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G H Hottendorf

Publications and source records attributed to G H Hottendorf.

At least 19 recordsLinked to original sources
PubMed1997

Poly-l-aspartic acid protects cultured human proximal tubule cells against aminoglycoside-induced electrophysiological alterations.

Cultured human proximal tubule cell monolayers maintained on permeable supports were treated simultaneously with the aminoglycoside antibiotic, gentamicin, and poly-L-aspartic acid (PAA), an inhibitor of aminoglycoside nephrotoxicity. Following 4 days of exposure, cell monolayers were placed into Ussing chambers to allow monitoring of transepithelial electrical properties. For each of the three cell isolates examined, aminoglycoside-induced alterations in electrogenic transport, reflected by changes in short-circuit current (Isc), as well as alterations in paracellular properties, indicated by changes in transepithelial electrical resistance (RT), were diminished in the presence of PAA. Alterations resulting from selective basolateral exposure to gentamicin were unchanged in the case of apically applied PAA and attenuated only when PAA acid was added basolaterally. This is the first demonstration of PAA inhibition of aminoglycoside-induced cellular alterations involving human cells.

Anti-Bacterial Agents↗
PubMed1995

Tobramycin gender-related nephrotoxicity in Fischer but not Sprague-Dawley rats.

Published reports suggest a gender-related difference in susceptibility to the nephrotoxicity of gentamicin which may also be strain-related in rats. However, certain ambiguities exist in the results obtained with the functional and morphologic determinants of nephrotoxicity used in these studies. Within the same experimental protocol we examined the potential gender-related differences in tobramycin nephrotoxicity in age-matched male and female rats of both the Sprague-Dawley (SD) and Fischer (F344) strains. Equal numbers of both genders were dosed at 30 mg/kg (F344) and 90 mg/kg (SD) twice daily for 9 days. Results of BUN, serum creatinine, whole body weight change and histologic score comparisons (P < 0.05) indicate that male F344 rats are more sensitive to tobramycin nephrotoxicity than F344 females but this gender-related susceptibility was not observed in SD rats.

Animals↗
PubMed1995

Renal brush border membrane vesicle aminoglycoside binding and nephrotoxicity.

The in vitro binding affinity (KD) of aminoglycoside (AG) antibiotics to renal brush border membranes (BBM) has previously been correlated with several variables (sex, age and toxic potential of specific antibiotics) influencing in vivo AG nephrotoxicity in rats. The initial intent of our study was to extend this correlation to the in vivo difference in sensitivity to tobramycin recently observed between two strains of rats. However, the tobramycin binding affinity (KD) failed to correlate with the in vivo strain difference in AG nephrotoxicity. In addition, a comparison of BBM vesicle tobramycin binding affinity between sexes failed to correlate with an earlier report of in vivo gender differences in tobramycin nephrotoxicity. Comparison of binding capacities for male Sprague-Dawley rats and male Fischer rats yielded the only instance where binding parameters correlated with the reports of in vivo nephrotoxicity comparisons. Preliminary examinations of tobramycin binding using renal BBM vesicles derived from a single human kidney revealed binding kinetics and characteristics similar to rat BBM binding. Tobramycin binding was rapid and saturable for each type of BBM vesicle preparation. Scatchard analyses indicated low affinity, high capacity binding characteristics, as well as a single binding site in each case. Polyaspartic acid, which blocks in vitro BBM tobramycin binding as well as in vivo nephrotoxicity in rats, also blocked binding of tobramycin to human BBM vesicles. These data indicate that AG binding is qualitatively similar for rat and human BBM vesicle preparations. However, examination of the quantitative kinetic aspects of AG binding to BBM vesicles (KD and binding capacities) suggests that these parameters may not be critical determinants in the pathogenesis of Ag nephrotoxicity.

Aminoglycosides↗
PubMed1994

Effects of polyaspartic acid on pharmacokinetics of tobramycin in two strains of rat.

