Jump to content

Rasagiline

From Wikipedia, the free encyclopedia

Rasagiline
Clinical data
Trade namesAzilect, others
Other namesTVP-1012; TVP1012; R(+)-AGN-1135; N-Propargyl-(R)-1-aminoindan; N-Propargyl-1(R)-aminoindan; (R)-PAI
AHFS/Drugs.comMonograph
MedlinePlusa606017
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth[1][2]
Drug classMonoamine oxidase inhibitor; Antiparkinsonian
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability36%[2]
Protein binding88–94%[2]
MetabolismLiver (CYP1A2)[2]
Metabolites• (R)-1-Aminoindan[2]
• 3-OH-PAI[2]
• 3-OH-AI[2]
Elimination half-life3 hours[2]
ExcretionUrine: 62%[2]
Feces: 7%[2]
Identifiers
  • (R)-N-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.301.709 Edit this at Wikidata
Chemical and physical data
FormulaC12H13N
Molar mass171.243 g·mol−1
3D model (JSmol)
  • C#CCN[C@H]2c1ccccc1CC2
  • InChI=1S/C12H13N/c1-2-9-13-12-8-7-10-5-3-4-6-11(10)12/h1,3-6,12-13H,7-9H2/t12-/m1/s1 checkY
  • Key:RUOKEQAAGRXIBM-GFCCVEGCSA-N checkY
  (verify)

Rasagiline, sold under the brand name Azilect among others, is a medication which is used in the treatment of Parkinson's disease.[2][6] It is used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advanced cases.[7] The drug is taken by mouth.[2]

Side effects of rasagiline include insomnia and orthostatic hypotension, among others.[2] Rasagiline acts as an inhibitor of the enzyme monoamine oxidase (MAO) and hence is a monoamine oxidase inhibitor (MAOI).[2] More specifically, it is a selective inhibitor of monoamine oxidase B (MAO-B).[2] The drug is thought to work by increasing levels of the monoamine neurotransmitter dopamine in the brain.[2] Rasagiline shows pharmacological differences from the related drug selegiline, including having no amphetamine-like metabolites, monoamine-releasing activity, or monoaminergic activity enhancer actions, which may result in clinical differences between the medications.[8][9]

Rasagiline was approved for medical use in the European Union in 2005[10] and in the United States in 2006.[2][11] Generic versions of rasagiline are available.[12][13][14]

Medical uses

[edit]

Parkinson's disease

[edit]

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 Parkinson's, and appears to be especially useful in dealing with non-motor symptoms like fatigue.[15][16][2]

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 was effective at slowing progression, but the higher dose was not, and this made no sense in light of standard dose-response pharmacology.[17][18]

MAO-B inhibitors like rasagiline may improve certain non-motor symptoms in Parkinson's disease.[19] These may include depression, sleep disturbances, and pain (particularly related to motor fluctuations), but are unlikely to include cognitive or olfactory dysfunctions.[19] 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.[19] Rasagiline has been reported to significantly improve quality of life in people with Parkinson's disease, but the effect sizes were trivial to small and may not be clinically meaningful.[19] It showed a large effect size relative to placebo for depression in people with Parkinson's disease.[19] In other studies, rasagiline appeared to reduce fatigue in people with Parkinson's disease.[19][20][21][22] However, its effect sizes for this effect in a large trial were described as trivial.[19]

Available forms

[edit]

Rasagiline is available in the form of 0.5 and 1 mg oral tablets.[2][12]

Contraindications

[edit]

Rasagiline has not been tested in pregnant women.[2]

Side effects

[edit]

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 disorders, may increase the risk of melanoma, and upon withdrawal, may cause high fever or confusion.[2]

Side effects when the drug is taken alone include flu-like symptoms, joint pain, depression, stomach upset, headache, dizziness, and insomnia.[2] When taken with levodopa, 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, and constipation.[2] When taken with Parkinson's drugs other than levodopa, side effects include peripheral edema, fall, joint pain, cough, and insomnia.[2]

In a 2013 meta-analysis, none of the most frequently reported side effects of rasagiline occurred significantly more often than with placebo.[23] It was concluded that rasagiline is well-tolerated.[23]

Rasagiline has been found to produce orthostatic hypotension as a side effect.[2] Rates of orthostatic hypotension in a selection of different clinical trials 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.[2][note 1] Orthostatic hypotension tends to be worst in the first 2 months of treatment and then tends to decrease with time.[2] Rasagiline can also cause hypotension while supine and unrelated to standing.[2] In a clinical trial, the rate of hypotension was 3.2% with rasagiline versus 1.3% with placebo.[2]

Rarely, rasagiline has been reported to induce impulse control disorders,[24][25][26][27][28] obsessive–compulsive symptoms,[29] hypersexuality,[30][31][32][27] and spontaneous orgasm or ejaculation.[33][34][35][36] Other rare adverse effects associated with rasagiline include pleurothotonus (Pisa syndrome),[37][38][39] livedo reticularis,[40] tendon rupture,[41] and hypoglycemia.[42]

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.[43][44][45][46][47][48][49][50]

A withdrawal syndrome associated with rasagiline has been reported.[51]

Overdose

[edit]

Rasagiline has been studied at single doses of up to 20 mg and at repeated doses of up to 10 mg/day and was well-tolerated at these doses.[52][53][54] However, in a dose-escalation study with concomitant levodopa therapy, a dosage of 10 mg/day rasagiline was associated with cardiovascular side effects including hypertension and orthostatic hypotension in some people.[2] The symptoms of rasagiline overdose may be similar to the case of non-selective MAOIs.[2] Onset of symptoms may be delayed by 12 hours and may not peak for 24 hours.[2] A variety of different symptoms may occur and the central nervous system and cardiovascular system are prominently involved.[2] Death may result and immediate hospitalization is warranted.[2] Serotonin syndrome has occurred with rasagiline overdose and body temperature should be monitored closely.[2] There is no specific antidote for overdose and treatment is supportive and based on symptoms.[2]

Interactions

[edit]

Rasagiline is contraindicated with known serotonergic agents like selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), triazolopyridines or serotonin antagonists and reuptake inhibitors (SARIs) like trazodone, and other monoamine oxidase inhibitors (MAOIs), as well as meperidine (pethidine), tramadol, methadone, propoxyphene, dextromethorphan, St. John's wort, and cyclobenzaprine, due to potential risk of serotonin syndrome.[1][2] However, the risk appears to be low, based on a large study of 1,504 people which looked for serotonin syndrome in people with Parkinson's disease who were treated with rasagiline plus antidepressants, rasagiline without antidepressants, or antidepressants plus Parkinson's drugs other than either rasagiline or selegiline, and in which no cases were identified.[15]

There is a risk of psychosis or bizarre behavior if rasagiline is used with dextromethorphan.[2]

There is a risk of non-selective MAO inhibition and hypertensive crisis if rasagiline is used with other MAOIs.[2]

Rasagiline may have a risk of hypertensive crisis in combination with sympathomimetic agents such as amphetamines, ephedrine, epinephrine, isometheptene, and pseudoephedrine.[1] However, based on widespread clinical experience with the related select I've MAO-B inhibitor selegiline, occasional use of over-the-counter sympathomimetics like pseudoephedrine appears to pose minimal risk of hypertensive crisis.[1] In any case, the combination of sympathomimetics with MAO-B inhibitors like rasagiline and selegiline should be undertaken with caution.[1]


