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Frovatriptan

PubChem CID
77992
Structure
Frovatriptan_small.png
Frovatriptan_3D_Structure.png
Molecular Formula
Synonyms
  • Frovatriptan
  • Frova
  • 158747-02-5
  • Miguard
  • Allergo filmtabletten
Molecular Weight
243.30 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-08-08
  • Modify:
    2025-01-18
Description
Frovatriptan is a member of carbazoles.
Frovatriptan is a triptan drug developed by Vernalis for the treatment of migraine headaches, in particular those associated with menstruation. Frovatriptan causes vasoconstriction of arteries and veins that supply blood to the head.
Frovatriptan is a Serotonin-1b and Serotonin-1d Receptor Agonist. The mechanism of action of frovatriptan is as a Serotonin 1b Receptor Agonist, and Serotonin 1d Receptor Agonist.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Frovatriptan.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

(6R)-6-(methylamino)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxamide
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C14H17N3O/c1-16-9-3-5-13-11(7-9)10-6-8(14(15)18)2-4-12(10)17-13/h2,4,6,9,16-17H,3,5,7H2,1H3,(H2,15,18)/t9-/m1/s1
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

XPSQPHWEGNHMSK-SECBINFHSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CN[C@@H]1CCC2=C(C1)C3=C(N2)C=CC(=C3)C(=O)N
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C14H17N3O
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 UNII

2.3.3 ChEBI ID

2.3.4 ChEMBL ID

2.3.5 DrugBank ID

2.3.6 DSSTox Substance ID

2.3.7 HMDB ID

2.3.8 KEGG ID

2.3.9 Metabolomics Workbench ID

2.3.10 NCI Thesaurus Code

2.3.11 Nikkaji Number

2.3.12 PharmGKB ID

2.3.13 Pharos Ligand ID

2.3.14 RXCUI

2.3.15 Wikidata

2.3.16 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • (+)-(R)-5,6,7,8-tetrahydro-6-(methylamino)carbazole-3-carboxamide succinate (1:1), monohydrate
  • 3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole
  • Allegro
  • Frova
  • frovatriptan
  • frovatriptan succinate
  • Frovelan
  • SB 209509
  • VML-251
  • VML251

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
243.30 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
1.2
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
2
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
243.137162174 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
243.137162174 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
70.9 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
18
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
333
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

Soluble
1.23e-01 g/L

3.2.3 LogP

0.9
0.9

3.2.4 Other Experimental Properties

MW = 379.4 ... white to off-white powder ... soluble in water /Succinate/
Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 1101

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; Milk, Human; Serotonin Receptor Agonists; Serotonin 5-HT1 Receptor Agonists; Triptans; Vasoconstrictor Agents
Human drug -> Prescription

5 Chemical Vendors

6 Drug and Medication Information

6.1 Drug Indication

For the acute treatment of migraine attacks with or without aura in adults.

6.2 Drug Classes

Breast Feeding; Lactation; Milk, Human; Serotonin Receptor Agonists; Serotonin 5-HT1 Receptor Agonists; Triptans; Vasoconstrictor Agents

6.3 Clinical Trials

6.3.1 ClinicalTrials.gov

6.3.2 EU Clinical Trials Register

6.4 Therapeutic Uses

Tryptamines; Carbazoles
National Library of Medicine, SIS; ChemIDplus Record for Frovatriptan(158747-02-5). Available from, as of March 15, 2006: https://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp
Frovatriptan is indicated for the acute treatment of migraine attacks with or without aura in adults. /Included in US product labeling/
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1555

