Purification and biological activity of natural variants synthesized by tridecaptin M gene cluster and in vitro drug-kinetics of this antibiotic class

The flexibility of the adenylation domains of non-ribosomal peptide synthetases (NRPSs) to different substrates creates a diversity of structurally similar peptides. In the present study, we investigated the antimicrobial activity of different natural variants synthesized by tridecaptin M gene cluster and performed the in vitro drug kinetics on this class. The natural variants were isolated and characterized using MALDI-MS and tandem mass spectrometry. All the peptides were studied for their antimicrobial activity in different pathogens, including colistin-resistant bacteria, and for haemolytic activity. Furthermore, in vitro drug kinetics was performed with tridecaptin M (or M1, the major product of the gene cluster). The natural variants displayed a varying degree of bioactivity with M11 showing the most potent antibacterial activity (MIC, 1–8 µg/ml), even against A. baumannii and P. aeruginosa strains. The in vitro kinetic studies revealed that tridecaptin M at a concentration of 16 µg/ml eradicated the bacteria completely in high-density culture. The compound demonstrated desirable post-antibiotic effect after two-hour exposure at MIC concentration. We also observed the reversal of resistance to this class of antibiotics in the presence of carbonyl cyanide m-chlorophenyl hydrazine (CCCP). Altogether, the study demonstrated that tridecaptins are an excellent drug candidate against drug-resistant Gram-negative bacteria. Future studies are required to design a superior tridecaptin by investigating the interactions of different natural variants with the target.

The Therapeutic Potential of Nanoparticles to Reduce Inflammation in Atherosclerosis

Chronic inflammation is one of the main determinants of atherogenesis. The traditional medications for treatment of atherosclerosis are not very efficient in targeting atherosclerotic inflammation. Most of these drugs are non-selective, anti-inflammatory and immunosuppressive agents that have adverse effects and very limited anti-atherosclerotic effects, which limits their systemic administration. New approaches using nanoparticles have been investigated to specifically deliver therapeutic agents directly on atherosclerotic lesions. The use of drug delivery systems, such as polymeric nanoparticles, liposomes, and carbon nanotubes are attractive strategies, but some limitations exist. For instance, nanoparticles may alter the drug kinetics, based on the pathophysiological mechanisms of the diseases. In this review, we will update pathophysiological evidence for the use of nanoparticles to reduce inflammation and potentially prevent atherogenesis in different experimental models.

FORMULATION AND EVALUATION OF GEL LOADED WITH MICROSPHERES OF APREMILAST FOR TRANSDERMAL DELIVERY SYSTEM

Objective: The main objective of the present research work was to formulate and evaluate gel loaded with microspheres of apremilast to increase bioavailability and to reduce the dosing frequency and to improve patient compliance. Methods: Gel loaded with microspheres of apremilast was prepared by solvent evaporation method by taking different ratios of polymers. Ethyl cellulose as a polymer, dichloromethane solvent is used as drug solubility, polyvinyl alcohol as a surfactant, and sodium alginate is used as gelling agent. Prepared gel loaded with microspheres was evaluated for drug interactions by Fourier transform infrared (FTIR), differential scanning calorimetry studies, and surface morphology by scanning electron microscopy (SEM), to select effective one among all formulations. The prepared formulations (F1–F6) were evaluated for pre-formulation studies, spreadability, viscosity, pH measurement, gel strength, homogeneity, drug content, in vitro diffusion studies, drug kinetics, and finally for stability studies. Results: Differential scanning calorimeter studies confirmed that there is no drug interaction between drug and excipients. FTIR spectroscopy studies confirmed that there is compatibility between drug and excipients. Regular and spherical shape particles with smooth surface were observed in the SEM photographs. The optimized gel loaded with microspheres of F4 formulation (drug: polymer in 1:4 ratio) is more effective compared to all formulations. The prepared gel showed acceptable physical properties such as spreadability (5.86±0.54 g.cm/s), viscosity (568 cps), pH (6.33±0.55), gel strength (38 s) and drug content (90.00±0.71%). In vitro diffusion studies have shown 80.1±1.92% drug release in 10 h. Drug kinetics follows zero order kinetics and n value was found to be 0.721. Stability studies were done for 3 months. Conclusion: All the results show that the gel loaded with microspheres of apremilast can be effectively used for the treatment of psoriasis and psoriatic arthritis.