Biomedical subjects

M M Jones

Publications and source records attributed to M M Jones.

At least 37 records · Page 2Linked to original sources

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↗

PubMed1996

Structure of 5-hydroxy-2-hydroxymethyl-1-methylpyrid-4-one and 13C NMR relaxation studies of its gadolinium(III) complex.

In order to further elucidate the properties and biological behavior of 5-hydroxy-2-hydroxymethyl-1-methylpyrid-4-one (M1), its X-ray structure has been determined, and the ability of its gadolinium complex to enhance the relaxation of 13C nuclei has been examined. X-ray analysis using Mo K alpha radiation shows that M1 crystallizes in the monoclinic space group C2/c with a complex intermolecular array of hydrogen bonding. No water molecules were present within the unit cell. Gd(M1)2NO3 x 3H2O has been prepared and found to be very soluble in water. The effect of low concentrations of Gd(III) on enhancing the 13C relaxation times of M1 was examined. Trace amounts of Gd(NO3)3 x 6H2O resulted in significant decreases in the relaxation time of certain carbon atoms relative to the control measurements, and these data indicate that carbon atoms which bear donor atoms for Gd(III) undergo a significantly greater relaxation than the other carbons. The water solubility and hydrophilic character of this complex suggest that it may prove useful for the determination of metal binding sites on peptides and oligonucleotides.

Carbon Isotopes↗

PubMed1996

In vivo studies of cadmium-induced apoptosis in testicular tissue of the rat and its modulation by a chelating agent.

In vivo CdCl2-induced apoptotic DNA fragmentation in the testes of the male Wistar rat has been demonstrated on agarose gel. Characteristic DNA migration patterns (laddering) provide evidence of apoptosis (programmed cell death) in testicular tissue of rats administered CdCl2 at a level of 0.03 mmol/kg 48 h previously. Evidence that administration of an appropriate cadmium chelating agent within the first 24 h can suppress some or all of the apoptotic changes in testicular DNA has also been obtained for the first time. A greater reduction in apoptosis is observed as the interval between the administration of the cadmium and that of the chelating agent is shortened. Administration of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) to male Wistar rats given CdCl2 is effective in the modulation of the typically apoptotic DNA fragmentation and associated histopathologic injury when the antagonist is given within approximately 1 h after the CdCl2 exposure. When the antagonist is given at later times there is a progressively more pronounced degradation of the DNA into oligonucleotides as seen in the typical electrophoretic DNA ladder pattern found with apoptosis. There is also a progressive increase in histopathological tissue changes as the antagonist is administered at progressively greater intervals after the cadmium.

Animals↗

PubMed1996

Assessment of the protective activity of monisoamyl meso-2,3-dimercaptosuccinate against methylmercury-induced maternal and embryo/fetal toxicity in mice.

The protective activity of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS), a new monoester of 2,3-dimercaptosuccinic acid (DMSA), on methylmercury-induced maternal and developmental toxicity was assessed in mice. A series of four Mi-ADMS injections was given s.c. at 0.25, 6, 24, and 48 h after oral administration of 25 mg/kg of methylmercury chloride (MMC) given on day 10 of gestation. Mi-ADMS effectiveness was tested at 0, 23.8, 47.6 and 95 mg/kg. Cesarean sections were performed on gestation day 18. All live fetuses were examined for external, internal, and skeletal abnormalities. Oral MMC administration resulted in an increase in the number of resorptions, and a decrease in fetal body weight, whereas the incidence of cleft palate, micrognathia, and skeletal variations was also increased in the fetuses of the MMC-treated groups. Although significant amelioration of MMC-induced embryolethality by Mi-ADMS was not noted at any dose, MMC-induced fetotoxicity was reduced by administration of this agent at 23.8, 47.6, and 95 mg/kg. However, the intrinsic toxicity of Mi-ADMS would be a restrictive factor for the possible therapeutic use of this chelator in pregnant women exposed to organic mercury.

Abnormalities, Drug-Induced↗

PubMed1996

Prevention of cisplatin nephrotoxicity by exogenous atrial natriuretic peptide.

