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Idebenone is a rapidly absorbed, safe and well-tolerated drug and is currently the only clinically proven treatment option for Leber's hereditary optic neuropathy (LHON) patients. Idebenone (Raxone®) is approved by the European Medicines Agency for the treatment of LHON and has been available on the European market since 2015. Due to its molecular mode of action of bypassing the defective mitochondrial complex I, idebenone leads to improved energy supply and a functional recovery of retinal ganglion cells during the acute stage of the disease, thereby preventing further vision loss and promoting recovery of vision. Thus, commencing treatment shortly after the onset of symptoms is likely to have the best therapeutic effect, a hypothesis that is supported by the available clinical data.

The knowledge of the interactions between solid lipid nanoparticles (SLN) and cell membranes is important to develop effective carrier systems for drug delivery applications. Loading idebenone (IDE), an antioxidant drug useful in the treatment of neurodegenerative diseases, into SLN improves IDE antioxidant activity in in vitro biological studies, but the mechanism by which IDE permeation through the blood-brain barrier (BBB) occurs are still unclear. Therefore, in this research, unloaded and IDE loaded SLN interaction with biomembrane models, consisting of dimyristoylphosphatidylcholine multilamellar vesicles (MLV), were studied by differential scanning calorimetry (DSC). In the experiments performed, unloaded and IDE loaded SLN where incubated with the biomembrane models and their interactions were evaluated through the variations in their calorimetric curves. The results of our DSC studies indicated that the SLN under investigation were able to go inside the phospholipid bilayers with a likely localization in the outer bilayers of the MLV from where they moved toward the inner layers by increasing the contact time between SLN and MLV. Furthermore, IDE loaded SLN were able to release IDE into the biomembrane model, thus facilitating IDE penetration into the bilayers while free IDE showed only a low ability to interact with this model of biomembranes. Our results suggest that these SLN could be regarded as a promising drug delivery system to improve IDE bioavailability and antioxidant activity.

Purpose There is still no therapy for patients with Leber hereditary optic neuropathy (LHON). Recent studies have confirmed the effectiveness of Idebenone for the treatment of specific groups of LHON patients. However, it is still unclear if this treatment can be interesting in all cases of LHON. We wanted to evaluate whether Idebenone therapy in association with vitamin B2 and vitamin C can modify the visual function in non selected LHON patients. Methods A retrospective review of visual acuity and Goldmann visual field performed in patients referred to the ophthalmology clinic for LHON before and after a therapy with Idebenone (up to 270 mg/day), vitamin B2 and vitamin C. Results Seventy five patients were included. Mean duration between LHON onset and inclusion was 36 months. Mean treatment duration was 25 months. Twenty seven per cent of patients presented visual improvement. A surface reduction of the central scotoma greater than 30 % was observed in 36.2 % of these patients. Conclusion There is an effect of Idebenone therapy on visual function of LHON patients. Due to the delay between symptoms onset and beginning of the treatment, improvement does not seem to be due to habituation to low vision. However, Idebenone therapy is unable to correct visual disability in LHON population.

Purpose To establish the long term benefit of oral idebenone 900mg/day in the treatment of Leber's Hereditary Optic Neuropathy (LHON). Methods Patients who participated in a 24-week, multi-centre (3 sites), double-masked, randomized, placebo controlled trial (RHODOS) were re-assessed at a single visit by means of Visual Acuity (VA) using ETDRS charts. Results Eighty-five patients were enrolled in the RHODOS study: 55 treated with idebenone (900mg/day) and 30 with placebo. At the end of the 24 week treatment period, the VA for patients randomized to placebo deteriorated. In contrast, in patients treated with 900mg/day idebenone, VA was preserved. In addition, in severely affected patients with off-chart vision at Baseline, only idebenone treated patients improved sufficiently to read at least 1 full line on the ETDRS chart (Klopstock et al., 2011). VA was repeated at a follow-up visit conducted 2.5 years (median) after treatment discontinuation. The difference in VA between placebo and idebenone treated patients was maintained. Specifically, in patients who during RHODOS received idebenone and who on average were protected from vision loss, VA did not deteriorate upon discontinuation of treatment. Conclusion These findings support the original conclusion that in selected patients with LHON, idebenone has significant therapeutic potential in preventing further vision loss and facilitating vision recovery. Commercial interest

The syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a disease marked by a clinical triad of (1) stroke-like episode (SLE) before age 40 years, (2) encephalopathy characterized by seizures and dementia, and (3) lactic acidosis and ragged red fibers. The development of SLEs, acute neurological deterioration marked by radiographic evidence of strokes that do not adhere to vascular territories, is a pathognomonic clinical feature of this disease. A wide array of other systemic features, including short stature, Wolff-Parkinson-White syndrome, and diabetes mellitus, and neurological symptoms, such as sensorineural hearing loss, depression, and migraines, are also frequent manifestations of the disorder. MELAS is caused by a mutation affecting the mitochondrial genome; more than 30 specific mutations have been recognized, although greater than 80% of cases result from a single adenine-to-guanine transition mutation affecting the mitochondrial tRNA(Leu) gene (m.3243A>G). In this review, we will discuss the mechanisms of mitochondrial inheritance, including concepts such as heteroplasmy and mitotic segregation that underlay the complex genetics of this disease. Clinical and radiographic features of SLEs will be discussed at length, as will hypotheses that attempt to explain the pathogenesis of these events. While current treatment is limited to cofactor supplementation, ongoing research into potential therapies such as idebenone and l-arginine will also be discussed.

