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1.
Eur Respir J ; 61(3)2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36328357

RESUMO

BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. METHODS: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L-1) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L-1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.


Assuntos
Antituberculosos , Isoniazida , Criança , Adolescente , Humanos , Pré-Escolar , Antituberculosos/uso terapêutico , Isoniazida/uso terapêutico , Pirazinamida/uso terapêutico , Etambutol/uso terapêutico , Rifampina/uso terapêutico
2.
Artigo em Inglês | MEDLINE | ID: mdl-33139294

RESUMO

Optimal dosing of children with tuberculous meningitis (TBM) remains uncertain and is currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampin, pyrazinamide, and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. A total of 100 Vietnamese children with TBM were treated with an 8-month antituberculosis regimen. Nonlinear mixed-effects modeling was used to evaluate the pharmacokinetic properties of the four drugs and to simulate different dosing strategies. The pharmacokinetic properties of rifampin and pyrazinamide in plasma were described successfully by one-compartment disposition models, while those of isoniazid and ethambutol in plasma were described by two-compartment disposition models. All drug models included allometric scaling of body weight and enzyme maturation during the first years of life. Cerebrospinal fluid (CSF) penetration of rifampin was relatively poor and increased with increasing protein levels in CSF, a marker of CSF inflammation. Isoniazid and pyrazinamide showed good CSF penetration. Currently recommended doses of isoniazid and pyrazinamide, but not ethambutol and rifampin, were sufficient to achieve target exposures. The ethambutol dose cannot be increased because of ocular toxicity. Simulation results suggested that rifampin dosing at 50 mg/kg of body weight/day would be required to achieve the target exposure. Moreover, low rifampin plasma exposure was associated with an increased risk of neurological disability. Therefore, higher doses of rifampin could be considered, but further studies are needed to establish the safety and efficacy of increased dosing.


Assuntos
Antituberculosos , Tuberculose Meníngea , Adulto , Antituberculosos/uso terapêutico , Povo Asiático , Criança , Etambutol , Humanos , Isoniazida , Pirazinamida , Tuberculose Meníngea/tratamento farmacológico
3.
Biomed Chromatogr ; 34(1): e4699, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31524294

RESUMO

In this study, we developed and validated two reliable high-performance liquid chromatography (HPLC) methods for the qualitative detection of six oral ß-lactams, which are commonly used in pediatric patients with acute respiratory infections (ARIs). Two distinct reverse-phase chromatographic separations of six ß-lactams were obtained. Four ß-lactams (cefadroxil, cephalexin, cefaclor and cefixime) in urine were separated using a gradient program with a mobile phase consisting of K2 HPO4 buffer (20 mm, pH 2.8) and acetonitrile on a LichroCART 250 × 4.6 mm, Purospher STAR C18 end-capped (5 µm) column. Two remained ß-lactams (amoxicillin and cefuroxime) were analyzed using a gradient elution with the mobile phase containing K2 HPO4 buffer (20 mm, pH 3.0) and acetonitrile on a LichroCart® Purospher Star C8 end-capped column (5 µm, 125 × 4.6 mm). Good linearity within the range of 0.3-30 µg/ml for cefadroxil, cephalexin, cefaclor and cefixime, and 0.2-20 µg/ml for amoxicillin and cefuroxime, was attained. The precisions were <14%. The accuracies ranged from 85.87 to 102.8%. The two validated methods were then applied to determine these six antibiotics in 553 urine samples of pediatric patients with ARIs. As a result, 32.2% were positive with one or more of six tested ß-lactams. Cefixime was the most commonly detected agent, accounting for 9.8% of enrolled patients.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Infecções Respiratórias/tratamento farmacológico , beta-Lactamas/urina , Doença Aguda , Adolescente , Criança , Pré-Escolar , Cromatografia de Fase Reversa/métodos , Humanos , Lactente , Recém-Nascido , Limite de Detecção , Modelos Lineares , Uso Excessivo de Medicamentos Prescritos , Reprodutibilidade dos Testes , beta-Lactamas/uso terapêutico
4.
BMC Infect Dis ; 16: 144, 2016 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-27039088

