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Biomedicine & Pharmacotherapy =... Jul 2022To analyse the concentrations of lamotrigine in maternal serum, colostrum, and serum of breastfed newborns, and to evaluate the effect of comedication with...
OBJECTIVE
To analyse the concentrations of lamotrigine in maternal serum, colostrum, and serum of breastfed newborns, and to evaluate the effect of comedication with enzyme-inducing antiseizure medication and valproic acid.
METHODS
This cohort study collected data from 158 women and 143 breastfed newborns. Maternal serum, milk (i.e., colostrum), and newborn serum samples were collected between the 2nd and 5th postnatal days, and lamotrigine concentrations were measured by high-performance liquid chromatography.
RESULTS
The median lamotrigine concentrations were 2.7 mg/L in maternal serum, 1.4 mg/L in milk, and 1.7 mg/L in newborn serum. The median milk/maternal serum concentration ratio was 0.60, the median newborn/maternal serum concentration ratio was also 0.60, and the median newborn serum/milk concentration ratio was 1.00. A significant correlation was observed between milk and maternal serum concentrations and between newborn serum and milk concentrations, maternal serum concentrations, maternal daily dose, and dose related to maternal body weight.
CONCLUSIONS
Exposure to lamotrigine in breastfed newborns is lower than exposure during pregnancy. However, by the same dose by the same mother, lamotrigine concentrations in both maternal serum and milk increase significantly after delivery. This finding, together with the immature function of eliminating enzymes in newborns, may be the reason for reaching concentrations in the reference range used for the general epileptic population in breastfed newborns. Therapeutic monitoring of breastfed newborns serum concentrations of lamotrigine is not mandatory; however, if signs of possible adverse events are noted, newborn serum concentrations should be analysed.
Topics: Anticonvulsants; Breast Feeding; Cohort Studies; Colostrum; Female; Humans; Infant, Newborn; Lamotrigine; Milk, Human; Mothers; Postpartum Period; Pregnancy
PubMed: 35617804
DOI: 10.1016/j.biopha.2022.113167 -
F1000Research 2021Women with epilepsy face difficult choices whether to continue antiepileptic drug treatment during pregnancy, as uncontrolled seizures carry great risk to mother and...
Women with epilepsy face difficult choices whether to continue antiepileptic drug treatment during pregnancy, as uncontrolled seizures carry great risk to mother and fetus but continuing treatment may have adverse effects on baby's development. This study aimed at evaluating antiepileptic drug entry into developing brain. Anaesthetised pregnant, non-pregnant adult females, postnatal and fetal rats were injected intraperitoneally with different doses, single or in combinations, of valproate and lamotrigine, within clinical range. Injectate included H-labelled drug. After 30min, CSF, blood and brain samples were obtained; radioactivity measured using liquid scintillation counting. Some animals were also exposed to valproate in feed throughout pregnancy and into neonatal period. Drug levels measured by liquid chromatography coupled to mass spectrometry (LC-MS). Results given as CSF or tissue/plasma% as index of drug entry. Entry of valproate into brain and CSF was higher at E19 and P4 compared to adult and was dose-dependent except at E19; placental transfer increased significantly at highest dose of 100mg/kg. Lamotrigine entry into the brain was dose dependent only at E19. Chronic valproate treatment, or combination of valproate and lamotrigine had little effect on either drug entry, except for reduced valproate brain entry in adult brain with chronic treatment. Placental transfer decreased significantly after chronic valproate treatment. LC-MS measurement of valproate in adults confirmed that rat plasma values were within the clinical range and CSF/plasma and brain/plasma ratios for LC-MS and H-valproate were similar. Results suggest that entry of valproate may be higher in developing brain, the capacity of barrier mechanism is mostly unaffected by doses within the clinical range, with or without addition of lamotrigine. Chronic valproate exposure may result in upregulation in cellular mechanisms restricting its entry into the brain. Entry of lamotrigine was little different at different ages and was not dose dependent.
Topics: Animals; Anticonvulsants; Brain; Female; Lamotrigine; Placenta; Pregnancy; Rats; Valproic Acid
PubMed: 34249340
DOI: 10.12688/f1000research.52607.2 -
Neurology Jan 2023Early life epilepsies are common and often debilitating, but no evidence-based management guidelines exist outside of those for infantile spasms. We conducted a...
BACKGROUND AND OBJECTIVES
Early life epilepsies are common and often debilitating, but no evidence-based management guidelines exist outside of those for infantile spasms. We conducted a systematic review of the effectiveness and harms of pharmacologic and dietary treatments for epilepsy in children aged 1-36 months without infantile spasms.
