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JAMA Neurology Jun 2023Prenatal antiseizure medication (ASM) exposure has been associated with adverse early neurodevelopment, but associations with a wider range of psychiatric end points...
IMPORTANCE
Prenatal antiseizure medication (ASM) exposure has been associated with adverse early neurodevelopment, but associations with a wider range of psychiatric end points have not been studied.
OBJECTIVE
To examine the association between prenatal exposure to ASM with a spectrum of psychiatric disorders in childhood and adolescence in children of mothers with epilepsy.
DESIGN, SETTING, AND PARTICIPANTS
This prospective, population-based register study assessed 4 546 605 singleton children born alive in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Of the 4 546 605 children, 54 953 with chromosomal disorders or uncertain birth characteristics were excluded, and 38 661 children of mothers with epilepsy were identified. Data analysis was performed from August 2021 to January 2023.
EXPOSURES
Prenatal exposure to ASM was defined as maternal prescription fills from 30 days before the first day of the last menstrual period until birth.
MAIN OUTCOMES AND MEASURES
The main outcome measure was diagnosis of psychiatric disorders (a combined end point and 13 individual disorders). Estimated adjusted hazard ratios (aHRs) using Cox proportional hazards regression and cumulative incidences with 95% CIs are reported.
RESULTS
Among the 38 661 children of mothers with epilepsy (16 458 [42.6%] exposed to ASM; 19 582 [51.3%] male; mean [SD] age at the end of study, 7.5 [4.6] years), prenatal valproate exposure was associated with an increased risk of the combined psychiatric end point (aHR, 1.80 [95% CI, 1.60-2.03]; cumulative risk at 18 years in ASM-exposed children, 42.1% [95% CI, 38.2%-45.8%]; cumulative risk at 18 years in unexposed children, 31.3% [95% CI, 28.9%-33.6%]), which was driven mainly by disorders within the neurodevelopmental spectrum. Prenatal exposure to lamotrigine, carbamazepine, and oxcarbazepine was not associated with an increased risk of psychiatric disorders, whereas associations were found for prenatal exposure to topiramate with attention-deficit/hyperactivity disorder (aHR, 2.38; 95% CI, 1.40-4.06) and exposure to levetiracetam with anxiety (aHR, 2.17; 95% CI, 1.26-3.72) and attention-deficit/hyperactivity disorder (aHR, 1.78; 95% CI, 1.03-3.07).
CONCLUSIONS AND RELEVANCE
Findings from this explorative study strengthen the evidence for the warning against the use of valproate in pregnancy and raise concern of risks of specific psychiatric disorders associated with topiramate and levetiracetam. This study provides reassuring evidence that lamotrigine, carbamazepine, and oxcarbazepine are not associated with long-term behavioral or developmental disorders but cannot rule out risks with higher doses.
Topics: Pregnancy; Child; Female; Male; Adolescent; Humans; Child, Preschool; Valproic Acid; Lamotrigine; Incidence; Levetiracetam; Topiramate; Prenatal Exposure Delayed Effects; Prospective Studies; Anticonvulsants; Epilepsy; Oxcarbazepine; Carbamazepine; Attention Deficit Disorder with Hyperactivity
PubMed: 37067807
DOI: 10.1001/jamaneurol.2023.0674 -
The Cochrane Database of Systematic... Aug 2023Prenatal exposure to certain anti-seizure medications (ASMs) is associated with an increased risk of major congenital malformations (MCM). The majority of women with... (Review)
Review
BACKGROUND
Prenatal exposure to certain anti-seizure medications (ASMs) is associated with an increased risk of major congenital malformations (MCM). The majority of women with epilepsy continue taking ASMs throughout pregnancy and, therefore, information on the potential risks associated with ASM treatment is required.
OBJECTIVES
To assess the effects of prenatal exposure to ASMs on the prevalence of MCM in the child.
SEARCH METHODS
For the latest update of this review, we searched the following databases on 17 February 2022: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to February 16, 2022), SCOPUS (1823 onwards), and ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP). No language restrictions were imposed.
SELECTION CRITERIA
We included prospective cohort controlled studies, cohort studies set within pregnancy registries, randomised controlled trials and epidemiological studies using routine health record data. Participants were women with epilepsy taking ASMs; the two control groups were women without epilepsy and untreated women with epilepsy.
