Daclatasvir Plus Asunaprevir Dual Therapy for Chronic HCV Genotype 1b Infection: Results of Turkish Early Access Program

Abstract: Background. Daclatasvir and asunaprevir dual therapy is approved for the treatment of HCV genotype 1b infection in several countries. Aim. To evaluate the efficacy and safety of daclatasvir and asunaprevir dual therapy in Turkish patients. Material and methods. Sixty-one patients with HCV genotype 1b were enrolled in the Turkish early access program. Most of the patients were in difficult-to-treat category. Patients were visited at each 4 week throughout the follow-up period. Laboratory findings and adverse events were recorded at each visit. Results. Fifty-seven of 61 enrolled patients completed 24 weeks of treatment. Two patients died as a result of underlying diseases at 12-14th weeks of treatment. Two patients stopped the treatment early as a consequence of virological breakthrough, and 2 patients had viral relapse at the post-treatment follow-up. Overall SVR12 rates were 90% (55/61) and 93.2% (55/59) according to intention-to-treat (ITT) and per protocol (PP) analysis respectively. In ITT analysis, SVR12 was achieved by 93% (13/14) in relapsers, 80% (12/15) in interferon-ineligible patients and 91% (20/22) in previous nonresponder patients. SVR12 rates were 86.5% and 91.4% in patients with cirrhosis according to ITT and PP analysis respectively. SVR12 was 95.8% in non-cirrhosis group in both analysis. Patients with previous protease inhibitor experience had an SVR12 of 87.5%. Common adverse events developed in 28.8% of patients. There were no treatment related severe adverse event or grade-4 laboratory abnormality. Conclusions. Daclatasvir and asunaprevir dual therapy is found to be effective and safe in difficult-to-treat Turkish patients with HCV genotype 1b infection.

Hemodynamic responses during and after multiple sets of stretching exercises performed with and without the Valsalva maneuver

OBJECTIVE: This study investigated the acute hemodynamic responses to multiple sets of passive stretching exercises performed with and without the Valsalva maneuver. METHODS: Fifteen healthy men aged 21 to 29 years with poor flexibility performed stretching protocols comprising 10 sets of maximal passive unilateral hip flexion, sustained for 30 seconds with equal intervals between sets. Protocols without and with the Valsalva maneuver were applied in a random counterbalanced order, separated by 48-hour intervals. Hemodynamic responses were measured by photoplethysmography pre-exercise, during the stretching sets, and post-exercise. RESULTS: The effects of stretching sets on systolic and diastolic blood pressure were cumulative until the fourth set in protocols performed with and without the Valsalva maneuver. The heart rate and rate pressure product increased in both protocols, but no additive effect was observed due to the number of sets. Hemodynamic responses were always higher when stretching was performed with the Valsalva maneuver, causing an additional elevation in the rate pressure product. CONCLUSIONS: Multiple sets of unilateral hip flexion stretching significantly increased blood pressure, heart rate, and rate pressure product values. A cumulative effect of the number of sets occurred only for systolic and diastolic blood pressure, at least in the initial sets of the stretching protocols. The performance of the Valsalva maneuver intensified all hemodynamic responses, which resulted in significant increases in cardiac work during stretching exercises. .

Minimal endoscopic changes in non-erosive reflux disease / Alterações endoscópicas mínimas na doença do refluxo não erosiva

