Association effect of the phytocannabinoid beta-caryophyllene and indomethacin carried in topical nanoemulgels: an evaluation by in vivo anti-inflammatory model.

The sesquiterpene ß-caryophyllene, classified as a phytocannabinoid compound, has been widely studied owing to its multi-target action. In addition, this compound has demonstrated application as a skin permeation promoter. In this context, this study aimed to evaluate the feasibility of associating ß-caryophyllene and indomethacin in the oily core of hydrogel thickened nanoemulsions, as well as, to evaluate the in vivo anti-inflammatory effect of this association by croton oil ear edoema induced model. After topical application, the nanoemulgels resulted in increased edoema mass when compared to the substances in their free form. Overall, the results differed from expected, and the data found may be owing to the specificities of the in vivo model applied, as well as the tested ratio between ß-caryophyllene and indomethacin (200:1). New perspectives arise from the data found regarding the evaluation of the association of terpenic compounds with indomethacin in nanoemulsified systems.

Co-delivery of beta-caryophyllene and indomethacin in the oily core of nanoemulsions potentiates the anti-inflammatory effect in LPS-stimulated macrophage model.

The potentiation of pharmacological effects can be achieved through several strategies, such as the association of substances and delivery in nanostructured systems. In practice, potentiation can be measured by the law of mass action and joint evaluation of the combination index (CI) and dose-response curves. In this context, this study aimed to evaluate the anti-inflammatory effect of the association of ß-caryophyllene and indomethacin in the free form and delivered in nanoemulsions using the in vitro model of LPS-stimulated murine macrophage. The results indicated potentiation of the anti-inflammatory effect of nanoemulsified substances compared to free substances, as well as synergistic action between the sesquiterpene and the selected NSAID. In comparison, the association of ß-caryophyllene and indomethacin in the free form inhibited the production of nitric oxide by 50% at 48.60 µg/mL (CI = 0.21), while the nanoemulsified association of these substances resulted in an IC50 of 1.45 µg/mL (CI = 0.14). In parallel, cytotoxicity assays on HaCaT and MRC-5 cell lines demonstrated the safety of IC50-equivalent concentrations of the anti-inflammatory action, and no irritating effects on the chorioallantoic membrane of embryonated eggs were observed (HET-CAM assay). The results suggest that ß-caryophyllene may be an alternative to replace an inert oily core in nanoemulsion systems when anti-inflammatory effects are desirable.

Lime and orange essential oils and d-limonene as a potential COVID-19 inhibitor: Computational, in chemico, and cytotoxicity analysis.

The COVID-19 pandemic has substantially impacted the world health systems, causing public health concerns, and the search for new compounds with antiviral activity is of extreme interest. Natural molecules with bioactive potential are a trend, with essential oils (Eos) being the focus of recent studies. Thus, this study evaluates in chemico the d-limonene inhibitory activities in the viral genome of SARS-CoV-2 and analyzes the cytotoxic potential and safety profile of d-limonene and lime and orange EOs with a high content of d-limonene. The EOs were extracted and characterized, and the in chemico computational analysis for the determination as a potential anti-SARS-CoV-2 was performed with d-limonene, the major compound in EOs. The cytotoxicity analysis of EOs and d-limonene was carried out with MRC-5 and HaCaT, and the preliminary safety profile was also evaluated by the HET-CAM assay. d-limonene was suggested as a promising compound for anti-SARS-CoV-2 research, since the molecule does not provide mutagenic and cytotoxic fragments, and does not have irritating potential when diluted, in addition to having favorable pharmacokinetic characteristics, through in chemico analysis. Collectively, the results reveal the antiviral potential of lime and orange EOs, as well as their major compound. In this sense, further studies should be conducted to understand the antiviral mechanisms.

Correlation between the Skin Permeation Profile of the Synthetic Sesquiterpene Compounds, Beta-Caryophyllene and Caryophyllene Oxide, and the Antiedematogenic Activity by Topical Application of Nanoemulgels.

