RESUMEN
BACKGROUND: Elagolix is an oral, gonadotropin-releasing hormone (GnRH) receptor antagonist, that significantly reduces dysmenorrhea and non-menstrual pelvic pain (NMPP) in women with moderate to severe endometriosis-associated pain. METHODS: Data were pooled from two 6-month, placebo-controlled, phase 3 studies (Elaris Endometriosis [EM]-I and II) in which 2 doses of elagolix were evaluated (150 mg once daily and 200 mg twice daily). Pooled data from > 1600 women, aged 18-49, were used to evaluate the efficacy of elagolix and health-related quality of life (HRQoL) in prespecified subgroups of women with various baseline characteristics. RESULTS: Of the 1686 women treated, 1285 (76.2%) completed the studies. The percentages of women with clinically meaningful reductions in dysmenorrhea and NMPP were generally consistent by subgroup. Significant treatment by subgroup interaction was demonstrated for dysmenorrhea response in baseline analgesic use (p < 0.01) and previous history of pregnancy (p < 0.05) subgroups, and for NMPP response in the baseline NMPP score (p < 0.05) and history of pregnancy (p < 0.05) subgroups. Patient-reported reduction in pain at month 3 was significant across all subgroups taking elagolix 200 mg BID, and significant across most subgroups with elagolix 150 mg QD. Women across subgroups experienced improvement within each domain of the Endometriosis Health Profile-30 (EHP-30), although significant treatment by subgroup interactions were observed in several categories. CONCLUSIONS: Elagolix was effective in reducing dysmenorrhea and NMPP, and improving HRQoL, compared with placebo across numerous subgroups of women with various baseline characteristics, covering a broad segment of the endometriosis disease and patient types. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: https://www.clinicaltrials.gov/ct2/show/NCT01620528 ; https://www.clinicaltrials.gov/ct2/show/NCT01931670 .
Asunto(s)
Endometriosis , Dismenorrea/tratamiento farmacológico , Endometriosis/complicaciones , Endometriosis/tratamiento farmacológico , Femenino , Humanos , Hidrocarburos Fluorados , Dolor Pélvico/tratamiento farmacológico , Dolor Pélvico/etiología , Pirimidinas , Calidad de VidaRESUMEN
In the last 20 years, N-Heterocyclic Carbene (NHC) ligands have been ubiquitous in biological and medicinal chemistry. Part of their success lies in the tremendous number of topologies that can be synthesized and thus finely tuned that have been described so far. This is particularly true in the case of those derivatives, including fluorine or fluorinated fragments on their NHC moieties, gaining much attention due to their enhanced biological properties and turning them into excellent candidates for the development of novel metallodrugs. Thus, this review summarizes the development that fluorinated-NHC transition metal complexes have had and their impact on cancer treatment.
Asunto(s)
Antineoplásicos/química , Complejos de Coordinación/química , Compuestos Heterocíclicos/química , Hidrocarburos Fluorados/química , Metano/análogos & derivados , Elementos de Transición/química , Animales , Antineoplásicos/farmacología , Química Farmacéutica , Complejos de Coordinación/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Flúor/química , Halogenación , Humanos , Metano/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Chlordane is a worldwide banned organochlorine insecticide because of its hazard to animal and human health. It is also a persistent organic pollutant, which can affect either the soil or the aquatic life. The same applies to other chlorinated cyclodiene insecticides, such as dieldrin and aldrin. In turn, organofluorine compounds have a widespread use in agriculture. Therefore, density functional calculations and docking studies showed that the bioisosteric replacement of chlorines in the above-mentioned compounds by fluorines improves some physicochemical parameters used to estimate the toxicity and environmental risk of these compounds, as well as the ligand-enzyme (GABAA receptor-chloride channel complex) interactions related to their insecticidal activity. This work is an effort to provide an improved new class of organofluorine pesticides.
