Design and development of 6-hydrazinonicotinyl-fatty acid-mimetic 99mTc-complex as a potential myocardial imaging agent

Abstract The goal of this work is to identify new fatty acid-mimetic 99mTc-complexes to be used as myocardial imaging agents that allow studying heart abnormalities in high-risk patients. In this sense, we designed a fatty acid-mimetic substructure including an amide moiety that, among other properties, could improve myocardial residence time. A diamide with a chain length of 15 atoms and porting a 6-hydrazinonicotinyl (HYNIC) chelator, and an analog with a short carbon-chain, were prepared with convergent organic synthetic procedures and radiolabeled with 99mTc using tricine as the sole coligand. The in vivo proofs of concept were performed using healthy mice. The new 99mTc-complexes were obtained with adequate radiochemical purity. The lipophilicities were in agreement with the length of the chains. While both 99mTc-complexes showed uptake in the myocardial muscle, the designed radiopharmaceutical with the longest chain length had preferential target-uptake and target-retention compared to other complexes described in the bibliography. Further studies, involving imaging assays, synthetic modifications, and assay of new coligands for 99mTc-HYNIC complexes, are currently ongoing.

Dermatitis por Paederus. Acerca de tres casos / Paederus dermatitis. About three cases

Resumen La "dermatitis por Paederus", es una dermatitis vesicante secundaria al contacto con coleópteros de este género. Se describen más de 600 especies de Paederus, con predominio en áreas tropicales y subtropicales, varias de ellas se asocian a dermatitis. Al ser apretado o aplastado contra la piel, la hemolinfa que contiene paederina, lesiona la epidermis, por medio del bloqueo de la mitosis de células epiteliales basales y células suprabasales. Se exponen tres casos clínicos dermatológicos con lesiones características compatibles con "dermatitis por Paederus". Se realiza además una revisión bibliográfica sobre el tema, a fin de exponer los puntos más importantes de esta patología de gran interés médico y que representa en muchas ocasiones desafíos diagnósticos.

Summary "Paederus dermatitis" is a vesicant dermatitis secondary to contact with this beetle. There are more than 600 species of Paederus described, with a predominance in tropical and subtropical areas, some of these are associated with dermatitis. When they are pressed or crushed against the skin, releases secretions with pederin, that causes an injury in the epidermis, by mitosis blocking of basal and suprabasal epithelial cells. This article describes three dermatological clinical cases with charac-teristic lesions compatible with "Paederus dermatitis". In addition a bibliographic review is presented in order to expose the most important points of this medical interest pathology, that frequently represents diagnostic challenges.

Adverse effects associated with favipiravir in patients with COVID-19 pneumonia: a retrospective study

ABSTRACT BACKGROUND: Favipiravir is generally used in treating coronavirus disease 2019 (COVID-19) pneumonia in Turkey. OBJECTIVE: To determine the side effects of favipiravir and whether it is a good treatment option. DESIGN AND SETTING: Retrospective study conducted in Atatürk Chest Diseases and Chest Surgery Training and Research Hospital, Ankara, Turkey. METHODS: 357 patients who completed favipiravir treatment at the recommended dose were included. 37 patients with drug side effects and 320 patients without drug side effects were examined in two groups. RESULTS: Side effects were observed in 37 (10.36%) out of 357 patients using favipiravir. The most common side effect was liver dysfunction, in 26 (7.28%) of the patients. The following other side effects were also observed: diarrhea (1.4%), nausea (0.84%), abdominal pain (0.28%) and thrombocytopenia (0.28%). One patient (0.28%) presented both increased transaminases and nausea. CONCLUSION: In this study, it was determined that favipiravir may constitute an alternative for treating COVID-19 pneumonia given that its side effects are generally well tolerated and not serious.

Synthesis and Biological Activity of Trolox Amide Derivatives

Abstract A series of Trolox amide derivatives were synthesized by modifying the carboxyl groups of Trolox. Thirty target compounds were obtained and characterized through nuclear magnetic resonance and mass spectrometry. Trolox derivatives were employed to explore the potential structure-antioxidant activity relationships. The antioxidant activities of these compounds were evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), ferric reducing antioxidant power (FRAP) and hydroxyl radical assays. DPPH scavenging activity test results illustrated that compounds exhibited scavenging activities similar to L-ascorbic acid and Trolox, with compounds 14a, 18a, 24a and 26a in particular exhibiting higher scavenging activities than L-ascorbic acid. The results demonstrated that compounds displayed ABTS scavenging activities similar to L-ascorbic acid and Trolox, with compounds 26a and 29a in particular having potency twofold higher. FRAP assay results indicated that compounds 11a, 19a, 25a, 29a and 30a had activity similar to Trolox. The results revealed that compounds 6a and 19a had similarly high hydroxyl radical-scavenging activities as Trolox. The results of α-glucosidase experiments uncovered that compounds 10a, 25a, 28a and 29a had excellent inhibitory activity, which was similar to that of acarbose and different from Trolox. The results of acetylcholinesterase and butyrylcholinesterase experiments demonstrated that some compounds had weak anticholinesterase activities. 26a and 29a are important Trolox derivatives with better biological activity profiles and deserve further study

Aliskiren attenuates cardiac dysfunction by modulation of the mTOR and apoptosis pathways

