Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antiepileptic drugs (AEDs) vary in their efficacy against generalized tonic-clonic, myoclonic, and absence seizures, suggesting different mechanisms of action. Phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) reduced the ability of mouse central neurons to sustain high-frequency repetitive firing of action potentials (SRF) at therapeutic free serum concentrations. Phenobarbital (PB) and the benzodiazepines (BZDs), diazepam (DZP), clonazepam (CZP), and lorazepam (LZP), also reduced SRF, but only at supratherapeutic free serum concentrations achieved in treatment of generalized tonic-clonic status epilepticus. These AEDs interact with sodium channels to slow the rate of recovery of the channels from inactivation. The BZDs and PB enhanced gamma-aminobutyric acid (GABA) responses evoked on mouse central neurons by binding to two different sites on the GABAA receptor channel. BZDs increased the frequency of GABA receptor channel openings. In contrast, barbiturates increased the open duration of these channels. VPA enhanced brain GABA concentration and may enhance release of GABA from nerve terminals. Ethosuximide (ESM) reduced a small transient calcium current which has been shown to be involved in slow rhythmic firing of certain neurons. Reduction of SRF, enhancement of GABA-ergic inhibition, and reduction of calcium current may be, in part, the bases for AED action against generalized tonic-clonic, myoclonic, and absence seizures, respectively.
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PMID:Antiepileptic drug actions. 255 Feb 16

Antiepileptic medication is widely prescribed for many neurological conditions, especially seizures. Although adverse reactions are noted, they generally fall into a category of mild effects which necessitate a therapeutic change--and little evaluation. We present a case of a severe reaction to two antiseizure medications. Characteristic findings of lymphadenopathy, fever, exfoliative dermatitis, eosinophilia and hepatic damage are well described as a hypersensitive reaction to phenytoin, often called "pseudolymphoma." Phenobarbital also produces a clinically indistinguishable syndrome of pseudolymphoma, which is not widely recognized. A case report and review of the literature are presented. We conclude that phenytoin and phenobarbital hypersensitivity reactions are probably mediated by a similar mechanism. This appears to be an extreme extension of the more common and less severe reactions to these medications. Clinical studies in primary care can better elucidate this potentially fatal reaction.
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PMID:Case report of antiepileptic drug hypersensitivity reaction: pseudolymphoma syndrome. 266 6

A variety of the anticonvulsant drugs, including carbamazepine, phenytoin, primidone, phenobarbital, clonazepam, valproic acid, and ethosuximide, are available for use in the treatment of patients with seizure disorders. These anticonvulsants vary in their efficacy against experimental seizures in animals and against seizures in humans. The mechanistic basis for this variability in anticonvulsant drug action remains uncertain, but numerous mechanisms of action have been proposed. We have used mouse neurons in primary dissociated cell culture to study the action of these anticonvulsant drugs on several aspects of membrane excitability and synaptic transmission. We have proposed that the anticonvulsant drugs can be classified according to their actions on sustained high frequency repetitive firing (SRF) of action potentials and on postsynaptic gamma-aminobutyric acid (GABA) responses. Phenytoin and carbamazepine were both effective against SRF but did not modify postsynaptic GABA responses at therapeutically relevant concentrations. Phenobarbital, benzodiazepines, and valproic acid modified both SRF and postsynaptic GABA responses. Ethosuximide had no effect on SRF or GABAergic mechanisms. Based on these results, we have proposed that blockade of SRF may underlie the action of phenytoin, carbamazepine, phenobarbital, valproic acid, and benzodiazepines against generalized tonic-clonic seizures in humans and maximal electroshock seizures in animals. Enhancement of GABAergic synaptic transmission may underlie efficacy of benzodiazepines and valproic-acid drugs against generalized absence seizures in humans and pentylenetetrazol-induced seizures in experimental animals. The mechanism of action of ethosuximide against generalized absence seizures in humans and pentylenetetrazol-induced seizures in experimental animals may be by a third, as yet unknown, mechanism.
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PMID:Anticonvulsant drugs: mechanisms of action. 287 24