The ability of atrial natriuretic peptide (ANP) to prevent cisplatin-induced nephrotoxicity was compared to the protective effect of 3% NaCl. ANP (1 microgram/kg/min), 3% NaCl or peptide buffer vehicle (50 microliters/min) were infused for 45 min to conscious unrestrained rats immediately after cisplatin administration (5 mg/kg i.v.). Measurements taken 72 h after drug treatment indicated that compared to animals receiving cisplatin only, ANP co-treated rats had lower post-treatment plasma creatinine concentrations (0.70 +/- 0.07 vs 1.3 +/- 0.17 mg/dl; P < 0.05), blood urea nitrogen (BUN) concentrations (44.2 +/- 5.8 vs. 65.5 +/- 2.1 mg/dl; P < 0.05) and higher post-treatment glomerular filtration rates (GFR) (0.71 +/- 0.18 vs. 0.14 +/- 0.03 ml/min; P < 0.05). ANP was as effective as 3% NaCl in preventing cisplatin nephrotoxicity in this model. The effect of ANP co-treatment on the anti-tumor activity of cisplatin was also examined using the Walker 256 carcinosarcoma model. ANP treatment did not result in any observable loss in anti-tumor activity. When ANP was administered 72 h after cisplatin treatment, improvement in GFR was observed for the duration of the infusion, confirming the beneficial effect of ANP on cisplatin-damaged kidneys. ANP may have a role in the treatment and prevention of cisplatin nephrotoxicity especially in clinical situations where treatment with a large fluid volume is contraindicated.

Animals↗

PubMed1996

Meso-2,3-dimercaptosuccinic acid mono-N-alkylamides: syntheses and biological activity as novel in vivo cadmium mobilizing agents.

Three meso-2,3-dimercaptosuccinic acid mono-N-alkylamides (meso-RNHCOCH(SH)CH(SH)-COOH, where R = CHMe2, Mi-PDMA; CH2CHMe2, Mi-BDMA; and CH2CH2CHMe2, Mi-ADMA), were prepared via a synthetic route using the sulfhydryl-protected anhydride. 2,2-Dimethyl-1,3-dithiolane-4,5-cis-dicarboxylic acid anhydride was opened up with 1 mol of corresponding amine to give the SH-protected monoamide. Subsequent deblocking of the vicinal dithiol functionality was accomplished by conversion of the dithiolane into the mercury complex followed by reaction with H2S to give the target molecule. The potential utility of these compounds in chronic cadmium intoxication was examined by evaluation of their cadmium mobilizing efficacy in vivo in cadmium-loaded female albino rats using sodium N-benzyl-D-glucamine-N-carbodithioate (BGDTC) as the standard drug. Compared to BGDTC, the new compounds were, except at the highest dosage studied, equally or more effective in decreasing retention of hepatic cadmium, while mostly less effective in decreasing renal cadmium. The greatest reductions were obtained with Mi-BDMS at 4 x 1.5 mmol/kg, where liver and kidney cadmium levels were reduced to 12% and 59% of control levels, while at the same dosage BGDTC induced a reduction to 50% and 13% of control levels. The order of the efficacy of the monoamides as hepatic cadmium mobilizing agents was found to be Mi-PDMA > Mi-BDMA > Mi-ADMA. However, the isopropyl analog, though very effective at reducing hepatic cadmium at a low dosage, was found to be more toxic than the isobutyl and isoamyl monoamides. While the new compounds were shown to be effective cadmium mobilizing agents, the specific compounds examined did not possess optimized structures in terms of the balance between effectiveness and toxicity.

Amides↗

PubMed1996

Cadmium mobilization by nitrogen donor chelating agents.

The relative abilities of a series of acyclic polyamine chelating agents containing only nitrogen donors (N-donors) to induce the urinary excretion of cadmium has been examined in the rat. The compounds examined include triethylenetetramine dihydrochloride (TRIEN), tris(2-aminoethyl)amine trihydrochloride (TREN), tetraethylenepentamine pentahydrochloride (TETRAEN), and pentaethylenehexamine hexahydrochloride (PENTAEN). Sodium N-methyl-D-glucamine-N-carbodithioate (NaG) was used as a positive control compound. The polyamines induced a significant increase in the urinary excretion of cadmium in rats that had been loaded with cadmium at least 4 d prior to the polyamine treatments. A comparison of these with similar data on macrocylic nitrogen donor systems, which form much more stable complexes with cadmium but are also ineffective in enhancing the excretion of cadmium from such aged deposits, suggests that the factors responsible for the relative inefficiency of these compounds may involve either a difficulty in penetrating cellular membranes or a slow rate of reaction with biologically bound cadmium. The occurrence of oliguria and anuria following the administration of the several of the polyamines indicates that their use is accompanied by significant renal damage in cadmium-exposed rats.

