Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial

Prospero, Nicholas A. Di; Baker, Angela; Jeffries, Neal; Fischbeck, Kenneth H.

doi:10.1016/s1474-4422(07)70220-x

Cited by 276 publications

(172 citation statements)

References 22 publications

(40 reference statements)

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“…The link between iron misregulation and oxidative damage is similar to current evidence regarding the pathogenesis of Friedreich's ataxia in which loss of frataxin impairs mitochondrial iron handling resulting in increased oxidative stress and cellular damage [21]. In the case of Friedreich's ataxia, clinical trials have shown benefit with antioxidant therapy such as idebenone [22,23], with clinical benefits particularly apparent in children and younger patients. This demonstrates the importance of early treatment instigation in these patients [23] and, in conjunction with the findings of this study, supports the case for early intervention in patients with neuroferritinopathy.…”

Section: Discussionsupporting

confidence: 62%

Neuroferritinopathy: a new inborn error of iron metabolism

Keogh

Jonas

Coulthard³

et al. 2012

Neurogenetics

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Neuroferritinopathy is an autosomal dominant progressive movement disorder which occurs due to mutations in the ferritin light chain gene (FTL1). It presents in mid-adult life and is the only autosomal dominant disease in a group of conditions termed neurodegeneration with brain iron accumulation (NBIA). We performed brain MRI scans on 12 asymptomatic descendants of known mutation carriers. All three harbouring the pathogenic c.460InsA mutation showed iron deposition; these findings show pathological iron accumulation begins in early childhood which is of major importance in understanding and developing treatment for NBIA.

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Section: Discussionsupporting

confidence: 62%

Neuroferritinopathy: a new inborn error of iron metabolism

Keogh

Jonas

Coulthard³

et al. 2012

Neurogenetics

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“…feriprone was given at the same time as idebenone, which is known to ameliorate the neurological effects of FA (29). Therefore, further studies with chelators alone in FA patients are essential.…”

Section: Discussionmentioning

confidence: 99%

The MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation

Whitnall

Rahmanto

Šuták

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

110

148

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There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich's ataxia (FA). The identification of potentially toxic mitochondrial (MIT) iron (Fe) deposits in FA suggests that Fe plays a role in its pathogenesis. This study used the muscle creatine kinase conditional frataxin (Fxn) knockout (mutant) mouse model that reproduces the classical traits associated with cardiomyopathy in FA. We examined the mechanisms responsible for the increased cardiac MIT Fe loading in mutants. Moreover, we explored the effect of Fe chelation on the pathogenesis of the cardiomyopathy. Our investigation showed that increased MIT Fe in the myocardium of mutants was due to marked transferrin Fe uptake, which was the result of enhanced transferrin receptor 1 expression. In contrast to the mitochondrion, cytosolic ferritin expression and the proportion of cytosolic Fe were decreased in mutant mice, indicating cytosolic Fe deprivation and markedly increased MIT Fe targeting. These studies demonstrated that loss of Fxn alters cardiac Fe metabolism due to pronounced changes in Fe trafficking away from the cytosol to the mitochondrion. Further work showed that combining the MITpermeable ligand pyridoxal isonicotinoyl hydrazone with the hydrophilic chelator desferrioxamine prevented cardiac Fe loading and limited cardiac hypertrophy in mutants but did not lead to overt cardiac Fe depletion or toxicity. Fe chelation did not prevent decreased succinate dehydrogenase expression in the mutants or loss of cardiac function. In summary, we show that loss of Fxn markedly alters cellular Fe trafficking and that Fe chelation limits myocardial hypertrophy in the mutant.ferritin ͉ iron chelators ͉ mitochondria ͉ transferrin receptor ͉ frataxin

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“…In these studies, idebenone consistently improved cardiac hypertrophy, which is an important feature of FRDA. Neurological symptoms have not been improved as much as cardiac problems, however higher doses of idebenone especially in younger patients seem to be much more promising for neurological efficacy [76,[85][86][87].…”

Section: Idebenonementioning

confidence: 99%

Clinical and pharmacological aspects of bath salt use: A review of the literature and case reports

Miotto¹,

Striebel²,

Cho

et al. 2013

Drug and Alcohol Dependence

121

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Abstract:Reactive oxygen species (ROS) are widely believed to cause or aggravate several human pathologies such as neurodegenerative diseases, cancer, stroke and many other ailments. Antioxidants are assumed to counteract the harmful effects of ROS and therefore prevent or treat oxidative stress-related diseases. In this report, recent human studies exploring the efficiency of antioxidants in prevention and treatment of various diseases are reviewed. Few antioxidants including edaravone (for ischemic stroke in Japan), Nacetylcysteine (for acetaminophen toxicity), alfa-lipoic acid (for diabetic neuropathy) and some flavonoids (polyphenolic compounds present in dietary plants), such as micronized purified flavonoid fraction (diosmin and hesperidin) and oxerutins (for chronic venous insufficiency) as well as baicalein and catechins (for osteoarthritis) have found accepted clinical use. However, despite much enthusiasm in the 1980s and 1990s, many well-known agents such as antioxidant vitamins and also more recently developed compounds such as nitrones have not successfully passed the scrutiny of clinical trials for prevention and treatment of various diseases. This has given rise to a pessimistic view of antioxidant therapy, however, the evidence from human epidemiological studies about the beneficial effects of dietary antioxidants and preclinical in vitro and animal data are compelling. We have probably wasted too much time on agents like antioxidant vitamins instead of focusing on more disease specific, target-directed, highly bioavailable antioxidants. We here discuss possible reasons for the lack of success in some clinical trials and seek to provide some suggestions to be considered if antioxidant therapy is to succeed as an effective therapeutic strategy.

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Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial

Cited by 276 publications

References 22 publications

Neuroferritinopathy: a new inborn error of iron metabolism

Neuroferritinopathy: a new inborn error of iron metabolism

The MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation

Clinical and pharmacological aspects of bath salt use: A review of the literature and case reports

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