BACKGROUND: Gastroesophageal reflux disease is an increasingly common condition worldwide causing a considerable economic impact. More than half the patients with clinical symptoms of reflux disease display no mucosal erosions on esophagogastroduodenoscopy, making it impossible to confirm the diagnosis without further investigations. AIM: To evaluate the correlation between minimal endoscopic changes on white-light esophagogastroduodenoscopy (carditis, mucosal thickening and invisibility of vessels) and histologic changes observed in distal esophageal biopsies in a sample of patients with symptoms suggestive of reflux disease, and to verify the specificity of these symptoms for non-erosive reflux disease. METHODS: Retrospective, cross-sectional study based on information retrieved from a digital database at a Brazilian hospital for the period March-October, 2012. The sample consisted of previously untreated, non-smoking subjects aged >18 years with symptoms suggestive of reflux disease but no esophageal erosions, submitted to esophagogastroduodenoscopy and distal esophageal biopsy. RESULTS: The final sample included 23 subjects. The most frequently observed change was invisibility of vessels (n=21; 91.3%), followed by mucosal thickening (n=15; 65.2%) and carditis (n=5; 21.7%). The correlation coefficient between each variable and the anatomopathological diagnosis was 0.386 for body mass index, 0.479 for mucosal thickening, -0.116 for invisibility of vessels, 0.306 for carditis and 0.462 for hiatal hernia. CONCLUSION: All patients displayed minimal endoscopic changes on esophagogastroduodenoscopy, but only mucosal thickening revealed a moderately significant correlation with severity of esophagitis, although increased body mass index values and the presence of hiatal hernia were also associated. .

RACIONAL: Doença do refluxo gastroesofágico é condição cada vez mais comum em todo o mundo causando impacto econômico considerável. Mais da metade dos pacientes com sintomas clínicos da doença não apresentam erosões endoscópicas da mucosa, o que torna impossível confirmar o diagnóstico sem outras investigações. OBJETIVO: Avaliar a correlação entre mudanças mínimas endoscópicas em endoscopia digestiva alta de luz branca (cardite, espessamento da mucosa e invisibilidade de vasos) e as alterações histológicas observadas em biópsias distais de uma amostra de pacientes com sintomas sugestivos de doença do refluxo, e para verificar a especificidade desses sintomas para a doença não-erosiva. MÉTODOS: Estudo retrospectivo, transversal, com base em informações obtidas a partir de uma base de dados digital em um hospital brasileiro no período de março/outubro de 2012. A amostra foi composta por indivíduos não tratados previamente, não fumantes, >18 anos, com sintomas sugestivos de doença do refluxo, mas sem erosões esofágicas submetidos à endoscopia digestiva alta e biópsia de esôfago distal. RESULTADOS: A amostra final incluiu 23 indivíduos. A alteração mais frequente foi invisibilidade dos vasos (n=21; 91,3%), seguido por espessamento de mucosa (n=15; 65,2%) e cardite (n=5; 21,7%). O coeficiente de correlação entre cada variável e o diagnóstico anatomopatológico foi 0,386 para o índice de massa corporal, 0,479 para espessamento de mucosa, -0,116 para a invisibilidade de vasos, 0,306 para carditis e 0,462 para hérnia hiatal. CONCLUSÃO: Todos os pacientes apresentaram alterações endoscópicas mínimas, mas apenas espessamento da mucosa revelou correlação moderadamente significativa com a gravidade da esofagite, apesar do aumento dos valores no índice de massa corporal e da presença de hérnia hiatal também estarem associados. .

Metoclopramida e ondansetrona alteram o bloqueio neuromuscular induzido por mivacurio? - um estudo randomizado / Do metoclopramide and ondansetrone alter mivacurium-induced neuromuscular blockade? - a randomised trial / La metoclopramida y la ondansetrona alteran el bloqueo neuromuscular inducido por mivacurio? - un estudio aleatorizado

