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Biomedical subjects

M A Basinger

Publications and source records attributed to M A Basinger.

At least 37 records · Page 2Linked to original sources
PubMed1989

Dithiocarbamate-induced biliary platinum excretion and the control of cis-platinum nephrotoxicity.

Treatment with any one of six different dithiocarbamates subsequent to the administration of cis-platinum (CDDP) is shown to promote the biliary excretion of platinum. The administration of the most effective of these compounds, sodium diethyldithiocarbamate (DDTC) at 1.57 mmol/kg, led to a 30-fold increase in the biliary excretion of platinum. For the other dithiocarbamates investigated, a similar dosage led to increases ranging from approximately 5-fold for sodium iminodiacetic acid dithiocarbamate, to 26-fold for sodium sarcosine dithiocarbamate. The presence of alkyl groups on the nitrogen of the dithiocarbamate increased the effectiveness of the compounds. There is no increase in the platinum levels of the brain when DDTC is used in this manner. A histopathological evaluation of the kidneys of rats given 15 mg CDDP/kg in 6.3% saline with and without the use of dithiocarbamates for renal protection shows significant additional protection due to the use of the dithiocarbamates. Dithiocarbamates given at an appropriate dosing schedule can lead to a significant reduction in the renal damage which is revealed by microphotographs. It is suggested that part of the renal protection obtained by the use of dithiocarbamates may be due to this shift of platinum excretion to the bile which obviates additional renal exposure to platinum. It was also found that the simultaneous injection of a dithiocarbamate with the cis-platinum has no obvious effect on the anti-cancer action of cis-platinum against the Walker 256 carcinosarcoma in rats.

Animals↗
PubMed1989

A phase II study of the efficacy of diamminedichloroplatinum (cisplatin) for the control of locally recurrent and intransit malignant melanoma of the extremities using tourniquet outflow-occlusion techniques.

A phase II trial was conducted with 15 patients (mean age of 65.7 years) with locally recurrent or intransit melanoma of the extremities. After total outflow occlusion with pneumatic tourniquet, the cell-cycle nonspecific anti-neoplastic agent cis-diamminedicholoroplatinum (CDDP) was infused intra-arterially in a mean dose of 26.7 mg/m2 per infusion (2.6 infusions per patient). The aim of this study was to determine the efficacy of CDDP infusion for control of intransit and recurrent melanoma of the extremities. Three to four weeks postinfusion, all visible residual disease was resected. Partial remissions were observed in ten patients (67%); five patients achieved stable disease status. No patient had complete regression of disease. At an average follow-up interval of 18.3 months (range 4-44 months), the mean local/regional disease-free survival was 14.8 months. Eighty per cent of patients (twelve of 15) had local/regional control of disease at an average follow-up of 14.8 months after CDDP infusion and surgical resection. Of five melanoma-related deaths, three patients had had no local/regional recurrence at the time of their demise. Three compartment syndromes resulted as a complication of the infusional therapy and occurred within 1-3 days of the treatment. In vitro growth of melanoma from lymph nodes draining the infused area was seen in all subjects studied. Outgrowth from tumor within the tourniquet infusion area was observed in two patients, both of whom experienced recurrences clinically at 24-months' postinfusion. Pharmacokinetic data of total CDDP concentrations from tissue and blood (n = 4) were available from pretreatment to 1 hour post-therapy. Biopsy data from patients pre- and post-treatment suggest substantial tumor uptake of CDDP as compared to local or distal normal skin, with minimal CDDP loss to the systemic circulation. Pharmacologic and clinical data of this phase II trial suggest that intraarterial infusion with tourniquet outflow-occlusion augments tumor tissue levels of CDDP within the infused extremity and enhances local control of high-risk and intransit disease.

Adult↗
PubMed1988

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.

Acute Kidney Injury↗
PubMed1988

N-alkyl-N-dithiocarboxy-D-glucamine analogs as cadmium antagonists: synthesis and evaluation of the n-propyl, n-butyl, and n-amyl derivatives.

N-(n-Propyl)-, N-(n-butyl)-, and N-(n-amyl)-N-dithiocarboxy-D-glucamine were newly synthesized by (a) addition of each n-alkylamine to glucose, (b) high-pressure catalytic reduction of each glucosamine thus formed to the corresponding glucamine, and (c) reaction of the resultant secondary amines with CS2 to form the dithiocarboxy derivatives. Each compound was evaluated as an antagonist of acute cadmium (Cd) toxicity and as a complexing agent for intracellular metallothionein-bound Cd (Cd-MT) in mice. N-Benzyl-N-dithiocarboxy-D-glucamine (BDCG) was used as a positive control compound. Each congener afforded partial or complete protection against the lethal effects of 10.0 mg/kg CdCl2.2.5 H2O, and retarded accumulation of Cd in livers and kidneys when given 2 h after the acutely toxic dose of Cd. Each derivative was also effective in mobilizing Cd from MT-bound sites in livers and kidneys of mice which had received a sub-lethal dose of CdCl2 along with 109CdCl2 2 weeks earlier. Excretion of mobilized Cd was almost exclusively by the fecal route. Potency of the analogs, as well as the octanol/aqueous partition coefficients, increased with the overall length of the N-(n-alkyl) carbon chain. Each compound readily complexed Cd from partially purified Cd-MT in vitro. Serum Cd from mice treated with BDCG was associated principally with proteins of high molecular weight.

