Aging-associated prostate smooth muscle hypercontractility in rats

Abstract Benign prostatic hyperplasia (BPH) is a multifactorial disease, highly associated with aging and characterized by increased prostate smooth muscle (PSM) contractility. Animal models have been employed to explore the aging-associated PSM hypercontractility; however, studies have focused in old animals, neglecting the initial alterations in early ages. The determination of prostatic dysfunctions onset is crucial to understand the BPH pathophysiology and to propose new BPH treatments. Considering that PSM contractility in 10-month-old rats has already been explored, the aim of the present study was to characterize the PSM contractility in younger rats. Male Wistar control (3.5-month-old), 6- and 8-month-old rats were used. Concentration-response curves to phenylephrine and electrical-field stimulation (EFS) were conducted in prostate from all groups. For the first time, we showed that 6- and 8-month-old rats exhibit PSM hypercontractility. The increased prostate contractility to phenylephrine starts around at 6-month-old, worsening during the aging. The 8-month-old rats exhibited hypercontractility to phenylephrine and EFS compared to the control and 6-month-old groups. Reduced phenylephrine potency was observed in 8-month-old rats, indicating an increased age-dependent prostate sensibility to this agonist. Collectively, our findings support the use of 6- and 8-month-old aged rats as new models to explore prostate hypercontractility in BPH.

Trends of vasopressor use in intensive care units in Colombia / Tendencias de consumo de vasopresores en unidades de cuidados intensivos de Colombia

Abstract Introduction Vasopressors are essential in the management of various types of shock. Objective To establish the trend of vasopressors use in the intensive care units (ICU) in a population of patients affiliated with the Colombian Health System, 2010-2017. Methods Observational trial using a population database of patients hospitalized in eleven ICUs in various cities in Colombia. The drugs dispensed to hospitalized patients over 18 years old, from January 2010 until December 2017 were considered. A review and analysis of the vasopressors dispensed per month was conducted, taking into account sociodemographic and pharmacological variables (vasopressor used and daily doses defined per 100/beds/day (DBD). Results 81,348 dispensations of vasopressors, equivalent to 26,414 treatments in 19,186 patients receiving care in 11 hospitals from 7 cities were reviewed. The mean age of patients was 66.3±18.1 years and 52.6 % were males. Of the total number of treatments recorded, 17,658 (66.8 %) were with just one vasopressor. Norepinephrine was the most frequently prescribed drug (75.9 % of the prescriptions dispensed; 60.5 DBD), followed by adrenaline (26.6 %; 41.6 DBD), dopamine (19.4%), dobutamine (16.0 %), vasopressin (8.5 %) and phenylephrine (0.9 %). The use of norepinephrine increased from 2010 to 2017 (+6.19 DBD), whilst the use of other drugs decreased, particularly the use of adrenaline (-60.6 DBD) and dopamine (-10.8 DBD). Conclusions Norepinephrine is the most widely used vasopressor showing a growing trend in terms of its use during the study period, which is supported by evidence in favor of its effectiveness and safety in patients with shock.

Resumen Introducción Los fármacos vasopresores son fundamentales en el manejo de los diferentes tipos de choque. Objetivo Determinar la tendencia de utilización de fármacos vasopresores en unidades de cuidados intensivos (UCI) en una población de pacientes afiliados al Sistema de Salud de Colombia, 2010-2017. Métodos Estudio observacional, a partir de una base de datos poblacional con pacientes hospitalizados en once UCI de diferentes ciudades de Colombia. Se obtuvieron las dispensaciones de pacientes mayores de 18 años hospitalizados desde enero de 2010 hasta diciembre de 2017. Se hizo revisión y análisis de la dispensación mensual de vasopresores. Se consideraron variables sociodemográficas y farmacológicas (medicamento vasopresor usado y dosis diarias definidas por 100 camas/día [DCD]). Resultados Se revisaron 81.348 dispensaciones de vasopresores, equivalentes a 26.414 terapias en 19.186 pacientes atendidos en 11 hospitales de 7 ciudades, cuya edad promedio fue 66,3±18,1 años y el 52,6 % eran hombres. Del total de terapias registradas, 17.658 (66,8 %) fueron con un solo vasopresor. La norepinefrina fue el más comúnmente prescrito (75,9 % de las dispensaciones; 60,5 DCD), seguido por adrenalina (26,6 %; 41,6 DCD), dopamina (19,4 %), dobutamina (16,0 %), vasopresina (8,5 %) y fenilefrina (0,9 %). El uso de norepinefrina se incrementó de 2010 a 2017 (+6,19 DCD), mientras que el de otros fármacos disminuyó, especialmente adrenalina (-60,6 DCD) y dopamina (-10,8 DCD). Conclusiones La norepinefrina es el fármaco vasopresor más utilizado y el que ha demostrado una tendencia de uso incremental durante el periodo de estudio, lo cual está respaldado por evidencia a favor de su efectividad y seguridad en pacientes con choque.

Seguridad del uso combinado de lidocaína y fenilefrina como midriáticos intracamerales en la cirugía de catarata / Safety of the combined use of lidocaine and phenylephrine as intracameral mydriatics in cataract surgery

Objetivo: Evaluar la seguridad ocular y sistémica de una combinación de lidocaína 2 por ciento y fenilefrina 1 por ciento administrada por vía intracameral para provocar midriasis intraoperatoria en la cirugía de catarata. Métodos: Se realizó un estudio prospectivo de serie de casos en 70 ojos de igual número de pacientes sometidos a facoemulsificación con implante de lente intraocular. El grupo midriasis intraoperatoria en la cirugía lo conformaron 35 pacientes dilatados con una inyección intracameral de lidocaína y fenilefrina antes de la cirugía, mientras otros 35 ojos se dilataron de manera tradicional, con un colirio midriático previo. Para la seguridad ocular se evaluaron múltiples parámetros del examen oftalmológico pre- y posoperatorio. Resultados: La presión intraocular, el espesor corneal central, la densidad celular del endotelio corneal y el edema corneal posoperatorio como hallazgo del segmento anterior se comportaron de manera similar en ambos grupos de estudio. Se reportó una complicación transoperatoria en el grupo de manera tradicional y un caso con edema quístico macular posoperatorio en el grupo midriasis intraoperatoria en la cirugía que no representaron diferencias significativas. Conclusión: La inyección de lidocaína más fenilefrina intracameral es una opción segura tanto ocular como sistémica para provocar midriasis durante la facoemulsificación(AU)

