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The current study developed an innovative design for the production of smart multifunctional core-double shell superparamagnetic nanoparticles (NPs) with a focus on the development of a pH-responsive drug delivery system tailored for the controlled release of Phenytoin, accompanied by real-time monitoring capabilities. In this regard, the ultra-small superparamagnetic iron oxide@silica NPs (IO@Si MNPs) were synthesized and then coated with a layer of gelatin containing Phenytoin as an antiepileptic drug. The precise saturation magnetization value for the resultant NPs was established at 26 emu g-1. The polymeric shell showed a pH-sensitive behavior with the capacity to regulate the release of encapsulated drug under neutral pH conditions, simultaneously, releasing more amount of the drug in a simulated tumorous-epileptic acidic condition. The NPs showed an average size of 41.04 nm, which is in the desired size range facilitating entry through the blood–brain barrier. The values of drug loading and encapsulation efficiency were determined to be 2.01 and 10.05%, respectively. Moreover, kinetic studies revealed a Fickian diffusion process of Phenytoin release, and diffusional exponent values based on the Korsmeyer-Peppas equation were achieved at pH 7.4 and pH 6.3. The synthesized NPs did not show any cytotoxicity. Consequently, this new design offers a faster release of PHT at the site of a tumor in response to a change in pH, which is essential to prevent epileptic attacks., Validerad;2024;Nivå 2;2024-05-28 (hanlid);Full text license: CC BY

The current study developed an innovative design for the production of smart multifunctional core-double shell superparamagnetic nanoparticles (NPs) with a focus on the development of a pH-responsive drug delivery system tailored for the controlled release of Phenytoin, accompanied by real-time monitoring capabilities. In this regard, the ultra-small superparamagnetic iron oxide@silica NPs (IO@Si MNPs) were synthesized and then coated with a layer of gelatin containing Phenytoin as an antiepileptic drug. The precise saturation magnetization value for the resultant NPs was established at 26 emu g-1. The polymeric shell showed a pH-sensitive behavior with the capacity to regulate the release of encapsulated drug under neutral pH conditions, simultaneously, releasing more amount of the drug in a simulated tumorous-epileptic acidic condition. The NPs showed an average size of 41.04 nm, which is in the desired size range facilitating entry through the blood–brain barrier. The values of drug loading and encapsulation efficiency were determined to be 2.01 and 10.05%, respectively. Moreover, kinetic studies revealed a Fickian diffusion process of Phenytoin release, and diffusional exponent values based on the Korsmeyer-Peppas equation were achieved at pH 7.4 and pH 6.3. The synthesized NPs did not show any cytotoxicity. Consequently, this new design offers a faster release of PHT at the site of a tumor in response to a change in pH, which is essential to prevent epileptic attacks., Validerad;2024;Nivå 2;2024-05-28 (hanlid);Full text license: CC BY

BACKGROUND Status epilepticus (SE) is a neurological emergency, with the current guidelines for second-line anticonvulsants may include phenytoin, levetiracetam, valproic acid, and phenobarbital. However, some studies suggest that levetiracetam may be better at stopping seizures in SE. This study aimed to compare the efficacy of intravenous (IV) levetiracetam and phenytoin in SE. METHODS We searched PubMed, ScienceDirect, Cochrane, and Google Scholar for randomized controlled trials (RCTs) on administering IV levetiracetam or phenytoin in patients with SE. RCTs were screened using eligibility criteria, and their quality was assessed using the Cochrane risk of bias tool. Heterogeneity was assessed using the I² test, and publication bias was evaluated using Egger’s test. All analyses were performed using Review Manager version 5.4 (The Cochrane Collaboration, UK) and Stata 17 (StataCorp LLC, USA). RESULTS 12 RCTs involving 2,137 patients (1,099 receiving levetiracetam) met the inclusion criteria. Pooled analysis showed that levetiracetam therapy had a significantly higher rate of seizure cessation than phenytoin (RR: 1.10, 95% CI = 1.05−1.14, p = 0.02, I² = 51%). Less adverse events were observed in the levetiracetam group (9.34%) than in the phenytoin group (11.62%; RR: 0.82, 95% CI = 0.66–1.02, p = 0.07). However, there was no significant difference regarding IV levetiracetam or phenytoin administration with the incidence of admission to critical care (RR: 1.01; 95% CI = 0.93–1.10, p = 0.80) and mortality (RR: 1.08; 95% CI = 0.54–2.15; p = 0.82). CONCLUSIONS IV levetiracetam was significantly better in the cessation of seizures in SE patients than phenytoin.

The thyroid hormones (THs) regulate various physiological mechanisms in mammals, such as cellular metabolism, cell structure, and membrane transport. The therapeutic drugs propylthiouracil (PTU) and phenytoin are known to induce hypothyroidism and decrease blood thyroid hormone levels. To analyze the impact of these two drugs on systemic metabolism, we focused on metabolic changes after treatment. Therefore, in a rat model, the metabolome of thyroid and liver tissue as well as from the blood plasma, after 2-week and 4-week administration of the drugs and after a following 2-week recovery phase, was investigated using targeted LC-MS/MS and GC-MS. Both drugs were tested at a low dose and a high dose. We observed decreases in THs plasma levels, and higher doses of the drugs were associated with a high decrease in TH levels. PTU administration had a more pronounced effect on TH levels than phenytoin. Both drugs had little or no influence on the metabolomes at low doses. Only PTU exhibited apparent metabolome alterations at high doses, especially concerning lipids. In plasma, acylcarnitines and triglycerides were detected at decreased levels than in the controls after 2- and 4-week exposure to the drug, while sphingomyelins and phosphatidylcholines were observed at increased levels. Interestingly, in the thyroid tissue, triglycerides were observed at increased concentrations in the 2-week exposure group to PTU, which was not observed in the 4-week exposure group and in the 4-week exposure group followed by the 2-week recovery group, suggesting an adaptation by the thyroid tissue. In the liver, no metabolites were found to have significantly changed. After the recovery phase, the thyroid, liver, and plasma metabolomic profiles showed little or no differences from the controls. In conclusion, although there were significant changes observed in several plasma metabolites in PTU/Phenytoin exposure groups, this study found that only PTU exposure led to adaptation-dependent ch

Phenytoin is the most common drug prescribed in patient diagnosed with seizure. Cerebral atrophy is an observed complication in phenytoin exposed patients. The side effects related to phenytoin administration include sedation, dizziness, swaying, rash and gum hypertrophy. In the following case report a 50-year-old male patient with complaints of poor response to oral commands, slurred speech, limited upper limb movements and neck rigidity, the patient is a known epileptic since 1 year on prescription and is alcoholic. Upon CT scan of brain, the impression was mild diffuse cerebellar atrophy probably due to long term phenytoin use. Hence frequent phenytoin level monitoring in patient prescribed with the same is mandatory. Keywords: phenytoin, epilepsy, cerebral atrophy

Toxic epidermal necrolysis is a cutaneous drug reaction which is a severe adverse effect that predominantly involves the skin and mucous membrane. Phenytoin is an anti-epileptic medication that belongs to the hydantoin class. Here we are going to present a case of 50-year-old male patient with phenytoin induced toxic epidermal necrolysis. The outcome of this study was to determine the severity of the adverse reaction and its management to improve the patient condition.   Keywords: Toxic epidermal necrolysis, phenytoin, erythromatous, adverse drug reaction, body surface area.