DATA COLLECTION AND ANALYSIS
Five authors independently selected studies for inclusion. Eight authors completed data extraction and/or risk of bias assessments. The primary outcome was the presence of an MCM. Secondary outcomes included specific types of MCM. Where meta-analysis was not possible, we reviewed included studies narratively.
MAIN RESULTS
From 12,296 abstracts, we reviewed 283 full-text publications which identified 49 studies with 128 publications between them. Data from ASM-exposed pregnancies were more numerous for prospective cohort studies (n = 17,963), than data currently available for epidemiological health record studies (n = 7913). The MCM risk for children of women without epilepsy was 2.1% (95% CI 1.5 to 3.0) in cohort studies and 3.3% (95% CI 1.5 to 7.1) in health record studies. The known risk associated with sodium valproate exposure was clear across comparisons with a pooled prevalence of 9.8% (95% CI 8.1 to 11.9) from cohort data and 9.7% (95% CI 7.1 to 13.4) from routine health record studies. This was elevated across almost all comparisons to other monotherapy ASMs, with the absolute risk differences ranging from 5% to 9%. Multiple studies found that the MCM risk is dose-dependent. Children exposed to carbamazepine had an increased MCM prevalence in both cohort studies (4.7%, 95% CI 3.7 to 5.9) and routine health record studies (4.0%, 95% CI 2.9 to 5.4) which was significantly higher than that for the children born to women without epilepsy for both cohort (RR 2.30, 95% CI 1.47 to 3.59) and routine health record studies (RR 1.14, 95% CI 0.80 to 1.64); with similar significant results in comparison to the children of women with untreated epilepsy for both cohort studies (RR 1.44, 95% CI 1.05 to 1.96) and routine health record studies (RR 1.42, 95% CI 1.10 to 1.83). For phenobarbital exposure, the prevalence was 6.3% (95% CI 4.8 to 8.3) and 8.8% (95% CI 0.0 to 9277.0) from cohort and routine health record data, respectively. This increased risk was significant in comparison to the children of women without epilepsy (RR 3.22, 95% CI 1.84 to 5.65) and those born to women with untreated epilepsy (RR 1.64, 95% CI 0.94 to 2.83) in cohort studies; data from routine health record studies was limited. For phenytoin exposure, the prevalence of MCM was elevated for cohort study data (5.4%, 95% CI 3.6 to 8.1) and routine health record data (6.8%, 95% CI 0.1 to 701.2). The prevalence of MCM was higher for phenytoin-exposed children in comparison to children of women without epilepsy (RR 3.81, 95% CI 1.91 to 7.57) and the children of women with untreated epilepsy (RR 2.01. 95% CI 1.29 to 3.12); there were no data from routine health record studies. Pooled data from cohort studies indicated a significantly increased MCM risk for children exposed to lamotrigine in comparison to children born to women without epilepsy (RR 1.99, 95% CI 1.16 to 3.39); with a risk difference (RD) indicating a 1% increased risk of MCM (RD 0.01. 95% CI 0.00 to 0.03). This was not replicated in the comparison to the children of women with untreated epilepsy (RR 1.04, 95% CI 0.66 to 1.63), which contained the largest group of lamotrigine-exposed children (> 2700). Further, a non-significant difference was also found both in comparison to the children of women without epilepsy (RR 1.19, 95% CI 0.86 to 1.64) and children born to women with untreated epilepsy (RR 1.00, 95% CI 0.79 to 1.28) from routine data studies. For levetiracetam exposure, pooled data provided similar risk ratios to women without epilepsy in cohort (RR 2.20, 95% CI 0.98 to 4.93) and routine health record studies (RR 0.67, 95% CI 0.17 to 2.66). This was supported by the pooled results from both cohort (RR 0.71, 95% CI 0.39 to 1.28) and routine health record studies (RR 0.82, 95% CI 0.39 to 1.71) when comparisons were made to the offspring of women with untreated epilepsy. For topiramate, the prevalence of MCM was 3.9% (95% CI 2.3 to 6.5) from cohort study data and 4.1% (0.0 to 27,050.1) from routine health record studies. Risk ratios were significantly higher for children exposed to topiramate in comparison to the children of women without epilepsy in cohort studies (RR 4.07, 95% CI 1.64 to 10.14) but not in a smaller comparison to the children of women with untreated epilepsy (RR 1.37, 95% CI 0.57 to 3.27); few data are currently available from routine health record studies. Exposure in utero to topiramate was also associated with significantly higher RRs in comparison to other ASMs for oro-facial clefts. Data for all other ASMs were extremely limited. Given the observational designs, all studies were at high risk of certain biases, but the biases observed across primary data collection studies and secondary use of routine health records were different and were, in part, complementary. Biases were balanced across the ASMs investigated, and it is unlikely that the differential results observed across the ASMs are solely explained by these biases.
