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Biomedical subjects

M M Jones

Publications and source records attributed to M M Jones.

At least 55 records · Page 3Linked to original sources
PubMed1995

Reduction of lead retention by mono-3-methylbutan-1-yl meso-2,3-dimercaptosuccinate in suckling rats.

The mono-3-methylbutan-1-yl (monoisoamyl) ester of meso-2,3-dimercaptosuccinic acid (Mi-ADMS) was previously found to be superior to meso-2,3-dimercaptosuccinic acid (DMSA) in mobilizing cadmium and mercury deposits in young and adult mice and rats. It was also tested to mobilize lead in and adult mice. It was also tested to mobilized lead in adult mice. The purpose of this study was to evaluate the ability of Mi-ADMS to chelate lead at a very young age, in sucking rats. Lead was applied intraperitoneally at the dose of 5 mg kg-1 in the form of lead acetate to six-day-old rats. Treatment with DMSA and Mi-ADMS was administered orally at the dose of 0.25 mmol kg-1, either as early (0.5 and 24 h) or a delayed (4th and 5th day after lead application) therapy. At the end of the experiment (6th day) lead was determined by atomic absorption spectrometry in the skeleton, liver, kidney and brain of the animals. Results showed that Mi-ADMS was more efficient than DMSA after early application in reducing the skeletal, kidney and brain content of lead. After delayed application it was either (skeleton and kidneys) or better (brain) than DMSA. There was no statistically significant influence of either chelator on liver lead content. The major finding is that Mi-ADMS at low doses causes a much higher reduction in brain retention of lead in sucklings than DMSA. This is important because the brain is considered to be the target organ of lead toxicity in the youngest age group.

Animals↗
PubMed1995

Bis-dithiocarbamates: effective chelating agents for mobilization of polonium-210 from rat.

The time dependence of organ distribution and excretion of intravenously (iv) injected 210Po was investigated after the single or repeated administration of N,N'-diethylamine-N-carbodithioate (diethyldithiocarbamate, DDTC) and three bis-dithiocarbamates: N,N'-dimethylethylenediamine-N,N'-biscarbodithioate (MeTTC), N,N'-diethylethylenediamine-N,N'-biscarbodithioate (EtTTC), and N,N'-di)20hydroxyethyl)ethylenediamine-N,N'-biscarbodithioate++ + (HOEtTTC). The biokinetics of iv injected 210Po was used as a model for the behaviour of 210Po absorbed into the blood from any other site of entry into the body. The most effective chelating agent was HOEtTTC, which was not only effective when injected subcutaneously (sc) immediately after 210Po, but also 1 h later. Toxic effects of DDTC were observed in a metabolic study when the effect of HOEtTTC was compared with that of DDTC. DDTC caused accumulation of 210Po in brain and transiently in liver. When HOEtTTC was administered, the faecal excretion of 210Po was increased from the very beginning. MeTTC, EtTTC and N-(2,3-dimercaptopropyl)phtalamidic acid (DMPA) were ineffective when the treatment started 1 h after iv injection of 210Po.

Aniline Compounds↗
PubMed1995

Combined chelation treatment for polonium after simulated wound contamination in rat.

Contaminated puncture wounds were simulated in rat by intramuscular injection of 210Po. The aim of the study was to determine the effectiveness of chelation treatment as a function of time, dosage, and route of chelate administration. Ten newly synthesized substances containing vicinal sulphydryl and carbodithioate groups were used and their effect was compared with that of chelators clinically applicable in man--BAL (2,3-dimercaptopropane-1-ol), DMPS (2,3-dimercaptopropane-1-sulphonate), DMSA (meso-2,3-dimercaptosuccinic acid), and DDTC (sodium diethylamine-N-carbodithioate). The results indicate first that complete removal of 210Po from the injection site is achieved by only two local injections of DMPS, beginning as late as 2 h after injection of 210Po. Second, many of the substances used merely induce translocation of 210Po from the injection site into other tissues. Third, a combined local treatment at the injection site with DMPS plus repeated systemic, subcutaneous, treatments with HOEtTTC (N,N'-di-(2-hydroxyethyl)ethylenediamine-N,N-biscarbodithioate), a derivative of DDTC, results after 2 weeks in a reduction of the estimated total body retention of 210Po to about one-third of that in untreated controls. In the latter case the cumulative excretion of 210Po increased from 8 to 54%, mainly via the faeces.

