RESUMO
Lisdexamfetamine (LDX) is a long-acting prodrug stimulant indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) and binge-eating disorder (BED) symptoms. In vivo hydrolysis of the LDX amide bond releases the therapeutically active d-amphetamine (d-AMPH). This study aims to describe the pharmacokinetics of LDX and its major metabolite d-AMPH in human oral fluid, urine and plasma after a single 70 mg oral dose of LDX dimesylate. Six volunteers participated in the study. Oral fluid and blood samples were collected for up to 72 h and urine for up to 120 h post-drug administration for the pharmacokinetic evaluation of intact LDX and d-AMPH. Samples were analyzed by LC-MS/MS. Regarding noncompartmental analysis, d-AMPH reached the maximum concentration at 3.8 and 4 h post-administration in plasma and oral fluid, respectively, with a mean peak concentration value almost six-fold higher in oral fluid. LDX reached maximum concentration at 1.2 and 1.8 h post-administration in plasma and oral fluid, respectively, with a mean peak concentration value almost three-fold higher in plasma. Intact LDX and d-AMPH were detected in the three matrices. The best fit of compartmental analysis was found in the one-compartment model for both analytes in plasma and oral fluid. There was a correlation between oral fluid and plasma d-AMPH concentrations and between parent to metabolite concentration ratios over time in plasma as well as in oral fluid.
Assuntos
Anfetamina/farmacocinética , Dimesilato de Lisdexanfetamina/farmacocinética , Saliva/metabolismo , Administração Oral , Adulto , Cromatografia Líquida , Humanos , Dimesilato de Lisdexanfetamina/administração & dosagem , Masculino , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
INTRODUCTION: Canis lupus familiaris is a domestic dog and many owners consider their pets as a family member. Medical bills with dogs are overcame only by the health care received by humans. Medical care is constantly progressing, and so is veterinary care. Metabolomics is the ''omic" technique aimed to the study of metabolome, low-molecular weight molecules, through biofluids or tissue samples. And it also allows to evaluate disease diagnosis and prognosis, therapeutic evaluation and toxicological studies. OBJECTIVES: The goal of this paper is to review the current and potential applications of metabolomics in domestic dogs. METHOD: ScienceDirect, Scopus, Reaxys and PubMed were searched for papers that performed canine metabolomics in any research area. RESULTS: We analysed 38 papers, published until April 2019 in canine metabolomics approach. Metabolomic research in dogs so far can be divided into three areas: (a) Metabolomics studies in veterinary science, such as improving pet dogs health and welfare. (b) Diet, breeds and species discrimination. (c) Use of dogs as animal model in different diseases and drug development (evaluation toxicity and effect). CONCLUSIONS: The results of this review showed that interest in metabolomics is growing in veterinary research. Several canine diseases have been evaluated with some promise for potential biomarker and/or disease mechanism discovery. Because canine metabolomics is a relatively new area, the researches spread across different research areas and with few studies in each area.
Assuntos
Cães/metabolismo , Metabolômica , AnimaisRESUMO
Lisdexamfetamine dimesylate (LDX), a long-acting prodrug stimulant indicated for the treatment of the attention-deficit/hyperactivity disorder (ADHD), was subjected to forced degradation studies by acid and alkaline hydrolysis and the degradation profile was studied. To obtain between 10-30% of degraded product, acid and alkaline conditions were assessed with solutions of 0.01 M, 0.1 M, 0.5 M, and 1 M of DCl and NaOD. These solutions were analyzed through 1 H NMR spectra. Acid hydrolysis produced no degradation in 0.01 M and 0.1 M DCl and 4.38%, 9.69%, and 17.75% of degradation LDX, respectively, in 0.5 M, 1 M (4h) and 1 M (4 + 12 h) DCl. And alkaline hydrolysis produced no degradation in 0.01 M and 0.1 M DCl and a degradation LDX extension of 8.5%, 14.30%, and 22.91%, respectively, in 0.5 M, 1 M (4h) and 1 M (4 + 12 h) NaOD. LDX solutions subjected to 1 M (4 + 12 h) acid and alkaline hydrolysis were evaluated by NMR spectra (1 H NMR, 13 C NMR, HSQC and HMBC). LDX degradation product (DP) was identified and its structure elucidated as a diastereoisomer of LDX: (2R)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl] hexanamide without their physical separation.
