Pharmacological and non-pharmacological efforts at prevention, mitigation, and treatment for COVID-19.

A global outbreak of the SARS-CoV-2 virus has infected millions of people over a short period of time. The communicability and increased mortality from the SARS-CoV-2 infection mandated the WHO to declare COVID-19 a worldwide pandemic. The virus outbreak has spread when there are no approved vaccines, treatments, or prophylactic therapies available. Researchers from all over the world have prioritised development of vaccines and antivirals. Several vaccine projects have seen successes in preclinical, phase I, and phase II clinical trials using recombinant DNA, mRNA, live attenuated virus, S-protein subunits, virus like particles, and viral vectors. Initial findings from antivirals such as remdesivir, favipiravir, danoprevir or lopinavir with ritonavir are presented. Immunomodulatory molecules such as sarilumab, tocilizumab, janus kinase inhibitors, and hyperimmune convalescent plasma have mixed outcomes from initial clinical findings; however, pending randomised controlled trials will assist national health institutions to make treatment recommendations for COVID-19. Where compassionate use of remdesivir has shown some benefits, therapies such as hydroxychloroquine have proven harmful due to their toxicities. This review discusses pharmacological interventions at play and evidence-based successes and limitations of non-pharmacological therapies such as social distancing, personal protective equipment, and ventilator support associated with the prevention and treatment of COVID-19.

Intracellular trafficking and cytotoxicity of a gelatine-doxorubicin conjugate in two breast cancer cell lines.

Details of intracellular pathways of cytotoxicity remain unclear for doxorubicin conjugates being studied to treat breast cancer tumours. A high molecular weight gelatine-doxorubicin conjugate was investigated with an emphasis on lysosome participation. The conjugate was synthesised and characterised. Cell uptake and cellular localisation in MCF-7 and triple negative breast cancer (TNBC) MDA-MB-231 cells were determined with fluorescence microscopy. Nuclear content of released DOX was determined by UHPLC. Cytotoxicity was determined by the MTT assay. Lysosome membrane permeabilization (LMP) was followed by lysosomal release of fluorescently labelled dextran. After incubation at an equivalent 10 µM DOX, conjugate lysosome accumulation was substantial in both cell lines by 24 h, at which time the conjugate cytotoxic effect was first observed. By 48 h, the conjugate was nearly fourfold more toxic in TNBC than in MCF-7 cells. The MCF-7 nucleus drug content from conjugate released DOX was small but confirmed intra-lysosomal drug release. The conjugate induced LMP in 100% of TNBC cells but LMP was virtually absent in MCF-7 cells. These results suggest that the conjugate induces cytotoxicity by a lysosomal pathway in MDA-MB-231 cells and has potential for treatment of TNBC tumours. Support: NIH/NCI R15CA135421, the Agnes Varis Trust for Women's Health.

A prospective analysis of co-processed non-ionic surfactants in enhancing permeability of a model hydrophilic drug.

Paracellular route is a natural pathway for the transport of many hydrophilic drugs and macromolecules. The purpose of this study was to prospectively evaluate the ability of novel co-processed non-ionic surfactants to enhance the paracellular permeability of a model hydrophilic drug metformin using Caco-2 (human colonic adenocarcinoma) cell model. A three-tier screen was undertaken to evaluate the co-processed blends based on cytotoxicity, cellular integrity, and permeability coefficient. The relative contribution of the paracellular and the transcellular route in overall transport of metformin by co-processed blends was determined. Immunocytochemistry was conducted to determine the distribution of tight-junction protein claudin-1 after incubation with the co-processed blends. It was found that novel blends of Labrasol and Transcutol-P enhanced metformin permeability by approximately twofold with transient reduction in the transepithelia electrical resistance (TEER) and minimal cytotoxicity compared with the control, with the paracellular pathway as the major route of metformin transport. Maximum permeability of metformin (∼10-fold) was mediated by Tween-20 blends along with >75% reduction in the TEER which was irreversible over 24-h period. A shift in metformin transport from the paracellular to the transcellular route was observed with some Tween-20 blends. Immunocytochemical analysis revealed rearrangement of the cellular borders and fragmentation on treatment with Tween-20 blends. In conclusion, cytotoxicity, cellular integrity, and permeability of the hydrophilic drugs can be greatly influenced by the polyoxyethylene residues and medium chain fatty acids in the non-ionic surfactants at clinically relevant concentrations and therefore should be thoroughly investigated prior to their inclusion in formulations.