Asunto(s)
Hidrocarburos Clorados/química , Hidrocarburos Fluorados/química , Modelos Teóricos , Plaguicidas/química , Receptores de GABA-A/química , Animales , Fenómenos Químicos , Halogenación , Humanos , Hidrocarburos Clorados/farmacología , Hidrocarburos Clorados/toxicidad , Hidrocarburos Fluorados/farmacología , Hidrocarburos Fluorados/toxicidad , Simulación del Acoplamiento Molecular , Plaguicidas/farmacología , Plaguicidas/toxicidadRESUMEN
The trifluoromethyl anion (CF3 - ) displays 13 C NMR chemical shift (175.0 ppm) surprisingly larger than neutral (CHF3 , 122.2 ppm) and cation (CF3 + , 150.7 ppm) compounds. This unexpected deshielding effect for a carbanion is investigated by density functional theory calculations and decomposition analyses of the 13 C shielding tensor into localized molecular orbital contributions. The present work determines the shielding mechanisms involved in the observed behaviour of the fluorinated anion species, shedding light on the experimental NMR data and demystify the classical correlation between electron density and NMR chemical shift. The presence of fluorine atoms induces the carbon lone pair to create a paramagnetic shielding on the carbon nucleus.
Asunto(s)
Hidrocarburos Fluorados/química , Aniones , Isótopos de Carbono , Espectroscopía de Resonancia MagnéticaRESUMEN
Among the realm of visible light photocatalytic transformations, late-stage difluoromethylation reactions (introduction of difluoromethyl groups in the last stages of synthetic protocols) have played relevant roles as the CF2X group substitutions exert positive impacts on the physical properties of organic compounds including solubility, metabolic stability, and lipophilicity, which are tenets of considerable importance in pharmaceutical, agrochemical, and materials science. Visible-light-photocatalyzed difluoromethylation reactions are shown to be accomplished on (hetero)aromatic and carbon-carbon unsaturated aliphatic substrates under mild and environmentally benign conditions.
Asunto(s)
Alquenos/química , Carbono/química , Hidrocarburos Fluorados/química , Catálisis , Estructura Molecular , Compuestos Orgánicos/químicaRESUMEN
This article reviews eight drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations.
Asunto(s)
Aprobación de Drogas , Amidas , Angiotensina II/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Azetidinas/uso terapéutico , Clonidina/análogos & derivados , Clonidina/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Hidrocarburos Fluorados/uso terapéutico , Piperazinas , Purinas , Pirazoles , Piridonas , Pirimidinas/uso terapéutico , Silicatos/uso terapéutico , Sulfonamidas/uso terapéutico , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Malaria represents a significant health issue, and novel effective drugs are needed to address parasite resistance that has emerged to the current drug arsenal. The most popular antimalarial drugs are focused on the 7-chloro-4-aminoquinoline [e.g., chloroquine (CQ), amodiaquine (AQ), isoquine (IQ), and tebuquine (TBQ)], artemisinin, and atovaquone systems. Recently, endochin has been used as a platform to design a variety of novel potent and safe antimalarial agents named endochin-like quinolones (ELQs). Also, antimalarial quinolones have been constructed from other quinolones drugs such as ICI-56780 and floxacrine. Trifluoromethyl substitution has provided a significant increase in the antimalarial response of many of the designed ELQs against Plasmodium-resistant strains and for in vivo models. In particular, attachment of a substituted trifluoromethoxy (or trifluoromethyl in some cases) biaryl side chain at 2-, 3-, 4-, or 6-position of the quinolone core has shown to be crucially important to generate selective and potent novel ELQs. Furthermore, 6-chloro and 7-methoxy moieties on the quinolone core have been identified as essential pharmacophores when the trifluoromethoxy biaryl side chain is placed at 2- or 3-position of the quinolone core. Methyl or ethyl ester attached at 3-position is essential when the trifluoromethoxy aryl side chain is attached at 6- or 7-position of the quinolone core. Some promising ELQs are currently under clinical trials, representing an excellent platform for the design of new potent, selective, effective, and safe antimalarial drugs against emergent resistance malarial models.
