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- Ben-Menachem, Elinor, 1945
(författare)
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Pregabalin pharmacology and its relevance to clinical practice.
- 2004
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Ingår i: Epilepsia. - : Wiley. - 0013-9580 .- 1528-1167. ; 45 Suppl 6, s. 13-8
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Forskningsöversikt (refereegranskat)abstract
- Pregabalin is a potent ligand for the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system that exhibits potent anticonvulsant, analgesic, and anxiolytic activity in a range of animal models. In addition, pregabalin has been shown to be a highly effective adjunctive therapy for partial seizures in clinical trials. Potent binding to the alpha-2-delta site reduces depolarization-induced calcium influx with a consequential modulation in excitatory neurotransmitter release. Pregabalin has no demonstrated effects on GABAergic mechanisms. Pregabalin demonstrates highly predictable and linear pharmacokinetics, a profile that makes it easy to use in clinical practice. Absorption is extensive, rapid, and proportional to dose. Time to maximal plasma concentration is approximately 1 h and steady state is achieved within 24-48 h. These characteristics reflect the observed onset of efficacy as early as day two in clinical trials. High bioavailability, a mean elimination half life (t(1/2)) of 6.3 h, and dose-proportional maximal plasma concentrations and total exposures predict a dose-response relationship in clinical practice and allow an effective starting dose of 150 mg/day in clinical practice without need for titration. Administration with food has no clinically relevant effect on the amount of pregabalin absorbed, providing for a dosing regimen uncomplicated by meals. Pregabalin does not bind to plasma proteins and is excreted virtually unchanged (<2% metabolism) by the kidneys. It is not subject to hepatic metabolism and does not induce or inhibit liver enzymes such as the cytochrome P450 system. Therefore, pregabalin is unlikely to cause, or be subject to, pharmacokinetic drug-drug interactions--an expectation that has been confirmed in clinical pharmacokinetic studies. However, dose adjustment may be necessary in patients with renal insufficiency. Thus, the pharmacological and pharmacokinetic profiles of pregabalin provide a predictable basis for its use in clinical practice.
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- Kimland, Elin, et al.
(författare)
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Levetiracetam-induced thrombocytopenia
- 2004
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Ingår i: Epilepsia. - : Wiley-Blackwell. - 0013-9580 .- 1528-1167. ; 45:7, s. 877-878
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Tidskriftsartikel (refereegranskat)
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- Azarbayjani, Faranak, et al.
(författare)
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Embryonic arrhythmia by inhibition of HERG channels : a common hypoxia-related teratogenic mechanism for antiepileptic drugs?
- 2002
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Ingår i: Epilepsia. - : Wiley. - 0013-9580 .- 1528-1167. ; 43:5, s. 457-468
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: There is evidence that drug-induced embryonic arrhythmia initiates phenytoin (PHT) teratogenicity. The arrhythmia, which links to the potential of PHT to inhibit a specific potassium channel (Ikr), may result in episodes of embryonic ischemia and generation of reactive oxygen species (ROS) at reperfusion. This study sought to determine whether the proposed mechanism might be relevant for the teratogenic antiepileptic drug trimethadione (TMO). METHODS: Effects on embryonic heart rhythm during various stages of organogenesis were examined in CD-1 mice after maternal administration (125-1,000 mg/kg) of dimethadione (DMO), the pharmacologically active metabolite of TMO. Palatal development was examined after administration of a teratogenic dose of DMO and after simultaneous treatment with DMO and a ROS-capturing agent (alpha-phenyl-N-tert-butyl-nitrone; PBN). The Ikr blocking potentials of TMO and DMO were investigated in HERG-transfected cells by using voltage patch-clamping tests. RESULTS: DMO caused stage-specific (gestation days 9-13 only) and dose-dependent embryonic bradycardia and arrhythmia at clinically relevant maternal plasma concentrations (3-11 mM). Hemorrhage in the nasopharyngeal part of the embryonic palate (within 24 h) preceded cleft palate in fetuses at term. Simultaneous treatment with PBN significantly reduced the incidence of DMO-induced cleft palate, from 40 to 13%. Voltage patch-clamping studies showed that particularly DMO (70% inhibition), but also TMO, had Ikr blocking potential at clinically relevant concentrations. CONCLUSIONS: TMO teratogenicity, in the same way as previously shown for PHT, was associated with Ikr-mediated episodes of embryonic cardiac arrhythmia and hypoxia/reoxygenation damage.
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- Börjesson, L., et al.
(författare)
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Comparison between fMRI and Wada test
- 2004
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Ingår i: Epilepsia. - : Wiley-Blackwell. - 0013-9580 .- 1528-1167. ; 45:Suppl. 3, s. 84-84
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Language lateralisation in patients with epilepsy is more often atypical compared to a normal population. The Wada procedure for testing language and memory has some shortcomings; it is invasive and there is always a risk that the patient becomes too sedated, leading to difficulties in performing the tests. fMR1have shown promising results, showing good correlation to the Wadaprocedure concerning language-lateralisation. The aim of this studywas to investigate if fMRI could be used to determine which hemisphere was language dominant and compare the fMR1 results with the Wada-tests with a focus on patients with a complicated lateralisation.Method: 4 subjects were tested and they had a heterogeneous (I left handed, I ambidexter and 2 right handed) lateralisation and one had a severe dyslexia. A standard Wada procedure was used and compared with a fMRl investigation using a language paradigm.Results: The patients studied showed different language lateralisation patterns (2 left hemisphere and 2 bilateral). In two patients the two tests were fully concordant, in the others the fMRI showed a more bilateral pattern.Conclusion: fMR1 adds valuable information in the pre-surgical investigation for patients with a complex language lateralisation.
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