DEFAR - Departamento de Farmácia

URI permanente desta comunidadehttp://www.hml.repositorio.ufop.br/handle/123456789/530

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Effects of Coffea arabica aqueous extracts and their main chemical constituents on hyperuricemia.
(2022) Coelho, Grazielle Brandão; Bernardes, Ana Catharina Fernandes Pereira Ferreira; Müller, Camila Martins de Sá; Serra, Vanessa de Assis Barros; Guimarães, Dênia Antunes Saúde
Aqueous extracts of Coffea arabica L., Rubiaceae, were prepared from green coffee beans, roasted coffee in three different conditions, and decaffeinated coffee. Caffeine, trigonelline, neochlorogenic, and chlorogenic acids were identified by HPLC/ DAD as the main chemical constituents in aqueous extracts, except for decaffeinated coffee. Effects of the extracts and substances on hyperuricemia were evaluated using the animal model of potassium oxonate-induced hyperuricemia. All extracts showed anti- hyperuricemic activity at all evaluated doses and were able to inhibit hepatic xanthine oxidase. Light roast beans’ aqueous extract (75 mg/kg) lowered serum uric acid (1.681 mg/dl) to levels comparable to the normouricemic control (1.628 mg/dl), and decaf- feinated coffee aqueous extract (75 mg/kg) displayed the highest percentage of liver xanthine oxidase inhibition (45.92%). The uricosuric effect of the extracts was observed in at least one evaluated dose. Light roast beans’ aqueous extract (225 mg/kg) promoted highest renal excretion of uric acid (32.97 mg/kg/5 h). All compounds detected presented hypouricemic effect, acting by uricostatic route. Chlorogenic and neochlorogenic acids demonstrated uricosuric, and uricostatic effects. These results support that Coffea arabic aqueous extracts and neochlorogenic and chlorogenic acids, trigonelline, and caffeine are promising agents for use in the treatment of hyperuricemia and gout.
Chemical analysis of Eruca sativa ethanolic extract and its effects on hyperuricaemia.
(2022) Teixeira, Arthur Ferrari; Souza, Jacqueline de; Dophine, Douglas Daniel; Souza Filho, José Dias de; Guimarães, Dênia Antunes Saúde
In vivo assays and chemical analyses were performed on the ethanolic extract from leaves of Eruca sativa. UHPLC-ESI-QTOF analysis confirmed the presence of glucosinolates and flavonol glucosides. The major flavonoid of the ethanolic extract, kaempferol-3,40 -di-O-β-glucoside, was isolated, a HPLC-DAD method developed and validated to quantify its content in the extract. In vivo experiments were carried out on Wistar rats with hyperuricaemia induced by potassium oxonate and uric acid. A hypouricaemic effect was observed in hyperuricaemic Wistar rats treated with ethanolic extract at dose of 125 mg/kg and kaempferol-3,40 -di-O-β-glucoside at dose of 10 mg/kg. The main anti-hyperuricaemic mechanism observed in the extract was uricosuric. Kaempferol-3,40 -di-O-β- glucoside was identified as an important component responsible for the total activity of the ethanolic extract and was considered as a good chemical and biological marker of the ethanolic extract of E. sativa. The obtained results indicated the potential of E. sativa in the treatment of hyperuricaemia and its comorbidities.
Stability and degradation kinetics of an ethanolic extract and tincture of aerial parts from lychnophora passerina (Brazilian arnica).
(2021) Ugoline, Bruno César de Albuquerque; Souza, Jacqueline de; Caldeira, Tamires Guedes; Guimarães, Dênia Antunes Saúde
Previous studies have demonstrated the anti-infammatory and antihyperuricemic activities of dried ethanolic extract of the aerial parts of Lychnophora passerina (Mart ex DC.) Gardner, Asteraceae, and then the potential to become a pharmaceutical product. However, many of the constituents present in these medicines can be degraded, raising serious concerns about the stability of products. Considering the impact on the quality of herbal medicines, this study evalu- ated the stability of a dried ethanolic extract and tincture of the aerial parts of L. passerina. For the accelerated stability study, the dried ethanolic extract and tincture were stored at 40±2 °C for 6 months. For the long-term stability study, the dried ethanolic extract was stored at 30±2 °C for 12 months. The organoleptic properties and goyazensolide content were analyzed. The pH, relative density, and dry residue were evaluated for the tincture. In addition, forced degradation and stability studies at room temperature (25±2 °C) were carried out. In glass bottles that were hermetically sealed and protected from light, the dried ethanolic extract remained stable for 3 months when stored at 30±2 °C and for 12 months at 25±2 °C. The tinctures remained stable for 6 months when stored at 25±2 °C. In addition, the dried ethanolic extract and tincture showed zero-order degradation kinetics. The dried ethanolic extract and tincture of L. passerina had greater stability when compared to preparations of other species of Lychnophora. Thus, this species could be directed for phar- maceutical preparations aimed at use by the population.