RESUMO

BACKGROUND: Among the various forms of TB, tuberculous meningitis (TBM) is the most severe, with about 30% mortality and 50% of survivors left with neurological sequelae. Children suffer more frequently from TBM than adults and outcomes are often poor due to difficulties in making the diagnosis and uncertainty regarding the best anti-tuberculosis drug regimen. The aim of this prospective study was to describe the pharmacokinetics of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of children with tuberculous meningitis treated with the standard TBM regimen. METHODS: We performed a prospective observational study of 100 consecutively treated children (≤ 15 years of age) with tuberculous meningitis in Ho Chi Minh City, Vietnam. Children were treated according to the 2006 WHO recommended pediatric treatment regimen consisting of isoniazid (5 mg/kg), rifampicin (10 mg/kg) and ethambutol (15 mg/kg) for 8 months, with the addition of pyrazinamide (25 mg/kg) for the first 3 months and streptomycin (15 mg/kg) for the first 2 months. Pyrazinamide, isoniazid and rifampicin concentrations were measured in plasma at day 14 and in cerebrospinal fluid (CSF) at 1 month by HPLC-UV. A naïve-pooled non-compartmental data analysis was used to describe the pharmacokinetic properties of drugs in the two-age groups of children ≤ 4 years or > 4 years of age. RESULTS: Younger children, when compared to older children, presented a higher body weight-normalized clearance and volume of distribution, and lower median total plasma exposures for the three studied drugs with -14%, -22% and -16% for Pyrazinamide, Isoniazid and Rifampicin, respectively. In CSF, individual concentrations of isoniazid and pyrazinamide were comparable to that in plasma in both age groups; but rifampicin concentrations were lower than the minimum inhibitory concentration of susceptible bacteria in all but two children. CONCLUSIONS: There is an age-dependent variation in the plasma and cerebrospinal fluid pharmacokinetics of rifampicin, isoniazid and pyrazinamide. The safety and efficacy of higher doses of rifampicin should be investigated for the treatment of childhood tuberculous meningitis.


Assuntos
Antituberculosos/uso terapêutico , Isoniazida/uso terapêutico , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , Tuberculose Meníngea/diagnóstico , Adolescente , Antituberculosos/farmacocinética , Arilamina N-Acetiltransferase/genética , Povo Asiático , Criança , Pré-Escolar , Feminino , Genótipo , Meia-Vida , Humanos , Lactente , Isoniazida/sangue , Isoniazida/líquido cefalorraquidiano , Masculino , Estudos Prospectivos , Pirazinamida/sangue , Pirazinamida/líquido cefalorraquidiano , Rifampina/sangue , Rifampina/líquido cefalorraquidiano , Tuberculose Meníngea/tratamento farmacológico , Vietnã
5.
BMC Infect Dis ; 16(1): 573, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27756256

RESUMO

BACKGROUND: Tuberculous meningitis in adults is well characterized in Vietnam, but there are no data on the disease in children. We present a prospective descriptive study of Vietnamese children with TBM to define the presentation, course and characteristics associated with poor outcome. METHODS: A prospective descriptive study of 100 consecutively admitted children with TBM at Pham Ngoc Thach Hospital, Ho Chi Minh City. Cox and logistic regression were used to identify factors associated with risk of death and a combined endpoint of death or disability at treatment completion. RESULTS: The study enrolled from October 2009 to March 2011. Median age was 32.5 months; sex distribution was equal. Median duration of symptoms was 18.5 days and time from admission to treatment initiation was 11 days. Fifteen of 100 children died, 4 were lost to follow-up, and 27/81 (33 %) of survivors had intermediate or severe disability upon treatment completion. Microbiological confirmation of disease was made in 6 %. Baseline characteristics associated with death included convulsions (HR 3.46, 95CI 1.19-10.13, p = 0.02), decreased consciousness (HR 22.9, 95CI 3.01-174.3, p < 0.001), focal neurological deficits (HR 15.7, 95CI 1.67-2075, p = 0.01), Blantyre Coma Score (HR 3.75, 95CI 0.99-14.2, p < 0.001) and CSF protein, lactate and glucose levels. Neck stiffness, MRC grade (children aged >5 years) and hydrocephalus were also associated with the combined endpoint of death or disability. CONCLUSIONS: Tuberculous meningitis in Vietnamese children has significant mortality and morbidity. There is significant delay in diagnosis; interventions that increase the speed of diagnosis and treatment initiation are likely to improve outcomes.


