Experimental study of local anesthetic and antiarrhythmic activities of fluorinated ethynylpiperidine derivatives

The chemical structure of piperidine has a unique ability to combine with other molecular fragments. This fact makes it possible to actively use it as an effective basis for the creation of new drug-like substances. Thus, the aim of the current investigation was to study the acute toxicity, local anesthetic potency, and antiarrhythmic activity of the two new synthesized piperidine derivatives under laboratory codes LAS-286 and LAS-294 (local anesthetic substances). The Bulbring & Wajda animal model and method of determining the nociception threshold during electrical stimulation was used to investigate the action of the substance during infiltration anesthesia. An antiarrhythmic activity was observed by the aconitine-induced rat arrhythmia model. Additionally, these compounds were studied in relation to molecular docking to delineate the structure-activity relationships. The tested piperidine derivatives had a low toxicity in the subcutaneous and intravenous administration routes. The experimental results showed a higher prolonged and pronounced local anesthetic activity for LAS-286 at a 0.5% concentration, compared to the reference preparations. The low dosage of 0.1 mg/kg of LAS-294 demonstrated a pronounced preventive antiarrhythmic effect in 90% of cases on the development of mixed arrhythmia, caused by aconitine. The results of molecular docking confirmed a higher binding affinity of the tested piperidines with the Nav1.4 and Nav1.5 macromolecules. The results of the present study are very promising, because these piperidines have shown a high biological activity, which can suggest a potential therapeutic application in the future.

Characterization of post-surgical critical patients with infections associated with healthcare after prolonged perfusion of remifentanil

SUMMARY INTRODUCTION Healthcare associated infections (HAI) are the most frequent complication of hospitalized patients. The aim of this study was to describe the clinical and epidemiological characteristics of critically ill post-surgical patients with a diagnosis of healthcare associated infections, after a pattern of sedoanalgesia of at least 4 days. METHODS All patients over 18 years of age with a unit admission of more than 4 days were consecutively selected. The study population was the one affected by surgical pathology where sedation was based as analgesic the opioid remifentanil for at least 96 hours in continuous perfusion. Patients who died during admission to the unit and those with combined analgesia (peripheral or neuroaxial blocks) were excluded. Data analysis was performed using the statistical package Stata version 7.0. RESULTS The patients admitted to the Post-Surgical Critical Care Unit (PCU) during study were 1789 and the population eligible was comprised of 102 patients. 56.86% of patients suffered IACS. The most frequent IACS was pneumonia associated with mechanical ventilation (30.96 per 1000 days of mechanical ventilation), Pseudomonas aeruginosa being the most frequently isolated germ. The germs with the greatest involvement in multiple drug resistance (MDROs) were enterobacteria, mainly Klebsiella pneumoniae resistant to extended-spectrum beta-lactamases (ESBL). CONCLUSIONS Pneumonia associated with mechanical ventilation is the most prevalent HAI and Pseudomonas aeruginosa is the main etiological agent. The groups of antibiotics most frequently used were cephalosporin and aminoglycosides. It is necessary to implement the prevention strategies of the different HAI, since most of them are avoidable.

