Radioiodination and bioevaluation of rolipram as a tracer for brain imaging: In silico study,molecular modeling and gamma scintigraphy

Brain imaging is considered one of the most fruitful applications of radioisotope scanning. Rolipram, a selective phospodiesterase‐4 inhibitor, has been labeled using [¹²⁵I] with chloramine‐T (Ch‐T) as an oxidizing agent. Factors, such as the amount of substrate, pH, the amount of oxidizing agent, temperature, and the reaction time, have been systematically studied to optimize the iodination process. In addition, bio‐distribution studies have indicated that the brain uptake of [¹²⁵I]iodorolipram is 7.6 ± 0.33 injected dose/g organ at 10 minutes post‐injection, which cleared from the brain with time until it reaches 1.30 ± 0.17% at 1 hour post‐injection. Therefore, iodorolipram could be considered as a potential, new selective radiotracer for brain imaging.     

Lipid nanocarriers as skin drug delivery systems: Properties,mechanisms of skin interactions and medical applications

During the past decades, lipid nanocarriers are gaining momentum with their multiple advantages for the management of skin diseases. Lipid nanocarriers enable to target the therapeutic payload to deep skin layers or even to reach the blood circulation making them a promising cutting-edge technology.Lipid nanocarriers refer to a large panel of drug delivery systems. Lipid vesicles are the most conventional, known to be able to carry lipophilic and hydrophilic active agents. A variety of lipid vesicles with high flexibility and deformability could be obtained by adjusting their composition; namely ethosomes, transfersomes and penetration enhancer lipid vesicles which achieve the best results in term of skin permeation. Others are designed with the objective to perform higher encapsulation rate and higher stability, such as solid lipid nanoparticles and nanostructured lipid nanocarriers.In this review, we attempted to give an overview of lipid based nanocarriers developed with the aim to enhance dermal and transdermal drug delivery. A special focus is put on the nanocarrier composition, behavior and interaction mechanisms with the skin. Recent applications of lipid-based nanocarriers for the management of skin diseases and other illnesses are highlighted as well.     

Enhanced in vitro activity of tigecycline in the presence of chelating agents

The lack of availability of novel antibiotic agents and the rise of resistance to existing therapies has led clinicians to utilise combination therapy to adequately treat bacterial infections. Here we examined how chelators may impact the in vitro activity of tigecycline (TIG) against Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae. Minimum inhibitory concentrations (MICs) were determined by broth dilution with and without various combinations of chelators (EDTA and other tetracyclines) and metal ions (i.e. calcium, magnesium). Trimethoprim (TMP) was used as a non-chelating control. Addition of metal ions led to increases in MICs, whilst addition of EDTA led to decreases in MICs. The chelating effects of EDTA were reversed by addition of magnesium and most profoundly calcium. Similar effects of EDTA and calcium were observed for tetracycline (TET) and TMP. When other tetracyclines (TET, oxytetracycline (OXY) and chlortetracycline (CHL)) were used as chelators at concentrations below their MICs, TIG MICs decreased for P. aeruginosa but not for E. coli. Some decreases in TIG MICs were observed for K. pneumoniae when TET and CHL were added. A dose-dependent decrease in TIG MIC was observed for TET and was reversed by the addition of calcium. The presence of effects of EDTA and calcium on TMP MICs indicates that mechanisms outside of TIG chelation likely play a role in enhanced activity. Full characterisation of an unexpected interaction such as TIG–TET with different microorganisms could provide valuable insights into the underlying mechanisms and design of physiologically viable chelators as candidates for future combinations regimens.     

Modified translationally controlled tumor protein-derived protein transduction domain enhances nasal delivery of exendin-4 as shown with insulin

Protein transduction domains (PTDs) have been shown to promote the delivery of therapeutic proteins or peptides into the living cells. In a previous study, we showed that the double mutant of TCTP-PTD 13, TCTP-PTD 13M2, was more effective in the delivery of insulin than the wild-type TCTP-PTD 13. In this study, we applied this approach to the nasal delivery of a different peptide, exendin-4, using as carriers, several modified TCTP-PTDs, such as TCTP-PTD 13M1, 13M2, and 13M3. Nasal co-administration of TCTP-PTD 13M2 with exendin-4 showed the highest exendin-4 uptake among the three analogs in normal rats, and also decreased blood glucose levels by 43.3% compared with that of exendin-4 alone and by 18.6% compared with that of exendin-4 plus TCTP-PTD 13 in diabetic mice. We also designed an additional covalently linked conjugate of TCTP-PTD 13M2 and exendin-4 and evaluated its hypoglycemic effect after subcutaneous or intranasal delivery. Subcutaneous administration of exendin-4 that its C-terminus is covalently linked to TCTP-PTD 13M2 showed hypoglycemic effect of 42.2% compared to that in untreated group, whereas intranasal delivery was not successful in diabetic mice. We conclude that a simple mixing TCTP-PTD 13M2 with peptide/protein drugs can be potentially a generally applicable approach for intranasal delivery into animals.     

Extracellular vesicles released in response to respiratory exposures: implications for chronic disease

Extracellular vesicles (EV) are secreted signaling entities that enhance various pathological processes when released in response to cellular stresses. Respiratory exposures such as cigarette smoke and air pollution exert cellular stresses and are associated with an increased risk of several chronic diseases. The aim of this review was to examine the evidence that modifications in EV contribute to respiratory exposure-associated diseases. Publications were searched using PubMed and Google Scholar with the search terms (cigarette smoke OR tobacco smoke OR air pollution OR particulate matter) AND (extracellular vesicles OR exosomes OR microvesicles OR microparticles OR ectosomes). All original research articles were included and reviewed. Fifty articles were identified, most of which investigated the effect of respiratory exposures on EV release in vitro (25) and/or on circulating EV in human plasma (24). The majority of studies based their main observations on the relatively insensitive scatter-based flow cytometry of EV (29). EV induced by respiratory exposures were found to modulate inflammation (19), thrombosis (13), endothelial dysfunction (11), tissue remodeling (6), and angiogenesis (3). By influencing these processes, EV may play a key role in the development of cardiovascular diseases and chronic obstructive pulmonary disease and possibly lung cancer and allergic asthma. The current findings warrant additional research with improved methodologies to evaluate the contribution of respiratory exposure-induced EV to disease etiology, as well as their potential as biomarkers of exposure or risk and as novel targets for preventive or therapeutic strategies.