Summary Background Most malaria deaths occur in rural areas. Rapid progression from illness to death can be interrupted by prompt, effective medication. Antimalarial treatment cannot rescue ...terminally ill patients but could be effective if given earlier. If patients who cannot be treated orally are several hours from facilities for injections, rectal artesunate can be given before referral and acts rapidly on parasites. We investigated whether this intervention reduced mortality and permanent disability. Methods In Bangladesh, Ghana, and Tanzania, patients with suspected severe malaria who could not be treated orally were allocated randomly to a single artesunate (n=8954) or placebo (n=8872) suppository by taking the next numbered box, then referred to clinics at which injections could be given. Those with antimalarial injections or negative blood smears before randomisation were excluded, leaving 12 068 patients (6072 artesunate, 5996 placebo) for analysis. Primary endpoints were mortality, assessed 7–30 days later, and permanent disability, reassessed periodically. All investigators were masked to group assignment. Analysis was by intention to treat. This study is registered in all three countries, numbers ISRCTN83979018, 46343627, and 76987662. Results Mortality was 154 of 6072 artesunate versus 177 of 5996 placebo (2·5% vs 3·0%, p=0·1). Two versus 13 (0·03% vs 0·22%, p=0·0020) were permanently disabled; total dead or disabled: 156 versus 190 (2·6% vs 3·2%, p=0·0484). There was no reduction in early mortality (56 vs 51 deaths within 6 h; median 2 h). In patients reaching clinic within 6 h (median 3 h), pre-referral artesunate had no significant effect on death after 6 h or permanent disability (71/4450 1·6% vs 82/4426 1·9%, risk ratio 0·86 95% CI 0·63–1·18, p=0·35). In patients still not in clinic after more than 6 h, however, half were still not there after more than 15 h, and pre-referral rectal artesunate significantly reduced death or permanent disability (29/1566 1·9% vs 57/1519 3·8%, risk ratio 0·49 95% CI 0·32–0·77, p=0·0013). Interpretation If patients with severe malaria cannot be treated orally and access to injections will take several hours, a single inexpensive artesunate suppository at the time of referral substantially reduces the risk of death or permanent disability. Funding UNICEF/UNDP/World Bank Special Programme for Research and Training in Tropical Diseases (WHO/TDR); WHO Global Malaria Programme (WHO/GMP); Sall Family Foundation; the European Union (QLRT-2000-01430); the UK Medical Research Council; USAID; Irish Aid; the Karolinska Institute; and the University of Oxford Clinical Trial Service Unit (CTSU).
INTRODUCTION: The tumour microenvironment of glioblastoma multiforme (GBM) demonstrates gradients in oxygen and nutrients due to an improperly formed tumour vasculature. Cancer cells obtain lipids ...for membrane biogenesis through anabolic cellular metabolism or internalisation of lipoproteins from the extracellular milieu. Growth rates of adult GBM cells have been demonstrated to be reduced in the absence of external lipid sources, indicating that de novo synthesis cannot generate the required lipid complement of highly proliferative cancer cells. Here, we evaluate the growth characteristics of paediatric glioma cell lines, to test the hypothesis that paediatric glioma cells demonstrate a similar growth response when cultured in lipoprotein deficient medium (LPDM) as compared to adult GBM cells. MATERIALS AND METHODS: Two paediatric GBM cell lines (KNS42 and SF188) and one paediatric grade I pilocytic astrocytoma (Res186) cell line were cultured in LPDM over a period of 7 days. Complementary experiments on adult counterparts were conducted using the U87 cell line as well as patient-derived tumour cells (GIN-8) isolated from the invasive margin of an adult GBM. Quantitative assessment of cell viability was conducted through crystal violet staining and resazurin-based PrestoBlue assays. RESULTS: Growth in LPDM reduced exponential growth rates and doubling times of KNS42 and SF188 cells after 3 days culture, reaching levels of significance (P<0.05) after 7 days. In contrast, cytostatic growth patterns were observed for Res186, U87 and GIN-8 cells after 3 days culture in LPDM. These cell lines demonstrated morphological changes reminiscent of differentiation (process elongation), whereas KNS42 and SF188 cells demonstrated a largely unaltered tumour cell membrane architecture. CONCLUSIONS: Culture of glioma cells utilising media depleted of external lipoproteins revealed an enhanced capacity of paediatric GBM cells to proliferate under acute metabolic stress compared to adult GBM and grade I paediatric glioma cells. This is suggestive of the ability of paediatric cells to utilise de novo cellular metabolism to generate lipids for proliferation, albeit at a rate that reduces doubling times. Metabolic differences between paediatric and adult cells likely portray differences at the genetic level. Growth of GBM cells under lipoprotein-deplete conditions has the potential to reveal essential metabolic pathways that will inform next-generation targeted treatment strategies.
Advances in therapy delivery systems are providing new opportunities for the treatment of malignancies of the central nervous system. There is opportunity for locally administered therapies that ...overcome the Blood Brain Barrier (BBB) to be implanted at the point of tumour resection surgery into or around the cavity left behind. This is particularly the case for Glioblastoma Multiforme (GBM). The pharmacodynamics of a therapy delivered in this way into brain tissue is of key importance to optimizing these therapies as the correct dose reaching the micro-deposits of malignant cells unreachable by surgery is thought to be key in slowing disease progression. We examine the particular case of a drug loaded poly(lactic-co-glycolic acid)/poly(ethylene-glycol) (PLGA/PEG) polymer particle paste designed to release drug to surrounding brain tissue post surgical implantation. By experimentally parameterizing the distribution, release and uptake kinetics we have modeled the biodistribution of methotrexate conjugated to a fluorescent moiety fluorescein isothiocyanate (FITC). We have also used micro-computerized tomography (µ-CT) to determine the microstructure of the PLGA/PEG construct and assess how the drug progresses out from the interior of the construct. The model consists of a system of reaction-diffusion equations describing the time evolution of spatially dependent concentrations of a drug in three different materials: normal brain tissue, cerebrospinal fluid (CSF) and the PLGA/PEG implant, each have their own diffusion tensors that describe the anisotropy of the brain. The model was built upon simple one-dimensional time course experiments measuring the rate at which a drug molecule can pass through a standardized volume of PLGA/PEG paste and the rate at which the drug is taken up by brain tissue. We simulated computationally a gap of CSF between the PLGA/PEG construct and the brain tissue to ascertain whether good tissue apposition was key to drug delivery. Known release rates of drugs from previous studies were also fitted to the model, allied to this their known logD values were used to test the model. We have been able to see that the chemical properties of the compounds studied, in particular the logD values, have a great effect on the simulated release, passage across the CSF and uptake in the brain tissue. Hence not having a CSF barrier between Allying these drug release and distribution models to models of tumour growth, the interaction of the polymer with the tissue and the polymer and the drug we aim to better select drugs according to chemical properties, simulate repurposed drugs and predict drug coverage where it is required to improve the control of GBM as a disease.
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