Plasmodium vivax: In vitro susceptibility of blood stages to synthetic trioxolane compounds and the diamidine DB75

et al. 2015

h Chloroquine (CQ) has been the mainstay of malaria treatment for more than 60 years. However, the emergence and spread of CQ resistance now restrict its use to only a few areas where malaria is endemic. The aim of the present study was to investigate whether a novel combination of a CQ-like moiety and an imipramine-like pharmacophore can reverse CQ resistance ex vivo. Between March to October 2011 and January to September 2013, two "reversed chloroquine" (RCQ) compounds (PL69 and PL106) were tested against multidrug-resistant field isolates of Plasmodium falciparum (n ‫؍‬ 41) and Plasmodium vivax (n ‫؍‬ 45) in Papua, Indonesia, using a modified ex vivo schizont maturation assay. The RCQ compounds showed high efficacy against both CQ-resistant P. falciparum and P. vivax field isolates. For P. falciparum, the median 50% inhibitory concentrations (IC 50 s) were 23.2 nM for PL69 and 26.6 nM for PL106, compared to 79.4 nM for unmodified CQ (P < 0.001 and P ‫؍‬ 0.036, respectively). The corresponding values for P. vivax were 19.0, 60.0, and 60.9 nM (P < 0.001 and P ‫؍‬ 0.018, respectively). There was a significant correlation between IC 50 s of CQ and PL69 (Spearman's rank correlation coefficient [r s ] ‫؍‬ 0.727, P < 0.001) and PL106 (r s ‫؍‬ 0.830, P < 0.001) in P. vivax but not in P. falciparum. Both RCQs were equally active against the ring and trophozoite stages of P. falciparum, but in P. vivax, PL69 and PL106 showed less potent activity against trophozoite stages (median IC 50 s, 130.2 and 172.5 nM) compared to ring stages (median IC 50 s, 17.6 and 91.3 nM). RCQ compounds have enhanced ex vivo activity against CQ-resistant clinical isolates of P. falciparum and P. vivax, suggesting the potential use of reversal agents in antimalarial drug development. Interspecies differences in RCQ compound activity may indicate differences in CQ pharmacokinetics between the two Plasmodium species.

Section: Discussionsupporting

confidence: 50%

Contrasting Ex Vivo Efficacies of “Reversed Chloroquine” Compounds in Chloroquine-Resistant Plasmodium falciparum and P. vivax Isolates

Wirjanata

Sebayang

et al. 2015

“…This phenomenon (i.e., microscopic assessment of schizont maturation producing higher IC 50 s than those derived from radioisotopic incorporation) has been described previously (46). In addition, even by applying the same methodology (i.e., [ 3 H]hypoxanthine incorporation) but using different assay durations, IC 50 estimates derived by a one-cycle assay (42 h) can be 2-to 6-fold higher than the estimates derived from the standard assay (72 h) (29). In our study, IC 50 s in chloroquine-sensitive and -resistant laboratory strains (K1 and 3D7, respectively) assessed by using the schizont maturation assay were indeed higher (700 to 1,000 nM) than the reported values derived by the isotopic assay (15 to 300 nM).…”

Section: Discussionmentioning

confidence: 99%

Ex VivoActivity of Histone Deacetylase Inhibitors against Multidrug-Resistant Clinical Isolates ofPlasmodium falciparumandP. vivax

Marfurt

Prayoga

et al. 2011

Histone acetylation plays an important role in regulating gene transcription and silencing in Plasmodium falciparum. Histone deacetylase (HDAC) inhibitors, particularly those of the hydroxamate class, have been shown to have potent in vitro activity against drug-resistant and -sensitive laboratory strains of P. falciparum, raising their potential as a new class of antimalarial compounds. In the current study, stage-specific ex vivo susceptibility profiles of representative hydroxamate-based HDAC inhibitors suberoylanilide hydroxamic acid (SAHA), 2-ASA-9, and 2-ASA-14 (2-ASA-9 and 2-ASA-14 are 2-aminosuberic acid-based HDAC inhibitors) were assessed in multidrug-resistant clinical isolates of P. falciparum (n ‫؍‬ 24) and P. vivax (n ‫؍‬ 25) from Papua, Indonesia, using a modified schizont maturation assay. Submicromolar concentrations of SAHA, 2-ASA-9, and 2-ASA-14 inhibited the growth of both P. falciparum (median 50% inhibitory concentrations [IC 50 s] of 310, 533, and 266 nM) and P. vivax (median IC 50 s of 170, 503, and 278 nM). Inverse correlation patterns between HDAC inhibitors and chloroquine for P. falciparum and mefloquine for P. vivax indicate species-specific susceptibility profiles for HDAC inhibitors. These HDAC inhibitors were also found to be potent ex vivo against P. vivax schizont maturation, comparable to that in P. falciparum, suggesting that HDAC inhibitors may be promising candidates for antimalarial therapy in geographical locations where both species are endemic. Further studies optimizing the selectivity and in vivo efficacy of HDAC inhibitors in Plasmodium spp. and defining drug interaction with common antimalarial compounds are warranted to investigate the role of HDAC inhibitors in antimalarial therapy.