To provide insight into polyaspartic acid nephroprotection and differences in aminoglycoside renal toxicity between two rat strains, the single-dose pharmacokinetics of tobramycin was examined in the presence and absence of polyaspartic acid. Following a single subcutaneous 6.5-mg/kg dose of tobramycin alone, higher aminoglycoside concentrations were measured in Sprague-Dawley rats than in Fischer rats (P < 0.05). Simultaneous administration of polyaspartic acid (50 mg/kg) and tobramycin did not alter the concentrations of tobramycin in serum. The amount of tobramycin in renal tissue and the amount recovered in urine over a 24-h period were greater in both rat strains when tobramycin and polyaspartic acid were given concomitantly. In summary, polyaspartic acid did not alter the concentrations in serum achieved after a single dose of tobramycin in two different rat strains but did result in higher renal concentrations and greater urinary excretion of tobramycin.

Animals↗
PubMed1993

Lack of in vivo evidence of a cytochrome P450 metabolite participating in aminoglycoside nephrotoxicity.

Recent in vitro evidence has suggested that the cytotoxicity of aminoglycosides may be mediated by a metabolite generated by the hepatic cytochrome P450 drug-metabolizing system. This postulate has been tested by pretreating rats with cobalt protoporphyrin IX (CoP) to suppress hepatic P450 levels prior to administration of gentamicin. CoP pretreatment was observed to suppress antipyrine clearance markedly but not to alter gentamicin nephrotoxicity.

Animals↗
PubMed1991

Differences in the sensitivity of Fischer and Sprague-Dawley rats to aminoglycoside nephrotoxicity.

Because of the anecdotal but unconfirmed inferences of the greater sensitivity of Fischer rats to aminoglycoside nephrotoxicity, an intrastudy comparison of the sensitivity of Fischer and Sprague-Dawley rats to aminoglycoside nephrotoxicity was undertaken. Tobramycin was administered at 3 dose levels to each strain of rat for 10 days. Nephrotoxicity was evaluated utilizing a spectrum of both functional and morphologic assessments of renal proximal tubular integrity. The results confirm that the aged matched Fischer rat is more sensitive to the nephrotoxic effect of tobramycin than the Sprague-Dawley. These results also suggest an opportunity to study quantitative and perhaps qualitative differences in pathogenic mechanisms of aminoglycoside nephrotoxicity in a single laboratory animal species.

Animals↗
PubMed1988

Comparative toxicities of cephalosporin antibiotics in a rabbit kidney cell line (LLC-RK1).

The rabbit kidney cell line LLC-RK1 was tested for its ability to discriminate the toxicities of six cephalosporin antibiotics according to their in vivo nephrotoxic potentials in rabbits. With the exception of cephalothin, which was markedly toxic to kidney cells in vitro, a good correlation between in vitro toxicity and in vivo nephrotoxicity was obtained, yielding the following toxicity rank order: ceftazidime less than cefazolin approximately cefoperazone less than cephaloglycin approximately cephaloridine. The addition of a kidney microsomal S9 fraction to the cell cultures desacetylated cephalothin as occurs in vivo and detoxified this antibiotic, providing it with the proper toxicity relative to the other cephalosporins. When compared with parent structures, desacetylated derivatives of other cephalosporins such as cephapirin were similarly found to be less toxic to LLC-RK1 cells. The acetylated cephalosporin cephaloglycin was not detoxified by the kidney S9 fraction and was desacetylated three to four times slower than cephalothin by renal esterases. Thus, the rate and extent of desacetylation of cephalosporins may play a role in their in vivo nephrotoxic potential. Our results further suggest that LLC-RK1 cells will provide a useful model for evaluating the potential nephrotoxicity of new cephalosporin antibiotics before in vivo studies.

Animals↗
PubMed1987

An in vitro model for assessing muscle irritation due to parenteral antibiotics.

