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Clinical Pharmacology : Advances and... 2018In critically ill patients, monitoring free phenytoin concentration is a valuable method for phenytoin-dosage adjustment. However, due to technical difficulties and the...
PURPOSE
In critically ill patients, monitoring free phenytoin concentration is a valuable method for phenytoin-dosage adjustment. However, due to technical difficulties and the high cost of these methods, the Sheiner-Tozer equation is routinely used for estimating free phenytoin concentration in clinical practice. There have been conflicting results concerning accuracy and precision of the Sheiner-Tozer equation for prediction of free phenytoin concentration in various patient populations. Therefore, this study was conducted to evaluate the accuracy and correlation of measured and calculated free phenytoin concentrations in neurointensive care patients with hypoalbuminemia.
METHODS
A total of 65 adult neurointensive care patients with hypoalbuminemia who were receiving phenytoin for prevention or treatment of seizures were recruited in this study. In addition to measuring free phenytoin concentration by HPLC, free phenytoin concentration was calculated using both conventional and revised Sheiner-Tozer equations. Eventually, the correlation and level of agreement between measured and calculated free phenytoin concentrations were evaluated.
RESULTS
The mean albumin concentration of studied patients was 2.63±0.57 g/dL. There was a significant but weak-moderate correlation between measured and calculated free phenytoin concentration using conventional and revised Sheiner-Tozer equations (=0.45 and =0.43, respectively). Conventional and revised Sheiner-Tozer equations were not able to predict free phenytoin concentrations accurately in 33.85% and 35.4% of patients, respectively. Although the sex of patients did not have a significant impact on the level of agreement, younger patients had a higher level of agreement.
CONCLUSION
Although there was a moderate correlation between calculated and measured free phenytoin concentration, the Sheiner-Tozer equation was not able to predict free phenytoin concentration accurately in all patients, especially in older patients. Therefore, monitoring free phenytoin serum concentration besides clinical outcomes should be considered for phenytoin-dose adjustment in critically ill patients.
PubMed: 30588130
DOI: 10.2147/CPAA.S186322 -
Indian Journal of Critical Care... Mar 2021Mahajan C, Singh BP, Kapoor I, Prabhakar H. Phenytoin Sodium and Acetate-Maleate Buffered Balanced Salt Solutions are Physically Incompatible! Indian J Crit Care Med...
Mahajan C, Singh BP, Kapoor I, Prabhakar H. Phenytoin Sodium and Acetate-Maleate Buffered Balanced Salt Solutions are Physically Incompatible! Indian J Crit Care Med 2021;25(3):352.
PubMed: 33790524
DOI: 10.5005/jp-journals-10071-23756 -
Biomedicine & Pharmacotherapy =... Sep 2023Phenytoin-induced liver injury (PHT ILII) is a serious condition that may necessitate discontinuation of the drug. This study investigates the mechanisms of PHT ILII and...
Revealing how phenytoin triggers liver damage and the potential protective effects of Balanites Aegyptiaca fruit extracts: Exploring Nrf2/MAPK/ Beclin-1 signaling pathways.
Phenytoin-induced liver injury (PHT ILII) is a serious condition that may necessitate discontinuation of the drug. This study investigates the mechanisms of PHT ILII and evaluates the protective effects of Balanites Aegyptiaca (BA) fruit extracts on the liver. We focus on the Nrf2/MAPK/NF-κB/Beclin-1 signaling pathways involved in oxidative stress and inflammation from drug-induced liver injury. Phytochemical analyses of BA fruit extracts (Bu-F and EA-F) are conducted. Molecular docking techniques explore the interaction between phenytoin (PHT) and the Nrf2/MAPK/NF-κB/Beclin-1 pathways. Thirty-six male rats are divided into Control, Bu-F, EA-F, PHT, Bu-F/PHT, and EA-F/PHT groups, and they are observed for 45 days. EA-F extract is rich in phenolics/flavonoids, while Bu-F extract mainly contains saponins.PHT ILII causes histological damage in liver tissues and affects Nrf-2, MAPK, TNF-α, IL-1β, Mcp-1, Beclin-1, iNOS expression, and liver function markers (ALT, AST, ALP). However, EA-F/Bu-F extracts effectively improve the histological structure and significantly reduce biochemical/immunohistochemical parameters, restoring them to near-normal levels. EA-F extract is particularly effective.In conclusion, the Nrf2/MAPK /Beclin-1 pathways play a critical role in the development of PHT ILII. BA fruit extracts show promise as hepato-protective agents, with the EA-F extract demonstrating superior efficacy. These results lay the groundwork for new treatments for PHT ILII and drug-induced liver injuries.
