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Progress in Neuro-psychopharmacology &... May 2024Increasing evidence suggests that the physiological changes of pregnancy may impact pharmacokinetics of antiseizure medications (ASM), and this may affect treatment... (Review)
Review
OBJECTIVE
Increasing evidence suggests that the physiological changes of pregnancy may impact pharmacokinetics of antiseizure medications (ASM), and this may affect treatment outcomes. The aim of this study was to quantify the pregnancy impact on the ASM pharmacokinetics.
METHODS
A systematic literature search was conducted in PubMed/EMBASE in November 2022 and updated in August 2023 for studies comparing levels of ASM in the same individuals during pregnancy and in the preconception/postpartum period. Alteration ratios between the 3rd trimester and baseline were estimated. We also performed a random-effects meta-analysis calculating between-timepoint differences in mean differences (MDs) and 95% confidence intervals (95%CIs) for dose-adjusted plasma concentrations (C/D ratios). Study quality was assessed using the ClinPK guidelines.
RESULTS
A total of 65 studies investigating 15 ASMs in 674 pregnancies were included. The largest differences were reported for lamotrigine, oxcarbazepine and levetiracetam (alteration ratio 0.42, range 0.07-2.45, 0.42, range 0.08-0.82 and 0.52, range 0.04-2.77 respectively): accordingly, C/D levels were lower in the 3rd trimester for lamotrigine, levetiracetam and the main oxcarbazepine metabolite monohydroxycarbazepine (MD = -12.33 × 10, 95%CI = -16.08 to -8.58 × 10 (μg/mL)/(mg/day), p < 0.001, MD = -7.16 (μg/mL)/(mg/day), 95%CI = -9.96 to -4.36, p < 0.001, and MD = -4.87 (μg/mL)/(mg/day), 95%CI = -9.39 to -0.35, p = 0.035, respectively), but not for oxcarbazepine (MD = 1.16 × 10 (μg/mL)/(mg/day), 95%CI = -2.55 to 0.24 × 10, p = 0.10). The quality of studies was acceptable with an average rating score of 11.5.
CONCLUSIONS
Data for lamotrigine, oxcarbazepine (and monohydroxycarbazepine) and levetiracetam demonstrate major changes in pharmacokinetics during pregnancy, suggesting the importance of therapeutic drug monitoring to assist clinicians in optimizing treatment outcomes.
PubMed: 38762161
DOI: 10.1016/j.pnpbp.2024.111030 -
International Journal of Molecular... Apr 2024This study presents the initial attempt at introducing a magnetic molecularly imprinted polymer (MIP) designed specifically for lamotrigine with the purpose of...
This study presents the initial attempt at introducing a magnetic molecularly imprinted polymer (MIP) designed specifically for lamotrigine with the purpose of functioning as a drug carrier. First, the composition of the magnetic polymer underwent optimization based on bulk polymer adsorption studies and theoretical analyses. The magnetic MIP was synthesized from itaconic acid and ethylene glycol dimethacrylate exhibiting a drug loading capacity of 3.4 ± 0.9 μg g. Structural characterization was performed using powder X-ray diffraction analysis, vibrating sample magnetometry, and Fourier transform infrared spectroscopy. The resulting MIP demonstrated controlled drug released characteristics without a burst effect in the phospahe buffer saline at pH 5 and 8. These findings hold promise for the potential nasal administration of lamotrigine in future applications.
