Bettina Riedel

Preoperative Methionine Loading Enhances Restoration of the Cobalamin-dependent Enzyme Methionine Synthase after Nitrous Oxide Anesthesia

Background:Prolonged exposure to nitrous oxide causes adverse effects mimicking those of cobalamin deficiency. This is explained by irreversible oxidation of cobalamin bound to the enzyme methionine synthase. The inactivation of methionine synthase by nitrous oxide in cultured human fibroblasts is decreased at high concentrations of methionine in culture medium. Methods:We investigated the possible protection against cobalamin inactivation by preoperative methionine loading in patients undergoing nitrous oxide anesthesia. Fourteen patients receiving anesthesia for 75–230 min were included. Half of these patients received a peroral methionine loading dose 2 h before anesthesia. Results:After nitrous oxide exposure, a considerable inactivation of methionine synthase in mononuclear white blood cells was seen in all patients, reaching a nadir after 5–48 h. In the patients not subjected to a methionine load, recovery of enzyme activity was not complete within 7 days. In the patients receiving a methionine load, the kinetics of inactivation of methionine synthase were similar, but the rate and extent of enzyme recovery was higher than in patients not receiving methionine, and in four patients, the enzyme activity even exceeded the preoperative level. The inactivation of methionine synthase was associated with a transient increase in plasma homocysteine, and the homocysteine concentration was still increased (mean 28.7%) 7 days after anesthesia in the patients not receiving methionine. A marked peak in homocysteine concentration was observed immediately after anesthesia in the methionine-loaded patients, but the homocysteine level was still increased (mean of 30.5%) after 7 days. The activity of the other cobalamin-dependent enzyme, meth-ylmalonyl coenzyme A mutase, in the mononuclear white blood cells, and the serum concentration of the cobalamin marker methylmalonic add, were not altered after nitrous oxide anesthesia or methionine loading or both. Conclusions:Our data suggest that short time exposure to nitrous oxide selectively impairs the function of the cobalamin-dependent methionine synthase. Furthermore, preoperative administration of methionine should be considered as a means to counteract adverse effects of nitrous oxide.

Transcobalamin Polymorphism 67A->G, but Not 776C->G, Affects Serum Holotranscobalamin in a Cohort of Healthy Middle-Aged Men and Women

Two polymorphic variants in the gene coding for transcobalamin II (TCN2), TCN2 776C- > G and TCN2 67A- > G, may alter serum holotranscobalamin (holoTC), which in turn may affect cellular uptake of cobalamin (Cbl) and thereby Cbl status indicators. We studied the effects of TCN2 776C- > G and TCN2 67A- > G on blood concentrations of holoTC, Cbl, methylmalonic acid (MMA), and total homocysteine (tHcy) in 2411 individuals (50-64 y) that had been selected on the basis of these TCN2 genotypes from 10601 Norwegian inhabitants. The serum holoTC concentration was lower in TCN2 67AG (55 ± 0.75 pmol/L) and 67GG (48 ± 2.14 pmol/L) than in 67AA (62 ± 0.67 pmol/L) (P < 0.001) but did not differ among TCN2 776C- > G genotypes. The polymorphisms interacted as serum holoTC determinants (P = 0.001) and the presence of TCN2 67AG and GG in strata of 776CC and CG, but not 776GG, increased the risk of having serum holoTC < 45.6 pmol/L [tertile 1 vs. tertiles 2 and 3: OR = 2.5 (95% CI 1.8-3.5) for 67AG; OR = 5.7 (95% CI 3.5-9.1) for 67GG in 776CC; OR = 2.1 (95% CI 1.6-2.9) for 67AG; and OR = 4.5 (95% CI 2.4-8.2) for 67GG in 776CG; all P < 0.001]. Plasma MMA, tHcy, and Cbl were not affected by either polymorphism. In summary, serum holoTC, but not plasma Cbl, MMA, or tHcy, varied according to TCN2 67A- > G genotypes. It remains to be determined whether this polymorphic effect on serum holoTC alters its diagnostic utility as Cbl status indicator.

