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Rasagiline

PubChem CID
3052776
Structure
Rasagiline_small.png
Rasagiline_3D_Structure.png
Molecular Formula
Synonyms
  • rasagiline
  • 136236-51-6
  • (R)-N-(2-Propynyl)-2,3-dihydroinden-1-amine
  • Azilect
  • (R)-N-2-Propynyl-1-indanamine
Molecular Weight
171.24 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-08-09
  • Modify:
    2025-01-25
Description
Rasagiline is an indane that consists of 1-aminoindane bearing an N-propargyl substituent. A selective, irreversible monoamine oxidase-B inhibitor. It has a role as an EC 1.4.3.4 (monoamine oxidase) inhibitor and a neuroprotective agent. It is a secondary amine, a member of indanes and a terminal acetylenic compound.
Rasagiline is an irreversible inhibitor of monoamine oxidase and is used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases.
Rasagiline is a Monoamine Oxidase Inhibitor. The mechanism of action of rasagiline is as a Monoamine Oxidase Inhibitor.
See also: Rasagiline Mesylate (active moiety of).

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Rasagiline.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

(1R)-N-prop-2-ynyl-2,3-dihydro-1H-inden-1-amine
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

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
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

RUOKEQAAGRXIBM-GFCCVEGCSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

C#CCN[C@@H]1CCC2=CC=CC=C12
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C12H13N
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 HMDB ID

2.3.9 KEGG ID

2.3.10 Metabolomics Workbench ID

2.3.11 NCI Thesaurus Code

2.3.12 Nikkaji Number

2.3.13 NSC Number

2.3.14 PharmGKB ID

2.3.15 Pharos Ligand ID

2.3.16 RXCUI

2.3.17 Wikidata

2.3.18 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • 2,3-dihydro-N-2-propynyl-1H-inden-1-amine-(1R)-hydrochloride
  • AGN 1135
  • AGN-1135
  • Azilect
  • N-2-propynyl-1-indanamine
  • N-propargyl-1-aminoindan mesylate
  • rasagiline
  • rasagiline hydrochloride
  • TVP 101
  • TVP 1022
  • TVP-101
  • TVP-1022
  • TVP1022

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
171.24 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
1.8
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
1
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
1
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
171.104799419 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
171.104799419 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
12 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
13
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
212
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
1
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Solubility

2.49e-02 g/L

3.2.3 Other Experimental Properties

White to off-white powder, freely soluble in water or ethanol and sparingly soluble in isopropanol. MW: 267.34. /Mesylate/
Thomson Health Care Inc.; Physicians' Desk Reference 62 ed., Montvale, NJ 2008, p. 3227

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Antiparkinson Agents; Monoamine Oxidase Inhibitors; Neuroprotective Agents
Human drug -> Prescription
Human drugs -> Anti-Parkinson drugs -> Human pharmacotherapeutic group -> EMA Drug Category

5 Chemical Vendors

6 Drug and Medication Information

6.1 Drug Indication

For the treatment of the signs and symptoms of idiopathic Parkinsons disease as initial monotherapy and as adjunct therapy to levodopa.
Azilect is indicated for the treatment of idiopathic Parkinson's disease (PD) as monotherapy (without levodopa) or as adjunct therapy (with levodopa) in patients with end-of-dose fluctuations.

6.2 LiverTox Summary

Rasagiline is an inhibitor of monamine oxidase used as adjunctive therapy in combination with levodopa and carbidopa in the management of Parkinson’s disease. Rasagiline has been associated with a low rate of serum enzyme elevations during treatment, but has not been linked to instances of clinically apparent acute liver injury.

6.3 Drug Classes

Breast Feeding; Lactation; Antiparkinson Agents; Monoamine Oxidase Inhibitors; Neuroprotective Agents
Antiparkinson Agents

6.4 FDA National Drug Code Directory

6.5 Drug Labels

Drug and label

6.6 Clinical Trials

6.6.1 ClinicalTrials.gov

6.6.2 EU Clinical Trials Register

6.6.3 NIPH Clinical Trials Search of Japan

6.7 EMA Drug Information

1 of 2
Medicine
Category
Human drugs
Therapeutic area
Parkinson Disease
Active Substance
rasagiline
INN/Common name
rasagiline
Pharmacotherapeutic Classes
Anti-Parkinson drugs
Status
This medicine is authorized for use in the European Union
Company
Teva B.V.
Market Date
2005-02-21
2 of 2
Category
Human drugs
Therapeutic area
Parkinson Disease
Active Substance
rasagiline
INN/Common name
rasagiline
Pharmacotherapeutic Classes
Anti-Parkinson drugs
Status
This medicine is authorized for use in the European Union
Company
Teva B.V.
Market Date
2015-01-12

