RESUMEN

Breast cancer is the second most common diagnosed type of cancer in women. Chronic neuropathic pain after mastectomy occurs frequently and is a serious health problem. In our previous single-center, prospective, randomized controlled clinical study, we demonstrated that the combination of serratus anterior plane block (SAM) and pectoral nerve block type I (PECS I) with general anesthesia reduced acute postoperative pain. The present report describes a prospective follow-up study of this published study to investigate the development of chronic neuropathic pain 12 months after mastectomy by comparing the use of general anesthesia alone and general anesthesia with SAM + PECS I. Additionally, the use of analgesic medication, quality of life, depressive symptoms, and possible correlations between plasma levels of interleukin (IL)-1 beta, IL-6, and IL-10 collected before and 24 h after surgery as predictors of pain and depression were evaluated. The results showed that the use of SAM + PECS I with general anesthesia reduced numbness, hypoesthesia to touch, the incidence of patients with chronic pain in other body regions and depressive symptoms, however, did not significantly reduce the incidence of chronic neuropathic pain after mastectomy. Additionally, there was no difference in the consumption of analgesic medication and quality of life. Furthermore, no correlation was observed between IL-1 beta, IL-6, and IL-10 levels and pain and depression. The combination of general anesthesia with SAM + PECS I reduced the occurrence of specific neuropathic pain descriptors and depressive symptoms. These results could promote the use of SAM + PECS I blocks for the prevention of specific neuropathic pain symptoms after mastectomy.Registration of clinical trial: The Research Ethics Board of the Hospital Sirio-Libanes/Brazil approved the study (CAAE 48721715.0.0000.5461). This study is registered at Registro Brasileiro de Ensaios Clinicos (ReBEC), and ClinicalTrials.gov, Identifier: NCT02647385.

Asunto(s)

Neoplasias de la Mama , Neuralgia , Nervios Torácicos , Femenino , Humanos , Mastectomía/efectos adversos , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/complicaciones , Estudios de Seguimiento , Interleucina-10 , Estudios Prospectivos , Calidad de Vida , Interleucina-6/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Neuralgia/complicaciones , Músculos

Asunto(s)

Anestesiología , COVID-19 , Humanos , Pandemias , SARS-CoV-2

RESUMEN

Pectin (PC) extracted from a solid residue from cassava roots (Manihot esculenta Crantz) was used to coat nanoparticles (NP) containing ß-carotene (BC) aiming at the gastrointestinal administration of this lipophilic nutraceutical. The NP were prepared by spontaneous emulsification method using food grade components. Pectin-coated NP have been successfully prepared as confirmed by the increased particle size and negative surface charges due to the pectin's anionic nature. NP showed spherical shape and monodisperse distribution, with a mean size of 21.3 nm (polydispersity index (PDI) 0.29) for BC PC T80-NP (nanoparticle with ß-carotene, pectin and Tween 80) and 261.4 nm (PDI 0.1) for BC PC T20-NP (nanoparticle with ß-carotene, pectin and Tween 20). BC was encapsulated at amounts of 530 and 324 µg/ml for BC PC T80-NP and BC PC T20-NP, respectively, with high encapsulation efficiency (> 95%), increasing its antioxidant capacity in vitro, besides no cytotoxic effect. However, only BC PC T20-NP was stable over a 90 days storage period (4°C) and revealed a strong interaction between pectin and mucin. These results suggest that pectin-coated BC PC T20-NP is a promising strategy to improve the bioavailability and permeation of BC for administration through mucosal surfaces.

