Why Have Antioxidants Failed in Clinical Trials?

Geisinger Clinic, Geisinger Center for Health Research, 100 North Academy Avenue, Danville, PA 17822, USA.
The American Journal of Cardiology (Impact Factor: 3.28). 06/2008; 101(10A):14D-19D. DOI: 10.1016/j.amjcard.2008.02.003
Source: PubMed


Antioxidant therapies have been evaluated in placebo-controlled trials involving tens of thousands of patients. Despite pathophysiologic, epidemiologic, and mechanistic data suggesting otherwise, these clinical trial results have been, to date, mostly negative in the setting of chronic preventative therapy. On the other hand, a much smaller number of trials involving handfuls of patients have been much more encouraging in terms of the acute benefit of antioxidants reflected by the data on N-acetylcysteine. However, the seemingly overwhelmingly data not supporting a role for antioxidants in the chronic suppression of atherosclerosis must be kept in perspective. Most antioxidant therapies that have been tested were not chosen because they were proved to be the best antioxidants, but rather because of their easy availability. An excellent example is vitamin E. Although easily available, it has many limitations as an antioxidant. In fact, in some studies, vitamin E has been shown to have some prooxidant effects. Another possible explanation for the lack of benefit in clinical trials is that the trials have not lasted long enough. It may be impossible to show the benefits of antioxidant therapy over several years if the therapy is trying to reverse the results of several decades of oxidative stress. It is critical to remember that the lack of benefits seen in clinical trials to date does not disprove the central role of oxidative stress in atherosclerosis. Rather, these results challenge us to evaluate optimal antioxidant therapies, the ideal study patients to study, and the appropriate trial duration.

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    • "Although antioxidant therapy or prevention of various diseases is expected owing to the clinical importance of oxidative damage, antioxidants have been of limited therapeutic success (Steinhubl, 2008). Antioxidant supplements have exhibited little effect on preventing cancer, myocardial infarction and atherosclerosis, but rather conversely have increased mortality (Bjelakovic et al., 2007; Hackam, 2007; Brambilla et al., 2008; Steinhubl, 2008; Hercberg et al., 2010); thus, it is very important to be aware of side effects in developing an effective antioxidant for the prevention of oxidative stress-related diseases. Under these situations, an ideal antioxidant molecule is expected to mitigate excess oxidative stress, but not disturb the redox homeostasis. "
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    ABSTRACT: Molecular hydrogen (H2) has been accepted to be an inert and nonfunctional molecule in our body. We have turned this concept by demonstrating that H2 reacts with strong oxidants such as hydroxyl radical in cells, and proposed its potential for preventive and therapeutic applications. H2 has a number of advantages exhibiting extensive effects: H2 rapidly diffuses into tissues and cells, and it is mild enough neither to disturb metabolic redox reactions nor to affect signaling reactive oxygen species; therefore, there should be no or little adverse effects of H2. There are several methods to ingest or consume H2; inhaling H2 gas, drinking H2-dissolved water (H2-water), injecting H2-dissolved saline (H2-saline), taking an H2 bath, or dropping H2-saline into the eyes. The numerous publications on its biological and medical benefits revealed that H2 reduces oxidative stress not only by direct reactions with strong oxidants, but also indirectly by regulating various gene expressions. Moreover, by regulating the gene expressions, H2 functions as an anti-inflammatory and anti-apoptotic, and stimulates energy metabolism. In addition to growing evidence obtained by model animal experiments, extensive clinical examinations were performed or are under investigation. Since most drugs specifically act to their targets, H2 seems to differ from conventional pharmaceutical drugs. Owing to its great efficacy and lack of adverse effects, H2 has promising potential for clinical use against many diseases.
    Preview · Article · Apr 2014 · Pharmacology [?] Therapeutics
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    • "One reason for these unfavorable results is that these antioxidants are not able to accumulate in mitochondria to effectively scavenge the superoxide anions. Thus, developing new types of antioxidants that have more potency, higher bioactivity, and more site-specificity, is of significant importance for the prevention and treatment of diabetes and atherosclerosis [8], [12]. "
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    ABSTRACT: Tetramethylpyrazine (TMP) is an active compound isolated from a Chinese herbal prescription that is widely used in traditional Chinese medicine for the treatment of inflammatory and cardiovascular diseases. We have previously reported that TMP acts as a potent antioxidant protecting endothelial cells against high glucose-induced damages. However, the molecular mechanism responsible for the antioxidant effect of TMP remains to be elucidated. In this study, we show that TMP increases nitric oxide production in endothelial cells and promotes endothelium-dependent relaxation in rate aortic rings. The antioxidant effect of TMP appears attributable to its ability to activate the mitochondrial biogenesis, as reflected in an up-regulation of complex III and amelioration of mitochondrial membrane potential. Furthermore, TMP is able to reverse high glucose-induced suppression of SIRT1 and the biogenesis-related factors, including PGC-1α, NRF1 and TFAM, suggesting a new molecular mechanism underlying the protective effect of TMP on the endothelium.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "Clinical studies with antioxidants have resulted in considerable controversy, with somewhat conflicting but largely negative results (30). In this context, our study has potential implications. "
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    ABSTRACT: Vascular calcification decreases compliance and increases morbidity. Mechanisms of this process are unclear. The role of oxidative stress and effects of antioxidants have been poorly explored. We investigated effects of the antioxidants lipoic acid (LA) and tempol in a model of atherosclerosis associated with elastocalcinosis. Male New Zealand white rabbits (2.5-3.0 kg) were fed regular chow (controls) or a 0.5% cholesterol (chol) diet+104 IU/day vitamin D2 (vitD) for 12 weeks, and assigned to treatment with water (vehicle, n=20), 0.12 mmol·kg-1·day-1 LA (n=11) or 0.1 mmol·kg-1·day-1 tempol (n=15). Chol+vitD-fed rabbits developed atherosclerotic plaques associated with expansive remodeling, elastic fiber disruption, medial calcification, and increased aortic stiffness. Histologically, LA prevented medial calcification by ∼60% and aortic stiffening by ∼60%. LA also preserved responsiveness to constrictor agents, while intima-media thickening was increased. In contrast to LA, tempol was associated with increased plaque collagen content, medial calcification and aortic stiffness, and produced differential changes in vasoactive responses in the chol+vitD group. Both LA and tempol prevented superoxide signals with chol+vitD. However, only LA prevented hydrogen peroxide-related signals with chol+vitD, while tempol enhanced them. These data suggest that LA, opposite to tempol, can minimize calcification and compliance loss in elastocalcionosis by inhibition of hydrogen peroxide generation.
    Full-text · Article · Feb 2014 · Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.]
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