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Ouabain

PubChem CID
439501
Structure
Ouabain_small.png
Ouabain_3D_Structure.png
Molecular Formula
Synonyms
  • ouabain
  • G-Strophanthin
  • Ouabaine
  • Gratus strophanthin
  • Ouabagenin L-rhamnoside
Molecular Weight
584.7 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-06-24
  • Modify:
    2025-01-18
Description
Ouabain appears as odorless, white crystals or crystalline powder as an octahydrate. Used to produce rapid digitalization in acute congestive heart failure. Also recommended in treatment of atrial or nodal paroxysmal tachycardia and atrial flutter. (EPA, 1998)
U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.
Ouabain is a steroid hormone that is a multi-hydroxylated alpha-L-rhamnosyl cardenoloide. It binds to and inhibits the plasma membrane Na(+)/K(+)-ATPase (sodium pump). It has been isolated naturally from Strophanthus gratus. It has a role as an EC 3.6.3.9 (Na(+)/K(+)-transporting ATPase) inhibitor, an EC 3.6.3.10 (H(+)/K(+)-exchanging ATPase) inhibitor, an EC 2.3.3.1 [citrate (Si)-synthase] inhibitor, an EC 3.1.3.41 (4-nitrophenylphosphatase) inhibitor, a plant metabolite, a cardiotonic drug, an ion transport inhibitor and an anti-arrhythmia drug. It is a cardenolide glycoside, a steroid hormone, an alpha-L-rhamnoside, a 14beta-hydroxy steroid, a 5beta-hydroxy steroid and an 11alpha-hydroxy steroid. It is a conjugate acid of an ouabain(1-).
A cardioactive glycoside consisting of rhamnose and ouabagenin, obtained from the seeds of Strophanthus gratus and other plants of the Apocynaceae; used like digitalis. It is commonly used in cell biological studies as an inhibitor of the NA(+)-K(+)-exchanging ATPase.
See also: Glycosides (annotation moved to).

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Ouabain.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

3-[(1R,3S,5S,8R,9S,10R,11R,13R,14S,17R)-1,5,11,14-tetrahydroxy-10-(hydroxymethyl)-13-methyl-3-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy-2,3,4,6,7,8,9,11,12,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2H-furan-5-one
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C29H44O12/c1-13-22(34)23(35)24(36)25(40-13)41-15-8-19(32)28(12-30)21-17(3-5-27(28,37)9-15)29(38)6-4-16(14-7-20(33)39-11-14)26(29,2)10-18(21)31/h7,13,15-19,21-25,30-32,34-38H,3-6,8-12H2,1-2H3/t13-,15-,16+,17+,18+,19+,21+,22-,23+,24+,25-,26+,27-,28+,29-/m0/s1
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

LPMXVESGRSUGHW-HBYQJFLCSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

C[C@H]1[C@@H]([C@H]([C@H]([C@@H](O1)O[C@H]2C[C@H]([C@@]3([C@@H]4[C@@H](CC[C@@]3(C2)O)[C@]5(CC[C@@H]([C@]5(C[C@H]4O)C)C6=CC(=O)OC6)O)CO)O)O)O)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C29H44O12
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

630-60-4
11018-89-6

2.3.2 Deprecated CAS

36-06-6

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 UN Number

2.3.6 ChEBI ID

2.3.7 ChEMBL ID

2.3.8 DrugBank ID

2.3.9 DSSTox Substance ID

2.3.10 HMDB ID

2.3.11 KEGG ID

2.3.12 Lipid Maps ID (LM_ID)

2.3.13 Metabolomics Workbench ID

2.3.14 Nikkaji Number

2.3.15 PharmGKB ID

2.3.16 Pharos Ligand ID

2.3.17 Wikidata

2.3.18 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Acocantherin
  • Acolongifloroside K
  • G Strophanthin
  • G-Strophanthin
  • Ouabain

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
584.7 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
-1.7
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
8
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
12
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
584.28327683 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
584.28327683 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
207 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
41
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
1080
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
15
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

Ouabain appears as odorless, white crystals or crystalline powder as an octahydrate. Used to produce rapid digitalization in acute congestive heart failure. Also recommended in treatment of atrial or nodal paroxysmal tachycardia and atrial flutter. (EPA, 1998)
U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.
Solid

3.2.2 Color / Form

Crystals from water
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 12th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2012., p. V4: 3435
Plates (+9 water molecules)
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 95th Edition. CRC Press LLC, Boca Raton: FL 2014-2015, p. 3-430

3.2.3 Melting Point

392 °F (EPA, 1998)
U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.
200 °C
PhysProp
200 °C
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 95th Edition. CRC Press LLC, Boca Raton: FL 2014-2015, p. 3-430

3.2.4 Solubility

10300 mg/L
Slightly soluble in water
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 95th Edition. CRC Press LLC, Boca Raton: FL 2014-2015, p. 3-430
Very soluble in alcohol
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 95th Edition. CRC Press LLC, Boca Raton: FL 2014-2015, p. 3-430
4.61e+00 g/L

3.2.5 LogP

-2
SANGSTER (1994)
log Kow = -2.00
Sangster J; LOGKOW Databank. Sangster Res. Lab., Montreal Quebec, Canada (1994)
-1.2

3.2.6 Optical Rotation

Specific optical rotation (c = 1 calculated as anhydrous form): -31 deg to -32.5 deg at 25 °C/D /Ouabain octahydrate/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1281

3.2.7 Decomposition

Melts with decomposition at 190 °C.
Larranaga, M.D., Lewis, R.J. Sr., Lewis, R.A.; Hawley's Condensed Chemical Dictionary 16th Edition. John Wiley & Sons, Inc. Hoboken, NJ 2016., p. 1017
When heated to decomposition it emits acrid smoke and irritating fumes.
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2787

3.2.8 Collision Cross Section

234 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

228.35 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

244.36 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

241.61 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111

3.2.9 Other Experimental Properties

Hygroscopic
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 95th Edition. CRC Press LLC, Boca Raton: FL 2014-2015, p. 3-430
Shiny plates (from water) which give up their water of crystallization at 130 °C. When anhydrous, decomposes at about 190 °C. Stable in air but affected by light. One gram dissolves in about 75 mL water, in 5 mL boiling water, in 100 mL alcohol, in 8 mL boiling alcohol. Also soluble in amyl alcohol, dioxane. Slightly solulble in ether, chloroform, ethyl acetate. Aqueous solutions are neutral to limus. /Ouabain octahydrate/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1281
Odorless; aqueous solutions are neutral to litmus paper; melts indistinctly and with decomposition at about 190 °C; white crystals or crystalline powder /Ouabain octahydrate/
Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980., p. 798

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceutical
S120 | DUSTCT2024 | Substances from Second NORMAN Collaborative Dust Trial | DOI:10.5281/zenodo.13835254
Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749

3.3.2 Lipids

Lipids -> Sterol Lipids [ST] -> Sterols [ST01] -> Cardanolides and derivatives [ST0112]

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 13C NMR Spectra

Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
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4.2 Mass Spectrometry