Asunto(s)

Manihot , Nanopartículas , Celulosa , Pectinas , beta Caroteno

RESUMEN

Hancornia speciosa is a medicinal plant with proven antihypertensive activity. The cyclitol l-(+)-bornesitol is the main constituent of its leaves and is a potent inhibitor of the angiotensin-converting enzyme. We herein investigated the pharmacokinetic properties of bornesitol administered orally to Wistar rats, as well as bornesitol permeation in Caco-2 cells. Bornesitol was isolated and purified from an ethanol extract of H. speciosa leaves. An ultra-high performance liquid chromatography coupled with electrospray ionization mass spectrometry (UPLC-ESI-MS/MS) method was developed and validated to quantify bornesitol in rat plasma based on Multiple Reaction Monitoring, using pentaerythritol as an internal standard. Pharmacokinetics was evaluated by the administration of single doses via intravenous in bolus (3 mg/kg) and gavage (3, 15 and 25 mg/kg). Bornesitol permeation was assayed in a transwell Caco-2 cells model, tested alone, or combined with rutin, or as a constituent of H. speciosa extract, using a developed and validated UPLC-ESI-MS/MS method. All assayed validation parameters (selectivity, residual effect, matrix effect, linearity, precision, accuracy and stability of analyte in plasma and solution) for the bioanalytical method met the acceptance criteria established by regulatory guidelines. Bornestiol reached peak plasma concentration within approximately 60 min after oral administration with a half-life ranging from 72.15 min to 123.69 min. The peak concentration and area under the concentration-time curve of bornesitol did not rise proportionally with the increasing doses, suggesting a non-linear pharmacokinetics in rats and the oral bioavailability ranged from 28.5%-59.3%. Bornesitol showed low permeability in Caco-2 cells, but the permeability apparently increased when it was administered either combined with rutin or as a constituent of H. speciosa extract. In conclusion, bornesitol was rapidly absorbed after a single oral administration to rats and followed a non-linear pharmacokinetics. The obtained data will be useful to guide further pre-clinical development of bornesitol-containing herbal preparations of H. speciosa as an antihypertensive agent.

Asunto(s)

Antihipertensivos/farmacocinética , Apocynaceae , Cromatografía Líquida de Alta Presión , Ciclitoles/farmacocinética , Extractos Vegetales/farmacocinética , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem , Administración Oral , Animales , Antihipertensivos/administración & dosificación , Antihipertensivos/sangre , Antihipertensivos/aislamiento & purificación , Apocynaceae/química , Disponibilidad Biológica , Células CACO-2 , Ciclitoles/administración & dosificación , Ciclitoles/sangre , Ciclitoles/aislamiento & purificación , Humanos , Inyecciones Intravenosas , Absorción Intestinal , Mucosa Intestinal/metabolismo , Masculino , Modelos Biológicos , Dinámicas no Lineales , Permeabilidad , Extractos Vegetales/administración & dosificación , Extractos Vegetales/sangre , Extractos Vegetales/aislamiento & purificación , Ratas Wistar

RESUMEN

Spondias mobin leaves have been traditionally used for treating cold sores. The study investigated the mechanism of antiherpes action of S. mombin extract, fractions, and geraniin. Different concentrations of samples were used to evaluate the in vitro antiherpes activity (anti-HSV-1) in virucidal, post-infection, attachment, and penetration assays. The mechanism of action of geraniin was investigated considering the glycoproteins gB and gD of HSV-1 surface as potential molecular targets. Molecular docking simulations were carried out for both in order to determine the possible binding mode position of geraniin at the activity sites. The binding mode position was posteriorly optimized considering the flexibility of the glycoproteins. The chemical analysis of samples was performed by LC-MS and revealed the presence of 22 substances, which are hydrolysable tannins, O-glycosylated flavonoids, phenolic acids, and a carbohydrate. The extract, tannin-rich fraction and geraniin showed important in vitro virucidal activity through blocking viral attachment but showed no relevant inhibition of viral penetration. The in silico approaches demonstrated a high number of potential strong intermolecular interactions as hydrogen bonds between geraniin and the activity site of the glycoproteins, particularly the glycoprotein gB. In silico experiments indicated that geraniin is at least partially responsible for the anti-herpes activity through interaction with the viral surface glycoprotein gB, which is responsible for viral adsorption. These results highlight the therapeutic potential of S. mombin anti-herpes treatment and provides support for its traditional purposes. However, further studies are required to validate the antiviral activities in vivo, as well as efficacy in humans.