Rasagiline is contraindicated with known serotonergic agents like selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), triazolopyridines or serotonin antagonists and reuptake inhibitors (SARIs) like trazodone, and other monoamine oxidase inhibitors (MAOIs), as well as meperidine (pethidine), tramadol, methadone, propoxyphene, dextromethorphan, St. John's wort, and cyclobenzaprine, due to potential risk of serotonin syndrome.[1][2] However, the risk appears to be low, based on a large study of 1,504 people which looked for serotonin syndrome in people with Parkinson's disease who were treated with rasagiline plus antidepressants, rasagiline without antidepressants, or antidepressants plus Parkinson's drugs other than either rasagiline or selegiline, and in which no cases were identified.[15]

There is a risk of psychosis or bizarre behavior if rasagiline is used with dextromethorphan.[2]

There is a risk of non-selective MAO inhibition and hypertensive crisis if rasagiline is used with other MAOIs.[2]

Rasagiline may have a risk of hypertensive crisis in combination with sympathomimetic agents such as amphetamines, ephedrine, epinephrine, isometheptene, and pseudoephedrine.[1] However, based on widespread clinical experience with the related select I've MAO-B inhibitor selegiline, occasional use of over-the-counter sympathomimetics like pseudoephedrine appears to pose minimal risk of hypertensive crisis.[1] In any case, the combination of sympathomimetics with MAO-B inhibitors like rasagiline and selegiline should be undertaken with caution.[1]

Pharmacology

[edit]

Pharmacodynamics

[edit]

Monoamine oxidase inhibitor

[edit]

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 involved in the metabolism of dopamine. 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 disease.[15]

Rasagiline acts as a selective and potent irreversible inhibitor of the monoamine oxidases (MAO) enzymes monoamine oxidase B (MAO-B) and monoamine oxidase A (MAO-A).[2] It is selective for inhibition of MAO-B over MAO-A, but can also inhibit MAO-A at high doses or concentrations.[1][2] MAO-B is involved in the metabolism of the monoamine neurotransmitter dopamine in the body and brain.[1][2] By inhibiting MAO-B, rasagiline is thought to increase dopamine levels.[1][2] 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.[1][2]

Rasagiline inhibits platelet MAO-B activity with single doses by 35% one-hour after 1 mg, 55% after 2 mg, 79% after 5 mg, and 99% after 10 mg in healthy young people.[1][55][2][54] With all dose levels, maximum inhibition is maintained for at least 48 hours after the dose.[1][54] With repeated doses, rasagiline reaches greater than 99% platelet MAO-B inhibition after 6 days of 2 mg/day, 3 days of 5 mg/day, and 2 days of 10 mg/day.[1][55][54] Similarly, repeated administration of 0.5, 1, and 2 mg/day rasagiline resulted in complete MAO-B inhibition.[2] Clinically relevant inhibition of MAO-B is thought to require 80% inhibition and above.[1] Following the last dose, platelet MAO-B levels remain significantly inhibited for 7 days and return to baseline after 2 weeks.[1][54] In people with Parkinson's disease, rasagiline at a dose of 1 mg/day achieved near-complete inhibition of platelet MAO-B after 3 days of dosing.[1] The recommended dosing schedule of rasagiline in Parkinson's disease (1 mg/day) has been described as somewhat questionable and potentially excessive from a pharmacological standpoint.[56]

The half-time for recovery of brain MAO-B following discontinuation of an MAO-B inhibitor (specifically selegiline) has been found to be approximately 40 days.[1] Similarly, recovery of brain MAO-B following rasagiline discontinuation was gradual and occurred over 6 weeks.[57][58] 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.[1]

Rasagiline is about 30 to 100 times more potent in inhibiting MAO-B than MAO-A in vitro and is about 17 to 65 times more potent in inhibiting MAO-B over MAO-A in vivo in rodents.[1] 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.[1][2] It is expected that at sufficiently high doses rasagiline would eventually become non-selective and additionally inhibit MAO-A in humans.[1][2] However, it is unknown what dose threshold would be required for this to occur.[1]

Rasagiline is the R(+)-enantiomer of AGN-1135, a racemic mixture of rasagiline (TVP-1012) and the S(–)-enantiomer (TVP-1022).[55][1] 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.[55][1] In addition, the S(–)-enantiomer is poorly selective for MAO-B over MAO-A.[1] As a result, the purified R(+)-enantiomer rasagiline was the form of the compound advanced for clinical development.[55][1]

Selegiline was the first selective MAO-B inhibitor.[59] Selegiline and rasagiline have similar selectivity for inhibition of MAO-B over MAO-A.[8][60] 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 (1 mg/day versus 5–10 mg/day, respectively).[8][1][60] In addition, selegiline is metabolized into levomethamphetamine and levoamphetamine.[61] These metabolites induce the release of norepinephrine and dopamine, have sympathomimetic and psychostimulant effects, and may contribute to the effects and side effects of selegiline.[8][62] In contrast to selegiline, rasagiline does not convert into metabolites with amphetamine-like effects.[1] The amphetamine metabolites of selegiline may contribute to significant clinical differences between selegiline and rasagiline.[8]

Rasagiline metabolizes into (R)-1-aminoindan which has no amphetamine-like effects and shows neuroprotective properties in cells and in animal models.[10]

Selective MAO-B inhibitors including rasagiline and selegiline have been found to increase dopamine levels in the striatum in rats in vivo.[63][64][65] 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.[63][64][65][66][67] 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.[68][69][67] Elevation of β-phenylethylamine may be involved in the effects of MAO-B inhibitors in the treatment of Parkinson's disease.[63][64][65][67]

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.[70][71][72] 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.[70][71][72][73] 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).[73][74][71][72] 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.[70][71][72]

Other actions

[edit]

Rasagiline is selective for inhibition of MAOs over interactions with other proteins, including α-adrenergic receptors, β-adrenergic receptors, muscarinic acetylcholine receptors, and other targets.[1][60]

The major metabolite of rasagiline, (R)-1-aminoindan, is either devoid of MAO inhibition or shows only weak inhibition of MAO-B.[1][56] It also has no amphetamine-like activity.[1][56] However, 1-aminoindan is not lacking in pharmacological activity.[1][56] Like rasagiline, 1-aminoindan shows neuroprotective activity in some experimental models.[1][56] In addition, 1-aminoindan has been found to enhance striatal dopaminergic neurotransmission and improve motor function independent of MAO inhibition in animal models of Parkinson's disease.[56]

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.[75][76] 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 IC50Tooltip half maximal inhibitory concentration values for dopamine reuptake inhibition in one study of 0.4 μM for amphetamine, 3.3 μM for 2-aminoindan, and 1 mM for 1-aminoindan.[76][77][78] In contrast to 2-aminoindan, which increased locomotor activity in rodents (+49%), 1-aminoindan suppressed locomotor activity (–69%).[76] On the other hand, 1-aminoindan has been found to enhance the psychostimulant-like effects of amphetamine in rodents.[77]

Whereas selegiline is a catecholaminergic activity enhancer, which may be mediated by agonism of the TAAR1, rasagiline does not possess this action.[66][79][9][80] Instead, rasagiline actually antagonizes selegiline's effects as a catecholaminergic activity enhancer, which may be mediated by TAAR1 antagonism.[9]

Rasagiline has been reported to directly bind to and inhibit glyceraldehyde-3-phosphate dehydrogenase (GAPDH).[8][81] This might play a modulating role in its clinical effectiveness for Parkinson's disease.[8][81] Selegiline also binds to and inhibits GAPDH.[8]