4.2.1 MS-MS

1 of 8
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Spectra ID
Ionization Mode
Positive
Top 5 Peaks

129.0699 100

91.0544 78.90

105.0699 59.49

141.0701 59.01

117.0699 55.45

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2 of 8
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Spectra ID
Ionization Mode
Positive
Top 5 Peaks

385.2009 100

355.1903 91.69

367.1903 82.68

337.1797 79.78

373.2008 78.78

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4.2.2 LC-MS

1 of 17
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Authors
Markus Kohlhoff, Natural Product Chemistry Lab (CPqRR/FIOCRUZ, Brazil)
Instrument
maXis (Bruker Daltonics)
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
10 eV
Fragmentation Mode
CID
Column Name
Waters Atlantis C18 3um 2.1x150mm
Precursor Adduct
[M+H]+
Top 5 Peaks

585.2913 999

586.2946 295

439.2333 226

403.212 146

421.2226 67

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License
CC BY-NC
2 of 17
View All
Authors
Markus Kohlhoff, Natural Product Chemistry Lab (CPqRR/FIOCRUZ, Brazil)
Instrument
maXis (Bruker Daltonics)
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
20 eV
Fragmentation Mode
CID
Column Name
Waters Atlantis C18 3um 2.1x150mm
Precursor Adduct
[M+H]+
Top 5 Peaks

403.2101 999

439.2311 775

385.1996 773

373.1996 731

355.1892 470

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License
CC BY-NC

4.2.3 Other MS

1 of 4
View All
Other MS
MASS: 3872 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63)
2 of 4
View All
MS Category
Experimental
MS Type
Other
MS Level
MS2
Precursor Type
[M-H]-
Precursor m/z
583.2760004
Ionization Mode
negative
Retention Time
2.353615753
Top 5 Peaks

371.184629 0.27

419.205413 0.15

437.215332 0.13

353.17413 0.12

401.194548 0.06

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4.3 UV Spectra

UV: 5-909 (Organic Electronic Spectral Data, Phillips et al, John Wiley & Sons, New York)
Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V2: 2069

4.4 IR Spectra

IR Spectra
IR: 18182 (Sadtler Research Laboratories IR Grating Collection)

4.5 Other Spectra

SADTLER REFERENCE NUMBER: 7549 (IR, PRISM)
Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979., p. C-499

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

For the treatment of atrial fibrillation and flutter and heart failure

7.2 Therapeutic Uses

/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Ouabain is included in the database.
NIH/NLM; ClinicalTrials.Gov. Available from, as of February 1, 2017: https://clinicaltrials.gov/ct2/results?term=Ouabain&Search=Search
/EXPL THER/ Up-regulation of placental soluble fms-like tyrosine kinase 1 (sFlt1) contributes to the pathogenesis of preeclampsia. To evaluate novel upstream pathways that regulate placental sFlt1 production, we screened a library of natural compounds (n=502) in human placental cell lines. Here, we report 3 compounds in the cardiac glycoside family, ouabain, gitoxigenin, and digitoxin, that inhibit placental sFlt1 production at nanomolar concentrations in vitro. We further characterized ouabain and demonstrated that it inhibits sFlt1 mRNA and protein expression in human placental cytotrophoblasts and explant cultures in a dose- and time-dependent manner. Ouabain down-regulated sFlt1 production by inhibiting hypoxia-inducible factor 1 (HIF-1alpha) protein expression in the placenta. Furthermore, we found that phosphorylation of heat-shock protein 27 (HSP27) was necessary for ouabain to inhibit HIF-1alpha translation. In a rat model of pregnancy-induced hypertension, ouabain reduced mean arterial pressure and enhanced placental HSP27 phosphorylation without any adverse effects on pups ...
Rana S et al; FASEB J 28 (10): 4324-34 (2014)
/EXPL THER/ Cytotoxicity and proliferative effects of ouabain on H460 lung cancer cells were evaluated by the MTT assay. The levels of integrin proteins in response to ouabain were determined by western blotting. Anchorage-independent growth and migration behaviors were performed by the wound healing assay and colony formation assay, respectively. Herein, the results suggested that exposure of the lung cancer cells to physiological concentrations of ouabain significantly altered the level of integrins. Ouabain suppressed integrin alpha-4, alpha-5, alpha-v, beta-3 and beta-4, whereas it had no significant effect on integrin beta-1 and beta-4. According to the switch patterns of integrins, ouabain treatment resulted in a dramatic reduction of cell colony size and inhibition of cancer cell migration. However, ouabain-induced integrin switch had only a slight effect on chemotherapeutic drug susceptibility. Ouabain may have a role in suppressing cancer metastasis via integrin regulation.
Ninsontia C, Chanvorachote P; Anticancer Res 34 (10): 5495-502 (2014)
A recent study confirmed the long-known clinical experience that ouabain has an inhibitory effect on cardiotoxicity induced by digitalis glycosides. Ouabain at a low dosage delayed the start of arrythmia induced by digoxin on guinea pig papillary muscle. In addition, ouabain at a low dosage but not at a high dosage delayed the development of digoxin-induced arrhythmia in anesthetized guinea pigs. Thus, the long-known characteristic dose dependency of ouabain effects has been confirmed.
Furstenwerth H; lnt J Clin Pract 64 (12) 1591-4 (2010)
For more Therapeutic Uses (Complete) data for Ouabain (11 total), please visit the HSDB record page.

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Ouabain, a cardiac glycoside similar to digitoxin, is used to treat congestive heart failure and supraventricular arrhythmias due to reentry mechanisms, and to control ventricular rate in the treatment of chronic atrial fibrillation.

8.2 MeSH Pharmacological Classification

Cardiotonic Agents
Agents that have a strengthening effect on the heart or that can increase cardiac output. They may be CARDIAC GLYCOSIDES; SYMPATHOMIMETICS; or other drugs. They are used after MYOCARDIAL INFARCT; CARDIAC SURGICAL PROCEDURES; in SHOCK; or in congestive heart failure (HEART FAILURE). (See all compounds classified as Cardiotonic Agents.)
Enzyme Inhibitors
Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

8.3 ATC Code

C - Cardiovascular system

C01 - Cardiac therapy

C01A - Cardiac glycosides

C01AC - Strophanthus glycosides

C01AC01 - G-strophanthin

8.4 Absorption, Distribution and Excretion

The effect of i.v.-administered ouabain starts immediately after injection, reaches a maximum after 5 min, last 5-7 hr and then rapidly declines.
Furstenwerth H; lnt J Clin Pract 64 (12) 1591-4 (2010)
It is poorly absorbed from alimentary tract, where much of oral dose appears to be destroyed.
Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-842
Four, 7 and 10% of (3)H-ouabain had been absorbed 1, 5 and 15 hr respectively after oral administration to guinea pigs. Percentage absorbed was constant at each of 3 dose levels. ... Similar results obtained in man. ... /It/ was absorbed from GI tract of rats by passive diffusion. Absorption of im dose probably depended more on tissue-blood flow than on rates of diffusion ... 67% of iv dose was excreted in 30-min bile of rats. ... /It/ was actively transported from liver to bile, and carbon tetrachloride pretreatment of rats reduced biliary excretion by depressing this transport.
The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972., p. 67
Plasma clearance of ouabain following iv admin was much faster in rat than in rabbit or dog. Levels of radioactivity in plasma, bile, and liver ... determined 20 min after iv administration ... showed that rat exhibited overall bile to plasma concentration ratio of 1500, whereas same ratio was much less for rabbit (2.9) and dog (9.3). Liver/plasma and bile/liver concentration ratios ... were ... much greater in rat (20 and 71) than in rabbit (2.5 and 1.3) or dog (3.3 and 2.7). This species variation is thought to be important factor in resistance of rat to toxic effects of ouabain relative to rabbit and dog.
The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 575
For more Absorption, Distribution and Excretion (Complete) data for Ouabain (7 total), please visit the HSDB record page.

