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Pyronaridine–Artesunate
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
Pyronaridine has an elimination profile that can be described as intermediate, with a duration of post-treatment suppressive anti-malarial activity after conventional dosing that is probably somewhat longer than that of lumefantrine but shorter than that of mefloquine and piperaquine. It could therefore ordinarily be considered as having some potential for preventive therapies, prophylaxis, and even mass drug administration. However, its propensity to accumulate in tissues with repeated doses probably means that these indications will not be pursued because of safety and ethical concerns. In any case, drugs such as piperaquine that have even slower elimination kinetics are probably better suited to these applications owing to the longer period of suppressive activity.
Machine learning techniques applied to the drug design and discovery of new antivirals: a brief look over the past decade
Published in Expert Opinion on Drug Discovery, 2021
Mateus Sá Magalhães Serafim, Valtair Severino dos Santos Júnior, Jadson Castro Gertrudes, Vinícius Gonçalves Maltarollo, Kathia Maria Honorio
For EBOV, Lane et al. (2019) combined a Bayesian model with SVM and RF to evaluate toxicity and kinetics of a given dataset with 868 compounds [62], one of which was identified in a previous study [140]. In this study, not only ML techniques were assessed for prediction, but also the experimental validation performed by the authors did corroborate the predicted results. Lane et al. (2020) also applied other Bayesian models in small compound datasets to predict drug repurposing for EBOV using the lysosomotropic potential. The authors built the models using extended-connectivity fingerprints of maximum diameter 6 (ECFP6) as descriptors and datasets containing 40 FDA-approved drugs to predict anti-Ebola activity [163], in which artesunate and pyronaridine were identified as potential anti-Ebola candidates since it showed a synergistic antiviral activity. Only pyronaridine showed in silico and in vitro lysosomotropic activity.
AQ-13 - an investigational antimalarial drug
Published in Expert Opinion on Investigational Drugs, 2019
Juliana Boex Mengue, Jana Held, Andrea Kreidenweiss
ACTs are the mainstay of chemotherapy of uncomplicated P. falciparum malaria – in both malaria-endemic and non-endemic countries. ACTs consist of an artemisinin-related compound combined to a partner drug with a different mechanism of action and a longer half-life. WHO currently recommends five ACTs: artesunate-amodiaquine, artesunate-mefloquine, artesunate-sulfadoxine/pyrimethamine, artemether-lumefantrine, and dihydroartemisinin-piperaquine [2]. A sixth ACT, artesunate-pyronaridine (Pyramax ®), is registered in malaria-endemic regions and is the only ACT for treatment of acute P. vivax malaria. WHO recommends artesunate-pyronaridine only in regions where other ACTs became less effective [18]. Unfortunately, artemisinin resistance may also accelerate parasite resistance to the partner drug. Parasite resistance to all of the individual partner molecules are widespread in South East Asia. In Cambodia, 50% of treatment failures were found for dihydroartemisinin-piperaquine [7,19–21]. In Africa, resistance to sulfadoxine-pyrimethamine and amodiaquine is also present but less frequently to other partner drugs. Treatment options for life-threatening severe malaria rely on artesunate monotherapy that rapidly kills P. falciparum parasites and leads to a fast parasite reduction – second and third line drugs are artemether and quinine. Atovaquone-proguanil is used for chemoprophylaxis and treatment of falciparum malaria mostly in travelers from northern countries.
Antimalarial drugs for treating and preventing malaria in pregnant and lactating women
Published in Expert Opinion on Drug Safety, 2018
Makoto Saito, Mary Ellen Gilder, Rose McGready, François Nosten
Because of the altered immunity and pharmacokinetics in pregnancy in addition to the sequestration of parasites to placenta, simple extrapolation of the efficacy results from non-pregnant population may not be necessarily valid. Although it has the safest profile among ACTs, the efficacy of AL can be lower possibly because of the suboptimal dosing for pregnant women. Dose optimization, usually by increasing the dosage, can be required for some antimalarials in pregnancy, and these alternate regimens require further evaluation of treatment efficacy and safety in pregnant women and their offspring. Clindamycin, doxycycline and atovaquone-proguanil are considered safe in pregnancy and can be options as partner drugs with artemisinins, although these combinations of short half-life drugs will lead to shorter post-treatment prophylaxis. Newer drugs, such as pyronaridine or naphthoquine require investigation of reproductive toxicity without delay. In the setting of malaria elimination, drug efficacy can be attenuated because of declining immunity, and this can theoretically be exacerbated by the relative immune suppression during pregnancy, resulting in the urgent need for antimalarials in the development pathway that are efficacious and safe in pregnancy.