RESUMEN

In the present study, a magnetic ion-imprinted polymer based on n-allylthiourea in the presence of 1-(2-pyridylazo)-2-naphthol (MIIP-PAN) was synthesized, characterized, and applied in the preconcentration of nickel ions by dispersive magnetic solid phase extraction (DMSPE) with FAAS detection. For comparison, non-imprinted polymer (MNIP-PAN) and imprinted polymer without PAN were synthesized. The characterization of the polymers was performed by FT-IR, DRX, TEM, TGA, VSM, and BET. Selectivity studies were performed comparing the competitive adsorption of Ni2+ with other cations on MIIP-PAN and MNIP-PAN, achieving higher relative selectivity coefficients for MIIP-PAN than for MNIP-PAN and NIP. Under optimized conditions, the method provided a preconcentration factor of 76.70, detection limit of 0.25 µg/L and intra-day (2.06 - 2.33 %) and inter-day (1.82 - 4.90 %) precision. The developed method was applied to samples of water, teas, and chocolate powder, and its precision was evaluated through tests of recovery and analysis of certified materials.

Asunto(s)

Impresión Molecular , Níquel , Propanolaminas , Níquel/análisis , Agua , Espectroscopía Infrarroja por Transformada de Fourier , Polímeros , Adsorción , Fenómenos Magnéticos , Extracción en Fase Sólida/métodos

RESUMEN

BACKGROUND: Few trials have examined the efficacy of esmolol to attenuate hemodynamic and respiratory responses during extubation. However, the most appropriate dose of esmolol and an optimal protocol for administering this beta-blocker are uncertain. METHODS: Ninety patients ASA physical status I, II, and III (aged 18...60 years) scheduled to procedures with general anesthesia and tracheal extubation were selected. Patients were randomized into esmolol and placebo group to evaluate the efficacy and safety of a single bolus dose of esmolol (2...mg.kg-1) on cardiorespiratory responses during the peri-extubation period. The primary outcome was the rate of tachycardia during extubation. RESULTS: The rate of tachycardia was significantly lower in esmolol-treated patients compared to placebo-treated patients (2.2% vs. 48.9%, relative risk (RR): 0.04, 95% confidence interval (95% CI)...=...0.01 to 0.32, p...=...0.002). The rate of hypertension was also significantly lower in the esmolol group (4.4% vs. 31.1%, RR: 0.14, 95% CI 0.03 to 0.6, p...=...0.004). Esmolol-treated patients were associated with higher extubation quality compared to patients who received placebo (p...<...0.001), with an approximately two-fold increase in the rate of patients without cough (91.1%) in the esmolol group compared to the placebo group (46.7%). The rate of bucking was approximately 5-fold lower in the esmolol group (8.9% vs. 44.5%, respectively, RR: 0.20 (95% CI, 0.1 to 0.5, p...=...0.002, with an NNT of 2.8). CONCLUSION: A single bolus dose of esmolol is an effective and safe therapeutic strategy to attenuate cardiorespiratory responses during the peri-extubation period.

Asunto(s)

Hipertensión , Propanolaminas , Humanos , Extubación Traqueal/efectos adversos , Hipertensión/tratamiento farmacológico , Hipertensión/etiología , Propanolaminas/farmacología , Propanolaminas/uso terapéutico , Antagonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/uso terapéutico , Taquicardia/tratamiento farmacológico , Taquicardia/etiología , Taquicardia/prevención & control , Anestesia General/efectos adversos , Método Doble Ciego , Frecuencia Cardíaca

RESUMEN

Abstract Background Few trials have examined the efficacy of esmolol to attenuate hemodynamic and respiratory responses during extubation. However, the most appropriate dose of esmolol and an optimal protocol for administering this beta-blocker are uncertain. Methods Ninety patients ASA physical status I, II, and III (aged 18-60 years) scheduled to procedures with general anesthesia and tracheal extubation were selected. Patients were randomized into esmolol and placebo group to evaluate the efficacy and safety of a single bolus dose of esmolol (2 mg.kg-1) on cardiorespiratory responses during the peri-extubation period. The primary outcome was the rate of tachycardia during extubation. Results The rate of tachycardia was significantly lower in esmolol-treated patients compared to placebo-treated patients (2.2% vs. 48.9%, relative risk (RR): 0.04, 95% confidence interval (95% CI) = 0.01 to 0.32, p= 0.002). The rate of hypertension was also significantly lower in the esmolol group (4.4% vs. 31.1%, RR: 0.14, 95% CI 0.03 to 0.6, p= 0.004). Esmolol-treated patients were associated with higher extubation quality compared to patients who received placebo (p< 0.001), with an approximately two-fold increase in the rate of patients without cough (91.1%) in the esmolol group compared to the placebo group (46.7%). The rate of bucking was approximately 5-fold lower in the esmolol group (8.9% vs. 44.5%, respectively, RR: 0.20 (95% CI, 0.1 to 0.5, p= 0.002, with an NNT of 2.8). Conclusion A single bolus dose of esmolol is an effective and safe therapeutic strategy to attenuate cardiorespiratory responses during the peri-extubation period.