Asunto(s)

Anacardiaceae , Antivirales , Herpes Simple , Herpesvirus Humano 1 , Herpesvirus Humano 2 , Humanos , Simulación del Acoplamiento Molecular , Extractos Vegetales , Hojas de la Planta , Células Vero , Replicación Viral

RESUMEN

Bipolar disorder is a chronic mood disorder characterized by episodes of mania and depression. The aim of this study was to investigate the effects of blackberry extract on behavioral parameters, oxidative stress and inflammatory markers in a ketamine-induced model of mania. Animals were pretreated with extract (200 mg/kg, once a day for 14 days), lithium chloride (45 mg/kg, twice a day for 14 days), or vehicle. Between the 8th and 14th days, the animals received an injection of ketamine (25 mg/kg) or vehicle. On the 15th day, thirty minutes after ketamine administration, the animals' locomotion was assessed using open-field apparatus. After the experiments, the animals were euthanized and cerebral structures were removed for neurochemical analyses. The results showed that ketamine treatment induced hyperlocomotion and oxidative damage in the cerebral cortex, hippocampus and striatum. In contrast, pretreatment with the extract or lithium was able to prevent hyperlocomotion and oxidative damage in the cerebral cortex, hippocampus, and striatum. In addition, IL-6 and IL-10 levels were increased by ketamine, while the extract prevented these effects in the cerebral cortex. Pretreatment with the extract was also effective in decreasing IL-6 and increasing the level of IL-10 in the striatum. In summary, our findings suggest that blackberry consumption could help prevent or reduce manic episodes, since this extract have demonstrated neuroprotective properties as well as antioxidant and anti-inflammatory effects in the ketamine-induced mania model.

Asunto(s)

Antocianinas , Frutas , Manía/metabolismo , Extractos Vegetales/farmacología , Rubus , Animales , Antimaníacos/farmacología , Conducta Animal/efectos de los fármacos , Catalasa/efectos de los fármacos , Catalasa/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Citocinas/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Antagonistas de Aminoácidos Excitadores/toxicidad , Glutatión Peroxidasa/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ketamina/toxicidad , Cloruro de Litio/farmacología , Manía/inducido químicamente , Manía/fisiopatología , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Prueba de Campo Abierto , Extractos Vegetales/química , Ratas , Superóxido Dismutasa/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo

RESUMEN

Aristolochia triangularis Cham., is one of the most frequently used medicinal plant in Southern Brazil. Preparations containing the leaves and/or stems are traditionally used as anti-inflammatory, diuretic, as well as antidote against snakebites. This study screened A. triangularis extracts, fractions and isolated compounds for different bioactivities. A weak antiproliferative activity against human lung cancer cell line (A549) was observed only for chloroform fraction obtained from stems (CFstems - CC50: 2.93 µg/mL). Also, a moderate antimicrobial activity against Staphylococcus aureus was detected just for chloroform fraction obtained from leaves (CFleaves -13-16 mm inhibition zone). Additionally, two semi-purified fractions (CFstems-4 and CFleaves-4) selectively inhibited HSV-1 replication (IC50 values of 0.40 and 2.61 µg/mL, respectively), while only CFleaves showed promising results against Leishmania amazonensis. Fractionation of extracts resulted in the isolation of one neolignan (-) cubebin and one lignan (+) galbacin. However, these compounds are not responsible for the in vitro bioactivities herein detected. The presence of aristolochic acid I and aristolochic acid II in the crude ethanol extract of stems (CEEstems) and leaves (CEEleaves) was also investigated. The HPLC analysis of these extracts did not display any peak with retention time or UV spectra comparable to aristolochic acids I and II.

