Will curcumin nanosystems be the next promising antiviral alternatives in COVID-19 treatment trials?

The COVID-19 has become of striking interest since the number of deaths is constantly rising all over the globe, and the search for an efficient treatment is more urgent. In light of this worrisome scenario, this opinion review aimed to discuss the current knowledge about the potential role of curcumin and its nanostructured systems on the SARS-CoV-2 targets. From this perspective, this work demonstrated that curcumin urges as a potential antiviral key for the treatment of SARS-CoV-2 based on its relation to the infection pathways. Moreover, the use of curcumin-loaded nanocarriers for increasing its bioavailability and therapeutic efficiency was highlighted. Additionally, the potential of the nanostructured systems by themselves and their synergic action with curcumin on molecular targets for viral infections have been explored. Finally, a viewpoint of the studies that need to be carried out to implant curcumin as a treatment for COVID-19 was addressed.

Influence of the freeze-drying process on the physicochemical and biological properties of pre-heated amphotericin B micellar systems.

The moderate heat treatment of amphotericin B (AmB) in its micellar form (M-AmB) results in superaggregates (H-AmB) that present a substantially lower toxicity and similar activity. The aim of this work was to evaluate the H-AmB behavior after a freeze-drying process. H-AmB and M-AmB micelles were evaluated before and after freeze-drying concerning their physicochemical and biological properties by spectrophotometry and activity/toxicity assay, respectively. Four concentrations of M-AmB and H-AmB were studied aiming to correlate their aggregation state and the respective biological behavior: 50 mg L(-1), 5 mg L(-1), 0.5 mg L(-1), and 0.05 mg L(-1). Then, potassium leakage and hemoglobin leakage from red blood cells were used to evaluate the acute and chronic toxicity, respectively. The efficacy of M-AmB and H-AmB formulations was assessed by potassium leakage from Candida albicans and by the broth microdilution method. After heating, in addition to an evident turbidity, a slight blueshift from 327 to 323 nm was also observed at the concentrations of 50 and 5 mg L(-1) for H-AmB. Additionally, an increase in the absorbance at 323 nm at the concentration of 0.5 mg L(-1) was detected. Concerning the toxicity, H-AmB caused significantly lower hemoglobin leakage than M-AmB. These results were observed for H-AmB before and after freeze-drying. However, there was no difference between H-AmB and M-AmB concerning their activity. Accordingly, the freeze-drying cycle did not show any influence on the behavior of heated formulations, highlighting the suitability of such a method to produce a new AmB product with a long shelf life and with both greater efficiency and less toxicity.

Development of oil-in-water microemulsions for the oral delivery of amphotericin B.

Amphotericin B (AmB) is a very efficient drug against serious diseases such as leishmaniasis and systemic fungal infections. However, its oral bioavailability is limited due to its poor solubility in water. Nevertheless, it is marketed as high-cost lipid parenteral formulations that may induce serious infusion-related side effects. In this study, oil-in-water (O/W) microemulsions (MEs) were developed and characterized with a view to their use as solubility enhancers and oral delivery systems for AmB. Therefore, different nonionic surfactants from the Tween(®) and Span(®) series were tested for their solubilization capacity in combination with several oils. Based on pseudoternary phase diagrams, AmB-loaded MEs with mean droplet sizes about 120 nm were successfully produced. They were able to improve the drug solubility up to 1000-fold. Rheological studies showed the MEs to be low-viscosity formulations with Newtonian behavior. Circular dichroism and absorption spectra revealed that part of the AmB in the MEs was aggregated as an AmB reservoir carrier. Cytotoxicity studies revealed limited toxicity to macrophage-like cells that may allow the formulations to be considered as suitable carriers for AmB.

Amphotericin B microemulsion reduces toxicity and maintains the efficacy as an antifungal product.

