New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies.

Cancer is a complex multifactorial disease whose pathophysiology involves multiple metabolic pathways, including the ubiquitin-proteasome system, for which several proteasome inhibitors have already been approved for clinical use. However, the resistance to existing therapies and the occurrence of severe adverse effects is still a concern. The purpose of this study was the discovery of novel scaffolds of proteasome inhibitors with anticancer activity, aiming to overcome the limitations of the existing proteasome inhibitors. Thus, a structure-based virtual screening protocol was developed using the structure of the human 20S proteasome, and 246 compounds from virtual databases were selected for in vitro evaluation, namely proteasome inhibition assays and cell viability assays. Compound 4 (JHG58) was shortlisted as the best hit compound based on its potential in terms of proteasome inhibitory activity and its ability to induce cell death (both with IC50 values in the low micromolar range). Molecular docking studies revealed that compound 4 interacts with key residues, namely with the catalytic Thr1, Ala20, Thr21, Lys33, and Asp125 at the chymotrypsin-like catalytic active site. The hit compound is a good candidate for additional optimization through a hit-to-lead campaign.

Innovative Aqueous Nanoemulsion Prepared by Phase Inversion Emulsification with Exceptional Homogeneity.

Formulating low-solubility or low-permeability drugs is a challenge, particularly with the low administration volumes required in intranasal drug delivery. Nanoemulsions (NE) can solve both issues, but their production and physical stability can be challenging, particularly when a high proportion of lipids is necessary. Hence, the aim of the present work was to develop a NE with good solubilization capacity for lipophilic drugs like simvastatin and able to promote the absorption of drugs with low permeability like fosphenytoin. Compositions with high proportion of two lipids were screened and characterized. Surprisingly, one of the compositions did not require high energy methods for high droplet size homogeneity. To better understand formulation factors important for this feature, several related compositions were evaluated, and their relative cytotoxicity was screened. Optimized compositions contained a high proportion of propylene glycol monocaprylate NF, formed very homogenous NE using a low-energy phase inversion method, solubilized simvastatin at high drug strength, and promoted a faster intranasal absorption of the hydrophilic prodrug fosphenytoin. Hence, a new highly homogeneous NE obtained by a simple low-energy method was successfully developed, which is a potential alternative for industrial application for the solubilization and protection of lipophilic actives, as well as (co-)administration of hydrophilic molecules.

Nose-to-brain delivery of perampanel formulated in a self-microemulsifying drug delivery system improves anticonvulsant and anxiolytic activity in mice.

Perampanel (PER) is a potent third-generation antiepileptic drug only available for oral administration. Additionally, PER has shown potential in managing epilepsy comorbidities such as anxiety. Previously, we demonstrated that the intranasal (IN) administration of PER, loaded in a self-microemulsifying drug delivery system (SMEDDS), improved brain-targeting and exposure in mice. Herein, we investigated PER brain biodistribution, its anticonvulsant and anxiolytic effects, and its potential olfactory and neuromotor toxicity after IN administration to mice (1 mg/kg). PER showed a rostral-caudal brain biodistribution pattern when administered intranasally. At short times post-nasal dosing, high PER concentrations were found in olfactory bulbs (olfactory bulbs/plasma ratios of 1.266 ± 0.183 and 0.181 ± 0.027 after IN and intravenous administrations, respectively), suggesting that a fraction of the drug directly reaches brain through the olfactory pathway. In the maximal electroshock seizure test, IN PER protected 60% of mice against seizure development, a substantially higher value than the 20% protected after receiving oral PER. PER also demonstrated anxiolytic effects in open field and elevated plus maze tests. Buried food-seeking test showed no signs of olfactory toxicity. Neuromotor impairment was found in rotarod and open field tests at the times of PER maximum concentrations after IN and oral administrations. Nevertheless, neuromotor performance was improved after repeated administrations. Compared with IN vehicle, PER IN administration decreased brain levels of L-glutamate (0.91 ± 0.13 mg/mL vs 0.64 ± 0.12 mg/mL) and nitric oxide (100 ± 15.62% vs 56.62 ± 4.95%), without interfering in GABA levels. Altogether, these results suggest that the IN PER delivery through the developed SMEDDS can be a safe and promising alternative to the oral treatment, which supports the design of clinical studies to evaluate the IN PER delivery to treat epilepsy and neurological-related conditions as anxiety.

