A study of the excretion of organic antimonials using a polarographic procedure

Goodwin, L. G.; Page, J. E.

doi:10.1042/bj0370198

Cited by 119 publications

(52 citation statements)

References 5 publications

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“…The supporters of this argument have probably overlooked a series of important and consistent observations: a) most of the rapidly excreted antimony in the urine is pentavalent 8 , b) pentavalent antimony is reduced to the trivalent state in vivo 8 29 , c) trivalent antimony can accumulate in livers from animals injected with pentavalent antimonials 8 , d) trivalent antimonials are much more active against both promastigotes and amastigotes than pentavalent compounds 22 25 26 . Taken together, these data indicate that, although most of the pentavalent antimony is rapidly excreted by the kidneys, the parasiticidal effect of the drug is probably dependent on the proportion of slowly excreted trivalent antimony that is generated and accumulated in vivo 25 .…”

Section: Discussionmentioning

confidence: 99%

An intermittent schedule is better than continuous regimen of antimonial therapy for cutaneous leishmaniasis in the municipality of Rio de Janeiro, Brazil

Azeredo-Coutinho

Mendonça

2002

Rev. Soc. Bras. Med. Trop.

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This study reviews a series of cutaneous leishmaniasis cases diagnosed and treated in outpatient units in the municipality of Rio de Janeiro, where the intermittent schedule of antimonial therapy was replaced by the continuous regimen. Both schedules were based on daily intramuscular injections of pentavalent antimonial. Forty-nine subjects received the intermittent regimen, consisting of three ten-day series alternated with ten-day rest intervals whereas seventy-one patients received the continuous regimen during 20 consecutive days. The study groups had similar composition regarding age, sex and clinical condition. The cure rate was significantly higher in the group receiving the intermittent schedule than in the group receiving continuous therapy (89.8% vs 63.3%). Moreover, loss to follow-up was significantly more frequent in the group receiving continuous therapy (19.7% vs 4.1% in the intermittent therapy). Under field conditions, the intermittent regimen provided higher effectiveness and adherence than the continuous schedule.

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Section: Discussionmentioning

confidence: 99%

An intermittent schedule is better than continuous regimen of antimonial therapy for cutaneous leishmaniasis in the municipality of Rio de Janeiro, Brazil

Azeredo-Coutinho

Mendonça

2002

Rev. Soc. Bras. Med. Trop.

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“…However, the clinical value of antimony therapy is now threatened because of the emergence of drug resistance (2) and co-infection with human immunodeficiency virus (3). Sb V is generally regarded as a pro-drug that first has to be activated by conversion to the trivalent form (Sb III ) (4). However, the site of reduction (host macrophage, amastigote, or both) and the mechanism of reduction (enzymatic or nonenzymatic) remain unclear (4 -8).…”

mentioning

confidence: 99%

Dual Action of Antimonial Drugs on Thiol Redox Metabolism in the Human Pathogen Leishmania donovani

Wyllie

Cunningham

Fairlamb

2004

Journal of Biological Chemistry

266

245

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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.Leishmania parasites cause a wide spectrum of human and animal infections ranging from life-threatening visceral disease to disfiguring mucosal and cutaneous forms of the disease. These "neglected" diseases are a significant cause of morbidity and mortality in 88 countries in the Americas, Africa, Asia, and Southern Europe; millions of people are at risk, and 400,000 new cases are reported annually (1). Leishmania spp. are obligate intracellular parasites of the vertebrate reticuloendothelial system, where they multiply as amastigotes in macrophage phagolysosomes; transmission is by blood-sucking sandflies, in which they proliferate as extracellular promastigotes. Treatment of the leishmaniases is far from ideal, and pentavalent antimonial (Sb V ) 1 preparations such as sodium stibogluconate (Pentostam) have been the front-line drugs for more than half a century. However, the clinical value of antimony therapy is now threatened because of the emergence of drug resistance (2) and co-infection with human immunodeficiency virus (3). Sb V is generally regarded as a pro-drug that first has to be activated by conversion to the trivalent form (Sb III ) (4). However, the site of reduction (host macrophage, amastigote, or both) and the mechanism of reduction (enzymatic or nonenzymatic) remain unclear (4 -8). The mode of action of these drugs is poorly understood. Sb III reversibly inhibits trypanothione reductase in vitro (9), but this has not been demonstrated in the intact parasite. However, inhibition of this unique and essential enzyme (10 -12) is of particular interest, because trypanothione (N 1 ,N 8Ϫ bis(glutathionyl) spermidine (T[SH] 2 )) is a key intermediate in the regulation of thiol redox homeostasis, as well as in defense against chemical (13,14) and oxidative stress (15, 16).Paradoxically, more is known about the mechanism of resistance to Sb III than its mode of action (17). A considerable body of evidence implicates trypanothione a...