Topics: Lamotrigine; Drug Carriers; Molecularly Imprinted Polymers; Molecular Imprinting; Spectroscopy, Fourier Transform Infrared; Drug Liberation; X-Ray Diffraction; Adsorption; Hydrogen-Ion Concentration
PubMed: 38731823
DOI: 10.3390/ijms25094605 -
Frontiers in Neurology 2024The risk of sudden unexpected death in epilepsy (SUDEP) increases with the frequency of generalized tonic-clonic seizures. Carbamazepine (CBZ) and lamotrigine (LTG) have... (Review)
Review
The risk of sudden unexpected death in epilepsy (SUDEP) increases with the frequency of generalized tonic-clonic seizures. Carbamazepine (CBZ) and lamotrigine (LTG) have been suggested to increase the risk. However, the prevailing viewpoint is that the choice of antiseizure medication (ASM) does not influence the occurrence. We have explored the approach to addressing this question in relevant studies to evaluate the validity of the conclusions reached. A systematic search was performed in PubMed to identify all controlled studies on SUDEP risk in individuals on CBZ or LTG. Studies were categorized according to whether idiopathic generalized epilepsy (IGE) or females were considered separately, and whether data were adjusted for seizure frequency. Eight studies on CBZ and six studies on LTG were identified. For CBZ, one study showed a significantly increased risk of SUDEP without adjustment for seizure frequency. Another study found significantly increased risk after statistical adjustment for seizure frequency and one study found increased risk with high blood levels. Five other studies found no increase in risk. For LTG, one study showed a significantly increased risk in patients with IGE as opposed to focal epilepsy, and another study showed a significantly increased risk in females. None of the subsequent studies on LTG and none of the studies on CBZ considered females with IGE separately. Taken together the available studies suggest that LTG, and possibly CBZ, may increase occurrence of SUDEP when used in females with IGE. Additional studies with sub-group analysis of females with IGE are needed.
PubMed: 38694773
DOI: 10.3389/fneur.2024.1385468 -
Pharmaceuticals (Basel, Switzerland) Mar 2024The antiepileptic drug lamotrigine (LTG) shows high pharmacokinetic variability due to genotype influence and concomitant use of glucuronidation inducers and inhibitors,...
BACKGROUND
The antiepileptic drug lamotrigine (LTG) shows high pharmacokinetic variability due to genotype influence and concomitant use of glucuronidation inducers and inhibitors, both of which may be frequently taken by elderly patients. Our goal was to develop a reliable quantification method for lamotrigine and its main glucuronide metabolite lamotrigine-N2-glucuronide (LTG-N2-GLU) in dried blood spots (DBS) to enable routine therapeutic drug monitoring and to identify altered metabolic activity for early detection of drug interactions possibly leading to suboptimal drug response.
RESULTS
The analytical method was validated in terms of selectivity, accuracy, precision, matrix effects, haematocrit, blood spot volume influence, and stability. It was applied to a clinical study, and the DBS results were compared to the concentrations determined in plasma samples. A good correlation was established for both analytes in DBS and plasma samples, taking into account the haematocrit and blood cell-to-plasma partition coefficients. It was demonstrated that the method is suitable for the determination of the metabolite-to-parent ratio to reveal the metabolic status of individual patients.
CONCLUSIONS
The clinical validation performed confirmed that the DBS technique is a reliable alternative for plasma lamotrigine and its glucuronide determination.
PubMed: 38675410
DOI: 10.3390/ph17040449 -
Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice.Cell Reports. Medicine Apr 2024Thalamocortical (TC) circuits are essential for sensory information processing. Clinical and preclinical studies of autism spectrum disorders (ASDs) have highlighted...
Thalamocortical (TC) circuits are essential for sensory information processing. Clinical and preclinical studies of autism spectrum disorders (ASDs) have highlighted abnormal thalamic development and TC circuit dysfunction. However, mechanistic understanding of how TC dysfunction contributes to behavioral abnormalities in ASDs is limited. Here, our study on a Shank3 mouse model of ASD reveals TC neuron hyperexcitability with excessive burst firing and a temporal mismatch relationship with slow cortical rhythms during sleep. These TC electrophysiological alterations and the consequent sensory hypersensitivity and sleep fragmentation in Shank3 mutant mice are causally linked to HCN2 channelopathy. Restoring HCN2 function early in postnatal development via a viral approach or lamotrigine (LTG) ameliorates sensory and sleep problems. A retrospective case series also supports beneficial effects of LTG treatment on sensory behavior in ASD patients. Our study identifies a clinically relevant circuit mechanism and proposes a targeted molecular intervention for ASD-related behavioral impairments.