Experiência: Objetivamos investigar os efeitos de metoclopramida e ondansetrona no bloqueio neuromuscular por mivacúrio. Métodos: Foram incluídos no estudo 75 pacientes ASA I-II, com idades entre 18 e 65 anos e agendados para cirurgia eletiva necessitando de intubação traqueal. Os pacientes receberam metoclopramida 10 mg, ondansetrona 4 mg ou salina normal 5 mL; grupo M, grupo O e grupo SN (n = 25) respectivamente. Antes da anestesia, os medicamentos em estudo foram administrados em um volume de 5 mL. O nível de colinesterase plasmática foram obtidos antes e 5 minutos depois da administração dos medicamentos em estudo e 5 minutos depois da administração de mivacúrio. Os tempos até o início e os níveis T25, T75, T25-75 e T90 foram comparados entre si, tendo sido investigadas as diferenças entre cada paciente. Depois de registrar T90, o estudo foi terminado, tendo início a cirurgia. Resultados: O tempo até o início foi significativamente mais breve no Grupo M versus os outros dois grupos. O tempo até o início no Grupo O foi significativamente mais breve versus grupo SN. No grupo M, T25, T75, T90 e os índices de recuperação foram significativamente maiores versus Grupo NS (p < 0,001). No Grupo O, T25 e T75 foram maiores versus Grupo NS (p < 0,01 e p < 0,05,respectivamente). No Grupo M, T75, T90 e índices de retorno da anestesia foram significativamente maiores versus Grupo O (p < 0,001, p < 0,01, p < 0,001, respectivamente). Nos Grupos M e O, os níveis plasmáticos de colinesterase diminuíram significativamente (p < 0,001). Depois da administração dos medicamentos em estudo e de mivacúrio. Houve também redução na colinesterase plasmática no Grupo NS 5 minutos após a administração de mivacúrio (p < 0,001). ...

Background: We aimed to investigate the effects of metoclopramide and ondansetrone on mivacurium neuromuscular blockade. Methods: Seventy five, ASA I-II patients, aged 18-65 and scheduled for elective surgery requiring tracheal intubation were included in the study. The patients received metoclopramide 10 mg, ondansetrone 4 mg or normal saline 5 mL; group M, group O, group NS (n = 25), respectively. Before anesthesia study drugs were administered in a volume of 5 mL. The level of plasma cholinesterase were obtained before and 5 minutes after the administration of study drugs and5 minutes after the administration of mivacurium. Onset time, T25, T75, T25-75, T90 levelswere compared with each other and differences between each patients were investigated. After recording T90, the study was terminated and surgery was started. Results: Onset time was significantly shorter in group M, than the other two groups. Onset time in group O was significantly shorter than in group NS. In Group M T25, T75, T90 and recovery indices were significantly greater than in Group NS (p < 0.001). In Group O T25, T75 were greater than Group NS (p < 0.01 and p < 0.05, respectively). In Group M T75, T90 and emergence indices were significantly higher than Group O (p < 0.001, p < 0.01, p < 0.001, respectively). In Groups M and O, plasma cholinesterase levels decreased significantly (p < 0.001) after administration of study drugs and mivacurium. Plasma cholinesterase also was reduced in Group NS 5 minutes after the administration of mivacurium (p < 0.001). Conclusion: Ondansetrone is believed to be more reliable agent than metoclopramide when used with mivacurium. .

Uptake of macromolecules by cercariae during skin penetration and transformation to schistosomula (Schistosoma mansoni)

Here, we observed the uptake of membrane-impermeant molecules by cercariae as they penetrate the skin and are transformed into schistosomula. We propose that membrane-impermeant molecules, Lucifer Yellow, Propidium iodide and Hoechst 33258 enter the parasite through both thenephridiopore and the surface membrane and then diffuse throughout the body of the parasite. We present a hypothesis that the internal cells of the body of the schistosomulum represent a new host-parasite interface, at which skin-derived growth factors may stimulate receptors on internal membranes during transformation of the cercariae into the schistosomulum.

Molluscicidal activity of Hammada scoparia (Pomel) Iljin leaf extracts and the principal alkaloids isolated from them against Galba truncatula

The molluscicidal activity of Hammada scoparia leaf extracts and the principal alkaloids isolated from them (carnegine and N-methylisosalsoline) were tested against the mollusc gastropod, Galba truncatula, the intermediate host of Fasciola hepatica in Tunisia. The results indicated that the molluscicidal activity was correlated with the presence of alkaloids. A significant molluscicidal value, according to the World Health Organization, was found with the methanol extract (LC50 = 28.93 ppm). Further fractionation of the methanolic extract led to the isolation of two principal alkaloids: carnegine and N-methylisosalsoline. These alkaloids are isoquinolines that have not previously been characterised for their molluscicidal activity. The N-methylisosalsoline possesses the highest molluscicidal activity (LC50 = 0.47 ìM against G. truncatula).

