RESUMEN

The continued increase of the demand for seed of the Pacific oyster (Crassostrea gigas) has driven the aquaculture industry to produce land-based hatcheries using broodstock conditioning. This has led to the need to create closed systems to control the main factors involved in reproduction (temperature and food). Additionally, reproductive synchronization of broodstocks may be considered to ensure homogeneous maturation and spawning among the organisms. In this work, we synchronized the broodstock reproductive stage of Pacific oysters in a recirculating aquaculture system (RAS) using a "preconditioning" process and evaluated the effect of the water quality and the CO2-carbonate system on preconditioned broodstock. The oysters were kept at 12 °C for 45 days in a RAS containing a calcium reactor (C2) or without a calcium reactor (C1, control). Water quality parameters were measured daily, and the oyster's condition and reproductive development were monitored using condition index, biometrics, and histology, on Days 0, 20, and 45. C1 and C2 systems kept the water quality within the ranges reported as favorable for bivalves. The calcium reactor kept the pH (8.03-8.10), alkalinity (200 mg/L as CaCO3), CO32- (≤ 80 µmol/kg), and Ω aragonite (≤ 1) closer to the ranges reported as optimal for bivalves. However, no significant differences were detected in the total weight and the condition index in C1 and C2. The preconditioning allowed to maintain the organisms in early reproductive development, allowing gametogenesis synchronization to start maturation.

Asunto(s)

Crassostrea , Animales , Dióxido de Carbono/farmacología , Calcio/farmacología , Calidad del Agua , Carbonatos/farmacología , Acuicultura , Calcio de la Dieta/farmacología

RESUMEN

Neglected tropical diseases are a major health problem throughout the world, and there are few effective and safe drugs. In this study, we report the design and synthesis of a novel series of carbonates of eugenol using different aliphatic alcohols and N,N-carbonyldiimidazole. Spectroscopic techniques, including 1 H nuclear magnetic resonance (NMR), 13 C NMR, Fourier transform infrared, and high-resolution mass spectrometry, were used to confirm the structures of the synthesized compounds. In vitro and in silico studies of prodrugs of eugenol were performed to determine their antiplasmodial, trypanocidal, and leishmanicidal activities, and also their cytotoxicity. Compounds were highly active against Leishmania braziliensis and Plasmodium falciparum, whereas the activity shown for Trypanosoma cruzi was moderate. Molecular docking was used to determine a possible mode of action of eugenol against the dihydroorotate dehydrogenase of the three parasites (TcDHODH, LbDHODH, and PfDHODH). Notably, the docking results showed that eugenol not only has binding energy similar to that of the natural substrate (-7.2 and -7.1, respectively) but also has interactions with relevant biological residues of PfDHODH. This result indicates that eugenol could act as a substrate for PfDHODH in the pyrimidine biosynthesis pathway of P. falciparum. In conclusion, the combination of certain aliphatic alcohols and eugenol through a carbonate bond could significantly increase the antiparasitic activity of this class of compounds, which merits further studies.

Asunto(s)

Leishmania braziliensis , Trypanosoma cruzi , Carbonatos/farmacología , Eugenol/farmacología , Simulación del Acoplamiento Molecular , Plasmodium falciparum , Relación Estructura-Actividad

RESUMEN

Pulmonary arterial hypertension (PAH) is characterized by the remodeling of pulmonary arteries, with an increased pulmonary arterial pressure and right ventricle (RV) overload. This work investigated the benefit of the association of human umbilical cord mesenchymal stem cells (hMSCs) with lodenafil, a phosphodiesterase-5 inhibitor, in an animal model of PAH. Male Wistar rats were exposed to hypoxia (10% O2) for three weeks plus a weekly i.p. injection of a vascular endothelial growth factor receptor inhibitor (SU5416, 20 mg/kg, SuHx). After confirmation of PAH, animals received intravenous injection of 5.105 hMSCs or vehicle, followed by oral treatment with lodenafil carbonate (10 mg/kg/day) for 14 days. The ratio between pulmonary artery acceleration time and RV ejection time reduced from 0.42 ± 0.01 (control) to 0.24 ± 0.01 in the SuHx group, which was not altered by lodenafil alone but was recovered to 0.31 ± 0.01 when administered in association with hMSCs. RV afterload was confirmed in the SuHx group with an increased RV systolic pressure (mmHg) of 52.1 ± 8.8 normalized to 29.6 ± 2.2 after treatment with the association. Treatment with hMSCs + lodenafil reversed RV hypertrophy, fibrosis and interstitial cell infiltration in the SuHx group. Combined therapy of lodenafil and hMSCs may be a strategy for PAH treatment.

