Chemistry:Idebenone

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Short description: Chemical compound
Idebenone
Idebenone.svg
Clinical data
Trade namesCatena, Raxone, Sovrima
AHFS/Drugs.comInternational Drug Names
License data
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability<1% (high first pass effect)
Protein binding>99%
Elimination half-life18 hours
ExcretionUrine (80%) and feces
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC19H30O5
Molar mass338.444 g·mol−1
3D model (JSmol)
  (verify)

Idebenone (pronounced eye-deb-eh-known, trade names Catena, Raxone, Sovrima, among others) is a drug that was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer's disease and other cognitive defects.[1] This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of neuromuscular diseases. In 2010, early clinical trials for the treatment of Friedreich's ataxia[2] and Duchenne muscular dystrophy[3] have been completed. (As of December 2013) the drug is not approved for these indications in North America or Europe. It is approved by the European Medicines Agency (EMA) for use in Leber's hereditary optic neuropathy (LHON) and was designated an orphan drug in 2007.[4]

Chemically, idebenone is an organic compound of the quinone family. It is also promoted commercially as a synthetic analog of coenzyme Q10 (CoQ10).

Uses

Indications that are or were approved in some territories

Nootropic effects and Alzheimer's disease

Idebenone improved learning and memory in experiments with mice.[5] In humans, evaluation of Surrogate endpoints like electroretinography, auditory evoked potentials and visual analogue scales also suggested positive nootropic effects,[6] but larger studies with hard endpoints are missing.

Research on idebenone as a potential therapy of Alzheimer's disease have been inconsistent, but there may be a trend for a slight benefit.[7][8] In May 1998, the approval for this indication was cancelled in Japan due to the lack of proven effects. In some European countries, the drug is available for the treatment of individual patients in special cases.[1]

Friedreich's ataxia (Sovrima)

Preliminary testing has been done in humans and found idebenone to be a safe treatment for Friedreich's ataxia (FA), exhibiting a positive effect on cardiac hypertrophy and neurological function.[9] The latter was only significantly improved in young patients.[10] In a different experiment, a one-year test on eight patients, idebenone reduced the rate of deterioration of cardiac function, but without halting the progression of ataxia.[11]

The drug was approved for FA in Canada in 2008 under conditions including proof of efficacy in further clinical trials.[12] However, on February 27, 2013, Health Canada announced that idebenone would be voluntarily recalled as of April 30, 2013 by its Canadian manufacturer, Santhera Pharmaceuticals, due to the failure of the drug to show efficacy in the further clinical trials that were conducted.[13] In 2008, the European Medicines Agency (EMA) refused a marketing authorisation for this indication.[1] As of 2013 the drug was not approved for FA in Europe[14] nor in the US, where there is no approved treatment.[15]

Leber's hereditary optic neuropathy (Raxone)

Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited (mother to all offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. Santhera completed a Phase III clinical trial in this indication in Europe with positive results,[16] and submitted an application to market the drug to European regulators in July 2011.[17] It is approved by EMA for this indication and was designated an orphan drug in 2007.[4]

Indications being explored

Duchenne muscular dystrophy (Catena)

After experiments in mice[18] and preliminary studies in humans, idebenone has entered Phase II clinical trials in 2005[3] and Phase III trials in 2009.[19]

Other neuromuscular diseases

Phase I and II clinical trial for the treatment of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) was conducted.[20] Phase I/II trial for primary progressive multiple sclerosis concluded that Idebenone did not inhibit disability progression.[21][22]

As of 2022, a phase III clinical trial is ongoing for the treatment of Parkinson's disease.[23]

Life style

Idebenone is claimed to have properties similar to CoQ10 in its antioxidant properties, and has therefore been used in anti-aging on the basis of free-radical theory. Clinical evidence for this use is missing. It has been used in topical applications to treat wrinkles.[24]

Pharmacology

In cellular and tissue models, idebenone acts as a transporter in the electron transport chain of mitochondria and thus increases the production of adenosine triphosphate (ATP) which is the main energy source for cells, and also inhibits lipoperoxide formation. Positive effects on the energy household of mitochondria has also been observed in animal models.[1][25] Clinical relevance of these findings has not been established.