Assuntos
Tuberculose Meníngea/diagnóstico , Tuberculose Meníngea/mortalidade , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Hidrocefalia/microbiologia , Lactente , Tempo de Internação , Modelos Logísticos , Perda de Seguimento , Masculino , Prognóstico , Estudos Prospectivos , Punção Espinal , Resultado do Tratamento , Tuberculose Meníngea/etiologia , Vietnã
6.
Biomed Chromatogr ; 30(7): 1104-1111, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26578224

RESUMO

A sensitive, simple method for quantification of chloroquine (CQ) and desethylchloroquine (MCQ) in whole blood and plasma from Plasmodium vivax patients has been developed using HPLC with diode array detection (DAD). Solid-phase extraction on Isolute-96-CBA was employed to process 100 µL of plasma/whole blood samples. CQ, MCQ and quinine were separated using a mobile phase of phosphate buffer 25 mm, pH 2.60-acetonitrile (88:12, v/v) with 2 mm sodium perchlorate on a Zorbax SB-CN 150 × 4.6 mm, 5 µm column at a flow rate of 1.2 mL/min, at ambient temperature in 10 min, with the DAD wavelength of 343 nm. The method was linear over the range of 10-5000 ng/mL for both CQ and MCQ in plasma and whole blood. The limit of detection was 4 ng/mL and limit of quantification was 10 ng/mL in both plasma and blood for CQ and MCQ. The intra-, inter- and total assay precision were <10% for CQ and MCQ in plasma and whole blood. In plasma, the accuracies varied between 101 and 103%, whereas in whole blood, the accuracies ranged from 97.0 to 102% for CQ and MCQ. The method is an ideal technique with simple facilities and instruments, bringing about good separation in comparison with previous methods. © 2016 The Authors Biomedical Chromatography Published by John Wiley & Sons Ltd.


Assuntos
Cloroquina/análogos & derivados , Cloroquina/sangue , Cromatografia Líquida de Alta Pressão/métodos , Malária Vivax/sangue , Humanos , Limite de Detecção , Padrões de Referência , Reprodutibilidade dos Testes , Espectrofotometria Ultravioleta , Vietnã
7.
Antimicrob Agents Chemother ; 55(7): 3624-6, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21576427

RESUMO

The recommended treatment for herpes simplex encephalitis (HSE) remains intravenous acyclovir. In resource-poor countries, however, intravenous formulations are usually unavailable or unaffordable. We report the penetration of acyclovir into the cerebrospinal fluid (CSF) in patients with HSE, treated with the oral prodrug valacyclovir at 1,000 mg three times daily. The oral therapy achieved adequate acyclovir concentrations in the CSF and may be an acceptable early treatment for suspected HSE in resource-limited settings.


Assuntos
Aciclovir/análogos & derivados , Antivirais/farmacocinética , Encefalite por Herpes Simples/tratamento farmacológico , Valina/análogos & derivados , Aciclovir/sangue , Aciclovir/líquido cefalorraquidiano , Aciclovir/farmacocinética , Aciclovir/uso terapêutico , Antivirais/sangue , Antivirais/líquido cefalorraquidiano , Antivirais/uso terapêutico , Encefalite por Herpes Simples/sangue , Feminino , Humanos , Masculino , Valaciclovir , Valina/sangue , Valina/líquido cefalorraquidiano , Valina/farmacocinética , Valina/uso terapêutico
8.
PLoS One ; 16(3): e0248846, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33770104