Asunto(s)

Humanos , Propanolaminas/uso terapéutico , Propanolaminas/farmacología , Hipertensión/etnología , Hipertensión/tratamiento farmacológico , Taquicardia/etnología , Taquicardia/prevención & control , Taquicardia/tratamiento farmacológico , Antagonistas Adrenérgicos beta/uso terapéutico , Antagonistas Adrenérgicos beta/farmacología , Extubación Traqueal/efectos adversos , Frecuencia Cardíaca , Anestesia General/efectos adversos

RESUMEN

INTRODUCTION AND OBJECTIVES: Although lidocaine is widely used to prevent cardiovascular changes resulting from laryngoscopy and orotracheal intubation, it is still unclear whether there are more efficacious drugs. This study aimed to compare the beta-blocker esmolol with lidocaine regarding the effects on hemodynamic response after orotracheal intubation. METHODS: The study has a prospective, randomized, double-blind, superiority design, and assessed 69 participants between 18 and 70 years of age, ASA I-II, scheduled for elective or emergency surgery under general anesthesia with orotracheal intubation. Participants were randomly allocated to receive 1.5 mg.kg-1 esmolol bolus followed by 0.1 mg.kg-1.min-1 esmolol infusion (n = 34) or 1.5 mg.kg-1 lidocaine bolus followed by 1.5 mg.kg-1.h-1 lidocaine infusion (n = 35). We recorded changes in heart rate, arterial blood pressure and incidence of adverse events. RESULTS: Post-intubation tachycardia episodes were significantly less frequent in the esmolol group (5.9% vs. 34.3%; Relative Risk (RR) 0.17; 95% Confidence Interval (95% CI) 0.04-0.71; Number Needed to Treat (NNT) 3.5; p = 0.015. After orotracheal intubation, mean heart rate was significantly lower in the esmolol group (74.5 vs. 84.5, p = 0.006). Similar results were observed in the subsequent 3 and 6 minutes (75.9 vs. 83.9, p = 0.023 and 74.6 vs. 83.0, p = 0.013, respectively). CONCLUSION: Esmolol was a safe and more effective intervention to reduce incidence of tachycardia and control heart rate immediately after tracheal intubation when compared to lidocaine.

Asunto(s)

Lidocaína , Propanolaminas , Presión Sanguínea , Método Doble Ciego , Frecuencia Cardíaca , Hemodinámica , Humanos , Intubación Intratraqueal/efectos adversos , Laringoscopía/efectos adversos , Lidocaína/farmacología , Lidocaína/uso terapéutico , Propanolaminas/farmacología , Propanolaminas/uso terapéutico , Estudios Prospectivos , Taquicardia/tratamiento farmacológico , Taquicardia/etiología , Taquicardia/prevención & control

RESUMEN

Abstract Introduction Controlled hypotension is a reversible procedure in which the patient's baseline mean arterial blood pressure is reduced by 30% and sustained at 60-70 mmHg during the procedure. It decreases blood loss and provides clear surgical field during the procedures. Objectives The purpose of this study was to compare the efficacy of controlled hypotension agents esmolol, remifentanil, and nitroglycerin in functional endoscopic sinus surgery, in terms of hemodynamic changes and impact on the surgical efficiency. Methods The research was carried out as a cohort study. Patients who underwent functional endoscopic sinus surgery were randomized into 3 groups. Controlled hypotension was achieved with remifentanil (Group R), esmolol (Group E) and nitroglycerin (Group N). The efficacy of the drugs was tested by comparing the length of time with the targeted mean arterial pressure, the amount of anesthetics used, surgical field bleeding score and surgeon's satisfaction. Results Between May to December 2015, 60 patients were included and randomized equally into 3 different study groups. The median of the length of time with the targeted mean arterial pressure was shorter in the Group R when compared with Group E (p = 0.01) and Group N (p = 0.14). The amount of volatile anesthetics used was 25.0 mL (15-51), 43.0 mL (21-105) and 40.0 mL (26-97) in Groups R, E and N, respectively (p < 0.001). While there was more bleeding with nitroglycerin, surgical field bleeding scores were lower in Group R when compared with esmolol (p = 0.001) and nitroglycerin (p < 0.001). The analysis of surgeon's satisfaction scores concluded that surgeons were more satisfied with the group R (100%), when compared with group E (60%) and group N (30%) (p < 0.001). Conclusion Less volatile agent, short time to achieve controlled hypotension, stable blood pressure, lower surgical field bleeding scores and larger length of time with the targeted mean arterial pressure were found as the advantages of Remifentanil. Less costly, efficiency of achieving the targeted median arterial pressure and less postoperative complications were the advantages of nitroglycerin. In functional endoscopic sinus surgery procedures, appropriate controlled hypotensive agents should be selected according to the patients' characteristics and advantages/disadvantages of the drugs.

