RESUMO
Muscle relaxants have broad application in anesthesiology. They can be used for safe intubation, preparing the patient for surgery, or improving mechanical ventilation. Muscle relaxants can be classified based on their mechanism of action into depolarizing and non-depolarizing muscle relaxants and centrally acting muscle relaxants. Non-depolarizing neuromuscular blocking drugs (NMBDs) (eg, tubocurarine, atracurium, pipecuronium, mivacurium, pancuronium, rocuronium, vecuronium) act as competitive antagonists of nicotine receptors. By doing so, these drugs hinder the depolarizing effect of acetylcholine, thereby eliminating the potential stimulation of muscle fibers. Depolarizing drugs like succinylcholine and decamethonium induce an initial activation (depolarization) of the receptor followed by a sustained and steady blockade. These drugs do not act as competitive antagonists; instead, they function as more enduring agonists compared to acetylcholine itself. Many factors can influence the duration of action of these drugs. Among them, electrolyte disturbances and disruptions in acid-base balance can have an impact. Acidosis increases the potency of non-depolarizing muscle relaxants, while alkalosis induces resistance to their effects. In depolarizing drugs, acidosis and alkalosis produce opposite effects. The results of studies on the impact of acid-base balance disturbances on non-depolarizing relaxants have been conflicting. This work is based on the available literature and the authors' experience. This article aimed to review the use of anesthetic muscle relaxants in patients with acid-base disturbances.
Assuntos
Equilíbrio Ácido-Base , Humanos , Equilíbrio Ácido-Base/efeitos dos fármacos , Fármacos Neuromusculares Despolarizantes/farmacologia , Bloqueadores Neuromusculares/farmacologia , Anestésicos/farmacologia , Fármacos Neuromusculares não Despolarizantes/farmacologia , Succinilcolina/farmacologia , Rocurônio/farmacologiaRESUMO
BACKGROUND: New therapies are created to address specific problems and enjoy popularity as they enter widespread clinical use. Broader use can reveal unknown adverse effects and impact the life cycle significantly. Succinylcholine, a depolarizing neuromuscular blocker, was the product of decades of research surrounding the ancient compound, curare. It was introduced into practice in the 1950s by Burroughs Wellcome and Company (BW Co) and was welcomed due to its rapidly acting muscle relaxation effects. Global clinical use revealed adverse effects, both minor and major, in particular, hyperkalemia and malignant hyperthermia. We investigated when practitioners and the manufacturer became aware of these adverse effects, how information about these side effects was disseminated, and whether the manufacturer met the regulatory requirements of the time, specifically regarding the timely reporting of adverse effects. SOURCES: Primary literature search using online and archived documents was conducted at the Wood Library-Museum of Anesthesiology, Schaumburg, IL. We consulted documents submitted by BW Co to federal authorities, through the Freedom of Information Act (FOIA), Food and Drug Administration (FDA) reports, promotional advertisements, package inserts, published articles, and textbooks. RESULTS: Initial clinical testing in humans in 1952 found no adverse effects on cardiovascular or respiratory systems. Fasciculations and myalgia were early side effects described in case reports in 1952. Large-scale clinical trials in 1953 found abnormally long recovery times among some patients; the discovery of abnormal pseudocholinesterase enzyme activity was not fully demonstrated until the early 1960s. Bradycardia was first reported in 1957 in children, and in 1959 in adults. In 1960, animal studies reported a transient increase in plasma potassium; further experiments in 1969 clearly demonstrated succinylcholine-induced hyperkalemia in burn patients. Malignant hyperthermia was first described in 1966. Similar cases of elevated temperatures and muscle rigidity were described globally but the underlying mechanism was not elucidated until the 1990s. Standard anesthesia textbooks did not report major side effects of succinylcholine until 1960 and included newly documented side effects with each edition. BW Co's packaging contained warnings as early as the 1950s but were later updated in 1962 and beyond to reflect the newly discovered hyperkalemia and malignant hyperthermia. CONCLUSION: Particularly given the regulatory environment of the time, BW Co appropriately reported the adverse effects of succinylcholine after market entry; it updated promotional and packaging material in a timely manner to reflect newly discovered adverse effects. The toxicity, though alarming and put clinicians on alert, did not seem to heavily impact succinylcholine's use, given its various desirable properties. It is still a choice muscle relaxant used today, although there are efforts to develop superior agents to replace succinylcholine.