RESUMO INTRODUCCIÓN Las infecciones asociadas a cuidados de salud (IACS) constituyen la complicación más frecuente de los pacientes hospitalizados. El objetivo de este estudio es describir las características clínicas y epidemiológicas de los pacientes críticos postquirúrgicos con diagnóstico de infección asociada a cuidados de salud, tras una pauta de sedoanalegia de al menos 4 días. MÉTODOS Se seleccionaron de manera consecutiva todos los pacientes mayores de 18 años con un ingreso en la Unidad de Reanimación Postquirúrgica (URP) superior a 4 días. La población de estudio fue aquella afectada por patología quirúrgica de cualquier origen donde la sedación se basó en cualquier hipnótico y como analgésico el opioide remifentanilo durante al menos 96 horas en perfusión continua. Se excluyeron los pacientes que fallecieron durante su ingreso en la unidad y aquellos pacientes con analgesia combinada (bloqueos periféricos o neuroaxiales). El análisis de los datos se realizó con paquete estadístico Stata versión 7.0. RESULTADOS El número de pacientes que ingresaron en la URP durante el periodo de estudio fueron de 1789. Tras aplicar los criterios de inclusión y exclusión, la población elegible quedó constituida por 102 pacientes. Un 56,86% de pacientes padecieron IACS. La IACS más frecuente fue la neumonía asociada a ventilación mecánica (30,96 por 1000 días de ventilación mecánica) siendo Pseudomona aeruginosa el germen más frecuentemente aislado. Los gérmenes con mayor implicación en las multirresistencias (MDROs) fueron las enterobacterias, principalmente Klebsiella pneumoniae resistente a betalactamasas de espectro extendido (BLEE). CONCLUSIONES La neumonía asociada a ventilación mecánica es la IACS más prevalente y Pseudomona aeruginosa es el principal agente etiológico. Los grupos de antibióticos más frecuentemente empleados fueron cefalosporinas y aminoglucósidos. Es necesario implementar las estrategias de prevención de las distintas IACS, ya que la mayoría de ellas son evitables.

Monoamine oxidase and transaminase screening: biotransformation of 2-methyl-6-alkylpiperidines by Neopestalotiopsis sp. CBMAI 2030.

High-throughput screening detected transaminases (TAs) and monoamine oxidases (MAOs) in fungi by applying a fluorogenic probe. Strains F026, F037, F041, F053, and F057 showed the highest enzymatic conversions (31, 60, 30, 40, and 32%, respectively) and where evaluated for their ability to transform piperidines. Strain F053 (Neopestalotiopsis sp. CBMAI 2030) revealed unusual enzymatic activity to deracemize 2-methyl-6-alkylpiperidines. Neopestalotiopsis sp. CBMAI 2030 was capable to convert 2-methyl-6-propylpiperidine, 2-methyl-6-butylpiperidine, and 2-methyl-6-pentylpiperidine in piperideine with 11, 14, and 24% conversion, respectively. The activity was enhanced by cultivating the fungus with 2-methyl-6-pentylpiperidine (38% conversion and 73% ee).

Nature-inspired enzymatic cascades to build valuable compounds.

Biocatalysis currently is focusing on enzymatic and multi-enzymatic cascade processes instead of single steps imbedded into chemical pathways. Alongside this scientific revolution, this review provides an overview on multi-enzymatic cascades that are responsible for the biosynthesis of some terpenes, alkaloids and polyethers, which are important classes of natural products. Herein, we illustrate the development of studies inspired by multi- and chemo-enzymatic approaches to build the core moieties of polyethers, polypeptide alkaloids, piperidines and pyrrolidines promoted by the joint action of oxidoreductases, hydrolases, cyclases, transaminases and imine reductases.

Avaliação da memória sob anestesia venosa total / The assessment of memory under total intravenous anesthesia / Evaluación de la memoria bajo anestesia venosa total

