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Archives of Disease in Childhood Aug 1981Saliva carbamazepine and phenytoin samples were used to monitor treatment in 35 children aged between 2 and 14 years during a 2-year period. All phenytoin levels and...
Saliva carbamazepine and phenytoin samples were used to monitor treatment in 35 children aged between 2 and 14 years during a 2-year period. All phenytoin levels and over half the carbamazepine levels that were above the therapeutic range were associated with adverse effects. Dose and carbamazepine saliva levels were significantly related but no such relationship was found for phenytoin. There was no apparent relationship between the saliva level of either drug and convulsion control.
Topics: Adolescent; Carbamazepine; Child; Child, Preschool; Drug Administration Schedule; Humans; Phenytoin; Saliva
PubMed: 7271302
DOI: 10.1136/adc.56.8.637 -
British Journal of Clinical Pharmacology Mar 2021Sodium channel 2 subunit α (SCN2A) mutations cause difficult-to-treat early-onset epilepsy. Effective treatment includes high-dose phenytoin or carbamazepine ±...
Sodium channel 2 subunit α (SCN2A) mutations cause difficult-to-treat early-onset epilepsy. Effective treatment includes high-dose phenytoin or carbamazepine ± ketogenic diet (KD). We describe an infant with early-onset SCN2A-epilepsy with subtherapeutic carbamazepine concentration during transition from phenytoin treatment to avoid long-term neurotoxicity. The transition from high-dose phenytoin (20 mg kg d , concentration: ≥20 mg/L) with KD, to carbamazepine (50-75 mg kg d , concentration: 9-12 mg/L) lasted 85 days, which we suspected was due to significant drug-drug and/or drug-food interactions. Model-based analysis of carbamazepine pharmacokinetics quantified significant time- and dose-dependent phenytoin-mediated CYP3A4 induction and carbamazepine concentration-dependent auto-induction (apparent clearance increased up to 2.5/3-fold). Lower carbamazepine concentrations under KD were modelled as decreased relative bioavailability (44%), potentially related to decreased fraction absorbed (unexpected for this lipophilic drug), increased intestinal/hepatic metabolism and/or decreased protein-binding with KD. This suggests importance of carbamazepine-concentration monitoring during KD-introduction/removal and necessity of high carbamazepine doses to achieve therapeutic concentrations, especially in infants treated with high-dose phenytoin.
Topics: Anticonvulsants; Carbamazepine; Diet, Ketogenic; Drug Interactions; Epilepsy; Food-Drug Interactions; Humans; Infant; NAV1.2 Voltage-Gated Sodium Channel; Pharmaceutical Preparations; Phenytoin
PubMed: 32737897
DOI: 10.1111/bcp.14503 -
Chemical & Pharmaceutical Bulletin Mar 2006A highly accurate nephelometric titration method was developed for the quantitative analysis of phenytoin sodium injection and tablets. The titration operating...
A highly accurate nephelometric titration method was developed for the quantitative analysis of phenytoin sodium injection and tablets. The titration operating conditions and the validation of the method were studied. Five batches of phenytoin sodium injection and tablets were determined by the proposed method and the control experiment methods, respectively. The results of the titration are comparable to those of control experiments. The proposed method is accurate and reproducible, which is considered suitable for the quantitative analysis of a large number of samples.
Topics: Anticonvulsants; Chromatography, High Pressure Liquid; Colloids; Excipients; Indicators and Reagents; Pharmaceutical Solutions; Phenytoin; Silver Nitrate; Tablets
PubMed: 16508198
DOI: 10.1248/cpb.54.384 -
British Medical Journal Jan 1970
Topics: Adult; Age Factors; Child; Drug Synergism; Humans; Phenytoin
PubMed: 5411605
DOI: 10.1136/bmj.1.5687.48 -
Anaesthesia Aug 1992A prospective, randomised trial was undertaken in 60 healthy adults to determine the efficacy of intravenously administered phenytoin in doses of 5 mg.kg-1 for the... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
A prospective, randomised trial was undertaken in 60 healthy adults to determine the efficacy of intravenously administered phenytoin in doses of 5 mg.kg-1 for the prevention of suxamethonium-induced fasciculations, a rise in serum K+ and myalgia. This was compared with tubocurarine pretreatment and no pretreatment (control group). Phenytoin pretreatment significantly reduced myalgia from 45% (nine patients) in the control group to 10% (two patients) (p less than 0.05). It also decreased the duration and mean intensity of fasciculations. Incidentally, phenytoin was also found to decrease significantly mean serum Na+ levels (p less than 0.001) both at 5 and 20 min after administration. Tubocurarine pretreatment (3 mg) resulted in a significant decrease in fasciculations, but myalgia, which occurred in five patients, remained the same. No significant correlation was found between muscle fasciculations, postoperative myalgia and K+ changes, but patients with myalgia had a significant decrease in mean serum Na+ levels at 5 and 20 min after suxamethonium (p less than 0.01).