Las cardiopatías infiltrativas se caracterizan por el depósito de sustancias en el miocardio que causan un impacto negativo en la arquitectura de la pared ventricular. La ataxia espino-cerebelosa de Friedreich es una enfermedad degenerativa, heredada, con carácter autosómico recesivo. Clínicamente se caracteriza por ataxia de extremidades y tronco, hiporreflexia, neuropatía periférica, retinopatía y cardiopatía, entre otros. La afectación cardíaca es muy frecuente y se detectan alteraciones en estudios pos-mortem en 95% a 100% de los pacientes. La tasa de mortalidad es elevada y se considera una enfermedad incurable, a pesar de la existencia actual de múltiples medicamentos en estudio basados en los fundamentos fisiopatológicos de esta afección. Infiltrative heart diseases are characterized by deposit of substances in the myocardium that cause a negative impact on the architecture of the ventricular wall. Friedreich's spino-cerebellar ataxia is a degenerative disease, inherited in an autosomal recessive pattern. Clinically it is characterized by limb and trunk ataxia, hyporeflexia, peripheral neuropathy, retinopathy and heart disease among others. Cardiac involvement is common and on post-mortem studies cardiac abnormalities are found in 95% to 100% of patients. The mortality rate is high and it is considered an incurable disease, despite the current existence of multiple medications being studied, based on the pathophysiological basis of this condition.

We have studied the effects of idebenone on mitochondrial function in cybrids derived from one normal donor (HQB17) and one patient harboring the G3460A/MT-ND1 mutation of Leber's Hereditary Optic Neuropathy (RJ206); and in XTC.UC1 cells bearing a premature stop codon at aminoacid 101 of MT-ND1 that hampers complex I assembly. Addition of idebenone to HQB17 cells caused mitochondrial depolarization and NADH depletion, which were inhibited by cyclosporin (Cs) A and decylubiquinone, suggesting an involvement of the permeability transition pore (PTP). On the other hand, addition of dithiothreitol together with idebenone did not cause PTP opening and allowed maintenance of the mitochondrial membrane potential even in the presence of rotenone. Addition of dithiothreitol plus idebenone, or of idebenol, to HQB17, RJ206 and XTC.UC1 cells sustained membrane potential in intact cells and ATP synthesis in permeabilized cells even in the presence of rotenone and malonate, and restored a good level of coupled respiration in complex I-deficient XTC.UC1 cells. These findings demonstrate that idebenol can feed electrons at complex III. If the quinone is maintained in the reduced state, a task that in some cell types appears to be performed by dicoumarol-sensitive NAD(P)H:quinone oxidoreductase 1 [Haefeli et al. (2011) PLoS One 6, e17963], electron transfer to complex III may allow reoxidation of NADH in complex I deficiencies., Highlights ► The mitochondrial effects of idebenone in living cells are poorly characterized. ► Idebenone can be toxic or beneficial depending on its oxidation-reduction state. ► Idebenone is toxic through opening of the permeability transition pore. ► Idebenol stimulates respiration and ATP synthesis in cells lacking complex I. ► Short-chain quinones can be developed for the treatment of complex I defects.

Las cardiopatías infiltrativas se caracterizan por el depósito de sustancias en el miocardio que causan un impacto negativo en la arquitectura de la pared ventricular. La ataxia espino-cerebelosa de Friedreich es una enfermedad degenerativa, heredada, con carácter autosómico recesivo. Clínicamente se caracteriza por ataxia de extremidades y tronco, hiporrefl exia, neuropatía periférica, retinopatía y cardiopatía, entre otros. La afectación cardíaca es muy frecuente y se detectan alteraciones en estudios pos-mortem en 95% a 100% de los pacientes. La tasa de mortalidad es elevada y se considera una enfermedad incurable, a pesar de la existencia actual de múltiples medicamentos en estudio basados en los fundamentos fisiopatológicos de esta afección. Infi ltrative heart diseases are characterized by deposit of substances in the myocardium that cause a negative impact on the architecture of the ventricular wall. Friedreich’s spino-cerebellar ataxia is a de- generative disease, inherited in an autosomal recessive pattern. Clinically it is characterized by limb and trunk ataxia, hyporefl exia, peripheral neuropathy, retinopathy and heart disease among others. Cardiac involvement is common and on post-mortem studies cardiac abnormalities are found in 95% to 100% of patients. The mortality rate is high and it is considered an incurable disease, despite the current existence of multiple medications being studied, based on the pathophysiological basis of this condition.

Introduction: Idebenone (IDE) is an antioxidant compound, structurally related to coenzyme Q10. Its therapeutic potential is growing in different application areas, as demonstrated by the number of experimental works and patents produced in very recent years. Areas covered: Cyclodextrin inclusion complexes, liposomes, microemulsions, prodrugs, polymeric and lipid nanoparticles have been explored to achieve different goals, such as topical administration, brain targeting or increasing the bioavailability of this highly lipophilic drug. This review summarizes the results of works published in the last 20 years for the delivery and targeting of this drug. Expert opinion: A direct comparison of the different carrier systems is not easy and could not even be significant, due to the large variables existing among them. However, the different forms of delivery can help increase idebenone solubility, stability and biochemical activity. Further studies will be developed in order to improve the controlled release a...

Oiling-out, also termed as demixing or liquid–liquid phase separation (LLPS), frequently occurs in the crystallization process of pharmaceuticals and normally results in slow crystal growth, uncontrollable crystal morphology, and low purity of products. In this work, the oiling-out and cooling crystallization of idebenone were investigated. The cooling crystallization and the purity of its products were found to depend upon whether an oiling-out occurred in the course of cooling. At low initial concentrations (e.g., 12 mg/mL), oiling-out did not take place, and the crystallization products possessed higher purity. At moderate initial concentrations (e.g., 25 mg/mL) small quantities of oil droplets formed and then coalesced into larger droplets, which subsequently crystallized into products with lower purity. When high initial concentrations (e.g., 31 mg/mL) were employed, large quantities of oil droplets formed a stable oil phase, and thus no products could be harvested. In addition to initial concentration, other parameters such as solvent, cooling rate, and seeding also affected the occurrence of oiling-out. On the basis of the above results, the approach to purifying idebenone through cooling crystallization will be found.