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“…It is generally believed that relatively nontoxic Sb(V) complexes may be prodrugs that could be reduced to the more toxic and active trivalent Sb(III) at or near the site of action (e.g. amastigotes) [9,10].Glutathione (g-l-Glu-l-Cys-Gly, GSH) is a potentially polydentate ligand, and is widely used as a model system for the binding of metal ions by peptides and proteins. It is present in many cells at millimolar concentration and generally is the most abundant nonprotein thiol.…”

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confidence: 99%

Interaction of antimony tartrate with the tripeptide glutathione

Sun

Yan

Cheng

2000

European Journal of Biochemistry

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The tripeptide glutathione (g-l-Glu-l-Cys-Gly, GSH) is thought to play an important role in the biological processing of antimony drugs. We have studied the complexation of the antileishmanial drug potassium antimony(III) tartrate to GSH in both aqueous solution and intact red blood cells by NMR spectroscopy and electrospray ionization mass spectrometry. The deprotonated thiol group of the cysteine residue is shown to be the only binding site for Sb (III), and a complex with the stoichiometry [Sb(GS) 3 ] is formed. The stability constant for [Sb(GS) 3 ] was determined to be log K 25 (I 0.1 m, 298 K) based on a competition reaction between tartrate and GSH at different pH* values. In spite of being highly thermodynamically stable, the complex is kinetically labile. The rate of exchange of GSH between its free and Sb-bound form is pH-dependent, ranging from slow exchange on the 1 H-NMR timescale at low pH (2 s 21 at pH 3.2) to relatively rapid exchange at biological pH (. 440 s 21 ). Such facile exchange may be important in the transport of Sb(III) in various biofluids and tissues in vivo. Our spin±echo 1 H-NMR data show that Sb(III) rapidly entered red blood cell walls and was complexed by intracellular glutathione.Keywords: antimony; glutathione; nuclear magnetic resonance; red blood cells.Leishmaniasis is a parasitic infection caused by various species of the protozoan Leishmania. It remains one of the largest killers in the tropical regions of America, Africa and Asia, with approximately 1.5 billion people at risk and 20 million cases being reported annually. Among the drugs used to treat this condition, several antimony-containing complexes, such as N-methylglucamine antimonate(V) (Glucantimew), sodium stibogluconate (Pentostamw), sodium antimony(III) gluconate (Triostamw) and potassium antimony(III) tartrate (Tartar emeticw), are currently the first choice [1±3], despite their toxicity [4]. Antimony complexes with mannan appear to be promising for further improving the stability and solubility of these drugs [5]. Despite extensive clinical use for several decades, the molecular basis for the selective antileishmanial action of these drugs remains unclear. Furthermore, clinical resistance to these drugs has been increasingly reported in recent years [6±8]. It is generally believed that relatively nontoxic Sb(V) complexes may be prodrugs that could be reduced to the more toxic and active trivalent Sb(III) at or near the site of action (e.g. amastigotes) [9,10].Glutathione (g-l-Glu-l-Cys-Gly, GSH) is a potentially polydentate ligand, and is widely used as a model system for the binding of metal ions by peptides and proteins. It is present in many cells at millimolar concentration and generally is the most abundant nonprotein thiol. In cells, one of its roles is as a substrate for glutathione peroxidase, an enzyme capable of both removing hydrogen peroxide from cells and repairing peroxidatively damaged membranes. It is also involved in metal detoxification, and an ATP-dependent glutathione S-conjugate pump has ...

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A study of the excretion of organic antimonials using a polarographic procedure

Cited by 119 publications

References 5 publications

An intermittent schedule is better than continuous regimen of antimonial therapy for cutaneous leishmaniasis in the municipality of Rio de Janeiro, Brazil

An intermittent schedule is better than continuous regimen of antimonial therapy for cutaneous leishmaniasis in the municipality of Rio de Janeiro, Brazil

Dual Action of Antimonial Drugs on Thiol Redox Metabolism in the Human Pathogen Leishmania donovani

Interaction of antimony tartrate with the tripeptide glutathione

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