6.8 Therapeutic Uses

Rasagiline is used as initial monotherapy or as adjunctive therapy to levodopa for the symptomatic treatment of idiopathic parkinsonian syndrome.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2696
Azilect (rasagiline mesylate) is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa. The effectiveness of Azilect was demonstrated in patients with early Parkinson's disease who were receiving Azilect as monotherapy and who were not receiving any concomitant dopaminergic therapy. The effectiveness of Azilect as adjunct therapy was demonstrated in patients with Parkinson's disease who were treated with levodopa.
FDA; Center for Drug Evaluation and Research; Label Information for Azilect (Rasagiline) (Last updated May 2006). Available from, as of February 20, 2009: https://www.fda.gov/cder/foi/label/2006/021641lbl.pdf

6.9 Drug Warnings

When used as monotherapy, postural hypotension was reported in approximately 3% of patients treated with 1 mg rasagiline and 5% of patients treated with placebo. In the monotherapy trial, postural hypotension did not lead to drug discontinuation and premature withdrawal in the rasagiline or placebo treated patients. When used as an adjunct to levodopa, postural hypotension was reported in approximately 6% of patients treated with 0.5 mg rasagiline, 9% of patients treated with 1 mg rasagiline and 3% of patients treated with placebo. Postural hypotension led to drug discontinuation and premature withdrawal from clinical trials in one (0.7%) patient treated with rasagiline 1 mg/day, no patients treated with rasagiline 0.5 mg/day and no placebo-treated patients. Clinical trial data suggest that postural hypotension occurs most frequently in the first two months of rasagiline treatment and tends to decrease over time.
FDA; Center for Drug Evaluation and Research; Label Information for Azilect (Rasagiline) (Last updated May 2006). Available from, as of February 20, 2009: https://www.fda.gov/cder/foi/label/2006/021641lbl.pdf
Data from epidemiologic studies indicate that patients with Parkinson's disease have an approximately twofold to fourfold greater risk of developing melanoma than the general population; however, it is unclear whether the observed increased risk is related to the underlying disease or to antiparkinsonian drug therapy. The risk of developing melanoma in patients receiving rasagiline appears to be greater than that in the general population but comparable to that in patients with Parkinson's disease. Because of these findings, patients and clinicians should monitor for melanomas frequently. The manufacturer recommends that dermatologic examinations be performed by qualified clinicians (e.g., dermatologists) periodically; the frequency of dermatologic examinations should be determined by the patient's dermatologist.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2697
In the monotherapy study, hallucinations were reported as an adverse event in 1.3% of patients treated with 1 mg rasagiline and in 0.7% of patients treated with placebo. In the monotherapy trial, hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 1.3% of the 1 mg rasagiline treated patients and in none of the placebo treated patients. When used as an adjunct to levodopa, hallucinations were reported as an adverse event in approximately 5% of patients treated with 0.5 mg/day, 4% of patients treated with 1 mg/day rasagiline and 3% of patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in about 1% of patients treated with 0.5 mg/day or 1 mg/day and none of the placebo treated patients. Patients should be cautioned of the possibility of developing hallucinations and instructed to report them to their health care provider promptly should they develop.
FDA; Center for Drug Evaluation and Research; Label Information for Azilect (Rasagiline) (Last updated May 2006). Available from, as of February 20, 2009: https://www.fda.gov/cder/foi/label/2006/021641lbl.pdf
Safety and efficacy of rasagiline have not been established in pediatric patients younger than 18 years of age.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2697
For more Drug Warnings (Complete) data for RASAGILINE (10 total), please visit the HSDB record page.

7 Pharmacology and Biochemistry

7.1 Pharmacodynamics

Rasagiline is a propargylamine and an irreversible inhibitor of monoamine oxidase (MAO). MAO, a flavin-containing enzyme, regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues. It is classified into two major molecular species, A and B, and is localized in mitochondrial membranes throughout the body in nerve terminals, brain, liver and intestinal mucosa. MAO-A is found predominantly in the GI tract and liver, and regulates the metabolic degradation of circulating catecholamines and dietary amines. MAO-B is the major form in the human brain and is responsible for the regulation of the metabolic degradation of dopamine and phenylethylamine. In ex vivo animal studies in brain, liver and intestinal tissues rasagiline was shown to be a potent,selective, and irreversible monoamine oxidase type B (MAO-B) inhibitor. At the recommended therapeutic doses, Rasagiline was also shown to be a potent and irreversible inhibitor of MAO-B in platelets. The selectivity of rasagiline for inhibiting only MAO-B (and not MAO-A) in humans and the sensitivity to tyramine during rasagiline treatment at any dose has not been sufficiently characterized to avoid restriction of dietary tyramine and amines contained in medications.

