Phenytoin Research Articles

Drug release profile of phenytoin-loaded starch-based biomaterials incorporating hierarchical microparticles with photothermal effects

This study aimed to synthesize phenytoin (PHT)-loaded water chestnut starch-based biomaterials and evaluate their drug release kinetics for use in transdermal drug delivery systems for antiepileptic therapy. Hierarchical microparticles (HMPs) extracted from human hair were also used to improve the PHT release efficiency. The physicochemical characteristics of PHT, HMPs, and the prepared biomaterials were evaluated by physical properties, antimicrobial activities, FE-SEM, FT-IR, XRD, 1H NMR, and 13C CPMAS solid-state NMR. The photothermal effect and the PHT release profile were confirmed through 808 nm NIR laser irradiation. After 30 min of the laser exposure, the temperature of the HMP-added biomaterials increased by 1.50–1.59 times compared to that of without the HMPs. PHT release in buffers and artificial skin test under NIR laser irradiation enhanced by 1.20–1.85 times owing to the photothermal effect. The release kinetics in pH buffer and artificial skin were determined using the Fickian diffusion and Korsmeyer-Peppas models. Additionally, to verify the transdermal penetration of PHT, drug-release simulations were conducted using rhodamine B in agar blocks and pig ears. The results implied that the photothermal effect of the HMPs enhanced the penetration of the drug.

Nano-strategies for advancing oral drug delivery: Porous silicon particles and cyclodextrin encapsulation for enhanced dissolution of poorly soluble drugs

Development of novel active pharmaceutical ingredients (API) for oral use often face challenges due to low bioavailability. Nanoparticle-based drug delivery systems and cyclodextrin (CD) encapsulation offer promising solutions by enhancing API solubility or dissolution rates. Porous silicon nanoparticles have shown potential to encapsulate APIs in their amorphous form within the pores, improving their dissolution rates compared to crystalline counterparts. A novel synthesis approach, circumventing the expensive and tedious synthesis from Si wafer material, has been developed using centrifugal Chemical Vapor Deposition (cCVD). Herein, various cCVD Si particles were evaluated for their ability to enhance the dissolution rate of the model drugs celecoxib (CEL), phenytoin (PHT), griseofulvin (GRI), diclofenac (DCF) and naproxen (NAP). Our findings demonstrate increased dissolution rates of all tested APIs when formulated with cCVD Si particles, compared to free API in pH 7.4 or pH 2.0. Particle characteristics were largely retained after loading, and the solid state of the loaded APIs were evaluated using Differential Scanning Calorimetry (DSC). Dissolution kinetics were influenced by the particle properties, mass loading and API characteristics. Loading of CD-CEL, −GRI and −DCF complexes into the cCVD Si particles showed a potential for further enhanced dissolution rates, representing the first reported investigation of this combination. In conclusion, the cCVD Si particles are promising for improving the dissolution rate of poorly soluble drugs, potentially due to precipitation of amorphous or metastable forms. Further enhancements were observed upon loading CD-drug complexes, thereby offering promising strategies for optimizing drug bioavailability.

Drug-induced hypersensitivity syndrome due to phenytoin: Case report and review of the literature.

Drug hypersensitivity syndrome (DIHS) is a rare but potentially fatal adverse drug reaction characterized by fever, rash, and visceral organ damage, particularly affecting the liver. Early recognition and appropriate management are crucial to prevent serious complications. However, there is limited information on the clinical presentation and management of DIHS, especially in the context of antiepileptic drugs. This case report aims to highlight the importance of recognizing subtle clinical signs and symptoms of DIHS, which can be easily overlooked, particularly in the context of antiepileptic drug use. We report a case of a 15-year-old male patient who developed DIHS after being prescribed phenytoin sodium for epilepsy. The patient presented with symptoms of fever, sore throat, rash, jaundice, and liver dysfunction. Initially, the patient did not receive glucocorticoids and experienced additional reactions to cefoxitin and phosphatidylcholine, likely due to cross-reactivity. The diagnosis of DIHS was made based on the patient's clinical presentation, including fever, extensive rash, organ involvement, and hematological abnormalities. The temporal association with the use of phenytoin sodium, along with the exclusion of other causes of fever and rash, supported the diagnosis. Upon initiation of glucocorticoid therapy with dexamethasone, the patient's symptoms significantly improved. The rash and pruritus decreased, and laboratory values showed improvement, with a decrease in liver enzymes and normalization of white blood cell counts. The patient's fever resolved within 48 hours of starting corticosteroids, and there was no evidence of ongoing inflammation as indicated by a decrease in C-reactive protein levels. Furthermore, the patient's 30-month follow-up revealed no recurrence of rash, liver dysfunction, or organic damage, indicating the long-term effectiveness of the treatment administered. This case highlights the importance of recognizing the subtle clinical signs and symptoms of DIHS, especially in the context of antiepileptic drug use. It underscores the potential benefits of early initiation of glucocorticoid therapy in managing DIHS. The case also serves as a reminder of the potential for drug cross-reactivity in DIHS and the need for cautious drug selection during the acute phase of the syndrome.

