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At least 163 records · Page 9Linked to original sources
PubMed2001

Glutathione-induced conversion of pentavalent antimony to trivalent antimony in meglumine antimoniate.

The standard treatment of human leishmaniases involves the use of pentavalent antimony [Sb(V)] compounds, including meglumine antimoniate. The mode of action of these compounds has not been fully elucidated. The possibility that Sb(III) is involved has been suggested; however, the biomolecule that may induce the conversion of Sb(V) to Sb(III) has not yet been identified. In the present study, we investigated both the ability of reduced glutathione (GSH) to promote the reduction of Sb(V) into Sb(III) in meglumine antimoniate and the effects of pH and temperature on this transformation. GSH did promote the reduction of Sb(V) into Sb(III) in a dose-dependent manner. When GSH and meglumine antimoniate were incubated together at a GSH/Sb molar ratio superior or equal to 5:1, all antimony was encountered in the reduced form, indicating a stoichiometry of 5:1 between GSH and Sb(V) in the reaction. The reaction between Sb(V) and GSH was favored at an acidic pH (pH 5) and an elevated temperature (37 degrees C), conditions found within the phagolysosome, in which Leishmania resides. For instance, about 30% of the Sb(V) (concentration, 2mM) was converted to Sb(III) following incubation for 3 days with 10 mM GSH at pH 5 and 37 degrees C. Our data support the hypothesis that Sb(V) would be converted by GSH, or a related thiol compound, to more toxic Sb(III) in the phagolysosome of macrophages.

Antimony↗
PubMed1999

Stage-specific activity of pentavalent antimony against Leishmania donovani axenic amastigotes.

The standard treatment of human visceral leishmaniasis involves the use of pentavalent antimony (SbV) compounds. In recent years increasing numbers of clinical failures of treatment with SbV have been reported, probably due to the development of parasite resistance to this compound. The mode of action and mechanisms of resistance to SbV have not been fully elucidated. In the present study an axenic amastigote culture was used to study the in vitro responses of Leishmania donovani to SbV. Susceptibility to both sodium stibogluconate and meglumine antimoniate was found to be stage specific. Amastigotes were 73 to 271 times more susceptible to SbV than were promastigotes. As opposed to SbV, trivalent antimony (SbIII) was similarly toxic to both developmental stages. When promastigotes were transformed to amastigotes, susceptibility to meglumine antimoniate developed after 4 to 5 days, upon the completion of differentiation. In contrast, with transformation from amastigotes to promastigotes, resistance to meglumine antimoniate was acquired rapidly, within 24 h, before the completion of differentiation. The culture of promastigotes at an acidic pH (5.5) or at an elevated temperature (37 degrees C) alone did not lead to the appearance of SbV susceptibility, emphasizing the requirement of both these environmental factors for the development of SbV susceptibility. A previously isolated sodium stibogluconate (Pentostam)-resistant L. donovani mutant (Ld1S.20) is also resistant to meglumine antimoniate, indicating cross-resistance to SbV-containing compounds. In contrast, no cross-resistance was found with SbIII, suggesting a mechanism of SbV resistance different from that described in Leishmania tarentolae. These data show that L. donovani susceptibility to SbV is parasite intrinsic, stage specific, and macrophage independent.

Animals↗
PubMed1983

[Kala-azar in childhood. 20 year review].

Authors have reviewed 43 patients with Kala-azar admitted to hospital from 1960 to 1980. Thirty two patients came from Madrid province and rest from surroundings. There was a male predominance. Disease was more common between children under two years old. Bone marrow examination was positive for parasites in 60% of patients and in the others diagnosis was established because an appropriate response to Antimonials. All patients were treated with N-metil-Glucamined and in two patients Neo-Stibosan was added later. Clinical response to treatment was to complete remission in all patients.

Adolescent↗
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↗
PubMed2000

Efficacy of second line drugs on antimonyl-resistant amastigotes of Leishmania infantum.

