Lisdexamfetamine and amphetamine pharmacokinetics in oral fluid, plasma, and urine after controlled oral administration of lisdexamfetamine.

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.

Assessment of lisdexamfetamine dimesylate stability and identification of its degradation product by NMR spectroscopy.

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.

O serviço de entrega de medicamentos em casa como forma de melhoria do acesso em saúde pública / Medication home delivery service as a way to improve access in public health

A Farmácia do Paraná, 2ª Regional de Saúde Metropolitana, implementou o serviço de entrega em casa de medicamentos do Componente Especializado da Assistência Farmacêutica na forma de um projeto piloto no ano de 2017. Este serviço atende aos usuários idosos portadores de doenças crônicas que utilizam medicamentos de uso contínuo previamente elencados para este serviço. A entrega em casa tem como objetivo facilitar o acesso dos usuários idosos ao seu tratamento tendo em vista a dificuldade de muitos em se deslocarem até a farmácia. Além disso, impacta no melhoramento do fluxo de atendimento a todos os usuários, diminuindo o tempo de espera. (AU)

The public pharmacy in the state of Paraná, which integrates the 2nd Health Regional Department of the City, implemented the home delivery service of medicines of the Brazilian Specialized Pharmaceutical Care Program as a pilot project in the year of 2017. This service attends the elderly users of the system that were previously listed for the program and need medicines of continuous use for chronic diseases. The medicine home delivery aims to facilitate the access to treatments by these elderly users that have difficulties to get to the pharmacy. In addition, it improves the service flow to all users, because it reduces the waiting time. (AU)

Simultaneous determination of cocaine/crack and its metabolites in oral fluid, urine and plasma by liquid chromatography-mass spectrometry and its application in drug users.

INTRODUCTION: A single LC-MS equipment was used to validate three methods for simultaneously analyzing cocaine (COC), benzoylecgonine (BZE), cocaethylene (CE), anhydroecgonine methyl ester (AEME) and anhydroecgonine (AEC) in oral fluid (OF), urine and plasma. METHODS: The methods were carried out using a Kinetex HILIC column for polar compounds at 30°C. Mobile phase with isocratic condition of acetonitrile: 13mM ammonium acetate pH 6.0: methanol (55:35:10 v/v/v) at 0.8mL/min flow rate was used. RESULTS: After buffer dilution (OF) and protein precipitation (urine and plasma), calibration curve ranges were 4.25-544ng/mL for oral fluid and 5-320ng/mL for urine and plasma with correlation coefficients (r) between 0.9947 and 0.9992. The lowest concentration of the calibration curves were the lower limit of quantification. No major matrix effect could be noted, demonstrating the efficiency of the cleaning procedure. DISCUSSION: The methods were fully validated and proved to be suitable for analysis of 124 cocaine and/or crack cocaine users. Among the subjects, 56.5% reported daily use of cocaine in the previous three months. Results show a high prevalence of the analytes, with BZE as the most prevalent (94 cases), followed by COC (93 cases), AEC (70 cases), CE (33 cases) and AEME (13 cases). In addition, the concentration of BZE in urine was higher compared to OF and plasma found in the real samples, showing the facility of accumulation in chronic users in matrices with a large detection window.

Method validation and determination of lisdexamfetamine and amphetamine in oral fluid, plasma and urine by LC-MS/MS.

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.

Lisdexamfetamine: A pharmacokinetic review.

Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice.

Fenproporex and amphetamine pharmacokinetics in oral fluid after controlled oral administration of fenproporex.

