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PubMedDate not supplied

Arsenic(III), but not antimony(III), induces DNA-protein crosslinks.

Antimony compounds are supposed to resemble to arsenicals in some toxicological features. Comparative investigations with antimony and arsenic were performed to collect data on the genotoxicity of antimony, on which the knowledge is scarce. In comparison to trivalent arsenic, trivalent antimony proved to be five times less cytotoxic in the neutral red assay and one order of magnitude less genotoxic in the cytokinesis-block micronucleus test using V79 Chinese hamster cells. The data obtained in the comet assay showed that the As(III)-mediated generation of DNA-protein crosslinks and DNA strand lesions seem to be two independent processes. In contrast, Sb(III) induced DNA strand lesions but not DNA-protein crosslinks. Further studies will have to investigate whether the genotoxicity of Sb(III) is mediated by an inhibition of DNA repair as it seems to be the case for As(III).

Animals↗

PubMed1964

THE EFFECTS OF ANTIMONY UPTAKE ON THE LOCATION AND PAIRING OF SCHISTOSOMA MANSONI.

The rate of uptake and elimination of antimony by both male and female schistosomes has been measured. It has been confirmed that the female schistosome is more susceptible to antimony therapy than the male since she absorbs more drug. The changes in location of the worms and the separation of the sexes following one or more injections of antimony potassium tartrate have been related to the different rates of uptake and elimination of the drug by the two sexes. The suppressive treatment of schistosomiasis is discussed in the light of these observations.

Animals↗

PubMedDate not supplied

[A comparative study between sodium stibogluconate BP 88R and meglumine antimoniate in the treatment of cutaneous leishmaniasis. I. The efficacy and safety].

Efficacy and safety of meglumine antimoniate and sodium stibogluconate BP 88R were compared in cutaneous leishmaniasis treatment in Corte de Pedra, Bahia, an endemic area of leishmaniasis due to Leishmania (Viannia) braziliensis. An open trial was developed with one hundred twenty seven patients who were diagnosed based on clinical criteria and Montenegro's skin test. Fifty eight patients were treated with meglumine antimoniate and 69 received sodium stibogluconate. Both groups received 20 mg/Sbv/kg/day for 20 days. Patients were followed every ten days during treatment and every month thereafter for three months. Sixty two percent patients cured with meglumine antimoniate and 55% cured with sodium stibogluconate (p = 0.42). Headache was more frequent during the first half of treatment in patients receiving sodium stibogluconate (p = 0.026). During the second half, patients treated with sodium stibogluconate showed a greater frequency of myalgia/arthralgia (p = 0.004) and abdominal pain/anorexia (p = 0.004). Three patients treated with sodium stibogluconate had severe side effects.

Adolescent↗

PubMed1991

Chemotherapy of trypanosomiasis: the potentiation of antimonial compounds by difluoromethylornithine (DFMO).

The currently available anti-leishmanial antimonial drugs, together with other antimony compounds were individually tested, in combination with difluoromethylornithine (DFMO), against experimental murine trypanosomiasis with central nervous system involvement. Satisfactory cure rates could be achieved using a combination treatment of DFMO with most of these anti-leishmanial drugs, but in general, only when they were administered at least twice daily. Of the compounds tested, the most effective was antimony dimercaptosuccinate (Astiban).

Animals↗

PubMed1990

Distribution of antimony in contaminated grassland: 1--Vegetation and soils.

Antimony concentrations in surface soils were found to decrease with increasing distance from an antimony smelter. This pattern was also found in moss bags exposed in the same area. At three sites close to the smelter, antimony concentrations in soil and vegetation were much higher than at a rural control site and published background levels. Maximum soil and plant concentrations on a dry weight basis of 1489 mg kg(-1) and 336 mg kg(-1), respectively, were found, compared to background levels of <1 mg kg(-1). Field exposure of grass in pots of uncontaminated soil and a laboratory experiment using soils from near the smelter suggested that the antimony in vegetation was largely due to continued aerial deposition and not to uptake from soil.

