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Biomedical subjects

G R Gale

Publications and source records attributed to G R Gale.

At least 55 records · Page 3Linked to original sources
PubMed1986

Effects of monoalkyl dithiocarabamates on mobilization of cadmium in the mouse.

Monoalkyl dithiocarbamates are capable of mobilizing cadmium from aged intracellular deposits in which the cadmium is largely present in metallothionein. The sodium salts of monomethyl, ethyl, n-propyl, and n-butyl dithiocarbamates have been prepared, characterized, and examined for their relative ability to mobilize cadmium from such aged deposits in the kidneys, liver, spleen, testes, brain, and pancreas as well as from the whole body, using sodium diethyl dithiocarbamate as the positive control. Alterations in the structure of the dithiocarbamates can be correlated with alterations in organ cadmium levels. The acute toxicity of these compounds is sufficiently greater than disubstituted dithiocarbamates that their use would appear to possess few advantages, although they do seem to be more effective in reducing testicular cadmium levels.

Animals↗
PubMed1986

Comparative antidotal effects of diethyldithiocarbamate, dimercaptosuccinate, and diethylenetriaminepentaacetate against cadmium-induced testicular toxicity in mice.

The compounds diethyldithiocarbamate (DDTC, Dithiocarb), 2,3-dimercaptosuccinic acid (DMSA), and diethylenetriaminepentaacetic acid (DTPA) were evaluated for effectiveness in protecting mouse testes following administration of an LD100 dose of CdCl2 X 2.5 H2O (Cd). Toxicologic responses were assessed by light microscopic techniques. DTPA gave the most effective testicular protection of the three compounds when given within 30 minutes prior to Cd, but only DDTC was effective when given 30 minutes or longer after Cd. Degenerative changes were minimal when DDTC was given as late as three hours after Cd, and were mild following a four-hour interval. However, the changes were marked, but less severe than in mice receiving Cd only, when DDTC was administered five hours after Cd.

Animals↗
PubMed1986

Effects of diethyldithiocarbamate and selected analogs on lead metabolism in mice.

Diethyldithiocarbamate (DDTC) and certain of its N,N-disubstituted analogs were evaluated for effectiveness in reducing organ concentrations and whole body burdens of lead (Pb) in mice which had received 0.06 mg of Pb(II) acetate along with 2.0 microCi of 210Pb 9 days earlier. CaNa2EDTA was used as a positive control for studies in which the compounds were administered ip, and meso-2,3-dimercaptosuccinic acid (DMSA) was used as a positive control for po studies. DDTC was more effective than EDTA in lowering the whole body Pb burdens after 5 ip injections, while N-methyl-N-dithiocarboxyglucamine (MDCG) was less active than EDTA. The other 4 analogs tested were inactive. When DDTC (1.5 mmoles/kg) was coadministered with EDTA (1.5 mmoles/kg), the reduction of total body Pb burdens was significantly greater than that attained with either compound alone at 3.0 mmoles/kg. DDTC was particularly effective in reducing hepatic and splenic Pb concentrations, but was less active than EDTA in lowering the Pb content of bone, kidneys, and brain. Excretion of Pb following ip treatment with EDTA, DDTC, or MDCG was predominantly by the fecal route. DDTC was significantly more effective than DMSA at an equimolar dose in reducing whole body Pb burdens when each was given po. However, po administration of DDTC caused a substantial increase in brain Pb levels.

Animals↗
PubMed1986

Comparative effects of parenteral and oral administration of selected dithiocarbamates on body burdens and organ distribution of cadmium in mice.

Diethyldithiocarbamate (DDTC), N-methyl-N-dithiocarboxyglucamine (MDCG), and 4-carboxamidopiperidine-N-dithiocarboxylate (CAP-N-DTC) were compared at equimolar doses administered by the ip and po routes for effectiveness in mobilizing metallothionein (MT)-bound cadmium (Cd) using 109Cd in mice. DDTC was highly effective by both routes in lowering hepatic, renal, and splenic Cd levels, but enhanced redistribution of Cd to testes and brain. While MDCG and CAP-N-DTC were much less active by the oral route, each effected a significant reduction of renal Cd levels, and MDCG reduced the testicular Cd burden. Neither analog lowered hepatic Cd levels impressively when given po.

Administration, Oral↗
PubMed1986

Effects of caffeine on acetaminophen-induced hepatotoxicity and cadmium redistribution in mice.