Asunto(s)
Antimaláricos/síntesis química , Diseño de Fármacos , Hidrocarburos Fluorados/química , Quinolonas/síntesis química , Antimaláricos/química , Antimaláricos/farmacología , Hidrocarburos Fluorados/farmacología , Malaria Falciparum/tratamiento farmacológico , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/efectos de los fármacos , Quinolonas/química , Quinolonas/farmacologíaRESUMEN
Perfluorinated compounds, including fluorotelomers, are important constituents of firefighting foams to extinguish fuel fires in the petrochemical industry, airports, and at fire-training sites. In this study, we monitored the biodegradation process in a co-contamination scenario with monoaromatic hydrocarbons commonly found in fuels (benzene, toluene) and fluorotelomers. The CO2 production rates were evaluated by a factorial design taking into account the effect of seasonality at in situ natural attenuation processes. Headspace analysis by gas chromatography with a thermal conductivity detector (GC-TCD) was applied to detect CO2 production, whereas monoaromatics were analyzed by gas chromatography coupled to mass spectrometry (GC-MS). According to our results, seasonality had a detectable effect during summer, yielding different CO2 production rates. Higher temperatures increased CO2 production rate, while higher concentrations of fluorotelomer inhibited the biodegradation process. On average, benzene and toluene were depleted 17.5 days earlier in control assays without fluorotelomers. Toluene removal efficiency was also notably higher than benzene. The noticeable decrease in degradation rates of monoaromatics was caused by perfluorinated compounds that are possibly linked to metabolic inhibition mechanisms. Fluorotelomer diminished catabolism in all of our batch cultures. In addition to this, an alternative production of by-products could be detected. Thus, we propose that transient components of the benzene and toluene degradation may be differentially formed, causing the benzene, toluene, and perfluorinated co-contaminations to go through switched metabolic stages under the presence of fluoride in a contamination scenario.
Asunto(s)
Hidrocarburos Aromáticos/metabolismo , Hidrocarburos Fluorados/metabolismo , Contaminantes del Suelo/metabolismo , Benceno/química , Benceno/metabolismo , Biodegradación Ambiental , Dióxido de Carbono , Incendios , Cromatografía de Gases y Espectrometría de Masas/métodos , Halogenación , Hidrocarburos Aromáticos/análisis , Hidrocarburos Aromáticos/química , Hidrocarburos Fluorados/análisis , Hidrocarburos Fluorados/química , Microbiología del Suelo , Contaminantes del Suelo/análisis , Contaminantes del Suelo/química , Tolueno/química , Tolueno/metabolismoRESUMEN
Liver X receptors (LXR) are important transcription factors involved in the regulation of carbohydrate and lipid metabolism. Recently, we described LXR receptors expression in the hypothalamus but their function in this brain area remains unknown. Here, we evaluated the function of LXR on the expression of factors produced in the hypothalamus in vitro and in vivo by Western blotting and immunocytochemistry. More precisely we studied the expression of GnRH and GHRH, αMSH and NPY in male Sprague-Dawley rats. The effects of two synthetic LXR agonists, T0901317 and GW3965, were first tested in vitro. Hypothalamic explants were treated with either T0901317 or GW3965 (10µM) for 2, 4, 6 and 8h. As a positive control the cholesterol ABCA1 and glucose GLUT2 transporters were used. No changes were observed in the expression of the factors evaluated in vitro. The effects of the LXR agonists were then tested in vivo. Rats were injected ICV into the third ventricle with either T0901317 or GW3965 (2.5µg/5µL ICV) and after 3.5h or 24h the hypothalami were dissected out and rapidly frozen for analysis. αMSH and GnRH expression was significantly increased after 3.5h of T0901317 treatment. Anterior/posterior hypothalamic ratio increases for αMSH expression and decreases for GnRH expression after 24h of LXR activation. Altogether these results show that LXR activation affects the expression of GnRH and αMSH, suggesting that LXR in the hypothalamus is capable of modulating hypothalamic responses related to appetite, sexual behavior and reproductive functions.
Asunto(s)
Hormona Liberadora de Gonadotropina/biosíntesis , Hipotálamo/metabolismo , Receptores X del Hígado/metabolismo , alfa-MSH/biosíntesis , Animales , Expresión Génica , Hormona Liberadora de Gonadotropina/genética , Hidrocarburos Fluorados/farmacología , Hipotálamo/efectos de los fármacos , Receptores X del Hígado/agonistas , Masculino , Ratas , Ratas Sprague-Dawley , Sulfonamidas/farmacología , alfa-MSH/genéticaRESUMEN
A nano-composite from biologically obtained chitin nanofillers homogenously dispersed in a poly(ε-caprolactone) matrix was successfully achieved by an ultrasonication-assisted non-toxic and non-aqueous methodology. For this purpose, biological chitin was obtained from lactic acid fermentation of shrimp wastes and converted into chitin whiskers by acidic hydrolysis in a novel process at low temperature (4°C) that enhanced the distribution and yield. Additionally, the polyester matrix was enzymatically produced in a non-toxic compressed fluid (1,1,1,2-tetrafluoroethane at 25bar and 65°C) medium. The homogeneous distribution of the nanofiller in the matrix was corroborated by confocal and atomic force microscopies. Films of the nanocomposite were physicochemically characterized to assess its adequate properties. Additionally, the qualitative viability of human fibroblasts and osteoblasts cells was studied on the produced nanocomposite films showing good biocompatibility.