Topics: Adult; Female; Humans; Male; Muscles; Pain, Postoperative; Phenytoin; Potassium; Prospective Studies; Sodium; Succinylcholine; Tubocurarine
PubMed: 1519714
DOI: 10.1111/j.1365-2044.1992.tb02386.x -
PLoS Computational Biology Jul 2014Sodium channel blockers are used to control electrical excitability in cells as a treatment for epileptic seizures and cardiac arrhythmia, and to provide short term...
Sodium channel blockers are used to control electrical excitability in cells as a treatment for epileptic seizures and cardiac arrhythmia, and to provide short term control of pain. Development of the next generation of drugs that can selectively target one of the nine types of voltage-gated sodium channel expressed in the body requires a much better understanding of how current channel blockers work. Here we make use of the recently determined crystal structure of the bacterial voltage gated sodium channel NavAb in molecular dynamics simulations to elucidate the position at which the sodium channel blocking drugs benzocaine and phenytoin bind to the protein as well as to understand how these drugs find their way into resting channels. We show that both drugs have two likely binding sites in the pore characterised by nonspecific, hydrophobic interactions: one just above the activation gate, and one at the entrance to the the lateral lipid filled fenestrations. Three independent methods find the same sites and all suggest that binding to the activation gate is slightly more favourable than at the fenestration. Both drugs are found to be able to pass through the fenestrations into the lipid with only small energy barriers, suggesting that this can represent the long posited hydrophobic entrance route for neutral drugs. Our simulations highlight the importance of a number of residues in directing drugs into and through the fenestration, and in forming the drug binding sites.
Topics: Bacterial Proteins; Benzocaine; Binding Sites; Computational Biology; Hydrophobic and Hydrophilic Interactions; Models, Biological; Molecular Dynamics Simulation; Phenytoin; Thermodynamics; Voltage-Gated Sodium Channels
PubMed: 24992293
DOI: 10.1371/journal.pcbi.1003688 -
Neurology India 2022Although epilepsy is a common neurological condition, there is paucity of nationwide data on treatment patterns and sociodemographic and clinical factors affecting... (Observational Study)
Observational Study
BACKGROUND
Although epilepsy is a common neurological condition, there is paucity of nationwide data on treatment patterns and sociodemographic and clinical factors affecting treatment decisions in India.
OBJECTIVE
To assess clinical profiles, usage pattern of antiepileptic drugs (AEDs), and seizure control among patients with epilepsy in India.
METHODS
This was a cross-sectional, observational, multicenter study on adult patients with epilepsy who were on AEDs for at least six months before enrollment. Data were collected from patient interviews and medical records.
RESULTS
Out of 800 enrolled patients, a majority (69.0%) had generalized onset seizure in the six months before enrollment. The median age at epilepsy onset was 20.0 (1.0-64.0) years; 40.0% of the patients were females, 48.5% were married, 99.1% were literate, and 67.0% belonged to the lower or upper-middle socioeconomic class. Overall, 459 patients (57.4%) received AEDs as combination therapy. Most patients received levetiracetam (37.0%), sodium valproate (18.5%), carbamazepine (17.3%), or phenytoin (13.8%) as monotherapy, and clobazam (59.7%), levetiracetam (52.9%), carbamazepine (26.4%), sodium valproate (24.8%), or phenytoin (24.0%) in combination therapy. Quality of life was comparable for first- and third-generation AEDs. Adverse drug reactions were mostly attributed to dose modification or switching between drugs. No serious adverse drug reactions or new safety concerns were identified.
CONCLUSIONS
Findings from this large, cross-sectional, observational, multicenter study indicate that first-generation AEDs sodium valproate and phenytoin continued to be used in a substantial number of patients on monotherapy and combination therapy in India, even though an increasing trend toward use of second-generation AEDs was noted in clinical practice.
Topics: Adult; Female; Humans; Young Adult; Middle Aged; Male; Phenytoin; Levetiracetam; Valproic Acid; Cross-Sectional Studies; Quality of Life; Epilepsy; Anticonvulsants; Carbamazepine; Seizures; Drug-Related Side Effects and Adverse Reactions
PubMed: 36352605
DOI: 10.4103/0028-3886.359162 -
Epilepsia Jun 2018De novo mutations of SCN8A, encoding the voltage-gated sodium channel Na 1.6, have been associated with a severe infant onset epileptic encephalopathy. Individuals with...
