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PubMed2005

Developmental toxicity of meglumine antimoniate and transplacental transfer of antimony in the rat.

Meglumine antimoniate (MA), a pentavalent antimonial (SbV) drug, has been used for the treatment of leishmaniases for over half a century but there is almost no data on its safety and kinetics during pregnancy. This study was undertaken to investigate the developmental toxicity of MA as well as the transplacental transfer of antimony (Sb) in rats. Wistar rats (approximately 20 per group) were treated subcutaneously (s.c.) with MA (0, 75, 150, 300 mg SbV/(kg BW day)) during pregnancy (days 1-20). An untreated control group was evaluated as well. Caesarean sections were performed on day 21 and implantations, living and dead fetuses, and resorptions were recorded. Fetuses were weighed and fixed in Bouin's solution and one-third of each litter was examined for soft-tissue anomalies. The remaining fetuses were cleared and stained with Alizarin red S for skeleton evaluation. No adverse effect of MA on the mothers was noted at any dose level. No embryotoxicity was observed at the lowest dose but, at the highest dose, MA increased embryolethality, reduced fetal weight and augmented the occurrence of some soft-tissue and skeleton variations. Therefore, the no-observed-adverse-effect level for MA-induced embryotoxicity was 75 mg SbV/(kg BW day). In a separate group of rats treated with 300 mg SbV/(kg BW day) s.c. during whole pregnancy, blood (0.2 mL) was taken from the tail vein 1, 2, 4, 6, 12 and 24 h after treatment on day 1 and thereafter every other day immediately before drug injection. Blood was also taken from fetuses removed on day 21, 24h after the last injection of MA. Blood levels of Sb were determined by ICP-MS and results showed that most of administered Sb was eliminated rapidly (in less than 6 h), but nadir blood concentrations increased gradually during treatment from 1 to 2 microg/g, 24h after the first dose, up to approximately 38 microg/g after the 20th dose. Levels of Sb in fetal blood were as high as 10-15 microg/g, i.e. approximately 30% their mothers' nadir levels near term. These findings indicated that repeated administration of MA during gestation led to an accumulation of Sb in mothers and fetuses.

Abnormalities, Drug-Induced↗
PubMed2003

The efficacy of treatment with intralesional meglumine antimoniate alone, compared with that of cryotherapy combined with the meglumine antimoniate or intralesional sodium stibogluconate, in the treatment of cutaneous leishmaniasis.

It would be very useful to have a more effective and more rapid method available for the treatment of cutaneous leishmaniasis (CL). The main aim of the present, Iranian study, was to see if the combination of cryotherapy and intralesional injections with meglumine antimoniate (C + MA) would be more effective than the injections given alone (MA) or the combination of cryotherapy plus intralesional sodium stibogluconate (C + SS). Forty patients (with 67 lesions) were treated with C + MA, another 40 (with 65 lesions) were treated with C + SS and 100 patients (with 180 lesions) were treated with MA. Follow-up for 6 months after the final treatment indicated that 89.5% of the lesions treated with C + MA, 92.3% of those treated with C + SS but only 50% of the lesions treated with MA only were completely cured. The frequencies of cure in the two cryotherapy groups were similar, both being significantly higher than that in the MA group (P < 0.05). The combination of cryotherapy with intralesional injections of meglumine antimoniate or sodium stibogluconate, which is much more effective than the use of intralesional meglumine antimoniate alone, should be promoted.

Adolescent↗
PubMed2003

Reduction of pentavalent antimony by trypanothione and formation of a binary and ternary complex of antimony(III) and trypanothione.

Several pentavalent antimony compounds have been used for the treatment of leishmaniasis for decades. However, the mechanism of these antimony drugs still remains unclear. One of their targets is thought to be trypanothione, a major low molecular mass thiol inside the parasite. We show that pentavalent antimony (Sb(V)) can be rapidly reduced to its trivalent state by trypanothione at mildly acidic conditions and 310 K ( k=4.42 M(-1) x min(-1) at pH 6.4), and that Sb(III) can be bound to trypanothione to form an Sb(III)-trypanothione complex. NMR data demonstrate that Sb(III) binds to trypanothione at the two thiolates of the cysteine residues, and that the binding is pH dependent and is strongest at biological pH with a stability constant log K=23.6 at 298 K (0.1 M NaNO(3)). The addition of low molecular monothiol ligands such as glutathione and cysteine to the Sb(III)-trypanothione complex results in the formation of a ternary complex. Thiolates from both trypanothione and monothiol bind to the Sb(III) center. The formation of the ternary complex is important, as the antileishmanial properties of the drugs are probably due to a complex between of Sb(III)-trypanothione and enzymes. Although thermodynamically stable, the complex is kinetically labile and the free and bound forms of thiolates exchange on the (1)H NMR timescale. Such a facile exchange may be crucial for the transport of Sb(III) within parasites.