Patient resuscitated after cardiopulmonary arrest exhibits abnormally increased phenytoin metabolic rate due to unknown factors: a case report

BackgroundFosphenytoin (FOS) is a prodrug of phenytoin (PHT) with a metabolism that exhibits Michaelis–Menten-type kinetics. Genetic polymorphisms of the metabolic enzymes of PHT make it challenging to predict its plasma concentrations. High plasma PHT concentrations are typically problematic, and several causes have been elucidated. In contrast, cases of patients with low PHT plasma concentrations that did not increase despite the administration of appropriate PHT doses have been reported, and the causes may include changes in plasma protein-binding rates, genetic mutations, and concomitant use of drugs that induce liver enzymes; however, even these factors do not explain the low PHT plasma concentrations in some cases.Case presentationWe encountered the case of a patient with plasma PHT concentrations that were continuously < 0.7 µg/mL after daily use of FOS for seizures that occurred after cardiopulmonary arrest. We analyzed the protein-unbound fraction, urinary metabolites, and related genes to investigate the cause. False negatives due to the measurement method, errors in dosage and administration method, and increased excretion of PHT were excluded. Hepatic metabolic activity of PHT increased to 4.6–6.1 times the normal level. The S/R ratio of 5-(p-hydroxyphenyl)-5-phenylhydantoin-glucuronide, a major PHT metabolite, was normal at 15.2, suggesting increased activities of CYP2C9 and CYP2C19. Furthermore, the protein-unbound fraction of PHT was 5.2–6.9%, CYP2C19*17 was wild type, and there was no concomitant drug use to induce both enzymes.ConclusionsThe low PHT plasma concentration in this patient was found to be caused by increased hepatic metabolic activity that could not be explained by known factors. Careful monitoring is necessary to consider the possibility of increased hepatic metabolic activity in similar cases.

Intravenous levetiracetam versus intravenous phenytoin as second Line treatment in pediatric convulsive status epilepticus- open label randomized controlled trial.

Benzodiazepines (BZDs) are recommended as the initial therapy of choice in status epilepticus (SE). The age-old second-line treatment for BZD refractory convulsive SE is intravenous phenytoin (PHT) based predominantly on nonrandomized clinical trial data. We did this study to compare the efficacy and safety of intravenous levetiracetam (LEV) and PHT as second-line antiseizure medication (ASM) for children with SE. A prospective, randomized controlled, open-label study was conducted in children 3 months to 15 years of age with SE in Pediatric Emergency. A total of 41 children were randomly allocated to either group 1 (Levetiracetam) or group 2 (Phenytoin) on the basis of computer-generated randomization. Children who were already on antiseizure medications, either LEV or PHT, or receiving these drugs outside for SE were excluded. Data analysis was done by SPSS V25. The most common age group presenting with SE was 12 months to 5 years. Clinical cessation of seizure 5 minutes after the completion of drugs was 85% (17/20) in Levetiracetam group and 90.5% (19/21) in Phenytoin group. Recurrence of seizure within 24 hours was noted in 35% (7/20) in Levetiracetam group and 38.1% (8/21) in Phenytoin group. There was no statistically significant difference noted in both the groups in terms of seizure cessation, adverse events, and recurrence. The efficacy and safety of LEV were found to be comparable to those of PHT in controlling seizure as second-line ASM in SE.