Amphotericin B remains the drug of choice for the treatment of most of the systemic fungal infections in immunodeficient patients. Because of the high incidence of adverse drug reactions the clinical use of Amphotericin B is rather limited. To reduce its toxicity new drug delivery systems has been suggested. Nevertheless, these carriers present several technological drawbacks that impair the development of a marketable product. The aim of this work was to develop an Amphotericin B microemulsion in order to increase its efficacy and decrease its toxicity compared to Fungizon, the widely know inexpensive micellar system of Amphotericin B. Amphotericin B loaded microemulsion showed an average size close to 300 nm by photon correlation spectroscopy. In the UV spectrum, the observation of the monomeric peak at 405 nm, which was independent of the sample dilution, revealed that the Amphotericin B molecules were strongly and individually bound to the microemulsion droplets. The new microemulsion formulation had the same efficacy than Fungizon against C. albicans. Concerning toxicity, Amphotericin B loaded microemulsion showed lower toxicity against human red blood cells compared to the commercial product. Taken together, these results suggested that microemulsion is an eligible drug carrier for Amphotericin B or other water insoluble molecules, and it has potential applications to targeting fungal cells. Additionally, a novel formulation of Amphotericin B-loaded microemulsion was prepared by a straightforward and fast procedure.

Adolescents: contraceptive knowledge and use, a Brazilian study.

The purpose of this study was to identify the knowledge and use of contraceptive methods by female adolescent students. The study was cross-sectional and quantitative, using a semi-structured questionnaire that was administered to 12- to 19-year-old female students in Maceió, Brazil. A representative and randomized sample was calculated, taking into account the number of hospital admissions for curettage. This study was approved by the Human Research Ethics Committee, and Epi Info software was used for data and result evaluation using the mean and chi-square statistical test. Our results show that the majority of students know of some contraceptive methods (95.5%), with the barrier/hormonal methods being the most mentioned (72.4%). Abortion and aborting drugs were inaccurately described as contraceptives, and 37.9% of the sexually active girls did not make use of any method. The barrier methods were the most used (35.85%). A significant association was found in the total sample (2,592) between pregnancy and the use of any contraceptive method. This association was not found, however, in the group having an active sexual life (559). The study points to a knowledge of contraceptive methods, especially by teenagers who have already been pregnant, but contraceptives were not adequately used. The low use of chemical methods of contraception brings the risk of pregnancy. Since abortion and aborting drugs were incorrectly cited as contraceptive methods, this implies a nonpreventive attitude towards pregnancy.

Development of superparamagnetic microparticles for biotechnological purposes.

Aqueous suspensions containing magnetic microparticles have been increasingly used in biosciences and biotechnology. This work describes an experimental procedure to produce superparamagnetic microparticles. The particles were prepared based on the coprecipitation of iron salts in alkaline medium. Afterwards, characterization was performed. Characterization data demonstrated that magnetite was the dominant phase in the analyzed sample, and 50% of them were in the size range of 0.5-5 microm. The results suggest that the experimental protocol provided a simple synthesis route to produce superparamagnetic microparticles. Such properties may be very useful for biotechnological purposes.

Influence of a lipophilic drug on the stability of emulsions: an important approach on the development of lipidic carriers.

The aim of this work was to investigate the influence of a lipophilic drug, Ibuprofen, on the stability of o/w emulsions. Five formulations were prepared by the phase inversion temperature (PIT) method, and Ibuprofen was incorporated into their oil phase. Emulsion stability was evaluated by short- and long-term studies. Concerning the former, stability under centrifugation showed an improved profile for Ibuprofen-loaded emulsions. The latter confirmed such findings. In conclusion, a rather resistant interfacial film may take place when Ibuprofen was incorporated into the emulsions. Therefore, the critical hydrophilic-lipophilic-balance (HLB) of o/w emulsions can be affected by a lipophilic drug into their oil phase. Such approach is of great importance on the development of lipid carriers for therapeutic drug targeting.

Synthesis and characterization of xylan-coated magnetite microparticles.

This work evaluates an experimental set-up to coat superparamagnetic particles in order to protect them from gastric dissolution. First, magnetic particles were produced by coprecipitation of iron salts in alkaline medium. Afterwards, an emulsification/cross-linking reaction was carried out in order to produce magnetic polymeric particles. The sample characterization was performed by X-ray powder diffraction, laser scattering particle size analysis, optical microscopy, thermogravimetric analysis and vibrating sample magnetometry. In vitro dissolution tests at gastric pH were evaluated for both magnetic particles and magnetic polymeric particles. The characterization data have demonstrated the feasibility of the presented method to coat, and protect magnetite particles from gastric dissolution. Such systems may be very promising for oral administration.