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.[82][83][84]

Pharmacokinetics

[edit]

Absorption

[edit]

Rasagiline is rapidly absorbed from the gastrointestinal tract with oral administration and has approximately 36% absolute bioavailability.[1][2] The peak and area-under-the-curve levels of rasagiline are linear and dose-proportional over a dose range of 0.5 to 10 mg.[1][2] The time to peak levels of rasagiline is 0.5 to 0.7 hours and steady-state peak levels are on average 8.5 ng/mL.[1][2]

At steady-state, the time to peak levels of rasagiline's major metabolite (R)-1-aminoindan is 2.1 hours, its peak levels are 2.6 ng/mL, and its area-under-the-curve levels are 10.1 ng/h/mL.[1]

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.[1][2] Because exposure to rasagiline is not substantially modified, rasagiline can be taken with or without food.[1][2]

Distribution

[edit]

The mean volume of distribution of rasagiline is 87 L or 182 to 243 L depending on the source.[1][2] It readily crosses the blood–brain barrier and enters the central nervous system.[1]

The plasma protein binding of rasagiline is 60 to 70% or 88 to 94% depending on the source.[1][2] In the case of the latter range, 61 to 63% of binding was to albumin.[2]

Metabolism

[edit]

Rasagiline is extensively metabolized in the liver.[1][2] It is metabolized primarily by hepatic N-dealkylation via the cytochrome P450 enzyme CYP1A2 which forms the major metabolite (R)-1-aminoindan.[1][2][53] It is also metabolized by hydroxylation via cytochrome P450 enzymes to form 3-hydroxy-N-propargyl-1-aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan (3-OH-AI).[2] Rasagiline and its metabolites also undergo conjugation via glucuronidation.[2]

Use of rasagiline should be monitored carefully in people taking other drugs that inhibit or induce CYP1A2.[2][85] Variants in CYP1A2 have been found to modify exposure to rasagiline in some studies but not others.[85][86] Tobacco smoking, a known inhibitor of CYP1A2, did not modify rasagiline exposure.[85] Drug transporters may be more important in influencing the pharmacokinetics of rasagiline than metabolizing enzymes.[86]

Exposure to rasagiline is increased in people with hepatic impairment.[1][2] 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%.[1][2] As a result, the dosage of rasagiline should be halved to 0.5 mg/day in people with mild hepatic impairment and rasagiline is considered to be contraindicated in people with moderate to severe hepatic impairment.[2]

Elimination

[edit]

Rasagiline is eliminated primarily in urine (62%) and to a much lesser extent in feces (7%).[2] Rasagiline is excreted unchanged in urine at an amount of less than 1%.[1] Hence, it is almost completely metabolized prior to excretion.[2]

The elimination half-life of rasagiline is 1.34 hours.[1] At steady-state, its half-life is 3 hours.[2] 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.[1][2]

The oral clearance of rasagiline is 94.3 L/h and is similar to normal liver blood flow (90 L/h).[1] This indicates that non-hepatic mechanisms are not significantly involved in the elimination of rasagiline.[1]

Moderate renal impairment did not modify exposure to rasagiline, whereas that of (R)-1-aminoindan was increased by 1.5-fold.[2] Since (R)-1-aminoindan is not an MAO inhibitor, mild to moderate renal impairment does not require dosage adjustment of rasagiline.[2] No data are available in the case of severe or end-stage renal impairment.[2]

Chemistry

[edit]

Rasagiline, also known as (R)-N-propargyl-1-aminoindan and by its former developmental code name TVP-1012, is a secondary cyclic benzylamine propargylamine.[1][55] It is the R(+)-enantiomer of the chiral racemic compound AGN-1135 (N-propargyl-1-aminoindan), whereas the S(–)-enantiomer is TVP-1022 ((S)-N-propargyl-1-aminoindan).[1][55] Rasagiline is a potent and selective MAO-B inhibitor, whereas TVP-1022 is a very weak and poorly selective MAO inhibitor.[1][55]

Both the hydrochloride and mesylate salts of rasagiline were studied and were found to have similar pharmacological, pharmacokinetic, and toxicological profiles.[1] However, the mesylate salt of rasagiline was ultimately selected for its use as a pharmaceutical drug due to favorable chemical stability.[1][2]

The propargyl moiety is essential in the pharmacodynamics of rasagiline.[1] It binds covalently and irreversibly with the flavin adenine dinucleotide (FAD) moiety of the MAO enzyme.[1] The selectivity of rasagiline for MAO-B over MAO-A depends on the maintenance of a distance of no more than two carbon atoms between the aromatic ring and the N-propargyl group.[1] The propargyl group of rasagiline is also essential for its neuroprotective and antiapoptopic actions, which are independent of its MAO inhibition.[1]

Rasagiline is closely structurally related to selegiline (R(–)-N-propargylmethamphetamine).[1] However, in contrast to selegiline, rasagiline is not a substituted amphetamine and is instead an 1-aminoindan derivative.[1] The chemical structures of the amphetamines and aminoindans are very similar.[87] However, whereas selegiline metabolizes into levomethamphetamine and levoamphetamine and can produce amphetamine-like effects, rasagiline does not do so.[1][75] Instead, it metabolizes into (R)-1-aminoindan (TVP-136) and has no such actions.[1][75][88][89]

SU-11739 (AGN-1133; N-methyl-N-propargyl-1-aminoindan), the N-methylated analogue of rasagiline, is also an MAO-B-preferring MAOI.[55][90][91] However, it is less selective for inhibition of MAO-B over MAO-A than rasagiline.[90][91] Another structurally related selective MAO-B inhibitor, ladostigil (N-propargyl-(3R)-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.[1]

Rasagiline and its metabolite (R)-1-aminoindan are structurally related to 2-aminoindan and derivatives like 5,6-methylenedioxy-2-aminoindane (MDAI), 5,6-methylenedioxy-N-methyl-2-aminoindane (MDMAI), and 5-iodo-2-aminoindane (5-IAI).[75]

History

[edit]

AGN-1135, 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.[92] Teva brought it to market in partnership with Lundbeck in the European Union and Eisai in the United States and elsewhere.

Prior to the discovery of rasagiline, a closely related analogue called SU-11739 (AGN-1133; J-508; N-methyl-N-propargyl-1-aminoindan) was patented in 1965.[93] At first, the N-methyl was necessary for the agent to be considered a ring cyclized analogue of pargyline with about 20 times the potency.[94] However, the N-methyl compound was a non-selective MAOI.[91] In addition, SU-11739 has been reported to have strong catecholamine-releasing actions.[95]

Racemic rasagiline was discovered and patented by Aspro Nicholas in the 1970s as a drug candidate for treatment of hypertension.[96]

Moussa B. H. Youdim was involved in developing selegiline as a drug for Parkinson's, in collaboration with Peter Reiderer.[97] He called the compound AGN 1135.[98] 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.[98] They called the mesylate salt of the R-isomer TVP-1012 and the hydrochloride salt, TVP-101.[98]

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.[96]

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 the European Union.[99] 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.[100]

It was approved by the European Medicines Agency for Parkinson's in 2005[10] and in the United States in 2006.[11]

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.[101][102] However, others have contended that rasagiline shows significant differences from and improvements over selegiline, like its lack of amphetamine metabolites and associated monoamine releasing agent effects, which may improve tolerability and safety.[101][8] Conversely, others have maintained that rasagiline may be less efficacious than selegiline due to its lack of catecholaminergic activity enhancer actions.[66][9][103][104]

