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Biomedical subjects

J Hannemann

Publications and source records attributed to J Hannemann.

17 recordsLinked to original sources
PubMed1992

Nephrotoxicity of acyclovir and cis-diamminedichloroplatinum(II)--effect of co-administration in rats.

The effect of co-administration of acyclovir and cis-diamminedichloroplatinum(II) (cisplatin) on nephrotoxicity in male Wistar rats was investigated. Animals received acyclovir (15 mg/kg body weight, s.c., three times per day for 5 days) or cisplatin (5 mg/kg body weight, i.p., one single injection) or a combination of both drugs. Acyclovir plasma levels were determined after one single acyclovir s.c. injection. Urines were monitored for volume, pH, osmolality and excretion of N-acetyl-beta-D-glucosaminidase (NAG), lysozyme and total protein. Concentrations of blood urea nitrogen and plasma creatinine were determined on day 6. Renal cortical slices were monitored to assess the accumulation of weak organic bases (tetraethylammonium) and acids (p-aminohippurate). Cisplatin induced a marked increase in the excretion of NAG, lysozyme and total protein and an increase in urine volume, plasma creatinine and blood urea nitrogen. Urine osmolality and accumulation of p-aminohippurate were depressed by cisplatin. Acyclovir treatment alone caused no significant symptoms of nephrotoxicity. Co-administration did not impair renal function more than cisplatin treatment alone, excepting a slight rise in lysozyme excretion on day 6. Short-term antiviral therapy with acyclovir, concomitant to cisplatin treatment, may bring, if at all, a slightly increased nephrotoxic risk.

Acyclovir↗
PubMed1991

Iron- and ascorbic acid-induced lipid peroxidation in renal microsomes isolated from rats treated with platinum compounds.

Renal microsomes isolated on day 3 from cisplatin (CDDP, single i.p. injection, 4 or 6 mg/kg)-treated rats were monitored for their susceptibility to lipid peroxidation as compared with microsomes from rats treated with carboplatin (CBDCA, 30 mg/kg), transplatin (TDDP, 6 mg/kg) or CDDP hydrolysis products (4 or 6 mg/kg) or from control animals. Cephaloridine (1 g/kg daily for 4 days, i.p. injection) was used as a positive control. The effect of CDDP on renal microsomal glucose-6-phosphatase activity was investigated in vivo and in vitro. Following treatment with CDDP and CDDP hydrolysis products vs CBDCA and TDDP treatment, microsomes revealed an enhanced susceptibility to lipid peroxidation in a Fe2+ and/or ascorbic acid stimulation system. Increased lipid peroxidation, expressed as an increase in malondialdehyde (MDA) generation, paralleled the alterations in body and kidney weight and the elevations of plasma creatinine and blood urea nitrogen concentrations. Injection of the antioxidant N,N'-diphenyl-p-phenylenediamine (DPPD, 0.5 g/kg, i.p.) at 24 h prior to CDDP treatment abolished the increased vulnerability of renal microsomes to lipid peroxidation. In vivo, only CDDP hydrolysis products exhibited a significant inhibitory effect on renal glucose-6-phosphatase activity. In vitro, rat renal and hepatic microsomal glucose-6-phosphatase activity was decreased by CDDP both time- and concentration-dependently. Nephrotoxicity induced by CDDP and CDDP hydrolysis products might be attributable to iron-dependent lipid peroxidation and microsomes might represent target organelles on a subcellular level.

Animals↗
PubMed1990

Nephrotoxicity of cisplatin, carboplatin and transplatin. A comparative in vitro study.

The present study was designed to compare the nephrotoxicity induced by the three platinum compounds cisplatin (CDDP), carboplatin (CBDCA) and transplatin (TDDP) in vitro and to obtain information to elucidate the mechanism of platinum compound-induced nephrotoxicity. Rat or rabbit renal cortical slices were incubated for different periods of time in platinum compound-containing media (0.42 or 1.67 mM) and thereafter monitored for platinum content, tetraethylammonium(TEA) and paraaminohippurate(PAH) accumulation and gluconeogenesis. Malondialdehyde(MDA) content of slices was determined as a parameter of lipid peroxidation. Activity of glucose-6-phosphatase of rat renal microsomes was investigated after platinum-compound exposure. In all series of experiments the effect of the antioxidant N,N'diphenyl-p-phenylenediamine (DPPD) was tested. CBDCA showed no effects on all parameters of renal cell function at all concentrations and all time points investigated, except for the activity of glucose-6-phosphatase, which was slightly affected by CBDCA. CBDCA-induced MDA production was lower, compared to CDDP, which showed marked toxic effects on TEA and PAH accumulation, gluconeogenesis and glucose-6-phosphatase activity. The onset of CDDP-induced alterations was dependent on drug concentration. MDA production was reduced by DPPD. Protection against the platinum compound-induced decrease in TEA and PAH accumulation was observed after the use of DPPD. DPPD had no protective effect on CDDP-induced inhibition of gluconeogenesis and glucose-6-phosphatase, which might indicate an effect on gluconeogenesis by direct inhibition of glucose-6-phosphatase. DPPD did not alter uptake of platinum compounds in rat renal cortical slices. TDDP showed different in vitro properties compared to in vivo conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Cyclosporine A induced lipid peroxidation and influence on glucose-6-phosphatase in rat hepatic and renal microsomes.