A rat skeletal muscle cell line (L6) was evaluated for its potential to discriminate the muscle-irritating liability of several parenteral antibiotics. The cells were exposed to clinical as well as diluted concentrations of tetracycline, cefoxitin, cephalothin, carbenicillin, erythromycin, ceforanide, cefazolin, and cephaloridine for 1 hr. Control cells were similarly exposed to culture media for 1 hr. The cells were subsequently assayed for their content of the muscle-associated enzyme creatine kinase (CK). Depletion of CK relative to control cultures was utilized as the index of cellular damage. The results of these analyses revealed the following ranking of antibiotic toxicity to L6 muscle cells: tetracycline, erythromycin, cefoxitin greater than cephalothin, carbenicillin greater than ceforanide, cefazolin greater than cephaloridine. The relative order of toxicity of these antibiotics to L6 cells is in good agreement with their reported muscle-irritating liability in man. The correlation between the results obtained in vitro and the irritancy data in vivo suggests that this model may be a useful adjunct to in vivo testing of parenteral antibiotics for muscle-irritation liability.

Animals↗
PubMed1987

Single-dose and multiple-dose intravenous toxicity studies of BMY-25282 in rats.

Single-dose and multiple-dose (daily X 5 and weekly X 5) intravenous toxicity studies in rats were conducted to determine the possible acute and delayed toxicity of BMY-25282 (7-N-(dimethylaminomethylene) mitomycin C), a potential anticancer drug. Rats in the single-dose study received either 0.05, 0.25, or 0.50 mg/kg (0.3, 1.5, or 3.0 mg/m2) of BMY-25282; rats in the daily X 5 multiple-dose study received doses of 0.005, 0.025, or 0.050 mg/kg (0.03, 0.15, and 0.3 mg/m2) of BMY-25282 once each day for 5 days; and rats in the weekly X 5 multiple-dose study received 0.05 mg/kg of BMY-25282. All doses were in 0.1% Pluronic F-68 diluent. Acute toxicities included gastrointestinal epithelial necrosis, myelosuppression, and splenic lymphoid depletion in the high and intermediate dose groups in the single-dose study and myelosuppression in the high dose group of the daily X 5 multiple-dose study. One death in a high dose male of the single-dose study was attributed to acute gastrointestinal and lymphoid toxicity. Between the interim necropsy on Day 5 or 9 and termination of the 9-week dose-free observation period, 9/20 rats of the high and intermediate dose groups of the single-dose study and 4/10 high dose rats in the daily X 5 multiple-dose study died, primarily due to hydrothorax and congestive heart failure caused by delayed, drug-related myocardial degeneration. The most prominent drug-related histopathologic changes observed in rats of both the single-dose study and the daily X 5 studies were myocardial degeneration (cardiomyopathy), glomerulopathy with tubular degeneration, and necrotizing arteritis. These three changes, observed at 0.5 and 0.25 mg/kg in the single-dose study and at 0.05 mg/kg/day in the multiple-dose (daily X 5) study, were delayed in onset and irreversible. Drug-related tubular degeneration and slight glomerulopathy were observed in male BMY-25282-treated rats in the weekly X 5 study, but cardiotoxicity, pulmonary arteritis, hydrothorax, and lethality were not observed. The diluent, Pluronic F-68, was not associated with any morphologic or clinico-pathologic changes. A single-dose of 0.05 mg/kg or 5 daily doses of 0.025 and 0.005 mg/kg of BMY-25282 were considered nontoxic doses in rats. A cumulative dose of 0.25 mg/kg, which caused cardiotoxicity in the daily X 5 study, was not cardiotoxic in the weekly X 5 study. These results indicate that the delayed cardiotoxicity of BMY-25282 is schedule dependent.

Animals↗
PubMed1987

Role of desacetylation in the detoxification of cephalothin in renal cells in culture.

The toxicity of three cephalosporin antibiotics to rabbit kidney cells in culture was compared to their known nephrotoxic potential in vivo (cephaloridine greater than cefazolin greater than cephalothin). While cephalothin is considered to be a relatively nonnephrotoxic cephalosporin when administered to many species including humans and rabbits, in several in vitro systems involving rabbit renal tissue, cephalothin was comparatively more toxic than anticipated based on in vivo data. Cephalothin is extensively desacetylated in rabbits to a less microbiologically active metabolite, desacetylcephalothin. When a microsomal S9 fraction from rabbit kidney was added to the in vitro assay in cultured rabbit renal cells, cephalothin was desacetylated and its toxicity to kidney cells was reduced. The addition of S9 in vitro provided a toxicity ranking of the cephalosporins that correlated with their known in vivo nephrotoxic potentials (cephaloridine greater than cefazolin greater than cephalothin). The in vitro detoxification of cephalothin by S9 was blocked by the coadministration of the esterase inhibitor, aminocarb. Desacetylcephalothin was relatively nontoxic to rabbit renal tissue in vitro. These results suggest that the desacetylation of cephalothin in vivo represents a previously unrecognized mechanism of detoxification of this cephalosporin antibiotic. Furthermore, this mechanism of detoxification may be applicable to other acetylated cephalosporins.

