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Seizure May 2024Seizures represent a significant comorbidity in children with acute encephalitis syndrome (AES). Despite this, there is a notable absence of randomized controlled trials... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of phenytoin and levetiracetam for acute symptomatic seizures in children with acute encephalitis syndrome: an open label, randomised controlled trial.
INTRODUCTION
Seizures represent a significant comorbidity in children with acute encephalitis syndrome (AES). Despite this, there is a notable absence of randomized controlled trials (RCTs) directly comparing antiseizure medications (ASMs) in children with AES.
MATERIALS AND METHODS
This RCT aimed to assess the efficacy and safety of phenytoin and levetiracetam in controlling seizures among children with AES. Both ASMs were administered with a loading followed by maintenance dose. After a 12-week period, children exhibiting a normal electroencephalogram and no seizure recurrence underwent tapering and discontinuation of ASM. Clinical follow-up occurred daily for the first week, and subsequently at 4, 12, and 24 weeks, evaluating seizure recurrence, incidence of status epilepticus, cognition, behavior, functional status, ASM acquisition cost, and adverse effects.
RESULTS
A total of 100 children (50 in each group) were enrolled. Within the first week, 5 and 3 children in the phenytoin and levetiracetam groups expired. Up to 1 week or death (whichever occurred earliest), 46 (92 %) and 44 (88 %) children remained seizure-free. Intention-to-treat analysis for both best and worst-case scenarios showed insignificant differences (p=0.52 and 1.0). No children experienced seizure recurrence after 1 week in either group. The number of patients with breakthrough status epilepticus, need for mechanical ventilation, duration of hospital stay, presence of epileptiform abnormalities in repeat electroencephalogram at 12 weeks, functional outcomes at 1, 12, and 24 weeks, as well as cognition and behavioral profiles at 24 weeks, were comparable in both groups (p>0.05 for all). However, the incidence of treatment-emergent adverse events (TEAEs) causally related to study medications was significantly higher in the phenytoin group (p=0.04).
CONCLUSION
Levetiracetam and phenytoin are comparable in efficacy in terms of achieving clinical seizure control in children with acute encephalitis syndrome, although levetiracetam group demonstrated fewer adverse effects.
Topics: Humans; Levetiracetam; Phenytoin; Anticonvulsants; Female; Male; Child, Preschool; Seizures; Child; Treatment Outcome; Infant; Acute Febrile Encephalopathy; Electroencephalography
PubMed: 38678766
DOI: 10.1016/j.seizure.2024.04.015 -
Journal of Emergencies, Trauma, and... 2024Phenytoin is one of the commonly used anti.seizure medications in nontraumatic seizures. However, its utility and safety in young patients with traumatic brain injury...
INTRODUCTION
Phenytoin is one of the commonly used anti.seizure medications in nontraumatic seizures. However, its utility and safety in young patients with traumatic brain injury (TBI) for the prevention of early-onset seizures (EOS) are debatable. We sought to explore the use of phenytoin as a seizure prophylaxis following TBI. We hypothesized that administering phenytoin is not effective in preventing EOS after TBI.
METHODS
This was a retrospective observational study conducted on adult TBI patients. EOS was defined as a witnessed seizure within a week postinjury. Data were compared as phenytoin versus no-phenytoin use, EOS versus no-EOS, and among TBI severity groups.
RESULTS
During 1 year, 639 TBI patients were included with a mean age of 32 years; of them, 183 received phenytoin as seizure prophylaxis, and 453 received no prophylaxis medication. EOS was documented in 13 (2.0%) patients who received phenytoin, and none had EOS among the nonphenytoin group. The phenytoin group was more likely to have a higher Marshall Score ( = 0.001), lower Glasgow Coma Scale (GCS) ( = 0.001), EOS ( = 0.001), and higher mortality ( = 0.001). Phenytoin was administrated for 15.2%, 43.2%, and 64.5% of mild, moderate, and severe TBI patients, respectively. EOS and no-EOS groups were comparable for age, gender, mechanism of injury, GCS, Marshall Score, serum phenytoin levels, liver function levels, hospital stay, and mortality. Multivariable logistic regression analysis showed that low serum albumin (odds ratio [OR] 0.81; 95% confidence interval [CI] 0.676.0.962) and toxic phenytoin level (OR 43; 95% CI 2.420.780.7) were independent predictors of EOS.