Objective: Evaluate the ocular and systemic safety of a combination of 2 percent lidocaine and 1 percent phenylephrine administered intracamerally to achieve intraoperative mydriasis in cataract surgery. Methods: A prospective study was conducted of a case series of 70 patients (70 eyes) who underwent phacoemulsification with intraocular lens implantation. The intraoperative mydriasis group was composed of 35 patients dilated with an intracameral injection of lidocaine and phenylephrine before surgery, whereas another 35 eyes were dilated by the conventional method, with mydriatic eye drops. Ocular safety evaluation was based on the analysis of a wide variety of pre- and postoperative ophthalmological examination parameters. Results: Intraocular pressure, central corneal thickness, corneal endothelial cell density and postoperative corneal edema as an anterior segment finding, behaved in a similar manner in both study groups. An intraoperative complication was reported in the conventional method group and a case with postoperative cystoid macular edema in the intraoperative mydriasis group group, neither of them exhibiting significant differences. Conclusion: Intracameral lidocaine plus phenylephrine injection is a safe ocular and systemic option to achieve mydriasis during phacoemulsification(AU)

Cardioprotective solutions exposure for 1 hour in hypoxia and low temperatures affects vascular reactivity differently

Abstract Introduction: Heart preservation benefits cardiac performance after operations decreasing morbidity but the contribution of the vascular reactivity has been neglected. Objective: We evaluated whether cardioprotective solutions, Krebs-Henseleit (KH), Bretschneider-HTK (BHTK), St. Thomas No. 1 (STH-1), and Celsior (CEL), affect vascular reactivity. Methods: Aortic rings from Wistar rats were used in two protocols. First, the rings were exposed to BHTK, STH-1 or CEL for 1 hour of hypoxia at 37 °C. Second, the rings were exposed to 10 °C or 20 °C for 1 hour under hypoxia. After treatment, the rings were immersed in KH at 37 °C, endothelial integrity was tested and concentration-response curves to phenylephrine were performed. Results: In the first protocol, the solutions did not damage the endothelium; CEL and BHTK reduced KCl-induced contractions but not STH-1; only CEL and BHTK reduced vascular reactivity; there was a positive correlation between Rmax and KCl concentration. At 20 °C, 1 hour under hypoxia, the solutions produced similar KCl-induced contractions without endothelial damage. CEL, BHTK and STH-1 decreased vascular reactivity. At 10 °C, STH-1 increased reactivity but CEL and BHTK decreased. After 1 hour under hypoxia in CEL or BHTK solutions, reactivity was similar at different temperatures. At 20 °C, endothelial damage after exposure to STH-1 produced more vasoconstriction than CEL and BHTK. However, at 10 °C, endothelial damage after CEL and BHTK exposure elicited more vasoconstriction while STH-1 showed a small vasoconstrictor response, suggesting endothelial damage. Conclusion: STH-1 decreased reactivity at 20 °C and increased at 10 °C. CEL promoted greater endothelial modulation at 10 °C than at 20 °C, while STH-1 promoted higher modulation at 20 °C than at 10 °C. Vascular tone was reduced by CEL and BHTK exposure, also depending on the KCl concentration.

Effect of different mydriatic regimens used for pupil dilation on the vital signs of premature infants for retinopathy of prematurity screening in a Philippine tertiary hospital: A randomized double-blind clinical trial

@#<p style="text-align: justify;"><strong>Objectives.</strong> To determine the safety and efficacy of three different mydriatic regimens in premature infants referred for retinopathy of prematurity (ROP) screening using (1) multiple alternate instillations of 0.5% cyclopentolate hydrochloride and 2.5% phenylephrine (MAI), (2) single instillation of 0.5%/0.5% tropicamide + phenylephrine (SI) and (3) single instillation of 0.5%/0.5% tropicamide + phenylephrine with a cotton wick placed in the inferior fornix (SIW) in a Philippine tertiary hospital.</p><p style="text-align: justify;"><strong>Methods.</strong> A randomized, double-blind, clinical trial included preterm infants for ROP screening at a Philippine tertiary hospital. After instillations via MAI, SI, and SIW, systolic blood pressure (SBP), diastolic pressure (DBP), mean arterial pressure (MAP), heart rate, and oxygen saturation were monitored. Pupillary dilation was also measured.</p><p style="text-align: justify;"><strong>Results.</strong> Sixty preterm infants, 20 to each intervention, were included. The MAI group did not have significant changes relative to its baseline vital signs. The use of SI produced lower DBP (p<0.0106) and MAP (p<0.0027) compared to MAI. The use of SI produced lower DBP (p<0.01) and MAP (p<0.003) compared to MAI. The SIW group exhibited significant increases in SBP (p<0.002) and in MAP (p<0.04) compared to MAI. This increase in SBP exceeded the clinical normal values for <37 weeks old infants. Pupillary dilation did not have significant differences among groups (p=0.24).</p><p style="text-align: justify;"><strong>Conclusion.</strong> Due to significant increase in SBP, it is recommended to discontinue SIW in preterm infants for ROP screening since it may promote the mydriatic's systemic absorption. Except for the clinically increased heart rate in infants aged ?37 weeks at examination, SI was found to be at par with the recommendation of the UK ROP Guidelines of May 2008.</p>

Comparison of two vasopressor protocols for preventing hypotension post-spinal anesthesia during cesarean section: a randomized controlled trial / 中华医学杂志(英文版)