7.2 MeSH Pharmacological Classification

Monoamine Oxidase Inhibitors
A chemically heterogeneous group of drugs that have in common the ability to block oxidative deamination of naturally occurring monoamines. (From Gilman, et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed, p414) (See all compounds classified as Monoamine Oxidase Inhibitors.)
Neuroprotective Agents
Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids. (See all compounds classified as Neuroprotective Agents.)

7.3 FDA Pharmacological Classification

1 of 2
FDA UNII
003N66TS6T
Active Moiety
RASAGILINE
Pharmacological Classes
Established Pharmacologic Class [EPC] - Monoamine Oxidase Inhibitor
Pharmacological Classes
Mechanisms of Action [MoA] - Monoamine Oxidase Inhibitors
FDA Pharmacology Summary
Rasagiline is a Monoamine Oxidase Inhibitor. The mechanism of action of rasagiline is as a Monoamine Oxidase Inhibitor.
2 of 2
Non-Proprietary Name
RASAGILINE
Pharmacological Classes
Monoamine Oxidase Inhibitors [MoA]; Monoamine Oxidase Inhibitor [EPC]

7.4 ATC Code

N04BD02
S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

N - Nervous system

N04 - Anti-parkinson drugs

N04B - Dopaminergic agents

N04BD - Monoamine oxidase b inhibitors

N04BD02 - Rasagiline

7.5 Absorption, Distribution and Excretion

Absorption
Rasagiline is rapidly absorbed following oral administration. The absolute bioavailability of rasagiline is about 36%.
Route of Elimination
Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway. After oral administration of 14C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total calculated recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine.
Volume of Distribution
87 L
After oral administration of (14)C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total calculated recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine.
FDA; Center for Drug Evaluation and Research; Label Information for Azilect (Rasagiline) (Last updated May 2006). Available from, as of February 20, 2009: https://www.fda.gov/cder/foi/label/2006/021641lbl.pdf
Rasagiline is rapidly absorbed; following oral administration, peak plasma concentrations are achieved in approximately 1 hour. The absolute bioavailability of rasagiline is about 36%. Following administration with a high-fat meal, peak plasma rasagiline concentrations and area under the plasma concentration-time curve (AUC) decreased by approximately 60 and 20%, respectively; because AUC is not substantially affected, rasagiline may be administered with or without food. Rasagiline readily crosses the blood-brain barrier. The mean steady-state or terminal half-life of rasagiline is 31 or 1.342 hours, respectively; however, there is no correlation between rasagiline's pharmacokinetic profile and its pharmacologic effects because the drug irreversibly inhibits MAO-B, and restoration of normal enzyme activity depends on the rate of de novo enzyme synthesis. Rasagiline is approximately 88-94% bound to plasma proteins, with 61-63% bound to albumin.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2698
IV studies in rats and dogs show that the volume of distribution (Vd) of rasagiline is several times that of total body water, indicating extensive tissue distribution. Tissue distribution of (14)C-rasagiline was studied in albino and pigmented rats, revealing peaks of tissue radioactivity between 0.25 and 0.5 hours. Distribution to large intestine, urinary bladder and lacrimal glands takes longer, whilst persistence (up to 24 hrs) was seen in eyes, skin and arterial walls of pigmented animals. In-vitro protein binding in plasma of animals is in the range of 70 to 90% and in human plasma in the range of 88 to 94%.
European Medicines Agency (EMEA), The European Agency for the Evaluation of Medicinal Products, European Public Assessment Report (EPAR) for Authorized Medicinal Products for Human Use; Azilect, Scientific Discussion (2005). Available from, as of February 25, 2009: https://www.emea.europa.eu/humandocs/PDFs/EPAR/Azilect/5289705en6.pdf
Oral studies with (14)C-rasagiline show that absorption is rapid in all species, with Cmax attained in less than 2 hours. Absolute bioavailability has been estimated as 53-69% in rats, 13-22% in dogs, and 36% in humans. Toxicokinetic analyses during the toxicology studies showed that exposure was linear at doses higher than the pharmacological selectivity for inhibition of MOA-B and was maintained up to about 5 mg/kg/day. However, kinetics became non-linear at higher doses, possibly indicating saturation of the elimination processes for both rasagiline and its metabolite aminoindan. Accumulation was seen only at the highest doses in the mouse and dog studies (60 and 21 mg/kg/day respectively).
European Medicines Agency (EMEA), The European Agency for the Evaluation of Medicinal Products, European Public Assessment Report (EPAR) for Authorized Medicinal Products for Human Use; Azilect, Scientific Discussion (2005). Available from, as of February 25, 2009: https://www.emea.europa.eu/humandocs/PDFs/EPAR/Azilect/5289705en6.pdf
For more Absorption, Distribution and Excretion (Complete) data for RASAGILINE (6 total), please visit the HSDB record page.