METHODS
We searched EMBASE, MEDLINE, PubMed, and the Cochrane Library for studies published from January 1, 1999, to August 19, 2021. Using prespecified criteria, we identified studies reporting data on children aged 1-36 months receiving pharmacologic or dietary treatments for epilepsy. We did not require that studies report etiology-specific data. We excluded studies of neonates, infantile spasms, and status epilepticus. We included studies administering 1 of 29 pharmacologic treatments and/or 1 of 5 dietary treatments reporting effectiveness outcomes at ≥ 12 weeks. We reviewed the full text to find any subgroup analyses of children aged 1-36 months.
RESULTS
Twenty-three studies met inclusion criteria (6 randomized studies, 2 nonrandomized comparative studies, and 15 prestudies/poststudies). All conclusions were rated low strength of evidence. Levetiracetam leads to seizure freedom in some infants (32% and 66% in studies reporting seizure freedom), but data on 6 other medications were insufficient to permit conclusions about effectiveness (topiramate, lamotrigine, phenytoin, vigabatrin, rufinamide, and stiripentol). Three medications (levetiracetam, topiramate, and lamotrigine) were rarely discontinued because of adverse effects, and severe events were rare. For diets, the ketogenic diet leads to seizure freedom in some infants (rates 12%-37%), and both the ketogenic diet and modified Atkins diet reduce average seizure frequency, but reductions are greater with the ketogenic diet (1 RCT reported a 71% frequency reduction at 6 months for ketogenic diet vs only a 28% reduction for the modified Atkins diet). Dietary harms were not well-reported.
DISCUSSION
Little high-quality evidence exists on pharmacologic and dietary treatments for early life epilepsies. Future research should isolate how treatments contribute to outcomes, conduct etiology-specific analyses, and report patient-centered outcomes such as hospitalization, neurodevelopment, functional performance, sleep quality, and patient and caregiver quality of life.
TRIAL REGISTRATION INFORMATION
This systematic review was registered in PROSPERO (CRD42021220352) on March 5, 2021.
Topics: Infant; Infant, Newborn; Child; Humans; Lamotrigine; Levetiracetam; Topiramate; Spasms, Infantile; Quality of Life; Epilepsy; Anticonvulsants; Diet, Ketogenic
PubMed: 36270899
DOI: 10.1212/WNL.0000000000201026 -
Journal of Cardiac Failure Apr 2022To compare the hazard for all-cause mortality and mortality due to heart failure (HF) between valproate (VPA) and levetiracetam (LEV)/lamotrigine (LTG) users in patients...
OBJECTIVE
To compare the hazard for all-cause mortality and mortality due to heart failure (HF) between valproate (VPA) and levetiracetam (LEV)/lamotrigine (LTG) users in patients aged ≥ 65 with comorbidities of epilepsy and HF.
METHODS
This was a cohort study using Danish registers during the period from January 1996 to July 2018. The study population included new users of LTG, LEV or VPA. A Cox regression model was used to compute crude and adjusted hazard ratios for the outcome, using an intention-to-treat approach. Average treatment effects (eg, 1-year absolute risks), risk differences and the ratio of risks were computed using the G-formula based on a Cox regression model for the outcomes at the end of the follow-up period.
RESULTS
We included 1345 subjects in the study population. VPA users (n = 696), when compared to LTG/LEV users (n = 649), had an increased hazard of mortality due to HF (hazard ratio [HR] 2.39; 95% CI 1.02-5.60) and to all-cause mortality (HR 1.37; 95% CI 1.01-1.85) in both crude and adjusted analyses. The 1-year absolute risks for all-cause mortality were 29% (95% CI 25%-33%) and 22% (95% CI 18%-26%) for VPA and LTG/LEV users. For mortality due to HF, 1-year absolute risks were 5% (95% CI 3%-7%) and 2% (95% CI 1%-4%) for VPA and LTG/LEV users. The average risk ratio, with LTG/LEV as the reference group, was 1.31 (95% CI 1.02-1.71) for all-cause mortality and 2.35 (95% CI 1.11-5.76) for HF mortality.
CONCLUSION
In older people with HF and epilepsy, treatment with VPA was associated with a higher risk of all-cause and HF mortality compared to treatment with LTG and LEV.
Topics: Aged; Anticonvulsants; Cohort Studies; Denmark; Epilepsy; Heart Failure; Humans; Lamotrigine; Levetiracetam; Prognosis; Valproic Acid
PubMed: 34438055
DOI: 10.1016/j.cardfail.2021.07.020 -
International Journal of Molecular... Oct 2023Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is...
Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is primary brain injury, making prevention of epileptogenesis after the initial event an optimal method of treatment. Despite this, no preventive therapy for epilepsy is currently available. The purpose of this study was to evaluate the effects of anakinra, lamotrigine, and their combination on epileptogenesis using the rat lithium-pilocarpine model of temporal lobe epilepsy. The study showed that there was no significant difference in the number and duration of seizures between treated and untreated animals. However, the severity of seizures was significantly reduced after treatment. Anakinra and lamotrigine, alone or in combination, significantly reduced neuronal loss in the CA1 hippocampus compared to the control group. However, the drugs administered alone were found to be more effective in preventing neuron loss in the hippocampal CA3 field compared to combination treatment. The treatment alleviated the impairments in activity level, exploratory behavior, and anxiety but had a relatively weak effect on TLE-induced impairments in social behavior and memory. The efficacy of the combination treatment did not differ from that of anakinra and lamotrigine monotherapy. These findings suggest that anakinra and lamotrigine, either alone or in combination, may be clinically useful in preventing the development of histopathological and behavioral abnormalities associated with epilepsy.
Topics: Rats; Animals; Epilepsy, Temporal Lobe; Pilocarpine; Lamotrigine; Lithium; Interleukin 1 Receptor Antagonist Protein; Anticonvulsants; Seizures; Hippocampus; Disease Models, Animal
PubMed: 37895080
DOI: 10.3390/ijms242015400 -
The International Journal of... Mar 2009The major burden of illness in bipolar disorder (BD) is in the depressive pole. Lamotrigine has been shown to be useful in the long-term prophylaxis of depressive... (Review)
Review
The major burden of illness in bipolar disorder (BD) is in the depressive pole. Lamotrigine has been shown to be useful in the long-term prophylaxis of depressive episodes in BD. Current guidelines recommend discontinuing lamotrigine in patients who develop rash. Our objective in this paper is to review literature to identify possible predictors of serious vs. benign rash that might help guide clinical decision-making and recommend titration strategy for re-introduction of lamotrigine, if indicated. We performed a search of the literature between 1966 and July 2008 to investigate the phenomenon of lamotrigine-induced rash and rechallenge procedures. The search identified six reports, and we were able to identify another case series from reviewing the bibliography of all of the above papers. We reviewed all the papers of lamotrigine rash rechallenge that resulted from the literature search. These papers describe 44 cases of lamotrigine rechallenge. Currently, there are 39 reported cases in the literature of successful lamotrigine rechallenge after a rash and five cases with rash recurrence. There are some characteristics of the rash that can help identify serious cases from benign ones. In addition, very slow titration of lamotrigine is crucial to the reduction of rash recurrence rate. Several cases that develop benign rash on lamotrigine can be rechallenged without adverse consequences. We believe that lamotrigine rechallenge in bipolar depression is an under-utilized option in our clinical armamentarium, and further studies are needed to guide us in this area.
Topics: Anticonvulsants; Bipolar Disorder; Databases, Bibliographic; Dose-Response Relationship, Drug; Drug Administration Schedule; Epilepsy; Exanthema; Humans; Lamotrigine; Triazines
PubMed: 18845017
DOI: 10.1017/S1461145708009504 -
Neurobiology of Disease Jun 2023Epilepsy is a comorbidity associated with Alzheimer's disease (AD), often starting many years earlier than memory decline. Investigating this association in the early...
Epilepsy is a comorbidity associated with Alzheimer's disease (AD), often starting many years earlier than memory decline. Investigating this association in the early pre-symptomatic stages of AD can unveil new mechanisms of the pathology as well as guide the use of antiepileptic drugs to prevent or delay hyperexcitability-related pathological effects of AD. We investigated the impact of repeated seizures on hippocampal memory and amyloid-β (Aβ) load in pre-symptomatic Tg2576 mice, a transgenic model of AD. Seizure induction caused memory deficits and an increase in oligomeric Aβ and fibrillary species selectively in pre-symptomatic transgenic mice, and not in their wildtype littermates. Electrophysiological patch-clamp recordings in ex vivo CA1 pyramidal neurons and immunoblots were carried out to investigate the neuronal alterations associated with the behavioral outcomes of Tg2576 mice. CA1 pyramidal neurons exhibited increased intrinsic excitability and lower hyperpolarization-activated I current. CA1 also displayed lower expression of the hyperpolarization-activated cyclic nucleotide-gated HCN1 subunit, a protein already identified as downregulated in the AD human proteome. The antiepileptic drug lamotrigine restored electrophysiological alterations and prevented both memory deficits and the increase in extracellular Aβ induced by seizures. Thus our study provides evidence of pre-symptomatic hippocampal neuronal alterations leading to hyperexcitability and associated with both higher susceptibility to seizures and to AD-specific seizure-induced memory impairment. Our findings also provide a basis for the use of the antiepileptic drug lamotrigine as a way to counteract acceleration of AD induced by seizures in the early phases of the pathology.