The morphological change of a neuroblastoma cell line, Neuro2a, induced by Propentofylline, bifemelane, idebenone and indeloxazine was examined. Neuro2a(a murine neuroblastoma cell line)showed dose-dependent neurite extension. Propentofylline markedly increased the intracellular cyclic AMP level of Neuro2a cells, suppressed DNA synthesis(67% at 1 mM), and induced multipolar(multiple-neurite-bearing)-type neuritogenesis. A similar type of neurite outgrowth was. induced by 8-bromo-cyclic AMP, which also elevated the intracellular cyclic AMP concentration. Bifemelane, idebenone and indeloxazine had also the multipolar-type neuritogenic effects. They, however, failed to induce these morphological changes more than 1 mM, probably owing to the toxic potency of these compounds as compared with propentofylline.

Effect of idebenone on the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-selective glutamate receptor was evaluated using Xenopus oocytes injected with RNAs encoding mouse alpha 1 and alpha 2 AMPA receptors. Concanavalin A augmented current responses of the RNA-injected oocytes to glutamate, kainate, and AMPA and these responses were further potentiated by 100 microM idebenone. The minimum concentration of idebenone that gave a significant potentiation was 10 microM for glutamate. These results suggest that idebenone acts on AMPA-selective glutamate receptor channels composed of alpha 1 and alpha 2 subunits.

Friedreich's ataxia (FRDA) is a neuro-degenerative disease causing limb and gait ataxia and hypertrophic cardiomyopathy. It results from a triplet expansion in the first intron of the frataxin gene encoding a mitochondrial protein of yet unknown function. Cells with low frataxin content display generalized deficiency of mitochondrial iron-sulfur cluster-containing proteins, which presumably denotes overproduction of superoxide radicals in these organelles. Idebenone, a short-chain quinone, may act as a potent free radical scavenger protecting mitochondria against oxidative stress. We therefore carried out an open trial of idebenone (oral supplementation; 5mg/kg/day) in a large series of FRDA patients and followed their left ventricular mass and function. Consistent and definitive worsening being observed in the natural course of the disease and cardiac hypertrophy having no chance of spontaneous reversal and to be subject to a placebo effect, the patient's heart status before and after the treatment was used to unambiguously establish the effect of the drug. After six months, heart ultrasound revealed more than 20% reduction of left ventricular mass in about half of the patients (p0.001) and no significant change in the other half. Since any measurable reversion of this pathogenic trait is highly significant, this demonstrates the efficiency of idebenone in controlling heart hypertrophy in FRDA. Owing to the absence of side effects of the drug, idebenone (up to 15mg/kg/day) should be prescribed for FRDA patients continuously as early as possible.

Idebenone (IDB) is a synthetic antioxidant and analog of coenzyme Q10. The percutaneous permeation of IDB was investigated in guinea pig skin after application of different formulations. The enhancing effects of various formulations [nanostructured lipid carriers (NLCs), nanoemulsion (NE), or oil solution] on the permeation of IDB were evaluated using ex vivo guinea pig skins. Furthermore, stability of different formulations and in which chemical stability of IDB was determined during storage. Permeation experiments revealed that formulations varied in their ability to enhance the skin permeation of IDB. For NLC formulation, the cumulative amount of IDB in the epidermis, dermis, and acceptor medium of diffusion cells was approximately threefold more than NE or oil solution at the end of 24-h experiment. No significant difference between NE and oil solution was observed in the enhancement of penetration efficacy of IDB. Different formulations resulted in stability with different properties. NLC formulation revealed preferentially more stable than NE. The residual percentage of IDB loaded in NLCs, NE, and oil solution was 90.1%, 65.4%, and 51.3%, respectively, when stored at 40°C under 75% RH and 3,000 lx light conditions for 180 days. The results obtained here demonstrated that the abilities of NLCs to improve the chemical stability of IDB and enhance the skin permeation are much better than NE and oil solution. These suggest that NLCs containing IDB have significant potential use for skin care as an alternative topical formulation.

Purpose Age related macular degeneration is one of the leading causes of blindness. Oxidative stress plays an important role in the pathogenesis of this disease. This study investigates the possible anti-apoptotic and cytoprotective effects of idebenone on retinal pigmentepithelial cells (ARPE19) under oxidative stress. Methods ARPE19 were treated with 1 to 100 µM idebenone. Cell viability (tetrazolium dye-reduction assay and live-dead assay) and expression of BAX and Bcl-2, two key modulators of apoptosis, and their mRNA were determined after 48 h and after H2O2 treatment. Results Idebenone concentrations from 1 to 20 µM showed no toxic effects ARPE19. Doses of 5 and 7.5 µM were most effective in increasing cell viability after H2O2 treatment. Further more RT-PCR and Western blot analysis yielded an increased expression of Bcl-2 and a decrease of BAX compared to those cells that were treated with H2O2 only. Conclusion In this study idebenone reduced oxidative stress and apoptotic cell death in cultured ARPE19 in vitro. Our results suggest that idebenone may help to protect these cells in vivo, and therefore might be helpful in preventing the progression of geographic atrophy in age related macular degeneration.

Major advances in understanding the pathogenesis of inherited metabolic disease caused by mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber’s hereditary optic neuropathy is the most common mitochondrial DNA disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber’s hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber’s hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the mitochondrial disorder, Leber’s hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.

