Publications

4,9-diaminoacridines with reported antiplasmodial activity were coupled to different trans-cinnamic acids, delivering a new series of conjugates inspired by the covalent bitherapy concept. The new compounds were more potent than primaquine against hepatic stages of Plasmodium berghei, although this was accompanied by cytotoxic effects on Huh-7 hepatocytes. Relevantly, the conjugates displayed nanomolar activities against blood stage P. falciparum parasites, with no evidence of hemolytic effects below 100 mu M. Moreover, the new compounds were at least 25-fold more potent than primaquine against P. falciparum gametocytes. Thus, the new antiplasmodial hits disclosed herein emerge as valuable templates for the development of multi-stage antiplasmodial drug candidates.

JTD Keywords: Acid-derivatives, Analogs, Antimalarial, Artemisinin, Bearing, Cinnamic acid, Covalent bitherapy, Diaminoacridine, Good health and well-being, Malaria, Multi-target, N-cinnamoylation, Plasmodium-falciparum, Primaquine, Quinacrine, Resistance

Malaria eradication has for decades been on the global health agenda, but the causative agents of the disease, several species of the protist parasite Plasmodium, have evolved mechanisms to evade vaccine-induced immunity and to rapidly acquire resistance against all drugs entering clinical use. Because classical antimalarial approaches have consistently failed, new strategies must be explored. One of these is nanomedicine, the application of manipulation and fabrication technology in the range of molecular dimensions between 1 and 100 nm, to the development of new medical solutions. Here we review the current state of the art in malaria diagnosis, prevention, and therapy and how nanotechnology is already having an incipient impact in improving them. In the second half of this review, the next generation of antimalarial drugs currently in the clinical pipeline is presented, with a definition of these drugs’ target product profiles and an assessment of the potential role of nanotechnology in their development. Opinions extracted from interviews with experts in the fields of nanomedicine, clinical malaria, and the economic landscape of the disease are included to offer a wider scope of the current requirements to win the fight against malaria and of how nanoscience can contribute to achieve them. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

JTD Keywords: antibody-bearing liposomes, antimalarial drugs, combination therapies, drug-delivery strategies, malaria diagnosis, malaria prophylaxis, malaria therapy, nanocarriers, nanomedicine, nanoparticles, nanotechnology, plasmodium, plasmodium-falciparum, red-blood-cells, targeted delivery, targeted drug delivery, vitro antimalarial activity, Antimalarial drugs, Isothermal amplification lamp, Malaria diagnosis, Malaria prophylaxis, Malaria therapy, Nanocarriers, Nanomedicine, Nanotechnology, Plasmodium, Targeted drug delivery

Purpose: To assess, with finite element (FE) calculations, whether immediate weight bearing would be possible after surgical stabilization either with cannulated screws or with a locking plate in a split fracture of the lateral tibial plateau (LTP). Methods: A split fracture of the LTP was recreated in a FE model of a human tibia. A three-dimensional FE model geometry of a human femur-tibia system was obtained from the VAKHUM project database, and was built from CT images from a subject with normal bone morphologies and normal alignment. The mesh of the tibia was reconverted into a geometry of NURBS surfaces. A split fracture of the lateral tibial plateau was reproduced by using geometrical data from patient radiographs. A locking screw plate (LP) and a cannulated screw (CS) systems were modelled to virtually reduce the fracture and 80 kg static body-weight was simulated. Results: While the simulated body-weight led to clinically acceptable interfragmentary motion, possible traumatic bone shear stresses were predicted nearby the cannulated screws. With a maximum estimation of about 1.7 MPa maximum bone shear stresses, the Polyax system might ensure more reasonable safety margins. Conclusions: Split fractures of the LTP fixed either with locking screw plate or cannulated screws showed no clinically relevant IFM in a FE model. The locking screw plate showed higher mechanical stability than cannulated screw fixation. The locking screw plate might also allow full or at least partial weight bearing under static posture at time zero.

JTD Keywords: Bone fixation, Finite element, Fracture fixation, Interfragmentary motion, Tibial plateau fractures, Weight bearing

In this study, a three-dimensional (3D) computational simulation of bone regeneration was performed in a human tibia under realistic muscle loading. The simulation was achieved using a discrete lattice modeling approach combined with a mechanoregulation algorithm to describe the cellular processes involved in the healing process namely proliferation, migration, apoptosis, and differentiation of cells. The main phases of fracture healing were predicted by the simulation, including the bone resorption phase, and there was a qualitative agreement between the temporal changes in interfragmentary strain and bending stiffness by comparison to experimental data and clinical results. Bone healing was simulated beyond the reparative phase by modeling the transition of woven bone into lamellar bone. Because the simulation has been shown to work with realistic anatomical 3D geometry and muscle loading, it demonstrates the potential of simulation tools for patient-specific pre-operative treatment planning.

JTD Keywords: Tissue differentiation, Computational analysis, Mechanical conditions, Bone regeneration, Weight-bearing, Proliferation, Osteoblast, Stiffness, Ingrowth, Scaffold