“…This may represent either reduced stability of DHA in predosed drug plates (35) or differences in in vitro drug partition and metabolism (14,16,37). High variability and fluctuations in IC 50 s for artemisinin and its derivatives have been reported for both P. falciparum laboratory strains and field isolates (15,34,41) and reflect, at least in part, the application of nonstandardized in vitro assay systems, including differences in levels of parasitemia at the start of the assay, parasite synchrony, duration of the assay, and quantification method of the drug response (9,12,13). These variations were also apparent in the IC 50 estimates derived from laboratory-adapted P. falciparum strains in the current study, for which drug susceptibility was assessed by the schizont maturation test as opposed to a reinvasion assay.…”

Section: Discussionmentioning

confidence: 99%

Comparative Ex Vivo Activity of Novel Endoperoxides in Multidrug-Resistant Plasmodium falciparum and P. vivax

Marfurt

Prayoga

et al. 2012

Self Cite

iThe declining efficacy of artemisinin derivatives against Plasmodium falciparum highlights the urgent need to identify alternative highly potent compounds for the treatment of malaria. In Papua Indonesia, where multidrug resistance has been documented against both P. falciparum and P. vivax malaria, comparative ex vivo antimalarial activity against Plasmodium isolates was assessed for the artemisinin derivatives artesunate (AS) and dihydroartemisinin (DHA), the synthetic peroxides OZ277 and OZ439, the semisynthetic 10-alkylaminoartemisinin derivatives artemisone and artemiside, and the conventional antimalarial drugs chloroquine (CQ), amodiaquine (AQ), and piperaquine (PIP). Ex vivo drug susceptibility was assessed in 46 field isolates (25 P. falciparum and 21 P. vivax). The novel endoperoxide compounds exhibited potent ex vivo activity against both species, but significant differences in intrinsic activity were observed. Compared to AS and its active metabolite DHA, all the novel compounds showed lower or equal 50% inhibitory concentrations (IC 50 s) in both species (median IC 50 s between 1.9 and 3.6 nM in P. falciparum and 0.7 and 4.6 nM in P. vivax). The antiplasmodial activity of novel endoperoxides showed different cross-susceptibility patterns in the two Plasmodium species: whereas their ex vivo activity correlated positively with CQ, PIP, AS, and DHA in P. falciparum, the same was not apparent in P. vivax. The current study demonstrates for the first time potent activity of novel endoperoxides against drug-resistant P. vivax. The high activity against drug-resistant strains of both Plasmodium species confirms these compounds to be promising candidates for future artemisinin-based combination therapy (ACT) regimens in regions of coendemicity.A pproximately 3.3 billion people (i.e., almost 50% of the world's population) are at risk of malaria with two Plasmodium species responsible for the majority of infections: P. falciparum and P. vivax (6,7,43). Traditionally, malaria control and research efforts have focused on P. falciparum, the dominant species in Africa. However, outside Africa, P. falciparum almost invariably coexists with P. vivax (7), with both species inflicting significant morbidity, particularly in infants and pregnant women (18,27).Chloroquine (CQ)-resistant P. falciparum is already well established, with emerging evidence that susceptibility to CQ in P. vivax is also declining across much of the world in which vivax is endemic. This combined threat is driving the investigation of alternative schizonticidal treatment regimens, such as artemisininbased combination therapy (ACT), for deployment against both P. falciparum and P. vivax (29). ACTs have become the mainstay of antimalarial chemotherapy, adopted in more than 100 countries worldwide (42). This huge demand for artemisinin and its derivatives relies on isolation from the plant source Artemisia annua and is vulnerable to harvest and production costs and intermittent supply (2, 11). Of particular concern are recent reports of prolonged ...