Effect on QTc interval by switching from methadone to equipotent R-methadone dose in methadone maintenance treatment patients.

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.

Development of UHPLC-MS/MS methods to quantify 25 antihypertensive drugs in serum in a cohort of patients treated for hypertension.

We developed three ultra-high pressure liquid chromatography coupled to mass spectrometry detection (UHPLC-MS/MS) methods to quantify 25 antihypertensive drugs in serum samples. Patient-reported drug lists were collected, and drug concentrations were analysed in samples from 547 patients, half with uncontrolled hypertension, and all treated with ≥ 2 antihypertensive drugs. For sample preparation, serum was mixed with deuterated internal standards and acetonitrile and precipitated. Aliquots of the supernatant were injected on UHPLC-MSMS with a C18 reversed phase column. The mobile phase was 0.1 % HCOOH (formic acid) in water and 0.1 % HCOOH in acetonitrile (except in methanol for spironolactone/canrenone) at a flow rate of 0.4 mL/min. The calibrators and internal controls were prepared in Autonorm™. The calibration ranges were wide, and the models were linear or quadratic with squared correlation coefficients ≥ 0.97. The limits of detection and quantification, specificity, carry-over, and matrix effects were acceptable. The accuracy of the internal controls was in the range 85-121 %, and the intermediate precision for all drugs was 4-28 %. The patient-reported antihypertensive drug use and the detected serum drug concentrations were in accordance with that most frequently prescribed nationally. The percent non-detectable level was 5-10 % for bendroflumethiazide, doxazosin, nifedipine, and ramipril. Often the drug dose chosen was lower than the recommended maximum daily dose. We report the maximum (Cmax) and minimum (Cmin) drug concentrations after drug intake. The inter-individual pharmacokinetic variability at Cmin was 18-fold for hydrochlorothiazide, 22-fold for losartan carboxyl acid, 26-fold for amlodipine, 44-fold for candesartan, and 50-fold for valsartan. Our methods are suitable for measuring antihypertensive drugs in patient serum for therapy control.

Developing a rapid semi-automated sample preparation with alkaline hydrolysis in a 96-well plate for quantification of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid in urine samples by UHPLC-MS/MS.

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.

[Drug safety associated with the change of digitalis drug in Norway]. / Legemiddelsikkerhet ved bytte av digitalispreparat i Norge.

BACKGROUND In 2011, following a period with delivery problems, the only registered digitoxin drug in Norway was replaced with digoxin. As a result, approximately 21 000 patients had to replace digitoxin with digoxin. There are important pharmacokinetic differences between digitoxin and digoxin (the general term for both drugs is digitalis), which must be taken into account when changing therapy. The aim of this study was to investigate compliance of drug security, during the transition from digitoxin to digoxin in Norway.MATERIAL AND METHOD Enquiries addressed to the Norwegian Poison Information Centre and reports of fatal adverse effects to the Regional Drug Information Centres (RELIS) regarding intake of digitalis were analysed. Serum concentrations of digitoxin and digoxin analyzed at Oslo University Hospital were reviewed. All data sources were reviewed for the years 2010-2014 and patients > 20 years were included.RESULTS The total number of enquiries addressed to the Norwegian Poison Information Centre, fatal adverse drug reactions reported to RELIS, and patient samples in the toxic range analyzed at Oslo University Hospital increased from 2012, timewise related to the transition to digoxin.INTERPRETATION Despite extensive information from the Norwegian Medicines Agency, a small, transient increase was observed in the number of overdoses and reported deaths from digitalis related to change in therapy. The cause of the overdose was in many cases unknown. This study revealed several cases of incorrect dosage, simultaneous use of digitoxin and digoxin, and washout time that was insufficient or lacking before initiation of digoxin.

Effects of Hemodialysis on Methadone Pharmacokinetics and QTc.

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.

Blood alcohol concentrations in apprehended drivers of cars and boats suspected to be impaired by the police.

OBJECTIVE: According to the Norwegian Road Traffic Act, car drivers are not allowed to operate a vehicle with a blood alcohol concentration (BAC) above 0.2 g/kg. Depending on the size of the boat or ship, boat drivers/captains/first mates are not allowed to conduct the boat with a BAC above 0.8 g/kg when driving small boats (length less than 15 m) and above 1.5 g/kg when running larger vessels/ships. The new Sea Act of June 2005 states that captains/first mates cannot conduct a ship if he/she has a BAC above 0.2 g/kg. Our aim was to determine the current median BAC in a large population of car and boat drivers in Norway. Our other aim was to study if median BAC was higher in boat drivers than in car drivers who were suspected by the police to be impaired. Furthermore, we wanted to investigate if the BAC levels were differently distributed by gender or age within and between these two groups. METHODS: The Norwegian Institute of Public Health analyzes blood samples from all car/boat drivers suspected of driving under the influence of alcohol and non-alcoholic drugs. In the present study, samples submitted between 01.05 and 01.09 in 2002-2004 were included. Drivers, who in addition tested positive for drugs or abuse substances other than ethanol were excluded. RESULTS: There were 321 boat drivers and 3,061 car drivers who were suspected to be under the influence of ethanol only. The median BAC in boat drivers (1.76 g/kg [range 0.02-3.54]) was significantly higher compared to that in car drivers (1.54 g/kg [range 0.00-4.27]). In the car driver group, the mean BAC did not differ significantly between men and women. The median level of BAC was significantly higher in men than in women in the boat driver group (1.77 g/kg with CI 1.69-1.85 vs. 1.27 g/kg with CI 0.78-1.76). CONCLUSIONS: Alcohol impairment of car drivers is known to be considered the most important contributing cause of car crash injuries. Driving a boat may demand the same degree of performance skills as driving a car. The median BAC in apprehended boat drivers was considerably high in the present study. The median BAC was also high in car drivers despite strict legislation. The population of drivers of cars in our study, however, is from previous studies known to contain a large proportion of heavy drinkers. Less is known about the drinking habits in boat drivers, and caution is needed in generalizing from our results. However, our results indicate the possible need for stricter legislation and more frequent police control that will hopefully prevent serious accidents caused by ethanol drinking at sea.

