Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON.

The aim of this study was to evaluate the therapeutic effect of idebenone in patients with OPA1-dominant optic atrophy (DOA). Sixteen patients with genetically confirmed OPA1-DOA were treated with 900 mg idebenone daily for 12 months. The primary endpoint was the best recovery/least deterioration of visual acuity. Secondary endpoints were the changes of visual acuity, colour vision, contrast sensitivity, visual field, peripapillary retinal nerve fibre layer thickness (pRNFLT), and visual-related quality of life. For the primary endpoint, a significant increase was observed for the right eye (p = .0027), for the left eye (p = .0111) and for the better-seeing eye (p = .0152). For visual fields, a significant improvement was observed for the left eye between baseline and 9 months (p = .0038). Regarding pRNFLT, a significant decrease was found for the left eye between baseline and 3 months (p = .0413) and between baseline and 6 months (p = .0448). In the visual function questionnaire, a significant improvement was observed in the subscale general vision (p = .0156) and in the composite score (p = .0256). In conclusion, best recovery of visual acuity improved, even though the amount of improvement was small. Furthermore, a maintenance of visual function after 12 months of idebenone intake could be observed as well as a significant improvement in vision-related quality of life.Whether this effect is due to idebenone treatment, the placebo effect, or is explainable by the natural progression of DOA, remains unclear. Trial registration: EU Clinical Trials Register, EudraCT Number: 2019-001493-28.

Idebenone (IDE), a synthetic short-chain analogue of coenzyme Q10, is a potent antioxidant able to prevent lipid peroxidation and stimulate nerve growth factor. Due to these properties, IDE could potentially be active towards cerebral disorders, but its poor water solubility limits its clinical application. Octanoyl-β-cyclodextrin is an amphiphilic cyclodextrin (ACyD8) bearing, on average, ten octanoyl substituents able to self-assemble in aqueous solutions, forming various typologies of supramolecular nanoassemblies. Here, we developed nanoparticles based on ACyD8 (ACyD8-NPs) for the potential intranasal administration of IDE to treat neurological disorders, such as Alzheimer\'s Disease. Nanoparticles were prepared using the nanoprecipitation method and were characterized for their size, zeta potential and morphology. STEM images showed spherical particles, with smooth surfaces and sizes of about 100 nm, suitable for the proposed therapeutical aim. The ACyD8-NPs effectively loaded IDE, showing a high encapsulation efficiency and drug loading percentage. To evaluate the host/guest interaction, UV-vis titration, mono- and two-dimensional NMR analyses, and molecular modeling studies were performed. IDE showed a high affinity for the ACyD8 cavity, forming a 1:1 inclusion complex with a high association constant. A biphasic and sustained release of IDE was observed from the ACyD8-NPs, and, after a burst effect of about 40%, the release was prolonged over 10 days. In vitro studies confirmed the lack of toxicity of the IDE/ACyD8-NPs on neuronal SH-SY5Y cells, and they demonstrated their antioxidant effect upon H2O2 exposure, as a general source of ROS.

UNASSIGNED: As the strongest prodromal marker of α-synuclein-specific neurodegeneration, idiopathic REM sleep behavior disorder (iRBD) is becoming a focus of interest in disease-modifying therapy. Idebenone has been widely portrayed as a potent antioxidant targeting mitochondrial dysfunction. Previous study has identified the effect of idebenone on Parkinson\'s disease with promising outcomes by regulating mitophagy. A novel indication of idebenone should be highlighted in iRBD population.
UNASSIGNED: The EITRS study is a randomized, double-blind, multi-center clinical study assessing the efficacy and safety of idebenone in the treatment of iRBD into synucleinopathies. One hundred forty-two patients (aged 40-75 years old) with clinically diagnosed iRBD are planned to be recruited with 80% statistical power and randomly assigned to idebenone (30 mg each time, three times a day) or matching placebo orally for 5 years. The assessment of rating scales, blood testing and neuroimaging examinations will be conducted at baseline, the 1st, 3rd and 5th year of follow-up. The primary efficacy endpoint is the 5-year conversion rate in patients with iRBD. The secondary endpoint is the safety and tolerability of idebenone in the treatment of iRBD. The study has been launched in July 2020.
UNASSIGNED: This is the first prospective study designed to identify the efficacy and safety of idebenone on the treatment of iRBD into synucleinopathies. The current results are expected to promote the development of evidence-based recommendations for the management of patients with iRBD. Furthermore, we hope to provide insights on a possible disease-modifying approach with robust evidence.
UNASSIGNED: Clinicaltrials.gov, identifier: NCT04534023.