Acetylation↗
PubMed1987

Correlation between renal membrane binding and nephrotoxicity of aminoglycosides.

The kinetics of aminoglycoside binding to renal brush border and basolateral membrane vesicles from rat renal cortex were studied by using [3H]amikacin. [3H]amikacin binding to renal membranes was found to be a rapid, saturable process with a fourfold greater affinity for basolateral membranes than for brush border membranes (Kd basolateral = 607 microM; Kd brush border = 2,535 microM). Renal membranes prepared from immature rats (2 to 3 weeks old) exhibited a significantly lower affinity compared with membranes from adults (Kd basolateral = 2,262 microM; Kd brush border = 6,216 microM). Additionally, the inhibitory behavior of several aminoglycosides versus [3H]amikacin binding to brush border membranes revealed the following rank order of potency: neomycin greater than tobramycin approximately gentamicin approximately netilmicin greater than amikacin approximately neamine greater than streptomycin. The relative insensitivity of immature rats to aminoglycoside-induced nephrotoxicity in vivo and the comparative nephrotoxicity of the various aminoglycosides suggest that renal membrane-binding affinity is closely correlated to the nephrotoxic potential of these antibiotics.

Aminoglycosides↗
PubMed1986

Pain on injection and muscle irritation: a comparison of animal models for assessing parenteral antibiotics.

Pain on injection due to parenteral administration of cephaloridine, cephalothin, and cefoxitin with or without 1% lidocaine was examined in a rat paw-lick model and the results compared with those obtained in a rabbit intramuscular model of irritation. In both animal models, cephaloridine caused similar or a slightly greater response than sterile water. Conversely, cefoxitin and cephalothin caused a much greater reaction than water in both models. The only major difference in the rankings by the two models was with formulations in which an anesthetic agent was incorporated into the diluent. As expected, the presence of a local anesthetic masked pain on injection but not muscle damage. The rat paw-lick model is an alternative to the traditional rabbit muscle irritation model for rapidly assessing both pain on injection and muscle irritation of parenteral formulations.

Animals↗
PubMed1986

Aminoglycoside nephrotoxicity.

Aminoglycosides are life-saving antibiotics in patients with gram negative sepsis. Renal dysfunction occurs in approximately 10% of all clinical courses of aminoglycosides. Because of close pharmacokinetic and toxicologic similarities, rats are excellent human surrogates for comparing the nephrotoxic potentials of these antibiotics. Comparisons in rats are also more sensitive than clinical comparisons due to the insensitivities of clinical renal function tests, the confounding influences present in seriously-ill patients and the inability to make morphologic comparisons in the clinic. The pathogenesis of aminoglycoside nephrotoxicity is still evolving despite extensive world-wide investigations. However, these investigations have facilitated the identification of several inhibitors of aminoglycoside nephrotoxicity. The clinical usefulness of these inhibitors must still be established.

Age Factors↗
PubMed1986

Functional-morphologic correlations in assessing renal toxicity.

