Should pregnant women receive lower or higher medication doses? / Skal gravide ha lavere eller høyere legemiddeldoser?

Choosing appropriate medication doses for pregnant women is a difficult balancing act, as the mother's need for treatment must be weighed against the risk of fetal harm. The latter is frequently considered to be the most pressing concern, with the result that drugs are discontinued or doses reduced. It is perhaps less well known that pregnant women often need higher medication doses than those who are not pregnant.

Overgangen fra digitoksin til digoksin i årene 2011­13.

BACKGROUND: The withdrawal of digitoxin and subsequent substitution with digoxin around 2012 may have led to an increased health risk for patients. The aim of this study was to follow individual patients during the switch. MATERIAL AND METHOD: Serum concentrations of digitoxin and digoxin, measured at the Department of Clinical Pharmacology at St Olavs University Hospital in the period 1 January 2011-31 December 2013 were reviewed. Patients who had switched from digitoxin to digoxin and whose serum concentrations of both drugs had been measured during this period were included. RESULTS: A total of 304 patients, 1686 samples and 1858 serum concentration analyses were included in the study. Therapeutic serum concentrations were measured in 171 patients (56.3 %) before the switch and 176 (57.9 %) after this had taken place. Altogether 108 patients (35.5 %) had therapeutic concentrations both before and after the change. For 58.9 % of the patients, the change resulted in a reduction in serum concentration of digitalis, calculated as digoxin equivalents. The proportion of patients with assumed supratherapeutic concentrations fell from 43.1 % to 33.9 %; however, the proportion of patients with toxic serum concentrations rose from 0.3 % to 3.0 %. INTERPRETATION: Although the switch led to a reduction in dose and serum concentration for many, a significant number of patients may have been put in harm's way.

Correction: Selective serotonin reuptake inhibitors and venlafaxine in pregnancy: Changes in drug disposition.

[This corrects the article DOI: 10.1371/journal.pone.0181082.].

Selective serotonin reuptake inhibitors and venlafaxine in pregnancy: Changes in drug disposition.

BACKGROUND: Pregnancy may cause changes in drug disposition. The clinical consequences may be profound and even counterintuitive; in some cases pregnant women may need more than twice their usual drug dose in order to maintain therapeutic drug levels. For antidepressants, evidence on drug disposition in pregnancy is scarce. The aim of this study was to determine the effects of pregnancy on serum levels of selective serotonin reuptake inhibitors (SSRIs) and venlafaxine in a large and naturalistic patient material, in order to provide tentative dose recommendations for pregnant women. METHODS: Using patient data from two routine therapeutic drug monitoring (TDM) services in Norway with linkage to the national birth registry, dose-adjusted serum drug concentrations of SSRIs and venlafaxine during pregnancy were compared to the women's own baseline (non-pregnant) values, using a linear mixed model. FINDINGS: Overall, the TDM databases contained 196,726 serum concentration measurements from 54,393 women. After data linkage and drug selection (SSRIs or venlafaxine only), we identified 367 analyses obtained from a total of 290 pregnancies in 281 women, and 420 baseline observations from the same women. Serum concentrations in the third trimester were significantly lower than baseline for paroxetine (-51%; 95% confidence interval [CI], -66%, -30%; p<0.001), fluvoxamine (-56%; CI, -75%, -23%; p = 0.004) and citalopram (-24%; CI, -38%, -7%; p = 0,007), and higher than baseline for sertraline (+68%; CI, +37%, +106%; p<0.001). For escitalopram, fluoxetine and venlafaxine concentrations did not change significantly. CONCLUSIONS: For paroxetine and fluvoxamine the pronounced decline in maternal drug serum concentrations in pregnancy may necessitate a dose increase of about 100% during the third trimester in order to maintain stable concentrations. For fluoxetine, venlafaxine, citalopram, escitalopram and sertraline, the present study indicates that dose adjustments are generally not necessary during pregnancy.

Changes in drug disposition of lithium during pregnancy: a retrospective observational study of patient data from two routine therapeutic drug monitoring services in Norway.