6.5 Drug Warnings

As with other 5-HT1 agonists, sensations of pain, tightness, pressure and heaviness have been reported in the chest, throat, neck and jaw after treatment with frova. These events have not been associated with arrhythmias or ischemic ECG changes in clinical trials with FROVA. Because 5-HT1 agonists may cause coronary vasospasm, patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of CAD. Patients shown to have CAD and those with Prinzmetal's variant angina should not receive 5-HT1 agonists. Patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud's syndrome following the use of any 5-HT1 agonist are candidates for further evaluation. If a patient has no response for the first migraine attack treated with frova, the diagnosis of migraine should be reconsidered before frovatriptan is administered to treat any subsequent attacks.
Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 1102
Cerebral hemorrhage, subarachnoid hemorrhage, stroke and other cerebrovascular events have been reported in patients treated with 5-HT1 agonists; and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g. stroke, hemorrhage, transient ischemic attack).
Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 1102
Frovatriptan is not indicated in the management of hemiplegic or basilar migraine. Frovatriptan is not indicated for use in cluster headache, which is present in an older, predominately male population. Safety and efficacy of frovatriptan in this condition have not been established. Frovatriptan is not intended for the prophylactic therapy of migraine.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1555
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556
For more Drug Warnings (Complete) data for FROVATRIPTAN (11 total), please visit the HSDB record page.

7 Pharmacology and Biochemistry

7.1 Pharmacodynamics

Frovatriptan is a second generation triptan 5-HT receptor agonist that binds with high affinity for 5-HT1B and 5-HT1D receptors. It is structurally distinct from, but pharmacologically related to other selective 5-HT1B/1D receptor agonists. Frovatriptan has no significant effects on GABAA mediated channel activity and has no significant affinity for benzodiazepine binding sites. Frovatriptan is believed to act on extracerebral, intracranial arteries and to inhibit excessive dilation of these vessels in migraine. Research has shown that migraine can be caused by the swelling of blood vessels around the brain. Frovatriptan eases the pain associated with migraine by narrowing these blood vessels. Frovatriptan has one of the highest affinities for the 5-HT1B of the second-generation triptan agonists.

7.2 MeSH Pharmacological Classification

Serotonin Receptor Agonists
Endogenous compounds and drugs that bind to and activate SEROTONIN RECEPTORS. Many serotonin receptor agonists are used as ANTIDEPRESSANTS; ANXIOLYTICS; and in the treatment of MIGRAINE DISORDERS. (See all compounds classified as Serotonin Receptor Agonists.)

7.3 FDA Pharmacological Classification

FDA UNII
H82Q2D5WA7
Active Moiety
FROVATRIPTAN
Pharmacological Classes
Mechanisms of Action [MoA] - Serotonin 1b Receptor Agonists
Pharmacological Classes
Mechanisms of Action [MoA] - Serotonin 1d Receptor Agonists
Pharmacological Classes
Established Pharmacologic Class [EPC] - Serotonin-1b and Serotonin-1d Receptor Agonist
FDA Pharmacology Summary
Frovatriptan is a Serotonin-1b and Serotonin-1d Receptor Agonist. The mechanism of action of frovatriptan is as a Serotonin 1b Receptor Agonist, and Serotonin 1d Receptor Agonist.

7.4 ATC Code

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

N02 - Analgesics

N02C - Antimigraine preparations

N02CC - Selective serotonin (5ht1) agonists

N02CC07 - Frovatriptan

7.5 Absorption, Distribution and Excretion

Absorption
Frovatriptan is rapidly absorbed from the duodenum, but has low oral bioavailability.
Route of Elimination
Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Less than 10% of frovatriptan was excreted in urine after an oral dose.
Volume of Distribution

4.2 L/kg [males]

3 L/kg [females]

Clearance

220 mL/min [male receiving IV dose of 0.8 mg]

130 mL/min [Female receiving IV dose of 0.8 mg]

Protein binding: Low (approximately 15%) to serum proteins.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556
Volume of distribution (VolD): Steady state : 4.2 L/kg in males and 3.0 L/kg in females.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556
The absolute bioavailability of an oral dose of frovatriptan is about 20% in males and 30% in females. The rate and extent of absorption are not affected by administration with food.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556
Elimination: Renal: Following a single oral 2.5 mg dose of radiolabeled frovatriptan, 32% of the dose was recovered in urine. Radiolabeled compounds excreted in the urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan, desmethyl frovatriptan and several other minor metabolites. Fecal: Following a single oral 2.5 mg dose of radiolabeled frovatriptan, 62% of the dose was recovered in feces.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556
For more Absorption, Distribution and Excretion (Complete) data for FROVATRIPTAN (7 total), please visit the HSDB record page.