Eremantholide C from aerial parts of Lychnophora trichocarpha, as drug candidate : fraction absorbed prediction in humans and BCS permeability class determination.
(2021) Caldeira, Tamires Guedes; Guimarães, Dênia Antunes Saúde; González Álvarez, Isabel; Bermejo, Marival; Souza, Jacqueline de
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.
Lychnopholide in PLA-PEG nanocapsules cures infection by drug resistant Trypanosoma cruzi strain in acute and chronic phases.
(2020) Branquinho, Renata Tupinambá; Mello, Carlos Geraldo Campos de; Oliveira, Maykon Tavares de; Reis, Levi Eduardo Soares; Vieira, Paula Melo de Abreu; Guimarães, Dênia Antunes Saúde; Mosqueira, Vanessa Carla Furtado; Lana, Marta de
Chagas disease remains neglected, and current chemotherapeutics present severe limitations. Lychnopholide (LYC) at low doses loaded in polymeric poly(d,l-lactide)-block-polyethylene glycol (PLA-PEG) nanocapsules (LYC-PLA-PEG-NC) exhibits anti-Trypanosoma cruzi efficacy in mice infected with a partially drug-resistant strain. This study reports the efficacy of LYC-PLA-PEG-NC at higher doses in mice infected with a T. cruzi strain resistant to benznidazole (BZ) and nifurtimox (NF) treated at both the acute phase (AP) and the chronic phase (CP) of infection by the oral route. Mice infected with the T. cruzi VL-10 strain were treated by the oral route with free LYC (12 mg/kg of body weight/day), LYC-PLA-PEG-NC (8 or 12 mg/kg/day), or BZ at 100 mg/kg/day or were not treated (controls). Treatment efficacy was assessed by hemoculture (HC), PCR, enzyme-linked immunosorbent assay (ELISA), heart tissue quantitative PCR (qPCR), and histopathology. According to classical cure criteria, treatment with LYC-PLA-PEG-NC at 12 mg/kg/day cured 75% (AP) and 88% (CP) of the animals, while at a dose of 8 mg/kg/day, 43% (AP) and 43% (CP) were cured, showing dose-dependent efficacy. The negative qPCR results for heart tissue and the absence of inflammation/fibrosis agreed with the negative results obtained by HC and PCR. Thus, the mice treated with the highest dose could be considered 100% cured, in spite of a low ELISA reactivity in some animals. No cure was observed in animals treated with free LYC or BZ or the controls. These results are exceptional in terms of experimental Chagas disease chemotherapy and provide evidence of the outstanding contribution of nanotechnology in mice infected with a T. cruzi strain totally resistant to BZ and NF at both phases of infection. Therefore, LYC-PLA-PEG-NC has great potential as a new treatment for Chagas disease and deserves further investigations in clinical trials.
In vivo anti-hyperuricemic activity of sesquiterpene lactones from Lychnophora species.