Aliskiren (ALS) is well known for its antihypertensive properties. However, the potential underlying the molecular mechanism and the anti-hypertrophic effect of ALS have not yet been fully elucidated. The aim of the present study was to investigate the role of ALS in mammalian target of rapamycin (mTOR) and apoptosis signaling using in vivo and in vitro models of cardiac hypertrophy. A rat model of cardiac hypertrophy was induced by isoproterenol treatment (5 mg·kg-1·day-1) for 4 weeks, with or without ALS treatment at 20 mg·kg-1·day-1. The expression of hypertrophic, fibrotic, and apoptotic markers was determined by RT-qPCR. The protein expression of apoptotic markers mTOR and p-mTOR was assessed by western blot analysis. The proliferation of H9C2 cells was monitored using the MTS assay. Cell apoptosis was analyzed using flow cytometry. In vivo, isoproterenol-treated rats exhibited worse cardiac function, whereas ALS treatment reversed these dysfunctions, which were associated with changes in p-mTOR, Bcl-2, Bax, and cleaved caspase-3 expression, as well as the number of apoptotic cells. In vitro, H9C2 cardiomyocyte viability was significantly inhibited and cardiac hypertrophy was induced by Ang II administration, but ALS reversed Ang II-induced H9C2 cardiomyocyte hypertrophy and death. Furthermore, Ang II triggered the activation of the mTOR and apoptosis pathways in hypertrophic cardiomyocytes that were inhibited by ALS treatment. These results indicated that ALS alleviated cardiac hypertrophy through inhibition of the mTOR and apoptosis pathways in cardiomyocytes.

The effects of favipiravir on hematological parameters of covid-19 patients

SUMMARY INTRODUCTION This study aims to evaluate changes in hematological parameters after the follow-up of patients who received treatment with favipiravir due to COVID-19 infections. METHODS Sixty-two cases receiving favipiravir treatment for at least five days due to COVID-19 infection were evaluated retrospectively. Parameters including age, gender, nasopharyngeal swab positivity, and chronic diseases were analyzed. Hematologic parameters were analyzed before and after the treatment. RESULTS The mean age of the patients receiving treatment with favipiravir was 63.7±12.3 years. Nasopharyngeal swab positivity was detected in 67.7%. The most common comorbid conditions detected in patients were hypertension in 25 cases (40.3%) and diabetes in 16 cases (25.8%). In the statistical analysis of the hematological parameters before and after treatment with favipiravir, WBC, PT-PTT-INR levels were found to be unaffected; the mean RBC was found to have decreased from 4.33 ± 0.58 M/uL to 4.16 ± 0.54 M/uL (p:0.003); the median hemoglobin level was found to have decreased from 12.3 g/dl to 11.9 g/dl (p:0.041); the hematocrit level decreased from 38.1% ± 4.8 to 36.9% ± 4.2 (p:0.026); the median neutrophil count decreased from 4.57 K/uL to 3.85 K/uL (p:0.001); the mean lymphocyte count increased from 1.22 ± 0.53 K/uL to 1.84 ± 1.19 K/uL (p:0.000); and the mean platelet count increased from 244.1 ± 85.1 K/uL to 281.9 ± 103.3 K/uL (p:0.005). CONCLUSION We concluded that the pathological effect of treatment with favipiravir on the hematologic system was the suppression in the erythrocyte series, and there were no adverse effects in other hematologic parameters.

RESUMO INTRODUÇÃO Este estudo tem como objetivo avaliar as alterações nos parâmetros hematológicos após o acompanhamento de pacientes que receberam tratamento com favipiravir devido à infecção por Covid-19. MÉTODOS Sessenta e dois casos em tratamento com favipiravir por pelo menos cinco dias devido à infecção por Covid-19 foram avaliados retrospectivamente. Parâmetros como idade, sexo, positividade do swab nasofaríngeo e doenças crônicas foram analisados. Os parâmetros hematológicos foram analisados antes e após o tratamento. RESULTADOS A idade média dos pacientes que receberam tratamento com favipiravir foi de 63,7±12,3 anos. A positividade do swab nasofaríngeo foi detectada em 67,7%. As condições comórbidas mais comuns detectadas nos pacientes foram hipertensão em 25 casos (40,3%) e diabetes em 16 casos (25,8%). Na análise estatística dos parâmetros hematológicos antes e após o tratamento com favipiravir, os níveis de leucócitos, PT-PTT-INR não foram afetados. Verificou-se que o RBC médio diminuiu de 4,33±0,58 M/uL para 4,16±0,54 M/uL (p=0,003); o nível médio de hemoglobina foi reduzido de 12,3 g/dl para 11,9 g/dl (p=0,041); o nível de hematócrito diminuiu de 38,1%±4,8 para 36,9%±4,2 (p=0,026); a contagem mediana de neutrófilos diminuiu de 4,57 K/uL para 3,85 K/uL (p=0,001); a contagem média de linfócitos aumentou de 1,22±0,53 K/uL para 1,84±1,19 K/uL (p=0,000); a contagem média de plaquetas aumentou de 244,1±85,1 K/uL para 281,9±103,3 K/uL (p=0,005). CONCLUSÃO Concluiu-se que o efeito patológico do tratamento com favipiravir no sistema hematológico foi a supressão na série eritrocitária e que não houve efeitos adversos em outros parâmetros hematológicos.

