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Artemisinins
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Kamala Thriemer, Julie A. Simpson, James S. McCarthy, Ric N. Price
Fully synthetic trioxolanes have also been produced (Vennerstrom et al., 2004), with two products developed for clinical use in humans. OZ277 (arterolane maleate) retains high efficacy against field isolates of both Plasmodium vivax and P. falciparum (Kocken et al., 2006; Kreidenweiss et al., 2006; Lanteri et al., 2014), and in phase I and II clinical studies was well tolerated (Gautam et al., 2011; Saha et al., 2014; Valecha et al., 2012, 2010). OZ277 is now available in India in a fixed-dose combination with piperaquine marketed as Synriam (Anthony et al., 2012). Phase III studies have shown Synriam to have efficacy and safety profiles comparable to those of artemether–lumefantrine against P. falciparum (Toure et al., 2016; Valecha et al., 2012) and P. vivax (Valecha et al., 2016).
Humanized mouse models infected with human Plasmodium species for antimalarial drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Alicia Moreno-Sabater, Jean Louis Pérignon, Dominique Mazier, Catherine Lavazec, Valerie Soulard
For these two reasons, the past decade has seen an unprecedented renewed focus on the discovery of new antimalarial drugs through extraordinary collaboration between academia (parasitologists, medicinal chemists, pharmacologists, clinicians) and industrial/private partnerships (e.g. Medicines for Malaria Venture). Cell-, chemistry-, and target-based approaches have already selected tens of thousands molecules [7,8]. The big challenge is to identify among them interesting compounds, advance them through preclinical and clinical development, to finally develop them into a registered antimalarial drug [9]. Indeed, several compounds recently entered Phase II testing or are in transition to Phase III evaluation [7,10,11]. Apart from two herbal medicines and the ozonide arterolane, preparations recently approved or in advanced stages of clinical development are mainly combinations of long known drugs. Given the high attrition rate even in advanced stages of development, only a few compounds with novel mechanisms will finally be introduced in therapy. In addition, none of the compounds corresponds to the ideal objective of SERCaP. Therefore, continued efforts are mandatory to keep the antimalarial pipeline filled, and for all the candidates that will emerge from the first screens, the major bottleneck will obviously be the translation into clinical development.
Malaria medicines to address drug resistance and support malaria elimination efforts
Published in Expert Review of Clinical Pharmacology, 2018
Jane Achan, Julia Mwesigwa, Chinagozi Precious Edwin, Umberto D’alessandro
Endoperoxide antimalarials like the artemisinins have played a major role against drug-resistant malaria [104] and the development of synthetic endoperoxides with similar or enhanced antimalarial properties and improved pharmacokinetics is promising [105]. The first clinical product of this kind was OZ277 (also known as Rbx11160 or arterolane) [106], which is one of the first fully synthetic trioxolane peroxides and a non-artemisinin antimalarial compound. It has rapid schizonticidal activity against all erythrocytic stages of P. falciparum but with no effect on hepatic stages [107]. Ranbaxy Gurgaon, Hiryama, India, has greatly advanced the clinical development of a fixed dose that consists of rapidly acting arterolane and longer acting piperaquine [103]. Clinical studies of this combination in acute uncomplicated P. falciparum malaria patients provide evidence of high clinical efficacy [108] with PCR-adjusted adequate clinical and parasitological response at day 28 of 100% with arterolane-piperaquine against 98.7% with artemether-lumefantrine [107]. This combination was recently approved by the Drug Controller General of India [109]. Additional studies in areas with artemisinin-resistant malaria are ongoing [110].
Pharmacotherapy for artemisinin-resistant malaria
Published in Expert Opinion on Pharmacotherapy, 2021
Erik Koehne, Ayola Akim Adegnika, Jana Held, Andrea Kreidenweiss
Unfortunately, synthetic endoperoxides like artefenomel or arterolane which share the similar antiplasmodial pharmacophore with artemisinins do not meet the expectation that arose from the first studies. New promising compounds are in development, but they still have to go the hard road of clinical development and it will take some time until they will (hopefully) be available. In this respect, it is reassuring that existing ACTs are still effective, provided that resistance to the combination partner is taken into account.