7.6 Metabolism / Metabolites

Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. In vitro experiments indicate that both routes of rasagiline metabolism are dependent on the cytochrome P450 (CYP) system, with CYP 1A2 being the major isoenzyme involved in rasagiline metabolism.
Rasagiline is extensively metabolized in the liver following oral administration. In vitro studies have shown that CYP1A2 is the predominant P450 isoform involved in the metabolic elimination of rasagiline. The primary human plasma metabolite formed following biotransformation of rasagiline is aminoindan. The proposed principal biotransformation pathways of rasagiline in human are N-dealkylation, hydroxylation of the indan ring, along with Phase II N or O-conjugation, including N-glucuronidation of the parent drug and of its metabolites. There was no bioconversion of rasagiline mesylate (R enantiomer) to its S enantiomer within the human body, as determined in plasma samples for healthy volunteers dosed with rasagiline. Rasagiline is not metabolized to amphetamine or methamphetamine.
European Medicines Agency (EMEA), The European Agency for the Evaluation of Medicinal Products, European Public Assessment Report (EPAR) for Authorized Medicinal Products for Human Use; Azilect, Scientific Discussion (2005). Available from, as of February 25, 2009: https://www.emea.europa.eu/humandocs/PDFs/EPAR/Azilect/5289705en6.pdf
An extensive first pass metabolism effect is evident, likely due to rasagiline binding to MAO sites in the intestine prior to passing the liver. Metabolism is rapid and extensive, with a similar profile in all tested species. The primary route of biotransformation is via N-dealkylation to form aminoindan and by hydroxylation to form 3-hydroxy-N-propargyl-1-aminoindan. Conjugation by sulfide or glucuronic acid occurs. Microsomal studies indicate CYP1A2 as the primary metabolising isotype, but rasagiline is neither an inducer nor inhibitor of cytochrome p450. The metabolism of rasagiline under inhibition, induction of CYP1A2 or in presence of concomitant substrate to the enzyme has been addressed clinically.
European Medicines Agency (EMEA), The European Agency for the Evaluation of Medicinal Products, European Public Assessment Report (EPAR) for Authorized Medicinal Products for Human Use; Azilect, Scientific Discussion (2005). Available from, as of February 25, 2009: https://www.emea.europa.eu/humandocs/PDFs/EPAR/Azilect/5289705en6.pdf
Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. The metabolism of rasagiline proceeds through two main pathways: N-dealkylation and/or hydroxylation to yield 1-aminoindan (AI), 3-hydroxy-N-propargyl-1 aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan (3-OH-AI). In vitro experiments indicate that both routes of rasagiline metabolism are dependent on the cytochrome P450 (CYP) system, with CYP 1A2 being the major isoenzyme involved in rasagiline metabolism. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway.
FDA; Center for Drug Evaluation and Research; Label Information for Azilect (Rasagiline) (Last updated May 2006). Available from, as of February 20, 2009: https://www.fda.gov/cder/foi/label/2006/021641lbl.pdf

7.7 Biological Half-Life

Rasagiline has a mean steady-state half life of 3 hours but there is no correlation of pharmacokinetics with its pharmacological effect because of its irreversible inhibition of MAO-B.
Rasagiline's mean steady-state half life is 3 hours ... .
FDA; Center for Drug Evaluation and Research; Label Information for Azilect (Rasagiline) (Last updated May 2006). Available from, as of February 20, 2009: https://www.fda.gov/cder/foi/label/2006/021641lbl.pdf
Rasagiline is eliminated with a half life of about 0.6 - 2 hours and ranging from 0.3 to 3.5 hours across the 0.5 to 20 mg dose range examined following oral administration.
European Medicines Agency (EMEA), The European Agency for the Evaluation of Medicinal Products, European Public Assessment Report (EPAR) for Authorized Medicinal Products for Human Use; Azilect, Scientific Discussion (2005). Available from, as of February 25, 2009: https://www.emea.europa.eu/humandocs/PDFs/EPAR/Azilect/5289705en6.pdf