Intranasal Microemulsion as an Innovative and Promising Alternative to the Oral Route in Improving Stiripentol Brain Targeting.

Stiripentol (STP) is a new-generation antiepileptic only available for oral administration. However, it is extremely unstable in acidic environments and undergoes gastrointestinal slow and incomplete dissolution. Thus, STP intranasal (IN) administration might overcome the high oral doses required to achieve therapeutic concentrations. An IN microemulsion and two variations were herein developed: the first contained a simpler external phase (FS6); the second one 0.25% of chitosan (FS6 + 0.25%CH); and the last 0.25% chitosan plus 1% albumin (FS6 + 0.25%CH + 1%BSA). STP pharmacokinetic profiles in mice were compared after IN (12.5 mg/kg), intravenous (12.5 mg/kg), and oral (100 mg/kg) administrations. All microemulsions homogeneously formed droplets with mean sizes ≤16 nm and pH between 5.5 and 6.2. Compared with oral route, IN FS6 resulted in a 37.4-fold and 110.6-fold increase of STP plasmatic and brain maximum concentrations, respectively. Eight hours after FS6 + 0.25%CH + 1%BSA administration, a second STP brain concentration peak was observed with STP targeting efficiency being 116.9% and direct-transport percentage 14.5%, suggesting that albumin may potentiate a direct STP brain transport. The relative systemic bioavailability was 947% (FS6), 893% (FS6 + 0.25%CH), and 1054% (FS6 + 0.25%CH + 1%BSA). Overall, STP IN administration using the developed microemulsions and significantly lower doses than those orally administrated might be a promising alternative to be clinically tested.

Fighting Epilepsy with Nanomedicines-Is This the Right Weapon?

Epilepsy is a chronic and complex condition and is one of the most common neurological diseases, affecting about 50 million people worldwide. Pharmacological therapy has been, and is likely to remain, the main treatment approach for this disease. Although a large number of new antiseizure drugs (ASDs) has been introduced into the market in the last few years, many patients suffer from uncontrolled seizures, demanding the development of more effective therapies. Nanomedicines have emerged as a promising approach to deliver drugs to the brain, potentiating their therapeutic index. Moreover, nanomedicine has applied the knowledge of nanoscience, not only in disease treatment but also in prevention and diagnosis. In the current review, the general features and therapeutic management of epilepsy will be addressed, as well as the main barriers to overcome to obtain better antiseizure therapies. Furthermore, the role of nanomedicines as a valuable tool to selectively deliver drugs will be discussed, considering the ability of nanocarriers to deal with the less favourable physical-chemical properties of some ASDs, enhance their brain penetration, reduce the adverse effects, and circumvent the concerning drug resistance.

An Insight into Symmetrical Cyanine Dyes as Promising Selective Antiproliferative Agents in Caco-2 Colorectal Cancer Cells.

Cancer remains one of the diseases with the highest worldwide incidence. Several cytotoxic approaches have been used over the years to overcome this public health threat, such as chemotherapy, radiotherapy, and photodynamic therapy (PDT). Cyanine dyes are a class of compounds that have been extensively studied as PDT sensitisers; nevertheless, their antiproliferative potential in the absence of a light source has been scarcely explored. Herein, the synthesis of eighteen symmetric mono-, tri-, and heptamethine cyanine dyes and their evaluation as potential anticancer agents is described. The influences of the heterocyclic nature, counterion, and methine chain length on the antiproliferative effects and selectivities were analysed, and relevant structure-activity relationship data were gathered. The impact of light on the cytotoxic activity of the most promising dye was also assessed and discussed. Most of the monomethine and trimethine cyanine dyes under study demonstrated a high antiproliferative effect on human tumour cell lines of colorectal (Caco-2), breast (MCF-7), and prostate (PC-3) cancer at the initial screening (10 µM). However, concentration-viability curves showed higher potency and selectivity for the Caco-2 cell line. A monomethine cyanine dye derived from benzoxazole was the most promising compound (IC50 for Caco-2 = 0.67 µM and a selectivity index of 20.9 for Caco-2 versus normal human dermal fibroblasts (NHDF)) and led to Caco-2 cell cycle arrest at the G0/G1 phase. Complementary in silico studies predicted good intestinal absorption and oral bioavailability for this cyanine dye.