JUSTIFICATIVA E OBJETIVOS: Neste estudo, objetivamos avaliar a memória implícita e explícita em pacientes submetidos à cirurgia abdominal sob anestesia venosa total (AVT) com propofol e remifentanil, na qual o nível de anestesia foi controlado pelo monitoramento do índice bispectral (BIS). MÉTODO: Anestesia venosa total foi administrada a 60 pacientes adultos para obter níveis de BIS de 40-60. Os pacientes foram randomicamente divididos em três grupos, de acordo com as gravações que ouviram. Os pacientes do grupo categoria (CT) ouviram uma fita gravada contendo cinco nomes de animais. Os pacientes do grupo recordar palavras (RP) ouviram uma fita gravada contendo cinco palavras de frequência média na língua turca, depois de adaptadas. Os pacientes do grupo controle (GC) ouviram os sons do mar até o fim da cirurgia. Duas horas após a cirurgia, os testes foram administrados a cada paciente na sala de recuperação para avaliar a memória. RESULTADOS: Houve uma diferença entre os escores dos grupos CT e GC no Miniexame do Estado Mental (MMSE); todos os escores foram > 20. Os resultados dos testes de categoria e recordar palavras, aplicados para avaliar a memória implícita, não foram estatisticamente diferentes entre os grupos. Não houve evidência de memória implícita em nenhum dos pacientes. Um paciente lembrou-se de ouvir "o som de água" como uma prova de memória explícita. Onze pacientes declararam não ter sonhado. CONCLUSÕES: Apesar de não termos encontrado nenhuma evidência de memória implícita sob anestesia adequada com AVT, um paciente apresentou memória explícita. Embora a profundidade adequada da anestesia fornecida pelo monitoramento do BIS corrobore nossos resultados para a memória implícita, ela não explica os resultados para a memória explícita.

BACKGROUND AND OBJECTIVES: In this study, we aimed to assess implicit and explicit memory in patients who had abdominal surgery under total intravenous anesthesia (TIVA) with propofol and remifentanil, in which anesthesia level was controlled by bispectral index (BIS) monitoring. METHOD: Total intravenous anesthesia was administered to 60 adult patients, to obtain BIS levels of 40-60. Patients were randomly allocated to three groups according to tapes they listened to. Patients in the category group (CT) listened to a tape containing five animal names. Patients in the word recognition group (WM) listened to a tape containing five intermediate-frequency words, adapted into Turkish. Patients in the control group (CG) listened to sea sounds until the end of surgery. Two hours after surgery, tests were administered to each patient in the recovery room to assess memory. RESULTS: There was a difference between the CT and CG groups in their Mini-Mental State Examination scores, all values were > 20. The results of the category and word recognition tests that were applied to assess implicit memory were not statistically different among the groups. There was no evidence of implicit memory in any of the patients. One patient remembered hearing 'the sound of water' as a proof of explicit memory. Eleven patients said they had dreamt. CONCLUSIONS: Although no evidence of implicit memory under adequate anesthesia with TIVA was found, one patient showed explicit memory. Although adequate depth of anesthesia provided by BIS monitoring supports our implicit memory results, it does not explain the explicit memory results.

JUSTIFICATIVA Y OBJETIVOS: En este estudio evaluamos la memoria implícita y explícita en pacientes sometidos a la cirugía abdominal bajo anestesia venosa total (AVT), con propofol y remifentanilo, en la cual el nivel de anestesia fue controlado por el monitoreo del índice bispectral (BIS). MÉTODO: Anestesia venosa total que fue administrada a 60 pacientes adultos para obtener niveles de BIS de 40-60. Los pacientes fueron aleatoriamente divididos en tres grupos de acuerdo con las grabaciones que oyeron. Los pacientes del grupo categoría (CT) oyeron una cinta grabada que contenía cinco nombres de animales. Los pacientes del grupo recordar palabras (RP), escucharon una cinta grabada que contenía cinco palabras de frecuencia media en lengua turca, después de haber sido adaptadas. Los pacientes del grupo control (GC) oyeron los sonidos del mar hasta el final de la cirugía. Dos horas después de la cirugía, los test fueron administrados a cada paciente en la sala de recuperación para evaluar la memoria. RESULTADOS: Hubo una diferencia entre las puntuaciones de los grupos CT y GC en el Mini Examen del Estado Mental (MMSE) y todas las puntuaciones fueron > 20. Los resultados de los test de categoría y recordar palabras aplicados para evaluar la memoria implícita no fueron estadísticamente diferentes entre los grupos. No hubo evidencia de memoria implícita en ninguno de los pacientes. Un paciente recordó escuchar "el sonido del agua" como una prueba de memoria explícita. Once pacientes dijeron que no habían soñado. CONCLUSIONES: A pesar de no haber encontrado ninguna evidencia de memoria implícita bajo anestesia adecuada con AVT, un paciente tuvo memoria explícita. Aunque la profundidad adecuada de la anestesia suministrada por el monitoreo del BIS corrobore nuestros resultados para la memoria implícita, ella no explica los resultados para la memoria explícita.

