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Antimalarial drugs impact chemical messenger secretion by blood platelets.

ABSTRACT: Background:Advances in antimalarial drug development are important for combating malaria. Among the currently identified antimalarial drugs, it is suggested that some interact directly with the malarial parasites while others interact indirectly with the parasites. While this approach leads to parasite elimination, little is known about how these antimalarial drugs impact immune cells that are also critical in malarial response. Methods:Herein, the effects of two common antimalarial drugs, chloroquine and quinine, on platelets were explored at both the bulk level, using high performance liquid chromatography, and the single cell level, using carbon-fiber microelectrode amperometry, to characterize any changes in chemical messenger secretion. Results:The data reveal that both drugs cause platelet activation and reduce the number of platelet exocytosis events as well as delay fusion pore opening and closing. Conclusions:This work demonstrates how chloroquine and quinine quantitatively and qualitatively impact in vitro platelet function. General significance:Overall, the goal of this work is to promote understanding about how antimalarial drugs impact platelets as this may affect antimalarial drug development as well as therapeutic approaches to treat malarial infection.

SUBMITTER: Xiong-Hang K

PROVIDER: S-EPMC7182713 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Antimalarial drugs impact chemical messenger secretion by blood platelets.

Xiong-Hang Kang K He Jiayi J Kemnetz-Ness Kaila K Haynes Christy C

Biochemistry and biophysics reports 20200422

<h4>Background</h4>Advances in antimalarial drug development are important for combating malaria. Among the currently identified antimalarial drugs, it is suggested that some interact directly with the malarial parasites while others interact indirectly with the parasites. While this approach leads to parasite elimination, little is known about how these antimalarial drugs impact immune cells that are also critical in malarial response.<h4>Methods</h4>Herein, the effects of two common antimalari ...[more]

PMID: 32346619

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Project description:According to the WHO, artemisinin-based combination therapies (ACTs) have been integral to the recent reduction in deaths due to Plasmodium falciparum malaria. ACT-resistant strains are an emerging problem and have evolved altered developmental stages, reducing exposure of the most susceptible stages to artemisinin drugs in popular ACTs. Lipophilicity, log K ow, is a guide in understanding and predicting pharmacokinetic properties such as terminal half-life which alters drug exposure. Consistent log K ow values are not necessarily available for artemisinin derivatives designed to extend terminal half-life, increase bioavailability, and reduce neurotoxicity. For other drugs used in ACTs, an assortment of experimental and computational log K ow values are available in the literature and in some cases, do not account for subtle but important differences between closely related structures such as between diastereomers. Quantum chemical methods such as density functional theory (DFT) used with an implicit solvent model allow for consistent comparison of physical properties including log K ow and distinguish between closely related structures. To this end, DFT, B3LYP/6-31G(d), with an implicit solvent model (SMD) was used to compute ΔG ow o and ΔG vow o for 1-octanol-water and olive oil-water partitions, respectively, for 21 antimalarial drugs: 12 artemisinin-based, 4 4-aminoquinolines and structurally similar pyronaridine, and 4 amino alcohols. The computed ΔG ow o was close to ΔG ow o calculated from experimental log K ow values from the literature where available, with a mean signed error of 2.3 kJ/mol and mean unsigned error of 3.7 kJ/mol. The results allow assignment of log K ow for α-and β-diastereomers of arteether, and prediction of log K ow for β-DHA and five experimental drugs. Linear least square analysis of log K ow and log K vow versus terminal elimination half-life showed strong linear relationships, once the data points for the 4-aminoquinoline drugs, mefloquine and pyronaridine were found to follow their own linear relationship, which is consistent with their different plasma protein binding. The linear relationship between the computed log K vow and terminal elimination half-life was particularly strong, R 2 = 0.99 and F = 467, and can be interpreted in terms of a simple pharmacokinetic model. Terminal elimination half-life for β-DHA and four experimental artemisinin drugs were estimated based on this linear relationship between log K vow and terminal t 1/2. The computed log K ow and log K vow values for epimers α- and β-DHA and α and β-arteether provide physical data that may be helpful in understanding their different pharmacokinetics and activity based on their different molecular geometries. Relative solubility of quinine and quinidine are found to be sensitive to thermal corrections to enthalpy and to vibrational entropy and do not follow the general trend of longer terminal t 1/2 with greater predicted log K ow. Geometric relaxation of α- and β-DHA in solvent and inclusion of thermal correction for enthalpy and entropy results in correct prediction that α-DHA is favored in aqueous environments compared to β-DHA. Predictions made regarding experimental drugs have implications regarding their potential use in response to artemisinin drug-resistant strains.

Project description:BackgroundUnderstanding pattern of antimalarials use at large scale helps ensuring appropriate use of treatments and preventing the spread of resistant parasites. We estimated the proportion of individuals in community surveys with residual antimalarials in their blood and identified the factors associated with the presence of the most commonly detected drugs, lumefantrine and/or desbutyl-lumefantrine (LF/DLF) or sulfadoxine-pyrimethamine (SP).MethodsA cross-sectional survey was conducted in 2015 in three regions of Tanzania with different levels of malaria endemicity. Interviews were conducted and blood samples collected through household surveys for further antimalarial measurements using liquid chromatography coupled to tandem mass spectrometry. In addition, diagnosis and treatment availability was investigated through outlet surveys. Multilevel mixed effects logistic regression models were used to estimate odds ratios for having LF/DLF or SP in the blood.ResultsAmongst 6391 participants, 12.4% (792/6391) had LF/DLF and 8.0% (510/6391) SP in the blood. Factors associated with higher odds of detecting LF/DLF in the blood included fever in the previous two weeks (OR = 2.6, p<0.001), living in districts of higher malaria prevalence (OR = 1.5, p<0.001) and living in a ward in which all visited drug stores had artemisinin-based combination therapies in stocks (OR = 2.7, p = 0.020). Participants in older age groups were less likely to have LF/DLF in the blood (OR = 0.9, p<0.001). Factors associated with higher odds of having SP in the blood included being pregnant (OR = 4.6, p<0.001), living in Mwanza (OR = 3.9, p<0.001 compared to Mbeya), fever in the previous two weeks (OR = 1.7, p<0.001) and belonging to older age groups (OR = 1.2, p<0.001).ConclusionThe most significant predictors identified were expected. History of fever in the past two weeks and young age were significant predictors of LF/DLF in the blood, which is encouraging. Antimalarial drug pressure was high and hence the use of recommended first-line drugs in combination with malaria Rapid Diagnostics Tests should be promoted to ensure appropriate treatment.

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Antimalarial drugs impact chemical messenger secretion by blood platelets.

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Antimalarial drugs impact chemical messenger secretion by blood platelets.

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