Self-Emulsifying Drug Delivery Systems: An Alternative Approach to Improve Brain Bioavailability of Poorly Water-Soluble Drugs through Intranasal Administration.

Efforts in discovering new and effective neurotherapeutics are made daily, although most fail to reach clinical trials. The main reason is their poor bioavailability, related to poor aqueous solubility, limited permeability through biological membranes, and the hepatic first-pass metabolism. Nevertheless, crossing the blood-brain barrier is the major drawback associated with brain drug delivery. To overcome it, intranasal administration has become more attractive, in some cases even surpassing the oral route. The unique anatomical features of the nasal cavity allow partial direct drug delivery to the brain, circumventing the blood-brain barrier. Systemic absorption through the nasal cavity also avoids the hepatic first-pass metabolism, increasing the systemic bioavailability of highly metabolized entities. Nevertheless, most neurotherapeutics present physicochemical characteristics that require them to be formulated in lipidic nanosystems as self-emulsifying drug delivery systems (SEDDS). These are isotropic mixtures of oils, surfactants, and co-surfactants that, after aqueous dilution, generate micro or nanoemulsions loading high concentrations of lipophilic drugs. SEDDS should overcome drug precipitation in absorption sites, increase their permeation through absorptive membranes, and enhance the stability of labile drugs against enzymatic activity. Thus, combining the advantages of SEDDS and those of the intranasal route for brain delivery, an increase in drugs' brain targeting and bioavailability could be expected. This review deeply characterizes SEDDS as a lipidic nanosystem, gathering important information regarding the mechanisms associated with the intranasal delivery of drugs loaded in SEDDS. In the end, in vivo results after SEDDS intranasal or oral administration are discussed, globally revealing their efficacy in comparison with common solutions or suspensions.

Taxifolin and Lucidin as Potential E6 Protein Inhibitors: p53 Function Re-Establishment and Apoptosis Induction in Cervical Cancer Cells.

Cervical cancer is the fourth leading cause of death in women worldwide, with 99% of cases associated with a human papillomavirus (HPV) infection. Given that HPV prophylactic vaccines do not exert a therapeutic effect in individuals previously infected, have low coverage of all HPV types, and have poor accessibility in developing countries, it is unlikely that HPV-associated cancers will be eradicated in the coming years. Therefore, there is an emerging need for the development of anti-HPV drugs. Considering HPV E6's oncogenic role, this protein has been proposed as a relevant target for cancer treatment. In the present work, we employed in silico tools to discover potential E6 inhibitors, as well as biochemical and cellular assays to understand the action of selected compounds in HPV-positive cells (Caski and HeLa) vs. HPV-negative (C33A) and non-carcinogenic (NHEK) cell lines. In fact, by molecular docking and molecular dynamics simulations, we found three phenolic compounds able to dock in the E6AP binding pocket of the E6 protein. In particular, lucidin and taxifolin were able to inhibit E6-mediated p53 degradation, selectively reduce the viability, and induce apoptosis in HPV-positive cells. Altogether, our data can be relevant for discovering promising leads for the development of specific anti-HPV drugs.

Intranasal delivery of lipid-based nanosystems as a promising approach for brain targeting of the new-generation antiepileptic drug perampanel.

