**6.2 Statins**

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

nephrotoxic drugs before CM administration [85].

*6.1.5 N-Acetylcysteine (NAC)*

(NAC) [36, 83], statins [84, 85], ascorbic acid [76, 86], and theophylline [87]. However, only statins have been approved for the prevention against the occurrence of CIN. Currently, the CM safety committee recommends the withdrawal of

NAC gives protection against CIN by improving the body's antioxidant abilities [88]. In vitro, NAC does this efficiently by scavenging hypochlorous acid as well as reacting with hydroxyl radicals [89]. In vivo due to its extensive degradation, it is likely that any antioxidant effect it exerts would be indirect, most probably by inducing glutathione synthesis. Different studies have suggested that NAC guards against glutathione depletion [90, 91] and elevates renal glutathione levels [92]; the latter has been demonstrated to result in the reduction of renal injury in ischemia reperfusion models [93, 94] and recently in CIN [95, 96]. Glutathione cannot enter the cell; instead, it must be formed inside the cell from glycine, glutamate, and cysteine [97]. Cysteine offers the active HS group which is crucial for the glutathione synthesis and thus is the rate-limiting factor in this process. NAC after deacylation produces cysteine that passes to the renal cells and serves as a precursor for glutathione synthesis. It can also produce vasodilator effects [98]. By ameliorating contrast-induced vasoconstriction, NAC can produce its nephron-protective role [99]. Increase in the medullary blood flow with NAC has also been demonstrated [100, 101]. The first clinical use of NAC for CIN was reported by Tepel et al. [83]. Eighty-three patients who had chronic renal impairment were randomly planned either to take oral NAC (600mg twice daily) and 0.45% saline intravenously, before and after administration of the CM, or to receive placebo and saline. NAC-receiving patients had lower incidence of CIN. Since then numerous studies have assessed the role of NAC against CIN. Those studies have been done mainly in patients undergoing coronary angiography [102]. Some 17 meta-analyses have been published as regards this subject [76, 86, 87, 103–116], 10 that approve its use (most of which were published early on). Most of these meta-analyses reported vast heterogeneity that makes it difficult to make clinical treatment recommendations relying on the provided data. Recently, results of the largest multicenter RCT of 2308 patients called "Acetylcysteine for Contrast-Induced Nephropathy Trial" (ACT) have been published [36]. It randomized patients in 46 centers in Brazil, to take 1200mg of oral NAC or placebo twice daily for 2 doses before and after the procedure. Intravenous hydration with normal saline, 1mL/kg/h, from 6–12h before to 6–12h after angiography, was strongly recommended. NAC was not able to significantly reduce the incidence of CIN (12.7% in the NAC group and 12.7% in the control

Ascorbic acid serves as an antioxidant [118]. It does this via reacting with most biologically relevant free radicals and oxidants such as superoxide ions and hydroxyl ion [119]. It donates an electron to devastating oxidizing radicals [120]; this oneelectron oxidation leads to the formation of AHˉ the ascorbyl radical also called semidehydroascorbic acid [121]. Consequently, the reactive free radical is reduced [122]. Ascorbic acid has been reported to result in vasodilatation in coronary [123] and brachial arteries [124]. Thus, vitamin C can have favorable effects on vascular dilatation, through its antioxidant actions on nitric oxide, but these findings are not consistent [125]. Through which pathway vitamin C may offer nephron protection against CIN is still currently uninvestigated. The first clinical use of ascorbic

**128**

group, p = 0.97) [117].

*6.1.6 Ascorbic acid*

Statins maintain nitric oxide formation, lower oxidative stress, and beneficially affect the endothelial function [101]. In one retrospective study of more than 1,000 patients with renal impairment undergoing coronary angiography, the risk of CIN was markedly decreased in patients who are receiving a statin before the procedure [128]. Another study of more than 29,000 patient recorded in a percutaneous cardiac intervention registry demonstrated that patients who received statins before the procedure had both a lower CIN incidence (p < 0.0001) and nephropathy that required dialysis (p < 0.03) [181]. Further studies looking into the benefit from statins are warranted [129].
