Widespread skeptic attitudes among people with epilepsy toward generic antiseizure drugs - A Swedish survey study.

PURPOSE: To explore associations between the characteristics of people with epilepsy (PWE) and their attitudes toward generic substitution of antiseizure drugs (ASDs) in epilepsy. METHODS: This was a cross-sectional survey study directed at adults with epilepsy using selected brand drugs: Keppra®, Lamictal®, Lyrica® or Topimax®. Symptoms of anxiety and depression, sense of self-efficacy, and beliefs about medicines were assessed. Caregivers were asked to answer for persons with intellectual or communicative difficulties. RESULTS: The total response rate was 41% (n = 178). Almost half (46%) of subjects stated that they would oppose generic substitution (Gen-NEG) if suggested by their neurologist, while 71% would worry about adverse effects and/or increased seizure frequency after a putative switch. Age ≥50 increased the odds of being Gen-NEG (adjusted OR: 2.20, 95% CI: 1.18-4.11). Negative associations with both Gen-NEG and worriers were found for education level of high-school diploma or above, employment/studies, and prior experience of generic ASD switch. The proportion of worriers was much higher among caregivers (21/22) compared to subjects with epilepsy (106/156). CONCLUSION: High proportions of PWE express concerns regarding generic substitution of ASDs. The elderly and caregivers seem to express particular concerns. Identifying ways to diminish negative outcomes and worries in connection with a switch is an important future field of research in order to ensure high quality, cost-effective health care for the most vulnerable people in our societies.

Quality of life after switching to generic levetiracetam - A prospective comparative study.

BACKGROUND: Improved quality of life (QoL) is one of the most important objectives in the treatment of epilepsy. Recent prospective, clinical studies proved no significant differences between brand antiepileptic drugs (AEDs) and their generic equivalents in terms of seizure control, pharmacokinetics, or safety. In this study, we focused on possible changes in QoL and adverse events in connection with generic substitution of levetiracetam (LEV). METHODS: This was a prospective, naturalistic, two-cohort, twin-center study. After a baseline period of 10 weeks, outpatients with epilepsy on stable treatment with Keppra® either continued on this brand (reference group, n = 16) or switched to generic LEV (1A Pharma®) (study group, n = 16) for an eight-week study period. The Quality of Life in Epilepsy Inventory-31 (QOLIE-31) and an adverse events' questionnaire were administered at inclusion, after baseline, and at the end of the study period. The study protocol included a close clinical follow-up with repeated LEV serum concentration measurements and nurse-led outpatient visits. RESULTS: Clinically relevant improvements in overall QOLIE-31 scores according to minimally important change (MIC) estimates were seen in both groups. QOLIE-31 subscales in both groups showed significantly less worry about seizures at the end of the study compared to scores at inclusion (study group: p = 0.01; reference group: p = 0.02). No significant deterioration in QoL or adverse events were observed following generic substitution. No switchbacks occurred. CONCLUSIONS: We found reduced seizure worries over time among people with epilepsy allocated to either generic switch or continued treatment with brand LEV. We hypothesize that the nurse-led structured follow-up had an impact on seizure worries and switchback rates because of reduced nocebo effects. Further studies on generic AED substitution, focusing on psychological outcome measures, are warranted to test this supposition.

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.

Hormone replacement therapy with estrogens may reduce lamotrigine serum concentrations: A matched case-control study.

Lamotrigine (LTG) is an antiepileptic drug that is metabolized via glucuronidation. Since the glucuronidizing enzyme is inducible by estrogens, LTG serum concentrations may fall by 50-60% when combined with hormonal contraceptives that contain ethinyl estradiol (EE). Little is known about a possible interaction between estrogens used for hormone replacement therapy (HRT) and LTG, and the few available data are conflicting. Data from serum samples analyzed for LTG were therefore retrieved from a routine therapeutic drug monitoring database. Users of HRT and EE were identified and matched with controls for age and dose. No enzyme-inducing or enzyme-inhibiting comedication was allowed. LTG serum concentration-to-dose ratios (CDRs) were calculated. Case groups and their respective control groups were compared by the Mann-Whitney U test. Seventy-nine HRT users (dose range 1-4 mg/day) and 200 EE users (dose range 20-40 µg/day), as well as 158 and 400 matching controls, respectively, could be included. Both EE users and HRT users had significantly lower mean LTG CDRs than their respective matched controls. These results suggest that HRT with estrogens may reduce serum LTG concentrations.

The steady-state assumption in oscillating and growing systems.

