Biomedical subjects

M A Basinger

Publications and source records attributed to M A Basinger.

At least 19 recordsLinked to original sources

PubMed1996

Prevention of cisplatin nephrotoxicity by exogenous atrial natriuretic peptide.

The ability of atrial natriuretic peptide (ANP) to prevent cisplatin-induced nephrotoxicity was compared to the protective effect of 3% NaCl. ANP (1 microgram/kg/min), 3% NaCl or peptide buffer vehicle (50 microliters/min) were infused for 45 min to conscious unrestrained rats immediately after cisplatin administration (5 mg/kg i.v.). Measurements taken 72 h after drug treatment indicated that compared to animals receiving cisplatin only, ANP co-treated rats had lower post-treatment plasma creatinine concentrations (0.70 +/- 0.07 vs 1.3 +/- 0.17 mg/dl; P < 0.05), blood urea nitrogen (BUN) concentrations (44.2 +/- 5.8 vs. 65.5 +/- 2.1 mg/dl; P < 0.05) and higher post-treatment glomerular filtration rates (GFR) (0.71 +/- 0.18 vs. 0.14 +/- 0.03 ml/min; P < 0.05). ANP was as effective as 3% NaCl in preventing cisplatin nephrotoxicity in this model. The effect of ANP co-treatment on the anti-tumor activity of cisplatin was also examined using the Walker 256 carcinosarcoma model. ANP treatment did not result in any observable loss in anti-tumor activity. When ANP was administered 72 h after cisplatin treatment, improvement in GFR was observed for the duration of the infusion, confirming the beneficial effect of ANP on cisplatin-damaged kidneys. ANP may have a role in the treatment and prevention of cisplatin nephrotoxicity especially in clinical situations where treatment with a large fluid volume is contraindicated.

Animals↗

PubMed1995

Protection from cisplatin nephrotoxicity by A68828, an atrial natriuretic peptide.

The ability of a 13 amino-acid analog of atrial natriuretic peptide (ANP), A68828, to prevent development of cisplatin toxicity was evaluated in a rat model. ANP (1 microgram/kg/min), A68828 (10 micrograms/kg/min), A68828 (50 micrograms/kg/min), or peptide buffer was given as an intravenous infusion over 1 h beginning 15 min prior to an infusion of 5 mg/kg cisplatin. Animals receiving cisplatin plus peptide buffer vehicle developed predictable renal failure, with mean plasma creatinine and blood urea nitrogen concentrations of 1.09 +/- 0.09 mg/dL and 50.13 +/- 5.96 mg/dL, 72 h after treatment. ANP and A68828 (10 micrograms/kg/min) attenuated the increase in these indices of nephrotoxicity (mean plasma creatinine 0.86 +/- .06 mg/dL and 0.76 +/- 0.11 mg/dL, respectively). Surprisingly, the higher dose of A68828 (50 micrograms/kg/min) did not reduce cisplatin nephrotoxicity (72-h plasma creatinine 1.61 +/- 0.34 mg/dL). These results indicate that a short-term infusion of ANP or the analog A68828 can reduce the severity of cisplatin toxicity. At high doses of A68828 the beneficial effects of treatment may be lost.

Animals↗

PubMed1995

The role of the renin-angiotensin system in cisplatin nephrotoxicity.

