Nephrotoxicity of antitumoral agents.
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Animals↗
Biomedical subjects
G Viotte
Publications and source records attributed to G Viotte.
Haematotoxicity of doxorubicin and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and of their association in rats.
Doxorubicin is an anthracycline widely used in the treatment of leukaemias, lymphomas and solid tumors. Doxorubicin cannot pass into the cerebrospinal fluid. Nitrosoureas are known to be lipophilic and to be able to penetrate the blood-brain barrier. CCNU is a nitrosourea used to treat Hodgkin's disease, brain tumors and other solid tumors. The authors have previously reported on the nephrotoxicity and hepatotoxicity of these drugs; the present paper reports their findings on haematotoxicity in female Wistar rats. In one group 40 rats received 10 mg/kg doxorubicin. In a second group 40 rats received 20 mg/kg CCNU, and a further 40 rats received 50 mg/kg CCNU. In a third group 60 rats received the association doxorubicin 10 mg/kg plus CCNU 20 mg/kg. Blood counts were performed on days 4, 8, 15, 21 and 28 after treatment. Leucopenia and severe thrombocytopenia were noted after doxorubicin administration. A biphasic decrease in the leucocyte count was observed after CCNU treatment. More severe alterations were observed when doxorubicin and CCNU were combined. Very few data on haematological abnormalities following treatment of human patients have been published. Similarities can be seen between the haematological side-effects noted in rats and those occurring in humans treated with these cytotoxic drugs. Female Wistar rats seemed to be a good model to evaluate the haematological tolerance of anthracycline, nitrosoureas or of their association. If multiple courses of these drugs have to be administered, the evolution of haematological alterations must be known: the decrease phase of blood cells is followed by a rebound phase. The drug should be avoided during this phase of granulocyte activation.
Animals↗
[Hepatopathy with a progressive course after one-time administration of (chloro-2-ethyl)-1-cyclohexyl-3-nitroso-1-uréa (CCNU) in rats].
A few cases of liver involvement have been reported in patients receiving treatment with CCNU. Nitrosourea CCNU is an antitumoral agent largely used in the treatment of some types of leukemia, Hodgkin's disease, bronchial or cerebral tumors. It was shown that CCNU induced pericholangitis and intra-hepatic cholestasis in rat: moderate after 20 mg/kg CCNU, these hepatic lesions were maximal on day 8. In the present report we were interested in the evolution of hepatic alterations a long time after cessation of drug administration. So we studied hepatic ultrastructure three months after a unique 20 mg/kg or 50 mg/kg CCNU administration. Lesions were stable after 20 mg/kg CCNU and no reversibility was observed 3 months after 50 mg/kg CCNU: evolution to cholangiolysis, to adenomatous transformation of parenchyma or biliary cirrhosis were noted.
Animals↗
[Hepatotoxicity of (chloro-2-ethyl)-1-cyclohexyl-3-nitroso-1-urea (CCNU) in the rat].
Few cases of liver involvement have been reported in patients receiving treatment with CCNU. CCNU is an anti-tumoral agent used in the treatment of leukemia, Hodgkin's disease and bronchial or cerebral tumors. A single daily dose of 20 or 50 mg/kg CCNU in female Wistar rats induces an important increase of transaminases, reaching 10 times initial level between day 2 and day 6, followed by a second and moderate increase between day 21 and day 28. Three-fold increased alkaline phosphatases and conjugated hyperbilirubinemia were noted for the two doses, and was greater for the higher dose. Histological and ultrastructural studies showed two types of lesions: during the first phase of transaminase elevation, edema and inflammatory infiltration of the portal spaces; during the second phase of transaminases elevation, numerous bundles of pericanalicular microfilaments and severe dilation of the biliary tract. Hepatic cells had few alterations although some necrotic foci were observed, particularly at the higher dose. So CCNU induced an intrahepatic cholestasis with pericholangitis in the rat.
Alkaline Phosphatase↗
The lysosomal toxicity of aminoglycosides: a morphometric approach.
