Piperaquine is an antiparasitic drug used in combination with

dihydroartemisinin Dihydroartemisinin (also known as dihydroqinghaosu, artenimol or DHA) is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds (artemisinin, artesunate, artemether, etc.) and is also available as ...

to treat

malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...

. Piperaquine was developed under the Chinese National Malaria Elimination Programme in the 1960s and was adopted throughout China as a replacement for the structurally similar antimalarial drug chloroquine. Due to widespread parasite resistance to piperaquine, the drug fell out of use as a

monotherapy Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can also ...

, and is instead used as a partner drug for artemisinin combination therapy. Piperaquine kills parasites by disrupting the detoxification of host

heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consis ...

Medical uses

Piperaquine is used in combination with

for the treatment of malaria. This combination is one of several artemisinin combination therapies recommended by the World Health Organization for treatment of

uncomplicated malaria Malaria is a Mosquito-borne disease, mosquito-borne infectious disease that affects humans and other animals. Malaria causes Signs and symptoms, symptoms that typically include fever, fatigue (medical), tiredness, vomiting, and headaches. In se ...

. This combination is also recommended by the World Health Organization for treatment of severe malaria after administration of

artesunate Artesunate (AS) is a medication used to treat malaria. The intravenous form is preferred to quinine for severe malaria. Often it is used as part of combination therapy, such as artesunate plus mefloquine. It is not used for the prevention of ma ...

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

Contraindications

chloroquine Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medi ...

, piperaquine can prolong the QT interval. Although large randomized clinical trials have not revealed evidence of

cardiotoxicity Cardiotoxicity is the occurrence of heart dysfunction as electric or muscle damage, resulting in heart toxicity. The heart becomes weaker and is not as efficient in pumping blood. Cardiotoxicity may be caused by chemotherapy (a usual example is th ...

, 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.

Pharmacology

Mechanism of action

Like chloroquine, piperaquine is thought to function by accumulating in the parasite digestive vacuole and interfering with the detoxification of

into

hemozoin Haemozoin is a disposal product formed from the digestion of blood by some blood-feeding parasites. These hematophagous organisms such as malaria parasites (''Plasmodium spp.''), ''Rhodnius'' and ''Schistosoma'' digest haemoglobin and release high ...

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 Cambodia (; also Kampuchea ; km, កម្ពុជា, UNGEGN: ), officially the Kingdom of Cambodia, is a country located in the southern portion of the Indochinese Peninsula in Southeast Asia, spanning an area of , bordered by Thailan ...

where in 2014 over 40% of dihydroartemisinin-piperaquine treatments failed to eliminate parasites from the patient's blood. 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. The mechanism by which parasites become resistant to piperaquine remains unclear. Amplification of the parasite proteases plasmepsin 2 and plasmepsin 3, both involved in degrading host hemoglobin, is associated with resistance to piperaquine. 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. In contrast, amplification of the gene for the parasite transporter '' PfMDR1'', a mechanism of parasite resistance to mefloquine, is inversely correlated with piperaquine resistance.

Pharmacokinetics

Piperaquine is a

lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...

drug and therefore is rapidly absorbed and

distributed Distribution may refer to: Mathematics *Distribution (mathematics), generalized functions used to formulate solutions of partial differential equations *Probability distribution, the probability of a particular value or value range of a varia ...

across much of the body. The drug reaches its maximal concentrations approximately 2 hours after administration.

Chemistry

Piperaquine is available as a base, and as a water-soluble tetraphosphate salt.

History

Piperaquine was discovered in the 1960s by two separate groups working independently of one another: the

Shanghai Pharmaceutical Industry Research Institute Shanghai (; , , Standard Mandarin pronunciation: ) is one of the four direct-administered municipalities of the People's Republic of China (PRC). The city is located on the southern estuary of the Yangtze River, with the Huangpu River flow ...

in China and the Rhone Poulenc in France. In the 1970s and 1980s piperaquine became the primary antimalarial drug of the Chinese National Malaria Control Programme due to increased parasite resistance to chloroquine. By the late 1980s, the use of piperaquine as an antimalarial monotherapy diminished as increasing parasite resistance to piperaquine was observed. Beginning in the 1990s, piperaquine was tested and adopted as a partner drug for artemisinin combination therapy.

References

Antimalarial agents Piperazines Quinolines Chloroarenes Chinese discoveries {{antiinfective-drug-stub