Local Delivery of Azithromycin Nanoformulation Attenuated Acute Lung Injury in Mice.

Humanity has suffered from the coronavirus disease 2019 (COVID-19) pandemic over the past two years, which has left behind millions of deaths. Azithromycin (AZ), an antibiotic used for the treatment of several bacterial infections, has shown antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as against the dengue, Zika, Ebola, and influenza viruses. Additionally, AZ has shown beneficial effects in non-infective diseases such as cystic fibrosis and bronchiectasis. However, the systemic use of AZ in several diseases showed low efficacy and potential cardiac toxicity. The application of nanotechnology to formulate a lung delivery system of AZ could prove to be one of the solutions to overcome these drawbacks. Therefore, we aimed to evaluate the attenuation of acute lung injury in mice via the local delivery of an AZ nanoformulation. The hot emulsification-ultrasonication method was used to prepare nanostructured lipid carrier of AZ (AZ-NLC) pulmonary delivery systems. The developed formulation was evaluated and characterized in vitro and in vivo. The efficacy of the prepared formulation was tested in the bleomycin (BLM) -mice model for acute lung injury. AZ-NLC was given by the intratracheal (IT) route for 6 days at a dose of about one-eighth oral dose of AZ suspension. Samples of lung tissues were taken at the end of the experiment for immunological and histological assessments. AZ-NLC showed an average particle size of 453 nm, polydispersity index of 0.228 ± 0.07, zeta potential of -30 ± 0.21 mV, and a sustained release pattern after the initial 50% drug release within the first 2 h. BLM successfully induced a marked increase in pro-inflammatory markers and also induced histological changes in pulmonary tissues. All these alterations were significantly reversed by the concomitant administration of AZ-NLC (IT). Pulmonary delivery of AZ-NLC offered delivery of the drug locally to lung tissues. Its attenuation of lung tissue inflammation and histological injury induced by bleomycin was likely through the downregulation of the p53 gene and the modulation of Bcl-2 expression. This novel strategy could eventually improve the effectiveness and diminish the adverse drug reactions of AZ. Lung delivery could be a promising treatment for acute lung injury regardless of its cause. However, further work is needed to explore the stability of the formulation, its pharmacokinetics, and its safety.

Impact of thymoquinone on cyclosporine A pharmacokinetics and toxicity in rodents.

OBJECTIVES: Cyclosporine A (CsA) is an immunosupprsant drug used to prevent graft rejection and in the treatment of several autoimmune diseases. Thyomquinone (TQ), a bioactive component of Nigella sativa, has strong antioxidant properties and has been used in prevention of many toxicities, hence its protective effect and pharmacokinetic interactions with CsA was investigated in this study. METHODS: For bioavailability study, the rats were divided into four groups: TQ (PO, 10 mg/kg) was given alone for 7 days, then TQ plus CsA for another 5 days, CsA was given by two routes (po) and (IP) in a dose of 10 mg/kg 1 h after administration of TQ. Blood samples were taken at the 12th day at specified times, CsA level was determined by immune assays. The protective effect of TQ was studied. Blood samples for lab investigations and histopathology were taken at the 28th day. KEY FINDINGS: Thyomquinone reduced the bioavailability of oral CsA by around 32% (P > 0.05). However, bioavailability of IP administered CsA was not affected. Chronic administration of CsA increased concentrations of fasting glucose and Cystatin C and produced marked s kidney alteration of parenchyma which was reversed by concomitant administration of TQ. CONCLUSIONS: A potential drug interaction between TQ and CsA, which may reduced its oral bioavailability. Independently TQ caused significant attenuation of CsA induced renal toxicity and diabetogenic effect.