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M A Basinger

Publications and source records attributed to M A Basinger.

51 records · Page 3Linked to original sources
PubMed1981

Structural requirements for chelate antidotal efficacy in acute antimony(III) intoxication.

The LD50 for i.p. potassium antimonyl tartrate was determined to be 54.6 mg/kg in mice, with a 95% confidence range of 48.4 to 61.7 mg/kg. An examination of the antidotal efficacy of a number of different structural types of chelating agents showed that very few types were able to act as antidotes when potassium antimonyl tartrate was administered i.p. to mice at a level of 120 mg/kg. The most effective antidotes, by a substantial margin, were the water soluble vicinal dithiols: 2,3-dimercaptosuccinic acid and sodium 2.3-dimercaptopropane-1-sulfonate, with the first of these being significantly better than the second. Appreciably less effective, but still useful, was D-penicillamine. At this level of administration of antimony(III), BAL is not an effective antidote. Among other chelating agents which were also not effective at this level of antimony(III) are tartaric acid, EDTA, cysteine, sodium diethyldithiocarbamate and potassium dithiooxalate.

Animals↗
PubMed1981

Tiron (sodium 4,5-dihydroxybenzene-1,3-disulfonate) as an antidote for acute uranium intoxication in mice.

Tiron (sodium 4,5-dihydroxybenzene-1,3-disulfonate) administered intraperitoneally was found to antagonize the lethal action of intraperitoneally induced uranium(VI) toxicity. In a comparative study Tiron was evaluated against Na3CaDTPA (sodium calcium diethylenetriaminepentaacetate). The ability of these compounds to detoxify the uranyl ion in simple and complexed form and their efficacy in delayed treatment regimens and determined. Toxicities of the complexes were assessed by the administration of uranyl acetate at levels of 40 mg/kg or 80 mg/kg complexed at a mole ratio of 3:1 or 2:1 of chelating agent to uranium, prior to injection, followed by two additional doses of chelating agent given one and three hours later at a 10:1 mole ratio of chelating agent to uranium. Therapy in delayed treatment regimens consisted of three injections of antidote given 20 minutes, one hour, and three hours, at a 10:1 mole ratio of chelating agent to uranium, subsequent to an injection of 40 mg/kg uranyl acetate. Survival rates for animals receiving multiple injections of Tiron were enhanced over those receiving Na3CaDTPA. The low inherent toxicity of Tiron may make it appropriate for possible clinical application.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed1980

Comparison of standard chelating agents for acute mercuric chloride poisoning in mice.

A comparison in mice has been made of the effectiveness of five chelating agents used clinically for acute mercuric chloride poisoning, or recommended for such use. The compounds examined were N-Acetyl-D,L-penicillamine (NAPA), D-penicillamine (DPA), 2,3-dimercaptosuccinic acid (DMSA), sodium 2,3-dimercaptopropanesulfonate (DMPS), and 2,3-dimercaptopropanol-1 (BAL). The test of effectiveness was their ability to reduce the mortality of acute mercuric chloride poisoning when administered 20 minutes after the mercury at chelate:mercury mole ratios of 10, 15, 20, and 30. All except BAL were found to be effective at the highest mole ratio tested, but N-Acetyl-D,L-penicillamine and sodium 2,3-dimercaptopropanesulfonate were significantly more effective than DMSA and BAL at mole ratios of 10:1. The relative effectiveness does not correlate with available data on stability constants. The toxicity of BAL itself becomes apparent at mole ratios of 20:1 and above.

Animals↗
PubMed1980

The relative effectiveness of some chelating agents in acute copper intoxication in the mouse.

The relative efficacy of 9 chelating agents in offsetting the acute toxicity of ip copper sulfate has been determined. Included in this group are almost all of the compounds which have been used in, or suggested for use in human cases of acute or chronic copper toxicity. Under the conditions used, sodium 2,3-dimercapto-1-propanesulfonate is by far the most effective antidote of the compounds examined.

