Usefulness of measuring the serum concentration of antihypertensive drugs in uncontrolled hypertension. / Serumkonsentrasjonsmåling av antihypertensiver er nyttig ved ukontrollert hypertensjon.

One-third of the adult population in Norway has hypertension. Despite receiving lifestyle advice and drug therapy, only half achieve the recommended blood pressure range. Measurements of serum drug concentrations can reveal poor medication adherence and can be used to personalise treatment.

Delayed neuropsychiatric syndrome after carbon monoxide poisoning. / Forsinket nevropsykiatrisk syndrom etter kullosforgiftning.

Background: Delayed neuropsychiatric syndrome (DNS) is a well-known complication following carbon monoxide (CO) poisoning and develops in up to 50 % of adult survivors. The syndrome is probably immunologically mediated. Common symptoms are slowness, Parkinsonism and cognitive impairment. Case presentation: A woman in her forties started to show gradually increasing symptoms of DNS a few days after an episode of severe CO poisoning. She received methylprednisolone 1 g intravenously on 3 consecutive days at around 7 weeks after the poisoning, with an immediate positive response to motor deficit symptoms. Thereafter, she gradually recovered and returned to full-time employment 4.5 months after the steroid treatment. Interpretation: The role of steroids in this patient's recovery is uncertain. However, successful high-dose steroid treatment for patients with ongoing DNS progression after CO poisoning has been reported previously in the literature. The authors recommend more attention to the risk of DNS after CO poisoning and further research on treatment options.

Systematic screening of substance use upon hospitalisation. / Systematisk kartlegging av rusbruk ved innleggelse.

Many people can improve their health by reducing their consumption of alcohol and habit-forming medications. By screening for this in connection with emergency hospital admissions, we can help to reduce use.

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.

Pre-injury dispensing of psychoactive prescription drugs in a ten years trauma population: a retrospective registry analysis.

BACKGROUND: The use of psychoactive prescription drugs is associated with increased risk of traumatic injury, and has negative impact on clinical outcome in trauma patients. Previous studies have focused on specific drugs or subgroups of patients. Our aim was to examine the extent of psychoactive drug dispensing prior to injury in a comprehensive population of trauma patients. METHODS: The Oslo University Hospital Trauma Registry provided data on all trauma patients admitted to the trauma centre between 2005 and 2014. We linked the data to Norwegian Prescription Database data from 2004. Opioids, benzodiazepines, z-hypnotics, gabapentinoids, and centrally acting sympathomimetics dispensed during the year before trauma of each patient were identified. We determined the pre-trauma annual prevalence of dispensing and mean annual cumulative defined daily doses (DDD) for each drug class, and compared results with corresponding figures in the general population, using standardised ratios. For each drug class, dispensing 14 days preceding trauma was analysed in patients sustaining severe injury and compared with patients sustaining non-severe injury. RESULTS: 12,713 patients (71% male) were included. Median age was 36 years. 4891 patients (38%) presented with severe injury (Injury Severity Score > 15). The ratio between annual prevalence of dispensed prescriptions for trauma patients and the general population, adjusted for age and sex, was 1.5 (95% confidence interval 1.4-1.6) for opioids, 2.1 (2.0-2.2) for benzodiazepines, 1.7 (1.6-1.8) for z-hypnotics, 1.9 (1.6-2.2) for gabapentinoids, and 1.9 (1.6-2.2) for centrally acting sympathomimetics. Compared with the general population, mean annual cumulative DDD of opioids and benzodiazepines dispensed to trauma patients were more than two and three times as high, respectively, in several age groups below 70 years. The prevalence of dispensing 14 days pre-trauma was higher in severely injured patients for opioids, benzodiazepines, and z-hypnotics compared with patients without severe injury. CONCLUSIONS: Our results support previous findings that the prevalence of psychoactive drug use is high among trauma patients. In terms of both frequency and amounts, the pre-injury dispensing of psychoactive drugs to trauma patients supersedes that of the general population, especially in younger patients.

Fatal Adverse Event with Dabigatran in Elderly Patient with Reduced Kidney Function.