Avaliação do efeito da cetamina associada à remifentanila na dor pós-operatória / Assessment of the effect of ketamine in combination with remifentanil on postoperative pain / Evaluación del Efecto de la Cetamina Asociada con el Remifentanilo en el Dolor Postoperatorio

JUSTIFICATIVA E OBJETIVOS: A associação de cetamina com remifentanila parece estar relacionada à analgesia de melhor qualidade e duração. O objetivo deste estudo foi avaliar se a cetamina associada à remifentanila promove melhora da analgesia pós-operatória. MÉTODO: Estudo prospectivo, aleatório, duplo encoberto em 40 pacientes submetidos à colecistectomia videolaparoscópica. A anestesia foi feita com remifentanila, propofol, atracúrio, 50% de oxigênio. Os pacientes do G1 receberam remifentanila (0,4 mcg.kg-1.min-1) e cetamina (5 mcg.kg-1.min-1); os do G2, remifentanila (0,4 mcg.kg-1.min-1) e solução salina. Foi administrado 0,1 mg.kg-1 de morfina no final da operação e a dor pós-operatória foi tratada com morfina, através de analgesia controlada pelo paciente (PCA). A intensidade da dor pós-operatória foi avaliada pela escala numérica de 0 a 10, durante 24 horas. Foram anotados o tempo para primeira complementação analgésica, a quantidade de morfina usada durante 24 horas e os efeitos adversos. RESULTADOS: Ocorreu diminuição da intensidade da dor entre a desintubação e os outros momentos avaliados no G1 e no G2. Não foi observada diferença significante na intensidade da dor entre os grupos. Não houve diferença entre G1 (22 ± 24,9 min) e G2 (21,5 ± 28,1 min) no tempo para a primeira dose de morfina e dose complementar de morfina consumida no G1 (29 ± 18,4 mg) e no G2 (25,1 ± 13,3 mg). CONCLUSÕES: A associação de cetamina (5 mcg.kg-1.min-1) a remifentanila (0,4 mcg.kg-1.min-1) para colecistectomia não alterou a intensidade da dor pós-operatória, o tempo para primeira complementação ou a dose de morfina em 24 horas.

BACKGROUND AND OBJECTIVES: The combination of ketamine and remifentanil seems to be associated with better analgesia and duration. The aim of this study was to evaluate whether a ketamineremifentanil combination promotes improved postoperative analgesia. METHODS: Prospective, randomized, double blind study of 40 patients undergoing video laparoscopic cholecystectomy. Anesthesia was performed with remifentanil, propofol, atracurium, and 50% oxygen. Group 1 (GI) patients received remifentanil (0.4 mcg.kg-1.min-1) and ketamine (5 mcg.kg-1.min-1) and Group 2 (G2) received remifentanil (0.4 mcg.kg-1.min-1) and saline solution. Morphine 0.1 mg.kg-1 was administered at the end of the procedure, and postoperative pain was treated with morphine via PCA. We evaluated the severity of postoperative pain by a numerical scale from zero to 10 during 24 hours. We registered the time to the first analgesic supplementation, amount of morphine used in the first 24 hours, and adverse effects. RESULTS: There was a decrease in pain severity between extubation and other times evaluated in G1 and G2. There was no significant difference in pain intensity between the groups. There was no difference between G1 (22 ± 24.9 min) and G2 (21.5 ± 28.1 min) regarding time to first dose of morphine and dose supplement of morphine consumed in G1 (29 ± 18.4 mg) and G2 (25.1 ± 13.3 mg). CONCLUSION: The combination of ketamine (5 mcg.kg-1.min-1) and remifentanil (0.4 mcg.kg-1.min-1) for cholecystectomy did not alter the severity of postoperative pain, time to first analgesic supplementation or dose of morphine in 24 hours.

