Aliskiren, a novel oral renin inhibitor, provides dose-dependent efficacy and placebo-like tolerability in Japanese patients with hypertension.

Aliskiren is a novel orally active renin inhibitor for the treatment of hypertension. This study evaluated the antihypertensive efficacy, safety and tolerability of aliskiren in Japanese patients with hypertension. Forty hundred and fifty-five Japanese men and women with a mean sitting diastolic blood pressure of 95-110 mmHg were randomized to receive once-daily double-blind treatment for 8 weeks with aliskiren 75, 150 or 300 mg or placebo. Aliskiren produced significant, dose-dependent reductions in mean sitting diastolic blood pressure (p<0.0005 vs. placebo for each dose) and mean sitting systolic blood pressure (p<0.001 vs. placebo for each dose). The placebo-corrected reductions in mean sitting systolic/diastolic blood pressure were 5.7/4.0, 5.9/4.5 and 11.2/7.5 mmHg in the aliskiren 75, 150 and 300 mg groups, respectively. After 8 weeks' treatment, 27.8%, 47.8%, 48.2% and 63.7% of patients in the placebo and aliskiren 75, 150 and 300 mg groups, respectively, achieved a successful treatment response (diastolic blood pressure <90 mmHg and/or reduced by > or =10 mmHg from baseline; p<0.005 vs. placebo for each dose). Aliskiren treatment was well tolerated, with the incidence of adverse events reported in the active treatment groups (53-55%) being similar to that in the placebo group (50%). This study, which is the first to assess the antihypertensive efficacy and safety of aliskiren in Japanese patients with hypertension, demonstrates that the once-daily oral renin inhibitor aliskiren provides significant, dose-dependent reductions in blood pressure with placebo-like tolerability.     

Effects of hypertension and type 2 diabetes mellitus on the risk of total cardiovascular events in Japanese patients with hypercholesterolemia: implications from the Japan Lipid Intervention Trial (J-LIT).

Hyperlipidemia, hypertension, and diabetes mellitus (DM) are well-established risk factors for cardiovascular disease. We analyzed the cardiovascular events in hyperlipidemic patients with or without DM who were administered open-labeled simvastatin in groups stratified by blood pressure level using data from the Japan Lipid Intervention Trial (J-LIT). Hyperlipidemic patients with DM (n=6,288) had significantly more cardiovascular events than those without DM (n=33,933). The incidence rates of total cardiovascular events in the Non-DM and DM groups were 15.40 and 25.76 per 1,000 patients for the 6-year period, respectively. The relative risk of total cardiovascular events in the DM vs. the Non-DM group was 1.68, and the relative risk was significantly higher in the DM than in the Non-DM group. The relative risks of total cardiovascular events were significantly higher in DM and Non-DM patients whose systolic blood pressure (SBP) was greater than or equal to 130 mmHg compared to that of Non-DM patients whose SBP was less than 130 mmHg, and in DM and Non-DM patients whose diastolic blood pressure (DBP) was greater than or equal to 80 mmHg compared to that of Non-DM patients whose DBP was less than 80 mmHg. In all groups stratified by SBP and DBP, relative risks of total cardiovascular events were higher in DM patients than in Non-DM patients. For patients with hypercholesterolemia and DM, blood pressure should be strictly controlled in order to prevent both coronary events and stroke. These results are in good agreement with the JNC 7 and the ESH/ESC guidelines for DM patients, which recommended that the SBP and DBP be less than 130 and 80 mmHg, respectively.     

Effects of ethylene glycol on hepatic microsomal cytochrome P-450

The effect of ethylene glycol on rat hepatic microsomal cytochrome P-450 was studied in vitro and in vivo. The destruction of cytochrome P-450 was not seen in vitro. The addition of 1 mM NADPH also did not change. When ethylene glycol was added to drinking water at a concentration of 1.0% for 7 days, there was no change in the contents of microsomal protein, cytochrome P-450, b5 and heme. While NADPH-cytochrome C reductase activity of the exposed group did not change, NADH-ferricyanide reductase activity increased significantly.     

ENDOSCOPIC SUBMUCOSAL DISSECTION FOR RECURRENT GASTRIC TUMORS

Endoscopic resection has been accepted as the standard treatment for intramucosal gastric tumors of differentiated type. However, the indication was limited to small tumors to achieve en bloc resection and prevent local recurrence in cases of conventional endoscopic mucosal resection (EMR) such as the strip biopsy and the cap technique. To avoid multi‐fragmental resection, we have developed endoscopic submucosal dissection (ESD) as a new endoscopic resection technique. ESD is a remarkable technique, because we make it possible to remove the lesions en bloc regardless of size, shape, coexisting ulcer, and location. However, it is difficult or impossible to resect recurrent tumors en bloc in conventional EMR owing to hard fibrosis, and some patients need laparotomy. Using ESD, we can dissect the submucosal layer as we directly look at the submucosa, and remove the lesion safely and reliably even in cases of hard fibrosis. The key to treatment of recurrent tumors in ESD are as follows: (i) using enough submucosal injection solution (we use a mixture of Glyceol and 1% 1900 kDa hyaluronic acid preparation); (ii) incising the mucosa without fibrosis; (iii) understanding characteristics of various cutting devices, and changing other devices in difficult situations. In these ways we can remove the majority of the recurrent tumors en bloc. Hence, we consider that ESD is a very effective treatment which achieves excellent en bloc and complete resection rates and enables patients with intramucosal gastric tumors to a recurrent‐free survival even in recurrent tumors.     