RESUMO

This study aimed to predict the impacts of shorter duration treatment regimens for multidrug-resistant tuberculosis (MDR-TB) on both MDR-TB percentage among new cases and overall MDR-TB cases in the WHO Southeast Asia Region. A deterministic compartmental model was constructed to describe both the transmission of TB and the MDR-TB situation in the Southeast Asia region. The population-level impacts of short-course treatment regimens were compared with the impacts of conventional regimens. Multi-way analysis was used to evaluate the impact by varying programmatic factors (eligibility for short-course MDR-TB treatment, treatment initiation, and drug susceptibility test (DST) coverage). The model predicted that overall TB incidence will be reduced from 246 (95% credible intervals (CrI), 221-275) per 100,000 population in 2020 to 239 (95% CrI, 215-267) per 100,000 population in 2035, with a modest reduction of 2.8% (95% CrI, 2.7%-2.9%). Despite the slight reduction in overall TB infections, the model predicted that the MDR-TB percentage among newly notified TB infections will remain steady, with 2.4% (95% CrI, 2.1-2.9) in 2020 and 2.5% (95% CrI, 2.3-3.1) in 2035, using conventional MDR-TB treatment. With the introduction of short-course regimens to treat MDR-TB, the development of resistance can be slowed by 38.6% (95% confidence intervals (CI), 35.9-41.3) reduction in MDR-TB case number, and 37.6% (95% CI, 34.9-40.3) reduction in MDR-TB percentage among new TB infections over the 30-year period compared with the baseline using the standard treatment regimen. The multi-way analysis showed eligibility for short-course treatment and treatment initiation greatly influenced the impacts of short-course treatment regimens on reductions in MDR-TB cases and percentage resistance among new infections. Policies which promote the expansion of short-course regimens and early MDR-TB treatment initiation should be considered along with other interventions to tackle antimicrobial resistance in the region.


Assuntos
Modelos Teóricos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Sudeste Asiático/epidemiologia , Humanos , Incidência , Reprodutibilidade dos Testes , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia
9.
Clin Pharmacol Ther ; 107(4): 1023-1033, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31956998

RESUMO

The most effective antituberculosis drug treatment regimen for tuberculous meningitis is uncertain. We conducted a randomized controlled trial comparing standard treatment with a regimen intensified by rifampin 15 mg/kg and levofloxacin for the first 60 days. The intensified regimen did not improve survival or any other outcome. We therefore conducted a nested pharmacokinetic/pharmacodynamic study in 237 trial participants to define exposure-response relationships that might explain the trial results and improve future therapy. Rifampin 15 mg/kg increased plasma and cerebrospinal fluid (CSF) exposures compared with 10 mg/kg: day 14 exposure increased from 48.2 hour·mg/L (range 18.2-93.8) to 82.5 hour·mg/L (range 8.7-161.0) in plasma and from 3.5 hour·mg/L (range 1.2-9.6) to 6.0 hour·mg/L (range 0.7-15.1) in CSF. However, there was no relationship between rifampin exposure and survival. In contrast, we found that isoniazid exposure was associated with survival, with low exposure predictive of death, and was linked to a fast metabolizer phenotype. Higher doses of isoniazid should be investigated, especially in fast metabolizers.


Assuntos
Antituberculosos/administração & dosagem , Antituberculosos/sangue , Tuberculose Meníngea/sangue , Tuberculose Meníngea/tratamento farmacológico , Adulto , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Levofloxacino/administração & dosagem , Levofloxacino/sangue , Masculino , Rifampina/administração & dosagem , Rifampina/sangue , Resultado do Tratamento , Tuberculose Meníngea/diagnóstico
10.
PLoS One ; 15(11): e0241760, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33147269

