DISTIGMINE BROMIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H32N4O4.2Br
Molecular Weight	576.322
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[Br-].[Br-].CN(CCCCCCN(C)C(=O)OC1=CC=C[N+](C)=C1)C(=O)OC2=CC=C[N+](C)=C2

InChI

InChIKey=GJHSNEVFXQVOHR-UHFFFAOYSA-L

InChI=1S/C22H32N4O4.2BrH/c1-23-13-9-11-19(17-23)29-21(27)25(3)15-7-5-6-8-16-26(4)22(28)30-20-12-10-14-24(2)18-20;;/h9-14,17-18H,5-8,15-16H2,1-4H3;2*1H/q+2;;/p-2

HIDE SMILES / InChI

Description
Sources: http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=1755
Curator's Comment: description was created based on several sources, including: http://www.medicines.org.uk/emc/PIL.3897.latest.pdf | http://www.torii.co.jp/iyakuDB/data/if/if_ubr_t.pdf

Distigmine is an acetylcholinesterase (AChE) inhibitor. Distigmine shows direct binding to muscarinic receptors in the rat bladder, and repeated oral administration of distigmine causes downregulation of muscarinic receptors in the rat bladder. The observed direct interaction of distigmine with the bladder muscarinic receptors may partly contribute to the therapeutic and/or side effects seen in the treatment of detrusor underactivity. It is usually used to treat myasthenia gravis, dysuria due to hypotonic bladder such as neurogenic bladder or after surgery. Common side effects are: nausea/vomiting, abdominal pain, diarrhea, increased salivation, hypersecretion in respiratory tract, sweating, bradycardia, miosis, difficulty in breathing. Distigmine has a greater risk of causing cholinergic crisis because of accumulation of the drug being more likely than with neostigmine or pyridostigmine and so distigmine is rarely used as a treatment for myasthenia gravis, unlike pyridostigmine and neostigmine.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Acetylcholinesterase 209 Target ID: CHEMBL220 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20610884 \| https://www.ncbi.nlm.nih.gov/pubmed/8100221	Inhibitor 8504	45.0 nM [IC50]
Muscarinic receptors (rat) 2 Target ID: Muscarinic receptors (rat) Sources: https://www.ncbi.nlm.nih.gov/pubmed/20410601	Binding Agent 1076	0.36 µM [Ki]
Nicotinic receptors (rat) 2 Target ID: Nicotinic receptors (rat) Sources: https://www.ncbi.nlm.nih.gov/pubmed/20410601	Binding Agent 1076	22.9 µM [Ki]

Conditions

Condition	Modality	Highest Phase	Product
Neurogenic bladder 6 Sources: http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=1755	Primary	Approved 8583	Ubretid Approved Use It is usually used to treat myasthenia gravis, dysuria due to hypotonic bladder such as neurogenic bladder or after surgery.
Myasthenia gravis 21 Sources: http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=1755	Primary	Approved 8583	Ubretid Approved Use It is usually used to treat myasthenia gravis, dysuria due to hypotonic bladder such as neurogenic bladder or after surgery.
Dysuria due to hypotonic bladder after surgery 2 Sources: http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=1755	Primary	Approved 8583	Ubretid Approved Use It is usually used to treat myasthenia gravis, dysuria due to hypotonic bladder such as neurogenic bladder or after surgery.

C_max

Value	Dose	Co-administered	Analyte	Population
4.4 ng/mL OTHER GOV'T https://www.info.pmda.go.jp/go/interview/1/480306_1231014F1054_1_003_1F.pdf#page=19 \| https://pubmed.ncbi.nlm.nih.gov/10475142/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		DISTIGMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
228.4 μg × h/L OTHER GOV'T https://www.info.pmda.go.jp/go/interview/1/480306_1231014F1054_1_003_1F.pdf#page=19 \| https://pubmed.ncbi.nlm.nih.gov/10475142/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		DISTIGMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
69.5 h OTHER GOV'T https://www.info.pmda.go.jp/go/interview/1/480306_1231014F1054_1_003_1F.pdf#page=19 \| https://pubmed.ncbi.nlm.nih.gov/10475142/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		DISTIGMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
83.2% OTHER GOV'T https://www.info.pmda.go.jp/go/interview/1/480306_1231014F1054_1_003_1F.pdf#page=22			DISTIGMINE plasma	Homo sapiens

Doses

Dose	Population	Adverse events
10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14686764/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/14686764/	Disc. AE: Rhabdomyolysis... AEs leading to discontinuation/dose reduction: Rhabdomyolysis Sources: https://pubmed.ncbi.nlm.nih.gov/14686764/
10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11868380/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/11868380/	Other AEs: Cholinergic crisis... Other AEs: Cholinergic crisis (grade 5) Sources: https://pubmed.ncbi.nlm.nih.gov/11868380/
10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16180710/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/16180710/	Disc. AE: Parkinsonism... AEs leading to discontinuation/dose reduction: Parkinsonism Sources: https://pubmed.ncbi.nlm.nih.gov/16180710/
5 mg 1 times / day multiple, oral Recommended Dose: 5 mg, 1 times / day Route: oral Route: multiple Dose: 5 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14611928/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/14611928/	Disc. AE: Psychotic disorder... AEs leading to discontinuation/dose reduction: Psychotic disorder Sources: https://pubmed.ncbi.nlm.nih.gov/14611928/
0.5 mg 1 times / day multiple, intramuscular Studied dose Dose: 0.5 mg, 1 times / day Route: intramuscular Route: multiple Dose: 0.5 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6132645/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/6132645/	Disc. AE: Diarrhoea... AEs leading to discontinuation/dose reduction: Diarrhoea (6.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/6132645/