Animals↗

PubMed1996

Microgravity decreases heart rate and arterial pressure in humans.

Spaceflight causes adaptive changes in cardiovascular physiology, such as postflight orthostatic intolerance, that can have deleterious effects on astronauts. In-flight cardiovascular data are difficult to obtain, and results have been inconsistent. To determine normative in-flight changes in Shuttle astronauts, we measured heart rate, arterial pressure, and cardiac rhythm disturbances for 24-h periods before, during, and after spaceflight on Shuttle astronauts performing their normal routines. We found that heart rate, diastolic pressure, variability of heart rate and diastolic pressure, and premature ventricular contractions all were significantly reduced in flight. Systolic pressure and premature atrial contractions also tended to be reduced in flight. These data constitute the first systematic evaluation of in-flight changes in basic cardiovascular variables in Shuttle astronauts and suggest that a microgravity environment itself does not present a chronic stress to the cardiovascular system.

Adult↗

PubMed1996

In vitro trypanocidal activity of tetraethylthiuram disulfide and sodium diethylamine-N-carbodithioate on Trypanosoma cruzi.

Tetraethylthiuram disulfide (disulfiram) (TETD) and sodium diethylamine-N-carbodithioate (DECD) were examined for their in vitro trypanocidal activity against Trypanosoma cruzi. Benznidazole (BNZ), the drug used clinically for the chemotherapy of Chagas' disease, was used as a positive control. Inhibition assays included evaluation against the epimastigote, trypomastigote, and amastigote forms. Tetraethylthiuram disulfide and its reductive metabolite DECD inhibited 64.6% and 69.7%, respectively, of epimastigotes at a concentration of 50 micrograms/ml after 72 hr and BNZ caused 69.1% inhibition at the same concentration. Both TETD and DECD were not as effective against tissue culture trypomastigotes as BNZ (TETD = 47.7%,; DECD = 46.1%; BNZ = 88.7%) at 50 micrograms/ml after 24 hr. However, TETD and DECD treatment of amastigote-infected 3T3 fibroblasts yielded 60 and 67% inhibition, respectively, as compared to BNZ with an inhibition of 62%. A possible mechanism of action of TETD and DECD is via interference with the essential metal metabolism of T. cruci. Since toxicity data for both TETD and DECD are available and both drugs are active against the parasite, these drugs are candidates for further study to determine if they are of potential clinical interest as a prophylactic or therapeutic agent against Chagas' disease.

Animals↗

PubMed1996

Inhibition of Trypanosoma cruzi epimastigotes in vitro by iron chelating agents.

The relative effectiveness of 20 iron chelating agents in suppressing the growth and multiplication of Trypanosoma cruzi epimastigotes has been examined in vitro. 1,2-Dimethyl-3-hydroxypyrid-4-one (L1) and several of its newly synthesised N-substituted analogs containing hydrophobic substituents were significantly more effective than deferoxamine, even though they possess only two donor sites for iron(III) while deferoxamine has six. Analogs with hydrophilic substituents were uniformly less active than L1 itself. Variations in effectiveness as the polarity of the compound is varied indicate that the ability to cross the cellular membrane is of critical importance in the determination of the in vitro trypanocidal activity of iron(III) chelating agents. A group of four tris(2-aminoethyl)amine based tris-imines were also screened, all of which had poor activity (0-28% inhibition). Among the other iron(III) chelating agents which showed a relatively high level of activity at 50 and 100 micrograms/ml were salicylhydroxamic acid (70 and 73% inhibition) and hydroxyurea (42 and 52% inhibition). N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid and acetohydroxamic acid exhibited only slight activity at 50 and 100 micrograms/ml. The best of these iron(III) chelating agents were as effective against the epimastigote form at both 50 and 100 micrograms/ml (74-82% inhibition) as benznidazole (81% inhibition), the drug currently used in the clinic.

Animals↗

PubMed1995

Antidotal efficacy of newly synthesized dimercaptosuccinic acid (DMSA) monoesters in experimental arsenic poisoning in mice.