8.5 Metabolism / Metabolites

Ouabain ... is not bound extensively to plasma albumin and ... /is/ excreted largely unchanged.
Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 673

8.6 Biological Half-Life

... Almost entirely eliminated by renal excretion, with a biological-half-life ... about 21 hr in normal adults but longer in elderly persons & much longer in renal failure.
Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980., p. 798

8.7 Mechanism of Action

Ouabain inhibits the Na-K-ATPase membrane pump, resulting in an increase in intracellular sodium and calcium concentrations. Increased intracellular concentrations of calcium may promote activation of contractile proteins (e.g., actin, myosin). Ouabain also acts on the electrical activity of the heart, increasing the slope of phase 4 depolarization, shortening the action potential duration, and decreasing the maximal diastolic potential.
Ouabain, an endogenous digitalis compound, has been detected in nanomolar concentrations in the plasma of several mammals and is associated with the development of hypertension. In addition, plasma ouabain is increased in several hypertension models, and the acute or chronic administration of ouabain increases blood pressure in rodents. These results suggest a possible association between ouabain and the genesis or development and maintenance of arterial hypertension. One explanation for this association is that ouabain binds to the alpha-subunit of the Na(+) pump, inhibiting its activity. Inhibition of this pump increases intracellular Na(+), which reduces the activity of the sarcolemmal Na(+)/Ca(2+) exchanger and thereby reduces Ca(2+) extrusion. Consequently, intracellular Ca(2+) increases and is taken up by the sarcoplasmic reticulum, which, upon activation, releases more calcium and increases the vascular smooth muscle tone. In fact, acute treatment with ouabain enhances the vascular reactivity to vasopressor agents, increases the release of norepinephrine from the perivascular adrenergic nerve endings and promotes increases in the activity of endothelial angiotensin-converting enzyme and the local synthesis of angiotensin II in the tail vascular bed. Additionally, the hypertension induced by ouabain has been associated with central mechanisms that increase sympathetic tone, subsequent to the activation of the cerebral renin-angiotensin system. Thus, the association with peripheral mechanisms and central mechanisms, mainly involving the renin-angiotensin system, may contribute to the acute effects of ouabain-induced elevation of arterial blood pressure.
Padilha AS et al; Braz J Med Biol Res 44 (9): 933-8 (2011)
The migratory capability of cancer cells is one of the most important hallmarks reflecting metastatic potential. Ouabain, an endogenous cardiac glycoside produced by the adrenal gland, has been previously reported to have anti-tumor activities; however, its role in the regulation of cancer cell migration remains unknown. The present study has revealed that treatment with ouabain at physiological concentrations is able to inhibit the migratory activities of human lung cancer H292 cells. The negative effects of ouabain were found to be mediated through the suppression of migration regulatory proteins, such as focal adhesion kinase (FAK), ATP-dependent tyrosine kinase (Akt), and cell division cycle 42 (Cdc42). We found that the observed actions of ouabain were mediated via a reactive oxygen species (ROS)-dependent mechanism because the addition of ROS scavengers (N-acetylcysteine and glutathione) could reverse the effect of ouabain on cell migration. Furthermore, ouabain was shown to inhibit the spheroidal tumor growth and decrease the cancer cell adhesion to endothelial cells. However, the compound had no significant effect on anoikis of the cells. ...
Pongrakhananon V et al; PLoS One 8 (7): e68623 (2013)
The steroid Na(+)/K(+) ATPase (NKA) blocker ouabain has been shown to exhibit pro-apoptotic effects in various cell systems; however, the mechanism involved in those effects is unclear. Here, we have demonstrated that incubation of HeLa cells during 24 hr with nanomolar concentrations of ouabain or digoxin causes apoptotic death of 30-50% of the cells. Ouabain caused the activation of caspases-3/7 and -9; however, caspase-8 was unaffected. The fact that compound Z-LEHD-FMK reduced both apoptosis and caspase-9 activation elicited by ouabain, suggest a mitochondrially-mediated pathway. This was strengthened by the fact that ouabain caused ATP depletion and the release of mitochondrial cytochrome c into the cytosol. Furthermore, upon ouabain treatment mitochondrial disruption and redistribution into the cytosol were observed. A mitochondrial site of action for ouabain was further corroborated by tight co-localization of fluorescent ouabain with mitochondria. Finally, in ouabain-treated cells the histamine-elicited elevation of cytosolic Ca(2+) concentration ([Ca(2+)]c) suggests an additional effect on the endoplasmic reticulum (ER) leading to Ca(2+) store depletion. We conclude that fluorescent ouabain is taken up and tightly co-localizes with mitochondria of HeLa cells. This indicates that apoptosis may be triggered by a direct action of ouabain on mitochondria.
Alonso E et al; Steroids 78 (11): 1110-8 (2013)
Ouabain, a potent inhibitor of the Na(+), K(+)-ATPase, was identified as an endogenous substance. Recently, ouabain was shown to affect various immunological processes. We have previously demonstrated the ability of ouabain to modulate inflammation, but little is known about the mechanisms involved. Thus, the aim of the present work is to evaluate the immune modulatory role of ouabain on zymosan-induced peritonitis in mice. Our results show that ouabain decreased plasma exudation (33%). After induction of inflammation, OUA treatment led to a 46% reduction in the total number of cells, as a reflex of a decrease of polymorphonuclear leukocytes, which does not appear to be due to cell death. Furthermore, OUA decreased TNF-alpha (57%) and IL-1beta (58%) levels, without interfering with IL-6 and IL-10. Also, in vitro experiments show that ouabain did not affect endocytic capacity. Moreover, electrophoretic mobility shift assay (EMSA) shows that zymosan treatment increased (85%) NF-kappaB binding activity and that ouabain reduced (30%) NF-kappaB binding activity induced by zymosan. Therefore, our data suggest that ouabain modulated acute inflammatory response, reducing the number of cells and cytokines levels in the peritoneal cavity, as well as NFkappaB activation, suggesting a new mode of action of this substance.
Leite JA et al; Mediators Inflamm 2015: 265798 doi: 10.1155/2015/265798 (2015)
For more Mechanism of Action (Complete) data for Ouabain (9 total), please visit the HSDB record page.