BACKGROUND@#Norepinephrine infusion decreases hypotension after spinal anesthesia during cesarean section. This study aimed to compare the efficacy of norepinephrine infusion and ephedrine bolus against post-spinal hypotension in parturients.@*METHODS@#In this double-blinded, randomized controlled clinical trial, parturients scheduled for elective cesarean section were randomly allocated to receive norepinephrine infusion (0.05 μg·kg-1·min-1) just before spinal anesthesia continuing for 30 min or ephedrine bolus (0.15 mg/kg) just before spinal anesthesia. A rescue bolus (5 μg norepinephrine for the norepinephrine group, and 5 mg ephedrine for the ephedrine group) was administered whenever hypotension occurred. Our primary outcome was the incidence of hypotension within 30 min of spinal anesthesia administration. Secondary outcomes included maternal and neonatal outcomes 30 min after spinal block, and neonatal cerebral oxygenation 10 min after birth.@*RESULTS@#In total, 190 patients were enrolled; of these patients, 177 were included in the final analysis. Fewer patients suffered hypotension in the norepinephrine group than in the ephedrine group (29.5% vs. 44.9%, odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.28-0.95, P = 0.034). Moreover, the tachycardia frequency was lower in the norepinephrine group than in the ephedrine group (OR: 0.22, 95% CI: 0.11-0.44, P < 0.001), and patients suffered less nausea and vomiting (OR: 0.28, 95% CI: 0.11-0.70, P = 0.004). There was no difference in Apgar scores and umbilical arterial blood gas analysis between the two groups. However, neonatal cerebral regional saturations were significantly higher after birth in the norepinephrine group than in the ephedrine group (mean difference: 2.0%, 95% CI: 0.55%-3.45%, P = 0.008).@*CONCLUSION@#In patients undergoing elective cesarean section with spinal anesthesia, norepinephrine infusion compared to ephedrine bolus resulted in less hypotension and tachycardia, and exhibited potential neonatal benefits.@*TRIAL REGISTRATION@#ClinicalTrials.gov, NCT02542748; https://clinicaltrials.gov/ct2/show/record/NCT02542748.

The effect of epinephrine for the treatment of spinal-hypotension: comparison with norepinephrine and phenylephrine, clinical trial / O efeito de epinefrina, norepinefrina e fenilefrina no tratamento da hipotensão pós-raquianestesia: estudo clínico comparativo

Abstract Background and objectives: Limited data are present on safety and efficiency of epinephrine for the prophylaxis and treatment of spinal-hypotension. This study was conducted to compare the effect of epinephrine with norepinephrine and phenylephrine on the treatment of spinal-hypotension and ephedrine requirement during cesarean delivery. Methods: One hundred and sixty parturients with uncomplicated pregnancies undergoing elective cesarean delivery under spinal anesthesia were recruited. They were allocated randomly to receive norepinephrine 5 µg.mL−1 (n = 40), epinephrine 5 µg.mL−1 (n = 40), phenylephrine 100 µg.mL−1 (n = 40) or 0.9% saline infusions (n = 40) immediately after induction of spinal anesthesia. Whenever systolic blood pressure drops to less than 80% of baseline, 5 mg of intravenous ephedrine was administered as rescue vasopressor. The incidence of hypotension, total number of hypotension episodes, the number of patients requiring ephedrine, the mean amount of ephedrine consumption and side effects were recorded. Results: There was no statistically significant difference in incidence of maternal hypotension between groups. The number of patients requiring ephedrine was significantly greater in group saline than in group phenylephrine (p< 0.001). However, it was similar between phenylephrine, norepinephrine, and epinephrine groups. The mean ephedrine consumption was significantly higher in group saline than in norepinephrine, epinephrine, phenylephrine groups (p= 0.001). Conclusion: There is no statistically significant difference in incidence of hypotension and ephedrine consumption during spinal anesthesia for cesarean delivery with the use of epinephrine when compared to norepinephrine or phenylephrine. Epinephrine can be considered an alternative agent for management of spinal hypotension.

Resumo Justificativa e objetivos: Existem dados limitados sobre segurança e eficiência da epinefrina na profilaxia e tratamento da hipotensão arterial associada à raquianestesia. O presente estudo foi realizado para comparar o efeito da epinefrina com norepinefrina e fenilefrina no tratamento da hipotensão após raquianestesia e necessidade de efedrina durante o parto cesáreo. Método: Foram recrutadas 160 parturientes com gestações não complicadas, submetidas a cesariana eletiva sob raquianestesia. Elas foram alocadas aleatoriamente para receber norepinefrina 5 µg.mL-1 (n = 40), epinefrina 5 µg.mL-1 (n = 40), fenilefrina 100 µg.mL-1 (n = 40) ou infusão de solução fisiológica NaCl a 0,9% (n = 40) imediatamente após a indução da raquianestesia. Sempre que houvesse redução da pressão arterial sistólica para valor inferior a 80% da linha de base, 5 mg de efedrina iv eram administrados como vasopressor de resgate. A incidência de hipotensão, o número total de episódios de hipotensão, o número de pacientes que necessitaram de efedrina, o consumo médio de efedrina e os efeitos colaterais foram registrados. Resultados: Não houve diferença estatisticamente significante na incidência de hipotensão materna entre os grupos. O número de pacientes que necessitaram de efedrina foi significantemente maior no grupo solução fisiológica do que no grupo fenilefrina (p< 0,001). No entanto, foi semelhante entre os grupos fenilefrina, norepinefrina e epinefrina. O consumo médio de efedrina foi significantemente maior no grupo solução fisiológica do que nos grupos norepinefrina, epinefrina e fenilefrina (p = 0,001). Conclusão: Não houve diferença estatisticamente significante na incidência de hipotensão e consumo de efedrina durante raquianestesia para parto cesáreo com uso de epinefrina quando comparada à norepinefrina ou fenilefrina. A epinefrina pode ser considerada como agente alternativo para o tratamento da hipotensão após raquianestesia.

