RESUMEN
Methadone (R,S-methadone) can prolong the QT interval. R-methadone inhibits cardiac potassium channel function less than S-methadone. We tested if switching from methadone to R-methadone would reduce corrected QT (QTc) intervals in methadone maintenance treatment (MMT) patients. Nine patients, with automatically read QTc intervals ≥450 ms, were required to detect a 20 ms (clinically relevant) reduction in QTc intervals with 15 ms standard deviation (SD) and 90% power. Nine stabilized MMT patients, using median (range) 70 (40-120) mg methadone, were included. Data (ECG recordings, serum samples, and withdrawal symptoms) were collected both before drug intake (Cmin ) and at 3 h after drug intake (Cmax ), and were collected on the day before the switch from methadone to equipotent R-methadone dose and at 14 and 28 days after the switch. A cardiologist calculated QTc intervals retrospectively. Serum electrolytes and methadone concentrations were measured. Mean QTc intervals at Cmin were 472 ms and 422 ms on methadone (automatically and manually read) and 414 ms on R-methadone (manually read). Mean (SD) change in QTc intervals was -8 (10) ms (p = 0.047) at Cmin but non-significant at Cmax . R-methadone showed a concentration-dependent relationship with QTc intervals. Switching to R-methadone reduced QTc intervals, but far less than the 20 ms considered clinically relevant.
Asunto(s)
Síndrome de QT Prolongado , Metadona , Humanos , Metadona/uso terapéutico , Estudios Retrospectivos , Síndrome de QT Prolongado/inducido químicamente , ElectrocardiografíaRESUMEN
A robust and simple high-throughput automatic sample preparation in a 96-well plate format for quantification of PEth16:0/18:1 with UHPLC-MS/MS in pre-treated frozen blood samples has been simplified as well as optimised regarding liquid handling parameters. To keep the air cushion in the pipetting step as small as possible, 300 µl pipette tips were used instead of 1000 µl tips for pipetting the minimum volume of 2-propanol required for the sample preparation. The 96-well plate was mixed vigorously to acquire a good reproducibility of the PEth results. A 96-wellplate with a well volume of 2.0 ml was used to eliminate cross contamination between the wells, and the calibration curve covered a concentration range from 0.03 to 5 µmol/l. The method was sensitive, and the limit of quantification was 0.005 µmol/l for PEth. The matrix effect in whole blood was small and corrected to 106% by using an isotope-labelled internal standard. There was no carry-over observed after the highest standard 5 µmol/l. The intermediate precision and accuracy were, respectively, less than 9% and 101% when using both the automated and manual sample preparation method. 19 external controls were analysed from an Equalis proficiency testing program for a period of 16 months, and our results were always within 79% of the assigned value. 114 samples were analysed by manual and automatic sample preparation with UHPLC-MS/MS in respectively whole blood and pre-treated frozen blood samples. The mean percentage difference of these measurements between the two methods was calculated in accordance with (Bland & Altman) to be (-4.8 ± 5.6) %.
Asunto(s)
Manejo de Especímenes , Espectrometría de Masas en Tándem , Cromatografía Líquida de Alta Presión/métodos , Congelación , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodosRESUMEN
A simple, sensitive, rapid and robust manual (in glass tubes) and semi-automatic method (in a 96-well plate format) for quantification of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid (THCA) in urine using a UHPLC-MS/MS have been developed. The methods involved hydrolysis with potassium hydroxide in a 96-well plate, followed by neutralization and dilution of the sample in one step with a stable solution of formic acid-methanol-acetonitrile-water (2.2%/35/35/30) before centrifugation. The total chromatographic run time was 4.9 min, with retention times of 1.6 min for THCA. The linear calibration range (5-4000 ng/ml) prepared in urine matrix was wide to avoid reanalyzing. The methods take especially precautions to totally eliminate the carry over after run of the highest standard and to eliminate adsorption of THCA on lab-ware during sample preparation. High content of organic solvent in the neutralization and dilution solution and in the initial composition of the mobile phase gradient are therefore necessary. Standards and quality controls was pH adjusted to 8.4 to increase the solubility of the hydrophobic THCA in urine and prevent adsorption during storage. A preliminary study revealed that adsorption of THCA during semi- automatic sample preparation in a 96-well plate (plastic) was less compared to manual sample preparation in glass tube. The intermediate precision and accuracy by the manual and semi-automated method were less than 10% and ranged from 88% to 114% respectively. Results from external controls from a proficiency testing programs were within 20% accuracy. 63 urine samples positive by immunoassay screening of cannabinoids were confirmed by UHPLC-MS/MS using routine manual preparation in glass tubes and semi-automatic sample preparation using 96-well plastic and glass coated plate. Percentage difference of the measurements were calculated and plotted according to Bland & Altman and the mean percentage difference was not significant.
Asunto(s)
Álcalis/química , Automatización de Laboratorios/métodos , Cromatografía Líquida de Alta Presión/métodos , Dronabinol/análogos & derivados , Detección de Abuso de Sustancias/métodos , Espectrometría de Masas en Tándem/métodos , Adsorción , Dronabinol/orina , Humanos , Concentración de Iones de Hidrógeno , HidrólisisRESUMEN
PURPOSE: Effects of hemodialysis on pharmacokinetic properties and QTc were studied in 4 patients taking daily methadone dose of 100 mg (range, 60-120 mg). METHODS: Methadone in serum, dialysate, and urine were measured by LC-MS/MS. QTc was calculated with Bazett's formula. FINDINGS: The serum Cmin methadone level was 1124 nmol/L (range, 547-1581 nmol/L). Methadone dialysate clearance was 17.1 mL/min (range, 13.7-20.6 mL/min). Total loss in dialysate was 2.30% (range, 1,25-3,70%) of daily methadone intake. QTc increased from 391 msec (range, 369-406 msec) to 445 msec (range, 407-479 msec), independently of serum methadone level, which may be explained by normalization of serum electrolytes. IMPLICATIONS: Methadone dose adjustment is not needed because of hemodialysis.