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Full-Text Articles in Neuroscience and Neurobiology
Disclosure Of Clinical Trial Results When Product Development Is Abandoned, Michael A. Rogawski, Howard J. Federoff
Disclosure Of Clinical Trial Results When Product Development Is Abandoned, Michael A. Rogawski, Howard J. Federoff
Michael A. Rogawski
Currently, sponsors are not required to report the outcomes of clinical research on drugs or devices that do not lead to an approved product. Consequently, the public cannot benefit from scientific information derived from all failed or abandoned drugs and devices. Provisions in the U.S. Food and Drug Administration Amendments Act of 2007 provide an opportunity for the Department of Health and Human Services to rectify this situation. By reporting the results of clinical trials of abandoned products in a publicly accessible database and in the peer-reviewed journal literature, sponsors would satisfy a core ethical obligation of clinical research and …
11beta-Hydroxylase Inhibitors Protect Against Seizures In Mice By Increasing Endogenous Neurosteroid Synthesis, Rafal Kaminski, Michael Rogawski
11beta-Hydroxylase Inhibitors Protect Against Seizures In Mice By Increasing Endogenous Neurosteroid Synthesis, Rafal Kaminski, Michael Rogawski
Michael A. Rogawski
Steroid 11β-hydroxylase (CYP11B1; EC 1.14.15.4) is a mitochondrial enzyme located in the zona fasciculata of the adrenal cortex and also in the brain that mediates the conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone (DOC) to corticosterone. Inhibitors of CYP11B1, such as metyrapone and etomidate, reduce glucocorticoid synthesis and raise levels of DOC providing greater availability for metabolic conversion to the GABA-A receptor modulating neurosteroid allotetrahydrodeoxycorticosterone (THDOC). Because THDOC is potent anticonvulsant, it is plausible that CYP11B1 inhibitors could protect against seizures. Here we demonstrate that metyrapone affords dose-dependent protection against 6-Hz seizures 30 min after injection (ED50, 191 mg/kg), but …
Revisiting Ampa Receptors As An Antiepileptic Drug Target, Michael A. Rogawski
Revisiting Ampa Receptors As An Antiepileptic Drug Target, Michael A. Rogawski
Michael A. Rogawski
In the 1990s there was intense interest in ionotropic glutamate receptors as therapeutic targets for diverse neurological disorders, including epilepsy. NMDA receptors were thought to play a key role in the generation of seizures, leading to clinical studies of NMDA receptor blocking drugs in epilepsy. Disappointing results dampened enthusiasm for ionotropic glutamate receptors as a therapeutic target. Eventually it became appreciated that another type of ionotropic glutamate receptor, the AMPA receptor, is actually the predominant mediator of excitatory neurotransmission in the central nervous system and moreover that AMPA receptors are critical to the generation and spread of epileptic activity. As …
Treatment Of Infantile Spasms: Emerging Insights From Clinical And Basic Science Perspectives, Carl Stafstrom, Barry Arnason, Tallie Baram, Anna Catania, Miguel Cortez, Tracy Glauser, Michael Pranzatelli, Raili Riikonen, Michael Rogawski, Shlomo Shinnar, John Swann
Treatment Of Infantile Spasms: Emerging Insights From Clinical And Basic Science Perspectives, Carl Stafstrom, Barry Arnason, Tallie Baram, Anna Catania, Miguel Cortez, Tracy Glauser, Michael Pranzatelli, Raili Riikonen, Michael Rogawski, Shlomo Shinnar, John Swann
Michael A. Rogawski
Infantile spasms is an epileptic encephalopathy of early infancy with specific clinical and electroencephalographic (EEG) features, limited treatment options, and a poor prognosis. Efforts to develop improved treatment options have been hindered by the lack of experimental models in which to test prospective therapies. The neuropeptide adrenocorticotropic hormone (ACTH) is effective in many cases of infantile spasms, although its mechanism(s) of action is unknown. This review describes the emerging candidate mechanisms that can underlie the therapeutic effects of ACTH in infantile spasms. These mechanisms can ultimately help to improve understanding and treatment of the disease. An overview of current treatments …
Seizure Protection By Intrapulmonary Delivery Of Propofol Hemisuccinate, Ashish Dhir, Dorota Zolkowska, Randall B. Murphy, Michael A. Rogawski
Seizure Protection By Intrapulmonary Delivery Of Propofol Hemisuccinate, Ashish Dhir, Dorota Zolkowska, Randall B. Murphy, Michael A. Rogawski
Michael A. Rogawski
The lung provides a portal of entry for drug delivery that could be used to administer anticonvulsant substances to prevent or abort seizures. Here we demonstrate that intrapulmonary propofol hemisucinate (PHS) rapidly confers seizure protection in various rodent chemoconvulsant models. Propofol is a powerful anticonvulsant substance at subanesthetic doses but it is a viscous, water-immiscible oil that is not suitable for intrapulmonary administration. We found that PHS can be formulated as an aqueous solution that is well tolerated when instilled into the lung. High dose intraperitoneal PHS induced loss-of-righting reflex in rats and mice. The onset of action of PHS …