The role of the renin-angiotensin system (RAS) in the pathogenesis of cisplatin nephrotoxicity was evaluated in an experimental rat model using a specific, nonpeptide angiotensin II(AII) receptor blocker, losartan. Rats were treated with a single dose of losartan (at 10 mg/kg and 30 mg/kg, i.p.) or saline, 2 h prior to cisplatin administration (5 mg/kg, i.p.). Renal function was assessed 3 and 7 days after cisplatin treatment. A second group of rats received losartan (10 mg/kg, i.p.) or saline, 2 h prior to cisplatin administration (5 mg/kg, i.p.), and losartan (10 mg/kg, i.p.) or saline daily for 6 days after cisplatin treatment. Renal function was assessed on day 7. Neither high- nor low-dose losartan pretreatment prevented development of cisplatin-induced nephrotoxicity. Blood urea nitrogen (BUN) and plasma creatinine values at 7 days were similar to those of animals receiving cisplatin alone (BUN: 17.12 +/- 1.1 and 22.17 +/- 2.2 vs. 20.58 +/- 2.4 mg/dL; creatinine: 1.04 +/- 0.05 and 0.82 +/- 0.09 vs. 0.84 +/- 0.06 mg/dL). A significant reduction in creatinine clearance with cisplatin treatment was seen 3 days after therapy, which was not prevented by pretreatment with losartan (GFR in controls: 2.1 +/- 0.16 mL/min; cisplatin: 0.24 +/- 0.05; cisplatin plus low-dose losartan: 0.05 +/- 0.03 and cisplatin plus high-dose losartan: 0.37 +/- 0.05). All groups of cisplatin-treated rats displayed systemic signs of cisplatin toxicity: reduced food intake and body weight. Rats receiving chronic losartan treatment had more rapid weight gain and lower BUN and plasma creatinine levels on day 7 than rats receiving cisplatin alone (BUN: 24.0 +/- 2.64 vs. 36.4 +/- 0.91 mg/dL; p < 0.05; plasma creatinine: 0.86 +/- 0.06 vs. 1.15 +/- 0.07 mg/dL; p < 0.05). Acute blockade of the AII receptor with losartan does not alter the onset or severity of cisplatin nephrotoxicity. Chronic blockade of the AII receptor may improve the rate of recovery of renal function in cisplatin-treated rats.

Angiotensin II↗

PubMed1994

Synthesis and iron(III) binding properties of 3-hydroxypyrid-4-ones derived from kojic acid.

In an attempt to reduce the toxicity of the 3-hydroxypyrid-4-ones, the more hydrophilic derivatives of kojic acid were explored and compared to the standard, 1,2-dimethyl-3-hydroxypyrid-4-one, L1. The synthesis and iron(III) binding properties of these chelators are described. Neither these compounds nor the clinically effective 1,2-dimethyl-3-hydroxypyrid-4 one is able to completely remove all of the iron(III) from the Fe(III)EDTA complex in sodium acetate buffered solutions, when the 3-hydroxypyrid-4-one: Fe(III) ratio is 6:1. The ability of these compounds to enhance the urinary excretion of iron in rats indicates that the behavior of the 3-hydroxypyrid-4-ones derived from kojic acid is comparable to the analogous derivatives of maltol and ethyl maltol. The structure of the iron(III) complex of 3-hydroxy-6-hydroxymethyl-1-methylpyrid-4-one was determined by x-ray diffraction and found to be similar to the previously reported structure of the iron(III) complex of L1.

Animals↗

PubMed1994

Effect of chelate treatments on kidney, bone and brain lead levels of lead-intoxicated mice.

The effects of chelating agent treatment with meso-2,3-dimercaptosuccinic acid (DMSA), Na2CaEDTA, Na2ZnEDTA, and Na3ZnDTPA on the organ lead levels of lead-loaded mice have been determined. At 1 mmol/kg/day i.p., all caused reductions in the lead levels of the kidney after four injections, but only Na2CaEDTA produced a significant reduction in brain lead. All chelating agents caused significant reductions in kidney and brain lead levels when administered at a daily dose of 1 mmol/kg/day for eight days, but only DMSA reduced the bone lead level. In animals given 50 mg Pb/kg or 100 mg Pb/kg, the administration of Na2CaEDTA or DMSA at 1 mmol/kg/day x 8 produced significant reductions in kidney, bone and brain lead levels, but DMSA produced greater reductions of bone lead in both groups and of kidney lead in the group given 100 mg Pb/kg. An examination of published data describing the effect of chelating agent treatment on brain lead levels indicates that DMSA produces a reduction in brain lead levels under all conditions examined to date.

