Piperaquine

Piperaquine, a bisquinoline, is a rapid acting blood schizontocide. The mode of action is unknown. 

Snyder C, Chollet J, Santo-Tomas J, Scheurer C, Wittlin S. (2007) In vitro and in vivo interaction of synthetic peroxide RBxlll60 (OZ277) with piperaquine in Plasmodium models. Exp Parasitol 115 296-300. 

Three currently-used artemisinin based combination therapies (ACT) artesunate-mefloquine, artemether-lumefantrine and dihydroartemisinin-piperaquine, have been proven highly simple, safe and effective in the treatment of multidrug resistant P. falciparum malaria. 

Dihydroartemisinin-piperaquine has been proved highly effective and well tolerated in South-East Asia. It is a four dose regimen 4 tablets on the 1st day and 2 tablets on the 2nd and 3rd day or 3 tablets per day for 3 days. 

Lindegardh N, Annerberg A, White NJ, Day NPJ (2008) Development and validation of a liquid chromatographic-tandem mass spectrometric method for determination of piperaquine in plasma stable isotope labeled internal standard does not always compensate for matrix effects. J Chromatogr B 862 227-236... 

Oil-soluble artemether and water-soluble sodium artesunate were developed and approved as new antimalarial drugs by the Chinese authorities in 1987. After 1992, dihydroartemisinin, Coartem (a combination of artemether and benflumetol), and Artekin (a combination of dihydroartemisinin and piperaquine) were also marketed as new antimalarial dmgs. Since then, over 10 million malaria patients on a global scale have been cured after administration of these drugs. As a result, artemether, artesunate, and Coartem were added by the World Health Organization to the ninth, eleventh, and twelfth Essential Medicine List respectively. 

The novel combination (Artekin ) of dihydroartemisinin and piperaquine has been assessed in 106 patients (76 children and 30 adults) with uncomplicated Plasmodium falciparum malaria in Cambodia (19). The respective doses of dihydroartemisinin and piperaquine, which were given at 0,8, 24, and 32 hours, were 9.1 mg/kg and 74 mg/kg in children and 6.6 and 53 mg/kg in adults. AH the patients became aparasitemic within 72 hours. Excluding the results in one child who died on day 4, there was a 97% 28-day cure rate (99% in children and 92% in adults). Patients who had recrudes-cent infections used low doses of Artekin. Adverse effects, most commonly gastrointestinal complaints, were reported by 22 patients (21%) but did not necessitate premature withdrawal. 

Denis MB, Davis TM, Hewitt S, Incardona S, Nimol K, Fandeur T, Poravuth Y, Lim C, Socheat D. Efficacy and safety of dihydroartemisinin-piperaquine (Artekin) in Cambodian children and adults with uncomplicated falciparum malaria. Clin Infect Dis 2002 35(12) 1469-76. 

Piperaquine is a sjmthetic 4-aminoquinoline with high blood schizonticidal activity, similar to that of chloro-quine (SEDA-13, 810). There is some evidence that piperaquine is active against chloroquine-resistant Plasmodium falciparum, but laboratory studies suggest a degree of cross-resistance. Piperaquine 600 mg/month... 

The bisquinoline known as piperaquine (137) was synthesized in 1966 at the Shanghai Pharmaceutical Industry Research Institute. Piperaquine was found to be active against chloroquine-resistant falciparum malaria. In order to delay resistance, it is used in combination therapy, including with dihydroartemisinin, a derivative of the Chinese plant product artemisinin, first isolated in 1972. 

In the last few years, variations on the basic stracmre have been launched in combination with other antimalarials (usually variations on the chloroquine structure) such as dihydroartemismin and piperaquine phosphate (Artekin), artemether and lumefantrine (Coartem), artesunate/mefloquine (Artequin) and artesunate, sulfamethoxypyrazine, and pyrimethamine (Co-Arinate). Currently, there is another fixed dose combination with an artemisinin derivative in clinical trials, pyronaridine/artesunate (Pyramax in Phase III). However, the tri-oxo scaffold system in artemisinins has led to the synthesis of not only artemisinin variations but to totally synthetic molecules with the trioxane moiety included, such as arterolane tosylate (81). This compound is in Phase II trials as a single agent under Ranbaxy and is in Phase I trials in combination with piperaquine phosphate, also under Ranbaxy. 

Several bisquinolines, such as piperaquine have notable activity and longer duration of action against chloroquine-resistant malaria (Fig. 16.19). In a recent study, bis(aminoacridine) derivatives with different linker were evaluated for their antiparasitic activityThe activity profile of these compounds was strongly dependent upon the nature and the length of the connecting linker between the heterocyclic rings. 

Taming J, Bergqvist Y, Day NP, Bergquist J, Arvidsson B, White NJ, Ashton M, Lindegardh N. Characterization of human urinary metabolites of the antimalarial piperaquine. Drug Metab Dispos 2006 34 2011-2019. 

Davis, T. M. E. Hamzah, J. Ilett, K. R Karunajeewa, H. A. Reeder, J. C. Batty, K. T. Hackett, S. Barrett, P. In vitro interactions between piperaquine, dihydroartemisinin, and other conventional and novel antimalarial drugs. Antimicrob. Agents Chemother. 2006, 50, 2883-2885. 

Artemisinin combinations In a retrospective study of 46 adults in Cote D Ivoire who were given a 3-day regimen of combinations with artemisinin (lumefantrine, n=20 amo-diaquine, n = I3 mefloquine, n = 7 and piperaquine + trimethoprim, n = 6) and who developed hepatorenal failure, 12 died and 34 recovered within a median of 3-12 days after withdrawal of the combination therapy [IH]. In a comparison of variables between those who died and those who survived. 

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