Sesquiterpene compounds are applied as permeation promoters in topical formulations. However, studies exploring their impact on nanostructured systems, changes in permeation profile, and consequently, its biological activity are restricted. This study aimed to investigate the correlation between the skin permeation of the major sesquiterpenes, beta-caryophyllene, and caryophyllene oxide from the oleoresin of Copaifera multijuga, after delivery into topical nanoemulgels, and the in vivo antiedematogenic activity. First, ten nanoemulgels were prepared and characterized, and their in vitro permeation profile and in vivo anti-inflammatory activity were evaluated. In equivalent concentrations, ß-caryophyllene permeation was greater from oleoresin nanoemulgels, resulting in greater in vivo antiedematogenic activity. However, an inverse relationship was observed for caryophyllene oxide, which showed its favored permeation and better in vivo anti-inflammatory effect carried as an isolated compound in the nanoemulgels. These results suggest that the presence of similar compounds may interfere with the permeation profile when comparing the profiles of the compounds alone or when presented in oleoresin. Furthermore, the correlation results between the permeation profile and in vivo antiedematogenic activity corroborate the establishment of beta-caryophyllene as an essential compound for this pharmacological activity of C. multijuga oleoresin.

A New, Rapid and Simple RP-HPLC Method for Stability Quantification of a Protease Inhibitor in Tablets.

Fosamprenavir calcium is a protease inhibitor widely used in the treatment and prevention of human immunodeficiency virus and acquired immunodeficiency syndrome. This protease inhibitor serves as a prodrug of amprenavir, offering better oral bioavailability. Although this drug was approved by the FDA in 2003, there are few methods established for quantifying the stability for quality control analysis of fosamprenavir-coated tablets. The purpose of the study was to develop and validate a method for determining the stability of fosamprenavir-coated tablets (Telzir®) that may be applied by any quality control laboratory. Chromatographic separation was performed using a Vertical RP-18 column programmed to run a gradient elution with sodium acetate buffer and acetonitrile. Flow rate was 1.2 mL min-1 for a total run time of 15 min. Ultraviolet detection was set at 264 nm and the use of a photodiode array detector in scan mode allowed selectivity confirmation by peak purity evaluation. The analyte peak was found to be adequately separated from degradation products generated during forced degradation studies. Thus, the proposed method was found to accurately indicate stability and was sufficient for routine quantitative analysis of fosamprenavir in coated tablets without interference from major degradation products and excipients.

Dissolving Microneedles Developed in Association with Nanosystems: A Scoping Review on the Quality Parameters of These Emerging Systems for Drug or Protein Transdermal Delivery.

The largest organ of the body provides the main challenge for the transdermal delivery of lipophilic or high molecular weight drugs. To cross the main barrier of the skin, the stratum corneum, many techniques have been developed and improved. In the last 20 years, the association of microneedles with nanostructured systems has gained prominence for its versatility and for enabling targeted drug delivery. Currently, the combination of these mechanisms is pointed to as an emerging technology; however, some gaps need to be answered to transcend the development of these devices from the laboratory scale to the pharmaceutical market. It is known that the lack of regulatory guidelines for quality control is a hindrance to market conquest. In this context, this study undertakes a scoping review of original papers concerning methods applied to evaluate both the quality and drug/protein delivery of dissolving and hydrogel-forming microneedles developed in association with nanostructured systems.

Effects of hydrolyzed collagen supplementation on skin aging: a systematic review and meta-analysis.