Animals↗

PubMed1994

Enhancement of iron excretion via monoanionic 3-hydroxypyrid-4-ones.

The ability of 3-hydroxypyrid-4-ones bearing either a carboxylic acid or sulfonic acid group to mobilize iron into the bile and urine of normal rats has been examined and compared with that produced by 1,2-dimethyl-3-hydroxypyrid-4-one (L1). The compounds tested were 3-hydroxy-1-methyl-4-oxopyridine-6-carboxylic acid and 1-[3-hydroxy-6-(hydroxymethyl)-4-oxopyridyl]-2-ethanesulfonic acid, whose synthesis, biological activity, and X-ray crystallographic properties are described. Although estimates of activity, based on polarity and membrane permeability, predict such compounds to be ineffective, they were found to have an iron-mobilizing ability similar to that of the compounds which do not bear any charge at physiological pH when given parenterally. When given orally, the 3-hydroxypyrid-4-one containing a carboxylate group enhanced the urinary excretion of iron, while the sulfonate analog did not substantially increase the excretion of iron in the urine relative to the controls. The results obtained here suggest that the previous emphasis on the preparation of 3-hydroxypyrid-4-ones that are electrically neutral at physiological pH is unnecessarily restrictive and that the presence of an appropriate group bearing a single negative charge is consistent with a high level of activity. It is proposed that such negatively charged molecules may gain access to the interior of cells in both the kidney and the liver via monoanionic transport systems. Such compounds may prove to be less toxic than the neutral 3-hydroxypyrid-4-ones.

Alkanesulfonates↗

PubMed1994

Cadmium mobilization by monoaralkyl- and monoalkyl esters of meso-2,3-dimercaptosuccinic acid and by a dithiocarbamate.

Syntheses and relative cadmium mobilizing properties are described for three new monoaralkyl esters (HOOCCH(SH)CH(SH)COOR, where R = phenylethyl ((CH2)2C6H5), MPhEDMS; R = 3-phenylpropyl ((CH2)3C6H5), MPhPDMS; and R = 2-phenoxyethyl ((CH2)2OC6H5). MPhOEDMS) of meso-2,3-dimercaptusuccinic acid. These were prepared by the reaction of the corresponding alcohol with meso-2,3-dimercaptosuccinic acid (DMSA) in aqueous HCl. When administered intraperitoneally to cadmium-loaded mice at 0.50 mmol/kg/day for four consecutive days, all induced significant reductions in the whole body cadmium levels. MPhEDMS, 60%; MPhPDMS, 66%; and MPhOEDMS, 58% in comparison with control levels. At the same dosage monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) and a dithiocarbamate, sodium N-benzyl-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbodithioate++ + (BLDTC) induced reductions of 65% and 57%, respectively. Hepatic and renal cadmium were also depleted significantly, while brain cadmium levels were unchanged. These compounds induced a significant reduction in the cadmium levels of the spleen, and one, MPhOEDMS, produced a 10% decrease in pancreatic cadmium. The manner in which the later injections removed smaller fractions of the total body cadmium is consistent with a bodily distribution of these compounds by which they are concentrated primarily in the kidneys and the liver, with much smaller amounts reaching other organs. It is proposed that these compounds enter renal and hepatic cells through an anion transport system.

Animals↗

PubMed1992

Mobilization of lead in mice by administration of monoalkyl esters of meso-2,3-dimercaptosuccinic acid.