Antiepileptic Drugs as Prophylaxis for Seizures after Excision of Brain Tumors

Abstract Background Seizures are the most common &amp; most serious side effect of cranial surgery. The latter condition requires chronic treatment with Antiepileptic drugs (AEDs) and comes with relevant socioeconomic sequelae. The routine prophylactic use of AEDs for people undergoing tumor resection has remained controversial due to the risk of postoperative seizures. Some Neurosurgeons are advocates to the use of AEDs to reduce the risk of these seizures. Objective To evaluate the efficacy of prophylactic AEDs routinely in brain tumor patients without previous history of seizures. Primary objective has been to identify the efficacy of AEDs in perioperative seizure prophylaxis. Secondary objective has been to highlight the most common type of post-operative AEDs. Methods All available studies from 2000-2021 including randomized or non-randomized clinical trials, prospective or retrospective observational cohort studies, and case series of six or more cases that address these criteria have been collected. Results Our search concluded that the most common type of post-operative seizure is the Early seizure which is of total 87 patients representing 12.3% of seizure reported patients, yet when comparing the P-value between the Early &amp; late seizure it has a P-value of 0.415 which is nonsignificant rendering the comparison redundant. The Most common types of AED used are Phenytoin (PHT) 89 (71.8%) &amp; Levetiracetam (LEV) 109 (81.8%). To measure the efficacy of AEDs two groups of patients with no history of AED administration or seizures preoperatively were created, one the control group of 268 participants were not administered AEDs postoperatively only 32 (11.94%) of them suffered from seizures postoperatively. The other group of 171 participants were administered the AEDs postoperatively only 25 (14.62%) of these participants suffered from postoperative seizure. Comparing both of these results statistically it had a P-value of 0.416 which is non-Significant statistically. On interpreting these results was that the AED have no influence in controlling the seizures. Conclusion Postoperative seizures are one of the main complications of brain tumor surgery. Neurosurgeons have a strong belief more of tradition that preventing seizures with Anti-Epileptic Drugs (AEDs) as a sort of seizure prophylaxis is not only effective but also necessary. Finally, there is not enough evidence of sufficient quality available to suggest that antiepileptic drugs AEDs treatment can or cannot be recommended to reduce Post-craniotomy seizures.

Development of UPLC–MS/MS method for the simultaneous quantification of valproic acid and phenytoin in human plasma and application to study pharmacokinetic interaction in epilepsy patients

Valproic acid and phenytoin are two prevalent antiepileptic medications known for their narrow indices and propensity for cardiovascular and respiratory system toxicity. Therefore, therapeutic drug monitoring (TDM) of valproic acid (VAL) and phenytoin (PHE) concentrations in patient plasma is extremely beneficial for improving clinical choices, avoiding adverse reactions, and optimizing treatment for individual patients. In this study, a rapid and sensitive ultra-performance liquid chromatographic tandem mass spectrometer (UPLC-MS/MS) method was developed and validated for the simultaneous quantitative determination of valproic acid (VAL) and phenytoin (PHE) in human plasma. Negative electron spray ionization (ESI-) mode with selective ion recording (SIR) was employed to determine the transitions of m/z 142.98 and m/z 250.93 for VAL and PHE, respectively. The internal standard (IS) betamethasone (BETA) was ionized using positive electron spray ionization (ESI+) and detected by multi-reaction monitoring (MRM) mode to obtain precursor ions and specific fragment ions for quantification, and the MRM transition was chosen to be m/z 393.17 → 355.16. The separation was performed using a Phenomenex Synergi Hydro-RP (4 μm, 250 × 4.6 mm, I.D.) with an isocratic mobile phase consisting of acetonitrile – water (75:25, v/v) at a flow rate of 0.8 mL/min. The column temperature was maintained at 25 °C. The lower limit of quantification of VAL and PHE was 3.6 μg/mL and 0.72 μg/mL, respectively, which resulted in a recovery of more than 85 % for most analytes. According to US-FDA bioanalytical technique validation, the specificity, intra- and inter-day precision and accuracy, matrix effect, carryover, dilution, and stability of all analytes were within acceptable ranges. This analytical method was successful in evaluating the levels of valproic acid and phenytoin in human plasma from epileptic patients.