8.8 Human Metabolite Information

8.8.1 Cellular Locations

  • Extracellular
  • Membrane

9 Use and Manufacturing

9.1 Uses

Ouabain is a cardiac glycoside commonly used in the laboratory for electrophysiological experiments in cardiac myocytes.
Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 7th ed. New York, NY: McGraw-Hill, 2008., p. 720
MEDICATION
MEDICATION (VET)

Use (kg; approx.) in Germany (2009): >10

Consumption (g per capita; approx.) in Germany (2009): 0.000122

Calculated removal (%): 45.4

For the treatment of atrial fibrillation and flutter and heart failure

9.1.1 Use Classification

Hazard Classes and Categories ->

9.2 Methods of Manufacturing

Obtained from the seeds of Strophanthus gratus ... ; also occurs in Acokanthera ouabaio Cathel and other A. spp, Apocynaceae.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1281
Derivation: From certain plants of the family Apocynaceae: Strophanthus spp. and the Acokanthera group of trees.
Larranaga, M.D., Lewis, R.J. Sr., Lewis, R.A.; Hawley's Condensed Chemical Dictionary 16th Edition. John Wiley & Sons, Inc. Hoboken, NJ 2016., p. 1017

9.3 General Manufacturing Information

EPA TSCA Commercial Activity Status
Card-20(22)-enolide, 3-[(6-deoxy-.alpha.-L-mannopyranosyl)oxy]-1,5,11,14,19-pentahydroxy-, (1.beta.,3.beta.,5.beta.,11.alpha.)-: ACTIVE
Hydrolysis yields one mol ouabagenin and one mol rhamnose.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1281

10 Identification

10.1 Analytic Laboratory Methods

An optimized flow-injection method for the determination of ouabain was based on its reaction with picric acid in alkaline media with spectrophotometric detection at 486 nm. The calibration graph was linear for 0.01-0.2 g/L ouabain, with relative std deviation between 0.62 and 2.16% and a sample throughput of 60/hr. This method was utilized for the determination of ouabain in injections.
Solich P et al; Anal Chim Acta 269 (2): 199-203 (1992)

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

1 of 3
View All
Pictogram(s)
Acute Toxic
Health Hazard
Signal
Danger
GHS Hazard Statements

H301 (97.6%): Toxic if swallowed [Danger Acute toxicity, oral]

H331 (100%): Toxic if inhaled [Danger Acute toxicity, inhalation]

H373 (97.6%): May causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]

Precautionary Statement Codes

P260, P261, P264, P270, P271, P301+P316, P304+P340, P316, P319, P321, P330, 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

Aggregated GHS information provided per 41 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Acute Tox. 3 (97.6%)

Acute Tox. 3 (100%)

STOT RE 2 (97.6%)

Acute toxicity - category 3

Acute toxicity - category 3

Specific target organ toxicity (repeated exposure) - category 2

11.1.3 Health Hazards

It is classified as extremely toxic. Probable oral lethal dose in humans is less than 5 mg/kg or a taste (less than 7 drops) for 70 kg (150-lb.) person. Exposure may result in respiratory and cardiac failure, and/or hyperalkemia. Patients with frequent premature ventricular heart beats or who have received any preparation of digitalis during preceding three weeks are prone to toxicity. (EPA, 1998)
U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.

11.1.4 Fire Hazards

When heated to decomposition, it emits acrid smoke and fumes. Hydrolysis yields one mole ouabagenin and one mole rhamnose. Stable in air, but affected by light (ouabain octahydrate) (EPA, 1998)
U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.

11.2 First Aid Measures

11.2.1 First Aid

Warning: Effects may be delayed up to 12 hours. Caution is advised. Vital signs should be monitored closely.

Signs and Symptoms of Ouabain Exposure: Acute ouabain exposure may produce the following signs and symptoms: nausea, vomiting, headache, lethargy, drowsiness, confusion, slowed pulse, varying degrees of heart block, and heart arrhythmias. Coma, respiratory failure, and heart failure may also occur.

Emergency Life-Support Procedures: Acute exposure to ouabain may require decontamination and life support for the victims. Emergency personnel should wear protective clothing appropriate to the type and degree of contamination. Air-purifying or supplied-air respiratory equipment should also be worn, as necessary. Rescue vehicles should carry supplies such as plastic sheeting and disposable plastic bags to assist in preventing spread of contamination.

Inhalation Exposure:

1. Move victims to fresh air. Emergency personnel should avoid self-exposure to ouabain.

2. Evaluate vital signs including pulse and respiratory rate, and note any trauma. If no pulse is detected, provide CPR. If not breathing, provide artificial respiration. If breathing is labored, administer oxygen or other respiratory support.

3. Obtain authorization and/or further instructions from the local hospital for administration of an antidote or performance of other invasive procedures.

4. Transport to a health care facility.

Dermal/Eye Exposure:

1. Remove victims from exposure. Emergency personnel should avoid self-exposure to ouabain.

2. Evaluate vital signs including pulse and respiratory rate, and note any trauma. If no pulse is detected, provide CPR. If not breathing, provide artificial respiration. If breathing is labored, administer oxygen or other respiratory support.

3. Remove and isolate contaminated clothing as soon as possible.

4. If eye exposure has occurred, eyes must be flushed with lukewarm water for at least 15 minutes.

5. Wash exposed skin areas thoroughly with water.

6. Obtain authorization and/or further instructions from the local hospital for administration of an antidote or performance of other invasive procedures.

7. Transport to a health care facility.

Ingestion Exposure:

1. Evaluate vital signs including pulse and respiratory rate, and note any trauma. If no pulse is detected, provide CPR. If not breathing, provide artificial respiration. If breathing is labored, administer oxygen or other respiratory support.

2. Obtain authorization and/or further instructions from the local hospital for administration of an antidote or performance of other invasive procedures.

3. Vomiting may be induced with syrup of Ipecac. If elapsed time since ingestion of ouabain is unknown or suspected to be greater than 30 minutes, do not induce vomiting and proceed to Step

4. Ipecac should not be administered to children under 6 months of age. Warning: Ingestion of ouabain may result in sudden onset of seizures or loss of consciousness. Syrup of Ipecac should be administered only if victims are alert, have an active gag-reflex, and show no signs of impending seizure or coma. If ANY uncertainty exists, proceed to Step

4. The following dosages of Ipecac are recommended: children up to 1 year old, 10 mL (1/3 oz); children 1 to 12 years old, 15 mL (1/2 oz); adults, 30 mL (1 oz). Ambulate (walk) the victims and give large quantities of water. If vomiting has not occurred after 15 minutes, Ipecac may be readministered. Continue to ambulate and give water to the victims. If vomiting has not occurred within 15 minutes after second administration of Ipecac, administer activated charcoal.

4. Activated charcoal may be administered if victims are conscious and alert. Use 15 to 30 g (1/2 to 1 oz) for children, 50 to 100 g (1-3/4 to 3-1/2 oz) for adults, with 125 to 250 mL (1/2 to 1 cup) of water.

