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PubMed1998

Fungal volatilization of arsenic and antimony and the sudden infant death syndrome.

Fungal volatilization of antimony and other group Vb elements has been proposed to have a causal role in the sudden infant death syndrome (SIDS; cot death). The ability of fungi to produce volatile arsenic and antimony compounds in pure culture was examined using Scopulariopsis brevicaulis, reported as an inhabitant of PVC cot mattress covers, and Phaeolus schweinitzii, a wood decay fungus known to be a good volatilizer of arsenic. Volatile arsenic compounds were detected from all cultures grown on arsenic-supplemented media, but antimony volatilization was not reliably detected. Although antimony levels above the baseline sensitivity of the analytical technique were detected in four (out of 24) of the samples analyzed, the concentrations recorded were too low to be reliably interpreted as evidence for volatilization. Our results are discussed in relation to hypotheses regarding the causes of SIDS.

Antimony↗
PubMed2003

[Cutaneous leishmaniasis].

Leishmaniasis is a vector-borne disease caused by an obligate intracellular protozoa, Leishmania, which resides in macrophages. The parasite is transmitted by an infected female sandfly. The incidence of cutaneous leishmaniasis approaches 2 million new cases per year with 90% of the cases occurring in the "Old World", while the "New World" accounts for the rest. Infection may be restricted to the skin with development of characteristic ulcers, or may affect the mucous membranes in its mucocutaneous form. The clinical diagnosis is verified by the presence of amastigotes in slit-skin smears. Therapeutic modalities include systemic treatments such as the pentavalent antimony compound sodium stibogluconate, liposomal formulations of amphotericin B, oral ketoconazole or itraconazole, as well as topical paromomycin sulphate, local heat, freezing with liquid nitrogen, or photodynamic therapy. An effective vaccine is not available.

Amphotericin B↗
PubMed2002

Visceral leishmaniasis in paediatrics.

Visceral leishmaniasis is a vector-borne systemic infection, which affects half a million people each year in many areas of the world. Typical disease manifests with fever, hepatosplenomegaly, pancytopenia, and progressive deterioration of the host. Although molecular methods appear promising as a non-invasive diagnostic tool, definite diagnosis still relies on the demonstration of the parasite in tissue. Pentavalent antimonial compounds remain the mainstay of treatment worldwide, except in India. During the past decade, short courses of lipid formulations of amphotericin B were assessed and proved effective; however, their cost precludes their wide use in developing countries. Miltefosine, an oral active agent, was recently identified, and might fulfil our expectations for an effective, safe, easily administered and affordable antileishmanial treatment.

Amphotericin B↗
PubMed2004

[Relapse of visceral leishmaniasis in HIV infection. Benefit of amphotericin B].

The reference treatment in visceral leishmaniasis is administration of antimonial compounds. Failures have been reported particularly in HIV-positive patients. The authors describe the case of a 40-year-old patient who, after 2 courses of N-methyl-glucamine, relapsed. Bone marrow cultures became negative only after adminstration of amphotericin B (1 mg x kg x d) for 28 days. He is still asymptomatic 18 months after he was cured. Amphotericin B, in case of relapse, seems to be a valuable alternative, until the availability of the liposomal form in our country.

Adult↗
PubMed2004

Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani.

Despite extensive use of antimonial compounds in the treatment of leishmaniasis, their mode of action remains uncertain. Here we show that trivalent antimony (Sb(III)) interferes with trypanothione metabolism in drug-sensitive Leishmania parasites by two inherently distinct mechanisms. First, Sb(III) decreases thiol buffering capacity by inducing rapid efflux of intracellular trypanothione and glutathione in approximately equimolar amounts. Second, Sb(III) inhibits trypanothione reductase in intact cells resulting in accumulation of the disulfide forms of trypanothione and glutathione. These two mechanisms combine to profoundly compromise the thiol redox potential in both amastigote and promastigote stages of the life cycle. Furthermore, we demonstrate that sodium stibogluconate, a pentavalent antimonial used clinically for the treatment for leishmaniasis, induces similar effects on thiol redox metabolism in axenically cultured amastigotes. These observations suggest ways in which current antimony therapies could be improved, overcoming the growing problem of antimony resistance.