Purpose: Dress Syndrome (Drug rash with eosinophilia and systemic symptoms) is a severe adverse drug reaction characterised by rash, fever, lymphadenopathy, and organ involvement. It is a severe, one-of-a-kind adverse medication reaction. DRESS is the most rarely seen severe adverse drug reaction, and it affects approximately 1 in a thousand to 1 in a ten thousand patients who take the drug. It is found that the mortality rate is nearly 10 %. The main objectives include - learn the importance of DRESS syndrome, recognize the signs and symptoms of DRESS, to know what diagnostic studies are indicated and to provide accurate treatment. Methods: The case of 11-year-old girl who came with history of head injury and was given phenytoin to treat it. Later she came with a complaint of numerous urticated papules and plaques on her trunk, neck, both upper and lower limbs, and febrile since 4days. And we used the Regi SCAR scoring system that grades DRESS cases as ‘no’, ‘possible’, ‘probable’ or ‘definite’ groups for diagnostic criteria of DRESS. And we also applied Naranjo’s causality assessment scale in the following case study. Results and conclusion: In the initial recognition of DRESS syndrome and the immediate withdrawal of offending drugs and continuing with a supportive therapy and corticosteroids as needed. Systemic corticosteroids can reduce symptoms of hypersensitivity reactions. Keywords: Drug Reaction with Eosinophilia and Systemic Symptoms, Phenytoin, Exfoliation of Skin, Corticosteroids.

Phenytoin is the most common drug prescribed in patient diagnosed with seizure. Cerebral atrophy is an observed complication in phenytoin exposed patients. The side effects related to phenytoin administration include sedation, dizziness, swaying, rash and gum hypertrophy. In the following case report a 50-year-old male patient with complaints of poor response to oral commands, slurred speech, limited upper limb movements and neck rigidity, the patient is a known epileptic since 1 year on prescription and is alcoholic. Upon CT scan of brain, the impression was mild diffuse cerebellar atrophy probably due to long term phenytoin use. Hence frequent phenytoin level monitoring in patient prescribed with the same is mandatory. Keywords: phenytoin, epilepsy, cerebral atrophy

Toxic epidermal necrolysis is a cutaneous drug reaction which is a severe adverse effect that predominantly involves the skin and mucous membrane. Phenytoin is an anti-epileptic medication that belongs to the hydantoin class. Here we are going to present a case of 50-year-old male patient with phenytoin induced toxic epidermal necrolysis. The outcome of this study was to determine the severity of the adverse reaction and its management to improve the patient condition.   Keywords: Toxic epidermal necrolysis, phenytoin, erythromatous, adverse drug reaction, body surface area.

Хистон деацетилазе (HDAC) су ензими који катализују деацетилацију лизинских остатака хистона, али је потврђено да деацетилују и протеине изван једра. Изоформа која хидролизује ацетил групе са не-хистонских протеина је хистон деацетилаза 6 (HDAC6), која је цинк-зависна металопротеаза и доминантно се налази у цитоплазми. Познато је да HDAC6 изоформа може да иницира процесе туморогенезе, неоангиогенезе и транзицију појединих врста канцерских ћелија ка метастатском фенотипу. Данас се у онколошкој терапији примењују неселективни HDAC инхибитори (пан-HDAC инхибитори), али због појединих нежељених дејстава неселективних инхибитора, селективна инхибиција HDAC6 инхибитора представља обећавајућу стратегију у развоју нових антиканцерских лекова. HDAC инхибитори се састоје из хетероцикличног носача (CAP групе), линкера и цинк-везивне групе (ZBG), при чему се увођењем волуминозне CAP групе, повећава селективност ка HDAC6 изоформи., Histone deacetylases (HDACs) are enzymes which perform deacetylation of lysine residues of histones, but it has been discovered they deacetylase some proteins outside of the nucleus. Isoform that is conducting these deacetylations is histone deacetylase 6 (HDAC6), which is zinc-dependent metalloprotease and it is predominantly located in the cytoplasm. It has been known that HDAC6 isoform can initiate processes such as tumorigenesis, neoangiogenesis and transition of some cancer cell lines towards metastasis. Today, nonselective HDAC inhibitors (pan-HDAC inhibitors) are being used in cancer treatment, but due to some of their side effects, selective inhibition of HDAC6 is regarded as promising strategy in development of new anticancer drugs. HDAC inhibitors are consisted from heterocyclic carrier (CAP group), linker and zinc-binding group (ZBG), whereby selectivity towards HDAC6 isoform is increased by introduction of bulky CAP groups.

Objectives The Pediatric Emergency Research Network (PERN) was launched in 2009 with the intent for existing national and regional research networks in pediatric emergency care to organize globally for the conduct of collaborative research across networks. Methods The Pediatric Emergency Research Network has grown from 5- to 8-member networks over the past decade. With an executive committee comprising representatives from all member networks, PERN plays a supportive and collaborative rather than governing role. The full impact of PERN's facilitation of international collaborative research, although somewhat difficult to quantify empirically, can be measured indirectly by the observed growth of the field, the nature of the increasingly challenging research questions now being addressed, and the collective capacity to generate and implement new knowledge in treating acutely ill and injured children. Results Beginning as a pandemic response with a high-quality retrospective case-controlled study of H1N1 influenza risk factors, PERN research has progressed to multiple observational studies and ongoing global randomized controlled trials. As a recent example, PERN has developed sufficient network infrastructure to enable the rapid initiation of a prospective observational study in response to the current coronavirus disease 2019 pandemic. In light of the ongoing need for translation of research knowledge into equitable clinical practice and to promote health equity, PERN is committed to a coordinated international effort to increase the uptake of evidence-based management of common and treatable acute conditions in all emergency department settings. Conclusions The Pediatric Emergency Research Network's successes with global research, measured by prospective observational and interventional studies, mean that the network can now move to improve its ability to promote the implementation of scientific advances into everyday clinical practice. Achieving this goal will invo