The actions of clinically used anticonvulsant drugs on sustained high frequency repetitive firing of action potentials and on responses to gamma aminobutyric acid (GABA) have been determined using mouse neurons in cell culture, and a classification of anticonvulsant drug actions has been developed based on these cellular actions. Actions of the anticonvulsant drugs were accepted as clinically relevant only if they occurred at concentrations achieved in cerebrospinal fluid or in plasma unbound to plasma proteins. Based on their cellular mechanisms of actions, drugs have been divided into 3 categories: (1) Phenytoin, carbamazepine and valproic acid limited sustained high frequency repetitive firing but did not alter GABA responses. (2) Phenobarbital and the benzodiazepines, clonazepam, diazepam and nitrazepam, augmented postsynaptic GABA responses. These drugs limited sustained high frequency repetitive firing only at concentrations above the therapeutic range in ambulatory patients, but equal to concentrations achieved in the acute treatment of status epilepticus. (3) Ethosuximide failed to reduce sustained high frequency repetitive firing or enhance GABA responses even at supertherapeutic concentrations. Limitation of sustained high frequency repetitive firing by anticonvulsant drugs correlated well with efficacy against generalized tonic-clonic seizures in man and against maximal electroshock seizures in experimental animals. Enhancement of postsynaptic GABA responses correlated with efficacy against generalized absence seizures in man and against pentylenetetrazol seizures in animals. Ethosuximide, however, did not alter GABA responses or sustained high frequency repetitive firing suggesting that its action against generalized absence seizures in man and pentylenetetrazol seizures in experimental animals occurs by an additional, as yet unknown, mechanism.
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PMID:Mechanisms of anticonvulsant drug action. 288 43

The synapse is a major regulatory site that has been implicated in modulating neuronal excitability and seizure discharge. Voltage-dependent calcium (Ca2+) entry at the synapse plays a major role in initiating neurotransmitter release and in regulating synaptic function. Thus, obtaining a molecular understanding of the effects of Ca2+ on synaptic modulation would provide important insights into the regulation of synaptic activity and, possibly, the biochemical basis for some forms of epilepsy. Calmodulin is a major Ca2+-binding protein in brain that has been implicated in mediating many of the second messenger effects of Ca2+ on neuronal function. The evidence implicating calmodulin in modulating synaptic excitability will be presented. Calmodulin was shown to be present at the synapse in association with synaptic vesicles and in the postsynaptic density. In addition, several calmodulin-regulated synaptic biochemical processes have been identified, including Ca2+- and calmodulin-regulated protein phosphorylation, vesicular neurotransmitter release, vesicle-membrane interactions, and neurotransmitter turnover. These results indicate that calmodulin may play an important role in synaptic modulation and provide a molecular approach to investigating the Ca2+ signal in brain. Several anticonvulsants have been shown to regulate some of calcium's effects on neuronal function. These anticonvulsants include phenytoin, carbamazepine, and the benzodiazepines. All of these compounds are effective against maximal electric shock (MES) seizure models in animals. Anticonvulsants were tested on several of the Ca2+-calmodulin-regulated synaptic biochemical systems. The results demonstrate that phenytoin, carbamazepine, and the benzodiazepines were effective in inhibiting calcium calmodulin protein kinase activity in membrane and purified kinase preparations, vesicle neurotransmitter release, vesicle-membrane interactions, and voltage-sensitive calcium uptake in intact synaptosomes. Phenobarbital, ethosuximide, trimethadione, valproic acid, and vinyl gamma-aminobutyric acid (GABA) were not effective in inhibiting these calcium-regulated processes. Thus, the effects of anticonvulsants on calcium-regulated processes were selective to a group of anticonvulsants that had been shown in several electrophysiological systems to antagonize some of the actions of calcium on neuronal excitability. These observations suggested the existence of specific membrane receptors that might mediate the effects of these anticonvulsants on neuronal function through the regulation of calcium-calmodulin-regulated processes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A molecular approach to the calcium signal in brain: relationship to synaptic modulation and seizure discharge. 301 Jun 80

Two actions of clinically used antiepileptic drugs have been studied using mouse neurons in primary dissociated cell culture. The antiepileptic drugs phenytoin, carbamazepine and valproic acid were demonstrated to limit sustained high frequency repetitive firing of action potentials at free serum concentrations that are achieved in patients being treated for epilepsy. Furthermore, an active metabolite of carbamazepine also limited sustained high frequency repetitive firing while inactive metabolites of phenytoin and carbamazepine did not limit sustained high frequency repetitive firing. Phenobarbital and clinically used benzodiazepines limited sustained high frequency repetitive firing of action potentials, but only at concentrations achieved during the treatment of generalized tonic-clonic status epilepticus. Ethosuximide did not limit sustained high frequency repetitive firing even at concentrations four times those achieved in the serum of patients treated for generalized absence seizures. Phenobarbital and clinically used benzodiazepines enhanced postsynaptic GABA responses at concentrations achieved free in the serum during treatment of generalized tonic-clonic or generalized absence seizures. However, phenytoin, carbamazepine, valproic acid and ethosuximide did not modify postsynaptic GABA responses at therapeutic free serum concentrations. These results suggest that the ability of antiepileptic drugs to block generalized tonic-clonic seizures and generalized tonic-clonic status epilepticus may be related to their ability to block high frequency repetitive firing of neurons. The mechanism underlying blockade of myoclonic seizures may be related to the ability of antiepileptic drugs to enhance GABAergic synaptic transmission. The mechanism underlying management of generalized absence seizures remains unclear.
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PMID:Anticonvulsant drug actions on neurons in cell culture. 304 14