The steady-state assumption, which states that the production and consumption of metabolites inside the cell are balanced, is one of the key aspects that makes an efficient analysis of genome-scale metabolic networks possible. It can be motivated from two different perspectives. In the time-scales perspective, we use the fact that metabolism is much faster than other cellular processes such as gene expression. Hence, the steady-state assumption is derived as a quasi-steady-state approximation of the metabolism that adapts to the changing cellular conditions. In this article we focus on the second perspective, stating that on the long run no metabolite can accumulate or deplete. In contrast to the first perspective it is not immediately clear how this perspective can be captured mathematically and what assumptions are required to obtain the steady-state condition. By presenting a mathematical framework based on the second perspective we demonstrate that the assumption of steady-state also applies to oscillating and growing systems without requiring quasi-steady-state at any time point. However, we also show that the average concentrations may not be compatible with the average fluxes. In summary, we establish a mathematical foundation for the steady-state assumption for long time periods that justifies its successful use in many applications. Furthermore, this mathematical foundation also pinpoints unintuitive effects in the integration of metabolite concentrations using nonlinear constraints into steady-state models for long time periods.

The Impact of Pharmacokinetic Interactions With Eslicarbazepine Acetate Versus Oxcarbazepine and Carbamazepine in Clinical Practice.

BACKGROUND: Eslicarbazepine acetate (ESL) is a new anti-epileptic drug (AED) chemically related to oxcarbazepine (OXC) and carbamazepine (CBZ) and is increasingly used in clinical practice. The purpose of the study was to investigate 2-way pharmacokinetic interactions between ESL and other AEDs as compared to OXC and CBZ. METHODS: Anonymous data regarding age, gender, use of AEDs, daily doses and serum concentration measurements of ESL, OXC, CBZ and lamotrigine (LTG) and other AEDs were retrieved from 2 therapeutic drug monitoring (TDM) databases in Norway. Drugs were categorized according to their known potential for interactions. Concentration/dose (C/D) ratios were calculated. RESULTS: Data from 1100 patients were available. The C/D ratios of ESL and OXC were unchanged in combination with enzyme-inducing AEDs or valproate (VPA). The C/D ratio of CBZ decreased by 40% and 22% in combination with other enzyme-inducing AEDs or VPA, respectively, pointing to an increased clearance. ESL demonstrated no significant enzyme-inducing effect on LTG metabolism although there was a 20% and 34% decrease in the C/D ratio of LTG in combination with OXC and CBZ, respectively. CONCLUSIONS: Possible pharmacokinetic interactions have been studied for ESL as compared to OXC and CBZ. The pharmacokinetics of ESL is not affected by enzyme-inducing AEDs or VPA and does not affect the metabolism of LTG in contrast to OXC and CBZ. The study demonstrates the value of using TDM databases to explore the potential for pharmacokinetic interactions of new AEDs.

Hierarchical decomposition of metabolic networks using k-modules.

The optimal solutions obtained by flux balance analysis (FBA) are typically not unique. Flux modules have recently been shown to be a very useful tool to simplify and decompose the space of FBA-optimal solutions. Since yield-maximization is sometimes not the primary objective encountered in vivo, we are also interested in understanding the space of sub-optimal solutions. Unfortunately, the flux modules are too restrictive and not suited for this task. We present a generalization, called k-module, which compensates the limited applicability of flux modules to the space of sub-optimal solutions. Intuitively, a k-module is a sub-network with low connectivity to the rest of the network. Recursive application of k-modules yields a hierarchical decomposition of the metabolic network, which is also known as branch decomposition in matroid theory. In particular, decompositions computed by existing methods, like the null-space-based approach, introduced by Poolman et al. [(2007) J. Theor. Biol. 249: , 691-705] can be interpreted as branch decompositions. With k-modules we can now compare alternative decompositions of metabolic networks to the classical sub-systems of glycolysis, tricarboxylic acid (TCA) cycle, etc. They can be used to speed up algorithmic problems [theoretically shown for elementary flux modes (EFM) enumeration] and have the potential to present computational solutions in a more intuitive way independently from the classical sub-systems.

Nonadherence to treatment causing acute hospitalizations in people with epilepsy: an observational, prospective study.

The aim was to assess the clinical relevance of antiepileptic drug (AED) nonadherence by means of therapeutic drug concentration monitoring (TDM). Two hundred eighty-two consecutive patients with epilepsy acutely admitted to hospital for seizures were included. Nonadherence was defined as having a serum concentration/dose ratio at admission of <75% of the patient's own control value (probable nonadherence: 50-75%; definite: <50%). Nonadherence was identified in 39% of patients (definite 24%; probable 15%). It was significantly more common in patients with generalized seizures compared to those with focal onset seizures, and in patients <30 years compared to older patients. When specifically asked, 44% of nonadherent patients claimed regular intake. Nonadherence is a major cause of seizure breakthrough in patients with epilepsy, particularly in young adults. Many patients seem to be unaware of missed drug intake. Prompt measurements of AED serum concentrations should be available as part of the emergency care for patients acutely hospitalized for seizures to permit this issue to be thoroughly addressed prior to discharge.

