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Biomedical subjects

B M Tune

Publications and source records attributed to B M Tune.

At least 55 records · Page 3Linked to original sources
PubMed1982

Prevention of cephalosporin nephrotoxicity by other cephalosporins and by penicillins without significant inhibition of renal cortical uptake.

Prevention of cephalosporin nephrotoxicity in animal models by probenecid or p-aminohippurate requires treatment regimen that produce sustained inhibition of cortical accumulation of the toxic antibiotic. In contrast, cephaloridine nephrotoxicity in the rabbit can be prevented by a limited single dose of cephalothin. In the present report further studies were done in which it was demonstrated that cephaloridine nephrotoxicity can be prevented by doses of other cephalosporins or penicillins that produce little or no reduction of the cortical concentrations of toxic cephalosporin. More limited studies revealed similar protection by benzylpenicillin against cephaloglycin, also without reduction of cortical concentration. Finally, similar limited-dose administration of penicillin eliminated tha additive toxicity of cefazolin and neomycin. This selective protection against the toxic cephalosporins by the less toxic or nontoxic cephalosporins and by the penicillins, without inhibition of overall cortical accumulation of the toxic antibiotic, may provide a subcellular probe for the study of the molecular basis of cephalosporin nephrotoxicity.

Animals↗
PubMed1982

Effects of ureteral obstruction on the toxicity of cephalosporins in the rabbit kidney.

The nephrotoxicity of the cephalosporin antibiotics is closely related to their secretory transport into the proximal tubular cell at the antiluminal (blood) site. The present report describes the effects of transient ureteral obstruction, which increases intracellular concentrations of secreted organic anions, on the cortical uptake and the proximal tubular toxicity of several cephalosporins given in mildly toxic doses. Unilateral obstruction for 1-2 hr increased the cytotoxicity of cephaloglycin and cefaclor, both of which are rapidly secreted across the tubular cell, but not of cephaloridine, which undergoes minimal secretion. Bilateral obstruction significantly increased the toxicity of cefaclor, which is rapidly secreted, but not of cefazolin, which is slowly secreted. Finally, there was a further augmentation of the effects of obstruction on the toxicity of cefaclor by a minimally toxic pretreatment regimen of neomycin. Studies of cortical antibiotic concentrations support the conclusion that the effects on toxicity are largely the result of the increased intracellular accumulation that results from obstruction.

Animals↗
PubMed1980

Cephalosporin nephrotoxicity. Transport, cytotoxicity and mitochondrial toxicity of cephaloglycin.

The cephalosporin antibiotics are secreted by the renal organic anion transport system. Several of them, including cephaloridine and caphaloglycin, produce a proximal renal tubular necrosis which can be prevented by inhibitors of organic anion transport. Although cephaloridine is actively transported into the tubular cell at the antiluminal side like other cephalosporins, it undergoes a limited rate of subsequent movement across the luminal membrane into the tubular fluid. The very high intracellular concentrations that result from this unusual process are believed to contribute to the significant toxicity of cephaloridine. Cephaloglycin is at least as toxic, but is secreted more normally across the proximal tubular cell. For this reason, studies were undertaken to evaluate the cytotoxicity, cortical concentrations and mitochondrial respiratory toxicity of this cephalosporin in the rabbit kidney. A dose of 100 mg/kg of caphaloglycin produces as much damage as does 150 mg/kg of cephaloridine. The steady-state cortex-to-serum concentration ratio of cephaloglycin, 5.6 +/- 0.8 S.E. (n = 5), is significantly lower (P < .001) than the corresponding measurement for cephaloridine, 121.9 +/- 1.2 (n = 7), and is not significantly different from that of p-aminohippurate. In further contrast to cephaloridine, the cortical concentration of cephaloglycin declines substantially, from 930 +/- 112 (n = 5) to 297 +/- 46 (n = 5) micrograms/g of wet tissue, over the first hour after cessation of infusion (P < .001) and is essentially unmeasurable by 2 hr. The fact that there is not the prolonged intracellular trapping of cephaloglycin that is seen with cephaloridine leads to the conclusion that the former must either bind more strongly to its target receptor or produce a more irreversible insult than does the latter cephalosporin. Several lines of evidence are presented which support this hypothesis. The most important of these are that cephaloglycin is cumulatively nephrotoxic, whereas cephaloridine is not, and that the in vivo toxicity of cephaloglycin to cortical mitochondria, unlike that of cephaloridine, is not significantly diminished by the mitochondrial isolation process. This very early in vivo respiratory toxicity of cephaloglycin and the lack of significant similar toxicity of cephalexin provide new evidence that the effect on mitochondria may have a pathogenic role in cephalosporin nephrotoxicity.

