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Epilepsia Open Sep 2023Response to antiseizure medications (ASMs) can be influenced by several gene polymorphisms, causing either lower efficacy or higher occurrence of adverse drug reactions...
Response to antiseizure medications (ASMs) can be influenced by several gene polymorphisms, causing either lower efficacy or higher occurrence of adverse drug reactions (ADRs). We investigated the clinical utility of salivary pharmacogenomic testing on epilepsy patients. A commercialized pharmacogenomic salivary test was performed in a cohort of epileptic patients. Genetic variants on five genes (i.e., CYP1A2, CYP2C9, CYP2C19, EPHX1, and ABCB1) involved in common ASMs metabolism were selected. Twenty-one individuals (median age [Q -Q ]: 15 [6.5-28] years) were enrolled. Six patients harboring the homozygous *1F allele in CYP1A2 could have reduced chance of response to stiripentol due to fast metabolism. CYP2C9 had reduced activity in 10 patients (alleles *2 and *3), potentially affecting phenytoin (PHT), phenobarbital (PB), primidone, lacosamide (LCM), and valproic acid metabolism. Seven patients, carrying the *2 allele of CYP2C19, had an increased risk of ADRs with clobazam (CLB), PB, PHT, LCM, brivaracetam; while one individual with the *17 allele in heterozygosity reported a CLB fast metabolism. Six patients showed a CC polymorphism of EPHX1 associated with the impaired efficacy of carbamazepine. ABCB1 polymorphisms related to drug-resistance (3435 CC) or drug-sensitive phenotype (CT or TT) were found in 6 out of 7 patients. Pharmacogenomic testing on saliva proved easy and safe in clinical practice to convey information for the management of epileptic patients, especially those resistant to treatment or sensitive to severe ADRs.
Topics: Humans; Anticonvulsants; Pharmacogenetics; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C19; Pilot Projects; Cytochrome P-450 CYP2C9; Saliva; Epilepsy; Phenytoin; Clobazam; Phenobarbital
PubMed: 36840436
DOI: 10.1002/epi4.12717 -
Central Nervous System Agents in... Apr 2024Seizures are a common presenting symptom of the central nervous system (CNS) and could occur from infections (such as toxins) or drugs.
BACKGROUND
Seizures are a common presenting symptom of the central nervous system (CNS) and could occur from infections (such as toxins) or drugs.
OBJECTIVE
The aim of this study was to present a systematic review of the association between infections, seizures, and drugs.
METHODS
Through February 18, 2024, according to the PRISMA guidelines and based on the PICO standard format, relevant, in-depth consequent guide approach and evidence-based options were selected associated with a knowledgeable collection of current, high-quality manuscripts.
RESULTS
Imbalance between inhibitory and excitatory neurotransmitters due to infections, drugs such as ticarcillin, amoxicillin, oxacillin, penicillin G, ampicillin, tramadol, venlafaxine, cyclosporine, tacrolimus, acyclovir, cellcept, the old generation of antiepileptic drugs, such as carbamazepine, phenytoin, and many other drugs could cause different stages of CNS disturbances ranging from seizure to encephalopathy. Infections could cause life-threatening status epilepticus by continuous unremitting seizures lasting longer than 5 minutes or recurrent seizures. Meningitis, tuberculosis, herpes simplex, cerebral toxoplasmosis, and many others could lead to status epilepticus. In fact, confusion, encephalopathy, and myoclonus were reported with drugs, such as ticarcillin, amoxicillin, oxacillin, penicillin G, ampicillin, and others. Penicillin G was reported as having the greatest epileptogenic potential. A high dose, in addition to prolonged use of metronidazole, was reported with seizure infection. Meropenem could decrease the concentration of valproic acid. Due to the inhibition of cytochrome P450 3A4, the combination of clarithromycin and erythromycin with carbamazepine needs vigilant monitoring.
CONCLUSION
Due to changes in drug metabolism, co-administration of antiseizure drugs and antibiotics may lead to an enhanced risk of seizures. In patients with neurocysticercosis, cerebral malaria, viral encephalitis, bacterial meningitis, tuberculosis, and human immunodeficiency virus, the evidence-based study recommended different mechanisms mediating epileptogenic properties of toxins and drugs.
PubMed: 38676494
DOI: 10.2174/0118715249288932240416071636 -
Children (Basel, Switzerland) Nov 2023Epilepsy is a chronic neurological disease characterized by the presence of spontaneous seizures, with a higher incidence in the pediatric population. Anti-seizure...
