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Chemical & Pharmaceutical Bulletin 2021Hydantoins, including the antiepileptic drug phenytoin, contain an amide nitrogen and an imide nitrogen, both of which can be alkylated. However, due to the higher...
Hydantoins, including the antiepileptic drug phenytoin, contain an amide nitrogen and an imide nitrogen, both of which can be alkylated. However, due to the higher acidity of its proton, N can be more easily alkylated than N under basic conditions. In this study, we explored methods for direct N-selective methylation of phenytoin and found that conditions using potassium bases [potassium tert-butoxide (BuOK) and potassium hexamethyldisilazide (KHMDS)] in tetrahydrofuran (THF) gave N-monomethylated phenytoin in good yield. The applicable scope of this reaction system was found to include various hydantoins and alkyl halides. To explore the function of methylated hydantoins, the effects of a series of methylated phenytoins on P-glycoprotein were examined, but none of methylated products showed inhibitory activity toward rhodamine 123 efflux by P-glycoprotein.
Topics: Anticonvulsants; Azides; Butanols; Hydantoins; Methylation; Phenytoin; Potassium
PubMed: 33790085
DOI: 10.1248/cpb.c20-00857 -
Therapeutic Drug Monitoring Apr 2023To understand the status of therapeutic drug monitoring (TDM) in China Mainland, and thus lay down the foundation for further improvement in TDM.
OBJECTIVE
To understand the status of therapeutic drug monitoring (TDM) in China Mainland, and thus lay down the foundation for further improvement in TDM.
METHODS
In the present study, a nationwide questionnaire survey was conducted, which was distributed and collected using a mobile-based application. Clinicians, pharmacists, and clinical laboratory physicians belonging to different levels of public hospitals were involved as subjects/objects. The contents of the survey included TDM implementation in their hospital and information regarding their opinions and suggestions on TDM work. Mann-Whitney test was used to compare the difference between top tertiary hospitals and non-top tertiary hospitals.
RESULTS
A total of 475 questionnaires were collected, 383 from top tertiary hospitals (3A hospitals) and 92 from non-top tertiary hospitals (other than 3A hospitals). A total of 240 clinicians, TDM pharmacists, and clinical laboratory physicians were involved, with an effective rate of 50.5%. Top tertiary hospitals were associated with certain advantages, such as the number of TDM testing facilities, annual sample size, number of monitoring varieties, and interpretation rate of monitoring reports, compared with non-top tertiary hospitals. In particular, β-lactamase inhibitor, olanzapine, carbamazepine, and glucocorticoids seemed to be the main projects that clinicians wanted to assess. The drugs for which TDM was commonly performed included vancomycin, valproic acid, carbamazepine, phenytoin sodium, and methotrexate. The most commonly used detection methods include high-performance liquid chromatography, immunization, 2D-LC, and LC-MS. The monitoring concentration range was found to be inconsistent for most of the drugs. Currently, no unified regulation exists for TDM charges in China, which is no more than ¥200 in general. Clinicians rely on pharmacists for professional guidance. Importantly, improvement in the interpretation of monitoring reports, proficiency testing, and cooperation with clinical departments may aid in improving the level of TDM service.
CONCLUSIONS
This survey objectively reflected the current status of TDM work in hospitals in China, and provided a strong reference base for devising strategies for improvement and effective execution of TDM work.
Topics: Humans; Drug Monitoring; Phenytoin; Surveys and Questionnaires; Carbamazepine; China; Benzodiazepines
PubMed: 36920501
DOI: 10.1097/FTD.0000000000001060 -
Acta Bio-medica : Atenei Parmensis Apr 2017Phenytoin is normally used in epilepsy treatment. One of the side effect affecting a significative part of the treated patients is the gingival overgrowth. It could... (Randomized Controlled Trial)
Randomized Controlled Trial
Phenytoin is normally used in epilepsy treatment. One of the side effect affecting a significative part of the treated patients is the gingival overgrowth. It could surely be a correlation between this stimulatory effect and the assessment of phenytoin in wound healing. In fact, some studies of the literature have shown that topical phenytoin promotes healing of traumatic wounds, burns and ulcers by decubitus or stasis (diabetic or venous) and we emphasize, in vitiligo, a particular attention into repigmentation. The related mechanism of action seems to be multifactorial. In the present paper topical phenytoin has been used as wound-healing agent in 19 documented cases of bedsores, divided in treated and placebo group. The used concentration of phenytoin was 5 mg/L dissolved in a water solution of 9 g NaCl /L (0.9% P/V of NaCl). Patches soaked with phenytoin solution were applied over the bedsores along 3 hours every 12 hours. Results showed that phenytoin treated patients healed their wounds significantly before (p<0.001) with respect to controls.
