Synthesis of antimicrobial agents. 3. Syntheses and antibacterial activities of 7-(4-hydroxypiperazin-1-yl)quinolones

A series of novel pyridone carboxylic acids having a 4-hydroxypiperazinyl group at the 7-position of norfloxacin and ciprofloxacin were prepared. The in vivo antibacterial efficacies of these compounds were superior to those of corresponding piperazinyl derivatives. From the results of the studies on the pharmacokinetic profile and toxicity, the 4-hydroxypiperazinyl derivatives were confirmed to be pharmacologically superior to corresponding piperazinyl derivatives. Thus, a 4-hydroxypiperazinyl group was revealed to be a beneficial substituent for potential use in future quinolone antibacterials.     

Synthesis of antimicrobial agents. 1. Syntheses and antibacterial activities of 7-(azole substituted)quinolones

A series of 6-fluoro- and 6,8-difluoro-7-(azole substituted)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids were prepared. Structure-activity relationship studies indicated that the antibacterial potency was better when the 6,8-substituents were fluorine atoms and the 7-substituent was either 1-imidazolyl, 20, or 4-methyl-1-imidazolyl, 25. From the results of studies on pharmacokinetic profile and toxicity, 20 and 25 were found to possess excellent antibacterial activities and to show high blood levels after oral administration to mice with low toxicity.     

Long-term results of first-line sequential high-dose carboplatin, etoposide and ifosfamide chemotherapy with peripheral blood stem cell support for patients with advanced testicular germ cell tumor

OBJECTIVE: Standard chemotherapy shows relatively low long-term survival in patients with poor-risk testicular germ cell tumor (GCT). First-line high-dose chemotherapy (HD-CT) may improve the result. High-dose carboplatin, etoposide, ifosfamide chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT) was investigated as first-line chemotherapy in patients with advanced testicular GCT. METHODS: Fifty-five previously untreated testicular GCT patients with Indiana 'advanced disease' criteria received three cycles of bleomycin, etoposide and cisplatin (BEP) followed by one cycle of HD-CT plus PBSCT, if elevated serum tumor markers were observed after three cycles of the BEP regimen. RESULTS: Thirty patients were treated with BEP alone, because the tumor marker(s) declined to normal range. Twenty-five patients received BEP and HD-CT. One patient died of rhabdomyolysis due to HD-CT. Three and six (13% and 25%) out of 24 patients treated with BEP and HD-CT achieved marker-negative and marker-positive partial responses, respectively. The other patients achieved no change. Fifteen (63%) are alive and 14 (58%) are free of disease at a median follow-up time of 54 months. Severe toxicity included treatment-related death (4%). CONCLUSIONS: HD-CT with peripheral stem cell support can be successfully applied in a multicenter setting. HD-CT demonstrated modest anticancer activity for Japanese patients with advanced testicular GCT and was well tolerated. This regimen might be examined for further investigation in randomized trials in first-line chemotherapy for patients with poor-risk testicular GCT.     

Plasma and tumor gastrin in patients with primary hyperparathyroidism

It is well known that primary hyperparathyroidism is often associated with peptic ulcer. The purpose of this study is to confirm the relationship between the gastrin-levels before and after parathyroidectomy in fourteen patients with primary hyperparathyroidism, and to determine the localization of gastrin in the surgically resected parathyroid tumor. The results obtained were as follows: 1) Three patients had peptic ulcer (gastric ulcer and duodenal ulcer), the incidence being 21%. 2) The basal serum gastrin levels were 123.0% +/- 68.1 pg/ml before operation and decreased to 90.2 +/- 44.5 pg/ml after operation. In the 3 patients with slightly elevated gastrin levels, the mean level before operation was 209.1 +/- 61.2 pg/ml. The gastrin level decreased to 116.4 +/- 62.0 pg/ml after operation. 3) Gastrin immunoreactivity was detected in 10 out of 14 tumors and its localization was at the periphery of tumor cells. From these results, we conclude that extragastric gastrin secretion from parathyroid tumors may be one of the cause of peptic ulcer in patients with primary hyperparathyroidism.     

