Development and characterization of liposomal formulations containing sesquiterpene lactones for the treatment of chronic gout.

Gout and hyperuricemia are characterized by high uric acid levels, and their treatment involves medications that have adverse effects. In this study, we evaluated oral liposomal formulations with eremantholide C and goyazensolide as a novel approach to reduce the toxicity associated with these substances while maintaining their anti-hyperuricemic activity. We characterized the formulations and evaluated them based on encapsulation efficiency and stability over 12 months and under simulated physiological environments. We determined the toxicity of the liposomal formulations in Caco-2 cells and the anti-hyperuricemic activity in rats. The formulations exhibited nanometric size, a narrow size distribution, and a negative zeta potential, indicating their stability and uniformity. The efficient encapsulation of the sesquiterpene lactones within the liposomes emphasizes their potential for sustained release and therapeutic efficacy. Stability evaluation revealed a small decrease in the eremantholide C concentration and a remarkable stability in the goyazensolide concentration. In Caco-2 cells, the liposomes did not exert toxicity, but did exhibit an antiproliferative effect. In vivo assays demonstrated that the liposomes reduced serum uric acid levels. Our study represents an advancement in gout and hyperuricemia treatment. The liposomal formulations effectively reduced the toxicity associated with the sesquiterpene lactones while maintaining their therapeutic effects.

Oral treatment with a chemically characterized parsley (Petroselinum crispum var. neapolitanum Danert) aqueous extract reduces thrombi formation in rats.

Petroselinum crispum var. neapolitanum Danert (Apiaceae) (PC), popularly known as parsley, is an herb native to the Mediterranean region widely cultivated around the world for culinary and ethnomedicinal purposes. The herb is traditionally used in various parts of the world to treat arterial hypertension, hemorrhoid, nose bleeding, hyperlipidemia, and pain, among other indications. The aim of this study was to evaluate the antithrombotic activity of an aqueous extract PC in rats. Aerial parts of a flat-leaf variety of parsley were extracted by decoction. In vivo thrombosis in rat models as well as ex vivo assays were used in the evaluation of PC antithrombotic effects. Intravenous administration of PC (25 mg/kg.b.w), 5 min before thrombosis induction, reduced the venous thrombus formation by 98.2%, while oral administration (125 mg/kg.b.w) impaired it by 76.2%. In the arterial thrombosis model, the oral administration of PC at 15 or 25 mg/kg.b.w, 60 min before thrombosis induction, increased the carotid artery occlusion time by 150% (37.0 ± 6.44 min) and 240% (more than 60 min), respectively. A HPLC-DAD-MS/MS profile of PC extract used in this study was provided. Apiin showed to be the most abundant phenolic compound in the extract. It also revealed the presence of many coumaric acid derivatives. Our results indicate that PC is a potential candidate for the development of a phytotherapeutic drug in the treatment of thromboembolic diseases and provide a detailed chemical profile useful for controlling PC extract production in view of phytotherapy.

Eremantholide C from aerial parts of Lychnophora trichocarpha, as drug candidate: fraction absorbed prediction in humans and BCS permeability class determination.

BACKGROUND: Lychnophora trichocarpha (Spreng.) Spreng. ex Sch.Bip has been used in folk medicine to treat pain, inflammation, rheumatism and bruises. Eremantholide C, a sesquiterpene lactone, is one of the substances responsible for the anti-inflammatory and anti-hyperuricemic effects of L. trichocarpha. OBJECTIVES: Considering the potential to become a drug for the treatment of inflammation and gouty arthritis, this study evaluated the permeability of eremantholide C using in situ intestinal perfusion in rats. From the permeability data, it was possible to predict the fraction absorbed of eremantholide C in humans and elucidate its oral absorption process. METHODS: In situ intestinal perfusion studies were performed in the complete small intestine of rats using different concentrations of eremantholide C: 960 µg/ml, 96 µg/ml and 9.6 µg/ml (with and without sodium azide), in order to verify the lack of dependence on the measured permeability as a function of the substance concentration in the perfusion solutions. RESULTS: Eremantholide C showed Peff values, in rats, greater than 5 × 10-5 cm/s and fraction absorbed predicted for humans greater than 85%. These results indicated the high permeability for eremantholide C. Moreover, its permeation process occurs only by passive route, because there were no statistically significant differences between the Peff values for eremantholide C. CONCLUSION: The high permeability, in addition to the low solubility, indicated that eremantholide C is a biologically active substance BCS class II. The pharmacological activities, low toxicity and biopharmaceutics parameters demonstrate that eremantholide C has the necessary requirements for the development of a drug product, to be administered orally, with action on inflammation, hyperuricemia and gout.

Machine learning and statistics to qualify environments through multi-traits in Coffea arabica.

Several factors such as genotype, environment, and post-harvest processing can affect the responses of important traits in the coffee production chain. Determining the influence of these factors is of great relevance, as they can be indicators of the characteristics of the coffee produced. The most efficient models choice to be applied should take into account the variety of information and the particularities of each biological material. This study was developed to evaluate statistical and machine learning models that would better discriminate environments through multi-traits of coffee genotypes and identify the main agronomic and beverage quality traits responsible for the variation of the environments. For that, 31 morpho-agronomic and post-harvest traits were evaluated, from field experiments installed in three municipalities in the Matas de Minas region, in the State of Minas Gerais, Brazil. Two types of post-harvest processing were evaluated: natural and pulped. The apparent error rate was estimated for each method. The Multilayer Perceptron and Radial Basis Function networks were able to discriminate the coffee samples in multi-environment more efficiently than the other methods, identifying differences in multi-traits responses according to the production sites and type of post-harvest processing. The local factors did not present specific traits that favored the severity of diseases and differentiated vegetative vigor. Sensory traits acidity and fragrance/aroma score also made little contribution to the discrimination process, indicating that acidity and fragrance/aroma are characteristic of coffee produced and all coffee samples evaluated are of the special type in the Mata of Minas region. The main traits responsible for the differentiation of production sites are plant height, fruit size, and bean production. The sensory trait "Body" is the main one to discriminate the form of post-harvest processing.

