The purpose of this study was to investigate the pharmacokinetic properties of colistin following intrapulmonary administration of colistin sulfate in rats. Colistin was infused or delivered in nebulized form at a dose of 0.35 mg/kg of body weight in rats, and plasma drug concentrations were measured for 4 h after administration. Bronchoalveolar lavages (BAL) were also conducted at 0.5, 2, and 4 h after intravenous (i.v.) administration and administration via nebulized drug to estimate epithelial lining fluid (ELF) drug concentrations. Unbound colistin plasma concentrations at distribution equilibrium (2 h postdosing) were almost identical after i.v. infusion and nebulized drug inhalation. ELF drug concentrations were undetectable in BAL samples after i.v. administration, but they were about 1,800 times higher than unbound plasma drug levels at 2 h and 4 h after administration of the nebulized drug. Simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was performed with a model characterized by a fixed physiological volume of ELF ( V _ELF ), a passive diffusion clearance ( Q _ELF ) between plasma and ELF, and a nonlinear influx transfer from ELF to the central compartment, which was assessed by reducing the nebulized dose of colistin by 10-fold (0.035 mg kg ⁻¹ ). The k _m was estimated to be 133 μg ml ⁻¹ , and the V _{max, in} -to- K _m ratio was equal to 2.5 × 10 ⁻³ liter h ⁻¹ kg ⁻¹ , which was 37 times higher than the Q _ELF (6.7 × 10 ⁻⁵ liter h ⁻¹ kg ⁻¹ ). This study showed that with the higher ELF drug concentrations after administration via nebulized aerosol than after intravenous administration, for antibiotics with low permeability such as colistin, nebulization offers a real potential over intravenous administration for the treatment of pulmonary infections.

The aim of this study was to evaluate the biopharmaceutical characteristics of three fluoroquinolones (FQs), ciprofloxacin (CIP), moxifloxacin (MXF), and grepafloxacin (GRX), after delivery via a nebulized aerosol to rats. Bronchoalveolar lavages (BAL) were conducted 0.5, 2, 4, and 6 h after FQ intravenous administration and nebulized aerosol delivery to estimate epithelial lining fluid (ELF) drug concentrations. Plasma drug concentrations were also measured, and profiles of drug concentrations versus time after intravenous administration and nebulized aerosol delivery were virtually superimposable, attesting for rapid and complete systemic absorption of FQs. ELF drug concentrations were systematically higher than corresponding plasma drug concentrations, whatever the route of administration, and average ELF-to-unbound plasma drug concentration ratios post-distribution equilibrium did not change significantly between the ways of administration and were equal: 4.0 ± 5.3 for CIP, 12.6 ± 7.3 for MXF, and 19.1 ± 10.5 for GRX (means ± standard deviations). The impact of macrophage lysis on estimated ELF drug concentrations was significant for GRX but reduced for MXF and CIP; therefore, simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was only performed for the latter two drugs. The model was characterized by a fixed volume of ELF ( V _ELF ), passive diffusion clearance ( Q _ELF ), and active efflux clearance (CL _out ) between plasma and ELF, indicating active efflux transport systems. In conclusion, this study demonstrates that ELF drug concentrations of these three FQs are several times higher than plasma drug concentrations, probably due to the presence of efflux transporters at the pulmonary barrier level, but no biopharmaceutical advantage of FQ nebulization was observed compared with intravenous administration.

Plasma sources suitable to generate low temperature plasmas has been fundamental for the advances in plasma medicine. In this research field, plasma sources must comply with stringent conditions for clinical applications. The main requirement to be met is the patient and operator’s safety and the ethical requirement of effectivity, which encompasses the electrical regulations, potential device toxicity and effectiveness in relation to the desired treatment. All these issues are addressed by the German pre-standard DIN SPEC 91315:2014–06 (DINSpec), which deals with the safety limits, risk assessment and biological efficacy of plasma sources aimed for medical applications. In this work, a low cost, user-friendly and flexible atmospheric pressure plasma jet (APPJ) device was characterized following the DINSpec guidelines. The device, which is still under development, proved to be safe for medical applications. It is capable of producing an APPJ with low patient leakage current and UV emission, gas temperature lower than 40 ∘C, production of harmful gases within the safety limits and low cytotoxicity. The most differentiating feature is that the device presented good antimicrobial efficacy even operating at frequency of the order of just a few hundred Hz, a value below that of most devices reported in the literature.

The increase in the prevalence of fungal infections worldwide and the rise in the occurrence of antifungal resistance suggest that new research to discover antifungal molecules is needed. The aim of this study was to evaluate the potential use of ellagic acid–cyclodextrin complexes (EA/HP-β-CD) for the treatment of oral candidiasis. First, the effect of EA/HP-β-CD on C. albicans planktonic cells and biofilms was evaluated. Then, the cytotoxicity of the effective concentration was studied to ensure safety of in vivo testing. Finally, the in vivo effectiveness was determined by using a murine model of induced oral candidiasis. Data was statistically analyzed. The minimal inhibitory concentration of EA/HP-β-CD was 25 µg/mL and a concentration of 10 times MIC (250 µg/mL) showed an inhibitory effect on C. albicans 48 h-biofilms. The complex at concentration 250 µg/mL was classified as slightly cytotoxic. In vivo experiments showed a reduction in fungal epithelial invasion after treatment with EA/HP-β-CD for 24 h and 96 h when compared to the negative control. In conclusion, the results demonstrated that EA/HP-β-CD has antifungal and anti-inflammatory effects, reducing the invasive capacity of C. albicans, which suggests that EA/HP-β-CD may be a promising alternative for the treatment of oral candidiasis.

The aim of this study was to increase the solubility of gallic acid (GA) for the treatment of Candida albicans biofilm, which is very difficult to treat and requires high drug concentrations. Cyclodextrins (CDs) were used for this purpose. Complexes were evaluated by phase-solubility studies, prepared by spray drying and characterized by drug loading, scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). The complexes were tested on C. albicans biofilm using in vitro and in vivo models. HPβCD formed soluble inclusion complexes with GA. The percentage of GA in GA/HPβCD was 10.8 ± 0.01%. The SEM and DSC analyses confirmed the formation of inclusion complexes. GA/HPβCD maintained the antimicrobial activity of the pure GA. GA/HPβCD was effective on C. albicans biofilms of 24 and 48h. The in vivo results showed an anti-inflammatory activity of GA/HPβCD with no difference in invading hypha counting among the groups. This study encourages the development of new antifungal agents.