DANTROLENE SODIUM ANHYDROUS

Details

Stereochemistry	ACHIRAL
Molecular Formula	C14H9N4O5.Na
Molecular Weight	336.2348
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure of DANTROLENE SODIUM ANHYDROUS

Structure Search

SMILES

[Na+].[O-][N+](=O)C1=CC=C(C=C1)C2=CC=C(O2)\C=N\N3CC(=O)[N-]C3=O

InChI

InChIKey=KSRLIXGNPXAZHD-HAZZGOGXSA-M

InChI=1S/C14H10N4O5.Na/c19-13-8-17(14(20)16-13)15-7-11-5-6-12(23-11)9-1-3-10(4-2-9)18(21)22;/h1-7H,8H2,(H,16,19,20);/q;+1/p-1/b15-7+;

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/15023108
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/9341133, http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf

Dantrolene is a drug which was approved by FDA for the treatment of chronic spasticity and malignant hyperthermia (a rare life-threatening clinical syndrome). Dantrolene effect was shown both in vivo and in vitro and proved to be mediated by interaction with Ryanodine receptor 1. The drug has a potential for hepatotoxicity and should be used as indicated in the label.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Ryanodine receptor 1 4 Target ID: P21817 Gene ID: 6261.0 Gene Symbol: RYR1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/15023108	Antagonist 2778		130.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Chronic spasticity 3 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf	Primary		Approved 8429	DANTRIUM Approved Use In Chronic Spasticity: Dantrium is indicated in controlling the manifestations of clinical spasticity resulting from upper motor neuron disorders (e.g., spinal cord injury, stroke, cerebral palsy, or multiple sclerosis). In Malignant Hyperthermia: Oral Dantrium is also indicated preoperatively to prevent or attenuate the development of signs of malignant hyperthermia in known, or strongly suspect, malignant hyperthermia susceptible patients who require anesthesia and/or surgery. Launch Date 1974
Malignant hyperthermia 3 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf	Preventing		Approved 8429	DANTRIUM Approved Use In Chronic Spasticity: Dantrium is indicated in controlling the manifestations of clinical spasticity resulting from upper motor neuron disorders (e.g., spinal cord injury, stroke, cerebral palsy, or multiple sclerosis). In Malignant Hyperthermia: Oral Dantrium is also indicated preoperatively to prevent or attenuate the development of signs of malignant hyperthermia in known, or strongly suspect, malignant hyperthermia susceptible patients who require anesthesia and/or surgery. Launch Date 1974

C_max

Value	Dose	Co-administered	Analyte	Population
9 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205579s000lbl.pdf	2.5 mg/kg single, intravenous dose: 2.5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		DANTROLENE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
77.7 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205579s000lbl.pdf	2.5 mg/kg single, intravenous dose: 2.5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		DANTROLENE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
8.7 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf	100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:		DANTROLENE blood	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
10.8 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205579s000lbl.pdf	2.5 mg/kg single, intravenous dose: 2.5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		DANTROLENE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
25 mg 1 times / day steady, oral (starting) Dose: 25 mg, 1 times / day Route: oral Route: steady Dose: 25 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf	Disc. AE: Hepatitis, Diarrhea... AEs leading to discontinuation/dose reduction: Hepatitis Diarrhea Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf

AEs

AE	Significance	Dose	Population
Diarrhea	Disc. AE	25 mg 1 times / day steady, oral (starting) Dose: 25 mg, 1 times / day Route: oral Route: steady Dose: 25 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf
Hepatitis	Disc. AE	25 mg 1 times / day steady, oral (starting) Dose: 25 mg, 1 times / day Route: oral Route: steady Dose: 25 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OAT1 599 OAT3 642 MRP4 204	CYP1A1 349 CYP1A2 1054 CYP3A 191 BCRP 561

Drug as perpetrator

Target	Modality	Activity
OAT3 644	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28630284/	yes [IC50 0.3 uM]
OAT1 603	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28630284/	yes [IC50 1.89 uM]
MRP4 238	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28630284/	yes [IC50 5.29 uM]