An elderly man with decreased kidney function was admitted to hospital with gastrointestinal bleeding. After remaining stable for 2 days in hospital, he became haemodynamically unstable and an adverse effect of dabigatran was suspected, but efforts to treat the patient failed and the following morning he passed away. In conjunction with the autopsy, blood samples from his hospital stay were analysed for dabigatran, revealing the highest concentration (6400 ng/mL) apparently reported to date. Supra-therapeutic dosing was, however, never suspected. Dabigatran is largely excreted through the kidneys. A possible cause of the high dabigatran concentrations could be a rapid decrease in kidney function that seemingly occurred over a period of 2 months, sometime between his initiation of treatment (eGFR 51-55 mL/min/1.73 m2 ) and subsequent hospital admission (eGFR 31 mL/min/1.73 m2 ). The increasing dabigatran concentrations in the patient was, however, not apparent to the prescribing doctor, as therapeutic drug monitoring of dabigatran is not recommended in current guidelines and no such analyses were performed. There may be a need to evaluate blood concentrations of dabigatran, in the light of the reported differences in interindividual concentrations, along with the increased risks of thromboembolic events with lower concentrations and major bleeding events with higher concentrations. Functional assays to assess concentrations of dabigatran in blood have been developed and are available in some hospitals to be used in suspected overdoses or before emergency surgeries. Methods to determine concentrations of dabigatran specifically have also been developed and can additionally be used for therapeutic drug monitoring in an outpatient setting, especially in high-risk individuals.

Zopiclone concentrations in oral fluid and blood after, administration of therapeutic doses of zopiclone.

PURPOSE: Little is known about the relationship between concentrations in oral fluid (OF) and blood for the widely prescribed hypnotic drug zopiclone. The purpose of this study was to investigate the usefulness of OF zopiclone concentrations to predict blood zopiclone concentrations in order to introduce OF testing as an alternative to more cumbersome blood testing. METHODS: 16 healthy young male volunteers received capsules of either 5 or 10mg zopiclone on two different study days separated by at least one week. Blood and OF were collected simultaneously at baseline and 9 times after intake of zopiclone on each study day. In addition an OF sample was collected 24-81h after intake. Lunch was served between samples taken 2.5 and 3.5h after intake. All samples were analysed for zopiclone, and the cut-off was 10ng/ml in blood and 0.2ng/ml in OF-buffer mixture. RESULTS: Zopiclone was detected in all OF samples during the study day. After 24-81h, all subjects were also positive for zopiclone in OF, except from three subjects ingesting the 5mg dose. In a single case zopiclone was detected in a baseline OF sample 14days after intake on an earlier study day. Zopiclone was detected in both OF and blood in 231 OF/blood pairs, and a significant but weak correlation between OF and blood concentration was seen (R2 of 0.30). The median (range) zopiclone OF/blood concentration ratio (ZOBCR) for all samples were 3.3 (0.8-18). The ZOBCR decreased when the OF volume increased. After 30 of 31 given doses of zopiclone, the ZOBCR was higher in samples collected before lunch than samples collected after lunch. DISCUSSION: Vast intra- and interindividual differences in ZOBCR were found, and the correlation between OF and blood concentration was less pronounced than reported in former studies. In accordance with earlier studies we found a negative correlation between ZOBCR and OF volume. The ZOBCR decreases in relation to recent intake of a meal, probably because stimulated saliva production causes "dilution" of saliva. OF zopiclone concentration appeared unsuitable for estimation of blood zopiclone concentration. Due to long detection time, analysis of zopiclone in OF might be useful to detect non-recent, previous intake.

Long-term Use of Z-Hypnotics and Co-medication with Benzodiazepines and Opioids.

Benzodiazepine-like drugs (z-hypnotics) are the most commonly used drugs for treatment of insomnia in Norway. Z-hypnotics are recommended for short-term treatment not exceeding 4 weeks. We aimed to study the use of z-hypnotics in the adult population in Norway with focus on recurrent use in new users, treatment intensity and co-medication with benzodiazepines and opioids in long-term users. Data were obtained from the Norwegian Prescription Database. New users in 2009 were followed through 2013. Recurrent z-hypnotic use was defined as new fillings at least once in each of the four 365-day follow-up periods. Age groups of 18-39, 40-64 and 65+ years were analysed separately for men and women. In 2013, 354,571 (8.9%) of the population filled at least one prescription of z-hypnotics and the prevalence was relatively stable over time. Among the 92,911 new users of z-hypnotics in 2009, 13,996 (16.8%) received z-hypnotics all four 365-day periods of follow-up. In these long-term recurrent users, the treatment intensity was high already the second year, with mean annual amounts of 199 and 169 DDDs per patient in men and women, respectively. The interquartile differences were greatest in the youngest age group. 27.9% of the long-term recurrent users of z-hypnotics used benzodiazepines the fourth year and 33.9% used opioids. The proportions with co-medication increased with level of z-hypnotic treatment intensity. Overall, many z-hypnotic users had medicines dispensed for longer periods than recommended, and co-medications with drugs that may reinforce the central depressing and intoxicating effects were common.