AUTHORS' CONCLUSIONS
Exposure in the womb to certain ASMs was associated with an increased risk of certain MCMs which, for many, is dose-dependent.
Topics: Pregnancy; Child; Female; Humans; Male; Prospective Studies; Topiramate; Lamotrigine; Phenytoin; Cohort Studies; Prenatal Exposure Delayed Effects; Epilepsy
PubMed: 37647086
DOI: 10.1002/14651858.CD010224.pub3 -
IUCrData Aug 2023The structure of the title Fe complex, [Fe(CH)(CHNO)], was determined at 130 K, and has ortho-rhom-bic (2) symmetry. It is of inter-est with respect to the class of...
The structure of the title Fe complex, [Fe(CH)(CHNO)], was determined at 130 K, and has ortho-rhom-bic (2) symmetry. It is of inter-est with respect to the class of triazine heterocyclic compounds: the triazine ring is substituted by two ferrocenyl and one morpholine groups. The crystal structure features C-H⋯O and C-H⋯N non-classical hydrogen bonds.
PubMed: 37693788
DOI: 10.1107/S2414314623006168 -
The Journal of Organic Chemistry Jul 2023Guanine is one out of five endogenous nucleobases and of key interest in drug discovery and chemical biology. Hitherto, the synthesis of guanine derivatives involves...
Guanine is one out of five endogenous nucleobases and of key interest in drug discovery and chemical biology. Hitherto, the synthesis of guanine derivatives involves lengthy multistep sequential synthesis of low overall diversity, resulting in the quest for innovation. Using a "single-atom skeletal editing" approach, we designed 2-aminoimidazo[2,1-][1,2,4]triazin-4(3)-one as a guanine isostere, conserving the biologically important HBA-HBD-HBD (HBA = hydrogen bond acceptor; HBD = hydrogen bond donor) substructure. We realized our design by a simple one-pot two-step method combining the Groebke-Blackburn-Bienaymé reaction (GBB-3CR) and a deprotection reaction to assemble the innovative guanine isosteres in moderate to good yields. Our innovative, diverse, short, and reliable multicomponent reaction synthesis will add to the toolbox of guanine isostere syntheses.
Topics: Drug Discovery; Cyclization
PubMed: 37431831
DOI: 10.1021/acs.joc.3c00467 -
JAMA Network Open Feb 2024Treatment options for COVID-19 are warranted irrespective of the presence of risk factors for severe disease. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Treatment options for COVID-19 are warranted irrespective of the presence of risk factors for severe disease.
OBJECTIVE
To assess the efficacy and safety of ensitrelvir in patients with mild to moderate COVID-19.
DESIGN, SETTING, AND PARTICIPANTS
This phase 3 part of a phase 2/3, double-blind, placebo-controlled randomized clinical trial was conducted from February 10 to July 10, 2022, with a 28-day follow-up period, at 92 institutions in Japan, Vietnam, and South Korea. Patients (aged 12 to <70 years) with mild to moderate COVID-19 within 120 hours of positive viral test results were studied.
INTERVENTIONS
Patients were randomized (1:1:1) to receive 125 mg of once-daily ensitrelvir (375 mg on day 1), 250 mg of once-daily ensitrelvir (750 mg on day 1), or placebo for 5 days.
MAIN OUTCOMES AND MEASURES
The primary end point was the time to resolution of the composite of 5 characteristic symptoms of SARS-CoV-2 Omicron infection, assessed using a Peto-Prentice generalized Wilcoxon test stratified by vaccination history. Virologic efficacy and safety were also assessed.