Urinary cytokine profiles according to the site of blockade of the renin-angiotensin system in nephrectomized rats / Perfil de citocinas urinárias de acordo com o local de bloqueio do sistema renina angiotensina em ratos nefrectomizados

Abstract Introduction: It is still unknown how the pharmacological inhibition of the Renin Angiotensin System (RAS) impacts the levels of inflammation and fibrosis biomarkers. Objective: This study sought to evaluate the effect of enalapril, candesartan and aliskiren on urinary levels of cytokines in a model of chronic kidney disease (CKD). Methods: Male Wistar rats were submitted to surgical removal of ¾ of renal parenchyma to induce CKD (¾ nephrectomy), or subjected to sham surgery (control). Animals were then randomized into five groups: Sham surgery receiving vehicle; ¾ Nephrectomy receiving vehicle; ¾ Nephrectomy receiving enalapril (10 mg/kg); ¾ Nephrectomy receiving candesartan (10 mg/kg) and ¾ Nephrectomy receiving aliskiren (10 mg/kg). Urine output, water intake, mean arterial pressure (MAP) and urinary concentrations of creatinine, urea, albuminuria, Na+, K+, interleukin (IL) -1β, IL-6, IL-10 and transforming growth factor beta (TGF-β) were measured. Results: Nephrectomy significantly impaired renal function, increased MAP and altered the levels of all evaluated cytokines in urine. Enalapril, candesartan and aliskiren improved renal function and decreased MAP and IL-6 when compared to vehicle-treated nephrectomized group. Candesartan and aliskiren decreased IL-1β, while only candesartan reduced TGF-β and only aliskiren increased IL-10. Conclusion: Enalapril, candesartan and aliskiren presented similar effects on improving renal function and reducing MAP and urinary levels of IL-6 in rats with CKD. On the other hand, cytokine profile differed according to the treatment, suggesting that differential mechanisms were triggered in response to the site of RAS blockade.

Resumo Introdução: Ainda não se sabe como a inibição farmacológica do Sistema Renina Angiotensina (SRA) afeta os níveis de biomarcadores de inflamação e fibrose. Objetivo: Este estudo pretendeu avaliar o efeito de enalapril, candesartan e alisquireno sobre os níveis urinários de citocinas em um modelo de doença renal crônica (DRC). Métodos: Ratos Wistar machos foram submetidos à remoção cirúrgica de ¾ do parênquima renal para induzir DRC (nefrectomia), ou submetidos à cirurgia fictícia (controle). Animais foram então randomizados em cinco grupos: Cirurgia fictícia recebendo veículo; Nefrectomia recebendo veículo; Nefrectomia recebendo enalapril (10 mg/kg); Nefrectomia recebendo candesartan (10 mg/kg) e Nefrectomia recebendo alisquireno (10 mg/kg). Débito urinário, ingesta hídrica, pressão arterial media (PAM) e concentrações urinárias de creatinina, ureia, albumina, Na+, K+, interleucina (IL) -1β, IL-6, IL-10 e fator de transformação e crescimento beta (TGF-β) foram medidas. Resultados: A nefrectomia comprometeu significativamente a função renal, aumentou a PAM e alterou os níveis de todas as citocinas avaliadas na urina. Enalapril, candesartan e alisquireno melhoraram a função renal e diminuíram a PAM e a IL-6 quando comparado aos grupo de animais nefrectomizados tratados com veículo. Candesartan e alisquireno reduziram IL-1β, enquanto somente candesartan diminuiu o TGF-β e somente alisquireno aumentou a IL-10. Conclusão: Enalapril, candesartan e alisquireno apresentaram efeitos similares em relação à melhora da função renal e redução da PAM e dos níveis urinários de IL-6 em ratos com DRC. Por outro lado, o perfil de citocinas diferiu de acordo com o tratamento, sugerindo que diferentes mecanismos sejam desencadeados em resposta ao local de bloqueio do SRA.

Effect of equipotent doses of bupivacaine and ropivacaine in high-fat diet fed neonatal rodent model / Efeito de doses equipotentes de bupivacaína e ropivacaína em modelo de roedor neonatal alimentado com dieta rica em gordura

Abstract Objectives: The increase in the prevalence of obesity presents a significant health and economic problem. Obesity has been reported to be a major contributor to variety of chronic diseases. Childhood obesity has been rising over the past decades leading to various complications in health. Millions of infants and children undergo surgery every year on various health grounds. The present investigation was undertaken to evaluate the effect of spinal anesthesia of equipotent doses of ropivacaine and bupivacaine on over-weight neonatal rats. Methods: The Sprague-Dawley rat pups were overfed on high fat diet to induce obesity. Behavioral assessments for sensory and motor blockade was made by evaluating thermal and mechanical withdrawal latencies at various time intervals following intrathecal injections of bupivacaine (5.0 mg·kg-1) and ropivacaine (7.5 mg·kg-1) in P14 rats. Spinal tissue was analyzed for apoptosis by determination of activated caspase-3 using monoclonal anti-activated caspase-3 and Fluoro-Jade C staining. Long-term spinal function in P30 rat pups was evaluated. Results: Exposure to intrathecal anesthesia in P14 increased thermal and mechanical latencies and was observed to increase apoptosis as presented by increase in activated caspase-3 and Fluro-Jade C positive cells. Significant alterations in spinal function were observed in high fat diet-fed pups as against non-obese control pups that were on standard diet. Bupivacaine produced more pronounced apoptotic effects on P14 pups; ropivacaine however produced long lasting effects as evidenced in motor function tests at P30. Conclusion: Ropivacaine and bupivacaine induced spinal toxicity that was more pronounced in over-fed rat pups as against normal controls.