Society and culture

[edit]

Names

[edit]

Rasagiline is the generic name of the drug and its INNTooltip International Nonproprietary Name and USANTooltip United States Adopted Name.[105][106] It is also known by its former developmental code name TVP-1012.[55] Rasagiline is marketed under the brand name Azilect, among others.[2][12]

Generic forms

[edit]

Lower-cost generic versions of rasagiline are available.[12][13][14]

Research

[edit]

Neurodegenerative diseases

[edit]

Rasagiline was under development for the treatment of Alzheimer's disease.[107] However, development was discontinued.[107]

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.[16][108]

Rasagiline has been reported to improve symptoms in people with freezing gait.[109][110]

Rasagiline has been studied in the treatment of amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease).[111][112][113][114]

Psychiatric disorders

[edit]

Rasagiline has been described as an emerging potential antidepressant.[115] MAO-B inhibitors have been found to reduce depressive symptoms in people with Parkinson's disease with a small effect size.[116][19] However, rasagiline does not appear to have been studied in the treatment of depression in people without Parkinson's disease[117] and it has not been developed nor approved for the treatment depression.[107] In an animal study, selegiline was effective in models of antidepressant-like activity, whereas rasagiline was ineffective.[118][119] The antidepressant effects of selegiline in animals appear to be independent of monoamine oxidase inhibition and may be related to its catecholaminergic activity enhancer (CAE) activity, which rasagiline lacks.[118][119]

Rasagiline has not been studied in the treatment of psychostimulant addiction as of 2015.[120]

Other conditions

[edit]

Rasagiline has been reported to improve restless legs syndrome (RLS).[121][122][123]

Notes

[edit]
  1. ^ Rates of orthostatic hypotension in a selection of individual clinical trials presented in the rasagiline FDA label were: 13% vs. 9% with placebo, 40–44% vs. 33% with placebo, 7% vs. 3% with placebo, 9% vs. 6% with placebo, and 3.1% vs. 0.6% with placebo.[2] In another trial, the rate of hypotension (not specifically orthostatic) was 3.2% vs. 1.3% with placebo.[2]

