Effect of monoisoamyl meso-2,3-dimercaptosuccinate on the pathology of acute cadmium intoxication.

The ability of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) to offset the characteristic organ pathology of intraperitoneally administered cadmium chloride (CdCl2) and that of the cadmium-cysteine complex has been examined in male Wistar rats. The tissues examined for damage were the testes, kidney, liver, pancreas, and bone marrow. At a high dose of CdCl2 (0.03 mmol/kg, ip) testicular damage was completely prevented by Mi-ADMS (0.50 mmol/kg, ip) given immediately. A decrease in the protective ability of the antagonist was observed following delayed administration of Mi-ADMS given at 1, 2, 4, and 24 h post CdCl2. At a lower dose of CdCl2 (0.006 mmol/kg, ip), Mi-ADMS furnished essentially full protection from testicular damage when given (0.50 mmol/kg, sc) at 0 and 1 h after CdCl2. The administration of cadmium-cysteine complex (0.01 mmol/kg, ip) induced notable renal tubular damage, which was antagonized by the administration of Mi-ADMS (0.50 mmol/kg, ip) as late as 4 h after the complex. At a 24-h delay, extensive tubular necrosis was found on sacrifice after 4 d. The administration of cadmium-cysteine complex ip reduced, but did not eliminate, the characteristic damage of the seminiferous tubules found for cadmium alone. There is a progressive reduction of testicular weight as the interval between cadmium and antagonist administration increases. The average kidney weights of the animals given CdCl2-cysteine complex were increased in comparison to normal controls. The antagonistic effects of Mi-ADMS treatment on cadmium intoxication in the kidneys and the testes of rats is very similar to that found for effective dithiocarbamate antagonists. In order to obtain complete protection of the testes from the deteterious effects of cadmium, such antagonists must be administered no later than about 1 h after the cadmium.

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.

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.

Coadministration of dimethyl sulfoxide reduces cisplatin nephrotoxicity.

The administration of dimethyl sulfoxide with cisplatin at a mole ratio of 200:1 results in a considerable reduction in the nephrotoxicity produced when cisplatin alone is administered to Sprague-Dawley rats at 7.5 mg/kg. Observed measures of nephrotoxicity which were significantly improved by the coadministration of cisplatin and DMSO over the values found for cisplatin alone include BUN, serum creatinine, creatinine clearance and histopathological evidence of renal damage. The weight loss associated with cisplatin administration was also significantly reduced by DMSO coadministration. The use of DMSO did not result in any observable loss in antitumor activity of cisplatin against the Walker 256 carcinosarcoma.

Dithiocarbamates of improved efficacy for the mobilization of retained cadmium from renal and hepatic deposits.

The preparation and properties of two novel cadmium-mobilizing dithiocarbamates namely, sodium N-(4-methylbenzyl)-and sodium N-(4-methoxybenzyl)-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbo dithioates derived from alpha-lactose and substituted benzylamines are described. These compounds are more effective than previously prepared compounds of this type for the mobilization of cadmium from its aged deposits in both the liver and the kidneys. An examination of the structural features of the more effective compounds for the mobilization of cadmium from its aged deposits reveals that the combination of a high molecular weight with a suitable amphipathic structure in which the polar and non-polar groups are in an appropriate balance are key features. A histopathological evaluation of the animals from which cadmium is removed by these compounds indicates no variations from the normal for the kidney and no evidence of hepatic damage resulting from the removal of the cadmium. On the basis of the trends observed in cadmium mobilizing efficacy, there are grounds for suspecting that agents which are significantly more effective than any prepared so far, should also be accessible.

Thioether suppression of cisplatin nephrotoxicity in the rat.

Six compounds containing a thioether group were examined as agents for the reduction of the nephrotoxicity caused by cisplatin (CDDP) in the rat. Of these, five were able to reduce the CDDP- induced nephrotoxicity when administered simultaneously with CDDP (8.0 mg/kg, iv). The compounds capable of reducing CDDP toxicity were L-methioninamide, cystathionine, methionyl-L-alanine, (methythio) acetic acid and 4-(methylthio) benzoic acid. Indices used to evaluate toxicity included body weight changes, BUN and serum creatinine levels and the histopathological examination of renal tissue. The platinum levels of renal tissue were determined but were found not to correlate well with other measures of renal function. Oral administration of the more effective of these compounds was found to provide a reduced level of protection against the nephrotoxicity caused by iv CDDP. The most effective of these compounds caused a very modest reduction in the anti-tumor activity of CDDP as measured against the L1210 murine leukemia.

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.

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.

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.

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.

Intracellular cadmium mobilization sequelae.

The consequences of the mobilization of aged intracellular cadmium from its in vivo deposits in mice by chelating agents were examined. The chelating agents used were BAL, sodium N-benzyl-D-glucamine dithiocarbamate (NaB), Diisopropyl meso-2,3-dimercaptosuccinate(Di-PDMS) and sodium N-(4-methoxybenzyl)-D-glucamine dithiocarbamate(4-Me0), all previously shown capable of causing statistically significant decreases in either renal or hepatic cadmium burdens in rodents. They were given at a level of 400 mumol/kg (i.p.) daily for 10 days to mice previously loaded with a total of 10 mg CdCl2.2.5 H2O/kg. Under these conditions a significant decrease in the renal cadmium level occurred following treatment with BAL, NaB, and 4-MeO; hepatic cadmium levels decreased significantly following treatment with NaB and 4-MeO. Pathological examination of the kidneys, liver, and testes in these animals showed that chelate mobilization of the cadmium produced no noticeable changes in the histopathology of these organs in comparison with that observed for the animals which had been given only cadmium and had undergone no chelate treatment. The results suggest that the mobilization of such aged cadmium from in vivo deposits need not result in any deleterious changes in the kidneys, liver or testes.