7.6 Metabolism / Metabolites

In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan to several metabolites including hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, and several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown.
In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan. Following administration of a single oral dose of radiolabeled frovatriptan 2.5 mg to healthy male and female subjects, 32% of the dose was recovered in urine and 62% in feces. Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown.
Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 1101
In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan to several metabolites including hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, and several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown. Route of Elimination: Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Less than 10% of frovatriptan was excreted in urine after an oral dose. Half Life: 26 hours

7.7 Biological Half-Life

26 hours
Elimination: Intravenous administration: Approximately 26 hours.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556

7.8 Mechanism of Action

Three distinct pharmacological actions have been implicated in the antimigraine effect of the triptans: (1) stimulation of presynaptic 5-HT<sub>1D</sub> receptors, which serves to inhibit both dural vasodilation and inflammation; (2) direct inhibition of trigeminal nuclei cell excitability via 5-HT<sub>1B/1D</sub> receptor agonism in the brainstem and (3) vasoconstriction of meningeal, dural, cerebral or pial vessels as a result of vascular 5-HT<sub>1B</sub> receptor agonism.
Frovatriptan is believed to act on extracerebral, intracranial arteries and to inhibit excessive dilation of these vessels in migraine. In anesthetized dogs and cats, intravenous administration of frovatriptan produced selective constriction of the carotid vascular bed and had no effect on blood pressure (both species) or coronary resistance (in dogs).
Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 1101
Frovatriptan succinate is a selective agonist of serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptors. Frovatriptan is structurally distinct from, but pharmacologically related to, other selective 5-HT1B/1D receptor agonists (e.g., almotriptan, naratriptan, rizatriptan, sumatriptan). Because the mechanisms involved in the pathogenesis of migraine are not clearly understood, the precise mechanism of action of 5-HT1 receptor agonists in the management of migraine has yet to be established. However, current data suggest that 5-HT1 receptor agonists, including frovatriptan, may ameliorate migraine through selective constriction of certain intracranial blood vessels, inhibition of neuropeptide release, and/or reduced transmission in the trigeminal pain pathway.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 2461
Frovatriptan has no significant effects on GABAA mediated channel activity and has not significant affinity for benzodiazepine binding sites. Frovatriptan is believed to act on extracerebral, intracranial arteries and to inhibit excessive dilation of these vessels in migraine.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1555

7.9 Human Metabolite Information

7.9.1 Cellular Locations

Membrane

8 Use and Manufacturing

8.1 Uses

Treatment of migraines /Succinate/
Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 1101
For the acute treatment of migraine attacks with or without aura in adults.

8.2 Formulations / Preparations

Oral: Tablets, film-coated: 2.5 mg (of frovatriptan), Frova, (Endo). /Frovatriptan succinate/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 2461

9 Safety and Hazards

9.1 Accidental Release Measures

9.1.1 Disposal Methods

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. 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 soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

9.2 Regulatory Information

9.2.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl frovatriptan succinate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Frovatriptan Succinate/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 3, 2006: https://www.fda.gov/cder/ob/

10 Toxicity

10.1 Toxicological Information

10.1.1 Toxicity Summary

Three distinct pharmacological actions have been implicated in the antimigraine effect of the triptans: (1) stimulation of presynaptic 5-HT<sub>1D</sub> receptors, which serves to inhibit both dural vasodilation and inflammation; (2) direct inhibition of trigeminal nuclei cell excitability via 5-HT<sub>1B/1D</sub> receptor agonism in the brainstem and (3) vasoconstriction of meningeal, dural, cerebral or pial vessels as a result of vascular 5-HT<sub>1B</sub> receptor agonism.