Eficacia del uso combinado de lidocaína y fenilefrina como midriáticos intracamerales en la cirugía de catarata / Efficacy of the combined use of lidocaine and phenylephrine as intracameral mydriatics in cataract surgery

RESUMEN Objetivo: Evaluar la eficacia de una combinación de lidocaína 2 por ciento y fenilefrina 1 por ciento administrada intracameralmente para provocar midriasis intraoperatoria en la cirugía de catarata. Métodos: Realizamos un estudio prospectivo, comparativo, de serie de casos en 70 ojos de igual número de pacientes quienes fueron sometidos a cirugía de catarata mediante facoemulsificación con implante de lente intraocular, en el Instituto Cubano de Oftalmología "Ramón Pando Ferrer" entre septiembre del año 2017 y febrero de 2018. 35 pacientes fueron dilatados con una combinación de fenilefrina y lidocaína inyectada en la cámara anterior justo antes de la cirugía (grupo midriáticos intracamerales) y otros 35 ojos se dilataron con un colirio midriático como se realiza cotidianamente y de manera tradicional (grupo midriáticos tópicos). La eficacia se evaluó mediante la medición del diámetro pupilar (pupilometría) realizada con un compás quirúrgico en diferentes momentos de la cirugía en ambos grupos de estudio. Los resultados de ambos grupos se compararon entre sí. Resultados: En ambos grupos de pacientes se lograron diámetros pupilares superiores a los 7 mm justo antes de la capsulorrexis, aunque fueron ligeramente mayor en el grupo midriáticos tópicos (8,17 vs. 7,55 mm). En las mediciones posteriores todas las pupilometrías del grupo midriáticos intracamerales fueron superiores y se mantuvieron por encima de los 7 mm, mientras las del grupo midriáticos tópicos sufrieron una reducción paulatina hasta el final de la cirugía (5,68 mm). Conclusiones: La combinación de lidocaína más fenilefrina aplicada de manera intracameral es efectiva para provocar una midriasis adecuada y mantenida durante la cirugía de catarata(AU)

ABSTRACT Objective: Evaluate the efficacy of the combination 2 percent lidocaine / 1 percent phenylephrine administered intracamerally to achieve intraoperative mydriasis in cataract surgery. Methods: A prospective comparative study was conducted of a case series of 70 patients (70 eyes) who underwent cataract surgery by phacoemulsification with intraocular lens implantation at Ramón Pando Ferrer Cuban Institute of Ophthalmology from September 2017 to February 2018. Of the total eyes, 35 were dilated with a combination of phenylephrine and lidocaine injected into the anterior chamber just before surgery (MIC group), whereas the remaining 35 were dilated with mydriatic eye drops in the habitual traditional manner (MT group). Efficacy was evaluated in the two study groups measuring the pupil diameter (pupilometry) with a surgical compass at several moments during the surgery. The results for each group were compared. Results: In both groups patients achieved pupil diameters above 7 mm just before capsulorhexis, though values were slightly higher in the MT group (8.17 vs. 7.55 mm). Later measurement showed that in the MIC group all pupilometries were higher, remaining above 7 mm, whereas in the MT group they underwent gradual reduction until the end of surgery (5.68 mm). Conclusions: The combination of lidocaine and phenylephrine administered intracamerally is effective to achieve appropriate, sustained mydriasis during cataract surgery(AU)

A via Nrf2 participa da maior modulação endotelial induzida pela prenhez sobre reatividade de aortas à fenilefrina / The Nrf2 pathway participates in the greater endothelial modulation induced by pregnancy on reactivity of aortas to phenylephrine

Alterações em diferentes vias de sinalização levam a disfunção vascular e endotelial e consequentemente a hipertensão. A hipertensão está relacionada diretamente com o aumento da produção de espécies reativas de oxigênio (ROS) e diminuição da biodisponibilidade de óxido nítrico (NO) nos vasos sanguíneos. A via do Nrf2 (fator nuclear eritróide 2) está envolvida nos mecanismos que levam ao aumento da biodisponibilidade vascular de NO, pois controla a expressão de enzimas antioxidantes. A ativação do Nrf2 é modulada por sua ligação com a Keap-1 (Kelch-like ECH-associated protein 1) e sua atividade é modulada pelo fator de transcrição Bach-1, que compete pelo mesmo sitio ativo no DNA com o Nrf2. Em ratas normotensas e em ratas espontaneamente hipertensas (SHR) é observada uma redução da pressão arterial ao final da prenhez, que tem sido associada à redução do estresse oxidativo e maior biodisponibilidade de NO. Com o aumento da biodisponibilidade de NO, é aumentada a modulação do endotélio sobre a reatividade vascular à agonistas vasoconstritores, como à fenilefrina (PE). Levantamos a hipótese que a prenhez altera a expressão e ou a atividade do Nrf2 e de seus inibidores Keap-1 e Bach-1 e que estas possíveis alterações estariam associadas à maior modulação endotelial sobre contração de aortas à PE. Para testarmos esta hipótese, a expressão de Nrf2, Keap-1 e Bach-1 e também das enzimas antioxidantes transcritas pelo Nrf2, como a NADP(H) quinona oxirredutase-1 (NQO1), SOD-1 e SOD-2 foram avaliadas em aortas de ratas prenhes e comparadas as aortas de ratas não-prenhes. A fim de identificarmos outros possíveis mecanismos alterados pela prenhez em ratas Wistar e SHR, avaliamos a expressão de NOXO-1, subunidade regulatória da NOX1 e de p47phox, subunidade regulatória de NOX2. A participação do Nrf2 na produção de NO endotelial em aortas de ratas prenhes, foi avaliada pela utilização de Brusatol, uma droga inibidora do Nrf2. Avaliamos também a participação do Nrf2 na reatividade de aortas de ratas prenhes à fenilefrina e à acetilcolina, utilizando o Brusatol. Todos os resultados foram comparados entre ratas não-prenhes normotensas (Wistar) e hipertensas (SHR) e entre ratas não-prenhes e prenhes nos grupos (análise de multivariância, post-test Tukey, p< 0,05). Os resultados mostraram que a expressão de Nrf2 está aumentada em aortas de ratas prenhes Wistar, apesar da expressão de Keap-1 e de Bach1 não estar alterada. Associado a expressão aumentada de Nrf2 observamos maior expressão de SOD-2, mas não de SOD-1 ou NQO1, em aortas de ratas prenhes. Em aortas de ratas SHR não prenhes, observamos entre todas as proteínas avaliadas, menor expressão de Bach-1 e de NQO1 quando comparadas às aortas de ratas normotensas. A prenhez reduziu ainda mais a expressão apenas de NQO1 em aortas de SHR. A prenhez reduziu a expressão de NOXO-1 e de p47phox em aortas de SHR, enquanto que em aortas de ratas Wistar reduziu apenas a expressão de NOXO-1. Os resultados obtidos neste estudo mostraram também que a incubação de HUVEC com Brusatol aumentou as concentrações intracelulares de ERO, mas não alterou as concentrações de NO, no entanto, reduziu significativamente a concentração de NOx estimulada pela ACh em aortas de ratas prenhes, Wistar ou SHR. Além disto, o Brusatol aumentou a reatividade à PE em aortas de ratas normotensas não prenhes e prenhes, igualando a reatividade de aortas de ratas prenhes as aortas de ratas não prenhes. No entanto, o Brusatol não alterou a reatividade de aortas de SHR, prenhes ou não-prenhes. Nenhum efeito significativo do Brusatol foi observado na reatividade à Acetilcolina em aortas de ratas Wistar ou SHR, prenhes ou não prenhes. Em conclusão, nossos resultados sugerem que a atividade da via de sinalização do Nrf2 está aumentada, favorecendo a maior atividade de enzimas antioxidantes como a SOD-2, que contribuiria para maior biodisponibilidade de NO e maior modulação endotélio-dependente da contração vascular à PE em aortas de ratas normotensas prenhes. No entanto, em aortas de SHR prenhes, este mecanismo parecer não ser mais importante que a redução da atividade de isoformas NOX e de suas subunidades regulatórias que contribuiria para menor geração de O2•- e consequentemente, maior biodisponibilidade de NO(AU)