Pharmacokinetics

Idebenone is well absorbed from the gut but undergoes excessive first pass metabolism in the liver, so that less than 1% reach the circulation. This rate can be improved with special formulations (suspensions) of idebenone and by administering it together with fat food; but even taking these measures bioavailability still seems to be considerably less than 14% in humans. More than 99% of the circulating drug are bound to plasma proteins. Idebenone metabolites include glucuronides and sulfates, which are mainly (~80%) excreted via the urine.[1]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 CHMP Assessment Report for Sovrima (Report). European Medicines Agency. 20 November 2008. pp. 6, 9–11, 67f. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000908/WC500070576.pdf. 
  2. ↑ Clinical trial number NCT00229632 for "Idebenone to Treat Friedreich's Ataxia" at ClinicalTrials.gov
  3. ↑ 3.0 3.1 Clinical trial number NCT00654784 for "Efficacy and Tolerability of Idebenone in Boys With Cardiac Dysfunction Associated With Duchenne Muscular Dystrophy (DELPHI)" at ClinicalTrials.gov
  4. ↑ 4.0 4.1 "Raxone". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/raxone. 
  5. ↑ "Effects of ligustrazine, tanshinone II A, ubiquinone, and idebenone on mouse water maze performance". Zhongguo Yao Li Xue Bao = Acta Pharmacologica Sinica 20 (11): 987–990. November 1999. PMID 11270979. 
  6. ↑ "Dose-effect relationship of idebenone in an experimental cerebral deficit model. Pilot study in healthy young volunteers with piracetam as reference drug". Arzneimittel-Forschung 48 (7): 720–726. July 1998. PMID 9706371. 
  7. ↑ "Safety and efficacy of idebenone versus tacrine in patients with Alzheimer's disease: results of a randomized, double-blind, parallel-group multicenter study". Pharmacopsychiatry 35 (1): 12–18. January 2002. doi:10.1055/s-2002-19833. PMID 11819153. 
  8. ↑ "Cognitive enhancement therapy for Alzheimer's disease. The way forward". Drugs 53 (5): 752–768. May 1997. doi:10.2165/00003495-199753050-00003. PMID 9129864. 
  9. ↑ "Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial". The Lancet. Neurology 6 (10): 878–886. October 2007. doi:10.1016/S1474-4422(07)70220-X. PMID 17826341. https://zenodo.org/record/1260260. 
  10. ↑ "Idebenone in Friedreich's ataxia". Expert Opinion on Pharmacotherapy 9 (13): 2327–2337. September 2008. doi:10.1517/14656566.9.13.2327. PMID 18710357. 
  11. ↑ "Idebenone treatment in Friedreich's ataxia: neurological, cardiac, and biochemical monitoring". Neurology 60 (10): 1679–1681. May 2003. doi:10.1212/01.wnl.0000068549.52812.0f. PMID 12771265. 
  12. ↑ "Heath Canada Fact Sheet - Catena". http://www.hc-sc.gc.ca/dhp-mps/prodpharma/notices-avis/conditions/catena_fs_fd_117672-eng.php. 
  13. ↑ Voluntary Withdrawal of Catena from the Canadian Market
  14. ↑ Margaret Wahl for Quest Magazine, MAY 28, 2010. FA Research: Idebenone Strikes Out Again
  15. ↑ NINDS Fact Sheet
  16. ↑ "A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy". Brain 134 (Pt 9): 2677–2686. September 2011. doi:10.1093/brain/awr170. PMID 21788663. 
  17. ↑ Staff (26 July 2011). "Santhera publishes pivotal trial results of idebenone and goes for EU approval". http://www.eurobiotechnews.eu/news/messages-archive/archive/article/santhera-publishes-pivotal-trial-results-of-idebenone-and-goes-for-eu-approval.html. 
  18. ↑ "Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance". European Heart Journal 30 (1): 116–124. January 2009. doi:10.1093/eurheartj/ehn406. PMID 18784063. 
  19. ↑ Clinical trial number NCT01027884 for "Phase III Study of Idebenone in Duchenne Muscular Dystrophy (DMD) (DELOS)" at ClinicalTrials.gov
  20. ↑ Clinical trial number NCT00887562 for "Study of Idebenone in the Treatment of Mitochondrial Encephalopathy Lactic Acidosis & Stroke-like Episodes (MELAS)" at ClinicalTrials.gov
  21. ↑ Clinical trial number NCT00950248 for "Double Blind Placebo-Controlled Phase I/II Clinical Trial of Idebenone in Patients With Primary Progressive Multiple Sclerosis (IPPoMS)" at ClinicalTrials.gov
  22. ↑ "Idebenone does not inhibit disability progression in primary progressive MS". Multiple Sclerosis and Related Disorders 45: 102434. October 2020. doi:10.1016/j.msard.2020.102434. PMID 32784117. 
  23. ↑ "Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2022 Update". Journal of Parkinson's Disease 12 (4): 1073–1082. 2022. doi:10.3233/JPD-229002. PMID 35527571. 
  24. ↑ "Clinical efficacy assessment in photodamaged skin of 0.5% and 1.0% idebenone". Journal of Cosmetic Dermatology 4 (3): 167–173. September 2005. doi:10.1111/j.1473-2165.2005.00305.x. PMID 17129261. 
  25. ↑ "[Effect of idebenone and various nootropic drugs on lipid peroxidation in rat brain homogenate in the presence of succinate]" (in ja). Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica 91 (5): 295–299. May 1988. doi:10.1254/fpj.91.295. PMID 3410376. 



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