The following six monoalkyl esters of meso-2,3-dimercaptosuccinic acid (DMSA) were synthesized and evaluated for relative activities in mobilizing lead from kidneys and brains of lead-bearing mice: n-propyl (Mn-PDMS), i-propyl (Mi-PDMS), n-butyl (Mn-BDMS), i-butyl (Mi-BDMS), n-amyl (Mn-ADMS) and i-amyl meso-2,3-dimercaptosuccinate (Mi-ADMS). DMSA was used as a positive control. When each was administered intraperitoneally (i.p.) as a single dose of 2.0 mmol/kg, DMSA lowered the kidney lead concentration 52%, while the monoesters effected reductions of 54-75%. Mn-ADMS was toxic at this dose. DMSA lowered the brain lead level 20% when given as a single dose, while the monoesters conferred reductions of 64-87%. When given as 5 daily i.p. injections at 0.5 mmol/kg, DMSA reduced the kidney lead concentration 45%, while the monoesters caused reductions of 56-73%. DMSA lowered the brain lead concentration 35% on the 5-day treatment regimen, while the monoesters evoked reductions of 59-75%. Mi-ADMS was equally effective when given orally or i.p. The i.p. LD50 value of this analog in mice is 3.0 mmol/kg, a value which lies between the reported LD50 doses of DMSA (16.0 mmol/kg) and dimercaprol (1.1 mmol/kg). It is suggested that the ability of these monoesters to cross cell membranes may account for their superiority to DMSA in mobilizing brain lead in this animal model.

Animals↗

PubMed1992

N-benzyl-N-lactyl dithiocarbamate treatment of mice after chronic cadmium administration.

Administration of N-benzyl-N-lactyl dithiocarbamate (BLDTC) to mice after chronic cadmium (Cd) administration evoked a prompt, dose-dependent reduction of the whole body burden; 75% of the retained Cd was mobilized and excreted after 20 i.p. injections of BLDTC at 1.0 mmol/kg/injection. This same dose regimen produced 71% and 98% reductions of the renal and hepatic Cd concentrations, respectively. There was no reduction by BLDTC of the endogenous level of any of seven other metals measured: iron, magnesium, selenium, copper, calcium, zinc, and manganese. Renal proximal tubular damage in mice which received Cd followed by BLDTC was much less than that observed in kidneys from mice which received Cd alone. Chronic Cd administration led to substantial epithelial vacuolar damage to renal distal tubules, and this process was not apparently reversed or antagonized by BLDTC treatment to the extent observed in proximal tubules.

Animals↗

PubMed1992

Control of the nephrotoxicity of cisplatin by clinically used sulfur-containing compounds.

Several clinically used sulfur-containing compounds were examined as potential antagonists for the nephrotoxicity of cis-platin in Sprague-Dawley rats. The compounds studied were biotin, captopril, cefoxitin, cephalexin, the sodium salt of penicillin G, sulfathiazole, and thiamine hydrochloride. Biotin, captopril, cephalexin, and sulfathiazole were found to have a significant effect in reducing the nephrotoxicity of cisplatin when administered simultaneously with cisplatin via an intravenous route in the rat. Biotin was the most effective in providing renal protection and sulfathiazole the least effective, based upon BUN, serum creatinine values, and weight changes, though all four of these compounds provided a considerable measure of protection against the typical cisplatin-induced nephrotoxicity. The effect of the simultaneous administration of cisplatin with biotin, cephalexin, and sulfathiazole was examined on the antitumor activity of cisplatin toward the L1210 murine leukemia in the DBA/2 mouse and the Walker 256 carcinosarcoma in the rat. With the L1210 murine leukemia no loss of antitumor activity was found for any of the compounds. With the Walker 256 carcinosarcoma some loss of antitumor activity was found with biotin. Both biotin and sulfathiazole are shown to be promising candidates for use in the suppression of the adverse effects of cisplatin, and other sulfur-containing compounds currently in clinical use may have equivalent or superior properties in this respect.

Animals↗

PubMed1992

Effect of dithiocarbamates and dithiocarbamate-induced cadmium mobilization on essential trace metal metabolism in the female rat.

