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Mechanism-based model of parasite growth and dihydroartemisinin pharmacodynamics in murine malaria.

ABSTRACT: Murine models are used to study erythrocytic stages of malaria infection, because parasite morphology and development are comparable to those in human malaria infections. Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) models for antimalarials are scarce, despite their potential to optimize antimalarial combination therapy. The aim of this study was to develop a mechanism-based growth model (MBGM) for Plasmodium berghei and then characterize the parasiticidal effect of dihydroartemisinin (DHA) in murine malaria (MBGM-PK-PD). Stage-specific (ring, early trophozoite, late trophozoite, and schizont) parasite density data from Swiss mice inoculated with Plasmodium berghei were used for model development in S-ADAPT. A single dose of intraperitoneal DHA (10 to 100 mg/kg) or vehicle was administered 56 h postinoculation. The MBGM explicitly reflected all four erythrocytic stages of the 24-hour P. berghei life cycle. Merozoite invasion of erythrocytes was described by a first-order process that declined with increasing parasitemia. An efflux pathway with subsequent return was additionally required to describe the schizont data, thus representing parasite sequestration or trapping in the microvasculature, with a return to circulation. A 1-compartment model with zero-order absorption described the PK of DHA, with an estimated clearance and distribution volume of 1.95 liters h(-1) and 0.851 liter, respectively. Parasite killing was described by a turnover model, with DHA inhibiting the production of physiological intermediates (IC(50), 1.46 ng/ml). Overall, the MBGM-PK-PD described the rise in parasitemia, the nadir following DHA dosing, and subsequent parasite resurgence. This novel model is a promising tool for studying malaria infections, identifying the stage specificity of antimalarials, and providing insight into antimalarial treatment strategies.

SUBMITTER: Patel K

PROVIDER: S-EPMC3535964 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Reduced susceptibility of Plasmodium falciparum toward artemisinin derivatives has been reported from the Thai-Cambodian and Thai-Myanmar borders. Following increasing reports from central Vietnam of delayed parasite clearance after treatment with dihydroartemisinin-piperaquine (DHA-PPQ), the current first-line treatment, we carried out a study on the efficacy of this treatment. Between September 2012 and February 2013, we conducted a 42-day in vivo and in vitro efficacy study in Quang Nam Province. Treatment was directly observed, and blood samples were collected twice daily until parasite clearance. In addition, genotyping, quantitative PCR (qPCR), and in vitro sensitivity testing of isolates was performed. The primary endpoints were parasite clearance rate and time. The secondary endpoints included PCR-corrected and uncorrected cure rates, qPCR clearance profiles, in vitro sensitivity results (for chloroquine, dihydroartemisinin, and piperaquine), and genotyping for mutations in the Kelch 13 propeller domain. Out of 672 screened patients, 95 were recruited and 89 available for primary endpoint analyses. The median parasite clearance time (PCT) was 61.7 h (interquartile range [IQR], 47.6 to 83.2 h), and the median parasite clearance rate had a slope half-life of 6.2 h (IQR, 4.4 to 7.5 h). The PCR-corrected efficacy rates were estimated at 100% at day 28 and 97.7% (95% confidence interval, 91.2% to 99.4%) at day 42. At day 3, the P. falciparum prevalence by qPCR was 2.5 times higher than that by microscopy. The 50% inhibitory concentrations (IC50s) of isolates with delayed clearance times (? 72 h) were significantly higher than those with normal clearance times for all three drugs. Delayed parasite clearance (PCT, ? 72 h) was significantly higher among day 0 samples carrying the 543 mutant allele (47.8%) than those carrying the wild-type allele (1.8%; P = 0.048). In central Vietnam, the efficacy of DHA-PPQ is still satisfactory, but the parasite clearance time and rate are indicative of emerging artemisinin resistance. (This study has been registered at ClinicalTrials.gov under registration no. NCT01775592.).

Project description:The efficacy of vaccines aimed at inhibiting the growth of malaria parasites in the blood can be assessed by comparing the growth rate of parasitaemia in the blood of subjects treated with a test vaccine compared to controls. In studies using induced blood stage malaria (IBSM), a type of controlled human malaria infection, parasite growth rate has been measured using models with the intercept on the y-axis fixed to the inoculum size. A set of statistical models was evaluated to determine an optimal methodology to estimate parasite growth rate in IBSM studies.Parasite growth rates were estimated using data from 40 subjects published in three IBSM studies. Data was fitted using 12 statistical models: log-linear, sine-wave with the period either fixed to 48 h or not fixed; these models were fitted with the intercept either fixed to the inoculum size or not fixed. All models were fitted by individual, and overall by study using a mixed effects model with a random effect for the individual.Log-linear models and sine-wave models, with the period fixed or not fixed, resulted in similar parasite growth rate estimates (within 0.05 log10 parasites per mL/day). Average parasite growth rate estimates for models fitted by individual with the intercept fixed to the inoculum size were substantially lower by an average of 0.17 log10 parasites per mL/day (range 0.06-0.24) compared with non-fixed intercept models. Variability of parasite growth rate estimates across the three studies analysed was substantially higher (3.5 times) for fixed-intercept models compared with non-fixed intercept models. The same tendency was observed in models fitted overall by study. Modelling data by individual or overall by study had minimal effect on parasite growth estimates.The analyses presented in this report confirm that fixing the intercept to the inoculum size influences parasite growth estimates. The most appropriate statistical model to estimate the growth rate of blood-stage parasites in IBSM studies appears to be a log-linear model fitted by individual and with the intercept estimated in the log-linear regression. Future studies should use this model to estimate parasite growth rates.

Project description:BackgroundLung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer.Methodology/principal findingsAntitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL) staining and decreased Ki-67 expression in tumors. Through natural killer (NK) cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-? and TNF-? and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+) T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect.Conclusions/significanceMalaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria parasite may provide a novel strategy or therapeutic vaccine vector for anti-lung cancer immune-based therapy.

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Mechanism-based model of parasite growth and dihydroartemisinin pharmacodynamics in murine malaria.

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