Molecularly imprinted polymer-based extended-gate field-effect transistor chemosensors for selective determination of antiepileptic drug.

Ultrathin molecularly imprinted polymer (MIP) films were deposited on the surfaces of ZnO nanorods (ZNRs) and nanosheets (ZNSs) by electropolymerization to afford extended-gate field-effect transistor sensors for detecting phenytoin (PHT) in plasma. Molecular imprinting efficiency was optimized by controlling the contents of functional monomers and the template in the precursor solution. PHT sensing was performed in plasma solutions with various concentrations by monitoring the drain current as a function of drain voltage under an applied gate voltage of 1.5V. The reliability and reproducibility of the fabricated sensors were evaluated through a solution treatment process for complete PHT removal and PHT adsorption-removal cycling, while selectivity was examined by analyzing responses to chemicals with structures analogous to that of PHT. Compared withthe ZNS/extracted-MIP sensor and sensors with non-imprinted polymer (NIP) films, the ZNR/extracted-MIP sensor showed superior responses to PHT-containing plasma due to selective PHT adsorption, achieving an imprinting factor of 4.23, detection limit of 12.9ng/mL, quantitation limit of 53.0ng/mL, and selectivity coefficients of 3-4 (against tramadol) and ~ 5 (against diphenhydramine). Therefore, we believe that the MIP-based ZNR sensing platform is promising for the practical detection of PHT and other drugs and evaluation of their proper dosages.

The Phenytoin Ataxia Enigma Unveiled ''A Case Report''.

Background: Phenytoin (PHT) has been approved for the treatment of epilepsy. It belongs to the category of medications with a limited therapeutic window and requires therapeutic drug monitoring (TDM). PTH has been observed to induce a variety of Adverse drug reactions (ADRs) including ataxia, dystonia, nystagmus, dyskinesia, etc. Phenytoin-induced ataxia is an uncommonly observed ADR of Phenytoin whose reports are extremely limited. Case: Herein, we present a case report of a 16-year-old Asian patient with a past history of epilepsy that was admitted to a tertiary care hospital due to the development of ataxia, giddiness, and vomiting when taking Phenytoin in addition to Oxcarbazepine, Clobazam, and Levetiracetam to treat seizures. On admission, Magnetic resonance imaging (MRI) findings revealed bilateral variable cerebrospinal fluid (CSF) lesions in the parieto-occipital region of the periventricular area (periventricular leukomalacia). Additionally, serum Phenytoin levels were observed to be in the toxic range (40μg/mL) due to which physicians confirmed the ADR to be due to Phenytoin toxicity. Thus, the Phenytoin drug was discontinued in the patient gradually and he was continued on clobazam, oxcarbazepine, and brivaracetam which led to reversal of the ADR in the patient. Conclusion: In this case, ataxia resulted from Phenytoin overdose, as confirmed by MRI and serum tests suggesting that TDM of Phenytoin is essential to prevent ADRs. Given the scarcity of ataxia cases caused by Phenytoin, awareness is lacking within the scientific community. Our aim is to provide insights to promote better monitoring and patient-centered treatment outcomes for epileptic patients.

Chemical Behavior and Bioactive Properties of Spinorphin Conjugated to 5,5'-Dimethyl- and 5,5'-Diphenylhydantoin Analogs.

