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Biomedical subjects

M M Jones

Publications and source records attributed to M M Jones.

At least 19 recordsLinked to original sources
PubMed2001

A rapid and facile method for the dereplication of purified natural products.

A new approach to the use of commercial databases for the dereplication of purified natural products has been developed. This is based on searching a text file that links each structure with its molecular weight and an exact count of the number of methyl, methylene, and methine groups it contains. Analysis of such a text file, constructed from a database containing more than 126,000 natural product structures, revealed that these data, readily measured using MS and NMR spectroscopy, are highly discriminating. The identification of an alkaloid and a sesquiterpene using this new approach is described.

Alkaloids↗
PubMed2000

Chelation of aluminium by combining DFO and L1 in rats.

The hypothesis that two known chelators 1, 2-dimethyl-3-hydroxypyrid-4-one (L1) and desferrioxamine (DFO) might be more efficient as combined treatment than as monotherapies in removing aluminium from the body was tested in a new acute rat model. Five-week old female rats received chelators: L1 (p.o.), DFO (i.p.) or L1+DFO as 100 or 200 mg/kg dose half an hour after a single i.p. administration of 6 mg Al/kg body weight in the form of chloride. Serum aluminium concentration and urinary aluminium and iron excretions were determined by electrothermal or flame atomic absorption spectrometry. Both chelators were effective only at the higher dose level. While DFO was more effective than L1 in enhancing urinary aluminium excretion, L1 was more effective than DFO in enhancing urinary iron excretion. In the combined treatment group L1 did not increase the DFO effect on aluminium and DFO did not increase the effect of L1 on iron elimination. However, in this group a simultaneous increase in both aluminium and iron elimination was observed. Our results support the usefulness of this animal model for preliminary in vivo testing of aluminium chelators. Urinary values were more useful because of the high variability of serum results. Result of combined chelators treatment should be confirmed in a different experimental model before extrapolation to other systems. This testing procedure of course does not provide all the relevant answers for evaluating the efficiency of chelating agents in aluminium toxicity.

Aluminum↗
PubMed2000

Mobilisation of cadmium by meso- and racemic-2,3-dimercaptosuccinic acid (DMSA) in rats.

A higher efficiency of cadmium binding with racemic than with meso-2,3-dimercaptosuccinic acid (rac-DMSA; meso-DMSA) was found in an in vitro speciation model by Fang et al. (1996). This finding has not yet been tested in vivo. This paper presents results on mobilisation of cadmium by meso- and rac-DMSA in rats. Cadmium chloride was administered as the radioactive isotope 109Cd intraperitoneally to all animals. One group was an untreated control and two groups were treated with meso- and rac-DMSA, respectively. Treatment with chelators was applied twice, immediately after 109Cd and 24 hr afterwards intraperitoneally at the dose of 1 mmol/kg, each. Six days later radioactivity was measured in the liver and kidneys. Whole-body counting was carried out on days 1, 2, 3 and 6 of the experiment. At the end of the experiment, both treatments caused a decrease in 109Cd whole-body retention with rac-DMSA being more efficient (decrease from 83% in control to 74% and 64% in groups treated with meso- and rac-DMSA, respectively). The same reduction of 109Cd was obtained by both chelators in the liver (from 57% to about 47%). In the kidney only rac-DMSA produced significant reduction of 109Cd (from 5.3% to 3.5%). In conclusion, these results show modest reduction of cadmium in the body by two isoforms of DMSA with rac-DMSA being slightly more efficient than meso-DMSA.

Analysis of Variance↗
PubMed2000

Mobilization and detoxification of polonium-210 in rats by 2,3-dimercaptosuccinic acid and its derivatives.

