Interaction between levofloxacin and vancomycin in rats--study of serum and organ levels.

The changes of pharmacokinetic parameters when levofloxacin (LVFX) and vancomycin (VCM) were administered concomitantly were studied in rats. There was an increase in the AUC and Tmax of LVFX with concomitant administration, but no effect on Cmax. There was also an increase in the AUC and T1/2 of VCM with concomitant administration, while Vd was reduced. Concomitant administration had no effect on the correlation between the serum and hepatic tissue concentrations of LVFX, but it markedly decreased the correlation between the serum and renal tissue concentrations of VCM. BUN was increased at 8 h after the administration of VCM. There have been reports that renal dysfunction can be caused by VCM, and our findings suggested that concomitant administration of LVFX and VCM must be performed with caution.

Effects of chlordane on parameters of liver and muscle toxicity in man and experimental animals.

An attempt was made to compare the toxic effects of the organochlorine insecticide 'chlordane' in man and rats. Analysis of blood for chlordane metabolites showed their presence in the descending order of trans-nonachlor, oxychlordane, heptachlorepoxide and cis-nonachlor. The total range of chlordane and its metabolites in the sera of workers was 9.84 +/- 4.47 ng/g. Serum levels of triglycerides (TG), creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) activities were also found to be higher in pest-control operators. In a simultaneous study, rats were administered 100 mg/kg body wt. of chlordane by stomach tube once a day for 4 days, whereas 50 mg/kg body wt. of chlordane was injected intraperitoneally once a day for 4 days. The data show that total cholesterol and serum TG as well as CPK and LDH activities are increased after chlordane treatment. The isoenzyme patterns suggest that an increase in CPK and LDH is related to skeletal muscle. Furthermore, the hepatotoxicity of chlordane was also studied in rats only. A significant increase in liver weight, its water content, total lipids, triglycerides and phospholipids was recorded. Chlordane induced lipid peroxidation in the liver, exhibiting a dose-response relationship. Although no appreciable effect on mitochondrial function and latent ATPase activity was observed, 2,4-dinitrophenol-stimulated ATPase activity was inhibited. Histological examination of the liver confirmed fatty infiltration induced by chlordane in rats.

Hepatic and muscle injuries in mice treated with heptachlor.

Heptachlor is a major component of the insecticide, chlordane. It is a health hazard but is still in use in some countries of Southeast Asia. To elucidate the toxicity of heptachlor its effects on mice after oral and intraperitoneal administration were studied. A 3-day group, 92-day group and 180-day group were given heptachlor intraperitoneally, orally and ad libitum, respectively. Results showed increased levels of serum alanine aminotransferase and decreased levels of serum cholinesterase activity. Serum creatine phosphokinase levels increased significantly. These may be due to the disruption of muscle membrane by chlordane. Results also showed significant variations of serum lipid levels from control as heptachlor has a known effect on lipid metabolism. Also the lipid peroxide levels expressed as TBA values were increased significantly, showing heptachlor's role in causing liver injury. These results suggest that the deterioration of membranes due to lipid peroxidation leads to liver and muscle injuries caused by heptachlor.

Effect of heptachlor on hepatic mitochondrial oxidative phosphorylation in rat.

In a study of the hepatotoxicity of heptachlor (1,4,5,6,7,8,8-heptachlor 3a, 4,7,7 a-tetrahydro-4,7-methanoindene), a major compound of chlordane, the effect of heptachlor on the respiratory activity (oxidative phosphorylation and electron transport) of rat liver mitochondria was investigated. Heptachlor at a final concentration of 50 microM with succinate as substrate decreased the respiratory control index (RCI) due to a marked inhibition of state 3 respiration and a slight inhibition of state 4 respiration. One hundred microM heptachlor with succinate as substrate suppressed the states 3 and 4 respiration almost completely. On the other hand, heptachlor at a final concentration ranging from 50 to 100 microM with beta-hydroxybutylate (beta-HB) slightly decreased the RCI and decreased the RCI hardly at all with ascorbate plus N,N,N',N', -tetramethylphenylene diamine (TMPD) as substrate. Heptachlor at a concentration of 50 microM in the presence of succinate also decreased the ADP/O ratio of mitochondria. The mode of inhibition of succinate oxidation by heptachlor apparently is a noncompetitive inhibition, as shown by Lineweaver-Burk plot.

Effect of chlordane on hepatic mitochondrial respiration.