Can a simple clinical test detect impairment of zopiclone and alcohol? - A randomized controlled trial.

PURPOSE: The risk of traffic accident involvement is increased among patients prescribed the z-hypnotic drug zopiclone. Clinical test observations able to indicate drug impairment are therefore essential. This study compared the findings of a simplified clinical test of impairment (SCTI) with those of a battery of computerized psychomotor tests of impairment (CPTI). METHODS: 16 healthy young male volunteers attended a research unit on four different study days, receiving in randomized order either placebo, zopiclone 5mg, zopiclone 10mg, or alcohol 50g. The SCTI was performed twice and the CPTI was performed three times on each study day, with blood samples being collected for drug analysis. RESULTS: The SCTI (and the CPTI) was able to demonstrate impairment at 1.5h, but no major impairment was found at 7h with the SCTI, after intake of both zopiclone and ethanol. The CPTI detected a significantly higher proportion of impaired observations than the SCTI, both for zopiclone and for ethanol, at all concentration levels. The sensitivity of the clinical tests in detecting blood drug concentrations often associated with impairment, due to zopiclone (above 23ng/ml) and alcohol (above 0.5g/l), was low, revealing 27 per cent and 18 per cent, respectively. The specificity, however, was higher, both for zopiclone (88 per cent) and for alcohol (96 per cent). DISCUSSION: The SCTI may be a useful tool, especially during roadside investigation, when the police are in doubt as to whether the apprehended driver is impaired or not. A subject, who has consumed zopiclone or alcohol, tested with the SCTI, with one or more subtests diverging from a habitual result, is likely to have a blood zopiclone concentration above 23ng/ml or a BAC above 0.5g/l. A negative result, however, is less helpful.

Individual psychomotor impairment in relation to zopiclone and ethanol concentrations in blood--a randomized controlled double-blinded trial.

AIMS: To investigate individual traffic-relevant impairment related to measured blood zopiclone and ethanol concentrations. Also, we aimed to study possible development of acute tolerance. DESIGN: A randomized controlled four-way cross-over double-blind trial. Study drugs were zopiclone 5 or 10 mg, 50 g ethanol or placebo. SETTING: Laboratory study with computerized tests: Connor's Continuous Performance test, Choice Reaction Time and Stockings of Cambridge. Altogether, the tests consisted of 15 test components, representing three levels of behaviour (automotive, control, executive planning), relevant to traffic safety. PARTICIPANTS: Sixteen healthy male volunteers. MEASUREMENTS: Each study day, 10 blood samples were collected from each volunteer. Fifteen psychomotor test components were registered at baseline and a further three times after intake. Impairment was defined as any individual deterioration in performance compared to individual baseline performance. FINDINGS: Blood drug concentrations up to 74 µg/l zopiclone and 0.100% ethanol were measured. We found a clear positive concentration-effect relationship for zopiclone and ethanol for both automotive and control behaviours, and a modest relationship for executive planning behaviour. Significant impairment started to be observed at concentrations above 16 µg/l zopiclone (automotive and control behaviour) and above 0.026% ethanol (automotive behaviour). Acute tolerance was found for both drugs. CONCLUSIONS: The hypnotic, zopiclone, can impair psychomotor performance at blood concentrations as low as 16 µg/l.

Psychomotor performance after intake of zopiclone compared with intake of ethanol: a randomized, controlled, double-blinded trial.

The sleep medicine zopiclone (eszopiclone) is commonly used in most Western countries. The focus on legislation for possible traffic-impairing nonalcohol drugs have caused a need for comparing traffic relevant behavior after intake of commonly used psychoactive drugs to blood alcohol concentrations (BACs). We aimed to compare psychomotor effects at 3 levels of behavior at different blood zopiclone concentrations to effects seen at different BACs. We performed a randomized double-blinded trial on 16 healthy volunteers who received either 10 or 5 mg zopiclone, 50 g ethanol or placebo in a crossover design. The volunteers performed computerized tests at baseline, 1, 3.5, and 6.5 hours after intake, accompanied by blood sampling. Impairment was found at all 3 behavior levels. For zopiclone, impairment was most pronounced at behavior level 1 (automotive behavior); a mean blood zopiclone concentration at 39 µg/L achieved 1 hour after intake of 10 mg zopiclone was accompanied by more impairment than BAC 0.074 %. At behavior levels 2 (control behavior) and 3 (executive planning), the psychomotor impairment accompanying approximately 39 µg/L zopiclone seemed comparable to a BAC of approximately 0.074%. No test components were impaired at 6.5 hours after intake.