Asunto(s)

Antihipertensivos/farmacología , Carbonatos/farmacología , Hipertensión Pulmonar/terapia , Hipertrofia Ventricular Derecha/terapia , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Inhibidores de Fosfodiesterasa 5/farmacología , Piperazinas/farmacología , Pirimidinas/farmacología , Administración Oral , Animales , Terapia Combinada/métodos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Modelos Animales de Enfermedad , Humanos , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/genética , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/fisiopatología , Hipoxia/genética , Hipoxia/metabolismo , Hipoxia/fisiopatología , Hipoxia/terapia , Indoles/farmacología , Masculino , Células Madre Mesenquimatosas/fisiología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Resultado del Tratamiento , Cordón Umbilical/citología , Cordón Umbilical/fisiología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo

RESUMEN

Alkalization is a step of cocoa processing and consists of the use of alkali and high temperature to improve the sensorial and technological qualities of cocoa. Intense food processing can select spores, which can compromise safety and quality of the final product. Thus, the aim of this study was to evaluate the fate of B. cereus and G. stearothermophilus spores during the alkalization of pre-roasted (Pr) nibs (held at 120 °C) and unroasted (Ur) nibs (held at 90 °C) using potassium carbonate (0, 2, 4 and 6% w/w). In all conditions, log-linear inactivation kinetics with a tail was observed. The inactivation rate (kmax) for B. cereus varied from 0.065 to 1.67 min-1, whereas the kmax for G. stearothermophilus varied from 0.012 to 0.063 min-1. For both microorganisms, the lowest kmax values were observed during Ur nibs alkalization. The carbonate concentration increase promoted kmax values reduction. The highest tail values were observed for G. stearothermophilus in Ur nibs alkalization, reaching 3.04 log spores/g. Tail formation and low kmax values indicated that cocoa alkalization does not cause significant reductions on bacterial spore population. Therefore, the microbiological control should be primarily ensured by the raw material quality and by avoiding recontamination in the cocoa chain.

Asunto(s)

Álcalis/química , Bacillus cereus/crecimiento & desarrollo , Cacao/química , Cacao/microbiología , Geobacillus stearothermophilus/crecimiento & desarrollo , Viabilidad Microbiana/efectos de los fármacos , Carbonatos/farmacología , Manipulación de Alimentos , Microbiología de Alimentos , Calor , Potasio/farmacología , Esporas Bacterianas

RESUMEN

OBJECTIVE: The combination of calcium phosphate with blood-derived growth factors (BDGF) has been widely used in bone regeneration procedures although its benefits are still unclear. The purpose of this study was to evaluate whether or not BDGF improves the efficacy of a modified carbonated calcium phosphate biomaterial in sinus floor augmentation. MATERIAL AND METHODS: Ten patients underwent 20 sinus floor augmentation procedures using nanostructured carbonated hydroxyapatite (cHA) microspheres alone or associated with BDGF in a randomized controlled clinical trial. The in vitro release of growth factors was assessed by an elution assay. Bone grafts were randomly implanted in the right and left maxillary sinuses of each participant, associated either with a 0.9% saline solution or BDGF. Bone gain was evaluated through cone beam tomography after 180 days. RESULTS: Nine women and one man composed the sample. The blood-derived concentrates were able to release high levels of growth factors and cytokines. A significant clinical advantage was observed in the use of the BDGF after fibrin polymerization around the biomaterial microspheres, optimizing the surgical procedures, thereby reducing the time and displacement, and improving the adaptation of the biomaterial in the maxillary sinus. No synergistic effect was observed in bone formation when cHA was associated with BDGF (p > 0.05). CONCLUSION: Equivalent new bone formation was observed for cHA in the presence or absence of the BDGF concentrate in bilateral sinus floor elevation after 6 months. Blood-derived growth factors did not improve bone repair when associated with calcium phosphate in sinus lift procedures.

Asunto(s)

Materiales Biocompatibles/farmacología , Regeneración Ósea/efectos de los fármacos , Sustitutos de Huesos/química , Sustitutos de Huesos/farmacología , Trasplante Óseo/métodos , Péptidos y Proteínas de Señalización Intercelular/sangre , Péptidos y Proteínas de Señalización Intercelular/farmacología , Elevación del Piso del Seno Maxilar/métodos , Anciano , Sustitutos de Huesos/síntesis química , Fosfatos de Calcio/química , Fosfatos de Calcio/farmacología , Carbonatos/química , Carbonatos/farmacología , Durapatita/química , Durapatita/farmacología , Femenino , Humanos , Masculino , Microscopía Electrónica de Rastreo , Microesferas , Persona de Mediana Edad , Nanoestructuras/química , Resultado del Tratamiento

RESUMEN

This study aimed to evaluate bone repair in rat dental sockets after implanting nanostructured carbonated hydroxyapatite/sodium alginate (CHA) and nanostructured carbonated hydroxyapatite/sodium alginate containing 5% strontium microspheres (SrCHA) as bone substitute materials. Twenty male Wistar rats were randomly divided into two experimental groups: CHA and SrCHA (n=5/period/group). After one and 6 weeks of extraction of the right maxillary central incisor and biomaterial implantation, 5 µm bone blocks were obtained for histomorphometric evaluation. The parameters evaluated were remaining biomaterial, loose connective tissue and newly formed bone in a standard area. Statistical analysis was performed by Mann-Withney and and Wilcoxon tests at 95% level of significance. The histomorphometric results showed that the microspheres showed similar fragmentation and bio-absorbation (p>0.05). We observed the formation of new bones in both groups during the same experimental periods; however, the new bone formation differed significantly between the weeks 1 and 6 (p=0.0039) in both groups. The CHA and SrCHA biomaterials were biocompatible, osteoconductive and bioabsorbable, indicating their great potential for clinical use as bone substitutes.