Influence of differences in tumor vascularity upon the effects of hyperthermia

Summary Utilizing two types of human renal carcinoma heterotransplanted in nude mice, we investigated the variations in hyperthermic effects (42.5°C for 30 min) caused by differences in tumor type with special reference to variations in tumor vascularity. In the hypovascular JRC1 strain, sporadic vascular dilation was observed throughout the tumors after heating. Destruction of tumor cells was observed mainly in the region of dilation. In the hypervascular JRC11 strain, homogenous vascular dilation was observed immediately after heating, mainly at the periphery of tumors. There was a decrease in the viability of cells in the center of the tumor. Therefore, the hypervascular tumors showed greater destruction mainly at the center where blood circulation was reduced. The range of necrosis was also greatly affected by the extent of vascular dilation caused by heating in hypovascular tumors.     

ENDOSCOPIC PANCREATIC STENTING IN CHRONIC PANCREATITIS WITH DUCTAL DILATION PROXIMAL TO A STRICTURE: A SAFE and EFFECTIVE PROTOCOL

After removal of intraductal stones, a 10‐Fr or 7‐Fr pancreatic stent was placed in 16 patients with upstream ductal dilation proximal to a stricture of the main pancreatic duct. Stents were removed after a mean duration of 52.5 days. Nine patients underwent repeated stenting. About one year after removal of the initial stent, when the remaining upstream ductal dilation was found on follow‐up pancreatograms, the next stent was replaced. Repeated stenting improved outflow of pancreatic juice more effectively than one‐time stenting. Correlation between long‐term pain relief without recurrence of intraductal stones and reduction of duct diameter was also shown. Stent occlusion was observed in 14 of 30 stents. Stent occlusion was frequently associated with recurrence of pancreatitis and intraductal stones, and was also associated with morphologic changes in the pancreatic ductal system. Although there were no significant differences between stent patency of the initial stents and that of the next stents, stent patency of 10‐Fr stents was superior to that of 7‐Fr stents. 10‐Fr stents should be removed within 8 weeks and 7‐Fr stents should be removed within 4 weeks for the prevention of stent occlusion. Repeated stenting with short‐term stenting is therefore considered a safe and effective protocol of endoscopic pancreatic stenting.     

Development of a simple analytical method to determine the serum concentration of denopamine by high performance liquid chromatography with electrochemical detection and its clinical application

Denopamine (DP) is a new, orally active, selectively positive inotropic agent and used for the treatment of chronic cardiac insufficiency. The therapeutic effects of DP is highly related to its serum concentrations. A simple analytical method has been developed to determine the serum concentration of DP by use of high performance liquid chromatography (HPLC) with electrochemical detection (ECD). In order to extract the DP from the serum, a disposable solid extraction column (Sep-Pak cartridge, C-18) was used. The average recovery was 84.6 +/- 2.7%. The working electrode potential was fixed at 400 mV with a T1 cell, 600 mV with a T2 cell and 650 mV with a Guard cell in ECD. The analysis was performed on a Nova-Pak cartridge C-18 reverse-phase column (100 mm X 8 mm i.d., 4 microns). The mobile phase consisted of 0.1 M potassium phosphate buffer (pH 6.0) and acetonitrile (83: 17, v/v), and the flow rate was 1.0 ml/min. DP and internal standard phenolphthalein (PP) were eluted at 16.5 and 36.0 min, respectively. The peak-height ratio of DP to PP was linearly correlated (r = 0.9998) over a concentrations range between 1.25 and 15.0 ng/ml in the serum. The lowest detectable concentration was 1.0 ng/ml in the serum. The coefficient of variation of reproducibility in the assay was 6.0% By using the present method, serum concentration of DP was measured for four healthy volunteers after a single oral administration of 10 mg DP tablet after a overnight fast. From these DP concentration profiles, pharmacokinetic parameters were calculated.(ABSTRACT TRUNCATED AT 250 WORDS)