Topics: Rats; Male; Animals; Phenytoin; Plant Extracts; NF-E2-Related Factor 2; Balanites; Beclin-1; NF-kappa B; Fruit; Molecular Docking Simulation; Oxidative Stress; Liver; MAP Kinase Signaling System; Chemical and Drug Induced Liver Injury
PubMed: 37541174
DOI: 10.1016/j.biopha.2023.115265 -
Clinical Pharmacology and Therapeutics Feb 2021Phenytoin is an antiepileptic drug with a narrow therapeutic index and large interpatient pharmacokinetic variability, partly due to genetic variation in CYP2C9.... (Review)
Review
Phenytoin is an antiepileptic drug with a narrow therapeutic index and large interpatient pharmacokinetic variability, partly due to genetic variation in CYP2C9. Furthermore, the variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotypes (updates on cpicpgx.org).
Topics: Alleles; Anticonvulsants; Cytochrome P-450 CYP2C9; Genetic Variation; Genotype; HLA-B Antigens; Humans; Pharmacogenetics; Phenytoin; Stevens-Johnson Syndrome
PubMed: 32779747
DOI: 10.1002/cpt.2008 -
The Cochrane Database of Systematic... Apr 2016Worldwide, phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset seizures, and that... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Worldwide, phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset seizures, and that valproate is more effective for generalised onset tonic-clonic seizures (with or without other generalised seizure types). This review is one in a series of Cochrane reviews investigating pair-wise monotherapy comparisons. This is the latest updated version of the review first published in 2001 and updated in 2013.
OBJECTIVES
To review the time to withdrawal, remission and first seizure of phenytoin compared to valproate when used as monotherapy in people with partial onset seizures or generalised tonic-clonic seizures (with or without other generalised seizure types).
SEARCH METHODS
We searched the Cochrane Epilepsy Group's Specialised Register (19 May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2015, Issue 4), MEDLINE (1946 to 19 May 2015), SCOPUS (19 February 2013), ClinicalTrials.gov (19 May 2015), and WHO International Clinical Trials Registry Platform ICTRP (19 May 2015). We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field.
SELECTION CRITERIA
Randomised controlled trials (RCTs) in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of valproate monotherapy versus phenytoin monotherapy.
DATA COLLECTION AND ANALYSIS
This was an individual participant data (IPD) review. Outcomes were time to: (a) withdrawal of allocated treatment (retention time); (b) achieve 12-month remission (seizure-free period); (c) achieve six-month remission (seizure-free period); and (d) first seizure (post-randomisation). We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), and the generic inverse variance method to obtain the overall pooled HR and 95% CI.
MAIN RESULTS
IPD were available for 669 individuals out of 1119 eligible individuals from five out of 11 trials, 60% of the potential data. Results apply to partial onset seizures (simple, complex and secondary generalised tonic-clonic seizures), and generalised tonic-clonic seizures, but not other generalised seizure types (absence or myoclonus seizure types). For remission outcomes: HR > 1 indicates an advantage for phenytoin; and for first seizure and withdrawal outcomes: HR > 1 indicates an advantage for valproate.The main overall results (pooled HR adjusted for seizure type) were time to: (a) withdrawal of allocated treatment 1.09 (95% CI 0.76 to 1.55); (b) achieve 12-month remission 0.98 (95% CI 0.78 to 1.23); (c) achieve six-month remission 0.95 (95% CI 0.78 to 1.15); and (d) first seizure 0.93 (95% CI 0.75 to 1.14). The results suggest no overall difference between the drugs for these outcomes. We did not find any statistical interaction between treatment and seizure type (partial versus generalised).
AUTHORS' CONCLUSIONS
We have not found evidence that a significant difference exists between phenytoin and valproate for the outcomes examined in this review. However misclassification of seizure type may have confounded the results of this review. Results do not apply to absence or myoclonus seizure types. No outright evidence was found to support or refute current treatment policies.
