Cytostatic versus cytocidal profiling of quinoline drug combinations via modified fixed-ratio isobologram analysis

Gorka, Alexander P.; Jacobs, Lauren; Roepe, Paul D.

doi:10.1186/1475-2875-12-332

Cited by 27 publications

(39 citation statements)

References 63 publications

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“…In clinical studies, artemether-LMF treatments have been found to select for wildtype pfcrt K76 (43,44), pfmdr1 N86 (43,45), and N1042 (45) alleles, as well as increased pfmdr1 copy numbers (40,46). Our finding of the PQ-CQ synergistic interaction in the CQR Dd2 strain was different from the additive effect observed earlier in the same strain (28), but similar to another observation in the CQR K1 strain (25). As speculated earlier, the inconsistent results for PQ-CQ interactions in different parasite strains may be due to other unknown factors rather than to the pfcrt mutations (28).…”

Section: Discussioncontrasting

confidence: 56%

“…Our finding of the PQ-CQ synergistic interaction in the CQR Dd2 strain was different from the additive effect observed earlier in the same strain (28), but similar to another observation in the CQR K1 strain (25). As speculated earlier, the inconsistent results for PQ-CQ interactions in different parasite strains may be due to other unknown factors rather than to the pfcrt mutations (28).…”

Section: Discussioncontrasting

confidence: 56%

“…Here, we investigated the interactions between PQ and the longer-acting schizonticide in commonly used ACTs in both asexual parasites and latestage gametocytes. Compared to the other antimalarials tested, PQ is clearly a weak blood stage schizonticide (17,19,25,28,29). However, besides its tissue schizonticide activity targeting relapsing malaria parasites, it has evident gametocytocidal activity and shortens gametocyte carriage times in vivo (6-8, 11, 12, 30).…”

Section: Discussionmentioning

confidence: 99%

“…Bray et al showed a synergistic effect when PQ was combined with CQ on CQR K1 and an additive effect on CQS D10 (26). More recently, Gorka et al found a cytostatic additive effect of PQ with CQ on CQR Dd2 and an antagonistic effect on CQS HB3 (28). In this study, we systematically evaluated five combinations of PQ with the longer-acting schizonticides in ACTs on three parasite strains, 3D7, HB3 and Dd2, representing both CQS and CQR phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the synergisms observed were true of all the ratios of the schizonticide to PQ tested ([PQ] high -[X] low to [PQ] low -[X] high ), which should correspond to PQ dosing at any time during schizonticide treatment (the interactions were not dependent on high or low plasma concentrations of one or the other drug). Of note, Dd2 was reported as hypersensitive to PQ when treated with very high bolus doses in a 50% lethal dose (LD 50 ) assay format (28). Bolus drug exposures measure cytotoxic effects that are missed in growth inhibition assays due to the latter's use of lower drug concentrations that require longer periods of continuous exposure which can mask the cytotoxic effects of drugs.…”

Section: Discussionmentioning

confidence: 99%

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In Vitro Activities of Primaquine-Schizonticide Combinations on Asexual Blood Stages and Gametocytes of Plasmodium falciparum

Cabrera

2015

Antimicrob Agents Chemother

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Currently, the World Health Organization recommends addition of a 0.25-mg base/kg single dose of primaquine (PQ) to artemisinin combination therapies (ACTs) for Plasmodium falciparum malaria as a gametocytocidal agent for reducing transmission. Here, we investigated the potential interactions of PQ with the long-lasting components of the ACT drugs for eliminating the asexual blood stages and gametocytes of in vitro-cultured P. falciparum strains. Using the SYBR green I assay for asexual parasites and a flow cytometry-based assay for gametocytes, we determined the interactions of PQ with the schizonticides chloroquine, mefloquine, piperaquine, lumefantrine, and naphthoquine. With the sums of fractional inhibitory concentrations and isobolograms, we were able to determine mostly synergistic interactions for the various PQ and schizonticide combinations on the blood stages of P. falciparum laboratory strains. The synergism in inhibiting asexual stages and gametocytes was highly evident with PQ-naphthoquine, whereas synergism was moderate for the PQ-piperaquine, PQ-chloroquine, and PQ-mefloquine combinations. We have detected potentially antagonistic interactions between PQ and lumefantrine under certain drug combination ratios, suggesting that precautions might be needed when PQ is added as the gametocytocide to the artemether-lumefantrine ACT (Coartem).A sexual multiplication of the malaria parasites in human blood is associated with the morbidity and mortality due to the disease. The gametocyte, the sexual stage of the parasites, is the obligatory link perpetuating the parasite's life cycle into the Anopheles vectors. While most antimalarial drugs target the asexual intraerythrocytic stages of the malaria parasites, it has been increasingly recognized that drugs with actions on the gametocyte stages are critical for severing this transmission link (1, 2). In particular, interruption of malaria transmission is a major challenge for malaria elimination (3). Among the currently used antimalarial drugs, primaquine (PQ) is the only one with gametocytocidal activity on late-stage gametocytes (4). This drug has been used since the 1950s primarily in combination with chloroquine (CQ) as a radical cure for preventing relapses due to Plasmodium vivax. Presently, it is used in combination with CQ or artemisinin combination therapies (ACTs) for radical cure of relapsing malaria parasites due to P. vivax and Plasmodium ovale. In 2012, the World Health Organization (WHO) recommended the addition of a single dose of 0.74 mg/kg PQ as a gametocytocidal agent to reduce P. falciparum transmission in low-transmission settings, particularly in areas under the threat of artemisinin resistance (5). Later in the same year, the WHO Malaria Advisory Committee modified their recommendation to a single 0.25-mg/kg PQ dose to alleviate concerns of serious toxicity in patients with glucose-6-phosphate dehydrogenase deficiency and in consideration of the benefits of disseminating PQ as a transmission blocking drug to a high proportion of patien...