Animals↗
PubMed1980

Relative efficacy of chelating agents as antidotes for acute nickel(II) acetate intoxication.

The relative efficacy of 14 chelating agents in alleviating acute nickel(II) acetate (ip) intoxication has been determined. The LD50 for ip nickel(II) acetate in mice was found to be 45.7 mg/kg with a 95% confidence limit of 39.2--53.3 mg/kg. For a level of 62 mg/kg ip of nickel(II) acetate (i.e. approximately LD90 or greater), the most effective antidotes were D-penicillamine and Na2CaEDTA, but several other chelating agents with rather different arrangements of donor atoms were almost as effective. The acetylation of the amino group in penicillamine to give N-Acetyl-D,L-penicillamine effectively destroys the antidotal action, as would be expected if coordination to the nitrogen were essential to the process.

Animals↗
PubMed1979

Restrictions on the applicability of mixed ligand chelate therapy (MLC) in acute cadmium intoxication.

An experimental study of the comparative effectiveness of single and mixed ligand chelates as antidotes for acute cadmium poisoning reveals few appreciable differences when the cadmium (as cadmium chloride or acetate) is administered ip. In each case the mixed ligand chelate system showed little or no improvement over the results obtained with the most effective of the individual components. This procedure, using mixed ligand chelate systems, may well be one which is limited to conditions more narrowly similar to those reported by Schubert and Derr (1978). It does not appear to possess the broad range of applicability which might be expected from the equilibrium principles on which it is based. By comparing our data with previous studies it can be seen that Na2CaEDTA is capable of offsetting the lethality of ip cadmium chloride when the latter is administered at rather higher levels that have previously been counteracted by any of the sulfur containing chelating agents tested to date.

Acute Disease↗
PubMedDate not supplied

Design of in vivo cadmium-mobilizing agents: synthesis and properties of monobenzyl meso-2,3-dimercaptosuccinate.

A novel method for the synthesis of monoesters of meso-2,3-dimercaptosuccinic acid (DMSA) is presented which utilizes the reaction of the vicinal sulfhydryl-protected anhydride with the corresponding alcohol in the presence of a base. The product is then treated successively with mercuric chloride to remove the protecting group and form the mercuric complex, and hydrogen sulfide to regenerate thiol groups by removal of mercury as HgS. This strategy was exploited to synthesize monobenzyl meso-2,3-dimercaptosuccinate (MBzDMS), C6H5CH2O(O)CCH(SH)CH(SH)C(O)OH, and demonstrates a feasible synthesis of monoesters difficult to obtain by direct esterification, via the use of the reactive anhydride. The resultant compound was found to be an effective cadminum-mobilizing agent when used with cadmium-exposed rats or mice and when administered by any one of several routes (ip, iv, po). This monobenzyl ester (MBzDMS) of DMSA was found to be somewhat less effective than the corresponding monoisoamyl ester (Mi-ADMS) in mobilizing cadmium from such cadmium deposits. The ability of MBzDMS to mobilize cadmium into the urine is significantly decreased by the coadministration of p-aminobenzoic acid, in support of the hypothesis that MBzDMS enters renal cells via an anion transport system. An analysis of the structural features of vicinal dithiols examined as antagonists for chronic cadmium intoxication allows a hypothesis to be formulated indicating essential features required for the design of effective new cadmium antagonists of this type.

Administration, Oral↗
PubMedDate not supplied

Structure/activity relationships affecting the ability of monoanionic 3-hydroxyprid-4-ones to mobilize iron.