Asunto(s)

Aristolochia/química , Fitoquímicos/química , Antibacterianos/farmacología , Antifúngicos/farmacología , Antiprotozoarios/farmacología , Antivirales/farmacología , Ácidos Aristolóquicos/química , Brasil , Fraccionamiento Químico , Cromatografía Líquida de Alta Presión/métodos , Humanos , Fitoquímicos/farmacología , Extractos Vegetales/farmacología

RESUMEN

The aim of this study is to describe the development of nanoemulsion-loaded hydrogels to deliver pentyl gallate (PG), a gallic acid n-alkyl ester, through the skin. PG is an antioxidant agent; however, it seems to be a promising agent for herpis labialis treatment. Aristoflex AVC® and chitosan were used as gelling agents for nanoemulsion thickening. The developed formulations presented suitable PG content (94.4-100.3% w/w), nanometric droplet sizes (162-297 nm), high zeta potentials, and a non-Newtonian pseudoplastic behavior. Both vehicles neither enhanced PG penetration nor delayed its release from the nanoemulsion. Formulations remained physically stable at 8°C during 3 months of storage.

Asunto(s)

Emulsiones/administración & dosificación , Ácido Gálico/análogos & derivados , Hidrogeles/administración & dosificación , Nanopartículas/administración & dosificación , Absorción Cutánea/efectos de los fármacos , Administración Tópica , Animales , Antioxidantes/administración & dosificación , Antioxidantes/metabolismo , Composición de Medicamentos , Emulsiones/metabolismo , Ácido Gálico/administración & dosificación , Ácido Gálico/metabolismo , Hidrogeles/metabolismo , Nanopartículas/metabolismo , Técnicas de Cultivo de Órganos , Piel/efectos de los fármacos , Piel/metabolismo , Absorción Cutánea/fisiología , Porcinos

RESUMEN

Surgery is the first-line treatment for early, localized, or operable breast cancer. Regional anesthesia during mastectomy may offer the prevention of postoperative pain. One potential protocol is the combination of serratus anterior plane block (SAM block) with pectoral nerve block I (PECS I), but the results and potential benefits are limited. Our study compared general anesthesia with or without SAM block + PECS I during radical mastectomy with axillary node dissection and breast reconstruction using evaluations of pain, opioid consumption, side effects and serum levels of interleukin (IL)-1beta, IL-6 and IL-10. This is a prospective, randomized controlled trial. Fifty patients were randomized to general anesthesia only or general anesthesia associated with SAM block + PECS I (25 per group). The association of SAM block + PECS I with general anesthesia reduced intraoperative fentanyl consumption, morphine use and visual analog pain scale scores in the post-anesthetic care unit (PACU) and at 24 h after surgery. In addition, the anesthetic protocol decreased side effects and sedation 24 h after surgery compared to patients who underwent general anesthesia only. IL-6 levels increased after the surgery compared to baseline levels in both groups, and no differences in IL-10 and IL-1 beta levels were observed. Our protocol improved the outcomes of mastectomy, which highlight the importance of improving mastectomy protocols and focusing on the benefits of regional anesthesia.

Asunto(s)

Anestesia General/métodos , Neoplasias de la Mama/cirugía , Mamoplastia/métodos , Mastectomía Radical Modificada/métodos , Bloqueo Nervioso/métodos , Dolor Postoperatorio/prevención & control , Adulto , Anciano , Analgésicos Opioides/uso terapéutico , Neoplasias de la Mama/sangre , Femenino , Humanos , Interleucina-10 , Interleucina-1beta/sangre , Interleucina-6/sangre , Persona de Mediana Edad , Dimensión del Dolor/efectos de los fármacos , Estudios Prospectivos , Resultado del Tratamiento