PubMed: 38670100
DOI: 10.1016/j.xcrm.2024.101534 -
Epilepsy & Behavior : E&B Apr 2024Revision of therapy is fundamental in epilepsy care, since only half of patients achieve seizure freedom and tolerate the first antiseizure medication (ASM). We studied...
OBJECTIVE
Revision of therapy is fundamental in epilepsy care, since only half of patients achieve seizure freedom and tolerate the first antiseizure medication (ASM). We studied the selection and retention of second antiseizure medication monotherapy in adults who discontinued treatment with one of the three most frequently prescribed first ASMs, and the impact of age or brain comorbidities.
METHODS
Using Swedish national registers, we conducted a population-based, retrospective cohort study from 2007 to 2019 on patients age ≥ 30 at the epilepsy diagnosis that had switched to a second monotherapy after the three most common initial monotherapies (n = 7369). Retention rates (RR) were estimated via Kaplan-Meier. Discontinuation of the second monotherapy was defined as 12-month prescription gap or initiation of a third ASM. Analyses were stratified by sex, age, and presence of stroke or dementia.
RESULTS
The three most commonly prescribed second ASMs were carbamazepine, levetiracetam, and lamotrigine. The 1-year retention rate was 63-76% in all patients. For groups with stroke or dementia, the maximal 1-year RRs were 77% and 87%, respectively. After five years, retention rates ranged from 12% to 39%. There were no major differences between ASMs, apart from in patients discontinuing carbamazepine, where lamotrigine had a superior retention compared to levetiracetam as second monotherapy.
SIGNIFICANCE
The three most often prescribed second ASMs seem to be suitable treatment options according to present guidelines. The second ASMs' retention rates were initially high in all studied patient groups but dropped to approximately the expected proportion of second monotherapy responders over the next five years. This suggests that therapy revision could be expedited.
PubMed: 38669974
DOI: 10.1016/j.yebeh.2024.109792 -
Cureus Mar 2024Recurrent painful ophthalmoplegic neuropathy (RPON) is a rare neurological disorder characterized by recurring ipsilateral headache and paresis of one or more ocular...
Recurrent painful ophthalmoplegic neuropathy (RPON) is a rare neurological disorder characterized by recurring ipsilateral headache and paresis of one or more ocular motor nerves. We report the case of a 56-year-old woman with systemic lupus erythematosus (SLE) and hypertension, who presented with severe recurring headaches, nausea, and vomiting. Initially misdiagnosed with cerebral venous sinus thrombosis, her symptoms persisted despite anticoagulant therapy. Further evaluation led to the diagnosis of RPON. Management included intravenous analgesia, hydration, and indomethacin for pain relief. Persistent headache episodes necessitated the introduction of lamotrigine, resulting in significant symptom improvement. However, discontinuation of lamotrigine led to a recurrence of symptoms, which resolved upon resuming the medication. This case contributes to the limited RPON literature, providing insights into its diagnosis and management, with the goal of enhancing awareness and improving patient care.
PubMed: 38665741
DOI: 10.7759/cureus.56924 -
Frontiers in Neurology 2024Poststroke seizure is a potential complication of stroke, which is the most frequent acute symptomatic seizure in adults. Patients with stroke may present with an... (Review)
Review
Poststroke seizure is a potential complication of stroke, which is the most frequent acute symptomatic seizure in adults. Patients with stroke may present with an abnormal or aggressive behavior accompanied by altered mental status and symptoms, such as hemiparesis, dysarthria, and sensory deficits. Although stroke manifestations that mimic seizures are rare, diagnosing poststroke seizures can be challenging when accompanied with negative postictal symptoms. Differential diagnoses of poststroke seizures include movement disorders, syncope, and functional (nonepileptic) seizures, which may present with symptoms similar to seizures. Furthermore, it is important to determine whether poststroke seizures occur early or late. Seizures occurring within and after 7 d of stroke onset were classified as early and late seizures, respectively. Early seizures have the same clinical course as acute symptomatic seizures; they rarely recur or require long-term antiseizure medication. Conversely, late seizures are associated with a risk of recurrence similar to that of unprovoked seizures in a patient with a focal lesion, thereby requiring long-term administration of antiseizure medication. After diagnosis, concerns regarding treatment strategies, treatment duration, and administration of primary and secondary prophylaxis often arise. Antiseizure medication decisions for the initiation of short-term primary and long-term secondary seizure prophylaxis should be considered for patients with stroke. Antiseizure drugs such as lamotrigine, carbamazepine, lacosamide, levetiracetam, phenytoin, and valproate may be administered. Poststroke seizures should be diagnosed systematically through history with differential diagnosis; in addition, classifying them as early or late seizures can help to determine treatment strategies.