Perampanel (PER), a new-generation antiepileptic drug effective against different types of seizures, has already demonstrated a potential in status epilepticus therapy. Considering the growing interest of intranasal (IN) administration for nose-to-brain delivery, PER could be envisioned as a good candidate for this route, especially if formulated in a lipid-based nanosystem. With that purpose, a hydrophobic formulation (FO1.2) and a self-microemulsifying drug delivery system (SMEDDS) (FH5) loaded with PER were developed and characterized. Following PER IN administration (1 mg/kg) to mice, its pharmacokinetics was characterized and compared with intravenous and oral routes. Histopathological toxicity was also examined after a 7-day repeated dose study. FH5 homogeneously formed nanodroplets upon dispersion (20.07 ± 0.03 nm), showing a sustained in vitro PER release profile up to 4 h. By IN route, PER brain delivery was more extensive with FH5 (Cmax and AUC of 52.32 ng/g and 190.35 ng.h/g for FO1.2; 93.87 ng/g and 257.75 ng.h/g for FH5). Maximum brain concentration and total brain exposure were higher than those obtained after oral dosage, with maximum PER concentrations reached significantly faster than post-oral administration (15 min vs 2 h). An improvement in PER plasmatic concentration was also obtained, demonstrated by high relative bioavailability values (134.1% for FH5 and 107.8% for FO1.2). PER absolute plasma bioavailability after IN delivery was 55.5% for FH5 and 44.6% for FO1.2, ensuring a somewhat improved targeting of PER to the brain by the IN route compared to the IV route. No signs of toxicity were found by histopathologic evaluation. Results suggest that IN administration of PER might be a feasible and safe approach for acute and chronic epilepsy management, especially using delivery systems as SMEDDS.

Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs.

Intranasal administration is a promising route for brain drug delivery. However, it can be difficult to formulate drugs that have low water solubility into high strength intranasal solutions. Hence, the purpose of this work was to review the strategies that have been used to increase drug strength in intranasal liquid formulations. Three main groups of strategies are: the use of solubilizers (change in pH, complexation and the use cosolvents/surfactants); incorporation of the drugs into a carrier nanosystem; modifications of the molecules themselves (use of salts or hydrophilic prodrugs). The use of high amounts of cosolvents and/or surfactants and pH decrease below 4 usually lead to local adverse effects, such as nasal and upper respiratory tract irritation. Cyclodextrins and (many) different carrier nanosystems, on the other hand, could be safer for intranasal administration at reasonably high concentrations, depending on selected excipients and their dose. While added attributes such as enhanced permeation, sustained delivery, or increased direct brain transport could be achieved, a great effort of optimization will be required. On the other hand, hydrophilic prodrugs, whether co-administered with a converting enzyme or not, can be used at very high concentrations, and have resulted in a fast prodrug to parent drug conversion and led to high brain drug levels. Nevertheless, the choice of which strategy to use will always depend on the characteristics of the drug and must be a case-by-case approach.

10ß-Hydroxyestra-1,4-diene-3,17-dione as potential antiproliferative agent: in vitro biological evaluation and in silico studies.

10ß-Hydroxyestra-1,4-diene-3,17-dione (HEDD) is a natural product described as having neuroprotective activity. However, the cytotoxic properties of this quinol are barely studied. Thus, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed in six cell lines (MCF-7, T47-D, LNCaP, HepaRG, Caco-2 and NHDF). Additionally, an in vitro estrogenicity assay and a cell viability analysis together with in silico molecular docking studies were carried out in order to understand the potential mechanism of cytotoxicity. Computational predictions of its pharmacokinetic and toxicity properties were also performed. Surprisingly, HEDD displayed marked cytotoxic activity, particularly against hormone-dependent cancer cells and the flow cytometry analysis revealed that HEDD markedly reduced the viability of hepatic cancer cells. Molecular docking studies suggested a high affinity towards the estrogen receptor α and 17ß-hydroxysteroid dehydrogenase type 1. Moreover, it was predicted that HEDD may have good oral bioavailability and a low maximum tolerated dose in humans.

Picolylamine-functionalized benz[e]indole squaraine dyes: Synthetic approach, characterization and in vitro efficacy as potential anticancer phototherapeutic agents.