In order to clarify the cytotoxicity of chlordane, an industrial product used as an insecticide, its effect on oxidative phosphorylation in rat hepatic mitochondria was studied. The respiration rate, RCI and ADP/O ratios were inhibited by chlordane-related compounds; the degree of inhibition was in the descending order of trans-chlordane, cis-chlordane, heptachlor and heptachlorepoxide. Of the indices indicating various respiratory activities, state 3 respiration was the most sensitively inhibited by these compounds, suggesting that they inhibit energy transfer. However, electron transport was inhibited also by high concentrations of chlordane constituents. The inhibitory effect of the chlordane constituents on respiratory activity varied depending on the species of respiratory substrate, suggesting site-specificity of these compounds. The release of K+ ions paralleled the results of the respiratory activity study. Heptachlorepoxide, a metabolic product of heptachlor, had less effect on mitochondria than heptachlor.

Effect of phenol and halogenated phenols on energy transfer reactions of rat liver mitochondria.

The in vitro effects of phenol and p-halogenated phenols on mitochondrial energy transfer reactions were examined using isolated rat liver mitochondria. The relationship between physiochemical properties of phenolic compounds and their effects on mitochondria were studied. Phenol and p-halogenated phenols induced the release of K+ ions from mitochondria, suggesting a change in permeability to K+ ions. A decrease in the respiratory control index, an increase in K+ release and stimulation of latent ATPase activity were observed with these compounds in the descending order of p-iodophenol, p-bromophenol, p-chlorophenol, p-fluorophenol and phenol. The concentrations of the phenolic compounds resulting in fifty percent inhibition of the respiratory control index and those resulting in fifty percent release of K+ ions significantly correlated with Hammett's substituent constant (sigma) and the hydrophobic binding constant (pi) of the compounds.

[Stimulative effect of chlordanes on guinea pig polymorphonuclear leukocytes].

To investigate the toxicity of chlordane, an organochlorine insecticide, effects of cis-Chlordane, trans-Chlordane, Heptachlor and Heptachlor epoxide were examined on stimulus responses of guinea pig polymorphonuclear leukocytes (PMNs). Results obtained were as follows. These chlordane-related compounds stimulated superoxide (O2-) generation, altered membrane potential and increased intracellular Ca2+ concentration ((Ca2+]i). As a significant tendency was not found in the stimulating effects of these compounds, the relationship between the effect and molecular structure of these substances remains unknown. Of these response reactions of PMN stimulated by chlordanes, stimulation of O2- generation lagged behind the others. Increase in [Ca2+]i was due to both acceleration of extracellular Ca2+ influx and Ca2+ release from intracellular pool. These results indicate that these chlordane-related compounds stimulate PMN and suggest a causal relationship between the stimulation of O2- generation by these substances and their toxicity.

The level and stability of residual catalase in cultured acatalasemic skin fibroblasts.

In an attempt to determine the level and heat stability of residual catalase in somatic cells of acatalasemic Japanese, skin fibroblasts from an acatalasemic subject were cultured, and the catalase activity of the cultured fibroblasts was compared with that of cultured normal fibroblasts. Catalase activity was determined using an oxygen electrode. The residual catalase activity in cultured acatalasemic fibroblasts was 10% of the normal. The heat stability at 55 degrees C of residual catalase in the acatalasemic fibroblasts was similar to that of normal fibroblasts.

Classification of potentially toxic chemicals based on their effects on mitochondrial respiration.

The classification of potentially toxic chemicals including environmental pollutants was made with respect to state 3 and state 4 respiration of mitochondria. The concentration of certain metals for 50% inhibition of respiratory control index (RCI; state 3/state 4) was lower than that of organic compounds tested. Various chemicals including environmental pollutants were classified into four groups by combination of effects on state 3 and state 4 respiration.

The effects of echinatin and its related compounds on the mitochondrial energy transfer reaction.

To investigate the mechanism by which various biological action of licorice root are brought about, the effects of echinatin as a small constituent of Glycyrrhiza echinata and several related compounds on mitochondrial energy transfer reactions were examined. The results obtained were as follows: 1) Echinatin, 4'-hydroxychalcone, chalcone and 3,4'-dihydroxychalcone at a low concentration cause deterioration of respiratory control and oxidative phosphorylation of isolated rat liver mitochondria. 2) Chalcone and 4'-hydroxychalcone stimulate both latent and DNP-ATPase activity of mitochondria. Echinatin inhibits DNP-ATPase activity while stimulating range latent ATPase activity in the low concentration. 3) Chalcone and 4'-hydroxychalcone induce a rapid potassium release from mitochondrial vesicles, while echinatin and 3,4'-dihydroxychalcone have lesser effect than the former two substances. From these results, it can be concluded that echinatin and several related compounds disturb the mitochondrial energy transfer reactions and membrane permeability.