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Journal of Pharmaceutical and... Jun 2024Alternative blood sampling strategy can enhance the application of therapeutic drug monitoring (TDM), then improve precision therapy and medication compliance. In...
Simultaneous monitoring of seven antiepileptic drugs by dried blood spot and dried plasma spot sampling: method validation and clinical application of a LC-MS/MS-based technique.
Alternative blood sampling strategy can enhance the application of therapeutic drug monitoring (TDM), then improve precision therapy and medication compliance. In developing nations, alternative sampling strategy that allows self-sampling and room temperature transport is especially important. This study validates the use of dried blood spot (DBS) and dried plasma spot (DPS) sampling along with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for analyzing seven common antiepileptic drugs (AEDs) (phenytoin, lamotrigine, levetiracetam, topiramate, carbamazepine, oxcarbazepine and its active metabolite 10,11-dihydro-10-hydroxy carbamazepine) and evaluates their applicability to clinical practice. Following simple protein precipitation with acetonitrile, the AEDs were separated on a C18 column by gradient elution with a mobile phase consisting of acetonitrile-water-0.1% formic acid at a flow rate of 0.65 mL/min. The method provided linear analysis over the tested concentration ranges, with a total run time of 7 min. Intra- and inter-assay precision for all quality controls were ≤12% with accuracies of 85.9%-113%. The average extraction efficiencies were 69.0%-92.4% for DBS and 65.9%-96.5% for DPS, and no significant matrix effects were observed. The AEDs were stable in all samples for seven days at room temprature and 40°C. There was good correlation between the dry and wet plasma concentrations with greater accuracy for DPS compared to DBS indicating that alternative sampling strategy using DBS and DPS are suitable for monitoring the concentrations of AEDs with satisfied performance and logistical advantages.
Topics: Anticonvulsants; Chromatography, Liquid; Tandem Mass Spectrometry; Liquid Chromatography-Mass Spectrometry; Carbamazepine; Drug Monitoring; Dried Blood Spot Testing; Reproducibility of Results; Acetonitriles
PubMed: 38493754
DOI: 10.1016/j.jpba.2024.116099 -
Health Science Reports Mar 2024Adverse cutaneous drug reactions (ACDRs) are common and potentially life-threatening, while also hindering patient compliance to medications. Given the regional...
BACKGROUND AND AIMS
Adverse cutaneous drug reactions (ACDRs) are common and potentially life-threatening, while also hindering patient compliance to medications. Given the regional differences in patterns and prevalence of ACDRs, it is important to study the epidemiology, as well as the clinical and outcome patterns of patients with ACDRs in Iran.
METHODS
This cross-sectional study on ACDRs was conducted among hospitalized patients in a referral university hospital in the city of Isfahan, Iran. The patients' demographics, clinical information, and outcomes, including age, gender, past medical history, medication history, drug reaction with eosinophilia and systemic symptoms (DRESS) diagnosis, Steven-Johnson Syndrome (SJS) diagnosis, toxic epidermal necrosis (TEN) diagnosis, treatment regimen (steroids or intravenous immunoglobulin [IVIG]) and outcome information, including intensive care requirements, severe medical complications, or death, were obtained from medical records.
RESULTS
A total of 195 patients with a mean age of 40 years and consisting of 61% females were included. Carbamazepine, lamotrigine, sodium valproate, and phenytoin are the most commonly reported medications. Rate of complications was 45% with DRESS, SJS, and TEN diagnosed in 26%, 47%, and 19%, respectively. Treatment was carried out with steroids and IVIG in 81% and 19%, respectively. Among patients, 15% required intensive care and 5% died. Diagnosis of TEN, older age, and baseline heart disease were predictors of mortality. Patients with SJS were younger and more likely to be males, and they were more likely to have eye complications. On the other hand, patients with the diagnosis of TEN were more likely to receive IVIG and intensive care, and had a higher mortality rate.
