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

A preliminary study of atorvastatin plasma concentrations in critically ill patients with sepsis

Objective: A lack of published pharmacokinetic data on statins in sepsis has prompted concerns about their safety and toxicity. This study determined single dose pharmacokinetics of Atorvastatin administered orally to acutely ill patients. Design, setting and participants: A prospective open label study conducted in a tertiary referral centre on 5 healthy volunteers, 5 acutely ill patients admitted to the medical ward and a heterogeneous cohort of 25 critically ill patients admitted to an intensive care unit. Intervention: All participants received a single oral dose of 20 mg of atorvastatin. Measurement and results: Plasma pharmacokinetics of atorvastatin as measured by maximal plasma concentration (Cmax) and area under the curve (AUC) (0-24) h. Critically ill patients with sepsis had a significantly higher Cmax and AUC as compared to healthy volunteers [110.5(86.5) vs. 5.9(2.50) ng/ml, p < 0.01 and 1,051(810) vs. 67(48) ng h/ml (p < 0.0001)], respectively. Atorvastatin concentrations in the plasma of critically ill patients with sepsis remained supratherapeutic for up to 20 h after a single dose. The AUC was significantly higher for those patients on concomitant CYP 450 inhibitor therapy as compared to those patients not on inhibitors (1,518 +/- 793 vs. 584 +/- 540 ng h/ml, p = 0.0260). Conclusions: Very high plasma concentrations were achieved in intensive care patients with sepsis. This can only be partly explained by altered metabolism of atorvastatin. Further investigations are essential to better describe the pharmacokinetics of statins in various groups of critically ill patients. Caution should be exercised prior to adopting high dose regimens in patients with severe sepsis