Animals↗
PubMed2004

[Efficacy and toxicity of pentavalent antimonials (Glucantime and Pentostam) in an American cutaneous leishmaniasis animal model: luminometry application].

The pentavalent antimonial compounds Glucantime and Pentostam are the first line drugs used in anti-Leishmania treatment. However, no in vivo studies have compared the efficacy and toxicity of these drugs where host variability has been controlled. Biochemical studies of Leishmania have detected differences between the two drugs with regard to DNA topoisomerase I inhibition, a phenomenon that possibly impacts treatment efficacy. To evaluate the clinical efficacy, hamsters were infected intradermally in the right hind foot with 10(6) promastigotes of a wild type or luciferase-transfected Leishmania panamensis. At three weeks post-inoculation, the animals were treated intramuscularly with either Glucantime or Pentostam (30, 60 or 120 mg SbV/kg per day for 20 days). To evaluate parasitological efficacy a luminometry assay was standardized for quantitation of amastigotes in hamster tissues. To evaluate toxicity, hamsters were treated intramuscularly with Glucantime or Pentostam (120, 160 or 240 mg SbV/kg per day for 20 days). Animals inoculated with either of the parasite strains and treated with either drug, showed a similar rate of lesion reduction, as compared to untreated controls (p<0.01). Parasite burden was also comparable, and no significant differences were found in the cure rate. No renal or hepatic alterations occurred as evidenced by normal serum levels of creatinine, aspartate aminotransferase, alanine aminotransferase and amylase. Hamsters treated with 120 mg SbV/kg per day for 20 days or higher doses of Pentostam showed macro- and microscopic signs of inflammation at the site of injection. These effects were absent in the animals treated with Glucantime. The results confirmed clinical observations regarding the similar efficacy of the two drugs, as well as the higher local toxicity of Pentostam.

Animals↗
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↗
PubMedDate not supplied

Treatment of visceral leishmaniasis (kala-azar) with aminosidine (= paromomycin)-antimonial combinations, a pilot study in Bihar, India.

A 20 d drug regimen of aminosidine (= paromomycin) at 12 mg/kg/d in combination with sodium stibogluconate at 20 mg/kg/d proved efficacious and well-tolerated in patients with visceral leishmaniasis in the State of Bihar, India. Eighteen of 22 evaluable patients achieved an ultimate cure. The remaining 4 patients, although not cleared of parasites, had their parasite grade reduced and also improved clinically. This confirms prior findings in Kenyan patients with kala-azar, and indicates that this regimen is a valid alternative to antimonial compounds alone in the State of Bihar, where cases of kala-azar not responding to antimonial drugs and intolerant of pentamidine are increasingly recorded.

Adolescent↗
PubMed1998

Antimony trichloride induces DNA damage and apoptosis in mammalian cells.

Antimony compounds are widely used in various manufacturing and semiconducting industries. Previously, it has been shown that antimony trichloride (SbCl3) elevates sister chromatid exchange (SCE) rates in V79 cells after a 28-h incubation. However, only limited data on its genotoxic effects are available so far. The present results demonstrate that a 4-h exposure to > 50 microM SbCl3 could induce micronuclei (MN) formation in cultured Chinese hamster ovary (CHO-K1) cells, human bronchial epithelial (BES-6) cells and human fibroblasts (HF). The order of sensitivity to SbCl3 determined by Sulforhodamine B (SRB)-staining survival assay is HF > BES-6 cells > CHO-K1 cells, with LD50 values in these cells being approximately 40, 80 and 180 microM, respectively. Apoptosis and DNA fragmentation was not found in cells immediately following 4-h SbCl3 treatment. However, DNA fragmentation was detected in CHO-K1 cells after 4-h SbCl3 treatment and a 16 h or more post incubation in fresh medium by 1.5% agarose gel electrophoresis. The delayed apoptosis was also observed under microscopic examination in HF, BES-6 and CHO-K1 cells after similar treatment protocol. In addition, an increase in calcium accumulation appeared in CHO-K1 cells and HF immediately after a 4-h SbCl3 treatment, or after a 24-h post incubation in fresh medium. The present results provide important genotoxic and cytotoxic information characterizing the cellular changes induced by short-term SbCl3 exposure in rodent and human cells.