Clinical characteristics of patients with drug hypersensitivity in Norway: a single‐centre study

Drug hypersensitivity reactions (DHRs) represent an important public health problem. Knowledge of their clinical characteristics will provide improved diagnostic approaches to this topic.

Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero

Importance Strategies to prevent autism in children exposed to antiepileptic drugs (AEDs) during pregnancy are important. Objective To explore whether folic acid supplementation and folate status in pregnancy are associated with reduced risk of autistic traits owing to in utero AED exposure. Design, Setting, and Participants The population-based, prospective Norwegian Mother and Child Cohort Study approached Norwegian-speaking women attending routine ultrasonographic examinations from June 1999 through December 31, 2008 (163 844 of 277 702 women refused). No exclusion criteria were applied beyond language. Questionnaires during and after pregnancy, analysis of blood samples, and linkage to the Medical Birth Registry of Norway were performed. Children aged 18 to 36 months of women with available information on use of AEDs and of folic acid supplementation (n = 104 946) were included in the analysis from March 1, 2016, through June 13, 2017. Exposures Maternal folic acid supplementation 4 weeks before to 12 weeks after conception. Plasma folate concentration was analyzed at gestational weeks 17 to 19. Main Outcomes and Measures Autistic traits were evaluated using the Modified Checklist for Autism in Toddlers and Social Communication Questionnaire. Odds ratios (ORs) for autistic traits in children by maternal use vs nonuse of folic acid supplements were adjusted for maternal health and socioeconomic factors. Folate concentrations and folic acid doses were associated with the degree of autistic traits. Results The overall mean (SD) age of the 104 946 mothers of participating children was 29.8 (4.6) years, with complete information available for analysis in 103 868. Mean (SD) age of women with epilepsy who received AED treatment was 29.4 (4.9); women with epilepsy who did not receive AED treatment, 29.1 (4.9); and without epilepsy, 29.8 (4.6) years. In the 335 children exposed to AEDs, the risk for autistic traits was significantly higher at 18 months of age (adjusted OR [AOR], 5.9; 95% CI, 2.2-15.8) and 36 months of age (AOR, 7.9; 95% CI, 2.5-24.9) when their mothers had not used folic acid supplements compared with children of mothers who had used supplements. Among women without epilepsy, the corresponding risks were lower at 18 months of age (AOR, 1.3; 95% CI, 1.2-1.4) and 36 months of age (AOR, 1.7; 95% CI, 1.5-1.9); among the 389 children of women with untreated epilepsy, the corresponding risks were not significant at 18 months of age (AOR, 1.0; 95% CI, 0.4-3.0) and 36 months of age (AOR, 2.5; 95% CI, 0.4-16.6). Degree of autistic traits was inversely associated with maternal plasma folate concentrations (&bgr; = −0.3; P = .03) and folic acid doses (&bgr; = −0.5; P < .001). Concentrations of AEDs were not associated with the degree of autistic traits. Conclusions and Relevance Risk of autistic traits in children exposed to AEDs in utero may be mitigated by periconceptional folic acid supplementation and folate status. Fertile women using AEDs should take folic acid supplements continuously.

Cross-reactivity of the CEDIA buprenorphine assay in drugs-of-abuse screening: influence of dose and metabolites of opioids