---

Resumo Introdução Hipotensão controlada é um procedimento reversível no qual a pressão arterial média basal do paciente é reduzida em 30% e mantida em 60-70 mmHg durante o procedimento. Isso diminui a perda de sangue e propicia um campo cirúrgico limpo durante os procedimentos. Objetivo Comparar agentes usados para hipotensão controlada: esmolol, remifentanil e nitroglicerina em cirurgia sinusal endoscópica funcional, em termos de alterações hemodinâmicas e impactos na eficácia cirúrgica. Método O estudo foi feito como de coorte. Pacientes submetidos à cirurgia sinusal endoscópica funcional foram randomizados em 3 grupos. A hipotensão controlada foi feita com remifentanil (Grupo R), esmolol (Grupo E) e nitroglicerina (Grupo R). A eficácia dos medicamentos foi testada com a comparação do período de tempo com a pressão arterial média desejada, a quantidade de anestésicos usados, o escore de sangramento no campo cirúrgico e a satisfação do cirurgião. Resultados Entre maio e dezembro de 2015, 60 pacientes foram incluídos e randomizados igualmente nos três grupos de estudo. A mediana do período com a pressão arterial desejada foi menor no Grupo R quando comparado ao Grupo E (p = 0,01) e Grupo N (p = 0,14). A quantidade de anestésicos voláteis usados foi de 25,0 mL (15 ± 51), 43,0 mL (21 ± 105) e 40,0 mL (26 ± 97) nos Grupos R, E e N, respectivamente (p < 0,001). Houve mais sangramento com nitroglicerina e escores de sangramento no campo cirúrgico foram menores no Grupo R quando comparados com esmolol (p = 0,001) e nitroglicerina (p < 0,001). A análise dos escores da satisfação do cirurgião concluiu que os cirurgiões estavam mais satisfeitos com o grupo R (100%) quando comparados ao grupo E (60%) e o grupo N (30%) (p < 0,001). Conclusão Agente menos volátil, pouco tempo para obter a hipotensão controlada, pressão arterial estável, menor escore de sangramento no campo cirúrgico e período de pressão arterial desejada curto foram considerados como vantagens do remifentanil. Menor custo, eficácia de obtenção da pressão arterial média desejada e menos complicações pós-operatórias foram as vantagens da nitroglicerina. Nos procedimentos de cirurgia sinusal endoscópica funcional, os agentes apropriados para obtenção de hipotensão controlada devem ser selecionados de acordo com as características dos pacientes e as vantagens/desvantagens dos fármacos.

Asunto(s)

Humanos , Nitroglicerina , Hipotensión Controlada , Propanolaminas , Estudios de Cohortes , Remifentanilo

RESUMEN

BACKGROUND: Esmolol is a beta-1 selective blocker that has been shown to reduce postoperative pain. Its antinociceptive effects have not been tested following mastectomy. OBJECTIVE: To evaluate the safety, efficacy and antinociception of intra-operative esmolol infusion after mastectomy. DESIGN: Randomised, double-blinded, placebo-controlled trial. SETTING: Tertiary referral centre, Brasília, Brazil. Recruitment: July 2015 to July 2017. PATIENTS: Seventy women scheduled for mastectomy, ASA I to III, aged 18 to 75 years. Four were excluded. INTERVENTIONS: All underwent general anaesthesia. The intervention group received a bolus of 0.5 mg kg-1 of esmolol over 10 min followed by a continuous infusion of 100 µg kg-1 min-1. The placebo group received saline. MAIN OUTCOME MEASURES: The primary outcome was pain at rest 24 h after mastectomy as measured by a 0 to 10 numeric rating scale. RESULTS: Pain scores at rest 24 h after mastectomy were lower in esmolol-treated patients compared with placebo (mean difference = -1.51, 95% confidence interval (CI), -2.36 to -0.65, P = 0.001). On arrival in the postanaesthesia care unit (PACU), the occurrence of pain was also lower in the esmolol group, at rest and on effort (P = 0.009 and P = 0.013, respectively), on discharge from PACU (P = 0.009 and P = 0.015), 12 h (P = 0.01 and P = 0.007) and on effort in the 24 postoperative hours (P = 0.003). Mean morphine consumption was reduced by 77% in the esmolol group compared with the placebo group (mean difference  = -2.52 mg, 95% CI = -3.67 to -1.38, P < 0.001). The length of hospital stay was shorter for the esmolol group (mean difference = -6.9 h, 95% CI, -13.4 to -0.31, P = 0.040). CONCLUSION: Esmolol was well tolerated, allowed a notable reduction in the dose of rescue analgesics and demonstrated superior efficacy compared to placebo for pain management after mastectomy. TRIAL REGISTRATION: ClinicalTrials/NCT02466542.

Asunto(s)

Neoplasias de la Mama , Analgésicos Opioides , Brasil , Método Doble Ciego , Femenino , Humanos , Mastectomía/efectos adversos , Dolor Postoperatorio/diagnóstico , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/etiología , Propanolaminas