Topics: Administration, Topical; Aged; Aged, 80 and over; Dermatologic Agents; Female; Humans; Male; Middle Aged; Phenytoin; Pressure Ulcer; Transdermal Patch; Wound Healing
PubMed: 28467333
DOI: 10.23750/abm.v88i1.5794 -
Clinical Pharmacology and Therapeutics Jul 2022Cytochrome P450 2C9 (CYP2C9) is responsible for the oxidative metabolism of about 15% of commonly used drugs, some of which are characterized by a narrow therapeutic...
Cytochrome P450 2C9 (CYP2C9) is responsible for the oxidative metabolism of about 15% of commonly used drugs, some of which are characterized by a narrow therapeutic window. CYP2C9 is highly polymorphic, and over 60 alleles have been described. CYP2C9*2 and CYP2C9*3 are the most common polymorphisms among White patients and both are associated with decreased activity. The evidence concerning the functional importance of less frequent variant alleles is scarce. The objective of the current study was to characterize the in vivo activity of CYP2C9 among carriers of CYP2C9*11, one of the "African" alleles and the fourth most common CYP2C9 variant allele among White patients by using two prototype substrates, phenytoin and (S)-warfarin. Single 300-mg phenytoin and 20-mg warfarin doses were given to 150 healthy Ethiopian Jewish participants who were nonsmokers, at least one week apart. (S)-warfarin oral clearance and phenytoin metabolic ratio (PMR) derived from the ratio of 5-(4-hydroxyphenyl)-5-phenylhydantoin in 24-hour urine collection to plasma phenytoin 12 hours (PMR 24/12) or 24 hours (PMR 24/24) post dosing, were used as markers of CYP2C9 activity. PMR 24/12 and PMR 24/24 were reduced by 50% and 62.2%, respectively, among carriers of CYP2C9*1/*11 (n = 13) as compared with carriers of CYP2C9*1/*1 (n = 127) (false discovery rate (FDR) q < 0.001). The respective decrease in (S)-warfarin oral clearance was 52.6% (FDR q < 0.001). In conclusion, the enzyme encoded by CYP2C9*11 is characterized by a more than 50% decrease in the enzymatic activity, resembling the extent of decrease associated with CYP2C9*3 ("no-function allele"). Among patients of African ancestry, CYP2C9*11 genetic analysis should be considered prior to prescribing of narrow therapeutic window drugs such as phenytoin, warfarin, nonsteroidal anti-inflammatory drugs, or siponimod.
Topics: Alleles; Anticoagulants; Cytochrome P-450 CYP2C9; Genotype; Humans; Phenytoin; Warfarin
PubMed: 35426132
DOI: 10.1002/cpt.2613 -
Veterinary World Nov 2021Digital dermatitis (DD) is one of the most common causes of lameness in dairy cattle. It is seen in nearly all dairy herds across the world and has substantial welfare...
BACKGROUND AND AIM
Digital dermatitis (DD) is one of the most common causes of lameness in dairy cattle. It is seen in nearly all dairy herds across the world and has substantial welfare and economic implications. In this study, we aimed to investigate the efficacy of phenytoin sodium topical treatment on painful ulcerative stage of bovine digital dermatitis (BDD).
MATERIALS AND METHODS
In total, 45 Holstein-Friesian dairy cows with DD were randomly assigned to one of the three topical treatment trials (15 each): Saline solution (first treatment, negative control), chlortetracycline spray (second treatment, positive control), or phenytoin sodium powder (third treatment, positive control) (third treatment). On day 0 (pre-treatment) and on days 7, 14, 21, and 28 post-treatment, the response of DD-affected cows to the medications used was evaluated by measuring lesion depth and size, as well as the total clinical score (lameness, pain, and discomfort).