Journal Article↗

PubMed1990

Distribution of antimony in contaminated grassland: 2--Small mammals and invertebrates.

Concentrations of antimony in invertebrates and small mammals from grasslands in the vicinity of an antimony smelter were significantly elevated compared to a control site. Higher concentrations of antimony were recorded in liver, lung and kidney tissue of herbivorous and insectivorous mammals from the contaminated sites. However, there is little evidence of bioaccumulation of antimony in food chains represented by the soil-vegetation-invertebrate-insectivore pathway of the grasslands, and little indication of significant accumulation by herbivorous mammals despite marked contamination of their diet.

Journal Article↗

PubMed2001

Preparation and crystal structure of the ternary uranium rare Earth antimonides (U(2/3)R(1/3))Sb(2) and (U(1/2)R(1/2))(3)Sb(7) with mixed U/R occupancy of the metal sites and a variety of antimony polyanions.

The ternary antimonides (U(2/3)R(1/3))Sb(2) (R = Y, Ce-Nd, Sm, Gd-Tm) and (U(1/2)R(1/2))(3)Sb(7) (R = Y, Gd-Ho) have been prepared by reaction of the uranium antimonide USb(2) with the corresponding rare earth antimonides RSb(2) and an excess of elemental antimony at high temperatures. The crystal structure of the isotypic series (U(2/3)R(1/3))Sb(2) has been determined from single-crystal X-ray data of (U(0.675(9))Gd(0.325(9)))Sb(2). It is isotypic with PbCl(2): Pnma, Z = 4, a = 754.6(1), b = 419.6(1), c = 1025.7(3) pm. The compounds of the other series crystallize with a new structure type, which has been determined for (U(0.49(1))Ho(0.51(1)))(3)Sb(7): Immm, Z = 4, a = 410.1(1), b = 1447.7(3), c = 1821.2(5) pm. In both structures, the metal positions have mixed occupancy and high coordination numbers. Both structures contain numerous weak Sb-Sb bonds, thus forming a band of antimony atoms in the structure of (U(2/3)Gd(1/3))Sb(2) and a chain and a three-dimensionally infinite network of antimony atoms in the structure of (U(1/2)Ho(1/2))(3)Sb(7). Analyses of the Sb-Sb bonding within the antimony polyanions on the basis of bond-length bond-strength considerations indicate that the uranium atoms have mixed or intermediate +3/+4 valence in these compounds. The structure of (U(1/2)Ho(1/2))(3)Sb(7) may be considered as a defect variant of the structure of Ce(6)MnSb(15).

Journal Article↗

PubMed2006

Double blind, randomized controlled trial, to evaluate the effectiveness of a controlled nitric oxide releasing patch versus meglumine antimoniate in the treatment of cutaneous leishmaniasis [NCT00317629].

BACKGROUND: Cutaneous Leishmaniasis is a worldwide disease, endemic in 88 countries, that has shown an increasing incidence over the last two decades. So far, pentavalent antimony compounds have been considered the treatment of choice, with a percentage of cure of about 85%. However, the high efficacy of these drugs is counteracted by their many disadvantages and adverse events. Previous studies have shown nitric oxide to be a potential alternative treatment when administered topically with no serious adverse events. However, due to the unstable nitric oxide release, the topical donors needed to be applied frequently, making the adherence to the treatment difficult. The electrospinning technique has allowed the production of a multilayer transdermal patch that produces a continuous and stable nitric oxide release. The main objective of this study is to evaluate this novel nitric oxide topical donor for the treatment of cutaneous leishmaniasis. METHODS AND DESIGN: A double-blind, randomized, double-masked, placebo-controlled clinical trial, including 620 patients from endemic areas for Leishmaniasis in Colombia was designed to investigate whether this patch is as effective as meglumine antimoniate for the treatment of cutaneous leishmaniasis but with less adverse events. Subjects with ulcers characteristic of cutaneous leishmaniasis will be medically evaluated and laboratory tests and parasitological confirmation performed. After checking the inclusion/exclusion criteria, the patients will be randomly assigned to one of two groups. During 20 days Group 1 will receive simultaneously meglumine antimoniate and placebo of nitric oxide patches while Group 2 will receive placebo of meglumine antimoniate and active nitric oxide patches. During the treatment visits, the medications will be daily administered and the presence of adverse events assessed. During the follow-up, the research group will visit the patients at days 21, 45, 90 and 180. The healing process of the ulcer, the health of the participants, recidivisms and/or reinfection will also be assessed. The evolution of the ulcers will be photographically registered. In case that the effectiveness of the patches is demonstrated, a novel and safe therapeutic alternative for one of the most important public health problems in many countries will be available to patients.