10.1.2 Drug Induced Liver Injury

Compound
frovatriptan
DILI Annotation
No-DILI-Concern
Label Section
No match
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 Carcinogen Classification

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

10.1.4 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

There is no published experience with frovatriptan during breastfeeding. If frovatriptan is required by the mother of an older infant, it is not a reason to discontinue breastfeeding, but until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. Painful, burning nipples and breast pain have been reported after doses of sumatriptan and other triptans. This has occasionally been accompanied by a decrease in milk production.

◉ Effects in Breastfed Infants

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

◉ Effects on Lactation and Breastmilk

A review of four European adverse reaction databases found 26 reported cases of, painful, burning nipples, painful breasts, breast engorgement and/or painful milk ejection in women who took a triptan while nursing. Pain was sometimes intense and occasionally led to decreased milk production. Pain generally subsided with time as the drug was eliminated. The authors proposed that triptans may cause vasoconstriction of the arteries in the breast, nipples, and the arteries surrounding the alveoli and milk ducts, causing a painful sensation and a painful milk ejection reflex.

10.1.5 Exposure Routes

Frovatriptan is rapidly absorbed from the duodenum, but has low oral bioavailability.

10.1.6 Symptoms

There is no direct experience of any patient taking an overdose of Frovatriptan. The maximum single dose of frovatriptan given to male and female patients with migraine was 40 mg (16 times the clinical dose) and the maximum single dose given to healthy male subjects was 100 mg (40 times the clinical dose) without significant adverse events.

10.1.7 Treatment

As with other 5-HT1 receptor agonists, there is no specific antidote for frovatriptan. The elimination half-life of frovatriptan is 26 hours, therefore if overdose occurs, the patient should be monitored closely for at least 48 hours and be given any necessary symptomatic treatment. (L1712)
L1712: RxList: The Internet Drug Index (2009). http://www.rxlist.com/

10.1.8 Interactions

Concurrent use /of frovatriptan/ with oral contraceptives has resulted in a 30% increase in the area under the plasma concentration-time curve (AUC) and peak plasma concentration of frovatriptan.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556
Concurrent use /of frovatriptan/ with ergotamine tartrate has resulted in a 25% decrease in the area under the plasma concentration-time curve (AUC) and peak plasma concentration of frovatriptan.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556
Concurrent use /of frovatriptan with selective serotonin reuptake inhibitors, such as: fluoxetine, fluvoxamine, paroxetine or sertraline/ may result in weakness, hyperreflexia, and incoordination; careful observation of the patients is recommended.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556
Concurrent use /of frovatriptan/ with propranolol increased the area under the plasma concentration-time curve (AUC) in males by 60% and in females by 29%. the peak plasma concentration was increased by 23% in males and 16% in females; however the half-life of frovatriptan in both populations, though slightly longer in females was not affected by concomitant administration of propranolol.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556
A delay of 24 hours between administration of dihydroergotamine, ergotamine, or methylsergide or other 5-hydroxytryptamine agonists and frovatriptan is recommended because of the possibility of additive and/or prolonged vasoconstriction.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556

10.1.9 Antidote and Emergency Treatment

/SRP:/ Basic treatment: Establish a patent airway. 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 normal saline 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 ... . /Poison A and B/
Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994., p. 139
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/
Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994., p. 139

10.1.10 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ Cerebral hemorrhage, subarachnoid hemorrhage, stroke and other cerebrovascular events have been reported in patients treated with 5-HT1 agonists; and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g. stroke, hemorrhage, transient ischemic attack).
Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 1102
/SIGNS AND SYMPTOMS/ Risk of coronary vasospasm, myocardial ischemia and/or infarction, life-threatening cardiac rhythm disturbances, and death associated with use of 5-HT1 receptor agonists. Use of frovatriptan not recommended in patients with known or suspected ischemic or vasospastic heart disease (see Cautions: Contraindications) or in patients in whom unrecognized coronary artery disease is likely (e.g., postmenopausal women, men older than 40 years of age, patients with risk factors such as hypertension, hypercholesterolemia, smoking, obesity, diabetes, family history of coronary artery disease) unless a prior cardiovascular evaluation provides satisfactory evidence that the patient does not have coronary artery disease, ischemic heart disease, or other underlying cardiovascular disease.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 2460