Asunto(s)
Quitina/química , Nanocompuestos/química , Nanopartículas/química , Poliésteres/química , Adulto , Animales , Candida/enzimología , Niño , Quitina/aislamiento & purificación , Fibroblastos , Tecnología Química Verde , Humanos , Hidrocarburos Fluorados/química , Hidrólisis , Lactobacillus plantarum/química , Lipasa/química , Osteoblastos , Tamaño de la Partícula , Penaeidae/químicaRESUMEN
There has been an increasing interest in the study of fluorinated derivatives of gamma-aminobutyric acid (GABA), an acetylcholine (AC) analog. This work reports a theoretical study on the effect of an α-carbonyl fluorination in AC, aiming at understanding the role of a distant fluorine relative to the positively charged nitrogen on the conformational folding of the resulting fluorinated AC. In addition, the chemical and structural changes were evaluated on the basis of ligand-enzyme (acetylcholinesterase) interactions. In an enzyme-free environment, the fluorination yields conformational changes relative to AC due to the appearance of some attractive interactions with fluorine and a weaker steric repulsion between the fluorine substituent and the carboxyl group, rather than to a possible electrostatic interaction Fâ â â N+ . Moreover, the gauche orientation in the N-C-C-O fragment of AC owing to the electrostatic gauche effect is reinforced after fluorination. For instance, the conformational equilibrium in AC is described by a competition between gauche and anti conformers (accounting for the N-C-C-O dihedral angle) in DMSO, while the population for a gauche conformer in the fluorinated AC is almost 100 % in both gas phase and DMSO. However, this arrangement is disrupted in the biological environment even in the fluorinated derivative (whose bioconformation-like geometry shows a ligand-protein interaction of -84.1â kcal mol-1 against -79.5â kcal mol-1 for the most stable enzyme-free conformation), which shows an anti N-C-C-O orientation, because the enzyme induced-fit takes place. Nevertheless, the most likely bioconformation for the fluorinated AC does not match the bioactive AC backbone nor the most stable enzyme-free conformation, thus revealing the role of fluorination on the bioconformational control of AC.
Asunto(s)
Acetilcolina/química , Halogenación , Hidrocarburos Fluorados/química , Teoría Cuántica , Acetilcolina/metabolismo , Hidrocarburos Fluorados/síntesis química , Conformación Molecular , Método de MontecarloRESUMEN
Two mononuclear MnIII complexes [Mn(3,5-F2salpn)(H2O)2][B(C6H5)4]·2H2O (1·2H2O) and [Mn(3,5-Cl2salpn)(OAc)(H2O)]·H2O (2·H2O), where H2salpn=1,3-bis(salicylidenamino)propane, have been prepared and characterized. The crystal structure of 1·H2O shows that this complex forms µ-aqua dimers with a short Mnâ¯Mn distance of 4.93Å. Under anaerobic conditions, the two complexes are stable in solution and possess trans-diaxial symmetry with the tetradentate Schiff base ligand symmetrically arranged in the equatorial plane. When left in air, these complexes slowly dimerize to yield high-valent [MnIV2(3,5-X2-salpn)2(µ-O)2] in which each X2-salpn ligand wraps the two Mn ions. This process is favored in basic medium where the deprotonation of the bound water molecule is concomitant with air oxidation. The two complexes catalyze the dismutation of superoxide (superoxide dismutase (SOD) activity) and peroxide (catalase (CAT) activity) in basic medium. The phenyl-ring substituents play an important role on the CAT reaction but have little effect on SOD activity. Kinetics and spectroscopic results indicate that 1 and 2 catalyze H2O2 disproportionation through a cycle involving MnIII2 and MnIV2 dimers, unlike related complexes with a more rigid and smaller chelate ring, which employ MnIII/MnVO monomers.