Journal Article↗

PubMed2006

Speciation of antimony by preconcentration of Sb(III) and Sb(V) in water samples onto nanometer-size titanium dioxide and selective determination by flow injection-hydride generation-atomic absorption spectrometry.

A novel method for prevention of the oxidation of Sb(III) during sample pretreatment, preconcentration of Sb(III) and Sb(V) with nanometer size titanium dioxide (rutile) and speciation analysis of antimony, has been developed. Antimony(III) could be selectively determined by flow injection-hydride generation-atomic absorption spectrometry, coexisting with Sb(V). Trace Sb(III) and Sb(V) were all adsorbed onto 50 m g TiO2 from 500 ml solution at pH 3.0 within 15 min, then eluted by 10 ml of 5 mol/l HCl solution. One eluent was directly used for the analysis of Sb(III); to the other eluent was added 0.5 g KI and 0.2 g thiourea to reduce Sb(V) to Sb(III), then the mixture was used for the determination of total antimony. The antimony(V) content is the mathematical difference of the two concentrations. Detection limits (based on 3sigma of the blank determinations, n=11) of 0.05 ng/ml for Sb(III) and 0.06 ng/ml for Sb(V), were obtained.

Journal Article↗

PubMedDate not supplied

Antimonial treatment of hamsters infected with Leishmania (Viannia) panamensis: assessment of parasitological cure with different therapeutic schedules.

The objective of the study was to establish the effective dose and route of administration of Glucantime for treating hamsters infected with Leishmania (Viannia) panamensis and to use this method to test new treatment regimens to attain clinical and parasitological cure. In the first experiments animals were inoculated subcutaneously in the hind foot with 5 x 10(6) promastigotes of L. panamensis (HOM/COL/84/1099) from a 6 d culture. One month after inoculation, Glucantime was administered intramuscularly (i.m.) at 20, 40 or 60 mg/kg/d for 20 d to groups of hamsters. Only 60 mg/kg/d resulted in both clinical improvement and parasite elimination from the skin and draining lymph node. In the second set of experiments, i.m., local and combined antimonial regimens were compared. The local regimen, of 4 intralesional (i.l.) injections of 4 mg of antimony at 5 d intervals, and the combined regimen (i.m. and i.l.), were more efficient at clearing parasites than the systemic (i.m.) schedule, especially when a low dosage of Glucantime (30 mg/kg/d x 20 d) was used. The results suggest that combining local treatment and low systemic dosages of antimonials results in clearance of L. panamensis.

Animals↗

PubMed2005

Differential toxicity of antimonial compounds and their effects on glutathione homeostasis in a human leukaemia monocyte cell line.