References

[edit]
  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn bo bp Chen JJ, Swope DM (August 2005). "Clinical pharmacology of rasagiline: a novel, second-generation propargylamine for the treatment of Parkinson disease". Journal of Clinical Pharmacology. 45 (8): 878–894. doi:10.1177/0091270005277935. PMID 16027398. S2CID 24350277. Archived from the original on 11 July 2012.
  2. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn bo bp bq br bs bt bu bv bw bx by bz ca "Azilect- rasagiline mesylate tablet". DailyMed. 30 June 2020. Retrieved 23 July 2024.
  3. ^ https://www.tga.gov.au/resources/prescription-medicines-registrations/rasagiline-jamp-rasagiline-gxmed-aa-med-pty-ltd
  4. ^ Anvisa (31 March 2023). "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 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  5. ^ "Azilect EPAR". European Medicines Agency. 21 February 2005. Retrieved 23 July 2024.
  6. ^ Oldfield V, Keating GM, Perry CM (2007). "Rasagiline: a review of its use in the management of Parkinson's disease". Drugs. 67 (12): 1725–1747. doi:10.2165/00003495-200767120-00006. PMID 17683172. S2CID 195688993.
  7. ^ Gallagher DA, Schrag A (2008). "Impact of newer pharmacological treatments on quality of life in patients with Parkinson's disease". CNS Drugs. 22 (7): 563–586. doi:10.2165/00023210-200822070-00003. PMID 18547126. S2CID 29707067.
  8. ^ a b c d e f g h i Gerlach M, Reichmann H, Riederer P (2012). "A critical review of evidence for preclinical differences between rasagiline and selegiline". Basal Ganglia. 2 (4): S9–S15. doi:10.1016/j.baga.2012.04.032.
  9. ^ a b c d Harsing LG, Timar J, Miklya I (August 2023). "Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline". International Journal of Molecular Sciences. 24 (17): 13334. doi:10.3390/ijms241713334. PMC 10487936. PMID 37686140.
  10. ^ a b c Schapira A, Bate G, Kirkpatrick P (August 2005). "Rasagiline". Nature Reviews. Drug Discovery. 4 (8): 625–626. doi:10.1038/nrd1803. PMID 16106586.
  11. ^ a b Silverman RB, Holladay MW (29 March 2014). The Organic Chemistry of Drug Design and Drug Action. Amsterdam Heidelberg: Academic Press. ISBN 978-0-12-382031-0.
  12. ^ a b c d "Drugs@FDA: FDA-Approved Drugs". accessdata.fda.gov. Food and Drug Administration. Retrieved 29 July 2024.
  13. ^ a b Wong A, Ng C (1 December 2021). "Rasagiline (Azilect): Uses, Side Effects, Dosage & Reviews". GoodRx. Retrieved 29 July 2024.
  14. ^ a b "Generic Azilect Availability". Drugs.com. 11 July 2024. Retrieved 29 July 2024.
  15. ^ a b c d Stocchi F, Fossati C, Torti M (2015). "Rasagiline for the treatment of Parkinson's disease: an update". Expert Opinion on Pharmacotherapy. 16 (14): 2231–2241. doi:10.1517/14656566.2015.1086748. PMID 26364897. S2CID 6823552.
  16. ^ a b Poewe W, Mahlknecht P, Krismer F (September 2015). "Therapeutic advances in multiple system atrophy and progressive supranuclear palsy". Movement Disorders. 30 (11): 1528–1538. doi:10.1002/mds.26334. PMID 26227071. S2CID 30312372.
  17. ^ Sviderski V (19 October 2011). "FDA Advisers Refuse Teva Plea to Expand Azilect Label". Reuters and Haaretz.
  18. ^ Katz R. "Peripheral and Central Nervous System Advisory Committee Background Package on Azilect" (PDF). FDA. Retrieved 7 December 2011.
  19. ^ a b c d e f g h Tsuboi T, Satake Y, Hiraga K, Yokoi K, Hattori M, Suzuki M, et al. (June 2022). "Effects of MAO-B inhibitors on non-motor symptoms and quality of life in Parkinson's disease: A systematic review". npj Parkinson's Disease. 8 (1): 75. doi:10.1038/s41531-022-00339-2. PMC 9192747. PMID 35697709.
  20. ^ Elbers RG, Verhoef J, van Wegen EE, Berendse HW, Kwakkel G (October 2015). "Interventions for fatigue in Parkinson's disease". The Cochrane Database of Systematic Reviews. 2015 (10): CD010925. doi:10.1002/14651858.CD010925.pub2. PMC 9240814. PMID 26447539.
  21. ^ Stocchi F (February 2014). "Benefits of treatment with rasagiline for fatigue symptoms in patients with early Parkinson's disease". European Journal of Neurology. 21 (2): 357–360. doi:10.1111/ene.12205. PMID 23790011.
  22. ^ Lim TT, Kluger BM, Rodriguez RL, Malaty IA, Palacio R, Ojo OO, et al. (November 2015). "Rasagiline for the symptomatic treatment of fatigue in Parkinson's disease". Movement Disorders. 30 (13): 1825–1830. doi:10.1002/mds.26429. PMID 26769459.
  23. ^ a b Solís-García del Pozo J, Mínguez-Mínguez S, de Groot PW, Jordán J (July 2013). "Rasagiline meta-analysis: a spotlight on clinical safety and adverse events when treating Parkinson's disease". Expert Opin Drug Saf. 12 (4): 479–486. doi:10.1517/14740338.2013.790956. PMID 23634791.
  24. ^ Vitale C, Amboni M, Erro R, Picillo M, Pellecchia MT, Barone P, et al. (June 2019). "Parkinson's disease management and impulse control disorders: current state and future perspectives". Expert Review of Neurotherapeutics. 19 (6): 495–508. doi:10.1080/14737175.2019.1620603. PMID 31148487.
  25. ^ Vitale C, Santangelo G, Erro R, Errico D, Manganelli F, Improta I, et al. (April 2013). "Impulse control disorders induced by rasagiline as adjunctive therapy for Parkinson's disease: report of 2 cases". Parkinsonism & Related Disorders. 19 (4): 483–484. doi:10.1016/j.parkreldis.2012.11.008. PMID 23305965.
  26. ^ Levy A, Lang AE (July 2017). "Recurrent Impulse Control Disorder Associated with Rasagiline Treatment of Parkinson's Disease". The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques. 44 (4): 447–448. doi:10.1017/cjn.2016.307. PMID 28767029.
  27. ^ a b 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.
  28. ^ 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.
  29. ^ Sevincok L, Kunt DA, Ozgur BG (August 2014). "Compulsive behaviors related to rasagiline: a case report". Journal of Clinical Psychopharmacology. 34 (4): 529–530. doi:10.1097/JCP.0000000000000161. PMID 24943393.
  30. ^ Stark R, Klucken T, Potenza MN, Brand M, Strahler J (2018). "A Current Understanding of the Behavioral Neuroscience of Compulsive Sexual Behavior Disorder and Problematic Pornography Use". Current Behavioral Neuroscience Reports. 5 (4): 218–231. doi:10.1007/s40473-018-0162-9. ISSN 2196-2979.
  31. ^ Reyes D, Kurako K, Galvez-Jimenez N (March 2014). "Rasagiline induced hypersexuality in Parkinson's disease". Journal of Clinical Neuroscience. 21 (3): 507–508. doi:10.1016/j.jocn.2013.04.021. PMID 24055209.
  32. ^ Simonet C, Fernández B, Cerdán DM, Duarte J (November 2016). "Hypersexuality induced by rasagiline in monotherapy in Parkinson's disease". Neurological Sciences. 37 (11): 1889–1890. doi:10.1007/s10072-016-2668-9. PMID 27401808.
  33. ^ Chen WH, Chu YH, Chen KY (2018). "Drug-Associated Spontaneous Orgasm: A Case Report and Systematic Review of Literature". Clinical Neuropharmacology. 41 (1): 31–37. doi:10.1097/WNF.0000000000000259. PMID 29194112.
  34. ^ Uca AU, Kozak HH (August 2014). "A case of rasagiline-induced spontaneous orgasms in a female patient". Parkinsonism & Related Disorders. 20 (8): 929–930. doi:10.1016/j.parkreldis.2014.04.004. PMID 24837642.
  35. ^ Chuang RS, Lang AE (October 2009). "Rasagiline-induced spontaneous ejaculation". Movement Disorders. 24 (14): 2160–2161. doi:10.1002/mds.22746. PMID 19735087.
