Potentiation of pro-inflammatory cytokine suppression and survival by microencapsulated dexamethasone in the treatment of experimental sepsis

Abstract

Cytokine inhibiting drugs are much more effective when delivered intracellularly to phagocytic cells in the microencapsulated form. Dexamethasone is a powerful inhibitor of TNF-α cytokine through inhibition of NF-κB which is a gene regulator of multiple pro-inflammatory cytokines. We have determined the effect of microencapsulated dexamethasone in pro-inflammatory cytokine release both in in vitro using whole blood model, and in vivo using peritonitis model of septic shock. Microspheres of 1-4 μm mean size were prepared by using albumin polymer matrix in a one-step spray drying method. Microencapsulated form of dexamethasone with concentration of 10(-1), 10(-2) and 10(-3) M was compared to an equivalent concentration of solution form of dexamethasone in the in vitro whole blood model. The results show microencapsulated dexamethasone inhibited tumor necrosis factor-alpha (TNF-α) and interleukin-beta (IL-1β) significantly in comparison with the solution form of dexamethasone. The in vivo peritonitis model also demonstrated significant inhibition of TNF-α and IL-1β cytokines in microencapsulated form in comparison with solution form of dexamethasone. In the in vivo study, the animal survival rate after 5 days was 90%, dexamethasone in solution with gentamicin was 40% and gentamicin alone was 30%. This study demonstrates significantly improved inhibition of TNF-α and IL-1β both in vivo and in vitro when dexamethasone was used in microencapsulated form.

Intra‐articular dexamethasone to inhibit the development of post‐traumatic osteoarthritis

“…In this context, dexamethasone emerges as an attractive candidate because of its pleiotropic protective properties. In various cell types and animal models it inhibits the induction of MMPs, prostaglandins, inflammatory cytokines, nitric oxide, and other oxygen‐derived radicals . The literature is inconsistent on whether dexamethasone inhibits or promotes apoptosis in different types of cells but, as described below, it protects the viability of chondrocytes exposed to IL‐1.…”

Microencapsulated drug delivery: a new approach to pro-inflammatory cytokine inhibition

“…The microcapsules are then desiccated and stored for use. The complete details of drug loading and microsphere characteristics for antisense oligonucleotide to NF-κB, dexamethasone and the antioxidant enzyme catalase are found in recent publications (Siwale et al, 2008; Gayakawad et al, 2009; Uddin et al, 2011). …”

“…However, the systemic administration of glucocorticoids is associated with well-known systemic side effects. Microencapsulated dexamethasone has been shown to inhibit TNF by 84%, IL1 by 93%, IL6 by 83% and IL8 by 81% after stimulation with endotoxin in a whole blood endotoxin mode (Uddin et al, 2011). This inhibition was significantly more effective in cytokine inhibition than the equivalent dose of dexamethasone given in solution.…”

Virus-Like Particle: The Next Generation Vaccine?

“…A robust formulation to deliver this next-generation VLP vaccine is urgently needed to make a highly efficient, cost-effective vaccine. Previously it has been found that nano-micro particle based formulation for small molecule drugs such as dexamethasone, antisense was very successful [10,11]. The similar biodegradable polymer based nanomicro particle can address the major production challenges to develop a sustainable platform in a less complicated manner, generating higher yields on a larger scale, reducing production time, and increasing costeffectiveness VLP formulation which will be next generation vaccine.…”