Animals↗
PubMed1995

In vivo and in vitro efficacy of a new carbodithioate for the mobilization of cadmium.

Female Wistar rats with chronic cadmium intoxication (oral exposure to low dosages of CdCl2 in drinking water over a period of 90 d) were used to examine the in vivo ability of a newly developed chelator, sodium N-(4-methylbenzyl)-4-O-(beta-D-galactopyranosyl)-D-glucamine-N- carbodithioate (MeBLDTC), singly and in combination with sodium 4-carboxy-amidopiperidine-N-carbodithioate (INADTC) as agents to induce the biliary and urinary excretion of cadmium. The combined administration of the two dithiocarbamates, which differ greatly in molecular weight and structural features, led to a synergistic increase in the biliary excretion of cadmium and an enhanced reduction of renal cadmium levels. The use of such a coadministration produced an increase in the biliary excretion of cadmium that was more than double that expected if the compounds acted in an additive fashion. Such mixed-chelation therapy has potential utility in the treatment of human chronic cadmium intoxication. The hepatocytes isolated from chronically Cd-intoxicated rats were used as an in vitro screening model system for the new chelator. The plasma membrane integrity study with MeBLDTC at 0.48 mmol/20 ml of hepatocyte incubate using the trypan blue exclusion test and lactate dehydrogenase (LDH) leakage test revealed no differences in the cell viability with or without chelator. The cellular metabolic competence measured as the rate of urea synthesis also did not show any marked deviation from that of controls when incubated with MeBLDTC at three different concentrations. In the hepatocyte cultures, MeBLDTC induced a significant removal of cadmium from the hepatocytes at concentrations as low as 0.04 mmol/20 ml.

Animals↗
PubMed1995

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.

Acute Disease↗
PubMed1995

Prolonged oral treatment with two monoesters of meso-2,3-dimercaptosuccinic acid for depleting inorganic mercury retention in suckling rats.

Two monoesters of meso-2,3-dimercaptosuccinic acid (DMSA), monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) and mono-n-hexyl meso-2,3-dimercaptosuccinate (Mn-HDMS) were compared to DMSA in their efficiency to mobilize 203Hg in mercury-laden suckling rats. Seven-day-old pups were given 203Hg (18.5 kBq) with a dose of 0.5 mg Hg/kg/day as HgCl2 for five days. Seven days after the beginning of Hg loading a ten-day oral treatment with DMSA, Mi-ADMS, or Mn-HDMS was administered at a dose of 0.25 mmol/kg/day. At the end of experiment, radioactivity was measured in the whole body, liver, both kidneys, and brain. Monoesters of DMSA were superior to DMSA in decreasing body and organ Hg retention. The highest reduction in comparison to controls in groups treated with DMSA, Mi-ADMS, or Mn-HDMS occurred in the kidneys (48%, 97%, and 96%), followed by reduction in the liver (24%, 84%, and 83%), and in the brain (8%, 23%, and 23%, respectively). For both, Mi-ADMS and Mn-HDMS, the reductions in the whole body and organs were significantly greater than in controls or DMSA-treated rats. No difference between the efficiency of the two DMSA-monoesters was found.

Administration, Oral↗
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↗
PubMed1995

Effects of monoisoamyl meso-2,3-dimercaptosuccinate on arsenite-induced maternal and developmental toxicity in mice.

The therapeutic efficacy of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS), on arsenite-induced maternal and developmental toxicity was evaluated in the pregnant mouse. Sodium arsenite (12 mg/kg) was intraperitoneally injected into Swiss mice on day 9 of gestation, whereas Mi-ADMS was given subcutaneously at 0.25, 5, 24, and 48 hr after arsenite exposure. Amelioration by Mi-ADMS of arsenite-induced maternal and embryofetal toxicity was assessed at 23.8, 47.5, and 95 mg/kg/day. Controls received 0.9% saline with or without arsenite. Cesarean sections were performed on gestation day 18. In the positive control group (treated with arsenite only), 20.8% of the pregnant animals died, whereas 37.5% of the dams were carrying completely resorbed litters. No arsenite-induced maternal lethality was seen following treatment with Mi-ADMS at 23.8, 47.5 and 95 mg/kg/day. Also, administration of the drug at these doses significantly reduced the embryolethality, as well as the incidence of some skeletal variations provoked by sodium arsenite. Although based on these findings, Mi-ADMS might be suggested as a potential antidote to prevent the arsenite-induced maternal and developmental toxicity, due to their reduced toxicity compared to Mi-ADMS, DMSA and DMPS would probably be more advisable for pregnant women exposed to arsenite.