5. Promote excretion by administering a saline cathartic or sorbitol to conscious and alert victims. Children require 15 to 30 g (1/2 to 1 oz) of cathartic; 50 to 100 g (1-3/4 to 3-1/2 oz) is recommended for adults.

6. Transport to a health care facility. (EPA, 1998)

U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.

11.3 Fire Fighting

(Non-Specific -- Medicine, n.o.s.) Cool containers that are exposed to flames with water from the side until well after fire is out. For massive fires use unmanned hose holder or monitor nozzles; if this is impossible, withdraw and let fire burn. Wear self-contained (positive pressure if available) breathing apparatus and full protective clothing.

(Non-Specific -- Medicine, n.o.s.) For small fires, use dry chemical, carbon dioxide, water spray, or foam. For large fires, use water spray, fog, or foam. (EPA, 1998)

U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.

11.4 Accidental Release Measures

11.4.1 Isolation and Evacuation

Excerpt from ERG Guide 151 [Substances - Toxic (Non-Combustible)]:

IMMEDIATE PRECAUTIONARY MEASURE: Isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids.

SPILL: Increase the immediate precautionary measure distance, in the downwind direction, as necessary.

FIRE: If tank, rail tank car or highway tank is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2024)

11.4.2 Disposal Methods

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.

11.5 Handling and Storage

11.5.1 Nonfire Spill Response

(Non-Specific -- Medcines, n.o.s.) Keep unnecessary people away; isolate hazard area and deny entry. Stay upwind; keep out of low areas. If water pollution occurs, notify appropriate authorities. Shut off ignition sources; no flares, smoking or flames in hazard area. Keep combustibles (wood, paper, oil, etc.) away from spilled material. Do not touch spilled material.

Small spills: absorb with sand or other noncombustible absorbent material and place into containers for later disposal.

Small dry spills: with clean shovel place material into clean, dry container and cover; move container from spill area.

Large spills: dike far ahead of spill for later disposal. (EPA, 1998)

U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.

11.6 Exposure Control and Personal Protection

11.6.1 Personal Protective Equipment (PPE)

For emergency situations, wear a positive pressure, pressure-demand, full facepiece self-contained breathing apparatus (SCBA) or pressure- demand supplied air respirator with escape SCBA and a fully-encapsulating, chemical resistant suit. (EPA, 1998)
U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.

11.7 Stability and Reactivity

11.7.1 Air and Water Reactions

No rapid reaction with air. No rapid reaction with water.

11.7.2 Reactive Group

Alcohols and Polyols

Esters, Sulfate Esters, Phosphate Esters, Thiophosphate Esters, and Borate Esters

Ethers

Hydrocarbons, Aliphatic Unsaturated

11.7.3 Reactivity Profile

When heated to decomposition, OUABAIN emits acrid smoke and fumes. Hydrolysis yields one mole ouabagenin and one mole rhamnose. Stable in air, but affected by light (ouabain octahydrate) [EPA, 1998].
U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.

11.8 Transport Information

11.8.1 DOT Label

Poison

11.9 Regulatory Information

New Zealand EPA Inventory of Chemical Status
Ouabain octahydrate: Does not have an individual approval but may be used under an appropriate group standard

11.9.1 CERCLA Reportable Quantities

Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Quabain is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 100 or 10,000 lbs. Extremely hazardous substances that are solids are subject to either of two threshold planning quantities ... The lower quantity applies only if the solid exists in powdered form and has a particle size less than 100 microns; or is handled in solution or in molten form; or meets the criteria for a National Fire Protection Association (NFPA) rating of 2, 3 or 4 for reactivity. If the solid does not meet any of these criteria, it is subject to the upper ... threshold planning quantity ... .
40 CFR 355 (USEPA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of February 27, 2017: https://www.ecfr.gov

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

IDENTIFICATION AND USE: Ouabain, a solid, is a cardiac glycoside commonly used in the laboratory for electrophysiological experiments in cardiac myocytes. It has been used as medication and as a veterinary drug. HUMAN EXPOSURE AND TOXICITY: Ouabain-induced reactive oxygen species generation and cell apoptosis on human glioma cells has been described. The number of ouabain binding sites, detected using (3)H ouabain, were significantly increased in the borderline hypertensive subjects irrespective of heredity. Endogenous ouabain levels increase in human essential hypertension. ANIMAL STUDIES: Retinal activity measured by electroretinography in animals and in isolated retinas has been shown to be rapidly reduced by exposure to ouabain. Intravitreal injection in rabbits has caused rapid loss of vision. In cats circumferential artery of iris is reported to be constricted by ouabain. Ouabain is an endogenous Na(+)/K(+)-ATPase inhibitor whose chronic administration induces hypertension. Ouabain treatment in rats produced cognitive deficits independent of locomotor effects associated with bipolar disorder. ECOTOXICITY STUDIES: Ouabain inhibited the efflux of ammonia (from the basolateral to the apical side) in preparation of isolated Carcinus gills.
Ouabain inhibits the Na-K-ATPase membrane pump, resulting in an increase in intracellular sodium and calcium concentrations. Increased intracellular concentrations of calcium may promote activation of contractile proteins (e.g., actin, myosin). Ouabain also acts on the electrical activity of the heart, increasing the slope of phase 4 depolarization, shortening the action potential duration, and decreasing the maximal diastolic potential.

12.1.2 Carcinogen Classification

Carcinogen Classification
No indication of carcinogenicity to humans (not listed by IARC).