PURPOSE: To reduce retention and toxicity of the alpha particle emitter polonium-210 in rats by newly developed chelating agents. MATERIALS AND METHODS: Repeated subcutaneous chelation was conducted after intravenous injection of 210Po nitrate. For reduction of 210Po retention the treatment with vicinal dithiols meso-and rac-2,3-dimercaptosuccinic acid (DMSA), mono-i-amylmeso-2,3-dimercapto succinate (Mi-ADMS) and mono-N-(i-butyl)-meso-2,3-dimercapto succinamide (Mi-BDMA) were used. For the reduction of toxic effects of 210Po, treatment effectiveness of Mi-BDMA was compared with that of N,N'-di(2-hydroxyethyl)ethylenediamine-N,N'-biscarbodithioate (HOEtTTC, reference compound). RESULTS: Treatment with meso-DMSA and rac-DMSA altered the main excretion route of 210Po, reduced its contents in the liver but increased its deposition in the kidneys. Treatment with Mi-ADMS or Mi-BDMA increased total excretion of 210Po, mainly via the faeces. Only Mi-BDMA decreased 210Po levels in the kidneys. The effectiveness of all chelators decreased with delay in the start of treatment. In a survival study, the lives of rats treated early with Mi-BDMA or delayed with HOEtTTC were prolonged three-fold when compared with rats receiving a lethal amount of 210Po only. CONCLUSIONS: Of the vicinal dithiols examined, Mi-BDMA was the best mobilizing chelating agent for 210Po and it reduced 210Po toxicity when the treatment started immediately. However, the detoxification efficacy of the immediate treatment with HOEtTTC, observed in our previous study, was superior to that of the present result with Mi-BDMA.

Animals↗
PubMed2000

Comparative efficacy of several potential treatments for copper mobilization in copper-overloaded rats.

D-Penicillamine (DPA) is effective in the treatment of Wilson's disease, whereas zinc salts are also used as a therapy for this disorder of copper transport. Recently, it has been shown that the copper chelators 1,4,7,11-tetraazaundecane tetrahydrochloride (TAUD) and tetraethylenepentamine pentahydrochloride (TETREN) could be useful for copper mobilization in rats. Because these agents could be potential clinical alternatives to DPA for patients with Wilson's disease who are intolerant to this drug, we examined whether oral administration of TAUD and TETREN could be effective in mobilizing copper in experimental copper-overloaded rats. The efficacy of a combined administration of zinc and DPA, TAUD, or TETREN was also assessed. Rats were copper loaded with 0.125% copper acetate in water for 12 wk. After this period, DPA, TAUD, and TETREN were administered by gavage at 0.67 mmol/kg/d for 5 d, and zinc was given at 2.5 mg Zn/kg/d. Twelve weeks of copper loading resulted in a 32-fold increase in total hepatic copper. TETREN was the most effective chelator in increasing the urinary excretion of copper. However, it did not reduce significantly the hepatic copper levels. In turn, combined administration of zinc and chelating agents significantly reduced the amount of copper found in the feces. Although TAUD and TETREN showed a similar or higher efficacy to DPA in mobilizing copper, concurrent treatment of chelating agents and zinc salts should be discarded according to the current results.

Animals↗
PubMed1999

Chelation therapy in aluminum-loaded rats: influence of age.

The influence of age at which aluminum (Al) exposure was initiated on the efficacy of chelation therapy in mobilizing Al was investigated in two groups of male rats exposed to this element at two different stages of the life cycle. Young (21 days old) and old (18 months) rats were exposed to 0 and 50 mg Al/kg/day administered as Al nitrate in drinking water for a preliminary period of 14 days followed by a period of 100 days, in which Al-exposed animals received 100 mg Al/kg/day. At the end of the period of exposure, Al-loaded rats in each age group were given one of the following treatments: s.c. deferoxamine (DFO), oral 1,2-dimethyl-3-hydroxypyrid-4-one (L1) and 1-(p-methylbenzyl)-2-ethyl-3-hydroxypyrid-4-one (MeBzEM) at doses of 0.89 mmol/kg/day for 5 consecutive days. Another group of Al-exposed rats received a concurrent administration of s.c. DFO and oral L1 both at 0.45 mmol/kg/day. During chelation therapy urines were collected daily. Control groups included rats exposed and unexposed to Al. Oral administration of L1 was the most effective treatment in enhancing urinary Al excretion in both age groups of Al-loaded rats. This beneficial effect was similar for old and young animals. Concurrent administration of DFO and L1 had no advantages over the use of either single agent, while MeBzEM was not effective in mobilizing Al from Al-exposed rats.