In a previous paper we have demonstrated that the induction, by direct drug pressure, of a resistance to Sb(III) antimony at physiological concentration in the amastigote stage of the parasite, led to a high cross-resistance to Sb(V) species in the form of Glucantime. In this paper, further chemoresistant clones were characterized. Axenic amastigotes of Leishmania infantum were adapted to survive in culture medium containing 4, 20, 30 and 120 microg/ml of potassium antimonyl tartrate Sb(II). These mutants were 12, 28, 35 and 44-fold more resistant to Sb(III) than the parental wild-type clone. They were able to resist at concentrations of Glucantime Sb(V) as high as 160 microg/ml when growing in THP-1 cells. We have investigated the efficacy of second line drugs in clinical use (pentamidine and amphotericin B) on the antimony-resistant mutants. Amphotericin B was toxic for both wild-type and chemoresistant mutants at concentrations ranging from 0.05 to 0.15 microM. Pentamidine which is extensively used when the first course of antimonial pentavalent compounds is unsuccessful, was more toxic for all the chemoresistant organisms than for the wild-type clone. In the same way, chemoresistant amastigotes growing within THP-1 cells were more susceptible to pentamidine than the wild-type clone. Our results showed that the resistance of the mutants was restricted to the antimony containing drugs and did not led to a cross-resistance against the other clinically relevant drugs. These results confirmed that these two drugs (pentamidine and amphotericin B) are good candidates to treat pentavalent antimonial unresponsiveness.

Amphotericin B↗
PubMed2003

[Liposomal amphotericin B treatment of cutaneous leishmaniasis contracted in Djibouti and resistant to meglumine antimoniate].

Pentavalent antimony (PA) compounds remain the main therapeutic agents of cutaneous leishmaniasis (CL). CL infection resistant to PA is difficult to cure, limited by severe side effects and requiring a long course treatment of parenteral administration of recommended second line drugs. We report a case of CL unresponsive to meglumine antimoniate contracted in Djibouti, successfully treated with a short course treatment of AmBisome. In this case the subject had a recurrent thick crusted erythematous lesion on his left elbow associated with spreading micropapula on arms and thorax. The diagnosis of CL was confirmed by direct examination and genomic amplification by PCR of skin samples, cultures were negative. A short course treatment of parenteral AmBisome (18 mg/kg) has lead to clinical cure with no side effects and no relapse. In our hospital, the high cost of medication was counterbalanced by easiest administration, reduction of hospitalization duration, absence of adverse events and a gain of comfort. For this patient, a short course treatment of AmBisome proved to be a suitable alternative to traditional drugs used in CL resistant to PA.

Adult↗
PubMed1966

Studies on the visual pigment and the indicator yellow analogues formed from 5,6-monoepoxyretinal.

1. A new visual pigment has been isolated from retinae of rats maintained on 5,6-monoepoxyretinal for a period of 6 months. 2. Indicator yellow analogues from 5,6-monoepoxyretinal, namely 5,6-monoepoxyretinylidenemethylamine and 5,6-monoepoxyretinal oxime, have been prepared in a homogeneous state, the latter being obtained crystalline. 5,6-Monoepoxyretinylidenedimethylammonium iodide has also been prepared. 3. The spectroscopic properties, analytical data and antimony trichloride colour reactions of these indicator yellow analogues confirm their Schiff base structure. 4. The nature of chromogens formed from 5,6-monoepoxyretinylideneamino compounds with antimony trichloride and concentrated sulphuric acid is obscure although the chromogens resemble one another very closely. 5. 5,6-Monoepoxyretinylidenemethylamine and 5,6-monoepoxyretinylidenedimethylammonium iodide are very labile, whereas 5,6-monoepoxyretinal oxime is quite stable. 6. Hydrolysis of 5,6-monoepoxyretinylidenemethylamine as a function of pH reveals that, though 5,6-monoepoxyretinylidenemethylammonium ions are stable, the un-ionized compound readily hydrolyses to 5,6-monoepoxyretinal. This hydrolysis can be prevented by excess of un-ionized methylamine and hastened by formaldehyde. 7. The bathochromic shift in the lambda(max.) of the ;acid form' of 5,6-monoepoxyretinylidenemethylamine is due to the formation of its ammonium salt. The spectrum of the ;acid form' is identical with that of 5,6-monoepoxyretinylidenedimethylammonium iodide in ethanol. This is also evidence for the quaternary state of the nitrogen atom during the ;acid shift' of 5,6-monoepoxyretinylidenemethylamine. 8. The significance of 5,6-monoepoxyretinal and the corresponding indicator yellow analogues in the formation and properties of a new visual pigment is discussed.

Animals↗