The discovery of new peptides and their derivatives is an outcome of ongoing efforts to identify a peptide with significant biological activity for effective usage as a possible therapeutic agent. Spinorphin peptides have been documented to exhibit numerous applications and features. In this study, biologically active peptide derivatives based on novel peptide analogues of spinorphin conjugated with 5,5'-dimethyl (Dm) and 5,5'-diphenyl (Ph) hydantoin derivatives have been successfully synthesized and characterized. Scanning electron microscopy (SEM) and spectral methods such as UV-Vis, FT-IR (Fourier Transform Infrared Spectroscopy), CD (Circular Dichroism), and fluorimetry were used to characterize the microstructure of the resulting compounds. The results revealed changes in peptide morphology as a result of the restructuring of the aminoacidic sequences and aromatic bonds, which is related to the formation of intermolecular hydrogen bonds between tyrosyl groups and the hydantoin moiety. Electrochemical and fluorescence approaches were used to determine some physicochemical parameters related to the biological behavior of the compounds. The biological properties of the spinorphin derivatives were evaluated in vivo for anticonvulsant activity against the psychomotor seizures at different doses of the studied peptides. Both spinorphin analog peptides with Ph and Dm groups showed activity against all three phases of the seizure in the intravenous Pentylenetetrazole Seizure (ivPTZ) test. This suggests that hydantoin residues do not play a crucial role in the structure of spinorphin compounds and in determining the potency to raise the seizure threshold. On the other hand, analogs with a phenytoin residue are active against the drug-resistant epilepsy test (6-Hz test). In addition, bioactivity analyses revealed that the new peptide analogues have the potential to be used as antimicrobial and antioxidant compounds. These findings suggest promising avenues for further research that may lead to the development of alternative medicines or applications in various fields beyond epilepsy treatment.

Molecular Docking Analysis of Four Drugs (Phenytoin, Amoxicillin, Aceclofenac and Ciprofloxacin) and Their Association With Four Human Leukocyte Antigen (HLA) Alleles.

Background Numerous reports have shown the role of human leukocyte antigen (HLA) alleles in the induction of cutaneous adverse drug reactions by moderating drug metabolism. Wetherefore aimed to investigate the docking patterns of four HLA alleles (HLA-B x 5101, HLA-B x 1501, HLA-A x 02:06 and HLA-B x 57:01) against four commercial drugs. Methodology Four drugs (phenytoin (PHT), amoxicillin (AMX), aceclofenac (ACE) and ciprofloxacin (CIP)) were investigated for their docking behavior against four HLA alleles (HLA-B x 5101, HLA-B x 1501, HLA-A x 02:06, and HLA-B x 57:01) using the SwissDock method. In addition, toxicity (Tox) and the search tool for interactions of chemicals (STITCH) (protein-drug interaction) analyses were also carried out using the predicating the small molecule pharmaco-kinetic (pk) properties using graph-based signature method (pkCSM) and STITCH free online servers, respectively. Results Toxicity analysis showed that two drugs (amoxicillin and ciprofloxacin) exhibit hepatotoxicity. The STITCH analysis of the drug amoxicillin revealed its interaction with two humanproteins. The drug phenytoin exhibited the lowest binding energy (LBE) with all four HLA alleles (HLA-B x 5101, HLA-B x 1501, HLA-A x 02:06, and HLA-B x 57:01). Conclusions The present findings provide new knowledge about the four drugs (phenytoin (PHT), amoxicillin (AMX), aceclofenac (ACE) and ciprofloxacin (CIP)) and their binding affinities with HLA alleles, which may cause cutaneous adverse drug reactions.

18‑α‑glycyrrhetinic acid induces apoptosis in gingival fibroblasts exposed to phenytoin.

Phenytoin (PHT)-induced gingival overgrowth is caused by the increased proliferation and reduced apoptosis of gingival fibroblasts in inflammatory gingiva. Licorice has long been used as a component of therapeutic preparations. It inhibits cell proliferation, induces cell apoptosis and has anti-inflammatory effects. 18-α-glycyrrhetinic acid (18α-GA), the active compound in licorice, promotes apoptosis in various types of cells. The present study determined whether 18α-GA affects apoptosis in gingival fibroblasts exposed to PHT. The present study aimed to establish a basis for the therapeutic application of 18α-GA to treat the gingival overgrowth induced by PHT. Human gingival fibroblasts from healthy donors were cultured to semi-confluence and then stimulated in serum-free DMEM containing PHT with or without 18α-GA for subsequent experiments. Apoptotic cells were detected by ELISA. Analysis of the distribution of cell cycle phases and the apoptotic cell population was performed by flow cytometry. The expression levels of mRNAs and proteins of apoptotic regulators were measured using reverse transcription-quantitative PCR and western blotting, respectively. Caspase (CASP) activities were assessed by an ELISA. Treatment with 18α-GA markedly increased the number of apoptotic cells, reduced BCL2 mRNA expression, increased CASP2 and receptor (TNFRSF)-interacting serine-threonine kinase 1 (RIPK1) domain containing adaptor with death domain, Fas (TNFRSF6)-associated via death domain, RIPK1, tumor necrosis factor receptor superfamily; member 1A, TNF receptor-associated factor 2, CASP2, CASP3 and CASP9 mRNA expression, and also upregulated the protein expression levels and activities of caspase-2, caspase-3 and caspase-9. These results demonstrated that 18α-GA induced apoptosis through the activation of the Fas and TNF pathways in the death receptor signaling pathway in gingival fibroblasts treated with PHT. 18α-GA exhibited therapeutic potential for the treatment of PHT-induced gingival overgrowth.

