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 |
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Routes of administration | By mouth |
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Pharmacokinetic data | |
Bioavailability | 36% |
Protein binding | 88 – 94% |
Metabolism | Liver (CYP1A2-mediated) |
Elimination half-life | 3 hours[ citation needed ] |
Excretion | Kidney and fecal |
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CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.301.709 |
Chemical and physical data | |
Formula | C12H13N |
Molar mass | 171.243 g·mol−1 |
3D model (JSmol) | |
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Rasagiline (Azilect, Azipron) is an irreversible inhibitor of monoamine oxidase-B [3] used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advanced cases. [4]
The racemic form of the drug was invented by Aspro Nicholas in the early 1970s. Moussa B.H. Youdim identified it as a potential drug for Parkinson's disease, and working with collaborators at Technion – Israel Institute of Technology in Israel and the drug company, Teva Pharmaceuticals, identified the R-isomer as the active form of the drug. [5] Teva brought it to market in partnership with Lundbeck in Europe and Eisai in the US and elsewhere. It was approved in Europe in 2005 and in the US in 2006.
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]
The FDA label contains warnings that rasagiline may cause severe hypertension or hypotension, may make people sleepy, may make motor control worse in some people, may cause hallucinations and psychotic-like behavior, may cause impulse control disorder, may increase the risk of melanoma, and upon withdrawal may cause high fever or confusion. [8]
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]
People who are taking meperidine, tramadol, methadone, propoxyphene, dextromethorphan, St. John’s wort, cyclobenzaprine, or another MAO inhibitor should not take rasagiline. [8]
The FDA drug label carries a warning of the risk of serotonin syndrome when rasagiline is used with antidepressants or with meperidine. [8] However the risk appears to be low, based on a multicenter retrospective study in 1504 people, which looked for serotonin syndrome in people with PD who were treated with rasagiline plus antidepressants, rasagiline without antidepressants, or antidepressants plus Parkinson's drugs other than either rasagiline or selegiline; no cases were identified. [6]
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 MAO inhibitors. [8]
Rasagiline is molecularly a propargyl amine derivative. [9] The form brought to market by Teva and its partners is the mesylate salt, and was designated chemically as: 1H-Inden-1-amine-2,3-dihydro-N-2-propynyl-(1R)-methanesulfonate. [8]
Parkinson's disease is characterized by the death of cells that produce dopamine, a neurotransmitter. An enzyme called monoamine oxidase (MAO) breaks down neurotransmitters. MAO has two forms, MAO-A and MAO-B. MAO-B is generally believed to break down dopamine; however, recent evidence suggests that MAO-A may mostly or entirely be responsible for dopamine metabolism. [10] Rasagiline prevents the breakdown of dopamine by irreversibly binding to MAO-B. Dopamine is therefore more available, somewhat compensating for the diminished quantities made in the brains of people with Parkinson's. [6]
Selegiline was the first selective MAO-B inhibitor. It is partly metabolized to levomethamphetamine (l-methamphetamine), one of the two enantiomers of methamphetamine, in vivo . [11] [12] While these metabolites may contribute to selegiline's ability to inhibit reuptake of the neurotransmitters dopamine and norepinephrine, they have also been associated with orthostatic hypotension and hallucinations in some people. [12] [13] [14] Rasagiline metabolizes into 1(R)-aminoindan which has no amphetamine-like characteristics [15] and has neuroprotective properties in cells and in animal models. [16]
It is selective for MAO type B over type A by a factor of fourteen. [17]
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]
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]
Racemic rasagiline was discovered and patented by Aspro Nicholas in the 1970s as a drug candidate for treatment of hypertension. [22]
Moussa B. H. Youdim, a biochemist, had been involved in developing selegiline as a drug for Parkinsons, in collaboration with Peter Reiderer. He wanted to find a similar compound that would have fewer side effects, and around 1977, at about the same time he moved from London to Haifa to join the faculty of Technion, he noticed that rasagiline could potentially be such a compound. [23] He called that compound, AGN 1135. [24]
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
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]
Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, especially for treatment-resistant depression and atypical depression. They are also used to treat panic disorder, social anxiety disorder, Parkinson's disease, and several other disorders.
Phenelzine, sold under the brand name Nardil, among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class which is primarily used as an antidepressant and anxiolytic. Along with tranylcypromine and isocarboxazid, phenelzine is one of the few non-selective and irreversible MAOIs still in widespread clinical use.
Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.
Tranylcypromine, sold under the brand name Parnate among others, is a monoamine oxidase inhibitor (MAOI). More specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.
Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Emsam, Selgin, among other names, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It is provided in the form of a capsule or tablet taken by mouth or orally disintegrating tablets taken on the tongue for Parkinson's disease and as a patch applied to skin for depression.
