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Rasagiline, sold under the brand name Azilect among others, is a medication which is used in the treatment of Parkinson's disease. It is used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advanced cases. The drug is taken by mouth.
of rasagiline include insomnia and orthostatic hypotension, among others. Rasagiline acts as an enzyme inhibitor of the enzyme monoamine oxidase (MAO) and hence is a monoamine oxidase inhibitor (MAOI). More specifically, it is a selective inhibitor of monoamine oxidase B (MAO-B). The drug is thought to work by increasing levels of the monoamine neurotransmitter dopamine in the brain. Rasagiline shows pharmacology differences from the related drug selegiline, including having no amphetamine-like , monoamine-releasing activity, or monoaminergic activity enhancer actions, which may result in clinical differences between the medications.
Rasagiline was approved for medical use in the European Union in 2005 and in the United States in 2006. Generic drug of rasagiline are available.
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 United States Food and Drug Administration (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 (1 mg) was effective at slowing progression, but the higher dose (2 mg) was not, contradicting standard dose-response pharmacology.,
MAO-B inhibitors like rasagiline may improve certain non-motor symptoms in Parkinson's disease. These may include depression, sleep disturbances, and pain (particularly related to motor fluctuations), but are unlikely to include cognitive or olfaction dysfunctions. The effects of MAO-B inhibitors like rasagiline on fatigue, autonomic dysfunctions, apathy, and impulse control disorders in people with Parkinson's disease remain unknown. Rasagiline has been reported to significantly improve quality of life in people with Parkinson's disease, but the were trivial to small and may not be clinically meaningful. It showed a large effect size relative to placebo for depression in people with Parkinson's disease. In other studies, rasagiline appeared to reduce fatigue in people with Parkinson's disease. However, its effect sizes for this effect in a large trial were described as trivial.
Side effects when the drug is taken alone include flu-like symptoms, joint pain, depression, stomach upset, headache, dizziness, and insomnia. When taken with levodopa, side effects include increased movement problems, accidental injury, hypotension, joint pain and joint swelling, dry mouth, rash, abnormal dreams and digestive problems including vomiting, loss of appetite, weight loss, abdominal pain, nausea, and constipation. When taken with Parkinson's drugs other than levodopa, side effects include peripheral edema, fall, joint pain, cough, and insomnia.
In a 2013 meta-analysis, none of the most frequently reported side effects of rasagiline occurred significantly more often than with placebo group. It was concluded that rasagiline is tolerability.
Rasagiline has been found to produce orthostatic hypotension as a side effect. Rates of orthostatic hypotension in a selection of different have been 1.2- to 5-fold higher than those of placebo, ranging from 3.1 to 44% with rasagiline and 0.6 to 33% with placebo. Orthostatic hypotension tends to be worst in the first 2months of treatment and then tends to decrease with time. Rasagiline can also cause hypotension while supine position and unrelated to standing. In a clinical trial, the rate of hypotension was 3.2% with rasagiline versus 1.3% with placebo.
Rarely, rasagiline has been reported to induce impulse control disorders,Galvez-Jimenez, N. (2008, July). Rasagiline-and selegiline-induced hypersexuality and other impulse control disorders (ICB) in Parkinson's disease (PD): Report of 3 cases. In MOVEMENT DISORDERS (Vol. 23, No. 9, pp. 1347-1347). COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA: WILEY-BLACKWELL.Senol, M., & Kendirli, M. (2018, October). Rasagiline as Adjunctive Therapy Induced Impulse Control Disorders in Parkinson's Disease. In MOVEMENT DISORDERS (Vol. 33, pp. S832-S832). 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: WILEY. obsessive–compulsive symptoms, hypersexuality, and spontaneous orgasm or ejaculation. Other rare adverse effects associated with rasagiline include pleurothotonus (Pisa syndrome), livedo reticularis, tendon rupture, and hypoglycemia.
Serotonin syndrome has been reported rarely with rasagiline both alone and in combination with selective serotonin reuptake inhibitors (SSRIs) like escitalopram, paroxetine, and sertraline and other MAOIs like linezolid.
A withdrawal syndrome associated with rasagiline has been reported.
There is a risk of psychosis or bizarre behavior if rasagiline is used with dextromethorphan.
There is a risk of non-selective MAO inhibition and hypertensive crisis if rasagiline is used with other MAOIs.
Rasagiline may have a risk of hypertensive crisis in combination with sympathomimetic agents such as , ephedrine, epinephrine, isometheptene, and pseudoephedrine. However, based on widespread clinical experience with the related selective MAO-B inhibitor selegiline, occasional use of over-the-counter sympathomimetics like pseudoephedrine appears to pose minimal risk of hypertensive crisis. In any case, the combination of sympathomimetics with MAO-B inhibitors like rasagiline and selegiline should be undertaken with caution.