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Section: Discussioncontrasting

confidence: 56%

Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

In Vitro Activities of Primaquine-Schizonticide Combinations on Asexual Blood Stages and Gametocytes of Plasmodium falciparum

Cabrera

2015

Antimicrob Agents Chemother

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Incompatibility of chemical protein synthesis inhibitors with accurate measurement of extended protein degradation rates

Chan

Martin

Liptrott

et al. 2017

Pharmacology Res & Perspec

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Protein synthesis inhibitors are commonly used for measuring protein degradation rates, but may cause cytotoxicity via direct or indirect mechanisms. This study aimed to identify concentrations providing optimal inhibition in the absence of overt cytotoxicity. Actinomycin D, cycloheximide, emetine, and puromycin were assessed individually, and in two‐, three‐, and four‐drug combinations for protein synthesis inhibition (IC 50) and cytotoxicity (CC 50) over 72 h. Experiments were conducted in HepG2 cells and primary rat hepatocytes (PRH). IC 50 for actinomycin D, cycloheximide, emetine, and puromycin were 39 ± 7.4, 6600 ± 2500, 2200 ± 1400, and 1600 ± 1200 nmol/L; with corresponding CC 50 values of 6.2 ± 7.3, 570 ± 510, 81 ± 9, and 1300 ± 64 nmol/L, respectively, in HepG2 cells. The IC 50 were 1.7 ± 1.8, 290 ± 90, 620 ± 920, and 2000 ± 2000 nmol/L, with corresponding CC 50 values of 0.98 ± 1.8, 680 ± 1300, 180 ± 700, and 1600 ± 1000 (SD) nmol/L, respectively, in PRH. CC 50 were also lower than the IC 50 for all drug combinations in HepG2 cells. These data indicate that using pharmacological interference is inappropriate for measuring protein degradation over a protracted period, because inhibitory effects cannot be extricated from cytotoxicity.

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The Biochemistry of Quinoline Antimalarial Drug Resistance

Callaghan

Roepe

2014

Handbook of Antimicrobial Resistance

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Mutations in the Plasmodium falciparum chloroquine-resistance transporter (PfCRT) have been shown to be central to the molecular mechanism of quinoline antimalarial drug resistance. However, additional facets to resistance biochemistry are emerging, and it is now clear that multiple quinoline drug resistance phenotypes exist in different regions of the globe. Different public health policies and drug use histories across the globe, along with natural genetic drift, have created this diversity, such that there are now dozens of distinct chloroquine-resistant (CQR) strains of P. falciparum. Some of these can be described in detail, but information is incomplete. This leads to some degree of continued uncertainty on how best to proceed in controlling malaria in some regions. This issue is even more critical for controlling chloroquine-resistant P. vivax, about which even less is known. This review summarizes key features of quinoline antimalarial drug resistance in P. falciparum malaria and suggests concepts relevant for "staying ahead of the resistance curve."

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Cytostatic versus cytocidal profiling of quinoline drug combinations via modified fixed-ratio isobologram analysis

Cited by 27 publications

References 63 publications

In Vitro Activities of Primaquine-Schizonticide Combinations on Asexual Blood Stages and Gametocytes of Plasmodium falciparum

In Vitro Activities of Primaquine-Schizonticide Combinations on Asexual Blood Stages and Gametocytes of Plasmodium falciparum

Incompatibility of chemical protein synthesis inhibitors with accurate measurement of extended protein degradation rates

The Biochemistry of Quinoline Antimalarial Drug Resistance

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