Squaraine dyes are a family of compounds known for their relevant photophysical and photochemical properties potentially useful as photosensitizing agents. Since pyridines have been introduced into the skeleton of several families of compounds to enhance their pharmacological activity, and this approach had not yet been performed on squaraines, novel dyes derived from benz[e]indole functionalized with picolyl- and dipicolylamine and N-ethyl and -hexyl chains were designed and synthesized. After being fully characterized, their interaction with human albumin was in vitro and in silico evaluated. Dyes were further assessed for their phototoxicity activity, and the most interesting ones were studied regarding cell localization and induction of morphological cell changes, genotoxicity, apoptosis and cell cycle arrest. The molecules with N-ethyl chains showed the greatest in vitro light-dependent cytotoxic effects, particularly the zwitterionic squaraine dye and the one bearing a single pyridine unit, which also exhibited a more significant interaction with human albumin. Phenotypically, the cells incubated with these squaraines became smaller and rounded after irradiation, the effects varying with the tested concentration. Genotoxic effects were observed even without irradiation, being more evident for the N-ethyl picolylamine-derived dye. The fluorescence emitted by Rhodamine 123 largely coincided with that emitted by the dyes, suggesting that they are found preferentially in mitochondria. After irradiation, an increase in the subG1 population was verified by propidium iodide-staining analysis by flow cytometry, indicative of cell death by apoptosis.

New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies.

The interest in the introduction of the oxime group in molecules aiming to improve their biological effects is increasing. This work aimed to develop new steroidal oximes of the estrane series with potential antitumor interest. For this, several oximes were synthesized by reaction of hydroxylamine with the 17-ketone of estrone derivatives. Then, their cytotoxicity was evaluated in six cell lines. An estrogenicity assay, a cell cycle distribution analysis and a fluorescence microscopy study with Hoechst 3358 staining were performed with the most promising compound. In addition, molecular docking studies against estrogen receptor α, steroid sulfatase, 17ß-hydroxysteroid dehydrogenase type 1 and ß-tubulin were also accomplished. The 2-nitroestrone oxime showed higher cytotoxicity than the parent compound on MCF-7 cancer cells. Furthermore, the oximes bearing halogen groups in A-ring evidenced selectivity for HepaRG cells. Remarkably, the Δ9,11-estrone oxime was the most cytotoxic and arrested LNCaP cells in the G2/M phase. Fluorescence microscopy studies showed the presence of condensed DNA typical of prophase and condensed and fragmented nuclei characteristic of apoptosis. However, this oxime promoted the proliferation of T47-D cells. Interestingly, molecular docking studies estimated a strong interaction between Δ9,11-estrone oxime and estrogen receptor α and ß-tubulin, which may account for the described effects.

Nose-to-brain delivery of phenytoin and its hydrophilic prodrug fosphenytoin combined in a microemulsion - formulation development and in vivo pharmacokinetics.

Phenytoin is a low aqueous solubility antiepileptic drug, but its phosphate ester prodrug fosphenytoin is soluble, although less permeable. In a previous study, the intranasal administration of aqueous-based formulations of fosphenytoin led to high but delayed phenytoin bioavailability compared to the intravenous route. In this work, we hypothesized that formulating an association of the prodrug fosphenytoin and the drug phenytoin (the active and diffusible form), could result in a faster and/or more effective brain targeting. Hence, nano or microemulsions containing both active drug and prodrug were developed and characterized regarding viscosity, osmolality, pH, mean size and in vitro drug release. Then, in vivo pharmacokinetics of a selected microemulsion containing fosphenytoin and phenytoin was evaluated in mice following intranasal administration and compared with a similar microemulsion containing fosphenytoin only. Both microemulsions led to higher brain drug levels at short time points than previously developed simpler aqueous based fosphenytoin formulations, likely due to the microemulsion's permeation enhancing effect. In addition, having a small amount of phenytoin in the formulation led to an equivalent maximum brain drug concentration and an overall higher absolute bioavailability, with a prolonged drug exposure. Hence, it can be concluded that if there is a need for a fast and prolonged therapeutic effect, a drug/phosphate ester prodrug combination in a microemulsion is ideal, but if a fast effect is all that is needed, having the prodrug alone could be enough, while considering a formulation with permeation enhancing components.