Animals↗
PubMed1994

Mobilization of iron by chiral and achiral anionic 3-hydroxypyrid-4-ones.

In the search for 3-hydroxypyrid-4-ones with enhanced iron-mobilizing ability, seven chiral, anionic amino acid derivatives of maltol (3-hydroxy-2-methyl-4-pyrone) have been synthesized, utilizing L-methionine, L-serine, L-leucine, L-phenylalanine, L-glutamic acid, and the D- and L-isomers of alanine. Two achiral, aromatic compounds were also synthesized and compared with the phenylalanine derivative. The biliary iron excretion following iv injection and the urinary iron excretion following po administration were measured using female Sprague-Dawley rats and compared to that of the standard, 1,2-dimethyl-3-hydroxypyrid-4-one (L1). While none of the compounds was as effective as L1 in enhancing the urinary excretion of iron, all monoanionic chelators increased excretion relative to the controls. All monoanionic compounds were at least equivalent to L1 in enhancing the biliary excretion of iron, with the methionine, leucine, and benzoate derivatives surpassing the standard and the other aromatic compounds also showing strong activity. The dianionic glutamate derivative showed low activity relative to the controls for both urinary and biliary iron excretion. No significant difference in iron excretion was observed due to variation in chirality; molecular weight and the number of negative charges appeared to have the greatest influence on the ability of the various derivatives to enhance iron excretion. In order to evaluate the relative purity of the stereoisomers, the alanine derivatives were analyzed by circular dichroism. Further characterization was provided by UV/vis spectroscopy for all compounds and X-ray crystallography for the novel dianionic derivative.

Animals↗
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

Single strand and double strand DNA damage-induced reciprocal recombination in yeast. Dependence on nucleotide excision repair and RAD1 recombination.

Single strand and double strand DNA damage-induced recombination were compared in the yeast Saccharomyces cerevisiae. The non-replicating plasmid pUC18-HIS3 was damaged in vitro and introduced into yeast cells; plasmid-chromosome recombinants were selected as stable His+ transformants. Single strand damage was produced by UV irradiation at 254 nm or by psoralen photoreaction at 390 nm. Double strand damage was produced by psoralen photoreaction at 350 nm or by restriction endonuclease digestion. Recombinants were classified as resulting from gene conversion without crossing over, single plasmid integration, or multiple plasmid integration. Single and double strand DNA damage produced different patterns of recombination. In repair proficient cells double strand damage induced primarily multiple plasmid integrations, while single strand damage induced higher proportions of gene conversions and single integrations. Reciprocal recombination depended on the RAD1 gene, which is involved in both excision repair and recombination; plasmid integration induced by all forms of damage was decreased in a rad1 disruption strain. Mutation of the RAD3 excision repair gene decreased plasmid integration induced by far UV irradiation and psoralen crosslinks, but not by double strand breaks, which are not substrates of nucleotide excision repair. Double strand break-induced plasmid integration was also decreased by disruption of RAD10, which forms a complex with RAD1; disruption of RAD4 had no effect. Thus, while nucleotide excision repair genes are involved in the processing of damaged DNA to generate recombination intermediates, RAD1 and RAD10 are additionally involved in reciprocal exchange.

DNA Damage↗
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

Apnea in postsurgical hypnotherapy of an esophageal cancer patient: a brief communication.

Use of clinical hypnosis in the postsurgical psychotherapy of an esophageal cancer patient who could not swallow involved reenactment of the successful surgery and producing hallucinations of taste and smell, as well as working through emotions relations to the surgery and her disease. An apnea that occurred in a late phase of the treatment was addressed with the familiar arm pumping technique that had been used as a deepening technique, resulting in the patient's resuming normal breathing. The experience reminds the practitioner of the possible unexpected professional demands when working in a medical environment. It also provides clues as to the underlying psychological mechanisms and their role in successful symptom removal. A 6-year follow-up confirmed the lasting effect of this brief psychotherapy.

Adaptation, Psychological↗