When caffeine (CAF) was given ip to BDF1 mice immediately after an otherwise hepatotoxic dose of acetaminophen (ACM), the hepatotoxic action of ACM was abolished and there was no concomitant redistribution of previously-administered cadmium (Cd) from livers to kidneys as occurred in mice which received ACM only. These observations were not in accord with the recently reported enhancement of ACM hepatotoxicity by CAF following coadministration in rats (Toxicology 34, 95-101, 1985). Conversely, pretreatment of mice with CAF for 3 days followed by ACM injection enhanced the hepatotoxicity of ACM and caused a greater mobilization of Cd from livers to kidneys than was found in mice given ACM alone. The ACM-CAF interaction in mice is thus similar to the ACM-ethanol interaction in rats (Gastroenterology 80, 140-148, 1981; J. Pharmacol. Exptl. Therap. 218, 805-810, 1981). It is proposed that CAF interferes with the metabolism of ACM when administered concomitantly, but induces the microsomal mixed function oxidase system when used in a pretreatment regimen, leading to a more rapid rate of formation of the hepatotoxic arylating ACM biotransformation product.

Acetaminophen↗
PubMed1985

Chemistry and antitumor evaluation of selected classical 2,4-diaminoquinazoline analogues of folic acid.

A series of six 2,4-diaminoquinazoline analogues of folic acid which bear close structural resemblance to methotrexate, 1a, were synthesized by unequivocal routes. Three of these have not been described previously, while complete structural characterization of the remaining compounds is presented for the first time. Each of the compounds was a potent inhibitor of dihydrofolate reductase (DHFR) from rat liver or L1210 leukemia cells having I50 values in a range similar to that of 1a. However, a wide divergence in inhibitory activity toward the growth of human gastrointestinal adenocarcinoma or L1210 leukemia cells in vitro was observed. Compounds having a normal folate configuration at positions 9 and 10 were more inhibitory than their isomeric reversed-bridge counterparts. The N-formyl modifications were the least active of the compounds studied. Unsubstituted or N-methyl modifications competed effectively with tritiated 1a for uptake into L1210 leukemia cells, while N-formyl modifications did not. Against an L1210 cell line resistant to 1a by virtue of altered transport and overproduction of DHFR, partial but not complete cross-resistance was observed for certain analogues. Of the three compounds selected for in vivo evaluation against L1210 leukemia in mice, two had a similar level of antitumor activity to that of 1a. The compound 5,8-dideazamethopterin, 2b, however, was slightly more active than 1a but at substantially reduced dose levels.

Adenocarcinoma↗
PubMed1985

Effects of diethyldithiocarbamate and selected analogs on cadmium metabolism following chronic cadmium ingestion.

Effects of ip treatment with diethyldithiocarbamate (DDTC), 4-carboxamidopiperidine-N-dithiocarboxylate (CAP-N-DTC), and N-methyl-N-dithiocarboxyglucamine (MDCG) on cadmium (Cd) levels in selected mouse organs and tissues were assessed after mice were offered deionized water containing 0.05 mg/ml of CdCl2 X 2.5 H2O, 10 mg/ml of sucrose, and 0.125 microCi/ml of carrier-free 109-CdCl2 as the sole drinking fluid for 15 days. Only 0.31 +/- 0.01 % of the ingested Cd was absorbed. Data obtained following treatment were compared with those obtained earlier in similar studies following ip Cd injection. In contrast to its action when administered after ip Cd injection, DDTC enhanced hepatic Cd burdens in mice which received Cd po. DDTC did, however, reduce renal Cd levels markedly after Cd ingestion, while enhancing brain Cd levels. CAP-N-DTC and MDCG, which were shown earlier to have no effect on Cd levels in striated muscle following ip Cd administration, effected significant reduction of muscle Cd concentrations after Cd administration po, while also reducing hepatic and renal Cd levels significantly. It was concluded that certain dithiocarbamates effectively mobilize and promote excretion of Cd which has been absorbed from one of the natural portals of entry.

Administration, Oral↗
PubMed1985

Effects of substituted dithiocarbamates on distribution and excretion of inorganic mercury in mice.

Diethyldithiocarbamate (DDTC) and six of its N,N-disubstituted congeners were evaluated for their relative efficacies in mobilizing and promoting excretion of mercury (Hg++) using mice which had been given 203Hg++; D-penicillamine (PEN) was used as a positive control compound. While none was as effective as PEN when compared on a molar dose basis, significant activity as assessed by reduction of whole body 203Hg burden, was observed following treatment with three of the analogs. The order of effectiveness was PEN greater than N-methyl-N-dithiocarboxyglucamine (MDCG) greater than di(carboxymethyl)dithiocarbamate (DCDC) greater than di(hydroxyethyl)dithiocarbamate (DHDC).

