(-)-linalool-Loaded Polymeric Nanocapsules Are a Potential Candidate to Fibromyalgia Treatment.

Fibromyalgia (FM) is a chronic disease that has as main characteristic generalized musculoskeletal pain, which can cause physical and emotional problems to patients. However, pharmacological therapies show side effects that hamper the adhesion to treatment. Given this, (-)-linalool (LIN), a monoterpene with several therapeutic properties already reported in scientific literature as anti-depressive, antinociceptive, anti-inflammatory, and antihyperalgesic also demonstrated therapeutic potential in the treatment of FM. Nevertheless, physicochemical limitations as high volatilization and poor water-solubility make its use difficult. In this perspective, this present research had performed the incorporation of LIN into polymeric nanocapsules (LIN-NC). Size, morphology, encapsulation efficiency, cytotoxicity, and drug release were performed. The antihyperalgesic effect of LIN-NC was evaluated by a chronic non-inflammatory muscle pain model. The results demonstrated that the polymeric nanocapsules showed particle size of 199.1 ± 0.7 nm with a PDI measurement of 0.13 ± 0.01. The drug content and encapsulation efficiency were 13.78 ± 0.05 mg/mL and 80.98 ± 0.003%, respectively. The formulation did not show cytotoxicity on J774 macrophages. The oral treatment with LIN-NC and free-LIN increased the mechanical withdrawal threshold on all days of treatment in comparison with the control group. In conclusion, LIN-NC is a promising proposal in the development of phytotherapy-based nanoformulations for future clinical applications.

Molecular Modeling and Physicochemical Properties of Supramolecular Complexes of Limonene with α- and ß-Cyclodextrins.

This study evaluated three different methods for the formation of an inclusion complex between alpha- and beta-cyclodextrin (α- and ß-CD) and limonene (LIM) with the goal of improving the physicochemical properties of limonene. The study samples were prepared through physical mixing (PM), paste complexation (PC), and slurry complexation (SC) methods in the molar ratio of 1:1 (cyclodextrin:limonene). The complexes prepared were evaluated with thermogravimetry/derivate thermogravimetry, infrared spectroscopy, X-ray diffraction, complexation efficiency through gas chromatography/mass spectrometry analyses, molecular modeling, and nuclear magnetic resonance. The results showed that the physical mixing procedure did not produce complexation, but the paste and slurry methods produced inclusion complexes, which demonstrated interactions outside of the cavity of the CDs. However, the paste obtained with ß-cyclodextrin did not demonstrate complexation in the gas chromatographic technique because, after extraction, most of the limonene was either surface-adsorbed by ß-cyclodextrin or volatilized during the procedure. We conclude that paste complexation and slurry complexation are effective and economic methods to improve the physicochemical character of limonene and could have important applications in pharmacological activities in terms of an increase in solubility.

Inclusion complex with ß-cyclodextrin is a key determining factor for the cardioprotection induced by usnic acid.

Ischemia-reperfusion (I/R) injury causes oxidative stress, leading to severe cardiac dysfunction. Thus, biologically active compounds with antioxidant properties may be viewed as a promising therapeutic strategy against oxidative-related cardiac disorders. Usnic acid (UA), a natural antioxidant, was complexed with ß-cyclodextrin (ßCD) to improve its bioavailability. Wistar male rats were orally treated with the free form of UA (50 mg/kg) or the inclusion complex UA/ßCD (50 mg/kg) for seven consecutive days. Afterward, hearts were subjected to I/R injury, and the cardiac contractility, rhythmicity, infarct size, and antioxidant enzyme activities were evaluated. Here, we show that neither UA nor UA/ßCD treatments developed signs of toxicity. After I/R injury, animals treated with UA/ßCD showed improved post-ischemic cardiac functional recovery while the release of cell injury biomarkers decreased. Following reduced cardiac damage, a lower incidence of ventricular arrhythmias and smaller myocardial infarct size were associated with reduced lipid peroxidation, along with preserved activity of antioxidant enzymes compared to untreated rats. Surprisingly, uncomplexed UA did not protect hearts against IR injury. Altogether, our results indicate that the inclusion complex UA/ßCD is a critical determining factor responsible for the cardioprotection action of UA, suggesting the involvement of an antioxidant-dependent mechanisms. Moreover, our findings support that UA/ßCD is a structurally engineered compound with active cardioprotective properties.

Anticonvulsant, sedative, anxiolytic and antidepressant activities of the essential oil of Annona vepretorum in mice: Involvement of GABAergic and serotonergic systems.

Annona vepretorum is an endemic species of the Caatinga biome, known in Northeastern Brazil as "araticum" and/or "pinha da Caatinga". In the present study it was evaluated the neuropharmacological potential of the essential oil obtained from the leaves of Annona vepretorum, as well as of the inclusion complexes of oil obtained with cyclodextrin. Thus, were used neuropharmacological tests already consolidated in the literature like open-field, elevated plus maze, rota-rod, tail suspension test, thiopental-induced sleep test, among others. The acute treatment of essential oil (EO) has anxiolytic, sedative, antiepileptic and antidepressant effects. The anxiolytic and anticonvulsant effects seems to be related to the GABAergic system, probably in the receptor subtypes that mediate the effects of the benzodiazepines, to generate anxiolytic activity. The sedative effect seems to be involved with other signaling pathways. The antidepressant effect of EO seems to be related to its action on serotonergic receptors. It was verified that some behavioral parameters were improved with the oil complexed with ß-cyclodextrin, but this effect was not uniform for all the doses and tests used. Further studies are needed in order to use other options for drug delivery systems. Thus, the essential oil of Annona vepretorum is a promising agent with neurobiological activity and a potential target for drug discovery, since the natural products such as medicinal plants have been a source of new therapeutic proposals.