Resumo Objetivos: O aumento da prevalência da obesidade é um problema sério de saúde e econômico. A obesidade tem sido relatada como um dos principais contribuintes para uma variedade de doenças crônicas. A obesidade infantil tem aumentado nas últimas décadas e levado a complicações de saúde. Milhões de bebês e crianças são submetidos a cirurgia todos os anos por diversos motivos de saúde. O presente estudo foi feito para avaliar o efeito da raquianestesia com doses equipotentes de ropivacaína e bupivacaína em ratos recém-nascidos com sobrepeso. Métodos: As crias de ratos Sprague-Dawley foram alimentadas em excesso com dieta rica em gordura para induzir obesidade. Avaliações comportamentais para bloqueio sensorial e motor foram feitas por meio da avaliação das latências de retirada térmicas e mecânicas em vários intervalos de tempo após injeções por via intratecal de bupivacaína (5,0 mg·kg-1) e ropivacaína (7,5 mg·kg-1) em ratos P14. Tecido medular foi analisado para apoptose por determinação da caspase-3 ativada, com o uso de anticorpo monoclonal anti-caspase 3 ativada e ecoloração com Fluoro-Jade C. A função da coluna vertebral em longo prazo em filhotes de ratos P30 foi avaliada. Resultados: A exposição à anestesia intratecal em P14 aumentou as latências térmicas e mecânicas e observamos aumento da apoptose, como apresentado pelo aumento da caspase-3 ativada e células positivas para Fluro-Jade C. Alterações significativas da função da coluna vertebral foram observadas em filhotes alimentados com dieta rica em gordura versus filhotes controles não obesos em dieta padrão. Bupivacaína produziu efeitos apoptóticos mais pronunciados sobre os filhotes P14; ropivacaína, entretanto, produziu efeitos duradouros, como evidenciado nos testes de função motora em P30. Conclusão: Ropivacaína e bupivacaína induziram toxicidade medular mais pronunciada nos filhotes de ratos sobrealimentados do que nos controles normais.

Anesthesia for cesarean section in a patient with isolated unilateral absence of a pulmonary artery / Anestesia para cesariana em paciente com ausência unilateral isolada de artéria pulmonar

Abstract Background and objectives: Congenital unilateral absence of a pulmonary artery (UAPA) is a rare anomaly. Although there are several reports regarding pregnancy in patients with unilateral absence of a pulmonary artery, there are no case reports describing anesthesia for Cesarean section in a patient with unilateral absence of a pulmonary artery. Case report: We present a patient with unilateral absence of a pulmonary artery who underwent Cesarean sections twice at the ages of 24 and 26 years under spinal anesthesia for surgery and epidural analgesia for postoperative pain relief. Both times, spinal anesthesia and epidural analgesia enabled successful anesthesia management without the development of either pulmonary hypertension or right heart failure. Conclusion: Spinal anesthesia combined with epidural analgesia is a useful anesthetic method for a Cesarean section in patients with unilateral absence of a pulmonary artery.

Resumo Justificativa e objetivos: A ausência congênita unilateral de uma artéria pulmonar (ACAP) é uma anomalia rara. Embora existam vários relatos sobre pacientes grávidas com ACAP, não há relatos de casos que descrevam anestesia para cesariana em pacientes com ACAP. Relato de caso: Apresentamos uma paciente com ACAP que foi submetida a duas cesarianas, aos 24 e 26 anos, sob raquianestesia para a cirurgia e analgesia epidural para a dor no pós-operatório. Nas duas cesarianas, a raquianestesia e a analgesia epidural possibilitaram o manejo bem-sucedido da anestesia, sem a ocorrência de qualquer hipertensão pulmonar ou insuficiência cardíaca direita. Conclusão: Raquianestesia combinada com analgesia epidural é um método anestésico útil para cesarianas em pacientes com ACAP.

Infrared image monitoring of local anesthetic poisoning in rats / Monitorização por imagem infravermelha da intoxicação por anestésico local em ratos

Abstract Background and objectives: To evaluate the thermographic predictive value of local anesthetic poisoning in rats that indicates the early recognition of thermal signs of intoxication and enable the immediate start of advanced life support. Methods: Wistar rats underwent intraperitoneal injection of saline and ropivacaine; they were allocated into pairs, and experiments performed at baseline and experimental times. For thermography, central and peripheral compartment were analyzed, checking the maximum and average differences of temperatures between groups. Thermographic and clinical observations were performed for each experiment, and the times in which the signs of intoxication occurred were recorded. In the thermal analysis, the thermograms corresponding to the times of interest were sought and relevant data sheets extracted for statistical analysis. Results: Basal and experimental: the display of the thermal images at times was possible. It was possible to calculate the heat transfer rate in all cases. At baseline it was possible to see the physiology of microcirculation, characterized by thermal distribution in the craniocaudal direction. It was possible to visualize the pathophysiological changes or thermal dysautonomias caused by intoxication before clinical signs occur, characterized by areas of hyper-radiation, translating autonomic nervous system pathophysiological disorders. In animals poisoned by ropivacaine, there was no statistically significant difference in heat transfer rate at the experimental time. Conclusions: The maximum temperature, medium temperature, and heat transfer rate were different from the statistical point of view between groups at the experimental time, thus confirming the systemic thermographic predictive value.