Introduction: The DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome is a rare but serious and potentially lethal occurrence of a set of signs and symptoms associated with the use certain types of drugs. This syndrome is characterized by a heterogeneous clinical manifestation that, in many cases, results in multisystemic involvement. Case presentation: A 24-year-old man from Calarcá, Colombia, visited the emergency department of the local hospital due to a three-day history of unquantified intermittent fever associated with asthenia, adynamia, anorexia, headache, myalgia, odynophagia, and upper abdominal pain. Due to his condition and based on laboratory findings, he was referred to the Clínica Central del Quindío. The patient, 20 days before the initial assessment, had been prescribed a pharmacological treatment with non-steroidal anti-inflammatory drugs and phenytoin due to a severe cranioencephalic trauma; he also presented with generalized skin rash, elevated transaminases, and moderate eosinophilia. Complementary studies reported mild pericardial effusion, so DRESS syndrome was suspected, and corticosteroid therapy was started, achieving the complete remission of the syndrome. Conclusion: Although the DRESS syndrome has a low incidence, it should always be suspected, especially in patients with cardiac and pericardial involvement. In this case, pericardial involvement was evident, demonstrating that individuals with this syndrome may present with rare symptoms that have a serious impact on their health, as they may significantly increase adverse outcomes and mortality risk., Introducción. El síndrome de DRESS (Drug Reaction with Eosinophilia and Systemic symptoms) consiste en la ocurrencia, si bien poco frecuente, pero grave y potencialmente mortal, de un conjunto de signos y síntomas asociados al consumo de cierto tipo de medicamentos. Este síndrome se caracteriza por tener una manifestación clínica heterogénea que, en muchos casos, causa compromiso multisistémico. Presentación del caso. Hombre de 24 años de Calarcá, Colombia, que asistió al servicio de urgencias del hospital local por presentar fiebre intermitente no cuantificada durante 3 días, junto con astenia, adinamia, anorexia, cefalea, mialgias, odinofagia y dolor abdominal superior, y que, debido a su condición y resultados de laboratorio, fue remitido a la Clínica Central del Quindío. El paciente, 20 días antes de la valoración inicial, había recibido tratamiento farmacológico con antiinflamatorios no esteroides y fenitoína por traumatismo craneoencefálico severo; además presentó rash cutáneo generalizado, elevación de transaminasas y eosinofilia moderada. En los estudios complementarios se reportó derrame pericárdico leve, por lo que se sospechó síndrome de DRESS y se inició corticoterapia, lográndose así la remisión completa de la enfermedad. Conclusión. Aunque el síndrome de DRESS tiene una baja incidencia, siempre debe sospecharse, en especial en pacientes que presentan compromiso cardiaco y pericárdico. En este caso se destaca la afectación pericárdica, demostrando que en este síndrome se pueden presentar manifestaciones poco frecuentes, pero con un gran impacto en su salud, ya que pueden aumentar considerablemente los desenlaces adversos y la mortalidad en estos pacientes.

Objectives The Pediatric Emergency Research Network (PERN) was launched in 2009 with the intent for existing national and regional research networks in pediatric emergency care to organize globally for the conduct of collaborative research across networks. Methods The Pediatric Emergency Research Network has grown from 5- to 8-member networks over the past decade. With an executive committee comprising representatives from all member networks, PERN plays a supportive and collaborative rather than governing role. The full impact of PERN's facilitation of international collaborative research, although somewhat difficult to quantify empirically, can be measured indirectly by the observed growth of the field, the nature of the increasingly challenging research questions now being addressed, and the collective capacity to generate and implement new knowledge in treating acutely ill and injured children. Results Beginning as a pandemic response with a high-quality retrospective case-controlled study of H1N1 influenza risk factors, PERN research has progressed to multiple observational studies and ongoing global randomized controlled trials. As a recent example, PERN has developed sufficient network infrastructure to enable the rapid initiation of a prospective observational study in response to the current coronavirus disease 2019 pandemic. In light of the ongoing need for translation of research knowledge into equitable clinical practice and to promote health equity, PERN is committed to a coordinated international effort to increase the uptake of evidence-based management of common and treatable acute conditions in all emergency department settings. Conclusions The Pediatric Emergency Research Network's successes with global research, measured by prospective observational and interventional studies, mean that the network can now move to improve its ability to promote the implementation of scientific advances into everyday clinical practice. Achieving this goal will invo

Objectives The Pediatric Emergency Research Network (PERN) was launched in 2009 with the intent for existing national and regional research networks in pediatric emergency care to organize globally for the conduct of collaborative research across networks. Methods The Pediatric Emergency Research Network has grown from 5- to 8-member networks over the past decade. With an executive committee comprising representatives from all member networks, PERN plays a supportive and collaborative rather than governing role. The full impact of PERN's facilitation of international collaborative research, although somewhat difficult to quantify empirically, can be measured indirectly by the observed growth of the field, the nature of the increasingly challenging research questions now being addressed, and the collective capacity to generate and implement new knowledge in treating acutely ill and injured children. Results Beginning as a pandemic response with a high-quality retrospective case-controlled study of H1N1 influenza risk factors, PERN research has progressed to multiple observational studies and ongoing global randomized controlled trials. As a recent example, PERN has developed sufficient network infrastructure to enable the rapid initiation of a prospective observational study in response to the current coronavirus disease 2019 pandemic. In light of the ongoing need for translation of research knowledge into equitable clinical practice and to promote health equity, PERN is committed to a coordinated international effort to increase the uptake of evidence-based management of common and treatable acute conditions in all emergency department settings. Conclusions The Pediatric Emergency Research Network's successes with global research, measured by prospective observational and interventional studies, mean that the network can now move to improve its ability to promote the implementation of scientific advances into everyday clinical practice. Achieving this goal will invo

Dual-drug delivery systems were constructed through coaxial techniques, which were convenient for the model drugs used the present work. This study aimed to fabricate core-shell electrospun nanofibrous membranes displaying simultaneous cell proliferation and antibacterial activity. For that purpose, phenytoin (Ph), a well-known proliferative agent, was loaded into a polycaprolactone (PCL) shell membrane, and as-prepared silver-chitosan nanoparticles (Ag-CS NPs), as biocidal agents, were embedded in a polyvinyl alcohol (PVA) core layer. The morphology, chemical composition, mechanical and thermal properties of the nanofibrous membranes were characterized by FESEM/STEM, FTIR and DSC. The coaxial PVA-Ag CS NPs/PCL-Ph nanofibers (NFs) showed more controlled Ph release than PVA/PCL-Ph NFs. There was notable improvement in the morphology, thermal, mechanical, antibacterial properties and cytobiocompatibility of the fibers upon incorporation of Ph and Ag-CS NPs. The proposed core-shell PVA/PCL NFs represent promising scaffolds for tissue regeneration and wound healing by the effective dual delivery of phenytoin and Ag-CS NPs., QC 20210903

