Lab on chip based self-adjustable liposomes for rapid wound healing: An in depth in vitro, in vivo and higher dose toxicity investigation.

Thanks to microfluidic technology, different nano-delivery systems are becoming clinically viable. Using a novel and rapid microfluidic hydrodynamic focusing (MHF) method (lipids on chip) we developed self-adaptable liposomes (SLs) containing cefpodoxime proxetil (CP) for the treatment of skin infections caused by Staphylococcus aureus. SLs were optimized using different flow rate ratios in the MHF method and the final formulation CPT3 was found to be the best in terms of particle size (68.27 ± 01.15 nm), % entrapment efficiency (% EE: 82 ± 1.5), polydispersity (PDI: 0.2 ± 0.012), and degree of deformability (DOD: 4.7 ± 0.18 nm). Rats (Sprague Dawley) treated with a self-adaptable CPT3 liposomal formulation recuperate skin injury, exhibited reduced bacterial counts (<106 CFU/mL) in the wounded region, and completely restored (100 %) on day 21. Rat survival, in vivo dermal pharmacokinetics and ex vivo-in vivo relationship were also investigated. Rats treated with an even 10-fold higher dose (100 mg/kg/day) of CP using an equivalent CPT3 formulation did not show any symptoms of toxicity as revealed by hematological, biochemical, and internal organ assessment observations. Finally, the developed CPT3 formulation with special interest in patients with high-risk skin injuries not only delivered CP in a controlled manner but was also clinically effective and safe as it did not produce any serious adverse events even at 10× higher doses in the infected rats.

A Comprehensive Review on Chemistry and Biology of Tafamidis in Transthyretin Amyloidosis.

Transthyretin amyloid cardiomyopathy and Transthyretin amyloid peripheral neuropathy are progressive disease conditions caused by Transthyretin amyloidosis (ATTR) fibril infiltration in the tissue. Transthyretin (TTR) protein misfolding and amyloid fibril deposits are pathological biomarkers of ATTR-related disorders. There are various treatment strategies targeting different stages in pathophysiology. One such strategy is TTR tetramer stabilization. Recently, a new TTR tetramer stabilizer, tafamidis, has been introduced that reduces the protein misfolding and amyloidosis and, consequently, disease progression in ATTR cardiomyopathy and peripheral neuropathy. This review will provide a comprehensive overview of the literature on tafamidis discovery, development, synthetic methods, pharmacokinetics, analytical methods and clinical trials. Overall, 7 synthetic methods, 5 analytical methods and 23 clinical trials have been summarized from the literature.

3D-QSAR and Molecular Docking Studies on Oxadiazole Substituted Benzimidazole Derivatives: Validation of Experimental Inhibitory Potencies Towards COX-2.

BACKGROUND: In past few decades, computational chemistry has seen significant advancements in design and development of novel therapeutics. Benzimidazole derivatives showed promising anti-inflammatory activity through the inhibition of COX-2 enzyme. OBJECTIVE: The structural features necessary for COX-2 inhibitory activity for a series of oxadiazole substituted benzimidazoles were explored through 3D-QSAR, combinatorial library generation (Combi Lab) and molecular docking. METHODS: 3D-QSAR (using kNN-MFA (SW-FB) and PLSR (GA) methods) and Combi Lab studies were performed by using VLife MDS Molecular Design Suite. The molecular docking study was performed by using AutoDockVina. RESULTS: Significant QSAR models generated by PLSR exhibited r2 = 0.79, q2 = 0.68 and pred_r2 = 0. 84 values whereas kNN showed q2 = 0.71 and pred_r2 = 0.84. External validation of developed models by various parameters assures their reliability and predictive efficacy. A library of 72 compounds was generated by combinatorial technique in which 11 compounds (A1-A5 and B1-B6) showed better predicted biological activity than the most active compound 27 (pIC50 = 7.22) from the dataset. These compounds showed proximal interaction with amino acid residues like TYR355 and/or ARG120 on COX-2(PDB ID: 4RS0). CONCLUSION: The present work resulted in the design of more potent benzimidazoles as COX-2 inhibitors with good interaction as compared to reference ligand. The results of the study may be helpful in the development of novel COX-2 inhibitors for inflammatory disorders.