RESUMEN

INTRODUCTION: Controlled hypotension is a reversible procedure in which the patient's baseline mean arterial blood pressure is reduced by 30% and sustained at 60-70 mmHg during the procedure. It decreases blood loss and provides clear surgical field during the procedures. OBJECTIVES: The purpose of this study was to compare the efficacy of controlled hypotension agents esmolol, remifentanil, and nitroglycerin in functional endoscopic sinus surgery, in terms of hemodynamic changes and impact on the surgical efficiency. METHODS: The research was carried out as a cohort study. Patients who underwent functional endoscopic sinus surgery were randomized into 3 groups. Controlled hypotension was achieved with remifentanil (Group R), esmolol (Group E) and nitroglycerin (Group N). The efficacy of the drugs was tested by comparing the length of time with the targeted mean arterial pressure, the amount of anesthetics used, surgical field bleeding score and surgeon's satisfaction. RESULTS: Between May to December 2015, 60 patients were included and randomized equally into 3 different study groups. The median of the length of time with the targeted mean arterial pressure was shorter in the Group R when compared with Group E (p = 0.01) and Group N (p = 0.14). The amount of volatile anesthetics used was 25.0 mL (15-51), 43.0 mL (21-105) and 40.0 mL (26-97) in Groups R, E and N, respectively (p < 0.001). While there was more bleeding with nitroglycerin, surgical field bleeding scores were lower in Group R when compared with esmolol (p = 0.001) and nitroglycerin (p < 0.001). The analysis of surgeon's satisfaction scores concluded that surgeons were more satisfied with the group R (100%), when compared with group E (60%) and group N (30%) (p < 0.001). CONCLUSION: Less volatile agent, short time to achieve controlled hypotension, stable blood pressure, lower surgical field bleeding scores and larger length of time with the targeted mean arterial pressure were found as the advantages of Remifentanil. Less costly, efficiency of achieving the targeted median arterial pressure and less postoperative complications were the advantages of nitroglycerin. In functional endoscopic sinus surgery procedures, appropriate controlled hypotensive agents should be selected according to the patients' characteristics and advantages/disadvantages of the drugs.

Asunto(s)

Hipotensión Controlada , Nitroglicerina , Estudios de Cohortes , Humanos , Propanolaminas , Remifentanilo

RESUMEN

The rupture of Fundão Dam is considered one of the largest environmental disasters in Brazilian history and one of the largest in the world involving tailings dams. The present study analyzed the changes in metal concentrations in the dissolved, suspended particulate matter (SPM) and sediment in the period just after (15 days) and six months after the dam rupture, together with the biological and cytogenotoxic effects, from the collapse site until the Doce River mouth in the Atlantic Ocean. After the dam rupture, the tailings were mainly transported as SPM. After six months, with the deposition, there was a decrease in metal concentrations in dissolved and SPM and increased levels were observed in the sediment. Cr, Ni, Cd and Hg levels in sediment were higher than the threshold effects level (TEL/NOAA), especially six months after the dam rupture. The water induced immediate negative biological effects at different levels of the trophic chain, together with Al, Fe, Mn and Zn accumulation in fish muscle. Both water and sediment also showed cytotoxic, genotoxic and mutagenic effects. These data demonstrate the importance of long-term monitoring with abiotic and biotic parameters to clarify the impacts of mining tailings and can help to direct future monitoring programs.

Asunto(s)

Metales Pesados , Contaminantes Químicos del Agua , Animales , Océano Atlántico , Brasil , Monitoreo del Ambiente , Metales Pesados/análisis , Minería , Propanolaminas , Ríos , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/toxicidad

RESUMEN

PURPOSE: To evaluate the analgesic effect of esmolol in patients submitted to laparoscopic gastroplasty. METHODS: Forty patients aged between 18 and 50 years with American Society of Anesthesiologists (ASA) physical status scores of II and III who underwent gastric bypass were allocated to two groups. Group 1 patients received a 0.5-mg/kg bolus of esmolol in 30 mL of saline before induction of anesthesia, followed by an infusion at 15 µg/kg/min until the end of surgery. Group 2 patients received 30 mL of saline as a bolus and then an infusion of saline. Anesthesia included fentanyl (3 µg/kg), propofol (2-4 mg/kg), rocuronium (0.6 mg/kg), and 2% sevoflurane, with remifentanil if necessary. The following parameters were evaluated: pain intensity over 24h, remifentanil consumption, the first analgesic request, morphine consumption, and side effects. RESULTS: Pain intensity was lower in the esmolol group except at T0 (after extubation) and 12h postoperatively. Remifentanil supplementation, recovery time, and postoperative morphine supplementation were lower in the esmolol group. No differences in the time to the first analgesic request or side effects were found between the groups. CONCLUSION: Intraoperative esmolol promotes reductions in pain intensity and the need for analgesic supplementation without adverse effects, thus representing an effective drug for multimodal analgesia in gastroplasty.

Asunto(s)

Antagonistas de Receptores Adrenérgicos beta 1/uso terapéutico , Gastroplastia/efectos adversos , Laparoscopía/efectos adversos , Dolor Postoperatorio/prevención & control , Propanolaminas/uso terapéutico , Adolescente , Adulto , Analgesia/métodos , Anestesia/métodos , Anestésicos/uso terapéutico , Método Doble Ciego , Femenino , Gastroplastia/métodos , Humanos , Periodo Intraoperatorio , Laparoscopía/métodos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Náusea y Vómito Posoperatorios/prevención & control , Estadísticas no Paramétricas , Resultado del Tratamiento , Adulto Joven

