Piperaquine

Piperaquine
	artenimol),; P01BX02 (WHO) (combination with arterolane)
Identifiers
	IUPAC name 1,3-bis[4-(7-chloroquinolin-4-yl)piperazin-1-yl]propane;
JSmol)	Interactive image;
Melting point	199 to 204 °C (390 to 399 °F) (dec.V
	SMILES C1CN(CCN1CCCN2CCN(CC2)C3=C4C=CC(=CC4=NC=C3)Cl)C5=C6C=CC(=CC6=NC=C5)Cl;
	InChI InChI=1S/C29H32Cl2N6/c30-22-2-4-24-26(20-22)32-8-6-28(24)36-16-12-34(13-17-36)10-1-11-35-14-18-37(19-15-35)29-7-9-33-27-21-23(31)3-5-25(27)29/h2-9,20-21H,1,10-19H2 ; Key:UCRHFBCYFMIWHC-UHFFFAOYSA-N ;
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Piperaquine is an antiparasitic drug used in combination with

artemisinin combination therapy. Piperaquine kills parasites by disrupting the detoxification of host heme

.

Medical uses

Piperaquine is used in combination with

uncomplicated malaria.^[1] This combination is also recommended by the World Health Organization for treatment of severe malaria after administration of artesunate.^[1]

Piperaquine is also registered for use in some countries in combination with arterolane.^[1] However, this combination is not recommended by the World Health Organization due to insufficient data.^[1]

Contraindications

Like chloroquine, piperaquine can prolong the QT interval. Although large randomized clinical trials have not revealed evidence of cardiotoxicity, the World Health Organization recommends not using piperaquine in patients with congenital QT prolongation or who are on other drugs that prolong the QT interval.^[1]

Pharmacology

Mechanism of action

Like chloroquine, piperaquine is thought to function by accumulating in the parasite

digestive vacuole and interfering with the detoxification of heme into hemozoin.^[2]

Resistance

Parasites that survive piperaquine treatment have been increasingly reported since 2010, particularly in Southeast Asia. The epicenter of piperaquine resistance appears to be western Cambodia where in 2014 over 40% of dihydroartemisinin-piperaquine treatments failed to eliminate parasites from the patient's blood.^[3] Characterizing piperaquine-resistant parasites has been technically challenging, as parasites that survive piperaquine treatment in patients appear to remain sensitive to piperaquine in vitro; i.e. piperaquine appears to have the same IC₅₀ in sensitive parasites and resistant parasites.^[3]

The mechanism by which parasites become resistant to piperaquine remains unclear. Amplification of the parasite proteases

plasmepsin 3, both involved in degrading host hemoglobin, is associated with resistance to piperaquine.^[4] Similarly, mutations in a gene related to chloroquine resistance, PfCRT, have been associated with piperaquine resistance; however, parasites that are resistant to chloroquine remain sensitive to piperaquine.^[4]^[3] In contrast, amplification of the gene for the parasite transporter PfMDR1, a mechanism of parasite resistance to mefloquine, is inversely correlated with piperaquine resistance.^[3]

Pharmacokinetics

Piperaquine is a

lipophilic drug and therefore is rapidly absorbed and distributed across much of the body.^[2] The drug reaches its maximal concentrations approximately 2 hours after administration.^[2]