Resumo Justificativa e objetivos: Estudar o valor preditivo termográfico na intoxicação por anestésico local em ratos que efetue o reconhecimento precoce dos sinais térmicos de intoxicação e possibilite o início imediato do suporte avançado de vida. Método: Ratos Wistar foram submetidos à injeção intraperitoneal de soro fisiológico e ropivacaína, alocados aos pares, e foram feitos experimentos em tempos basal e experimental. Para o estudo termodinâmico foram analisados o compartimento central e o periférico, verificaram-se as diferenças das temperaturas máximas e médias entre os grupos. Foram feitas observações clínicas e termográficas para cada experimento e anotados os tempos em que os sinais de intoxicação ocorriam. Foram buscados na análise termográfica os termogramas correspondentes aos tempos de interesse e extraídas as planilhas de dados correspondentes, para análise estatística. Resultados: Foi possível a visibilização das imagens térmicas nos momentos basal e experimental. Foi possível calcular a taxa de transferência de calor em todos os casos. No momento basal foi possível observar a fisiologia da microcirculação, caracterizada por distribuição térmica no sentido craniocaudal. Foi possível visibilizar as alterações fisiopatológicas ou disautonomias térmicas causadas pela intoxicação antes que os sinais clínicos ocorressem, caracterizadas por áreas de hiperradiação e traduziram perturbações fisiopatológicas do Sistema Nervoso Autônomo. Nos animais intoxicados por ropivacaína houve diferença estatisticamente significativa na taxa de transferência de calor no momento experimental. Conclusões: Constatou-se que a temperatura máxima, a temperatura média e a taxa de transferência de calor foram diferentes do ponto de vista estatístico entre os grupos no momento experimental, o que corrobora o valor preditivo termográfico sistêmico.

Cytotoxic effects of local anesthesia through lidocaine/ropivacaine on human melanoma cell lines / Efeitos citotóxicos de anestesia local com lidocaína/ropivacaína em linhagens celulares de melanoma humano

Abstract Background: Local anesthetics (LAs) are generally considered as safe, but cytotoxicity has been reported for several local anesthetics used in humans, which is not well investigated. In the present study, the cytotoxicity of lidocaine, ropivacaine and the combination of lidocaine and ropivacaine were evaluated on human melanoma cell lines. Melphalan, a nitrogen mustard alkylating agent, was used as a control agent for comparison of cytotoxic activity. Methods: Melanoma cell lines, A375 and Hs294T, were exposed to 1 h to different concentrations of above agents. Cell-viability after exposure was determined by flow cytometry. Results: Investigated LAs showed detrimental cytotoxicity on studied melanoma cell lines in time- (p < 0.001), concentration- (p < 0.001), and agent dependant. In both A375 and Hs294T cell lines, minimum cell viability rates were found after 72 h of exposure to these agents. Lidocaine 2% caused a reduction of vital cells to 10% ± 2% and 14% ± 2% in A375 and Hs294T, respectively after 72 h of exposure. Ropivacaine 0.75% after 72 h reduced viable cells to 15% ± 3% and 25% ± 3% in A375 and Hs294T, respectively. Minimum cell viability after 72 h exposure to the combination was 10% ± 2% and 18% ± 2% in A375 and Hs294T, respectively. Minimum cell viability after 72 h exposure to melphalan was 8% ± 1% and 12% ± 2%, in A375 and Hs294T, respectively. Conclusion: LAs have cytotoxic activity on human melanoma cell lines in a time-, concentration- and agent-dependant manner. Apoptosis in the cell lines was mediated through activity of caspases-3 and caspases-8.

Resumo Justificativa: Os anestésicos locais (ALs) são geralmente considerados como seguros, mas citotoxicidade foi relatada em vários anestésicos locais usados em seres humanos, a qual não é bem investigada. No presente estudo, a citotoxicidade de lidocaína e ropivacaína e da combinação de lidocaína e ropivacaína foi avaliada em linhagens celulares de melanoma humano. Melfalano, um agente alquilante de mostarda nitrogenada, foi usado como um agente de controle para a comparação da atividade citotóxica. Métodos: Linhagens celulares de melanoma, A375 e Hs294T foram expostas por uma hora a concentrações diferentes dos agentes mencionados acima. A viabilidade celular após a exposição foi determinada por citometria de fluxo. Resultados: Os ALs investigados mostraram citotoxicidade prejudicial nas linhagens celulares de melanoma estudadas dependente do tempo (p < 0,001), da concentração (p < 0,001) e do agente. Em ambas as linhagens de células A375 e Hs294T, níveis mínimos de viabilidade celular foram encontrados após 72 horas de exposição a esses agentes. Lidocaína a 2% provocou uma redução das células vitais para 10% ± 2% e 14% ± 2% em A375 e Hs294T, respectivamente, após 72 horas de exposição. Ropivacaína a 0,75% após 72 horas reduziu as células viáveis para 15% ± 3% e 25% ± 3%, em A375 e Hs294T, respectivamente. A viabilidade celular mínima após exposição de 72 horas para a combinação foi de 10% ± 2% e 18% ± 2% em A375 e Hs294T, respectivamente. A viabilidade celular mínima após exposição de 72 horas ao melfalano foi de 8% ± 1% e 12 ± 2, em A375 e Hs294T, respectivamente. Conclusão: Os ALs têm atividade citotóxica em linhagens de celulares de melanoma humano de modo dependente do tempo, da concentração e do agente. A apoptose nas linhagens celulares foi mediada por meio da atividade das caspases-3 e caspases-8.

