title: Nitrone-based therapeutics for neurodegenerative diseases: their use alone or in combination with lanthionines.
abstract: The possibility of free radical reactions occurring in biological processes led to the development and employment of novel methods and techniques focused on determining their existence and importance in normal and pathological conditions. For this reason the use of nitrones for spin trapping free radicals became widespread in the 1970s and 1980s, when surprisingly the first evidence of their potent biological properties was noted. Since then widespread exploration and demonstration of the potent biological properties of phenyl-tert-butylnitrone (PBN) and its derivatives took place in preclinical models of septic shock and then in experimental stroke. The most extensive commercial effort made to capitalize on the potent properties of the PBN-nitrones was for acute ischemic stroke. This occurred during 1993-2006, when the 2,4-disulfonylphenyl PBN derivative, called NXY-059 in the stroke studies, was shown to be safe in humans and was taken all the way through clinical phase 3 trials and then was deemed to be ineffective. As summarized in this review, because of its excellent human safety profile, 2,4-disulfonylphenyl PBN, now called OKN-007 in the cancer studies, was tested as an anti-cancer agent in several preclinical glioma models and shown to be very effective. Based on these studies this compound is now scheduled to enter into early clinical trials for astrocytoma/glioblastoma multiforme this year. The potential use of OKN-007 in combination with neurotropic compounds such as the lanthionine ketamine esters is discussed for glioblastoma multiforme as well as for various other indications leading to dementia, such as aging, septic shock, and malaria infections. There is much more research and development activity ongoing for various indications with the nitrones, alone or in combination with other active compounds, as briefly noted in this review.
authors: Experimental Therapeutics, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. Electronic address: robert-floyd@omrf.ouhsc.edu.
authors: Robert A
authors: RA
authors: Floyd
authors: Laboratorio de Immunofarmacologia, Instituto Oswaldo Cruz, IOC, Fiocruz, Rio de Janeiro, Brazil.
authors: Hugo C
authors: HC
authors: Castro Faria Neto
authors: Laboratorio de Immunofarmacologia, Instituto Oswaldo Cruz, IOC, Fiocruz, Rio de Janeiro, Brazil; Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors: Guy A
authors: GA
authors: Zimmerman
authors: Department of Pathology and Department of Neurosciences, University of Toledo Medical Center, Toledo, OH.
authors: Kenneth
authors: K
authors: Hensley
authors: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors: Rheal A
authors: RA
authors: Towner
mesh_terms: D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001557:Benzenesulfonates / Q000008:administration & dosage; D003497:Cyclic N-Oxides / Q000008:administration & dosage*; D004338:Drug Combinations; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D007097:Imines / Q000008:administration & dosage; D009369:Neoplasms / Q000188:drug therapy; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000473:pathology; D013440:Sulfides / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D003497:Cyclic N-Oxides; D004338:Drug Combinations; D005609:Free Radicals; D007097:Imines; C552724:OKN 007; D013440:Sulfides; C029217:phenyl-N-tert-butylnitrone; C001520:lanthionine; D000409:Alanine
keywords: Aging; Cancer; Dementia; Free radicals; Glioblastoma multiforme; Glioma; Lanthionine; Malaria dementia; NXY-059; Nitrones; OKN-007; PBN; Septic shock; Spin trapping