Background Androgen deprivation therapy (ADT) is a standard treatment for high-risk biochemically-recurrent, non-metastatic prostate cancer (BRPC) but is not curative and associated with toxicity. Racemetyrosine (SM-88) is an amino-acid analogue used with methoxsalen, phenytoin, and sirolimus (MPS) to enhance SM-88 activity. Method A phase 1b/2, open-label trial in BRPC and rising PSA. Patients were given daily SM-88 (230 mg BID), methoxsalen (10 mg), phenytoin (50 mg), and sirolimus (0.5 mg)). Outcome measures included changes in PSA, circulating tumor cells (CTCs) and imaging. Results 34 subjects were screened, 23 treated and 21 remained on study for ≥12 weeks. The median PSA was 6.4 ng/ml (range 1.7-80.1); doubling-time 6.2 months (range 1.4-36.6) and baseline testosterone 319.1 ng/ml (range 2.5-913.7). Median duration of therapy was 6.5 months (2.6-14.0). CTCs (median 48.5 cells/4 ml (range 15-268) at baseline) decreased a median of 65.3% in 18 of 19 patients. For patients who achieved an absolute CTC nadir count of <10 cells/4 ml (n = 10), disease control was 100% i.e. no metastases or PSA progression, while on trial (p = 0.005). PSA fell by ≥50% in 4.3% (1 subject). No patients developed metastatic disease while on treatment (metastases free survival =100%). There were no treatment-related adverse events (AEs) and quality of life was unchanged from baseline on the EORTC QLQ-C30 and QLQ-PR25. Testosterone levels rose slightly on SM-88 and were unrelated to efficacy or toxicity. Conclusions Use of SM-88 was associated with disease control while maintaining QOL. SM-88 may delay the need for ADT and the associated hormonal side effects. Larger trials are planned.Trial registration number, date of registration - NCT02796898, June 13, 2016.

Introduction: The DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome is a rare but serious and potentially lethal occurrence of a set of signs and symptoms associated with the use certain types of drugs. This syndrome is characterized by a heterogeneous clinical manifestation that, in many cases, results in multisystemic involvement. Case presentation: A 24-year-old man from Calarcá, Colombia, visited the emergency department of the local hospital due to a three-day history of unquantified intermittent fever associated with asthenia, adynamia, anorexia, headache, myalgia, odynophagia, and upper abdominal pain. Due to his condition and based on laboratory findings, he was referred to the Clínica Central del Quindío. The patient, 20 days before the initial assessment, had been prescribed a pharmacological treatment with non-steroidal anti-inflammatory drugs and phenytoin due to a severe cranioencephalic trauma; he also presented with generalized skin rash, elevated transaminases, and moderate eosinophilia. Complementary studies reported mild pericardial effusion, so DRESS syndrome was suspected, and corticosteroid therapy was started, achieving the complete remission of the syndrome. Conclusion: Although the DRESS syndrome has a low incidence, it should always be suspected, especially in patients with cardiac and pericardial involvement. In this case, pericardial involvement was evident, demonstrating that individuals with this syndrome may present with rare symptoms that have a serious impact on their health, as they may significantly increase adverse outcomes and mortality risk., Introducción. El síndrome de DRESS (Drug Reaction with Eosinophilia and Systemic symptoms) consiste en la ocurrencia, si bien poco frecuente, pero grave y potencialmente mortal, de un conjunto de signos y síntomas asociados al consumo de cierto tipo de medicamentos. Este síndrome se caracteriza por tener una manifestación clínica heterogénea que, en muchos casos, causa compromiso multisistémico. Presentación del caso. Hombre de 24 años de Calarcá, Colombia, que asistió al servicio de urgencias del hospital local por presentar fiebre intermitente no cuantificada durante 3 días, junto con astenia, adinamia, anorexia, cefalea, mialgias, odinofagia y dolor abdominal superior, y que, debido a su condición y resultados de laboratorio, fue remitido a la Clínica Central del Quindío. El paciente, 20 días antes de la valoración inicial, había recibido tratamiento farmacológico con antiinflamatorios no esteroides y fenitoína por traumatismo craneoencefálico severo; además presentó rash cutáneo generalizado, elevación de transaminasas y eosinofilia moderada. En los estudios complementarios se reportó derrame pericárdico leve, por lo que se sospechó síndrome de DRESS y se inició corticoterapia, lográndose así la remisión completa de la enfermedad. Conclusión. Aunque el síndrome de DRESS tiene una baja incidencia, siempre debe sospecharse, en especial en pacientes que presentan compromiso cardiaco y pericárdico. En este caso se destaca la afectación pericárdica, demostrando que en este síndrome se pueden presentar manifestaciones poco frecuentes, pero con un gran impacto en su salud, ya que pueden aumentar considerablemente los desenlaces adversos y la mortalidad en estos pacientes.

Objectives The Pediatric Emergency Research Network (PERN) was launched in 2009 with the intent for existing national and regional research networks in pediatric emergency care to organize globally for the conduct of collaborative research across networks. Methods The Pediatric Emergency Research Network has grown from 5- to 8-member networks over the past decade. With an executive committee comprising representatives from all member networks, PERN plays a supportive and collaborative rather than governing role. The full impact of PERN's facilitation of international collaborative research, although somewhat difficult to quantify empirically, can be measured indirectly by the observed growth of the field, the nature of the increasingly challenging research questions now being addressed, and the collective capacity to generate and implement new knowledge in treating acutely ill and injured children. Results Beginning as a pandemic response with a high-quality retrospective case-controlled study of H1N1 influenza risk factors, PERN research has progressed to multiple observational studies and ongoing global randomized controlled trials. As a recent example, PERN has developed sufficient network infrastructure to enable the rapid initiation of a prospective observational study in response to the current coronavirus disease 2019 pandemic. In light of the ongoing need for translation of research knowledge into equitable clinical practice and to promote health equity, PERN is committed to a coordinated international effort to increase the uptake of evidence-based management of common and treatable acute conditions in all emergency department settings. Conclusions The Pediatric Emergency Research Network's successes with global research, measured by prospective observational and interventional studies, mean that the network can now move to improve its ability to promote the implementation of scientific advances into everyday clinical practice. Achieving this goal will invo

The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.

BackgroundBenzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups.MethodsIn this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075.FindingsBetween Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly

Background: The unwell returned traveller can pose unique diagnostic dilemmas to treating clinicians. We present a case of West Nile virus infection presenting with gastrointestinal disturbance, further complicated by encephalitis, in a returned immunocompromised traveller. Case Presentation: A 63 year old woman with a past history of follicular lymphoma, hypogammaglobulinaemia and cyclical neutropaenia was admitted to hospital with a diarrhoeal illness immediately after returning to Australia from abroad. Travel history included cruise travel on the Danube River followed by several weeks' travel in South-eastern Europe including Serbia and Croatia with exposure to rural areas and mosquito bites, but no exposure to unpasteurised foods, animal or farm contacts. On Day 5 of her illness, the patient developed confusion, nominal aphasia and a slow affect. Brain computed tomography (CT) and magnetic resonance imaging (MRI) were unremarkable. Cerebrospinal fluid (CSF) analysis demonstrated a mildly raised protein and a mild lymphocytic pleocytosis. Empiric treatment for meningoencephalitis was commenced with aciclovir, piperacillin-tazobactam and ampicillin along with intravenous immunoglobulins (IVIg) to treat hypogammaglobulinaemia. The patient required intubation for mechanical ventilation on Day 10 following progressive neurological impairment with fluctuating conscious state and unco-ordinated motor responses. A second MRI demonstrated new changes affecting bilateral thalami, mesial temporal structures and the brainstem. Electroencephalography showed subclinical seizure activity, which was treated with phenytoin and levetiracetam. Investigations, including CSF bacterial cultures, nucleic acid amplification for enterovirus and herpes multiplex, cryptococcal antigen and treponemal serology, were negative. Diagnosis of flavivirus was considered due to exposure to an area with local outbreak, supported by suggestive MRI changes with bilateral thalamic and basal ganglia i

Background: The unwell returned traveller can pose unique diagnostic dilemmas to treating clinicians. We present a case of West Nile virus infection presenting with gastrointestinal disturbance, further complicated by encephalitis, in a returned immunocompromised traveller. Case Presentation: A 63 year old woman with a past history of follicular lymphoma, hypogammaglobulinaemia and cyclical neutropaenia was admitted to hospital with a diarrhoeal illness immediately after returning to Australia from abroad. Travel history included cruise travel on the Danube River followed by several weeks' travel in South-eastern Europe including Serbia and Croatia with exposure to rural areas and mosquito bites, but no exposure to unpasteurised foods, animal or farm contacts. On Day 5 of her illness, the patient developed confusion, nominal aphasia and a slow affect. Brain computed tomography (CT) and magnetic resonance imaging (MRI) were unremarkable. Cerebrospinal fluid (CSF) analysis demonstrated a mildly raised protein and a mild lymphocytic pleocytosis. Empiric treatment for meningoencephalitis was commenced with aciclovir, piperacillin-tazobactam and ampicillin along with intravenous immunoglobulins (IVIg) to treat hypogammaglobulinaemia. The patient required intubation for mechanical ventilation on Day 10 following progressive neurological impairment with fluctuating conscious state and unco-ordinated motor responses. A second MRI demonstrated new changes affecting bilateral thalami, mesial temporal structures and the brainstem. Electroencephalography showed subclinical seizure activity, which was treated with phenytoin and levetiracetam. Investigations, including CSF bacterial cultures, nucleic acid amplification for enterovirus and herpes multiplex, cryptococcal antigen and treponemal serology, were negative. Diagnosis of flavivirus was considered due to exposure to an area with local outbreak, supported by suggestive MRI changes with bilateral thalamic and basal ganglia i

Background: In adults, seizure disorder is a one of major health concern in terms of burden of disease, nature of illness, and its impact on individual, family, and community. The present study was undertaken to assess clinical types, pathogenesis and clinical profile of seizures in adult and to study clinical correlation of seizures with EEG and Neuro imaging and hospital outcome after antiepileptic treatment. Methods: Total 130 cases of age >12 years to till age presenting with new onset seizures were included in the study, during the period of one year from July 2014 -October 2016. A detailed history was taken, clinical examination, laboratory investigation and EEG, CT/ MRI were done. Results: The mean age of cases was 27.8

Background: In adults, seizure disorder is a one of major health concern in terms of burden of disease, nature of illness, and its impact on individual, family, and community. The present study was undertaken to assess clinical types, pathogenesis and clinical profile of seizures in adult and to study clinical correlation of seizures with EEG and Neuro imaging and hospital outcome after antiepileptic treatment. Methods: Total 130 cases of age >12 years to till age presenting with new onset seizures were included in the study, during the period of one year from July 2014 -October 2016. A detailed history was taken, clinical examination, laboratory investigation and EEG, CT/ MRI were done. Results: The mean age of cases was 27.8

BackgroundThe choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied.MethodsIn a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents - levetiracetam, fosphenytoin, and valproate - in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death.ResultsA total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group tha

ObjectiveTo assess the impact of CYP2C9 variation on phenytoin patient response and clinician prescribing practice where genotype was unknown during treatment.MethodsA retrospective analysis of Resource on Genetic Epidemiology Research on Adult Health and Aging cohort participants who filled a phenytoin prescription between 1996 and 2017. We used laboratory test results, medication dispensing records, and medical notes to identify associations of CYP2C9 genotype with phenytoin blood concentration, neurologic side effects, and medication dispensing patterns reflecting clinician prescribing practice and patient response.ResultsAmong 993 participants, we identified 69% extensive, 20% high-intermediate, 10% low-intermediate, and 2% poor metabolizers based on CYP2C9 genotypes. Compared with extensive metabolizer genotype, low-intermediate/poor metabolizer genotype was associated with increased dose-adjusted phenytoin blood concentration [21.3 pg/mL, 95% confidence interval (CI): 13.6-29.0 pg/mL; P < 0.01] and increased risk of neurologic side effects (hazard ratio: 2.40, 95% CI: 1.24-4.64; P < 0.01). Decreased function CYP2C9 genotypes were associated with medication dispensing patterns indicating dose decrease, use of alternative anticonvulsants, and worse adherence, although these associations varied by treatment indication for phenytoin.ConclusionCYP2C9 variation was associated with clinically meaningful differences in clinician prescribing practice and patient response, with potential implications for healthcare utilization and treatment efficacy.