Short-chain quinones are described as potent antioxidants and in the case of idebenone have already been under clinical investigation for the treatment of neuromuscular disorders. Due to their analogy to coenzyme Q10 (CoQ10), a long-chain quinone, they are widely regarded as a substitute for CoQ10. However, apart from their antioxidant function, this provides no clear rationale for their use in disorders with normal CoQ10 levels. Using recombinant NAD(P)H:quinone oxidoreductase (NQO) enzymes, we observed that contrary to CoQ10 short-chain quinones such as idebenone are good substrates for both NQO1 and NQO2. Furthermore, the reduction of short-chain quinones by NQOs enabled an antimycin A-sensitive transfer of electrons from cytosolic NAD(P)H to the mitochondrial respiratory chain in both human hepatoma cells (HepG2) and freshly isolated mouse hepatocytes. Consistent with the substrate selectivity of NQOs, both idebenone and CoQ1, but not CoQ10, partially restored cellular ATP levels under conditions of impaired complex I function. The observed cytosolic-mitochondrial shuttling of idebenone and CoQ1 was also associated with reduced lactate production by cybrid cells from mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) patients. Thus, the observed activities separate the effectiveness of short-chain quinones from the related long-chain CoQ10 and provide the rationale for the use of short-chain quinones such as idebenone for the treatment of mitochondrial disorders.

Idebenone [2,3-dimethoxy-5-methyl-6(10-hydroxydecyl)-1,4-benzoquinone] is a synthetic short-chain analogue of coenzyme Q10 (CoQ10). A variety of quinones (including idebenone) have also been shown to affect the mitochondrial permeability transition pore (PTP), a high-conductance inner membrane channel modulated by the proton electrochemical gradient and by many signaling molecules. The PTP links oxidative stress to cell death, and may be involved in the pathogenesis of Leber's hereditary optic neuropathy (LHON) and possibly to other conditions with complex I deficiency. Given these complex effects of idebenone, we have investigated its effects on bioenergetics and PTP modulation in intact cells. Our results indicate that: (i) idebenone promotes CsA-sensitive opening of the PTP and subsequent loss of pyridine nucleotides; (ii) dithiothreitol prevents PTP opening and its detrimental consequences; (iii) idebenol does not cause PTP opening, and stimulates electron transfer at complex III of the respiratory chain; and (iv) idebenol-stimulated respiration is coupled to ATP synthesis both in rotenone-treated normal cells and in RJ206 cells (harboring the 3460/ND1 LHON mutation) and XTC.UC1 thyroid oncocytoma cells (bearing a disruptive frameshift mutation in the MT-ND1 gene, which impairs complex I assembly). Thus, under proper experimental conditions idebenol, can be a useful tool to bypass complex I defiencies.

OPINION STATEMENT: Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease with variable penetrance. Three primary mitochondrial DNA mutations, affecting the respiratory complex I, are necessary but not sufficient to cause blindness. Reduced efficiency of ATP synthesis and increased oxidative stress are believed to sensitize the retinal ganglion cells to apoptosis. Different therapeutic strategies are considered to counteract this pathogenic mechanism. However, potential treatments for the visual loss are complicated by the fact that patients are unlikely to benefit after optic atrophy occurs. There is no proven therapy to prevent or reverse the optic neuropathy in LHON. Results from a recent trial with idebenone hold promise to limit neurodegeneration and improve final outcome, promoting recovery of visual acuity. Other therapeutic options are under scrutiny, including gene therapy, agents increasing mitochondrial biogenesis, and anti-apoptotic drugs.

Increasing the lipophilicity and/or amphiphilicity of drugs is a potential strategy to improve loading and retention in lipid-based carriers, such as liposomes or lipid nanoparticles.Idebenone (IDE), an antioxidant compound structurally related to coenzyme Q, or amphiphilic prodrugs of IDE with lipoamino acids, were loaded in neutral or negatively charged SUVET unilamellar liposomes to achieve a controlled release.Technological properties of these systems in the presence of loaded drugs were evaluated in terms of vesicle size, homogeneity, and surface charge, as well as in vitro drug release. The effect of liposomal carrier on the in vitro antioxidant activity of the prodrugs was evaluated from using different biochemical assays on murine astrocyte cultures.Although a good loading efficiency was obtained, liposomes were not able to release efficiently the encapsulated drugs, at least in the in vitro serum-free conditions used for the biological tests. However, in some cases, such as in the comet assay, encapsulation of IDE prodrugs in liposomes allowed for the improvement of their protective activity, compared to the free compounds, against the oxidative damage induced on cultured astrocytes.Experimental in vitro data suggested that the high affinity shown by these lipophilic IDE derivatives for the liposomal carriers negatively affect their biological activity.

