ORCID Profile
0000-0002-4613-3672
Current Organisation
University of Melbourne
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Publisher: American Society for Microbiology
Date: 18-05-2021
DOI: 10.1128/AAC.02346-20
Abstract: Most deaths from severe falciparum malaria occur within 24 h of presentation to a hospital. Intravenous (i.v.) artesunate is the first-line treatment for severe falciparum malaria, but its efficacy may be compromised by delayed parasitological responses.
Publisher: The Royal Society
Date: 10-2016
Abstract: Automatic identification of the necrotic zone boundary is important in the assessment of treatments on in vitro tumour spheroids. This has been difficult especially when the difference in cell density between the necrotic and viable zones of a tumour spheroid is small. To help overcome this problem, we developed novel one-dimensional pair-correlation functions (PCFs) to provide quantitative estimates of the radial distance of the necrotic zone boundary from the centre of a tumour spheroid. We validate our approach on synthetic tumour spheroids in which the position of the necrotic zone boundary is known a priori . It is then applied to nine real tumour spheroids imaged with light sheet-based fluorescence microscopy. PCF estimates of the necrotic zone boundary are compared with those of a human expert and an existing standard computational method.
Publisher: Cold Spring Harbor Laboratory
Date: 03-11-2020
DOI: 10.1101/2020.11.02.366112
Abstract: The efficacy of Artemisinin-based Combination Therapies (ACTs), the first- line treatments of uncomplicated falciparum malaria, has been declining in malaria endemic countries due to the emergence of malaria parasites resistant to these com- pounds. Novel alternative therapies are needed urgently to prevent the likely surge in morbidity and mortality due to failing ACTs. This study investigates the efficacy of the combination of two novel drugs, OZ439 and DSM265, using a biologically informed within-host mathematical model that accounts for the pharmacodynamic interaction between the two drugs. Model parameters were estimated using data from healthy volunteers infected with falciparum malaria collected from four trials: three that administered OZ439 and DSM265 alone, and the fourth a combination of OZ439-DSM265. Posterior predictive simulations of the model were performed to determine efficacious dosing regimens. One such regimen that predicted at least 90% of infected in iduals cured 42 days after the administration of the drugs, while within the tolerable dose range, is 800 mg of OZ439 and 450 mg of DSM265. Our model can be used to inform future phase 2 and 3 clinical trials of OZ439-DSM265, fast-tracking the deployment of this combination therapy in the regions where ACTs are failing.
Publisher: American Society for Microbiology
Date: 18-03-2021
DOI: 10.1128/AAC.01539-20
Abstract: Ensuring continued success against malaria depends on a pipeline of new antimalarials. Antimalarial drug development utilizes preclinical murine and experimental human malaria infection studies to evaluate drug efficacy.
Publisher: Oxford University Press (OUP)
Date: 28-06-2021
DOI: 10.1093/JAC/DKAB181
Abstract: The efficacy of artemisinin-based combination therapies (ACTs), the first-line treatments for uncomplicated falciparum malaria, has been declining in malaria-endemic countries due to the emergence of malaria parasites resistant to these compounds. Novel alternative therapies are needed urgently to prevent the likely surge in morbidity and mortality due to failing ACTs. This study investigates the efficacy of the combination of two novel drugs, OZ439 and DSM265, using a biologically informed within-host mathematical model. A within-host model was developed, which accounts for the differential killing of these compounds against different stages of the parasite’s life cycle and accommodates the pharmacodynamic interaction between the drugs. Data of healthy volunteers infected with falciparum malaria collected from four trials (three that administered OZ439 and DSM265 alone, and the fourth a combination of OZ439 and DSM265) were analysed. Model parameters were estimated in a hierarchical Bayesian framework. The posterior predictive simulations of our model predicted that 800 mg of OZ439 combined with 450 mg of DSM265, which are within the safe and tolerable dose range, can provide above 90% cure rates 42 days after drug administration. Our results show that the combination of OZ439 and DSM265 can be a promising alternative to replace ACTs. Our model can be used to inform future Phase 2 and 3 clinical trials of OZ439/DSM265, fast-tracking the deployment of this combination therapy in the regions where ACTs are failing. The dosing regimens that are shown to be efficacious and within safe and tolerable limits are suggested for future investigations.
Publisher: Public Library of Science (PLoS)
Date: 06-2021
DOI: 10.1371/JOURNAL.PMED.1003614
Abstract: In 2017, an estimated 14 million cases of Plasmodium vivax malaria were reported from Asia, Central and South America, and the Horn of Africa. The clinical burden of vivax malaria is largely driven by its ability to form dormant liver stages (hypnozoites) that can reactivate to cause recurrent episodes of malaria. Elimination of both the blood and liver stages of the parasites (“radical cure”) is required to achieve a sustained clinical response and prevent ongoing transmission of the parasite. Novel treatment options and point-of-care diagnostics are now available to ensure that radical cure can be administered safely and effectively. We quantified the global economic cost of vivax malaria and estimated the potential cost benefit of a policy of radical cure after testing patients for glucose-6-phosphate dehydrogenase (G6PD) deficiency. Estimates of the healthcare provider and household costs due to vivax malaria were collated and combined with national case estimates for 44 endemic countries in 2017. These provider and household costs were compared with those that would be incurred under 2 scenarios for radical cure following G6PD screening: (1) complete adherence following daily supervised primaquine therapy and (2) unsupervised treatment with an assumed 40% effectiveness. A probabilistic sensitivity analysis generated credible intervals (CrIs) for the estimates. Globally, the annual cost of vivax malaria was US$359 million (95% CrI: US$222 to 563 million), attributable to 14.2 million cases of vivax malaria in 2017. From a societal perspective, adopting a policy of G6PD deficiency screening and supervision of primaquine to all eligible patients would prevent 6.1 million cases and reduce the global cost of vivax malaria to US$266 million (95% CrI: US$161 to 415 million), although healthcare provider costs would increase by US$39 million. If perfect adherence could be achieved with a single visit, then the global cost would fall further to US$225 million, equivalent to $135 million in cost savings from the baseline global costs. A policy of unsupervised primaquine reduced the cost to US$342 million (95% CrI: US$209 to 532 million) while preventing 2.1 million cases. Limitations of the study include partial availability of country-level cost data and parameter uncertainty for the proportion of patients prescribed primaquine, patient adherence to a full course of primaquine, and effectiveness of primaquine when unsupervised. Our modelling study highlights a substantial global economic burden of vivax malaria that could be reduced through investment in safe and effective radical cure achieved by routine screening for G6PD deficiency and supervision of treatment. Novel, low-cost interventions for improving adherence to primaquine to ensure effective radical cure and widespread access to screening for G6PD deficiency will be critical to achieving the timely global elimination of P . vivax .
No related grants have been discovered for Saber Dini.