12.1.3 Acute Effects

12.1.4 Interactions

Intracerebroventricular (ICV) administration of ouabain, a specific Na-K-ATPase inhibitor, in rats mimics the manic phenotypes of bipolar disorder and thus has been proposed as one of the best animal models of mania. Bipolar mania has been known to be associated with dysfunctions of medial prefrontal cortex (mPFC), a brain area critically involved in mental functions; however, the exact mechanism underlying these dysfunctions is not yet clear. The present study investigated synaptic transmission, synaptic plasticity, and dopamine release in Sprague-Dawley rat mPFC following ICV administration of ouabain (5 uL of 1 mM ouabain). The electrophysiological results demonstrated that ouabain depressed the short- and the long-term synaptic plasticity, represented by paired-pulse facilitation and long-term potentiation, respectively, in the mPFC. These ouabain-induced alterations in synaptic plasticity can be prevented by pre-treatment with lithium (intraperitoneal injection of 47.5 mg/kg lithium, twice a day, 7 days), which acts as an effective mood stabilizer in preventing mania. The electrochemical results demonstrated that ICV administration of ouabain enhanced dopamine release in the mPFC, which was not affected by pre-treatment with lithium. These findings suggested that alterations in synaptic plasticity and dopamine release in the mPFC might underlie the dysfunctions of mPFC accompanied with ouabain administration-induced bipolar mania.
Sui L et al; J Neural Transm (Vienna) 120 (8): 1191-9 (2013)
Brain-derived neurotrophic factor (BDNF) is a well-known and well-studied neurotrophin. Most biological effects of BDNF are mediated by the activation of TrkB receptors. This neurotrophin regulates several neuronal functions as cell proliferation, viability, and differentiation. Ouabain is a steroid that binds to the Na(+)/K(+) ATPase, inducing the activation of several intracellular signaling pathways. Previous data from our group described that ouabain treatment increases retinal ganglion cells survival (RGC). The aim of the present study was to evaluate, if this cardiac glycoside can have a synergistic effect with BDNF, the classical trophic factor for retinal ganglion cells, as well as investigate the intracellular signaling pathways involved. Our work demonstrated that the activation of Src, PLC, and PKCdelta participates in the signaling cascade mediated by 50 ng/mL BDNF, since their selective inhibitors completely blocked the trophic effect of BDNF. We also demonstrated a synergistic effect on RGC survival when we concomitantly used ouabain (0.75 nM) and BDNF (10 ng/mL). Moreover, the signaling pathways involved in this synergistic effect include Src, PLC, PKCdelta, and JNK. Our results suggest that the synergism between ouabain and BDNF occurs through the activation of the Src pathway, JNK, PLC, and PKCdelta.
de Rezende Correa G et al; Cell Mol Neurobiol 35 (5): 651-60 (2015)
The present study aimed to investigate the effects of mood stabilizers, specifically lithium (Li) and valproate (VPA), on mitochondrial superoxide, lipid peroxidation, and proteins involved in cell death signaling pathways in the brains of rats subjected to the ouabain-induced animal model of mania. Wistar rats received Li, VPA, or saline twice a day for 13 days. On the 7th day of treatment, the animals received a single intracerebroventricular injection of ouabain or aCSF. After the ICV injection, the treatment with mood stabilizers continued for 6 additional days. The locomotor activity of rats was measured using the open-field test. In addition, we analyzed oxidative stress parameters, specifically levels of phosphorylated p53 (pp53), BAX and Bcl-2 in the brain of rats by immunoblot. Li and VPA reversed ouabain-related hyperactivity. Ouabain decreased Bcl-2 levels and increased the oxidative stress parameters BAX and pp53 in the brains of rats. Li and VPA improved these ouabain-induced cellular dysfunctions; however, the effects of the mood stabilizers were dependent on the protein and brain region analyzed. These findings suggest that the Na(+)/K(+)-ATPase can be an important link between oxidative damage and the consequent reduction of neuronal and glial density, which are both observed in BD, and that Li and VPA exert protective effects against ouabain-induced activation of the apoptosis pathway.
Valvassori SS; J Psychiatr Res 65: 63-70 (2015)
Docosahexaenoic acid (DHA) might prevent heart failure or optimize drug treatments by improving cardiac contraction. We investigated whether DHA-enriched avian glycerophospholipids (GPL-DHA) exert cardioprotection in ouabain-treated rats after 4 weeks of dietary supplementation with 10, 35 or 60 mg DHA per kg body weight versus none (DHA10, DHA35, DHA60 and control groups, respectively). The contractile responsiveness to different doses of ouabain (10(-7) to 10(-4) M), ouabain intoxication (at 3 X 10(-4) M), and relative variations in cardiac energy metabolism were determined using (31)P NMR in isolated perfused rat hearts. The fatty acid composition of cardiac membranes was analyzed by gas chromatography. DHA accretion in the heart was dose-dependent (+8%, +30% and +45% for DHA10, DHA35 and DHA60, respectively). The cardiac phosphocreatine content significantly increased at the baseline in DHA35 (+45%) and DHA60 groups (+85%), and at the different doses of ouabain in the DHA60 group (+73% to 98%). The maximum positive inotropy achieved at 10(-4) M ouabain was significantly increased in all DHA groups versus control (+150%, +122.5% and +135% for DHA10, DHA35 and DHA60, respectively), and ouabain intoxication was delayed. The increase in myocardial phosphocreatine content and the improved efficacy of ouabain on myocardial contraction without toxicity suggest the potential of GPL-DHA as a dietary supplement or ingredient for functional food, and possibly as a co-treatment with digitalis drugs in humans.
Bernard M et al; Food Funct 7 (2): 798-804 (2016)
For more Interactions (Complete) data for Ouabain (16 total), please visit the HSDB record page.

12.1.5 Antidote and Emergency Treatment

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 revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
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 revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
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 TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) 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 revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160-1
In the event of acute poisoning /with cardiac glycosides/, the stomach must be emptied and activated charcoal given to reduce absorption of the cardiac glycoside. If absorption has occurred, treatment with arrhythmic drugs, atropine to prevent bradycardia, and/or the administration of F(ab)fragments of anti-digoxin (digitoxin; -oubain) antibodies should be considered.
American Herbal Products Association's Botanical Safety Handbook Ed. by Michael McGuffin et al; p.139 (1997)

