Search

Summary Background DSM265 is a novel, long-duration inhibitor of plasmodium dihydroorotate dehydrogenase (DHODH) with excellent selectivity over human DHODH and activity against blood and liver stages of Plasmodium falciparum. This study aimed to assess the efficacy of DSM265 in patients with P falciparum or Plasmodium vivax malaria infection. Methods This proof-of-concept, open-label, phase 2a study was conducted at the Asociación Civil Selva Amazónica in Iquitos, Peru. Patients aged 18–70 years, weighing 45–90 kg, who had clinical malaria (P falciparum or P vivax monoinfection) and fever within the previous 24 h were eligible. Exclusion criteria were clinical or laboratory signs of severe malaria, inability to take oral medicine, and use of other antimalarial treatment in the preceding 14 days. Patients were divided into cohorts of those with P falciparum (cohort a) or P vivax (cohort b) infection. Two initial cohorts received single oral doses of 400 mg DSM265. Patients were followed up for efficacy for 28 days and safety for 35 days. Further cohorts received escalated or de-escalated doses of DSM265, after safety and efficacy assessment of the initial dose. The primary endpoints were the proportion of patients achieving PCR-adjusted adequate clinical and parasitological response (ACPR) by day 14 for patients infected with P falciparum and the proportion of patients achieving a crude cure by day 14 for those infected with P vivax. Cohort success, the criteria for dose escalation, was defined as ACPR (P falciparum) or crude cure (P vivax) in at least 80% of patients in the cohort. The primary analysis was done in the intention-to-treat population (ITT) and the per-protocol population, and safety analyses were done in all patients who received the study drug. This study is registered at ClinicalTrials.gov (NCT02123290). Findings Between Jan 12, 2015, and Dec 2, 2015, 45 Peruvian patients (24 with P falciparum [cohort a] and 21 with P vivax [cohort b] infection) were sequentially enrolled. For patients with P falciparum malaria in the per-protocol population, all 11 (100%) in the 400 mg group and eight (80%) of ten in the 250 mg group achieved ACPR on day 14. In the ITT analysis, 11 (85%) of 13 in the 400 mg group and eight (73%) of 11 in the 250 mg group achieved ACPR at day 14. For the patients with P vivax malaria, the primary endpoint was not met. In the per-protocol analysis, none of four patients who had 400 mg, three (50%) of six who had 600 mg, and one (25%) of four who had 800 mg DSM265 achieved crude cure at day 14. In the ITT analysis, none of five in the 400 mg group, three (33%) of nine in the 600 mg group, and one (14%) of seven in the 800 mg group achieved crude cure at day 14. During the 28-day extended observation of P falciparum patients, a resistance-associated mutation in the gene encoding the DSM265 target DHODH was observed in two of four recurring patients. DSM265 was well tolerated. The most common adverse events were pyrexia (20 [44%] of 45) and headache (18 [40%] of 45), which are both common symptoms of malaria, and no patients had any treatment-related serious adverse events or adverse events leading to study discontinuation. Interpretation After a single dose of DSM265, P falciparum parasitaemia was rapidly cleared, whereas against P vivax, DSM265 showed less effective clearance kinetics. Its long duration of action provides the potential to prevent recurrence of P falciparum after treatment with a single dose, which should be further assessed in future combination studies. Funding The Global Health Innovative Technology Fund, the Bill & Melinda Gates Foundation, the National Institutes of Health (R01 AI103058), the Wellcome Trust, and the UK Department of International Development.

This study, funded by AFILOG, focuses on the threat caused by the large heat releases from warehouse fires. The objective is to improve the understanding of the propagation of the fire inside the warehouse and to quantify the heat fluxes experienced in the vicinity of the warehouse. This will ultimately help refine the modelling tool presently employed by INERIS [1] to evaluate the thermal effects from warehouse fires on nearby populations and/or other industrial installations. Such an evaluation is important, for example, to help land-use planning. Medium-scale experiments of warehouse fires (see Figures 1 and 2) were conducted in a purposedly built 3 metres high building with a section of 4.3 4 m2. One side of the building was open and the top was covered with a plywood. This roof was meant to help the propagation of the fire and then disappear so as to be representative of a fully-developed fire in a large warehouse. Four steel racks were set up inside the building on which were stacked 40 cm 40 cm 50 cm high wood cribs made of pine sticks. To monitor the fire propagation, 52 measurements of temperature were undertaken with thermocouples throughout the storage area. Outside the building, heat fluxes were measured at a total of 20 locations in front of the building and on the two sides. The heat flux metres were located at different distances from the building and different heights. Videos were recorded from 4 cameras around the building and an infrared camera. The images allowed to time events such as the appearance and propagation of smoke, the collapse of the roof and stacks and to determine the shape and size of the flames. The fire was set by a burner located beneath the third rack towards the rear of the building. The heat release rate from the fire was deduced from the measurement of the total mass loss. The influence of a number of parameters on the longitudinal fire propagation along the racks, the lateral propagation from one rack to another and the shape and height of the flame once the roof collapsed was investigated. These parameters were the stockage compacity, the thickness of the roof and the number of rack shelves. The most important results will be presented and compared where appropriate to previous work, in particular to studies on fire propagation in warehouses [eg. 2] Thermal effects of fire warehouses on their surroundings have been less studied and will be analysed here in some details. In particular, the measured heat fluxes will be compared with the values predicted by the in-house tool FNAP. The limitations of FNAP which assumes a solid parallelepipedic flame will be discussed in the light of the observations of the shapes and heights of the flames. Future steps aimed to improve FNAP and to carry out full-scale experiments will be briefly presented.