Asunto(s)

Alginatos/farmacología , Regeneración Ósea/efectos de los fármacos , Sustitutos de Huesos/farmacología , Carbonatos/farmacología , Durapatita/farmacología , Nanoestructuras/uso terapéutico , Estroncio/farmacología , Alveolo Dental/efectos de los fármacos , Alginatos/química , Animales , Regeneración Ósea/fisiología , Sustitutos de Huesos/química , Trasplante Óseo/métodos , Carbonatos/química , Durapatita/química , Ácido Glucurónico/química , Ácido Glucurónico/farmacología , Ácidos Hexurónicos/química , Ácidos Hexurónicos/farmacología , Masculino , Nanoestructuras/química , Osteogénesis/efectos de los fármacos , Osteogénesis/fisiología , Distribución Aleatoria , Ratas Wistar , Reproducibilidad de los Resultados , Espectroscopía Infrarroja por Transformada de Fourier , Estroncio/química , Factores de Tiempo , Alveolo Dental/fisiología , Resultado del Tratamiento

RESUMEN

ABSTRACT Objective: This study aimed to evaluate bone repair in rat dental sockets after implanting nanostructured carbonated hydroxyapatite/sodium alginate (CHA) and nanostructured carbonated hydroxyapatite/sodium alginate containing 5% strontium microspheres (SrCHA) as bone substitute materials. Methods: Twenty male Wistar rats were randomly divided into two experimental groups: CHA and SrCHA (n=5/period/group). After one and 6 weeks of extraction of the right maxillary central incisor and biomaterial implantation, 5 μm bone blocks were obtained for histomorphometric evaluation. The parameters evaluated were remaining biomaterial, loose connective tissue and newly formed bone in a standard area. Statistical analysis was performed by Mann-Withney and and Wilcoxon tests at 95% level of significance. Results: The histomorphometric results showed that the microspheres showed similar fragmentation and bio-absorbation (p>0.05). We observed the formation of new bones in both groups during the same experimental periods; however, the new bone formation differed significantly between the weeks 1 and 6 (p=0.0039) in both groups. Conclusion: The CHA and SrCHA biomaterials were biocompatible, osteoconductive and bioabsorbable, indicating their great potential for clinical use as bone substitutes.

Asunto(s)

Animales , Masculino , Estroncio/farmacología , Regeneración Ósea/efectos de los fármacos , Carbonatos/farmacología , Durapatita/farmacología , Sustitutos de Huesos/farmacología , Alveolo Dental/efectos de los fármacos , Nanoestructuras/uso terapéutico , Alginatos/farmacología , Osteogénesis/efectos de los fármacos , Osteogénesis/fisiología , Estroncio/química , Factores de Tiempo , Regeneración Ósea/fisiología , Carbonatos/química , Distribución Aleatoria , Reproducibilidad de los Resultados , Trasplante Óseo/métodos , Resultado del Tratamiento , Ratas Wistar , Espectroscopía Infrarroja por Transformada de Fourier , Durapatita/química , Sustitutos de Huesos/química , Alveolo Dental/fisiología , Ácido Glucurónico/farmacología , Ácido Glucurónico/química , Nanoestructuras/química , Alginatos/química , Ácidos Hexurónicos/farmacología , Ácidos Hexurónicos/química

RESUMEN

Few efforts have been made in Mexico to monitor Rhagoletis pomonella (Walsh) (Diptera: Tephritidae) in commercial hawthorn (Crataegus spp.) crops. Therefore, the main objectives of this study were to evaluate infestation levels of R. pomonella in feral and commercial Mexican hawthorn and to assess the efficacy of different trap-lure combinations to monitor the pest. Wild hawthorn was more infested than commercially grown hawthorn at the sample site. No differences among four commercial baits (Biolure, ammonium carbonate, CeraTrap, and Captor + borax) were detected when used in combination with a yellow sticky gel (SG) adherent trap under field conditions. However, liquid lures elicited a slightly higher, although not statistically different, capture. Cage experiments in the laboratory revealed that flies tended to land more often on the upper and middle than lower-bottom part of polyethylene (PET) bottle traps with color circles. Among red, orange, green, and yellow circles attached to a bottle trap, only yellow circles improved fly captures compared with a colorless trap. A PET bottle trap with a red circle over a yellow background captured more flies than a similar trap with yellow circles. An SG adherent yellow panel trap baited with ammonium carbonate was superior to the improved PET bottle trap (red over a yellow background) baited with different liquid proteins, but a higher proportion of females and no differences in fly detection were measured in PET traps baited with protein lures. These trials open the door for future research into development of a conventional nonadherent trap to monitor or control R. pomonella.

Asunto(s)

Carbonatos/farmacología , Control de Insectos/instrumentación , Feromonas/farmacología , Fototaxis , Tephritidae/fisiología , Animales , Color , Crataegus/crecimiento & desarrollo , Femenino , Masculino , México , Odorantes/análisis , Tephritidae/efectos de los fármacos