CONCLUSIONS
In this study, the prophylactic use of phenytoin in TBI was ineffective in preventing EOS. Large-scale matched studies and well-defined hospital protocols are needed for the proper utility of phenytoin post-TBI.
PubMed: 38681877
DOI: 10.4103/jets.jets_93_23 -
The American Journal of Emergency... Jul 2023Tacrolimus is commonly used for immunosuppression in patients following solid organ transplantation. For transplant patients with COVID-19 infection, early treatment is...
Tacrolimus is commonly used for immunosuppression in patients following solid organ transplantation. For transplant patients with COVID-19 infection, early treatment is indicated due to the risk of progression to severe disease. However, the first line agent, nirmatrelvir/ritonavir, has multiple drug-drug interactions. We report a case of tacrolimus toxicity in a patient with a history of renal transplant due to enzyme inhibition related to nirmatrelvir/ritonavir. An 85-year-old woman with a history of multiple comorbidities presented to the emergency department (ED) with weakness, increasing confusion, poor oral intake, and inability to walk. She had been recently diagnosed with COVID-19 infection and was prescribed nirmatrelvir/ritonavir due to her underlying comorbidities and immune suppression. In the ED, she was dehydrated and had an acute kidney injury (creatinine 2.1 mg/dL, up from a baseline of 0.8 mg/dL). The tacrolimus concentration on initial labs was 143 ng/mL (5-20 ng/mL) and it continued to rise despite being held, to a peak of 189 ng/mL on hospital day 3. The patient was treated with phenytoin for enzyme induction and the tacrolimus concentration began to fall. She was discharged to a rehabilitation facility after a 17 day hospitalization. ED physicians must be cognizant of drug-drug interactions when prescribing nirmatrelvir/ritonavir and evaluating patients recently treated with the drug to identify toxicity due to these interactions.
Topics: Humans; Female; Aged, 80 and over; Ritonavir; COVID-19; COVID-19 Drug Treatment; Tacrolimus; Antiviral Agents
PubMed: 37173153
DOI: 10.1016/j.ajem.2023.04.045 -
The American Journal of Gastroenterology Jan 2024To investigate human leukocyte antigen alleles associated with liver injury due to antiepileptic drugs (AEDs) in African Americans (AA).
INTRODUCTION
To investigate human leukocyte antigen alleles associated with liver injury due to antiepileptic drugs (AEDs) in African Americans (AA).
METHODS
In this study, 21 AA with AED drug-induced liver injury (DILI), 176 AA with DILI due to non-AEDs, and 5816 AA population controls were included.
RESULTS
HLA-B*53:01 was significantly associated with aromatic AED-DILI (odds ratio: 4.52, 95% confidence interval: 2.42-8.44, P = 1.46 × 10 -5 ). Phenytoin DILI showed the strongest association with HLA-B*53:01 (odds ratio: 9.17; 95% confidence interval: 3.61-23.28, P = 1.1 × 10 -5 ). The HLA-B*53:01 allele was carried by 8 of 9 AA phenytoin DILI cases.
DISCUSSION
HLA-B*53:01 is a significant risk factor of liver injury due to antiepileptics, particularly phenytoin, in AA.
Topics: Humans; Alleles; Anticonvulsants; Black or African American; Chemical and Drug Induced Liver Injury; HLA-B Antigens; Phenytoin; Risk Factors
PubMed: 37552102
DOI: 10.14309/ajg.0000000000002454 -
Brain Injury Aug 2023Levetiracetam is used for seizure prophylaxis in patients presenting with subarachnoid hemorrhage (SAH) or traumatic brain injury (TBI). We aim to characterize the...
BACKGROUND/OBJECTIVE
Levetiracetam is used for seizure prophylaxis in patients presenting with subarachnoid hemorrhage (SAH) or traumatic brain injury (TBI). We aim to characterize the optimal levetiracetam dosage for seizure prophylaxis.