Assuntos
Estimulantes do Sistema Nervoso Central/análise , Estimulantes do Sistema Nervoso Central/metabolismo , Dimesilato de Lisdexanfetamina/análise , Dimesilato de Lisdexanfetamina/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Estabilidade de MedicamentosRESUMO
Lisdexamfetamine (LDX) is a long-acting prodrug stimulant indicated for the treatment of attention-deficit/hyperactivity disorder and binge-eating disorder symptoms. In vivo hydrolysis of LDX amide bond releases the therapeutically active d-amphetamine (d-AMPH). Since toxicological tests in biological samples can detect AMPH from the use of some legal medications, efficient methods are needed in order to correctly interpret the results. The aim of this study was to develop and validate an LC-MS/MS method for the simultaneous quantification of LDX and its main biotransformation product AMPH in human oral fluid, plasma and urine. Calibration curve range for both analytes was 1-128 ng/mL in oral fluid and plasma and 4-256 ng/mL in urine, being the lowest concentration the limit of quantification. Accuracy of the determined values of the target analytes for the five control levels ranged from 94.8 to 111.7% for oral fluid, from 91.3 to 100.2% for plasma and from 94.8 to 109.8% for urine. Imprecision for the five control levels did not exceeded 12.8% for oral fluid, 16.2% for plasma and 17.1% for urine. The method developed for the three matrices was validated and was also successfully applied to assess real samples, showing for the first time the detection of LDX in oral fluid.
Assuntos
Anfetamina/análise , Cromatografia Líquida , Testes de Química Clínica/métodos , Dimesilato de Lisdexanfetamina/análise , Espectrometria de Massas em Tandem , Anfetamina/sangue , Anfetamina/urina , Testes de Química Clínica/normas , Humanos , Dimesilato de Lisdexanfetamina/sangue , Dimesilato de Lisdexanfetamina/urina , Reprodutibilidade dos Testes , Saliva/químicaRESUMO
PURPOSE: There are no pharmacokinetics studies in oral fluid reported in the literature, as well as there are no data on correlation of drug levels in plasma, urine, and oral fluid in order to propose alternative matrices to monitor the use of mazindol by drivers. The present work aimed to study, preliminarily, mazindol's pharmacokinetics in plasma and oral fluid, as well as investigate the correlation of drug levels in urine, plasma, and oral fluid. METHOD: Blood, urine, and oral fluid samples from seven healthy male volunteers were collected at 0, 1, 2, 4, 5, 6, 8, 10, and 24 h after administration of tablets of 2 mg mazindol and analyzed by a previously validated method by LC-MS with liquid-liquid extraction. Levels of the drug found were higher in plasma when compared with oral fluid and higher in urine in relation to plasma. The study of the mazindol's pharmacokinetics showed that the most suitable model to describe the variation of the concentration over time is the compartment open model with absorption and elimination following the first-order kinetics, and confirming literature data, drug is metabolized, being the major metabolite detected, but not quantified. CONCLUSION: It was not found a good correlation between the concentrations of mazindol in urine and plasma, but between plasma and oral fluid, there was a good correlation, suggesting this as an alternative matrix to plasma. However, studies involving more subjects are needed.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacocinética , Mazindol/farmacocinética , Administração Oral , Adulto , Estimulantes do Sistema Nervoso Central/sangue , Estimulantes do Sistema Nervoso Central/urina , Voluntários Saudáveis , Humanos , Masculino , Mazindol/sangue , Mazindol/urina , Modelos Biológicos , Saliva/química , Adulto JovemRESUMO
Brazil is one of the countries most affected by abuse of stimulant medications by professional drivers, especially fenproporex, amfepramone and mazindol. Even though their sale is banned, they can be found in illegal markets, such as those located on the country's borders. The use of oral fluid to monitor drug levels has many advantages over plasma and urine because it is noninvasive, easier to collect and more difficult to adulterate. The aim of this study was to develop and validate a sensitive and specific method to quantify mazindol in human oral fluid by liquid chromatography-mass spectrometry (LC-MS). The LC system consisted of an LC-MS system operated in selected ion monitoring mode. The mobile phase was composed of water at pH 4.0, acetonitrile and methanol (60:15:25 v/v/v) at a flow rate of 1.0 mL/min and propranolol was used as internal standard. Total running time was 10 min. The lower limit of quantification was 0.2 ng/mL and the method exhibited good linearity within the 0.2-20 ng/mL range (r = 0.9987). A rapid, specific, sensitive, linear, precise and accurate method was developed for determination of mazindol in human oral fluid according to European Medicines Agency guidelines, and is suitable for monitoring mazindol levels in oral fluid of professional drivers.