RESULTS
The cure rate in cows treated with phenytoin (86.66%) on day 28 was significantly improved compared to cows treated with either chlortetracycline (60%) or normal saline (6.66 %).
CONCLUSION
Our findings highlight the superiority of phenytoin over the commonly used antibacterial agent, chlortetracycline, in the topical treatment of BDD, and subsequently suggest that phenytoin should be considered a suitable alternative treatment option for the treatment of BDD.
PubMed: 35017837
DOI: 10.14202/vetworld.2021.2907-2912 -
Seizure Mar 2018Phenytoin is an effective anticonvulsant for focal epilepsy. Its use can be associated with long-term adverse effects including cerebellar ataxia. Whilst phenytoin is...
PURPOSE
Phenytoin is an effective anticonvulsant for focal epilepsy. Its use can be associated with long-term adverse effects including cerebellar ataxia. Whilst phenytoin is toxic to Purkinje cells in vitro; the clinical and radiological phenotype and mechanism of cerebellar degeneration in vivo remain unclear. We describe the prevalence, clinical and radiological characteristics of phenytoin-related ataxia.
METHODS
Patients with epilepsy receiving treatment with phenytoin were recruited from the Epilepsy clinics at Royal Hallamshire Hospital, Sheffield, UK. Neurological examination was performed on all patients after recruitment. Patients were categorised into those with and without ataxia. We determined the severity of ataxia clinically (SARA score) and the pattern of cerebellar involvement by neuroimaging (MRI volumetry and MR spectroscopy).
RESULTS
Forty-seven patients were recruited. Median duration of epilepsy was 24 years, median duration of phenytoin treatment was 15 years and current median phenytoin daily dose was 325 mg. Fifty-five percent of patients complained of poor balance. Clinical evidence of ataxia was seen in 40% patients. Gait, stance and heel-shin slide were the predominant features of cerebellar dysfunction. MRI demonstrated structural, volumetric and functional deficits of the cerebellum. Only one patient with ataxia had phenytoin levels above the normal range.
CONCLUSIONS
Cerebellar ataxia is present in 40% of patients with epilepsy and chronic exposure to phenytoin. Patients on long-term phenytoin have reduced cerebellar volume even if they have no clinical evidence of ataxia. Evidence of structural deficits on imaging suggests a predilection for vermian involvement.
Topics: Antibodies; Anticonvulsants; Ataxia; Brain; Epilepsy; Female; Folic Acid; GTP-Binding Proteins; Gliadin; Humans; Longitudinal Studies; Male; Neuroimaging; Neurologic Examination; Phenytoin; Protein Glutamine gamma Glutamyltransferase 2; Sensation Disorders; Transglutaminases
PubMed: 29427835
DOI: 10.1016/j.seizure.2018.01.019 -
Neurologia May 2023No formal indication currently exists for seizure prophylaxis in neurosurgical oncology patients. Neither have specific recommendations been made on the use of... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
No formal indication currently exists for seizure prophylaxis in neurosurgical oncology patients. Neither have specific recommendations been made on the use of antiepileptic drugs (AED) in seizure-free patients with meningiomas scheduled for surgery. AEDs are generally prescribed on a discretionary basis, taking into consideration a range of clinical and radiological risk factors. We present a systematic review and meta-analysis exploring the effectiveness of antiepileptic prophylaxis in patients with meningioma and no history of seizures.
METHODS
We performed a systematic review of the PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Embase, and clinicaltrials.gov databases. Of a total of 4368 studies initially identified, 12 were selected for extraction of data and qualitative analysis. Based on the clinical data presented, we were only able to include 6 studies in the meta-analysis. We performed heterogeneity studies, calculated a combined odds ratio, evaluated publication bias, and conducted a sensitivity analysis.