Drug as victim

Target	Modality	Activity
BCRP 561	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/22115838/	yes
CYP1A1 349	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/7902259/	yes
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/7902259/	yes
CYP3A 191	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/7902259/	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:4317	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:4317
MolPort	MolPort-003-846-133	https://www.molport.com/shop/molecule-link/MolPort-003-846-133
ZINC	ZINC000252679615	http://zinc15.docking.org/substances/ZINC000252679615

PubMed

Title	Date	PubMed
Dantrolene hepatitis.	1976 Apr 12	946274
Dantrolene-associated hepatic injury. Incidence and character.	1977 Apr	838213
Pleuropericardial reaction to treatment with dantrolene.	1979 Dec 21	501885
Dantrolene and suxamethonium. The effect of pre-operative dantrolene on the action of suxamethonium.	1979 Feb	375768
Hepatitis from dantrolene sodium.	1979 Jan	761834
Dantrolene and lymphocytic lymphoma.	1980 Apr	6893628
Treatment of neuroleptic malignant syndrome with dantrolene.	1982 Jul 3	6123782
[Neuroleptic malignant syndrome. Beneficial effects of dantrolene on hyperthermia and hypertonia (author's transl)].	1982 Mar 27	7079122
Beneficial effects of dantrolene in the treatment of neuroleptic malignant syndrome: a report of two cases.	1983 Apr	6682201
Neuroleptic malignant syndrome: response to dantrolene sodium.	1983 Feb	6824251
Neuroleptic malignant syndrome: successful treatment with dantrolene and bromocriptine.	1983 Jul	6614876
Pneumonitis, pleural effusion and pericarditis following treatment with dantrolene.	1984 May	6736987
Hyperkalemia and cardiovascular collapse after verapamil and dantrolene administration in swine.	1984 May	6711841
[Cardiac failure caused by an overdose of dantrolene].	1986	3826797
Prevention of amphotericin B-induced rigors by dantrolene.	1986 Aug	3729640
Sudden bilateral sensorineural hearing loss during treatment with dantrolene sodium (dantrium).	1988 Jan	3343565
Trimipramine-induced neuroleptic malignant syndrome after transient psychogenic polydipsia in one patient.	1989 Apr	2925603
Treatment of lethal catatonia with electroconvulsive therapy and dantrolene sodium: a case report.	1990 Jul	2399829
[Successful treatment of levodopa-induced neuroleptic malignant syndrome (NMS) with disseminated intravascular coagulation (DIC) in a patient with Parkinson's disease].	1991 Jan	2044308
Management of neuroleptic malignant syndrome--a series of eight cases.	1993 Feb	8101521
Successful treatment of an episode of malignant hyperthermia using a large dose of dantrolene.	1993 Jan-Feb	8442973
[Freeman-Sheldon syndrome: generalized muscular rigidity after anesthetic induction].	1994 May-Jun	8059048
[Clinical study of neuroleptic malignant syndrome in demented patients--examination of our case and reported cases].	1994 Sep	7999444
Induction or protection of limbic seizures in mice by mGluR subtype selective agonists.	1995 Aug	8532155
Dantrolene treatment of opioid-induced myoclonus.	1995 Dec	7486124
Clinical effects of intravenously administered dantrolene.	1995 Mar	7861811
Development of an animal model for neuroleptic malignant syndrome: heat-exposed rabbits with haloperidol and atropine administration exhibit increased muscle activity, hyperthermia, and high serum creatine phosphokinase level.	1996 Dec 16	9017254
[A case of malignant syndrome triggered by the use of haloperidol and chrorpromazine].	1997 Apr	9128030
Malignant hyperthermia induced by general anesthesia for bone marrow harvesting.	1997 Mar	9052921
Early bicarbonate loading and dantroline for ziprasidone/haloperidol-induced neuroleptic malignant syndrome.	2006 Apr	16669738
Neuroleptic malignant syndrome with delayed onset of fever following risperidone administration.	2006 Dec	17119106
Secretion of brain-derived neurotrophic factor from brain microvascular endothelial cells.	2006 Mar	16553631
Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+ increase are reciprocally modulated in rat cardiomyocytes.	2006 Oct 31	17079870
Neuroleptic malignant syndrome induced by metoclopramide in an infant with Freeman-Sheldon syndrome.	2006 Sep	16931708
KATP channel knockout worsens myocardial calcium stress load in vivo and impairs recovery in stunned heart.	2007 Apr	17189350
Transitional cell carcinoma in the paediatric population: be aware of unusual aetiologies.	2007 Nov	17924939
A novel compound heterozygous dysferlin mutation in Miyoshi myopathy siblings responding to dantrolene.	2007 Nov	17868276
Identification of functional type 1 ryanodine receptors in human dendritic cells.	2007 Oct 19	17707769
Pharmacologic profiling of human and rat cytochrome P450 1A1 and 1A2 induction and competition.	2008 Dec	18493746
Quantitative investigation of the role of breast cancer resistance protein (Bcrp/Abcg2) in limiting brain and testis penetration of xenobiotic compounds.	2008 Jun	18322075
Cellular imaging predictions of clinical drug-induced liver injury.	2008 Sep	18524759
Dantrolene, a therapeutic agent for malignant hyperthermia, inhibits catecholaminergic polymorphic ventricular tachycardia in a RyR2(R2474S/+) knock-in mouse model.	2010 Nov	20944434
Stimulation of cytosolic and mitochondrial calcium mobilization by indomethacin in Caco-2 cells: modulation by the polyphenols quercetin, resveratrol and rutin.	2012 Dec	23022152
Diphenyl ditelluride induces hypophosphorylation of intermediate filaments through modulation of DARPP-32-dependent pathways in cerebral cortex of young rats.	2012 Feb	21863293
Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model.	2013 Dec	24052561
The calcium signaling pathway regulates leydig cell steroidogenesis through a transcriptional cascade involving the nuclear receptor NR4A1 and the steroidogenic acute regulatory protein.	2013 Jan	23183170
Tributyltin-induced endoplasmic reticulum stress and its Ca(2+)-mediated mechanism.	2013 Oct 1	23743301
Genomic models of short-term exposure accurately predict long-term chemical carcinogenicity and identify putative mechanisms of action.	2014	25058030
Comparative gene and protein expression analyses of a panel of cytokines in acute and chronic drug-induced liver injury in rats.	2014 Oct 3	25051504
Caffeine induces cardiomyocyte hypertrophy via p300 and CaMKII pathways.	2014 Sep 25	25093688