Aging↗
PubMed1998

Comparative aluminum mobilizing actions of deferoxamine and four 3-hydroxypyrid-4-ones in aluminum-loaded rats.

The efficacy of the Al chelating drugs deferoxamine (DFO) and the hydoxypyridones (HPs): 1,2-dimethyl-3-hydroxypyrid-4-one (L1), 1-[3-hydroxy-2-methyl-4-oxopyridyl]-2-ethanesulfonic acid (L6), 1-benzyl-(4-carboxylic acid)-3-hydroxy-2-methyl-4-oxopyridine (Bzcal) and 1-(p-methylbenzyl)-2-ethyl-3-hydroxypyrid-4-one (MeBzEM) in increasing Al excretion and reducing tissue Al accumulation has been compared in adult male rats which had previously received Al nitrate nonahydrate i.p. at 0.16 mmol/kg per day for 2 months. At the end of this period, DFO was injected s.c. and the HPs were given by gavage at 0.89 mmol/kg per day for five consecutive days. Total urines were collected 24 h after each chelator administration. Following chelation treatment animals were killed and samples of brain, bone, liver, kidney, and spleen were collected. DFO administration increased to about 4 x the cumulative urinary Al elimination for 5 days, while the excretion of Al into urine caused by Bzcal, L1, and MeBzEM administration was about twice that of the control group. On the other hand, treatment with Bzcal, DFO, and MeBzEM for 5 days significantly reduced the Al levels in bone by 31, 33, and 29%, and the Al concentrations in brain by 46, 69, and 71%, respectively. These results suggest that oral administrations of MeBzEM and Bzcal can be potential alternatives to parenteral administration of DFO in Al removal.

Aluminum↗
PubMed1998

Concurrent administration of D-penicillamine and zinc has no advantages over the use of either single agent on copper excretion in the rat.

The present study was conducted to examine in rats whether the combined use of D-penicillamine (DPA) and a zinc salt, or the administration of a DPA/Zn complex could have some advantages over the use of either single agent on the excretion of copper. In a first experiment, three groups of adult male Sprague Dawley rats were given by gavage one of the following treatments for 5 days: 0.5 mmol/kg/day of DPA, 0.046 mmol/kg/day of zinc acetate dihydrate, and 0.5 mmol/kg/day of DPA plus 0.046 mmol/kg/day of zinc acetate dihydrate. A fourth group of rats (control group) received deionized water during the same period. An increase in the urinary excretion of copper was observed following DPA treatment, which continued for at least 5 days after the administration of this compound was stopped. The amount of copper present in the feces, including that in the diet, was approximately 60 times greater than that normally present in control urines. During the period of zinc acetate administration, the amount of copper in the feces was slightly, but significantly greater than that during control, D-penicillamine, or D-penicillamine plus zinc acetate administration. No differences between the treated groups and the control group were found in brain, liver, kidney and spleen concentrations of rats 5 days after the end of the treatment period. In a second experiment, a similar comparison between D-penicillamine and sodium bis(3-mercapto-D-valinato)zinc hexahydrate (Na2[Zn(DPA)2] x 6H2O), both given by gavage, also showed no significant differences in the urinary excretion of copper in rats.

Administration, Oral↗
PubMed1998

Ultrastructural effects of the chelating agent 1,10-phenanthroline on Trypanosoma cruzi epimastigotes in vitro.

