RESUMEN
Organic nitrates are widely used to restore endogenous nitric oxide (NO) levels reduced by endothelial nitric oxide synthase dysfunction. However, these drugs are associated with undesirable side effects, including tolerance. This study aims to investigate the cardiovascular effects of the new organic nitrate 1,3-diisobutoxypropan-2-yl nitrate (NDIBP). Specifically, we assessed its effects on blood pressure, vascular reactivity, acute toxicity, and the ability to induce tolerance. In vitro and ex vivo techniques showed that NDIBP released NO both in a cell-free system and in isolated mesenteric arteries preparations through a process catalyzed by xanthine oxidoreductase. NDIBP also evoked endothelium-independent vasorelaxation, which was significantly attenuated by 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl 3-oxide (PTIO, 300 µM), a nitric oxide scavenger; 1-H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 µM), a soluble guanylyl cyclase inhibitor; tetraethylammonium (TEA, 3 mM), a potassium channel blocker; febuxostat (500 nM), a xanthine oxidase inhibitor; and proadifen (10 µM), an inhibitor of cytochrome P450 enzyme. Furthermore, this organic nitrate did not induce tolerance in isolated vessels and presented low toxicity following acute oral administration. In vivo changes on cardiovascular parameters were assessed using normotensive and renovascular hypertensive rats. NDIBP evoked a reduction of blood pressure that was significantly higher in hypertensive animals. Our results suggest that NDIBP acts as a NO donor, inducing blood pressure reduction without having the undesirable effects of tolerance. Those effects seem to be mediated by activation of NO-sGC-cGMP pathway and positive modulation of K+ channels in vascular smooth muscle.
Asunto(s)
Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Arterias Mesentéricas/efectos de los fármacos , Nitratos/uso terapéutico , Donantes de Óxido Nítrico/uso terapéutico , Vasodilatadores/uso terapéutico , Animales , Antihipertensivos/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Femenino , Hipertensión/metabolismo , Masculino , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/metabolismo , Canales de Potasio/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Guanilil Ciclasa Soluble/metabolismo , Vasodilatadores/metabolismo , Xantina Deshidrogenasa/metabolismoRESUMEN
Structural diversity characterizes natural products as prototypes for design of lead compounds. The aim of this study was to synthetize, and to evaluate the toxicity and antitumor action of a new piperine analogue, the butyl 4-(4-nitrobenzoate)-piperinoate (DE-07). Toxicity was evaluated against zebrafish, and in mice (acute and micronucleus assays). To evaluate the DE-07 antitumor activity Ehrlich ascites carcinoma model was used in mice. Angiogenesis, Reactive Oxygen Species (ROS) production and cytokines levels were investigated. Ninety-six hours exposure to DE-07 did not cause morphological or developmental changes in zebrafish embryos and larvae, with estimated LC50 (lethal concentration 50%) higher than 100 µg/mL. On the acute toxicity assay in mice, LD50 (lethal dose 50%) was estimated at around 1000 mg/kg, intraperitoneally (i.p.). DE-07 (300 mg/kg, i.p.) did not induce increase in the number of micronucleated erythrocytes in mice, suggesting no genotoxicity. On Ehrlich tumor model, DE-07 (12.5, 25 or 50 mg/kg, i.p.) induced a significant decrease on cell viability. In addition, there was an increase on ROS production and a decrease in peritumoral microvessels density. Moreover, DE-07 induced an increase of cytokines levels involved in oxidative stress and antiangiogenic effect (IL-1ß, TNF-α and IL-4). No significant clinical toxicological effects were recorded in Ehrlich tumor transplanted animals. These data provide evidence that DE-07 presents low toxicity, and antitumor effect via oxidative and antiangiogenic actions by inducing modulation of inflammatory response in the tumor microenvironment.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Antiinflamatorios/farmacología , Carcinoma de Ehrlich/tratamiento farmacológico , Neovascularización Patológica , Oxidantes/farmacología , Estrés Oxidativo , Piperidinas/farmacología , Microambiente Tumoral , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/toxicidad , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/toxicidad , Carcinoma de Ehrlich/inmunología , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patología , Citocinas/metabolismo , Masculino , Ratones , Oxidantes/síntesis química , Oxidantes/toxicidad , Piperidinas/síntesis química , Piperidinas/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Pez Cebra/embriologíaRESUMEN
BACKGROUND: No specific quality-of-life scale for stroke patients has previously been translated and evaluated for reproducibility, for use in the Portuguese language. Internationally, the instrument for this purpose is the Stroke Impact Scale 2.0 (SIS). Use of of SIS enables comprehensive analysis on the impact of mild and moderate stroke on patients' lives. The aims here were to translate SIS into Portuguese, adapt it culturally, evaluate its reproducibility and correlate it with SF-36 among stroke patients. DESIGN AND SETTING: Translation and validation study. METHODS: The process of initial and retrograde translation was performed, in addition to cultural adaptation to the Brazilian language and culture. SIS was applied to 40 patients, who answered the questions three times. On the first day, the scale was applied twice by two independent researchers (to evaluate interobserver reproducibility). Fifteen days later, the scale was applied for a third time by another researcher (intraobserver reproducibility). The intraclass correlation coefficient (ICC) was used to measure the reproducibility of the SIS scale. RESULTS: The reproducibility of the whole scale was very good (ICC: 0.73 to 0.99). Intraobserver reproducibility in all domains was also very good (ICC: 0.85 to 0.95). Comparison of SIS with SF-36 showed that the domains of strength, mobility and activities of daily living (ADLs) correlated moderately with the functional capacity domain, as did the ADL domain with general health status. The other correlations were weak. The depression domain showed a moderate negative correlation with the memory and communication domains. CONCLUSION: The translation of the SIS 2.0 scale was easy to understand and it had good reproducibility among stroke patients.
