Rasagiline
Clinical data | |
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Trade names | Azilect, Azipron, others |
Other names | VP-1012, N-propargyl-1(R)-aminoindan[1] |
AHFS/Drugs.com | Monograph |
MedlinePlus | a606017 |
License data |
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Pregnancy category |
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Routes of administration | By mouth |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | 36% |
Protein binding | 88 – 94% |
Metabolism | Liver (CYP1A2-mediated) |
Elimination half-life | 3 hours[citation needed] |
Excretion | Kidney and fecal |
Identifiers | |
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JSmol) | |
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Rasagiline (Azilect, Azipron) is an
The racemic form of the drug was invented by Aspro Nicholas in the early 1970s.
Rasagiline is used to treat symptoms of Parkinson's disease both alone and in combination with other drugs. It has shown efficacy in both early and advanced Parkinsons, and appears to be especially useful in dealing with non-motor symptoms like fatigue.[6][7][8]
Rasagiline has not been tested in pregnant women and is Pregnancy Category C in the US.[8]
Side effects
The FDA label contains warnings that rasagiline may cause severe
Side effects when the drug is taken alone include flu-like symptoms, joint pain, depression, stomach upset, headache, dizziness, and insomnia. When taken with L-DOPA, side effects include increased movement problems, accidental injury, sudden drops in blood pressure, joint pain and swelling, dry mouth, rash, abnormal dreams and digestive problems including vomiting, loss of appetite, weight loss, abdominal pain, nausea, constipation.[8] When taken with Parkinson's drugs other than L-DOPA, side effects include peripheral edema, fall, joint pain, cough, and insomnia.[8]
Interactions
People who are taking
The FDA drug label carries a warning of the risk of
There is a risk of psychosis or bizarre behavior if rasagiline is used with dextromethorphan and there is a risk of non-selective MAO inhibition and hypertensive crisis if rasagiline is used with other
Chemistry
Rasagiline is molecularly a
Pharmacology
Mechanism of action
It is selective for MAO type B over type A by a factor of fourteen.[17]
Metabolism
Rasagiline is broken down via CYP1A2,[18] part of the cytochrome P450 metabolic path in the liver. It is contraindicated in patients with hepatic insufficiency and its use should be monitored carefully in patients taking other drugs that alter the normal effectiveness of this metabolic path.[8]
History
Prior to the discovery of rasagiline, a closely related analog called SU-11739 (AGN 1133) was patented.[19] At first, the N-methyl was necessary for the agent to be considered a ring cyclized analog of pargyline with ca. twenty-times the potency.[20] However, the N-methyl compound was a non-selective MAOI.[21]
In 1996 Youdim, in collaboration with scientists from Technion and the US National Institutes of Health, and using compounds developed with Teva Pharmaceuticals, published a paper in which the authors wrote that they were inspired by the racemic nature of deprenyl and the greater activity of one of its stereoisomers, L-deprenyl, which became selegiline, to explore the qualities of the isomers of the Aspro compound, and they found that the R-isomer had almost all the activity; this is the compound that became rasagiline.[24] They called the mesylate salt of the R-isomer TVP-1012 and the hydrochloride salt, TVP-101.[24]
Teva and Technion filed patent applications for this racemically pure compound, methods to make it, and methods to use it to treat Parkinsons and other disorders, and Technion eventually assigned its rights to Teva.[22]
Teva began development of rasagiline, and by 1999 was in Phase III trials, and entered into a partnership with Lundbeck in which Lundbeck agreed to share the costs and obtained the joint right to market the drug in Europe.[25] In 2003 Teva partnered with Eisai, giving Eisai the right to jointly market the drug for Parkinson's in the US, and to co-develop and co-market the drug for Alzheimers and other neurological diseases.[26]
It was approved by the European Medicines Agency for Parkinson's in 2005[16] and in the US in 2006.[9]: 255
Research
Rasagiline was tested for efficacy in people with multiple system atrophy in a large randomized, placebo-controlled, double-blind disease-modification trial; the drug failed.[7]
Teva conducted clinical trials attempting to prove that rasagiline did not just treat symptoms, but was a disease-modifying drug - that it actually prevented the death of the dopaminergic neurons that characterize Parkinson's disease and slowed disease progression. They conducted two clinical trials, called TEMPO and ADAGIO, to try to prove this. The FDA advisory committee rejected their claim in 2011, saying that the clinical trial results did not prove that rasagiline was neuroprotective. The main reason was that in one of the trials, the lower dose was effective at slowing progression, but the higher dose was not, and this made no sense in light of standard dose-response pharmacology.[27][28]
See also
References
- S2CID 29736753.
- ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
- S2CID 195688993.
- S2CID 29707067.
- PMID 17617893.
- ^ S2CID 6823552.
- ^ S2CID 30312372.
- ^ a b c d e f g h i j Azilect Prescribing Information Label last revised May, 2014
- ^ ISBN 9780123820310
- S2CID 235786369.
- PMID 1658311.
- ^ ISBN 978-1609133450.
- S2CID 20471004.
- )
- S2CID 24350277. Archived from the originalon 2012-07-11. Retrieved 2008-08-18.
- ^ PMID 16106586.
- PMID 16366596.
- PMID 18488080.
- ^ US 3201470, Huebner CF, issued 17 August 1965, assigned to CIBA
- PMID 5972038.
- PMID 16402116.
- ^ a b US 3513244, Gittos MW, James JW, Wiggins LF, "Methods of lowering blood pressure in animals by administering secondary and tertiary amines", issued 19 May 1970, assigned to Aspro Nicholas Ltd. 5453446 was the patent at issue in "Teva v Watson" (PDF). Archived from the original (PDF) on 23 April 2016.
- ^ Sielg-Itzkovich J (13 November 2010). "Making armor for the brain". The Jerusalem Post.
- ^ )
- PMID 12090555.
- ^ Eisai Press Release. May 15, 2003
- ^ Sviderski V (19 October 2011). "FDA Advisers Refuse Teva Plea to Expand Azilect Label". Reuters and Haaretz.
- ^ Katz R, et al. "Peripheral and Central Nervous System Advisory Committee Background Package on Azilect" (PDF). FDA. Retrieved December 7, 2011.
External links
- "Rasagiline". Drug Information Portal. U.S. National Library of Medicine.
- "Rasagiline mesylate". Drug Information Portal. U.S. National Library of Medicine.