(2019) Bernardes, Ana Catharina Fernandes Pereira Ferreira; Coelho, Grazielle Brandão; Araújo, Marcela Carolina de Paula Michel; Guimarães, Dênia Antunes Saúde
Hyperuricemia is the main cause of gout, an inflammation induced by uric acid deposition in joints. Drugs available present side effects, so there is a need for new treatment alternatives. Lychnophora species are used in folk medicine to treat inflammation, rheumatism and muscle pain. Goyazensolide (10 mg/kg), eremantholide C (25 mg/kg) and lychnopholide (25 mg/kg), sesquiterpene lactones isolated from Lychnophora species were previously studied and showed anti-hyperuricemic effects in mice. However, the mechanisms of this effect were not elucidated. The methodology of this study consisted in treatment of hyperuricemic-induced rats, and comparison between control groups, clinically used anti-hyperuricemic drugs and sesquiterpene lactones. Urine and blood were collected for uric acid quantification. Xanthine oxidase inhibition was measured in liver homogenates. Results showed that all evaluated sesquiterpene lactones presented anti-hyperuricemic activity at the doses of 5 and 10 mg/kg and can act through one or both mechanisms, depending on the dose administrated. Goyazensolide and lychnopholide at dose of 5 mg/kg showed important uricosuric effect. Goyazensolide and lychnopholide at dose of 10 mg/kg, and eremantholide C (5 and 10 mg/kg) presented notable inhibition of hepatic xanthine oxidase activity and uricosuric effect. Thus, these sesquiterpene lactones are promising hypouricemic agent to treat hyperuricemia and gout.
Polymorphic characterization and implications on biopharmaceutics properties of potential anti-inflammatory drug candidate eremantholide C from Lychnophora trichocarpha (Brazilian Arnica).
(2019) Caldeira, Tamires Guedes; Guimarães, Dênia Antunes Saúde; Lacerda, Dâmaris Laignier Rodrigues de; Mussel, Wagner da Nova; Yoshida, Maria Irene; Souza, Jacqueline de
Objectives: To perform the polymorphic and physicochemical characterization of the potential anti-inflammatory drug, eremantholide C (EREC), as well as to evaluate the influence of these characteristics on its biopharmaceutics classification. Methods Eremantholide C was obtained from chloroformic extract of Lychnophora trichocarpha and crystallized in two distinct solvents: chloroform (EREC 1) and ethyl acetate (EREC 2). To evaluate the polymorphism, EREC samples were submitted to melting point, purity, infrared spectroscopy, differential scanning calorimetry (DSC), X-ray powder diffraction, optical microscopy and scanning electron microscopy analysis. In addition, EREC samples crystallized after intrinsic dissolution study were submitted to DSC and X-ray powder diffraction analysis. Key findings EREC 1 showed fusion at 234.7–241.6 °C, while EREC 2 showed fusion at 238.6–243.7 °C. No polymorphic transitions were observed during the intrinsic dissolution experiment. A single sharp endothermic peak was obtained for the EREC samples. X-ray diffraction showed no crystallographic differences between the EREC samples. EREC 1 and EREC 2 showed birefringence under polarized light and indefinite morphology; however, the shape of the crystals was common to the two samples. Conclusions: Eremantholide C does not present classical or morphological polymorphism; therefore, there is no influence of crystalline transitions in the solubility and consequently in its biopharmaceutics classification and oral absorption process.
Lychnophora pinaster ethanolic extract and its chemical constituents ameliorate hyperuricemia and related inflammation.
(2019) Müller, Camila Martins de Sá; Coelho, Grazielle Brandão; Araújo, Marcela Carolina de Paula Michel; Guimarães, Dênia Antunes Saúde
Ethnopharmacological relevance: Lychnophora pinaster, known as “Brazilian arnica” is used in folk medicine as alcoholic extract to treat inflammation, pain, rheumatism and bruises. Aim of the study: Evaluate the effects of the Lychnophora pinaster's ethanolic extract and its chemical constituents on inflammation and hyperuricemia. Materials and methods: Ethanolic and hexanic extracts were obtained from the aerial parts of L. pinaster. Sesquiterpene E-lychnophoric acid was isolated from hexanic extract and identified by RMN, GC/MS and IR. In vivo anti-hyperuricemic and anti-inflammatory effects of the ethanolic extracts from L. pinaster (40, 125, 375 mg/kg), E-lychnophoric acid and other constituents previous isolated from L. pinaster and identified in the ethanolic extract by HPLC/UV/DAD (rutin, quercetin and vitexina flavonoids, caffeic, cinnamic and chlorogenic acids, lupeol and stigmasterol, at dose of 15 mg/kg) were assayed by experimental model of oxonate-induced hyperuricemia in Swiss mice, liver xanthine oxidase (XOD) inhibition and by MSU-induced paw edema in mice. Results: Ethanolic extract and all its components presented anti-hyperuricemic activity by inhibiting the hepatic xanthine oxidase activity. Ethanolic extract and its chemical constituents, except quercetin and vitexin, were able to reduce paw edema size induced by urate crystals. Hypouricemic and anti-inflammatory results obtained for the ethanolic extract (40, 125, 375 mg/kg) and E-lychnophoric acid (15 mg/kg) were similar those obtained for standard drugs, allopurinol (10 mg/kg) and indomethacin (3 mg/kg). Conclusion: Ethanolic extract and E-lychnophoric, chlorogenic, cinnamic and caffeic acids, rutin, lupeol and stigmasterol presented anti-inflammatory and anti-hyperuricemic actvities. These compounds are responsible for the activities presented by the ethanolic extract of L. pinaster. Ethanolic extract and its chemical constituents can be considered promising agents in the therapeutic of inflammation, hyperuricemia and gout.