CONCLUSION
Our study provides insight into the demographics and clinical patterns of Iranian patients with ACDRs. This will help in predicting rates of complications, treatments, and outcomes in patients and therefore make proper management decisions.
PubMed: 38486684
DOI: 10.1002/hsr2.1969 -
Wounds : a Compendium of Clinical... Feb 2024Although phenytoin's potential benefits in wound healing, pain relief, and infection control across various wound types have been previously reported, its use in wound...
BACKGROUND
Although phenytoin's potential benefits in wound healing, pain relief, and infection control across various wound types have been previously reported, its use in wound care remains limited.
OBJECTIVE
To conduct a comprehensive review to assess the efficacy of topical phenytoin compared with standard and alternative treatments for different wound types.
MATERIALS AND METHODS
The authors last searched Cochrane Library, PubMed, PubMed Central, and MEDLINE in June 2023. All English-language human RCTs and NRCTs from any time were included. The RoB 2 was used to assess quality of randomized trials, and the ROBINS-I was used to assess the quality of nonrandomized trials. Studies with a low risk of bias or some concerns in no more than 1 domain were included. Data collected and analyzed included wound type, interventions, sample size, outcome measures, and adverse effects.
RESULTS
The search yielded 101 studies, of which 17 RCTs and 8 NRCTs were eligible for inclusion. Of the included studies, 56% had a low risk of bias in all domains. The sample sizes varied between 20 and 130 (median, 60), with a total sample size of 1653 patients. Phenytoin improved wound healing in 17 of the 24 studies that evaluated it (71%), increased granulation tissue in 9 of the 10 studies that evaluated it (90%), provided analgesic effects in 7 of the 13 studies that evaluated it (54%), and inhibited bacterial contaminants in 6 of the 8 studies that evaluated it (75%). Adverse effects were rare (29%), minimal, and transient.
CONCLUSION
Phenytoin enhances wound healing and offers analgesic and antibacterial properties with minimal adverse effects. Further research is needed on optimal dosage of phenytoin, as well as frequency, delivery vehicles, and effects on other postoperative wounds.
BACKGROUND
Although phenytoin's potential benefits in wound healing, pain relief, and infection control across various wound types have been previously reported, its use in wound care remains limited.
OBJECTIVE
To conduct a comprehensive review to assess the efficacy of topical phenytoin compared with standard and alternative treatments for different wound types.
MATERIALS AND METHODS
The authors last searched Cochrane Library, PubMed, PubMed Central, and MEDLINE in June 2023. All English-language human RCTs and NRCTs from any time were included. The RoB 2 was used to assess quality of randomized trials, and the ROBINS-I was used to assess the quality of nonrandomized trials. Studies with a low risk of bias or some concerns in no more than 1 domain were included. Data collected and analyzed included wound type, interventions, sample size, outcome measures, and adverse effects.
RESULTS
The search yielded 101 studies, of which 17 RCTs and 8 NRCTs were eligible for inclusion. Of the included studies, 56% had a low risk of bias in all domains. The sample sizes varied between 20 and 130 (median, 60), with a total sample size of 1653 patients. Phenytoin improved wound healing in 17 of the 24 studies that evaluated it (71%), increased granulation tissue in 9 of the 10 studies that evaluated it (90%), provided analgesic effects in 7 of the 13 studies that evaluated it (54%), and inhibited bacterial contaminants in 6 of the 8 studies that evaluated it (75%). Adverse effects were rare (29%), minimal, and transient.
CONCLUSION
Phenytoin enhances wound healing and offers analgesic and antibacterial properties with minimal adverse effects. Further research is needed on optimal dosage of phenytoin, as well as frequency, delivery vehicles, and effects on other postoperative wounds.