The effects of two dithiocarbamates (both of which induce an increase in the excretion of cadmium) on the biliary and urinary excretion of the essential trace elements zinc, copper, iron, magnesium, and calcium have been examined in the female Sprague-Dawley rat to estimate what alterations in the excretion of essential metals accompanies the use of these compounds. The dithiocarbamates studied were sodium diethyldithiocarbamate (DDTC) and sodium N-(4-methylbenzyl)-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbod ithioate (MeBLDTC). DDTC induced a modest decrease in the biliary and urinary excretion of copper. The biliary excretion of both zinc and iron was significantly enhanced when MeBLDTC was given ip to normal rats, while those of copper, magnesium, and calcium were not significantly affected by this compound. DDTC treatment of normal female rats which had not been administered cadmium resulted in a slight decrease in the iron level of the liver. Treatment of rats with cadmium chloride resulted in a significant increase in the zinc and iron levels of the kidney, liver, and pancreas and an increase in the copper levels of the kidney and the liver. After a treatment with MeBLDTC, which reduced hepatic cadmium levels, only some of the levels of these essential metals were modified toward the levels found in untreated controls. Cadmium-loaded animals from which hepatic cadmium had been mobilized by MeBLDTC did not differ in renal or hepatic histopathology from the control (untreated) animals or from the group which had received cadmium only.

Animals↗

PubMed1992

Association between increased atrial natriuretic peptide and reduced cisplatin nephrotoxicity in rats.

Plasma atrial natriuretic peptide (ANP) concentrations were monitored in two experimental models of protection from cisplatin nephrotoxicity. Sprague-Dawley rats made diabetic with streptozotocin (65 mg/kg) were protected from cisplatin-induced nephrotoxicity when compared to control rats as indicated by reduced plasma creatinine (0.49 +/- 0.02 vs. 0.9 +/- 0.06 mg/dl; P less than .001) and blood urea nitrogen concentrations (18.51 +/- 1.4 vs. 43.08 +/- 2.1 mg/dl; P less than .001). Plasma ANP was also increased with experimental diabetes (76.5 +/- 8.98 fmol/ml) vs. normoglycemic controls (43.8 +/- 8.9 fmol/ml; P less than .02). When diabetic rats were treated with insulin, the renal protection observed with the diabetic state was reversed (creatinine, 0.70 +/- .05 mg/dl); plasma ANP concentrations were also reduced (52.2 +/- 15.2 fmol/ml). Renal platinum concentrations were significantly lower in the diabetic group and the reversal of diabetic-induced renal protection with insulin was associated with increased renal platinum concentrations. In rats given a single i.p. dose of cisplatin (5 mg/kg), a reduction in cisplatin-induced nephrotoxicity was observed when 5% NaCl was the vehicle of choice compared to that seen in rats given the same dose of drug in 0.9% saline (creatinine, 0.43 +/- 0.07 with 5% NaCl vs. 0.63 +/- 0.03 with 0.09% NaCl). NaCl (5%) administration also resulted in increased plasma ANP concentrations when compared to rats receiving equivalent volumes of 0.9% NaCl (88.4 +/- 6.2 vs. 50.5 +/- 5.6 fmol/ml, respectively). These data suggest that increased endogenous ANP may be a mechanism of renal protection common to both experimental diabetes and hypertonic saline administration. Chronically increased ANP may prevent renal accumulation of platinum in the kidney.

Animals↗

PubMed1991

A comparative study of the influence of vicinal dithiols and a dithiocarbamate on the biliary excretion of cadmium in rat.