7.8 Mechanism of Action

The precise mechanisms of action of rasagiline is unknown. One mechanism is believed to be related to its MAO-B inhibitory activity, which causes an increase in extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline's beneficial effects seen in models of dopaminergic motor dysfunction.
The anti-Parkinson drug rasagiline (Azilect), an irreversible and selective monoamine oxidase (MAO)-B inhibitor, was shown to possess neuroprotective activities, involving multiple survival pathways among them the up-regulation of protein kinase C (PKC)alpha, PKCepsilon, the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w and the induction of brain-derived- and glial cell line-derived neurotrophic factors (BDNF, GDNF). More recently, employing conventional neurochemical techniques, as well as transcriptomic and proteomic screening tools, combined with a biology-based clustering method, it was shown that rasagiline also possesses neurorescue/neurogenesis activity in mice midbrain dopaminergic neurons when given chronically, post-MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). This action was attributed to the activation of cell signaling mediators associated with neurotrophic factors responsive-tyrosine kinase receptor (Trk) pathway, including ShcC, SOS, AF6, Rin1, and Ras and the increase in the Trk-downstream effecter phosphatidylinositol 3 kinase (PI3K) protein and its substrate, Akt/PKB. ...
Mandel SA et al; Neurochem Res 32 (10): 1694-9 (2007)
The anti-Parkinson's disease drug rasagiline, the anti-Alzheimer's disease drug ladostigil, and their propargyl moiety, propargylamine, enhanced the expression levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, endogenous neurotrophic factors associated with activation of phosphatidylinositol 3-kinase, protein kinase, and mitogen-activated protein kinase cell signaling/survival pathways. ...
Weinreb O et al; Ann N Y Acad Sci 1122: 155-68 (2007)
Rasagiline mesylate, a propargylamine, is an irreversible monoamine oxidase-B (MAO-B) inhibitor. MAO is a mitochondrial enzyme that regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues. There appear to be at least 2 isoforms of MAO, MAO-A and MAO-B, which differ in localization and substrate specificity. MAO-A, predominantly found in the GI tract and liver, regulates the metabolic degradation of circulating catecholamines and dietary amines (e.g., tyramine). MAO-B, predominantly found in the brain, regulates the metabolic degradation of dopamine and phenylethylamine. Inhibition of MAO-A in the periphery results in systemic absorption of dietary amines (e.g., tyramine), which, in substantial amounts, can cause release of norepinephrine and subsequent substantial increases in blood pressure. Inhibition of MAO-B results in increased extracellular concentrations of dopamine and, therefore, enhanced dopaminergic activity in the striatum. While the precise mechanisms of activity of rasagiline have not been fully characterized, data from ex vivo animal studies indicate that the drug potently and irreversibly inhibits MAO-B in brain, liver, and intestinal tissues; the selectivity of rasagiline in inhibiting MAO-B (and not MAO-A) in humans has not been fully elucidated to avoid restriction of dietary tyramine and sympathomimetic amines.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2698

7.9 Human Metabolite Information

7.9.1 Cellular Locations

  • Cytoplasm
  • Membrane

8 Use and Manufacturing

8.1 Uses

Rasagiline is an irreversible inhibitor of monoamine oxidase and is used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases.
Wishart DS et al; DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 2006 1;34. Available from, as of Jan 30, 2009: https://www.drugbank.ca
Therap Cat: Antiparkinsonian
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1398

8.1.1 Use Classification

Human drugs -> Anti-Parkinson drugs -> Human pharmacotherapeutic group -> EMA Drug Category

8.2 Methods of Manufacturing

Preparation: M.B.H. Youdim et al., EP 436492; eidem. US 5457133 (1991, 1995 both to Teva).
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1398

8.3 Formulations / Preparations

Oral: Tablets: 0.5 mg (of rasagiline) Azilect (Teva Neuroscience); 1 mg (of rasagiline) Azilect (Teva Neuroscience). /Rasagiline mesylate/
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2698

9 Safety and Hazards

9.1 Hazards Identification

9.1.1 GHS Classification

Pictogram(s)
Irritant
Signal
Warning
GHS Hazard Statements

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]

H319 (100%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

H335 (100%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

Precautionary Statement Codes

P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary
The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

9.2 Accidental Release Measures

9.2.1 Disposal Methods

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

9.3 Regulatory Information

9.3.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl rasagline mesylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Rasagline mesylate/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 10, 2009: https://www.fda.gov/cder/ob/

10 Toxicity

10.1 Toxicological Information

10.1.1 Hepatotoxicity

Rasagiline has been reported to cause serum enzyme elevations in a small proportion of patients treated long term, although the abnormalities were usually mild and self-limiting. Rasagiline has not been implicated in cases of acute liver injury, but such instances have been reported with other less specific MAO inhibitors.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

10.1.2 Drug Induced Liver Injury

Compound
rasagiline
DILI Annotation
Ambiguous DILI-concern
Severity Grade
3
Label Section
Adverse reactions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

10.1.3 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

No clinical use of rasagiline during breastfeeding has been reported. Rasagiline might reduce serum prolactin and interfere with milk production. An alternate drug may be preferred, especially while nursing a newborn or preterm infant.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

Animal studies show that rasagiline reduces serum prolactin. The clinical relevance of these findings in nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