RESUMO

BACKGROUND AND OBJECTIVES: Treatment guidelines do not recommend antibiotic use for acute respiratory infections (ARI), except for streptococcal pharyngitis/tonsillitis and pneumonia. However, antibiotics are prescribed frequently for children with ARI, often in absence of evidence for bacterial infection. The objectives of this study were 1) to assess the appropriateness of antibiotic prescriptions for mild ARI in paediatric outpatients in relation to available guidelines and detected pathogens, 2) to assess antibiotic use on presentation using questionnaires and detection in urine 3) to assess the carriage rates and proportions of resistant intestinal Enterobacteriaceae before, during and after consultation. MATERIALS AND METHODS: Patients were prospectively enrolled in Children's Hospital 1, Ho Chi Minh City, Vietnam and diagnoses, prescribed therapy and outcome were recorded on first visit and on follow-up after 7 days. Respiratory bacterial and viral pathogens were detected using molecular assays. Antibiotic use before presentation was assessed using questionnaires and urine HPLC. The impact of antibiotic usage on intestinal Enterobacteriaceae was assessed with semi-quantitative culture on agar with and without antibiotics on presentation and after 7 and 28 days. RESULTS: A total of 563 patients were enrolled between February 2009 and February 2010. Antibiotics were prescribed for all except 2 of 563 patients. The majority were 2nd and 3rd generation oral cephalosporins and amoxicillin with or without clavulanic acid. Respiratory viruses were detected in respiratory specimens of 72.5% of patients. Antibiotic use was considered inappropriate in 90.1% and 67.5%, based on guidelines and detected pathogens, respectively. On presentation parents reported antibiotic use for 22% of patients, 41% of parents did not know and 37% denied antibiotic use. Among these three groups, six commonly used antibiotics were detected with HPLC in patients' urine in 49%, 40% and 14%, respectively. Temporary selection of 3rd generation cephalosporin resistant intestinal Enterobacteriaceae during antibiotic use was observed, with co-selection of resistance to aminoglycosides and fluoroquinolones. CONCLUSIONS: We report overuse and overprescription of antibiotics for uncomplicated ARI with selection of resistant intestinal Enterobacteriaceae, posing a risk for community transmission and persistence in a setting of a highly granular healthcare system and unrestricted access to antibiotics through private pharmacies. REGISTRATION: This study was registered at the International Standard Randomised Controlled Trials Number registry under number ISRCTN32862422: http://www.isrctn.com/ISRCTN32862422.


Assuntos
Antibacterianos/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Infecções Respiratórias/diagnóstico , Amoxicilina/farmacologia , Amoxicilina/uso terapêutico , Amoxicilina/urina , Antibacterianos/uso terapêutico , Antibacterianos/urina , Cefalosporinas/farmacologia , Cefalosporinas/uso terapêutico , Cefalosporinas/urina , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Prescrições de Medicamentos/estatística & dados numéricos , Farmacorresistência Bacteriana , Enterobacteriaceae/crescimento & desenvolvimento , Enterobacteriaceae/isolamento & purificação , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pacientes Ambulatoriais , Estudos Prospectivos , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/patologia , Índice de Gravidade de Doença , Vietnã
11.
Org Lett ; 9(2): 287-9, 2007 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-17217286

RESUMO

Conditions were found for the successful Effenberger alpha,alpha'-annulation of 3,3-dimethyl-2,4,6-triprenyl cyclohexanone silyl enol ethers with malonyl chloride to give the corresponding bicyclo[3.3.1]nonane-trione in 35% yield, this result allowing a short synthesis of (+/-)-clusianone. An isomeric rearranged bicyclo[3.3.1]nonane-trione was also isolated in 25% yield, and changing the Lewis acid resulted in formation of a lavandulyl-substituted phloroglucinol derivative in 38% yield. The mechanism of formation of these two last products mimics the biogenetic pathway to PPAPs. [reaction: see text].