Comparison of zopiclone concentrations in oral fluid sampled with Intercept(®) oral specimen collection device and Statsure Saliva Sampler™ and concentrations in blood.

A clinical study of zopiclone was performed using doses of 5 and 10 mg. Samples of oral fluid were collected using the Statsure and Intercept devices, and blood samples were collected simultaneously. Concentrations of zopiclone in samples of oral fluid and blood were determined with liquid chromatography-mass spectrometry, and concentrations in undiluted oral fluid were calculated. The concentrations of zopiclone in oral fluid were generally higher when using the Intercept compared to the Statsure device; the median oral fluid/whole blood concentration ratios were 3.8 (range 1.5-15.9) and 1.9 (range 1.2-4.6), respectively (n = 21). The correlation between zopiclone concentrations in oral fluid collected with the two devices was fairly poor, r(2) = 0.35. The results indicate that the type of sampling device may significantly affect the analytical result for zopiclone in sampled oral fluid.

Impairment related to blood drug concentrations of zopiclone and zolpidem compared to alcohol in apprehended drivers.

BACKGROUND: About 3-7% of the adult population receives prescribed hypnotics. The benzodiazepine-like hypnotics, zopiclone and zolpidem, are the most commonly prescribed and may cause traffic-relevant impairment similar to that found for benzodiazepines. We investigated the relationship between blood zopiclone and zolpidem concentrations and driving impairment, as assessed by the clinical test for impairment. We compared these groups of drivers to a group suspected of alcohol-related impairment. METHODS: Blood samples from suspected impaired drivers during 2000-2007, screened for approximately 25 possible impairing drugs with only one single drug detected, were studied in relation to the assessment of impairment. The 79 zopiclone positive drivers, the 43 zolpidem positive drivers, and the 3480 alcohol positive drivers were divided into groups depending on blood drug concentrations. RESULTS/DISCUSSION: The proportion of drivers judged as impaired tended to increase the higher the blood zopiclone concentrations. Such a positive relationship was not found for zolpidem. For alcohol the proportion of impaired drivers was significantly related to blood alcohol concentrations (BACs). There were few drivers with low zopiclone or zolpidem concentrations included, which may have obscured any positive significant relationship. The percentage of impaired drivers among drivers with blood zopiclone concentrations above 130 microg/l roughly corresponded to the percentage of impaired drivers among drivers with BACs higher than 0.1%.

Road traffic accident risk related to prescriptions of the hypnotics zopiclone, zolpidem, flunitrazepam and nitrazepam.

BACKGROUND: Despite the high prescription rate of benzodiazepine-like hypnotics (z-hypnotics), there is limited information on the road traffic accident risk associated with the use of these drugs. We wanted to investigate whether filling a prescription for zopiclone or zolpidem was associated with increased risk of road traffic accidents at a national population level. Nitrazepam and flunitrazepam were used as comparator drugs. METHOD: All Norwegians 18-69 years (3.1 million) were followed-up from January 2004 until the end of September 2006. Information on prescriptions, road traffic accidents and emigration/death was obtained from three Norwegian population-based registries. The first week after the hypnotics had been dispensed was considered to be the exposure period. Standardized incidence ratios (SIRs) were calculated by comparing the incidence of accidents in the exposed person-time to the incidence of accidents in the unexposed person-time. RESULTS: During exposure, 129 accidents were registered for zopiclone, 21 for zolpidem, 27 for nitrazepam and 18 for flunitrazepam. The SIRs were (SIR for all ages and both sexes combined; 95% CI): z-hypnotics (zopiclone+zolpidem) 2.3; 2.0-2.7, nitrazepam 2.7; 1.8-3.9 and flunitrazepam 4.0; 2.4-6.4. The highest SIRs were found among the youngest users for all hypnotics. CONCLUSIONS: This study found that users of hypnotics had a clearly increased risk of road traffic accidents. The SIR for flunitrazepam was particularly high.