10.1.11 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ The carcinogenic potential of frovatriptan was evaluated in an 84-week study in mice (4, 13, and 40 mg/kg/day), a 104 week study in rats (8.5, 27, and 85 mg/kg/day) and a 26-week study in p53 (+/-) transgenic mice (20, 62.5, 200, and 400 mg/kg/day). There were no increases in tumor incidence in the 84 week mouse study at doses producing 140 times the exposure achieved at the maximum recommended daily human dose based on blood AUC comparisons. In the rat study, there was a statistically significant increase in the incidence of pituitary adenomas in males only at a dose that produced 250 times the exposure achieved at the maximum recommended daily human dose based on the AUC comparisons. In the transgenic mouse study, there was an increased incidence of subcutaneous sarcomas in females dosed at 390 and 630 times the human exposure based on AUC comparisons. The incidence of sarcomas was not increased at lower doses that achieved exposures 180 and 60 times the human exposure. These sarcomas were physically associated with subcutaneously implanted animal identification transponders. There were no other increases in tumor incidence of any type in any dose group. These sarcomas are not considered to be relevant ot humans.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in rats receiving oral doses of frovatriptan throughout the period of organogenesis at doses of 100, 500, and 1000 mg/kg/day revealed a dose related increased incidence of litters and total numbers of fetuses with dilated ureters, unilateral and bilateral pelvic cavitation, hydronephrosis and hydroureters. A no-effect dose from renal effects was not established. This signifies a syndrome of related effects on a specific organ in the developing embryo which is consistent with a slight delay in fetal maturation. This delay was also indicated by a treatment related increased incidence of incomplete ossification of the sternebrae, skull and nasal bones in all treated groups. Slightly lower fetal weights and an increased incidnece of early embryonic deaths were observed in treated rats. When pregnant rabbits were dosed throughout organogenesis at doses up to 80 mg/kg/day.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in male and female rats at doses of 100, 500, and 1000 mg/kg/day showed an increase at all dose levels in the number of females that mated on the first day of pairing compared to control animals. This occurred in conjunction with a prolongation of the estrous cycle. Females also had a decreased mean number of corpora lutea and a lower number of live fetuses per litter, which suggested a partial impairment of ovulation. There were no other fertility-related effects.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556
/GENOTOXICITY/ Frovatriptan was clastogenic in human lymphocyte cultures, in the absence of metabolic activation. In the bacterial reverse mutation assay (Ames test), frovatriptan produced an equivocal response in the absence of metabolic activation. No mutagenic or clastogenic activities were seen in an in vitro mouse lymphoma assay, an in vivo mouse bone marrow micronucleus test or an ex vivo assay for unscheduled DNA synthesis in rat liver.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556
/OTHER TOXICITY INFORMATION/ When pigmented rats were given a single oral dose of 5 mg/kg of radiolabeled frovatriptan, the radioactivity in the eye after 28 days was 87% of the value measured after 8 hours. This suggests that frovatriptan and/or its metabolites may bind to the melanin of the eye. Because there could be accumulation in melanin rich tissues over time, this raises the possibility that frovatriptan could cause toxicity in these tissues after extended use. However, no effects on the retina related to treatment with frovatriptan were noted in the toxicity studies. Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials and no specific recommendations for ophthalmologic monitoring are made, prescribers should be aware of the possibility of long-term ophthalmologic effects.
Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 1102

10.1.12 Populations at Special Risk

Safety and effectiveness of Frova in pediatric patients have not been established; therefore, Frova is not recommended for use in patients under 18 years of age. Postmarketing experience with other triptans includes a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events that are similar in nature to those reported rarely in adults.
Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 1103

10.1.13 Protein Binding

Binding to serum proteins is low (approximately 15%). Reversible binding to blood cells at equilibrium is approximately 60%.