Rasagiline acts as a selective and potent irreversible inhibitor of the monoamine oxidases (MAO) monoamine oxidase B (MAO-B) and monoamine oxidase A (MAO-A). It is selective for inhibition of MAO-B over MAO-A, but can also inhibit MAO-A at high doses or concentrations. MAO-B is involved in the metabolism of the monoamine neurotransmitter dopamine in the body and brain. By inhibiting MAO-B, rasagiline is thought to increase dopamine levels. In the case of Parkinson's disease, increased dopamine levels in the striatum are thought to be responsible for rasagiline's therapeutic effectiveness in treating the condition.
Rasagiline inhibits platelet MAO-B activity with single doses by 35% one-hour after 1mg, 55% after 2mg, 79% after 5mg, and 99% after 10mg in healthy young people. With all dose levels, maximum inhibition is maintained for at least 48hours after the dose. With repeated doses, rasagiline reaches greater than 99% platelet MAO-B inhibition after 6days of 2mg/day, 3days of 5mg/day, and 2 days of 10mg/day. Similarly, repeated administration of 0.5, 1, and 2mg/day rasagiline resulted in complete MAO-B inhibition. Clinically relevant inhibition of MAO-B is thought to require 80% inhibition and above. Following the last dose, platelet MAO-B levels remain significantly inhibited for 7days and return to baseline after 2weeks. In people with Parkinson's disease, rasagiline at a dose of 1mg/day achieved near-complete inhibition of platelet MAO-B after 3days of dosing. The recommended dosing schedule of rasagiline in Parkinson's disease (1mg/day) has been described as somewhat questionable and potentially excessive from a pharmacological standpoint.
The half-time for recovery of brain MAO-B following discontinuation of an MAO-B inhibitor (specifically selegiline) has been found to be approximately 40days. Similarly, recovery of brain MAO-B following rasagiline discontinuation was gradual and occurred over 6weeks. The clinical effectiveness of rasagiline in Parkinson's disease has been found to persist during a 6-week washout phase with discontinuation of the medication.
Rasagiline is about 30 to 100times more potent in inhibiting MAO-B than MAO-A in vitro and is about 17 to 65times more potent in inhibiting MAO-B over MAO-A in vivo in rodents. Rasagiline does not importantly potentiate the pressor effects of tyramine challenge in humans, indicating that it is selective for MAO-B inhibition and does not meaningfully inhibit MAO-A. It is expected that at sufficiently high doses rasagiline would eventually become non-selective and additionally inhibit MAO-A in humans. However, it is unknown what dose threshold would be required for this to occur.
Rasagiline is the R(+)-enantiomer of AGN-1135, a racemic mixture of rasagiline (TVP-1012) and the S(–)-enantiomer (TVP-1022). Virtually all of the MAO-inhibiting activity of AGN-1135 lies in the R(+)-enantiomer rasagiline, with this enantiomer having 1,000-fold greater inhibitory potency of MAO-B than the S(–)-enantiomer. In addition, the S(–)-enantiomer is poorly selective for MAO-B over MAO-A. As a result, the purified R(+)-enantiomer rasagiline was the form of the compound advanced for clinical development.
Selegiline was the first selective MAO-B inhibitor. Selegiline and rasagiline have similar selectivity for inhibition of MAO-B over MAO-A. However, rasagiline is 5- to 10-fold more potent than selegiline at inhibiting MAO-B, which results in the former being used at lower doses clinically than the latter (1mg/day versus 5–10mg/day, respectively). In addition, selegiline is drug metabolism into levomethamphetamine and levoamphetamine. These metabolites induce the release of norepinephrine and dopamine, have sympathomimetic and psychostimulant effects, and may contribute to the effects and of selegiline. In contrast to selegiline, rasagiline does not convert into with amphetamine-like effects. The amphetamine metabolites of selegiline may contribute to significant clinical differences between selegiline and rasagiline.
Rasagiline metabolizes into ( R)-1-aminoindan which has no amphetamine-like effects and shows neuroprotective properties in cells and in animal models.
Selective MAO-B inhibitors including rasagiline and selegiline have been found to increase dopamine levels in the striatum in rats in vivo. It has been theorized that this might be due to strong inhibition of the metabolism of β-phenylethylamine, which is an endogenous MAO-B substrate that has monoaminergic activity enhancer and norepinephrine–dopamine releasing agent actions. β-Phenylethylamine has been described as "endogenous amphetamine" and its brain levels are dramatically increased (10- to 30-fold) by MAO-B inhibitors like selegiline. Elevation of β-phenylethylamine may be involved in the effects of MAO-B inhibitors in the treatment of Parkinson's disease.