Modifications in different signaling pathways lead to vascular and endothelial dysfunction and, consequently, hypertension. Hypertension is directly related to an increase in the production of reactive oxygen species (ROS) and a decrease in the bioavailability of nitric oxide (NO) in blood vessels. The Nrf2 (erythroid nuclear factor 2) pathway is involved in the mechanisms that lead to the increased vascular bioavailability of NO, as it controls the expression of antioxidant enzymes. The activation of Nrf2 is modulated by Keap-1 (Kelch-like ECH-associated protein 1) and its activity is modulated by the transcription factor Bach-1, which competes for the same active site in DNA with Nrf2. In normotensive rats and spontaneously hypertensive rats (SHR), a reduction in blood pressure at the end of pregnancy is observed, which has been associated with a reduction in oxidative stress and greater bioavailability of NO. This increased NO bioavailability has been associated with the higher endothelium modulation over blood vessel reactivity to vasoconstrictor agonists, such as phenylephrine (PE), observed in pregnant rats. We hypothesized that pregnancy alters the expression and/or activity of Nrf2 and its inhibitors Keap-1 and Bach-1 and that these changes are associated with greater endothelial modulation on the contraction of aortas to PE. To test this hypothesis, the expression of Nrf2, Keap-1 and Bach-1 and the antioxidant enzymes transcribed by Nrf2, such as NADP (H) quinone oxidoreductase-1 (NQO1), SOD-1 and SOD-2 were evaluated in aortas of pregnant rats and compared to aortas of non-pregnant rats. In order to identify other possible mechanisms altered by pregnancy in Wistar rats and SHR, we evaluated the expression of NOXO-1, NOX1 regulatory subunit and p47phox, NOX2 regulatory subunit. The role of Nrf2 in the production of endothelial NO in aortas of pregnant rats was evaluated by use of Brusatol, an inhibitor of Nrf2. We also evaluated the role of Nrf2 in the reactivity of aortas of pregnant rats to phenylephrine and acetylcholine, using Brusatol. All results were compared between normotensive (Wistar) and hypertensive (SHR) non-pregnant rats and between pregnant and non-pregnant rats in the groups (multivariate analysis, Tukey post-test, p< 0.05). The results showed that the expression of Nrf2 is increased in aortas of pregnant Wistar rats, although the expression of Keap-1 and Bach-1 is not altered. The increased expression of Nrf2 was associated with the greater expression of SOD-2, but not of SOD-1 or NQO1, in aortas of pregnant rats. In aortas of non-pregnant SHR rats, we observed among all evaluated proteins, lower expression of Bach-1 and NQO1 when compared to the aortas of normotensive rats. Pregnancy reduced even more the expression of NQO1 in SHR aortas. Pregnancy reduced the expression of NOXO-1 and p47phox in SHR aortas, whereas in aorta of Wistar rats it reduced only the expression of NOXO-1. The results obtained in this study also showed that the incubation of HUVEC with Brusatol increased the intracellular concentrations of ROS, but did not alter the concentrations of NO, however, Brusatol significantly reduced the concentration of NOx stimulated by ACh in aortas of pregnant rats, Wistar or SHR. Moreover, Brusatol increased the reactivity to PE in aortas of pregnant normotensive rats and pregnant, matching the reactivity of aortas of pregnant rats to aortas of non-pregnant rats. However, Brusatol did not alter the reactivity of pregnant or non-pregnant SHR aortas. No significant effect of Brusatol was observed in the reactivity to Acetylcholine in aortas of Wistar rats or SHR, pregnant or non-pregnant rats. In conclusion, our results suggest that the activity of the Nrf2 signaling pathway is increased, favoring the greater activity of antioxidant enzymes such as SOD-2, which would contribute to greater bioavailability of NO and greater endothelium-dependent modulation of vascular contraction to PE in aortas of pregnant normotensive rats. However, in pregnant SHR aortas, this mechanism appears to be no more important than the lower the activity of NOX isoforms and their regulatory subunits that would contribute to lower O2•- generation and, consequently, greater NO bioavailability(AU)

Evaluation of the bioequivalence of two formulations containing the combination of 400 mg of acetaminophen (paracetamol), 4 mg of phenylephrine and 4 mg of chlorpheniramine in capsules: open-label, three-way crossover study, partially replicated in healthy volunteers of both sexes