The in vitro effect of cyclosporine A (CsA) on lipid peroxidation (LPO) in hepatic and renal microsomes (male Wistar rats) were investigated either with different CsA concentrations (0.3-1000 micrograms/ml), incubation time 3 h or for different periods of time (0.5-3.0 h) at a CsA concentration of 1000 micrograms/ml. LPO was monitored by measuring the formation of malondialdehyde (MDA) using the thiobarbituric acid assay. Furthermore the influence of CsA on the microsomal enzyme glucose-6-phosphatase was investigated. CsA caused a time- and concentration-dependent increase of LPO in hepatic and renal microsomes. The lowest CsA concentration which produced a significant increase in MDA production amounted to 1 microgram/ml for hepatic microsomes and 3 micrograms/ml for renal microsomes. Under identical experimental conditions, the MDA production by hepatic microsomes was 3 to 5 fold higher than by renal microsomes. Addition of the radical scavenger alpha-tocopherol (1 mM) to the incubation medium decreased the CsA-caused microsomal MDA production. Regarding the microsomal enzyme, CsA decreased the specific activity of glucose-6-phosphatase in a time- and concentration-dependent fashion. Compared to microsomal MDA production, higher CsA concentrations were necessary to effect on specific enzyme activity. The results suggest, that production of free radicals and subsequently lipid peroxidation could participate in cyclosporine A induced hepato- and nephrotoxicity.

Animals↗
PubMed1988

Cisplatin-induced lipid peroxidation and decrease of gluconeogenesis in rat kidney cortex: different effects of antioxidants and radical scavengers.

The present in vitro study was performed to investigate the effect of the nephrotoxic anticancer agent cisplatin (CP) on lipid peroxidation, on pyruvate-stimulated gluconeogenesis and on p-aminohippurate (PAH) accumulation in rat renal cortical slices. In addition, the inhibitory effects of the antioxidants and radical scavengers N,N'-diphenyl-p-phenylenediamine (DPPD), (+)-cyanidanol-3 or alpha-tocopherol on CP-induced lipid peroxidation and CP-induced decrease of gluconeogenesis and the inhibitory effect of DPPD on CP-induced decrease of PAH accumulation were evaluated. Slices were incubated in a CP-containing medium for different periods of time (7.5-300 min) and at different concentrations (0.025-1.5 mg/ml). Lipid peroxidation was monitored by measuring the production of malondialdehyde (MDA). Accumulation of PAH was expressed as slice to medium concentration ratio. Pyruvate-stimulated gluconeogenesis, measured as glucose production, was determined after a subsequent 60- or 15-min incubation in a pyruvate-containing, CP-free medium. CP led to a time- and concentration-dependent increase in MDA production, a time- and concentration-dependent decrease of pyruvate-stimulated gluconeogenesis and a time-dependent decrease of PAH accumulation in renal cortical slices. Decrease of gluconeogenesis preceded MDA production and decrease of PAH accumulation. Antioxidants reduced CP-induced MDA production and CP-induced decrease of accumulation of PAH, but did not reverse CP-induced decrease of gluconeogenesis. This might indicate, that the generation of free radicals and subsequent lipid peroxidation may play a role, at least in part, in inducing CP nephrotoxicity. There could be more than one mechanism of CP-induced nephrotoxicity, since decrease of gluconeogenesis preceded MDA production and decrease of PAH accumulation and could not be inhibited by antioxidants and radical scavengers.

Animals↗
PubMed1988

Inhibition of lactate-dehydrogenase by cisplatin and other platinum-compounds: enzyme leakage of LDH is not a suitable method to measure platinum-compound-induced kidney cell damage in vitro.

The effects of three platinum-compounds on the activity of hog muscle lactate-dehydrogenase (LDH), cytosolic LDH released from rat renal cortical slices and cytosolic LDH isolated from rat kidney cells were investigated. In vitro, cisplatin inhibited the activity of LDH in a concentration-dependent manner. At a concentration of 0.25 mg/ml, cisplatin, transplatin and cisplatin-hydrolysis-products inhibited the activity of LDH time-dependently. These observations make it doubtful to use LDH-enzyme leakage experiments to demonstrate damage of kidney cells by platinum-compounds. The nonnephrotoxic compound transplatin had an enhanced inhibitory effect on the activity of LDH compared to the nephrotoxic compounds cisplatin or cisplatin-hydrolysis-products (transplatin greater than cisplatin greater than cisplatin-hydrolysis-products). Thus, LDH-enzyme inhibition seems not to be related to the nephrotoxicity of cisplatin.

Animals↗
PubMed1985

Cephaloridine-induced lipid peroxidation initiated by reactive oxygen species as a possible mechanism of cephaloridine nephrotoxicity.

Rat kidney microsomes reduced cephaloridine when incubated anaerobically with NADPH. Superoxide anion was generated in a concentration- and time-dependent manner when cephaloridine was incubated with rat kidney microsomes. Cephaloridine increased the in vitro peroxidation of rat kidney microsomal lipids in a concentration- and time-dependent manner. Cephaloridine-induced lipid peroxidation was inhibited by a combination of superoxide dismutase and catalase, by the hydroxyl radical scavengers, mannitol, (+)-cyanidanol-3 and by the singlet oxygen scavenger histidine in a concentration-dependent manner. It is proposed that cephaloridine nephrotoxicity may occur through the transfer of an electron from reduced cephaloridine to oxygen and subsequent formation of the superoxide anion, hydrogen peroxide, the hydroxyl radical and singlet oxygen. These activated oxygen species then are very likely to react with membrane lipids to induce lipid peroxidation and nephrotoxicity.

Anaerobiosis↗