Trivalent antimonial compounds (Sb(III)), originally used in the treatment of leishmaniasis, are now being proposed as a novel therapy for acute promyelocytic leukaemia (APL). Here, we examine the effects of Sb(III) and pentavalent antimonial drugs (Sb(V)) on glutathione homeostasis, oxidative stress and apoptosis in the human leukaemia monocyte cell line, THP-1. Although growth of THP-1 macrophages is unaffected by Sb(V), macrophages are extremely sensitive to Sb(III). On exposure to Sb(III), intracellular free glutathione (GSH) levels in macrophages decrease linearly by 50% over 4h, associated with efflux of both GSH and accumulation of intracellular glutathione disulphide (GSSG). Together these effects increase the redox potential of the GSSG/GSH couple from -282 to -225mV. Sb(III)-induced GSH efflux from THP-1 macrophages is accompanied by the concomitant efflux of Sb(III) at a constant molar ratio of 3 (GSH) to 1 (Sb(III)), respectively. Sb(III) directly inhibits glutathione reductase activity in macrophages, significantly retarding the regeneration of GSH from GSSG, following diamide oxidation. Sb(III)-treated THP-1 macrophages go on to exhibit elevated levels of reactive oxygen species and show the early signs of apoptosis. The absence of these effects in Sb(V)-treated THP-1 cells suggests that macrophages do not efficiently reduce Sb(V) to Sb(III). Collectively, these findings suggest that Sb(III) seriously compromises thiol homeostasis in THP-1 macrophages and that this may be an early defining event in the mode of action of antimonials against leukaemia cells.

Antimony Potassium Tartrate↗

PubMed1997

Pentavalent antimonial-induced torsade de pointes.

Unexplained sudden deaths following use of pentavalent antimonial drugs have been described, presumably owing to ventricular arrhythmias. A patient is reported with QT interval prolongation and syncopal episodes related to torsade de pointes following treatment of visceral leishmaniasis with meglumine antimoniate. This is the first reported case of documented torsade de pointes following treatment with pentavalent antimonial drugs.

Aged↗

PubMed1993

Synthesis of antimony complexes of yeast mannan and mannan derivatives and their effect on Leishmania-infected macrophages.

Antimony(Sb)-yeast mannan complexes were synthesized as a strategy to introduce Sb into macrophages infected with Leishmania amastigotes. The complexes were taken up by endocytosis after specific recognition by alpha-D-mannosyl receptors on the macrophage membrane. About 90% of the intracellular parasites were destroyed by Sb-mannan in vitro, whereas the corresponding Sb concentration used as the pentavalent antimonial drug glucantime destroyed about 60% of the amastigotes. None of the Sb complexes prepared with mannan acid or basic derivatives was as effective as the simple Sb-mannan complex in clearing macrophage infection by Leishmania (L) amazonensis. The leishmanicidal effect of Sb-mannan was also demonstrated in vivo with infected hamsters. The alternative use of Sb-mannan complex in the treatment of human leishmaniasis is envisaged on the basis of parasite-killing efficiency and the use of a low antimony dose.

Animals↗

PubMed1994

Pancreatitis induced by pentavalent antimonial agents during treatment of leishmaniasis.

Pentavalent antimony (Sbv), formulated as sodium stibogluconate or meglumine antimoniate, is the standard treatment for the leishmaniases. In 16 of 17 consecutive, prospectively observed patients in Washington D.C., serum levels of amylase and lipase rose to abnormal values after therapy with sodium stibogluconate was started; 12 of 17 had symptoms of pancreatitis. Sbv therapy was continued to completion in 7 of 17 patients and interrupted in 10 of 17. Pancreatitis improved in every patient after Sbv therapy was stopped. Sbv treatment was resumed after brief interruptions in 6 of 10 patients. All six of these patients had flares of pancreatitis, but each completed therapy. Subsequently, we measured amylase and lipase levels in stored sera from 32 patients treated in Peru with either sodium stibogluconate or meglumine antimoniate for mucosal leishmaniasis. In all 32 Peruvian patients, serum amylase and lipase rose to abnormal levels during Sbv therapy; 11 of 32 had symptoms of pancreatitis. Standard Sbv regimens induce pancreatitis in almost all patients, but continued therapy is often tolerated; pancreatitis subsides when therapy is stopped, and rechallenge may be tolerated after a brief halt in treatment.

Adult↗

PubMed2004

The heat shock protein HSP70 and heat shock cognate protein HSC70 contribute to antimony tolerance in the protozoan parasite leishmania.

