PENTAMIDINE DIHYDROCHLORIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C19H26N4O2.2Cl
Molecular Weight	413.341
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure of PENTAMIDINE DIHYDROCHLORIDE

Structure Search

SMILES

[Cl-].[Cl-].NC(=[NH2+])C1=CC=C(OCCCCCOC2=CC=C(C=C2)C(N)=[NH2+])C=C1

InChI

InChIKey=HWURPQUPKQFGJI-UHFFFAOYSA-N

InChI=1S/C19H24N4O2.2ClH/c20-18(21)14-4-8-16(9-5-14)24-12-2-1-3-13-25-17-10-6-15(7-11-17)19(22)23;;/h4-11H,1-3,12-13H2,(H3,20,21)(H3,22,23);2*1H

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf
Curator's Comment: description was created based on several sources, including: http://www.drugbank.ca/drugs/DB00738 https://en.wikipedia.org/wiki/Pentamidine

Pentamidine (formulated as a salt, pentamidine diisethionate or dimesilate) is an antimicrobial medication given for prevention and treatment of pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii), a severe interstitial type of pneumonia often seen in patients with HIV infection. The drug is also the mainstay of treatment for stage I infection with Trypanosoma bruceigambiense (West African trypanosomiasis). Pentamidine is also used as a prophylactic against PCP in patients receiving chemotherapy and in some patients who have undergone organ transplantation, as they also have a depressed immune system as a direct side-effect of the drugs used. The mortality of untreated PCP is very high. Additionally, pentamidine has good clinical activity in treating leishmaniasis, and yeast infections caused by the organism Candida albicans. Pentamidine is also used as a prophylactic antibiotic for children undergoing treatment for leukemia. Studies suggest that the pentamidine isethionate interferes with microbial nuclear metabolism by inhibition of DNA, RNA, phospholipid and protein synthesis. However, the mode of action is not fully understood.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
tRNA (cytosine(38)-C(5))-methyltransferase 6 Target ID: O14717 Gene ID: 1787.0 Gene Symbol: TRDMT1 Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275129/	Binding Agent 1064		204.4 µM [EC50]
DNA 278 Target ID: CHEMBL2366046 Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e2ad9d3c-b6c3-4f70-87e0-722a8ff94ccb#nlm34090-1	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pneumocystis jiroveci pneumonia (PJP) in high-risk, HIV-infected patients 6 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf	Preventing		Approved 8429	NEBUPENT Approved Use Pentamidine Launch Date 1985

C_max

Value	Dose	Analyte	Population
751 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8056699	3.9 mg/kg 1 times / day multiple, intravenous dose: 3.9 mg/kg route of administration: Intravenous experiment type: MULTIPLE co-administered:	PENTAMIDINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
18.8 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf	4 mg/kg 1 times / day multiple, irrigation dose: 4 mg/kg route of administration: Irrigation experiment type: MULTIPLE co-administered:	PENTAMIDINE unknown	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
612 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf	4 mg/kg single, intravenous dose: 4 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	PENTAMIDINE unknown	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
6734 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8056699	3.9 mg/kg 1 times / day multiple, intravenous dose: 3.9 mg/kg route of administration: Intravenous experiment type: MULTIPLE co-administered:		PENTAMIDINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
6.4 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf	4 mg/kg single, intravenous dose: 4 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		PENTAMIDINE unknown	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
1600 mg single, intravenous Overdose Dose: 1600 mg Route: intravenous Route: single Dose: 1600 mg Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display	unhealthy, 17 n = 1 Health Status: unhealthy Condition: Pneumonia due to Pneumocystis carinii Age Group: 17 Population Size: 1 Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display	Other AEs: Impaired renal function, Hepatic impairment... Other AEs: Impaired renal function Hepatic impairment Hypotension Cardiopulmonary arrest Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display
600 mg 1 times / month multiple, respiratory Highest studied dose Dose: 600 mg, 1 times / month Route: respiratory Route: multiple Dose: 600 mg, 1 times / month Sources: https://pubmed.ncbi.nlm.nih.gov/8750367 Page: p.1167	unhealthy, 37.9 ± 7.5 n = 76 Health Status: unhealthy Condition: Pneumonia due to Pneumocystis carinii Age Group: 37.9 ± 7.5 Sex: M+F Population Size: 76 Sources: https://pubmed.ncbi.nlm.nih.gov/8750367 Page: p.1167	Sources: https://pubmed.ncbi.nlm.nih.gov/8750367 Page: p.1167
300 mg 1 times / month multiple, respiratory Recommended Dose: 300 mg, 1 times / month Route: respiratory Route: multiple Dose: 300 mg, 1 times / month Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf Page: p.6	unhealthy Health Status: unhealthy Condition: Pneumonia due to Pneumocystis carinii Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf Page: p.6	Disc. AE: Acute pancreatitis... AEs leading to discontinuation/dose reduction: Acute pancreatitis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf Page: p.6
4 mg/kg 1 times / day multiple, intramuscular Recommended Dose: 4 mg/kg, 1 times / day Route: intramuscular Route: multiple Dose: 4 mg/kg, 1 times / day Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display	unhealthy Health Status: unhealthy Condition: Pneumonia due to Pneumocystis carinii Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display	Disc. AE: Hypotension, Hypoglycemia... Other AEs: Extravasation, Injection site ulceration... AEs leading to discontinuation/dose reduction: Hypotension (grade 3-5) Hypoglycemia (grade 5) Acute pancreatitis (grade 5) Cardiac arrhythmias (grade 5) Cardiac arrhythmias (grade 5) Other AEs: Extravasation Injection site ulceration Injection site necrosis Slough injection site Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display
4 mg/kg 1 times / day multiple, intravenous Recommended Dose: 4 mg/kg, 1 times / day Route: intravenous Route: multiple Dose: 4 mg/kg, 1 times / day Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display	unhealthy Health Status: unhealthy Condition: Pneumonia due to Pneumocystis carinii Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display	Disc. AE: Hypotension, Hypoglycemia... Other AEs: Extravasation, Injection site ulceration... AEs leading to discontinuation/dose reduction: Hypotension (grade 3-5) Hypoglycemia (grade 5) Acute pancreatitis (grade 5) Cardiac arrhythmias (grade 5) Cardiac arrhythmias (grade 5) Other AEs: Extravasation Injection site ulceration Injection site necrosis Slough injection site Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
Kir4.1 6	OCT1 327 P-gp 1537 MRP transporters 10