RESULTS
A total of 1821 patients were randomized, of whom 1030 (347 in the 125-mg ensitrelvir group, 340 in the 250-mg ensitrelvir group, and 343 in the placebo group) were randomized in less than 72 hours of disease onset (primary analysis population). The mean (SD) age in this population was 35.2 (12.3) years, and 552 (53.6%) were men. A significant difference was observed between the 125-mg ensitrelvir group and the placebo group (P = .04 with a Peto-Prentice generalized Wilcoxon test). The difference in median time was approximately 1 day between the 125-mg ensitrelvir group and the placebo group (167.9 vs 192.2 hours; difference, -24.3 hours; 95% CI, -78.7 to 11.7 hours). Adverse events were observed in 267 of 604 patients (44.2%) in the 125-mg ensitrelvir group, 321 of 599 patients (53.6%) in the 250-mg ensitrelvir group, and 150 of 605 patients (24.8%) in the placebo group, which included a decrease in high-density lipoprotein level (188 [31.1%] in the 125-mg ensitrelvir group, 231 [38.6%] in the 250-mg ensitrelvir group, and 23 [3.8%] in the placebo group). No treatment-related serious adverse events were reported.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, 125-mg ensitrelvir treatment reduced the time to resolution of the 5 typical COVID-19 symptoms compared with placebo in patients treated in less than 72 hours of disease onset; the absolute difference in median time to resolution was approximately 1 day. Ensitrelvir demonstrated clinical and antiviral efficacy without new safety concerns. Generalizability to populations outside Asia should be confirmed.
TRIAL REGISTRATION
Japan Registry of Clinical Trials Identifier: jRCT2031210350.
Topics: Female; Humans; Male; COVID-19; Drugs, Chinese Herbal; Indazoles; Risk Factors; SARS-CoV-2; Triazines; Triazoles; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged
PubMed: 38335000
DOI: 10.1001/jamanetworkopen.2023.54991 -
Proceedings of the National Academy of... Oct 2023Voltage-gated sodium (Na) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Na channels serve as the...
Voltage-gated sodium (Na) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Na channels serve as the primary targets for several classes of widely used and investigational drugs, including local anesthetics, antiepileptic drugs, antiarrhythmics, and analgesics. In this study, we present cryogenic electron microscopy (cryo-EM) structures of human Na1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 Å and 2.7 Å, respectively. A 3D EM reconstruction of ligand-free Na1.7 was also obtained at 2.1 Å resolution. RLZ resides in the central cavity of the pore domain and is coordinated by residues from repeats III and IV. Whereas one LTG molecule also binds to the central cavity, the other is found beneath the intracellular gate, known as site BIG. Therefore, LTG, similar to lacosamide and cannabidiol, blocks Na channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure-activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Na channels. Our findings reveal the molecular basis for these drugs' mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs.
Topics: Humans; Anticonvulsants; Lamotrigine; Cannabidiol; Sodium; Voltage-Gated Sodium Channels
PubMed: 37782796
DOI: 10.1073/pnas.2309773120 -
Molecules (Basel, Switzerland) May 20231,3,5-triazine derivatives, also called s-triazines, are a series of containing-nitrogen heterocyclic compounds that play an important role in anticancer drug design and... (Review)
Review
1,3,5-triazine derivatives, also called s-triazines, are a series of containing-nitrogen heterocyclic compounds that play an important role in anticancer drug design and development. To date, three s-triazine derivatives, including altretamine, gedatolisib, and enasidenib, have already been approved for refractory ovarian cancer, metastatic breast cancer, and leukemia therapy, respectively, demonstrating that the s-triazine core is a useful scaffold for the discovery of novel anticancer drugs. In this review, we mainly focus on s-triazines targeting topoisomerases, tyrosine kinases, phosphoinositide 3-kinases, NADP+-dependent isocitrate dehydrogenases, and cyclin-dependent kinases in diverse signaling pathways, which have been extensively studied. The medicinal chemistry of s-triazine derivatives as anticancer agents was summarized, including discovery, structure optimization, and biological applications. This review will provide a reference to inspire new and original discoveries.
Topics: Humans; Female; Triazines; Antineoplastic Agents; Drug Design; Breast Neoplasms; Structure-Activity Relationship; Drug Screening Assays, Antitumor
PubMed: 37298753
DOI: 10.3390/molecules28114278