The effect of two vicinal dithiols, 2,3-dimercaptopropan-1-ol (BAL) and N-(2,3-dimercaptopropyl)phthalamidic acid (DMPA), and a dithiocarbamate, sodium N-(4-methoxybenzyl)-D-glucamine dithiocarbamate (MeOBGDTC), on the biliary excretion of cadmium was examined in rats. Tissue cadmium levels were also determined following the measurements of biliary excretion of cadmium. At 30 min after the injection of CdCl2.2.5H2O (1 mg/kg, iv) each rat was given 400 mumol/kg ip of one of the compounds, BAL, DMPA or MeOBGDTC. While all the compounds increased the biliary excretion of cadmium, the most effective was MeOBGDTC, whose administration resulted in a 580% increase in biliary cadmium content. The effectiveness of the MeOBGDTC may be due to the presence of both nonpolar and nonionizing polar groups attached to nitrogen. MeOBGDTC was able to mobilize cadmium to the bile even after the occurrence of the synthesis of metallothionein and the incorporation of the cadmium into it. An attempt was also made to determine the chemical nature of the Cd-MeOBGDTC complex present in the bile by comparing a newly synthesized authentic sample of Cd(MeOBGDTC)2 complex with the hot dioxane extract of the freeze-dried bile samples using thin-layer chromatography and proton NMR. The results suggested that cadmium excreted in the bile in part, is complexed to MeOBGDTC and glutathione.

Animals↗

PubMed1991

The relative nephrotoxicity of cisplatin, cis-[Pt(NH3)2(guanosine)2]2+, and the hydrolysis product of cisplatin in the rat.

An examination of the comparative nephrotoxicity in the rat of cisplatin, its hydrolysis product (mostly cis-[Pt(NH3)2Cl(H2O)]+ under the conditions applied), and cis-[Pt(NH3)2(guanosine)2]2+ revealed that these compounds differed significantly in the extent of renal damage they produced following their i.v. injection in Sprague-Dawley rats. The hydrolysis product was found to be the most toxic of the three complexes studied and produced nephrotoxicity at doses lower than those at which cisplatin was nephrotoxic. Under the conditions used, the i.v. administration of cis-[Pt(NH3)2(guanosine)2]2+ resulted in no observable signs of nephrotoxicity at levels at which an equimolar dose of cisplatin produces clear evidence of renal function impairment and morphological alterations. The nephrotoxicity of these complexes appears to be generally related to the ease with which they undergo nucleophilic substitution reactions. The lack of substantial nephrotoxicity found for cis-[Pt(NH3)2(guanosine)2]2+ suggests that the products resulting from the action of the DNA repair processes on platinated DNA do not contribute significantly to the nephrotoxicity of cisplatin. Renal platinum levels found following the administration of these compounds correlated with the degree of nephrotoxicity produced by each compound, but no general correlation of nephrotoxicity and renal platinum levels was found. The nephrotoxicity of cis-[Pt(NH3)2Cl(H2O)+ on a molar basis was estimated to be approximately 3 times as great as that of cisplatin itself.

Animals↗

PubMed1991

Relative effectiveness of some compounds for the control of cisplatin-induced nephrotoxicity.

Several procedures which have been reported as effective for the control of cisplatin induced nephrotoxicity were compared in the Sprague-Dawley rat using the same dose of cisplatin. The treatments examined were based on the use of sodium thiosulfate, sodium diethyldithiocarbamate (DDTC), glutathione (GSH), sodium N-methyl-D-glucamine dithiocarbamate (NaG) and S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721). The differences in the effectiveness of the procedures were assessed using BUN and serum creatinine values, histopathological examination, body weight changes, and renal platinum levels as indices. The effect of such treatments on the antineoplastic activity of cisplatin were examined with both the Walker 256 carcinosarcoma in the rat and the L1210 murine leukemia in mice. Under the conditions used, GSH was found to be more effective than the other nucleophiles in protecting against the nephrotoxicity of cisplatin while providing the least amount of interference with the antitumor activity as measured against the Walker 256 carcinosarcoma and the L1210 murine leukemia. Simultaneous i.v. administration of cisplatin and any of the sulfur-containing nucleophiles leads to a significant protection against the nephrotoxicity but reduced the anti-neoplastic activity of cisplatin when measured against the Walker 256 carcinosarcoma.

Animals↗

PubMed1990

L-methionine antagonism of cis-platinum nephrotoxicity.