Convulsive status epilepticus (SE) is a relatively common emergency condition affecting individuals of all ages. The primary goal of treatment is prompt termination of seizures. Where first-line treatment with benzodiazepine has failed to achieve this, a condition known as established SE (ESE), there is uncertainty about which agent to use next. The Established Status Epilepticus Treatment Trial (ESETT) is a 3-arm (valproate (VPA), fosphenytoin (FOS), levetiracetam (LEV)), phase III, double-blind randomized comparative effectiveness study in patients aged 2 years and above with established convulsive SE. Enrollment was completed in January 2019, and the results are expected later this year. We discuss lessons learnt during the conduct of the study in relation to the following: ethical considerations; trial design and practical implementation in emergency settings, including pediatric and adult populations; quality assurance; and outcome determination where treating emergency clinicians may lack specialist expertise. We consider that the ESETT is already informing both clinical practice and future trial design. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Several distinct classes of drugs, such as anticonvulsants, immunosuppressants, and calcium channel blockers, caused gingival overgrowth. One of the main drugs associated with the gingival overgrowth is the anti-epileptic such as phenytoin, which affects gingival tissues by altering extracellular matrix metabolism. In our study, we evaluate the effect of phenytoin, a drug whose active substance is phenytoin, on gingival fibroblasts of healthy volunteers. Gene expression of 29 genes was investigated in gingival fibroblasts' cell culture treated with phenytoin compared with untreated cells. Among the studied genes, only 13 genes (CXCL5, CXCL10, CCR1, CCR3, CCR5, CCR6, IL-1A, IL-1B, IL-5, IL-7, IL-6R, BMP-2, and TNFSF-10) were statistically significant. All but one gene resulted downregulated after 24 h of treatment with phenytoin. BPM2 was the only, although weakly, up-expressed gene. Probably, we have not highlighted overexpression of the other inflammatory molecules because the study was performed on healthy people. Many studies show that phenytoin induces the overexpression of these cytokines but, probably, in our study, the drug does not have the same effect because we used gingival fibroblasts of healthy people.

Herpes simplex virus encephalitis (HSVE) commonly presents with severe amnesia due to virus-mediated destruction of key regions in the temporal lobes, although language and executive impairment has been described. Little is known however of the long-term cognitive changes in these patients, including changes that may happen with cortical reorganization. We describe a patient with HSVE who presented with a highly unusual late-onset language syndrome, which may reflect distal cortical changes after her original injury.Copyright © 2018 Informa UK Limited, trading as Taylor & Francis Group.

X-linked lissencephaly with abnormal genitalia is a rare and devastating syndrome. The authors present an infant with a multisystem phenotype where the intestinal manifestations were as life limiting as the central nervous system features. Severe chronic diarrhea resulted in failure to thrive, dehydration, electrolyte derangements, long-term hospitalization, and prompted transition to palliative care. Other multisystem manifestations included megacolon, colitis, pancreatic insufficiency hypothalamic dysfunction, hypothyroidism, and hypophosphatasia. A novel aristaless-related homeobox gene mutation, c.1136G>T/p.R379L, was identified. This case contributes to the clinical, histological, and molecular understanding of the multisystem nature of this disorder, especially the role of ARX in the development of the enteroendocrine system.Copyright © The Author(s) 2017.

Herpes simplex virus encephalitis (HSVE) commonly presents with severe amnesia due to virus-mediated destruction of key regions in the temporal lobes, although language and executive impairment has been described. Little is known however of the long-term cognitive changes in these patients, including changes that may happen with cortical reorganization. We describe a patient with HSVE who presented with a highly unusual late-onset language syndrome, which may reflect distal cortical changes after her original injury.Copyright © 2018 Informa UK Limited, trading as Taylor & Francis Group.

X-linked lissencephaly with abnormal genitalia is a rare and devastating syndrome. The authors present an infant with a multisystem phenotype where the intestinal manifestations were as life limiting as the central nervous system features. Severe chronic diarrhea resulted in failure to thrive, dehydration, electrolyte derangements, long-term hospitalization, and prompted transition to palliative care. Other multisystem manifestations included megacolon, colitis, pancreatic insufficiency hypothalamic dysfunction, hypothyroidism, and hypophosphatasia. A novel aristaless-related homeobox gene mutation, c.1136G>T/p.R379L, was identified. This case contributes to the clinical, histological, and molecular understanding of the multisystem nature of this disorder, especially the role of ARX in the development of the enteroendocrine system.Copyright © The Author(s) 2017.

Epilepsy is a chronic neurological condition, characterized by recurrent seizures. Treatment with conventional anti-epileptic drugs (AED) results in only 33% of patients having no seizure recurrence after a prolonged period. Some evidence suggests that the lack of effectiveness of AED penetration into the brain parenchyma could be one of the mechanisms for resistance to treatment. Furthermore, AED side effects often prevent large increases in their dose. It was for these reasons that a new alternative approach to therapy, intracranial implantation of polymer-based drug delivery systems aimed at improving the bioavailability of AED, was investigated in this PhD research project. Genetic Absent Epilepsy Rats from Strasbourg (GAERS) is a strain of rat that has 100% of the animals with recurrent generalised non-convulsive seizures. This animal model has become the gold standard to study the mechanisms underlying absence epilepsy. After validating an automated spike and wave discharges (SWDs) detection algorithm applied to GAERS’ electroencephalograms (EEG) and demonstrating some effects of enrofloxacin on the GAERS’ epileptic activity, in vitro characterisation and in vivo testing of the antiepileptic efficacy of Poly(D,L-lactide-co-glycolide) (PLGA) polymers loaded with anticonvulsants, either phenytoin or lacosamide, were performed. PLGA is a biodegradable copolymer that it is very well tolerated by the brain and can be used as a passive release substrate. In prospective randomized masked experiments, GAERS underwent surgery for implantation of skull electrodes, skull electrodes and blank polymers, or skull electrodes and AED loaded polymers. The polymers were implanted bilaterally and subdurally on the surface of the cortex. Electroencephalogram recordings were started at day 7 post-surgery and continued for eight weeks. The number of SWDs and mean duration of one SWD were compared week-by-week between the groups. Although temporary changes were seen, phenytoin loade

Drug-induced gingival enlargement manifests as an abnormal growth of the gingiva due to an adverse drug reaction in patients treated with anticonvulsants, immunosuppressants and calcium channel blockers. The enlargement affects the normal oral hygiene practice and may even interfere with masticatory functions. It may gradually becomes a source of pain and could lead to disfigurement and cosmetic problem, interfere with mastication and speech, impede effective tooth cleaning or force the teeth out of alignment. It is a serious concern for both the patient and the clinician due to unaesthetic appearance and formation of new niches for Periodonto-pathogenic bacteria. Among the anticonvulsants, Phenytoin has most frequently been described to be associated with Gingival Enlargement. This case report presents gingival hyperplasia as a side effect of Phenytoin use in a 17-year-old female patient on this drug for the last 1 year.