Lysosomes of kidney proximal tubule cells have been described as an early target involved in aminoglycoside-induced nephrotoxicity. These organelles concentrate these molecules and are overloaded with osmiophilic lamellar material. Biochemical alterations of lysosomes have already been described. In this study 6 aminoglycosides were given i.p. at the doses of 10 and 50 mg/kg for 4-7-15 days. A morphometric study of the lysosomal system of rat kidney proximal tubules is described first using Delesse's principle on electron micrographics. After aminoglycoside treatment, lysosomal volume rose from 3.3% in controls up to 10% or more of the cell volume. Concomitantly lysosomes were overloaded with myeloid bodies up to 50% or more of their own volume. Individual measurements of lysosome sections were performed on micrographics: perimeter and area. Size distributions were compared to each other using the Kolmogorov-Smirnov statistical test. Since the observed distribution could not be compared with a normal, Poisson, or any other theoretical distribution, the size distribution of perimeters has been successfully likened to a sum of individual normal subpopulations, the means of which follow a geometrical progression of rate square root 2 from a constant value of 1.23 micron, with standard errors of 15% of their respective mean value. When converted to membrane area values the progression rate becomes 2 and suggests fusion of identical size lysosomes during their intracellular life.
Animals↗
[Can fosfomycin reduce the nephrotoxicity of aminoglycosides?].
Fosfomycin is an active antibiotic on Gram positive and Gram negative bacteria with a low toxicity in animals. To treat severe infections, it is recommended to associate fosfomycin with gentamicin. Wistar rats were given one of the following regimens for eight days : 100, 500 or 1 000 mg/kg fosfomycin, 50 mg/kg gentamicin or dibekacin, association of 100, 500, or 1 000 mg/kg fosfomycin and 50 mg/kg gentamicin or dibekacin. Control rats were given a saline solution. No renal histological alterations were identified with fosfomycin 100 mg/kg. Tubular dilatation and brush border rarefaction were observed with fosfomycin 500 and 1 000 mg/kg. These abnormalities did not seem related to fosfomycin itself but rather to the sodium load induced by fosfomycin treatment. A decrease in alanine aminopeptidase activity was noted for all doses of fosfomycin. Renal concentrations of gentamicin and dibekacin were not decreased by concomitant administration of fosfomycin. Fosfomycin, 100 mg/kg, did not change the nephrotoxic potential of gentamicin or dibekacin. Fosfomycin, 500 mg/kg, protected the kidney from the action of gentamicin or dibekacin. This effect seemed to be more pronounced for dibekacin than for gentamicin. Fosfomycin, 1 000 mg/kg, did not induce a more protective effect against the nephrotoxicity of these two aminoglycosides. Thus, we observed that fosfomycin combined with gentamicin or dibekacin reduced the degree of proximal tubular cell alterations, induced less modifications in alanine aminopeptidase, less lysosomal alterations, and a minor modification in sphingomyelinase activity.
Aminoglycosides↗
Influence of dosage regimen on experimental tobramycin nephrotoxicity. A biochemical approach.
Many factors play a role in aminoglycoside nephrotoxicity. To study the influence of dosage regimens, Wistar rats were injected for 8 days with a total daily dose of 10, 20, or 50 mg/kg tobramycin intraperitoneally either in one single (1) or in thrice (3) daily injections. The results were different according to the dose. With 10 or 20 mg/kg, serum creatinine did not increase. Alanine aminopeptidase activities decreased whatever the rhythm of administration. gamma-Glutamyl-transpeptidase and N-acetyl-beta-D-glucosaminidase activities were unchanged. Sphingomyelinase and cathepsin B activities were diminished with three injections and not affected with one injection. Renal tobramycin content was not significantly different with (1) or with (3). Lysosomal structural latency was decreased in rats treated three times a day. With 50 mg/kg, serum creatinine was significantly increased and was higher with one injection daily. Alanine aminopeptidase decreased with only one injection daily and gamma-glutamyl-transpeptidase was unchanged. N-acetyl-beta-D-glucosaminidase was increased with (1) and with (3). Sphingomyelinase and cathepsin B activities were significantly decreased. No differences were observed in rats treated once or thrice daily. Renal tobramycin content was similar with (1) and (3). The lysosomal structural latency was significantly decreased and to the same degree for both regimens. In conclusion, based on this study and on other related studies in the literature it is presently very difficult to determine the real relationship between dosage frequency and development of nephrotoxicity.