Topics: Humans; Phenytoin; Anti-Bacterial Agents; Wound Healing; Analgesics; Pain
PubMed: 38479432
DOI: No ID Found -
The Lancet Regional Health. Europe Mar 2024The short- and long-term consequences of restricted fetal growth cause considerable concern, and how prenatal exposure to different antiseizure medications (ASMs)...
BACKGROUND
The short- and long-term consequences of restricted fetal growth cause considerable concern, and how prenatal exposure to different antiseizure medications (ASMs) affects fetal growth remains uncertain.
METHODS
This was a population-based cohort study of liveborn singleton children born in Denmark, Finland, Iceland, Norway, and Sweden from 1996 to 2017. Prenatal exposure was defined as maternal filling of prescriptions for ASM during pregnancy registered in national prescription registries and primary outcomes were adjusted odds ratios (aORs) of microcephaly or being born small for gestational age.
FINDINGS
We identified 4,494,918 children (males: 51.3%, 2,306,991/4,494,918), including 38,714 (0.9%) children of mothers with epilepsy. In the overall population, prenatal monotherapy exposure with carbamazepine (aOR: 1.25 (95% CI: 1.12-1.40)), pregabalin (aOR: 1.16 (95% CI: 1.02-1.31)), oxcarbazepine (aOR: 1.48 (95% CI: 1.28-1.71)), clonazepam (aOR: 1.27 (95% CI: 1.10-1.48)), and topiramate (aOR: 1.48 (95% CI: 1.18-1.85)) was associated with risk of being born small for gestational age, and carbamazepine was associated with microcephaly (aOR: 1.43 (95% CI: 1.17-1.75)). In children of mothers with epilepsy, prenatal exposure to carbamazepine (aOR: 1.27 (95% CI: 1.11-1.47)), oxcarbazepine (aOR: 1.42 (95% CI: 1.18-1.70)), clonazepam (aOR: 1.40 (95% CI: 1.03-1.89)), and topiramate (aOR: 1.86 (95% CI: 1.36-2.54)) was associated with being born small for gestational age; carbamazepine, with microcephaly (aOR: 1.51 (95% CI: 1.17-1.95)). No associations with small for gestational age and microcephaly were identified after prenatal exposure to lamotrigine, valproate, gabapentin, levetiracetam, phenobarbital, acetazolamide, phenytoin, clobazam, primidone, zonisamide, vigabatrin, ethosuximide and lacosamide, but except for lamotrigine, valproate, gabapentin, and levetiracetam, numbers of exposed children were small.
INTERPRETATION
Prenatal exposure to carbamazepine, oxcarbazepine, clonazepam, and topiramate was associated with increased risk of being born small for gestational age in both the overall population and in children of women with epilepsy suggesting that prenatal exposure to these drugs is associated with fetal growth restriction.
FUNDING
The NordForsk Nordic Program on Health and Welfare (83539), the Independent Research Fund Denmark (1133-00026B), the Danish Epilepsy Association, the Central Denmark Region, the Novo Nordisk Foundation (NNF16OC0019126 and NNF22OC0075033), and the Lundbeck Foundation (R400-2022-1205).
PubMed: 38476755
DOI: 10.1016/j.lanepe.2024.100849 -
Journal of Neurosciences in Rural... 2024
PubMed: 38476420
DOI: 10.25259/JNRP_468_2023 -
Chemistry & Biodiversity May 2024N-Arylenaminones are highly versatile compounds which can be synthesized in relatively simple ways. In this work we explored the synthesis of the four monosubstituted...
N-Arylenaminones are highly versatile compounds which can be synthesized in relatively simple ways. In this work we explored the synthesis of the four monosubstituted N-(4-R-phenyl)enaminones 3 a (R=NO), 3 b (R=F), 3 c (R=H), and 3 d (R=OMe) with the goal of determining the influence of the substituents' electronic effects on tautomer stability and biological activity. These compounds were analyzed by means of Density Functional Theory calculations (DFT), to evaluate the relative stability of the possible tautomers. We found that the enaminone structure is the most stable with respect to the ketoimine and iminoenol forms. In addition, all four compounds display anticonvulsant activity, with 3 d being the one that mostly increased latency and mostly decreased the number of convulsions with respect to the control group. The suggested mechanism of action involves blockage of the voltage-dependent Na channels, considering that these molecules meet the structural characteristics needed to block the receptor, as is the case of the positive control molecules phenytoin (PHT) and valproic acid (VPA).