RESUMEN

BACKGROUND: Patients undergoing abdominal surgery for solid tumours frequently develop major postoperative complications, which negatively affect quality of life, costs of care and survival. Few studies have identified the determinants of perioperative complications in this group. METHODS: We performed a prospective observational study including all patients (age > 18) undergoing abdominal surgery for cancer at a single institution between June 2011 and August 2013. Patients undergoing emergency surgery, palliative procedures, or participating in other studies were excluded. Primary outcome was a composite of 30-day all-cause mortality and infectious, cardiovascular, respiratory, neurologic, renal and surgical complications. Univariate and multiple logistic regression analyses were performed to identify predictive factors for major perioperative adverse events. RESULTS: Of a total 308 included patients, 106 (34.4%) developed a major complication during the 30-day follow-up period. Independent predictors of postoperative major complications were: age (odds ratio [OR] 1.03 [95% CI 1.01-1.06], p = 0.012 per year), ASA (American Society of Anesthesiologists) physical status greater than or equal to 3 (OR 2.61 [95% CI 1.33-5.17], p = 0.003), a preoperative haemoglobin level lower than 12 g/dL (OR 2.13 [95% CI 1.21-4.07], p = 0.014), intraoperative use of colloids (OR 1.89, [95% CI 1.03-4.07], p = 0.047), total amount of intravenous fluids (OR 1.22 [95% CI 0.98-1.59], p = 0.106 per litre), intraoperative blood losses greater than 500 mL (2.07 [95% CI 1.00-4.31], p = 0.043), and hypotension needing vasopressor support (OR 4.68 [95% CI 1.55-27.72], p = 0.004). The model had good discrimination with the area under the ROC curve being 0.80 (95% CI 0.75-0.84, p < 0.001). CONCLUSIONS: Our findings suggest that a perioperative strategy aimed at reducing perioperative complications in cancer surgery should include treatment of preoperative anaemia and an optimal fluid strategy, avoiding fluid overload and intraoperative use of colloids.

Asunto(s)

Abdomen/cirugía , Procedimientos Quirúrgicos Electivos/estadística & datos numéricos , Neoplasias/epidemiología , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Anemia/epidemiología , Pérdida de Sangre Quirúrgica/estadística & datos numéricos , Brasil/epidemiología , Coloides/uso terapéutico , Comorbilidad , Femenino , Fluidoterapia/estadística & datos numéricos , Estudios de Seguimiento , Estado de Salud , Hemoglobinas , Humanos , Hipotensión/epidemiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo

RESUMEN

Several beneficial effects on the skin have been reported for coumestrol (COU), such as protection against photoaging and improvement of skin elasticity and thickness in postmenopausal women. However no reports on the effect of COU on wound healing were found. Nevertheless, COU has low aqueous solubility, which is a crucial limitation for biological tests. The present study was designed as a two-step experiment to evaluate the wound healing effect of COU. First, we used fibroblasts and the experimental in vitro artificial wound model, scratch assay, to compare the effects of COU free, dissolved in dimethyl sulfoxide (DMSO) or Dulbecco's modified Eagle's medium (DMEM), or associated with hydroxypropyl-ß-cyclodextrin (HPßCD). The 50 µM (66.1%) and 10 µM (56.3%) COU/HPßCD association induced cell proliferation and migration in inflicted wounds. Subsequently, the in vivo wound healing experimental model (Wistar rats) revealed that COU/HPßCD incorporated into hypromellose (HPMC) hydrogel had similar efficacy in wound healing in comparison to the positive control (Dersani®), with the advantage that 50% wound healing was achieved within a shorter period. In summary, the results successfully demonstrated, for the first time, the wound healing effect of COU/HPßCD incorporated into HPMC hydrogel and describe the feasibility of the biological tests with the use of HPßCD instead DMSO.

Asunto(s)

2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Antiinflamatorios/administración & dosificación , Cumestrol/administración & dosificación , Hidrogeles/administración & dosificación , Derivados de la Hipromelosa/administración & dosificación , Cicatrización de Heridas/efectos de los fármacos , 2-Hidroxipropil-beta-Ciclodextrina/química , Animales , Antiinflamatorios/química , Cumestrol/química , Hidrogeles/química , Derivados de la Hipromelosa/química , Masculino , Fitoestrógenos/administración & dosificación , Fitoestrógenos/química , Ratas Wistar , Piel/efectos de los fármacos , Piel/lesiones