Animals↗
PubMed1985

Effects of diethyldithiocarbamate and N-methyl-N-dithiocarboxyglucamine on murine hepatic cadmium-metallothionein in vitro.

A study was made of the effects of diethyldithiocarbamate (DDTC) and N-methyl-N-dithiocarboxyglucamine (MDCG) on partially purified cadmium-metallothionein (Cd-MT) in vitro obtained from livers of mice previously injected with CdCl2 containing 109CdCl2. Analytical Sephadex G-75 gel filtration showed that MDCG effected a time-dependent removal of Cd from MT, and 99% of the Cd was recovered as the soluble Cd(MDCG)2 complex after 24 hr of incubation. Only a portion of Cd of Cd-MT was complexed by DDTC after 24 hr of incubation; 44% remained as Cd-MT, and the net loss following centrifugation prior to application of the samples to the column corresponded to 56% of the Cd originally present. It was proposed that MDCG complexes the 4 g-atoms of Cd in cluster A of MT as well as the 3 g-atoms in cluster B, while DDTC complexes only the 4 g-atoms of Cd in cluster A.

Animals↗
PubMed1984

Effects of sodium N-methyl-N-dithiocarboxyglucamine on cadmium distribution and excretion.

Sodium N-methyl-N-dithiocarboxyglucamine (MDCG) was evaluated for its efficacy in mobilizing and promoting excretion of metallothionein-bound 109Cd using mice which had received 0.03 mg of CdCl2 . 2 . 5H2O along with 1.0 muCi of 109CdCl2 three weeks earlier. The MDCG-induced change in the fecal excretion of Cd ranged from a 15-fold increase over the control rate at the lowest dose level used (2.2 mmol/kg; 684 mg/kg) up to a 72-fold increase at the highest dose (8.8 mmol/kg; 2736 mg/kg) following three daily injections. The latter treatment regimen resulted in a fecal excretion of almost 30% of the administered Cd over a 3-day period of observation. Urinary Cd excretion was insignificant in both the control and treated groups. The whole body burden of Cd was reduced by over 50% following seven thrice-weekly i.p. injections of MDCG at 8.8 mmol/kg. There was a 60-65% reduction in both the liver and kidney Cd levels following the same treatment regimen. Radioassay of ten other organs and tissues revealed only modest changes. Testicular Cd was decreased slightly at the highest dose level, and heart tissue from each treated group contained slightly more Cd than controls. Results indicated a rather marked specificity of MDCG in lowering the Cd content of two organs most susceptible to Cd-induced toxicity.

Animals↗
PubMed1984

Comparative effects of N,N-disubstituted dithiocarbamates and dimercaptosuccinate on mobilization of methylmercury in mice.

Diethyldithiocarbamate (DDTC) and five of its N,N-disubstituted analogs were compared with dimercaptosuccinate (DMSA) for effectiveness in mobilizing and promoting excretion of methylmercury (MeHg) following administration of a sublethal dose of MeHg labeled with Me203Hg. The previously reported effectiveness of DMSA was confirmed. Of the dithiocarbamates assessed, only di(carboxymethyl)-dithiocarbamate (DCDC) was active in mobilizing MeHg, and its activity on a molar dose basis was less than that of DMSA. The disparate structural requirements of dithiocarbamates as antagonists of MeHg and of cadmium were discussed.

Aged↗
PubMed1984

Effects of substituted dithiocarbamates on the testicular toxicity of cadmium.

Five substituted dithiocarbamates were evaluated for effectiveness in protecting mouse testes following administration of an LD100 dose of CdCl2 X 2.5 H2O (Cd). Toxicologic responses were assessed by light microscopic, electron microscopic, and computerized image analysis techniques. Diethyldithiocarbamate (DDTC) was the most effective antagonist. N-ethyl-N-hydroxyethyldithiocarbamate (EHDC), N-methyl-N-hydroxyethyldithiocarbamate (MHDC), and dimethyldithiocarbamate (DMDC) were moderately to minimally effective, while di-(hydroxyethyl)dithiocarbamate (DHDC) afforded no protection. Degenerative changes increased progressively in severity as the time interval between administration of Cd and DDTC was increased, but remained minimal when DDTC was given as late as two hours after Cd.

Animals↗
PubMed1984

Heterocyclic N-dithiocarboxylates as cadmium antagonists: 4-hydroxypiperidine- and 4-carboxamidopiperidine-N-dithiocarboxylate.