The efficacy of four newly synthesized monoesters of meso-2,3-dimercaptosuccinic acid (DMSA), mono-i-amyl- (Mi-ADMS), mono-n-amyl- (Mn-ADMS), mono-i-butyl- (Mi-BDMS), and mono-n-butyl-meso-2,3-dimercaptosuccinate (Mn-BDMS) in increasing survival and arsenic elimination in experimental arsenic poisoning was investigated. Male mice (strain NMRI) received arsenite sc (survival study: 130 mumol/kg, 7 mice/group; elimination study: 85 mumol/kg (LD5) together with a tracer dose of 73As(III), 6 mice/group). After 30 min mice were treated with 0.7 mmol/kg of DMSA or a monoester ip or via gastric tube (ig). Control animals received saline ip. In the survival study mice were observed for 30 days. In the elimination study, the 73-arsenic content of several organs (blood, liver, heart, lung, kidneys, spleen, testes, brain, small intestine, large intestine, muscle, and skin) was measured 0.5, 2, 4, 6, and 8 hr after the arsenic injection using a gamma counter. Survival increased correspondingly well with the increase of arsenic elimination. DMSA, Mi-ADMS, Mn-ADMS, Mi-BDMS, and Mn-BDMS markedly decreased arsenic content in most organs as soon as 1.5 hr after treatment. Only in small and large intestine were higher arsenic amounts found, indicating a shift in arsenic elimination from the renal to the fecal route, and thereby suggesting a protective effect for the kidneys. Given ip, the monoesters turned out to be similarly as effective as the parent drug DMSA. Following ig treatment, the DMSA monoesters Mi-ADMS and Mn-ADMS seemed to be superior to DMSA with regard to survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

A comparison of misoprostol and prostaglandin E2 gel for preinduction cervical ripening and labor induction.

OBJECTIVE: Our purpose was to compare the safety and efficacy of intravaginal misoprostol versus intracervical prostaglandin E2 (dinoprostone) gel for preinduction cervical ripening and induction of labor. STUDY DESIGN: One hundred thirty-five patients with indications for induction of labor and unfavorable cervices were randomly assigned to receive either intravaginal misoprostol or intracervical dinoprostone. Fifty microgram tablets of misoprostol were placed in the posterior vaginal fornix every 3 hours for a maximum of six doses. Prostaglandin E2 in gel form, 0.5 mg, was placed into the endocervix every 6 hours for a maximum of three doses. Medication was not given after either spontaneous rupture of membranes or beginning of active labor. RESULTS: Among 135 patients enrolled, 68 received misoprostol and 67 received dinoprostone. The average interval from start of induction to vaginal delivery was shorter in the misoprostol group (903.3 +/- 482.1 minutes) than in the dinoprostone group (1410.9 +/- 869.1 minutes) (p < 0.001). Oxytocin augmentation of labor occurred more often in the dinoprostone group (65.7%) than in the misoprostol group (33.8%) (p < 0.001). There were no significant differences between routes of delivery. Ten of the misoprostol-treated patients (14.7%) and 13 of the dinoprostone-treated patients (19.4%) had cesarean deliveries. There was a higher prevalence of tachysystole (six or more uterine contractions in a 10-minute window for two consecutive 10-minute periods) in the misoprostol group (36.7%) than in the dinoprostone group (11.9%) (p < 0.001). However, there were no significant differences in frequency of uterine hyperstimulation or hypertonus. There was a higher prevalence of meconium passage in the misoprostol group (27.9%) than in the dinoprostone group (10.5%) (p < 0.05). There was no significant difference in frequency of abnormal fetal heart rate tracings, 1- or 5-minute Apgar scores < 7, neonatal resuscitations, or admissions to the neonatal intensive care unit between the two groups. CONCLUSIONS: Vaginally administered misoprostol is an effective agent for cervical ripening and induction of labor; however when given at this dosage, it is associated with a higher prevalence of tachysystole and meconium passage than is dinoprostone. Further studies to compare the safety of misoprostol to that of dinoprostone and to delineate an optimal dosing regimen for misoprostol are needed.

Adult↗

PubMed1995

Misoprostol: an effective agent for cervical ripening and labor induction.