Skin aging has become a recurring concern even for younger people, mainly owing to increased life expectancy. In this context, the use of nutricosmetics as supplements has increased in recent years. Moreover, numerous scientific studies have shown the benefits of hydrolyzed collagen supplementation in improving the signs of skin aging. The objective of this study was to summarize the evidence on the effects of hydrolyzed collagen supplementation on human skin through a systematic review followed by a meta-analysis of clinical trials focusing on the process of skin aging. A literature search was conducted in the Medline, Embase, Cochrane, LILACS (Latin American and Caribbean Health Sciences Literature), and Journal of Negative Results in BioMedicine databases. Eligible studies were randomized, double-blind, and controlled trials that evaluated oral supplementation with hydrolyzed collagen as an intervention and reported at least one of the following outcomes: skin wrinkles, hydration, elasticity, and firmness. After retrieving articles from the databases, 19 studies were selected, with a total of 1,125 participants aged between 20 and 70 years (95% women). In the meta-analysis, a grouped analysis of studies showed favorable results of hydrolyzed collagen supplementation compared with placebo in terms of skin hydration, elasticity, and wrinkles. The findings of improved hydration and elasticity were also confirmed in the subgroup meta-analysis. Based on results, ingestion of hydrolyzed collagen for 90 days is effective in reducing skin aging, as it reduces wrinkles and improves skin elasticity and hydration.

Anti-inflammatory activity of Brunfelsia uniflora root extract: phytochemical characterization and pharmacologic potential of this under-investigated species.

Brunfelsia uniflora (Pohl) D. Don roots have been widely used in folk medicine for treating inflammatory conditions. However, few studies have elucidated compounds that justify their traditional use. This study was conducted to characterize the phytochemical profile and evaluate the in vitro antioxidant capacity, and in vivo anti-inflammatory activity of extracts obtained from B. uniflora roots by comparing an herbal remedy (HR) with the crude hydroalcoholic extract (CHE). In the phytochemical analysis, scopoletin was identified as the marker compound. In quantitative analyses, CHE showed better results than HR. Furthermore, CHE had an effective anti-inflammatory activity. Animals treated with CHE (200 mg/kg) showed an 89.1% and a 73.8% reduction in edema volume after 1 hour of edema induction compared with those treated with negative control and positive control (indomethacin), respectively. These results show that B. uniflora root extracts have promising antioxidant and anti-inflammatory activities, thus corroborating their application in ethnomedicine.

In vitro cytotoxic and genotoxic effects of Cissus verticillata and Sphagneticola trilobata used for treatment of Diabetes Mellitus in Brazilian folk medicine

Cissus verticillata and Sphagneticola trilobata have been used in Brazilian folk medicine for Diabetes Mellitus treatment, although their pharmacological and toxicological profile has not been clearly established. Thus, the aim of this study was to evaluate the preclinical toxicity of the aqueous extracts of C. verticillata and S. trilobata. The main groups of secondary metabolites were investigated, and the species differed by the presence of coumarins in C. verticillata and by tannins in S. trilobata extracts. The highest contents of phenolic compounds and flavonoids were quantified in C. verticillata infusion with 2.594 ± 0.04 mg equivalents of gallic acid g-1 of extract and 1.301 ± 0.015 mg equivalents of catechin g-1 of extract, respectively. While the extract of S. trilobata showed minimum values of these compounds, with 0.002 ± 0.001 mg equivalents of gallic acid g-1 extract and 0.005 ± 0.0004 mg equivalents of catechin g-1 of extract, respectively. These differences implied the results of in vitro antioxidant activity evaluated using ferric reducing antioxidant power (FRAP), in which the sample of C. verticillata at 5 mg mL-1 showed a value of 122 µM ferrous sulfate equivalents (FSE), while S. trilobata showed 0.93 µM FSE at the same concentration. With respect to cytotoxic assay with murine fibroblast cell line (3T3) only S. trilobata exhibited cytotoxic effects measured by MTT and Sulforhodamine B assays, evidenced by the cell viability value of approximately 16%, in both tests after 24 and 72 hours of exposure of the cells to 5 mg mL-1 of the extract. Comparatively, at 5 mg mL-1 the C. verticillata extract showed cell viability of 142% and 95%, respectively, after 24 hours of cell exposure. On the other hand, both species showed genotoxic profiles evidenced by chromosomal aberrations by Allium cepa bioassay, observed by the higher percentage values of chromosome bridges, chromosome loss, and disturbed anaphase for all concentrations of both extracts than those of the negative control. The results support the characterization of the toxicological profile for both species and create an alert regarding the use of S. trilobata, which should be avoided.