Methylthioninium chloride

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Methylthioninium chloride
Systematic (IUPAC) name
3,7-bis(Dimethylamino)-phenothiazin-5-ium chloride
Identifiers
CAS number 61-73-4
ATC code none
PubChem 6099
Chemical data
Formula C16H18ClN3S 
Mol. mass 319.85 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Half life ?
Excretion ?
Therapeutic considerations
Pregnancy cat.

?

Legal status

investigational

Routes oral

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Methylthioninium chloride (INN, or methylene blue, proposed trade name Rember) is an investigational drug being developed by the University of Aberdeen and TauRx Therapeutics that has been shown in early clinical trials to be an inhibitor of Tau protein aggregation.[1][2] The drug is of potential interest for the treatment of patients with Alzheimer's disease. Its development appears to be related to claim 7 of 6953794 Patent US Inhibition of Tau-Tau Association via CAMBIA Patent Lens+US #show – espacenetUS . TauRx Therapeutics has suggested that the mechanism by which methylene blue might delay or reverse neurodegeneration in Alzheimer's disease is as an inhibitor of Tau protein aggregation. While methylene blue arguably has an effect on Tau aggregation, it also has an effect on mitochondrial function which is likely to play an important role. In vitro studies suggest that methylene blue might be an effective remedy for both Alzheimer's and Parkinson's disease by enhancing key mitochondrial biochemical pathways. It can disinhibit and increase complex IV, whose inhibition correlates with Alzheimer's disease. [3]

2008 clinical trial results

The University of Aberdeen held a Phase IIB clinical trial[4][5] on 321 people with mild Alzheimer's disease in the United Kingdom and Singapore and found that taking the drug 3 times a day over a period of 50 weeks slows down the development of Alzheimer's disease by about 81%.[6]

The patients were split into four groups: one group taking a dose of 30 mg, another taking a dose of 60 mg, a third taking a dose of 100 mg and the fourth taking a placebo. The 60 mg dosage gave the best results, giving an 81% reduction in mental degression compared to those on the placebo. Only those on the placebo experienced a decline in mental function.

A larger Phase 3 trial is planned for 2009 with an idea to see whether methylene blue can prevent the formation of the disease in the first place.[7] TauRx are also looking into starting a trial of the drug on patients suffering from Parkinson's disease; as methylene blue also has effects on the synuclein fibres in the brain.[8]

Debate began soon after the announcement over the funding of the drug under the UK's National Health Service.[9]

The initial press release from TauRx has been characterized as "very aggressively worded".[10] A lengthy article at the Alzheimer Research Forum provoked further comments.[11]

Phase III trial

The form of the prodrug used in the Phase III clinical trial (NCT01689233) has been changed to TRx0237 (tradename LMTX), which is said to be better tolerated and more conducive to maintaining blinding in the trial. A smaller amount of the same prodrug is given to control subjects as a blinding agent.[12][13]

See also

References

  1. "Experimental Alzheimer's drug shows early promise". Associated Press via azcentral.com. 2008-07-29. Retrieved 2008-07-31. 
  2. Marchione, Marilynn (2008-07-30). "Experimental Alzheimer's drug shows early promise". Associated Press. Retrieved 2008-07-30. 
  3. Atamna H, Nguyen A, Schultz C, Boyle K, Newberry J, Kato H, Ames BN (March 2008). "Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways". FASEB J. 22 (3): 703–712. PMID 17928358. doi:10.1096/fj.07-9610com. 
  4. "Four Alzheimer's Clinical Trials Address a Variety of Treatment Targets - Amyloid, Tau, Synapse Formation" (Press release). Alzheimer's Association. 2008-07-29. 
  5. TauRx Therapeutics, University of Aberdeen (2008-07-29). "New treatment halts progress of Alzheimer's disease". University of Aberdeen. Retrieved 2008-07-31. 
  6. Rose, David (2008-07-30). "New drug Rember brings 'unprecedented' Alzheimer’s treatment advance". The Times. Retrieved 2008-07-30. 
  7. Wilkinson, Emma (2008-07-29). "Alzheimer's drug 'halts' decline". BBC. Retrieved 2008-07-30. 
  8. "TauRx- Alzheimer's disease". TauRx Therapeutics. Retrieved 2008-08-01. 
  9. "Lyndsay Moss: Alzheimer's 'wonder drug' fuels funds debate". The Scotsman. 2008-07-31. 
  10. David Ewing Duncan. "Desperate for a cure". Portfolio.com. 
  11. Gabrielle Strobel (2008-08-07). "Chicago: out of the blue—a tau-based treatment for AD?". Alzheimer Research Forum. Retrieved 2009-01-15. 
  12. "Will Tau Drug Show Its True Colors in Phase 3 Trials?". 
  13. Zelicia Gerald, Waldemar Ockert (January 2013). "Alzheimer's disease market: hope deferred". Nature Reviews Drug Discovery. 12 (19-20). doi:10.1038/nrd3922. 

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