Assuntos
Estimulantes do Sistema Nervoso Central/análise , Cromatografia Líquida de Alta Pressão/métodos , Mazindol/análise , Saliva/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Condução de Veículo , Brasil , Estimulantes do Sistema Nervoso Central/química , Estabilidade de Medicamentos , Humanos , Modelos Lineares , Masculino , Mazindol/química , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: This study aimed to develop a liquid oral formulation containing losartan potassium, an angiotensin II receptor antagonist drug used for its antihypertensive activity, and to perform a preliminary stability assessment under different temperatures and packages to ensure paediatric therapeutic adherence and facilitate the hospital routine. METHODS: A syrup containing losartan potassium (1.0 and 2.5 mg/mL) (excipients: potassium sorbate, sucrose (85%), water, citric acid and raspberry flavouring) was prepared. The packaging was carried out in amber polyethylene terephthalate (PET) and amber glass bottles (in triplicate) under the following conditions: (a) room temperature (15-30°C); (b) refrigeration (2-8°C); and (c) oven temperature (40°C) for 28 days. An analytical method by high performance liquid chromatography using a reverse-phase column was also developed and validated for quantitative determination of the drug in the formulations. RESULTS: The analytical method showed satisfactory linearity, detection and quantification limits, precision, accuracy and robustness. Samples at room temperature maintained content values between 90% and 110% for 7 days, while those stored under refrigeration maintained a homogeneous appearance and content between 90% and 110% for a period of 21 days. Values of pH stayed in a narrow range. Viscosity results were between 40.1 and 49.2 centipoise (cp) for glass bottles and 42.4 and 54.7 cp for PET bottles. CONCLUSIONS: A simple and economical losartan potassium liquid formulation was produced and was shown to be stable under refrigeration for 21 days in both PET and glass packages.
RESUMO
Stability-indicating LC methods using a UV detector and a charged aerosol detector (CAD) simultaneously were validated for the assessment of alogliptin (ALG) in tablets. The analysis was performed on a C8 column (250 × 4.6 mm, 5 µm) at a flow of 0.8 mL/min, using acetonitrile-10 mM ammonium acetate buffer (pH 3.5; 90 + 10, v/v) as mobile phase and UV detection at 275 nm. Validation followed the International Conference on Harmonization guidelines. The method was linear over the range of 25-200 µg/mL. Normality of the residuals showed a normal distribution, no autocorrelation, and homoscedasticity. LODs were 6.25 and 2.65 µg/mL and LOQs were 20.85 and 8.84 µg/mL for the CAD and the UV detector, respectively. The methods were precise and accurate. Excipients and degradation products did not interfere in the methods in studies of specificity. None of the factors studied in the analysis of robustness had a significant effect on the quantification of the ALG by the Pareto chart. The results of the assay obtained with LC-CAD and LC-UV were similar. The methods could be considered interchangeable and stability-indicating, and can be applied as an appropriate QC tool for analysis of ALG in tablets.
Assuntos
Piperidinas/análise , Uracila/análogos & derivados , Ácido Benzoico/análise , Cromatografia Líquida , Estabilidade de Medicamentos , Excipientes/análise , Limite de Detecção , Manitol/análise , Piperidinas/administração & dosagem , Comprimidos , Uracila/administração & dosagem , Uracila/análiseRESUMO
INTRODUCTION: Even after removal of some stimulants, like fenproporex, amfepramone and mazindol, from Brazilian market, the use of these substances is still high, especially by drivers. Mazindol is the second most used anorectic agent in the world acting as an indirect sympathomimetic agonist, having stimulatory action on central nervous system. Plasma is a good matrix to monitor since it reflects the psychomotor effects of these drugs, but unlike urine has an invasive collection; drug levels and detection time are quite low. METHOD: The method involved a liquid-liquid extraction of the samples and a LC-MS analysis was fully validated. Method was used to analyze samples of urine and plasma collected from health volunteers in a period of 24h. Metabolite of mazindol was synthesized using alkaline conditions. RESULTS: After validation the method proved to be adequate to analyze samples collected from health volunteers. Method was linear in the concentration range of 0.1-10ng/mL (r=0.9982) for plasma and 5-50ng/mL (r=0.9973) for urine. DISCUSSION: Analysis of the samples showed that mazindol can be detected after 1h of administration and that concentration levels in urine were always higher than in plasma. Mazindol metabolite was detected only in urine.