Antimicrobial and antitumor activity of S-methyl dithiocarbazate Schiff base zinc(II) complexes.

Schiff bases (SB) obtained from S-methyl dithiocarbazate and aromatic aldehydes: salicylaldehyde (H2L1), o-vanillin (H2L2), pyridoxal (H2L3) and 2,6-diformyl-4-methylphenol (H3L4), and their corresponding Zn(II)-complexes (1-4), are synthesized. All compounds are characterized by elemental analyses, infrared, UV-Vis, nuclear magnetic resonance spectroscopy and mass spectrometry. The structures of H2L2 and [Zn2(L1)2(H2O)(DMF)] (1a) (DMF = dimethylformamide) are solved by single crystal X-ray diffraction. The SB coordinates the metal center through the Ophenolate, Nimine and Sthiolate atoms. The radical scavenging activity is tested using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, with all ligand precursors showing IC50 values ~40 µM. Cytotoxicity studies with several tumor cell lines (PC-3, MCF-7 and Caco-2) as well as a non-tumoral cell line (NHDF) are reported. Interestingly, 1 has relevant and selective antiproliferative effect against Caco-2 cells (IC50 = 9.1 µM). Their antimicrobial activity is evaluated in five bacterial strains (Klebsiella pneumoniae, Acinetobacter baumannii, Listeria monocytogenes, Pseudomonas aeruginosa and Staphylococcus aureus) and two yeast strains (Candida albicans and Candida tropicalis) with some compounds showing bacteriostatic and fungicidal activity. The minimal inhibitory concentration (MIC90) of HnL against Mycobacterium tuberculosis is also reported, with H2L2 and H3L4 showing very high activity (MIC90 < 0.6 µg/mL). The ability of the compounds to bind bovine serum albumin (BSA) and DNA is evaluated for H3L4 and [Zn2(L4)(CH3COO)] (4), both showing high binding constants to BSA (ca. 106 M-1) and ability to bind DNA. Overall, the reported compounds show relevant antitumor and antimicrobial properties, our data indicating they may be promising compounds in several fields of medicinal chemistry.

Intranasal fosphenytoin: The promise of phosphate esters in nose-to-brain delivery of poorly soluble drugs.

Intranasal administration could increase both safety and efficacy of drugs acting on the central nervous system, but low solubility severely limits administration through this route. Phenytoin's prodrug, fosphenytoin, is hydrophilic and freely soluble in water, but less permeable since it is dianionic. We aimed to assess whether this phosphoester prodrug could be a suitable alternative to phenytoin in intranasal delivery. Secondly, we aimed to compare simple formulation strategies in fosphenytoin delivery. Fosphenytoin formulations containing thermosensitive and/or mucoadhesive (hydroxypropyl methylcellulose, HPMC) polymers were developed, guided by viscosity, gelling temperatures, osmolality, and in vitro drug release tests. Then, a pharmacokinetic study was performed, comparing an intravenous fosphenytoin solution, an intranasal fosphenytoin solution, and intranasal fosphenytoin mucoadhesive formulations with or without albumin. Formulations containing HPMC allowed high drug strengths, and had a relatively fast release profile, which was not changed by albumin. Intranasal administration of a formulation with HPMC and albumin prolonged drug concentration over time and led to complete or even increased absolute bioavailability. Moreover, phenytoin's blood levels did not reach the high peak obtained with intravenous administration. In conclusion, the use of phosphate ester prodrugs could be an efficient and safe strategy to increase the intranasal bioavailability of poorly soluble drugs.

Nanoemulsions and thermosensitive nanoemulgels of phenytoin and fosphenytoin for intranasal administration: Formulation development and in vitro characterization.