RESUMEN

The aim of this study was to evaluate the impact of group psychotherapy and the use of a phosphodiesterase-5 inhibitor (PDE-5i) in the early rehabilitation stage of patients with prostate cancer undergoing radical prostatectomy (RP). Fifty-six patients undergoing RP for prostate cancer were randomised into four groups, and 53 completed the protocol: Group 1 - control (n = 11), Group 2 - group psychotherapy (n = 16), Group 3 - lodenafil 80 mg/one tablet per week (n = 12) and Group 4 - group psychotherapy + lodenafil 80 mg/one tablet per week (n = 14). The groups were individually evaluated for erectile function (IIEF-5) and quality of life - QoL (SF-36) weekly, with two meetings held a week apart before the RP and 12 weekly meetings after surgery. The ages ranged from 39 to 76 years, average 61.84. There were no significant medication side effects. Only Group 4 showed improvement in intimacy with a partner and satisfaction with their sex life (P = 0.045 and P = 0.013 respectively), and with no significant worsening of the IIEF-5 (P = 0.250) reported. All groups showed worsening in the final result of the role limitations caused by physical problems (P = 0.009) and role limitations caused by emotional problems (P = 0.002) of the SF-36, but Group 4 had a significantly higher score for the role limitations caused by physical problems (P = 0.009) than the other groups. In conclusion, precocious integral treatment involving group psychotherapy and PDE-5i before and after RP led to less deterioration of erectile function and other domains related to physical aspects (SF-36), with improvement in intimacy with their partner and satisfaction in their sex life, being superior to single treatments.

Asunto(s)

Carbonatos/uso terapéutico , Disfunción Eréctil/tratamiento farmacológico , Erección Peniana/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Piperazinas/uso terapéutico , Prostatectomía/efectos adversos , Psicoterapia , Pirimidinas/uso terapéutico , Calidad de Vida/psicología , Adulto , Anciano , Carbonatos/farmacología , Terapia Combinada , Disfunción Eréctil/etiología , Disfunción Eréctil/psicología , Humanos , Masculino , Persona de Mediana Edad , Erección Peniana/psicología , Inhibidores de Fosfodiesterasa 5/farmacología , Piperazinas/farmacología , Estudios Prospectivos , Prostatectomía/psicología , Neoplasias de la Próstata/psicología , Neoplasias de la Próstata/cirugía , Pirimidinas/farmacología , Resultado del Tratamiento

RESUMEN

Hydroxyapatite serves as a bioactive material for biomedical purposes, because it shares similarities with the inorganic part of the bone. However, how this material deposits on metallic surfaces using biomimetic matrices remains unclear. In this study, we deposited dihexadecyl phosphate, a phospholipid that bears a simple chemical structure, on stainless steel and titanium surfaces using the Langmuir-Blodgett (LB) technique; we employed the resulting matrix to grow carbonated hydroxyapatite. We obtained the calcium phosphate coating via a two-step process: we immersed the surfaces modified with the LB films into phosphate buffer, and then, we exposed the metal to a solution that simulated the concentration of ions in the human plasma. The latter step generated carbonated hydroxyapatite, the same mineral existing in the bone. The free energy related to the surface roughness and composition increased after we modified the supports. We investigated the film morphology by scanning electron and atomic force microscopies and determined surface composition by infrared spectroscopy and energy dispersive X-ray. We also studied the role of the surface roughness and the surface chemistry on cell viability. The surface-modified Ti significantly increased osteoblastic cells proliferation, supporting the potential use of these surfaces as osteogenic materials.

Asunto(s)

Carbonatos/química , Durapatita/química , Metales/química , Organofosfatos/química , Animales , Carbonatos/farmacología , Supervivencia Celular/efectos de los fármacos , Durapatita/farmacología , Humanos , Microscopía de Fuerza Atómica , Microscopía Electrónica de Rastreo , Organofosfatos/farmacología , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Presión , Ratas , Espectrometría por Rayos X , Espectroscopía Infrarroja por Transformada de Fourier , Acero Inoxidable/química , Propiedades de Superficie , Temperatura

RESUMEN

To simulate daily episodes of high absorption associated with the intake of diets with high N content, four wethers (42 ± 3.4 kg body weight), fitted with permanent catheters in the femoral artery and splanchnic vessels, were infused with 340 µmol into the mesenteric vein for 3 h, during the morning meal, over seven consecutive days. On the 7th day, mass transfers of , urea, glucose, lactate, ß-OH-butyrate and O2 were measured across portal-drained viscera (PDV), liver and splanchnic tissues during the last 90 min of the infusion. Measurements were repeated on the following day, at the same time, without the infusion. Plasma concentration in the portal vein (+332 µm; p = 0.006), portal absorption (+424 µmol/min; p < 0.001), liver uptake (+375 µmol/min; p = 0.003) and urea N production (+338 µmol/min; p = 0.059) were higher during infusion. Mass transfers of urea, glucose, lactate, ß-OH-butyrate and O2 across the PDV, and glucose, lactate, ß-OH-butyrate and O2 across the liver, were not altered by the infusion. Results suggest that a daily, discontinuous increase in portal flow during a meal stimulates liver removal and urea N production but does not significantly affect liver glucose production and O2 consumption in sheep.