Nanopartículas lipídicas têm sido desenvolvidas para aplicação tópica de fármacos e ativos cosméticos. Neste trabalho, foi proposta a primeira aplicação de um lipídeo natural não-refinado biodegradável e biocompatível - manteiga de cupuaçu (Theobroma grandiflorum) - para a preparação de nanopartículas lipídicas, as quais foram denominadas teosferas. As teosferas foram preparadas por emulsificação-evaporação do solvente (EES) e por homogeneização à alta pressão (HAP), apresentando tamanho nanométrico e distribuição granulométrica estreita quando preparadas por ambos os métodos. O trabalho teve continuidade com a preparação de teosferas pelo método de EES utilizando manteiga de cupuaçu ou sua mistura com óleo de castanha do Brasil (Bertholletia excelsa) - também derivado da biodiversidade Amazônica - visando a incorporação de antioxidantes. Idebenona (IDB) foi selecionada por sua conhecida ação antioxidante e pela sua utilização em formulações cosméticas antienvelhecimento. IDB foi incorporada nas teosferas com eficiência de encapsulação superior a 99%, sendo que os estudos de liberação in vitro mostraram que a liberação de IDB a partir das teosferas foi mais lenta em comparação à IDB livre. Estes experimentos foram capazes ainda de demonstrar as características elásticas das teosferas. Além disso, foi evidenciada in vitro a atividade antioxidante superior das teosferas contendo IDB em relação ao ativo livre. Visando possibilitar a aplicação tópica de teosferas contendo IDB, em um trabalho subseqüente, suspensões de teosferas preparadas por HAP foram incorporadas em géis hidrofílicos. As formulações apresentaram características pseudoplásticas e demonstraram efeito oclusivo in vitro, o qual foi dependente da composição dos colóides. Finalmente, os estudos de permeação in vitro utilizando pele humana demonstraram que teosferas e nanocápsulas de núcleo lipídico, utilizadas neste estudo de modo comparativo, modificaram a permeção da IDB, permitindo a acumulação do ativo nas camadas superficiais da pele. Lipid nanoparticles have been developed for administration of active substances to the skin, both for pharmaceutical and cosmetic uses. In the present work, we proposed the first use of a none-refined natural biodegradable and biocompatible lipid – Cupuaçu seed butter (Theobroma grandiflorum) – for the preparation of lipid nanoparticles, which were called theospheres. Theospheres were prepared by emulsification-solvent evaporation (ESE) and by high pressure homogenization technique (HPH), presenting size in nanometrical range and narrow particle size distribution for both methods. Taking these results into account, the next step of this work was the preparation of theospheres by ESE method using Cupuaçu seed butter with or without Brazil nut (Bertholletia excelsa) seed oil - another ingredient derived from an Amazonian fruit - intending the encapsulation of an antioxidant. Idebenone (IDB) has been selected due to its known antioxidant action and because it has been used in antiaging cosmetic formulations. IDB was incorporated in the theospheres presenting encapsulation efficiency higher than 99%. The in vitro release evaluation demonstrated that the release of IDB from theospheres was lower than that of free drug. Besides, the in vitro release study highlighted the elastic characteristics of theospheres. Additionally, IDB-loaded theospheres showed higher antioxidant activity compared to free IDB. Viewing the cutaneous administration, theosphere suspensions prepared by HPH technique were incorporated into hydrogels. The rheograms of the semi-solid formulations exhibited a non-Newtonian behavior presenting pseudoplastic characteristics. In vitro occlusion study highlighted the dependence of the occlusive effect on the lipidic composition of the theospheres. Finally, in vitro human skin permeation studies showed that theospheres and lipid-core nanocapsules, used in this study in a comparative way, changed the permeation of IDB, increasing the accumulative amount of IDB in the upper skin layer.

Background Leber's hereditary optic neuropathy (LHON) is caused by mutations in the complex I subunits of the respiratory chain. Although patients have been treated with idebenone since 1992, the efficacy of the drug is still a matter of debate. Methods We evaluated the effect of idebenone in fibroblasts from LHON patients using enzymatic and polarographic measurements. Results Complex I activity was 42% greater in treated fibroblasts compared to controls (p = 0.002). Despite this complex I activity improvement, the effects on mitochondrial respiration were contradictory, leading to impairment in some cases and stimulation in others. Conclusion These results indicate that idebenone is able to compensate the complex I deficiency in LHON patient cells with variable effects on respiration, indicating that the patients might not be equally likely to benefit from the treatment.

PURPOSE OF REVIEW: Degenerative ataxias are a heterogeneous group of disorders that are clinically characterized by progressive ataxia. They can be subdivided into three major groups: the acquired ataxias, which are due to exogenous or endogenous nongenetic causes, the hereditary ataxias, and the nonhereditary degenerative ataxias. On the basis of a review of the literature published in 2009 and 2010, this review gives an update of the most recent developments in the field of ataxia. RECENT FINDINGS: Using advanced methods of molecular genetic analysis, novel genes for recessive and dominant ataxias were identified. Recent imaging studies in dominantly inherited spinocerebellar ataxias (SCAs) focussed on the analysis of connectivity in the brain. Novel clinical assessment methods were developed and validated in large patient cohorts. Although a phase 3 trial of idebenone in Friedreich ataxia (FRDA) failed, a smaller phase 2 trial of riluzole in a mixed population of ataxia patients suggested a possible antiataxic action of this compound. SUMMARY: Recent molecular advances underline the diversity of degenerative ataxias. With the progress in the development of clinical assessment methods for ataxia, the methodological requirements to run large interventional trials are now met.

Solid lipid nanoparticles (SLN) are regarded as interesting drug delivery systems and their preparation techniques have gained a great deal of attention.To evaluate the feasibility of preparing idebenone (IDE) loaded SLN from O/W microemulsions by the phase-inversion temperature (PIT) method. Since SLN have been proposed to improve drug delivery to the brain, IDE was chosen as model drug due to its activity in the treatment of neurodegenerative diseases.Cetyl palmitate was used as solid lipid to prepare SLN containing two surfactant/cosurfactant mixtures, isoceteth-20/glyceryl oleate (SLN A) and ceteth-20/glyceryl oleate (SLN B) by the PIT method.All the formulations tested showed a mean particle diameter ranging from 30 to 95 nm and a single peak in size distribution. Stability tests showed that SLN B were more stable than SLN A. IDE release was dependent both on the type of primary surfactant used and the amount of loaded drug. IDE-loaded SLN were effective in inhibiting 2,2'-azobis-(2-amidinopropane)dihydrochloride (APPH)-induced lactic dehydrogenase (LDH) release and reactive oxygen species (ROS) production in primary cultures of astrocytes obtained from rat cerebral cortex. It is noteworthy that SLN B2 (containing ceteth-20 as primary surfactant and 0.7% w/w IDE) were able to prevent entirely both the LDH release and ROS production induced by APPH.The PIT method provided SLN with good technological properties. The tested SLN could be regarded as interesting carriers to overcome the blood brain barrier and increase the efficacy of the loaded drug.

