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Pharmacological Reports : PR Dec 2023Overwhelming evidence indicates that some naturally occurring coumarins and terpenes are widely used in folk medicine due to their various therapeutic effects affecting...
Anticonvulsant effects of isopimpinellin and its interactions with classic antiseizure medications and borneol in the mouse tonic-clonic seizure model: an isobolographic transformation.
BACKGROUND
Overwhelming evidence indicates that some naturally occurring coumarins and terpenes are widely used in folk medicine due to their various therapeutic effects affecting the brain. Antiseizure medications (ASMs) are the principal treatment option for epilepsy patients, although some novel strategies based on naturally occurring substances are intensively investigated. This study was aimed at determining the influence of isopimpinellin (ISOP-a coumarin) when administered either separately or in combination with borneol (BOR-a monoterpenoid), on the antiseizure potencies of four classic ASMs (carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), and valproate (VPA)) in the mouse model of maximal electroshock-induced (MES) tonic-clonic seizures.
MATERIALS
Tonic-clonic seizures were evoked experimentally in mice after systemic (ip) administration of the respective doses of ISOP, BOR, and classic ASMs. Interactions for two-drug (ISOP + a classic ASM) and three-drug (ISOP + BOR + a classic ASM) mixtures were assessed isobolographically in the mouse MES model.
RESULTS
ISOP (administered alone) had no impact on the anticonvulsant potencies of four classic ASMs. Due to the isobolographic transformation of data, the combination of ISOP + VPA exerted an antagonistic interaction, whereas the two-drug mixtures of ISOP + CBZ, ISOP + PHT, and ISOP + PB produced additive interactions in the mouse MES model. The three-drug combinations of ISOP + BOR with CBZ and PHT produced additive interactions, while the three-drug combinations of ISOP + BOR with PB and VPA exerted synergistic interactions in the mouse MES model.
CONCLUSIONS
The most intriguing interaction was that for ISOP + VPA, for which the addition of BOR evoked a transition from antagonism to synergy in the mouse MES model.
Topics: Humans; Animals; Mice; Anticonvulsants; Drug Interactions; Seizures; Carbamazepine; Phenobarbital; Phenytoin; Electroshock; Drug Combinations; Disease Models, Animal; Dose-Response Relationship, Drug
PubMed: 37821793
DOI: 10.1007/s43440-023-00532-x -
Scientific Reports May 2024A growing body of evidence suggests that adverse drug reactions (ADRs) are a major cause of morbidity and mortality in the healthcare system. Fifteen to twenty-five... (Observational Study)
Observational Study
A growing body of evidence suggests that adverse drug reactions (ADRs) are a major cause of morbidity and mortality in the healthcare system. Fifteen to twenty-five percent of patients with epilepsy discontinued antiseizure drugs (ASDs) within 6 months of therapy owing to intolerable adverse drug reactions. In Ethiopia, the prevalence of antiseizure adverse drug reactions and associated factors was not extensively conducted in advanced settings like Jimma Medical Centers. Hence, the objective of this study is to assess patterns of adverse drug reactions and associated factors among ambulatory epileptic patients at tertiary hospitals in Ethiopia. A hospital-based prospective observational study was spanned for 1 year. Two hundred ninety patients were consecutively recruited into the study from all epileptic patients attending the ambulatory clinic. Relevant data were collected through patient interviews and medical chart reviews. The causality assessment was done by using the Naranjo Probability Scale. Epi-Data manager version 4.6.0.4 was used for data entry and statistical analysis was performed by Statistical Package for Social Science version 25.0 (SPSS). Stepwise backward logistic regression analysis was done to identify factors that increase the risk of antiseizure adverse drug reactions. The mean (± SD) age of the participants were 29.91(± 11.26) years. The overall prevalence of ADR was 33.8% (95% CI 29.2-39.9%). A total of 110 adverse drug reactions were identified among 98 patients with an average of 1.12 per patient. ADRs were frequently reported with phenobarbital (52.04%) and phenytoin (34.70%). The commonly identified adverse drug reactions were epigastric pain (27.55%) and central nervous system drowsiness (23.46%). Comorbidity (AOR = 5.91, 95% CI (2.14-16.32), seizure-free period of fewer than 2 years (AOR = 1.94, 95% CI (1.18-3.19), and polytherapy (AOR = 1.35, 95% CI (1.80-2.26) were significantly associated with adverse drug reactions. This trial had a comparatively high percentage of adverse medication reactions. Adverse medication reactions were more common in patients with polytherapy, comorbidities, and seizure-free durations less than two years. Therefore, medical practitioners should advise patients who exhibit these traits on how to reduce or avoid bad drug responses or provide comfort in the event of small incidents.