12.1.6 Human Toxicity Excerpts

/HUMAN EXPOSURE STUDIES/ The extent of contracture induced by ouabain on preparations of the greater saphenous vein obtained from patients undergoing elective coronary bypass surgery was investigated. The medical pretreatment of the various donor patients was similar but differed with regard to the duration of preoperative digitalization ranging from several days to months. Whereas the maximal contraction induced by noradrenaline was not influenced by prior digitalization, the contracture evoked by ouabain showed a strong dependency on the duration of preoperative digitalization. In patients without or with only short-term preoperative digitalization the spasm exerted by ouabain amounted to 48.8% and 49.2%, respectively, of the maximal contraction induced by noradrenaline, and decreased to zero in patients with long-term digitalization. From this result it is concluded that, in patients after coronary artery bypass grafting who did not receive cardiac glycosides for long-term treatment, the acute administration of glycosides may be a mechanism responsible for the early occlusion of saphenous vein bypass grafts.
Zerkowski HR, Wagner J; Thorac Cardiovasc Surg 30 (5): 250 (1982)
/ALTERNATIVE and IN VITRO TESTS/ The steroid Na(+)/K(+) ATPase (NKA) blocker ouabain has been shown to exhibit pro-apoptotic effects in various cell systems; however, the mechanism involved in those effects is unclear. Here, we have demonstrated that incubation of HeLa cells during 24 hr with nanomolar concentrations of ouabain or digoxin causes apoptotic death of 30-50% of the cells. Ouabain caused the activation of caspases-3/7 and -9; however, caspase-8 was unaffected. The fact that compound Z-LEHD-FMK reduced both apoptosis and caspase-9 activation elicited by ouabain, suggest a mitochondrially-mediated pathway. This was strengthened by the fact that ouabain caused ATP depletion and the release of mitochondrial cytochrome c into the cytosol. Furthermore, upon ouabain treatment mitochondrial disruption and redistribution into the cytosol were observed. A mitochondrial site of action for ouabain was further corroborated by tight co-localization of fluorescent ouabain with mitochondria. Finally, in ouabain-treated cells the histamine-elicited elevation of cytosolic Ca(2+) concentration ([Ca(2+)]c) suggests an additional effect on the endoplasmic reticulum (ER) leading to Ca(2+) store depletion. We conclude that fluorescent ouabain is taken up and tightly co-localizes with mitochondria of HeLa cells. This indicates that apoptosis may be triggered by a direct action of ouabain on mitochondria.
Alonso E et al; Steroids 78 (11): 1110-8 (2013)
/ALTERNATIVE and IN VITRO TESTS/ A human steroid hormone, ouabain, has been shown to play a role in several types of cancer cell behavior; however, its effects on cancer metastasis are largely unknown. Herein, we demonstrate that sub-toxic concentrations of ouabain facilitate cancer cell detachment from the extracellular matrix in human lung cancer cells. Ouabain at concentrations of 0-10 pM significantly enhanced cell detachment in dose- and time- dependent manners, while having minimal effect on cell viability. The detachment-inducing effect of ouabain was found to be mediated through focal-adhesion kinase and ATP-dependent tyrosine kinase pathways. Alpha-5 and beta-1 integrins were found to be down-regulated in response to ouabain treatment. Since detachment of cancer cells is a prerequisite process for metastasis to begin, these insights benefit our understanding over the molecular basis of cancer biology.
Ruanghirun T et al; Anticancer Res 34 (5): 2231-8 (2014)
/ALTERNATIVE and IN VITRO TESTS/ Ouabain stimulates activation of various signaling cascades such as protein kinase B (Akt) and Extracellular-signaling-regulated kinase 1/2 (ERK 1/2) in various cell lines. Retinoic acid (RA) is commonly used to induce neuroblastoma differentiation in cultures. Upon RA administration, human neuroblastoma cell line, SK-N-SH demonstrated neurite extensions, which is an indicator of neuronal cell differentiation. Here we report that ouabain-induced signaling is altered under the action of 1 uM RA in human neuroblastoma SK-N-SH cells. RA increased the expression of p110alpha subunit of phosphoinositide 3-kinase (PI3K), Akt and beta1 subunit of Na(+)/K(+)-ATPase. Ouabain activated Akt and ERK 1/2 in differentiated SK-N-SH cells; this effect was not observed in non-differentiated SK-N-SH cells. Long-term incubation of non-differentiated SK-N-SH with 1 uM ouabain led to a decrease in the number of cells; this effect was reduced in differentiated SK-N-SH cells. Taken together, these results suggest that ouabain leads to cell death in neuroblastoma cells rather than neuronal cells due to the different response to ouabain manifested by activation of Akt and ERK 1/2. RA increases the expression of p110alpha subunit of PI3K, Akt and beta1 subunit of Na(+)/K(+)-ATPase. Ouabain induces activation of Akt and ERK 1/2 in differentiated SK-N-SH cells but not in non-differentiated cells. 1 uM ouabain leads to a decrease in the number of cells in non-differentiated SK-N-SH. Reduction of ouabain-induced cell death in differentiated SK-N-SH.
Akkuratov EE et al; CNS Neurol Disord Drug Targets 14 (10): 1343-9 (2015)
For more Human Toxicity Excerpts (Complete) data for Ouabain (10 total), please visit the HSDB record page.

12.1.7 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Acute Exposure/ Retinal activity measured by electroretinography in animals and in isolated retinas has been shown to be rapidly reduced by exposure to ouabain. Intravitreal injection in rabbits has caused rapid loss of vision, without gross inflammation, but with extensive loss of cells of retina evident hystologically in 2 months, while pigment epithelium, ciliary processes, lens, and cornea remained morphologically normal. ... In cats circumferential artery of iris is reported to be constricted by ouabain.
Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 683
/LABORATORY ANIMALS: Acute Exposure/ In the present study we examined (1) the arrhythmogenic toxicity of ouabain (5 ug/kg/min intravenously) in anesthetized guinea pigs of 1-5 days and 3 months of age, and (2) the state of Na+-Ca2+ in the sarcolemmal vesicles isolated from these age groups. Guinea pigs of 1-5 days old tolerated 75% more ouabain than the young adults without significant alteration in the maximal inotropic response. Sodium-dependent 45Ca2+ uptake was substantially lower in the vesicles isolated from hearts of 3-day-old animals, which was characterized by a lower rate of 45Ca2+ uptake (60% Vmax), as compared to the young adults. There was no significant difference in the affinity for 45Ca2+ (Km). The apparent rate of Na+-dependent 45Ca2+ efflux was also lower in the vesicles from 3-day-old guinea pigs. However, the percent extrusion of 45Ca2+ appeared to be unchanged.
Khatter JC et al; Dev Pharmacol Ther 12 (3): 128-36 (1989)
/LABORATORY ANIMALS: Acute Exposure/ The effects of ouabain on the secretion of pancreatic juice stimulated by secretin was investigated in 28 anesthetized dogs. The pancreas was hemodynamically isolated in situ and perfused at a constant flow rate with the animal's own blood conducted from the left femoral artery by means of a peristaltic pump. Drugs were introduced into the blood perfusing the pancreas. Secretin (0.03 to 0.3 units) was injected as a bolus; its effects lasted for 15 min. The volume of pancreatic juice excreted during this period was measured and expressed as an incremental output after subtraction of the resting output for 15 min. Then, ouabain was injected 2 min before the injection of a second dose of secretin. The effects of the drugs were then deduced by comparing the secretory response to the second dose of secretin with that to the first. The pancreatic juice secretion rate following secretion injections alone was 11.3 +/- 0.7 uL/min. Ouabain (10 ug) addition to the perfusion circulation inhibited about 36%, 32%, and 32% of control values of pancreatic secretion induced by 0.03, 0.1, and 0.3 units of secretin, respectively. A combination of ouabain (10 ug) and acetazolamide (10 mg) inhibited pancreatic secretion more than either drug alone, 54%, 53%, and 46% of control values for the three doses of secretin, respectively. Bicarbonate concentration in pancreatic juice was increased by the ouabain dose (10 ug) from 20 mmol/L in the control to about 70 mmol/L. Chloride concentration was decreased by the ouabain dose from 120 mmol/L in the control to about 75 mmol/L. Sodium and protein concentrations were not altered by drug addition.
Iwatsuki K et al; Clin Exp Pharmacol Physiol 16 (3): 139-45 (1989)
/LABORATORY ANIMALS: Acute Exposure/ To evaluate possible roles of endogenous Na+-K+-ATPase inhibitors in vasoconstricted blood pressure elevation produced by acute volume expansion, we administered ouabain (Na+-K+-ATPase inhibitor) intravenously (30 ug/kg) for 10 min to dogs, 3 hr after volume expansion with dextran in lactated Ringer's solution (20 mL/kg, for 1 hr). Acute volume expansion resulted in the elevation of blood pressure associated with an increase in cardiac output. In some dogs the blood pressure remained elevated with gradual increase in total peripheral resistance (Group I) or with sustained high cardiac output (Group II), and in other dogs (Group III) it returned to the control level. Ouabain administration elevated the blood pressure and total peripheral resistance in these groups and sham dogs which did not have volume expansion. And these effects of ouabain were not correlated with the degree of blood pressure or vasoconstriction produced by volume expansion. Thus, it is not likely that endogenous Na+-K+-ATPase inhibitors increased to produce vasoconstricted hypertension after acute volume expansion.
Otsuka A et al; Basic Res Cardiol 84 (3): 319-25 (1989)
For more Non-Human Toxicity Excerpts (Complete) data for Ouabain (31 total), please visit the HSDB record page.