Topics: Anticonvulsants; Density Functional Theory; Animals; Seizures; Structure-Activity Relationship; Mice; Molecular Structure
PubMed: 38472742
DOI: 10.1002/cbdv.202400056 -
RSC Advances Mar 2024An innovative molecularly imprinted polymer membrane (MIPM) was prepared with polyvinylidene difluoride (PVDF) as the support, phenytoin (PHT) as the single template,...
Fabrication of a surface molecularly imprinted polymer membrane based on a single template and its application in the separation and extraction of phenytoin, phenobarbital and lamotrigine.
An innovative molecularly imprinted polymer membrane (MIPM) was prepared with polyvinylidene difluoride (PVDF) as the support, phenytoin (PHT) as the single template, methacrylic acid as the functional monomer, ethylene glycol dimethacrylate as the cross-linking reagent, azobisisobutyronitrile as the initiator, and acetonitrile-dimethylformamide (1 : 1.5, v/v) as the porogen. These materials were characterized scanning electron microscopy, Fourier transform infrared spectroscopy, Brunauer-Emmett-Teller measurements and X-ray photoelectron spectroscopy. Their adsorption performances were evaluated through a series of experiments including isothermal adsorption, kinetic adsorption, selective adsorption, adsorption-desorption, reusability, and preparation reproducibility. Additionally, the application was explored by investigating the extraction recovery of MIPMs towards PHT, phenobarbital (PHB) and lamotrigine (LTG) in different matrices including methanol, normal saline (NS), phosphate buffer solution (PBS) and plasma. The results showed that MIPMs with rough and porous surfaces were successfully constructed, which offered good preparation reproducibility, reusability and selectivity. The adsorption capacities of MIPMs towards PHT, PHB and LTG were 2.312, 2.485 and 2.303 mg g, respectively, while their corresponding imprinting factors were 8.538, 12.122 and 4.562, respectively. The adsorption equilibrium of MIPMs was achieved within 20 min at room temperature without stirring or ultrasonication. The extraction recoveries of MIPMs for PHT, PHB or LTG in methanol, NS and PBS were more than 80% with an RSD% value of less than 3.64. In the case of plasma, the extraction recovery of MIPMs for PHT and PHB was more than 80% with an RSD% value of less than 2.41, while that of MIPMs for LTG was more than 65% with an RSD% value of less than 0.99. All the results indicated that the preparation method for MIPMs was simple, stable, and reliable, and the prepared MIPMs possessed excellent properties to meet the extraction application of PHT, PHB and LTG in different matrices.
PubMed: 38469200
DOI: 10.1039/d4ra00294f -
Cureus Feb 2024We present a case of a three-year-old girl with a rare genetic epilepsy with developmental delay. She was born to a non-consanguineous parentage and required...
We present a case of a three-year-old girl with a rare genetic epilepsy with developmental delay. She was born to a non-consanguineous parentage and required resuscitation soon after delivery via cesarean section. The patient had her first seizure within 36 hours of life, which progressed into refractory epilepsy. She required multiple hospital admissions due to prolonged seizures. Despite being tried on multiple drug combinations over the years, she responded only to phenytoin. Basic imaging and other investigations, including genetic analysis, revealed a fibroblast growth factor 12 (FGF12) mutation. Mutations in these genes cause refractory early-onset seizures associated with severe developmental delay. Due to early and appropriate intervention with phenytoin, she had good seizure control which probably resulted in a better developmental outcome.