Efecto del aliskireno sobre la angiogénesis en modelo de membrana alantocoriónica (MAC) de pollo / Effect of aliskiren on angiogenesis in chick embryo chorioallantoic membrane (CAM) assay

La acción antiangiogénica de los inhibidores del receptor de angiotensina II (ARA II), ha sido documentada previamente, sin embargo, no ha sido descrita la relación entre angiogénesis e inhibidores directos de la renina (DRIs), los cuales participan regulando el sistema renina-angiotensina-aldosterona (SRAA). El objetivo fue demostrar el efecto antiangiogénico de aliskireno, un DRI, en membranas alantocoriónicas (MAC) de pollo, para lo cual fueron instilados aliskireno y enalapril sobre MAC en distintas concentraciones para realizar su comparación posterior. En secciones histológicas seriadas se registró el número de vasos sanguíneos presentes en 9000 µm2 bajo microscopio de luz a máximo aumento, y se realizó análisis estadístico utilizando ANOVA y el test de Tukey para demostrar posibles diferencias. Los receptores tratados con aliskireno, en ambas concentraciones utilizadas, presentaron menor densidad vascular, en comparación con los controles, siendo ésta estadísticamente significativa a mayor concentración. Aliskireno en concentraciones altas tiene un efecto antiangiogénico en un modelo experimental de MAC. Este hallazgo plantea la necesidad de estudios posteriores, dada la proyección que podría tener el uso inhibidores directos de la renina. A partir de estos resultados, se podría pensar en la factibilidad del uso de aliskireno para la modulación de la angiogénesis en diversas enfermedades crónicas no transmisibles.

Angiogenesis is the formation of new blood vessels from pre-existing ones. Antiangiogenic effect of angiotensin receptor blockers has been reported, however, the relationship between direct renin inhibitors and angiogenesis has not been well described. To assess the antiangiogenic effect of aliskiren, a direct renin inhibitor, on chick embryo chorioallantoic membrane (CAM) assay. Aliskiren and enalapril were instilled in different concentrations and compared. In serial histological sections, the number of blood vessels per 9000 µm2 area under observation through optical microscope using maximum zoom, was registered. Statistical analysis using Anova and Tukey test in order to show possible differences, was performed. Receptors treated with aliskiren presented lower vascular density, which was statistically significant when a higher concentration was administered. High concentrations of aliskiren have an antiangiogenic effect on CAM assay. This finding means further studies are needed, because of the usefulness direct renin inhibitors could have. These results, also, might enhance the possibility of using aliskiren for regulating angiogenesis in the context of non-transmissible chronic diseases.

Faster onset time of supraclavicular brachial plexus block using local anesthetic diluted with dextrose / Tempo mais rápido de início do bloqueio do plexo braquial supraclavicular usando anestésico local diluído com dextrose

Abstract Background and objectives: A high sodium concentration is known to antagonize local anesthetics when infiltrated around neural tissue. Thus, we hypothesized that the onset time for sensory and motor blockade, in supraclavicular brachial plexus block using ropivacaine diluted with dextrose would be shorter than with saline. Methods: Patients scheduled for upper limb surgery were randomized to receive ultrasound guided supraclavicular brachial plexus block with 0.5% ropivacaine. Evaluation of sensory and motor blockade was performed every 5 min for 60 min. Patients were followed-up on postoperative day 1, and between days 7 and 10 for the presence of any complications. Twenty-five patients in each group were analyzed. Results: Mean time for onset of analgesia for the dextrose group was 37.6 ± 12.9 min while the mean time for the saline group was 45.2 ± 13.9 min with a p-value of 0.05. The effect size was 0.567, which was moderate to large. No major complications were observed. Conclusion: We conclude that there was a decrease in onset time of analgesia when dextrose was used as a diluent instead of saline for ultrasound guided supraclavicular block.

Resumo Justificativa e objetivos: A alta concentração de sódio é conhecida por antagonizar anestésicos locais quando infiltrado em torno de tecido neural. Portanto, a nossa hipótese foi a de que o tempo de início para os bloqueios sensorial e motor, em bloqueio do plexo braquial supraclavicular com ropivacaína diluída com dextrose, seria menor do que com solução salina. Métodos: Os pacientes agendados para cirurgia em membro superior foram randomizados para receber bloqueio do plexo braquial supraclavicular com ropivacaína a 0,5%g guiado por ultrassom. A avaliação dos bloqueios sensorial e motor foi feita a cada cinco minutos durante 60 minutos. Os pacientes foram acompanhados no pós-operatório no primeiro dia e entre os dias 7-10 para presença de qualquer complicação. Foram analisados 25 pacientes em cada grupo. Resultados: A média do tempo para o início da analgesia no grupo dextrose foi de 37,6 ± 12,9 minutos, enquanto que no grupo solução salina foi de 45,2 ± 13,9 minutos, com um valor-p de 0,05. O tamanho do efeito foi 0,567, o que foi de moderado a grande. Complicações maiores não foram observadas. Conclusão: Concluímos que houve uma redução do tempo de início da analgesia quando dextrose em vez de solução salina foi usada como diluente para bloqueio supraclavicular guiado por ultrassom.

Association of clonidine and ropivacaine in brachial plexus block for shoulder arthroscopy / Associação de clonidina e ropivacaína no bloqueio de plexo braquial para artroscopia de ombro

Abstract Background and objectives: Arthroscopy for shoulder disorders is associated with severe and difficult to control pain, postoperatively. The addition of clonidine to local anesthetics for peripheral nerve block has become increasingly common, thanks to the potential ability of this drug to reduce the mass of local anesthetic required and to prolonging analgesia postoperatively. The present study aimed to evaluate the success of brachial plexus block for arthroscopic rotator cuff surgery using local anesthetic with or without clonidine. Method: 53 patients of both genders, between 18 and 70 years old, American Society of Anesthesiologists I or II, who were scheduled to undergo arthroscopic shoulder surgery were selected. Patients were then randomized into two groups. The verbal numerical pain scale and the presence of motor block were obtained in the post-anesthetic recovery room and 6, 12, 18 and 24 h postoperatively. Results: The association of clonidine (0.15 mg) to a solution of 0.33% ropivacaine (30 mL) in brachial plexus block for shoulder arthroscopy has not diminished the visual numeric pain scale values, nor the need for opioid rescue postoperatively. There was a lower incidence of nausea/vomiting postoperatively and a significant motor block time prolongation in the group of patients who received clonidine as adjuvant. Conclusions: The use of brachial plexus block with local anesthetic for analgesic postoperative control is well established in the literature. The addition of clonidine in the dose proposed for prolongation of the analgesic effect and reduction of opioid rescue proved unhelpful.