Epilepsy is a chronic neurological disease characterized by the presence of spontaneous seizures, with a higher incidence in the pediatric population. Anti-seizure medication (ASM) may produce adverse drug reactions (ADRs) with an elevated frequency and a high severity. Thus, the objective of the present study was to analyze, through intensive pharmacovigilance over 112 months, the ADRs produced by valproic acid (VPA), oxcarbazepine (OXC), phenytoin (PHT), and levetiracetam (LEV), among others, administered to monotherapy or polytherapy for Mexican hospitalized pediatric epilepsy patients. A total of 1034 patients were interviewed; 315 met the inclusion criteria, 211 patients presented ADRs, and 104 did not. A total of 548 ASM-ADRs were identified, and VPA, LEV, and PHT were the main culprit drugs. The most frequent ADRs were drowsiness, irritability, and thrombocytopenia, and the main systems affected were hematologic, nervous, and dermatologic. LEV and OXC caused more nonsevere ADRs, and PHT caused more severe ADRs. The risk analysis showed an association between belonging to the younger groups and polytherapy with ADR presence and between polytherapy and malnutrition with severe ADRs. In addition, most of the severe ADRs were preventable, and most of the nonsevere ADRs were nonpreventable.
PubMed: 38002866
DOI: 10.3390/children10111775 -
Expert Opinion on Drug Safety Jan 2024Recently, case reports of priapism associated with the use of some anti-seizure medications began to emerge in the literature. We aimed to investigate if there is a... (Review)
Review
BACKGROUND
Recently, case reports of priapism associated with the use of some anti-seizure medications began to emerge in the literature. We aimed to investigate if there is a potential safety signal of priapism among individual anti-seizure medications and to search the literature for relevant published cases.
RESEARCH DESIGN AND METHODS
We conducted a disproportionality analysis using OpenVigil 2.1 to query the United States Food and Drug Administration's Adverse Event Reporting System (FAERS) database. Literature search was conducted in PubMed/MEDLINE, Scopus and Web of Science up to 12 July 2023.
RESULTS
We identified positive signal of priapism for valproic acid and its derivatives ( = 23, chi-squared = 59.943, PRR = 4.566), gabapentin ( = 20, chi-squared = 9.790, PRR = 2.060), lamotrigine ( = 16, chi-squared = 8.318, PRR = 2.120), levetiracetam ( = 16, chi-squared = 10.766, PRR = 2.329), topiramate ( = 14, chi-squared = 28.067, PRR = 3.972) and carbamazepine ( = 8, chi-squared = 6.147, PRR = 2.568), as well as published cases of priapism associated with these drugs. We also found published cases of priapism for pregabalin and phenytoin in the literature and FAERS, and at least one reported adverse event of priapism in FAERS for clonazepam, lacosamide, ethosuximide, oxcarbazepine, and vigabatrin in which they were considered primary suspect.
CONCLUSIONS
Our study identified signals for priapism for several anti-seizure medications, but these results need to be confirmed in well-designed pharmacoepidemiological studies.
Topics: Male; Humans; United States; Pharmacovigilance; Priapism; Anticonvulsants; Gabapentin; Levetiracetam; Adverse Drug Reaction Reporting Systems; United States Food and Drug Administration
PubMed: 38062555
DOI: 10.1080/14740338.2023.2293208 -
Osteoporosis International : a Journal... Oct 2023Among those who use of liver-enzyme inducing anticonvulsant medication for more than 2 years, 27% have a prevalent vertebral fracture on vertebral fracture assessment...
UNLABELLED
Among those who use of liver-enzyme inducing anticonvulsant medication for more than 2 years, 27% have a prevalent vertebral fracture on vertebral fracture assessment (VFA) lateral spine imaging. VFA imaging at the time of bone densitometry may be appropriate for older individuals who are chronic users of these medications.
PURPOSE
It is unclear whether prevalent vertebral fractures are associated with use of anticonvulsant drugs, especially those that induce liver enzymes (LEI) that metabolize drugs and vitamin D. Our purpose was to estimate the prevalence of vertebral fracture on densitometric lateral spine images according to duration of prior anticonvulsant medication use.
METHODS
Our study population was 11,822 individuals (mean [sd] age 76.1 [6.8] years, 94% female) who had bone densitometry with VFA between 2010 and 2018. Cumulative prior exposure to LEI anticonvulsants (carbamazepine, phenobarbital, phenytoin, valproic acid, n = 538), non-LEI anticonvulsants (clonazepam, gabapentin, levetiracetam, others, n = 2786), and other non-clonazepam benzodiazepines (n = 5082) was determined using linked pharmacy records. Prevalent vertebral fractures were identified on VFA images using the modified ABQ method. Logistic regression models were used to estimate the association of anticonvulsant drug exposure with prevalent vertebral fractures.
RESULTS
Prevalence of one or more vertebral fractures was 16.1% for the entire analytic cohort, and 27.0%, 19.0%, and 18.5% for those with ≥ 2 years of prior LEI anticonvulsant use, non-LEI anticonvulsant use, and other benzodiazepine use, respectively. Adjusted for multiple covariates, use of prior LEI anticonvulsant medication for ≥ 2 years was associated with prevalent fracture on VFA (OR 1.48 [95% CI 1.04, 2.10]).