OBJECTIVE: Our purpose was to compare the safety and efficacy of intravaginal misoprostol versus intracervical prostaglandin E2 gel (dinoprostone) for preinduction cervical ripening and induction of labor. STUDY DESIGN: Two hundred seventy-six patients with indications for induction of labor and unfavorable cervices were randomly assigned to receive either intravaginal misoprostol or intracervical dinoprostone. Twenty-five micrograms of misoprostol were placed in the posterior vaginal fornix every 3 hours, with a potential maximum of eight doses. Prostaglandin E2 in gel form, 0.5 mg, was placed in the endocervix every 6 hours, with a maximum of three doses. Further medication was withheld with the occurrence of spontaneous rupture of membranes, entry into active phase of labor, or a "prolonged contraction response." RESULTS: Among those evaluated, 138 received misoprostol and 137 received dinoprostone. The average interval from start of induction to vaginal delivery was shorter in the misoprostol group (1323.0 +/- 844.4 minutes) than in the dinoprostone group (1532.4 +/- 706.5 minutes) (p < 0.05). Need for oxytocin augmentation of labor occurred more commonly in the dinoprostone group (72.6%) than in the misoprostol group (45.7%) (p < 0.0001). There were no significant differences in the routes of delivery. Twenty-eight of the misoprostol-treated patients (20.3%) and thirty-eight of the dinoprostone-treated patients (27.7%) required abdominal delivery. Complications such as uterine tachysystole and thick meconium passage occurred with similar frequency in the two treatment groups. CONCLUSIONS: Intravaginal administration of misoprostol appears to be as effective as intracervical dinoprostone for cervical ripening and labor induction. Complications associated with prostaglandin administration were not statistically different between the two treatment groups. The cost of misoprostol ($0.36/100 micrograms) is much less than that of dinoprostone ($75/0.5 mg).

Cervix Uteri↗

PubMed1995

Chelating agent inhibition of Trypanosoma cruzi epimastigotes in vitro.

A number of chelating agents and some of their derivatives are as effective as, or superior to, benznidazole, the compound currently in clinical use, in the suppression of the reproduction of epimastigotes of Trypanosoma cruzi, the protozoa that causes Chagas' disease. All compounds were examined at a culture concentration of 5 micrograms/mL. The most effective compounds included N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine, sodium diethylamine-N-carbodithioate, piperidine-N-carbodithioate and several of its analogs, a number of other carbodithioates with two nonpolar groups on the nitrogen, and tetraethylthiuram disulfide, a prodrug of sodium diethylamine-N-carbodithioate and widely used in the treatment of alcoholism. The introduction of additional ionic or nonionic polar groups on the chelating molecule generally results in a loss of tyrpanocidal activity. Common commercially available chelating agents which exhibited no activity included D-penicillamine, meso-2,3-dimercaptosuccinic acid, and triethylenetetramine tetrahydrochloride. Dose-response data on the culture indicated that some of these compounds exhibited inhibition of Trypanosoma cruzi epimastigotes at concentrations as low as 0.625 microgram/mL. It is proposed that the mechanism of action of these compounds is based on their ability to interfere with the essential metal metabolism at intracellular sites of the epimastigote involving iron, copper, or zinc. The results also indicate that a certain degree of hydrophobicity may be necessary for the groups attached to the literal metal-bonding structure if the compounds are to successfully inhibit the epimastigotes of Trypanosoma cruzi. The development of antiprotozoal drugs which are chelating agents specifically designed to selectively disrupt the essential metal metabolism of Trypanosoma cruzi should furnish a new generation of drugs which can be used in the treatment of Chagas' disease.

Animals↗

PubMed1995

Effect of chelators, monoisoamyl meso-2,3-dimercaptosuccinate and N-(4-methylbenzyl)-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbodit hioate, on cadmium and essential element levels in mice.

In experiments performed on male mice (ICR) the mobilizing effect of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) and a dithiocarbamate analogue, N-(4-methylbenzyl)-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbod ithioate (MeBLDTC) on the cadmium deposits was studied. The influence of these compounds on the changes in the level of essential elements caused by cadmium was explored. CdCl2.H2O was injected intravenously. The chelators were administered every 48 h over 12 d. Both compounds are effective in mobilizing cadmium from the body in animal experiments. On an equimolar basis MeBLDTC was superior to Mi-ADMS. Mi-ADMS can, however, be administered orally. Both compounds were able to correct, at least partly, the changes in the level of essential elements caused by cadmium.

Animals↗