Resumo Justificativa e objetivos: A artroscopia para afecções do ombro associa-se a dor de forte intensidade no pós-operatório, de difícil manejo. A adição de clonidina ao anestésico local em bloqueios periféricos tornou-se progressivamente maior graças à potencial habilidade dessa droga em reduzir a massa de anestésicos locais necessários e prolongar a analgesia no pós-operatório. O presente estudo teve como objetivo avaliar o sucesso do bloqueio de plexo braquial para a cirurgia artroscópica de manguito rotador com o uso de anestésico local associado ou não à clonidina. Método: Foram selecionados 53 pacientes de ambos os sexos, entre 18 e 70 anos, ASA I ou II, que seriam submetidos à cirurgia de ombro por artroscopia. Os pacientes foram então randomizados em dois grupos. A escala numérica verbal de dor e a presença de bloqueio motor eram obtidas na sala de recuperação pós-anestésica (SRPA) e com seis, 12, 18 e 24 horas de pós-operatório. Resultados: A associação de clonidina (0,15 mg) à solução de ropivacaína 0,33% (30 mL) no bloqueio de plexo braquial para artroscopia de ombro não diminuiu os valores da escala visual numérica de dor, nem a necessidade de resgate com opioides no pós-operatório. Houve uma menor incidência de náuseas e vômitos no pós-operatório (NVPO) e aumento considerável do tempo de bloqueio motor no grupo de pacientes que recebeu clonidina como adjuvante. Conclusões: O uso do bloqueio de plexo braquial com anestésico local para controle analgésico pós-operatório está consolidado na literatura. A adição de clonidina na dose proposta para prolongamento do efeito analgésico e redução de resgate com opioides mostrou-se pouco útil.

Comparative effects of vitamin C on the effects of local anesthetics ropivacaine, bupivacaine, and lidocaine on human chondrocytes / Efeitos comparativos de vitamina C sobre os efeitos dos anestésicos locais ropivacaína, bupivacaína e lidocaína em condrócitos humanos

BACKGROUND: Intra-articular injections of local anesthetics are commonly used to enhance post-operative analgesia following orthopedic surgery as arthroscopic surgeries. Nevertheless, recent reports of severe complications due to the use of intra-articular local anesthetic have raised concerns. OBJECTIVES: The study aims to assess use of vitamin C in reducing adverse effects of the most commonly employed anesthetics - ropivacaine, bupivacaine and lidocaine - on human chondrocytes. METHODS: The chondrocyte viability following exposure to 0.5% bupivacaine or 0.75% ropivacaine or 1.0% lidocaine and/or vitamin C at doses 125, 250 and 500 µM was determined by LIVE/DEAD assay and annexin V staining. Expression levels of caspases 3 and 9 were assessed using antibodies by Western blotting. Flow cytometry was performed to analyze the generation of reactive oxygen species. RESULTS: On exposure to the local anesthetics, chondrotoxicity was found in the order ropivacaine < bupivacaine < lidocaine. Vitamin C effectively improved the reduced chondrocyte viability and decreased the raised apoptosis levels following exposure to anesthesia. At higher doses, vitamin C was found efficient in reducing the generation of reactive oxygen species and as well down-regulate the expressions of caspases 3 and 9. CONCLUSIONS: Vitamin C was observed to effectively protect chondrocytes against the toxic insult of local anesthetics ropivacaine, bupivacaine and lidocaine.

JUSTIFICATIVA: Injeções de anestésicos locais por via intra-articular são comumente usadas para melhorar a analgesia no período pós-operatório de cirurgia ortopédica como artroscopia. No entanto, relatos recentes de complicações graves devido ao uso de anestésico local por via intra-articular causou preocupações. OBJETIVOS: O objetivo do estudo foi avaliar o uso de vitamina C para reduzir os efeitos adversos dos anestésicos mais comumente usados (ropivocaína, bupivacaína e lidocaína) sobre condrócitos humanos. MÉTODOS: A viabilidade dos condrócitos após a exposição à bupivacaína a 0,5% ou ropivacaína a 0,75% ou lidocaína a 1,0% e/ou vitamina C em doses de 125, 250 e 500 µM foi determinada pelo ensaio Vivo/Morto e coloração com anexina V. Os níveis de expressão das caspases 3 e 9 foram avaliados com o uso de anticorpos pela técnica Western blotting. Citometria de fluxo foi feita para analisar a geração de espécies reativas ao oxigênio. RESULTADOS: Na exposição aos anestésicos locais, condrotoxicidade foi encontrada na seguinte ordem: ropivacaína < bupivacaína < lidocaína. A vitamina C efetivamente melhorou a redução da viabilidade dos condrócitos e diminuiu os níveis elevados de apoptose após a exposição à anestesia. Em doses mais altas, a vitamina C foi eficiente para reduzir a geração de espécies reativas ao oxigênio e assim regular negativamente a expressão das caspases 3 e 9. CONCLUSÕES: Observamos que a vitamina C foi eficaz na proteção dos condrócitos contra a agressão tóxica dos anestésicos locais ropivacaína, bupivacaína e lidocaína.