Topics: Humans; Female; Male; Anticonvulsants; Epilepsy; Adult; Prospective Studies; Ethiopia; Drug-Related Side Effects and Adverse Reactions; Adolescent; Young Adult; Middle Aged; Risk Factors; Prevalence
PubMed: 38773234
DOI: 10.1038/s41598-024-61393-9 -
Journal of Nanobiotechnology Apr 2024Improving the efficiency of antiseizure medication entering the brain is the key to reducing its peripheral toxicity. A combination of intranasal administration and...
Improving the efficiency of antiseizure medication entering the brain is the key to reducing its peripheral toxicity. A combination of intranasal administration and nanomedicine presents a practical approach for treating epileptic seizures via bypassing the blood-brain barrier. In this study, phenytoin (PHT) loaded layered double hydroxide nanoparticles (BSA-LDHs-PHT) were fabricated via a coprecipitation - hydrothermal method for epileptic seizure control. In this study, we expound on the preparation method and characterization of BSA-LDHs-PHT. In-vitro drug release experiment shows both rapid and continuous drug release from BSA-LDHs-PHT, which is crucial for acute seizure control and chronic epilepsy therapy. In-vivo biodistribution assays after intranasal administration indicate excellent brain targeting ability of BSA-LDHs. Compared to BSA-Cyanine5.5, BSA-LDHs-Cyanine5.5 were associated with a higher brain/peripheral ratio across all tested time points. Following intranasal delivery with small doses of BSA-LDHs-PHT, the latency of seizures in the pentylenetetrazole-induced mouse models was effectively improved. Collectively, the present study successfully designed and applied BSA-LDHs-PHT as a promising strategy for treating epileptic seizures with an enhanced therapeutic effect.
Topics: Mice; Animals; Phenytoin; Administration, Intranasal; Tissue Distribution; Seizures; Epilepsy; Nanoparticles; Hydroxides
PubMed: 38566094
DOI: 10.1186/s12951-024-02405-8 -
Journal of Cancer Research and... Apr 2024There are emerging but inconsistent evidences about anti-epileptic drugs (AEDs) as radio- or chemo-sensitizers to improve survival in glioblastoma patients. We conducted...
INTRODUCTION
There are emerging but inconsistent evidences about anti-epileptic drugs (AEDs) as radio- or chemo-sensitizers to improve survival in glioblastoma patients. We conducted a nationwide population-based study to evaluate the impact of concurrent AED during post-operative chemo-radiotherapy on outcome.
MATERIAL AND METHODS
A total of 1057 glioblastoma patients were identified by National Health Insurance Research Database and Cancer Registry in 2008-2015. Eligible criteria included those receiving surgery, adjuvant radiotherapy and temozolomide, and without other cancer diagnoses. Survival between patients taking concurrent AED for 14 days or more during chemo-radiotherapy (AED group) and those who did not (non-AED group) were compared, and subgroup analyses for those with valproic acid (VPA), levetiracetam (LEV), or phenytoin were performed. Multivariate analyses were used to adjust for confounding factors.
RESULTS
There were 642 patients in the AED group, whereas 415 in the non-AED group. The demographic data was balanced except trend of more patients in the AED group had previous drug history of AEDs (22.6% vs. 18%, P 0.078). Overall, the AED group had significantly increased risk of mortality (HR = 1.18, P 0.016) compared to the non-AED group. Besides, an adverse dose-dependent relationship on survival was also demonstrated in the AED group (HR = 1.118, P 0.0003). In subgroup analyses, the significant detrimental effect was demonstrated in VPA group (HR = 1.29,P 0.0002), but not in LEV (HR = 1.18, P 0.079) and phenytoin (HR = 0.98, P 0.862).
CONCLUSIONS
Improved survival was not observed in patients with concurrent AEDs during chemo-radiotherapy. Our real-world data did not support prophylactic use of AEDs for glioblastoma patients.
Topics: Humans; Female; Anticonvulsants; Male; Glioblastoma; Middle Aged; Brain Neoplasms; Aged; Chemoradiotherapy, Adjuvant; Adult; Cohort Studies; Phenytoin; Registries; Levetiracetam; Valproic Acid
PubMed: 38687925
DOI: 10.4103/jcrt.jcrt_750_22 -
Brain Sciences May 2024Epilepsy is a neurological disease that affects approximately 50 million people worldwide. Despite an existing abundance of antiepileptic drugs, lifelong disease...