This study was carried out in order to compare the relative bioavailability of two different formulations containing 400 mg of acetaminophen + 4 mg of phenylephrine hydrochloride + 4 mg of chlorpheniramine maleate, Test formulation (Cimegripe®) and Reference formulation (Resfenol®) in 84 healthy volunteers of both sexes under fasting conditions. The study was conducted in a single dose, randomized, open-label, crossover 3-way and partially replicated. The tolerability was evaluated by the monitoring of adverse events and vital signs, results of clinical and laboratory tests. Plasma concentrations were quantified by validated bioanalytical methods using the ultra-performance liquid chromatography coupled to tandem mass spectrometry. The Cmax, Tmax, AUC0-t, AUC0-inf, T1/2 and Kel pharmacokinetic parameters were calculated from these obtained concentrations. The 90% confidence intervals were constructed for the ratio reference/test from the geometric average of the Cmax and AUC parameters which were comprised between 80% and 125%. Only the Cmax parameter of the phenylephrine was applied the scaled average bioequivalence due to the intraindividual coefficient of variation > 30% obtained, thus extending the acceptance limits of the interval. It can be concluded that the two formulations were bioequivalent in terms of rate and absorption extent and thus interchangeable

Evaluation of relaxant responses properties of cinnamon essential oil and its major component, cinnamaldehyde on human and rat corpus cavernosum

ABSTRACT Cinnamomum cassia (Cinnamon) is a well-known traditional medicine with therapeutic benefits for centuries. We evaluated the effects of cinnamon essential oil (CEO) and its main component cinnamaldehyde (CA) on human corpus cavernosum (HCC) and rat CC. The essential oil of cinnamon was analyzed for the confirmation of the oil profile. HCC specimens from patients undergoing penile prosthesis surgery (age 48-69 years) were utilized for functional studies. In addition, erectile responses in anesthetized control and diabetic rats were evaluated in vivo after intracavernosal injection of CEO and CA, and rat CC strips were placed in organ baths. After precontraction with phenylephrine (10µM), relaxant responses to CEO and CA were investigated. CA (96.9%) was found as the major component. The maximum relaxation responses to CEO and CA were 96.4±3.5% and 96.0±5.0% in HCC and 97.5±5.5% and 96.8±4.8% in rat CC, respectively. There was no difference between control and diabetic rats in relaxation responses to CEO and CA. The relaxant responses obtained with essential oil and CA were not attenuated in the presence of nitric oxide synthase (NOS) inhibitor, and soluble guanylate cyclase inhibitor (sGS) in CC. In vivo, erectile responses in diabetic rats were lower than in control rats, which was restored after intracavernosal injection of CEO and CA. CEO and CA improved erectile function and relaxation of isolated strips of rat CC and HCC by a NO/cGMP-independent mechanism. Further investigations are warranted to fully elucidate the restorative effects of CEO and CA on diabetic erectile dysfunction.

Curcuma Longa Abolishes Phenylephrine-Induced Contractions in Isolated Aortic Artery of Rats

Curcuma longa has biological effects. Its cardiovascular activities are yet to be scientifically studied. Objectives: To investigate the vasorelaxant effects of the aqueous extract of Curcuma longa (AECL). Methods: Aortic annuli of normotensive rats, with or without endothelium, were set up in a data storage system with nutrient solution in recipients, with scientifically recommended temperature, aeration and tension. Over contraction by Phenylephrine, the AECL (1, 3, 10, 30, 100, 300 and 1000 µg/mL) was incubated before and after incubation with atropine or L-name or indomethacin. An AECL concentration-response curve was also built over contractions caused by elevation of extracellular K+. Data were significant when p < 0.05, with GraphPad Prism 6.0 software resolutions. Results: The AECL induced 100% vasorelaxation also in the endothelium-free annuli. The part of the endothelium-dependent effect had EC50 = 4.32 ± 0.05 µg/mL. With inhibition of NO production, the EC50 increased to 126.50 ± 2.35 µg/mL; after inhibition of prostacyclin production, to 124.6 ± 0.05 µg/mL; and after muscarinic blockade, to 437.10 ± 0.2 µg/mL. Opening of K+ channels (relaxation of 56.98%) and VOCC blockade (relaxation of 31.56%) were evident. Conclusion: AECL induced significant vasorelaxation, being more significant in the presence of endothelium. The muscarinic pathway seems to be the main one involved in this effect, followed by the NO production and prostacyclin pathways. The activity in K+ channels by AECL was more significant than its VOCC blockade. The use of other models and tools to study action mechanisms will be important and elucidating

Efficacy of preoperative nonsteroidal anti-inflammatory drug and the re-dilation technique in minimizing miosis after femtosecond laser in cataract surgery / Eficácia do AINE pré-operatório e da técnica de re-dilatação em minimizar a miose na cirurgia de catarata com laser de femtosegundo

ABSTRACT Purpose: To assess the efficacy of using a nonste­roidal anti-inflammatory drug preoperatively and of applying the re-dilation technique when necessary to minimize pupil size variation when comparing the degree of mydriasis before femtosecond laser pretreatment with that at the beginning of phacoemulsification. Methods: This retrospective study included patients who underwent cataract surgery using the LenSx (Alcon Laboratories, Inc., Fort Worth, TX). Our routine dilating regimen with flurbiprofen, tropicamide, and phenylephrine was used. The re-dilation technique was applied on eyes that manifested with a pupillary diameter that was smaller than the programmed capsulotomy diameter after laser pretreatment. The technique consists of overcoming pupillary contraction by instilling tropicamide and phenylephrine before phacoemulsification. Pupil size was assessed before femtosecond laser application and at the beginning of phacoemulsification. Results: Seventy-five eyes (70 patients) were included. Nine (12%) eyes underwent the re-dilation technique. There was no significant difference in mean pupillary diameter and mean pupillary area between the two studied surgical time points (p=0.412 and 0.437, respectively). The overall pupillary area constriction was 2.4 mm2. Immediately before opening the wounds for phacoemulsification, none of the eyes presented with a pupillary diameter <5 mm, and 61 (85.3%) eyes had a pupillary diameter >6 mm. Conclusion: Preoperative administration of nonsteroidal anti-inflammatory drug and the re-dilation technique resulted in no significant pupil size variation in eyes that were pretreated with the femtosecond laser, when comparing the measurements made before the laser application and at the beginning of phacoemulsification. This approach can avoid the need to proceed with cataract extraction with a constricted pupil.