Current attempts to remove iron from individuals suffering from iron overload have encountered difficulty due to the toxicity of the administered chelating agent. In a search for iron chelators of potentially reduced toxicity, nine monoanionic compounds have been examined. To determine the chemical features which govern their ability to induce the excretion of iron, the compounds were administered to female Sprague-Dawley rats. All carboxylate derivatives were tested for biliary excretion following iv injection, as well as for urinary excretion following iv or po injection. Sulfonate derivatives were tested for biliary and urinary excretion as well, but only one representative compound was tested po. The biological activity of the new pyridinones was compared to that of 1,2-dimethyl-3-hydroxypyrid-4-one, L1, which served as the standard. While none of the chelators was able to surpass L1 in both urinary and biliary iron excretion, all of the chelators at least equaled L1 in one of these two areas following iv administration. Two derivatives surpassed the standard in mobilizing iron into the bile, and all others were statistically equivalent. In terms of urinary excretion, two compounds were equivalent to L1 after iv administration, although none of the compounds equaled L1 when administered orally. The structure of (1,4-dihydro-3-hydroxy-2-methyl-4-oxo-1- pyridyl)methanecarboxylic acid was determined by X-ray diffraction, as this compound showed higher activity than previously reported by other investigators. We speculate that these chelators utilize organ-specific, monoanionic transport systems in the liver and kidneys to mobilize iron and that their toxicity may be substantially less than that of their neutral analogs.

Animals↗
PubMedDate not supplied

Chelate antidotes for sodium vanadate and vanadyl sulfate intoxication in mice.

Eighteen different chelating agents, including all of those previously shown to have a protective action in vanadium intoxication, have been compared as antidotes for acute vanadium intoxication using mice. Of these compounds, those found to be effective antidotes for both vanadate (VO3(-3)) and vanadyl (VO2+) include ascorbic acid, deferoxamine, D-penicillamine, sodium calcium diethylenetriaminepentaacetic acid (Na3CaDTPA), Na2CaEDTA, glutathione, Tiron, and ethylenediaminetetra(methylene phosphonate). Of the compounds examined, ascorbic acid appeared to be the most promising for human use. When administered at the levels used in this study, it is an effective antidote for intoxication due to either the vanadate or the vanadyl ion. Certain compounds are able to act as antidotes for vanadate solely by virtue of their action as a reducing agent; when these compounds are unable to form complexes with the reduction product (vanadyl ion), they are effective antidotes for the higher oxidation state only when the concentration of vanadyl produced is less than the level that results in toxic effects.

Animals↗
PubMedDate not supplied

In vivo screening of potential antidotes for chronic cadmium intoxication.

Nineteen chelating agents have been screened under identical conditions of metal loading in an attempt to establish their relative ability to mobilize cadmium from the liver and kidney in mice with chronic cadmium intoxication. The compounds investigated were divided into five groups: polyaminocarboxylic acids, monothiols, dithiols, macrocycles, and a miscellaneous category. Only 2,3-dimercaptopropanol (BAL) and sodium diethyldithiocarbamate (NaDDTC) were able to produce a statistically significant (at the 95% level) reduction in the cadmium content of the kidney. The closely related dithiols sodium 2,3-dimercaptopropane-1-sulfonate and 2,3-dimercaptosuccinic acid produced statistically significant increases in the liver cadmium contents, as did N-(2-mercaptopropionyl)-glycine. The reduction in kidney cadmium levels produced by both BAL and NaDDTC was just under 40%.

Animals↗
PubMedDate not supplied

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.

Animals↗
PubMedDate not supplied

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.

Animals↗
PubMedDate not supplied

Thiol and thioether suppression of cis-platinum-induced nephrotoxicity in rats bearing the Walker 256 carcinosarcoma.

An examination of eighteen thiols and thio ethers revealed that the simultaneous administration of several of these with cis-platinum (CDDP) at 7.5 mg/kg (25 mumols/kg) iv, as a single injection to rats bearing the Walker 256 carcinosarcoma led to significant reduction in the nephrotoxicity typically found with cis-platinum, and no apparent interference in its anti-neoplastic action towards this tumor. The thiols and thiol ethers were administered at a twenty-fold molar excess to the CDDP and were combined with the CDDP immediately prior to administration. The most effective compounds in suppression nephrotoxicity were D-, and L-methionine, methyl and ethyl L-methioninate, and N-acetyl-D, L-methionine.

Animals↗