METHODS
This retrospective cohort study included adult patients at an academic tertiary hospital presenting with SAH or TBI who received levetiracetam at a total daily dose (TDD) equivalent to or greater than 1000 mg. The primary outcome was combined seizure incidence, including clinical and subclinical seizures.
RESULTS
We identified 139 patients (49.6% male, mean age 53 years) for inclusion. For patients receiving a 1000-mg TDD, the administration was 500 mg twice daily. For patients receiving >1000-mg TDD, 77/78 patients received 1000 mg twice daily and one patient received 750 mg twice daily. Patients receiving 1000-mg TDD had a higher seizure incidence than those receiving >1000-mg TDD (p = 0.01), despite no difference in examined confounders, including history of alcoholism (p = 0.49), benzodiazepine use (p = 0.28), or propofol use (p = 0.17). No difference in adverse effects was observed (anemia, p = 0.44; leukopenia, p = 0.60; thrombocytopenia, p = 0.86).
CONCLUSIONS
Patients may experience a reduced incidence of clinical and electroencephalographic seizures with levetiracetam dosing >1000-mg TDD.
Topics: Adult; Humans; Male; Middle Aged; Female; Levetiracetam; Anticonvulsants; Piracetam; Phenytoin; Retrospective Studies; Seizures; Brain Injuries, Traumatic; Subarachnoid Hemorrhage
PubMed: 36856437
DOI: 10.1080/02699052.2023.2184495 -
Pharmaceutics Jan 2024Hot melt extrusion (HME) offers a high-throughput process to manufacture amorphous solid dispersions. A variety of experimental and model-based approaches exist to...
Hot melt extrusion (HME) offers a high-throughput process to manufacture amorphous solid dispersions. A variety of experimental and model-based approaches exist to predict API solubility in polymer melts, but these methods are typically aimed at determining the thermodynamic solubility and do not take into account kinetics of dissolution or the associated degradation of the API during thermal processing, both of which are critical considerations in generating a successful amorphous solid dispersion by HME. This work aims to develop a material-sparing approach for screening manufacturability of a given pharmaceutical API by HME using physically relevant time, temperature, and shear. Piroxicam, ritonavir, and phenytoin were used as model APIs with PVP VA64 as the dispersion polymer. We present a screening flowchart, aided by a simple custom device, that allows rapid formulation screening to predict both achievable API loadings and expected degradation from an HME process. This method has good correlation to processing with a micro compounder, a common HME screening industry standard, but only requires 200 mg of API or less.
PubMed: 38258087
DOI: 10.3390/pharmaceutics16010076 -
Wounds : a Compendium of Clinical... Feb 2024Although phenytoin's potential benefits in wound healing, pain relief, and infection control across various wound types have been previously reported, its use in wound...
BACKGROUND
Although phenytoin's potential benefits in wound healing, pain relief, and infection control across various wound types have been previously reported, its use in wound care remains limited.
OBJECTIVE
To conduct a comprehensive review to assess the efficacy of topical phenytoin compared with standard and alternative treatments for different wound types.
MATERIALS AND METHODS
The authors last searched Cochrane Library, PubMed, PubMed Central, and MEDLINE in June 2023. All English-language human RCTs and NRCTs from any time were included. The RoB 2 was used to assess quality of randomized trials, and the ROBINS-I was used to assess the quality of nonrandomized trials. Studies with a low risk of bias or some concerns in no more than 1 domain were included. Data collected and analyzed included wound type, interventions, sample size, outcome measures, and adverse effects.
RESULTS
The search yielded 101 studies, of which 17 RCTs and 8 NRCTs were eligible for inclusion. Of the included studies, 56% had a low risk of bias in all domains. The sample sizes varied between 20 and 130 (median, 60), with a total sample size of 1653 patients. Phenytoin improved wound healing in 17 of the 24 studies that evaluated it (71%), increased granulation tissue in 9 of the 10 studies that evaluated it (90%), provided analgesic effects in 7 of the 13 studies that evaluated it (54%), and inhibited bacterial contaminants in 6 of the 8 studies that evaluated it (75%). Adverse effects were rare (29%), minimal, and transient.