Topics: Anticonvulsants; Epilepsies, Partial; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Humans; Phenytoin; Randomized Controlled Trials as Topic; Seizures; Valproic Acid
PubMed: 27123830
DOI: 10.1002/14651858.CD001769.pub3 -
European Journal of Clinical... Oct 2022Management and dose adjustment are a major concern for clinicians in the absence of specific clinical outcome data for patients on antiepileptic drugs (AEDs), in the... (Review)
Review
Management and dose adjustment are a major concern for clinicians in the absence of specific clinical outcome data for patients on antiepileptic drugs (AEDs), in the event of short-term (5 days) nirmatrelvir/ritonavir co-exposure. Therefore, in this report, we identified drugs that require dose adjustment because of drug-drug interactions (DDIs) between nirmatrelvir/ritonavir and AEDs. We hereby used four databases (Micromedex Drug Interaction, Liverpool Drug Interaction Group for COVID-19 Therapies, Medscape Drug Interaction Checker, and Lexicomp Drug Interactions) and DDI-Predictor.In the light of applying the DDI-Predictor, for carbamazepine, clobazam, oxcarbazepine, eslicarbazepine, phenytoin, phenobarbital, pentobarbital, rufinamide, and valproate as CYP3A4 inducers, we recommend that a dose adjustment of short-term nirmatrelvir/ritonavir as a substrate (victim) drug would be more appropriate instead of these AEDs to avoid impending DDI-related threats in patients with epilepsy.
Topics: Anticonvulsants; Carbamazepine; Clobazam; Cytochrome P-450 CYP3A Inducers; Drug Interactions; Humans; Oxcarbazepine; Pentobarbital; Phenobarbital; Phenytoin; Ritonavir; Valproic Acid; COVID-19 Drug Treatment
PubMed: 35930055
DOI: 10.1007/s00228-022-03370-7 -
CNS Drugs Dec 2022Drug-drug interactions between direct oral anticoagulants (DOAC) and antiseizure medications via the cytochrome P450 (CYP) or the P-glycoprotein (P-gp) systems may lead...
BACKGROUND AND OBJECTIVE
Drug-drug interactions between direct oral anticoagulants (DOAC) and antiseizure medications via the cytochrome P450 (CYP) or the P-glycoprotein (P-gp) systems may lead to under-anticoagulation. The clinical relevance of these interactions is unclear. We aimed to elucidate the risk of thromboembolism with concurrent DOAC and CYP/P-gp modulating antiseizure medications.
METHODS
In this propensity score-weighted population-based retrospective cohort study, we used competing risk regression analyses to determine the risks of ischemic stroke, venous thromboembolism, and death in DOAC recipients taking CYP/P-gp-modulating antiseizure medications (phenytoin, valproate, levetiracetam, carbamazepine, or phenobarbital) versus those taking CYP/P-gp-neutral antiseizure medications (pregabalin, gabapentin, or clobazam). We also performed secondary analyses for the epilepsy and atrial fibrillation subgroups.
RESULTS
Among DOAC users, CYP/P-gp-modulating antiseizure medications were collectively associated with an increased risk of ischemic stroke (adjusted hazard ratio 1.28, 95% confidence interval 1.05-1.57, p = 0.017). In addition, phenytoin (adjusted hazard ratio 1.34, 95% confidence interval 1.07-1.68, p = 0.011) and valproate (adjusted hazard ratio 1.38, 95% confidence interval 1.10-1.74, p = 0.006) were associated with increased mortality. In the epilepsy subgroup, the risk of ischemic stroke and venous thromboembolism did not differ between CYP/P-gp-modulating and CYP/P-gp-neutral antiseizure medications.
CONCLUSIONS
Although CYP/P-gp-modulating antiseizure medications were associated with an increased risk of ischemic stroke when paired with DOAC in the primary analysis, such a phenomenon was not found among patients with epilepsy who took phenytoin, valproate, or levetiracetam with DOAC. Therefore, these antiseizure medication options among patients with epilepsy with concurrent DOAC should not be restricted solely based on their potential drug-drug interactions. Yet, the increased mortality during concurrent use of DOAC with phenytoin or valproate might call for caution.
Topics: Humans; Venous Thromboembolism; Valproic Acid; Phenytoin; Levetiracetam; Retrospective Studies; Anticoagulants; Ischemic Stroke
PubMed: 36424415
DOI: 10.1007/s40263-022-00971-9 -
Journal of Separation Science Jul 2022Phenytoin is a powerful antiseizure drug with complex pharmacokinetic properties, making it an interesting model drug to use in preclinical in vivo investigations,...
A sensitive LC-MS/MS method for quantification of phenytoin and its major metabolite with application to in vivo investigations of intravenous and intranasal phenytoin delivery.