RESULTS
AED prophylaxis in patients with meningioma and no history of seizures did not significantly reduce the incidence of post-operative seizures in comparison to controls (Mantel-Haenszel combined odds ratio, random effects model: 1.26 [95% confidence interval, 0.60-2.78]; 2041 patients). However, we are unable to establish a robust recommendation against this treatment due to the lack of prospective studies, the presence of selection bias in the studies reviewed, the likelihood of underestimation of seizure frequency during follow-up, and the strong influence of one study on the overall effect.
CONCLUSIONS
Despite the limitations of this review, the results of the meta-analysis do not support the routine use of seizure prophylaxis in patients with meningioma and no history of seizures.
Topics: Humans; Meningioma; Phenytoin; Anticonvulsants; Incidence; Meningeal Neoplasms
PubMed: 35781420
DOI: 10.1016/j.nrleng.2022.03.002 -
Pharmaceutics Oct 2021An acute epileptic seizure is a seizure emergency fatal condition that requires immediate medical attention. IV phenytoin sodium remains the second line therapeutic...
An acute epileptic seizure is a seizure emergency fatal condition that requires immediate medical attention. IV phenytoin sodium remains the second line therapeutic agent for the immediate treatment of status epilepticus. Phenytoin sodium formulated as nanolipid carriers (NLCs) seems to be promising as an intranasal delivery system for controlling acute seizures. Three different nanosized phenytoin sodium loaded NLCs (<50 nm, 50-100 nm and >100 nm) were prepared by melt emulsification and was further characterised. In vitro drug release studies showed immediate drug release from phenytoin sodium loaded NLCs of <50 nm size, which is highly essential for acute seizure control. The ex vivo permeation study indicated greater permeation from <50 nm sized NLC through the olfactory epithelium compared to thecontrol drug solution. Invivo pharmacokinetic studies revealed higher drug concentration in CSF/brain within 5 min upon intranasal administration of <50 nm sized phenytoin sodium NLCs than the control drug solution and marketed IV phenytoin sodium, indicating direct and rapid nose to brain drug transport through the olfactory epithelium. The study has shown that formulation strategies can enhance olfactory uptake, and phenytoin sodium NLCs of desired particle sizes (<50 nm) offer promising potential for nose to brain direct delivery of phenytoin sodium in treating acute epileptic seizures.
PubMed: 34683933
DOI: 10.3390/pharmaceutics13101640 -
PloS One 2022Many clinical interventions are trialled to manage medical complications following Traumatic Brain Injury (TBI). However, published evidence for the effects of those... (Review)
Review
BACKGROUND
Many clinical interventions are trialled to manage medical complications following Traumatic Brain Injury (TBI). However, published evidence for the effects of those clinical interventions is limited. This article is an overview of common complications and their management from published systematic reviews in TBI.
METHODS AND FINDINGS
A health science electronic database search for published systematic reviews for management of common complications in TBI was conducted in the last decade till 31st January 2021. Methodological quality and evidence were critically appraised using the Grading of Recommendations, Assessment, Development and Evaluations and Revised-Assessment of Multiple Systematic review tools. Overall, only six systematic reviews complied with search criteria, these evaluated fatigue, spasticity and post traumatic seizures (29 RCTs, 13 cohort studies, n = 5639 participants). No systematic reviews for other common TBI-related complications met criteria for this review. The included reviews varied from 'moderate to high' in methodological quality. The findings suggest beneficial treatment effect of anti-epileptic drugs (phenytoin/levetiracetam) compared with placebo in reducing early seizure incidence, but no significant benefit of phenytoin over levetiracetam, valproate, or neuroprotective agent for early or late posttraumatic seizures. There was 'limited' evidence for spasticity-related interventions, and 'insufficient' evidence of cardiorespiratory training on fatigue levels.
CONCLUSIONS
Despite the high prevalence and associated functional impact of TBI-related complications, there is limited evidence to guide treating clinicians for management of common TBI complications. More robust studies are needed to build evidence in this population.