PubMed: 38465135
DOI: 10.7759/cureus.53906 -
3 Biotech Apr 2024The most promising anticonvulsant phytocompounds were explored in this work using docking, molecular dynamic (MD) simulation, and Molecular Mechanics-Poisson-Boltzmann...
UNLABELLED
The most promising anticonvulsant phytocompounds were explored in this work using docking, molecular dynamic (MD) simulation, and Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) approaches. A total of 70 phytochemicals were screened against α-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA), -methyl-d-aspartate (NMDA), voltage-gated sodium ion channels (VGSC), and carbonic anhydrase enzyme II (CA II) receptors, and the docking results were compared to the reference drug phenytoin. Amentoflavone displayed the highest affinity for AMPA and VGSC receptors, with docking scores of - 10.4 and - 10.1 kcal/mol, respectively. Oliganthin H-NMDA and epigallocatechin-3-gallate-CA II complexes showed docking scores of - 10.9 and - 6.9 kcal/mol, respectively. All four complexes depicted a high dock score compared to the phenytoin complex at the binding site of the corresponding proteins. The MD simulation investigated the stabilities and favorable conformation of apoproteins and ligand/reference-bound complexes. The results revealed that proteins AMPA, VGSC, and CA II were more efficiently stabilized by lead phytochemicals than phenytoin binding. Additionally, principal component analysis and MM-PBSA results suggested that these lead phytocompounds have good compactness and strong binding free energy. Further, physicochemical and pharmacokinetic studies revealed that these final lead phytochemicals would be suitable for oral intake, have sufficient intestinal permeability, and have the ability to cross the blood-brain barrier (BBB). Comprehensively, this study predicted amentoflavone as the best lead phytochemical out of the 70 anticonvulsant phytocompounds that can be used to treat epilepsy.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s13205-024-03948-1.
PubMed: 38456083
DOI: 10.1007/s13205-024-03948-1 -
Chemical Biology & Drug Design Mar 2024The research involves the synthesis of a series of new pyridine analogs 5(i-x) and their evaluation for anti-epileptic potential using in silico and in vivo models....
Synthesis, in silico screening, and biological evaluation of novel pyridine congeners as anti-epileptic agents targeting AMPA (α-amino-3-hydroxy-5-methylisoxazole) receptors.
The research involves the synthesis of a series of new pyridine analogs 5(i-x) and their evaluation for anti-epileptic potential using in silico and in vivo models. Synthesis of the compounds was accomplished by using the Vilsmeier-Haack reaction principle. AutoDock 4.2 was used for their in silico screening against AMPA (-amino-3-hydroxy-5-methylisoxazole) receptor (PDB ID:3m3f). For in vivo testing, the maximal electroshock seizure (MES) model was used. The physicochemical, pharmacokinetic, drug-like, and drug-score features of all synthesized compounds were assessed using the online Swiss ADME and Protein Plus software. The in silico results showed that all the synthesized compounds 5(i-x) had 1-3 interactions and affinities ranging from -6.5 to -8.0 kJ/mol with the targeted receptor compared to the binding affinities of the standard drug phenytoin and the original ligand of the target (P99), which were -7.6 and -6.8 kJ/mol, respectively. In vivo study results showed that the compound 5-Carbamoyl-2-formyl-1-[2-(4-nitrophenyl)-2-oxo-ethyl]-pyridinium gave 60% protection against epileptic seizures compared to 59% protection afforded by regular phenytoin. All of them met Lipinski's rule of five and had drug-likeness and drug score values of 0.55 and 0.8, respectively, making them chemically and functionally like phenytoin. According to the findings of the studies, the synthesized derivatives have the potential to be employed as a stepping stone in the development of novel anti-epileptic drugs.
Topics: Humans; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Phenytoin; Anticonvulsants; Seizures; Pyridines
PubMed: 38453241
DOI: 10.1111/cbdd.14498