The influence of seasonality on the content of goyazensolide and on anti-inflammatory and anti-hyperuricemic effects of the ethanolic extract of Lychnophora passerina (Brazilian arnica).

ETHNOPHARMACOLOGICAL RELEVANCE: Lychnophora passerina (Mart ex DC) Gardn (Asteraceae), popularly known as Brazilian arnica, is used in Brazilian folk medicine to treat pain, rheumatism, bruises, inflammatory diseases and insect bites. AIM OF THE STUDY: Investigate the influence of the seasons on the anti-inflammatory and anti-hyperuricemic activities of ethanolic extract of L. passerina and the ratio of the goyazensolide content, main chemical constituent of the ethanolic extract, with these activities. MATERIALS AND METHODS: Ethanolic extracts of aerial parts of L. passerina were obtained from seasons: summer (ES), autumn (EA), winter (EW) and spring (EP). The sesquiterpene lactone goyazensolide, major metabolite, was quantified in ES, EA, EW and EP by a developed and validated HPLC-DAD method. The in vivo anti-hyperuricemic and anti-inflammatory effects of the ethanolic extracts from L. passerina and goyazensolide were assayed on experimental model of oxonate-induced hyperuricemia in mice, liver xanthine oxidase (XOD) inhibition and on carrageenan-induced paw edema in mice. RESULTS: HPLC method using aqueous solution of acetic acid 0.01% (v/v) and acetonitrile with acetic acid 0.01% (v/v) as a mobile phase in a gradient system, with coumarin as an internal standard and DAD detection at 270nm was developed. The validation parameters showed linearity in a range within 10.0-150.0µg/ml, with intraday and interday precisions a range of 0.61-3.82. The accuracy values of intraday and interday analysis within 87.58-100.95%. EA showed the highest goyazensolide content. From the third to the sixth hour after injection of carrageenan, treatments with all extracts at the dose of 125mg/kg were able to reduce edema. Goyazensolide (10mg/kg) showed significant reduction of paw swelling from the second hour assay. This sesquiterpene lactone was more active than extracts and presented similar effect to indomethacin. Treatments with ES, EA and EP (125mg/kg) and goyazensolide (10mg/kg) reduced serum urate levels compared to hyperuricemic control group and were able to inhibit liver XOD activity. One of the mechanisms by which ES, EA, EP and goyazensolide exercise their anti-hyperuricemic effect is by the inhibition of liver XOD activity. Goyazensolide was identified as the main compound present in ES, EA, EW and EP and it is shown to be one of the chemical constituents responsible for the anti-inflammatory and anti-hyperuricemic effects of the ethanolic extracts. CONCLUSION: The anti-inflammatory and anti-hyperuricemic activities of the ethanolic extracts from L. passerina were not proportionally influenced by the variation of goyazensolide content throughout the seasons. The involvement of goyazensolide on in vivo anti-inflammatory and anti-hyperuricemic activities of L.passerina extracts was confirmed, as well as the possibility of participation of other constituents on these effects. This study demonstrated that the aerial parts of L. passerina may be collected in any season for use as anti-inflammatory agent. For use in hyperuricemia, the best seasons for the collection are summer, autumn and spring. The ethanolic extract of L. passerina and goyazensolide can be considered promising agents in the therapeutic of inflammation, hyperuricemia and gout.

Comparison of bidirectional lamivudine and zidovudine transport using MDCK, MDCK-MDR1, and Caco-2 cell monolayers.

Bidirectional transport studies were conducted using Caco-2, MDCK, and MDCK-MDR1 to determine P-gp influences in lamivudine and zidovudine permeability and evaluate if zidovudine permeability changes with the increase of zidovudine concentration and/or by association of lamivudine. Transport of lamivudine and zidovudine separated and coadministrated across monolayers based on these cells were quantified using LC-MS-MS. Drug efflux by P-gp was inhibited using GG918. Bidirectional transport of lamivudine and zidovudine was performed across MDCK-MDR1 and Caco-2 cells. Statistically significant transport decrease in B --> A direction was observed using MDCK-MDR1 for zidovudine and MDCK-MDR1 and Caco-2 for lamivudine. Results show increased transport in B --> A and A --> B directions as concentration increases but data from P(app) increase in both directions for both drugs in Caco-2, decrease in MDCK, and does not change significantly in MDCK-MDR1. Zidovudine transport in A --> B direction increases when coadministrated with increasing lamivudine concentration but does not change significantly in B --> A direction. Zidovudine and lamivudine are P-gp substrates, but results assume that P-gp does not affect significantly lamivudine and zidovudine. Their transport in monolayers based on Caco-2 cells increase proportionally to concentration (in both directions) and zidovudine transport in Caco-2 cell monolayer does not show significant changes with lamivudine increasing concentrations.