CONCLUSION
LEI anticonvulsant use for ≥ 2 years is associated with higher vertebral fracture prevalence. Lateral spine VFA imaging at the time of bone densitometry may be appropriate for older individuals who have used LEI anticonvulsant medications for ≥ 2 years.
Topics: Humans; Female; Child; Male; Spinal Fractures; Anticonvulsants; Bone Density; Spine; Benzodiazepines; Liver; Absorptiometry, Photon
PubMed: 37380883
DOI: 10.1007/s00198-023-06820-9 -
Biomedicines Dec 2023Mitochondria are potential targets responsible for some drug- and xenobiotic-induced organ toxicities. However, molecular mechanisms of drug-induced mitochondrial...
Mitochondria are potential targets responsible for some drug- and xenobiotic-induced organ toxicities. However, molecular mechanisms of drug-induced mitochondrial toxicities are mostly unknown. Here, multiple in vitro assays were used to investigate the effects of 22 psychotropic drugs on mitochondrial function. The acute extracellular flux assay identified inhibitors of the electron transport chain (ETC), i.e., aripiprazole, phenytoin, and fluoxetine, an uncoupler (reserpine), substrate inhibitors (quetiapine, carbamazepine, buspirone, and tianeptine), and cytotoxic compounds (chlorpromazine and valproic acid) in HepG2 cells. Using permeabilized HepG2 cells revealed minimum effective concentrations of 66.3, 6730, 44.5, and 72.1 µM for the inhibition of complex-I-linked respiration for quetiapine, valproic acid, buspirone, and fluoxetine, respectively. Assessing complex-II-linked respiration in isolated rat liver mitochondria revealed haloperidol is an ETC inhibitor, chlorpromazine is an uncoupler in basal respiration and an ETC inhibitor under uncoupled respiration (IC = 135 µM), while olanzapine causes a mild dissipation of the membrane potential at 50 µM. This research elucidates some mechanisms of drug toxicity and provides some insight into their safety profile for clinical drug decisions.
PubMed: 38137493
DOI: 10.3390/biomedicines11123272 -
Nutrition in Clinical Practice :... Dec 2023Concomitant administration of enteral nutrition (EN) and phenytoin decreases phenytoin absorption. Concerns over impaired nutrition, however, may prevent EN from being...
BACKGROUND
Concomitant administration of enteral nutrition (EN) and phenytoin decreases phenytoin absorption. Concerns over impaired nutrition, however, may prevent EN from being held surrounding phenytoin administration. This study aimed to evaluate whether EN holding guidelines impacted nutrition goal achievement in patients taking phenytoin.
METHODS
Adult patients administered enteral phenytoin for acute or chronic seizures while receiving EN during a neurocritical care admission 6 months before and after EN holding guideline implementation were eligible. Patients without phenytoin concentrations or a clinical registered dietitian assessment were excluded. The primary outcome was the percentage of nutrition daily goals attained before and after implementation. Secondary end points included the incidence of hypoglycemia, differences in measured phenytoin concentrations, and rates of therapeutic (10-20 mcg/ml) and high-therapeutic (15-20 mcg/ml) concentration attainment. Concentrations were adjusted for hypoalbuminemia using the Winter-Tozer equation.
RESULTS
Fifty-five patients representing 412 patient days and 1110 phenytoin administrations were included with 29 preimplementation and 26 postimplementation patients. Median percent attainment of daily EN goals was consistent preimplementation and postimplementation (86% vs 83%, P = 0.48). No significant change in rates of days with hypoglycemia was observed. Adjusted phenytoin concentrations were similar before and after implementation (14.1 vs 15.2 mcg/ml, P = 0.45), but the preimplementation cohort had a lower proportion of high-therapeutic concentrations (23% vs 36%, P = 0.018).
CONCLUSION
Holding EN for phenytoin did not impact attainment of daily nutrition goals and was not associated with increased rates of hypoglycemia. This is the first study to evaluate the effect of EN holding on nutrition goals in patients receiving phenytoin.
Topics: Adult; Humans; Phenytoin; Goals; Enteral Nutrition; Hypoglycemia
PubMed: 37537901
DOI: 10.1002/ncp.11051 -
Molecular Pharmaceutics Jul 2023Effective control of post-operative inflammation after tissue repair remains a clinical challenge. A tissue repair patch that could appropriately integrate into the...