In 2021, it was discovered that MAO-A is solely or almost entirely responsible for striatal dopamine catabolism in the rodent brain and that MAO-B is not importantly involved. (2025). 9780323998550, Elsevier. ISBN 9780323998550 In contrast, MAO-B appears to mediate tonic γ-aminobutyric acid (GABA) synthesis from putrescine in the striatum, a minor and alternative metabolic pathway of GABA synthesis, and this synthesized GABA in turn inhibits dopaminergic neurons in this brain area. (2025). 9780123646170 ISBN 9780123646170 MAO-B specifically mediates the transformations of putrescine into γ-aminobutyraldehyde (GABAL or GABA aldehyde) and N-acetylputrescine into N-acetyl-γ-aminobutyraldehyde ( N-acetyl-GABAL or N-acetyl-GABA aldehyde), metabolic products that can then be converted into GABA via aldehyde dehydrogenase (ALDH) (and an unknown deacetylase enzyme in the case of N-acetyl-GABAL). These findings may warrant a rethinking of the pharmacological actions of MAO-B inhibitors like selegiline and rasagiline in the treatment of Parkinson's disease.
The major metabolite of rasagiline, ( R)-1-aminoindan, is either devoid of MAO inhibition or shows only weak inhibition of MAO-B. It also has no amphetamine-like activity. However, 1-aminoindan is not lacking in pharmacological activity. Like rasagiline, 1-aminoindan shows neuroprotective activity in some experimental models. In addition, 1-aminoindan has been found to enhance striatum dopaminergic neurotransmission and improve motor function independent of MAO inhibition in of Parkinson's disease.
2-Aminoindan, a closely related positional isomer of 1-aminoindan, is known to inhibit the reuptake and induce the release of dopamine and norepinephrine and to produce psychostimulant-like effects in rodents, albeit with lower potency than amphetamine, but rasagiline does not metabolize into this compound. (2025). 9780124158160, Elsevier. ISBN 9780124158160 1-Aminoindan has been found to inhibit the reuptake of norepinephrine 28-fold less potently than 2-aminoindan and to inhibit the reuptake of dopamine 300-fold less potently than 2-aminoindan, with values for dopamine reuptake inhibition in one study of 0.4μM for amphetamine, 3.3μM for 2-aminoindan, and 1mM for 1-aminoindan. (1998). 9783211830376 ISBN 9783211830376 In contrast to 2-aminoindan, which hyperlocomotion in rodents (+49%), 1-aminoindan hypoactivity (–69%). On the other hand, 1-aminoindan has been found to enhance the psychostimulant-like effects of amphetamine in rodents.
Whereas selegiline is a catecholaminergic activity enhancer, which may be mediated by agonist of the TAAR1, rasagiline does not possess this action. Instead, rasagiline actually antagonizes selegiline's effects as a catecholaminergic activity enhancer, which may be mediated by TAAR1 antagonism.
Rasagiline has been reported to directly bind to and enzyme inhibitor glyceraldehyde-3-phosphate dehydrogenase (GAPDH). This might play a modulating role in its clinical effectiveness for Parkinson's disease. Selegiline also binds to and inhibits GAPDH.
Rasagiline has been found to bind reversibly to α-synuclein, a major protein involved in the pathophysiology of Parkinson's disease, and this action might be neuroprotective.
At steady-state, the time to peak levels of rasagiline's major metabolite ( R)-1-aminoindan is 2.1hours, its peak levels are 2.6ng/mL, and its area-under-the-curve levels are 10.1ng/h/mL.
Taking rasagiline with food (as a high-fat meal) increases peak levels by approximately 60% and area-under-the-curve levels by approximately 20%, whereas time to peak levels is unchanged. Because exposure to rasagiline is not substantially modified, rasagiline can be taken with or without food.
The plasma protein binding of rasagiline is 60 to 70% or 88 to 94% depending on the source. In the case of the latter range, 61 to 63% of binding was to albumin.
Use of rasagiline should be monitored carefully in people taking other drugs that enzyme inhibitor or enzyme inducer CYP1A2. Variants in CYP1A2 have been found to modify exposure to rasagiline in some studies but not others. Tobacco smoking, a known inhibitor of CYP1A2, did not modify rasagiline exposure. may be more important in influencing the pharmacokinetics of rasagiline than metabolizing enzymes.
Exposure to rasagiline is increased in people with hepatic impairment. In those with mild hepatic impairment, peak levels of rasagiline are increased by 38% and area-under-the-curve levels by 80%, whereas in people with moderate hepatic impairment, peak levels are increased by 83% and area-under-the-curve levels by 568%. As a result, the dosage of rasagiline should be halved to 0.5mg/day in people with mild hepatic impairment and rasagiline is considered to be contraindication in people with moderate to severe hepatic impairment.