Relationship between methadone and EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine) in urine samples from Norwegian prisons.

BACKGROUND: Methadone maintenance treatment is a widely used therapy in the rehabilitation of opioid addiction the world over. Methadone is metabolised in the body to a number of inactive metabolites, but primarily to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). The Division of Forensic Toxicology and Drug Abuse (DFTDA) of the Norwegian Institute of Public Health carries out drug analysis of urine samples from inmates of prisons throughout Norway. Methadone and EDDP in the urine are also tested for upon request. The results are stored in a secure database at the DFTDA. OBJECTIVES: The aims of the present study were (1) to observe variations in methadone and EDDP concentrations in urine in relation to urine pH in a large set of urine samples obtained from prison inmates and (2) to analyse samples testing methadone-positive/EDDP-negative and investigate whether such results could occur naturally, without sample tampering. METHODS: All urine samples that tested positive for methadone over the period 2004-2005 were collected from the DFTDA database, and the relation between methadone and EDDP excretion in urine, and urinary pH was determined. Samples that tested positive for methadone but negative for EDDP were picked out and studied individually. RESULTS: A total of 1539 urine samples (cases) had tested positive for methadone in our database for the period 2004-2005. There was a strong correlation between the concentration of methadone in urine and urine pH in these samples, with higher concentrations of methadone present at lower pH levels. Cases that tested positive for methadone but negative for EDDP were rare - a total of five (0.3% of all cases tested). These cases were studied in more detail. CONCLUSION: Methadone excretion in urine is dependent on urinary pH. Methadone-positive/EDDP-negative results may suggest sample tampering in some, but not all, cases.

[Khat--a new drug of abuse in Norway]. / Khat--et nytt rusmiddel i Norge.

BACKGROUND: The stimulating drug, Khat, is a drug of abuse that has become known in Norway due to increased immigration from East-Africa, especially Somalia. METHOD: Review of recent literature. RESULTS: Khat is present in leaves from the tree Catha Edulis and is taken by chewing the leaves. The biologically active compounds are cathinone, cathine and norephedrine. Analysis of cathinone in urine can be performed at the Norwegian Institute of Public Health. The effects of khat are similar to, but weaker than those of amphetamine. Khat stimulates the central nervous system causing increased alertness, euphoria and occasionally psychosis, and increases activity in the peripheral sympathetic nervous system leading to palpitations, increased blood pressure, large pupils and red eyes. Tannin in khat damages teeth and causes constipation. With increased use of khat in the society it is important for the clinician to have some knowledge of the effects of khat.

Simultaneous determination of 6 beta-blockers, 3 calcium-channel antagonists, 4 angiotensin-II antagonists and 1 antiarrhythmic drug in post-mortem whole blood by automated solid phase extraction and liquid chromatography mass spectrometry. Method development and robustness testing by experimental design.

A method for the simultaneous determination of the beta-blockers atenolol, sotalol, metoprolol, bisoprolol, propranolol and carvedilol, the calcium-channel antagonists diltiazem, amlodipine and verapamil, the angiotensin-II antagonists losartan, irbesartan, valsartan and telmisartan, and the antiarrhythmic drug flecainide, in whole blood samples from forensic autopsies was developed. Sample clean-up was achieved by precipitation and solid phase extraction (SPE) with a mixed-mode column. Quantification was performed by reversed phase high performance liquid chromatography with positive electrospray ionization mass spectrometric detection (HPLC-MS). The method has been developed and robustness tested by systematically searching for satisfactory conditions using experimental designs including factorial and response surface designs. With the exception of amlodipine, the concentration limit of quantification (cLOQ) covered low therapeutic concentration levels for all the compounds. Within assay precisions and accuracies (bias) were 3.4-21% RSD and from -24 to 21% for the concentration range 1.00-5.00 microM, respectively. Between assay precisions were 4.4-28% RSD for the concentration range from 0.1 to 5 microM and recoveries varied from 9 to 103%. The method is used for determination of cardiovascular drugs in post-mortem whole blood samples from forensic autopsy cases.