Brain uptake of Tc99m-HMPAO correlates with clinical response to the novel redox modulating agent EPI-743 in patients with mitochondrial disease

Blankenberg, Francis G.; Kinsman, Stephen L.; Cohen, Bruce H.; Goris, Michael L.; Spicer, Kenneth; Perlman, Susan; Krane, Elliot J.; Kheifets, Viktoria; Thoolen, Martin; Miller, Guy; Enns, Gregory M.

doi:10.1016/j.ymgme.2012.09.023

Cited by 31 publications

(34 citation statements)

References 35 publications

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“…Comparison of these outcomes with a literature review of 180 children with Leigh syndrome associated with the similar mutations of this EPI-743-treated trial cohort showed a better outcome than frequent rapidly degenerative outcomes and early childhood death in the historical group, although these EPI-743 treated cases may have been more stable before treatment [44]. As a result of these 2 initial open trials of EPI-743, a randomized, placebo-controlled trial in genetically-proven Leigh syndrome is in progress [42,43].…”

Section: Epi-743mentioning

confidence: 82%

“…No adverse events were observed that were considered related to drug treatment. In a follow-up report of this same protocol, including 22 patients, there was a significant correlation of the changes of technicium-99m-HMPAQ-SPECT cerebellar uptake and the clinical response evaluated by the Newcastle Mitochondrial Disease Scale (adult or pediatric) before and after 3 months of treatment with EPI-743 [42].…”

Section: Epi-743mentioning

confidence: 85%

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Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Kerr

2013

Neurotherapeutics

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Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q 10 (CoQ 10 ; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ 10 ), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ 10 ), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, openlabel/controlled, or double-blind/placebo-controlled/crossover. Primary outcomes have ranged from single, clinicallyrelevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes.

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Section: Epi-743mentioning

confidence: 82%

Section: Epi-743mentioning

confidence: 85%

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Kerr

2013

Neurotherapeutics

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“…Furthermore, the MELAS subgroup (n ¼ 5) in this study showed a significant relationship between whole-brain uptake of HMPAO and the Newcastle score (r ¼ 0.917; P ¼ .028). 27 …”

Section: Mitochondrial Disordersmentioning

confidence: 99%

Clinical Trials in Mitochondrial Disease

Enns

Cohen

2017

Journal of Inborn Errors of Metabolism and Screening

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Mitochondrial dysfunction results in the production of an abnormally high amount of reactive oxygen and nitrogen species, which results in redox imbalance and glutathione deficiency. Therapeutics such as EPI-743 (a-tocotrienol quinone) and RP103 (cysteamine bitartrate) have the theoretical potential to improve redox imbalance by increasing intracellular glutathione and are currently under investigation in multiple clinical trials. This review provides an update on the use of these compounds in clinical trials related to primary and secondary mitochondrial disorders. These clinical trials have not only provided hope to affected patients and their families and caregivers, but also will serve as important stepping stones for further studies as our understanding of mitochondrial disease pathogenesis continues to improve.

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“…They strongly recommended the use of the NMDAS in the evaluation of patients with mitochondrial disease. In addition to the periodic monitoring of the clinical status of patients, the NMDAS has also been used in studies evaluating treatments in adult patients with various forms of mitochondrial disease 15,16,17 . The NMDAS and NPMDS both not only allow the clinical status of mitochondrial disease patients to be evaluated over time but also facilitate the assessment of the patients' quality of life.…”

Section: Npmds Score Mean ± Sd Median (Range)mentioning

confidence: 99%

The Newcastle Pediatric Mitochondrial Disease Scale: translation and cultural adaptation for use in Brazil

Campolina-Sampaio

Lasmar

Ribeiro

et al. 2016

Arq. Neuro-Psiquiatr.

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Objective The aim of this study was to translate and adapt the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) to Portuguese for use in Brazil. Methods The scale was applied in 20 pediatric patients with mitochondrial disease, in three groups: myopathy (n = 4); Leigh syndrome (n = 8); and encephalomyopathy (n = 8). Scores were obtained for the various dimensions of the NPMDS, and comparisons were drawn between the groups. Results There was a statistically significant difference between the myopathy group and the Leigh syndrome group (p = 0.0085), as well as between the myopathy and encephalomyopathy groups (p = 0.01). Conclusions The translation of the NPMDS, and its adaptation to the socioeconomic and cultural conditions in Brazil, make the NPMDS score useful as an additional parameter in the evaluation and monitoring of pediatric patients with MD in Brazil.

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Brain uptake of Tc99m-HMPAO correlates with clinical response to the novel redox modulating agent EPI-743 in patients with mitochondrial disease

Cited by 31 publications

References 35 publications

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Clinical Trials in Mitochondrial Disease

The Newcastle Pediatric Mitochondrial Disease Scale: translation and cultural adaptation for use in Brazil

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