Status epilepticus (SE) is defined as a continuous seizure that lasts more than 30 minutes or as serial seizures in which the patient does not regain a premorbid level of consciousness. This condition exists primarily in two forms: convulsive (focal or generalized) and nonconvulsive (absence or partial complex) SE. Protracted or serial convulsive seizures represent a medical emergency with a current mortality rate of 10%. As in any urgent or life-threatening situation, the initial treatment is directed at support and maintenance of vital functions. Specific anticonvulsant management is usually begun with intravenous lorazepam. This benzodiazepine is replacing diazepam in many medical centers because it has a longer duration of action and causes less respiratory depression. Concurrent intravenous loading with phenytoin is usually necessary for sustained control of seizures. Phenobarbital may be required as a third drug if seizures persist or recur. In cases of refractory status epilepticus, barbiturate coma, continuous anticonvulsant intravenous infusion, or general anesthesia may be necessary.
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PMID:Status epilepticus in children and adults. 305 85

Amygdala-kindled female rats were used to compare the effects of seven antiepileptic drugs that are clinically used for treatment of partial epilepsy with complex symptomatology, on generalized seizures, focal seizures, or electrographic seizure activity at the focus. As a second approach of drug evaluation, drug effects on mean latency, severity, and duration of the seizures were determined. Anticonvulsant potencies obtained were compared with those determined in the maximal electroshock seizure test in female rats. Phenobarbital, phenytoin, carbamazepine, valproic acid, diazepam, clonazepam, but not primidone dose-dependently suppressed generalized motor seizures in kindled rats; however, except for the benzodiazepines, ED50S were substantially higher than those determined in the maximal electroshock seizure test. Compared with their effect on generalized motor seizures, all drugs were much less potent in blocking focal seizures and afterdischarges recorded from the amygdala. The data suggest that with respect to behavioral and pharmacologic characteristics of the amygdala kindling model, fully kindled rats may be a useful model for drug-resistant complex partial seizures with secondary generalization. Results of experiments with novel inhibitors of GABA uptake, which were inactive in the maximal electroshock seizure test but highly potent against kindled seizures, suggest that such drugs might be more effective than current antiepileptic drugs for treatment of partial epilepsy.
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PMID:Is amygdala kindling in rats a model for drug-resistant partial epilepsy? 308 32

Seizures in the newborn are a distinctive sign of underlying disease. Different convulsive patterns are described. The most common neurologic syndrome consists of subtle seizures. The most important cause is ischemic encephalopathy. Hypocalcemia is the main metabolic disease. Hypoglycemia seems not to be of special relevance for pathogenesis of newborn seizures. Other episodic symptoms of non-epileptic origin should be considered in the differential diagnosis. It is critical to diagnose the cause and to treat it, since the prognosis depends on the underlying disturbance. Phenobarbital is the anticonvulsive drug of first choice. Duration of treatment is determinated of an preexisting brain damage. Newborns with normal neurological evaluation don't need any longer anticonvulsive treatment after cessation of seizures. The EEG is an important prognostic tool.
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PMID:[Neonatal spasms--a review of symptoms, etiology, therapy and prognosis]. 310 Aug 62

Phenobarbital (PB) brain and blood concentrations were measured together with brain and blood pH in newborn piglets before and at the end of seizure activity induced by pentylenetetrazol or bicuculline. Seizures induced a significant elevation of arterial blood pressure and profound changes in the blood gases and in the acid-base balance, with a marked reduction in brain tissue pH. Despite an intense brain acidosis, however, and a significant rise in blood/brain [H+] gradient, phenobarbital brain concentrations were not reduced during seizures but, on the contrary, were increased in 7 of 11 piglets. These data suggest that contrary to the pH partition hypothesis, brain uptake of PB is concomitantly increased during seizures and brain acidosis.
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PMID:Effect of seizures on brain phenobarbital concentration in newborn piglets. 310 21


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