This study reports the development of nanoemulsions intended for intravenous administration of thalidomide (THD). The formulations were prepared by spontaneous emulsification method and optimized with respect to thalidomide (0.01-0.05%, w/w), and hydrophilic emulsifier (polysorbate 80; 0.5-4.0%, w/w) content. The formulations were evaluated concerning physical appearance and drug crystallization; droplet size; zeta potential and drug assay. Only the formulation containing 0.01% THD and 0.5% polysorbate kept its properties in a satisfactory range over the evaluated period (60 days), i.e. droplet size around 200nm, drug content around 95% and zeta potential around -30mV. The transmission electron microscopy revealed emulsion droplets almost spherical in shape confirming the results obtained by photon correlation spectroscopy. Drug crystallization observed for higher content (THD 0.05%, w/w) nanoemulsions was investigated. The crystals observed at optical microscopy presented a different crystal habit compared to that of the raw material used. It was speculated whether the kind of THD polymorph employed could influence nanoemulsion formulation. Formulations were prepared with either one of THD polymorphs (β- or α-) and crystals were characterized by fourier transformed infrared spectroscopy (FTIR) and X-ray diffraction (XRD). It was observed that regardless of the polymorph employed (β- or α-), drug crystallization occurs in the α-form. THD solubility in oils was not influenced by the polymorphic form. In addition, the in vitro dissolution profile of the selected formulation (THD 0.01%, w/w; polysorbate 0.5%, w/w) was assessed by bulk-equilibrium reverse dialysis sac technique and demonstrated a release profile similar to that of a THD acetonitrile solution, with around 95% THD being dissolved within 4h. Finally, a pharmacokinetic simulation of an intravenous infusion of 250mL of the selected nanoemulsion suggests that the parenteral administration of a dose as low as 25mg might lead to therapeutic plasma concentrations of thalidomide.
The combination of tools such as time‐kill assay with subsequent application of mathematical modeling can clarify the potential of new antimicrobial compounds, since minimal inhibitory concentration (MIC) value does not provide a very detailed characterization of antimicrobial activity. Recently, our group has reported that the 8‐hydroxy‐5‐quinolinesulfonic acid presents relevant antifungal activity. However, its intrinsic acidity could lead to an ionization process, decreasing fungal cell permeability. To overcome this potential problem and enhance activity, the purpose of this study was to synthesize and evaluate a novel series of hybrids between the 8‐hydroxyquinoline core and sulfonamide and to prove their potential using broth microdilution method, obtaining the pharmacodynamic parameters of the most active derivatives combining time‐kill studies and mathematical modeling and evaluating their toxicity. Compound 5a was the most potent, being active against all the fungal species tested, with low toxicity in normal cells. 5a and 5b have presented important antibacterial activity against Staphylococcus aureus strain. The EC50 values obtained by combination of time‐kill studies with mathematical model were similar to those of MIC, which confirms the potential of compounds. In addition, these derivatives are non‐irritant molecules with the absence of topical toxicity. Finally, 5a and 5b are promising candidates for treatment of dermatomycosis and candidiasis.
Copaiba oil is used as a popular medicine in the Amazonian forest region, especially due to its anti-inflammatory properties. In this paper, we describe the formulation of hydrogel containing copaiba oil nanoemulsions (with positive and negative charges), its skin permeation, and its anti-inflammatory activity in two in vivo models: mouse ear edema and rat paw edema. Three hydrogels were tested (Carbopol, hydroxyethylcellulose and chitosan), but only Carbopol and hydroxyethylcellulose hydrogels presented good stability and did not interfere with the nanoemulsions droplet size and polydispersity index. In skin permeation assay, both formulations, positively charged nanoemulsion (PCN) and negatively charged nanoemulsion (NCN), presented a high retention in epidermis (9.76 ± 2.65 μg/g and 7.91 ± 2.46 μg/cm, respectively) followed by a smaller retention in the dermis (2.43 ± 0.91 and 1.95 ± 0.56 μg/cm, respectively). They also presented permeation to the receptor fluid (0.67 ± 0.22 and 1.80 ± 0.85 μg/cm, respectively). In addition, anti-inflammatory effect was observed to NCN and PCN with edema inhibitions of 69 and 67% in mouse ear edema and 32 and 72% in rat paw edema, respectively. Histological cuts showed the decrease of inflammatory factors, such as dermis and epidermis hyperplasia and inflammatory cells infiltration, confirming the anti-inflammatory effect from both copaiba oil nanoemulsions incorporated in hydrogel.
A modified E max -pharmacokinetic-pharmacodynamic (PK-PD) model was previously proposed in literature for describing the antimicrobial activity of b-lactam antibiotics based on in vitro experiments. However, bacteria behave differently in vitro and in vivo. Thus, the aims of this study were to model the killing effect of piperacillin (PIP) against Escherichia coli on immunocompromised infected rats using this model and to compare the parameters obtained in vitro and in vivo for the same bacteria/drug combination. The PK-PD parameters determined in vitro and in vivo were as follows: generation rate constant of 1.30 ± 0.10 and 0.76 ± 0.20 h À1 , maximum killing effect of 3.11 ± 0.27 and 1.38 ± 0.20 h À1 and concentration to produce 50% of the maximum effect of 5.44 ± 0.03 and 1.31 ± 0.27 lg ml À1 , respectively. The comparison between the in vitro and in vivo parameters was not straightforward and had to take into consideration the intrinsic differences of the models involved. So far, the main application of the PK-PD model evaluated is for the comparison of different antimicrobial agent's potency and efficacy, under equivalent conditions.
Clioquinol was used in the 1950s‐1970s as antimicrobial but its oral formulations were withdrawn from the market due to suspected neurotoxicity. Currently, there is possibility of repositioning of oral clioquinol formulations.
To evaluate the antifungal activity and toxicological parameters of clioquinol and the other two 8‐hydroxyquinoline derivatives using alternative animal models and to study the interaction dynamic of clioquinol with Candida albicans.
We used Toll‐deficient Drosophila melanogaster to test the protective effect of 8‐hydroxyquinolines against C. albicans infection. Toxicological parameters were investigated in chicken embryo. A mathematical model‐based analysis of the time‐kill data of clioquinol was performed to obtain pharmacodynamic characteristics.
Clioquinol fully protected D. melanogaster from the infection. The 8‐hydroxyquinolines did not cause changes in opening of the beak and movement of the chicken embryo; however, clioquinol and compound 2 increased arterial pulsation. Compound 3 was lethal at 1 mg mL−1. Effective concentration found in modelling indicated that clioquinol was highly effective against C. albicans (0.306 μg mL−1) in easily achievable serum levels; clioquinol rapidly achieved kill rate reaching the maximum effect after 13 hours.
These results support the potential of clioquinol to be used as a systemic antifungal agent.
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