  36. ^ Abdel-Hamid IA, Ali OI (July 2021). "Spontaneous Ejaculation: A Focused Review for the Clinicians". Sexual Medicine Reviews. 9 (3): 406–422. doi:10.1016/j.sxmr.2020.11.001. PMID 33262094.
  37. ^ Solla P, Cannas A, Orofino G, Marrosu F (March 2015). "Rasagiline and Pisa syndrome in Parkinson's disease patients". Neurol Sci. 36 (3): 485–386. doi:10.1007/s10072-014-2024-x. PMID 25481627.
  38. ^ Valentino F, Cosentino G, Fierro B, Realmuto S, Mastrilli S, Savettieri G, et al. (October 2014). "Insidious onset of Pisa syndrome after rasagiline therapy in a patient with Parkinson's disease". Neurol Sci. 35 (10): 1615–1617. doi:10.1007/s10072-014-1806-5. PMID 24770981.
  39. ^ Fasano A, Di Matteo A, Vitale C, Squintani G, Ferigo L, Bombieri F, et al. (December 2011). "Reversible Pisa syndrome in patients with Parkinson's disease on rasagiline therapy". Mov Disord. 26 (14): 2578–2580. doi:10.1002/mds.23918. PMID 22170277.
  40. ^ Strowd LC, Lee AD, Yosipovitch G (June 2012). "Livedo reticularis associated with rasagiline (azilect)". J Drugs Dermatol. 11 (6): 764–765. PMID 22648227.
  41. ^ Lefaucheur R, Fetter D, Gaillon G, Borden A, Maltête D (2014). "Tendon rupture as an adverse effect of rasagiline". Clin Neuropharmacol. 37 (2): 62. doi:10.1097/WNF.0000000000000023. PMID 24614673.
  42. ^ Ibrahim FA, Rashid F, Hussain AA, Alawadi F, Bashier A (February 2017). "Rasagiline-induced severe recurrent hypoglycemia in a young woman without diabetes: a case report". J Med Case Rep. 11 (1): 29. doi:10.1186/s13256-017-1202-x. PMC 5289042. PMID 28148284.
  43. ^ Aboukarr A, Giudice M (2018). "Interaction between Monoamine Oxidase B Inhibitors and Selective Serotonin Reuptake Inhibitors". Can J Hosp Pharm. 71 (3): 196–207. PMC 6019085. PMID 29955193.
  44. ^ Suphanklang J, Santimaleeworagun W, Supasyndh O (December 2015). "Combination of Escitalopram and Rasagiline Induced Serotonin Syndrome: A Case Report and Review Literature". J Med Assoc Thai. 98 (12): 1254–1257. PMID 27004312.
  45. ^ Hébant B, Guillaume M, Desbordes M, Gaillon G, Maltête D, Lefaucheur R (December 2016). "Combination of paroxetine and rasagiline induces serotonin syndrome in a parkinsonian patient". Rev Neurol (Paris). 172 (12): 788–789. doi:10.1016/j.neurol.2016.10.002. PMID 27838092.
  46. ^ Duval F, Flabeau O, Razafimahefa J, Spampinato U, Tison F (September 2013). "Encephalophaty associated with rasagiline and sertraline in Parkinson's disease: possible serotonin syndrome". Mov Disord. 28 (10): 1464. doi:10.1002/mds.25416. PMID 23495033.
  47. ^ Fernandes C, Reddy P, Kessel B (March 2011). "Rasagiline-induced serotonin syndrome". Mov Disord. 26 (4): 766–767. doi:10.1002/mds.23649. PMID 21370275.
  48. ^ Bandrés Liso AC, Toyas Miazza C (2009). "[Clinical manifestation of confusion and hallucinations caused by an interaction between rasagiline and escitalopram]". Farm Hosp (in European Spanish). 33 (3): 173–175. doi:10.1016/s1130-6343(09)71160-2. PMID 19712602.
  49. ^ Hilli J, Korhonen T, Laine K (November 2009). "Lack of clinically significant interactions between concomitantly administered rasagiline and escitalopram". Prog Neuropsychopharmacol Biol Psychiatry. 33 (8): 1526–1532. doi:10.1016/j.pnpbp.2009.08.014. PMID 19733607.
  50. ^ Hisham M, Sivakumar MN, Nandakumar V, Lakshmikanthcharan S (2016). "Linezolid and Rasagiline - A culprit for serotonin syndrome". Indian J Pharmacol. 48 (1): 91–92. doi:10.4103/0253-7613.174573. PMC 4778217. PMID 26997732.
  51. ^ Solla P, Ercoli T, Masala C, Orofino G, Fadda L, Corda DG, et al. (February 2022). "Rasagiline Withdrawal Syndrome in Parkinson's Disease". Brain Sci. 12 (2): 219. doi:10.3390/brainsci12020219. PMC 8870166. PMID 35203982.
  52. ^ Rascol O (October 2005). "Rasagiline in the pharmacotherapy of Parkinson's disease--a review". Expert Opinion on Pharmacotherapy. 6 (12): 2061–2075. doi:10.1517/14656566.6.12.2061. PMID 16197359.
  53. ^ a b Lecht S, Haroutiunian S, Hoffman A, Lazarovici P (June 2007). "Rasagiline - a novel MAO B inhibitor in Parkinson's disease therapy". Therapeutics and Clinical Risk Management. 3 (3): 467–474. PMC 2386362. PMID 18488080.
  54. ^ a b c d e Thébault JJ, Guillaume M, Levy R (October 2004). "Tolerability, safety, pharmacodynamics, and pharmacokinetics of rasagiline: a potent, selective, and irreversible monoamine oxidase type B inhibitor". Pharmacotherapy. 24 (10): 1295–1305. doi:10.1592/phco.24.14.1295.43156. PMID 15628826.
  55. ^ a b c d e f g h i j Finberg JP (February 2020). "The discovery and development of rasagiline as a new anti-Parkinson medication". Journal of Neural Transmission. 127 (2): 125–130. doi:10.1007/s00702-020-02142-w. PMID 31974721.
  56. ^ a b c d e f Müller T (October 2014). "Pharmacokinetic/pharmacodynamic evaluation of rasagiline mesylate for Parkinson's disease". Expert Opinion on Drug Metabolism & Toxicology. 10 (10): 1423–1432. doi:10.1517/17425255.2014.943182. PMID 25196265.
  57. ^ Malaty IA, Fernandez HH (August 2009). "Role of rasagiline in treating Parkinson's disease: Effect on disease progression". Ther Clin Risk Manag. 5 (4): 413–419. doi:10.2147/tcrm.s4321. PMC 2695242. PMID 19753135.
  58. ^ Freedman NM, Mishani E, Krausz Y, Weininger J, Lester H, Blaugrund E, et al. (October 2005). "In vivo measurement of brain monoamine oxidase B occupancy by rasagiline, using (11)C-l-deprenyl and PET". J Nucl Med. 46 (10): 1618–1624. PMID 16204711.
  59. ^ Hoffman GR, Olson MG, Schoffstall AM, Estévez RF, Van den Eynde V, Gillman PK, et al. (December 2023). "Classics in Chemical Neuroscience: Selegiline, Isocarboxazid, Phenelzine, and Tranylcypromine". ACS Chemical Neuroscience. 14 (23): 4064–4075. doi:10.1021/acschemneuro.3c00591. PMID 37966854.
  60. ^ a b c Youdim MB, Gross A, Finberg JP (January 2001). "Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B". British Journal of Pharmacology. 132 (2): 500–506. doi:10.1038/sj.bjp.0703826. PMC 1572573. PMID 11159700.
  61. ^ Heinonen EH, Anttila MI, Lammintausta RA (December 1994). "Pharmacokinetic aspects of l-deprenyl (selegiline) and its metabolites". Clinical Pharmacology and Therapeutics. 56 (6 Pt 2): 742–749. doi:10.1038/clpt.1994.204. PMID 7995016.
  62. ^ Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present--a pharmacological and clinical perspective". Journal of Psychopharmacology. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC 3666194. PMID 23539642.
  63. ^ a b c Finberg JP (April 2019). "Inhibitors of MAO-B and COMT: their effects on brain dopamine levels and uses in Parkinson's disease". Journal of Neural Transmission. 126 (4): 433–448. doi:10.1007/s00702-018-1952-7. PMID 30386930.
  64. ^ a b c Finberg JP (July 2010). "Pharmacology of Rasagiline, a New MAO-B Inhibitor Drug for the Treatment of Parkinson's Disease with Neuroprotective Potential". Rambam Maimonides Med J. 1 (1): e0003. doi:10.5041/RMMJ.10003. PMC 3721659. PMID 23908775.
  65. ^ a b c Lamensdorf I, Youdim MB, Finberg JP (October 1996). "Effect of long-term treatment with selective monoamine oxidase A and B inhibitors on dopamine release from rat striatum in vivo". J Neurochem. 67 (4): 1532–1539. doi:10.1046/j.1471-4159.1996.67041532.x. PMID 8858937.