Antimony↗
PubMed2004

Antimony distribution and environmental mobility at an historic antimony smelter site, New Zealand.

A historic antimony smelter site at Endeavour Inlet, New Zealand has smelter residues with up to 17 wt.% antimony. Residues include coarse tailings (cm scale particles, poorly sorted), sand tailings (well sorted) and smelter slag (blocks up to 30 cm across). All of this material has oxidised to some degree over the ca. 100 years since the site was abandoned. Oxidation has resulted in acidification of the residues down to pH 2-5. Smelter slag contains pyrrhotite (FeS) and metallic antimony, and oxidation is restricted to surfaces only. The coarse tailings are the most oxidised, and few sulfide grains persist. Unoxidised sand tailings contain 10-20 vol.% stibnite (Sb2S3) containing up to 5% As, with subordinate arsenopyrite (FeAsS), and minor pyrite (FeS2). The sand tailings are variably oxidised on a scale of 2-10 cm, but original depositional layering is preserved during oxidation and formation of senarmontite (Sb2O3). Oxidation of sand tailings has resulted in localised mobility of both Sb and As on the cm scale, resulting in redistribution of these metalloids with iron oxyhydroxide around sand grain boundaries. Experiments demonstrate that Sb mobility decreases with time on a scale of days. Attenuation of both As and Sb occurs due to adsorption on to iron oxyhydroxides which are formed during oxidation of the smelter residues. There is no detectable loss of Sb or As from the smelter site into the adjacent river, <50 m away, which has elevated Sb (ca. 20 microg/l) and As (ca. 7 microg/l) from mineralised rocks upstream. Despite the high concentrations of Sb and As in the smelter residues, these metalloids are not being released into the environment.

Adsorption↗
PubMed2003

American cutaneous leishmaniasis unresponsive to antimonial drugs: successful treatment using combination of N-methilglucamine antimoniate plus pentoxifylline.

BACKGROUND: American cutaneous leishmaniasis is characterized by single or multiple ulcerations. Cytokines, among other factors, have been shown to influence lesion development and tumoral necrosis factor-alpha is a major cytokine implicated in pathogenesis of ulcers. OBSERVATIONS: We tested oral pentoxifylline, a known tumoral necrosis factor-alpha inhibitor, at doses of 400 mg (2-3x/day), associated to N-methylglucamine antimoniate (15 mg/kg/day) in two patients with American cutaneous leishmaniasis unresponsive to antimonial drugs. We observed a satisfactory response with quick cure of skin lesions of these patients. CONCLUSIONS: Our results suggest that oral pentoxifylline in association to N-methylglucamine antimoniate should be consider in refractory cutaneous leishmaniasis patients.

Administration, Oral↗
PubMed2001

[Direct determination of selenium and bismuth in antimony and antimony compound by hydride generation-atomic fluorescence spectrometry].

The interference of Sb in determination of Se and Bi in antimony powder and antimony compound has been studied in different acidity, it is found that the interference of antimony has been reduced apparently in high acidity. Simultaneously, according to the difference of hydride generation reaction between Sb5+ and Sb3+, a sensitive and rapid method has been developed and used to determine Se and Bi in real samples. The recovery of the method is 95%-105% for practical samples. Detection limits are 0.00004 x 10(-2) (content) for Se and 0.0001 x 10(-2) mg.L-1 (content) for Bi respectively. The relative standard deviations of Se are 2.4% (content = 0.00169 x 10(-2) mg.L-1) and 5.4% (content = 0.00056 x 10(-2) mg.L-1). The relative standard deviations of Bi are 5.0% (content = 0.00024 x 10(-2) mg.L-1) and 1.3% (content = 0.00229 x 10(-2) mg.L-1). The method has been applied to determination of Se and Bi in practical samples with satisfactory results.

Antimony↗
PubMed1988

Pharmacokinetics of antimony during treatment of visceral leishmaniasis with sodium stibogluconate or meglumine antimoniate.