Phenytoin is a low solubility anticonvulsant drug. It has, nonetheless, other possible therapeutic indications, such as neuropathic pain, including trigeminal neuralgia, or wound healing. Its use has decreased due to side effects, but nasal/intranasal administration could significantly increase drug safety and efficacy. The aim of this work was to develop and study nanoemulsions and thermosensitive nanoemulgels of phenytoin and fosphenytoin, in combination, for intranasal administration, with immediate and sustained release profiles. Nanoemulsions were prepared by adding the aqueous phase, containing gelling polymers in the case of nanoemulgels, to emulsion preconcentrates, followed, in the optimized procedure, by premix membrane emulsification. Formulation design and optimization was guided by drug strength, rheological behavior, osmolality, mean droplet size and polydispersity. Fosphenytoin interfered significantly with Carbopol but not with Pluronic's gelation, and allowed to achieve drug strengths equivalent to 22 or 27 mg/g of phenytoin in lead nanoemulsions, and 16.7 mg/g of phenytoin in the lead nanoemulgel. The final selected low viscosity nanoemulsions had an immediate or prolonged fosphenytoin release profile, depending of anhydrous phase proportion (10% or 40%, respectively). The thermosensitive nanoemulgel, with 10% anhydrous phase, showed prolonged drug release. Future studies will establish whether they are more suited for topical effects or therapeutic brain delivery.

When is the Best Time for Corrective Surgery in Patients with Tetralogy of Fallot between 0 and 12 Months of Age?

OBJECTIVE: To identify the best time for corrective surgery of tetralogy of Fallot (TF) in children aged 0-12 months and to report the most frequent complications during the first 3 years postoperatively. METHODS: Systematic review of studies published between 2000 and 2017 on corrective surgery for TF. Articles were selected through search of electronic databases (PubMed, SciELO, Scopus, Lilacs, Google Scholar, and Cochrane). Length of stay in intensive care unit, duration of mechanical ventilation, and peri/postoperative complications were analyzed for data discussion and research interpretation. CONCLUSION: Definitive corrective surgery is the best alternative, and the earlier it is performed, the lower the occurrence of harmful effects and the greater the chances of cardiorespiratory recovery. This systematic review suggests that the best time to perform definitive corrective surgery for TF in the first year of life is during 3-6 months of age in children with no or mild symptoms. Children with severe symptoms should undergo surgery immediately.

Antioxidant Status, Antidiabetic Properties and Effects on Caco-2 Cells of Colored and Non-Colored Enriched Extracts of Sweet Cherry Fruits.

This study aimed to compare three different extracts of Saco sweet cherry, namely the non-colored fraction, colored fraction, and total extract concerning phenolic composition, antioxidant and antidiabetic potential, and erythrocytes' protection and effects on Caco-2 cells. Twenty-two phenolic compounds were identified using high-performance liquid chromatography with diode-array detection. Hydroxycinnamic acids were the most predominant in both the non-colored fraction and total extract, while cyanidin-3-O-rutinoside was the main anthocyanin found in the colored fraction. The total extract was the most effective against 1,1-diphenyl-2-picrylhydrazyl, nitric oxide, and superoxide radicals, and in the inhibition of α-glucosidase enzyme. The colored fraction revealed the best activity against hemoglobin oxidation and hemolysis. Regarding to Caco-2 cells, the colored extract exhibited the highest cytotoxic effects, while the total extract was the most efficient in protecting these cells against oxidative damage induced by tert-butyl hydroperoxide.

When is the best time for corrective surgery in patients with tetralogy of fallot between 0 and 12 months of age?

Abstract Objective: To identify the best time for corrective surgery of tetralogy of Fallot (TF) in children aged 0-12 months and to report the most frequent complications during the first 3 years postoperatively. Methods: Systematic review of studies published between 2000 and 2017 on corrective surgery for TF. Articles were selected through search of electronic databases (PubMed, SciELO, Scopus, Lilacs, Google Scholar, and Cochrane). Length of stay in intensive care unit, duration of mechanical ventilation, and peri/postoperative complications were analyzed for data discussion and research interpretation. Conclusion: Definitive corrective surgery is the best alternative, and the earlier it is performed, the lower the occurrence of harmful effects and the greater the chances of cardiorespiratory recovery. This systematic review suggests that the best time to perform definitive corrective surgery for TF in the first year of life is during 3-6 months of age in children with no or mild symptoms. Children with severe symptoms should undergo surgery immediately.