Pleural mesothelioma in a European spotted fallow deer (Cervus dama).

An adult, captive European spotted fallow deer (Cervus dama) was submitted for necropsy due to sudden death. Gross lesions consisted of serosanguinous fluid in the thoracic cavity with multiple, often confluent, nodules covering visceral and parietal pleura. Microscopic examination revealed tubular structures lined by cuboidal cells covering a delicate fibrous stroma. Gross and microscopic morphology was consistent with a mesothelioma.

Tonsillar granular cell tumour in a cat.

Granular cell tumour was diagnosed in a cat based on light and electron microscopic findings. Immunohistochemical findings for S-100 protein and neuron-specific enolase were negative, unlike its human counterpart.

Choroid plexus carcinoma in a dog.

Choroid plexus carcinoma was diagnosed in a 5-year-old female mixed breed dog which was euthanized due to progressive neurologic disease. Diagnosis of the tumour was based on gross and light microscopic findings following a complete necropsy. The chemical staining patterns in the case are compared with human choroid plexus tumours. The criteria for the distinction between benign and malignant variants of choroid plexus tumours are discussed.

Dependence on chelating agent properties of nephrotoxicity and testicular damage in male mice during cadmium decorporation.

An examination of the histopathological appearance of the kidneys of mice treated with cadmium chloride (s.c.) and simultaneously given 1 of 3 chelating agents (i.p.) reveals that the extent of nephrotoxicity is greatest when L-cysteine is the chelating agent. When either of 2 dithiocarbamates capable of mobilizing cadmium from its intracellular deposits, i.e. sodium N-methyl-D-glucamine dithiocarbamate (NaG) or sodium N-benzyl-D-glucamine dithiocarbamate (NaB) is used as the chelating agent, no morphological renal damage was evident. Under these same conditions the testes of the mice were protected to the extent of 95% by both of the dithiocarbamates, whereas the protection afforded by the L-cysteine was only about 50%. One factor governing the extent of nephrotoxicity appears to be the stability of the cadmium complexes which are formed and the manner in which this affects their behavior in vivo. Complexes which are preferentially excreted in the bile, cause little or no renal damage.

Meso-2,3-dimercaptosuccinic acid and sodium N-benzyl-N-dithiocarboxy-D-glucamine as antagonists for cadmium intoxication.

Orally administered meso-2,3-dimercaptosuccinic acid (DMSA) is an effective antagonist for acute oral cadmium chloride (1 mmol/kg) intoxication in mice when administered up to 8 h after cadmium ingestion. Administration of sodium N-benzyl-N-dithiocarboxy-D-glucamine (NaB) i.p. along with DMSA p.o. resulted in kidney and liver cadmium levels only marginally smaller than those obtained with DMSA alone. Both chelation treatment regimens permitted survival of 80% or more of the animals, in comparison to a survival rate of 40-50% in untreated animals. Intraperitoneally administered NaB by itself is a very effective antagonist for cadmium chloride administered intraperitoneally in either acute or chronic cadmium intoxication. A dose-response study was made of the mobilization of cadmium from the liver and kidney of cadmium-loaded mice by NaB; this showed that NaB is one of the most effective cadmium mobilizing agents developed to date. We have also confirmed the earlier report of Kojima and his co-workers of the ability of NaB to remove cadmium from animals which have been treated with cadmium over an extended period of time. NaB causes a very large increase in the biliary excretion of cadmium. Nuclear magnetic resonance (NMR) spectra of 113Cd in bile from treated animals and model solutions indicates that such cadmium is undergoing rapid ligand exchange.

Pineoblastoma in a cockatiel.

Pineoblastoma, a primitive neoplasm of pineal gland origin, was diagnosed in a cockatiel based on gross, histopathological, and electron-microscopic findings.

The effect of zinc on the dithiocarbamate-induced mobilization of cadmium deposits in mice.

In comparison with similar experiments in which no zinc acetate was used, the addition of small amounts of zinc acetate to sodium N-methyl-N-dithiocarboxyglucamine produces a significant increase in the amount of cadmium mobilized from the liver and kidneys of mice loaded ip with 10 mg CdCl2.2.5H2O/kg 2 wk prior to the initiation of treatment. Neither treatment results in the transport of significant amounts of cadmium to the brain. The injection of zinc acetate alone did not produce this effect. Experiments in which zinc acetate in drinking water was administered to cadmium-loaded animals showed that the liver and kidney cadmium levels were significantly increased, presumably via zinc-mediated processes in which cadmium from other organs was mobilized to the liver and kidneys.

Antagonists for acute oral cadmium chloride intoxication.

An examination has been carried out on the relative efficacy of a number of chelating agents when acting as antagonists for oral cadmium chloride intoxication in mice. The compounds were administered orally after the oral administration of cadmium chloride at 1 mmol/kg. Of the compounds examined, several were useful in terms of enhancing survival, but by far the most effective in both enhancing survival and leaving minimal residual levels of cadmium in the liver and the kidney, was meso-2,3-dimercaptosuccinic acid (DMSA). Several polyaminocarboxylic acids also enhanced survival. The most effective of these in reducing liver and kidney levels of cadmium were diethylenetriaminepentaacetic acid (DTPA), trans-1,2-diaminocyclohexane-N,N,N'N'-tetraacetic acid (CDTA), and triethylenetetraminehexaacetic acid (TTHA). D-Penicillamine (DPA) was found to promote survival but also led to kidney cadmium levels higher than those found in the controls. Sodium 2,3-dimercaptopropane-1-sulfonate (DMPS) was as effective in promoting survival as DMSA but left levels of cadmium in the kidney and liver that were approximately four times greater than those found with DMSA.