RESUMO
Chagas disease reactivation in HIV-positive people is an opportunistic infection with 79 to 100% mortality. It commonly involves the central nervous system (CNS). Early treatment with trypanocidal drugs such as benznidazole (BNZ) is crucial for this severe manifestation of Trypanosoma cruzi infection. However, limited BNZ clinical pharmacology data are available, especially its concentration in the CNS. We report a series of HIV-positive patients undergoing treatment for T. cruzi meningoencephalitis, their clinical response, and cerebrospinal fluid (CSF) and plasma BNZ concentrations. Measurements were carried out using leftover samples originally obtained for routine medical care. A high-performance liquid chromatography/tandem mass spectrometry bioanalytical method designed for BNZ plasma measurements was adapted and validated for CSF samples. Six patients were enrolled in this study from 2015 to 2019. A total of 6 CSF and 19 plasma samples were obtained. Only three of the CSF samples had detectable BNZ levels, all under 1 µg/ml. Fifteen plasma samples had detectable BNZ, and 13 were above 2 µg/ml, which is the putative trypanocidal level. We observed BNZ concentrations in human CSF and plasma. CSF BNZ concentrations were low or not measurable in all patients, suggesting that the usual BNZ doses may be suboptimal in HIV-positive patients with T. cruzi meningoencephalitis. While drug-drug and drug-disease interactions may be in part responsible, the factors leading to low CSF BNZ levels remain to be studied in detail. These findings highlight the potential of therapeutic drug monitoring in BNZ treatment and suggest that the use of higher doses may be useful for Chagas disease CNS reactivations.
Assuntos
Doença de Chagas , Infecções por HIV , Meningoencefalite , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Doença de Chagas/tratamento farmacológico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Meningoencefalite/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêuticoRESUMO
Pharmacological treatment of Chagas disease with benznidazole (BNZ) is effective in children in all stages, but it is controversial in chronically infected adults. We report the pharmacokinetics and pharmacodynamics in six adult patients with Chagas disease treated with the new BNZ formulation (ABARAX®) in doses between 2.5-5.5 mg/Kg/day. All but one patient had plasmatic BNZ concentrations within the expected range. All patients finalised treatment with nondetectable Trypanosoma cruzi quantitative polymerase chain reaction, which remained nondetectable at the six month follow-up. Our data suggests parasitological responses with the new BNZ and supports the hypothesis that treatment protocols with lower BNZ doses may be effective.
Assuntos
Doença de Chagas/tratamento farmacológico , Nitroimidazóis/farmacocinética , Tripanossomicidas/farmacocinética , Trypanosoma cruzi/efeitos dos fármacos , Adulto , Doença de Chagas/metabolismo , Química Farmacêutica , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Nitroimidazóis/administração & dosagem , Nitroimidazóis/sangue , Reação em Cadeia da Polimerase em Tempo Real , Tripanossomicidas/administração & dosagem , Tripanossomicidas/sangue , Trypanosoma cruzi/isolamento & purificação , Adulto JovemRESUMO
Pharmacological treatment of Chagas disease with benznidazole (BNZ) is effective in children in all stages, but it is controversial in chronically infected adults. We report the pharmacokinetics and pharmacodynamics in six adult patients with Chagas disease treated with the new BNZ formulation (ABARAX®) in doses between 2.5-5.5 mg/Kg/day. All but one patient had plasmatic BNZ concentrations within the expected range. All patients finalised treatment with nondetectable Trypanosoma cruziquantitative polymerase chain reaction, which remained nondetectable at the six month follow-up. Our data suggests parasitological responses with the new BNZ and supports the hypothesis that treatment protocols with lower BNZ doses may be effective.
Assuntos
Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/farmacocinética , Tripanossomicidas/farmacocinética , Trypanosoma cruzi/efeitos dos fármacos , Química Farmacêutica , Doença de Chagas/metabolismo , Seguimentos , Nitroimidazóis/administração & dosagem , Nitroimidazóis/sangue , Reação em Cadeia da Polimerase em Tempo Real , Tripanossomicidas/administração & dosagem , Tripanossomicidas/sangue , Trypanosoma cruzi/isolamento & purificaçãoRESUMO
Monitoring the drug benznidazole in biological fluids is a powerful tool for clinical diagnostic and pharmacological studies in chagasic patients. However, research in this concern needs to be done. The accurate quantitation of this drug in complex matrices represents a highly challenging task complicated by the absence of sensitive analytical methods. It follows that sample processing strategies, preparation/cleanup procedures, and chromatographic/ionization/detection parameters, were evaluated for method optimization. The summation of this work generated a rapid, selective, sensitive methodology based on reversed-phase chromatography-tandem mass spectrometry for the analysis of benznidazole in urine samples. To the best of our knowledge, this is a first report of a LC-MS/MS platform employed for this application. Matrix effect was determined; a 90% of signal suppression was observed. The limits of detection and quantification were 0.75 and 4.85 µg L(-1); respectively. The latter allowed the method's application to the detection of benznidazole in clinical studies and pharmacological monitoring analysis.