Evaluation of the correlation of functional and morphologic assessments of renal toxicity are obviously important to the toxicologic pathologist. All clinical assessments of the nephrotoxicity of drugs are based on renal function tests while preclinical assessments involve functional and/or morphologic assessments in laboratory animals. However, there are considerable concerns about the sensitivity of the tests available to monitor renal function. In an attempt to assess the relative sensitivity of functional and morphologic indicators of nephrotoxicity, three data bases were examined for their ability to rank the nephrotoxicity of the three most widely used aminoglycosides. The functional data base was comprised of reported comparative clinical trial data and the morphologic data base was composed of preclinical studies available in the literature which used morphology as the basis of comparison. A third data base involved biochemical or mechanistic comparisons of aminoglycosides and represented data that was not based on clinical function test results or morphologic analysis. When these three data bases were compared, it was obvious that clinical function tests could not discriminate between the nephrotoxic liability of the three aminoglycosides. The preclinical renal morphology data base and the biochemical mechanistic data base both clearly discriminated the drugs one from another and ranked the three aminoglycosides in the same order. Several conclusions were suggested by these results. Comparisons of the nephrotoxic potentials of drugs in patients utilizing available renal function tests may be inconclusive primarily because clinical renal function tests are insensitive. Comparisons of the nephrotoxic liabilities of drugs in laboratory animals utilizing morphologic assessments of renal tissue damage may be the best comparison available.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoglycosides↗
PubMed1986

Inhibition of renal membrane binding and nephrotoxicity of aminoglycosides.

The initial event in the renal tubular reabsorption of nephrotoxic aminoglycosides involves binding to brush border membranes. This primary event was measured in renal brush border membrane vesicles prepared from rat renal cortex utilizing [3H]gentamicin. In order to gain structure-activity information regarding this interaction the effect of substances having chemical similarities to aminoglycosides (sugars, polyamines and amino acids) on gentamicin binding to brush border membranes was determined. Polyamino acids were found to possess the greatest inhibitory potency. In addition to polymers of cationic amino acids (lysine, ornithine, arginine and histidine), polymers of neutral (asparagine) and acidic (aspartic and glutamic acid) amino acids also exhibited inhibition of the membrane binding of gentamicin. Inasmuch as inhibition of renal membrane binding has the potential to decrease aminoglycoside nephrotoxicity, several polyamino acids that inhibited membrane binding were tested in vivo for potential protective activity vs. gentamicin- and amikacin-induced nephrotoxicity. Polyasparagine90 and polyaspartic acid100 inhibited gentamicin and amikacin nephrotoxicity completely when coadministered to rats with the aminoglycosides. Polylysine20 provided complete and partial inhibition of gentamicin and amikacin nephrotoxicity, respectively. Whereas in vivo distribution studies revealed that cortical levels of [3H]amikacin were elevated slightly by the coadministration of polyaspartic acid, brush border and basolateral membranes contained significantly lower levels of the aminoglycoside (46 and 41% inhibition, respectively). These results question the role of charge per se in the binding of aminoglycosides to renal membranes and further confirm the importance of membrane binding in the pathogenesis of aminoglycoside nephrotoxicity.

Amikacin↗
PubMed1985

Review and evaluation of the NCI/NTP carcinogenesis bioassays.

A comparison of the carcinogenesis bioassay results obtained by the National Cancer Institute (NCI) and the National Toxicology Program (NTP) indicates that approximately one-half of the bioassays directed by both institutions were positive for carcinogenicity. The more recent 85 bioassays completed by NTP reveal a higher proportion of studies interpreted as demonstrating no evidence of carcinogenicity than represented in the initial 198 bioassays conducted by NCI. Of the 100 NCI bioassays that were not positive for carcinogenicity 3 (3%) were classified in the category of "no evidence for carcinogenicity in two animal species." Of the 43 NTP bioassays that were not positive for carcinogenicity 36 (84%) were placed in the category of "no carcinogenic effects." The reason for this shift from a 33:1 positive to negative ratio in the NCI bioassays to an approximately 1:1 ratio in the NTP bioassays appears to be a difference in interpretation of the adequacy of the testing. For example, 6 of the 36 NTP negative bioassays involved testing in only one species. Uniform criteria for concluding that a bioassay is negative must be developed and the results of all existing and future carcinogenesis bioassays must be interpreted with these exclusive criteria. Other bioassay problems are explored, including the incomplete validation of the carcinogenesis bioassay protocol by confirmatory results with positive and negative reference agents, the apparent lack of bioavailability data for some orally administered negative compounds, the continued use of mouse hepatic neoplasia as a single discriminating parameter, the variability in the inter- and intrastudy incidence of spontaneous tumors, and the continued reliance on the maximum tolerated dose.

Animals↗