1. Investigación

Chagas disease (CD) is a parasitic zoonosis endemic in Central and South America affecting nearly 10 million people, with 100 million people at high risk of contracting the disease. Treatment is only effective when received at the early stages of the disease and it involved two drugs (nifurtimox (NFX) and benznidazole (BNZ)). Both treatments require multiple daily administrations of high doses, suffer from variable efficacy and insufficient efficacy in chronic CD, many side effects, and a very long duration of treatment that results in poor compliance, while combined available therapies that lead to reduced duration of treatment are not available and polypharmacy reduces compliance and increases the cost further. Here we present self-nanoemulsified drug delivery systems (SNEDDS) able to produce easily scalable combined formulations of NFX and BNZ that can allow for tailoring of the dose and can be easily converted to oral solid dosage form by impregnation on mesoporous silica particles. SNEDDS demonstrated an enhanced solubilisation capacity for both drugs as demonstrated by flow-through studies and in vitro lipolysis studies. High loading of SNEDDS to Syloid 244 and 3050 silicas (2:1 w/w) allowed clinically translatable amounts of both NFX and BNZ to be loaded. Tablets prepared from NFX-BNZ combined SNEDDS loaded on Syloid 3050 silicas demonstration near complete dissolution in the flow through cell apparatus compared to NFX and BNZ commercial tablets respectively (Lampit® and Rochagan®). NFX-BNZ-SNEDDS demonstrated nanomolar efficacy in epimastigotes and amastigotes of T. cruzi with acceptable selectivity indexes and demonstrated enhanced survival and reduced parasitaemia in acute murine experimental models of CD. Thus, the results presented here illustrate the ability for an easily scalable and personalised combination oral therapy prepared from GRAS excipients, enabling treatment access worldwide for the treatment of CD.

Leishmaniasis is a neglected disease presenting cutaneous, mucosal and visceral forms and affecting an estimated 12 million mostly low-income people. Treatment of cutaneous leishmaniasis (CL) is recommended to expedite healing, reduce risk of scarring, prevent parasite dissemination to other mucocutaneous (common with New World species) or visceral forms and reduce the chance of relapse, but remains an unmet need. Available treatments are painful, prolonged (>20 days) and require hospitalisation, which increases the cost of therapy. Here we present the development of optimised topical self-nanoemulsifying drug delivery systems (SNEDDS) loaded with buparvaquone (BPQ, a hydroxynapthoquinone from the open Malaria Box) for the treatment of CL from New World species. The administration of topical BPQ-SNEDDS gels for 7 days resulted in a reduction of parasite load of 99.989 ± 0.019 % similar to the decrease achieved with intralesionally administered Glucantime® (99.873 ± 0.204 %) in a L. amazonensis BALB/c model. In vivo efficacy was supported by ex vivo permeability and in vivo tape stripping studies. BPQ-SNEDDS and their hydrogels demonstrated linear flux across non-infected CD-1 mouse skin ex vivo of 182.4 ± 63.0 μg cm-2 h-1 and 57.6 ± 10.8 μg cm-2 h-1 respectively localising BPQ within the skin in clinically effective concentrations (227.0 ± 45.9 μg and 103.8 ± 33.8 μg) respectively. These levels are therapeutic as BPQ-SNEDDS and their gels showed nanomolar in vitro efficacy against L. amazonensis and L. braziliensis amastigotes with excellent selectivity index toward parasites versus murine macrophages. In vivo tape stripping experiments indicated localisation of BPQ within the stratum corneum and dermis. Histology studies confirmed the reduction of parasitism and indicated healing in animals treated with BPQ-SNEDDS hydrogels. These results highlight the potential clinical capability of nano-enabled BPQ hydrogels towards a non-invasive treatment for CL.

Blended learning has risen in popularity over the last two decades as it has shown to be an effective approach for accommodating an increasingly diverse student population in Higher Education as well as enriching the learning environment through the incorporation of online teaching resources. The act of blending significant elements of the learning environment such as face-to-face, online and self-paced learning leads to better student experiences and outcomes, and more efficient teaching and course management practices if combined appropriately. For this reason, an appropriate systematic and dynamic approach of blended learning design is crucial for a positive outcome starting with planning for integrating blended elements into a course followed by creating blended activities and implementing them. Evaluating their effectiveness and knowing in which environments they work better and finally improving the blended activities designed from both the student’s and instructor’s perspective is critical for the next delivery of the course. This work aims to provide useful examples and increase awareness of Higher Education educators about how traditional face-to-face learning can be transformed into blended courses with the aim of increasing student engagement with both in-class and online approaches while being time effective for the instructor.

One of the main objectives of the WHO is controlling transmission of parasitic protozoa vector-borne diseases. A quick and precise diagnosis is critical in selecting the optimal therapeutic regime that avoids unnecessary treatments and the emergence of resistance. Molecular assays based on loopmediated isothermal amplification (LAMP) techniques are a good alternative to light microscopy and antigen-based rapid diagnostic tests in developing countries, since they allow for a large amount of genetic material generated from a few copies of DNA, and use primers that lead to high sensitivity and specificity, while the amplification process can be performed in isothermal conditions without the need of sophisticated equipment to interpret the results. In this review, the main advances in the development of LAMP assays for the diagnosis of malaria, leishmaniasis and Chagas' disease are discussed as well as the feasibility of their implementation in developing countries and use as point- of-care diagnostic tests.

Nano-enabled lipid based drug delivery systems offer a platform to overcome challenges encountered with current failed leads in the treatment of parasitic and infectious diseases. When prepared with FDA or EMA approved excipients, they can be readily translated without the need for further toxicological studies, while they remain affordable and amenable to scale-up. Buparvaquone (BPQ), a hydroxynapthoquinone with in vitro activity in the nanomolar range, failed to clinically translate as a viable treatment for visceral leishmaniasis due to its poor oral bioavailability limited by its poor aqueous solubility (BCS Class II drug). Here we describe a self-nanoemulsifying system (SNEDDS) with high loading and thermal stability up to 6 months in tropical conditions able to enhance the solubilisation capacity of BPQ in gastrointestinal media as demonstrated by flow-through cell and dynamic in vitro lipolysis studies. BPQ SNEDDS demonstrated an enhanced oral bioavailbility compared to aqueous BPQ dispersions (probe – sonicated) resulting in an increased plasma AUC0-24 by 55% that is four fold higher than any previous reported values for BPQ formulations. BPQ SNEDDS can be adsorbed on low molecular glycol chitosan polymers forming solid dispersions that when compressed into tablets allow the complete dissolution of BPQ in gastrointestinal media. BPQ SNEDDS and BPQ solid SNEDDS demonstrated potent in vitro efficacy in the nanomolar range (<37 nM) and were able to near completely inhibit parasite replication in the spleen and 48 ± 48 and 56 ± 23% inhibition of the parasite replication in the liver respectively compared to oral miltefosine after daily administration over 10 days. The proposed platform technology can be used to elicit a range of cost-effective and orally bioavailable non-invasive formulations for a range of antiparasitic and infectious disease drugs that are needed for closing the global health innovation gap.