Open Access. Powered by Scholars. Published by Universities.®
- Discipline
Articles 1 - 7 of 7
Full-Text Articles in Medicine and Health Sciences
Neurosteroid Replacement Therapy For Catamenial Epilepsy, Doodipala S. Reddy, Michael A. Rogawski
Neurosteroid Replacement Therapy For Catamenial Epilepsy, Doodipala S. Reddy, Michael A. Rogawski
Michael A. Rogawski
Perimenstural catamenial epilepsy, the cyclical occurrence of seizure exacerbations near the time of menstruation, affects a high proportion of women of reproductive age with drug refractory epilepsy. Enhanced seizure susceptibility in perimenstrual catamenial epilepsy is believed to be due to the withdrawal of the progesterone-derived GABA-A receptor modulating neurosteroid allopregnanolone as a result of the fall in progesterone at the time of menstruation. Studies in a rat pseudopregnancy model of catamenial epilepsy indicate that following neurosteroid withdrawal there is enhanced susceptibility to chemoconvulsant seizures. There is also a transitory increase in the frequency of spontaneous seizures in epleptic rats that …
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 …
Diverse Mechanisms Of Antiepileptic Drugs In The Development Pipeline, Michael A. Rogawski
Diverse Mechanisms Of Antiepileptic Drugs In The Development Pipeline, Michael A. Rogawski
Michael A. Rogawski
There is a remarkable array of new chemical entities in the current antiepileptic drug (AED) development pipeline. In some cases, the compounds were synthesized in an attempt improve upon the activity of marketed AEDs. In other cases, the discovery of antiepileptic potential was largely serendipitous. Entry into the pipeline begins with the demonstration of activity in one or more animal screening models. Results from testing in a panel of such models provide a basis to differentiate agents and may offer clues as to the mechanism. Target activity may then be defined through cell-based studies, often years after the initial identification …
The Neurobiology Of Antiepileptic Drugs For The Treatment Of Nonepileptic Conditions, Michael A. Rogawski, Wolfgang Löscher
The Neurobiology Of Antiepileptic Drugs For The Treatment Of Nonepileptic Conditions, Michael A. Rogawski, Wolfgang Löscher
Michael A. Rogawski
Antiepileptic drugs (AEDs) are commonly prescribed for nonepileptic conditions, including migraine headache, chronicneuropathic pain, mood disorders, schizophrenia and various neuromuscular syndromes. In many of these conditions, as in epilepsy, the drugs act by modifying the excitability of nerve (or muscle) through effects on voltage-gated sodium and calciumchannels or by promoting inhibition mediated by γ-aminobutyric acid (GABA) A receptors. In neuropathic pain, chronic nerveinjury is associated with the redistribution and altered subunit compositions of sodium and calcium channels that predisposeneurons in sensory pathways to fire spontaneously or at inappropriately high frequencies, often from ectopic sites. AEDs maycounteract this abnormal activity by …