Assuntos
Fármacos Neuromusculares Despolarizantes/história , Succinilcolina/história , Animais , Aprovação de Drogas/história , Aprovação de Drogas/legislação & jurisprudência , Desenvolvimento de Medicamentos/história , Indústria Farmacêutica/história , História do Século XX , Humanos , Hiperpotassemia/induzido quimicamente , Hiperpotassemia/história , Hipertermia Maligna/etiologia , Hipertermia Maligna/história , Fármacos Neuromusculares Despolarizantes/efeitos adversos , Fármacos Neuromusculares Despolarizantes/farmacologia , Vigilância de Produtos Comercializados , Espasmo/tratamento farmacológico , Espasmo/história , Succinilcolina/efeitos adversos , Succinilcolina/farmacologia , Estados Unidos , United States Food and Drug Administration/históriaRESUMO
Malignant hyperthermia (MH) is a life-threatening disease that occurs during general anaesthesia following exposure to succinylcholine (SCh), a depolarizing muscle relaxant, and volatile anaesthetics. Susceptibility to MH most commonly arises from mutations in the RyR1 gene, the Ca2+ release channel of skeletal muscle. Fulminant MH (f-MH) is the most dangerous form of MH, which presents a hypermetabolic cascade state, including very high temperature and carbon dioxide production, increased heart rate and oxygen consumption, mixed acidosis, rigid muscles, and rhabdomyolysis. Dantrolene is the only specific drug therapy for MH on the market. Without dantrolene, the reported mortality of f-MH is as high as 42.3%. Based on the participation of catecholamine in the hyperhaemodynamic response of f-MH and the demonstrated effective control of catecholamine release of magnesium sulfate, combined with the fact that magnesium and calcium have opposite effects on muscle contraction, I hypothesized that magnesium sulfate could be a choice for delaying the progression of f-MH while waiting for dantrolene treatment.
Assuntos
Anestesia Geral/efeitos adversos , Sulfato de Magnésio/farmacologia , Hipertermia Maligna/tratamento farmacológico , Hipertermia Maligna/patologia , Anestésicos/farmacologia , Cálcio/metabolismo , Catecolaminas/metabolismo , Dantroleno/farmacologia , Progressão da Doença , Febre/metabolismo , Hemofiltração , Humanos , Magnésio/metabolismo , Modelos Teóricos , Músculo Esquelético/metabolismo , Fármacos Neuromusculares Despolarizantes/farmacologia , Consumo de Oxigênio , Rabdomiólise/terapia , TemperaturaRESUMO
Piperamides, which are secondary metabolites in the genus Piper, have potent insecticidal activity, and have thus inspired the development of novel insecticides. In this study, piperovatine, a piperamide from Piper piscatorum (Piperaceae), was investigated using a two-electrode voltage clamp to clarify its detailed mode of action against voltage-gated sodium channels, a classic target. In Xenopus oocytes expressing voltage-gated sodium channels from German cockroach (Blattella germanica), piperovatine induced inward currents depending on repetitive openings. For instance, maximal currents were generated with 10 µM piperovatine following 100 trains of depolarizing pulses with frequency 25 Hz. Piperovatine also shifted the half-activation voltage after conditioning pulses from -35 mV to -45 mV. In addition, piperovatine-modified currents were correlated with not only the number of prior conditioning pulses but also the proportion of activated channels. Finally, piperovatine was found to stabilize voltage-gated sodium channels in the fast-inactivated state after opening, and inhibit transition to the slow-inactivated state. These results suggest that piperovatine preferably binds to activated channels and stabilizes voltage sensors at the conformation acquired during depolarization.
