Antimicrobial Adjuvants - A Novel Approach to Manage Antimicrobial Resistance

Antibiotic resistance is one of the most prevalent, complex and serious global health issues, and needs to be monitored and controlled with medicine. Many approaches have been used to reduce the emergence and impact of resistance to antibiotics. The antimicrobial adjuvant approach is considered as novel, more effective and less expensive. The said approach not only suppresses the emergence of resistance but also conserves the activity of existing antibiotics by offering a promising strategy that is also complementary to the discovery of new antibiotics. This review contains an outline of the basic types of antibiotic adjuvant, their structure, the basis of their operation, their substrate antibiotics and the challenges in this field, as well as the role of potential compounds, namely β-lactamase inhibitors, efflux pump inhibitors and permeability enhancers in antibiotic resistance and their possible solutions.

Cell Barrier Characterization in Transwell Inserts by Electrical Impedance Spectroscopy

We describe an impedance-based method for cell barrier integrity testing. A four-electrode electrical impedance spectroscopy (EIS) setup can be realized by simply connecting a commercial chopstick-like electrode (STX-1) to a potentiostat allowing monitoring cell barriers cultivated in transwell inserts.Subsequent electric circuit modeling of the electrical impedance results the capacitive properties of the barrier next to the well-known transepithelial electrical resistance (TEER). The versatility of the newmethod was analyzed by the EIS analysis of a Caco-2 monolayer in response to (a) different membrane coating materials, (b) two different permeability enhancers ethylene glycol-bis(2-aminoethylether)-N,N,N’,N’-tetraacetic acid (EGTA) and saponin, and (c) sonoporation. For the different membrane coating materials, the TEERs of the standard and new protocol coincide and increase during cultivation, while the capacitance shows a distinct maximum for three different surface materials (no coating, Matrigel®, and collagen I). The permeability enhancers cause a decline in the TEER value, but only saponin alters the capacitance of the cell layer by two orders of magnitude. Hence, cell layer capacitance and TEER represent two independent properties characterizing the monolayer. The use of commercial chopstick-like electrodes to access the impedance of a barrier cultivated in transwell inserts enables remarkable insight into the behavior of the cellular barrier with no extra work for the researcher. This simple method could evolve into a standard protocol used in cell barrier research.

Applying Biopharmaceutical Classification System criteria to predict the potential effect of Cremophor® RH 40 on fexofenadine bioavailability at higher doses

Aim: To study the impact of various permeability enhancers on fexofenadine bioavailability. Furthermore, to predict the potential effect of Cremophor® RH 40 on fexofenadine pharmacokinetics at higher doses using Biopharmaceutical Classification System criteria. Experimental methods: The effect of the dose increase (60–360 mg) on the dissolution and permeability behavior of fexofenadine-Cremophor RH 40 formulations was studied in humans. The Biopharmaceutical Classification System criteria of the drug was determined. Results & conclusion: Cremophor RH 40 improved the dissolution and bioavailability of fexofenadine. The pharmacokinetics increased linearly with the dose increase. Absorption number (An) was significantly increased after addition of Cremophor RH 40 in comparison to an unprocessed drug. Similar An values were observed throughout the same dose range. The dose number (D0) values were <1 whereas, all the dissolution number (Dn) values were >1 at the same dose level.

Non-electrophilic TRPA1 agonists, menthol, carvacrol and clotrimazole, open epithelial tight junctions via TRPA1 activation

Activation of the transient receptor potential A1 channel (TRPA1) by electrophilic agonists was reported to induce the opening of tight junctions (TJs). Because compounds that increase TJ permeability can be paracellular permeability enhancers, we investigated the effect of non-electrophilic TRPA1 activators, including food ingredients (menthol and carvacrol) and medication (clotrimazole), on epithelial permeability. We show that all three compounds induced increase of the permeability of fluorescein isothiocyanate-conjugated dextran (4 kDa) and decrease of transepithelial electrical resistance, accompanied by Ca2+ influx and cofilin activation in epithelial MDCK II monolayers. These phenotypes were attenuated by pretreatment of a TRPA1 antagonist, suggesting TRPA1-mediated opening of TJs. These results suggest that non-electrophilic TRPA1 activators with established safety can be utilized to regulate epithelial barriers.

Delivery of Niacinamide to the Skin Using Microneedle-Like Particles

The stratum corneum is the outermost skin layer that obstructs the delivery of active ingredients found in cosmeceutical products. Chemical peels and microbeads have been used to overcome this layer, but these methods can cause side effects and are not environmentally friendly. While microneedles do not share the dangers mentioned above, they are currently only available as patches, which makes them unsuitable to be used with products that are usually applied onto a large area of the skin surface. Therefore, the aim of this study was to develop microneedle-like particles (MLP) whose needles would disrupt the skin during the rubbing process. A modified approach taken from conventional micromolding techniques was used to make the MLPs. The experimental results show that the fabricated structures had the required mechanical strength. Furthermore, after the application of the MLPs, the permeability of two fluorescent dyes, fluorescein sodium salt and sulforhodamine B increased to 217.6% ± 25.6% and 251.7% ± 12.8% respectively. Additionally, the permeability of a model drug, niacinamide, was shown to have increased to 193.8% ± 29.9%. Cryosectioned porcine slices also confirmed the ability of MLPs to enhance skin permeability by revealing a deeper penetration of the applied fluorescent dye. Altogether, the results demonstrate the potential of MLPs to be used as safe skin permeability enhancers that can be applied all over the skin.

Comparative research of effects of permeability enhancers on the effectiveness of model protein (insulin) administered via the inhalation route

Relevance.Inhalation administration of compounds with peptide and protein structure may be promising in provision of emergency medical assistance in emergency situations, including radiation injuries. The development of inhalation dosage forms for compounds with peptide and protein structure requires the selection of excipients to increase their bioavailability.Intention.To assess effects of permeability enhancers on the effectiveness of a model biologically active substance of protein nature (insulin) by inhalation.Methods.The experiments were carried out in outbred white male rats with initial weight of 180–220 g. To assess the effectiveness of insulin and permeability enhancers, they were administered via intranasal and intratracheal routes using a MicroSprayer® IA-2B instillation probe (Penn Century, USA). The list of biological membrane permeability enhancers under investigation (Sigma-Aldrich, USA) includes the following substances: methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, Tween-80, sodium methyl oleate, oleic acid, sodium taurocholate, sodium glycocholate, Pluronic F-68, tesit, Brij-35, saponin, cetylpyridine.Results and Discussion. Insulin bioavailability without permeability enhancers does not exceed 0.5% when administered intranasally. When assessing effects of multiple doses of permeability enhancers on food and water consumption in animals over time, decreased parameters under study were observed in the control and experimental groups compared to intact animals. Multiple intratracheal administration of solutions to rats can lead to some infectious complications.Conclusion. Such excipients as sodium taurocholate, dimethyl-β-cyclodextrin and Тween-80 in a concentration of 5 % increase bioavailability and intensity of biological effects of insulin when administered intranasally. The surfactants Brij-35, Тween-80 and sodium taurocholate in a concentration of 0.25 % increase the duration of biological effects of insulin when administered intratracheally. Sodium taurocholate and Tween-80 in a concentration of 0.25 % have the lowest toxicity during multiple intratracheal administration.