Isocarboxazid is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class used as an antidepressant. Along with phenelzine and tranylcypromine, it is one of only three classical MAOIs still available for clinical use in the treatment of psychiatric disorders in the United States, though it is not as commonly employed in comparison to the others.
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate dopamine-related activity. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons that synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes that regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase or DOPA decarboxylase, monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Also, any endogenous or exogenous chemical substance that acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids, which enhance dopamine release indirectly in the reward pathways, and some substituted amphetamines, which enhance dopamine release directly by binding to and inhibiting VMAT2.
Moclobemide, sold under the brand names Amira, Aurorix, Clobemix, Depnil and Manerix among others, is a reversible inhibitor of monoamine oxidase A (RIMA) drug primarily used to treat depression and social anxiety. It is not approved for use in the United States, but is approved in other Western countries such as Canada, the UK and Australia. It is produced by affiliates of the Hoffmann–La Roche pharmaceutical company. Initially, Aurorix was also marketed by Roche in South Africa, but was withdrawn after its patent rights expired and Cipla Medpro's Depnil and Pharma Dynamic's Clorix became available at half the cost.
Levomethamphetamine is the levorotatory (L-enantiomer) form of methamphetamine. Levomethamphetamine is a sympathomimetic vasoconstrictor that is the active ingredient in some over-the-counter (OTC) nasal decongestant inhalers in the United States.
Omigapil is a drug that was developed by Novartis and tested in clinical trials for its ability to help treat Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). The development for PD and ALS have been terminated due to lack of benefit, but Santhera Pharmaceuticals bought the compound for development for the treatment of congenital muscular dystrophy (CMD).
In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutrition. At present, no cure for the disease is known, but medications or surgery can provide relief from the symptoms.
Pargyline (brand name Eutonyl) is an irreversible selective monoamine oxidase (MAO)-B inhibitor drug (IC50 for MAO-A is 0.01152 μmol/L and for MAO-B is 0.00820 μmol/L) It was brought to market in the US and the UK by Abbott in 1963 as an antihypertensive drug branded "Eutonyl". It was one of several MAO inhibitors introduced in the 1960s including nialamide, isocarboxazid, phenelzine, and tranylcypromine. By 2007 the drug was discontinued and as of 2014 there were no generic versions available in the US. In addition to its actions as an MAOI, pargyline has been found to bind with high affinity to the I2 imidazoline receptor (an allosteric site on the MAO enzyme).
Benzofuranylpropylaminopentane is a drug with an unusual monoamine-release potentiating mechanism of action. It can loosely be grouped with the stimulant or antidepressant drug families, but its mechanism of action is quite different.
Monoamine oxidase B, also known as MAOB, is an enzyme that in humans is encoded by the MAOB gene.
Carbidopa/levodopa/entacapone, sold under the brand name Stalevo among others, is a dopaminergic fixed-dose combination medication that contains carbidopa, levodopa, and entacapone for the treatment of Parkinson's disease.
Safinamide is a drug used as an add-on treatment for Parkinson's disease with "off" episodes; it has multiple modes of action, including the inhibition of monoamine oxidase B.
Ladostigil (TV-3,326) is a novel neuroprotective agent being investigated for the treatment of neurodegenerative disorders like Alzheimer's disease, Lewy body disease, and Parkinson's disease. It acts as a reversible acetylcholinesterase and butyrylcholinesterase inhibitor, and an irreversible monoamine oxidase B inhibitor, and combines the mechanisms of action of older drugs like rivastigmine and rasagiline into a single molecule. In addition to its neuroprotective properties, ladostigil enhances the expression of neurotrophic factors like GDNF and BDNF, and may be capable of reversing some of the damage seen in neurodegenerative diseases via the induction of neurogenesis. Ladostigil also has antidepressant effects, and may be useful for treating comorbid depression and anxiety often seen in such diseases as well.
Mofegiline (MDL-72,974) is a selective, irreversible inhibitor of monoamine oxidase B (MAO-B) and semicarbazide-sensitive amine oxidase (SSAO) which was under investigation for the treatment of Parkinson's disease and Alzheimer's disease, but was never marketed.
Moussa B. H. Youdim is an internationally renowned Israeli neuroscientist specializing in neurochemistry and neuropharmacology. He is the discoverer of both monoamine oxidase (MAO) B inhibitors l-deprenyl (Selegiline) and rasagiline (Azilect) as anti-Parkinson drugs which possess neuroprotective activities. He is currently professor emeritus at Technion - Faculty of Medicine and President of Youdim Pharmaceuticals.
Opicapone, sold under the brand name Ongentys, is a medication which is administered together with levodopa in people with Parkinson's disease. Opicapone is a catechol-O-methyltransferase (COMT) inhibitor.