Dendritic thickness: a morphometric parameter to classify mouse retinal ganglion cells

To study the dendritic morphology of retinal ganglion cells in wild-type mice we intracellularly injected these cells with Lucifer yellow in an in vitro preparation of the retina. Subsequently, quantified values of dendritic thickness, number of branching points and level of stratification of 73 Lucifer yellow-filled ganglion cells were analyzed by statistical methods, resulting in a classification into 9 groups. The variables dendritic thickness, number of branching points per cell and level of stratification were independent of each other. Number of branching points and level of stratification were independent of eccentricity, whereas dendritic thickness was positively dependent (r = 0.37) on it. The frequency distribution of dendritic thickness tended to be multimodal, indicating the presence of at least two cell populations composed of neurons with dendritic diameters either smaller or larger than 1.8 æm ("thin" or "thick" dendrites, respectively). Three cells (4.5 percent) were bistratified, having thick dendrites, and the others (95.5 percent) were monostratified. Using k-means cluster analysis, monostratified cells with either thin or thick dendrites were further subdivided according to level of stratification and number of branching points: cells with thin dendrites were divided into 2 groups with outer stratification (0-40 percent) and 2 groups with inner (50-100 percent) stratification, whereas cells with thick dendrites were divided into one group with outer and 3 groups with inner stratification. We postulate, that one group of cells with thin dendrites resembles cat ß-cells, whereas one group of cells with thick dendrites includes cells that resemble cat a-cells.

Genital Sensory Stimulation Shifts Estradiol Intraoviductal Signaling from Nongenomic to Genomic Pathways, Independently from Prolactin Surges

Estradiol (E2) accelerates oviductal egg transport through nongenomic pathways involving oviductal protein phosphorylation in non-mated rats, and through genomic pathways in mated rats. Here we investigated the ability of cervico-vaginal stimulation (CVS) to switch the mode of action of E2 in the absence of other male-associated components. Pro-estrous rats were subjected to CVS with a glass rod and 12 hours later were injected subcutaneously with E2 and intrabursally with the RNA synthesis inhibitor Actinomycin D or the protein phosphorylation inhibitor H-89. The number of eggs in the oviduct, assessed 24 h later, showed that Actinomycin D, but not H-89 blocked the E2-induced egg transport acceleration. This clearly indicates that CVS alone, without other mating-associated signals, is able to shift E2 signaling from nongenomic to genomic pathways. Since mating and CVS activate a neuroendocrine reflex that causes iterative prolactin (PRL) surges, the involvement of PRL pathway in this phenomenon was evaluated. Prolactin receptor mRNA and protein expression in the rat oviduct was demonstrated by RT-PCR and Western blot, but their levels were not different on day 2 of the cycle (C2) or pregnancy (P2). Activated ST AT 5a/b (phosphorylated) was detected by Western blot on P2 in the ovary, but not in the oviduct, showing that mating does not stimulate this PRL signalling pathway in the oviduct. Other rats subjected to CVS in the evening of pro-estrus were treated with bromoergocriptine to suppress PRL surges. In these rats, H-89 did not block the E2-induced acceleration of egg transport suggesting that PRL surges are not essential to shift E2 signaling pathways in the oviduct. We conclude that CVS is one of the components of mating that shifts E2 signaling in the oviduct from nongenomic to genomic pathways, and this effect is independent of PRL surges elicited by mating.

Bloqueio neuromuscular prolongado após administração de mivacúrio: relato de caso / Prolonged neuromuscular block after mivacurium: case report