Epilepsy is a neurological disease that affects approximately 50 million people worldwide. Despite an existing abundance of antiepileptic drugs, lifelong disease treatment is often required but could be improved with alternative drugs that have fewer side effects. Given that epileptic seizures stem from abnormal neuronal discharges predominately modulated by the human sodium channel Nav1.2, the quest for novel and potent Nav1.2 blockers holds promise for epilepsy management. Herein, an in vivo approach was used to detect new antiepileptic compounds using the maximum electroshock test on mice. Pre-treatment of mice with extracts from the plant ameliorated the tonic hind limb extensor phase of induced convulsions. Subsequently, an in silico approach identified potential Nav1.2 blocking compounds from using a combination of computational techniques, including molecular docking, prime molecular mechanics/generalized Born surface area (MM/GBSA) analysis, and molecular dynamics (MD) simulation studies. The molecular docking and MM/GBSA analysis indicated that out of 82 compounds known to be present in , seven exhibited relatively strong binding affinities to Nav1.2 that ranged from -6.555 to -13.476 kcal/mol; similar or with higher affinity than phenytoin (-6.660 kcal/mol), a known Na-channel blocking antiepileptic drug. Furthermore, MD simulations revealed that two compounds: 6-C-glucosyl-8-C-arabinosyl apigenin and pelargonidin-3-rhamnoside could form stable complexes with Nav1.2 at 300 K, indicating their potential as lead antiepileptic agents. In summary, the combination of in vivo and in silico approaches supports the potential of phytochemicals as natural antiepileptic therapeutic agents.
PubMed: 38928545
DOI: 10.3390/brainsci14060545 -
Pharmaceutics Aug 2023Therapeutic drug monitoring (TDM) is the clinical practice of measuring drug concentrations. TDM can be used to determine treatment efficacy and to prevent the...
Therapeutic drug monitoring (TDM) is the clinical practice of measuring drug concentrations. TDM can be used to determine treatment efficacy and to prevent the occurrence or reduce the risk of drug-induced side effects, being, thus, a tool of personalized medicine. Drugs for which TDM is applied should have a narrow therapeutic range and exhibit both significant pharmacokinetic variability and a predefined target concentration range. The aim of our study was to assess the current status of TDM in Greek public hospitals and estimate its progress over the last 20 years. All Greek public hospitals were contacted to provide data and details on the clinical uptake of TDM in Greece for the years 2003 and 2021 through a structured questionnaire. Data from 113 out of 132 Greek hospitals were collected in 2003, whereas for 2021, we have collected data from 98 out of 122 hospitals. Among these, in 2003 and 2021, 64 and 51 hospitals, respectively, performed TDM. Antiepileptics and antibiotics were the most common drug categories monitored in both years. The total number of drug measurement assays decreased from 2003 to 2021 (153,313 ± 7794 vs. 90,065 ± 5698; = 0.043). In direct comparisons between hospitals where TDM was performed both in 2003 and 2021 (n = 35), the mean number of measurements was found to decrease for most drugs, including carbamazepine (198.8 ± 46.6 vs. 46.6 ± 10.1, < 0.001), phenytoin (253.6 ± 59 vs. 120 ± 34.3; = 0.001), amikacin (147.3 ± 65.2 vs. 91.1 ± 71.4; = 0.033), digoxin (783.2 ± 226.70 vs. 165.9 ± 28.9; < 0.001), and theophylline (71.5 ± 28.7 vs. 11.9 ± 6.4; = 0.004). Only for vancomycin, a significant increase in measurements was recorded (206.1 ± 96.1 vs. 789.1 ± 282.8; = 0.012). In conclusion, our findings show that TDM clinical implementation is losing ground in Greek hospitals. Efforts and initiatives to reverse this trend are urgently needed.
PubMed: 37765152
DOI: 10.3390/pharmaceutics15092181 -
Pharmaceutics May 2024Carbamazepine (CBZ) is commonly prescribed for epilepsy and frequently used in polypharmacy. However, concerns arise regarding its ability to induce the metabolism of...
Applying Physiologically Based Pharmacokinetic Modeling to Interpret Carbamazepine's Nonlinear Pharmacokinetics and Its Induction Potential on Cytochrome P450 3A4 and Cytochrome P450 2C9 Enzymes.
Carbamazepine (CBZ) is commonly prescribed for epilepsy and frequently used in polypharmacy. However, concerns arise regarding its ability to induce the metabolism of other drugs, including itself, potentially leading to the undertreatment of co-administered drugs. Additionally, CBZ exhibits nonlinear pharmacokinetics (PK), but the root causes have not been fully studied. This study aims to investigate the mechanisms behind CBZ's nonlinear PK and its induction potential on CYP3A4 and CYP2C9 enzymes. To achieve this, we developed and validated a physiologically based pharmacokinetic (PBPK) parent-metabolite model of CBZ and its active metabolite Carbamazepine-10,11-epoxide in GastroPlus. The model was utilized for Drug-Drug Interaction (DDI) prediction with CYP3A4 and CYP2C9 victim drugs and to further explore the underlying mechanisms behind CBZ's nonlinear PK. The model accurately recapitulated CBZ plasma PK. Good DDI performance was demonstrated by the prediction of CBZ DDIs with quinidine, dolutegravir, phenytoin, and tolbutamide; however, with midazolam, the predicted/observed DDI AUC ratio was 0.49 (slightly outside of the two-fold range). CBZ's nonlinear PK can be attributed to its nonlinear metabolism caused by autoinduction, as well as nonlinear absorption due to poor solubility. In further applications, the model can help understand DDI potential when CBZ serves as a CYP3A4 and CYP2C9 inducer.