Sodium 4-hydroxypiperidine-N-dithiocarboxylate(HP-N-DTC) and sodium 4-carboxamidopiperidine-N-dithiocarboxylate (CAP-N-DTC) were synthesized by the reaction of each piperidine analog with CS2 in the presence of NaOH. Following isolation and characterization, each dithiocarboxylate (DTC) when added to an aqueous solution of CdCl2 formed a water-insoluble complex with Cd which was shown by elemental analyses to consist of DTC:Cd in a 2:1 molar ratio. HP-N-DTC was a highly effective antagonist of acute Cd toxicity in mice, while CAP-N-DTC was less effective. When seven equimolar doses of each DTC were administered to mice which had received a non-lethal dose of CdCl2 along with 1.0 microCi of 109CdCl2 50 days earlier, both effected marked reductions of renal Cd levels. CAP-N-DTC was much more effective than HP-N-DTC in reducing the whole body Cd burden, apparently due to its more rapid depletion of hepatic Cd accompanied by an enhanced rate of Cd excretion. The data illustrate that subtle structural modifications of this class of heavy metal binding agents can yield compounds with impressive differences in pharmacologic activity.

Animals↗
PubMed1983

Effects of combined treatment with diethyldithiocarbamate and dihydroxyethyldithiocarbamate on distribution and excretion of cadmium.

Diethyldithiocarbamate (DDTC) rapidly mobilizes metallothionein-bound cadmium (Cd) from kidneys, liver, and spleen, but promotes a redistribution which results in higher Cd burdens in lungs, testes, and brain. Dihydroxyethyldithiocarbamate (DHDC) is less potent than DDTC in mobilizing renal Cd, but does not promote Cd redistribution to brain. Combined treatment with DDTC and DHDC, at one-half the molar dose of each when used alone, effected virtually as extensive renal Cd depletion as did DDTC alone, and enhanced slightly Cd mobilization from intestine and testes. Redistribution of Cd to brain was much less after combined treatment than was observed following treatment with DDTC alone.

Animals↗
PubMed1981

Ureolytic and urease-activating properties of commercial laboratory animal bedding.

Five types of commercial laboratory animal bedding were assessed for endogenous ureolytic activity using a sensitive method which measures the rate of evolution of 14C-carbon dioxide from 14C-urea. On a weight basis, the highest levels of urease activity were found in heat-treated hardwood chips and a regular grade of crushed corncobs. A deodorant-treated type of crushed corncobs had a moderately high level of activity, while pelleted corncobs and pelleted alfalfa were almost devoid of urease activity. A heat-stable activator of bacterial urease was found in hardwood chips and crushed corncobs.

Animals↗
PubMed1979

Schedule-dependency assessments of ribonucleoside diphosphate reductase inhibitors when used in combination with platinum compounds plus cyclophosphamide in the treatment of advanced L1210 leukemia.

Each of three ribonucleoside diphosphate reductase inhibitors was used as a third drug in combination with selected antitumor platinum (Pt) agents and cyclophosphamide (CY) in the treatment of advanced L1210 leukemia in C57BL/6 x DBA/2 mice. Each was synergistic with the various Pt plus CY combinations but the effect was highly schedule dependent. The collective cure rate was 68% when hydroxyurea (HU) was given as a single injection with Pt plus CY; the cure rate was 15% when HU was administered on a divided-dose schedule with Pt plus CY. The collective cure rate was 53% when guanazole was given as a single injection with Pt plus CY, but was only 8% when it was given on a divided-dose schedule with Pt plus CY. The effect of 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone, when used as a third drug with the various Pt plus CY regimens, was not schedule dependent as assessed by the collective cure rate. A therapeutic synergy between CY and each of the three ribonucleoside diphosphate reductase inhibitors was also observed.

Animals↗
PubMed1979

Reduction of the renal toxicity of cis-dichlorodiammineplatinum(II) by probenecid.

Probenecid, when administered sc to F344 rats 1 hour prior to an iv LD50 dose of cis-dichlorodiammineplatinum(II) (CDPP), reduced significantly the peak BUN and serum creatinine levels which occurred 4 days following CDDP. Renal histopathology was similarly reduced by probenecid pretreatment. In BDF, mice, the LD50 value of CDDP administered ip without probenecid pretreatment was 17 mg/kg; the LD50 dose with probenecid was increased to greater than 19 mg/kg. Probenecid pretreatment did not influence the therapeutic response to CDDP when the letter was administered to BDF mice bearing L1210 leukemia.

Animals↗