Asunto(s)

Carbonatos/farmacología , Venas Mesentéricas , Oxígeno/sangre , Ovinos/metabolismo , Circulación Esplácnica/fisiología , Equilibrio Ácido-Base , Amoníaco/sangre , Animales , Carbonatos/administración & dosificación , Carbonatos/sangre , Carbonatos/farmacocinética , Inyecciones Intravenosas , Masculino , Oxígeno/metabolismo , Ovinos/sangre

RESUMEN

Oryzias latipes (Adrianichthyidae), known as Japanese medaka or Japanese killifish, is a small 2-4 cm long fish common in rice paddies in coastal Southeast Asia and is also a popular aquarium fish. It has been widely used as a research model because of its small size and because it is very easy to rear. Alkalinity stress is considered to be one of the major stressors on fish in saline-alkaline water. As very little is known about molecular genetic responses of aquatic organisms to alkalinity stress, we examined genome-wide gene expression profiles of Japanese medaka in response to carbonate alkalinity stress. Adult fish were exposed to freshwater and high carbonate alkaline water in the laboratory. We designed a microarray containing 26,429 genes for measuring gene expression change in the gills of the fish exposed to high carbonate alkalinity stress. Among these genes, 512 were up-regulated and 501 were down-regulated in the gills. These differentially expressed genes can be divided into gene groups using gene ontology, including biological processes, cellular components and molecular function. These gene groups are related to acid-base and ion regulation, cellular stress response, metabolism, immune response, and reproduction processes. Biological pathways including amino sugar and nucleotide sugar metabolism, porphyrin and chlorophyll metabolism, metabolism of xenobiotics by cytochrome P450, drug metabolism, aminoacyl-tRNA biosynthesis, glycine, serine and threonine metabolism, ascorbate and aldarate metabolism, pentose and glucuronate interconversions, glutathione metabolism, and fructose and mannose metabolism were significantly up-regulated. Alkalinity stress stimulates the energy and ion regulation pathways, and it also slows down the pathways related to the immune system and reproduction.

Asunto(s)

Álcalis/farmacología , Perfilación de la Expresión Génica , Oryzias/genética , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/genética , Transcriptoma/genética , Equilibrio Ácido-Base/efectos de los fármacos , Equilibrio Ácido-Base/genética , Animales , Carbonatos/farmacología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Oryzias/sangre , Oryzias/inmunología , Concentración Osmolar , Consumo de Oxígeno/efectos de los fármacos , Consumo de Oxígeno/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los Resultados , Reproducción/efectos de los fármacos , Reproducción/genética , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética

RESUMEN

BACKGROUND: Millions of men around the world suffer from erectile dysfunction, for which phosphodiesterase 5 inhibitors (PDE-5 inhibitors) are currently the first treatment option. Sexual activity and alcohol consumption are closely related, and the simultaneous use of alcohol and PDE-5 inhibitors can happen. Lodenafil carbonate is a new PDE-5 inhibitor, developed by a Brazilian pharmaceutical company. OBJECTIVE: This work aimed at evaluating the cardiovascular safety of lodenafil carbonate, with and without simultaneous alcohol consumption. METHODS: Fifteen male volunteers received 160 mg lodenafil carbonate (LC), in three different moments. Participants were assigned to three groups, treated with LC in fasting condition, with alcohol or receiving only placebo. The volunteers were continuously monitored during 24 hours for physical impairment, blood pressure, heart rate, QT interval and lodenafil's pharmacokinetic parameters. RESULTS: Lodenafil carbonate alone or with alcohol did not induce clinically relevant modifications in arterial blood pressure or heart rate. A statistically significant decrease in blood pressure was seen four hours after LC and alcohol intake, and an increase in heart rate six hours after intake of lodenafil carbonate alone. The QTc interval was not significantly modified. Lodenafil carbonate bioavailability was increased in 74% when drug intake was associated with alcohol. CONCLUSION: These results show that the use of lodenafil carbonate did not have clinically relevant effects on blood pressure or heart rate, and was not associated with QT interval prolongation. The association of lodenafil carbonate and alcohol affected its pharmacokinetic properties, increasing the bioavailability of the drug.

Asunto(s)

Consumo de Bebidas Alcohólicas , Carbonatos/farmacología , Sistema Cardiovascular/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Pirimidinas/farmacología , Adolescente , Adulto , Consumo de Bebidas Alcohólicas/metabolismo , Consumo de Bebidas Alcohólicas/fisiopatología , Análisis de Varianza , Disponibilidad Biológica , Presión Sanguínea/efectos de los fármacos , Carbonatos/farmacocinética , Sistema de Conducción Cardíaco/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa/farmacocinética , Piperazinas/farmacocinética , Pirimidinas/farmacocinética , Adulto Joven

RESUMEN

FUNDAMENTO: A disfunção erétil afeta um grande número de homens no mundo e os inibidores de PDE 5 (iPDE5) estão entre os principais métodos de tratamento desses pacientes. O consumo social de álcool e o ato sexual apresentam uma relação considerável. Portanto, a associação entre álcool e iPDE5 pode ocorrer. O carbonato de lodenafila é um novo iPDE5 desenvolvido por uma empresa brasileira. OBJETIVO: Avaliar a repercussão cardiovascular do carbonato de lodenafila, associado ou não ao álcool, assim como as alterações na farmacocinética que esta associação possa determinar. MÉTODOS: Estudo realizado com 15 voluntários sadios que receberam em momentos diferentes o carbonato de lodenafila (CL) na dose de 160 mg em jejum, CL (160 mg) com álcool, ou somente placebo. Esses pacientes foram monitorados por 24 horas, sendo avaliado o quadro clínico, a pressão arterial (PA), a frequência cardíaca (FC), o intervalo QT e também os dados de farmacocinética. RESULTADOS: O carbonato de lodenafila, isoladamente ou associado com álcool, não determinou alterações clínicas significativas na PA ou FC, embora tenha ocorrido diminuição da PA estatisticamente significativa após 4 horas, nos voluntários que receberam medicamento e álcool, assim como um aumento da FC após 6 horas nos pacientes que receberam o CL. A análise do intervalo QT corrigido não mostrou alteração significativa. O álcool aumentou a biodisponibilidade do medicamento em 74 por cento. Houve somente 2 queixas de cefaleia leve, possivelmente associada ao medicamento. CONCLUSÃO: O carbonato de lodenafila, mesmo associado ao álcool, não determinou repercussões clínicas importantes na PA, FC, ou alterações no intervalo QTc; a ingestão com álcool, por sua vez, aumentou significativamente sua biodisponibilidade.