The elimination half-life of rasagiline is 1.34hours. At steady-state, its half-life is 3hours. As rasagiline acts as an irreversible inhibitor of MAO-B, its actions and duration of effect are not dependent on its half-life or sustained concentrations in the body.
The oral clearance of rasagiline is 94.3L/h and is similar to normal liver blood flow (90L/h). This indicates that non-hepatic mechanisms are not significantly involved in the elimination of rasagiline.
Moderate renal impairment did not modify exposure to rasagiline, whereas that of ( R)-1-aminoindan was increased by 1.5-fold. Since ( R)-1-aminoindan is not an MAO inhibitor, mild to moderate renal impairment does not require dosage adjustment of rasagiline. No data are available in the case of severe or end-stage renal impairment.
Both the hydrochloride and mesylate salts of rasagiline were studied and were found to have similar pharmacology, pharmacokinetic, and toxicology profiles. However, the mesylate salt of rasagiline was ultimately selected for its use as a pharmaceutical drug due to favorable chemical stability.
The propargyl moiety is essential in the pharmacodynamics of rasagiline. It binds covalent bond and irreversibly with the flavin adenine dinucleotide (FAD) moiety of the MAO enzyme. The selectivity of rasagiline for MAO-B over MAO-A depends on the maintenance of a distance of no more than two between the aromatic ring and the N-propargyl group. The propargyl group of rasagiline is also essential for its neuroprotective and apoptosis actions, which are independent of its MAO inhibition.
Rasagiline is closely structurally related to selegiline ( R(–)- N-propargylmethamphetamine). However, in contrast to selegiline, rasagiline is not a substituted amphetamine and is instead an 1-aminoindan derivative. The chemical structures of the amphetamines and are very similar. However, whereas selegiline drug metabolism into levomethamphetamine and levoamphetamine and can produce amphetamine-like effects, rasagiline does not do so. Instead, it metabolizes into ( R)-1-aminoindan (TVP-136) and has no such actions.
SU-11739 (AGN-1133; N-methyl- N-propargyl-1-aminoindan), the N-methyl group analogue of rasagiline, is also an MAO-B-preferring MAOI. However, it is less selective for inhibition of MAO-B over MAO-A than rasagiline. Another structurally related selective MAO-B inhibitor, ladostigil ( N-propargyl-(3 R)-aminoindan-5-yl- N-propylcarbamate; TV-3326), was developed from structural modification of rasagiline and additionally acts as an acetylcholinesterase inhibitor due to its carbamate moiety.
Rasagiline and its metabolite ( R)-1-aminoindan are structurally related to 2-aminoindan and derivatives like MDAI (MDAI), MDMAI (MDMAI), and 5-iodo-2-aminoindane (5-IAI).
Prior to the discovery of rasagiline, a closely related analogue called SU-11739 (AGN-1133; J-508; N-methyl- N-propargyl-1-aminoindan) was in 1965. At first, the N-methyl was necessary for the agent to be considered a ring cyclized analogue of pargyline with about 20times the potency. However, the N-methyl compound was a non-selective MAOI. In addition, SU-11739 has been reported to have strong catecholamine-releasing actions.
Racemic rasagiline was discovered and patented by Aspro Nicholas in the 1970s as a drug candidate for treatment of hypertension. 5453446 was the patent at issue in
Moussa B. H. Youdim was involved in developing selegiline as a drug for Parkinson's, in collaboration with Peter Reiderer. He called the compound AGN 1135. 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. (1996). 9783211828915 ISBN 9783211828915 They called the mesylate salt of the R-isomer TVP-1012 and the hydrochloride salt, TVP-101.
Teva and Technion filed patent applications for this racemically pure compound, methods to make it, and methods to use it to treat Parkinson's disease and other disorders, and Technion eventually assigned its rights to Teva.
Teva began drug 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 the European Union. 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 Alzheimer's disease and other neurological diseases.
It was approved by the European Medicines Agency for Parkinson's in 2005 and in the United States in 2006. (2014). 9780123820310, Academic Press. ISBN 9780123820310
Following its approval, rasagiline was described by some authors as a "me-too drug" that offered nothing new in terms of effectiveness and tolerability compared to selegiline. However, others have contended that rasagiline shows significant differences from and improvements over selegiline, like its lack of amphetamine and associated monoamine releasing agent effects, which may improve tolerability and drug safety. Conversely, others have maintained that rasagiline may be less efficacious than selegiline due to its lack of catecholaminergic activity enhancer actions.
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.
Rasagiline has been reported to improve symptoms in people with freezing gait.
Rasagiline has been studied in the treatment of amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease).
Rasagiline has not been studied in the treatment of psychostimulant addiction as of 2015.
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