The in vitro effects of the metal chelator 1,10-phenanthroline (OPHEN) on the ultrastructure of Trypanosoma cruzi epimastigotes were investigated. Epimastigotes treated with OPHEN display swelling and electron-dense deposits in the kinetoplast, mitochondrion, and cisternae of the endoplasmic reticulum. These morphological alterations are dose-dependent and first appear at an OPHEN concentration of 5.0 microg/ml. Analytical electron microscope examination indicates that the metallic portion of the electron-dense deposits is predominantly calcium.

Animals↗
PubMed1998

Effect of cadmium chelating agents on organ cadmium and trace element levels in mice.

In experiments performed on male mice (CD-1, Charles River), the mobilizing effects of repeated administration of the carbodithioate analogue BLDTC [N-benzyl-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbodithioate+ ++] and CaDTPA (calcium trisodium pentetate) on cadmium deposits in the liver, kidneys, brain and testes were compared. The antidotes were injected alternately every 48 h over a period of 16 d (8 doses in total) following a previous loading with 20 doses of CdCl2.2.5 H2O (single doses of 3 mg kg-1 i.p.). The experiments confirmed BLDTC to be one of the most effective cadmium mobilizing agents. The administration of CaDTPA, which is known as a useful antidote in acute cadmium intoxication, increased the mobilizing effect of BLDTC. Cadmium elevated the concentration of zinc in all organs examined and the level of copper in the liver, kidneys and testes. This accumulation of trace elements was only partially corrected by the chelators. The antidotes administered alone exert only a negligible effect on the trace element levels in the organs.

Animals↗
PubMed1998

Aluminium distribution and excretion: a comparative study of a number of chelating agents in rats.

The present study was conducted to assess in rats the comparative effects of a number of chelating agents on the urinary excretion and tissue distribution of A1. Adult male Sprague-Dawley rats received a single intraperitoneal dose of aluminium (A1) nitrate nonahydrate (0.24 mmol/kg). Ten min. after A1 injection 1,2-dimethyl-3-hydroxypyrid-4-one, 2,3-dihydroxybenzoic acid, picolinic acid, methylmalonic acid, ethylenediamine-di(o-hydroxyphenylacetic) acid, 1-benzyl-2-methyl-3-hydroxypyrid-4-one, 1-(p-methylbenzyl)-2-methyl-3-hydroxypyrid-4-one, 1-(p-methoxy-benzyl)-2-methyl-3-hydroxypyrid-4-one, 1-(p-chlorobenzyl)-2-methyl-3-hydroxypyrid-4-one, 1-benzyl-2-ethyl-3-hydroxypyrid-4-one, 1-(p-methyl-benzyl)-2-ethyl-3-hydroxypyrid-4-one, 1-[3-hydroxy-2-methyl-4-oxopyridyl]-2-ethanesulfonic acid and 1-benzyl-(4-carboxylic acid)-3-hydroxy-2-methyl-4-oxopyridine were given by gavage at 1.79 mmol/kg. A control group received similar volumes of distilled water. An additional group of rats received a subcutaneous injection of desferrioxamine at 1.79 mmol/ kg. Urine samples were collected daily for three consecutive days and the animals were killed after this period. Samples of brain, bone, liver, kidney and spleen were collected. Although desferrioxamine, 1,2-dimethyl-3-hydroxypirid-4-one, 1-(p-methylbenzyl)-2-methyl-3-hydroxypyrid-4-one, 1-(p-methoxybenzyl)-2-methyl-3- hydroxypyrid-4-one, 1-(p-methylbenzyl)-2-ethyl-3-hydroxypyrid-4-one, 1-[3-hydroxy-2-methyl-4-oxopyridyl]-2-ethanesulfonic acid and 1-benzyl-(4-carboxylic acid)-3-hydroxy-2-methyl-4-osopyridine significantly enhanced the total excretion of A1 into urine, only treatment with 1-(p-chlorobenzyl)-2-methyl-3-hydroxypyrid-4-one and 1-benzyl-2-ethyl-3-hydroxypyrid-4-one significantly reduced A1 concentrations in all analyzed tissues. No beneficial effects of the remaining chelators on Al mobilization were observed. Further studies on the effects of some 3-hydoxrypyrid-4-ones on A1 removal can be of interest for the treatment of A1 accumulation and toxicity.