  66. ^ a b c Miklya I (November 2016). "The significance of selegiline/(-)-deprenyl after 50 years in research and therapy (1965-2015)". Molecular Psychiatry. 21 (11): 1499–1503. doi:10.1038/mp.2016.127. PMID 27480491.
  67. ^ a b c Youdim MB, Tipton KF (March 2002). "Rat striatal monoamine oxidase-B inhibition by l-deprenyl and rasagiline: its relationship to 2-phenylethylamine-induced stereotypy and Parkinson's disease". Parkinsonism Relat Disord. 8 (4): 247–253. doi:10.1016/s1353-8020(01)00011-6. PMID 12039419.
  68. ^ Youdim MB, Edmondson D, Tipton KF (April 2006). "The therapeutic potential of monoamine oxidase inhibitors". Nat Rev Neurosci. 7 (4): 295–309. doi:10.1038/nrn1883. PMID 16552415.
  69. ^ Heinonen EH, Lammintausta R (1991). "A review of the pharmacology of selegiline". Acta Neurologica Scandinavica. Supplementum. 136: 44–59. doi:10.1111/j.1600-0404.1991.tb05020.x. PMID 1686954.
  70. ^ a b c Nadeem MS, Hosawi SB, Murtaza BN, Kazmi I (2023). "Mechanism of action of anti-Parkinson's drugs". How Synthetic Drugs Work: Insights Into Molecular Pharmacology of Classic and New Pharmaceuticals. Elsevier. pp. 195–213. doi:10.1016/b978-0-323-99855-0.00009-9. ISBN 978-0-323-99855-0.
  71. ^ a b c d Nam MH, Sa M, Ju YH, Park MG, Lee CJ (April 2022). "Revisiting the Role of Astrocytic MAOB in Parkinson's Disease". International Journal of Molecular Sciences. 23 (8): 4453. doi:10.3390/ijms23084453. PMC 9028367. PMID 35457272.
  72. ^ a b c d Cho HU, Kim S, Sim J, Yang S, An H, Nam MH, et al. (July 2021). "Redefining differential roles of MAO-A in dopamine degradation and MAO-B in tonic GABA synthesis". Experimental & Molecular Medicine. 53 (7): 1148–1158. doi:10.1038/s12276-021-00646-3. PMC 8333267. PMID 34244591.
  73. ^ a b Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H (2002). "GABA and GABA Receptors in the Central Nervous System and Other Organs". A Survey of Cell Biology. International Review of Cytology. Vol. 213. pp. 1–47. doi:10.1016/s0074-7696(02)13011-7. ISBN 978-0-12-364617-0. PMID 11837891. {{cite book}}: |journal= ignored (help)
  74. ^ Seiler N (June 2004). "Catabolism of polyamines". Amino Acids. 26 (3): 217–233. doi:10.1007/s00726-004-0070-z. PMID 15221502.
  75. ^ a b c d Pinterova N, Horsley RR, Palenicek T (2017). "Synthetic Aminoindanes: A Summary of Existing Knowledge". Frontiers in Psychiatry. 8: 236. doi:10.3389/fpsyt.2017.00236. PMC 5698283. PMID 29204127. 2-AI selectively inhibited just NET, and for SERT and DAT it has low potency. Apart from inhibitory actions on transporter molecules, aminoindanes have been shown to cause transporter-mediated release (reverse transport) of monoamines: MDAI released 5-HT and NE, 5-IAI released 5-HT and DA, and 2-AI released NE and DA (33).
  76. ^ a b c Brandt SD, Braithwaite RA, Evans-Brown M, Kicman AT (2013). "Aminoindane Analogues". Novel Psychoactive Substances. Elsevier. pp. 261–283. doi:10.1016/b978-0-12-415816-0.00011-0. ISBN 978-0-12-415816-0.
  77. ^ a b Speiser Z, Levy R, Cohen S (1998). "Effects of N-propargyl-1-(R)aminoindan (Rasagiline) in models of motor and cognition disorders". MAO — the Mother of all Amine Oxidases. Journal of Neural Transmission. Supplement. Vol. 52. pp. 287–300. doi:10.1007/978-3-7091-6499-0_29. ISBN 978-3-211-83037-6. PMID 9564629. {{cite book}}: |journal= ignored (help)
  78. ^ Horn AS, Snyder SH (March 1972). "Steric requirements for catecholamine uptake by rat brain synaptosomes: studies with rigid analogs of amphetamine". The Journal of Pharmacology and Experimental Therapeutics. 180 (3): 523–530. PMID 5012779.
  79. ^ Miklya I (June 2014). "Essential difference between the pharmacological spectrum of (-)-deprenyl and rasagiline". Pharmacological Reports. 66 (3): 453–458. doi:10.1016/j.pharep.2013.11.003. PMID 24905523.
  80. ^ Berry MD (January 2007). "The potential of trace amines and their receptors for treating neurological and psychiatric diseases". Reviews on Recent Clinical Trials. 2 (1): 3–19. doi:10.2174/157488707779318107. PMID 18473983. In addition, the compounds previously described by Knoll and colleagues [33, 34], along with a series of trace amine derivatives synthesized by Ling et al. [35] are potential TAAR ligands. Although neither of these classes of compound appear to have been examined for efficacy at TAAR, their strong structural similarity to trace amines suggests that such studies are warranted.
  81. ^ a b Deftereos SN, Andronis CA (July 2010). "Discordant effects of rasagiline doses in Parkinson disease". Nat Rev Neurol. 6 (7): 1p following 410. doi:10.1038/nrneurol.2010.2-c1. PMID 20653097.
  82. ^ Oliveri V (April 2019). "Toward the discovery and development of effective modulators of α-synuclein amyloid aggregation". European Journal of Medicinal Chemistry. 167: 10–36. doi:10.1016/j.ejmech.2019.01.045. PMID 30743095.
  83. ^ Kakish J, Lee D, Lee JS (December 2015). "Drugs That Bind to α-Synuclein: Neuroprotective or Neurotoxic?". ACS Chemical Neuroscience. 6 (12): 1930–1940. doi:10.1021/acschemneuro.5b00172. PMID 26378986.
  84. ^ Kakish J, Tavassoly O, Lee JS (February 2015). "Rasagiline, a suicide inhibitor of monoamine oxidases, binds reversibly to α-synuclein". ACS Chemical Neuroscience. 6 (2): 347–355. doi:10.1021/cn5002914. PMID 25514361.
  85. ^ a b c Bilal R, Ahmad NS, Zaffar S, Mazhar MU, Siddiqui WA, Tariq S (2022). "Rasagiline Pharmacokinetics in CYP1A2 Variant Healthy Smokers & Non-smokers in Different Doses". Pak J Med Sci. 38 (3Part–I): 589–594. doi:10.12669/pjms.38.3.4940. PMC 9002453. PMID 35480532.
  86. ^ a b Zubiaur P, Matas M, Martín-Vílchez S, Soria-Chacartegui P, Villapalos-García G, Figueiredo-Tor L, et al. (September 2022). "Polymorphism of Drug Transporters, Rather Than Metabolizing Enzymes, Conditions the Pharmacokinetics of Rasagiline". Pharmaceutics. 14 (10): 2001. doi:10.3390/pharmaceutics14102001. PMC 9610285. PMID 36297437.
  87. ^ Simão AY, Antunes M, Cabral E, Oliveira P, Rosendo LM, Brinca AT, et al. (April 2022). "An Update on the Implications of New Psychoactive Substances in Public Health". International Journal of Environmental Research and Public Health. 19 (8): 4869. doi:10.3390/ijerph19084869. PMC 9028227. PMID 35457736.
  88. ^ Dashtipour K, Chen JJ, Lew MF (2008). "Rasagiline for the management of Parkinson's disease". Therapy. 5 (2): 203–214. doi:10.2217/14750708.5.2.203 (inactive 12 November 2024). ISSN 1475-0708.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
  89. ^ Abassi ZA, Binah O, Youdim MB (October 2004). "Cardiovascular activity of rasagiline, a selective and potent inhibitor of mitochondrial monoamine oxidase B: comparison with selegiline". British Journal of Pharmacology. 143 (3): 371–378. doi:10.1038/sj.bjp.0705962. PMC 1575354. PMID 15339864.
  90. ^ a b Weinreb O, Amit T, Bar-Am O, Youdim MB (November 2010). "Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity". Progress in Neurobiology. 92 (3): 330–344. doi:10.1016/j.pneurobio.2010.06.008. PMID 20600573.
  91. ^ a b c Youdim MB, Bakhle YS (January 2006). "Monoamine oxidase: isoforms and inhibitors in Parkinson's disease and depressive illness". British Journal of Pharmacology. 147 (Suppl 1): S287–S296. doi:10.1038/sj.bjp.0706464. PMC 1760741. PMID 16402116.
  92. ^ Lakhan SE (July 2007). "From a Parkinson's disease expert: Rasagiline and the future of therapy". Molecular Neurodegeneration. 2 (1): 13. doi:10.1186/1750-1326-2-13. PMC 1929084. PMID 17617893.
  93. ^ US 3201470, Huebner CF, issued 17 August 1965, assigned to CIBA 
  94. ^ Huebner CF, Donoghue EM, Plummer AJ, Furness PA (November 1966). "N-methyl-n-2-propynyl-l-indanamine. A protent monoamine oxidase inhibitor". Journal of Medicinal Chemistry. 9 (6): 830–832. doi:10.1021/jm00324a009. PMID 5972038.
  95. ^ Miklya I (March 2008). "(-)-deprenil, az N-metilprogargilamin-1-aminoindan (J-508) és a J-508 dezmetil analógjának (rasagilin) összehasonlító farmakológiai analízise" [A comparison of the pharmacology of (-)-deprenyl to N-methylpropargylamine-1-aminoindane (J-508) and rasagiline, the desmethyl-analogue of J-508] (PDF). Neuropsychopharmacol Hung (in Hungarian). 10 (1): 15–22. PMID 18771016.
  96. ^ 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.
  97. ^ Sielg-Itzkovich J (13 November 2010). "Making armor for the brain". The Jerusalem Post.
  98. ^ a b c Finberg JP, Lamensdorf I, Commissiong JW, Youdim MB (1996). "Pharmacology and neuroprotective properties of rasagiline". Deprenyl — Past and Future. Vol. 48. pp. 95–101. doi:10.1007/978-3-7091-7494-4_9. ISBN 978-3-211-82891-5. PMID 8988465. {{cite book}}: |journal= ignored (help)
  99. ^ Kupsch A (May 2002). "Rasagiline. Teva Pharmaceutical". Current Opinion in Investigational Drugs. 3 (5): 794–797. PMID 12090555.
  100. ^ "Teva and Eisai Sign Agreement for Co-development of Rasagiline for Alzheimer's disease, and Co-promotion for Parkinson's Disease, in the U.S." Eisai (Press release). 15 May 2003. Archived from the original on 15 July 2003. Retrieved 23 July 2024.
  101. ^ a b Knudsen Gerber DS (January 2011). "Selegiline and rasagiline: twins or distant cousins?". Consult Pharm. 26 (1): 48–51. doi:10.4140/TCP.n.2011.48. PMID 21224199.
  102. ^ "Rasagiline. Parkinson's disease: a simple me-too". Prescrire Int. 15 (86): 220. December 2006. PMID 17167927.
  103. ^ Binde CD, Tvete IF, Gåsemyr J, Natvig B, Klemp M (September 2018). "A multiple treatment comparison meta-analysis of monoamine oxidase type B inhibitors for Parkinson's disease". Br J Clin Pharmacol. 84 (9): 1917–1927. doi:10.1111/bcp.13651. PMC 6089809. PMID 29847694.
  104. ^ Knoll J (February 1998). "(-)Deprenyl (selegiline), a catecholaminergic activity enhancer (CAE) substance acting in the brain". Pharmacol Toxicol. 82 (2): 57–66. doi:10.1111/j.1600-0773.1998.tb01399.x. PMID 9498233.
  105. ^ "Rasagiline". PubChem. Retrieved 29 July 2024.
  106. ^ "Rasagiline". ChemSpider. 21 July 2022. Retrieved 29 July 2024.
  107. ^ a b c "Rasagiline - Teva Pharmaceutical Industries". AdisInsight. 5 November 2023. Retrieved 29 July 2024.
  108. ^ Palma JA, Kaufmann H (February 2015). "Novel therapeutic approaches in multiple system atrophy". Clin Auton Res. 25 (1): 37–45. doi:10.1007/s10286-014-0249-7. PMC 4265580. PMID 24928797.
  109. ^ Giladi N (2008). "Medical treatment of freezing of gait". Mov Disord. 23 (Suppl 2): S482–S488. doi:10.1002/mds.21914. PMID 18668620.
  110. ^ Coria F, Cozar-Santiago Mdel P (February 2008). "Rasagiline improves freezing in a patient with primary progressive freezing gait". Mov Disord. 23 (3): 449–451. doi:10.1002/mds.21868. PMID 18067186.
  111. ^ Dorst J, Genge A (October 2022). "Clinical studies in amyotrophic lateral sclerosis". Curr Opin Neurol. 35 (5): 686–692. doi:10.1097/WCO.0000000000001099. PMID 35942672.
  112. ^ Statland JM, Moore D, Wang Y, Walsh M, Mozaffar T, Elman L, et al. (February 2019). "Rasagiline for amyotrophic lateral sclerosis: A randomized, controlled trial". Muscle Nerve. 59 (2): 201–207. doi:10.1002/mus.26335. PMC 6545236. PMID 30192007.
  113. ^ Ludolph AC, Schuster J, Dorst J, Dupuis L, Dreyhaupt J, Weishaupt JH, et al. (August 2018). "Safety and efficacy of rasagiline as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomised, double-blind, parallel-group, placebo-controlled, phase 2 trial". Lancet Neurol. 17 (8): 681–688. doi:10.1016/S1474-4422(18)30176-5. PMID 29934198.
  114. ^ Rato ML, Duarte GS, Mestre T, de Carvalho M, Ferreira JJ (October 2018). "Strong nocebo effect in amyotrophic lateral sclerosis trials might mask conclusions". Lancet Neurol. 17 (10): 842. doi:10.1016/S1474-4422(18)30310-7. PMID 30264722.
  115. ^ Fasipe OJ (June 2019). "The emergence of new antidepressants for clinical use: Agomelatine paradox versus other novel agents". IBRO Rep. 6: 95–110. doi:10.1016/j.ibror.2019.01.001. PMC 6562183. PMID 31211282.
  116. ^ Huang YH, Chen JH, Loh EW, Chan L, Hong CT (2021). "The effect of monoamine oxidase-B inhibitors on the alleviation of depressive symptoms in Parkinson's disease: meta-analysis of randomized controlled trials". Ther Adv Psychopharmacol. 11: 2045125320985993. doi:10.1177/2045125320985993. PMC 7816524. PMID 33520156.
  117. ^ "rasagiline[title] (depress*[title] OR antidepress*[title] OR dysthym*[title])". PubMed. Archived from the original on 29 July 2024. Retrieved 29 July 2024.
  118. ^ a b Knoll J, Zelena D, Timar J, Baghy K, Mervai Z, Miklya I (January 2020). "Synthetic enhancer compounds, besides acting on biogenic amine system, influence the glutamate transmission and stress response" (PDF). Behav Brain Res. 378: 112290. doi:10.1016/j.bbr.2019.112290. PMID 31610214. The precise mechanism behind the enhancer activity is not yet clarified. Recent data demonstrated, that antidepressant effect of DEP, or its action on the hippocampal long-term potentiation is independent from the MAO-B inhibition, as rasagiline, a potent MAO-B inhibitor was lack[ing] of these effects [36].
  119. ^ a b Ishikawa T, Okano M, Minami A, Tsunekawa H, Satoyoshi H, Tsukamoto Y, et al. (February 2019). "Selegiline ameliorates depression-like behaviors in rodents and modulates hippocampal dopaminergic transmission and synaptic plasticity". Behav Brain Res. 359: 353–361. doi:10.1016/j.bbr.2018.10.032. PMID 30359642.
  120. ^ McCreary AC, Müller CP, Filip M (2015). "Psychostimulants: Basic and Clinical Pharmacology". Int Rev Neurobiol. 120: 41–83. doi:10.1016/bs.irn.2015.02.008. PMID 26070753.
  121. ^ de Biase S, Pellitteri G, Gigli GL, Valente M (November 2019). "Advancing synthetic therapies for the treatment of restless legs syndrome". Expert Opinion on Pharmacotherapy. 20 (16): 1971–1980. doi:10.1080/14656566.2019.1654997. PMID 31424287.
  122. ^ Babacan-Yildiz G, Gursoy E, Kolukisa M, Celebi A (2012). "Restless legs syndrome responsive to rasagiline treatment: a case report". Clinical Neuropharmacology. 35 (2): 88–89. doi:10.1097/WNF.0b013e31824c1c3f. PMID 22421586.
  123. ^ Alvarez M, Grogan P (12 February 2013). "A Tale of Two Restless Sisters (P02.067)". Neurology. 80 (7_supplement). doi:10.1212/WNL.80.7_supplement.P02.067. ISSN 0028-3878.
Retrieved from "https://wiki.riteme.site/w/index.php?title=Rasagiline&oldid=1262722011"