Assuntos
Inseticidas/metabolismo , Piper , Extratos Vegetais/metabolismo , Ácido Sórbico/análogos & derivados , Canais de Sódio Disparados por Voltagem/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Baratas , Relação Dose-Resposta a Droga , Drosophila melanogaster , Feminino , Inseticidas/isolamento & purificação , Inseticidas/farmacologia , Fármacos Neuromusculares Despolarizantes/isolamento & purificação , Fármacos Neuromusculares Despolarizantes/metabolismo , Fármacos Neuromusculares Despolarizantes/farmacologia , Extratos Vegetais/isolamento & purificação , Ácido Sórbico/isolamento & purificação , Ácido Sórbico/metabolismo , Ácido Sórbico/farmacologia , Xenopus laevisRESUMO
INTRODUCTION: Over 5,300 inguinal hernia repairs (IHR) were performed in the Military Health System in 2015. Chronic pain can be a debilitating complication, occurring in up to 34% of patients after IHR and impacts mission readiness. Gabapentin has been shown to be effective for postoperative analgesia in a variety of operations. We evaluated the effect of a short course of perioperative gabapentin on chronic pain after IHR. METHODS: This was a double-blinded, randomized study involving male patients ≥18 years old with an initial inguinal hernia and no history of chronic pain or psychiatric disorder. Patients chose laparoscopic or open surgery and were then randomized to receive gabapentin 300 mg before surgery, then three times daily for 6 doses or placebo. There were 50 patients randomized to both the gabapentin and placebo groups for a total of 100 patients. Main outcomes were pain and health status, assessed with a visual analogue scale (VAS) and the Short Form-12v2 (SF-12v2). Assessments were performed preoperatively and 1, 6, 12, and 24 months postoperatively. Analysis of variance was used to compare groups. RESULTS: From the initial 100 patients, 19 withdrew or were excluded. Thus, 81 patients remained, 40 receiving gabapentin and 41 placebo. Throughout the 24-month follow-up, there was no difference in VAS pain scores between the gabapentin and placebo groups (p = 0.867). Beyond 1 month of follow-up, SF-12v2 physical component score (PCS) scores were improved in the gabapentin group (p = 0.039). When comparing open to laparoscopic groups, SF-12v2 PCS scores were improved in the laparoscopic group (p = 0.046) and SF-12v2 mental component summary scores were improved in the open group (p = 0.041). CONCLUSIONS: Perioperative gabapentin was not effective in decreasing chronic pain after IHR; however, patient perception of physical health, as measured by SF-12v2, did improve.
Assuntos
Aminas/farmacologia , Ácidos Cicloexanocarboxílicos/farmacologia , Hérnia Inguinal/tratamento farmacológico , Procedimentos de Cirurgia Plástica/métodos , Qualidade de Vida/psicologia , Resultado do Tratamento , Ácido gama-Aminobutírico/farmacologia , Adjuvantes Anestésicos/farmacologia , Adjuvantes Anestésicos/uso terapêutico , Adulto , Aminas/uso terapêutico , Androstanóis/farmacologia , Androstanóis/uso terapêutico , Anestésicos Locais/farmacologia , Anestésicos Locais/uso terapêutico , Antieméticos/farmacologia , Antieméticos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Ácidos Cicloexanocarboxílicos/uso terapêutico , Método Duplo-Cego , Feminino , Fentanila/farmacologia , Fentanila/uso terapêutico , Gabapentina , Hérnia Inguinal/cirurgia , Humanos , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Lidocaína/farmacologia , Lidocaína/uso terapêutico , Masculino , Midazolam/farmacologia , Midazolam/uso terapêutico , Pessoa de Meia-Idade , Fármacos Neuromusculares Despolarizantes/farmacologia , Fármacos Neuromusculares Despolarizantes/uso terapêutico , Ondansetron/farmacologia , Ondansetron/uso terapêutico , Placebos/uso terapêutico , Propofol/farmacologia , Propofol/uso terapêutico , Rocurônio , Succinilcolina/farmacologia , Succinilcolina/uso terapêutico , Ácido gama-Aminobutírico/uso terapêuticoAssuntos
Fármacos Neuromusculares Despolarizantes/farmacocinética , Succinilcolina/farmacocinética , Apneia/induzido quimicamente , Apneia/genética , Butirilcolinesterase/deficiência , Butirilcolinesterase/genética , Canais de Cálcio/genética , Canais de Cálcio Tipo L , Humanos , Hiperpotassemia/induzido quimicamente , Hiperpotassemia/genética , Hipertermia Maligna/etiologia , Hipertermia Maligna/genética , Erros Inatos do Metabolismo/induzido quimicamente , Erros Inatos do Metabolismo/genética , Fármacos Neuromusculares Despolarizantes/efeitos adversos , Fármacos Neuromusculares Despolarizantes/farmacologia , Farmacogenética , Polimorfismo de Nucleotídeo Único/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Succinilcolina/efeitos adversos , Succinilcolina/farmacologiaRESUMO