BACKGROUND: Fenproporex hydrochloride (FEN) is an anorectic drug used in the treatment of obesity, and its major metabolite is amphetamine (AMP), another central nervous system stimulant. The concentration versus time profile of FEN and its metabolite AMP has been described in classic biological matrices such as plasma and urine; however, there are no reports of such data in oral fluid. OBJECTIVE: The aim of this study is to describe the pharmacokinetics of FEN and AMP in oral fluid after intake of FEN. METHODS: Twenty-five milligrams of FEN (1 capsule of Desobesi-m) was orally administered to 6 male volunteers, and oral fluid samples were collected with a Quantisal device during 24.00 hours after drug ingestion. These samples were submitted to solid-phase microextraction before analysis by gas chromatography-mass spectrometry in the selected-ion-monitoring mode, using deuterium-labeled AMP as internal standard. RESULTS: After FEN administration, both analytes could be detected in oral fluid of all volunteers with an initial detection time varying from 0.50 to 1.00 hour. FEN peak concentrations occurred between 1.00 and 1.50 hours after administration and were between 70.7 and 227.5 µg/L. For AMP, peak concentration occurred between 1.50 and 4.00 hours, reaching 33.0-150.9 µg/L. CONCLUSION: The authors observed that oral administration of FEN resulted in significant amounts of FEN and AMP in oral fluid, showing that oral fluid could be a biological matrix suitable for pharmacokinetic studies for both analytes. Using a compartmental approach, FEN data were best fitted by 1-compartment model with first-order input and output, whereas AMP followed a 2-compartment model with first-order input and output.

Which amphetamine-type stimulants can be detected by oral fluid immunoassays?

INTRODUCTION: The use of oral fluid for monitoring drug consumption on roads has many advantages over conventional biological fluids; therefore, several immunoassays have been developed for this purpose. In this work, the ability of 3 commercial immunoassays to detect amphetamine-type stimulants (ATSs) in oral fluid was assessed. In addition, it was reviewed the main controlled ATSs available worldwide, as well as the oral fluid immunological screening tests that have been used for identifying ATSs in drivers. MATERIALS AND METHODS: The analytical specificity of amphetamine direct enzyme-linked immunosorbent assay (ELISA), methamphetamine direct ELISA (Immunalysis Corporation), and Oral-View saliva multidrug of abuse test (Alfa Scientific Designs) was evaluated using ATS-spiked oral fluid. Legislation and published articles that report the use of immunological screening tests to detect ATS consumption in conductors were reviewed, including the kit's technical information, project reports, police and drug databases. RESULTS AND DISCUSSION: Even at high concentrations, the tested assays were not able to detect methylphenidate, fenproporex, or diethylpropion, controlled ATSs legally marketed in many countries. CONCLUSIONS: This evidences the need to develop new kits that enable one to control the misuse of prescription ATSs on roads through oral fluid immunoassays.

Determination of amphetamine-type stimulants in oral fluid by solid-phase microextraction and gas chromatography-mass spectrometry.

A method for the simultaneous identification and quantification of amphetamine (AMP), methamphetamine (MET), fenproporex (FEN), diethylpropion (DIE) and methylphenidate (MPH) in oral fluid collected with Quantisal™ device has been developed and validated. Thereunto, in-matrix propylchloroformate derivatization followed by direct immersion solid-phase microextraction and gas chromatography-mass spectrometry were employed. Deuterium labeled AMP was used as internal standard for all the stimulants and analysis was performed using the selected ion monitoring mode. The detector response was linear for the studied drugs in the concentration range of 2-256 ng mL(-1) (neat oral fluid), except for FEN, whereas the linear range was 4-256 ng mL(-1). The detection limits were 0.5 ng mL(-1) (MET), 1 ng mL(-1) (MPH) and 2 ng mL(-1) (DIE, AMP, FEN), respectively. Accuracy of quality control samples remained within 98.2-111.9% of the target concentrations, while precision has not exceeded 15% of the relative standard deviation. Recoveries with Quantisal™ device ranged from 77.2% to 112.1%. Also, the goodness-of-fit concerning the ordinary least squares model in the statistical inference of data has been tested through residual plotting and ANOVA. The validated method can be easily automated and then used for screening and confirmation of amphetamine-type stimulants in drivers' oral fluid.