Animals↗
PubMed1988

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.

Administration, Oral↗
PubMed1988

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.

Administration, Oral↗
PubMed1987

Chelating-agent suppression of cadmium-induced hepatotoxicity.

The administration of sodium N-methyl-N-dithiocarboxy-D-glucamine (NaG) at 500 mg/kg, i.p., or sodium calcium diethylenetriaminepentaacetic acid (DTPA) at 632.5 mg/kg, i.p., reduces the serum enzyme levels characteristic of hepatic damage following the intravenous administration of cadmium chloride (3.5 mg CdCl2.2.5H2O/kg). Some effect on serum enzyme levels was found even when the interval between administration of cadmium chloride and that of the antagonist was as great as 4 h. The enzymes examined included aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (SGPT), and alkaline phosphatase (AP). A histopathological examination of the livers of such animals also reveals the presence of a significant protective action.

Alanine Transaminase↗
PubMed1986

Inhibition of cis-diamminedichloroplatinum (II)--induced renal toxicity in the rat.

The hydroxyl-containing dithiocarbamates, sodium (di(hydroxyethl)-dithiocarbamate (NaY) and sodium N-methyl, N-dithiocarboxy-D-glucamine (NaG), appear to possess definite advantages over sodium diethyldithiocarbamate (DDTC) in reducing the cis-dichlorodiammineplatinum (Cis-Pt)-induced renal damage in rats given Cis-Pt as an IV bolus of 7.5 mg/kg 1 h before the IP administration of the dithiocarbamate. Renal damage, as estimated by blood urea nitrogen (BUN) values and serum creatinine levels, was less at all times up until sacrifice in animals given NaY or NaG than in those given DDTC. An even more effective method for suppression of Cis-Pt renal toxicity is to use a combination of procedures. The most efficacious combination involves a 24-h pretreatment with DDTC or NaG plus acetazolamide and normal saline hydration 30 min before administration of Cis-Pt, followed by post-treatment with NaG. With this combination therapy renal function can be almost completely spared. Although DDTC or NaG pretreatment is highly effective when used in conjunction with NaG post-treatment, DDTC or NaG pretreatment alone has no renal sparing effect on renal function or renal platinum accumulation. In experiments in which antidotes were given 1 h after Cis-Pt and the animals were followed up for 75 days, a chronic interstitial nephritis at 75 days, suggesting a persistent cell-mediated immune response to Cis-Pt-induced renal damage, may be the basis for chronically abnormal renal function resulting from Cis-Pt. Treatment with all three dithiocarbamates, NaY, NaG, and DDTC, reduced the intensity of this cellular reaction and also reduced platinum levels in the kidneys. Although NaY and NaG are effective heavy metal chelators and renal function is spared and kidney platinum levels are substantially reduced by the dithiocarbamates, no parallel loss of antineoplastic activity by Cis-Pt on the rat Walker carcinoma was observed. Since the dithiocarbamates have no known human toxicity that would disqualify their clinical use, phase 1 clinical trials are indicated.

Animals↗
PubMed1986

Control of some aspects of cis-platinum nephrotoxicity.

The elevations of blood urea nitrogen and serum creatinine caused by cis-platinum in rats can be prevented by a combination of procedures centered around the administration of sodium N-methyl-N-dithiocarboxyglucamine (NaG), before and very soon after the cis-platinum is administered in hypertonic (4.5%) saline. Elevations in-blood urea nitrogen and serum creatinine levels subsequent to such treatment are largely eliminated. These same procedures appear to have no effect on the anti-tumor action of the cis-platinum, as measured by tumor size and mass and by survival times, in female Sprague-Dawley rats inoculated with the Walker 256 carcinoma. The degree of myelosuppression, as measured by the white blood cell count is also slightly reduced. White blood cell counts returned to normal values more rapidly in animals treated with NaG than in those treated with cis-platinum alone. An examination of the dose-response curve for the suppression of cis-platinum nephrotoxicity by NaG shows that this can be achieved with mole ratios of NaG: cis-platinum as low as 1:1 given after appropriate pretreatment. A preliminary structure-activity study on the suppression of cis-platinum induced elevations in blood urea nitrogen and serum creatinine by four closely related dithiocarbamates shows that this can also be achieved effectively by several dithiocarbamates in which the nitrogen atom bears polar substituents.

Animals↗
PubMed1986

Structural effects in the dithiocarbamate-enhanced biliary excretion of cadmium.