Synaptic vesicle protein 2A mitigates parthanatos via apoptosis-inducing factor in a rat model of pharmacoresistant epilepsy.

Synaptic vesicle protein 2A (SV2A) is a unique therapeutic target for pharmacoresistant epilepsy (PRE). As seizure-induced neuronal programmed death, parthanatos was rarely reported in PRE. Apoptosis-inducing factor (AIF), which has been implicated in parthanatos, shares a common cytoprotective function with SV2A. We aimed to investigate whether parthanatos participates in PRE and is mitigated by SV2A via AIF. An intraperitoneal injection of lithium chloride-pilocarpine was used to establish an epileptic rat model, and phenytoin and phenobarbital sodium were utilized to select PRE and pharmacosensitive rats. The expression of SV2A was manipulated via lentivirus delivery into the hippocampus. Video surveillance was used to assess epileptic ethology. Biochemical tests were employed to test hippocampal tissues following a successful SV2A infection. Molecular dynamic calculations were used to simulate the interaction between SV2A and AIF. Parthanatos core index, PARP1, PAR, nuclear AIF and MIF, γ-H2AX, and TUNEL staining were all increased in PRE. SV2A is bound to AIF to form a stable complex, successfully inhibiting AIF and MIF nuclear translocation and parthanatos and consequently mitigating spontaneous recurrent seizures in PRE. Moreover, parthanatos deteriorated after the SV2A reduction. SV2A protected hippocampal neurons and mitigated epileptic seizures by inhibiting parthanatos via binding to AIF in PRE.

Different fetal effects on fingers from exposure to phenytoin, phenobarbital, and carbamazepine.

Exposure at conception to phenytoin (PHT), phenobarbital (PB), and carbamazepine (CBZ) has been associated with several different effects on the fetus, including hypoplasia of the distal phalanges, dysmorphic facial features, and structural abnormalities such as oral clefts and neural tube defects. One question is whether each of these antiepileptic drugs (AEDs) has the same effects or just similar effects. A systematic examination of the fingers of children exposed at conception to PHT, PB, or CBZ, as monotherapy, has been used to address this question. The findings in the examinations of the fingers of 115 AED-exposed children (40, PHT; 34, PB; 41, CBZ) and their parents were compared to the findings in 111 age- and sex-matched children and their parents. The evaluations used were both subjective assessments and objective measurements. Shortening and narrowing of the fifth fingernail and an increased frequency of arch patterns in the dermal ridges were more common in PHT-exposed children. A significant decrease in the length of the nail, but not width, occurred in the PB-exposed children. Stiffness of the interphalangeal joints was more common in the CBZ-exposed children. The findings in children exposed to PHT, PB, or CBZ, as monotherapy, showed that all three exposures in early pregnancy affected the fingers, but the effects were not the same. The most striking effects were present in PHT-exposed children.

Synthesis, Theoretical Study, and Anticonvulsant Evaluation of N-Arylenaminones.

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=NO2), 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).

Transmucosal administration of pentobarbital and phenytoin solution induces euthanasia in bearded dragons (Pogona vitticeps).

