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Full-Text Articles in Medicine and Health Sciences
Intrinsic Severity As A Determinant Of Antiepileptic Drug Refractoriness, Michael A. Rogawski, Michael R. Johnson
Intrinsic Severity As A Determinant Of Antiepileptic Drug Refractoriness, Michael A. Rogawski, Michael R. Johnson
Michael A. Rogawski
For the most part, resistance to medications in epilepsy is independent of the choice of antiepileptic drug. This simple clinical observation constrains the possible biological mechanisms for drug refractory epilepsy by imposing a requirement to explain resistance for a diverse set of chemical structures that act on an even more varied group of molecular targets. To date, research on antiepileptic drug refractoriness has been guided by the “drug transporter overexpression” and the “reduced drug-target sensitivity” hypotheses. These concepts posit that drug refractoriness is a condition separate from the underlying epilepsy. Inadequacies in both hypotheses mandate a fresh approach to the …
What Clinical Observations On The Epidemiology Of Antiepileptic Drug Intractability Tell Us About The Mechanisms Of Pharmacoresistance, Michael Rogawski
What Clinical Observations On The Epidemiology Of Antiepileptic Drug Intractability Tell Us About The Mechanisms Of Pharmacoresistance, Michael Rogawski
Michael A. Rogawski
In the past several years, there have been important advances in the clinical epidemiology of antiepileptic drug resistance, as reviewed by Mohanraj and Brodie. It would appear that by and large, intractability is independent of the choice of antiepileptic drug (AED). Many patients will become seizure free on the first agent tried, irrespective of which one their physician decides to pick. Nonresponders to the first drug are in a different category: it is likely that they will continue to have seizures no matter which medicine or combination of medicines is tried. This simple clinical observation puts important constraints on the …
Brivaracetam: A Rational Drug Discovery Success Story, Michael Rogawski
Brivaracetam: A Rational Drug Discovery Success Story, Michael Rogawski
Michael A. Rogawski
Levetiracetam, the alpha-ethyl analogue of the nootropic piracetam, is a widely used antiepileptic drug (AED) that provides protection against partial seizures and is also effective in the treatment of primary generalized seizure syndromes including juvenile myoclonic epilepsy. Levetiracetam was discovered in 1992 through screening in audiogenic seizure susceptible mice and, 3 years later, was reported to exhibit saturable, stereospecific binding in brain to a approximately 90 kDa protein, later identified as the ubiquitous synaptic vesicle glycoprotein SV2A. A large-scale screening effort to optimize binding affinity identified the 4-n-propyl analogue, brivaracetam, as having greater potency and a broadened spectrum of activity …
New Molecular Targets For Antiepileptic Drugs: Alpha2delta, Sv2a, And Kv7/Kcnq/M Potassium Channels, Michael A. Rogawski, Carl W. Bazil
New Molecular Targets For Antiepileptic Drugs: Alpha2delta, Sv2a, And Kv7/Kcnq/M Potassium Channels, Michael A. Rogawski, Carl W. Bazil
Michael A. Rogawski
Many currently prescribed antiepileptic drugs (AEDs) act via voltage-gated sodium channels, through effects on gamma-aminobutyric acid-mediated inhibition, or via voltage-gated calcium channels. Some newer AEDs do not act via these traditional mechanisms. The molecular targets for several of these nontraditional AEDs have been defined using cellular electrophysiology and molecular approaches. Here, we describe three of these targets: alpha(2)delta, auxiliary subunits of voltage-gated calcium channels through which the gabapentinoids gabapentin and pregabalin exert their anticonvulsant and analgesic actions; SV2A, a ubiquitous synaptic vesicle glycoprotein that may prepare vesicles for fusion and serves as the target for levetiracetam and its analog brivaracetam …