Purpose The cloned enzyme donor immunoassay (CEDIA) for buprenorphine is applied for both urine drugs-of-abuse screening and compliance monitoring. Sensitivity, specificity, and optimal cutoff of this assay have differed between studies. This may indicate that cross-reactivity has to be taken into account during assay evaluation. We therefore investigated the performance of the CEDIA buprenorphine assay for use in our patient population and explored the impact of cross-reactivity on assay accuracy. Methods The CEDIA buprenorphine assay and high-performance liquid chromatography–tandem mass spectrometry were employed to analyze drugs-of-abuse in urine samples from a healthy drug-naïve male volunteer after intake of two tablets of a prescription drug containing 400 mg paracetamol +30 mg codeine phosphate, and in urine samples (n=2,272) from drug-addicted patients. Receiver operating characteristic analyses were performed to express the diagnostic accuracy of the CEDIA buprenorphine assay. Results CEDIA buprenorphine was positive in one urine sample from the drug-naïve person after intake of the prescription drug. Twenty-five (1.1%) of the patient urine samples were positive for buprenorphine by CEDIA, but negative by high-performance liquid chromatography–tandem mass spectrometry. Codeine, morphine, and their respective metabolites were prevalent in samples that were false positive for buprenorphine. The specificity of the CEDIA buprenorphine assay increased to 99.7% when the cutoff was increased from 5 ng/mL to 10 ng/mL. Conclusion Intake of a therapeutic dose of codeine can yield a false-positive CEDIA buprenorphine result. Additive effects from metabolites of codeine contribute to cross-reactivity in concentrations much lower than listed in the manufacturer’s cross-reactivity guide. Raising the cutoff from 5 ng/mL to 10 ng/mL increased the diagnostic accuracy. Clinicians should be informed about the risk of false-positive results with the CEDIA buprenorphine assay.

Verbal abilities in children of mothers with epilepsy: Association to maternal folate status

Objective To examine the effect of maternal folic acid supplementation and maternal plasma folate and antiepileptic drug (AED) concentrations on language delay in AED-exposed children of mothers with epilepsy. Methods Children of mothers with and without epilepsy enrolled from 1999 to 2008 in the Norwegian Mother and Child Cohort study were included. Information on medical history, AED use, and folic acid supplementation during pregnancy was collected from parent-completed questionnaires. Maternal plasma folate and maternal plasma and umbilical cord AED concentrations were measured in blood samples from gestational weeks 17 to 19 and immediately after birth, respectively. Language development at 18 and 36 months was evaluated by the Ages and Stages Questionnaires. Results A total of 335 AED-exposed children of mothers with epilepsy and 104,222 children of mothers without epilepsy were surveyed. For those with no maternal periconceptional folic acid supplementation, the fully adjusted odds ratio (OR) for language delay in AED-exposed children compared to the controls at 18 months was 3.9 (95% confidence interval [CI] 1.9–7.8, p < 0.001) and at 36 months was 4.7 (95% CI 2.0–10.6, p < 0.001). When folic supplementation was used, the corresponding ORs for language delay were 1.7 (95% CI 1.2–2.6, p = 0.01) and 1.7 (95% CI 0.9–3.2, p = 0.13), respectively. The positive effect of folic acid supplement use on language delay in AED-exposed children was significant only when supplement was used in the period from 4 weeks before the pregnancy and until the end of the first trimester. Conclusion Folic acid use early in pregnancy may have a preventive effect on language delay associated with in utero AED exposure.

Conversion factors for assessment of driving impairment after exposure to multiple benzodiazepines/z-hypnotics or opioids

AIMS Norway has introduced legal concentration limits in blood for 28 non-alcohol drugs in driving under the influence cases. As of 2016 this legislation also regulates the assessment of combined effects of multiple benzodiazepines and opioids. We herein describe the employed methodology for the equivalence tables for concentrations of benzodiazepines/z-hypnotics and opioids implemented in the Norwegian Road Traffic Act. METHODS Legislative limits corresponding to impairment at blood alcohol concentrations (BAC) of 0.02%, 0.05% and 0.12% were established for 15 different benzodiazepines and opioids. This was based on a concept of a linear relationship between blood drug concentration and impairment in drug naïve users. Concentration ratios between these drugs were used to establish conversion factors and calculate net impairment using diazepam and morphine equivalents. RESULTS Conversion factors were established for 14 benzodiazepines/z-hypnotics (alprazolam, bromazepam, clobazam, clonazepam, etizolam, flunitrazepam, lorazepam, nitrazepam, nordiazepam, oxazepam, phenazepam, temazepam, zolpidem and zopiclone) and two opioids (methadone and oxycodone). CONCLUSIONS Conversion factors to calculate diazepam and morphine equivalents for benzodiazepines/z-hypnotics and selected opioids, respectively, have been operative in the Norwegian Road Traffic Act as of February 2016. Calculated equivalents can be applied by the courts to meter out sanctions.