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Epilepsia 1995Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear... (Review)
Review
Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium channels, gamma-aminobutyric acid type A (GABAA) receptors, or calcium channels. Benzodiazepines and barbiturates enhance GABAA receptor-mediated inhibition. Phenytoin (PHT), carbamazepine (CBZ), and possibly valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing sodium-channel inactivation. Ethosuximide (ESM) and VPA reduce a low threshold (T-type) calcium-channel current. The mechanisms of action of the new AEDs are not fully established. Gabapentin (GBP) binds to a high-affinity site on neuronal membranes in a restricted regional distribution of the central nervous system. This binding site may be related to a possible active transport process of GBP into neurons; however, this has not been proven, and the mechanism of action of GBP remains uncertain. Lamotrigine (LTG) decreases sustained high-frequency repetitive firing of voltage-dependent sodium action potentials that may result in a preferential decreased release of presynaptic glutamate. The mechanism of action of oxcarbazepine (OCBZ) is not known; however, its similarity in structure and clinical efficacy to CBZ suggests that its mechanism of action may involve inhibition of sustained high-frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin (VGB) irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underline the clinical efficacy of VGB.
Topics: Acetates; Action Potentials; Amines; Animals; Anticonvulsants; Barbiturates; Benzodiazepines; Calcium Channels; Carbamazepine; Central Nervous System; Cyclohexanecarboxylic Acids; Epilepsy; Gabapentin; Humans; Ion Channels; Lamotrigine; Phenytoin; Rats; Receptors, GABA; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Sodium Channels; Triazines; Trimethadione; Valproic Acid; Vigabatrin; gamma-Aminobutyric Acid
PubMed: 8784210
DOI: 10.1111/j.1528-1157.1995.tb05996.x -
Medicines (Basel, Switzerland) Jun 2023Adverse effects of antiseizure medications (ASMs) remain one of the major causes of non-adherence. Cosmetic side effects (CSEs) are among the most commonly reported... (Review)
Review
Adverse effects of antiseizure medications (ASMs) remain one of the major causes of non-adherence. Cosmetic side effects (CSEs) are among the most commonly reported side effects of ASMs. In this context, alopecia is one of the CSEs that has a high intolerance rate leading to poor therapeutical compliance. We performed a literature review concerning alopecia as a secondary effect of ASMs. There are 1656 individuals reported with ASM-induced alopecia. Valproate (983), lamotrigine (355), and carbamazepine (225) have been extensively reported. Other ASMs associated with alopecia were cenobamate (18), levetiracetam (14), topiramate (13), lacosamide (7), vigabatrin (6), phenobarbital (5), gabapentin (5), phenytoin (4), pregabalin (4), eslicarbazepine (3), brivaracetam (2), clobazam (2), perampanel (2), trimethadione (2), rufinamide (2), zonisamide (2), primidone (1), and tiagabine (1). There were no reports of oxcarbazepine and felbamate with drug-induced alopecia. Hair loss seen with ASMs was diffuse and non-scarring. Telogen effluvium was the most common cause of alopecia. A characteristic feature was the reversibility of alopecia after ASM dose adjustment. Alopecia should be considered one important adverse effect of ASMs. Patients reporting hair loss with ASM therapy should be further investigated, and specialist consultation is recommended.
PubMed: 37367730
DOI: 10.3390/medicines10060035 -
Cleveland Clinic Journal of Medicine 1989Given the advantages of modern medical management, most pregnant epileptic women should experience no significant increase in seizure frequency. With good prenatal... (Review)
Review
Given the advantages of modern medical management, most pregnant epileptic women should experience no significant increase in seizure frequency. With good prenatal medical and obstetric care, complications of pregnancy and delivery in epileptic women differ little from those in the general population. In any case, monotherapy should be employed if possible, and anticonvulsant levels should be monitored closely during pregnancy and immediately after delivery. Dosage adjustments should be made appropriately. Since such an adjustment will usually be made in the second or third trimester, one would not expect it to produce an increased number of malformations. Trimethadione should be absolutely avoided and valproic acid used only with caution and with monitoring of alpha fetoprotein and uterine ultrasound. Although it is true that there is an increased incidence of malformations in children of epileptic women (with or without anticonvulsants), the great majority of these babies are normal. Vitamin K should be given to the mother before delivery, and the newborn should receive 1 mg vitamin K at birth. Unless the infant becomes symptomatic, breast feeding should be allowed. If seizures occur for the first time during pregnancy, the patient should be appropriately evaluated. Status epilepticus in pregnant women calls for aggressive and careful treatment. Finally, it should be remembered that oral contraceptives, especially the "mini pill," have a higher failure rate in women taking anticonvulsants. Discussing this problem with the patient is helpful.