RESUMEN

Lack of GABAB receptors in GABAB1 knockout mice decreases neonatal ARC kisspeptin 1 (Kiss1) expression in the arcuate nucleus of the hypothalamus (ARC) in females, which show impaired reproduction as adults. Our aim was to selectively impair GABAB signaling during a short postnatal period to evaluate its impact on the reproductive system. Neonatal male and female mice were injected with the GABAB antagonist CGP 55845 (CGP, 1 mg/kg body wt sc) or saline from postnatal day 2 (PND2) to PND6, three times per day (8 AM, 1 PM, and 6 PM). One group was killed on PND6 for collection of blood samples (hormones by radioimmunoassay), brains for gene expression in the anteroventral periventricular nucleus-periventricular nucleus continuum (AVPV/PeN), and ARC micropunches [quantitative PCR (qPCR)] and gonads for qPCR, hormone contents, and histology. A second group of mice was injected with CGP (1 mg/kg body wt sc) or saline from PND2 to PND6, three times per day (8 AM, 1 PM, and 6 PM), and left to grow to adulthood. We measured body weight during development and parameters of sexual differentiation, puberty onset, and estrous cycles. Adult mice were killed, and trunk blood (hormones), brains for qPCR, and gonads for qPCR and hormone contents were obtained. Our most important findings on PND6 include the CGP-induced decrease in ARC Kiss1 and increase in neurokinin B (Tac2) in both sexes; the decrease in AVPV/PeN tyrosine hydroxylase (Th) only in females; the increase in gonad estradiol content in both sexes; and the increase in primordial follicles and decrease in primary and secondary follicles. Neonatally CGP-treated adults showed decreased ARC Kiss1 and ARC gonadotropin-releasing hormone (Gnrh1) and increased ARC glutamic acid decarboxylase 67 (Gad1) only in males; increased ARC GABAB receptor subunit 1 (Gabbr1) in both sexes; and decreased AVPV/PeN Th only in females. We demonstrate that ARC Kiss1 expression is chronically downregulated in males and that the normal sex difference in AVPV/PeN Th expression is abolished. In conclusion, neonatal GABAergic input through GABAB receptors shapes gene expression of factors critical to reproduction.

Asunto(s)

Núcleo Arqueado del Hipotálamo/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Hipotálamo Anterior/metabolismo , Receptores de GABA-B/metabolismo , Animales , Animales Recién Nacidos , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Estradiol/metabolismo , Femenino , Hormona Folículo Estimulante/metabolismo , Antagonistas de Receptores de GABA-B/farmacología , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Glutamato Descarboxilasa/genética , Glutamato Descarboxilasa/metabolismo , Hormona Liberadora de Gonadotropina/genética , Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo Anterior/efectos de los fármacos , Kisspeptinas/genética , Kisspeptinas/metabolismo , Hormona Luteinizante/metabolismo , Masculino , Ratones , Ovario/efectos de los fármacos , Ovario/metabolismo , Ácidos Fosfínicos/farmacología , Propanolaminas/farmacología , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Pubertad/efectos de los fármacos , Pubertad/genética , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Receptores de GABA-B/genética , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Reproducción/efectos de los fármacos , Reproducción/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Diferenciación Sexual/efectos de los fármacos , Diferenciación Sexual/genética , Taquicininas/genética , Taquicininas/metabolismo , Testículo/efectos de los fármacos , Testículo/metabolismo , Testosterona/metabolismo , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismo

RESUMEN

Multidrug resistance (MDR) in cancer arises from cross-resistance to structurally- and functionally-divergent chemotherapeutic drugs. In particular, MDR is characterized by increased expression and activity of ATP-binding cassette (ABC) superfamily transporters. Sphingolipids are substrates of ABC proteins in cell signaling, membrane biosynthesis, and inflammation, for example, and their products can favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key regulatory enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Stressed cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after UGCG mediates incorporation into GlcCer. Given that cancer cells seem to mobilize UGCG and have increased GSL content for ceramide clearance, which ultimately contributes to chemotherapy failure, here we investigated how inhibition of GSL biosynthesis affects the MDR phenotype of chronic myeloid leukemias. We found that MDR is associated with higher UGCG expression and with a complex GSL profile. UGCG inhibition with the ceramide analog d-threo-1-(3,4,-ethylenedioxy)phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4) greatly reduced GSL and monosialotetrahexosylganglioside levels, and co-treatment with standard chemotherapeutics sensitized cells to mitochondrial membrane potential loss and apoptosis. ABC subfamily B member 1 (ABCB1) expression was reduced, and ABCC-mediated efflux activity was modulated by competition with nonglycosylated ceramides. Consistently, inhibition of ABCC-mediated transport reduced the efflux of exogenous C6-ceramide. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, which typically overcomes drug resistance through distinct mechanisms. This work sheds light on the involvement of GSL in chemotherapy failure, and its findings suggest that targeted GSL modulation could help manage MDR leukemias.

Asunto(s)

Transportadoras de Casetes de Unión a ATP/metabolismo , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Glicoesfingolípidos/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Proteínas de Neoplasias/metabolismo , Transportadoras de Casetes de Unión a ATP/genética , Glucosiltransferasas/antagonistas & inhibidores , Glucosiltransferasas/genética , Glucosiltransferasas/metabolismo , Glicoesfingolípidos/genética , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Proteínas de Neoplasias/genética , Propanolaminas/farmacología , Pirrolidinas/farmacología

