Idebenone

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Idebenone
Idebenone.svg
Systematic (IUPAC) name
2-(10-hydroxydecyl)-5,6-dimethoxy-3-methyl-
cyclohexa-2,5-diene-1,4-dione
Clinical data
Trade names Catena, Raxone, Sovrima
AHFS/Drugs.com International Drug Names
Legal status
  • Investigational
Pharmacokinetic data
Bioavailability <1% (high first pass effect)
Protein binding >99%
Biological half-life 18 hours
Excretion Urine (80%) and feces
Identifiers
CAS Number 58186-27-9 YesY
ATC code N06BX13 (WHO)
PubChem CID: 3686
ChemSpider 3558 YesY
UNII HB6PN45W4J YesY
KEGG D01750 YesY
ChEMBL CHEMBL252556 YesY
Chemical data
Formula C19H30O5
Molecular mass 338.439 g/mol
  • O=C1/C(=C(\C(=O)C(\OC)=C1\OC)C)CCCCCCCCCCO
  • InChI=1S/C19H30O5/c1-14-15(12-10-8-6-4-5-7-9-11-13-20)17(22)19(24-3)18(23-2)16(14)21/h20H,4-13H2,1-3H3 YesY
  • Key:JGPMMRGNQUBGND-UHFFFAOYSA-N YesY
  (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.

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.[4] In humans, evaluation of Surrogate endpoints like electroretinography, auditory evoked potentials and visual analogue scales also suggested positive nootropic effects,[5] 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.[6][7] 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.[8] The latter was only significantly improved in young patients.[9] 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.[10]

The drug was approved for FA in Canada in 2008 under conditions including proof of efficacy in further clinical trials.[11] 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.[12] 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[13] nor in the US, where there is no approved treatment.[14]

Indications being explored

Duchenne muscular dystrophy (Catena)

After experiments in mice[15] and preliminary studies in humans, idebenone has entered Phase II clinical trials in 2005[3] and Phase III trials in 2009.[16]

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,[17] and submitted an application to market the drug to European regulators in July 2011.[18] In January 2013, the request for marketing authorisation was refused by the EMA.[19]

Other neuromuscular diseases

Phase I and II clinical trials for the treatment of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)[20] and primary progressive multiple sclerosis[21] are ongoing as of December 2013.

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.[22]

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][23] 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 Lua error in package.lua at line 80: module 'strict' not found.
  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. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Heath Canada Fact Sheet - Catena
  12. ↑ Voluntary Withdrawal of Catena from the Canadian Market
  13. ↑ Margaret Wahl for Quest Magazine, MAY 28, 2010. FA Research: Idebenone Strikes Out Again
  14. ↑ NINDS Fact Sheet
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Clinical trial number NCT01027884 for "Phase III Study of Idebenone in Duchenne Muscular Dystrophy (DMD) (DELOS)" at ClinicalTrials.gov
  17. ↑ Klopstock T, et al (2011) A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain.134(Pt 9):2677-86.
  18. ↑ Staff, European Biotechnology News, July 26, 2011. Santhera publishes pivotal trial results of idebenone and goes for EU approval
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  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. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  23. ↑ Lua error in package.lua at line 80: module 'strict' not found.


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