OBJECTIVE: To evaluate the efficacy of the energotropic drug idebenon in hereditary neuromuscular pathology.
METHODS: A total of 9 patients with hereditary myopathies were examined during treatment with idebenone. Determination of muscle strength was carried out on the British medical research Council scale (0 points - no active movements, 5 points - no muscle weakness). The examination was performed before and 1 month after the start of treatment. Treatment regimen: idebenone was prescribed in a daily dose of 90 mg.
RESULTS: In the general group of patients with hereditary ataxia, the median strength of the biceps muscle of the shoulder during treatment increased from 3.5 to 4.0 points (p>0.05). The median strength of the ilio-lumbar muscle increased from 3.0 to 4.0 points (p>0.05). Before treatment, the median number of sit-ups was 0, and after 1 month - 2 (p>0.05).
CONCLUSIONS: We used the energotropic drug idebenon, a synthetic analog of the natural substance coenzyme Q10, which is involved in electron transfer in the mitochondrial respiratory chain complex III, for the treatment of patients with hereditary myopathies. In the general group of patients, there was an increase in muscle strength, although it did not reach statistical significance. Before the advent of energotropic drugs, the use of various methods of treating hereditary myopathies did not lead to an increase in muscle strength in patients. Therefore, the identified positive dynamics is of great importance in providing medical care to these patients and improving their quality of life.
UNASSIGNED: Оценить эффективность энерготропного препарата идебенон при наследственной нервно-мышечной патологии.
UNASSIGNED: Всего обследованы 9 больных с наследственными миопатиями на фоне лечения идебеноном. Определение мышечной силы проводили по шкале Британского медицинского исследовательского совета (BMRC) (0 баллов — отсутствие активных движений, 5 баллов — отсутствие мышечной слабости). Обследование проводили до и через 1 мес после начала лечения. Идебенон назначали в суточной дозе 90 мг.
UNASSIGNED: В общей группе больных наследственными атаксиями медиана силы двуглавой мышцы плеча на фоне лечения увеличилась с 3,5 до 4,0 баллов (p>0,05). Медиана силы подвздошно-поясничной мышцы увеличилась с 3,0 до 4,0 баллов (p>0,05). До начала лечения медиана количества приседаний составила 0, через 1 мес — 2 (p>0,05).
UNASSIGNED: Для лечения больных наследственными миопатиями был применен энерготропный препарат идебенон — синтетический аналог природного вещества коэнзима Q10, участвующего в переносе электронов в III комплексе дыхательной цепи митохондрий. В общей группе обследуемых отмечено увеличение мышечной силы, хотя и не имеющее статистической значимости. До появления энерготропных препаратов применение различных методов лечения наследственных миопатий не приводило к увеличению мышечной силы. Поэтому выявленная положительная динамика у больных имеет большое значение при оказании медицинской помощи и улучшении качества их жизни.

BACKGROUND: Rebaudioside A (RA) and its monoglucosyl derivative, as like rebaudioside D (RD) are the most popular stevia glycosides but possess poor solubility in water, which limited their application as edible surfactants, the applications as in micellar solubilization and drug delivery. Meanwhile, effect of the monoglucosyl attached to RA moiety remains unclear.
RESULTS: Monoglucosyl rebaudioside A (RAG1) was synthesized via hydrolyzing the transglycosylation product of RA with 95% of RA converted. RAG1 content in raw reaction mixture was as high as 69.5% of total glycosides, and harvested with a content of 88.2% by simple filtration. The RAG1 exhibited an aqueous solubility of 87 folds of RA or 391 folds of RD at 25 °C. The surface activity of RAG1 solution was higher than RA and invincible to RD. The RAG1 micelles promoted aqueous solubility of idebenone (IDE) up to 500 folds higher at 25 °C. The cumulative release rate of IDE encapsulated in RAG1 micelles was 777.5% or 456.7% higher of that of free IDE in simulated gastric/intestinal fluids in 14 h, respectively. The RAG1-IDE remained the same in 98 days at 25 °C.
CONCLUSIONS: The α-linked glucosyl to RA induced higher hydrophilicity and surface activity than that resulted by β-linked glucosyl, making RAG1 not only dramatically raise the aqueous solubility of RA, but also endow IDE folds higher in bioaccessibility, yet making the capsule stable at storage. The results would provide a new edible delivery nanocarrier for encapsulation of hydrophobic bioactive components. © 2021 Society of Chemical Industry.

OBJECTIVE: Leber\'s hereditary optic neuropathy (LHON) is a mitochondrial neuropathy that causes acute vision loss. Idebenone, a short-chain ubiquinone analog that preserves mitochondrial function is thought to suppress disease progression in early-onset LHON patients. We investigated the effects of idebenone in Japanese LHON patients.
METHODS: Prospective, interventional, non-comparative study in patients with definite LHON diagnosis, under trial registration number UMIN000017939.
METHODS: Fifty-seven patients received 900 mg/day idebenone for 24 weeks. We measured baseline best-corrected visual acuity, visual fields, critical fusion frequency and retinal ganglion cell layer complex thickness; we assessed efficacy at 24 and 48 weeks, and safety throughout.
RESULTS: Patients were predominantly male (91.2%) and most had an mt.11778G>A mutation (94.7%). All patients tolerated idebenone therapy well. Data from the 51 mt.11778 patients were compared with their baseline data. At 48 weeks, significant improvement in best-corrected visual acuity was observed in 17 patients (33.3%). Furthermore, 25.5% of patients showed improvements in visual fields and 33.3% in critical fusion frequency. However, retinal ganglion cell layer complex thickness was significantly reduced. Among patients who started idebenone >1 year after disease onset, visual improvement was found in 12 (38.7%). Among patients who developed LHON before 19 years of age, visual improvement was found in 11 (42.3%).
CONCLUSIONS: Idebenone\'s potential and favorable safety profile were confirmed in Japanese LHON patients. However, this study had no placebo group; therefore, we need to undertake a prospective intervention study to further investigate the therapeutic effects of Idebenone in Japanese LHON patients.

