Recent advances in treatment of Leber's hereditary optic neuropathy / 眼科新进展

Leber's hereditary optic neuropathy (LHON) is an inherited mitochondrial disorder characterized by bilateral progressive vision loss.Current management includes therapies directed at enhancing mitochondrial function and preventing oxidative damage.This article reviews the progress of treatments from mitochondria cocktail,idebenone,gene therapy,EPI-743,brimonidine,traditional Chinese medicine and physical therapy,providing a new insight in the treatments of LHON.

Use of Idebenone for the Treatment of Leber's Hereditary Optic Neuropathy

Abstract Leber's hereditary optic neuropathy (LHON) is one of the most frequent mitochondrial disorders. It is caused by mutations in genes of the mitochondrial DNA coding for subunits of the respiratory chain and leads to severe bilateral vision loss, from which spontaneous recovery is infrequent. Retinal ganglion cells show a selective vulnerability to mitochondrial dysfunction in LHON. Idebenone is the first medication approved for LHON. It is a short-chain benzoquinone, which is an analogue of coenzyme Q10, but with distinct properties and mechanisms of action. Idebenone is a potent antioxidant and inhibitor of lipid peroxidation. Importantly, it facilitates electron flux directly to complex III, bypassing the dysfunctional complex I of the mitochondrial respiratory chain, thereby increasing adenosine triphosphate (ATP) production. In the Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) randomized placebo-controlled clinical trial, 85 patients with LHON were enrolled, in the first 5 years after symptom onset, and randomized to either idebenone 900 mg/d for 6 months or placebo. Idebenone was well tolerated, and although the prespecified primary end point (best recovery in visual acuity [VA]) did not reach statistical significance, all secondary end points (change in best VA, change of VA of best eye at baseline, and change of VA in all eyes) showed a trend toward visual recovery in favor of idebenone. An increasing body of evidence shows that idebenone is effective and safe for the treatment of patients with LHON, including a large retrospective open-label study, several case reports and case series, an expanded access program, and ongoing post-authorization clinical studies. Here, we review the literature on idebenone for the treatment of patients with LHON.

Preparation and Dissolution Rate in vitro of Idebenone Solid Dispersion / 中国药房

OBJECTIVE:To prepare Idebenone solid dispersion,and to investigate its dissolution rate in vitro. METHODS:Us-ing Poloxamer 407(P407)as carrier,the influence of preparation methods(solvent method,melting method)and the ratio of the drug to P407(1∶1,1∶3,1∶8)on the dissolution of drug were investigated by single factor design. The state of idebenone in ma-trix of solid dispersion was further determined by using differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD). RESULTS:Idebenone solid dispersion prepared by solvent method(the ratio of the drug to poloxamer was 1∶3)showed dissolution rate of 80%. The majority of idebenone existed in the solid dispersion at amorphous forms or molecular state. CONCLU-SIONS:Idebenone solid dispersions with high dissolution rate in vitro is prepared successfully.

Chitosan Nanoparticles for Topical Co-administration of the Antioxidants Glutathione and Idebenone: Characterization and In vitro Release.

Aims: The aim of this study was to explore the potential of novel nanoparticles (NPs) intended for topical administration of the hydrophilic antioxidant Glutathione and the lipophilic Idebenone. Glutathione was introduced into the NPs using two approaches: i) covalently bonded to Chitosan; ii) physically complexed with Idebenone and Sulfobutylether--cyclodextrin. Methodology: NPs were formulated using the ionic gelation technique, by dissolving the polysaccharide-forming matrix (Chitosan, Glycol chitosan, Glutathionyl Chitosan) in water or in slightly acidic solution. Idebenone was physically entrapped whereas glutathione was either physically entrapped or covalently bonded to chitosan. Physicochemical characterization of the resulting NPs included size, zeta potential measurements, antioxidant association efficiency, differential scanning calorimetry (DSC) and stability studies. Antioxidants in vitro release from the most stable NPs was assessed with Franz diffusion cells, and the in vitro antioxidant activity was evaluated by the 2,2- diphenyl-1-picrylhydrazyl (DPPH) radical test. NP cytotoxicity was assessed on immortalized human keratinocytes (HaCaT) cell line. Results: The NPs showed smaller particle size in acidic solution than in aqueous medium, whereas zeta potential values were always positive, irrespective of the medium. Stability studies led to the choice of the aqueous formulation where Glutathione was covalently bonded to Chitosan for this study. DSC highlighted amorphization of Idebenone in these NPs. In vitro release studies showed that only Idebenone was released from the NPs. The antioxidant activity test revealed a strong effect (close to 100%) of Idebenone loaded into NPs while its aqueous solution showed no activity. No cytotoxicity in human keratinocytes was observed for the investigated NPs. Conclusion: The results of this study suggest that Idebenone can be loaded into a hydrophilic delivery system without organic solvents, often used for its solubilization, possessing high antioxidant activity. Therefore, these nanocarriers represent a promising strategy for the design of formulations for topical treatments with antioxidants.

Cardiopatía dilatada en ataxia de Friedreich: el punto sin retorno / Dilated cardiomyopathy in Friedreich's ataxia: point of no return

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.

The role of idehenone in the treatment of nervous system diseases New knowledge and new findings / 国际脑血管病杂志

Idebenone is a synthetic analogue of coenzyme Q10. As a potent antioxidant,idebenone operates under low oxygen tension situations, protects cell membranes and mitochondria from oxidative damage through inhibiting lipid peroxidation, thereby protects against cerebral ischemia and nervous system damage. Idebenone also interacts with the mitochondrial electron transport chain and maintains the formation of ATP under ischemic conditions. Because idebenone has a good tolerability and safety, it is expected as a neuroprotective agent for the treatment of acute ischernic stroke. Studies in recent years have showed that idebenone has a certain therapeutic effect in a variety of nervous system diseases involving mitochondrial dysfunction and oxidative stress damage, such as mitochodrial encephalomyopathy, lactic acidosis, stroke-like episodes syndrome, Friedreich's ataxia, Alzheimer's diseases, Leber's hereditary optic neuropathy, and Duchenne muscular dystrophy. At present, some clinical trials in the mitochondria-related diseases and neuromuscular diseases are underway, and their results are expected to further expand the indications of idebenone.