Aluminum↗
PubMed1997

Cadmium-induced apoptosis in the urogenital organs of the male rat and its suppression by chelation.

Cadmium-induced apoptosis is shown to occur, in vivo, in several organs of the male Wistar rat urogenital system, 48 h after cadmium administration i.p. at a dose of 0.03 mmol/kg. Characteristic DNA fragmentation (as measured by an enzyme-linked immunosorbent-assay, ELISA) and histopathologically observed changes characteristic of apoptosis are found in the kidney, prostate, seminal vesicles, testes, and epididymis. TUNEL assay also demonstrates the apoptosis. Such changes are absent from bladder and vas deferens tissue. Timely administration of an appropriate chelating agent capable of reaching intracellular cadmium binding sites can suppress the processes leading to apoptosis. Administration of monoisomyl meso-2,3-dimercaptosuccinate (Mi-ADMS, 0.5 mmol/kg i.p.) to cadmium-treated rats is effective in greatly reducing typical histopathologic signs of apoptosis and the associated chromatin DNA fragmentation as revealed by ELISA when the antagonist is administered 1 h after cadmium. Administration of the chelating agent at law times results in greater degradation of DNA into oligonucleotides and more prominent histopathological evidence of apoptotic changes in the affected organs of the rat urogenital system. There is also a progressive increase in apoptotic changes indicated by TUNEL assay, as the antagonist is administered at progressively greater intervals after cadmium.

Animals↗
PubMed1997

Selenite suppression of cadmium-induced testicular apoptosis.

The characteristic apoptotic ladder-like patterns of rat testicular DNA on agarose gel electrophoresis which results from treatment with CdCl2 are suppressed by the administration of Na2SeO3. The examination of testicular tissue using an ELISA programmed cell death detection procedure confirmed this selenite suppression of cadmium-induced apoptosis. The administration of the Na2SeO3 at either 0.5, 1, 2 h prior to or 0.5, 1, 2 h after the administration of the CdCl2 appear to be almost equally effective at suppressing the apoptotic response. These results are in accord with previous studies on the Na2SeO3 suppression of cadmium induced necrotic changes in tissues and suggest that Na2SeO3 interferes with both necrosis and apoptosis.

Animals↗
PubMed1997

Reduction of subacute lethal radiotoxicity of polonium-210 in rats by chelating agents.

The protective effect of N,N'-di(2-hydroxyethyl)ethylene-diamine-N,N'-biscarbodithioate (HOEtTTC) against the subacute lethal radiotoxicity of polonium-210 was investigated in a survival study and by histopathological and haematological examinations of some organs and tissues in Sprague-Dawley rats. This effect was compared with that of N,N'-diethylamine-N-carbodithioate (diethy dithiocarbamate, DDTC). In the survival study, rats injected in intravenously solely with a lethal amount of 210Po (1.45 MBq kg-1 body mass) died within 14-44 days while 90% of rats treated with HOEtTTC survived for 5 months until sacrificed. When treated with DDTC all rats died within 36-93 days. In the histopathological examination, relevant changes resulting from incorporation of 210Po were found in lymph nodes, thymus and humeral bone marrow. After the treatment with HOEtTTC no pathological changes were observed. In the haematological examination, severe reduction in blood and femoral bone marrow (BM) cell counts was revealed in rats injected with 210Po. This reduction was reversed by treatment with HOEtTTC. Treatment with DDTC led only to partial recovery of blood and BM cell count. In conclusion, under the conditions of the experiment only HOEtTTC was fully effective in reducing subacute lethal radiotoxicity of 210Po.

Animals↗
PubMed1997

Combined oral treatment with racemic and meso-2,3-dimercaptosuccinic acid for removal of mercury in rats.