Effects of OM-853 on behavioral responses in the forced swim test were studied. OM-853 significantly reduced the duration of immobility without any change in the exploratory activity. Imipramine also reduced the duration of immobility, but idebenone did not. On the other hand, vinpocetine enhanced the duration with a suppressive effect on ambulation. The anti-immobility effect of OM-853 was reversed by pretreatment with haloperidol. These results demonstrate that the effect of OM-853 on the swim test is different from that of idebenone and vinpocetine. Furthermore, the present results suggest that OM-853 may exert its anti-immobility activity through facilitated transmission of the dopaminergic and/or adrenergic systems.

Introduction Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a maternally-inherited multisystem disorder. Mitochondrial angiopathy mediated by nitric oxide, a metabolite of L-arginine, is among the proposed pathophysiologic mechanisms of stroke-like episodes (SLEs) in MELAS. There are very few reports on long-term prevention of SLEs with oral L-arginine and idebenone treatment in MELAS adult patients. Case report A 38-year-old patient with MELAS and SLEs was treated with oral L-arginine and idebenone for 27 months. She remained free of attacks throughout the treatment period except when she stopped her treatment on two occasions during which she had recurrent cerebral metabolic attacks. The patient experienced no side effect of treatment with L-arginine and idebenone. Conclusion Our observation suggests long-term safety and potential benefit of oral L-arginine and idebenone in the prevention of recurrence of SLEs in adult MELAS patients.

Importance of the field Idebenone is a synthetic short chain benzoquinone that acts as an electron carrier in the mitochondrial electron transport chain, thereby, facilitating the production of ATP. In addition, idebenone is an antioxidant and can inhibit lipid peroxidation and may protect cell membranes and mitochondria from oxidative damage. High dose idebenone (Catena(®)) is approved in Canada for the symptomatic treatment of Friedreich's ataxia and is currently under clinical investigation for use in a number of mitochondrial and neuromuscular diseases. Areas covered in this review This review summarizes the pharmacology, pharmacokinetic and clinical efficacy/safety data of idebenone and its metabolites and provides an update of the clinical trials completed and in progress. What the reader will gain Following oral administration, idebenone is rapidly metabolized via oxidative shortening by a number CYP isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) to yield QS10, QS8, QS6 and QS4. Idebenone and these metabolites concomitantly undergo conjugation via glucuronidation and sulfatation to yield conjugated moieties represented as idebenone-C, QS10-C, QS8-C, QS6-C and QS4-C. Previous reports in the literature were only able to quantify plasma concentrations of idebenone measured together with its conjugates. More recently, highly sensitive and specific liquid chromatography method with tandem mass spectrometric methods have been developed, allowing the quantification of the parent molecule idebenone and its main metabolite QS10, separately. Take home message After absorption, idebenone is rapidly metabolized by first pass metabolism and shows dose-proportional pharmacokinetics in healthy subjects in daily doses up to 2250 mg. The recent development of advanced analytical techniques allows the detection of idebenone and unconjugated metabolites in plasma and consequently opens the possibility for evaluation of pharmacokinetic/pharmacodynamic relationships which will be helpful to further understand the metabolism and therapeutic potential of idebenone. In clinical studies, idebenone was safe and well tolerated at doses up to 2250 mg/day.

In our chronic experiments (over several months), the activity and protein amount of glycerol-3-phosphate dehydrogenase (GPDH) in mitochondria isolated from the liver of adult male and female inbred Lewis strain euthyroid (EU), hyperthyroid (TH), and hypothyroid (HY) rats were analyzed by biochemical and Western blot methods. The TH status was induced by intraperitoneal injections of 3,3',5-triiodo- L-thyronine and the HY status with 0.05% solution of methimazole in drinking water. The TH status led to a significant increase and the HY status to a significant decrease of enzyme activity and protein amount in both male and female animals. These changes were, however, more pronounced in females. The EU and TH female rats also showed a significantly higher activity and the TH female rats showed also a significantly higher enzyme amount in comparison with males, while the HY rats showed low levels in both sexes. The glycerol-3-phosphate-dependent oxygen consumption of freshly isolated rat liver mitochondria from the TH animals was higher in comparison with the EU animals and it was activated by idebenone, a synthetic analogue of coenzyme Q, in both the EU and TH rats. Measurements of serum thyroid hormone levels and analysis of anatomical parameters (relative heart and thyroid gland weights) confirmed that our procedures inducing the TH and HY states are efficient and reliable and that determination of GPDH can serve as an additional criterion for the evaluation of the thyroid hormone status.