Safety concerns related to magnetic field exposure.

The recent development of superconducting magnets has resulted in a huge increase in human exposure to very large static magnetic fields of up to several teslas (T). Considering the rapid advances in applications and the great increases in the strength of magnetic fields used, especially in magnetic resonance imaging, safety concerns about magnetic field exposure have become a key issue. This paper points out some of these safety concerns and gives an overview of the findings about this theme, focusing mainly on mechanisms of magnetic field interaction with living organisms and the consequent effects.

Micro-emultocrit technique: a valuable tool for determination of critical HLB value of emulsions.

The aim of this work was to develop a methodology for rapid determination of the critical hydrophilic-lipophilic balance (HLB) value of lipophilic fractions of emulsions. The emulsions were prepared by the spontaneous emulsification process with HLB value from 4.3 to 16.7. The preparations were stored at 2 different temperatures (25 degrees C and 4 degrees C) and their physicochemical behavior was evaluated by the micro-emultocrit technique and the long-term stability study. The experimental data show a reverse relationship between HLB values of the surfactant mixtures and emulsion stability. A close correlation between the results for both stability procedures was observed, suggesting the use of micro-emultocrit to predict stabilities of such systems. In addition, it was found that the critical HLB of the Mygliol 812 was 15.367.

Micro-emultocrit technique: A valuable tool for determination of critical HLB value of emulsions.

The aim of this work was to develop a methodology for rapid determination of the critical hydrophilic-lipophilic balance (HLB) value of lipophilic fractions of emulsions. The emulsions were prepared by the spontaneous emulsification process with HLB value from 4.3 to 16.7. The preparations were stored at 2 different temperatures (25°C and 4°C) and their physicochemical behavior was evaluated by the micro-emultocrit technique and the long-term stability study. The experimental data show a reverse relationship between HLB values of the surfactant mixtures and emulsion stability. A close correlation between the results for both stability procedures was observed, suggesting the use of micro-emultocrit to predict stabilities of such systems. In addition, it was found that the critical HLB of the Mygliol 812 was 15.367.

Similarity between the in vitro activity and toxicity of two different Fungizone/Lipofundin admixtures.

PURPOSE: Amphotericin B (AmB), an antifungal agent that presents a broad spectrum of activity, remains the gold standard in the antifungal therapy. However, sometimes the high level of toxicity forbids its clinical use. The aim of this work was to evaluate and compare the efficacy and toxicity in vitro of Fungizon (AmB-D) and two new different AmB formulations. METHODS: three products were studied: Fungizon, and two Fungizon /Lipofundin admixtures, which were diluted through two methods: in the first one, Fungizon was previously diluted with water for injection and then, in Lipofundin (AmB-DAL); the second method consisted of a primary dilution of AmB-D as a powder in the referred emulsion (AmB-DL). For the in vitro assay, two cell models were used: Red Blood Cells (RBC) from human donors and Candida tropicallis (Ct). The in vitro evaluation (K+ leakage, hemoglobin leakage and cell survival rate-CSR) was performed at four AmB concentrations (from 50 to 0.05 mg x L(-1)). RESULTS: The results showed that the action of AmB was not only concentration dependent, but also cellular type and vehicle kind dependent. At AmB concentrations of 50 mg x L(-1), although the hemoglobin leakage for AmB-D was almost complete (99.51), for AmB-DAL and AmB-DL this value tended to zero. The p = 0.000 showed that AmB-D was significantly more hemolytic. CONCLUSION: The Fungizon-Lipofundin admixtures seem to be the more valuable AmB carrier systems due to their best therapeutic index presented.