Racemic dimercaptosuccinic acid (DMSA) was found more efficient than the meso-isoform in enhancing the removal of mercury in rats. However, racemic-DMSA has recently been found more toxic. The efficiency of combined oral treatment with the two isoforms of DMSA for removal of mercury has now been evaluated. Female albino rats were treated orally for four days with meso- (M) and/or racemic- (R) DMSA (1 mmol/kg each), five days after a single intraperitoneal administration of 203Hg with 0.5 mg HgCl2/kg. The animals were divided into six groups according to the number of treatments with each isomer: control (untreated), 4M, 1R + 3M, 2R + 2M, 3R + 1M, and 4R. Whole body, kidney, liver and brain mercury contents were measured nine days after 203Hg administration. In all treated groups retention in the whole body and kidneys was greatly reduced. The groups treated with racemic-DMSA, regardless of the number of doses, showed a greater removal of mercury than the group treated with meso-DMSA alone (4M). All treatments were less efficient in reducing liver retention, and the brain retention was not affected. It was concluded that even a single application of the more toxic racemic-DMSA during a four-day oral treatment regimen is sufficient to improve the removal by meso-DMSA of mercury from rats.

Animals↗
PubMed1997

Comparative in vivo lead mobilization of meso- and rac-2,3-dimercaptosuccinic acids in albino Wistar rats.

Comparison of the racemic and meso forms of 2,3-dimercaptosuccinic acid (DMSA) in lead mobilization from lead-loaded albino Wistar rats demonstrates that the racemic form is significantly more effective in reducing femur lead levels. After four oral doses at 0.5 mmol/kg, femur lead levels were reduced to 87% of control values by meso-DMSA and to 50% of control levels by rac-DMSA. Similarly, when the dose was increased to 1.0 mmol/kg, femur lead levels were reduced to 69% of control levels by meso-DMSA and to 45% of control levels by rac-DMSA. A similar pattern was found for renal lead levels. Brain lead concentrations were significantly lower in treated groups than in control groups, but no differences were found between rac- and meso-DMSA. Rac-DMSA is more soluble than meso-DMSA in acetonitrile, ethyl acetate, and ethyl ether. The partition coefficient of rac-DMSA in the n-octanol/water system was found to be about 2.8. These results indicate that rac-DMSA deserves further attention as a possible substitute for meso-DMSA.

Animals↗
PubMed1997

Synthesis and in vitro trypanocidal activity of some novel iron chelating agents.

This report describes the syntheses and in vitro trypanocidal activity of a number of iron (III) chelators against epimastigotes of Trypanosoma cruzi. The compounds examined included a number of lipophilic N-alkyl derivatives of 2-ethyl- and 2-methyl-3-hydroxypyrid-4-ones, N,N'-bis(o-hydroxybenzyl)-(+/-)-trans-1,2-diaminocyclohexane, cyclotetrachromotropylene and four commercially available carboxy derivatives of pyridine, pyrazine, and pyarazole. Benznidazole, the drug clinically used in the treatment of Chagas' disease in humans, served as standard. All compounds were screened in vitro against Trypanosoma cruzi epimastigotes at 50 and 100 micrograms/ml for 72 h of exposure. At 100 micrograms/ml dosage, at least 4 compounds exhibited high epimastigote growth inhibition (65-69%) comparable to benznidazole (72%), whereas 9 compounds showed moderate to fair activity (53-64%) in the in vitro assay. At the lower concentration (50 micrograms/ml), the inhibitory activity of the best of these compounds was reduced significantly (39-48%) compared to the standard drug (59%). The activity of all the carboxylic acids remained in the lower range (4-25%). It is hypothesized that the enhanced activity of some of the compounds is due to their increased lipophilicity which enables them to successfully pass through the cellular membrane of Trypanosoma cruzi epimastigotes. The trypanocidal activities of the most effective compounds were significantly reduced when tested in the presence of added ferric ion.

Animals↗