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
Kir4.1 6	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28993158/	yes [IC50 0.097 uM]
BCRP 773	activator 214 Sources: https://pubmed.ncbi.nlm.nih.gov/22200378/	yes

Drug as victim

Target	Modality	Activity
MRP transporters 10	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/19261919/	yes
OCT1 327	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/28362799/	yes
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/19261919/	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:45081	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:45081
ChemicalBook	CB4476092	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4476092
MolPort	MolPort-001-792-506	https://www.molport.com/shop/molecule-link/MolPort-001-792-506
ZINC	ZINC000001530775	http://zinc15.docking.org/substances/ZINC000001530775
eMolecules	1012733	https://www.emolecules.com/cgi-bin/more?vid=1012733

PubMed

Title	Date	PubMed
Efficacy of trimethoprim and sulfamethoxazole in the prevention and treatment of Pneumocystis carinii pneumonitis.	1974 Mar	4365115
[Nephrotoxic effect of pentamidine in the treatment of interstitial pneumonia in 2 children with acute lymphoblastic leukemia].	1979 Dec	294951
Visceral leishmaniasis unresponsive to antimonial drugs. II. Response to high dosage sodium stibogluconate or prolonged treatment with pentamidine.	1985	3006295
Extrapyramidal symptoms in AIDS patients given low-dose metoclopramide or chlorpromazine.	1985 Nov 23	2865637
Sciatic nerve damage associated with pentamidine.	1985 Oct	2996869
Pentamidine and renal toxicity.	1985 Sep 12	4022063
Hypoglycemic coma from pentamadine in an AIDS patient.	1986 Jul	3487333
Pentamidine and hematuria.	1986 Jul	3487266
Pentamidine-induced hypoglycemia in patients with the acquired immune deficiency syndrome.	1986 Mar	3485027
Torsade de pointes during administration of pentamidine isethionate.	1987 Sep	3499072
Aggressive psychosis in AIDS patient on high-dose steroids.	1987 Sep 26	2888983
Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A prospective, noncrossover study.	1988 Aug 15	3260759
Recurrent ventricular tachycardia due to pentamidine-induced cardiotoxicity.	1988 Dec	3263912
Tremor induced by trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome (AIDS).	1988 Jul 1	2967659
Risk factors for hypoglycemia associated with pentamidine therapy for Pneumocystis pneumonia.	1988 Jul 15	3259989
Cationic antitrypanosomal and other antimicrobial agents in the therapy of experimental Pneumocystis carinii pneumonia.	1988 Jun	3137861
Ventricular tachycardia due to pentamidine isethionate.	1988 May	3364459
Comparison of dosages, intervals, and drugs in the prevention of Pneumocystis carinii pneumonia.	1988 May	3260765
Torsades de pointes during intravenous pentamidine isethionate therapy.	1989 Jan 15	2783374
Renal insufficiency with nebulised pentamidine.	1989 Oct 28	2572780
Nephrotoxicity and hyperkalemia in patients with acquired immunodeficiency syndrome treated with pentamidine.	1989 Sep	2773964
Pentamidine-induced torsades de pointes in a renal transplant recipient with Pneumocystis carinii pneumonia.	1990 Apr	2321077
Analogues of 1,5-bis(4-amidinophenoxy)pentane (pentamidine) in the treatment of experimental Pneumocystis carinii pneumonia.	1990 Apr	2319567
Structure-activity relationships of analogs of pentamidine against Plasmodium falciparum and Leishmania mexicana amazonensis.	1990 Jul	2201254
Ventricular tachycardia and torsades de pointes complicating pentamidine therapy of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome.	1990 Oct 1	2220597
[Transitory acute kidney insufficiency and insulin-dependent after treatment of kala-azar with pentamidine and N-methylglucamine antimony].	1991 May	1859238