Asunto(s)
Antioxidantes , Catalasa/química , Complejos de Coordinación , Hidrocarburos Clorados , Hidrocarburos Fluorados , Manganeso/química , Superóxido Dismutasa/química , Antioxidantes/síntesis química , Antioxidantes/química , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Hidrocarburos Clorados/síntesis química , Hidrocarburos Clorados/química , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/química , Bases de Schiff/síntesis química , Bases de Schiff/químicaRESUMEN
OBJECTIVES: Activators of soluble guanylyl cyclase (sGC) act preferentially in conditions of enzyme oxidation or haem group removal. This study was designed to investigate the effects of the sGC activator BAY 60-2770 in murine airways inflammation and human eosinophil chemotaxis. METHODS: C57Bl/6 mice treated or not with BAY 60-2770 (1 mg/kg/day, 14 days) were intranasally challenged with ovalbumin (OVA). At 48 h, bronchoalveolar lavage fluid (BALF) was performed, and circulating blood, bone marrow and lungs were obtained. Human eosinophils purified from peripheral blood were used to evaluate the cell chemotaxis. RESULTS: OVA-challenge promoted marked increases in eosinophil number in BAL, lung tissue, circulating blood and bone marrow, all of which were significantly reduced by BAY 60-2770. The IL-4 and IL-5 levels in BALF were significantly reduced by BAY 60-2770. Increased protein expression of iNOS, along with decreases of expression of sGC (α1 and ß1 subunits) and cGMP levels were detected in lung tissue of OVA-challenged mice. BAY 60-2770 fully restored to baseline the iNOS and sGC subunit expressions, and cGMP levels. In human isolated eosinophils, BAY 60-2770 (1-5 µM) had no effects on the cGMP levels and eotaxin-induced chemotaxis; however, prior incubation with ODQ (10 µM) markedly elevated the BAY 60-2770-induced cyclic GMP production, further inhibiting the eosinophil chemotaxis. CONCLUSIONS: BAY 60-2770 reduces airway eosinophilic inflammation and rescue the sGC levels. In human eosinophils under oxidized conditions, BAY 60-2770 elevates the cGMP levels causing cell chemotaxis inhibition. BAY 60-2770 may reveal a novel therapeutic target for asthma treatment.
Asunto(s)
Benzoatos/farmacología , Compuestos de Bifenilo/farmacología , Eosinófilos/efectos de los fármacos , Hidrocarburos Fluorados/farmacología , Inflamación/tratamiento farmacológico , Guanilil Ciclasa Soluble/efectos de los fármacos , Animales , Antiasmáticos/farmacología , Asma/tratamiento farmacológico , Asma/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Quimiotaxis/efectos de los fármacos , GMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Eosinófilos/metabolismo , Humanos , Inflamación/inmunología , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ovalbúmina/inmunología , Guanilil Ciclasa Soluble/metabolismoRESUMEN
Osteoporosis is a chronic disease that impairs proper bone remodeling. Guided bone regeneration is a surgical technique that improves bone defect in a particular region through new bone formation, using barrier materials (e.g. membranes) to protect the space adjacent to the bone defect. The polytetrafluorethylene membrane is widely used in guided bone regeneration, however, new membranes are being investigated. The purpose of this study was to evaluate the effect of P(VDFTrFE)/BT [poly(vinylidene fluoride-trifluoroethylene)/barium titanate] membrane on in vivo bone formation. Twenty-three Wistar rats were submitted to bilateral ovariectomy. Five animals were subjected to sham surgery. After 150 days, bone defects were created and filled with P(VDF-TrFE)/BT membrane or PTFE membrane (except for the sham and OVX groups). After 4 weeks, the animals were euthanized and calvaria samples were subjected to histomorphometric and computed microtomography analysis (microCT), besides real time polymerase chain reaction (real time PCR) to evaluate gene expression. The histomorphometric analysis showed that the animals that received the P(VDF-TrFE)/BT membrane presented morphometric parameters similar or even better compared to the animals that received the PTFE membrane. The comparison between groups showed that gene expression of RUNX2, BSP, OPN, OSX and RANKL were lower on P(VDF-TrFE)/BT membrane; the gene expression of ALP, OC, RANK and CTSK were similar and the gene expression of OPG, CALCR and MMP9 were higher when compared to PTFE. The results showed that the P(VDF-TrFE)/BT membrane favors bone formation, and therefore, may be considered a promising biomaterial to support bone repair in a situation of osteoporosis.