Cognitive Safety is Largely Ignored in Clinical Drug Trials: A Study of Registered Study Protocols.

BACKGROUND AND OBJECTIVE: The number of reports on suspected drug-induced memory impairment submitted to the US Food and Drug Administration increased 30-fold from 2000 to 2022. Drugs are the most common cause of reversible dementia. However, there is very little research on drug-induced cognitive impairment. The aim of this study was to investigate if and how an assessment of cognitive safety was included in recent, registered, controlled, clinical drug trials. METHODS: The clinical trials registry ( www. CLINICALTRIALS: gov ) was searched for randomized controlled clinical trials with available study protocols. After excluding irrelevant trials such as surgical procedures, local or short-term treatment, and dietary supplements, 803 trials were included in this study. The protocols were manually reviewed for information on if, and how, cognitive safety had been assessed. Trial drugs were categorized into those targeting the central nervous system or not, as well as older and newer drugs. Methods used for the assessment of cognitive function were categorized into questionnaires, screening instruments, and neuropsychological tests. If the trial results were published, we examined whether the publication contained any data on cognitive safety that had emerged from the trial. RESULTS: The start dates of the screened trials ranged from 31 July, 2009, to 4 April, 2021. Out of the 803 trials, 52 (6.5%) actively assessed cognitive safety. The remaining trials relied solely on spontaneous reporting. Of 429 trials studying a new drug, 32 (7.5%) actively assessed cognitive safety. One hundred and fifty-eight trials examined drugs intended to, or known to have, pharmacological effects on the central nervous system. Of these, 21 (13.5%) assessed cognitive safety. Most of the trials that assessed cognitive safety used either crude screening tools or questionnaires. CONCLUSIONS: Cognitive safety is largely ignored by recent controlled clinical trials. This applies even to trials assessing new drugs and trials assessing central nervous system drugs. There is an urgent need for drug manufacturers, regulatory authorities, and the medical profession to address the cognitive safety of drugs.

Is dietary caffeine involved in seizure precipitation?

Caffeine acts as a central nervous stimulant by blocking A1 and A2A adenosine receptors. Its effect on seizures is complex. Animal studies and case reports indicate that acute caffeine exposure may induce seizures, whereas chronic exposure might have an opposite effect. Patients acutely hospitalized for seizures (n = 174) were asked for their consumption of caffeinated beverages 24 h prior to admission as well as their habitual caffeine intake. Twenty-four-hour caffeine consumption was also recorded in a later telephone interview on a seizure-free day (n = 154). Thus, the patients served as their own controls. Categorized data were analyzed using the Wilcoxon's signed-ranks test. No difference was found between the intake of caffeine 24 h prior to the seizure and the habitual consumption (p = 0.37) or the consumption on a seizure-free day (p = 0.13). Thus, caffeine does not appear to be a common seizure precipitant.

Relating fatty acid composition in human fingertip blood to age, gender, nationality and n-3 supplementation in the Scandinavian population.

This study investigated data obtained from whole blood fatty acid (FA) composition of 3476 Norwegian and Swedish individuals, which provided background information including age, gender, nationality and self-motivated n-3 supplement consumption. The aim of this paper was to statistically relate this background information on the subjects to their whole blood FA profile, focusing mainly on the n-3 polyunsaturated FA (PUFA). Results showed that age had significant effects on the content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in blood lipids for the Norwegian individuals, while n-3 PUFA supplementation had a positive effect on EPA and DHA content in whole blood for the investigated population. Gender differences were also found for individual FA. A correlation also exists with previous studies on the FA profiling of blood lipids, further validating the test procedure.

Benzoylated uronic acid building blocks and synthesis of N-uronate conjugates of lamotrigine.

A chemoenzymatic approach towards benzoylated uronic acid building blocks has been investigated starting with benzoylated hexapyranosides using regioselective C-6 enzymatic hydrolysis as the key step. Two of the building blocks were reacted with the antiepileptic drug lamotrigine. Glucuronidation of lamotrigine using methyl (2,3,4-tri-O-benzoyl-α-D-glycopyranosyl bromide)uronate proceeded to give the N2-conjugate. However, lamotrigine-N2-glucuronide was most efficiently synthesised from methyl (2,3,4-tri-O-acetyl-α-D-glucopyranosyl bromide)uronate. Employing nitromethane as solvent with CdCO(3) as a base lamotrigine-N2 glucuronide was prepared in a high yield (41%). Also methyl (2,3-di-O-benzoyl-4-deoxy-4-fluoro-α-D-glucosyl bromide)uronate underwent N-glucuronidation, but the product was unstable, eliminating hydrogen fluoride to give the corresponding enoate conjugate.

Expression of UDP-glucuronosyltransferase 1A4 in human placenta at term.