Iron chelators are a new therapeutical approach for patients with Friedreich’s ataxia, on the basis that oxidative cell damage that occurs in these patients is due to the increasing deposits of mitochondrial iron pools. The objective of the study was to evaluate the effects of the combined therapy of idebenone and low oral doses of deferiprone on the neurological signs and cardiac function parameters. This study was designed as a prospective open-label single-arm study. Twenty Friedreich’s ataxia patients were treated with idebenone (20 mg/kg/day) and deferiprone (20 mg/kg/day) for 11 months. Patients were evaluated before the start and throughout the study with the International Cooperative Ataxia Rating Scale (ICARS) scores, echocardiographic measurements and MRI (magnetic resonance imaging) techniques to asses brain iron deposits in the dentate nucleus. No significant differences were observed in total ICARS scores when comparing baseline status and the end of the study in the whole group of patients. Posture and gait scores increased significantly after 11 months of therapy (Wilcoxon’s test, p = 0.04) and kinetic function improved significantly (Wilcoxon’s test, p = 0.015). Echocardiography data showed a significant reduction of the interventricular septum thickness (Wilcoxon’s test, p = 0.04) and in the left ventricular mass index (Wilcoxon’s test, p = 0.038) after the start of the therapy. The MRI values in the dentate nucleus showed a statistically significant reduction (Wilcoxon’s test p = 0.007) between baseline conditions and after 11 months of the therapy. Combined therapy with idebenone and deferiprone in patients with FDRA indicates a stabilizing effect in neurologic dysfunctions due to an improvement in the kinetic functions, with a worsening of gait and posture scores. Heart hypertrophy parameters and iron deposits in dentate nucleus improved significantly. Combined therapy was well tolerated with mild side effects, apart from the risk of neutropenia and progressive reduction of plasma iron parameters.

Objective To assess the efficacy of idebenone on neurological function in patients with Friedreich ataxia. Design Randomized, double-blind, placebo-controlled intervention trial. Setting Children's Hospital of Philadelphia and the University of California at Los Angeles. Participants Seventy ambulatory pediatric patients (age, 8-18 years) with a baseline International Cooperative Ataxia Rating Scale (ICARS) score of 10 to 54. Interventions Participants were randomized into 1 of 3 treatment arms: 450 or 900 mg of idebenone per day (in those with a body weight ≤ or >45 kg, respectively; n = 22); 1350 or 2250 mg of idebenone per day (n = 24); or placebo (n = 24). Main Outcome Measures Mean change from baseline to week 24 in ICARS score was the primary efficacy variable. Mean change in Friedreich Ataxia Rating Scale (FARS) score, performance measures, and activities of daily living were the secondary efficacy variables. Results Patients who received idebenone improved by 2.5 points on mean ICARS score compared with baseline, while patients in the placebo group improved by 1.3 points. Patients who took idebenone also improved by 1.6 points on the FARS, while patients taking placebo declined by 0.6 points. For both end points, the difference between the idebenone and placebo groups was not statistically different. Conclusions Idebenone did not significantly alter neurological function in Friedreich ataxia during the 6-month study. Larger studies of longer duration may be needed to assess the therapeutic potential of drug candidates on neurological function in Friedreich ataxia. Trial Registration clinicaltrials.gov Identifier:NCT00537680

Reason for Withdrawal Protocol withdrawn from publication in Issue 8 2012. Authors unable to proceed with review. To view the published versions of this article, please click the 'Other versions' tab.

Analogues of mitoQ and idebenone were synthesized to define the structural elements that support oxygen consumption in the mitochondrial respiratory chain. Eight analogues were prepared and fully characterized, then evaluated for their ability to support oxygen consumption in the mitochondrial respiratory chain. While oxygen consumption was strongly inhibited by mitoQ analogues 2–4 in a chain length-dependent manner, modification of idebenone by replacement of the quinone methoxy groups by methyl groups (analogues 6 – 8) reduced, but did not eliminate, oxygen consumption. Idebenone analogues 6 – 8 also displayed significant cytoprotective properties toward cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate.

Coenzyme Q10 (CoQ10, or ubiquinone) is an electron carrier of the mitochondrial respiratory chain (electron transport chain) with antioxidant properties. In view of the involvement of CoQ10 in oxidative phosphorylation and cellular antioxidant protection a deficiency in this quinone would be expected to contribute to disease pathophysiology by causing a failure in energy metabolism and antioxidant status. Indeed, a deficit in CoQ10 status has been determined in a number of neuromuscular and neurodegenerative disorders. Primary disorders of CoQ10 biosynthesis are potentially treatable conditions and therefore a high degree of clinical awareness about this condition is essential. A secondary loss of CoQ10 status following HMG-Coa reductase inhibitor (statins) treatment has be implicated in the pathophysiology of the myotoxicity associated with this pharmacotherapy. CoQ10 and its analogue, idebenone, have been widely used in the treatment of neurodegenerative and neuromuscular disorders. These compounds could potentially play a role in the treatment of mitochondrial disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological and muscular diseases, from primary CoQ10 deficiency to neurodegenerative disorders. We also briefly report a case of the myopathic form of CoQ10 deficiency.

Idebenone, a quinone analogue, has been used in the treatment of Friedreich ataxia (FRDA). Several small trials have shown that idebenone decreases left ventricle hypertrophy at 5 mg kg−1 day−1. High doses up to 75 mg kg−1 day−1 are safe. Treatment with high doses (up to 45 mg kg−1 day−1) has led to slightly improved ataxia scores. We will discuss idebenone, in vitro and in vivo studies, and FRDA.

Background: Coenzyme Q10 (CoQ10) and its analogs are used therapeutically by virtue of their functions as electron carriers, antioxidant compounds, or both. However, published studies suggest that different ubiquinone analogs may produce divergent effects on oxidative phosphorylation and oxidative stress. Methodology/Principal Findings: To test these concepts, we have evaluated the effects of CoQ10, coenzyme Q2 (CoQ2), idebenone, and vitamin C on bioenergetics and oxidative stress in human skin fibroblasts with primary CoQ10 deficiency. A final concentration of 5 mM of each compound was chosen to approximate the plasma concentration of CoQ10 of patients treated with oral ubiquinone. CoQ10 supplementation for one week but not for 24 hours doubled ATP levels and ATP/ADP ratio in CoQ10 deficient fibroblasts therein normalizing the bioenergetics status of the cells. Other compounds did not affect cellular bioenergetics. In COQ2 mutant fibroblasts, increased superoxide anion production and oxidative stress-induced cell death were normalized by all supplements. Conclusions/Significance: These results indicate that: 1) pharmacokinetics of CoQ10 in reaching the mitochondrial respiratory chain is delayed; 2) short-tail ubiquinone analogs cannot replace CoQ10 in the mitochondrial respiratory chain under conditions of CoQ10 deficiency; and 3) oxidative stress and cell death can be counteracted by administration of lipophilic or hydrophilic antioxidants. The results of our in vitro experiments suggest that primary CoQ10 deficiencies should be treated with CoQ10 supplementation but not with short-tail ubiquinone analogs, such as idebenone or CoQ2. Complementary administration of antioxidants with high bioavailability should be considered if oxidative stress is present.