Asunto(s)
Compuestos de Bario/química , Hidrocarburos Fluorados/química , Osteogénesis , Osteoporosis/cirugía , Titanio/química , Compuestos de Vinilo/química , Animales , Materiales Biocompatibles/química , Regeneración Ósea , Trasplante Óseo , Huesos/metabolismo , Catepsina K/metabolismo , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Metaloproteinasa 9 de la Matriz/metabolismo , Membranas Artificiales , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoporosis/metabolismo , Ligando RANK/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Receptores de Calcitonina/metabolismo , Microtomografía por Rayos XRESUMEN
Fluorination reactions of medicinal and biologically-active compounds will be discussed. Late stage fluorination strategies of medicinal targets have recently attracted considerable attention on account of the influence that a fluorine atom can impart to targets of medicinal importance, such as modulation of lipophilicity, electronegativity, basicity and bioavailability, the latter as a consequence of membrane permeability. Therefore, the recourse to late-stage fluorine substitution on compounds with already known and relevant biological activity can provide the pharmaceutical industry with new leads with improved medicinal properties. The fluorination strategies will take into account different fluorinating reagents, either of nucleophilic or electrophilic, and of radical nature. Diverse families of organic compounds such as (hetero)aromatic rings, and aliphatic substrates (sp(3), sp(2), and sp carbon atoms) will be studied in late-stage fluorination reaction strategies.
Asunto(s)
Descubrimiento de Drogas , Hidrocarburos Fluorados/síntesis química , Flúor/química , Halogenación , Hidrocarburos Fluorados/química , Estructura MolecularRESUMEN
The poly(vinylidene-trifluoroethylene)/barium titanate (PVDF) membrane enhances in vitro osteoblast differentiation and in vivo bone repair. Here, we hypothesized that this higher bone repair could be also due to bone resorption inhibition mediated by a microRNA (miR)/RANKL circuit. To test our hypothesis, the large-scale miR expression of bone tissue grown on PVDF and polytetrafluoroethylene (PTFE) membranes was evaluated to identify potential RANKL-targeted miRs modulated by PVDF. The animal model used was rat calvarial defects implanted with either PVDF or PTFE. At 4 and 8 weeks, the bone tissue grown on membranes was submitted to a large-scale analysis of miRs by microarray. The expression of miR-34a and some of its targets, including RANKL, were evaluated by real-time polimerase chain reaction and osteoclast activity was detected by tartrate-resistant acid phosphatase (TRAP) staining. Among more than 250 miRs, twelve, including miR-34a, were simultaneously higher expressed (≥2 fold) at 4 and 8 weeks on PVDF. The higher expression of miR-34a was concomitant with a reduced expression of all its evaluated targets, including RANKL. Additionally, more TRAP-positive cells were observed in bone tissue grown on PTFE compared with PVDF in both time points. In conclusion, our results suggest that the higher bone formation induced by PVDF could be, at least in part, triggered by a miR-34a increase and RANKL decrease, which may inhibit osteoclast differentiation and activity, and bone resorption.
Asunto(s)
Compuestos de Bario/química , Regeneración Ósea , Hidrocarburos Fluorados/química , MicroARNs/metabolismo , Osteoblastos/citología , Ligando RANK/metabolismo , Titanio/química , Compuestos de Vinilo/química , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Huesos/metabolismo , Diferenciación Celular , Expresión Génica , Membranas Artificiales , Osteoblastos/metabolismo , Osteogénesis , Ratas WistarRESUMEN
OBJECTIVE: To evaluate the inhibitory effect of soluble guanylate cyclase (sGC) stimulator, BAY 41-2272 (5-cyclopropyl-2-[1-(2-fluorobenzyl)- 1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4-ylamine) or activator, BAY 60-2770 (4-({(4- carboxybutyl) [2- (5-fluoro-2-{[40-(trifluoromethyl) biphenyl- 4-yl]methoxy}phenyl)ethyl] amino}methyl)benzoic acid), in human and rabbit prostate smooth muscle contractility. MATERIALS AND METHODS: In rabbit or human prostate, contractions induced by electrical field stimulation or phenylephrine (PE) were carried out in the presence of sGC stimulator, BAY 41-2272, or sGC activator, BAY 60-2770. The potency (pEC50) and maximal response (Emax) values were determined. Immunohistochemistry analysis for sGC α1-subunit and quantification of intracellular levels of cyclic guanosine monophosphate (cGMP) were also performed. RESULTS: In rabbit prostate, BAY 60-2770 (30 and 300 nM) inhibited the contractions induced by PE and electrical field stimulation. The coincubation with sGC inhibitor, ODQ, produced greater inhibitions on PE-induced contractions in comparison with BAY 60-2770 alone, mainly due to greater cGMP accumulation (70- and 5.7-fold, respectively). BAY 41-2272 (300 nM) increased and decreased, respectively, cGMP levels and PE-induced contractions, but in the presence of ODQ these effects were reversed. In human prostate, immunohistochemistry analysis revealed the presence of sGC α1-subunit on the transition zone. BAY 60-2770 (300 nM) reduced significantly Emax induced by PE in human prostate. CONCLUSION: sGC activator seems to be a promising alternative to treat benign prostatic hyperplasia because it increases cGMP levels even when sGC is oxidized.
