Structure-activity relationships of antibacterial 6,7- and 7,8-disubstituted 1-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids.

Previous quantitative and qualitative structure-activity studies in antibacterial monosubstituted 1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids prompted us to synthesize the 6,7,8-polysubstituted compounds. In this paper, the preparation and antibacterial activity of the 6,7- and 7,8-disubstituted compounds and their derivatives are described. Among these compounds, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid (34) possessed many significant activities and was more active than oxolinic acid (84) against Gram-positive and Gram-negative bacteria. Structure-activity relationships are discussed.

Effect of 4-(4'-chlorobenzyloxy)benzyl nicotinate (KCD-232) on triglyceride and fatty acid metabolism in rats.

The effects of KCD-232, a new hypolipidemic agent with a structure of 4-(4'-chlorobenzyloxy) benzyl nicotinate, on triglyceride (TG) and fatty acid (FA) metabolism were studied in rats. KCD-232 dose-dependently reduced both liver and serum TG levels. From in vivo and in vitro studies, the hypotriglyceridemic action of KCD-232 was shown to be based on the inhibition of hepatic TG synthesis due to both decreased FA synthesis and increased FA oxidation in the liver. Of two metabolites of KCD-232, i.e. 4-(4'-chlorobenzyloxy)benzoic acid (MII) and nicotinic acid, MII was found to be responsible for the decreased synthesis and increased oxidation of FA in the liver, the latter apparently being due to increased mitochondrial oxidation activated by MII. MII was demonstrated to form a xenobiotic TG in which one fatty acid moiety was substituted by MII and to form a thioester with CoA by rat liver microsomes. This thioester, MII-CoA, inhibited fatty acid syntheses from [14C]acetate, [14C] acetyl-CoA and [14C]malonyl-CoA in cell-free enzyme systems from rat liver both with and without an NADPH-generating system, whereas MII as such showed no effect. MII-CoA were therefore considered to be a chemical entity for the inhibition of hepatic fatty acid synthesis by KCD-232 and was suggested to inhibit fatty acid synthetase directly.

Effect of 4-(4'-chlorobenzyloxy)benzyl nicotinate (KCD-232) on cholesterol metabolism in rats.

The effects of 4-(4'-chlorobenzyloxy)benzyl nicotinate (KCD-232), a new hypolipidemic agent, on serum cholesterol level and cholesterol biosynthesis were studied in normolipidemic rats. KCD-232 dose-dependently reduced the serum cholesterol level. The in vivo incorporation of [14C]-acetate and 3H from [3H]water into liver digitonin-precipitable sterols was inhibited by oral administration of KCD-232, while that of [14C]mevalonic acid into the sterols was not inhibited. Hepatic 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activity was suppressed significantly by the oral administration of the drug. A KCD-232 metabolite, 4-(4'-chlorobenzyloxy)benzoic acid (MII), strongly inhibited [14C]acetate incorporation and weakly inhibited [14C]mevalonic acid incorporation into the sterols in liver slices. MII also significantly inhibited the sterol synthetic rate measured with [3H]water and the HMG-CoA reductase activity in dispersed hepatocytes. MII and its CoA thioester (MII-CoA) inhibited the incorporation of [14C]acetate, [14C]acetyl-CoA and [14C]HMG-CoA into nonsaponifiable lipids in a cell-free enzyme system from rat liver. MII-CoA further showed a weak inhibition of [14C]-mevalonic acid incorporation into nonsaponifiable lipids in the system, while MII showed no effect on mevalonic acid incorporation. These results indicate that KCD-232 possesses a major inhibitory site for sterol synthesis on HMG-CoA reductase due to both MII and MII-CoA, and a possible second site of action beyond mevalonic acid due to MII-CoA. The latter inhibitory site, however, is considered to play a minor role in the inhibition of sterol synthesis in vivo.

A modified method of mixed lymphocyte reaction: establishment of the assay system and its application to extracts of fungal cultures.