5 patients with visceral leishmaniasis were treated with sodium stibogluconate (2 patients) or meglumine antimoniate (3 patients) given intramuscularly at a dose of 10 mg antimony (Sb) per kg body weight daily for 30 d. Blood samples were obtained at intervals during treatment and blood Sb concentrations measured by anodic stripping voltametry. The pharmacokinetics of both drugs were remarkably similar, with peak concentrations of approximately 10 mg/litre occurring 2 h after the initial dose. Most of the Sb was eliminated rapidly, but nadir Sb concentrations increased gradually during treatment from 0.04-0.08 mg/litre 24 h after the first dose to 0.19-0.33 mg/litre 24 h after the 30th dose. For both drugs, the data were best described by a two compartment, three term pharmacokinetic model representing an initial absorption phase with a mean half-life of 0.85 h, a rapid elimination phase with a mean half-life of 2.02 h, and a slow elimination phase with a mean half-life of 76 h. The slow terminal elimination phase may be related to in vivo conversion of pentavalent Sb to trivalent Sb, which could contribute to the toxicity associated with long-term high dose therapy.

Antimony↗
PubMed2001

Two successive single crystal phase transitions involving the coordination sphere of antimony in PhSb(dmit), the first organo-antimony(III) dithiolene complex.

PhSb(dmit) (dmit(2)(-), 4,5-dithiolato-1,3-dithiole-2-thione), the first neutral organo-antimony dithiolene complex, has been synthesized by addition of PhSbCl(2) on a suspension of Na(2)(dmit). The complex was characterized by spectroscopic ((1)H and (13)C NMR and IR) methods and elemental analysis. Its crystal structure was determined by X-ray diffraction at room temperature in the monoclinic P2(1)/c space group, with a = 12.580(3), b = 8.9756(18), c = 15.905(3) A, beta = 109.06(3) degrees, V = 1697.5(6) A(3), Z = 4. A coordinating THF molecule was found in the structure and the coordination geometry around the antimony atom is of distorted pseudopentagonal bipyramid type, if taking into account the Sb.O and secondary Sb.S interactions, as well as the stereochemically active 5s(2) lone pair. The intermolecular Sb.S and S.S contacts, shorter than the sum of van der Waals radii of corresponding atoms, lead to the formation of a three-dimensional polymeric network in the solid state. A second X-ray diffraction experiment, performed at 85 K, revealed a very similar monoclinic unit cell with the noncentrosymmetrical space group P2(1) with a = 12.613(3), b = 8.9876(18), c = 15.109(3) A, beta = 107.01(3) degrees, V = 1637.8(6), Z = 4. The structural differences with the first one are basically due to the rotation of the THF ligand in the coordination sphere of the antimony center, leading to the loss of every inversion center found at room temperature. A temperature variable X-ray diffraction study on a PhSb(dmit) single-crystal allowed the detection, with a remarkable accuracy, of two successive first-order phase transitions, the first occurring at T = 162.5 K, while the second was observed at T = 182.5 K. Subsequently, a third set of X-ray data was collected at 180 K and the resulting structure (monoclinic, P2(1)/c, a = 16.736(3), b = 8.9653(18), c = 33.132(7) A, beta = 91.98(3) degrees, V = 4968.2(17), Z = 12) derives from the two others by a common b axis, a 3-fold cell volume increase, and the presence of only one-third of the inversion centers present at room temperature. A DSC analysis, showing two endothermic peaks at the expected temperatures, confirms the occurrence of the two structural phase transitions, also in agreement with preliminary Raman data.

Journal Article↗
PubMed1994

Antimony determination in tissues and serum of hamsters infected with Leishmania garnhami and treated with meglumine antimoniate.

Hamsters were experimentally infected with Leishmania garnhami and then treated for 10 days with N-methyl-glucamine antimoniate (Glucantime); 60 mg/kg/day by intramuscular (im) or intralesional (il) routes. Hydride generation-atomic absorption spectroscopy was used to determine the concentrations of SbIII and SbV in the blood serum and total Sb in the tissues of the hamsters from 1 to 30 days after initiation of the treatment. Serum concentrations of SbIII and SbV were always similar. Total Sb concentrations were significantly higher in the relatively parasite-rich spleen and lesion than in any other tissue, whether treatment had been given im or il. Reduction of SbV to SbIII is probably associated with decreasing size and healing of the leishmanial ulcers. Tissue Sb kinetics is related to Leishmania behaviour and attention is drawn to the use of antimonial pentavalent compounds for diseases, other than leishmaniasis, that can affect the heart, liver and/or spleen, such as Chagas disease.

Animals↗
PubMed1990

Retention of antimony in skin biopsies of leishmaniasis patients after treatment with N-methylglucamine antimoniate.

Leishmaniasis patients were treated with N-methylglucamine antimoniate by intravenous injections of 10 or 20 mg of Sb per kilogram of body weight per day for 10 or 20 days. Digests of skin biopsies taken from the site of lesion before and after treatment were analyzed for antimony by instrumental neutron activation (INAA). The detection limit of the assay was 20 ng, and no Sb could be measured in digests of samples (less than 2.45 mg) taken before treatment. Biopsies taken after injections of Sb showed concentrations in the range of 8.32 to 70.68 ng/g skin. We discuss the usefulness of INAA in the study of Sb in small samples of tissues.