RESUMEN

Abstract Purpose To evaluate the analgesic effect of esmolol in patients submitted to laparoscopic gastroplasty. Methods Forty patients aged between 18 and 50 years with American Society of Anesthesiologists (ASA) physical status scores of II and III who underwent gastric bypass were allocated to two groups. Group 1 patients received a 0.5-mg/kg bolus of esmolol in 30 mL of saline before induction of anesthesia, followed by an infusion at 15 µg/kg/min until the end of surgery. Group 2 patients received 30 mL of saline as a bolus and then an infusion of saline. Anesthesia included fentanyl (3 µg/kg), propofol (2-4 mg/kg), rocuronium (0.6 mg/kg), and 2% sevoflurane, with remifentanil if necessary. The following parameters were evaluated: pain intensity over 24h, remifentanil consumption, the first analgesic request, morphine consumption, and side effects. Results Pain intensity was lower in the esmolol group except at T0 (after extubation) and 12h postoperatively. Remifentanil supplementation, recovery time, and postoperative morphine supplementation were lower in the esmolol group. No differences in the time to the first analgesic request or side effects were found between the groups. Conclusion Intraoperative esmolol promotes reductions in pain intensity and the need for analgesic supplementation without adverse effects, thus representing an effective drug for multimodal analgesia in gastroplasty.

Asunto(s)

Humanos , Masculino , Femenino , Adolescente , Adulto , Adulto Joven , Dimensión del Dolor , Gastroplastia/efectos adversos , Laparoscopía/efectos adversos , Antagonistas de Receptores Adrenérgicos beta 1/uso terapéutico , Dolor Postoperatorio/prevención & control , Propanolaminas/uso terapéutico , Gastroplastia/métodos , Método Doble Ciego , Resultado del Tratamiento , Laparoscopía/métodos , Estadísticas no Paramétricas , Náusea y Vómito Posoperatorios/prevención & control , Analgesia/métodos , Periodo Intraoperatorio , Anestesia/métodos , Anestésicos/uso terapéutico , Persona de Mediana Edad

RESUMEN

The increased circulation of norepinephrine, found in the diseased heart as a result of sympathetic nervous system overactivation, is responsible for its cardiotoxic effects including pathological hypertrophy, cell death, and oxidative stress. Bucindolol is a third generation adrenergic blocker, which acts on the ß1 and ß2 receptors, and has additional α1 antagonist activity. Thus, the aim of this study was to investigate the action of bucindolol on oxidative stress, hypertrophy, cell survival, and cell death signaling pathways in H9c2 cardiac cells exposed to norepinephrine. H9c2 cells were incubated with 10 µM norepinephrine for 24 h in the presence or absence of bucindolol (10 µM) treatment for 8 h. Western blot was used to determine the expression of proteins for hypertrophy/survival and death signaling pathways. Flow cytometry was used to assess cell death via caspase-3/7 activity and propidium iodide and reactive oxygen species via measuring the fluorescence of CM-H2DCFDA. Norepinephrine exposure resulted in an increase in oxidative stress as well as cell death. This was accompanied by an increased protein expression of LC3B-II/I. The protein kinase B/mammalian target of the rapamycin (Akt/mTOR) pathway which is involved in cardiac remodeling process was activated in response to norepinephrine and was mitigated by bucindolol. In conclusion, bucindolol was able to modulate cardiac remodeling which is mediated by oxidative stress.

Asunto(s)

Norepinefrina/farmacología , Estrés Oxidativo/efectos de los fármacos , Propanolaminas/farmacología , Remodelación Ventricular/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular , Proteínas Asociadas a Microtúbulos/metabolismo , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo

RESUMEN

The cholesterol-ester transfer protein (CETP) exchanges lipids between high-density lipoproteins (HDLs) and low-density lipoproteins (LDLs). The excessive transport of lipids from HDLs to LDLs mediated by this protein can cause an alteration in the deposition of lipoproteins onto the arterial walls, thus promoting the development of arteriosclerosis. Different CETP inhibitors have been tested in recent years, but none has been confirmed as being effectively palliative for the disease. We employed in silico databases and molecular docking as a computational method to predict how potential CETP inhibitors could interact with the active site of the CETP protein. Upon previously comparing two computer software packages to determine which generated a greater number of accurate CETP-inhibitor-complex structures, we chose the more appropriate program for our studies. We then abstracted a series of databases of known CETP inhibitors and noninhibitors exhibiting different 50% concentrations of CETP-inhibitory (INH) activity, to generate virtual structures for docking with different combinations of the CETP receptor. From this process, we obtained as the most suitable structure 4F2A_1OB_C_PCW-it accordingly having a greater area under the receiver operating characteristic curve. The molecular docking of known compounds in comparison with the respective conformation of this inhibitor enabled us to obtain ΔGs (in kcal/mol) from which data we made a first exploration of unknown compounds for CETP-INH activity. Thus, the 4F2A_1OB_C_PCW structure was docked with DrugBank-Approved commercial compounds in an extensive database, whose status had already been established from pharmacokinetics and toxicology. In this study, we present a group of potential compounds as CETP-inhibitor candidates.

