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Título: STUDIES ON THE BEHAVIOR OF MEGLUMINE ANTIMONIATE IN THE HUMAN BODY IN RHESUS MONKEYS
Instituição: PONTIFÍCIA UNIVERSIDADE CATÓLICA DO RIO DE JANEIRO - PUC-RIO
Autor(es): FLAVIA DE ALMEIDA VIEIRA
Colaborador(es): NORBERT FRITZ MIEKELEY - Orientador
ARMANDO SCHUBACH - Coorientador
Catalogação: 29/09/2008 Idioma(s): PORTUGUESE - BRAZIL
Tipo: TEXT Subtipo: THESIS
Referência [pt]: http://www.maxwell.lambda.ele.puc-rio.br/Busca_etds.php?strSecao=resultado&nrSeq=12257@1
Referência [en]: http://www.maxwell.lambda.ele.puc-rio.br/Busca_etds.php?strSecao=resultado&nrSeq=12257@2
Resumo:
Clinical applications of antimonials in the treatment of leishmaniasis are a unique opportunity to investigate the metabolism of antimony and its species in the human body. In this work, inductively coupled plasma mass spectrometry (ICPMS), without or in combination with ion chromatography (IC) and flow injection hydride generation (FI-HG), has been used for the determination of total antimony concentrations [Sb] and three of its expected species, Sb (III), Sb (V) and trimethyl antimony (TMSbV), in clinical samples of leishmaniasis patients and/or of rhesus monkeys (Mucaca mulatta) treated with meglumine antimoniate (AM). Different drug administration schemes were evaluated, including low and high dose administration (5 mg or 20 mg of Sb5+ per kg of body mass). Total [Sb] was assayed after wet decomposition of the samples by HNO3/H2O2. Speciation analysis was performed on plasma and urine samples using IC on-line coupled to the ICPMS instrument. Two PRP-X100 anion exchange columns were used for species separation employing EDTA (isocratic elution: 4.7 mmol L-1, 2.5% v/v methanol, pH 4.7) or EDTA/phosphate buffer (step elution: 1st eluent - 20 mmol L-1 EDTA + 2 mmol L-1 KHP, at pH 4.5; 2nd eluent - 50 mmol L-1 (NH4)2HPO4 at pH 8.3) as the mobile phases. Performance characteristics of all methods were evaluated and are presented. Stability tests showed that all studied antimony species are sufficiently stable to allow speciation analysis within 24 hours after collection. In humans, as well as in rhesus monkeys, the concentrations of antimony in urine and/or plasma samples measured after the administration period of MA, showed rapid excretion kinetics (t1/2 ~ 3 days) of the drug followed by two slower ones. Significantly higher concentrations of [Sb] were measured in erythrocyte fractions than in corresponding plasma samples, excepting the very initial phase of drug administration (first 12 hours). Bio-reduction of Sb5+ to Sb3+ was observed and confirmed as an important metabolic process during the slow elimination phase. No evidence for the formation of TMSbV was so far obtained in our studies. Antimony concentrations in tissue samples of rhesus monkeys 60 d after the last AM administration were highest in thyroid, followed by liver and spleen. Liver concentrations were at least 1000 times the basal concentrations. Hair and nail samples from treated patients and monkeys had also very high Sb concentrations, which matched drug administration history and showed also that incorporation of Sb into these tissues is continuing, even after ceasing AM application. In human hair, more than 300 days are required for the return of antimony concentrations to basal levels.
Descrição Arquivo
COVER, ACKNOWLEDGEMENTS, RESUMO, ABSTRACT, SUMMARY AND LISTS  PDF
CHAPTER 1  PDF
CHAPTER 2  PDF
CHAPTER 3  PDF
CHAPTER 4  PDF
CHAPTER 5  PDF
CHAPTER 6  PDF
CHAPTER 7  PDF
REFERENCES  PDF
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