Asunto(s)
Benzoatos/farmacología , Compuestos de Bifenilo/farmacología , Hidrocarburos Fluorados/farmacología , Contracción Muscular/efectos de los fármacos , Próstata/efectos de los fármacos , Próstata/fisiología , Pirazoles/farmacología , Piridinas/farmacología , Animales , Humanos , Masculino , ConejosRESUMEN
Although the anticonvulsant activity of 3-hydroxy-3-ethyl-3-phenylproionamide (HEPP) is well-known, its use is limited by the pharmacotoxicological profile. We herein tested its fluorinated and chlorinated derivatives (F-HEPP and Cl-HEPP) with two seizure models, maximal electroshock seizures (MES), and intraperitoneal pentylenetetrazole (PTZ) administration. Neurotoxicity was examined via the rotarod test. With in silico methods, binding was probed on possible protein targets-GABAA receptors and the sodium channel Nav1.2. The median effective doses (ED50) of HEPP, F-HEPP, and Cl-HEPP in the MES seizure model were 129.6, 87.1, and 62.0 mg/kg, respectively, and 66.4, 43.5, and in the PTZ seizure model 43.5 mg/kg. The HEPP-induced neurotoxic effect, which occurred at twice the ED50 against MES (p < 0.05), did not occur with F-HEPP or Cl-HEPP. Docking studies revealed that all tested ligands bound to GABAA receptors on a site near to the benzodiazepine binding site. However, on the sodium channel open pore Nav1.2, R-HEPP had interactions similar to those reported for phenytoin, while its enantiomer and the ligands F-HEPP and Cl-HEPP reached a site that could disrupt the passage of sodium. Our results show that, as anticonvulsant agents, parahalogen substituted compounds have an advantageous pharmacotoxicological profile compared to their precursor.
Asunto(s)
Anticonvulsivantes , Hidrocarburos Clorados , Hidrocarburos Fluorados , Fenilpropionatos , Convulsiones/tratamiento farmacológico , Animales , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Electrochoque , Hidrocarburos Clorados/efectos adversos , Hidrocarburos Clorados/farmacología , Hidrocarburos Fluorados/efectos adversos , Hidrocarburos Fluorados/química , Hidrocarburos Fluorados/farmacología , Masculino , Ratones , Simulación del Acoplamiento Molecular , Canal de Sodio Activado por Voltaje NAV1.2/metabolismo , Fenilpropionatos/efectos adversos , Fenilpropionatos/química , Fenilpropionatos/farmacología , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Convulsiones/metabolismoRESUMEN
The hydrolysis of chitin treated under supercritical conditions was successfully carried out using chitinases obtained by an optimized fermentation of the fungus Lecanicillium lecanii. The biopolymer was subjected to a pretreatment based on suspension in supercritical 1,1,1,2-tetrafluoroethane (scR134a), which possesses a critical temperature and pressure of 101°C and 40bar, respectively, followed by rapid depressurization to atmospheric pressure and further fibrillation. This methodology was compared to control untreated chitins and chitin subjected to steam explosion showing improved production of reducing sugars (0.18mg/mL), enzymatic hydrolysis and high acetylation (FA of 0.45) in products with degrees of polymerization between 2 and 5.