JUSTIFICATIVA Y OBJETIVOS: La asociación de la cetamina con el Remifentanilo parece estar asociada con una analgesia de mejor calidad y duración. El objetivo de este estudio fue evaluar si la cetamina asociada al Remifentanilo genera una mejoría de la analgesia postoperatoria. MÉTODO: Se hizo un estudio prospectivo, aleatorio y doble ciego en 40 pacientes sometidos a la colecistectomía videolaparoscópica. La anestesia se realizó con de Remifentanilo, propofol, atracurio y 50% de oxígeno. Los pacientes del G1 recibieron Remifentanilo (0,4 mcg.kg-1.min-1) y cetamina (5 mcg.kg-1.min-1); los del G2, Remifentanilo (0,4 mcg.kg-1.min-1) y solución salina. Fue administrado 0,1 mg.kg-1 de morfina al final de la operación y el dolor postoperatorio se trató con morfina por medio de analgesia controlada por el paciente (PCA). La intensidad del dolor postoperatorio fue mensurada por la escala numérica de 0 a 10, durante 24h. Se anotó el tiempo para la primera complementación analgésica, la cantidad de morfina utilizada durante 24 h y los efectos adversos. RESULTADOS: Ocurrió una reducción de la intensidad del dolor entre el momento de la desentubación y los otros momentos calculados en el G1 y en el G2. No fue observada ninguna diferencia significativa en la intensidad del dolor entre los grupos. No hubo diferencia entre G1 (22 ± 24,9 min.) y G2 (21,5 ± 28,1 min.) en el tiempo para la primera dosis de morfina y dosis complementaria de morfina consumida en el G1 (29 ± 18,4 mg) y en el G2 (25,1 ± 13,3 mg). CONCLUSIONES: La asociación de la cetamina (5 mcg.kg-1.min-1) con el Remifentanilo (0,4 mcg.kg-1.min-1) para la colecistectomía no alteró la intensidad del dolor postoperatorio, el tiempo para la primera complementación o la dosis de morfina en 24h.

Assessment of the effect of ketamine in combination with remifentanil on postoperative pain.

BACKGROUND AND OBJECTIVES: The combination of ketamine and remifentanil seems to be associated with better analgesia and duration. The aim of this study was to evaluate whether a ketamine- remifentanil combination promotes improved postoperative analgesia. METHODS: Prospective, randomized, double blind study of 40 patients undergoing video laparoscopic cholecystectomy. Anesthesia was performed with remifentanil, propofol, atracurium, and 50% oxygen. Group 1 (GI) patients received remifentanil (0.4 mcg.kg(-1).min(-1)) and ketamine (5 mcg.kg(-1).min(-1)) and Group 2 (G2) received remifentanil (0.4 mcg.kg(-1).min(-1)) and saline solution. Morphine 0.1 mg.kg(-1) was administered at the end of the procedure, and postoperative pain was treated with morphine via PCA. We evaluated the severity of postoperative pain by a numerical scale from zero to 10 during 24 hours. We registered the time to the first analgesic supplementation, amount of morphine used in the first 24 hours, and adverse effects. RESULTS: There was a decrease in pain severity between extubation and other times evaluated in G1 and G2. There was no significant difference in pain intensity between the groups. There was no difference between G1 (22 ± 24.9 min) and G2 (21.5 ± 28.1 min) regarding time to first dose of morphine and dose supplement of morphine consumed in G1 (29 ± 18.4 mg) and G2 (25.1 ± 13.3 mg). CONCLUSION: The combination of ketamine (5 mcg.kg(-1).min(-1)) and remifentanil (0.4 mcg.kg(-1).min(-1)) for cholecystectomy did not alter the severity of postoperative pain, time to first analgesic supplementation or dose of morphine in 24 hours.