RESUMEN

Cardiac glycosides (CGs) are natural compounds used traditionally to treat congestive heart diseases. Recent investigations repositioned CGs as potential anticancer agents. To discover novel cytotoxic CG scaffolds, we selected the cardenolide glucoevatromonoside (GEV) out of 46 CGs for its low nanomolar anti-lung cancer activity. GEV presented reduced toxicity toward non-cancerous cell types (lung MRC-5 and PBMC) and high-affinity binding to the Na+/K+-ATPase α subunit, assessed by computational docking. GEV-induced cell death was caspase-independent, as investigated by a multiparametric approach, and culminates in severe morphological alterations in A549 cells, monitored by transmission electron microscopy, live cell imaging and flow cytometry. This non-canonical cell death was not preceded or accompanied by exacerbation of autophagy. In the presence of GEV, markers of autophagic flux (e.g. LC3I-II conversion) were impacted, even in presence of bafilomycin A1. Cell death induction remained unaffected by calpain, cathepsin, parthanatos, or necroptosis inhibitors. Interestingly, GEV triggered caspase-dependent apoptosis in U937 acute myeloid leukemia cells, witnessing cancer-type specific cell death induction. Differential cell cycle modulation by this CG led to a G2/M arrest, cyclin B1 and p53 downregulation in A549, but not in U937 cells. We further extended the anti-cancer potential of GEV to 3D cell culture using clonogenic and spheroid formation assays and validated our findings in vivo by zebrafish xenografts. Altogether, GEV shows an interesting anticancer profile with the ability to exert cytotoxic effects via induction of different cell death modalities.

RESUMEN

Cardiac glycosides (CGs) are natural compounds widely used to treat several cardiac conditions and more recently have been recognized as potential antitumor agents. They are known as Na,K-ATPases ligands, which is a promising drug target in cancer. In this study, the short and long-lasting cytotoxic effects of the natural cardenolide digitoxigenin monodigitoxoside (DGX) were evaluated against two non-small cell lung cancer lines (A549 and H460 cells). It was found that DGX induced cytotoxic effects in both cells and the apoptotic effects were more pronounced on H460 cells. In long-term analysis, using the clonogenic and the cumulative population doubling (CPD) assays, DGX showed a reduction of cell survival, after 15days without re-treatment. To better understand DGX effects in A549 cells, several assays were conducted. In cell cycle analysis, DGX caused an arrest in S and G2/M phases. This compound also increased the number of cells in subG1 phase in a concentration- and time-dependent manner. The presence of ß-galactosidase positive cells, large nucleus and flattened cells indicated senescence. Additionally, DGX inhibited Na,K-ATPase activity in A549 cells, as well as in purified pig kidney and in human red blood cell membrane preparations, at nanomolar range. Moreover, results of molecular docking showed that DGX binds with high efficiency (-11.4Kcal/mol) to the Na,K-ATPase (PDB:4HYT). Taken together, our results highlight the potent effects of DGX both in A549 and H460 cells, and disclose its link with Na,K-ATPase inhibition.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Digitoxigenina/análogos & derivados , Neoplasias Pulmonares/tratamiento farmacológico , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Células A549 , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/patología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Digitoxigenina/farmacología , Humanos , Neoplasias Pulmonares/patología , Simulación del Acoplamiento Molecular , Porcinos , Factores de Tiempo

RESUMEN

Cardenolides are cardiac glycosides, mostly obtained from natural sources. They are well known for their inhibitory action on the Na,K-ATPase, an effect that regulates cardiovascular alterations such as congestive heart failure and atrial arrhythmias. In recent years, they have also sparked new interest in their anticancer potential. In the present study, the cytotoxic effects of the natural cardenolide convallatoxin (CON) were evaluated on non-small cell lung cancer (A549 cells). It was found that CON induced cytostatic and cytotoxic effects in A549 cells, showing essentially apoptotic cell death, as detected by annexin V-propidium iodide double-staining, as well as changes in cell form. In addition, it prompted cell cycle arrest in G2/M and reduced cyclin B1 expression. This compound also increased the number of cells in subG1 in a concentration- and time-dependent manner. At a long term, the reduction of cumulative population doubling was shown along with an increase of ß-galactosidase positive cells and larger nucleus, indicative of senescence. Subsequently, CON inhibited the Na,K-ATPase in A549 cells at nM concentrations. Interestingly, at the same concentrations, CON was unable to directly inhibit the Na,K-ATPase, either in pig kidney or in red blood cells. Additionally, results of docking calculations showed that CON binds with high efficiency to the Na,K-ATPase. Taken together, our data highlight the potent anticancer effects of CON in A549 cells, and their possible link with non-classical inhibition of Na,K-ATPase.