PubMed: 38931859
DOI: 10.3390/pharmaceutics16060737 -
Journal of Neurosciences in Rural... 2024
PubMed: 38476420
DOI: 10.25259/JNRP_468_2023 -
ACS Chemical Neuroscience Mar 2024Voltage-gated sodium channel (Na) inhibitors are used to treat neurological disorders of hyperexcitability such as epilepsy. These drugs act by attenuating neuronal...
Voltage-gated sodium channel (Na) inhibitors are used to treat neurological disorders of hyperexcitability such as epilepsy. These drugs act by attenuating neuronal action potential firing to reduce excitability in the brain. However, all currently available Na-targeting antiseizure medications nonselectively inhibit the brain channels Na1.1, Na1.2, and Na1.6, which potentially limits the efficacy and therapeutic safety margins of these drugs. Here, we report on XPC-7724 and XPC-5462, which represent a new class of small molecule Na-targeting compounds. These compounds specifically target inhibition of the Na1.6 and Na1.2 channels, which are abundantly expressed in excitatory pyramidal neurons. They have a > 100-fold molecular selectivity against Na1.1 channels, which are predominantly expressed in inhibitory neurons. Sparing Na1.1 preserves the inhibitory activity in the brain. These compounds bind to and stabilize the inactivated state of the channels thereby reducing the activity of excitatory neurons. They have higher potency, with longer residency times and slower off-rates, than the clinically used antiseizure medications carbamazepine and phenytoin. The neuronal selectivity of these compounds is demonstrated in brain slices by inhibition of firing in cortical excitatory pyramidal neurons, without impacting fast spiking inhibitory interneurons. XPC-5462 also suppresses epileptiform activity in an ex vivo brain slice seizure model, whereas XPC-7224 does not, suggesting a possible requirement of Nav1.2 inhibition in 0-Mg- or 4-AP-induced brain slice seizure models. The profiles of these compounds will facilitate pharmacological dissection of the physiological roles of Na1.2 and Na1.6 in neurons and help define the role of specific channels in disease states. This unique selectivity profile provides a new approach to potentially treat disorders of neuronal hyperexcitability by selectively downregulating excitatory circuits.
Topics: Humans; Neurons; Voltage-Gated Sodium Channels; Epilepsy; Brain; Seizures; Action Potentials
PubMed: 38359277
DOI: 10.1021/acschemneuro.3c00757 -
Cureus Oct 2023The evaluation of the skin of the decedent is an essential component of the assessment by the forensic pathologist or the medical examiner. Age-associated cutaneous...
The evaluation of the skin of the decedent is an essential component of the assessment by the forensic pathologist or the medical examiner. Age-associated cutaneous changes, primary diseases of the skin, and systemic conditions with mucocutaneous manifestations can be present. Importantly, several dermatoses can be misinterpreted for traumatic injuries; specifically, adverse reactions to medications can mimic assault, burns, elder abuse, and mutilation or torture. A male with corticosteroid-induced dermatitis mimicking an acute burn is described. A female with thalidomide embryopathy is reported with extensive deformities of her hands and feet with multiple absent digits mimicking a severe injury resulting from mutilation or torture. Another female is described who had hydroxychloroquine-associated hyperpigmentation; her physician misinterpreted the cutaneous hyperpigmentation as bruises and notified Adult Protective Services. Reactions to medications can also mimic assault, burns, and elder abuse. Drug reaction with eosinophilia and systemic symptoms (particularly when associated with phenytoin) can mimic assault. Albeit rarely, the antihypertensive irbesartan can result in dramatic edema of the face and eyelids similar to that observed following an assault. Drug-induced erythema multiforme can mimic a localized burn, and Stevens-Johnson syndrome or vancomycin infusion reaction can mimic an extensive burn. Several medications can mimic bruising observed in victims of elder abuse; they include amiodarone, arsenic, and tetracyclines (such as minocycline and doxycycline). In summary, an important aspect of the forensic evaluation during an autopsy includes a complete cutaneous examination; to aid in differentiating medication-associated dermatoses that can mimic traumatic injury, the evaluation of the decedent by a forensic dermatologist may be helpful to establish the etiology of observed skin changes.
PubMed: 38021749
DOI: 10.7759/cureus.47734