10.1.4 Interactions

Antidepressant Agents, Selective Serotonin-reuptake Inhibitors (SSRIs): Potential pharmacologic interaction resembling serotonin syndrome (hyperthermia, rigidity, myoclonus, autonomic instability with rapid vital sign fluctuations, and mental status changes that may progress to extreme agitation, delirium, coma, and death). Concomitant use generally should be avoided. At least 14 days should elapse between discontinuance of rasagiline and initiation of an SSRI.Because both fluoxetine and its principal metabolite have relatively long half-lives, the manufacturer of rasagiline recommends that at least 5 weeks (or longer with high-dose or long-term fluoxetine therapy) elapse between discontinuance of fluoxetine therapy and initiation of rasagiline.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2697
Inhibitors of CYP1A2: Pharmacokinetic interaction observed during concomitant use with ciprofloxacin (increased plasma rasagiline concentrations). Dosage of rasagiline should be limited ... in patients receiving the drug concomitantly with ciprofloxacin or other CYP1A2 inhibitors.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2697
St. John's wort (Hypericum perforatum): Concomitant use is contraindicated.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2698
Potential pharmacologic interaction (resembling serotonin syndrome) with meperidine (coma, severe hypertension or hypotension, severe respiratory depression, seizures, malignant hyperpyrexia, excitation, peripheral vascular collapse, and death). Concomitant use with meperidine, methadone, propoxyphene, or tramadol is contraindicated. At least 14 days should elapse between discontinuance of rasagiline and initiation of meperidine.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2698
For more Interactions (Complete) data for RASAGILINE (12 total), please visit the HSDB record page.

10.1.5 Antidote and Emergency Treatment

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1

10.1.6 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ Hypertensive crisis (i.e., cheese reaction), manifested as marked elevations in systemic blood pressure, may occur at any dose of rasagiline following ingestion of foods containing large amounts of tyramine or drug preparations containing sympathomimetic amines. Hypertensive crisis may be fatal and requires immediate treatment or hospitalization. Patients should be advised to avoid foods containing large amounts of tyramine and drug preparations containing sympathomimetic amines during and for 2 weeks following discontinuance of rasagiline. Patients also should be instructed on how to recognize manifestations of a hypertensive crisis and to immediately notify a clinician if such manifestations occur.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2697
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2697
/OTHER TOXICOLOGY INFORMATION/ Antidepressant Agents, Selective Serotonin-reuptake Inhibitors (SSRIs): Potential pharmacologic interaction resembling serotonin syndrome (hyperthermia, rigidity, myoclonus, autonomic instability with rapid vital sign fluctuations, and mental status changes that may progress to extreme agitation, delirium, coma, and death). Concomitant use generally should be avoided. At least 14 days should elapse between discontinuance of rasagiline and initiation of an SSRI.Because both fluoxetine and its principal metabolite have relatively long half-lives, the manufacturer of rasagiline recommends that at least 5 weeks (or longer with high-dose or long-term fluoxetine therapy) elapse between discontinuance of fluoxetine therapy and initiation of rasagiline.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2697