To assess the efficacy of transmucosal euthanasia solution to induce euthanasia. 6 bearded dragons (Pogona vitticeps). An initial dose of euthanasia solution containing pentobarbital and phenytoin sodium was administered transmucosally in conscious lizards (100 mg/kg pentobarbital dose), followed by a second dose 20 minutes later (400 mg/kg pentobarbital dose). The presence of movement, leakage of euthanasia solution, behaviors consistent with oral irritation, respiratory rate, heart rate, palpebral and corneal reflex, and response to noxious stimuli were recorded until death, confirmed by the absence of Doppler cardiac flow and cardiac electrical activity. The time to loss of all parameters was calculated. Postmortem evaluation allowed for histopathologic evaluation of the oral cavity and gastrointestinal tract to detect potential mucosal damage from the alkaline euthanasia solution. The median time to death was 300 minutes (range, 300 to 360 minutes), median time to respiratory arrest was 30 minutes (range, 30 to 50 minutes), and median time to loss of deep pain response was 30 minutes (range, 20 to 50 minutes). Signs consistent with oral irritation occurred in 4 of 6 (66.7%) lizards, including 2 lizards that exhibited whole-body spasms after euthanasia solution administration. Histopathologic changes indicating peracute mucosal ulceration, suspected to be from caustic causes, were identified in 1 (1/6 [16.7%]) lizard. Transmucosal euthanasia solution administration resulted in clinical euthanasia within 6 hours. This method should be utilized only after premedication with analgesic and/or anesthetic medications due to the potential for acute mucosal ulceration and behaviors that may be distressing in client-owned animals.

Intranasal delivery of phenytoin loaded layered double hydroxide nanoparticles improves therapeutic effect on epileptic seizures

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.

Effectiveness of Levetiracetam versus phenytoin in preventing seizure in traumatic brain injury patients: A systematic review and meta-analysis

ObjectiveTraumatic brain injury (TBI) and the subsequent Post-traumatic seizure (PTS) is a growing public health concern. Generally, anti-seizure drugs (ASDs) are recommended for PTS prophylaxis and treatment. This meta-analysis aimed to review the current state of knowledge and the evidence for the efficacy and safety of Levetiracetam (LEV) on the incidence of seizure in TBI patients compared to Phenytoin (PHT). MethodsA search was carried out based on PubMed, MEDLINE, Europe PMC database, and Cochrane Library up to November 2023. A total of 16 studies (3 randomized clinical trials, 10 retrospective cohort studies, and 3 prospective cohort studies) including 5821 TBI patients included in our meta-analysis. We included studies comparing LEV and PHT after brain injury in both adults and children. Risk of bias assessment was done for randomized controlled trials (RCTs) with a risk-of-bias tool (RoB-2) and the Newcastle–Ottawa Scale (NOS) was used to assess the quality of cohort studies. Two RCTs in our meta-analysis had a high risk of bias, therefore we applied sensitivity analysis to evaluate the robustness of our results. ResultsThe most commonly reported dosage for LEV was 500 mg twice daily and for PHT it was 5 mg/kg. There was no significant difference between LEV and PHT groups in reducing the early seizure incidence (OR = 0.85; 95% CI = [0.60, 1.21]; p = 0.375, fixed-effect, I2 = 21.75%). The result of sensitivity analysis for late seizure showed no significant difference between LEV and PHT in reducing the late seizure occurrence after TBI (OR = 0.87; 95% CI = [0.21, 3.67]; p = 0.853, fixed-effect, I2 = 0%). The mortality in TBI patients treated with LEV was not statistically significant compared to the PHT group (OR = 1.11; 95% CI = [0.92, 1.34], p = 0.266). The length of stay in the hospital was not significantly different between the LEV and PHT groups (MD = –1.33; 95% CI = [–4.55, 1.90]; p = 0.421). However, in comparison to PHT, LEV shortened the length of ICU stay (MD = –2.25; 95% CI = [–3.58, –0.91]; p =0.001). In terms of adverse effects, more patients in the PHT group have experienced adverse events compared to LEV but the difference was not significant (OR = 0.69; 95% CI = [0.44, 1.08]; p = 0. 11). ConclusionThe results of our meta-analysis showed LEV and PHT have similar effects on the occurrence of early and late seizures in TBI patients. Therefore, none of the drugs is superior to the other in reducing PTS. However, treating TBI patients with LEV did not shorten the length of hospital stay in comparison to PHT but reduced the length of ICU stay significantly. The analysis showed that patients in the LEV experienced fewer side effects than in the PHT group, while it was not sufficiently clear whether all reported side effects were related to the drug alone or other factors. The mortality was similar between the LEV and PHT groups. Finally, we recommend more high-quality randomized controlled trials to confirm the current findings before making any recommendations in practice.