L-Methionine administered simultaneously with cis-platinum (CDDP) iv results in a significant reduction of the nephrotoxicity normally associated with CDDP without any apparent effect on the antineoplastic activity for rats bearing the Walker 256 carcinosarcoma. CDDP given with L-methionine at a 1:20 mole ratio can be administered to rats at doses up to 35 mg/kg iv with the survival of all treated animals (3/3) and up to 56 mg/kg iv (bolus injection) with the survival of 3/6 animals, while CDDP administered alone at these levels is lethal. A reduced level of protection against the nephrotoxicity was also achieved at lower mole ratios of L-methionine to CDDP. Renal function was monitored using BUN and serum creatinine levels, and gastrointestinal toxicity by weight changes during the course of the experiments. A histopathological examination of the kidneys was also performed to evaluate the protection provided by L-methionine. Under the conditions used, the reaction between L-methionine and CDDP does not appear to proceed so rapidly as to interfere with the antitumor activity of the CDDP. The examination of structural analogs as agents for the control of CDDP-induced nephrotoxicity revealed that the C-S-C-group is the essential group for the protective action in these structures. Although L-methionine can provide renal protection in rats given high doses of CDDP, it does not prevent the accumulation of platinum in the kidney.

Animals↗

PubMed1990

L-methionine suppresses pathological sequelae of cis-platinum in the rat.

The pathological changes characteristically observed in the kidney, bone marrow, thymus, spleen, and duodenum of the rat given 12.2 mg/kg of cis-platinum (CDDP) ip are reduced or eliminated when a CDDP solution containing a 20-fold excess of L-methionine to cis-platinum is administered. L-Methionine was also effective in reducing the renal toxicity induced by CDDP when given orally 20 min before the iv administration of 7.5 mg CDDP/kg. L-Methionine did not compromise the efficacy of CDDP when the antitumor activity of the combination of L-methionine and CDDP was measured against the Walker 256 carcinosarcoma in the rat. No significant reduction in the antitumor activity of the CDDP resulted from the parenteral administration of L-Methionine when evaluated against the L1210 murine leukemia. The oral administration of L-methionine (500 mg/kg) 30 min after the administration of CDDP has no significant effect on the antitumor activity of CDDP in mice bearing the L1210 murine leukemia. The results suggest that L-methionine may have some practical utility in the control of certain aspects of CDDP toxicity.

Animals↗

PubMed1989

Control of nephrotoxicity in the rat during repeated cis-platinum treatments.

The nephrotoxicity of cis-platinum (CDDP) in the rat can be controlled throughout a series of weekly administrations of CDDP (each of 5 mg kg-1, i.v.) for at least three weeks by a combination of protective measures involving pretreatment with dithiocarbamates and diuretics and the administration of appropriate dithiocarbamates given 1 h after the CDDP. The use of dithiocarbamates with polar substitutents is effective in removing both renal and hepatic deposits of platinum from rats subsequent to its administration and in this respect these compounds are significantly superior to meso-2,3-dimercaptosuccinic acid (DMSA) in the rate at which platinum is removed and in the amounts removed. The most effective of the dithiocarbamates remove ca. 70% of the platinum from the kidneys and the liver; the least effective remove ca. 50% of the platinum from these organs when given at a level of 1.57 mmol kg-1 i.p. for 6 days subsequent to the administration of CDDP. Acetazolamide was shown to be much less effective in preventing renal damage than the dithiocarbamates and was not effective in reducing renal or hepatic levels of platinum. Pretreatment with sodium diethyldithiocarbamate 12 h prior to the administration of the CDDP was more effective in preventing renal damage than the administration of this compound 30 min before the cis-platinum. Several dithiocarbamates are found to be superior to sodium diethyldithiocarbamate in reducing renal platinum burdens of rats given CDDP at the level of 6 mg kg-1, and dose-response curves for the removal of renal and hepatic platinum were determined for sodium N-methyl-D-glucamine dithiocarbamate (NaG).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