A modified mixed lymphocyte reaction (MLR) assay was developed to screen immunosuppressive agents. In the MLR, irradiation of splenocytes with UV light was employed for the preparation of stimulator cells, and the highest response was observed with the combination of splenocytes of C3H/He mice as a stimulator and those of C57BL/6 as a responder. The blastogenesis of the responder cells was quantified by a colorimetric method using MTT in 96-well microculture plates. For screening immunosuppressive substances, the MLR in combination with a cytotoxicity test can distinguish immunosuppressors from cytotoxic agents. The applications of this assay system to extracts of fungal culture was also described.

Effect of KCD-232, a new hypolipidemic agent, on serum lipoprotein changes in hepatoma-bearing rats.

Changes in serum lipoprotein profiles were characterized in Donryu rats subcutaneously implanted with an ascites hepatoma line of AH109A cells and the effect of a new hypolipidemic agent with a structure of 4-(4'-chlorobenzyloxy)benzyl nicotinate (KCD-232) was estimated. With the growth of hepatoma for periods of up to three weeks, a striking decrease in the high density lipoprotein (HDL) fraction and an enormous increase in the VLDL + LDL (very low density lipoprotein + low density lipoprotein) fraction were found in hepatoma-bearing rats when either precipitation method or electrophoresis was used. These lipoprotein profiles were not influenced by sex. Judging from the electrophoretogram, the increase in VLDL + LDL fraction was due mainly to an increase in VLDL fraction. The oral administration of KCD-232 significantly suppressed the hepatoma-induced increase in VLDL + LDL with little or no influence on the hepatoma-induced decrease in HDL. There existed a positive correlation between the hepatoma weight and (VLDL + LDL)-cholesterol concentration and a negative one between hepatoma and HDL-cholesterol.

Holocord astrocytoma--case report.

A rare case of intramedullary holocord astrocytoma extending from the medulla oblongata to the conus medullaris is reported. A 27-year-old male who had been suffering from nuchalgia for a few years was admitted to our department because of lumbago and gait disturbance. Neurological examination revealed sensory disturbances in various locations, weakness of the right lower extremity, mild swallowing disturbance, and bowel and bladder difficulties. Magnetic resonance (MR) images and myelograms showed a long cystic lesion extending from the medulla oblongata to the thoracolumbar spinal cord. Gadolinium-diethylenetriaminepenta-acetic acid (Gd-DTPA)-enhanced images detected a solid tumor located at the Th6-7 level. Two syrinx-subarachnoid shunts were placed at the upper cervical and Th12 levels. The solid neoplasm at the Th7 level was partially resected and histologically diagnosed as astrocytoma. Differentiation between cystic lesions and solid masses in the spinal cord is difficult. The usefulness of Gd-DTPA-enhanced MR imaging in the diagnosis of holocord tumor and the pathogenesis of secondary syringomyelia are discussed.

[Human and animal studies on the pharmacokinetics of norfloxacin in renal failure].

The pharmacokinetics of norfloxacin (NFLX) was studied in 5 patients with chronic renal failure and rats with renal obstruction. The drug was orally given to patients on on- and off-dialysis days in a crossover fashion. Serum levels of NFLX showed a similar profile during both on- and off-dialysis days, and the hemodialysis treatment did not affect the elimination of the drug from the serum. The mean serum elimination half-life was 8.8 +/- 1.2 hours (standard error) for on- dialysis day and it was 7.0 +/- 0.8 hours for off-dialysis day. The urinary recovery of NFLX for 24 hours was less than 0.1% of administered doses in these patients. Rats with renal obstruction exhibited higher drug levels in serum for longer periods of time and elevated biliary excretion ratios in comparison to sham-operated rats, and no significant change in the fraction of biliary metabolites was observed. The biliary excretion of NFLX was likely to be enhanced in patients with renal failure.

[Isolated intraventricular hemorrhage due to a ruptured vertebral artery aneurysm].

A rare case of ruptured aneurysm originating from the vertebral artery, and presenting an isolated clot in the fourth ventricle is reported. The patient underwent surgery via a right lateral suboccipital craniectomy on the third day. As the aneurysm was huge and partially thrombosed, trapping was performed and completed successfully. If isolated intraventricular hematoma was found without obvious parenchymal hemorrhage or subarachnoid clot, the diagnosis of vertebral artery aneurysm should be considered as a possibility in addition to posterior inferior cerebellar artery aneurysm. Complete vertebral angiography is indispensable for the recognition of this condition.