10.2 Ecological Information

10.2.1 Environmental Fate / Exposure Summary

Frovatriptan's production and use as a drug for the treatment of migraine headaches may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 3.7X10-9 mm Hg at 25 °C indicates frovatriptan will exist solely in the particulate phase in the atmosphere. Particulate-phase frovatriptan will be removed from the atmosphere by wet or dry deposition. Frovatriptan contains the indole chromophore which absorbs at wavelengths >290 nm and therefore may be susceptible to direct photolysis by sunlight. If released to soil, frovatriptan is expected to have no mobility based upon an estimated Koc of 6200. An estimated pKa value of 10.6 (secondary amine) indicates that frovatriptan will exist primarily as a cation in the environment. Volatilization from moist soil surfaces is not expected to be an important fate process because cations do not volatilize. Frovatriptan is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation data were not available. If released into water, frovatriptan is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process since cations do not volatilize. An estimated BCF of 2 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to frovatriptan may occur through inhalation and dermal contact with this compound at workplaces where frovatriptan is produced or used. Exposure to frovatriptan among the general population may be limited to those administered this substance as a drug. (SRC)

10.2.2 Artificial Pollution Sources

Frovatriptan's production and use as a drug for the treatment of migraine headaches(1) may result in its release to the environment through various waste streams(SRC).
(1) PDR; Physicians Desk Reference. 60th ed. Thomson PDR. Montvale, NJ p.1101 (2006)

10.2.3 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 6200(SRC), determined from a structure estimation method(2), indicates that frovatriptan is expected to be immobile in soil(SRC). An estimated pKa value of 10.6 (secondary amine)(3) indicates that frovatriptan will exist primarily as a cation in the environment. Volatilization of frovatriptan from moist soil surfaces is not expected to be an important fate process(SRC) because cations do not volatilize. Frovatriptan is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.7X10-9 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992)
(3) SPARC; pKa/property server. Ver 3. Jan, 2006. Available at https://ibmlc2.chem.uga.edu/sparc/ as of Apr 20, 2006.
(4) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 6200(SRC), determined from a structure estimation method(2), indicates that frovatriptan is not expected to adsorb to suspended solids and sediment(SRC). An estimated pKa value of 10.6 (secondary amine)(3) indicates that frovatriptan will primarily exist in cation form in the environment. Volatilization from water surfaces is not expected(SRC) because cations do not volatilize. According to a classification scheme(4), an estimated BCF of 2(SRC), from an estimated log Kow of 1.3(5) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2005).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992)
(3) SPARC; pKa/property server. Ver 3. Jan, 2006. Available at https://ibmlc2.chem.uga.edu/sparc/ as of Apr 20, 2006.
(4) Franke C et al; Chemosphere 29: 1501-14 (1994)
(5) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995)
(6) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), frovatriptan, which has an estimated vapor pressure of 3.7X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase frovatriptan may be removed from the air by wet or dry deposition(SRC). Frovatriptan contains the indole chromophore which absorbs at wavelengths > 290 nm(3) and therefore may be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
(3) Weast RC, ed; Handbook of Chemistry and physics. 57th ed., Cleveland: CRC Press Inc., p. C-349 (1976)

10.2.4 Environmental Abiotic Degradation

Frovatriptan is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Frovatriptan contains the indole chromophore which absorbs at wavelengths > 290 nm(2) and therefore may be susceptible to direct photolysis by sunlight(SRC).
(1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990)
(2) Weast RC, ed; Handbook of Chemistry and Physics. 57th ed., Cleveland: CRC Press Inc., p. C-349 (1976)

10.2.5 Environmental Bioconcentration

An estimated BCF of 2 was calculated for frovatriptan(SRC), using an estimated log Kow of 1.3(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).
(1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995)
(2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

10.2.6 Soil Adsorption / Mobility

Using a structure estimation method based on molecular connectivity indices(1), the Koc of frovatriptan can be estimated to be 6200(SRC). According to a classification scheme(2), this estimated Koc value suggests that frovatriptan is expected to be immobile in soil. An estimated pKa value of 10.6 (secondary amine)(3) indicates that frovatriptan will exist primarily as a cation in the environment and cations generally adsorb to soil and sediment more strongly than their neutral counterparts(4).
(1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992)
(2) Swann RL et al; Res Rev 85: 17-28 (1983)
(3) SPARC; pKa/property server. Ver 3. Jan, 2006. Available at https://ibmlc2.chem.uga.edu/sparc/ as of Apr 20, 2006.
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)