PubMed: 38660095
DOI: 10.3389/fneur.2024.1337960 -
Cureus Mar 2024Nystagmus is a well-known side effect of antiseizure medicines (ASMs), but it is often underestimated and overlooked. Here, we describe a case in which nystagmus during...
Nystagmus is a well-known side effect of antiseizure medicines (ASMs), but it is often underestimated and overlooked. Here, we describe a case in which nystagmus during eye closure was identified early using routine electroencephalography (EEG). A 34-year-old man developed focal epilepsy after head trauma at the age of 25 years. The patient was treated with carbamazepine but liver dysfunction was observed; therefore, treatment was attempted with lacosamide (LCM) and lamotrigine. With an increase in the LCM dose, steep potential changes suggestive of horizontal nystagmus were observed in the electrooculogram, F7, and F8 on EEG, and the patient complained of eye shaking during eye closure. These symptoms and EEG findings improved with LCM dose reduction. If the presence of nystagmus is identified on EEG coincidentally and a patient's subjective symptoms with ASM are confirmed, it is advisable to taper and/or discontinue the causative agent.
PubMed: 38659559
DOI: 10.7759/cureus.56884 -
Addiction & Health Feb 2024The likelihood of substance dependency in offspring is increased in cases when there is a family history of drug or alcohol use. Mothering is limited by maternal... (Review)
Review
The likelihood of substance dependency in offspring is increased in cases when there is a family history of drug or alcohol use. Mothering is limited by maternal addiction because of the separation. Maternal separation (MS) leads to the development of behavioural and neuropsychiatric issues in the future. Despite the importance of this issue, empirical investigations of the influences of maternal substance use and separation on substance use problems in offspring are limited, and studies that consider both effects are rare. This study aims to review a few studies on the mechanisms, treatments, genetics, epigenetics, molecular and psychological alterations, and neuroanatomical regions involved in the dependence of offspring who underwent maternal addiction and separation. The PubMed database was used. A total of 95 articles were found, including the most related ones in the review. The brain's lateral paragigantocellularis (LPGi), nucleus accumbens (NAc), caudate-putamen (CPu), prefrontal cortex (PFC), and hippocampus, can be affected by MS. Dopamine receptor subtype genes, alcohol biomarker minor allele, and preproenkephalin mRNA may be affected by alcohol or substance use disorders. After early-life adversity, histone acetylation in the hippocampus may be linked to brain-derived neurotrophic factor (BDNF) gene epigenetics and glucocorticoid receptors (GRs). The adverse early-life experiences differ in offspring›s genders and rewire the brain›s dopamine and endocannabinoid circuits, making offspring more susceptible to dependence. Related psychological factors rooted in early-life stress (ELS) and parental substance use disorder (SUD). Treatments include antidepressants, histone deacetylase inhibitors, lamotrigine, ketamine, choline, modafinil, methadone, dopamine, cannabinoid 1 receptor agonists/antagonists, vitamins, oxytocin, tetrahydrocannabinol, SR141716A, and dronabinol. Finally, the study emphasizes the need for multifaceted strategies to prevent these outcomes.
PubMed: 38651025
DOI: 10.34172/ahj.2024.1478