Animals↗
PubMedDate not supplied

Clinical, serologic, and parasitologic follow-up after long-term allopurinol therapy of dogs naturally infected with Leishmania infantum.

Canine leishmaniasis usually is treated with antimony compounds, but frequent relapses, adverse effects, high costs, and development of resistance to long-term antimonial therapy emphasize the importance of searching for alternative antileishmanial drugs. Allopurinol was used at a dosage of 10 mg/kg/day PO to treat 10 dogs naturally infected with Leishmania infantum for a period of 2-24 months. Nine dogs recovered within 2-6 months of chemotherapy, and no relapses were observed during the treatment of up to 20 months. However, 3 of 4 dogs relapsed after treatment was discontinued. These dogs again recovered clinically when therapy was resumed. Parasite-specific immunoglobulin concentrations (IgG2) were high in all dogs before therapy and remained high even in clinically cured dogs during or after therapy. On the other hand, specific IgG1 reactions, which have been shown to be detectable in symptomatic animals, persisted in 7 dogs for long periods after clinical recovery. Three of these dogs relapsed within 2-4 weeks after interrupting therapy. However, 1 dog with no detectable specific IgG1 reaction at the end of therapy did not relapse in the following 4 months. Parasites could be detected in 8 of 9 dogs after clinical improvement by in vitro cultivation or polymerase chain reaction (PCR) testing of lymph node aspirates. In 4 of these dogs, parasites also were detected in blood samples by PCR. Hence, these clinically cured dogs must be regarded as reservoirs of Leishmania and allopurinol cannot be recommended in endemic areas.

Allopurinol↗
PubMedDate not supplied

Electrocardiographic alterations during treatment of mucocutaneous leishmaniasis with meglumine antimoniate and allopurinol.

The electrocardiographic (ECG) changes in Bolivian patients with mucocutaneous leishmaniasis, treated with meglumine antimoniate and allopurinol, were evaluated. Electric changes due to the antimonial compound appeared in 45% of the patients, and consisted of repolarization alteration, principally affecting the T wave and the S-T segment. The changes disappeared within 2 months following the end of the antimonial treatment. In patients with associated Chagas disease and leishmaniasis, antimonial therapy did not aggravate the ECG changes characteristic of Chagasic cardiopathy.

Adolescent↗
PubMed2003

Influence of arsenic on antimony methylation by the aerobic yeast Cryptococcus humicolus.

The anamorphic basidomycetous yeast Cryptococcus humicolus was shown by hydride generation-gas chromatography-atomic absorption spectrometry to methylate inorganic antimony compounds to mono-, di-, and trimethylantimony species under oxic growth conditions. Methylantimony levels were positively correlated with initial substrate concentrations up to 300 mg Sb l(-1) as potassium antimony tartrate (K-Sb-tartrate). Increasing concentrations of K-Sb-tartrate increased the ratio of di- to trimethylantimony species, indicating that methylation of dimethylantimony was rate limiting. Antimony methylation capability in C. humicolus was developed after the exponential growth phase and was dependent upon protein synthesis in the early stationary phase. Inclusion of inorganic arsenic (III) or (V) species alongside antimony in culture incubations enhanced antimony methylation. Pre-incubation of cells with inorganic arsenic (III) further induced antimony methylation capability, whereas pre-incubation with inorganic antimony (III) did not. Exposure of cells to inorganic arsenic-either through pre-incubation or provision during cultivation-influenced the antimony speciation; involatile trimethylantimony species was the sole methylated antimony species detected, i.e. mono- and dimethylantimony species were not detected. Competitive inhibition of antimony methylation was observed at high arsenic loadings. These data indicate that antimony methylation is a fortuitous process, catalysed at least in part by enzymes responsible for arsenic methylation.

Aerobiosis↗
PubMed1988

The potentiation of arsenicals with difluoromethylornithine (DFMO): experimental studies in murine trypanosomiasis.