RESUMO Objetivo: Avaliar a eficácia do uso de anti-inflamatório não-esteróide no pré-operatório e aplicação da técnica de re-dilatação quando necessária para minimizar a variação do tamanho pupilar ao comparar o grau de midríase antes do tra­tamento com laser de femtosegundo no início da facoemulsificação. Métodos: Esse estudo retrospectivo incluiu pacientes que foram submetidos à cirurgia de catarata usando o LenSx (Alcon Laboratories, Inc., Fort Worth, TX). Nosso regime de di­latação de rotina com flurbiprofeno, tropicamida e fenilefrina foi usado. A técnica de re-dilatação doi aplicada em olhos que se manifestaram com um diâmetro pupilar menor do que o diâmetro da capsulotomia programado após o pré-tratamento a laser. A técnica consiste em superar a contração pupilar pela instilação de tropicamida e fenilefrina antes da facoemulsificação. O tamanho pupilar foi avaliado antes da aplicação do laser de femtosegundo e no inicio da facoemulsificação. Resultados: Setenta e cinco olhos (70 pacientes) foram incluídos. Nove (12%) olhos foram submetidos à técnica de re-dilatação. Não houve diferença significativa no diâmetro pupilar médio e na área pupilar média entre os dois tempos cirúrgicos estudados (p=0,412 e 0,437, respectivamente). A constrição global da área pupilar foi de 2,4 mm2. Imediatamente antes de abrir as incisões para a facoemulsificação, nenhum dos olhos apresentava diâmetro pupilar <5 mm e 61 (85,3%) olhos apresentavam um diâmetro pupilar >6 mm. Conclusões: O administração pré-operatória de anti-inflamatório não-esteróide e da técnica de re-dilatação resultaram em uma variação significativa do tamanho pupilar em olhos que foram pré-tratados com laser de femtosegundo, comparando as medidas realizadas antes da aplicação do laser e no inicio da facoemulsificação. Essa abordagem pode evitar a necessidade de prosseguir com a extração da catarata com uma pupila contraída.

Midriáticos intracamerales en la cirugía de catarata / Intracameral mydriatics in cataract surgery

RESUMEN Durante la cirugía de catarata, la inducción de la dilatación de la pupila (midriasis) y el mantenimiento de un grado adecuado de esta a lo largo de toda la operación son elementos críticos para la eliminación y el reemplazo exitoso del cristalino. Una pupila pequeña o un cierre pupilar durante la cirugía hacen que esta sea un desafío desde el punto de vista técnico y aumente el riesgo de complicaciones transquirúrgicas, por lo que una midriasis adecuada y mantenida ha permanecido hasta nuestros días como un pilar fundamental para maximizar la seguridad y los resultados refractivos de la cirugía de catarata moderna. Esta midriasis se consigue habitualmente con la aplicación previa de colirios anticolinérgicos y simpaticomiméticos, con los cuales el tiempo de espera para la dilatación pupilar es frecuentemente más largo que el procedimiento quirúrgico; tienen una significativa absorción sistémica que pueden aumentar el riesgo de efectos secundarios cardiovasculares, y el efecto midriático tiende a desaparecer durante la cirugía. Con el objetivo de acceder a la información actualizada sobre los fármacos midriáticos más usados de modo intracameral, sus dosis y formas de aplicación durante la cirugía de catarata, se realiza el presente trabajo de revisión(AU)

ABSTRACT In cataract surgery, induction and maintenance of an adequate degree of pupil dilation (mydriasis) throughout the operation are critical elements for the successful removal and replacement of the crystalline lens. A small pupil or pupil closure during surgery pose a technical challenge and increase the risk of intraoperative complications. This is the reason why adequate, maintained mydriasis has remained to this day a fundamental pillar to maximize both safety and satisfactory refractive results in modern cataract surgery. Mydriasis is normally achieved with the previous application of anticholinergic and sympathomimetic eye drops, for which the waiting time for pupil dilation is often longer than the surgical procedure, they have significant systemic absorption which may increase the risk of cardiovascular side effects, and the mydriatic effect tends to vanish during surgery. A bibliographic review was conducted with the purpose of accessing updated information about the most commonly used intracameral mydriatic drugs, their doses and modes of application during cataract surgery(AU)

Late cardiac perconditioning by phenylephrine in an isolated rat heart model is mediated by mitochondrial potassium channels

The present study was designed to investigate the effect of early and late administration of phenylephrine during ischemia against regional ischemia-reperfusion injuries in an isolated rat heart model. All animals were randomly divided into experimental groups: (I) IR (Ischemic/ reperfusion): the hearts underwent 35 min of regional ischemia followed by 60 min of reperfusion; (II) 5HD-IR-0: the hearts were perfused for 5 min with 5HD (5-hydroxydecanoate, specific mKATP channel blocker, 100 µM) at the onset of regional ischemia; (III) 5HD-IR-20: the hearts were perfused for 5 min with 5HD 20 min after regional ischemia; (IV) PE-IR-10: the hearts were perfused for 5 min with phenylephrine 10 min after regional ischemia; (V) PE-IR-30: the hearts were perfused for 5 min with phenylephrine (100 µM) 30 min after regional ischemia; (VI) PE-5HD-IR-10 group: the hearts were perfused for 5 min with 5HD at the onset of regional ischemia after which phenylephrine was administrated as in group IV; and (VII) PE-5HD-IR-30: the hearts were perfused for 5 min with 5HD 20 min after the ischemia and then phenylephrine was administrated as in group V. The hemodynamic parameters were recorded throughout the experiment. Ischemia-induced arrhythmias, myocardial infarct size (IS), creatin kinase-MB isoenzyme (CK-MB), plasma lactate dehydrogenase (LDH) activities, and coronary blood flow (CBF) were measured in all animals. Perfusion of phenylephrine 30 min after the regional ischemia curtailed the myocardial infarct size, reduced CK-MB, and improved cardiac function and CBF. Administration of 5HD 30 min after the ischemia abolished cardioprotective effects of phenylephrine in the late phase. These results suggest the involvement of mKATP in the mechanism of phenylephrine-induced late preconditioning.