Animals↗
Comparative nephrotoxicity of four aminoglycosides: biochemical and ultrastructural modifications of lysosomes.
In 1982, aminoglycosides still are widely prescribed and considered indispensable for the treatment of severe gram-negative infections. All the aminoglycosides are nephrotoxic, but both experimental works and clinical investigations indicate that they do not all have the same nephrotoxic potential. Within the renal tubular cell in several animal species and in man, the initial and the most extensive changes are those that occur in the lysosomes. We compared the effects of gentamicin, tobramycin, netilmicin and, amikacin on (a) lysosomal structural latency, (b) the activity of several enzymes, either lysosomal or those contained in the proximal tubular cell brush border, and (c) the accumulation of myeloid bodies in the lysosomes. From our results, it appears that gentamicin is the aminoglycoside that induces the greatest number of lysosomal changes whereas amikacin induces the least, with the effects of netilmicin and tobramycin quite close to those of amikacin. Other works comparing the nephrotoxicity of aminoglycosides reveal the same high nephrotoxic potential of gentamicin.
Amikacin↗
Renal histological and biochemical changes induced in the rat by dibekacin.
Among presently available aminoglycosides, dibekacin has the least toxic effect on the functions of the cochlea and the vestibule. We investigated the potential nephrotoxicity of dibekacin at various dose levels and durations of treatment. In the rat, the injection of high doses (50 mg/kg for 8 days) produced: 1) a reduction in renal function and the onset of cellular necrosis; 2) the appearance of myeloid bodies in the cells of the proximal tubule; 3) accumulation of the drug in the renal cortex at a concentration of 4.4 micrograms/mg of protein; 4) a reduction in the lysosomal latency of N-acetyl-beta-D-glucosaminidase; and 5) disorders of the activity of cortical enzymes cathepsin B and sphingomyelinase. The effect of dibekacin is similar to that of the other aminoglycosides, but it would seem to be less nephrotoxic than gentamicin.
Acetylglucosaminidase↗
[Pharmacokinetics of dibekacin in patients with chronic renal impairment].
The pharmacokinetics of dibekacin were studied in 23 patients with varying degrees of renal insufficiency. Creatinine clearance was between 4 and 51 ml/min. Chronic renal insufficiency did not affect maximum serum concentrations, nor the time required to reach a peak level after an intramuscular injection of 1 mg/kg of dibekacin. The maximum concentration was 4 to 5 mcg/ml and the peak obtained within the first hour. Renal insufficiency caused a very marked prolongation in the serum half-life of elimination. This rose from 6 hours in moderate renal insufficiency to 50 hours in a patient with a clearance of a few millilitres. Whatever the degree of renal insufficiency, it should be noted that urinary concentrations remained markedly higher than the MIC of organisms sensitive to the aminoglycoside. Dibekacin is highly dialysable, being virtually totally extracted during a 6 hours dialysis session using a membrane of 1 m2 surface area. An outline of dose adaptations in relation to the degree of renal insufficiency is suggested on the basis of these pharmacokinetic data.
Adult↗
[Functional, histological, biochemical renal modifications. Comparative study of dibekacin, gentamicin, tobramycin, netilmicin and amikacin].