Topics: Brain Injuries, Traumatic; Fatigue; Humans; Levetiracetam; Phenytoin; Seizures; Systematic Reviews as Topic
PubMed: 36048787
DOI: 10.1371/journal.pone.0273998 -
The Cochrane Database of Systematic... Aug 2015Head injury is a common event and can cause a spectrum of motor and cognition disabilities. A frequent complication is seizures. Antiepileptic drugs (AED) such as... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Head injury is a common event and can cause a spectrum of motor and cognition disabilities. A frequent complication is seizures. Antiepileptic drugs (AED) such as phenytoin are often used in clinical practice with the hopes of preventing post-traumatic epilepsy. Whether immediate medical intervention following head trauma with either AEDs or neuroprotective drugs can alter the process of epileptogenesis and lead to a more favorable outcome is currently unknown. This review attempted to address the effectiveness of these treatment interventions. This review updates and expands on the earlier Cochrane review.
OBJECTIVES
To compare the efficacy of antiepileptic drugs and neuroprotective agents with placebo, usual care or other pharmacologic agents for the prevention of post-traumatic epilepsy in people diagnosed with any severity of traumatic brain injury.
SEARCH METHODS
We searched The Cochrane Epilepsy Group's specialized register, CENTRAL, MEDLINE, ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (ICTRP) in January 2015. We searched EMBASE, Biological Abstracts and National Research Register in September 2014 and SCOPUS in December 2013. The Cochrane Epilepsy Group performed handsearches of relevant journals.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) that include AEDs or neuroprotective agents compared with placebo, another pharmacologic agent or a usual care group. The outcomes measured included a seizure occurring within one week of trauma (early seizure), seizure occurring later than one week post-trauma (late seizure), mortality and any adverse events.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed study quality and extracted the data. We calculated risk ratios (RR) and 95% confidence intervals (CI) for each outcome. We used random-effects models in the meta-analyses and performed pre-defined subgroup and sensitivity analyses.
MAIN RESULTS
This review included 10 RCTs (reported in 12 articles) consisting of 2326 participants The methodological quality of the studies varied. The type of intervention was separated into three categories; AED versus placebo or standard care, alternative neuroprotective agent versus placebo or standard care and AED versus other AED. Treatment with an AED (phenytoin or carbamazepine) decreased the risk of early seizure compared with placebo or standard care (RR 0.42, 95% CI 0.23 to 0.73; very low quality evidence). There was no evidence of a difference in the risk of late seizure occurrence between AEDs and placebo or standard care (RR 0.91, 95% CI 0.57 to 1.46; very low quality evidence). There was no evidence of a significant difference in all-cause mortality between AEDs and placebo or standard care (RR 1.08 95% CI 0.79 to 1.46,very low quality of evidence). Only one study looked at other potentially neuroprotective agents (magnesium sulfate) compared with placebo. The risk ratios were: late seizure 1.07 (95% CI 0.53 to 2.17) and all-cause mortality 1.20 (95% CI 0.80 to 1.81). The risk ratio for occurrence of early seizure was not estimable.Two studies looked at comparison of two AEDs (levetiracetam, valproate) with phenytoin used as the main comparator in each study. The risk ratio for all-cause mortality was 0.53 (95% CI 0.30 to 0.94). There was no evidence of treatment benefit of phenytoin compared with another AED for early seizures (RR 0.66, 95% 0.20 to 2.12) or late seizures(RR 0.77, 95% CI 0.46 to 1.30).Only two studies reported adverse events. The RR of any adverse event with AED compared with placebo was 1.65 (95% CI 0.73 to 3.66; low quality evidence). There were insufficient data on adverse events in the other treatment comparisons.
AUTHORS' CONCLUSIONS
This review found low-quality evidence that early treatment with an AED compared with placebo or standard care reduced the risk of early post-traumatic seizures. There was no evidence to support a reduction in the risk of late seizures or mortality. There was insufficient evidence to make any conclusions regarding the effectiveness or safety of other neuroprotective agents compared with placebo or for the comparison of phenytoin, a traditional AED, with another AED.
Topics: Adult; Anticonvulsants; Carbamazepine; Cause of Death; Child; Craniocerebral Trauma; Epilepsy; Humans; Levetiracetam; Magnesium Sulfate; Neuroprotective Agents; Phenytoin; Piracetam; Randomized Controlled Trials as Topic; Valproic Acid
PubMed: 26259048
DOI: 10.1002/14651858.CD009900.pub2