Assuntos
Materiais Biomiméticos/síntese química , Compostos Bicíclicos com Pontes/síntese química , Cicloexanonas/síntese química , Hidrocarbonetos Clorados/química , Benzofenonas , Benzoquinonas , Materiais Biomiméticos/química , Compostos Bicíclicos com Pontes/química , Cicloexanonas/química , Estrutura Molecular , Estereoisomerismo
12.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1061-1062: 256-262, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28756357

RESUMO

An accurate and reliable high-performance liquid chromatography with time-programmed fluorescence detection was developed and validated to measure levofloxacin in human plasma and cerebrospinal fluid (CSF). After solid phase extraction process using Evolute® ABN 96 fixed well plate; levofloxacin and internal standard-enoxacin were separated using a mobile phase consisting of phosphate buffer 10mM with 0.025% triethylamine pH 3.0 - acetonitrile (88:12, v/v) on a Purosphere RP-8e column (5µm, 125×4.0mm) at a flow rate of 1.2mL/min at 35°C. The excitation/emission wavelengths were set to 269/400nm and 294/500nm, for enoxacin and levofloxacin, respectively. The method was linear over the concentration range of 0.02 to 20.0µg/mL with a limit of detection of 0.01µg/mL. The relative standard deviation of intra-assay and inter-assay precision for levofloxacin at four quality controls concentrations (0.02, 0.06, 3.0 and 15.0µg/mL) were less than 7% and the accuracies ranged from 96.75% to 101.9% in plasma, and from 93.00% to 98.67% in CSF. The validated method was successfully applied to quantify levofloxacin in a considerable quantity of plasma (826) and CSF (477) samples collected from 232 tuberculous meningitis patients, and the preliminary intensive pharmacokinetics analysis from 14 tuberculous meningitis patients in Vietnam is described in this paper.


Assuntos
Antibacterianos/sangue , Antibacterianos/líquido cefalorraquidiano , Cromatografia Líquida de Alta Pressão/métodos , Levofloxacino/sangue , Levofloxacino/líquido cefalorraquidiano , Tuberculose Meníngea/tratamento farmacológico , Adulto , Antibacterianos/farmacocinética , Estabilidade de Medicamentos , Enoxacino , Humanos , Levofloxacino/farmacocinética , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Extração em Fase Sólida , Espectrometria de Fluorescência
13.
PLoS One ; 9(7): e102047, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25004128

RESUMO

SETTING: In most developing countries, paediatric tuberculosis is treated with split tablets leading to potential inaccuracy in the dose delivery and drug exposure. There is no data on the quality of first-line drugs content in split fixed-dose combination tablets. OBJECTIVE: To determine Isoniazid, Pyrazinamide and Rifampicin content uniformity in split FDC tablets used in the treatment of childhood tuberculosis. DESIGN: Drug contents of 15 whole tablets, 30 half tablets and 36 third tablets were analysed by high performance liquid chromatography. The content uniformity was assessed by comparing drug content measured in split portions with their expected amounts and the quality of split portions was assessed applying qualitative specifications for whole tablets. RESULTS: All whole tablets measurements fell into the USP proxy for the three drugs. But a significant number of half and third portions was found outside the tolerated variation range and the split formulation failed the requirements for content uniformity. To correct for the inaccuracy of splitting the tablets into equal portions, a weight-adjustment strategy was used but this did not improve the findings. CONCLUSION: In split tablets the content of the three drugs is non-uniform and exceeded the USP recommendations. There is an absolute need to make child-friendly formulations available for the treatment of childhood tuberculosis.


Assuntos
Isoniazida/análise , Pirazinamida/análise , Rifampina/análise , Química Farmacêutica/normas , Combinação de Medicamentos , Humanos , Isoniazida/uso terapêutico , Pirazinamida/uso terapêutico , Controle de Qualidade , Rifampina/uso terapêutico , Comprimidos , Tuberculose Pulmonar/tratamento farmacológico
14.
Artigo em Inglês | MEDLINE | ID: mdl-24200840