Effective control of post-operative inflammation after tissue repair remains a clinical challenge. A tissue repair patch that could appropriately integrate into the surrounding tissue and control inflammatory responses would improve tissue healing. A collagen-based hybrid tissue repair patch has been developed in this work for the local delivery of an anti-inflammatory drug. Dexamethasone (DEX) was encapsulated into PLGA microspheres and then co-electrocompacted into a collagen membrane. Using a simple process, multiple drugs can be loaded into and released from this hybrid composite material simultaneously, and the ratio between each drug is controllable. Anti-inflammatory DEX and the anti-epileptic phenytoin (PHT) were co-encapsulated and released to validate the dual drug delivery ability of this versatile composite material. Furthermore, the Young's modulus of this drug-loaded collagen patch was increased to 20 KPa using a biocompatible riboflavin (vitamin B2)-induced UV light cross-linking strategy. This versatile composite material has a wide range of potential applications which deserve exploration in further research.
Topics: Humans; Dexamethasone; Pharmaceutical Preparations; Anti-Inflammatory Agents; Collagen; Inflammation; Riboflavin; Microspheres
PubMed: 37226701
DOI: 10.1021/acs.molpharmaceut.3c00048 -
Pharmacogenetics and Genomics Jul 2024This umbrella review was conducted to summarize the association between HLA*1502 allele with antiepileptic induced Stevens-Johnson syndrome (SJS) and toxic epidermal... (Review)
Review
PURPOSE
This umbrella review was conducted to summarize the association between HLA*1502 allele with antiepileptic induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).
METHODS
Pubmed, Scopus and EMBASE were searched for eligible reviews in May 2023. Two authors independently screened titles and abstracts and assessed full-text reviews for eligibility. The quality of meta-analyses and case-control studies was appraised with Assessing the Methodological Quality of Systematic Reviews 2 and Newcastle-Ottawa Scale, respectively. Narrative summaries of each antiepileptic drug were analyzed. Preestablished protocol was registered on the International Prospective Register of Systematic Reviews Registry(ID: CRD42023403957).
RESULTS
Included studies are systematic reviews, meta-analyses and case-control studies evaluating the association of HLA-B*1502 allele with the following antiepileptics. Seven meta-analyses for carbamazepine, three meta-analyses for lamotrigine (LTG), three case-control studies for oxcarbazepine, nine case-control studies for phenytoin and four case-control studies for phenobarbitone were included. The findings of this umbrella review suggest that there is a strong association between HLA-B-1502 with SJS/TEN for carbamazepine and oxcarbazepine and a milder association for lamotrigine and phenytoin.
CONCLUSION
In summary, although HLA-B*1502 is less likely to be associated with phenytoin or lamotrigine-induced SJS/TEN compared to carbamazepine-induced SJS/TEN, it is a significant risk factor that if carefully screened, could potentially reduce the development of SJS/TEN. In view of potential morbidity and mortality, HLA-B*1502 testing may be beneficial in patients who are initiating lamotrigine/phenytoin therapy. However, further studies are required to examine the association of other alleles with the development of SJS/TEN and to explore the possibility of genome-wide association studies before initiation of treatment.
Topics: Stevens-Johnson Syndrome; Humans; Anticonvulsants; HLA-B15 Antigen; Carbamazepine; Lamotrigine; Genetic Predisposition to Disease; Alleles
PubMed: 38527170
DOI: 10.1097/FPC.0000000000000531 -
Aquatic Toxicology (Amsterdam,... Jun 2024Phenytoin, an antiepileptic drug, induces neurotoxicity and abnormal embryonic development and reduces spontaneous locomotor activity in fish. However, its effects on...
Phenytoin, an antiepileptic drug, induces neurotoxicity and abnormal embryonic development and reduces spontaneous locomotor activity in fish. However, its effects on other endpoints remain unclear. Therefore, we investigated the effects of phenytoin on the swimming behavior and reproductive ability of Japanese medaka. Abnormalities in swimming behavior, such as imbalance, rotation, rollover, and vertical swimming, were observed. However, when phenytoin exposure was discontinued, the behavioral abnormality rates decreased. Phenytoin exposure also significantly reduced reproductive ability. By investigating reproduction-related gene expression of gnrh1, gnrh2, fshb, and lhb remained unchanged in males and females. In contrast, kiss1 expression was significantly suppressed due to phenytoin exposure in males and females. kiss2 expression was also significantly suppressed in females but not in males. We filmed videos to examine phenytoin exposure effects on sexual behavior. Females showed no interest in the male's courtship. As the kisspeptin 1 system controls sexual behavior in Japanese medaka, phenytoin exposure may have decreased kiss1 expression, which decreased female reproductive motivation; hence, they did not spawn eggs. This is the first study to show that phenytoin exposure induces behavioral abnormalities, and suppresses kiss1 expression and reproductive performance in Japanese medaka.
PubMed: 38943866
DOI: 10.1016/j.aquatox.2024.107007