PRALIDOXIME

Details

Stereochemistry	ACHIRAL
Molecular Formula	C7H9N2O
Molecular Weight	137.1592
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	1
Stereo Comments	Assumed E-isomer as in USP/NF chloride salt record

SHOW SMILES / InChI

Structure Search

SMILES

C[N+]1=C(\C=N\O)C=CC=C1

InChI

InChIKey=JBKPUQTUERUYQE-UHFFFAOYSA-O

InChI=1S/C7H8N2O/c1-9-5-3-2-4-7(9)6-8-10/h2-6H,1H3/p+1

HIDE SMILES / InChI

Description
Sources: https://www.drugs.com/mmx/pralidoxime-chloride.html
Curator's Comment: description was created based on several sources, including https://www.drugbank.ca/drugs/DB00733 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21175_Atnaa_prntlbl.pdf | http://reference.medscape.com/drug/protopam-2pam-antidote-pralidoxime-343744 | https://www.ncbi.nlm.nih.gov/pubmed/27450532

Pralidoxime is a cholinesterase reactivator used as the antidote to organophosphate pesticides or acetylcholinesterase inhibitors (nerve agents) in conjunction with atropine and diazepam. Organophosphates bind to the esteratic site of acetylcholinesterase, which results initially in reversible inactivation of the enzyme. Acetylcholinesterase inhibition causes acetylcholine to accumulate in synapses, producing continuous stimulation of cholinergic fibers throughout the nervous systems. If given within 24 hours after organophosphate exposure, pralidoxime reactivates the acetylcholinesterase by cleaving the phosphate-ester bond formed between the organophosphate and acetylcholinesterase. Pralidoxime is indicated as an adjunct in the treatment of moderate and severe poisoning caused by organophosphate pesticides that have anticholinesterase activity or by chemicals with anticholinesterase activity such as some chemicals used as nerve agents during chemical warfare. Pralidoxime is also indicated as an adjunct in the management of the overdose of cholinesterase inhibitors, such as ambenonium, neostigmine, and pyridostigmine, used in the treatment of myasthenia gravis. Pralidoxime, used in conjunction with atropine, reverses nicotinic effects, such as muscle weakness and fasciculation, respiratory depression, and central nervous system (CNS) effects, associated with toxic exposure to organophosphate anticholinesterase pesticides and chemicals and with cholinesterase inhibitor overdose. Atropine, by antagonizing the action of cholinesterase inhibitors at muscarinic receptor sites, reverses muscarinic effects, such as tracheobronchial and salivary secretion, bronchoconstriction, bradycardia, and, to a moderate extent, CNS effects.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Acetylcholinesterase 207 Target ID: CHEMBL220 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27450532	Activator 1430		31.4 µM [Kd]
Butyrylcholinesterase 46 Target ID: CHEMBL1914 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24571195	Activator 1430

Conditions

Condition	Modality	Targets	Highest Phase	Product
Organophosphate poisoning 12 Sources: https://www.drugs.com/mmx/pralidoxime-chloride.html	Curative		Approved 8429	PROTOPAM CHLORIDE Approved Use PROTOPAM Chloride is indicated as an antidote: 1.In the treatment of poisoning due to those pesticides and chemicals (e.g., nerve agents) of the organophosphate class which have anticholinesterase activity and 2.In the control of overdosage by anticholinesterase drugs used in the treatment of myasthenia gravis. The principal indications for the use of PROTOPAM Chloride are muscle weakness and respiratory depression. In severe poisoning, respiratory depression may be due to muscle weakness. Launch Date 1964

C_max

Value	Dose	Analyte	Population
3988 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20804498	700 mg single, intramuscular dose: 700 mg route of administration: Intramuscular experiment type: SINGLE co-administered:	PRALIDOXIME plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
7.5 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/014134s022lbl.pdf	1000 mg single, intramuscular dose: 1000 mg route of administration: Intramuscular experiment type: SINGLE co-administered:	PRALIDOXIME plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
9.9 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/014134s022lbl.pdf	1000 mg single, intramuscular dose: 1000 mg route of administration: Intramuscular experiment type: SINGLE co-administered:	PRALIDOXIME plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
10070 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20804498	700 mg single, intramuscular dose: 700 mg route of administration: Intramuscular experiment type: SINGLE co-administered:		PRALIDOXIME plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
2.94 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20804498	700 mg single, intramuscular dose: 700 mg route of administration: Intramuscular experiment type: SINGLE co-administered:	PRALIDOXIME plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
3 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/014134s022lbl.pdf	1000 mg single, intramuscular dose: 1000 mg route of administration: Intramuscular experiment type: SINGLE co-administered:	PRALIDOXIME plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
3 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/014134s022lbl.pdf	1000 mg single, intramuscular dose: 1000 mg route of administration: Intramuscular experiment type: SINGLE co-administered:	PRALIDOXIME plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
100% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/014134s022lbl.pdf	1000 mg single, intramuscular dose: 1000 mg route of administration: Intramuscular experiment type: SINGLE co-administered:		PRALIDOXIME plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
2000 g 2 times / day multiple, oral Dose: 2000 g, 2 times / day Route: oral Route: multiple Dose: 2000 g, 2 times / day Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	healthy, adult n = 29 Health Status: healthy Age Group: adult Population Size: 29 Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	Other AEs: Lymphocytosis, Thymol turbidity test increased... Other AEs: Lymphocytosis (5 patients) Thymol turbidity test increased (4 patients) Urobilinogen urine positive (11 patient) Change in ECG (9 patients) Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975
4 g single, oral Dose: 4 g Route: oral Route: single Dose: 4 g Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	healthy, adult n = 10 Health Status: healthy Age Group: adult Population Size: 10 Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975
45 mg/kg single, intramuscular Dose: 45 mg/kg Route: intramuscular Route: single Dose: 45 mg/kg Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	healthy, adult Health Status: healthy Age Group: adult Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975
45 mg/kg single, intravenous Dose: 45 mg/kg Route: intravenous Route: single Dose: 45 mg/kg Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	healthy, adult Health Status: healthy Age Group: adult Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	Other AEs: Hypertension, Headache... Other AEs: Hypertension Headache Visual accommodation disturbance of Epigastric discomfort Vomiting Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975