Determination of intestinal permeability using in situ perfusion model in rats : challenges and advantages to BCS classification applied to digoxin.
(2018) Caldeira, Tamires Guedes; Ruiz Picazo, Alejandro; Lozoya Agullo, Isabel; Guimarães, Dênia Antunes Saúde; González Álvarez, Marta; Souza, Jacqueline de; González Álvarez, Isabel; Bermejo, Marival
The purpose of this work was to describe the closed loop in situ perfusion method in rats and to compare the difficulties and advantages with other methods proposed by regulatory agencies for BCS classification and finally to illustrate its application to evaluate the permeability of digoxin at relevant clinical concentrations. Digoxin was evaluated at two concentration levels: 1.0 μg/ml (with and without sodium azide 65.0 μg/ml) and 6.0 μg/ ml. These concentrations correspond to the ratio of the highest dose strength (0.25 mg) and the highest single dose administered (1.5 mg) and the 250 ml of water. In situ closed loop perfusion studies in rats were performed in the whole small intestine and also in duodenum, jejunum and ileum segments to evaluate the relevance of Pgp secretion in the overall permeability. A kinetic modelling approach involving passive permeation and efflux transport mechanism allowed the estimation of the passive diffusional component and the Michaelis-menten parameters. The estimated Km value demonstrated that at clinical luminal concentrations the efflux process is not saturated and then it could be inhibited by other drugs, excipients or food components leading to the already reported clinical drug-drug and drug-food interations. The present data confirms from a mechanistic point of view these interactions.
Development and validation of a stability indicating method for quantification of the sesquiterpene lactone eremantholide C from Lychnophora trichocarpha (Brazilian arnica).
(2017) Henriques, Bárbara Oliveira; Guimarães, Dênia Antunes Saúde; Caldeira, Tamires Guedes; Souza, Jacqueline de
Pharmacological activities as anti-inflammatory, anti-hyperuricemic, anti-gouty arthritis, antitumor and trypanocidal activities of the aerial parts from Lychnophora trichocarpha (Spreng.) Spreng. ex Sch.Bip., Asteraceae (Brazilian arnica) have already been proved. Eremantholide C is a sesquiterpene lactone and one of the active chemical constituents responsible for these activities presented by L. trichocarpha. Therefore, the aim of this work was to develop and validate a stability indicating HPLC method for eremantholide C. Eremantholide C stability was evaluated in L. trichocarpha ethanolic extract and in its isolated form. Analytical conditions employed C18 column, acetonitrile/water in gradient elution, flow of 0.8 ml/min at 30 °C. To correct for the loss of analyte during sample preparation the use of coumarin as an internal standard was necessary. The developed method provides good separation and resolution of the peaks, allowing quantification of eremantholide C, isolated or directly in the ethanolic extract, in internal standard presence. Validation results showed that this method is linear in the concentration range 2–180 μg/ml, precise, accurate and specific. Stability studies showed that L. trichocarpha ethanolic extract and eremantholide C remain stable for 6 months when stored at room temperature and impermeable glass bottle, therefore they can be used safely and effectively within this period. While at 40 °C there was stability loss, at 8 °C a stability increase was observed for the extract and the isolated eremantholide C. Forced degradation studies showed that eremantholide C degraded under acidic and alkaline conditions and was stable for three days under neutral and oxidative conditions, and when exposed to high temperature. Thus, with the development of a stability indicative method and the application of it in eremantholide C stability studies, the results can guide the development of new products that adequately preserve the original features of the biologically active substance with quality, safety and efficacy.

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