3-octyloxy-2H-1-benzopyran-2-one) and TA276 (sodium 7-hydroxy-3-octyloxy-2H-1-benzopyran-2-one-4-oxide) were newly developed as radical scavengers. In vitro, TA276 scavenged both superoxide anions (. O(2)(-)) and hydroxyl radicals (. OH). TA248 also trapped. O(2)(-), but had less activity on. OH. In vivo, left ventricular contractile functions were determined in pentobarbital-anesthetized open-chest dogs. A regional portion of the left ventricular wall was made ischemic for 20 min by ligating the left anterior descending coronary artery and then reperfused for 60 min. TA248 (3 mg/kg) and TA276 (3 mg/kg) injected i.v. 10 min before occlusion significantly improved myocardial stunning that is contractile dysfunction observed after reperfusion following brief ischemia. Glibenclamide (1 mg/kg) injected i.v. 20 min before occlusion significantly worsened the myocardial stunning. Pretreatment with glibenclamide completely abolished the beneficial effect of TA276 on myocardial stunning, whereas it only partially attenuated that of TA248, showing some improvement even in the presence of glibenclamide. Because of the incomplete scavenging activity of TA248, residual. OH may play some roles in improvement of myocardial stunning with TA248 in the presence of glibenclamide. We speculate that the. OH may eject glibenclamide from its binding site on K(ATP) channels, leading to opening of the channels.