Topics: Mice; Humans; Animals; Alzheimer Disease; Anticonvulsants; Lamotrigine; Hippocampus; Amyloid beta-Peptides; Seizures; Mice, Transgenic; Disease Models, Animal; Memory Disorders
PubMed: 37001613
DOI: 10.1016/j.nbd.2023.106106 -
Seizure Aug 2018The aim of this study was to assess the association between human leukocyte antigen (HLA) variants and lamotrigine (LTG)-induced cutaneous adverse drug reactions (cARDs). (Meta-Analysis)
Meta-Analysis Review
PURPOSE
The aim of this study was to assess the association between human leukocyte antigen (HLA) variants and lamotrigine (LTG)-induced cutaneous adverse drug reactions (cARDs).
METHODS
A comprehensive literature search was conducted on the relationship of HLA alleles with LTG-induced cADRs in Asian populations, through PubMed, Embase, and Cochrane Library. The last search was in February 2018. The pooled odds ratio (OR) with 95% confidence interval (95% CI) was used to access the strength of the association between an HLA allele and LTG-induced cADRs.
RESULTS
A total of 11 studies met the inclusion criteria and were enrolled in our meta- analysis, which were based on Chinese, Korean, and Thai populations. Among these populations, we observed that HLA-B*1502 is a risk allele for LTG-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Chinese populations (pooled OR 2.4, 95% CI: 1.20-4.78, P = 0.01), HLA-A*2402 was found to be a significant risk allele for both SJS/TEN (pooled OR 3.50, 95% CI: 1.61-7.59, P = 0.002) and maculopapular eruption (MPE) (pooled OR 2.14, 95% CI: 1.10-4.16, P = 0.03), and HLA-B*3303 was considered to be a protective marker for MPE in Chinese and Korean populations (pooled OR 0.2, 95% CI 0.06-0.64, P = 0.007).
CONCLUSIONS
In Asian populations, HLA-B*1502 is a risk factor for LTG-induced bullous lesions such as SJS/TEN in Chinese populations, and HLA-A*2402 is associated with the susceptibility to either SJS/TEN or MPE. HLA-A*3303 is a protective allele against LTG-induced MPE in Chinese and Korean populations.
Topics: Anticonvulsants; Asian People; HLA Antigens; Humans; Lamotrigine; Pharmacogenomic Variants; Skin Diseases; Triazines
PubMed: 30015149
DOI: 10.1016/j.seizure.2018.06.024 -
Arquivos de Neuro-psiquiatria Dec 2007Juvenile myoclonus epilepsy (JME) is a common epileptic syndrome, the etiology of which is genetically determined. Its onset occurs from 6 through 22 years of age, and... (Review)
Review
Juvenile myoclonus epilepsy (JME) is a common epileptic syndrome, the etiology of which is genetically determined. Its onset occurs from 6 through 22 years of age, and affected patients present with myoclonic jerks, often associated with generalized tonic-clonic seizures - the most common association - and absence seizures. JME is non-progressive, and there are no abnormalities on clinical examination or intellectual deficits. Psychiatric disorders may coexist. Generalized polyspike-and-waves are the most characteristic electroencephalographic pattern. Usual neuroimaging studies show no abnormalities. Atypical presentations should be entertained, as they are likely to induce misdiagnosis. Prevention of precipitating factors and therapy with valproic acid (VPA) are able to control seizures in the great majority of patients. Whenever VPA is judged to be inappropriate, other antiepileptic drugs such as lamotrigine may be considered. Treatment should not be withdrawn, otherwise recurrences are frequent.
Topics: Adolescent; Adult; Anticonvulsants; Child; Diagnosis, Differential; Electroencephalography; Humans; Lamotrigine; Myoclonic Epilepsy, Juvenile; Triazines; Valproic Acid
PubMed: 18345445
DOI: 10.1590/s0004-282x2007000700036 -
Blood Mar 2019
Topics: Biopsy; Bone Marrow; Dexamethasone; Drug Resistant Epilepsy; Etoposide; Ferritins; Humans; Interleukin-2 Receptor alpha Subunit; Lacosamide; Lamotrigine; Leukopenia; Lymphohistiocytosis, Hemophagocytic; Male; Middle Aged; Thrombocytopenia; Transaminases
PubMed: 30846511
DOI: 10.1182/blood-2018-11-885509