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BACKGROUND: Millions of men around the world suffer from erectile dysfunction, for which phosphodiesterase 5 inhibitors (PDE-5 inhibitors) are currently the first treatment option. Sexual activity and alcohol consumption are closely related, and the simultaneous use of alcohol and PDE-5 inhibitors can happen. Lodenafil carbonate is a new PDE-5 inhibitor, developed by a Brazilian pharmaceutical company. OBJECTIVE: This work aimed at evaluating the cardiovascular safety of lodenafil carbonate, with and without simultaneous alcohol consumption. METHODS: Fifteen male volunteers received 160 mg lodenafil carbonate (LC), in three different moments. Participants were assigned to three groups, treated with LC in fasting condition, with alcohol or receiving only placebo. The volunteers were continuously monitored during 24 hours for physical impairment, blood pressure, heart rate, QT interval and lodenafil's pharmacokinetic parameters. RESULTS: Lodenafil carbonate alone or with alcohol did not induce clinically relevant modifications in arterial blood pressure or heart rate. A statistically significant decrease in blood pressure was seen four hours after LC and alcohol intake, and an increase in heart rate six hours after intake of lodenafil carbonate alone. The QTc interval was not significantly modified. Lodenafil carbonate bioavailability was increased in 74 percent when drug intake was associated with alcohol. CONCLUSION: These results show that the use of lodenafil carbonate did not have clinically relevant effects on blood pressure or heart rate, and was not associated with QT interval prolongation. The association of lodenafil carbonate and alcohol affected its pharmacokinetic properties, increasing the bioavailability of the drug.

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FUNDAMENTO: La disfunción eréctil afecta a un gran número de hombres en el mundo y los inhibidores de PDE5 (iPDE5) están entre los principales métodos de tratamiento de estos pacientes. El consumo social de alcohol y el acto sexual presentan una relación considerable. Por lo tanto, puede ocurrir una asociación entre alcohol e iPDE5. El carbonato de lodenafila es un nuevo iPDE5 desarrollado por una empresa brasileña. OBJETIVO: Evaluar la repercusión cardiovascular del carbonato de lodenafila, asociado o no al alcohol, así como las alteraciones en la farmacocinética que esta asociación pueda determinar. MÉTODOS: Estudio realizado con 15 voluntarios sanos que recibieron en momentos diferentes el carbonato de lodenafila (CL) en la dosis de 160mg en ayunas, CL (160 mg) con alcohol, o solamente placebo. Estos pacientes fueron monitoreados por 24 horas, siendo evaluado el cuadro clínico, la presión arterial (PA), la frecuencia cardíaca (FC), el intervalo QT y también los datos de farmacocinética. RESULTADOS: El carbonato de lodenafila, aisladamente o asociado con alcohol, no determinó alteraciones clínicas significativas en la PA o FC, aunque se haya registrado una disminución de la PA estadísticamente significativa después de 4 horas en los voluntarios que recibieron medicamento y alcohol, así como un aumento de la FC después de 6 horas en los pacientes que recibieron el CL. El análisis del intervalo QT corregido no mostró alteración significativa. El alcohol aumentó la biodisponibilidad del medicamento en un 74 por ciento. Se registraron sólo 2 quejas de cefalea leve, posiblemente asociada al medicamento. CONCLUSIÓN: El carbonato de lodenafila, aun asociado al alcohol, no determinó repercusiones clínicas importantes en la PA, FC, o alteraciones en el intervalo QTc; la ingestión con alcohol, a su vez, aumentó significativamente su biodisponibilidad.

Asunto(s)

Adolescente , Adulto , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Consumo de Bebidas Alcohólicas , Carbonatos/farmacología , Sistema Cardiovascular/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Pirimidinas/farmacología , Análisis de Varianza , Consumo de Bebidas Alcohólicas/metabolismo , Consumo de Bebidas Alcohólicas/fisiopatología , Disponibilidad Biológica , Presión Sanguínea/efectos de los fármacos , Carbonatos/farmacocinética , Sistema de Conducción Cardíaco/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacocinética , Piperazinas/farmacocinética , Pirimidinas/farmacocinética , Adulto Joven