Assuntos
Doença de Chagas/urina , Cromatografia Líquida/métodos , Nitroimidazóis/urina , Espectrometria de Massas em Tandem/métodos , Tripanossomicidas/urina , Criança , Humanos , Extração Líquido-Líquido/métodos , Nitroimidazóis/isolamento & purificação , Tripanossomicidas/isolamento & purificaçãoRESUMO
Chagas disease is an endemic infection in Latin America with a high health impact. Caused by the parasite Trypanosoma cruzi, it has expanded to non-endemic regions such as North America and European countries via immigration of infected people. This infectious disease has been rising in the ranking of international health priorities due to the growing migration flows from endemic to non-endemic areas. Benznidazole (BZN), a nitroheterocyclic drug, is one of the two trypanocidal drugs currently in clinical use, associated with significant adverse drug reactions (ADRs). Mammalian metabolism of BNZ has been poorly studied, including the potential role of metabolites on both toxicity and anti-parasitic activity. High-resolution UPLC/MS/MS was used to analyze three plasma samples obtained from pediatric patients under BNZ treatment in steady state. Spectroscopic and structural criteria were applied to identify BNZ and accompanying substances from chromatographic signals. From all detected species, two can be undoubtedly associated with the BNZ and N-benzylacetamide molecules, the second one being a fragment of the parent drug (BZN). From the obtained results, two hypotheses could be formulated. The first one is to relate the presence of N-benzyl acetamide with the hepatic metabolism of BNZ. The second hypothesis has to do with the possible trypanocidal activity of this metabolite, as well as its role in the development of side effects, associated with the pharmacotherapy. Complementary studies should be carried out to determine the possible association of this metabolite with the BNZ treatment stages, patient's clinical features, ADRs, and trypanocidal effectiveness.
Assuntos
Acetamidas/metabolismo , Nitroimidazóis/metabolismo , Tripanossomicidas/metabolismo , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Humanos , Espectrometria de Massas em TandemRESUMO
BACKGROUND: Benznidazole (BNZ) is safe and effective for the treatment of paediatric Chagas disease. Treatment of adults is also effective in many cases, but discouraged in breastfeeding women because no information on BNZ transfer into breast milk is available. We aimed to evaluate the degree of BNZ transfer into breast milk in lactating women with Chagas disease. PATIENTS AND METHODS: Prospective cohort study of lactating women with Chagas disease treated with BNZ administered for 30â days. Patients and their breastfed infants were evaluated at admission, the 7th and 30th day of treatment (and monthly thereafter, for 6â months). BNZ was measured in plasma and milk by high performance liquid chromatography. The protocol was registered in ClinicalTrials.gov (#NCT01547533). RESULTS: 12 lactating women with chronic Chagas disease were enrolled (median age 28.5â years, range 20-34). Median BNZ dose was 5.65â mg/kg/day twice daily. Five mothers had adverse drug events (45%), but no adverse drug reactions or any untoward outcomes were observed in the breastfed infants. Median milk BNZ concentration was 3.8â mg/L (range 0.3-5.9) and 6.26â mg/L (range 0.3-12.6) in plasma. Median BNZ milk to plasma ratio was 0.52 (range 0.3-2.79). Median relative BNZ dose received by the infant (assuming a daily breast milk intake of 150â mL/kg/day) was 12.3% of the maternal dose per kg (range 5.5%-17%). CONCLUSIONS: The limited transference of BNZ into breast milk and the reassuring normal clinical evaluation of the breastfed babies suggest that maternal BNZ treatment for Chagas disease during breast feeding is unlikely to present a risk for the breastfed infant. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01547533.
Assuntos
Doença de Chagas/metabolismo , Imunossupressores/farmacocinética , Leite Humano/metabolismo , Nitroimidazóis/farmacocinética , Adulto , Aleitamento Materno , Doença de Chagas/tratamento farmacológico , Cromatografia Líquida de Alta Pressão , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Prospectivos , Adulto JovemRESUMO
INTRODUCTION: Chagas disease, caused by the parasite Trypanosoma cruzi, can lead to long term cardiac morbidity. Treatment of children with benznidazole is effective, but no pediatric pharmacokinetics data are available and clinical pharmacology information on the drug is scarce. PATIENTS AND METHODS: Prospective population pharmacokinetic (PK) cohort study in children 2-12 years old with Chagas disease treated with oral benznidazole 5-8 mg/kg/day BID for 60 days. (clinicaltrials.gov #NCT00699387). RESULTS: Forty children were enrolled in the study. Mean age was 7.3 years. A total of 117 samples were obtained from 38 patients for PK analysis. A one compartment model best fit the data. Weight-corrected clearance rate (CL/F) showed a good correlation with age, with younger patients having a significantly higher CL/F than older children and adults. Simulated median steady-state benznidazole concentrations, based on model parameters, were lower for children in our study than for adults and lowest for children under 7 years of age. Treatment was efficacious in the 37 patients who completed the treatment course, and well tolerated, with few, and mild, adverse drug reactions (ADRs). DISCUSSION: Observed benznidazole plasma concentrations in children were markedly lower than those previously reported in adults (treated with comparable mg/kg doses), possibly due to a higher CL/F in smaller children. These lower blood concentrations were nevertheless associated to a high therapeutic response in our cohort. Unlike adults, children have few adverse reactions to the drug, suggesting that there may be a direct correlation between drug concentrations and incidence of ADRs. Our results suggest that studies with lower doses in adults may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT00699387.