Objective: Stabilizers, especially carbohydrate polymers, have been shown to be necessary for the stabilization of drug nanocrystals. However, the impacts of select stabilizers on the in vitro and in vivo efficacy of therapeutics have rarely been reported. The aim of this study was to evaluate the importance of stabilizers in the formulation of drug nanocrystals.Research design and methods: Idebenone nanocrystals (IDBNC) stabilized by various stabilizers were formulated using a milling method. The in vitro dissolution profiles in water and in situ absoprtion were compared. Finally, an in vivo pharmacokinetic study was performed.Results: The IDBNC profiles were found to have acceptable sizes and similar morphology and crystallinity. The dissolution profiles of IDBNC stabilized by different stabilizers were notably different, indicating the critical influence of stabilizers on the release rate of IDB. The Soluplus-stabilized IDBNC (IDBNC400 nm/Soluplus) achieved better absorption than HPMC stabilized IDBNC (IDBNC400 nm/HPMC). The pharmacokinetic study demonstrated that Soluplus-stabilized IDBNC had preferable kinetics, with an AUC0-24h of IDBNC400 nm/Soluplus (3.08-fold relative to IDB suspension), compared to IDBNC400 nm/HPMC (1.88-fold).Conclusions: Choice of stabilizer plays an important role in the formulation of IDBNC. We anticipate that the role of stabilizers in the pharmacokinetic disposition of IDBNC has significant implications for a wide range of other drug crystal formulations.

Adapted forms for administration to infants are limited. The proposed study was performed to propose oral liquid formulations of idebenone in Ora-Plus and either Ora-Sweet or Ora-Sweet SF, Ora-Blend, Ora-Blend SF and Inorpha. Each formulation was stored in 30 ml amber glass bottle at 5 or 25 °C for 90 days. Idebenone contents in these suspensions, determined by a stability-indicating high-performance liquid chromatography method, remained stable at least 90 days in Inorpha when stored at the two temperatures. In Ora-Blend, the stability was estimated at 14 days and in other suspensions at 20 days at the two temperatures. After 90 days storage, the pH of Ora-Plus and Ora-Sweet or Ora-Sweet SF changed between -0.10 and -0.25 units. For others suspensions, the pH changes were not significant (< -0.09 unit). No change was observed in color, odor or visual microbiology. To conclude, we recommended the use of idebenone in Inorpha vehicle stable for at least 90 days at 25 °C.

Dominant optic atrophy (DOA) arises from mutations in the OPA1 gene that promotes fusion of the inner mitochondrial membrane and plays a role in maintaining ATP levels. Patients display optic disc pallor, retinal ganglion cell (RGC) loss and bilaterally reduced vision. We report a randomized, placebo-controlled trial of idebenone at 2000 mg/kg/day in 56 Opa1 mutant mice (B6;C3-Opa1(Q285STOP)), with RGC dendropathy and visual loss, and 63 wildtype mice. We assessed cellular responses in the retina, brain and liver and RGC morphology, by diolistic labeling, Sholl analysis and quantification of dendritic morphometric features. Vision was assessed by optokinetic responses. ATP levels were raised by 0.57 nmol/mg (97.73%, p=0.035) in brain from idebenone-treated Opa1 mutant mice, but in the liver there was an 80.35% (p=0.011) increase in oxidative damage. NQO1 expression in Opa1 mutant mice was reduced in the brain (to 30.5%, p=0.002) but not in retina, and neither expression level was induced by idebenone. ON-center RGCs failed to show major recovery, other than improvements in secondary dendritic length (by 53.89%, p=0.052) and dendritic territory (by 2.22 × 10(4) μm(2) or 90.24%, p=0.074). An improvement in optokinetic response was observed (by 12.2 ± 3.2s, p=0.003), but this effect was not sustained over time. OFF-center RGCs from idebenone-treated wildtype mice showed shrinkage in total dendritic length by 2.40 mm (48.05%, p=0.025) and a 47.37% diminished Sholl profile (p=0.029). Visual function in wildtype idebenone-treated mice was impaired (2.9 fewer head turns than placebo, p=0.007). Idebenone appears largely ineffective in protecting Opa1 heterozygous RGCs from dendropathy. The detrimental effect of idebenone in wildtype mice has not been previously observed and raises some concerns.