Renin-angiotensin system blockers regulate the metabolism of isolated fat cells in vitro

Due to the presence of the renin-angiotensin system (RAS) in tissues and its specific influence on white adipose tissue, fat cells are possible targets of pharmacological RAS blockers commonly used as anti-hypertensive drugs. In the present study, we investigated the effects of different RAS blockers on fat cell metabolism, more specifically on lipolysis, lipogenesis and oxidation of energy substrates. Isolated primary adipocytes were incubated with different RAS blockers (aliskiren, captopril and losartan) in vitro for 24 h and lipolysis, lipogenesis and glucose oxidation capacities were determined in dose-response assays to a β-adrenergic agonist and to insulin. Although no change was found in lipolytic capacity, the RAS blockers modulated lipogenesis and glucose oxidation in a different way. While captopril decreased insulin-stimulated lipogenesis (−19% of maximal response and −60% of insulin responsiveness) due to reduced glucose derived glycerol synthesis (−19% of maximal response and 64% of insulin responsiveness), aliskiren increased insulin-stimulated glucose oxidation (+49% of maximal response and +292% of insulin responsiveness) in fat cells. Our experiments demonstrate that RAS blockers can differentially induce metabolic alterations in adipocyte metabolism, characterized by a reduction in lipogenic responsiveness or an increase in glucose oxidation. The impact of RAS blockers on adipocyte metabolism may have beneficial implications on metabolic disorders during their therapeutic use in hypertensive patients.

Nivel de autoconcepto en niños con secuelas de quemaduras: estudio comparativo / Self-concept level in children with burns sequelae: A comparative study

Introducción: Autoconcepto es el conjunto de ideas y actitudes que se tiene acerca de sí mismo. Nuestro objetivo fue evaluar si existen diferencias en el nivel de autoconcepto de niños de 8-12 años con y sin secuelas de quemaduras, e identificar variables predictoras del autoconcepto en los niños con secuelas. Pacientes y método: Estudio comparativo, transversal de 109 niños con secuelas de quemaduras de 8 a 12 años de edad, con 109 niños sin secuelas de quemaduras, del mismo grupo de edad y nivel socioeconómico. Se utilizó la escala de autoconcepto de Piers-Harris, que entrega medida de autoconcepto general y dimensiones: conductual, estatus intelectual y escolar, apariencia y atributos físicos, ansiedad, popularidad, felicidad y satisfacción. Resultados: No hubo diferencias significativas en el nivel de autoconcepto general ni en sus dimensiones al comparar ambos grupos (p > 0,05). Dentro del grupo con secuelas de quemaduras la variable número de secuelas resultó ser un factor protector para las dimensiones ansiedad, popularidad, felicidad-satisfacción y autoconcepto general. La variable localización surgió como factor de riesgo para la dimensión conductual. Discusión: La ausencia de diferencias en autoconcepto entre niños con secuelas de quemaduras y sin ellas es similar a lo reportado por la literatura. El hallazgo en factores de riesgo y protectores motiva a continuar investigando, incorporando antecedentes premórbidos y familiares.

Introduction: Self-concept is the set of ideas and attitudes that a person has about him/herself. Objective: To evaluate whether there are differences in the level of self-concept in children 8-12 years old with and without burns sequelae. To identify predictive variables of self-concept in children with sequelae. Patients and method: A comparative cross-sectional study of self-concept in 109 children with burns sequelae, from 8 to 12 years old, with 109 children without burns sequelae, and of the same age and socioeconomic status. The Piers-Harris self-concept scale is used, which provides a general measurement of self-concept and behavioural, intellectual and school status, appearance, and physical attributes, anxiety, popularity, happiness and satisfaction dimensions. Results: There were no significant differences in the level of general self-concept or their dimensions (P > .05). In the group with burns sequelae, the protective factor was the variable number of sequels was associated with the dimensions of anxiety, popularity, happiness-satisfaction and general self-concept. The location variable emerged as a risk factor for the behavioural dimension. Discussion: The absence of differences in self-concept between children with burns sequelae and children without them is similar to that reported in the literature. The finding in the risk and protective factors encourages to further research, and perhaps incorporating pre-morbidity and family background.

Myocardial contractility impairment with racemic bupivacaine, non-racemic bupivacaine and ropivacaine. A comparative study

PURPOSE: To study racemic bupivacaine, non-racemic bupivacaine and ropivacaine on myocardial contractility. METHODS: Isolated Wistar papillary muscles were submitted to 50 and 100 mM racemic bupivacaine (B50 and B100), non-racemic bupivacaine (NR50 and NR100) and ropivacaine (R50 and R100) intoxication. Isometric contraction data were obtained in basal condition (0.2 Hz), after increasing the frequency of stimulation to 1.0 Hz and after 5, 10 and 15 min of local anesthetic intoxication. Data were analyzed as relative changes of variation. RESULTS: Developed tension was higher with R100 than B100 at D1 (4.3 ± 41.1 vs -57.9 ± 48.1). Resting tension was altered with B50 (-10.6 ± 23.8 vs -4.7 ± 5.0) and R50 (-14.0 ± 20.5 vs -0.5 ± 7.1) between D1 and D3. Maximum rate of tension development was lower with B100 (-56.6 ± 38.0) than R50 (-6.3 ± 37.9) and R100 (-1.9 ± 37.2) in D1. B50, B100 and NR100 modified the maximum rate of tension decline from D1 through D2. Time to peak tension was changed with NR50 between D1 and D2. CONCLUSIONS: Racemic bupivacaine depressed myocardial contractile force more than non-racemic bupivacaine and ropivacaine. Non-racemic and racemic bupivacaine caused myocardial relaxation impairment more than ropivacaine. .