CONCLUSION
Phenytoin enhances wound healing and offers analgesic and antibacterial properties with minimal adverse effects. Further research is needed on optimal dosage of phenytoin, as well as frequency, delivery vehicles, and effects on other postoperative wounds.
BACKGROUND
Although phenytoin's potential benefits in wound healing, pain relief, and infection control across various wound types have been previously reported, its use in wound care remains limited.
OBJECTIVE
To conduct a comprehensive review to assess the efficacy of topical phenytoin compared with standard and alternative treatments for different wound types.
MATERIALS AND METHODS
The authors last searched Cochrane Library, PubMed, PubMed Central, and MEDLINE in June 2023. All English-language human RCTs and NRCTs from any time were included. The RoB 2 was used to assess quality of randomized trials, and the ROBINS-I was used to assess the quality of nonrandomized trials. Studies with a low risk of bias or some concerns in no more than 1 domain were included. Data collected and analyzed included wound type, interventions, sample size, outcome measures, and adverse effects.
RESULTS
The search yielded 101 studies, of which 17 RCTs and 8 NRCTs were eligible for inclusion. Of the included studies, 56% had a low risk of bias in all domains. The sample sizes varied between 20 and 130 (median, 60), with a total sample size of 1653 patients. Phenytoin improved wound healing in 17 of the 24 studies that evaluated it (71%), increased granulation tissue in 9 of the 10 studies that evaluated it (90%), provided analgesic effects in 7 of the 13 studies that evaluated it (54%), and inhibited bacterial contaminants in 6 of the 8 studies that evaluated it (75%). Adverse effects were rare (29%), minimal, and transient.
CONCLUSION
Phenytoin enhances wound healing and offers analgesic and antibacterial properties with minimal adverse effects. Further research is needed on optimal dosage of phenytoin, as well as frequency, delivery vehicles, and effects on other postoperative wounds.
Topics: Humans; Phenytoin; Anti-Bacterial Agents; Wound Healing; Analgesics; Pain
PubMed: 38479432
DOI: No ID Found -
Pediatric Critical Care Medicine : a... May 2024To compare levetiracetam and phenytoin as prophylaxis for the short-term development of status epilepticus (SE) during care of pediatric patients with acute severe...
Levetiracetam or Phenytoin as Prophylaxis for Status Epilepticus: Secondary Analysis of the "Approaches and Decisions in Acute Pediatric Traumatic Brain Injury Trial" Dataset, 2014-2017.
OBJECTIVES
To compare levetiracetam and phenytoin as prophylaxis for the short-term development of status epilepticus (SE) during care of pediatric patients with acute severe traumatic brain injury (TBI).
DESIGN
Nonprespecified secondary analysis using propensity score matching.
SETTING
We used the Approaches and Decisions in Acute Pediatric TBI Trial (ADAPT NCT04077411) dataset (2014-2017).
SUBJECTS
Patients less than 18 years old with Glasgow Coma Scale Score less than or equal to 8 who received levetiracetam or phenytoin as a prophylactic anticonvulsant therapy.
INTERVENTION
None.
MEASUREMENT AND MAIN RESULTS
Of the 516 total patients who qualified for the case-control study, 372 (72.1%) patients received levetiracetam, and 144 (27.9%) received phenytoin. After propensity score matching, the pair-matched analysis with 133 in each group failed to identify an association between levetiracetam versus phenytoin use and occurrent of SE (3.8% vs. 0.8%, p = 0.22), or mortality (i.e., in-hospital, 30-d and 60-d). However, on closer inspection of the statistical testing, we cannot exclude the possibility that selecting levetiracetam rather than phenytoin for prophylaxis was associated with the following: up to a mean difference of 7.3% greater prevalence of SE; up to a mean difference of 13.9%, 12.1%, and 13.9% greater mortality during the hospital stay, and 30-, and 60-days after hospital arrival, respectively. Last, analysis of 6 months Glasgow Outcome Scale Extended score in those without premorbid comorbidities, there was an association between favorable outcomes and use of phenytoin rather than levetiracetam prophylaxis.
