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)

We are selectively breeding mice prone (WSP) and resistant (WSR) to ethanol withdrawal seizures assessed by handling induced convulsions (HIC). The possibility that differences between the lines in HIC scores are a result of differences in general CNS excitability not specific to ethanol withdrawal was examined. Using treatments which produce generalized seizures (electroconvulsive shock, strychnine, and flurothyl) and gamma amino-butyric acid (GABA) antagonists (picrotoxin, bicuculline, and pentylentetrazol), the ED50 for seizures was determined in the selected lines. In addition, the sensitivity of WSP and WSR mice to the anticonvulsant actions of ethanol against each treatment was determined. Neither the convulsant amperage 50 (CA50) for ECS nor the ED50 for any drug treatment differed for the selected lines. When ethanol (1.5 g/kg) was administered prior to ECS, there was a dramatic differential suppression of ECS in the lines: the CA50 of WSR mice was elevated 5-fold, whereas the CA50 of WSP mice increased only two fold. Ethanol pretreatment also elevated the ED50 for strychnine and flurothyl in WSR mice significantly more than WSP mice, but the line difference was smaller than for the anticonvulsant effect against ECS. The ED50s for the GABA antagonists were not different between the WSR and WSP lines after ethanol pretreatment. We conclude that genetic selection is producing lines of mice that differ specifically in the degree of seizure severity caused by withdrawal from ethanol physical dependence and not in generalized CNS excitability. An increased sensitivity to the anticonvulsant effects of ethanol against some convulsant treatments has appeared as a correlated response to selection in the WSR line.
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PMID:Specific ethanol withdrawal seizures in genetically selected mice. 654 39

The anticonvulsant activity of phenytoin-lipid conjugates obtained by covalent binding of 3-hydroxy-methylphenytoin to dimyristoylglycerides via a succinidyl linkage, to 2-(1,3-dimyristoylglyceryl)butyric acid and to 3-myristoyl-2-myristoylmethylpropionic acid was evaluated in the maximal electroshock (MES) test and the seizure threshold test with subcutaneous pentetrazol. The phenytoin-lipid conjugates were less active than the parent drug in the MES test after intraperitoneal administration as suspensions, but exhibited comparable activity when injected as a solution in dimethylsulphoxide. They also protected mice from MES-induced seizures following oral administration of aqueous suspensions of the compounds or when incorporated into emulsions. The anticonvulsant activity could be correlated to in-vitro pancreatic lipase-mediated hydrolysis. The bis-deacyl derivatives were at least as active but in some cases also more toxic than phenytoin. Oral administration of two of the lipid conjugates resulted in a faster onset of the anticonvulsant activity compared with the administration of an equimolar dose of phenytoin itself. All compounds were inactive in the subcutaneous pentetrazol test. It is concluded that the lipids act as prodrugs of phenytoin, which is generated by lipolysis upon oral administration.
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PMID:Anticonvulsant activity of phenytoin-lipid conjugates, a new class of phenytoin prodrugs. 760 80

Progress made in the development of new antiepileptics (AEs) is justified by the high percentage of refractory patients to the available medical therapy (25%), although only a minority of cases are deemed suitable for surgical therapy. Yet, the ideal AE, that is, with a well-known mechanism of action, effective in monotherapy for all epileptic fits, with a perfect pharmacokinetic profile, with no adverse or teratogenic effects, with no drug interactions and available under many formulations, is far from being developed. The new AEs arise either from modification of already marked drug molecules or clinical formulations or from the effectiveness on the excitatory/inhibitory balance of the major neurotransmitters involved in the pathogenesis of seizures, the gamma-amino-butyric acid (GABA) as the inhibitory, and the glutamate (GLU) as the excitatory one. However, the mechanism remains unknown in a few of them. Those new AEs already marketed in Portugal (Vigabatrin), soon to be (Lamotrigine, Oxcarbazepine) or available abroad only (Gabapentin, Zonisamide) are review with special emphasis on their pharmacokinetic profile, side effects, interaction with other AEs, and clinical use. In conclusion, these new drugs have brought a very important advancement in the management of refractory patients, but the development of well-designed comparative trials involving both monotherapy and polytherapy has become important in order to develop useful strategies in the drug management of epilepsy.
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PMID:[New antiepileptic medications]. 774 11