Topics: Abnormalities, Drug-Induced; Anticonvulsants; Epilepsy; Female; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications; Prenatal Care
PubMed: 2659208
DOI: 10.3949/ccjm.56.s1.195 -
Biomolecules Aug 2014In Parkinson's disease and some atypical Parkinson's syndromes, aggregation of the α-synuclein protein (α-syn) has been linked to neurodegeneration. Many triggers for... (Review)
Review
In Parkinson's disease and some atypical Parkinson's syndromes, aggregation of the α-synuclein protein (α-syn) has been linked to neurodegeneration. Many triggers for pathological α-syn aggregation have been identified, including port-translational modifications, oxidative stress and raised metal ions, such as Ca2+. Recently, it has been found using cell culture models that transient increases of intracellular Ca2+ induce cytoplasmic α-syn aggregates. Ca2+-dependent α-syn aggregation could be blocked by the Ca2+ buffering agent, BAPTA-AM, or by the Ca2+ channel blocker, Trimethadione. Furthermore, a greater proportion of cells positive for aggregates occurred when both raised Ca2+ and oxidative stress were combined, indicating that Ca2+ and oxidative stress cooperatively promote α-syn aggregation. Current on-going work using a unilateral mouse lesion model of Parkinson's disease shows a greater proportion of calbindin-positive neurons survive the lesion, with intracellular α-syn aggregates almost exclusively occurring in calbindin-negative neurons. These and other recent findings are reviewed in the context of neurodegenerative pathologies and suggest an association between raised Ca2+, α-syn aggregation and neurotoxicity.
Topics: Animals; Calcium; Humans; Intracellular Space; Neurodegenerative Diseases; Protein Binding; Protein Multimerization; alpha-Synuclein
PubMed: 25256602
DOI: 10.3390/biom4030795 -
Canadian Medical Association Journal Jun 1963The main clinical types of epilepsy and their treatment are described. The treatment of choice in petit mal epilepsy is trimethadione (Trimedone) 0.3 g., three to six...
The main clinical types of epilepsy and their treatment are described. The treatment of choice in petit mal epilepsy is trimethadione (Trimedone) 0.3 g., three to six times a day, or acetazolamide (Diamox) 125-250 mg., three to four times a day. Phenobarbital is usually given as well to prevent grand mal seizures. Diphenylhydantoin sodium (Dilantin Sodium), 100 mg., and/or phenobarbital, 30-100 mg., three to four times a day, is recommended in patients with focal and grand mal epilepsy. Psychomotor automatisms are a form of focal seizure. Primidone (Mysoline), in doses of 125-250 mg. two to three times a day, is a very useful anticonvulsant in patients with myoclonic features, psychomotor automatisms and grand mal seizures. Primidone should be started in small doses. Drug reactions, especially cerebellar ataxia in the case of diphenylhydantoin and blood dyscrasias in the case of some drugs, should be recognized. Excessive drowsiness can be avoided by proper dosage and proper timing of drug administration. Patients should be seen regularly at least two to three times a year. The objective of treatment is to achieve optimum control of seizures by using the appropriate drug in adequate dosage. Social adaptation is good in the majority of patients, who should be encouraged to carry on their life independently, usually free to marry and have children. Attention to special occupational hazards has to be considered. Education of employers and employees is often necessary. Special work arrangements are occasionally indicated for selected patients. Patients should be seizure-free for two to three years before permission is given to drive an automobile.
Topics: Acetazolamide; Anticonvulsants; Automatism; Child; Epilepsy; Epilepsy, Absence; Epilepsy, Tonic-Clonic; Humans; Phenobarbital; Phenytoin; Primidone; Seizures
PubMed: 13969008
DOI: No ID Found -
Frontiers in Pharmacology 2021AMPA receptors are responsible for fast excitatory synaptic transmission in the mammalian brain. Post-translational protein -palmitoylation of AMPA receptor subunits...