RESUMEN

INTRODUCTION: Oral treatment with phosphodiesterase type 5 inhibitor (PDE5) is considered the first-line treatment for patients with erectile dysfunction (ED). Lodenafil carbonate (LC) is a novel PDE5. AIM: This is a phase II, prospective, randomized, double-blind, and placebo controlled clinical trial of LC. MAIN OUTCOME MEASURES: Efficacy end points were International Index of Sexual Function (IIEF) erectile domain, IIEF questions 3 and 4, and Sexual Encounter Profile (SEP) questions 2 and 3, before and after the use of LC or placebo. METHODS: Seventy-two men older than 18 years, with ED for at least 6 months with stable sexual relationship were enrolled. Patients were randomized to placebo or LC 80 mg, 40 mg, or 20 mg and followed for 4 weeks. RESULTS: IIEF erectile domain scores before and after the use of medications were (mean +/- standard deviation [SD]): placebo: 11.9 +/- 3.4 and 12.6 +/- 5.5; LC 20 mg: 15.8 +/- 4.1 and 18.9 +/- 6.6; LC 40 mg: 11.9 +/- 4.4 and 15.4 +/- 8.1; LC 80 mg: 14.2 +/- 4.7 and 22.8 +/- 6.0 (ANOVA P < 0.01). The SEP-2 scores before and after the use of medications were (Mean +/- SD): placebo: 71.0 +/- 33.1 and 51.2 +/- 43.1; LC 20 mg 70.3 +/- 34.2 and 75.5 +/- 31.5; LC 40 mg: 48.4 +/- 42.1 and 60.8 +/- 42.5; LC 80 mg: 68.6 +/- 33.5 and 89.6 +/- 26.0. The SEP-3 scores were: placebo 23.3 +/- 27.6 and 33.6 +/- 42.3; LC 20 mg: 32.3 +/- 38.9 and 51.2 +/- 41.7; LC 40 mg: 39.7 +/- 44.7 and 46.7 +/- 41.1; LC 80 mg* 17.2 +/- 29.5 and 74.3 +/- 36.4 (*P < 0.05 for difference to placebo). CONCLUSIONS: The drug was well tolerated. Adverse reactions were mild and self-limited and included headache, rhinitis, flushing, color visual disorders, and dyspepsia. This study showed that the dosage of 80 mg of LC was significantly more efficacious than placebo and well tolerated.

Asunto(s)

Carbonatos/uso terapéutico , Disfunción Eréctil/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Administración Oral , Adulto , Anciano , Carbonatos/farmacología , Método Doble Ciego , Esquema de Medicación , Tolerancia a Medicamentos , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa 5 , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Estudios Prospectivos , Pirimidinas/farmacología

RESUMEN

Nitrergic nerves and endothelial cells release nitric oxide (NO) in the corpus cavernosum, a key mediator that stimulates soluble guanylyl cyclase to increase cGMP levels causing penile erection. Phosphodiesterase 5 (PDE5) inhibitors, such as sildenafil, prolong the NO effects by inhibiting cGMP breakdown. Here, we report a novel PDE5 inhibitor, lodenafil carbonate, (Bis-(2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-benzenesulfonyl]piperazin-1-yl}-ethyl)carbonate) that is a dimer of lodenafil. We therefore aimed to compare the effects of sildenafil, lodenafil and lodenafil carbonate on in vitro human and rabbit cavernosal relaxations, activity of crude PDE extracts from human platelets, as well as stability and metabolic studies in rat, dog and human plasma. Pharmacokinetic evaluations after intravenous and oral administration were performed in male beagles. Functional experiments were conducted using organ bath techniques. Pharmacokinetics was studied in beagles by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), following oral or intravascular administration. All PDE5 inhibitors tested concentration-dependently relaxed (0.001-100 microM) phenylephrine-precontracted rabbit and human corpus cavernosum. The cavernosal relaxations evoked by either acetylcholine (0.01-100 microM) or electrical field stimulation (EFS, 1-20 Hz) were markedly potentiated by sildenafil, lodenafil and lodenafil carbonate. Lodenafil carbonate was more potent to inhibit the cGMP hydrolysis in PDE extracts compared with lodenafil and sildenafil. Following intravascular and single oral administration of lodenafil carbonate, only lodenafil and norlodenafil were detected in vivo. These results indicate that lodenafil carbonate works as a prodrug, being lodenafil the active moiety of lodenafil carbonate.

Asunto(s)

Carbonatos/farmacología , Disfunción Eréctil/tratamiento farmacológico , Pene/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Pirimidinas/farmacología , Administración Oral , Adulto , Animales , Carbonatos/administración & dosificación , Carbonatos/farmacocinética , Cromatografía Liquida , GMP Cíclico/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Estimulación Eléctrica , Humanos , Inyecciones Intravenosas , Masculino , Pene/metabolismo , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/farmacocinética , Piperazinas/administración & dosificación , Piperazinas/farmacocinética , Profármacos , Purinas/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Conejos , Ratas , Citrato de Sildenafil , Sulfonas/farmacología , Espectrometría de Masas en Tándem

RESUMEN

Benzothiazole (BT) is a toxic and poorly biodegradable contaminant, usually found in wastewater from rubber related applications. This compound could be effectively eliminated using advanced treatment processes. This paper compares experimental results on detoxification systems based on ozone oxidation, activated carbon adsorption, and simultaneous adsorption-oxidation using ozone in the presence of activated carbon. The effect of pH (2-11), and the presence of radical scavengers (tert-butyl alcohol and sodium carbonate) on process rates and removal efficiencies are assessed at laboratory scale. The experimental system consisted of a 1 L differential circular flow reactor and an ozone generator rated at 5 g O3/h. Results show that ozone oxidation combined with activated carbon adsorption increases the overall BT oxidation rate with respect to the ozonation process and activated carbon adsorption. In the presence of free radical scavenger, only a 44% reduction in BT removal rate is observed in the simultaneous treatment, as compared with 72% when ozonation treatment is used, suggesting that BT oxidation reactions mainly take place on the activated carbon surface.