Similarity between the in vitro activity and toxicity of two different fungizone™ / lipofundin™ admixtures

OBJETIVO: A anfotericina B é um agente antifúngico de largo espectro bastante empregado na terapia antifúngica. Entretanto, esta molécula apresenta um alto nível de toxicidade que, na maioria das vezes, impede o seu uso contínuo na terapêutica médica. O objetivo deste artigo foi comparar a eficácia e a toxicidade in vitro do Fungizon™ (AmB-D) e de dois sistemas carreadores de AmB. MÉTODOS: Três produtos foram avaliados: o Fungizon™ , e dois sistemas oriundos da mistura entre o Fungizon™ e o Lipofundin™ , uma emulsão de uso parenteral. Tais sistemas foram obtidos por duas técnicas: Na primeira diluiu-se previamanete o Fungizon™ com água para injetáveis e em seguida inseriu-se o Lipofundin™ (AmB-DAL); o segundo método consistiu na diluíção extemporânea do Fungizon™ com a referida emulsão (AmB-DL). Dois modelos celulares foram empregados no estudo: os eritrócitos (RBC) oriundos de doadores humanos e a Candida tropicalis (Ct). A avaliação in vitro (liberação de K+ e hemoglobina, e o índice de sobrevivência celular-CSR) foi realizado com quatro concentrações de AmB (entre 50 e 0.05mg.L-1). RESULTADOS: Os resultados demonstram que a ação da AmB não só foi dependente da concentração como também variou de acordo com o modelo celular e o veículo que diluiu o Fungizon™ . Nas concentrações de 50 mg.L-1, apesar da liberação de hemoglobina ser quase que total para AmB-D (99.51), para a AmB-DAL e AmB-DL este valor tendeu a zero. Um p = 0.000 demonstrou que AmB-D foi significativamente mais hemolítico. CONCLUSÃO: A mistura Fungizon™ -Lipofundin™ aparenta ser um bom sistema para carrear a AmB tendo em vista seu elevado índice terapêutico demonstrado.

Evaluation of the relationship of the molecular aggregation state of amphotericin B in medium to its genotoxic potential.

This work analyzes the genotoxicity potential, in the G2 phase of the cellular cycle, of an amphotericin B (AmB) commercially available form (Fungizone), and correlates it with the physicochemical properties of this product in aqueous media. The genotoxic studies were performed using peripheral blood lymphocytes from human donors. The chromosome aberrations and mitotic index were determined. Absorption spectra of Fungizone were obtained by dispersion of the stock solution in water for injection at various AmB concentrations, and using different cuvette path lengths for spectrophotometric determination. The absorption spectra of Fungizone in water are concentration dependent. High concentrations of Fungizone present a spectrum with an intense band at 340 nm, characteristic of AmB self-association. Conversely, at low concentrations, the spectra are similar to those obtained with AmB in methanol, with a positive band at 409 nm, assigned to AmB monomeric form. Similarly, the cytogenetic analysis shows an important decrease on the mitotic index, which is also concentration dependent when compared with control. Furthermore, the chromosome aberrations present a small, not statistically significant, increase only at the highest concentration. The results suggest that the Fungizone presents a cytotoxicity similar to membrane pore formation in mammalian cells that depends on the existence of self-associated AmB. In the presence of only monomeric forms, this phenomenon disappears. However, no genotoxicity was observed in this study.

Amphotericin B/emulsion admixture interactions: an approach concerning the reduction of amphotericin B toxicity.

Mixing Fungizone with a fat emulsion used for nutritional purpose (Intralipid or Lipofundin ) was reported to decrease Amphotericin B (AmB) toxicity in clinical use. In an effort to understand the reason for this phenomenon, spectral and morphological analyses were done for the Fungizone and Fungizone /Lipofundin admixture (FLmix). The absorption spectra analyses showed that not only Fungizone but also FLmix presented spectra that were concentration dependent. Moreover, the spectra of FLmix remained stable until the concentration of 5 x 10(-7) M, and only at 5 x 10(-8) M did they become similar in shape to the Fungizone spectra. Morphological studies revealed that even though emulsion droplets with or without Fungizone presented the same particle size, the former was less electron dense compared with Lipofundin alone. These results suggest a kind of association between Fungizoneand Lipofundin that remains over the whole range of concentrations. This hypothesis was confirmed by in vitro studies in which FLmix presented an important selectivity against human and fungal cells compared with Fungizone. These findings suggest that parenteral emulsions should be able to reduce the AmB toxicity probably by changing the AmB self-association state by binding it with emulsion droplets.