AMPA receptors are responsible for fast excitatory synaptic transmission in the mammalian brain. Post-translational protein -palmitoylation of AMPA receptor subunits GluA1-4 reversibly regulates synaptic AMPA receptor expression, resulting in long-lasting changes in excitatory synaptic strengths. Our previous studies have shown that GluA1 C-terminal palmitoylation-deficient (GluA1C811S) mice exhibited hyperexcitability in the cerebrum and elevated seizure susceptibility without affecting brain structure or basal synaptic transmission. Moreover, some inhibitory GABAergic synapses-targeting anticonvulsants, such as valproic acid, phenobarbital, and diazepam, had less effect on these AMPA receptor palmitoylation-deficient mutant mice. This work explores pharmacological effect of voltage-gated ion channel-targeted anticonvulsants, phenytoin and trimethadione, on GluA1C811S mice. Similar to GABAergic synapses-targeting anticonvulsants, anticonvulsive effects were also reduced for both sodium channel- and calcium channel-blocking anticonvulsants, which suppress excess excitation. These data strongly suggest that the GluA1C811S mice generally underlie the excessive excitability in response to seizure-inducing stimulation. AMPA receptor palmitoylation site could be a novel target to develop unprecedented type of anticonvulsants and GluA1C811S mice are suitable as a model animal for broadly evaluating pharmacological effectiveness of antiepileptic drugs.
PubMed: 34483921
DOI: 10.3389/fphar.2021.711737 -
The Journal of Biological Chemistry Sep 1998Phenytoin and related xenobiotics can be bioactivated by embryonic prostaglandin H synthase (PHS) to a teratogenic free radical intermediate. The mechanism of free...
Free radical intermediates of phenytoin and related teratogens. Prostaglandin H synthase-catalyzed bioactivation, electron paramagnetic resonance spectrometry, and photochemical product analysis.
Phenytoin and related xenobiotics can be bioactivated by embryonic prostaglandin H synthase (PHS) to a teratogenic free radical intermediate. The mechanism of free radical formation was evaluated using photolytic oxidation with sodium persulfate and by EPR spectrometry. Characterization of the products by mass spectrometry suggested that phenytoin photolyzes to a nitrogen-centered radical that rapidly undergoes ring opening to form a carbon-centered radical. PHS-1 was incubated with teratogen (phenytoin, mephenytoin, trimethadione, phenobarbital, and major metabolites) or its vehicle and the free radical spin trap alpha-phenyl-N-t-butylnitrone, and incubations were analyzed by EPR spectrometry. There was no alpha-phenyl-N-t-butylnitrone radical adduct in control incubations. For phenytoin, a putative unstable nitrogen-centered radical adduct and a stable carbon-centered radical adduct were detected. Free radical spin adducts also were detected for all other teratogens and metabolites except carbamazepine. The PHS inhibitor eicosatetraynoic acid abolished the free radical EPR signal. Incubation of 2'-deoxyguanosine with phenytoin and PHS-1 resulted in a 5-fold increase in its oxidation to 8-hydroxy-2'-deoxyguanosine. This is the first direct chemical evidence for PHS-catalyzed bioactivation of phenytoin and related teratogens to a free radical intermediate that initiates DNA oxidation, which may constitute a common molecular mechanism of teratologic initiation.
Topics: Biotransformation; Catalysis; Deoxyguanosine; Electron Spin Resonance Spectroscopy; Free Radicals; Oxidation-Reduction; Phenytoin; Photochemistry; Prostaglandin-Endoperoxide Synthases; Teratogens
PubMed: 9737965
DOI: 10.1074/jbc.273.39.25079 -
Seizure Dec 2006The bioethical principles of autonomy, beneficence, non-maleficence and justice, complemented by ethics committee evaluation, define conduct of clinical trials of... (Review)
Review
INTRODUCTION
The bioethical principles of autonomy, beneficence, non-maleficence and justice, complemented by ethics committee evaluation, define conduct of clinical trials of anti-epileptic medications (AEM).
BACKGROUND INFORMATION
Increased teratogenicity for offspring of women with epilepsy is presented in both lay and scientific literature. SPECIFIC DRUGS--OLDER GENERATION: Teratogenicity of phenobarbitone (PB), phenytoin (PHT), valproate (VPA) and carbamazepine (CBZ) is acknowledged, with drugs, such as trimethadione, being removed from the market because of teratogenicity. SPECIFIC DRUGS--NEW GENERATION: Insufficient data allowed definitive commentary concerning teratogenicity of newer AEM, such as lamotrigine (LTG), gabapentin (GBP), tiagabine (TGB) or levetiracetam (LEV). All those suggestions favour some over others with specific AEM combinations being questioned. PREGNANCY REGISTRIES: Lack of information sporn AEM-specific plus national and international birth registries which endorse VPA, CBZ and LTG dose related concerns.