In this study, we evaluate the nephrotoxic potential of dibekacin (D) compared to gentamicin (G), tobramycin (T), amikacin (A) and netilmicin (N). The mean features of aminoglycoside nephrotoxicity are: a lysosomal membrane fragilization, a lysosomal phospholipidosis characterized by a decrease activity of sphingomyelinase, an increase lysosomal volume with both an increase of individual size and an increase number of lysosomes, a cell necrosis and renal failure. We have quantified these parameters biochemically and morphometrically. We can classify, considering doses and durations, the aminoglycosides as gentamicin greater than or equal to netilmicin greater than dibekacin = tobramycin greater than amikacin for decreasing nephrotoxic incidence.
Amikacin↗
Changes in the lysosomes and mitochondria isolated from the liver, kidney and heart of rats treated with perhexiline maleate.
A seven-days treatment, with Perhexilline Maleate induces changes in the structural latency of lysosomes isolated from liver or kidney and of the respiratory activity of mitochondria isolated from liver, kidney or heart. While the effect on lysosomal structural latency appears very similar in the liver and kidney lysosomes, the oxidative properties of liver mitochondria appears clearly more disturbed than those of the heart or kidney. It is concluded that liver mitochondria might be strongly involved in the mechanism of Perhexiline Maleate hepatotoxicity.
Acetylglucosaminidase↗
Changes in the renal function of rats treated with cefoxitin and a comparison with other cephalosporins and gentamicin.
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Acetylglucosaminidase↗
[Diclofurime: a new antihypertensive agent. Effectiveness and kidney tolerance].
Diclofurime is a non-inotropic arterial vasodilator and an antagonist to calcium transport. We studied its antihypertensive effect in 16 hypertensive subjects. When given alone at an average dose of 240 mg/day, it induced an overall significant diminution of systolic and diastolic arterial pressure. Among the 16 subjects studied, diclofurime lowered arterial pressure below 150/90 mm Hg in seven, induced an improvement in arterial pressure in six, and showed no effect in three. When hypertension is not controlled with 450 mg diclofurime in 3 doses/day, it may be given in association with acebutolol. Diclofurime is well tolerated. The most troublesome side effects noted were headache, cardiac erethism, asthenia and edema in the lower limbs. These clinical signs were usually transient. Among these 32 patients side effects required interruption of treatment in three. Laboratory follow-up was made on day 78 and 180 after initiation of treatment. No significant change in results was noted. Renal function was studied in seven patients having normal renal function and in six chronic renal failure patients whose inulin clearance was about 30 ml min-I. It was observed that in the normal subject, the injection of a loading dose of 40 mg diclofurime followed by a maintenance dose of 80 mg during one hour induced a slight increase in glomerular filtration and a greater increase in renal blood flow; the filtered fraction was thus diminished. Diclofurime induced a clear and sustained increase in excretion of water and sodium chloride without modifying urinary excretion of potassium. In severe renal failure, no significant changes in glomerular filtration, renal blood flow or electrolyte excretion were observed with diclofurime.
Adult↗
Gentamicin-induced nephrotoxicity: a cell biology approach.
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Acetylglucosaminidase↗
[Functional, histological, ultrastructural and biochemical study of rat kidney treated with fosfomycin and gentamycin, administered separately or together].
Wistar rats received by intraperitoneal injection for 8 days different doses of Fosfomycin, a new antibiotic. No renal pathological changes are seen under light microscopy after these treatments. Ultrastructural study reveal an intact cellular structure of the proximal tubule. Fosfomycin induces no change in the lysosomal structural latency and enzymatic study show no change in the activities of our hydrolases (alanine-aminopeptidase, alpha-galactosidase, N-acetyl-beta-D-glucosaminidase and sphingomyelinase), after treatment by 100 and 500 mg/kg Fosfomycin. At 1000 mg/kg, Fosfomycin induces an inhibition in enzymatic activities of the four hydrolases. Fosfomycin does not modify the activity of Gentamicin on the proximal tubular cell and induces neither protection nor potentialization of its nephrotoxic effect.
Acetylglucosaminidase↗
[Aminoglycoside nephrotoxicity. III. Changes in subcellular elements].
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Aminoglycosides↗