JUSTIFICATIVA E OBJETIVOS: Com a introdução de novos fármacos com ação de curta duração, houve aumento do número de procedimentos realizados em caráter ambulatorial. O mivacúrio com duração de ação entre 15 e 30 minutos e metabolismo enzimático tornou-se opção de bloqueador neuromuscular para estes procedimentos. O relato de caso tem como objetivo chamar a atenção para a ocorrência de bloqueio neuromuscular prolongado após administração do mivacúrio e as condutas que foram adotadas. RELATO DO CASO: Descreve-se um caso de paciente programado para procedimento de curta duração em regime ambulatorial e que apresentou bloqueio neuromuscular prolongado após administração do mivacúrio. O diagnóstico foi posteriormente confirmado pela demonstração de níveis reduzidos de atividade da colinestesterase plasmática. CONCLUSÕES: A investigação laboratorial pré-operatória, mesmo incluindo a dosagem da atividade da colinesterase, não previne a possibilidade do bloqueio neuromuscular prolongado devido à possibilidade de alteração qualitativa da atividade da enzima, não existindo recomendação para investigação sistemática. Ocorrendo esta complicação, deve-se sedar o paciente e manter ventilação mecânica até a completa recuperação da força muscular e realizar exames laboratoriais para o diagnóstico definitivo. É de responsabilidade do anestesiologista a coleta de amostra sangüínea para realização de testes quantitativos e qualitativos da colinesterase plasmática. Paciente e familiares devem ser orientados quanto à importância da investigação para classificação da variante atípica da colinesterase plasmática e suas implicações anestésicas.

Tratamiento médico de la enfermedad hidatídica / Medical treatment of the hydatidic disease

Se presenta una puesta al día sobre el tratamiento médico de la enfermedad hidatídica, poniendo especial énfasis en sus indicaciones del pre, postoperatorio y el manejo de la enfermedad hidatídica propiamente tal. Además se analiza el mecanismo de acción, farmacocinética, pautas de administración y efectos adversos tanto de los benzoimidazoles como de las isoquinoleinas, puesto que ambos quimioterápicos son de uso común en esta patología.

Efecto de algunos relajantes musculares no despolarizantes sobre la duración del mivacurio / Effects of non-depolarizing muscle relaxants on the duration of mivacurium

La interacción entre el Mivacurio y varios relajantes musculares provoca un retardo de su recuperación. Nosotros comprobamos que pequeñas dosis de dÆTubocurarina prolongan la duración de dos administraciones sucesivas de Mivacurio. Esta investigación tiene entre sus objetivos establecer si el mismo efecto se puede observar después de otros bloqueadores neuro-musculares y si es consistente con las diferentes maneras de usarlos. A tal fin se anestesiaron 224 pacientes con Enflurano asignándose aleatoriamente a dos grupos controles que recibieron 100 microgramas/Kg -1 de Mivacurio, bien como bolo o en forma de cebado, mientras que a los demás se les administró: Recuronio (60 microgramas/Kg -1), Vecuronio (10 microgramas/Kg -1), Atracurio (60 microgramas/Kg -1), d'Tubocurarina (50 microgramas/Kg -1) o Pancuronio (8 microgramas/Kg -1), antes, después o mezclados con 90 microgramas/Kg -1 de Mivacurio. El efecto clínico se determinó electromiográficamente demostrándose que estos agentes prolongan la duración del Mivacurio, los tres últimos de modo significativo e independiente de la forma como fueron utilizados. Se revisan algunas hipótesis al respecto que no aclaran definitivamente los resultados, pero estos hallazgos deben considerarse como una herramienta en el estudio de la interacción entre los relajantes musculares no despolarizantes y evidencia para nuevas teorías.

Alcaloides isoquinolínicos de la corteza y flores de Erythrina fusca Loureiro / Isoquinolinic alcaloids from the bark and flowers of the Erythrina fusca Loureiro

De la corteza y flores de Erythrina fusca Loureiro se aislaron los alcaloides isoquinolínicos (+) -epieritratidina y 8-(+)-oxoerisodina, los cuales fueron identificados con base en sus constantes espectroscópicas. Se determinó la actividad antimicrobiana de extractos crudos y fracciones frente a bacterias y hongos. Se evaluó la actividad farmacólogica de extractos crudos y fracciones frente a ratas tipo WISTAR

Citotoxidad de los componentes de Palicourea ovalis / Citotoxicity of the constituents of Palicourea ovalis

De las flores y frutos de Palicourea ovalis se aislaron 4 alcaloides, uno de los cuales se identificó como calicantina, un derivado de la isoquinolina. Calicantina se identificó inequívocamente mediante métodos espectroscópicos y espectrométricos. La citotoxidad de los alcaloides se determinó en células VERO-YARU y se encontró que presentan una citotoxicidad comparable a la del 2,4-dinetofenol