Electrophysiological data suggest that an abnormal oscillatory pattern of discharge in cortical and thalamic neurons may be the major mechanism underlying primary generalised epilepsy. No neurochemical or anatomical substrate for this theory has hitherto been demonstrated in humans and the pathophysiology of primary generalised epilepsy remains unknown. By means of PET and the benzodiazepine (BZ) ligand [11C]flumazenil it has been previously shown that the BZ receptor density is reduced in the epileptic foci of patients with partial epilepsy. In the present study the method was further developed and used in a comparative analysis of cortical, cerebellar, and subcortical BZ receptor binding in patients with primary generalised tonic and clonic seizures (n = 8), and healthy controls (n = 8). Patients with generalised seizures had an increased BZ receptor density in the cerebellar nuclei (p = 0.006) and decreased density in the thalamus (p = 0.003). No significant changes were seen in the cerebral and cerebellar cortex or in the basal ganglia. The observed alterations suggest that the gamma-amino-butyric acid (GABA)-BZ system may be affected in the cerebello-thalamocortical loop of patients with generalised epilepsy and indicate possible targets for selective pharmacological treatment.
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PMID:In vivo demonstration of altered benzodiazepine receptor density in patients with generalised epilepsy. 802 64

The effects of muscimol, amino-oxyacetic acid (AOAA), diamino-N-butyric acid (DABA), bicuculline, picrotoxin, diazepam and phenobarbitone on the protective effect of clonidine against pentylenetetrazol-induced seizures were studied in mice. Muscimol, AOAA, DABA, phenobarbitone and diazepam significantly protected mice against pentylenetetrazol-induced seizures and also significantly potentiated the protective effect of clonidine against the seizures. Bicuculline and picrotoxin significantly potentiated seizures induced by pentylenetetrazol and significantly attenuated both the protective effects of muscimol and clonidine against the seizures. These data suggest that activation of gamma-aminobutyric acid systems may underlie the protective effect of clonidine against seizures induced by pentylenetetrazol in mice.
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PMID:gamma Aminobutyric acid mediation of the anticonvulsant effect of clonidine on pentylenetetrazol-induced seizures in mice. 805 98

The effects of muscimol, aminooxyacetic acid (AOAA), diamino-n-butyric acid (DABA), baclofen, bicuculline, picrotoxin, strychnine, diazepam, phenobarbitone and phenytoin on cimetidine-induced seizures were studied in mice. Cimetidine (400-1000 mg/kg, i.p.) induced dose-dependent tonic convulsion. Muscimol, AOAA and DABA effectively protected mice against cimetidine-induced seizures. Bicuculline and picrotoxin significantly potentiated the seizures induced by cimetidine and effectively antagonized the protective effects of muscimol, AOAA and DABA against the seizures. Diazepam and phenobarbitone significantly protected the mice against cimetidine-induced seizures while phenytoin and strychnine did not significantly alter the seizures. These results indicate that the attenuation of central gamma-aminobutyric acid neurotransmission may underlie cimetidine-induced seizures in mice.
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PMID:Cimetidine-induced seizures in mice. Antagonism by some GABAergic agents. 827 50

Vigabatrin is a structural analogue of gamma amino butyric acid (GABA), which binds irreversibly to GABA-transaminase causing increased brain levels of GABA. It is an important advance in the medical management of children with epilepsy. It appears to be particularly effective in the treatment of infantile spasms, especially when caused by tuberous sclerosis. It is also effective in the treatment of partial seizures and some generalized seizures including those of the Lennox-Gastaut syndrome. However, myoclonic seizures may be made worse by vigabatrin. It is not yet approved for use in the United States but it is approved throughout most of the rest of the world including Canada and Mexico. Release in the United States is expected in the near future.
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PMID:Vigabatrin. 909 66

Current frontline antiepileptic drugs tend to fall into several cellular mechanistic categories, and these categories often correlate with the clinical spectrum of action of the various antiepileptic drugs. Many antiepileptic drugs effective in control of partial and generalized tonic-clonic seizures are use- and voltage-dependent blockers of sodium channels. This mechanism selectively dampens pathologic activation of sodium channels, without interacting with normal sodium channel function. Examples include phenytoin, carbamazepine, valproic acid, and lamotrigine. Many antiepileptic drugs effective in control of generalized absence seizures block low threshold calcium currents. Low threshold calcium channels are present in high densities in thalamic neurons, and these channels trigger regenerative bursts that drive normal and pathologic thalamocortical rhythms, including the spike wave discharges of absence seizures. Examples include ethosuximide, trimethadione, and methsuximide. Several antiepileptic drugs that have varying clinical actions interact with the gamma-amino-butyric acid (GABA)ergic system. Diazepam and clonazepam selectively augment function of a subset of GABAA receptors, and these drugs are broad-spectrum antiepileptic drugs. In contrast, barbiturates augment function of all types of GABAA receptors, and are ineffective in control of generalized absence seizures, but effective in control of many other seizure types. Tiagabine and vigabatrin enhance cerebrospinal levels of GABA by interfering with reuptake and degradation of GABA, respectively. These antiepileptic drugs are effective in partial seizures. Lamotrigine is effective against both partial and generalized seizures, including generalized absence seizures. Its sole documented cellular mechanism of action is sodium channel block, a mechanism shared by phenytoin and carbamazepine. These drugs are ineffective against absence seizures. Consequently, unless there are unique aspects to the sodium channel block by lamotrigine, it seems unlikely that this mechanism alone could explain its broad clinical efficacy. Therefore, lamotrigine may have as yet uncharacterized cellular actions, which could combine with its sodium channel blocking actions, to account for its broad clinical efficacy.
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PMID:Antiepileptic drug cellular mechanisms of action: where does lamotrigine fit in? 942 23

Successful treatment of seizure disorders in small animals requires proper patient assessment, understanding the principles of antiepileptic drug (AED) therapy, designing a strategy for pharmacotherapy, and plans for emergency treatment. Several levels of assessment are needed in managing an epileptic patient to include the diagnosis, effectiveness of therapy, and health-related quality of life assessments. Three levels of diagnosis are important in determining the appropriate AED therapy: 1) confirmation that an epileptic seizure has occurred, and if so, the seizure type(s) manifested; 2) diagnosis of the seizure etiology; and 3) determination of an epileptic syndrome. Monotherapy is the initial goal of treating any cat or dog with epilepsy to reduce possible drug-drug interactions and adverse effects. Unfortunately, many of the AEDs useful in people cannot be prescribed to small animals either due to inappropriate pharmacokinetics (too rapid of an elimination), and potential hepatotoxicity. Thus, the most commonly used AEDs in veterinary medicine are from the same mechanistic category, that of enhancing inhibition of the brain. Antiepileptic drugs can be classified into three broad mechanistic categories: 1) enhancement of inhibitory processes via facilitated action of gamma amino-butyric acid (GABA); 2) reduction of excitatory transmission; and 3) modulation of membrane cation conductance. Pharmacotherapy strategies should be designed based on the decision when to start treatment, choice of the appropriate AED, and proper AED monitoring and adjustment. Information is presented for the current AEDs of choice, phenobarbital and bromide. Additional guidelines are provided for administration of newer AEDs, felbamate and gabapentin. All owners should be aware that emergency therapy may be necessary if recurrent or severe seizures occur in their pet. A rapid, reliable protocol is presented for the emergency management of seizuring cats and dogs in the hospital and at home. Home treatment with per rectal administration of diazepam in the dog has proven to be an effective means of reducing seizure frequency and owner anxiety. Treating each animal as an individual, applying the philosophy that seizure prevention is better than intervention, and consulting specialists to help formulate or revise treatment plans will lead to improved success in treating seizure disorders in the cat and dog.
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PMID:Antiepileptic drug therapy. 977 9

All the benzodiazepines (BZDs) in clinical use have the capacity to promote the binding of the major inhibitory neurotransmitter, gamma-amino-butyric acid (GABA), to sub-types of GABA receptors which exist as multi-subunit ligand-gated chloride channels. Thus, the BZDs facilitate the actions of GABA in the brain. The BZDs in use as antiepileptic drugs are diazepam, clonazepam, clobazam, nitrazepam, and lately, also lorazepam and midazolam as emergency therapy. The BZDs have a wide-spectrum of proven clinical efficacy in the prevention of different kind of seizures. Clonazepam and clobazam, as well as nitrazepam in some cases, can be useful as an adjunct treatment in refractory epilepsies. However, the clinical use of BZDs for the prophylactic treatment of epilepsy is associated with two major problems which have limited the long-term use of these drugs: the potential for side-effects, especially sedative effects, and the high risk of development of tolerance. Despite the limitations of BZDs in the prophylactic treatment of epilepsies, these drugs play a prominent role in clinical practice in the emergency management of acute seizures and status epilepticus. Diazepam, clonazepam and lorazepam are all considered first-line agents in the emergency management of acute seizures and status epilepticus. Furthermore, the value of midazolam as an emergency therapy in epilepsy has been increasingly recognized in recent years.
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PMID:Benzodiazepines in the treatment of epilepsy in people with intellectual disability. 1003 Apr 38


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