Adolescent↗
PubMedDate not supplied

Clinical healing of antimony-resistant cutaneous or mucocutaneous leishmaniasis following the combined administration of interferon-gamma and pentavalent antimonial compounds.

In an open trial, longer courses of pentavalent antimonials (Sbv) at sub-optimal doses (10 mg/kg body weight), in association with recombinant human interferon-gamma (IFN-gamma) (100 micrograms/m2 of body surface area) were administered, by daily intramuscular injections, to 13 patients with diagnoses of cutaneous or mucocutaneous leishmaniasis unresponsive to Sbv. Four patients presented with large skin ulcers, and 9 had mucosal involvement as the main manifestation, the latter affecting the nose (3 cases), nose and septum (2 cases), nose and oral cavity (1 case), and nose, pharynx and larynx (3 cases). Except for one case with severe involvement of the upper respiratory tract, the lesions were fully resolved by the end of therapy (mean duration 40 +/- 12 [SD] d, range 30-60 d) in the 11 patients who completed therapy. The main side effects were headache and fever (7 cases), together with leucopenia and eosinophilia (4 cases). It is concluded that combined administration of low doses of Sbv plus IFN-gamma may provide a novel therapeutic approach for the treatment of antimony-resistant cutaneous or mucocutaneous leishmaniasis. The possible mechanisms by which IFN-gamma contributes to resolution of the disease are discussed.

Adolescent↗
PubMed2005

Critical appraisal of available thermodynamic data for the complexation of antimony(III) and antimony(V) by low molecular mass organic ligands.

Antimony is an element of increasing environmental significance but one whose chemical speciation has received little attention and, until recently, one which had not been modelled in any comprehensive way. This paper reports thermodynamic data for computer speciation models of antimony in aqueous, multicomponent solutions of environmental and biological interest involving low molecular mass organic ligands. The available data have been critically evaluated and entered into a thermodynamic database. The JESS suite of computer programs has been used to develop the thermodynamically-consistent mass balance equations used for modelling purposes. No data could be found for Sb(V) complexes and only a few of the existing data for Sb(III) complexes can be considered as being reliably described.

Antimony↗
PubMed1990

Suppression of both antimony-susceptible and antimony-resistant Leishmania donovani by a bis(benzyl)polyamine analog.

It was recently demonstrated that a bis(benzyl)polyamine analog (MDL 27695; N,N'-bis(3-[(phenylmethyl)amino]propyl)-1,7-diaminoheptane) possessed potent antimalarial activity in vitro and in vivo (A. J. Bitonti, J. A. Dumont, T. L. Bush, M. L. Edwards, D. M. Stemerick, P. P. McCann, and A. Sjoerdsma, Proc. Natl. Acad. Sci. USA 86:651-655, 1989). We now report that MDL 27695 also has potent antileishmanial activity, eliminating 77 to 100% of Leishmania donovani amastigotes from mouse peritoneal macrophages in vitro at 1 microM. Administration of 15 mg of MDL 27695 per kg three times per day for 5 days to L. donovani-infected mice suppressed parasite burdens in liver, spleen, and bone marrow by 83 to 96, 90, and 87%, respectively, and by 99.9% in livers of mice given the same dose two times per day for 10 days. Liver parasites were suppressed 74% in L. donovani-infected hamsters treated three times per day for 4 days with 5 mg of MDL 27695 per kg. The 50% effective doses for MDL 27695 were 2.5 mg/kg in mice and about 1 mg/kg in hamsters. In hamsters, MDL 27695 was equally effective against both antimony-susceptible and antimony-resistant L. donovani, suggesting a different mechanism of action for the two types of drugs. Coadministration of N1,N4-bis(butadienyl)-butanediamine (MDL 72527) to mice to inhibit host polyamine oxidase, and hence the formation of oxidative metabolites of MDL 27695, did not affect the antileishmanial activity of MDL 27695. Thus, the mechanism of action of MDL 27695 does not appear to be related to its oxidation to toxic metabolites but may involve interference with DNA and RNA syntheses as found previously in Plasmodium falciparum (Bitonti et al., Proc. Natl. Acad. Sci. USA 86:651-655, 1989).

Animals↗
PubMed1993

Immunochemotherapy for visceral leishmaniasis: a controlled pilot trial of antimony versus antimony plus interferon-gamma.