Antimony-containing drugs are still the drugs of choice in the treatment of infections caused by the parasite Leishmania. Resistance to antimony is now common in some parts of the world, and several mechanisms of resistance have been described. By transfecting cosmid banks and selecting with potassium antimonyl tartrate (SbIII), we have isolated a cosmid associated with resistance. This cosmid contains 2 copies of the heat shock protein 70 (HSP70) and 1 copy of the heat shock cognate protein 70 (HSC70). Several data linked HSP70 to antimony response and resistance. First, several Leishmania species, both as promastigotes and amastigotes, increased the expression of their HSP70 proteins when grown in the presence of 1 or 2 times the Effect Concentration 50% of SbIII. In several mutants selected for resistance to either SbIII or to the related metal arsenite, the HSP70 proteins were found to be overexpressed. This increase was also observed in revertant cells grown for several passages in the absence of SbIII, suggesting that this increased production of HSP70 is stable. Transfection of HSP70 or HSC70 in Leishmania cells does not confer resistance directly, though these transfectants were better able to tolerate a shock with SbIII. Our results are consistent with HSP70 and HSC70 being a first line of defense against SbIII until more specific and efficient resistance mechanisms take over.

Animals↗

PubMed1998

A cluster of cases of severe cardiotoxicity among kala-azar patients treated with a high-osmolarity lot of sodium antimony gluconate.

In India, sodium antimony gluconate is the drug of choice for kala-azar. Due to increasing unresponsiveness to this drug in the current epidemic that began in the early 1970s, daily doses of 20 mg/kg/day for 30 days or more is recommended as opposed to the 10 mg/kg/day dose for 6-10 days used in the past. Of the 130-150 patients treated annually at our center with locally made sodium antimony gluconate, serious cardiotoxicity has occurred in less than 10%. During April 1995 at the University Hospital in Varanasi, we encountered life-threatening cardiotoxicity after 3-28 days of therapy in each of the eight patients being treated with a new lot of this drug made by a different manufacturer. Of the eight patients, six each developed congestive heart failure and/or prolongation of the corrected QT interval (QTc), and three died as a direct consequence of drug-induced toxicities. In three instances, the life-threatening complications occurred with a cumulative dose of less than 300 mg/kg. In patients with prolonged QTc, ventricular premature beats and ventricular tachycardia were recorded; in one patient, the ventricular tachycardia progressed to torsade de pointes, culminating in ventricular fibrillation and death. Since switching to different lots of this drug, we have not seen further clustering of dangerous cardiotoxicity. The antimony content of the implicated drug was comparable with that in lots from other manufacturers that did not show overt toxicity, but the osmolarity was approximately 300 mOsm/L higher. The simple technique of measuring of osmolarity may help identify inappropriately manufactured drug.

Adult↗

PubMed1999

[Torsades de pointes during treatment of leishmaniasis with meglumine antimoniate].

Antimonial agents are the main drug to treat all forms of leishmaniasis. Meglumine antimoniate is the drug available in Spain and it is usually well tolerated. Nevertheless, this drug frequently alters ventricular repolarization, but few cases of sudden death, presumably related to ventricular arrhythmias, have been reported. We present a case of torsade de pointes during treatment with meglumine antimoniate coexisting with a severe hypokalemia probably due to an acute transitory tubulopathy.

Aged↗

PubMedDate not supplied

Cytogenetic observations after meglumine antimoniate therapy for visceral leishmaniasis.

Few data are available concerning the genotoxic effects of antimonial salts therapy in humans. A patient suffering from visceral leishmaniasis was treated for 15 days with a cumulative dose meglumine antimoniate 42.5 g. Peripheral blood lymphocytes sampled before treatment, 7 days later, and at the end of therapy (day 15) were examined for the presence of structural chromosome aberrations, sister chromatid exchanges (SCEs), and micronuclei in binucleated cells. The treatment resulted in an increase of binucleated cells carrying micronuclei, with no changes in chromosome structural aberrations or in mean SCE frequency. On the basis of these observations and of experimental results reported in the literature, we conclude that therapy with meglumine antimoniate apparently does not represent a mutagenic or carcinogenic risk to humans.

Animals↗