AEs

AE	Significance	Dose	Population
Urobilinogen urine positive	11 patient	2000 g 2 times / day multiple, oral Dose: 2000 g, 2 times / day Route: oral Route: multiple Dose: 2000 g, 2 times / day Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	healthy, adult n = 29 Health Status: healthy Age Group: adult Population Size: 29 Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975
Thymol turbidity test increased	4 patients	2000 g 2 times / day multiple, oral Dose: 2000 g, 2 times / day Route: oral Route: multiple Dose: 2000 g, 2 times / day Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	healthy, adult n = 29 Health Status: healthy Age Group: adult Population Size: 29 Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975
Lymphocytosis	5 patients	2000 g 2 times / day multiple, oral Dose: 2000 g, 2 times / day Route: oral Route: multiple Dose: 2000 g, 2 times / day Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	healthy, adult n = 29 Health Status: healthy Age Group: adult Population Size: 29 Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975
Change in ECG	9 patients	2000 g 2 times / day multiple, oral Dose: 2000 g, 2 times / day Route: oral Route: multiple Dose: 2000 g, 2 times / day Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	healthy, adult n = 29 Health Status: healthy Age Group: adult Population Size: 29 Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975
Epigastric discomfort		45 mg/kg single, intravenous Dose: 45 mg/kg Route: intravenous Route: single Dose: 45 mg/kg Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	healthy, adult Health Status: healthy Age Group: adult Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975
Headache		45 mg/kg single, intravenous Dose: 45 mg/kg Route: intravenous Route: single Dose: 45 mg/kg Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	healthy, adult Health Status: healthy Age Group: adult Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975
Hypertension		45 mg/kg single, intravenous Dose: 45 mg/kg Route: intravenous Route: single Dose: 45 mg/kg Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	healthy, adult Health Status: healthy Age Group: adult Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975
Visual accommodation disturbance of		45 mg/kg single, intravenous Dose: 45 mg/kg Route: intravenous Route: single Dose: 45 mg/kg Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	healthy, adult Health Status: healthy Age Group: adult Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975
Vomiting		45 mg/kg single, intravenous Dose: 45 mg/kg Route: intravenous Route: single Dose: 45 mg/kg Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975	healthy, adult Health Status: healthy Age Group: adult Sources: https://www.tandfonline.com/doi/abs/10.1080/00039896.1967.10664975

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	P-gp 1537 BCRP 561

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
BCRP 561	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939658/	no
P-gp 1537	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939658/	no

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:8354	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:8354
ZINC	ZINC000004577910	http://zinc15.docking.org/substances/ZINC000004577910

PubMed

Title	Date	PubMed

Patents

Sample Use Guides

In Vivo Use Guide

1-2 g IV infusion (10-20 mg/mL) over 15-30 min, repeat in 1 hr if necessary and repeat q12hr thereafter PRN; if not practical or if pulmonary edema present or fluid restriction necessary administer as 50 mg/mL over 5 min; a second bolus of 1-2 g may be indicated after about 1 hr if muscle weakness has not been relieved; may repeat q10-12hr prn Alternatively, administer 30 mg/kg IV (IM, SC if no IV access) over 20 min; follow by 4-8 mg/kg/hr maintenance IV infusion Use with atropine, which affects muscarinic receptors; pralidoxime's actions most striking at nicotonic sites (increase muscle strength 10-40 min) IM: 600 mg IM x3 doses; administer each dose 15 minutes apart for mild symptoms, or in rapid succession for severe symptoms; not to exceed 1800 mg total dose initially; if symptoms persist may repeat series of three injections 1 hr after last injection

Route of Administration: Other

In Vitro Use Guide

The stock solutions of the nerve agents, sarin and VX were prepared freshly in 2-propanol and stored under refrigeration. Appropriate quantity of the individual NA (sarin and VX) was added to the suspension of enzyme hAChE in phosphate buffer at 37 C and incubated for ten minutes to achieve 95–98% inhibition of the control activity. The oxime (Pralidoxime) solution of particular concentration (1.0–0.01 mkM) was added to the nerve agent inhibited hAChE and the reactivation profile was monitored over the time period of sixty minutes at different time intervals. Spontaneous reactivation of the inhibited hAChE was determined using the same protocol (reaction mixture containing enzyme and OP but no oxime), but the spontaneous reactivation was found to be insignificant. All the values were corrected for their oxime induced hydrolysis of ATChI.

Name

Type

Language

PRALIDOXIME

Common Name

English

PRALIDOXIME [VANDF]

Common Name

English

PRALIDOXIME ION

Common Name

English

PRALIDOXIME [MART.]

Common Name

English

Pralidoxime [WHO-DD]

Common Name

English

PRALIDOXIME CATION

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000175742