Patents

Sample Use Guides

In Vivo Use Guide

For Use in Chronic Spasticity: 25 mg once daily for seven days, then 25 mg t.i.d. for seven days, 50 mg t.i.d. for seven days, 100 mg t.i.d. (adults). For Malignant Hyperthermia: administer 4 to 8 mg/kg/day of oral drug in 3 or 4 divided doses for one or two days prior to surgery, with the last dose being given approximately 3 to 4 hours before scheduled surgery with a minimum of water.

Route of Administration: Oral

In Vitro Use Guide

Whole skeletal muscle fascicles were incubated with dantrolene at concentrations of 5, 15 and 25 uM. Dantrolene inhibited twitch tensions of skeletal muscle fascicles, probably by indirectly preventing the release of calcium from the SR.

Name

Type

Language

DANTROLENE SODIUM ANHYDROUS

Common Name

English

2,4-IMIDAZOLIDINEDIONE, 1-(((5-(4-NITROPHENYL)-2-FURANYL)METHYLENE)AMINO)-, SODIUM SALT

Common Name

English

1-((5-(P-NITROPHENYL)FURFURYLIDENE)AMINO)HYDANTOIN SODIUM SALT

Common Name

English

DANTROLENE SODIUM SALT ANHYDROUS [MI]

Common Name

English

2,4-IMIDAZOLIDINEDIONE, 1-((E)-((5-(4-NITROPHENYL)-2-FURANYL)METHYLENE)AMINO)-, SODIUM SALT (1:1)

Systematic Name

English

Code System Code Type Description

MERCK INDEX

m4085