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S J Kohlhepp

Publications and source records attributed to S J Kohlhepp.

25 records · Page 2Linked to original sources
PubMed1984

Nephrotoxicity of the constituents of the gentamicin complex.

Commercial gentamicin C is a mixture of gentamicin C1, C1a, and C2. The nephrotoxicity of each of these constituents was compared with that of the gentamicin complex. After seven days the mean creatinine level in serum was 0.8 mg/dl in rats given C2 and 0.5 mg/dl in rats given C1, C1a, or the gentamicin complex (P less than .001). Toxicity attributable to C1a was not detected until day 14, and only minimal toxicity was noted in C1-treated rats after 21 days. Nephrotoxicity caused by the gentamicin complex was similar to that caused by C2. By a new high-pressure liquid chromatographic method, the renal concentration of C1, C1a, and C2 was quantified in rats given the gentamicin complex. The results indicated an early, preferential renal accumulation of C2. Subsequently, the C2 content of 12 commercial lots of gentamicin C was measured. The C2 concentration ranged from 12.4 to 20.1 mg/ml. In short, experimental nephrotoxicity from gentamicin C is largely the result of the C2 constituent, and the concentration of this constituent in commercial preparations of gentamicin varies by as much as 7.7 mg/dl.

Animals↗
PubMed1984

The influence of aminoglycoside antibiotics on the in vitro function of rat liver ribosomes.

There are few studies of the influence of aminoglycoside antibiotics on the ribosomes of higher eukaryotic organisms. To this end, cytoplasmic ribosomes were prepared from rat liver. In vitro, poly(U)-directed ribosome protein synthesis was studied in the presence and absence of selected aminoglycosides. Misreading of poly(U) was also assessed. Consistent with earlier studies using different sources of ribosomes, paromomycin inhibited cell-free protein synthesis and caused poly(U) misreading. In contrast to the findings of other studies in cell-free ribosomes of eukaryotic organisms, netilmicin, tobramycin, and neomycin were most active in inhibiting protein synthesis, and gentamicin C2 and neomycin caused appreciable misreading. Thus the previous suggestion that a paromamine fragment (found in paromomycin) might be a structural requirement for in vitro inhibition of protein synthesis and misreading is not substantiated by the results in rat liver ribosomes. Commercial gentamicin C is a mixture of gentamicins C1, C1a, and C2. Despite nearly identical chemical structures, the three constituents displayed greatly different propensities for inducing poly(U) misreading. C2 was the most active, followed by C1a. In summary, selected aminoglycoside antibiotics caused inhibition and mistranslation of poly(U) messenger in an in vitro ribosome system prepared from rat liver. These effects were not limited to paromamine-containing aminoglycoside antibiotics. Gentamicin C2 caused much more poly(U) misreading than the other two constituents of the gentamicin C complex.

Aminoglycosides↗
PubMed1982

Gentamicin does not chelate calcium.

The influence of increasing gentamicin concentrations on ionized calcium concentration was determined in pH-controlled, phosphate-buffered saline and normal human serum with an ion-specific calcium electrode. No evidence of calcium chelation was found.

Calcium↗
PubMed1980

Amikacin nephrotoxicity in the rat.

When amikacin was administered to Fischer rats at a dose of 120 mg/kg/day for up to 14 days, renal proximal tubule cells became vacuolated, but BUN and creatinine remained normal. Renal cortical drug levels rose steadily throughout the treatment period. When, in a second trial of the same duration, the drug dose was tripled, focal proximal tubular necrosis, then regeneration, occurred and the animals became azotemic. Tissue drug concentrations peaked and began to decline during the treatment period, having reached levels more than three times higher than achieved at the lower dose. Ultrastructural changes were similar to those observed with other aminoglycosides. The results indicate that amikacin is less nephrotoxic than gentamicin and more toxin than tobramycin and netilmicin in the Fischer rat.

Amikacin↗
PubMed1979

Synthesis and identification of products derived from the metabolism of the carcinostatic 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea by rat liver microsomes.

Liver microsomal metabolism of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea in the presence of reduced nicotinamide adenine dinucleotide phosphate and O2 was shown to produce seven metabolites that included the parent urea. A cytochrome P-450-dependent monohydroxylation of the cyclohexyl ring occurred in 3 positions, cis-3, trans-3, and cis-4, and on the methyl group to form a trans-4-hydroxymethyl derivative. In addition, monohydroxylation of the 2-chloroethyl carbon attached to the N-1 urea nitrogen yielded an alpha-hydroxy metabolite. A ring-hydroxylated derivative remained unidentified while the structures of all other such derivatives were established by comparison with compound synthesized, purified by high-pressure liquid chromatography, and characterized by mass spectral and nuclear magnetic resonance analyses. It was tentatively concluded that some parent urea is formed by a cytochrome P-450 dependent reaction because of a requirement for reduced nicotinamide adenine dinucleotide phosphate and inhibition by CO. Microsomes from rats pretreated with phenobarbital showed about a 3-fold increase in hydroxylation rate while phenobarbital-treated mice microsomes were induced 8-fold. However, in both species, the induced hydroxylation rate was about 4 nmol/min/mg protein. When microsomes from phenobarbital-induced rats were used, a mixture of 80% CO:20% O2 decreased the rate of formation of all metabolites to 14% of that in 80% N2:20% O2.

Animals↗
PubMedDate not supplied

Urinary metabolites of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea.

Urinary metabolites of ring 14C-labeled 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (Methyl CCNU) from rats have been isolated and characterized by high-performance liquid chromatography and mass spectrometry. About 44% of the cyclohexyl moiety of CCNU was excreted in 24 hr and included approximately 10% of the excreted dose as free amines and 40% as conjugates that could be converted to amines by hydrolysis. Amine composition of free base plus hydrolyzable conjugates was 55% hydroxycyclohexylamines (3-trans, 3-cis, 4-cis, and 4-trans) and 30% cyclohexylamine. This strongly supports previous studies which indicated that CCNU is largely hydroxylated in vivo as well as in vitro. Rats pretreated with phenobarbital excreted high relative amounts of cis-4-hydroxy derivatives (41%), again showing a high degree of correlation between in vitro and in vivo results. Treatment of urine with beta-glucuronidase gave no apparent increase in free amines. However, sulfatase was about 25% as effective as alkaline hydrolysis for releasing free amines from whole urine. Major urinary metabolites were found to have m.w. of about 629, 413, 329, and 243 and represented 55%, 20%, 20%, and 5% of total excreted 14C, respectively. It was concluded that the higher m.w. metabolites may be conjugates of peptides possibly derived from active site-directed inactivation of specific enzymes. Previous work has shown that enzymes such as chymotrypsin and glutathione reductase are inhibited by isocyanates in this manner. Hydroxylated metabolites of Methyl CCNU had a pattern similar to that of CCNU. The major free (12%) and conjugated amine (54%) metabolites of Methyl CCNU in the urine in decreasing order of quantity present were cis-3-hydroxy-trans-4-methylcyclohexylamine, trans-4-methylcyclohexylamine, trans-4-hydroxymethylcyclohexylamine, and trans-3-hydroxy-trans-4-methyl-cyclohexylamine.

Amines↗