The efficacy of melarsoprol in the treatment of chronic T. b. brucei infections in mice can be increased approximately 5 times if DL-a-difluoromethylornithine (DFMO) is given in the drinking water at the same time. A more detailed study substantiated the concept that a reduction in both the size and the rate of replacement of the trypanothione pool are the key factors in the efficiency of melarsoprol chemotherapy. It was therefore best to give the melarsoprol towards the end of the DFMO regimen, and as a guanylhydrazone (TBG) also blocks trypanothione (polyamine) biosynthesis, if TBG/DFMO are given together the treatment period can be reduced to 8 days. The antimony compound, sodium stibogluconate (Pentostam), used in combination with DFMO can also cure these infections and demonstrates that arsenic could be substituted by antimony in the treatment of CNS infections.

Animals↗
PubMed1998

A case of Post-kala-azar dermal leishmaniasis.

Only a few cases of Post-kala-azar dermal leishmaniasis have been reported in Japan, especially recently. We describe a case of a 32-year-old woman who developed rose-colored nodules on her forearms two years after Kala-azar. A skin biopsy specimen from a nodule revealed not only granulomatous changes but also many amastigotes of Leishmania donovani in macrophages. Rose-colored nodules were also distributed on her face and neck. Treatment with antimony compound was very effective.

Adult↗
PubMedDate not supplied

Nephrotoxicity attributed to meglumine antimoniate (Glucantime) in the treatment of generalized cutaneous leishmaniasis.

BACKGROUND: Pentavalent antimonials have became of basic importance for the treatment of leishmaniasis. Their most severe side effects have been reported to be increased hepatic enzyme levels and electrocardiographic abnormalities. Nephrotoxicity has been rarely related. OBSERVATIONS: We report a case of generalized cutaneous leishmaniasis involving a 50-year old male patient who was submitted to treatment with meglumine antimoniate (Glucantime). He developed acute renal failure (ARF) due to acute tubular necrosis (ATN), followed by death after receiving a total of 53 ampoules of Glucantime. CONCLUSIONS: The treatment with Glucantime was responsible by ARF diagnosed in this patient. The previous urine osmolarity and serum creatinine levels were normal and the autopsy showed ATN. It should be pointed out if ARF may also be explained by massive deposits of immunocomplexes by leishmania antibodies and antigens due to the antigenic break by the antimonial compound, since our patient presented countless lesions covering the entire tegument, similar to the Hexheimer phenomenon, but at the autopsy no glomerular alterations were seen.

Antiprotozoal Agents↗
PubMed2006

Novel compounds active against Leishmania major.

Leishmania major is an important trypanosomatid pathogen that causes leishmaniasis, which is a serious disease in much of the Old World. Current treatments include a small number of antimony compounds that, while somewhat effective, are limited by serious side effects. We have screened a small portion of a unique chemical library and have found at least three novel compounds that are effective against L. tarentolae and L. major in vitro and in a murine macrophage model of L. major infection. These compounds were effective in both assays at doses significantly lower than those of sodium stibogluconate (Pentostam) and represent possible candidates for drug development.

Animals↗
PubMed2002

Role of the Multidrug Resistance Protein 1 in protection from heavy metal oxyanions: investigations in vitro and in MRP1-deficient mice.

The Multidrug Resistance Protein 1 (MRP1) is a membrane pump that mediates the efflux of a wide variety of xenobiotics, including arsenical and antimonial compounds, as demonstrated by the study of MRP1-transfected cell lines. We have previously shown that mrp1(-/-) cells are hypersensitive to sodium arsenite, sodium arsenate, and antimony potassium tartrate. We now report that the retroviral vector-mediated overexpression of MRP1 and of the two subunits of gamma-GCS (heavy and light) resulted in higher intracellular glutathione levels and in a greater level of resistance to sodium arsenite and antimony potassium tartrate, compared to the overexpression of MRP1 and gamma-GCS heavy alone. These observations further demonstrate that glutathione is an important component of MRP1-mediated cellular resistance to arsenite and antimony. However, the constitutive expression of MRP1 did not protect mice from the lethality of sodium arsenite and antimony potassium tartrate nor reduced the tissue accumulation of arsenic in mice injected i.p. with sodium arsenite. It is conceivable that, in vivo, other pump(s) effectively vicariate for MRP1-mediated transport of heavy metal oxyanions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