AEs

AE	Significance	Dose	Population
Rhabdomyolysis	Disc. AE	10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14686764/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/14686764/
Cholinergic crisis	grade 5	10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11868380/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/11868380/
Parkinsonism	Disc. AE	10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16180710/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/16180710/
Psychotic disorder	Disc. AE	5 mg 1 times / day multiple, oral Recommended Dose: 5 mg, 1 times / day Route: oral Route: multiple Dose: 5 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14611928/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/14611928/
Diarrhoea	6.5% Disc. AE	0.5 mg 1 times / day multiple, intramuscular Studied dose Dose: 0.5 mg, 1 times / day Route: intramuscular Route: multiple Dose: 0.5 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6132645/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/6132645/

PubMed

Title	Date	PubMed
Central and peripheral activity of cholinesterase inhibitors as revealed by yawning and fasciculation in rats.	2001 Mar	11274994
Effects of the selective acetylcholinesterase inhibitor TAK-802 on the voiding behavior and bladder mass increase in rats with partial bladder outlet obstruction.	2005 Sep	16094081
Screening procedure for the analysis of distigmine bromide in serum by high-performance liquid chromatography-electrospray ionization mass spectrometry.	2007 Jun 1	17331815
Ubretid (distigmine bromide) taken to treat urinary retention prolongs the effect of suxamethonium.	2008	18685952
[Acute poisoning due to distigmine bromide].	2008 Apr	18516941
Treatment strategy according to findings on pressure-flow study for women with decreased urinary flow rate.	2009	19841751
Marked hydronephrosis and hydroureter after distigmine therapy in an adult male patient with paraplegia due to spinal cord injury: a case report.	2009 Aug 6	19918519
[Treatment approach to congenital myasthenic syndrome in a patient with acetylcholine receptor deficiency].	2009 Jan	19172815
Effect of distigmine bromide on the central cholinergic system.	2009 Mar	18515453
Pharmacokinetic and pharmacodynamic analysis of acetylcholinesterase inhibition by distigmine bromide in rats.	2010	20610884
Demonstration of muscarinic and nicotinic receptor binding activities of distigmine to treat detrusor underactivity.	2010	20410601
[Bizerine: new anticholinesterase drug with selective gastrointestinal action].	2010 Aug	20919551
[Establishing indicators for diagnosis of cholinergic crisis].	2010 Oct	21077286

Patents

Sample Use Guides

In Vivo Use Guide

For dysuria due to hypotonic bladder such as neurogenic bladder or after surgery, for adults, take 1 tablet (5 mg of the active ingredient) daily. For myasthenia gravis, for adults, take 1-4 tablet(s) (5-20 mg of the active ingredient) daily in 1-4 divided dose(s). Start with 1 tablet (5 mg) daily, and the dose should be adjusted according to symptoms.

Route of Administration: Oral

In Vitro Use Guide

Distigmine (30 nM—10 uM) inhibited specific [3H]oxotremorine-M binding in the bladder, submaxillary gland and cerebral cortex of rats in a concentration-dependent manner. The Ki values for distigmine did not differ significantly among tissues.

Name

Type

Language

UBRETID

Preferred Name

English

DISTIGMINE BROMIDE

Official Name

English

PYRIDINIUM, 3,3'-(1,6-HEXANEDIYLBIS((METHYLIMINO)CARBONYL)OXY)BIS(1-METHYL-, BROMIDE (1:2)

Common Name

English

DISTIGMINE DIBROMIDE

Code

English

BC-51

Code

English

HEXAMARIUM BROMIDE

Common Name

English

distigmine bromide [INN]

Common Name

English

3,3'-(1,6-HEXANEDIYLBIS((METHYLIMINO)CARBONYL)OXY)BIS(1-METHYLPYRIDINIUM)DIBROMIDE

Common Name

English

DISTIGMINE BROMIDE [JAN]

Common Name

English

HEXAMETHYLENEBIS(N-METHYLCARBAMINOYL-1-METHYL-3-HYDROXYPYRIDINIUM BROMIDE)

Common Name

English

UBRITIL

Brand Name

English

Distigmine bromide [WHO-DD]

Common Name

English

3-HYDROXY-1-METHYLPYRIDINIUM BROMIDE HEXAMETHYLENEBIS-(N-METHYLCARBAMATE)

Systematic Name

English

DISTIGMINE BROMIDE [MART.]

Common Name

English

DISTIGMINE BROMIDE [MI]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C47792