OBJECTIVES: Pregnancy may cause changes in drug disposition, dose requirements and clinical response. For lithium, changes in disposition during pregnancy have so far been explored in a single-dose study on 4 participants only. The aim of this study was to determine the effect of pregnancy on serum levels of lithium in a larger patient material in a naturalistic setting. DESIGN: A retrospective observational study of patient data from 2 routine therapeutic drug monitoring services in Norway, linked to the Medical Birth Registry of Norway. SETTING: Norway, October 1999 to December 2011. MEASUREMENTS: Dose-adjusted drug concentrations of lithium during pregnancy were compared with the women's own baseline (non-pregnant) values, using a linear mixed model. RESULTS: Overall, coupling 196 726 serum concentration measurements from 54 393 women to the national birth registry identified 25 serum lithium concentration analyses obtained from a total of 14 pregnancies in 13 women, and 63 baseline analyses from the same women. Dose-adjusted serum concentrations in the third trimester were significantly lower than baseline (-34%; CI -44% to -23%, p<0.001). CONCLUSIONS: Pregnancy causes a clinically relevant decline in maternal lithium serum concentrations. In order to maintain stable lithium concentrations during the third trimester of pregnancy, doses generally need to be increased by 50%. Individual variability in decline implies that lithium levels should be even more closely monitored throughout pregnancy and in the puerperium than in non-pregnant women to ensure adequate dosing.

Novel psychoactive substances. / Nye psykoaktive stoffer.

There has been a significant increase in the number of new intoxicants on the illegal drugs market globally, also in Norway. The substances are given the name NPS: Novel Psychoactive Substances, and are mainly sold over the Internet. Uncertain dosage of potent substances entails a risk of accidental overdose, and therefore serious intoxication and death. In this article we provide an overview of current knowledge with regard to these substances.

Can physical exercise or food deprivation cause release of fat-stored cannabinoids?

The aim of this study was to evaluate whether physical exercise or food deprivation may increase cannabinoid levels in serum or urine in abstinent chronic cannabis users. The study took place in a drug detoxification ward parallel to study participants receiving treatment. Six chronic, daily cannabis users (one female, five males, average age 30.0 years; BMI 20.8) were exposed to a 45-min. moderate-intensity workout and a 24-hr period of food deprivation. Serum samples were drawn prior to and after interventions and analysed for ∆9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-∆9-tetrahydrocannabinol (THCCOOH) by liquid chromatography-tandem mass spectrometry (LCMSMS), and all voided urine was tested for THCCOOH by LCMSMS and normalized to the creatinine levels, yielding ng/mg ratios. There were no major differences in the measured cannabinoid levels in serum or urine before and after physical exercise or food deprivation. We conclude that exercise and/or food deprivation are unlikely to cause sufficient cannabinoid concentration changes to hamper correct interpretations in drug testing programmes.

Comparison of driving simulator performance with real driving after alcohol intake: a randomised, single blind, placebo-controlled, cross-over trial.

The purpose of this study was to establish and validate a driving simulator method for assessing drug effects on driving. To achieve this, we used ethanol as a positive control, and examined whether ethanol affects driving performance in the simulator, and whether these effects are consistent with performance during real driving on a test track, also under the influence of ethanol. Twenty healthy male volunteers underwent a total of six driving trials of 1h duration; three in an instrumented vehicle on a closed-circuit test track that closely resembled rural Norwegian road conditions, and three in the simulator with a driving scenario modelled after the test track. Test subjects were either sober or titrated to blood alcohol concentration (BAC) levels of 0.5g/L and 0.9g/L. The study was conducted in a randomised, cross-over, single-blind fashion, using placebo drinks and placebo pills as confounders. The primary outcome measure was standard deviation of lateral position (SDLP; "weaving"). Eighteen test subjects completed all six driving trials, and complete data were acquired from 18 subjects in the simulator and 10 subjects on the test track, respectively. There was a positive dose-response relationship between higher ethanol concentrations and increases in SDLP in both the simulator and on the test track (p<0.001 for both). In the simulator, this dose-response was evident already after 15min of driving. SDLP values were higher and showed a larger inter-individual variability in the simulator than on the test track. Most subjects displayed a similar relationship between BAC and SDLP in the simulator and on the test track; however, a few subjects showed striking dissimilarities, with very high SDLP values in the simulator. This may reflect the lack of perceived danger in the simulator, causing reckless driving in a few test subjects. Overall, the results suggest that SDLP in the driving simulator is a sensitive measure of ethanol impaired driving. The comparison with real driving implies relative external validity of the simulator.