Phenytoin is a powerful antiseizure drug with complex pharmacokinetic properties, making it an interesting model drug to use in preclinical in vivo investigations, especially with regards to formulations aiming to improve drug delivery to the brain. Moreover, it has a major metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin, which can be simultaneously studied to achieve a better assessment of its behaviour in the body. Here, we describe the development and validation of a sensitive LCMS/MS method for quantification of phenytoin and 5-(4-hydroxyphenyl)-5-phenylhydantoin in rat plasma and brain which can be used in such preclinical studies. Calibration curves produced covered a range of 7.81 to 250 ng/mL (plasma) and 23.4 to 750 ng/g (brain tissue) for both analytes. The method was validated for specificity, sensitivity, accuracy, and precision and found to be within the acceptable limits of ±15% over this range in both tissue types. The method when applied in two in vivo investigations: validation of a seizure model and to study the behaviour of a solution of intranasally administered phenytoin as a foundation for future studies into direct nose-to-brain delivery of phenytoin using specifically developed particulate systems, was highly sensitive for detecting phenytoin and 5-(4-hydroxyphenyl)-5-phenylhydantoin in rat plasma and brain.
Topics: Administration, Intravenous; Animals; Calibration; Chromatography, Liquid; Phenytoin; Rats; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 35588117
DOI: 10.1002/jssc.202200025 -
Neurosciences (Riyadh, Saudi Arabia) Jul 2016To evaluate the efficacy and safety of levetiracetam (LEV) in the management of seizures in neonates. (Clinical Trial)
Clinical Trial
OBJECTIVE
To evaluate the efficacy and safety of levetiracetam (LEV) in the management of seizures in neonates.
METHODS
A prospective non-blind, single arm clinical trial conducted in the Department of Neonatology and Pediatric Intensive Care, Mohamad Kermanshahi, and Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran from May 2014 to December 2014. Fifty out of 60 newborns with gestational age >/=30 weeks with clinically diagnosed seizures were included. Levetiracetam was administered orally with an initial dose of 10 mg/kg twice a day. The patients were observed continuously by Neuro Intensive Care nurses, and visited daily by a neuropediatrician in the first 7 days and then at days 14, 30, and 90 after the start of LEV administration. Clinical examination was performed for every patient, and seizure number, antiepileptic medication, and adverse events were detailed at every visit.
RESULTS
47 infants were seizure free under LEV at the end of the first week, 47 remained seizure free at 4 weeks, and 46 remained seizure free at 11 weeks. No immediate and long-term side effects were noted in our patients.
CONCLUSION
This study investigated the efficacy and safety of LEV in neonatal seizure control but confirmation with further randomized controlled trials is required.
Topics: Anticonvulsants; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Iran; Levetiracetam; Male; Phenobarbital; Phenytoin; Piracetam; Seizures; Treatment Outcome
PubMed: 27356654
DOI: 10.17712/nsj.2016.3.20150726 -
Journal of Pharmacy & Pharmaceutical... 2018The U.S. Pharmacopeia defines excipients as substances other than the active pharmaceutic ingredient (API) that are added in a drug delivery system in order to aid in...
PURPOSE
The U.S. Pharmacopeia defines excipients as substances other than the active pharmaceutic ingredient (API) that are added in a drug delivery system in order to aid in the manufacturing process and enhance stability, bioavailability, safety, effectiveness and delivery of the drug. The 1968 phenytoin intoxication outbreak in Brisbane, Australia, is a classic example of an API-excipient interaction. When administered with CaSO4 the absorption of phenytoin was reduced due to an interaction between the API and the excipient. When CaSO4 was replaced by lactose, the amount of drug absorbed was much higher, resulting in the observed intoxication. It was hypothesized that phenytoin was converted to a calcium salt prior to ingestion. The purpose of this study was to mechanistically investigate the interactions between excipients and phenytoin to confirm the hypothesis of the previous reports.
METHODS
Titration experiments with phenytoin and calcium salt were performed. Isothermal micro calorimetry was used to determine incompatibilities between excipients, phenytoin and milk. NMR was used to characterize the compounds. Dissolution tests containing CaSO4, lactose or sorbitol as excipients were also performed. Both Canadian and United States of America commercially available capsules were tested with milk and water.
RESULTS
The calorimeter results indicate that phenytoin sodium interacts with CaSO4 in aqueous media and the dissolution profile of CaSO4 containing capsules showed a reduced dissolution rate. In addition, phenytoin sodium also interacts with lactose through a Maillard reaction that can occur at body temperature. Likewise, commercial Phenytoin sodium products interacted with milk and the products containing lactose showed browning in water.
CONCLUSION
In Canada and the USA, the reference product contains lactose as an excipient in the formulation, whereas the Canadian generic formulations do not contain lactose. Any clinical relevance of these difference has not been determined. A new incompatibility between phenytoin and lactose has been discovered and an incompatibility with calcium was confirmed, which may have implications in regard to excipients and food effects. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Topics: Anticonvulsants; Calcium Sulfate; Calorimetry; Chromatography, High Pressure Liquid; Humans; Lactose; Phenytoin; Solubility
PubMed: 29702046
DOI: 10.18433/jpps29745