Asunto(s)
Encuestas Epidemiológicas , Calidad de Vida , Accidente Cerebrovascular/psicología , Traducciones , Brasil , Características Culturales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
ABSTRACT BACKGROUND: No specific quality-of-life scale for stroke patients has previously been translated and evaluated for reproducibility, for use in the Portuguese language. Internationally, the instrument for this purpose is the Stroke Impact Scale 2.0 (SIS). Use of of SIS enables comprehensive analysis on the impact of mild and moderate stroke on patients' lives. The aims here were to translate SIS into Portuguese, adapt it culturally, evaluate its reproducibility and correlate it with SF-36 among stroke patients. DESIGN AND SETTING: Translation and validation study. METHODS: The process of initial and retrograde translation was performed, in addition to cultural adaptation to the Brazilian language and culture. SIS was applied to 40 patients, who answered the questions three times. On the first day, the scale was applied twice by two independent researchers (to evaluate interobserver reproducibility). Fifteen days later, the scale was applied for a third time by another researcher (intraobserver reproducibility). The intraclass correlation coefficient (ICC) was used to measure the reproducibility of the SIS scale. RESULTS: The reproducibility of the whole scale was very good (ICC: 0.73 to 0.99). Intraobserver reproducibility in all domains was also very good (ICC: 0.85 to 0.95). Comparison of SIS with SF-36 showed that the domains of strength, mobility and activities of daily living (ADLs) correlated moderately with the functional capacity domain, as did the ADL domain with general health status. The other correlations were weak. The depression domain showed a moderate negative correlation with the memory and communication domains. CONCLUSION: The translation of the SIS 2.0 scale was easy to understand and it had good reproducibility among stroke patients.
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Calidad de Vida , Traducciones , Encuestas Epidemiológicas , Accidente Cerebrovascular/psicología , Brasil , Reproducibilidad de los Resultados , Características CulturalesRESUMEN
OBJECTIVE: The present study was designed to investigate interfacial quality between both Epiphany and Epiphany SE and the surrounding dentin having conventional gutta-percha/AH plus root filling as reference for comparison. STUDY DESIGN: A sample of 36 human maxillary canines was prepared and assigned to experimental groups of 12 teeth each, designated as G1, Resilon/Epiphany; G2, Resilon/Epiphany SE; and G3, gutta-percha/AH Plus. After the filling procedures, each specimen was horizontally sectioned at 3, 6, and 8 mm from the apex and a metallographic preparation was performed to enable the evaluation under Confocal Laser Scanning Microscopy (CLSM). The integrity of the interface was determined by calculating the ratio between the total sealer/dentin interface and the sealer/dentin interface that presented gap-containing regions. Additionally, the width of each gap was measured and pooled per each specimen for comparison. Statistical analysis was performed using nonparametric methods. RESULTS: Nonbonding AH Plus/gutta-percha root fillings showed a significantly higher amount of gap-free regions (P < .05). In the same way, nonbonding AH plus root fillings displayed significantly narrower gaps compared with the 2 adhesive root-filling groups (P < .05). CONCLUSIONS: Under the present in vitro conditions, the quality of the interfacial adaptation of the current adhesive root fillings is compromised even when teeth with simple anatomic features were obturated under well-monitored laboratory conditions.
Asunto(s)
Adaptación Marginal Dental , Cavidad Pulpar/ultraestructura , Dentina/ultraestructura , Materiales de Obturación del Conducto Radicular/química , Diente Canino , Recubrimiento Dental Adhesivo , Resinas Epoxi/química , Gutapercha/química , Humanos , Ensayo de Materiales , Microscopía Confocal , Microscopía Fluorescente , Propiedades de Superficie , Ápice del Diente/ultraestructuraRESUMEN
OBJECTIVE: This study was designed to quantitatively evaluate the amount of dentin debris extruded from the apical foramen by comparing the conventional sequence of the ProTaper Universal nickel-titanium (NiTi) files with the single-file ProTaper F2 technique. STUDY DESIGN: Thirty mesial roots of lower molars were selected, and the use of different instrumentation techniques resulted in 3 groups (n=10 each). In G1, a crown-down hand-file technique was used, and in G2 conventional ProTaper Universal technique was used. In G3, ProTaper F2 file was used in a reciprocating motion. The apical finish preparation was equivalent to ISO size 25. An apparatus was used to evaluate the apically extruded debris. Statistical analysis was performed using 1-way analysis of variance and Tukey multiple comparisons. RESULTS: No significant difference was found in the amount of the debris extruded between the conventional sequence of the ProTaper Universal NiTi files and the single-file ProTaper F2 technique (P>.05). In contrast, the hand instrumentation group extruded significantly more debris than both NiTi groups (P<.05). CONCLUSIONS: The present results yielded favorable input for the F2 single-file technique in terms of apically extruded debris, inasmuch as it is the most simple and cost-effective instrumentation approach.