Asunto(s)

Carbón Orgánico/química , Ozono/química , Tiadiazoles/toxicidad , Eliminación de Residuos Líquidos/métodos , Purificación del Agua/métodos , Adsorción , Biodegradación Ambiental , Carbonatos/farmacología , Depuradores de Radicales Libres/farmacología , Concentración de Iones de Hidrógeno , Oxidación-Reducción , Tiadiazoles/aislamiento & purificación , Tiadiazoles/metabolismo , Factores de Tiempo , Alcohol terc-Butílico/farmacología

RESUMEN

In the present study, several stimuli were tested to liberate Toxoplasma gondii sporozoites from oocysts. Incubation in Na(2)CO(3)-CO(2) buffer at 40 degrees C with ultrasound, followed by incubation at 40 degrees C with bile or deoxycholic acid, was the only method that resulted in 95% liberation of motile infective sporozoites. A protocol of reproducibly high efficiency is provided, that compares favorably with any of the methods previously published.

Asunto(s)

Oocistos/fisiología , Toxoplasma/fisiología , Animales , Bilis/química , Dióxido de Carbono/farmacología , Carbonatos/farmacología , Gatos , Ratones , Oocistos/efectos de los fármacos , Ratas , Esporozoítos/efectos de los fármacos , Esporozoítos/fisiología , Toxoplasma/efectos de los fármacos , Ultrasonido

RESUMEN

BACKGROUND: We have evidence for enterohepatic cycling of bilirubin experimentally and in vivo in humans. This study was designed to investigate whether Zn salts might inhibit such cycling of bilirubin. MATERIALS AND METHODS: Micellar bile salt solutions with unconjugated bilirubin were prepared, appropriate concentrations of Zn salts were added, and unconjugated bilirubin precipitation was measured. Hamsters and Wistar rats were fed a chow diet or a chow diet enriched with 1% ZnSO4, and bilirubin secretion rates were monitored. RESULTS: Unconjugated bilirubin was precipitated maximally (90%) after a 10-min incubation with 5 mM Zn salts in the pH range of 6.8-9.0. In control hamsters, total bilirubin secretion rates into bile were 36.0 +/- 2.8 nmol h(-1) 100g(-1) body weight, whereas they were 25.0 +/- 3.3 nmol h-1 100(-1) g in the ZnSO4 group (P < 0.05). CONCLUSIONS: Zn salts that flocculate at physiological pH adsorb unconjugated bilirubin almost completely from unsaturated micellar BS solutions. In addition, Zn salts administered orally suppress biliary bilirubin secretion rates in hamsters. These findings suggest that the administration of Zn salts may inhibit the enterohepatic cycling of unconjugated bilirubin in humans who are predisposed to pigment gallstone formation due to diet, disease or drugs.

Asunto(s)

Bilirrubina/metabolismo , Hígado/metabolismo , Sulfato de Zinc/farmacocinética , Animales , Ácidos y Sales Biliares/química , Ácidos y Sales Biliares/farmacología , Fístula Biliar/metabolismo , Bilirrubina/química , Carbonatos/química , Carbonatos/farmacología , Precipitación Química , Colelitiasis/metabolismo , Cricetinae , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Masculino , Mesocricetus , Ratas , Ratas Wistar , Acetato de Zinc/química , Acetato de Zinc/farmacología , Compuestos de Zinc/química , Compuestos de Zinc/farmacología , Sulfato de Zinc/química

RESUMEN

Cells of Rhv. sulfidophilum were grown under different conditions in the presence of 32P-phosphate and the corresponding H and L membrane fractions obtained and fractionated by SDS-PAGE. Both membranes showed almost identical polypeptide composition. The bacteriochlorophyll (Bchl) specific content in H was always lower that in L. As described before, oxygen did not regulate gene expression. Under high light, an almost two- to threefold decrease of the cellular specific Bchl content was observed. Pulse and chase experiments showed that transitions from aerobiosis to light-anaerobiosis did not quantitatively affect the Bchl content of the membranes, although a turnover of the 32P-phosphate and 35S-methionine was observed. LHI beta was the only polypeptidic subunit of the Bchl-binding polypeptides that was phosphorylated in vivo, and phosphotyrosine was the only phosphorylated amino acid detectable. The phosphorylated LHI beta was determined to be insoluble in the organic solvent mixture of (vol/vol) 1:1 chloroform-methanol containing ammonium acetate (0.1 m final concentration). Treatment with a chaotropic agent such as Na2CO3 solubilized the phosphorylated LHI beta, indicating that part of this posttranslationally modified polypeptide was not inserted in a transmembrane position. These results were used to speculate about the regulatory properties of this posttranslational modification of LHI beta on membrane differentiation.

Asunto(s)

Alphaproteobacteria/metabolismo , Proteínas Bacterianas , Membrana Celular/metabolismo , Complejos de Proteína Captadores de Luz , Proteínas del Complejo del Centro de Reacción Fotosintética/metabolismo , Alphaproteobacteria/crecimiento & desarrollo , Bacterioclorofilas/metabolismo , Carbonatos/farmacología , Electroforesis en Gel de Poliacrilamida , Regulación Bacteriana de la Expresión Génica , Luz , Fosforilación , Fotosíntesis/fisiología , Proteínas del Complejo del Centro de Reacción Fotosintética/aislamiento & purificación