Assuntos
Doença de Chagas/metabolismo , Nitroimidazóis/sangue , Nitroimidazóis/farmacocinética , Tripanossomicidas/sangue , Tripanossomicidas/farmacocinética , Adulto , Doença de Chagas/sangue , Doença de Chagas/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Humanos , Modelos Lineares , Masculino , Nitroimidazóis/efeitos adversos , Nitroimidazóis/uso terapêutico , Tripanossomicidas/efeitos adversos , Tripanossomicidas/uso terapêuticoRESUMO
OBJECTIVE: Chagas disease constitutes a major public health problem in Latin America. Correctly designed pharmacokinetic, safety, and bioequivalence studies are desirable in order to fill the knowledge gaps that presently exist on available drugs. It is necessary to develop accurate, simple, reproducible, and sensitive high-performance liquid chromatography (HPLC)/UV methods for the quantization of benznidazole (BNZ) in human plasma and urine for clinical applications, specially in pediatric patients. METHODS: Quantization of BNZ in human plasma involved freeze-drying and re-suspension in organic solvent followed by reverse phase HPLC with UV detection. Analysis of BNZ in urine involved liquid/liquid extraction followed by reverse phase HPLC with UV detection. RESULTS: Limits of quantization (LOQ) were 0.32 µg/ml for plasma and 5.2 µg/ml for urine. No metabolite interferences were showed in both methods. CONCLUSION: The LOQ of methods seems appropriate in pediatric clinical contexts. Both procedures were applied with good results, to the quantization of BNZ in plasma and urine of patients treated for Chagas disease.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Nitroimidazóis/sangue , Nitroimidazóis/urina , Doença de Chagas/tratamento farmacológico , Criança , Liofilização , Humanos , Nitroimidazóis/uso terapêutico , Manejo de Espécimes/métodos , Tripanossomicidas/sangue , Tripanossomicidas/uso terapêutico , Tripanossomicidas/urinaRESUMO
BACKGROUND: Due to migration, Chagas disease is a significant public health problem in Latin America, and in other nonendemic regions. The 2 drugs currently available for the treatment, nifurtimox and benznidazole (BNZ), are associated with a high risk of toxicity in therapeutic doses. Excretion of drug into human breast milk is a potential source of unwanted exposure and pharmacologic effects in the nursing infant. However, this phenomenon was not evaluated until now, and measurement techniques for both drugs in milk were not developed. METHODS: In this work, we described the development of a simple and fast method to quantify BNZ in human milk using a pretreatment that involves acid protein precipitation followed by tandem microfiltration, and reverse phase high-performance liquid chromatography/ultraviolet analysis. It is simple because it takes only 3 steps to obtain a clean extracted solution that is ready to inject into the high-performance liquid chromatography equipment. It is fast because a complete analysis of a sample takes only 36 minutes. RESULTS: Although the human breast milk composition is very variable, and lipids are one of the most difficult compounds to clean up on a milk sample, the procedure has proven to be robust and sensitive with a limit of detection of 0.3 µg/mL and quantization of 0.9 µg/mL. Despite a 70% recovery value, which could be considered a relatively low result, this recovery is reproducible (coefficient of variation <10%) and the analytical response under the linear range is very good (r = 0.9969 adjusted). Real samples of human breast milk from patients in treatment with BNZ were dosed to support the validation process of the method. CONCLUSIONS: The method described is fast, specific, accurate, precise, and sufficiently sensitive in the clinical context for the quantification of BNZ in human milk. For all these reasons, it is suitable for clinical risk evaluation studies.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Leite Humano/química , Nitroimidazóis/análise , Monitoramento de Medicamentos/métodos , Feminino , Voluntários Saudáveis , Humanos , Lactação/metabolismo , Nitroimidazóis/química , Nitroimidazóis/farmacocinética , Tripanossomicidas/análise , Tripanossomicidas/química , Tripanossomicidas/farmacocinéticaRESUMO
Chagas disease is a neglected parasitic disease endemic in the Americas. It mainly affects impoverished populations and the acute phase of the infection mostly affects children. Many cases have also been detected in nonendemic countries as a result of recent migratory trends. The chronic phase is relatively asymptomatic, but 30% of patients with chronic infection eventually develop cardiac and digestive complications that commonly lead to death or disability. Only two drugs are available for the treatment of Chagas disease, benznidazole and nifurtimox. These drugs have been shown to be effective in the treatment of both acute and early chronic phases in children, but the pharmacokinetics of these drugs have never been studied in this population. We have set out to conduct a pharmacokinetics study of benznidazole in a pediatric population with Chagas disease. The results of this study are expected to allow better estimation of the optimal doses and schedule of pharmacotherapy for Chagas disease in children.