Pentamidine-associated nephrotoxicity and hyperkalemia in patients with AIDS.	1991 Nov	1763529
High pentamidine levels associated with hypoglycemia and azotemia in a patient with Pneumocystis carinii pneumonia.	1992 Aug	1424505
Treatment of experimental pneumocystosis: review of 7 years of experience and development of a new system for classifying antimicrobial drugs.	1992 Sep	1416885
Pentamidine, the drug of choice for the treatment of cutaneous leishmaniasis in Surinam.	2002 Nov	12453009
T wave alternans and Torsades de Pointes after the use of intravenous pentamidine.	2002 Sep	12380935
A reverse turn structure induced by a D,L-alpha-aminoxy acid dimer.	2003 Nov 26	14624594
Search of chemical scaffolds for novel antituberculosis agents.	2005 Apr	15809316
A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.	2005 Feb	15342952
Pentamidine-induced long QT syndrome and block of hERG trafficking.	2005 Jan	15340016
Detection of immunotoxicity using T-cell based cytokine reporter cell lines ("Cell Chip").	2005 Jan 15	15588918
Pentamidine is an antiparasitic and apoptotic drug that selectively modifies ubiquitin.	2005 Oct	17191940
Use of Leishmania donovani field isolates expressing the luciferase reporter gene in in vitro drug screening.	2005 Sep	16131481
Novel synthesis of nicotinamide derivatives of cytotoxic properties.	2006 Jul 1	16524735
[Cutaneous leishmaniasis--an import from Belize].	2007	17987367
Cellulose biosynthesis pathway is a potential target in the improved treatment of Acanthamoeba keratitis.	2007 May	17225099
Using the zebrafish lateral line to screen for ototoxicity.	2008 Jun	18408970
The diamidine DB75 targets the nucleus of Plasmodium falciparum.	2009 May 14	19442305
Identification of human Ether-à-go-go related gene modulators by three screening platforms in an academic drug-discovery setting.	2010 Dec	21158687
Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation.	2010 Feb 9	20144237
Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2.	2011 Jul 14	21599003
Synthetic chromanol derivatives and their interaction with complex III in mitochondria from bovine, yeast, and Leishmania.	2011 Oct 17	21809846
Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model.	2013 Dec	24052561
Utilization of human nuclear receptors as an early counter screen for off-target activity: a case study with a compendium of 615 known drugs.	2015 Jun	25752796
Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis.	2015 May 18	25811541

Patents

Sample Use Guides

In Vivo Use Guide

The recommended adult dosage is 300 mg once every four weeks administered via the Respirgard® II nebulizer. The dose should be delivered until the nebulizer chamber is empty (approximately 30 to 45 minutes). The flow rate should be 5 to 7 liters per minute from a 40 to 50 pounds per square inch (PSI) air or oxygen source. Alternatively, a 40 to 50 PSI air compressor can be used with flow limited by setting the flowmeter at 5 to 7 liters per minute or by setting the pressure at 22 to 25 PSI. Low pressure (less than 20 PSI) compressors should not be used.

Route of Administration: Irrigation

In Vitro Use Guide

Pentamidine was found to be active against T. whipplei strains both in axenic medium and in cell culture, with minimum inhibitory concentration ranges of 0.125-0.25mg/L.

Name

Type

Language

PENTAMIDINE DIHYDROCHLORIDE

Common Name

English

PENTAMIDINE DIHYDROCHLORIDE [MI]

Common Name

English

BENZENECARBOXIMIDAMIDE, 4,4'-(1,5-PENTANEDIYLBIS(OXY))BIS-, DIHYDROCHLORIDE

Common Name

English

4,4'-(PENTAMETHYLENEDIOXY)DIBENZAMIDINE DIHYDROCHLORIDE

Systematic Name

English

Code System Code Type Description

CAS

50357-45-4