Drug-induced gingival enlargement manifests as an abnormal growth of the gingiva due to an adverse drug reaction in patients treated with anticonvulsants, immunosuppressants and calcium channel blockers. The enlargement affects the normal oral hygiene practice and may even interfere with masticatory functions. It may gradually becomes a source of pain and could lead to disfigurement and cosmetic problem, interfere with mastication and speech, impede effective tooth cleaning or force the teeth out of alignment. It is a serious concern for both the patient and the clinician due to unaesthetic appearance and formation of new niches for Periodonto-pathogenic bacteria. Among the anticonvulsants, Phenytoin has most frequently been described to be associated with Gingival Enlargement. This case report presents gingival hyperplasia as a side effect of Phenytoin use in a 17-year-old female patient on this drug for the last 1 year.

Early maladaptive internalization of synaptic GABAA receptors (GABAAR) and externalization of NMDA receptors (NMDAR) may explain the time-dependent loss of potency of standard anti-epileptic drugs (AED) in refractory status epilepticus (SE). We hypothesized that correcting the effects of changes in GABAAR and NMDAR would terminate SE, even when treatment is delayed 40 minutes. SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAAR agonist midazolam, the NMDAR antagonist ketamine and the AED valproate were injected 40 min after SE onset in combination or as monotherapy. The midazolam-ketamine-valproate combination was more efficient than triple-dose midazolam, ketamine or valproate monotherapy or higher-dose dual therapy in reducing several parameters of SE severity. Triple therapy also reduced SE-induced acute neuronal injury and spatial memory deficits. In addition, simultaneous triple therapy was more efficient than sequential triple therapy: giving the three drugs simultaneously was more efficient at stopping seizures than the standard practice of giving them sequentially. Furthermore, midazolam-ketamine-valproate therapy suppressed seizures far better than the midazolam-fosphenytoin-valproate therapy, which follows evidence-based AES guidelines. These results show that a treatment aimed at correcting maladaptive GABAAR and NMDAR trafficking can reduce the severity of SE and its long-term consequences.

The purpose of this article is to describe the clinical and electroencephalographic features of patients diagnosed with non-convulsive status epilepticus (NCSE) with uncommon cognitive and behavioral involvement. We present two cases with sub-acute cognitive impairment and neuropsychiatric disorders (including anxiety and transient behavioral changes) as their first manifestation of NCSE. A neuropsychological profile demonstrated executive dysfunction. In addition, the neurological examination revealed automatisms and 24-hour video EEG showed epileptiform activity. Although neuroimaging studies showed frontotemporal abnormalities, both neurophysiological and cognitive improvement after specific antiseizure drug treatment confirmed the diagnosis of non-convulsive status. Theoretical considerations between mental status changes and focal epilepsy will be reviewed. Our cases raise awareness of the importance of considering NCSE, a treatable condition, in the differential diagnosis of rapidly-progressive cognitive impairment with neuropsychiatric symptoms. © 2016 The Authors

Background: Convulsive status epilepticus (CSE) is the most common life-threatening childhood neurological emergency. Despite this, there is a lack of high quality evidence supporting medication use after first line benzodiazepines, with current treatment protocols based solely on non-experimental evidence and expert opinion. The current standard of care, phenytoin, is only 60% effective, and associated with considerable adverse effects. A newer anti-convulsant, levetiracetam, can be given faster, is potentially more efficacious, with a more tolerable side effect profile. The primary aim of the study presented in this protocol is to determine whether intravenous (IV) levetiracetam or IV phenytoin is the better second line treatment for the emergency management of CSE in children. Methods/Design: 200 children aged between 3 months and 16 years presenting to 13 emergency departments in Australia and New Zealand with CSE, that has failed to stop with first line benzodiazepines, will be enrolled into this multicentre open randomised controlled trial. Participants will be randomised to 40 mg/kg IV levetiracetam infusion over 5 min or 20 mg/kg IV phenytoin infusion over 20 min. The primary outcome for the study is clinical cessation of seizure activity five minutes following the completion of the infusion of the study medication. Blinded confirmation of the primary outcome will occur with the primary outcome assessment being video recorded and assessed by a primary outcome assessment team blinded to treatment allocation. Secondary outcomes include: Clinical cessation of seizure activity at two hours; Time to clinical seizure cessation; Need for rapid sequence induction; Intensive care unit (ICU) admission; Serious adverse events; Length of Hospital/ICU stay; Health care costs; Seizure status/death at one-month post discharge. Discussion: This paper presents the background, rationale, and design for a randomised controlled trial comparing levetiracetam to phenytoin in chil

The drug rash with eosinophilia and systemic symptoms syndrome (DRESS) is a severe hypersensitive reaction induced by the use of medications. More than 100 drugs associated with this syndrome have been reported and, although most patients have a favorable clinical course, about 10% develop multiple organ failure; some cases may result in the death of the patient. This paper presents a clinical case of DRESS syndrome associated with anticonvulsive therapy that evolved to fulminant hepatic failure. The etiology, pathogenesis, clinical manifestations, diagnostic process and possible treatment of this condition are addressed., El síndrome de reacción a drogas con eosinofilia y síntomas sistémicos (DRESS, por sus siglas en inglés) es una reacción severa de hipersensibilidad inducida por el uso de medicamentos. Se han reportado más de 100 fármacos asociados a este síndrome y, aunque la mayoría de los pacientes tiene una evolución clínica favorable, cerca del 10% desarrolla falla orgánica múltiple e incluso culmina en la muerte. El presente artículo presenta un caso clínico de síndrome DRESS asociado a terapia anticonvulsivante que evolucionó a falla hepática fulminante; aquí se discuten la etiología, patogenia, manifestaciones clínicas, proceso diagnóstico y posible tratamiento.

Early maladaptive internalization of synaptic GABAA receptors (GABAAR) and externalization of NMDA receptors (NMDAR) may explain the time-dependent loss of potency of standard anti-epileptic drugs (AED) in refractory status epilepticus (SE). We hypothesized that correcting the effects of changes in GABAAR and NMDAR would terminate SE, even when treatment is delayed 40 minutes. SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAAR agonist midazolam, the NMDAR antagonist ketamine and the AED valproate were injected 40 min after SE onset in combination or as monotherapy. The midazolam-ketamine-valproate combination was more efficient than triple-dose midazolam, ketamine or valproate monotherapy or higher-dose dual therapy in reducing several parameters of SE severity. Triple therapy also reduced SE-induced acute neuronal injury and spatial memory deficits. In addition, simultaneous triple therapy was more efficient than sequential triple therapy: giving the three drugs simultaneously was more efficient at stopping seizures than the standard practice of giving them sequentially. Furthermore, midazolam-ketamine-valproate therapy suppressed seizures far better than the midazolam-fosphenytoin-valproate therapy, which follows evidence-based AES guidelines. These results show that a treatment aimed at correcting maladaptive GABAAR and NMDAR trafficking can reduce the severity of SE and its long-term consequences.