CONFLICT OF INTEREST
Competing influences of AEM and epilepsy-specific factors need delineation although appear more teratogenetic than does epilepsy alone.
CLINICAL TRIALS
Most trials focus upon refractory epilepsy with potentially enhanced risks. Informed consent demands discussion of possible teratogenicity and exclusion of women unwilling to practice adequate contraception.
DISCUSSION
Trials must respect legal and ethical dictates including the exclusion of women unwilling to practice reliable contraception. Automatic exclusion from a trial, subsequent to confirmed pregnancy, is unlikely to protect the foetus as potential for teratogenicity already has occurred. Autonomy should empower prospective parents to decide continued trial participation consequent to detailed informed consent without coercion. All options demand review, including responsibility to future AEM users.
Topics: Anticonvulsants; Clinical Trials as Topic; Epilepsy; Female; Humans; Informed Consent; Patient Selection; Personal Autonomy; Pregnancy; Pregnancy Complications
PubMed: 17011799
DOI: 10.1016/j.seizure.2006.08.008 -
GeroScience Jun 2023Liposome-mediated delivery is a possible means to overcome several shortcomings with C. elegans as a model for identifying and testing drugs that retard aging. These...
Liposome-mediated delivery is a possible means to overcome several shortcomings with C. elegans as a model for identifying and testing drugs that retard aging. These include confounding interactions between drugs and the nematodes' bacterial food source and failure of drugs to be taken up into nematode tissues. To explore this, we have tested liposome-mediated delivery of a range of fluorescent dyes and drugs in C. elegans. Liposome encapsulation led to enhanced effects on lifespan, requiring smaller quantities of compounds, and enhanced uptake of several dyes into the gut lumen. However, one dye (Texas red) did not cross into nematode tissues, showing that liposomes cannot ensure the uptake of all compounds. Of six compounds previously reported to extend lifespan (vitamin C, N-acetylcysteine, glutathione (GSH), trimethadione, thioflavin T (ThT), and rapamycin), this effect was reproduced for the latter four in a condition-dependent manner. For GSH and ThT, antibiotics abrogated life extension, implying a bacterially mediated effect. With GSH, this was attributable to reduced early death from pharyngeal infection and associated with alterations of mitochondrial morphology in a manner suggesting a possible innate immune training effect. By contrast, ThT itself exhibited antibiotic effects. For rapamycin, significant increases in lifespan were only seen when bacterial proliferation was prevented. These results document the utility and limitations of liposome-mediated drug delivery for C. elegans. They also illustrate how nematode-bacteria interactions can determine the effects of compounds on C. elegans lifespan in a variety of ways.
Topics: Animals; Caenorhabditis elegans; Liposomes; Aging; Longevity; Bacteria; Sirolimus
PubMed: 37140725
DOI: 10.1007/s11357-023-00800-x -
American Journal of Obstetrics and... May 1986Fetal echocardiography is a well-established technique for the prenatal identification of congenital heart disease. One of the indications for its use is the presence of... (Review)
Review
Fetal echocardiography is a well-established technique for the prenatal identification of congenital heart disease. One of the indications for its use is the presence of extracardiac anomalies, as such coexistent defects may have important implications for obstetric and neonatal management. We have reviewed the obstetric and pediatric literature to examine reported associations. If a fetus is suspected to have hydrocephalus, microcephaly, holoprosencephaly, agenesis of the corpus callosum, Meckel-Gruber syndrome, esophageal atresia, duodenal atresia, diaphragmatic hernia, omphalocele, or renal dysplasia, cardiac evaluation should be pursued. Furthermore, echocardiography may be of help in differential diagnosis of some anomalies (for instance, skeletal dysplasias). Maternal diabetes and phenylketonuria, as well as exposure to phenytoin, trimethadione, or isotretinoin, may result in multiple systemic defects, including congenital heart disease.
Topics: Abdominal Muscles; Abnormalities, Drug-Induced; Abnormalities, Multiple; Central Nervous System; Chromosome Aberrations; Chromosome Disorders; Congenital Abnormalities; Digestive System Abnormalities; Echocardiography; Female; Fetal Heart; Heart Defects, Congenital; Humans; Infant, Newborn; Phenylketonurias; Pregnancy; Pregnancy Complications; Pregnancy in Diabetics; Prenatal Diagnosis; Respiratory System Abnormalities; Urogenital Abnormalities
PubMed: 2939723
DOI: 10.1016/0002-9378(86)90773-8