Amlexanox-loaded nanoliposomes showing enhanced anti-inflammatory activity in cultured macrophages: A potential formulation for treatment of oral aphthous stomatitis

Oral aphthous stomatitis is a common disorder treated with the immunomodulatory drug Amlexanox (AMX), that was administered as a mucoadhesive paste (Aphthasol®). This product was discontinued by FDA in 2014 due to the associated undesired adverse reactions of the formulation. Here, we have developed AMX-loaded nanoliposome formulation as a potential alternative for the localised oromucosal delivery of AMX. Nanoliposomes were prepared using Soya phosphatidylcholine (SPC) and Cholesterol (Chol) mixtures at three different molar ratios to formulate vesicles using thin-film hydration, and were characterised for size, zeta potential and entrapment efficiency. The optimal formulation was found to be SPC:Chol 3:1 with drug entrapment efficiency of 94%, post sonication. To evaluate anti-inflammatory activity, macrophages developed by differentiation of human leukaemia monocytic cell line, THP-1, were polarised by Interferon gamma (IFNγ) and lipopolysaccharide (LPS) to M1 state. Macrophages M1 cells treated with D-L1 formulation (SPC:Chol 3:1, 500 μg/mL total lipid, and 27.6 μM AMX) showed a significant suppression in TNF-α expression levels (43 ± 2.7% of untreated control, p < 0.05) compared to those treated with either empty liposomes or AMX alone. Notably, %TNF-α dramatically decreased to 57 ± 4.05% of control, for cells treated with drug-free liposomes (500μg/mL total lipid) indicating the anti-inflammatory activity of SPC lipid component per se, which led to synergistic effect as evident from the augmentation of AMX anti-inflammatory activity in D-L1 formulation. Our findings highlight the potential of using AMX nanoliposomes as a promising advanced formulation for reviving AMX treatment for management of inflammatory conditions of oral mucosa

Amlexanox-loaded nanoliposomes showing enhanced anti-inflammatory activity in cultured macrophages: A potential formulation for treatment of oral aphthous stomatitis

Oral aphthous stomatitis is a common disorder treated with the immunomodulatory drug Amlexanox (AMX), that was administered as a mucoadhesive paste (Aphthasol®). This product was discontinued by FDA in 2014 due to the associated undesired adverse reactions of the formulation. Here, we have developed AMX-loaded nanoliposome formulation as a potential alternative for the localised oromucosal delivery of AMX. Nanoliposomes were prepared using Soya phosphatidylcholine (SPC) and Cholesterol (Chol) mixtures at three different molar ratios to formulate vesicles using thin-film hydration, and were characterised for size, zeta potential and entrapment efficiency. The optimal formulation was found to be SPC:Chol 3:1 with drug entrapment efficiency of 94%, post sonication. To evaluate anti-inflammatory activity, macrophages developed by differentiation of human leukaemia monocytic cell line, THP-1, were polarised by Interferon gamma (IFNγ) and lipopolysaccharide (LPS) to M1 state. Macrophages M1 cells treated with D-L1 formulation (SPC:Chol 3:1, 500 μg/mL total lipid, and 27.6 μM AMX) showed a significant suppression in TNF-α expression levels (43 ± 2.7% of untreated control, p < 0.05) compared to those treated with either empty liposomes or AMX alone. Notably, %TNF-α dramatically decreased to 57 ± 4.05% of control, for cells treated with drug-free liposomes (500 μg/mL total lipid) indicating the anti-inflammatory activity of SPC lipid component per se, which led to synergistic effect as evident from the augmentation of AMX anti-inflammatory activity in D-L1 formulation. Our findings highlight the potential of using AMX nanoliposomes as a promising advanced formulation for reviving AMX treatment for management of inflammatory conditions of oral mucosa.This research was funded by the Egyptian Government missions sector PhD scholarship awarded to A.Y.M. and was supported by the self-funded PhD project for A.A.Authors would like to thank the University of Leicester Core Biotechnology Services Electron Microscopy Facility, for the use of their Transmission Electron Microscope. Authors would also like to thank Dr Abdullah Isreb, Dr Sim Singhrao and Dr Sarah Dennison from University of Central Lancashire (UCLan), as well as Abdulwahhab Khedr and Mohamed Soliman from De Montfort University for their support and scientific discussions. Authors are grateful to Dr Julie Burrows and Dr Antony Ashton from UCLan for training A.A. on the basics of in vitro cell culture techniques and bioassays used in this work. Authors would like to thank Dr Gail Welsby for providing A.A. training for the use of the fluorescence microscope. Thanks to the technical staff in JB Firth analytical suite at UCLan for their assistance and training of A.A. on some of the analytical techniques used in this work. Authors are grateful to Dr Philip Welsby for providing the aspirin used in this project as in-kind contribution.Scopu

SARS-CoV-2 vaccination modelling for safe surgery to save lives: data from an international prospective cohort study

Background: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results: NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion: As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population