CONCLUSIONS
In ADAPT, the decision to use prophylactic levetiracetam versus phenytoin failed to show an association with occurrence of subsequent SE, or mortality. However, we are unable to exclude the possibility that selecting levetiracetam rather than phenytoin for prophylaxis was associated with greater prevalence of SE and mortality. We are unable to make any recommendation about one prophylactic anticonvulsant medication over the other, but recommend that further larger, contemporary studies in severe pediatric TBI are carried out.
PubMed: 38717237
DOI: 10.1097/PCC.0000000000003526 -
Frontiers in Genetics 2023Specific alleles in human leukocyte antigens (HLAs) are associated with an increased risk of developing drug hypersensitivity reactions induced by abacavir,...
Specific alleles in human leukocyte antigens (HLAs) are associated with an increased risk of developing drug hypersensitivity reactions induced by abacavir, allopurinol, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, or flucloxacillin. Transplant patients are genotyped for HLA as a routine practice to match a potential donor to a recipient. This study aims to investigate the feasibility and potential impact of repurposing these HLA genotype data from kidney transplant patients to prevent drug hypersensitivity reactions. A cohort of 1347 kidney transplant recipients has been genotyped in the Leiden University Medical Center (LUMC) using next-generation sequencing (NGS). The risk alleles and were retrieved from the NGS data. Medical history, medication use, and allergic reactions were obtained from the patient's medical records. Carrier frequencies found were compared to a LUMC blood donor population. A total of 13.1% of transplant cohort patients carried at least one of the five risk alleles and therefore had an increased risk of drug-induced hypersensitivity for specific drugs. , were found in carrier frequencies of 4.61%, 1.19%, 4.46%, and 3.35% respectively. No carrier was found. In total nine carriers received flucloxacillin and seven carriers within our cohort received allopurinol. Our study shows that repurposing HLA genotype data from transplantation patients for the assignment of HLA risk alleles associated with drug hypersensitivity is feasible. The use of these data by physicians while prescribing drugs or by the pharmacist when dispensing drugs holds the potential to prevent drug hypersensitivity reactions. The utility of this method was highlighted by 13.1% of the transplant cohort patients carrying an actionable HLA allele.
PubMed: 37908589
DOI: 10.3389/fgene.2023.1289015 -
Neuropharmacology Apr 2024Na channels are essential for the genesis of action potentials in most neurons. After opening by membrane depolarization, Na channels enter a series of inactivated...
Na channels are essential for the genesis of action potentials in most neurons. After opening by membrane depolarization, Na channels enter a series of inactivated states (e.g. the fast, intermediate, and slow inactivated states; or I, I, and I). The inactivated Na channel may recover via the open state upon membrane repolarization, giving rise to "resurgent" Na currents which could be critical for densely repetitive or burst discharges. We incubated CHO-K1 cells transfected with human Na1.7 cDNA and measured resurgent currents with whole-cell patch recordings. We found I is the major inactivated state responsible for the genesis of resurgent currents. Rufinamide, in therapeutic concentrations, could selectively bind to I to slow the recovery process and dose-dependently inhibit resurgent currents. The other Na channel-inhibiting antiseizure medications (ASM), such as phenytoin and lacosamide (selectively binds to I and I, separately), fail to show a similar inhibitory effect in clinically relevant concentrations. Resurgent currents are decreased with lengthening of the prepulse, presumably because of redistribution of the channel from I to I. Rufinamide could accentuate the decrease to mimic a use-dependent inhibitory effect. The molecular action of slowing of recovery from inactivation by binding to I also explains the highly correlative inhibitory effect of rufinamide on both transient and resurgent Na currents. The modest but correlative inhibition of both currents may make a novel synergistic effect and thus strong-enough suppression of pathological repetitive and especially burst discharges. Rufinamide may thus have a unique spectrum of therapeutic applications for disorders with excessive neural excitabilities.
Topics: Animals; Cricetinae; Humans; Action Potentials; Neurons; CHO Cells; Triazoles
PubMed: 38228283
DOI: 10.1016/j.neuropharm.2024.109835