10.1.7 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Acute Exposure/ Single dose toxicity studies were conducted by the intravenous route in rats and by the oral route in mice, rats and dogs. Studies were initially conducted with the hydrochloride salt and subsequently with the more stable mesylate salt. Single dose bridging studies were undertaken which established the essentially similar toxicity and kinetics profiles of the hydrochloride and mesylate salts in rats and dogs. Mortalities were induced in rats by intravenous doses greater than or equal to 69 mg/kg/day. Mortalities were induced in mice at oral doses of greater than or equal to 206 mg/kg, in rats at oral doses greater than or equal to 155 mg/kg and in dogs at oral doses of greater than or equal to 84 mg/kg. Death was a result of the functional neuropharmacological changes that can be anticipated when excessive doses of a molecule capable of inhibiting the oxidation of biogenic amines are administered. The maximal non-lethal oral dose for rats and mice was about 100 mg/kg/day and the maximum tolerable dose (MTD) in dogs was 42 mg/kg. These doses represent considerable multiples of the recommended clinically relevant maximum dose of 1 mg/patient/day.
European Medicines Agency (EMEA), The European Agency for the Evaluation of Medicinal Products, European Public Assessment Report (EPAR) for Authorized Medicinal Products for Human Use; Azilect, Scientific Discussion (2005). Available from, as of February 25, 2009: https://www.emea.europa.eu/humandocs/PDFs/EPAR/Azilect/5289705en6.pdf
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The rat and dog were selected for the conduct of repeat dose toxicity studies, both species having been shown to be pharmacologically responsive to rasagiline-induced inhibition of MAO-B. Repeat dose intravenous toxicity studies of 4-week duration were conducted at maximum doses of 3 mg/kg/day in rats and 5 mg/kg/day in dogs. Repeat dose oral toxicity studies of up to 26 week duration were conducted in rats employing doses spanning the range 0.14 to 17 mg/kg/day and of up to 52 week duration in dogs employing doses spanning 0.28 to 21.0 mg/kg/day. When the multiples of the systemic exposures to rasagiline and aminoindan across the range of doses used for the repeat dose toxicity studies in rats and dogs are compared with the clinically relevant human exposure at the maximum recommended daily dose of 1 mg/day/patient, it is observed that the lowest doses used for the repeat dose toxicity studies afforded at least 7-fold the mean Cmax and AUC last values for PAI (rasagiline) in humans receiving 1 mg/day. The highest doses used for the repeat dose toxicology studies afforded at least 250-fold Cmax and AUC last values for PAI in humans receiving 1 mg/day. After intravenous and oral dosing the principal manifestations of toxicity were related to the loss of selectivity for MAO-B (i.e. reduced food intake and weight gain and hyperactivity and/or aggression in rats). At the higher oral doses these findings were sometimes accompanied by increases in liver weight and changes in hepatocyte morphology in rats. The liver changes were consistent with changes observed in rats treated with hepatic microsomal enzyme inducers, there was however no evidence from studies that measured hepatic microsomal proteins to support this hypothesis. Suspected changes in thyroid and bladder morphology identified in the rat 13-week oral study were not corroborated by findings in either the 4-week or 26-week rat oral studies. The no adverse effect level (NOAEL) defined after 26 weeks treatment of rats and 52 weeks treatment of dogs was 5.1 mg/kg/day (for both rats and dogs). In terms of AUC last values, the animal NOAELs afford multiples of at least 15-fold with respect to exposure to PAI at the clinical dose of 1 mg/patient/day.
European Medicines Agency (EMEA), The European Agency for the Evaluation of Medicinal Products, European Public Assessment Report (EPAR) for Authorized Medicinal Products for Human Use; Azilect, Scientific Discussion (2005). Available from, as of February 25, 2009: https://www.emea.europa.eu/humandocs/PDFs/EPAR/Azilect/5289705en6.pdf
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Two year carcinogenicity studies were conducted in CD-1 mice at oral (gavage) doses of 1, 15, and 45 mg/kg and in Sprague-Dawley rats at oral (gavage) doses of 0.3, 1, and 3 mg/kg (males) or 0.5, 2, 5, and 17 mg/kg (females). In rats, there was no increase in tumors at any dose tested. Plasma exposures at the highest dose tested were approximately 33 and 260 times, in male and female rats, respectively, the expected plasma exposures in humans at the maximum recommended dose (MRD) of 1 mg/day.
FDA; Center for Drug Evaluation and Research; Label Information for Azilect (Rasagiline) (Last updated May 2006). Available from, as of February 20, 2009: https://www.fda.gov/cder/foi/label/2006/021641lbl.pdf
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In the mice study, the doses administered were 1, 15 and 45 mg/kg/day. Increased incidences of combined lung adenomas/adenocarcinomas were observed in both genders, with a lower safety margin (based on human and animal exposure) in males (rasagiline exposure ratios of mice, to humans treated with 1 mg/day (AUC mice/AUC humans) were 6, 213 and 1418 for males and 4, 144 and 419 for females dosed with 1, 15 and 45 mg/kg/day, respectively.). Historical control data showed a wide range of incidences of lung tumors (combined adenoma/carcinoma in males up to 46% and in females up to 28.6%). Although it is recognized that even at 45 mg/kg/day the observed incidence of combined bronchiolar/alveolar adenoma and/or carcinoma was only slightly above the testing laboratory's historical control range for females and was within the historical control range for males CD-1 mice, there was a clear dose-related increase (13/13; 11/12; 23/19; 24/20 respectively in male/female controls, 1, 15 and 45 mg/kg/day dose groups). Furthermore, safety margin at NOEL for males was only 6 (even if it should be noted that there is a 15 fold increase in between the low and intermediate doses).
European Medicines Agency (EMEA), The European Agency for the Evaluation of Medicinal Products, European Public Assessment Report (EPAR) for Authorized Medicinal Products for Human Use; Azilect, Scientific Discussion (2005). Available from, as of February 25, 2009: https://www.emea.europa.eu/humandocs/PDFs/EPAR/Azilect/5289705en6.pdf
For more Non-Human Toxicity Excerpts (Complete) data for RASAGILINE (11 total), please visit the HSDB record page.