Asunto(s)

Antineoplásicos Fitogénicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Estrofantinas/farmacología , Células A549 , Animales , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Eritrocitos/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Riñón/efectos de los fármacos , Riñón/enzimología , Neoplasias Pulmonares/tratamiento farmacológico , Simulación del Acoplamiento Molecular , ATPasa Intercambiadora de Sodio-Potasio/química , Porcinos

RESUMEN

Antioxidants are substances that defend cells against damage, kidnapping and destroying free radicals. They have been largely used in the food industry due the possibility to control the oxidation process, aimed to increase shelf life. Thus, esterification reaction to obtain ascorbyl linoleate catalyzed by Novozym 435 lipase assisted by ultrasound bath was investigated. In this work, molecular sieve (4 Å) was added to the reaction medium to remove the water formed during the esterification reaction to improve the process performance. According to the results, ascorbyl linoleate production up to 90 % was reached after 1 h of reaction time carried out using ultrasound bath, 1:9 molar ratio of substrates L-ascorbic acid to linoleic acid, 20 mL of tert-butanol as organic solvent, 5 wt% of Novozym 435 lipase, 10 wt% of molecular sieve at 70 °C.

Asunto(s)

Ácido Ascórbico/análogos & derivados , Ácidos Linoleicos/síntesis química , Lipasa/química , Ácido Ascórbico/síntesis química , Ácido Ascórbico/química , Enzimas Inmovilizadas , Proteínas Fúngicas , Ácidos Linoleicos/química

RESUMEN

Thalidomide (THD) is a BCS class II drug with renewed and growing therapeutic applicability. Along with the low aqueous solubility, additional poor biopharmaceutical properties of the drug, i.e. chemical instability, high crystallinity, and polymorphism, lead to a slow and variable oral absorption. In this view, we developed solid dispersions (SDs) containing THD dispersed in different self-emulsifying carriers aiming at an enhanced absorption profile for the drug. THD was dispersed in lauroyl macrogol-32 glycerides (Gelucire® 44/14) and α-tocopherol polyethylene glycol succinate (Kolliphor® TPGS), in the presence or absence of the precipitation inhibitor polyvinylpyrrolidone K30 (PVP K30), by means of the solvent method. Physicochemical analysis revealed the formation of semicrystalline SDs. X-ray diffraction and infrared spectroscopy analyses suggest that the remaining crystalline fraction of the drug in the SDs did not undergo polymorphic transition. The impact of the solubility-enhancing formulations on the THD biopharmaceutical properties was evaluated by several in vitro techniques. The developed SDs were able to increase the apparent solubility of the drug (up to 2-3x the equilibrium solubility) for a least 4 h. Dissolution experiments (paddle method, 75 rpm) in different pHs showed that around 80% of drug dissolved after 120 min (versus 40% of pure crystalline drug). Additionally, we demonstrated the enhanced solubility obtained via SDs could be translated into increased flux in a parallel artificial membrane permeability assay (PAMPA). In summary, the results demonstrate that SDs could be considered an interesting and unexplored strategy to improve the biopharmaceutical properties of THD, since SDs of this important drug have yet to be reported.