Twenty-four Kenyan patients with visceral leishmaniasis were treated for 30 days with either conventional therapy (daily pentavalent antimony, n = 14) or experimental immunochemotherapy (daily antimony plus interferon-gamma [IFN-gamma] every other day, n = 10). All 24 patients responded clinically to treatment, and microscopic splenic aspirate scores rapidly decreased in both groups. As judged by splenic aspirate culture results, IFN-gamma-treated patients responded more quickly (50% versus 22% culture-negative after one week and 75% versus 58% culture-negative after two weeks). While not statistically significant, these differences raise the possibility that combination therapy using IFN-gamma, which was safe and well-tolerated, may accelerate the early parasitologic response in patients with visceral leishmaniasis.

Adolescent↗
PubMed1991

In vitro activity of meglumine antimoniate, a pentavalent antimonial drug, on Leishmania promastigotes.

1. The activity of a pentavalent antimonial drug glucantime on the growth of promastigote forms of Leishmania strains involved in South American cutaneous and mucocutaneous leishmaniasis was investigated. A marked difference in susceptibility to glucantime among four different strains and cloned lines obtained from a single strain was observed. For the sensitive strains (L. braziliensis M2903 and L. guyanensis M1176), the cell growth was reduced in a dose-dependent manner for drug concentrations at a range of 0.23 to 23 mM. However, despite the relative sensitivity of the assay, no significant increase of effect was observed in the presence of higher drug concentrations. For the resistant strains (L. amazonensis M10996 and L. braziliensis LTB259) a dose-response line is obtained at a higher concentration range (20 mM to 70 mM). 2. The influence of the drug on surface properties, respiratory activity and incorporation of radiolabelled leucine by a sensitive strain -L. guyanensis M1176-was studied as an approach to its site of action. Despite the increased intensity of self-agglutination for cells growing in the presence of glucantime, no significant change was observed in electrophoretic mobility or Concanavalin A reactivity. Since the oxygen uptake of glucose-stimulated promastigotes was only slightly reduced in the presence of 23 mM glucantime at 28 degrees C, the reduction was not sufficient to explain the total growth inhibition observed. A significant decrease of 14C-leucine incorporation into the cold TCA-insoluble fraction of drug-treated cells was observed within the same concentration range that reduces promastigote growth.

Animals↗
PubMed2005

Antimony mobility in Japanese agricultural soils and the factors affecting antimony sorption behavior.

The mobility of antimony (Sb) in Japanese agricultural soils was studied by radiotracer experiments using 124Sb tracer. The soil-solution distribution coefficients (Kd) of Sb were measured for 110 soil samples. These Kds ranged from 1 to 2065 L kg(-1); the geometric mean was 62 L kg(-1) excluding one extremely high value, 2065 L kg(-1). Experimental measurement of Kd showed a decrease with both increasing pH and increasing phosphate concentration. The latter suggested that one aspect of the Sb sorption phenomena in Japanese soil was influenced by specific adsorption of anions such as phosphate. However, other aspects could not be explained by this specific adsorption mechanism, because only 20-40% of soil-sorbed Sb could be extracted by phosphate solution.

Adsorption↗
PubMed1986

Carcinogenic effects of antimony trioxide and antimony ore concentrate in rats.

This study was initiated because of a suspected increase in incidence of lung cancer in antimony smelter workers in England. Three groups of 8-mo-old Wistar-derived rats (90 males and 90 females per group) were exposed by inhalation to either Sb2O3 [time-weighted average (TWA) 45 mg/m3], Sb ore concentrate (TWA 36 + 40 mg/m3), or filtered air (controls) for 7 h/d, 5 d/wk, for up to 52 wk and sacrificed 20 wk after terminating exposures. Serial sacrifices (5 rats/sex/group) were performed at 6, 9, and 12 mo. Autopsies and histopathological examinations were performed on all animals. The dusts and animal tissues were analyzed for Sb, arsenic, and other inorganic elements by atomic absorption and proton-induced X-ray emission methods. The most significant findings were the presence of lung neoplasms in 27% of females exposed to Sb2O3 and 25% of females exposed to Sb ore concentrate (p less than 0.01). None of the male rats in any group or the female controls developed lung neoplasms. There were no significant differences in incidences of cancer of other organs between exposed and control rats. These results were compared with other published results, including an animal inhalation study with Sb2O3 in which lung tumors were also induced. Higher concentrations of arsenic were found in tissues from female rats than from male rats. For example, arsenic levels in blood of control males, control females, Sb2O3 males, Sb2O3 females, Sb ore males, and Sb ore females were 60, 123, 115, 230, 71, and 165 micrograms arsenic/g dry blood, respectively, 9 mo after initiating exposures.

Animals↗