A PROSPECTIVE STUDY TO ASSESS THE QUALITY OF LIFE AMONG THE PATIENTS OF GENERALIZED TONIC-CLONIC SEIZURE RECEIVING TREATMENT PHENYTOIN PLUS CLOBAZAM VERSUS SODIUM VALPROATE PLUS CLOBAZAM THERAPY

Objectives: The objective of the study was to compare effect of phenytoin plus clobazam (Group 1) and sodium valproate plus clobazam therapy (Group 2) on quality of life among generalized tonic-clonic seizures (GTCS) patients attending neurology out-patient department at the tertiary care center in Gwalior district. Methods: The present study was a prospective study conducted between period of February 2019 and January 2020 on 45–45 patients each receiving either phenytoin plus clobazam or sodium valproate plus clobazam dual therapy for the treatment of patients with GTCS. Frequency, percentage, mean, standard deviation, independent student t-test, Chi-square test, and one-way repeated measures of ANOVA were applied, and Bonferroni adjustment was calculated using SPSS version 20 software. P&lt;0.05 was considered to be statistically significant. Results: For question 1, in Group 1, mean score was 3.29±0.45 at 0 month (baseline), which reduced to 2.51±0.50 and 2.11±0.48 at 3 and 6 months, respectively. In Group 2, mean score was 3.31±0.46 at 0 month, which reduced to 2.35±0.48 and 1.95±0.29 at 3 and 6 months. For question 2, in Group 1, mean score was 3.44±0.54 at 0 month (baseline), which reduced to 2.55±0.54 and 2.22±0.51 at 3 and 6 months, respectively. In Group 2, mean score was 3.64±0.48 at 0 month, which reduced to 2.77±0.55 and 2.44±0.54 at 3 and 6 months, respectively. There was statistically significant improvement seen within the group at 3 and 6 months as compared to baseline in both groups for question 1, question 2, question 3, question 4; p&lt;0.01. Conclusion: It can be concluded that both combinations of our study groups have a better impact on quality of life from baseline till the end of the study. However, on comparison between them, we have not found a statistically significant difference.

In Rat Organotypic Hippocampal Slice Cultures, Conventional Antiepileptic Medications are Unable to Inhibit Epileptiform Activity

Context and Goal: Prior research has shown that organotypic hippocampal slice cultures (OHSCs) can elicit tonic-clinic seizure-like events (SLEs), which resemble the electroencephalographic correlates of limbic seizures in humans and animals. We have investigated whether OHSCs can be used as in vitro models of limbic seizures to research seizures processes and vetting novel antiepileptic substances. Experimental Strategy: The interface method was used to cultivate OHSCs. Under submerged conditions, the levels of extracellular potassium and neuronal activity were observed. Lowering magnesium concentrations or administering the potassium channel blocker 4-aminopyridine both caused SLEs. Analysis was done on the impact of common antiepileptic medications (AEDs) on SLEs, including carbamazepine, phenytoin, valproic acid, clonazepam, diazepam, and phenobarbital sodium. Important Outcomes: AEDs did not stop the over 93% of OHSCs from happening induction of SLEs or cease current seizure activity even in the presence of hazardous dosages. The postnatal age at explanation (P2–P10), the manner of seizure provocation, and the length of in vitro cultivation (2 months) had no bearing on this chemoresistance. GABAA-agonist muscimol or glutamate antagonists were able to reversibly block SLEs. Inferences and Conclusions: Unlike animal models of thermoresistant seizures, where responders and nonresponses may only be distinguished after an experiment, we describe an easy to set up in vitro model of tonic-clinic SLEs that is a priori thermoresistant. OHSCs may be useful for investigating the mechanisms underlying medication-resistant seizures and for the discovery of novel anticonvulsive substances that may one day be used to treat drugresistant epilepsy.