Physicochemical Characterization and Antinociceptive Effect of ß-cyclodextrin/Lippia pedunculosa Essential Oil in Mice.

BACKGROUND: Some research studies have shown that Lippia pedunculosa essential oil (EOLP) has interesting biological activities. However, its low water solubility is the main challenge to achieve its therapeutic potential. In this context, Cyclodextrins (CDs) have been widely used in order to overcome this problem due to your capability to improve the physicochemical properties of drugs. OBJECTIVE: In this perspective, the main goal of this study was to investigate how the improvement of the physicochemical properties of inclusion complexes (EOLP and ß-CD) enhance the antinociceptive effect in mice. METHODS: To achieve that, we prepared samples by Physical Mixture (PM), Paste Complexation (PC) and Slurry Complexation (SC) methods, followed by their physicochemical characterization. In addition, it was evaluated if the use of ß-CD enhances the antinociceptive effect of EOLP in mice. RESULTS: The analysis showed that rotundifolone (72.02%) was the major compound of EOLP and we found out based on DSC results that ß-CD protected it from oxidation. In addition, TG techniques demonstrated that the best inclusion methods were PC and SC, due to their greater weight loss (10.8 and 11.6%, respectively) in the second stage (171-312°C), indicating that more complexed oil was released at the higher temperature than oil free. Other characteristics, such as changes in the typical crystalline form, and reduced particle size were observed by SEM and laser diffraction, respectively. The SC was the most effective complexation method, once the presence of rotundifolone was detected by FTIR. Based on that, SC method was used in all mice tests. In this regard, the number of paw licks was reduced for both compounds (all doses), but EOLP was more effective in reducing the nociceptive behavior. CONCLUSION: Therefore, CDs seem not to be a good tool to enhance the pharmacological properties of EOs rich in peroxide compounds such as rotundifolone.

Polyphenols rich Passiflora leschenaultii leaves modulating Farnesoid X Receptor and Pregnane X Receptor against paracetamol-induced hepatotoxicity in rats.

The hepatoprotective effect of P. leschenaultii. (DC) leaves was investigated in rats under paracetamol induced oxidative stress. Leaf acetone extract (200 and 400mg/kg) were administered daily via gavage for 14days before paracetamol (2000mg/kg, p.o.) treatment. After the experiment, the levels of serum biochemical parameters and enzymatic antioxidant levels were determined. Furthermore, liver tissues were analyzed histopathologically. Additionally, the molecular docking studies of the identified compounds against PXR and FXR proteins were also performed. The assessment revealed that the acetone extract significantly reduced the elevated levels of SGPT, SGOT and ALP in serum. Moreover, the enzymatic antioxidants such as SOD, CAT and LPO were also retained normally by the plant extract. From histopathological analysis, it was clearly evident that the cellular architecture of plant extract treated rat liver tissues were not affected by the paracetamol induction at the higher dose. The results of docking studies also revealed that the identified compounds showed steric interactions (between nonpolar atoms) with amino acid groups. Collectively, the present study suggests that P. leschenaultii leaves extract protects the liver from paracetamol induced hepatic damage.

Gelatin-based membrane containing usnic acid-loaded liposome improves dermal burn healing in a porcine model.

There are a range of products available which claim to accelerate the healing of burns; these include topical agents, interactive dressings and biomembranes. The aim of this study was to assess the effect of a gelatin-based membrane containing usnic acid/liposomes on the healing of burns in comparison to silver sulfadiazine ointment and duoDerme® dressing, as well as examining its quantification by high performance liquid chromatography. The quantification of the usnic acid/liposomes was examined using high performance liquid chromatography (HPLC) by performing separate in vitro studies of the efficiency of the biomembranes in terms of encapsulation, drug release and transdermal absorption. Then, second-degree 5cm2 burn wounds were created on the dorsum of nine male pigs, assigned into three groups (n=3): SDZ - animals treated with silver sulfadiazine ointment; GDU - animals treated with duoDerme®; UAL - animals treated with a gelatin-based membrane containing usnic acid/liposomes. These groups were treated for 8, 18 and 30days. In the average rate of contraction, there was no difference among the groups (p>0.05). The results of the quantification showed that biomembranes containing usnic acid/liposomes were controlled released systems capable of transdermal absorption by skin layers. A macroscopic assay did not observe any clinical signs of secondary infections. Microscopy after 8days showed hydropic degeneration of the epithelium, with intense neutrophilic infiltration in all three groups. At 18days, although epidermal neo-formation was only partial in all three groups, it was most incipient in the SDZ group. Granulation tissue was more exuberant and cellularized in the UAL and GDU groups. At 30days, observed restricted granulation tissue in the region below the epithelium in the GDU and UAL groups was observed. In the analysis of collagen though picrosirius, the UAL group showed greater collagen density. Therefore, the UAL group displayed development and maturation of granulation tissue and scar repair that was comparable to that produced by duoDerme®, and better than that produced by treatment with sulfadiazine silver ointment In addition, the UAL group showed increased collagen deposition compared to the other two groups.