10.2.7 Volatilization from Water / Soil

An estimated pKa value of 10.6 (secondary amine)(1) indicates that frovatriptan will exist primarily as a cation in the environment. Frovatriptan is expected to be essentially nonvolatile from moist soil and water surfaces since cations do not volatilize. Frovatriptan is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.7X10-9 mm Hg(SRC), determined from a fragment constant method(2).
(1) SPARC; pKa/property server. Ver 3. Jan, 2006. Available at https://ibmlc2.chem.uga.edu/sparc/ as of Apr 20, 2006.
(2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)

10.2.8 Environmental Water Concentrations

While data specific to frovatriptan were not located(SRC, 2006), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).
(1) Heberer T; Tox Lett 131: 5-17 (2002)
(2) Koplin DW et al; Environ Sci Toxicol 36: 1202-211 (2002)

10.2.9 Milk Concentrations

It is not known whether frovatriptan is distributed into human breast milk. However, frovatriptan is distributed into the milk of lactating rats with the maximum concentration being four times higher than that seen in blood.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1556

10.2.10 Probable Routes of Human Exposure

Occupational exposure to frovatriptan may occur through inhalation and dermal contact with this compound at workplaces where frovatriptan is produced or used. Exposure to frovatriptan among the general population may be limited to those administered this substance as a drug. (SRC)

11 Associated Disorders and Diseases

12 Literature

12.1 Consolidated References

12.2 NLM Curated PubMed Citations

12.3 Thieme References

12.4 Wiley References

12.5 Chemical Co-Occurrences in Literature

12.6 Chemical-Gene Co-Occurrences in Literature

12.7 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 Chemical-Target Interactions

14.2 Drug-Drug Interactions

14.3 Drug-Food Interactions

Take with or without food. Food does not affect bioavailability, but delays maximum concentrations by one hour.

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 NORMAN Suspect List Exchange Classification

16.13 EPA DSSTox Classification

16.14 MolGenie Organic Chemistry Ontology

17 Information Sources

  1. CAS Common Chemistry
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    https://creativecommons.org/licenses/by-nc/4.0/
  2. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  3. DrugBank
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    https://www.drugbank.ca/legal/terms_of_use
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    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  5. FDA Global Substance Registration System (GSRS)
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  6. Hazardous Substances Data Bank (HSDB)
  7. Human Metabolome Database (HMDB)
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  9. FDA Pharm Classes
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  10. Open Targets
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  11. Toxin and Toxin Target Database (T3DB)
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  13. ClinicalTrials.gov
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    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  14. Comparative Toxicogenomics Database (CTD)
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    http://ctdbase.org/about/legal.jsp
  15. Drug Gene Interaction database (DGIdb)
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    http://www.dgidb.org/downloads
  16. 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
  17. Therapeutic Target Database (TTD)
  18. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  19. Drugs and Lactation Database (LactMed)
  20. Drugs@FDA
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  21. EU Clinical Trials Register
  22. Japan Chemical Substance Dictionary (Nikkaji)
  23. KEGG
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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
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  24. Metabolomics Workbench
  25. NCI Thesaurus (NCIt)
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  26. NLM RxNorm Terminology
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    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  27. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    Frovatriptan
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  28. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
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    https://www.whocc.no/copyright_disclaimer/
  29. PharmGKB
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    https://www.pharmgkb.org/page/policies
  30. Pharos
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    https://pharos.nih.gov/about
  31. Thieme Chemistry
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    https://creativecommons.org/licenses/by-nc-nd/4.0/
  32. Wikidata
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    https://www.nlm.nih.gov/copyright.html
  37. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  38. PATENTSCOPE (WIPO)
  39. NCBI
CONTENTS