Asunto(s)

Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Compuestos de Anilina/farmacología , Área Bajo la Curva , Tampones (Química) , Cristalización , Bases de Datos de Compuestos Químicos , Humanos , Concentración 50 Inhibidora , Ligandos , Simulación del Acoplamiento Molecular , Propanolaminas/farmacología , Quinolinas/farmacología , Curva ROC , Suero

RESUMEN

OBJECTIVE: To describe the successful management of 2 dogs with septic shock and persistent tachycardia using norepinephrine and esmolol, a short-acting beta receptor antagonist. SERIES SUMMARY: Two cases are reviewed. In the first case, septic shock with ventricular tachycardia was diagnosed in a 4-year-old neutered female Great Dane that underwent jejunoileal resection and anastomosis for a partial mesenteric torsion. The patient's tachyarrhythmias failed to respond to lidocaine, and an esmolol infusion was used for heart rate control. The condition of the dog improved and she was discharged after 4 days of hospitalization. The second case was a 7-year-old neutered female Cavalier King Charles Spaniel with septic peritonitis. Following surgery for intestinal resection and anastomosis, supraventricular tachycardia developed that was not responsive to volume resuscitation and was treated with an esmolol infusion. The condition of the dog improved and she was discharged after 6 days of hospitalization. Both patients were doing well at the time of long-term follow-up. NEW OR UNIQUE INFORMATION PROVIDED: This case series highlights a novel method of managing dogs in septic shock with persistent tachycardia based on recently published data in the human literature. The use of esmolol may be considered in certain veterinary patients with septic shock to improve persistent tachycardia not related to hypovolemia.

Asunto(s)

Enfermedades de los Perros/tratamiento farmacológico , Choque Séptico/veterinaria , Taquicardia Supraventricular/veterinaria , Antagonistas de Receptores Adrenérgicos beta 1/administración & dosificación , Animales , Procedimientos Quirúrgicos del Sistema Digestivo/veterinaria , Perros , Quimioterapia Combinada/veterinaria , Femenino , Norepinefrina/administración & dosificación , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/veterinaria , Propanolaminas/administración & dosificación , Choque Séptico/complicaciones , Choque Séptico/tratamiento farmacológico , Taquicardia Supraventricular/complicaciones , Taquicardia Supraventricular/tratamiento farmacológico , Vasoconstrictores/administración & dosificación

RESUMEN

Carazolol (CZL) is a known agonist of ß3 and antagonist of ß1 and ß2 adrenoceptors (AR), used in the animal production industry to improve meat quality by reducing animal stress and skeletal muscle (SM) proteolysis. Here we sought to better understand the direct effect CZL has on SM. We study CZL effect on calcium (Ca2+) regulation by enzymatic activity kinetics of the Ca2+-ATPase (SERCA), in isolated sarcoplasmic reticulum (SR) from SM and on the mechanical properties of isolated muscle. In isolated SR from SM previously incubated with 0.03 mM CZL, but absent during SR isolation and during SERCA activity determination, the activity was reduced by 45%. Thermal analysis of SERCA activity with CZL shifted the transition temperature of inactivation (Ti) from Ti = 47 to 44 °C. When isolated SR from fast and slow SM was exposed to CZL, inhibition of SERCA occurred in a dose dependent manner. Slow and fast SM Ti of SERCA shifted to a lower temperature in the presence of CZL and a second transition appears at temperatures <40 °C. In isolated extensor digitorum longus (EDL) and soleus muscles, CZL reduces the contraction force and increases susceptibility to fatigue. However, recovery force after fatigue in either muscle was higher. Our results suggest that Carazolol penetrates the plasma membrane and interacts with SERCA, thus having an important effect on skeletal muscle function. The inhibition of SERCA may lead to a decrement in SR Ca2+-release promoting further failure in muscle contraction.

Asunto(s)

Músculo Esquelético/efectos de los fármacos , Propanolaminas/metabolismo , Propanolaminas/farmacología , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Animales , Calcio/metabolismo , Masculino , Músculo Esquelético/metabolismo , Propanolaminas/química , Ratas , Ratas Wistar , Receptores Adrenérgicos beta 3/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/química

RESUMEN

AIM: To examine the interference of ß-blockers with the chemokine stromal cell-derived factor-1 (SDF-1) found in cell homing receptors, C-X-C chemokine receptor type 4 (CXCR-4) and CXCR-7, and regulatory proteins of homing pathways, we administered atenolol, carvedilol, metoprolol, and propranolol for 30 days using an orogastric tube to hypertensive rats. METHOD: We collected blood samples before and after treatment and quantified the levels of SDF-1 with enzyme-linked immunosorbent assay (ELISA). On day 30 of treatment, the spontaneously hypertensive rats (SHR) were euthanized, and heart, liver, lung, and kidney tissues were biopsied. Proteins were isolated for determining the expression of CXCR-4, CXCR-7, GRK-2 (G protein-coupled receptors kinase 2), ß-arrestins (ß1-AR and ß2-AR), and nuclear factor kappa B (NFκB). RESULTS: We found that the study drugs modulated these proteins, and metoprolol and propranolol strongly affected the expression of ß1-AR (P = .0102) and ß2-AR (P = .0034). CONCLUSION: ß-blockers modulated tissue expression of the proteins and their interactions following 30 days of treatment. It evidences that this class of drugs can interfere with proteins of cell homing pathways.