10.1.8 Populations at Special Risk

As with other MAOI's, Azilect is contraindicated in patients with pheochromocytoma. /Rasagiline mesylate/
FDA; Center for Drug Evaluation and Research; Label Information for Azilect (Rasagiline) (Last updated May 2006). Available from, as of February 20, 2009: https://www.fda.gov/cder/foi/label/2006/021641lbl.pdf
Following daily administration for 7 days, the area under the plasma concentration-time curve (AUC) or peak plasma concentration of rasagiline was increased by 2- or 1.4-fold, respectively, in patients with mild (Child-Pugh score of 5-6) hepatic impairment and by seven- or twofold, respectively, in patients with moderate (Child-Pugh score of 7-9) hepatic impairment. Dosage adjustment is recommended in patients with mild hepatic impairment. Use is not recommended in patients with moderate or severe (Child-Pugh score of 7 or greater) hepatic impairment.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2697

10.1.9 Protein Binding

Plasma protein binding ranges from 88-94% with mean extent of binding of 61-63% to human albumin over the concentration range of 1-100 ng/ml.

11 Associated Disorders and Diseases

12 Literature

12.1 Consolidated References

12.2 NLM Curated PubMed Citations

12.3 Springer Nature References

12.4 Thieme References

12.5 Wiley References

12.6 Chemical Co-Occurrences in Literature

12.7 Chemical-Gene Co-Occurrences in Literature

12.8 Chemical-Disease Co-Occurrences in Literature

13 Patents

13.1 Depositor-Supplied Patent Identifiers

13.2 WIPO PATENTSCOPE

13.3 Chemical Co-Occurrences in Patents

13.4 Chemical-Disease Co-Occurrences in Patents

13.5 Chemical-Gene Co-Occurrences in Patents

14 Interactions and Pathways

14.1 Protein Bound 3D Structures

14.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

14.2 Chemical-Target Interactions

14.3 Drug-Drug Interactions

14.4 Drug-Food Interactions

  • Avoid St. John's Wort. Co-administration of rasagiline with this herb is contraindicated.
  • Avoid tyramine-containing foods and supplements. Avoid food containing high amounts of tyramine (>150mg) as these may increase the risk of hypertensive reaction. Tyramine-containing foods include cheese, red wine, fava beans, pickled food, cured food, and alcoholic beverages.
  • Take with or without food.

15 Biological Test Results

15.1 BioAssay Results

16 Classification

16.1 MeSH Tree

16.2 NCI Thesaurus Tree

16.3 ChEBI Ontology

16.4 KEGG: ATC

16.5 KEGG: Target-based Classification of Drugs

16.6 KEGG: Drug Groups

16.7 WHO ATC Classification System

16.8 FDA Pharm Classes

16.9 ChemIDplus

16.10 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

16.11 ChEMBL Target Tree

16.12 UN GHS Classification

16.13 NORMAN Suspect List Exchange Classification

16.14 EPA DSSTox Classification

16.15 MolGenie Organic Chemistry Ontology

17 Information Sources

  1. BindingDB
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    https://www.bindingdb.org/rwd/bind/info.jsp
  2. Drug Gene Interaction database (DGIdb)
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    http://www.dgidb.org/downloads
  3. DrugBank
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    https://www.drugbank.ca/legal/terms_of_use
  4. IUPHAR/BPS Guide to PHARMACOLOGY
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    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
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  6. CAS Common Chemistry
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    https://creativecommons.org/licenses/by-nc/4.0/
  7. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
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    https://www.cancer.gov/policies/copyright-reuse
  9. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
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    https://echa.europa.eu/web/guest/legal-notice
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  12. Hazardous Substances Data Bank (HSDB)
  13. Human Metabolome Database (HMDB)
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    http://www.hmdb.ca/citing
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    http://www.ebi.ac.uk/Information/termsofuse.html
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    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
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  21. Drug Induced Liver Injury Rank (DILIrank) Dataset
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  22. European Medicines Agency (EMA)
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
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    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
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    Rasagiline
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
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    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  28. National Drug Code (NDC) Directory
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
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    LICENSE
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    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
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  32. NCI Thesaurus (NCIt)
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  33. NIPH Clinical Trials Search of Japan
  34. NLM RxNorm Terminology
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    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
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    https://www.pharmgkb.org/page/policies
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  38. RCSB Protein Data Bank (RCSB PDB)
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    https://www.rcsb.org/pages/policies
  39. Springer Nature
  40. Thieme Chemistry
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    https://creativecommons.org/licenses/by-nc-nd/4.0/
  41. Wikidata
  42. Wikipedia
  43. Wiley
  44. PubChem
  45. Medical Subject Headings (MeSH)
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    https://www.nlm.nih.gov/copyright.html
    Monoamine Oxidase Inhibitors
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  46. GHS Classification (UNECE)
  47. MolGenie
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  48. PATENTSCOPE (WIPO)
  49. NCBI
CONTENTS