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The Challenge of Parasite Control
Published in Eric S. Loker, Bruce V. Hofkin, Parasitology, 2023
Eric S. Loker, Bruce V. Hofkin
In the face of resistance to chloroquine and other anti-malarials in the 1990s, artemisinin was looked upon as something of a wonder drug: a fast-acting, highly effective means to treat Plasmodium infection, at a time when the prospect of untreatable malaria was a real possibility. Yet in about 2007, worrisome reports of decreased artemisinin efficacy, first in Cambodia and then spreading to other areas of Southeast Asia, raised the specter of resistance to this drug as well. To combat this possibility, artemisinin is only used in combination with other drugs. Such combinations are now considered to be the mainstay of malaria treatment and along with the use of insecticide-treated bed nets and focal insecticide use, artemisinin-based combination therapy (ACT) has substantially reduced the burden of malaria worldwide (Figure 9.26). Its efficacy has been tested in various combinations. Piperaquine is a common example, often used in ACT for the treatment of uncomplicated malaria caused by P. falciparum. Related to chloroquine, piperaquine presumably works via a similar mechanism. It was originally developed in the mid-1960s in China as an alternative to chloroquine in the face of spreading chloroquine resistance. Usage declined in the 1980s as piperaquine-resistant strains of P. falciparum arose. It remains effective when paired with artemisinin, yet concerns about possible resistance to this two-drug combination has led to the suggestion that triple combination therapy may eventually be warranted.
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
DHA–piperaquine is a fixed-dose combination with tablets containing 40 mg of DHA and 320 mg of piperaquine and a pediatric formulation of 20 mg of DHA plus 160 mg of piperaquine. The target dose is 4 mg of DHA per kilogram per day and 18 mg of piperaquine per kilogram per day, administered once daily for 3 days for adults and children (Chapter 172, Dihydroartemisinin–Piperaquine).
The Challenge of Parasite Control
Published in Eric S. Loker, Bruce V. Hofkin, Parasitology, 2015
Eric S. Loker, Bruce V. Hofkin
Artemisinin, originally isolated from a Chinese herb as previously described, has been used to treat malaria for over a thousand years. Until recently, all strains of P. falciparum were susceptible to artemisinin. Its use is carefully monitored and it is only used in combination with other drugs. Such combinations are now considered to be the mainstay of malaria treatment and along with the use of insecticide-treated bed nets and focal insecticide use, artemisinin-based combination therapy (ACT) has substantially reduced the burden of malaria in sub-Saharan Africa (Figure 9.21). Its efficacy has been tested with a variety of antimalarial drugs. Its use with piperaquine is currently recommended by the World Health Organization for the treatment of uncomplicated malaria caused by P. falciparum. Related to chloroquine, piperaquine presumably works via a similar mechanism. It was originally developed in the mid-1960s in China as an alternative to chloroquine in the face of spreading chloroquine resistance. Usage declined in the 1980s as piperaquine-resistant strains of P. falciparum arose. It remains highly effective, however, when paired with artemisinin. Yet even the above described precautions may not be enough to prevent resistance, and the recent report of artemisinin-resistant P. falciparum in Southeast Asia is cause for concern. Other innovative strategies for reducing the problem of drug resistance will be considered in Chapter 10.
AQ-13 - an investigational antimalarial drug
Published in Expert Opinion on Investigational Drugs, 2019
Juliana Boex Mengue, Jana Held, Andrea Kreidenweiss
Malaria chemotherapies in the pipeline are either based on previously registered drug combinations and are now developed as new formulations particularly for pediatrics (e.g. dihydroartemisinin-piperaquine dispersible) or are combined to new partner drugs (e.g. artemisinin-piperaquine). Naphthoquine is a 4-aminoquinoline derivative that is co-formulated to artemisinin and is a promising new ACT with the potential for single dose administration [26]. Interestingly, several molecules with novel mechanisms of action are investigated as well as 4-aminoquinoline derivatives. Ferroquine is a CQ derivative with a ferrocene molecule at its lateral chain that is also active against CQ resistant parasites. Ferroquine is tested in an ongoing phase 2b study (NCT02497612) in combination with OZ439, a next-generation artemisinin, for single dose treatment of uncomplicated P. falciparum malaria [27,28]. Fosmidomycin, an antibiotic combined to a second antibiotic clindamycin or to piperaquine, is developed as a new non-ACT for uncomplicated malaria [30,31]. Molecules with new chemical scaffolds include KAF156 (combined to lumefantrine), KAE609, DSM256, and MMV048. They are all in phase 2 trials and are developed towards a medicine for single-exposure, radical cure [32].
Pharmacotherapy for the prevention of malaria in pregnant women: currently available drugs and challenges
Published in Expert Opinion on Pharmacotherapy, 2018
Brioni R. Moore, Timothy M. E. Davis
Piperaquine (PQ) is a bisquinoline antimalarial drug that has recently seen a resurgence in use due to its therapeutic combination with the artemisinin derivatives. It was originally used as monotherapy for antimalarial prophylaxis in China but this led to the development of P. falciparum drug resistance and subsequent cessation of use [33]. Its long t1/2 means that it is an attractive partner drug when combined with rapidly acting schizonticides such as dihydroartemisinin (DHA). DHA-PQ has been relatively comprehensively investigated, is a WHO recommended treatment for uncomplicated malaria [34], and is currently undergoing extensive review as potential IPTp. The recent reemergence of PQ resistance in Southeast Asia [35] could, however, have significant implications for its future use.
The early preclinical and clinical development of ganaplacide (KAF156), a novel antimalarial compound
Published in Expert Opinion on Investigational Drugs, 2018
Robin Koller, Ghyslain Mombo-Ngoma, Martin P. Grobusch
Leong et al. assessed ganaplacide as part of a combination therapy. This was an open label, randomized, single-dose study in healthy male volunteers, combining ganaplacide with piperaquine, an approved aminoquinoline antimalarial. Safety, pharmacokinetics and potential QT interval corrected using Fridericia’s formula (ΔQTcF) interactions of ganaplacide and piperaquine were assessed. Subjects were randomized to three parallel treatment arms. Patients in the first arm received 800 mg ganaplacide plus 1280 mg piperaquine, the second arm was treated with 800 mg ganaplacide and the third with 1280 mg piperaquine alone [17]. Co-administration of piperaquine and ganaplacide had no overall effect on AUC of either compound, but the Cmax values of both ganaplacide and piperaquine increased by ~ 23% and ~ 70%, respectively. This interaction did not result in any safety issues of concerns. Both drugs were well tolerated and no serious adverse events occurred, both when administered separately and in combination. Adverse events of grades 1 and 2 were observed in 87.5%, 79.2%, and 58.3% of participants, respectively, for the ganaplacide plus piperaquine, piperaquine, and ganaplacide treatment arms during the 61-day follow-up. The most common adverse events were nausea and headache. There were no electrocardiogram (ECG) changes of note; however, there was a positive ΔQTcF trend in the ganaplacide-piperaquine arm when either ganaplacide or piperaquine concentrations increased. That notwithstanding, there were no significant differences in maximum ΔQTcF between the combination compared to the other arms [17].