Asunto(s)

Antagonistas Adrenérgicos beta/farmacología , Antihipertensivos/farmacología , Movimiento Celular/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Antagonistas de Receptores Adrenérgicos beta 1/farmacología , Animales , Atenolol/farmacología , Carbazoles/farmacología , Carvedilol , Quimiocina CXCL12/sangre , Modelos Animales de Enfermedad , Quinasa 2 del Receptor Acoplado a Proteína-G/metabolismo , Hipertensión/sangre , Hipertensión/fisiopatología , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Metoprolol/farmacología , Miocardio/metabolismo , FN-kappa B/metabolismo , Propanolaminas/farmacología , Propranolol/farmacología , Ratas Endogámicas SHR , Receptores CXCR/metabolismo , Receptores CXCR4/metabolismo , Transducción de Señal/efectos de los fármacos , beta-Arrestina 1/metabolismo , Arrestina beta 2/metabolismo

RESUMEN

The wide tissue distribution of the adrenergic ß3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. This is the first combined comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r²ncv = 0.993 and 0.984 and values of r²test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation (q², r², r²m, etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC50 = 8.561).

Asunto(s)

Agonistas de Receptores Adrenérgicos beta 3/química , Fármacos Antiobesidad/química , Hipoglucemiantes/química , Propanolaminas/química , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Fármacos Antiobesidad/farmacología , Sitios de Unión , Diseño de Fármacos , Humanos , Hipoglucemiantes/farmacología , Modelos Moleculares , Estructura Molecular , Propanolaminas/farmacología , Relación Estructura-Actividad Cuantitativa , Electricidad Estática

RESUMEN

Hot-melt extrusion (HME) has gained increasing attention in the pharmaceutical industry; however, its potential in the preparation of solid self-emulsifying drug delivery systems (S-SMEDDS) is still unexplored. This study sought to prepare enteric S-SMEDDS by HME and evaluate the effects of the process and formulation variables on S-SMEDDS properties via Box-Behnken design. Liquid SMEDDS were developed, and carvedilol was used as a class II model drug. Mean size, polydispersity index (PdI) and zeta potential of the resulting microemulsions were determined. The extrudates were then obtained by blending the lipid mixture and HPMCAS using a twin-screw hot-melt extruder. SEM, optical microscopy and PXRD were used to characterize the extrudates. In vitro microemulsion reconstitution and drug release were also studied. L-SMEDDS gave rise to microemulsions with low mean size, PdI and zeta potential (140.04 ±â€¯7.22 nm, 0.219 ±â€¯0.011 and -9.77 ±â€¯0.86 mV). S-SMEDDS were successfully prepared by HME, and an HMPCAS matrix was able to avoid microemulsion reconstitution and retain drug release in pH 1.2 (12.97%-25.54%). Conversely, microemulsion reconstitution and drug release were gradual in pH 6.8 and complete for some formulations. Extrudates prepared at the lowest drug concentration and highest temperature and recirculation time promoted a complete and rapid drug release in pH 6.8 giving rise to small and uniform microemulsion droplets.

Asunto(s)

Química Farmacéutica/métodos , Sistemas de Liberación de Medicamentos , Emulsiones/química , Carbazoles/administración & dosificación , Carbazoles/farmacocinética , Carvedilol , Química Farmacéutica/instrumentación , Liberación de Fármacos , Calor , Concentración de Iones de Hidrógeno , Lípidos/química , Metilcelulosa/análogos & derivados , Metilcelulosa/química , Tamaño de la Partícula , Propanolaminas/administración & dosificación , Propanolaminas/farmacocinética , Solubilidad

RESUMEN

In cancers, apoptosis signaling pathways and cell survival and growth pathways responsible for resistance to conventional treatments, such as Pi3K/Akt/mTOR and mitogen-activated protein kinase (MAPK) become dysregulated. Recently, alternative treatments to promote tumor cell death have become important. The present study reports on the antitumor and cytoprotective action of gold nanoparticles (GNPs) and carvedilol in combination and in isolated application. Apoptosis was analyzed by FITC/propidium iodide staining flow cytometry; caspase-3, caspase-8, Bcl-2 and MAPK/ERK activity by immunofluorescence microscopy; gene expression of proteins related to cell death as Akt, mTOR, EGFR, MDR1, survivin, FADD and Apaf, by the real-time PCR; and western blot analysis for MAPK/ERK, Akt and mTOR. Oxidative stress evaluation was performed by reduced glutathione (GSH) and malondialdehyde (MDA) levels. Intracellular GNPs targets were identified by transmission electron microscopy. After exposure to a combination of GNPs (6.25 µg/ml) and carvedilol (3 µM), death as promoted by apoptosis was detected using flow cytometry, for expression of pro-apoptotic proteins FADD, caspase-3, caspase-8 and sub-regulation of anti-apoptotic MAPK/ERK, Akt, mTOR, EGFR and MDR1 resistance. Non-tumor cell cytoprotection with GSH elevation and MDA reduction levels was detected. GNPs were identified within the cell near to the nucleus when combined with carvedilol. The combination of GNP and carvedilol promoted downregulation of anti-apoptotic and drug resistance genes, over-regulation of pro-apoptotic proteins in tumor cells, as well as cytoprotection of non-tumor cells with reduction of apoptosis and oxidative stress.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carbazoles/farmacología , Oro/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Nanopartículas del Metal/administración & dosificación , Propanolaminas/farmacología , Apoptosis/efectos de los fármacos , Carbazoles/administración & dosificación , Carvedilol , Receptores ErbB/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Estrés Oxidativo/efectos de los fármacos , Propanolaminas/administración & dosificación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo