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)

Despite old age being the commonest time of life to develop epilepsy, relatively little is known about the condition in later years. Antiepileptic drugs (AEDs) are the mainstay of treatment and valproic acid (VPA) has been prescribed for older patients with seizures for over 35 years. VPA is available in a variety of formulations. The drug is generally rapidly absorbed, although there are no data on the extent of oral absorption in the elderly. The volume of distribution (Vd) and elimination half-life have been compared in older and younger patients. One study reported no change in either parameter between elderly and younger patients (Vd: 0.16 vs 0.14 L/kg; elimination half-life: 15.3 vs 13.0h), the other found an increase in both for older patients (Vd: 0.19 vs 0.13 L/kg; elimination half-life 14.9 vs 7.2h). Total VPA clearance is similar in young and elderly subjects. The drug does not induce the metabolism of hepatic enzymes, but can act as a metabolic inhibitor, raising plasma concentrations of lamotrigine, phenobarbital (phenobarbitone), carbamazepine-10-11-epoxide, lorazepam, nimodipine and zidovudine. Concomitant use of VPA may also lead to an elevation in phenytoin, diazepam, warfarin, amitriptyline and chlorpromazine concentrations. A number of enzyme-inducing AEDs such as phenytoin, phenobarbital, primidone and carbamazepine can increase the clearance of VPA. Plasma concentrations of VPA may also rise when the drug is administered with felbamate, stiripentol, aspirin (acetylsalicylic acid), naproxen, phenylbutazone, isoniazid, fluoxetine and chlorpromazine. The majority of elderly patients present with partial and/or secondary generalised seizures, although a few have long-standing primary generalised seizures. Results from meta-analyses and randomised studies of patients comparing VPA with other AED monotherapies suggest that the drug is as effective as carbamazepine, phenytoin and phenobarbital in treating these seizure types. Although some of these studies recruited older patients, there have been no randomised double-blind trials examining the efficacy of VPA with other AEDs in an exclusively elderly cohort. There is no direct correlation between efficacy and plasma VPA concentrations. The majority of older patients require lower doses of AEDs than younger adults. Higher VPA doses may be needed in patients taking drugs which induce hepatic microsomal enzymes. Once-daily dosing of the controlled-release preparation can help to improve compliance and may render some frail elderly people seizure free. There is a perception that the elderly are generally more susceptible to the adverse effects of AEDs than younger adults, although there are few data to validate this claim. Dose-dependent and idiosyncratic reactions may be more frequent. Common adverse effects of VPA include gastrointestinal symptoms and tremor. Slow-dose escalation and controlled-release preparations may minimise these. In summary, VPA is a long established AED. Its broad spectrum of action and dosing schedule are favourable properties for its use in older people. To accurately establish the place of this and other AEDs in treating elderly patients with epilepsy, well designed clinical trials are urgently required in this vulnerable population.
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PMID:Drug treatment of epilepsy in elderly people: focus on valproic Acid. 1253 14

Defects in the assembly of dolichol-linked oligosaccharide or its transfer to proteins result in severe, multi-system human diseases called Type I congenital disorders of glycosylation. We have identified a novel CDG type, CDG-Ij, resulting from deficiency in UDP-GlcNAc: dolichol phosphate N-acetyl-glucosamine-1 phosphate transferase (GPT) activity encoded by DPAGT1. The patient presents with severe hypotonia, medically intractable seizures, mental retardation, microcephaly, and exotropia. Metabolic labeling of cultured dermal fibroblasts from the patient with [2-(3)H]-mannose revealed lowered incorporation of radiolabel into full-length dolichol-linked oligosaccharides and glycoproteins. In vitro enzymatic analysis of microsomal fractions from the cultured cells indicated that oligosaccharyltransferase activity is normal, but the GPT activity is reduced to approximately 10% of normal levels while parents have heterozygous levels. The patient's paternal DPAGT1 allele contains a point mutation (660A>G) that replaces a highly conserved tyrosine with a cysteine (Y170C). The paternal allele cDNA produces a full-length protein with almost no activity when over-expressed in CHO cells. The maternal allele makes only about 12% normal mature mRNA, while the remainder shows a complex exon skipping pattern that shifts the reading frame encoding a truncated non-functional GPT protein. Thus, we conclude that the DPAGT1 gene defects are responsible for the CDG symptoms in this patient. Hum Mutat 22:144-150, 2003.
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PMID:Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1 Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation Type Ij. 1287 55

The molecular regulation of seizure-induced neuronal death may involve interactions between proteins of the Bcl-2 and 14-3-3 families. To further examine these pathways we performed subcellular fractionation on hippocampi obtained following a brief period of status epilepticus in the rat. Western blotting determined seizures induced caspase-8 cleavage and increased Bcl-w levels within the cytoplasm. Bax, Bad and Bid were largely present within the cytoplasm before and after seizures, although some Bax and, following seizures, truncated Bid was detected in mitochondria. Levels of 14-3-3 were significantly reduced in the cytoplasm and microsomal fractions. These data establish the expression and distribution profile of key Bcl-2 family proteins and the signaling chaperone 14-3-3 in the rat and provide additional evidence for the activation of programmed cell death pathways by seizures.
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PMID:Subcellular distribution of Bcl-2 family proteins and 14-3-3 within the hippocampus during seizure-induced neuronal death in the rat. 1503 20

Experimental and human data suggest programmed (active) cell death may contribute to the progressive hippocampal atrophy seen in patients with refractory temporal lobe epilepsy. Death-associated protein (DAP) kinase is a novel calcium/calmodulin-activated kinase that functions in apoptosis mediated by death receptors. Because seizure-induced neuronal death involves both death receptor activation and calcium, we examined DAP kinase expression, localization, and interactions in hippocampal resections from patients with intractable temporal lobe epilepsy (n = 10) and autopsy controls (n = 6). Expression and phosphorylation of DAP kinase was significantly increased in epilepsy brain compared with control. DAP kinase and DAP kinase-interacting protein 1 (DIP-1) localized to mitochondria in control brain, whereas levels of both were increased in the cytoplasm and microsomal (endoplasmic reticulum) fraction in epilepsy samples. Coimmunoprecipitation analysis showed increased DAP kinase binding to calmodulin, DIP-1, and the Fas-associated protein with death domain (FADD) in epilepsy samples. Finally, immunohistochemistry determined DAP kinase was coexpressed with DIP-1 in neurons. This study provides the first description of DAP kinase and DIP-1 in human brain and suggests DAP kinase is a novel molecular regulator of neuronal death in epilepsy.
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PMID:Death-associated protein kinase expression in human temporal lobe epilepsy. 1504 87

In the present study, the expression of pro-inflammatory transcripts was assessed across the brain of mice having undertaken pilocarpine-induced seizures. Pilocarpine-induced marked neurodegeneration and demyelination in multiple regions of the forebrain. The pattern of genes encoding toll-like receptor type 2 (TLR2) and I kappa B alpha (index of NF-kappa B activation) was associated with the neurodegenerating areas, but this was not the case for the mRNA encoding other inflammatory proteins. Scattered tumor necrosis factor-alpha (TNF-alpha)-expressing cells were found across brain, whereas the signals for monocyte-chemoattractant protein-1 and microsomal prostaglandin mPGES E synthase were robust in thalamus and cerebral cortex and weak in the hippocampus and amygdala. TLR2 and TNF-alpha transcripts were expressed mainly in microglia/macrophages. Cyclooxygenase-2 was induced specifically in the hippocampus and piriform cortex. A low increase in interleukin-12 mRNA was detected in the brain, but the signal for interferon gamma (IFN-gamma) remained undetectable. Although pro-inflammatory markers were induced in a different manner across the CNS, their patterns were not characteristic of those caused by other inflammatory challenges, such as endotoxin. These data suggest a different mechanism involved in regulating the innate immune reaction in response to seizures and could have direct implications for the neuropathology associated with epilepsy.
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PMID:Innate immune reaction in response to seizures: implications for the neuropathology associated with epilepsy. 1647 16

Epilepsy is one of the most widespread pathologies of human brain, affecting approximately 1% of world population. Despite the development of new methods of seizure control, chronic administration of antiepileptic drugs (AEDs) remains the treatment of choice. Nevertheless, pharmacotherapy is not always effective. In the case of single drug treatment, the number of non-responding patients is as high as 30%. Moreover, chronic medication with currently available AEDs may result in severe side-effects and undesired drug interactions. That is why in recent years intensive research has been carried out aiming at the development of new therapeutic strategies in epilepsy. The goal of this review is to assemble current literature data on stiripentol (STP), a novel anticonvulsant unrelated to any other AEDs. STP potentiates central gamma-aminobutyric acid (GABA) transmission and is characterized by nonlinear pharmacokinetics and inhibition of liver microsomal enzymes. STP has proved its anticonvulsant potency in different types of animal seizures, as well as in clinical trials. The drug seems a good candidate for adjunctive therapy in intractable epilepsy.
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PMID:Stiripentol. A novel antiepileptic drug. 1588 13

Being a woman with epilepsy is not the same as being a man with epilepsy. Epilepsy affects sexual development, menstrual cycle, aspects of contraception, fertility, and reproduction. MENSTRUAL CYCLE, EPILEPSY, AND FERTILITY: The diagnosis of epilepsy and the use of antiepileptic drugs (AEDs) present women of childbearing age with many problems; both the disease and its treatment can alter the menstrual cycle and fertility. CONTRACEPTION IN EPILEPSY: There are no contraindications to the use of nonhormonal methods of contraception in women with epilepsy (see Table 3). Nonenzyme-inducing AEDs (valproate sodium, benzodiazepines, ethosuximide, and levetiracetam) do not show any interactions with the combined oral contraceptive pill. There are interactions between the COCP and hepatic microsomal-inducing AEDs (phenytoin, barbiturates, carbamazepine, topiramate [doses above 200 mg/day], and oxcarbazepine) and also lamotrigine. SEXUALITY: The majority of women with epilepsy appear to have normal sex lives, although in some women with epilepsy, both the desire and arousal phases may be inhibited. PRECONCEPTION COUNSELING: Preconception counseling should be available to all women with epilepsy who are considering pregnancy. Women with epilepsy should be aware of a number of issues relating to future pregnancy, including methods and consequences of prenatal screening, genetics of their seizure disorder, teratogenicity of AEDs, folic acid and vitamin K supplements, labor, breast feeding, and childcare. PREGNANCY: The lowest effective dose of the most appropriate AED should be used, aiming for monotherapy where possible. Recent pregnancy databases have suggested that valproate is significantly more teratogenic than carbamazepine, and the combination of valproate sodium and lamotrigine is particularly teratogenic. Most pregnancies are uneventful in women with epilepsy, and most babies are delivered healthy with no increased risk of obstetric complications in women. BREAST FEEDING: All women with epilepsy should be encouraged to breastfeed their babies. The AED concentration profiled in breast milk follows the plasma concentration curve. The total amount of drug transferred to infants via breast milk is usually much smaller than the amount transferred via the placenta during pregnancy. However, as drug elimination mechanisms are not fully developed in early infancy, repeated administration of a drug such as lamotrigine via breast milk may lead to accumulation in the infant. THE CARE OF CHILDREN OF MOTHERS WITH EPILEPSY: Although there is much anxiety about the possible risks to a child from the mother's epilepsy, there is little published evidence. The risk of the child being harmed depends on the type of seizure and its severity and frequency, and this risk is probably small if time is taken to train mothers and caregivers in safety precautions. MENOPAUSE: During menopause, about 40% of women report worsening of their seizure disorder, 27% improve, and a third had no change. Hormone replacement therapy is significantly associated with an increase in seizure frequency during menopause, and this is more likely in women with a history of catamenial epilepsy. BONE HEALTH: Women with epilepsy are at increased risk of fractures, osteoporosis, and osteomalacia.
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PMID:Best practice guidelines for the management of women with epilepsy. 1630 85

Cerebral microsomal membrane properties were assessed in the chronic condition of generalized seizure induced by picrotoxin (PTX) in rats. PTX-induced seizures resulted in increased lysophosphatidyl glycerol, phosphatidylcholine and phosphatidic acid components, while phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol were significantly reduced by 19-73%. The cholesterol (CHL) content increased considerably by 25% without alteration in total phospholipids content. Microsomal membrane was more fluidized in the epileptic condition. Possible consequences of microsomal membrane alterations are discussed in terms of deregulation of Ca2+ homeostasis. In conclusion, alterations in the microsomal membrane properties may have a significant influence on the cerebral function in the chronic epileptic condition.
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PMID:Picrotoxin-induced convulsions alters rat brain microsomal membrane structural properties. 1636 91

Endogenous PGE(2) dynamically regulates membrane excitability, synaptic transmission and plasticity. Neonatal seizures are associated with a number of activity-dependent changes in brain development including altered synaptogenesis and synaptic plasticity as well as reduction in neurogenesis. Thus, it is reasonable to hypothesize that alteration of cyclooxygenase-2 (COX-2) expression induced by neonatal seizure may influence brain development. We evaluated the expression of COX-2 and microsomal prostaglandin E synthase (mPGES) by Western blot analysis and immnohistochemistry in flurothyl-induced neonatal seizure and also studied the effect of celecoxib on seizure induction. Seven to 10 days old Sprague-Dawley rats were used for control (n = 18) and experimental group (n = 30). Recurrent seizure group showed more increased level of COX-2 expression than control group. However, the level of mPGES-2 expression was similar in both groups, and mPGES-1 was not detected. Hippocampus of control rats showed endogenous COX-2 expression, which was localized mainly in CA3 region. This localization pattern was similar in recurrent seizure rats, but intensity of COX-2 expression was more increased than in control rats. Celecoxib treatment significantly delayed the seizure attack and also reduced COX-2 expression. In conclusion, this study suggests that COX-2 expression is related to epileptogenesis in flurothyl-induced neonatal seizure model and shows the possibility that its inhibition lessens functional impairments that occurred in neonatal seizure.
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PMID:Cyclooxygenase-2 expression and effect of celecoxib in flurothyl-induced neonatal seizure. 1643 15

Both estrogen and progesterone influence seizure activity in women with epilepsy, with estrogen generally demonstrating proconvulsant and progesterone anticonvulsant effects. Women with epilepsy exhibit a variety of endocrine disturbances, probably due to a combination of factors, including the epilepsy syndrome and the effect of interictal and ictal epileptic discharges in the brain. The direct effects of some antiepileptic drugs (AEDs) further increase this risk, apparently related to a specific drug's effect on hepatic microsomal enzymes of the cytochrome P-450 system. AEDs that induce hepatic microsomal enzymes also interact with hormonal contraception to increase estrogen's metabolism and progesterone's protein binding, decreasing concentrations of both hormones and thus reducing contraceptive efficacy. Some evidence indicates that concurrent use of hormonal contraceptives and lamotrigine significantly decreases the plasma concentration of lamotrigine, suggesting that close monitoring is warranted. Nevertheless, hormonal contraception confers comparable or superior efficacy compared with such other contraceptives as the intrauterine device and barrier methods and remains an appropriate option in women with epilepsy. Importantly, concurrent use of hormonal contraception and AEDs does not adversely affect seizure control. Careful patient management, including the use of increased estrogen doses (> or =50 microg) in patients receiving enzyme-inducing AEDs, may further minimize the risk for unintended pregnancy. Special considerations in women of childbearing age include decreased compliance and disease prevention. Although adequate seizure control is the critical requirement of an AED, the potential for interactions with hormonal contraception and the increased risk for endocrine disturbances caused by drugs that alter hepatic microsomal enzymes suggest additional potential advantages for AED treatment that does not affect these enzymes. Both the constellation of physicians treating women with epilepsy and the patients themselves have a poor understanding of the spectrum of reproductive health issues involved, and increased awareness is needed to improve patient management.
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PMID:Antiepileptic drugs and hormonal contraceptives in adolescent women with epilepsy. 1656 41


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