MULTICENTER STUDY DESIGN OF THE EX VIVO EVALUATION OF ENDOCYTOSCOPY IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Optical technological innovations enable us to visualize cellular nuclei endoscopically. Herein is described a protocol design for a multicenter study for the ex vivo evaluation of endocytoscopy. The present study was performed by the Endoscopy Forum Japan study group.     

Primary Adenocarcinoma in the Urethrorectal Fistula

A 60-year-old Japanese man was hospitalized because of urinary leakage from the anus on October 3, 1994. Retrograde urethrography detected a fistula between the bulbous urethra and the rectum. Urethrocystoscopy revealed a tumor on the urethrorectal fistula. Tumor biopsy showed a well differentiated adenocarcinoma. Cystourethrectomy with fistulectomy, and ileal conduit urinary diversion were performed. Pathological examination revealed primary adenocarcinoma in the fistula with invasion to the prostatic urethra and bladder wall. The patient showed no evidence of a recurrence as of August, 1996.     

Protodioscin isolated from fenugreek (Trigonella foenumgraecum L.) induces cell death and morphological change indicative of apoptosis in leukemic cell line H-60, but not in gastric cancer cell line KATO III

Protodioscin (PD) was purified from fenugreek (Trigonella foenumgraecum L.) and identified by Mass, and 1H- and 13C-NMR. The effects of PD on cell viability in human leukemia HL-60 and human stomach cancer KATO III cells were investigated. PD displayed strong growth inhibitory effect against HL-60 cells, but weak growth inhibitory effect on KATO III cells. Morphological change showing apoptotic bodies was observed in the HL-60 cells treated with PD, but not in KATO III cells treated with PD. Flow cytometric analysis showed that the hypodiploid nuclei of HL-60 cells were increased to 75.2, 96.3, and 100% after a 3-day treatment with 2.5, 5, and 10 microM PD, respectively. The fragmentation by PD of DNA to oligonucleosomal-sized fragments, that is a characteristic of apoptosis, was observed to be both concentration- and time-dependent in the HL-60 cells. These findings suggest that growth inhibition by PD of HL-60 cells results from the induction of apoptosis by this compound in HL-60 cells.     

NMDA antagonist MK-801 does not interfere with the use of spatial representation in a familiar environment

There is disagreement among researchers concerning whether glutamatergic N-methyl-D-aspartate (NMDA) receptors play a role in constructing spatial representations. Therefore, the authors reexamined the effects of the NMDA antagonist on a spatial discrimination task using rats in a water pool. The authors confirmed that MK-801 impaired acquisition of the spatial discrimination task (Experiment 1). When rats were pretrained before drug treatment, MK-801 induced learning deficits in the novel environment but not in the familiar environment (Experiment 2). Moreover, in a familiar environment, MK-801 did not impair spatial learning, even when the task was completely novel for the rats (Experiment 3). These results suggest that NMDA receptors play an important role in the construction of spatial representations but not in the use of them.     

Comparative studies of commercially available particle agglutination assay and enzyme-linked immunosorbent assay for screening of human T-cell leukemia virus type I antibodies in blood donors.

Human T-cell leukemia virus type I (HTLV-I) transmission during blood transfusion can be prevented by screening for and eliminating blood containing anti-HTLV-I antibodies. For this purpose, we evaluated two commercial test kits for HTLV-I antibodies, Serodia-ATLA (particle agglutination assay [PA]) and Eitest-ATL (enzyme-linked immunosorbent assay [ELISA]), by using serum samples from Japanese blood donors. Of 2,316 serum samples, 39 (1.7%), 34 (1.5%), and 28 (1.2%) were positive for the antibody by PA, ELISA, and immunofluorescence (IF), respectively. The coincidence rate for antibody-positive and antibody-negative results was 99.5% between PA and IF, whereas it was 99.6% between ELISA and IF. The serum samples which were positive by IF were also positive by PA, whereas 2 of 26 IF-positive samples were negative by ELISA. All the samples positive by both PA and ELISA were shown to be positive by IF unequivocally. The samples positive by only one of the two methods (PA or ELISA) were different. Eleven and eight serum samples that were negative by IF but positive by PA and ELISA, respectively, were further studied for HTLV-I antibody by radioimmunoprecipitation. Three of the former but none of the latter were found to be positive for antibody. Moreover, a PA-positive but IF-negative serum sample was shown to have significantly decreased PA titers after 2-mercaptoethanol treatment. The PA was further shown to detect not only IgG antibody but also IgM antibody to HTLV-I after separation of this serum sample by high-performance liquid chromatography.     

Pharmacokinetics of bisoprolol and its effect on dialysis refractory hypertension

The efficacy, safety, and pharmacokinetics of bisoprolol were investigated following oral administration once daily for 12 weeks in hyperreninemic patients with dialysis-refractory hypertension. Mean blood pressure rapidly fell from 132 to 112 mmHg in the 5.0-mg/day (n = 6) and from 142 to 128 mmHg in the 2.5-mg/day patients (n = 5), which were accompanied by a fall in plasma renin activity. On nondialysis days, Cmax and T1/2 were significantly higher in patients than in healthy control subjects. However, Cmax in the 2.5-mg/day patients was almost equal to that in healthy control subjects receiving 5.0 mg/day of bisoprolol. Plasma bisoprolol was dialyzable. During the course of the study, dialysis hypotension and bradycardia occurred in two patients receiving 5.0 mg/day of bisoprolol. In conclusion, a daily dose of 2.5 mg bisoprolol seems to be an adequate and relatively effective dose in our patients with dialysis-refractory hypertension.