RESUMO

Acidosis is an important cause of mortality in severe falciparum malaria. Lactic acid is a major contributor to metabolic acidosis, but accounts for only one-quarter of the strong anion gap. Other unidentified organic acids have an independent strong prognostic significance for a fatal outcome. In this study, a simultaneous bio-analytical method for qualitative and quantitative assessment in plasma and urine of eight small organic acids potentially contributing to acidosis in severe malaria was developed and validated. High-throughput strong anion exchange solid-phase extraction in a 96-well plate format was used for sample preparation. Hydrophilic interaction liquid chromatography (HILIC) coupled to negative mass spectroscopy was utilized for separation and detection. Eight possible small organic acids; l-lactic acid (LA), α-hydroxybutyric acid (aHBA), ß-hydroxybutyric acid (bHBA), p-hydroxyphenyllactic acid (pHPLA), malonic acid (MA), methylmalonic acid (MMA), ethylmalonic acid (EMA) and α-ketoglutaric acid (aKGA) were analyzed simultaneously using a ZIC-HILIC column with an isocratic elution containing acetonitrile and ammonium acetate buffer. This method was validated according to U.S. Food and Drug Administration guidelines with additional validation procedures for endogenous substances. Accuracy for all eight acids ranged from 93.1% to 104.0%, and the within-day and between-day precisions (i.e. relative standard deviations) were lower than 5.5% at all tested concentrations. The calibration ranges were: 2.5-2500µg/mL for LA, 0.125-125µg/mL for aHBA, 7.5-375µg/mL for bHBA, 0.1-100µg/mL for pHPLA, 1-1000µg/mL for MA, 0.25-250µg/mL for MMA, 0.25-100µg/mL for EMA, and 30-1500µg/mL for aKGA. Clinical applicability was demonstrated by analyzing plasma and urine samples from five patients with severe falciparum malaria; five acids had increased concentrations in plasma (range LA=177-1169µg/mL, aHBA=4.70-38.4µg/mL, bHBA=7.70-38.0µg/mL, pHPLA=0.900-4.30µg/mL and aKGA=30.2-32.0) and seven in urine samples (range LA=11.2-513µg/mL, aHBA=1.50-69.5µg/mL, bHBA=8.10-111µg/mL, pHPLA=4.30-27.7µg/mL, MMA=0.300-13.3µg/mL, EMA=0.300-48.1µg/mL and aKGA=30.4-107µg/mL). In conclusion, a novel bioanalytical method was developed and validated which allows for simultaneous quantification of eight small organic acids in plasma and urine. This new method may be a useful tool for the assessment of acidosis in patients with severe malaria, and other conditions complicated by acidosis.


Assuntos
Acidose/induzido quimicamente , Ácidos/análise , Cromatografia Líquida/métodos , Malária/fisiopatologia , Espectrometria de Massas/métodos , Compostos Orgânicos/análise , Ácidos/efeitos adversos , Calibragem , Humanos , Limite de Detecção , Compostos Orgânicos/efeitos adversos , Padrões de Referência , Reprodutibilidade dos Testes
15.
PLoS Negl Trop Dis ; 5(8): e1282, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21886850

RESUMO

BACKGROUND: Although increased capillary permeability is the major clinical feature associated with severe dengue infections the mechanisms underlying this phenomenon remain unclear. Dextran clearance methodology has been used to investigate the molecular sieving properties of the microvasculature in clinical situations associated with altered permeability, including during pregnancy and in various renal disorders. In order to better understand the characteristics of the vascular leak associated with dengue we undertook formal dextran clearance studies in Vietnamese dengue patients and healthy volunteers. METHODOLOGY/PRINCIPAL FINDINGS: We carried out serial clearance studies in 15 young adult males with acute dengue and evidence of vascular leakage a) during the phase of maximal leakage and b) one and three months later, as well as in 16 healthy control subjects. Interestingly we found no difference in the clearance profiles of neutral dextran solutions among the dengue patients at any time-point or in comparison to the healthy volunteers. CONCLUSIONS/SIGNIFICANCE: The surface glycocalyx layer, a fibre-matrix of proteoglycans, glycosaminoglycans, and plasma proteins, forms a complex with the underlying endothelial cells to regulate plasma volume within circumscribed limits. It is likely that during dengue infections loss of plasma proteins from this layer alters the permeability characteristics of the complex; physical and/or electrostatic interactions between the dextran molecules and the glycocalyx structure may temporarily restore normal function, rendering the technique unsuitable for assessing permeability in these patients. The implications for resuscitation of patients with dengue shock syndrome (DSS) are potentially important. It is possible that continuous low-dose infusions of dextran may help to stabilize the permeability barrier in patients with profound or refractory shock, reducing the need for repeated boluses, limiting the total colloid volume required. Formal clinical studies should help to assess this strategy as an alternative to conventional fluid resuscitation for severe DSS.