The dithiocarbamate enhancement of the biliary excretion of cadmium in rats loaded with cadmium (by either the oral or sc route) was found to be strongly dependent on the structure of the groups attached to the nitrogen atom of the dithiocarbamate moiety. Those dithiocarbamates containing hydroxyl-bearing attached groups were found to be capable of causing the greatest enhancement of the cadmium content of the bile. For the compounds of this type that were examined, this enhancement of biliary cadmium content varied from 30-fold to over 2000-fold. No enhancement of the biliary excretion of cadmium was found subsequent to the administration of sodium diethyldithiocarbamate, though this compound is known to cause a significant increase in the fecal excretion of cadmium.

Administration, Oral↗
PubMed1985

Antidotes for gold (sodium bis[thiosulfato]gold[I]) intoxication in mice.

Eight compounds were examined to determine their relative efficacy as antidotes in acute gold intoxication in mice after the intraperitoneal injection of 200 mg/kg of Na3 [Au(S2O3)2] X 2H2O. Of the compounds examined, 2,3 dimercaptosuccinic acid was the most effective antidote. It was noted that with D-penicillamine those animals which did not survive died sooner (in a matter of hours) than the corresponding control animals which had received no antidote (about 3 days). In subsequent experiments in which Na3 [Au(S2O3)2] X 2H2O was administered at the lower level of 140 mg/kg, 2,3 dimercaptosuccinic acid showed itself to be capable of reducing kidney gold levels by a factor of about 5 and liver gold levels by a factor of approximately 2.

Animals↗
PubMed1983

Ethylenediaminetetra(methylenephosphonic) acid (EDTPO) as a therapeutic chelating agent.

Ethylenediaminetetra(methylenephosphonic) acid (EDTPO), when administered as its calcium salt, is an effective antidote for acute intoxication by a number of metal ions. Significant antidotal action was found for the following cations: Cd2+, Ni2+, Zn2+, Pb2+, Be2+ and UO2+(2). Because EDTPO is capable of chelating more than one calcium ion, better results were obtained when the Ca2EDTPO complex was administered.

Animals↗
PubMed1983

Antidotes for acute bismuth intoxication.

Nine chelating agents were tested as antidotes for acute bismuth intoxication in mice. Of these, those with sulfhydryl groups, adjacent aromatic hydroxy groups or appropriately positioned phosphonate groups proved themselves to be effective antidotes. Of the compounds currently approved for therapeutic use, D-penicillamine was the most effective.

Acute Disease↗
PubMed1982

A hypothesis for the selection of chelate antidotes for toxic metals.

The problem of finding antidotes for toxic metal species for which antidotes have not been previously reported can be approached via a consideration of the metal-ion preferences of chelating agents already in clinical use. The metal ion preferences of six types of chelating agents together with information on antidotes used for other elements in the same family in the periodic table can be used to obtain a preliminary notion of which of these six structural types might furnish efficacious antidotes. The results of animal tests on a few of these chelate types can then serve as a guide in the selection of further compounds for testing. The data from the literature on antidotes for 20 toxic metal ions is summarized to assist the selection process.

Animals↗
PubMed1982

A comparison of diethyldithiocarbamate and EDTA as antidotes for acute cadmium intoxication.

For mice which have been given the cadmium equivalent of CdCl2 X 2 1/2H2O at a level of 10 mg/kg, diethyldithiocarbamate (DDTC) administration at 500 mg/kg leads to a higher survival rate than is found with Na2CaEDTA under identical conditions. This occurs when the interval between administration of the cadmium salt and the antidote is either one or two hours. The surviving animals, however, are found to have appreciable levels of cadmium in their brain, liver and kidney when they were treated with DDTC, though their behavior appeared to be normal. The use of 50 mg/kg of DDTC after 2 hr in such cadmium poisoned mice also leads to a higher survival rate and reduced amounts of cadmium retained in the brain, liver and kidney. Unlike the other chelating agents which have been reported as useful in acute cadmium intoxication, DDTC appears to act by forming a lipid soluble complex which is largely immobilized in lipid containing tissues of the animal's body.

Acute Disease↗
PubMed1982

Antidotes for acute beryllium sulfate intoxication in mice.

Eleven water soluble chelating agents were tested as antidotes for acute beryllium sulfate intoxication in mice. The most effective of these was sodium 4,5-dihydroxy-1,3-benzenedisulfonate (Tiron). At the level of administration of beryllium used, aurin tricarboxylic acid is not an antidote.

Animals↗
PubMed1982

Antagonism of acute copper(II)-induced renal lesions by sodium 2,3-dimercaptopropanesulfonate.

Acute copper(II) sulfate poisoning in the mouse induces renal tubular degeneration and necrosis. Timely administration of sodium 2,3-dimercaptopropane-sulfonate (DMPS) effectively prevented the development of the morphological renal sequelae of copper intoxication. During the time course of this study (5 days), no copper-induced hepatic lesions were observed. DMPS and its preformed copper complex possess low inherent toxicity with no hepatorenal lesions occurring over a 5-day period. These findings suggest that DMPS may be an effective antidote in acute and chronic copper poisoning in humans.

Acute Kidney Injury↗