The placenta contains a large variety of metabolizing enzymes, among them UDP-glucuronosyltransferase (UGT). Several UGT2B isozymes have so far been detected in human placenta, but little is known on placental expression of UGT1A isozymes. The antiepileptic drug lamotrigine (LTG) is a UGT1A4-substrate, and its serum concentration falls by over 50% during pregnancy, leading to impaired seizure control. The placenta may be involved in this. Microsomes from term placentas of 4 LTG-users and 10 healthy control subjects were prepared. Western blot analysis detected UGT1A proteins in all placentas. The presence of UGT1A4 in placenta from LTG users was confirmed with UGT1A4 commercial standard and a specific UGT1A4 primary antibody. Since LTG is primarily metabolized by UGT1A4 and this isozyme is shown to be present in placenta at term, it may be hypothesized that the placenta is involved in the fall of LTG serum concentrations during pregnancy.

[Do urine tests for drugs of abuse cover the substances of interest?]. / Dekker rusmiddeltester i urin de aktuelle misbruksstoffene?

BACKGROUND: In Norway several hundred thousand urine samples are analysed annually to reveal substance abuse. Our laboratory analyses substances with a potential of abuse in about 60,000 urine specimens annually. We wished to find out if our standard panel of analyses can detect most of these substances. MATERIAL AND METHODS: In summer 2009, our department analysed ten substances that were not included in our standard test panel in all urine specimens received on an arbitrarily chosen weekday during five consecutive weeks. In addition, four other laboratories each sent 250 urine specimens to us to be analysed for the same ten substances. RESULTS: 1 854 urine specimens were analysed in total. Substances that were not covered by our standard test panel were detected in 123 samples (6.6 %): i.e. Pregabalin in 83 (4.5 %), methylphenidate in 33 (1.8 %), tramadol in four (0.2 %) and lorazepam in one (0.05 %) sample. The percentage of samples containing substances of abuse not covered by our standard test panel was: 20.8 % in Bergen, 9.8 % in Kristiansand, 8.0 % in Tromsø, 2.8 % in Oslo and 2.3 % in Trondheim. INTERPRETATION: This study indicates that most drugs of abuse are detected by common routine urine analyses. Laboratories that offer analyses of drugs of abuse in urine should have methods available to detect pregabalin and methylphenidate in addition to or included in the standard panel.

Rash during lamotrigine treatment is not always drug hypersensitivity: A retrospective cohort study among children and adults.

Purpose Cutaneous adverse drug reactions (cADRs) are a major cause of lamotrigine (LTG) discontinuation. Remarkable variation in their reported incidence suggests confounders and diverse terms and definitions. The aim of this study was to identify immunological cADRs and to throw light on classification and differential diagnoses in children and adults. Methods Hospital records of 2683 patients with epilepsy (1897 adults, 786 children) were retrospectively screened. Of these, 403 patients (236 adults, 167 children) with first time exposure to LTG were reviewed. Skin reactions were categorized into possible or probable cADRs due to LTG hypersensitivity, and other skin reactions (OSRs) unlikely to be caused by this mechanism. Results 29 of 403 patients (7.2%) reported emergent skin symptoms within 3 months of treatment with LTG of which 20 (5%: 5.9% adults, 3.6% children) were categorized as possible or probable cADRs. Concomitant infection appeared to be present in several cases, particularly in children. OSRs were found in 4.2% of the children using LTG, compared to 0.8% of the adults (p = 0.04). Conclusions Rash during the early phase of LTG treatment is not always drug hypersensitivity. Whenever skin symptoms occur, other potential causes should receive attention to avoid needless discontinuation, particularly in children. However, when early symptoms and signs of severe cADRs are suspected, LTG should promptly be discontinued.

[Dosing of digitoxin in clinical practice]. / Dosering av digitoksin i klinisk praksis.

BACKGROUND: In 2007, new Norwegian guidelines suggested that serum concentrations of digitoxin should be in the interval 8 - 15 nmol/l, which is about 50 % lower than previous recommendations. MATERIAL AND METHODS: We studied trends in dosing and serum concentrations of digitoxin in the period 2000 - 08, based on 13 054 serum samples sent to our laboratory for analysis in that period. RESULTS: The median serum concentration of digitoxin was stable until the end of 2006 (at about 25 nmol/l); then it gradually decreased from 2007 until the end of 2008 (to 19 nmol/l). The mean daily dose decreased from 66 microg to 56 microg in the study period. At a given dose, patients above 85 years of age had serum concentrations that were almost twice as high as those for patients younger than 55 years. This age effect was particularly pronounced from 65 years. INTERPRETATION: Serum concentrations of digitoxin have gradually decreased after 2007, but are often higher than the new reference range. To obtain serum concentrations within the new reference interval, doses at least as low as those currently recommended should be used, particularly in the oldest patients.