Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Dalfampridine extended release tablets: 1 year of postmarketing safety experience in the US

Michele Jara,1 Graham Barker,2 Herbert R Henney 3rd1 1Acorda Therapeutics, Inc, Ardsley, NY, USA; 2Biogen Idec, Inc, Maidenhead, Berkshire, UK Background: Dalfampridine extended release tablets (dalfampridine-ER; prolonged-, modified, or sustained-release fampridine in some countries) were approved in the US to improve walking in patients with multiple sclerosis, as demonstrated by improvement in walking speed. Postmarketing safety experience is available from exposure of approximately 46,000 patients in the US from product approval through March 2011. Objective: To provide a descriptive analysis of all spontaneously reported postmarketing adverse events (AEs) for dalfampridine-ER since product launch. Methods: AE data were extracted from the safety database from product launch through March 31, 2011; AEs were classified using the Medical Dictionary for Regulatory Activities. Seizure cases were reviewed for patient demographics, time to event from treatment onset, and presence of additional risk factors. Results: The most frequently reported postmarketing AEs were similar to those reported during clinical development: dizziness, insomnia, balance disorder, headache, nausea, urinary tract infection, asthenia, and back pain (all included in US product labeling). New clinically significant findings are related to lack of efficacy and inappropriate dosing. Of the approximately 46,000 patients exposed, 85 seizures were reported (~5.4/1000 patient-years), of which 82 were reported or confirmed by a health care practitioner (~5.2/1000 patient-years). Beyond the intrinsic multiple sclerosis-related seizure risk, more than half of the 85 cases (62%) had an additional potential risk factor for seizure including a previous history of convulsions, renal impairment, incorrect dosing, or use of concurrent medications with a labeled seizure risk. Duration of treatment prior to the seizure ranged from one dose to 365 days; 26/85 (31%) patients suffered a seizure within a week of starting treatment. Conclusion: Spontaneous safety data from the US postmarketing experience were consistent with the safety profile seen during clinical development. Although first-year seizure incidence was not substantially different from that observed in dalfampridine-ER clinical trials, patients should be monitored for concomitant use of drugs that lower seizure threshold. Keywords: dalfampridine, fampridine, multiple sclerosis, adverse events, postmarketing safety, seizur