OBJECTIVE
De novo mutations of SCN8A, encoding the voltage-gated sodium channel Na 1.6, have been associated with a severe infant onset epileptic encephalopathy. Individuals with SCN8A encephalopathy have a mean age of seizure onset of 4-5 months, with multiple seizure types that are often refractory to treatment with available drugs. Anecdotal reports suggest that high-dose phenytoin is effective for some patients, but there are associated adverse effects and potential for toxicity. Functional characterization of several SCN8A encephalopathy variants has shown that elevated persistent sodium current is one of several common biophysical defects. Therefore, specifically targeting elevated persistent current may be a useful therapeutic strategy in some cases.
METHODS
The novel sodium channel modulator GS967 has greater preference for persistent as opposed to peak current and nearly 10-fold greater potency than phenytoin. We evaluated the therapeutic effect of GS967 in the Scn8a mouse model carrying an SCN8A patient mutation that results in elevated persistent sodium current. We also performed patch clamp recordings to assess the effect of GS967 on peak and persistent sodium current and excitability in hippocampal neurons from Scn8a mice.
RESULTS
GS967 potently blocked persistent sodium current without affecting peak current, normalized action potential morphology, and attenuated excitability in neurons from heterozygous Scn8a mice. Acute treatment with GS967 provided dose-dependent protection against maximal electroshock-induced seizures in Scn8a and wild-type mice. Chronic treatment of Scn8a mice with GS967 resulted in lower seizure burden and complete protection from seizure-associated lethality observed in untreated Scn8a mice. Protection was achieved at a chronic dose that did not cause overt behavioral toxicity or sedation.
SIGNIFICANCE
Persistent sodium current modulators like GS967 may be an effective precision targeting strategy for SCN8A encephalopathy and other functionally similar channelopathies when elevated persistent sodium current is the primary dysfunction.
Topics: Action Potentials; Animals; Anticonvulsants; Brain Diseases; Disease Models, Animal; Drug Administration Schedule; Electroshock; Epilepsy; Female; Hippocampus; Humans; Male; Mice; Mice, Transgenic; Mutation; NAV1.6 Voltage-Gated Sodium Channel; Neurons; Off-Label Use; Phenytoin; Pyridines; Triazoles
PubMed: 29782051
DOI: 10.1111/epi.14196 -
Acta Biochimica Et Biophysica Sinica Sep 2015Voltage-gated sodium channel (VGSC) activity enhances cell behaviors related to metastasis, such as motility, invasion, and oncogene expression. Neonatal alternative...
Voltage-gated sodium channel (VGSC) activity enhances cell behaviors related to metastasis, such as motility, invasion, and oncogene expression. Neonatal alternative splice form of Nav1.5 isoform is expressed in metastatic breast cancers. Furthermore, aberrant Notch signaling pathway can induce oncogenesis and may promote the progression of breast cancers. In this study, we aimed to analyze the effect of the nNav1.5 inhibitor phenytoin and Notch signal inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT) on triple negative breast cancer cell line (MDA-MB-231) via inhibition of nNav1.5 VGSC activity and Notch signaling, respectively. In order to determine the individual and combined effects of these inhibitors, the 4-[3-(4-iyodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1) test, wound healing assay, and zymography were performed to detect the proliferation, lateral motility, and matrix metalloproteinase-9 (MMP9) activity, respectively. The expressions of nNav1.5, Notch4, MMP9, and tissue inhibitor of metalloproteinases-1 (TIMP1) were also detected by quantitative real-time reverse transcriptase-polymerase chain reaction. DAPT caused an antiproliferative effect when the doses were higher than 10 µM, whereas phenytoin showed no inhibitory action either alone or in combination with DAPT on the MDA-MB-231 cells. Furthermore, it was found that the lateral motility was inhibited by both inhibitors; however, this inhibitory effect was partially rescued when they were used in combination. Meanwhile, the results showed that the MMP9 activity and the ratio of MMP9 mRNA to TIMP1 mRNA were only decreased by DAPT. Thus, we conclude that the combined effect of DAPT and phenytoin is not as beneficial as using DAPT alone on MDA-MB-231 breast cancer cells.
Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dipeptides; Drug Interactions; Female; Humans; In Vitro Techniques; Matrix Metalloproteinase 9; NAV1.5 Voltage-Gated Sodium Channel; Phenytoin; Proto-Oncogene Proteins; RNA, Messenger; Receptor, Notch4; Receptors, Notch; Tissue Inhibitor of Metalloproteinase-1
PubMed: 26206582
DOI: 10.1093/abbs/gmv066 -
BMJ (Clinical Research Ed.) Nov 1992
Review
Topics: Dose-Response Relationship, Drug; Drug Monitoring; Humans; Phenytoin; Plasma; Time Factors
PubMed: 1467727
DOI: 10.1136/bmj.305.6863.1215