A controlled double blind randomised open multicentre study was carried out on 104 patients with multi-infarct dementia (MID) from a mild to a moderate degree. The patients were randomly assigned to balanced blocks in each center and treated for 90 days either with idebenone (CV-2619) 90 mg/daily or placebo, after a 2-week turn-in period. The Gottfries Rating Scale, SCAG, Rey's A Figure Test, Rey's 15 Words Test, Token Test, Verbal Fluidity Test and the Blessed Dementia Test were used for assessment. The data were statistically analyzed using parametric and non-parametric tests. Seven patients were excluded (5 idebenone + 2 placebo) after a few days treatment, for reasons not related to drug administration; therefore, 97 patients were assessed for efficacy and 104 for tolerability. A certain placebo effect was found in the examination results but it never achieved the efficacy levels of idebenone. The latter is particularly effective for improving recent and remote memory, attention, orientation, vigilance and verbal comprehension and the effects continued even after a month of placebo treatment. There were no important adverse reactions and neither laboratory parameters nor clinical vital signs were significantly altered.

Idebenone is a new cerebro-active drug, effective in dementia disorders, particularly indicated in primary degenerative dementias, i.e. Alzheimer's disease. This new molecule acts as an electron trapper and a free radical scavenger protecting mitochondrial membranes from lipid peroxidation. A multicentric, double-blind trial of idebenone (45 mg twice daily orally) vs. placebo was carried out on 102 elderly patients affected by Alzheimer-type dementia of mild or moderate severity. Idebenone was administered for 4 consecutive months, 45 mg twice daily. Clinical evaluations were performed at the time of enrollment (t0) and monthly thereafter (t30, t60, t90 and t120) and at follow-up (t150 ). Tolerability to idebenone treatment was good and was associated with a statistically significant improvement of memory, attention and behaviour. It is worthwhile noting that these cognitive and behavioral findings were observed after the first month of treatment with enhancement evident in the following period.

A randomized, multicentre study on idebenone vs. oxiracetam was carried out in order to evaluate the therapeutic efficacy of idebenone in subjects with senile cognitive decline. Seventy-nine patients were enrolled: 39 treated with idebenone 45 mg twice daily p.o. and 40 treated with oxiracetam 800 mg twice daily p.o. Idebenone proved to be more effective and was shown to be statistically significant in the following test: SCAG, Rey's 15 Words, Gottfries Rating Scale. The greater efficacy of idebenone was confirmed by the efficacy judgement given by the investigators. The tolerability of both treatments can be said to be most satisfactory: none of the patients left the study because of side-effects. No significant variations were observed in the vital signs.

In this randomized double-blind, placebo controlled, multicentre study on 108 elderly patients with mild to moderate mental deterioration of vascular origin, idebenone — a benzoquinone derivative with a hydroxyalkyl side chain — proved to be therapeutically effective in the treatment of multi-infarct dementia. The oral administration of idebenone 45 mg/day b.i.d. for 120 days significantly improved the scores of the following test in comparison with placebo: Mini Mental State, Randt Memory Test, Gottfries Rating Scale, Token Test, Toulouse Pieron Test, indicating improvements in memory attention and cognitivity. The drug was well tolerated and effective in patients with multi-infarct dementria. No changes in laboratory parameters were observed either before or after treatment.

Bifemelane hydrochloride (bifemelane), idebenone and indeloxazine hydrochloride (indeloxazine) are used clinically to reduce apathy and other emotional disturbances in patients with cerebrovascular disease. In gerbil brains, ischemia affects many monoaminergic neurotransmitters and their metabolites. In the present study, the effects of treatment with bifemelane, idebenone and indeloxazine on ischemia-induced changes in monoamines and their metabolites were studied in ischemic gerbil brains. Although these drugs had no effect on the monoaminergic neurotransmitters or their metabolites in sham-operated animals, in the ischemic brains both dopamine and serotonin turnovers were abnormal after idebenone or indeloxazine treatment. Bifemelane, in contrast, tended to correct the ischemia-induced changes in the dopaminergic and serotonergic systems in the cerebral cortex, hippocampus and thalamus + midbrain. From the present results and those in previous reports, we conclude that bifemelane is more appropriate than idebenone or indeloxazine as a treatment for the ischemia-induced changes in monoaminergic neurotransmitter systems.

A high-performance liquid chromatographic determination of idebenone, a new cerebral metabolism-improving agent, in rat serum and brain has been developed. After separation of idebenone on a reversed-phase column, idebenone was reduced once in a platinum catalyst reduction column connected on-line, then monitored quantitatively by electrochemical detection. A linear relationship between the peak-height ratio of idebenone to the internal standard and idebenone concentration was observed in the range 0.015-50 ng with a detection limit of 5 pg (signal-to-noise ratio = 5). This method was satisfactorily rapid and sensitive, and was successfully applied to the determination of idebenone in rat serum and brain tissues.