Animals↗
PubMed1979

Effect of cephaloridine on respiration by renal cortical mitochondria.

The effects of the nephrotoxic antibiotic, cephaloridine, were studied in rabbit renal cortical mitochondria. Mitochondria from animals which received a toxic dose of 200 mg/kg of the drug 2 hr before sacrifice (in vivo exposure) had significantly decreased rates of respiration compared with those of mitochondria from untreated control animals. In vitro exposure of normal mitochondria to cephaloridine resulted in a qualitatively similar decrease of respiration. With both in vivo and in vitro exposure, inhibition was greatest with ADP-dependent respiration using succinate as substrate. The severity of in vitro inhibition of respiration showed some correlation to the degree of in situ cytotoxicity at different cephaloridine concentrations. The results are in agreement with the finding of a reduction of rates of respiration in renal tubule suspensions after similar in vivo and in vitro exposure to cephaloridine. These studies provide preliminary evidence that cephaloridine nephrotoxicity may be mediated through an inhibitory effect on mitochondrial respiration.

Adenosine Diphosphate↗
PubMed1979

Interaction of aminoglycosides and cephaloridine in the rabbit kidney.

Toxic doses of aminoglycosides augment organic anion transport in the rat kidney. Studies in rabbits and guinea pigs have shown that the nephrotoxicity of cephalosporins is closely related to their active transport by the organic anion carrier in the proximal renal tubule. We have examined the effects of the aminoglycosides neomycin and gentamicin on cephaloridine transport and cytotoxicity in the rabbit kidney. There was no effect of these aminoglycosides on renal cortical cephaloridine uptake. In several regimens of combined administration, there was also no additive nephrotoxicity of the aminoglycosides and cephaloridine, even though some degree of tubular necrosis was seen in the single drug control groups in each protocol. These results are in agreement with those of studies in the rat and provide evidence that the cellular mechanisms of nephrotoxicity of the cephalosporins and aminoglycosides are not closely related.

Aminoglycosides↗
PubMed1975

Relationship between the transport and toxicity of cephalosporins in the kidney.

Large doses of cephaloridine cause acute necrosis of the proximal renal tubule that can be prevented by probenecid and other organic anions. Although there is little or no net secretion of cephaloridine by the mammalian kidney, the degree of cephaloridine uptake by the cortex of the rabbit kidney is substantial; this uptake is also prevented by probenecid and other organic anions. Cortical concentrations of cephaloridine were measured in control and probenecid-treated animals of different mammalian species. Evidence of cephaloridine trnsport was found in the guinea pig and the rat as well as in the rabbit. The degree of reduction of cortex-to-serum ratios by probenecid (control cortex-to-serum minus probenecid-treated cortex-to-serum ratios) correlated with the sensitivity to the nephrotoxicity of the drug. This degree or reduction was greatest in the rabbit, intermediate in the guinea pig, and least in the rat. In addition, the newborn rabbit, which is more resistant to the toxicity of cephaloridine than the adult, also had significantly lower cortical concentrations of cephaloridine. Finally, the acute tubular necrosis produced by extremely large doses of cefazolin in the adult rabbit was prevented by probenecid. It was concluded (1) that the nephrotoxicity of cephaloridine is related to its renal cortical transport with high intracellular concentrations of drug; and (2) that this relationship between transport and toxicity exists for cefazolin as well, although the toxicity is of a different order of magnitude. The unusual mechanism of cephaloridine transport in the proximal tubule was contrasted with that of the other cephalosporins in an attempt to explain its greater degree of nephrotoxicity.

Acute Kidney Injury↗