Anaphylactic reaction with hydroxyethyl starch during anesthesia: A case report

BACKGROUND: Hydroxyethyl starch (HES), a class of synthetic colloid solutions, has been widely used to treat perioperative hypovolemia. The use of HES, however, is associated with the risk of allergic reactions.CASE: An 83-year-old man was scheduled to undergo an open reduction and internal fixation of a pertrochanteric fracture under spinal anesthesia. He had no history of allergy. Five minutes after HES administration, hypotension, agitation, and skin rash were developed. HES infusion was terminated due to a suspected anaphylactic reaction. The vital signs recovered following administration of phenylephrine, dexamethasone, and hydrocortisone. Serum tryptase and total immunoglobulin E levels were elevated in plasma samples collected following the commencement of the allergic reaction during surgery.CONCLUSIONS: In the present report, the risk of anaphylactic reaction with HES and the laboratory tests needed to support the diagnosis are highlighted.

Use of methylene blue in vasoplegic syndrome that developed during non-cardiac surgery: A case report

BACKGROUND: Vasoplegic syndrome is an increasingly recognized disease in perioperative medicine and is characterized by severe hypotension, normal or elevated cardiac output, and decreased systemic vascular resistance. It occurs commonly after cardiopulmonary bypass but may also occur after other types of surgery.CASE: Vasoplegic syndrome developed in our patient during posterior lumbar interbody fusion because of administering nicardipine after phenylephrine. However, the blood pressure did not increase as expected despite simultaneous use of norepinephrine and vasopressin to increase the reduced systemic vascular resistance.CONCLUSIONS: We present a case of vasoplegic syndrome that developed during posterior lumbar interbody fusion and was treated successfully with methylene blue.

A pilot study on the role of autonomic function testing in predicting hypotension in patients undergoing cesarean section under spinal anesthesia

BACKGROUND: Maternal hypotension is a common complication during obstetric spinal anesthesia. This study was conducted to investigate the role of autonomic function testing in predicting maternal hypotension during spinal anesthesia induced to conduct Cesarean sections (C-section). METHODS: This study was conducted on 32 parturients undergoing C-section under spinal anesthesia. Sympathetic function tests included measuring diastolic blood pressure changes in response to hand gripping and systolic blood pressure changes response to moving from a supine to a standing position. Sympathetic dysfunction is said to exist when there are abnormal responses to both sympathetic function tests. Parasympathetic function tests included measuring heart rate responses to deep breathing and heart rate responses to moving from a supine to a standing position. Parasympathetic dysfunction is said to exist when there are abnormal responses to both parasympathetic function tests. After the onset of spinal anesthesia, blood pressure was measured every minute until childbirth. RESULTS: Hypotension occurred in 22 of the 32 parturients. There was no correlation between sympathetic dysfunction and hypotension incidence, but 12 of the 12 (100%) of the positive group and 10 of the 20 (50%) of the negative group experiencing parasympathetic dysfunction, respectively, experienced hypotension with a significant difference of P = 0.004. The group experiencing parasympathetic dysfunction had statistically significantly higher phenylephrine requirements were also greater in the parasympathetic dysfunction positive group (P < 0.003). CONCLUSIONS: This study's findings suggested that the parasympathetic function tests may be useful methods for predicting the incidence of maternal hypotension during spinal anesthesia induced for C-section.

Effects of fetal position on maternal hemodynamics after spinal anesthesia for cesarean delivery

BACKGROUND: Aortocaval compression by the gravid uterus is a known physiological phenomenon that is classically claimed to cause supine hypotension in full-term pregnant women. This study aimed to investigate the effects of fetal position on maternal hemodynamics after spinal anesthesia during cesarean delivery. METHODS: In total, 71 women with intrauterine pregnancy over 36 weeks of gestation who were scheduled for elective cesarean delivery under spinal anesthesia were enrolled in the study. Based on the fetal position, the women were divided into two groups: right position group (group R) and left position group (group L). Occurrence of hypotension, requirement for rescue bolus injections of phenylephrine, and the total amount of infused phenylephrine before delivery were recorded in each group. RESULTS: There was no statistically significant difference in the occurrence of hypotension between the two groups (P = 0.075); however, the amount of phenylephrine required before delivery was significantly greater in group R (P = 0.028). There was a statistically significant decrease in the systolic blood pressure compared with the baseline values in group R, and this change persisted until 15 min after spinal anesthesia. CONCLUSIONS: There was no difference according to fetal position in the number of patients who showed hypotension before delivery after spinal anesthesia.

Sugammadex associated profound bradycardia and sustained hypotension in patient with the slow recovery of neuromuscular blockade: A case report

BACKGROUND: New complications associated with sugammadex have been increased since its widespread use. We report a case of an 80-year-old male who experienced profound bradycardia and sustained hypotension after administration of sugammadex. CASE: Following administration of 200 mg sugammadex after laparoscopic cholecystectomy, sudden bradycardia (29 beats/min) developed for 10 seconds and his train-of-four (TOF) ratio remained at 0.2 for 5 min. An additional 200 mg sugammadex was administered and profound bradycardia (21–30 beats/min) and hypotension (60/40 mmHg) developed. Atropine at 0.5 mg was administered, but the effect lasted only 30 s. Profound bradycardia occurred four more times at 30 s intervals, and ephedrine and phenylephrine were injected intermittently to increase the patient's heart rate and blood pressure. The TOF ratio became 0.9 about 10 min after administration of additional sugammadex. CONCLUSIONS: Awareness must be heightened regarding the possibility of sugammadexinduced bradycardia and hypotension, and more attention should be paid to patients with slow recovery times following muscle relaxation, despite the use of sugammadex.