Assuntos
Capilares/fisiopatologia , Permeabilidade Capilar , Dengue/patologia , Dextranos/metabolismo , Taxa de Depuração Metabólica , Adulto , Dextranos/farmacocinética , Humanos , Masculino
16.
Trials ; 12: 25, 2011 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-21288325

RESUMO

BACKGROUND: Tuberculous meningitis is the most severe form of tuberculosis. Mortality for untreated tuberculous meningitis is 100%. Despite the introduction of antibiotic treatment for tuberculosis the mortality rate for tuberculous meningitis remains high; approximately 25% for HIV-negative and 67% for HIV positive patients with most deaths occurring within one month of starting therapy. The high mortality rate in tuberculous meningitis reflects the severity of the condition but also the poor antibacterial activity of current treatment regimes and relatively poor penetration of these drugs into the central nervous system. Improving the antitubercular activity in the central nervous system of current therapy may help improve outcomes. Increasing the dose of rifampicin, a key drug with known poor cerebrospinal fluid penetration may lead to higher drug levels at the site of infection and may improve survival. Of the second generation fluoroquinolones, levofloxacin may have the optimal pharmacological features including cerebrospinal fluid penetration, with a ratio of Area Under the Curve (AUC) in cerebrospinal fluid to AUC in plasma of >75% and strong bactericidal activity against Mycobacterium tuberculosis. We propose a randomized controlled trial to assess the efficacy of an intensified anti-tubercular treatment regimen in tuberculous meningitis patients, comparing current standard tuberculous meningitis treatment regimens with standard treatment intensified with high-dose rifampicin and additional levofloxacin. METHODS/DESIGN: A randomized, double blind, placebo-controlled trial with two parallel arms, comparing standard Vietnamese national guideline treatment for tuberculous meningitis with standard treatment plus an increased dose of rifampicin (to 15 mg/kg/day total) and additional levofloxacin. The study will include 750 patients (375 per treatment group) including a minimum of 350 HIV-positive patients. The calculation assumes an overall mortality of 40% vs. 30% in the two arms, respectively (corresponding to a target hazard ratio of 0.7), a power of 80% and a two-sided significance level of 5%. Randomization ratio is 1:1. The primary endpoint is overall survival, i.e. time from randomization to death during a follow-up period of 9 months. Secondary endpoints are: neurological disability at 9 months, time to new neurological event or death, time to new or recurrent AIDS-defining illness or death (in HIV-positive patients only), severe adverse events, and rate of treatment interruption for adverse events. DISCUSSION: Currently very few options are available for the treatment of TBM and the mortality rate remains unacceptably high with severe disabilities seen in many of the survivors. This trial is based on the hypothesis that current anti-mycobacterial treatment schedules for TBM are not potent enough and that outcomes will be improved by increasing the CSF penetrating power of this regimen by optimising dosage and using additional drugs with better CSF penetration. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN61649292.


Assuntos
Antituberculosos/uso terapêutico , Levofloxacino , Ofloxacino/administração & dosagem , Projetos de Pesquisa , Rifampina/administração & dosagem , Tuberculose Meníngea/tratamento farmacológico , Adulto , Antituberculosos/efeitos adversos , Avaliação da Deficiência , Método Duplo-Cego , Quimioterapia Combinada , Infecções por HIV/complicações , Infecções por HIV/mortalidade , Humanos , Exame Neurológico , Ofloxacino/efeitos adversos , Rifampina/efeitos adversos , Tamanho da Amostra , Fatores de Tempo , Resultado do Tratamento , Tuberculose Meníngea/complicações , Tuberculose Meníngea/diagnóstico , Tuberculose Meníngea/mortalidade , Vietnã/epidemiologia
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