Recent adverse event reports have raised the question of increased angioedema risk associated with exposure to levetiracetam. To help address this question, the Observational Health Data Sciences and Informatics research network conducted a retrospective observational new-user cohort study of seizure patients exposed to levetiracetam (n = 276,665) across 10 databases. With phenytoin users (n = 74,682) as a comparator group, propensity score-matching was conducted and hazard ratios computed for angioedema events by per-protocol and intent-to-treat analyses. Angioedema events were rare in both the levetiracetam and phenytoin groups (54 vs. 71 in per-protocol and 248 vs. 435 in intent-to-treat). No significant increase in angioedema risk with levetiracetam was seen in any individual database (hazard ratios ranging from 0.43 to 1.31). Meta-analysis showed a summary hazard ratio of 0.72 (95% confidence interval [CI] 0.39-1.31) and 0.64 (95% CI 0.52-0.79) for the per-protocol and intent-to-treat analyses, respectively. The results suggest that levetiracetam has the same or lower risk for angioedema than phenytoin, which does not currently carry a labeled warning for angioedema. Further studies are warranted to evaluate angioedema risk across all antiepileptic drugs.

Epilepsy is a Central Nervous System (CNS) disease caused by abnormal neuron signalling causing repeated seizures. CNS is protected by a barrier known as blood-brain barrier (BBB). The selective membrane on the BBB which only allow small lipophilic particle to pass through complicates the penetration of antiepileptic drugs. Phenytoin is a classic antiepileptic drug (AED) listed on the World Health Organization’s List of Essential Medicines, which exhibits potent therapeutic efficacy in controlling seizure attacks thus signifying its importance in a basic healthcare system. However, due to poor solubility and bioavailability of phenytoin, large dosage had to be given in its salt form (phenytoin sodium) to reach therapeutic concentration with numerous side effects. Hence, incorporating phenytoin in a nanocarrier would increase its bioavailability while minimizing the dosage required with reduced side effects. From the formulation study, it was discovered that phenytoin could only be retained in alkali solution. Therefore to address the solubility issue of phenytoin, a two-step method based on the pH solubility profile of phenytoin was used to formulate phenytoin into the nanoemulsion. First step involves the formulation of blank nanoemulsion (without phenytoin) through magnetic stirring followed by high shear homogenization. Second step involves the incorporation of phenytoin onto the nanocarrier by adjusting pH of blank nanoemulsion to alkali condition. Incorporation of phenytoin was confirmed through Transmission Electron Microscopy (TEM) which showed the position of phenytoin on the surface of oil droplets. Mixture Experimental Design (MED) and Artificial Neural Network (ANN) were employed to optimize the composition of phenytoin-loaded nanoemulsion. Effects of isopropyl myristate (3.00-6.00%, wt%), Tween 80:85 (1.50-3.00% wt%), glycerol (4.00-7.00%, wt%), and water (84.00- 91.50%, wt%) on the droplet size of nanoemulsion were investigated. The optimum formulation

Epilepsy is a Central Nervous System (CNS) disease caused by abnormal neuron signalling causing repeated seizures. CNS is protected by a barrier known as blood-brain barrier (BBB). The selective membrane on the BBB which only allow small lipophilic particle to pass through complicates the penetration of antiepileptic drugs. Phenytoin is a classic antiepileptic drug (AED) listed on the World Health Organization’s List of Essential Medicines, which exhibits potent therapeutic efficacy in controlling seizure attacks thus signifying its importance in a basic healthcare system. However, due to poor solubility and bioavailability of phenytoin, large dosage had to be given in its salt form (phenytoin sodium) to reach therapeutic concentration with numerous side effects. Hence, incorporating phenytoin in a nanocarrier would increase its bioavailability while minimizing the dosage required with reduced side effects. From the formulation study, it was discovered that phenytoin could only be retained in alkali solution. Therefore to address the solubility issue of phenytoin, a two-step method based on the pH solubility profile of phenytoin was used to formulate phenytoin into the nanoemulsion. First step involves the formulation of blank nanoemulsion (without phenytoin) through magnetic stirring followed by high shear homogenization. Second step involves the incorporation of phenytoin onto the nanocarrier by adjusting pH of blank nanoemulsion to alkali condition. Incorporation of phenytoin was confirmed through Transmission Electron Microscopy (TEM) which showed the position of phenytoin on the surface of oil droplets. Mixture Experimental Design (MED) and Artificial Neural Network (ANN) were employed to optimize the composition of phenytoin-loaded nanoemulsion. Effects of isopropyl myristate (3.00-6.00%, wt%), Tween 80:85 (1.50-3.00% wt%), glycerol (4.00-7.00%, wt%), and water (84.00- 91.50%, wt%) on the droplet size of nanoemulsion were investigated. The optimum formulation

Background: Several drugs can be associated with hyperpigmentation of mucosa or skin. They include antibiotic, antimalarial, antineoplastic, and psychotropic medications.Purpose: To describe a 42-year-old woman with amitriptyline-associated photo-distributed hyperpigmentation and to review psychotropic drug-induced hyperpigmentation of the skin.Materials and Methods: The features of a woman with amitriptyline-induced hyperpigmentation are presented. Using PubMed, the following terms were searched and relevant citations were assessed and discussed for context: amitriptyline, chlorpromazine, citalopram, desipramine, drug-associated, drug-induced, Fontana Masson, hyperpigmentation, imipramine, melanin, melanophages, mirtazapine, phenytoin, psychotropic, sertraline, thioridazine, tricyclic antidepressant.Results: Photo-distributed hyperpigmentation on the upper back of a woman developed six and a half years after initiation of amitriptyline therapy. Biopsy of the affected area showed pigment-laden melanophages and intradermal melanin deposition.Conclusions: Psychotropic drugs associated with cutaneous hyperpigmentation include amitriptyline, chlorpromazine, citalopram, desipramine, imipramine, mirtazapine, phenytoin, sertraline, and thioridazine. The hyperpigmentation may initially appear many years after starting the medication. Pathology typically shows melanophages and melanin in the dermis. Fontana Masson stain confirms the presence of melanin; Perl stain for hemosiderin or iron is negative. Discontinuation of the drug may result in spontaneous improvement. Further studies are needed to better understand the role of Q-switched laser in treating drug-induced hyperpigmentation.