Asunto(s)

Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Membranas Artificiales , Talidomida/química , Talidomida/metabolismo , Química Farmacéutica , Portadores de Fármacos/administración & dosificación , Permeabilidad/efectos de los fármacos , Solubilidad , Talidomida/administración & dosificación , Difracción de Rayos X

RESUMEN

Previous studies have demonstrated the antiherpes activity of pentyl gallate (PG), suggesting that it could be a promising candidate for the topical treatment of human herpes labialis. PG low aqueous solubility represents a major drawback to its incorporation in topical dosage forms. Hence, the feasibility of incorporating PG into nanoemulsions, the ability to penetrate the skin, to inhibit herpes simplex virus (HSV)-1 replication, and to cause dermal sensitization or toxicity were evaluated. Oil/water nanoemulsions containing 0.5% PG were prepared by spontaneous emulsification. The in vitro PG distribution into porcine ear skin after topical application of nanoemulsions was assessed, and the in vitro antiviral activity against HSV-1 replication was evaluated. Acute dermal toxicity and risk of dermal sensitization were evaluated in rat model. Nanoemulsions presented nanometric particle size (from 124.8 to 143.7 nm), high zeta potential (from -50.1 to -66.1 mV), loading efficiency above 99%, and adequate stability during 12 months. All formulations presented anti-HSV-1 activity. PG was able to reach deeper into the dermis more efficiently from the nanoemulsion F4. This formulation as well as PG were considered safe for topical use. Nanoemulsions seem to be a safe and effective approach for topically delivering PG in the treatment of human herpes labialis infection.

Asunto(s)

Antivirales/administración & dosificación , Antivirales/uso terapéutico , Ácido Gálico/análogos & derivados , Herpes Labial/tratamiento farmacológico , Administración Tópica , Animales , Antivirales/toxicidad , Estabilidad de Medicamentos , Emulsiones , Ácido Gálico/administración & dosificación , Ácido Gálico/uso terapéutico , Ácido Gálico/toxicidad , Herpesvirus Humano 1/efectos de los fármacos , Irritantes , Masculino , Ratas , Ratas Wistar , Absorción Cutánea , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/patología , Solubilidad , Porcinos , Replicación Viral/efectos de los fármacos

RESUMEN

Cardiac glycosides consist of a large family of naturally derived compounds that are clinically used to treat congestive heart failure, and also present anticancer properties. In this study, the cytotoxic effects of two cardenolides, digitoxigenin monodigitoxoside (DGX) and convallatoxin (CON) were screened in four human tumour cell lines. Both compounds showed anti-proliferative effects in all tumour cells, at nanomolar concentrations. Since the human lung cancer cell line A549 was the most sensitive, we investigated the anti-proliferative, anti-migratory and anti-invasive effects of these cardenolides. DGX and CON reduced A549 cell migration, being able to reduce more than 90% of cell invasion. Their effects on the expression of key regulators of metastatic mechanism showed decreased levels of MMP-2, MMP-9 and p-FAK. Both compounds also presented low toxicity for healthy cells. Finally, this work provides the first insights into the effects of these cardenolides on key steps of lung cancer metastasis.

Asunto(s)

Cardenólidos/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Digitoxigenina/análogos & derivados , Neoplasias Pulmonares/patología , Células A549 , Glicósidos Cardíacos/farmacología , Línea Celular Tumoral , Digitoxigenina/farmacología , Humanos , Metástasis de la Neoplasia/tratamiento farmacológico , Estrofantinas/farmacología

RESUMEN

Five new polyoxygenated marine steroids-punicinols A-E (1-5)-were isolated from the gorgonian Leptogorgia punicea and characterized by spectroscopic methods (IR, MS, 1H, 13C and 2-D NMR). The five compounds induced in vitro cytotoxic effects against lung cancer A549 cells, while punicinols A and B were the most active, with IC50 values of 9.7 µM and 9.6 µM, respectively. The synergistic effects of these compounds with paclitaxel, as well as their effects on cell cycle distribution and their performance in the clonogenic assay, were also evaluated. Both compounds demonstrated significant synergistic effects with paclitaxel.

Asunto(s)

Antozoos/química , Esteroides/química , Esteroides/farmacología , Animales , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Espectroscopía de Resonancia Magnética/métodos , Paclitaxel/farmacología