Análisis de dos dosificaciones de mivacurio sobre las respuestas neuromusculares y cardiovasculares durante la anestesia en el paciente pediátrico ambulatorio / Neuromuscular and cardiovascular responses of two doses of mivacurium during ambulatory anestheria in pediatric patientes

El mivacurio es un relajante muscular no despolarizante de corta acción sintetizado recientemente. Decidimos evaluar sus efectos neuromusculares y cardiovasculares por dosis respuesta en pacientes pediátricos. Método: Se estudiaron 60 pacientes entre 2 a 10 años de edad con estado físico I-II según ASA para cirugía electiva ambulatoria en procedimientos cortos (1 hora de duración) que requerían intubación endotraqueal: La anestesia fue bajo halothano-óxido nitroso y oxígeno. A treinta niños se le administró mivacurio a dosis de 150 µg/kg y treinta pacientes recibieron una dosis de 250 µg/kg ambos en bolo por vía endovenosa. La dosis se estimo a 2 x DE95. La respuesta neuromuscular se midió a través de la fuerza de contracción en forma indirecta del nervio cubital por estimulo de tren de cuatro a 2 HZ. La frecuencia cardiaca, presión arterial se evalúo cada minuto durante la inducción. Resultados: A dosis de 150 mg/kg de mivacurio el tiempo de latencia fue de 3.50 ñ 0.65 min; el tiempo de acción de 13.00 ñ 2.87 min y el tiempo de recuperación al 25 por ciento (T1) fue de 12.03 ñ 2.13 min. A la dosis de 250 µg/kg el periodo de latencia fue de 3.24 ñ 0.66 min, el periodo de acción de 14.08 ñ 2.76 min, y el tiempo de recuperación (T1) de 16.01 ñ 3.22 min. No hubo diferencias significativas en ambos grupos. Por otra parte, las variaciones cardiovasculares no fueron significativas, a pesar de que hubo discreta disminución en la presión arterial con elevación mínima en la frecuencia cardiaca a dosis de 250 µg/kg. en un niño se observo rash pasajero. NO se observaron diferencias significativas al comparar los efectos neuromusculares y cardiovasculares con dosis de mivacurio de 150-250 µg/kg en pacientes pediátricos en edades comprendidas de 2 a 10 años en anestesia general con halotano-oxígeno-óxido nitroso para cirugía ambulatoria

Composiçäo química de Annonacacans Warming: parte 2 / Chemical composition of Annona cacans Warming: part 2

Annona cacans Warming is a native tree of the south and southeast of Brazil. Its fruits are reported to be laxative by the natives. Like other specimens of the Annoma genus, its main coumpounds are benzilisoquinoline alkaloids, as it was reported in a previous paper. The present work presents the isolation and identification of four flavonoids and p-coumaric acid from parts of the plant.

Effects of central epinephrine synthesis inhibition on stress-induced prolactin secretion in male rats

1. The present study was designed to examine the role of central epinephrine pathways in the control of stress-induced prolactin secretion in male adulto Wistar rats. 2. Intracerebroventricular adminsitration of two epinephrine synthesis inhibitors, SKF64139 (5 and 10 µg/rat) and LY 134046 (10 and 20 µg/rat), 6 h before the onset of immobilization stress blocked prolactin secretion in a dose-dependent manner. Prolactin values before stress were about 4.0 ng/ml and increased to almost 50 ng/ml in the control group. SKF 64139 injection in the higher dose (10 µg/rat) induced a complete blockade of the stress-induced prolactin release, whereas partial blockade was observed after the higher dose (20 µg/rat) of LY 134046. 3.Salbutamol pretreatment (10 µg/rat) completely restored stress-induced prolactin secretion in animals receiving a central injection of both epinephrine synthesis inhibitors under the same conditions as described above. 4. It is suggested that epinephrine pathways in the brain play an important role in the control of prolactin release occuring during immobilization stress