12.1.8 Non-Human Toxicity Values

LD50 Rat iv 14 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2787
LD50 Mouse ip 11 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2787
LD50 Mouse iv 2200 ug/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2787
LD50 Cat ip 100 ug/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2787

12.1.9 Ongoing Test Status

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of December 8, 2016: http://actor.epa.gov/dashboard/]

12.1.10 Protein Binding

60%

12.2 Ecological Information

12.2.1 Ecotoxicity Excerpts

/AQUATIC SPECIES/ The effects of inhibitors on the efflux of ammonia (from the basolateral to the apical side, Jb----a) were studied in preparation of isolated Carcinus gills immersed in dilute seawater (DSW) that was identical to the perfusion solution. Adding 10(-4) M amiloride to the solution bathing the gill preparations reduces the efflux of ammonia by 29% relative to the control value. Under experimental conditions, it appears that only about 1% of the amiloride-sensitive influx of Na+ (Ja----b) can be exchanged with NH4+ on an equimolar basis. The ammonium ion is apparently transported at the basolateral side by a carrier-mediated process. Kinetic analyses of the influx of ammonium ions revealed a Km of 36.99 uM and a maximum velocity (Vmax) equal to 19.6 umol/g/h. Basolaterally applied ouabain (5 x 10(-3) M) and NaCN (10(-3) M) reduced the efflux of ammonia by 46.7 and 42.2%, respectively, suggesting an interaction of NH4+ with the basolaterally located Na+/K+ exchanger in which NH4+ appears to be able to substitute for K+.
Lucu C et al; J Exp Zool 249 (1): 1-5 (1989)

12.2.2 Natural Pollution Sources

Ouabain occurs naturally in the seeds of Strophantus gratus and in Acokanthera ouabaio and other Acokanthera species (Apocynaceae)(1).
(1) O'Neil MJ, ed; The Merck Index. 15th ed., Cambridge, UK: Royal Society of Chemistry, p. 1281 (2013)

12.2.3 Plant Concentrations

Ouabain occurrence in plants(1):
Genus species
Strophanthus gratus
Family
Apocynaceae
common name(s)
Ouabain
Part
Seed
Concn (ppm)
36,000-76,000
Genus species
Acokanthera schimperi
Family
Apocynaceae
common name(s)
Arrow-poison Tree
Part
Seed
Concn (ppm)
1,000-5,000
Genus species
Acokanthera schimperi
Family
Apocynaceae
common name(s)
Arrow-poison Tree
Part
Wood
Concn (ppm)
2,000
(1) US Dept Agric; US Dept Agric, Agric Res Service. 1992-2016. Dr. Duke's Phytochemical and Ethnobotanical Databases. Ouabain. Available from, as of Nov 29, 2016: https://phytochem.nal.usda.gov/phytochem/search

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Nature Journal References

14.5 Chemical Co-Occurrences in Literature

14.6 Chemical-Gene Co-Occurrences in Literature

14.7 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Protein Bound 3D Structures

16.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

16.2 Chemical-Target Interactions

16.3 Drug-Drug Interactions

17 Biological Test Results

17.1 BioAssay Results

18 Taxonomy

The LOTUS Initiative for Open Natural Products Research: frozen dataset union wikidata (with metadata) | DOI:10.5281/zenodo.5794106

19 Classification

19.1 MeSH Tree

19.2 ChEBI Ontology

19.3 LIPID MAPS Classification

19.4 KEGG: Metabolite

19.5 KEGG: Lipid

19.6 KEGG: Phytochemical Compounds

19.7 KEGG: Natural Toxins

19.8 KEGG : Glycosides

19.9 WHO ATC Classification System

19.10 ChemIDplus

19.11 CAMEO Chemicals

19.12 ChEMBL Target Tree

19.13 UN GHS Classification

19.14 NORMAN Suspect List Exchange Classification

19.15 CCSBase Classification

19.16 EPA DSSTox Classification

19.17 EPA TSCA and CDR Classification

19.18 LOTUS Tree

19.19 MolGenie Organic Chemistry Ontology

20 Information Sources

  1. BindingDB
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  2. Comparative Toxicogenomics Database (CTD)
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  7. CAS Common Chemistry
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  8. ChemIDplus
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  9. EPA Chemicals under the TSCA
    Card-20(22)-enolide, 3-[(6-deoxy-.alpha.-L-mannopyranosyl)oxy]-1,5,11,14,19-pentahydroxy-, (1.beta.,3.beta.,5.beta.,11.alpha.)-
    https://www.epa.gov/chemicals-under-tsca
    EPA TSCA Classification
    https://www.epa.gov/tsca-inventory
  10. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  11. European Chemicals Agency (ECHA)
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    3-(6-deoxy-α-L-mannopyranosyloxy)-1,5,11a,14,19-pentahydroxycard-20(22)-enolide
    https://echa.europa.eu/substance-information/-/substanceinfo/100.010.128
    3-(6-deoxy-α-L-mannopyranosyloxy)-1,5,11a,14,19-pentahydroxycard-20(22)-enolide (EC: 211-139-3)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/45350
  12. FDA Global Substance Registration System (GSRS)
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  13. Hazardous Substances Data Bank (HSDB)
  14. Human Metabolome Database (HMDB)
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  16. NJDOH RTK Hazardous Substance List
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  18. LOTUS - the natural products occurrence database
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    https://lotus.nprod.net/
  19. Open Targets
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  20. CCSbase
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  22. Hazardous Chemical Information System (HCIS), Safe Work Australia
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  24. MassBank of North America (MoNA)
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  25. NORMAN Suspect List Exchange
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    https://creativecommons.org/licenses/by/4.0/
    OUABAIN
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    https://www.norman-network.com/nds/SLE/
  26. NIST Mass Spectrometry Data Center
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    https://www.nist.gov/srd/public-law
  27. Japan Chemical Substance Dictionary (Nikkaji)
  28. KEGG
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  29. LIPID MAPS
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  30. Natural Product Activity and Species Source (NPASS)
  31. MassBank Europe
  32. Metabolomics Workbench
  33. Nature Chemical Biology
  34. PharmGKB
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  38. SpectraBase
    OUABAIN,(3-BETA-O-ALPHA-L-RHAMNOSID,5-BETA-OH,11-ALPHA-OH)
    https://spectrabase.com/spectrum/IHCx1hY3hcs
  39. Springer Nature
  40. WHO Anatomical Therapeutic Chemical (ATC) Classification
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  44. PubChem
  45. GHS Classification (UNECE)
  46. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  47. PATENTSCOPE (WIPO)
  48. NCBI
CONTENTS