BACKGROUND: The duration of neuromuscular block (NMB) following succinylcholine administration is characterised by a high interindividual variability. However, this has not yet been quantified in a large sample of surgical patients. The significance of underlying clinical factors is unknown. OBJECTIVE: The objective of this study was to profile the variability in NMB duration following a standard dose of succinylcholine and to investigate contributing clinical and genetic factors. DESIGN: A prospective, observational study. SETTING: Tertiary referral centre. PATIENTS: In a total of 1630 surgical patients undergoing a rapid sequence induction and intubation, clinical risk factors for a prolongation in NMB duration following succinylcholine were assessed. In a subset of 202 patients, additional biochemical and molecular genetic investigations of butyrylcholinesterase were performed. INTERVENTION: A standard 1âmgâkg dose of succinylcholine after administration of an induction drug and an opioid. MAIN OUTCOME: NMB duration measured as the time between administration of succinylcholine until reappearance of palpable muscular response to supramaximal transcutaneous ulnar nerve stimulation. RESULTS: NMB varied from 80âs to 44âmin with a median duration of 7.3âmin. Sixteen percent of patients had NMB duration in excess of 10âmin. A multivariable survival model identified physical status, sex, age, hepatic disease, pregnancy, history of cancer and use of etomidate or metoclopramide as independent risk factors for a prolonged NMB. Three novel butyrylcholinesterase variants were identified: p.Ile5Thr; p.Val178Ile; and p.Try231Ser. CONCLUSION: Neuromuscular blockade duration in excess of 10âmin occurred in 16% of a general surgical population following a single dose of succinylcholine. The multivariable model of clinical risk factors for prolonged NMB revealed a negative predictive value of 87%, thereby indicating that absence of such risk factors may reliably predict a shorter duration of NMB. In patients with clinical risk factors for a prolonged NMB or with butyrylcholinesterase mutations, an alternative to succinylcholine should be considered.
Assuntos
Butirilcolinesterase/genética , Bloqueio Neuromuscular/métodos , Fármacos Neuromusculares Despolarizantes/administração & dosagem , Succinilcolina/administração & dosagem , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fármacos Neuromusculares Despolarizantes/farmacologia , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Succinilcolina/farmacologia , Fatores de TempoRESUMO
One of the first intracellular signals after antigen binding by the antigen receptor of B lymphocytes is the increased intracellular Ca(2+) concentration ([Ca(2+)]i), which is followed by several intracellular signaling events like the nuclear translocation of the transcription factor NF-AT controlling the fate of B lymphocytes after their activation. Extracellular ATP, which is released from cells under several pathological conditions, is considered a danger-associated signal serving as an immunomodulator. We investigated the interaction of antigen receptor (BCR) and P2X7 receptor (P2X7R) activation on [Ca(2+)]i signaling and on nuclear translocation of the transcription factor NF-AT in human B lymphocytes. Although the P2X7R is an ATP-gated Ca(2+)-permeable ion channel, P2X7R activation inhibits the BCR-mediated [Ca(2+)]i responses. This effect is mimicked by cell membrane depolarization induced by an increase in the extracellular K(+) concentration or by application of the Na(+) ionophore gramicidin, but is abolished by stabilization of the membrane potential using the K(+) ionophore valinomycin, by extracellular Mg(2+), which is known to inhibit P2X7R-dependent effects, or by replacing Na(+) by the less P2X7R-permeable Tris(+) ion. Furthermore, P2X7R activation by ATP inhibits the BCR-dependent translocation of the transcription factor NF-ATc1 to the nucleus. We therefore conclude that extracellular ATP via the P2X7R mediates inhibitory effects on B cell activation. This may be of relevance for understanding of the activation of the BCR under pathological conditions and for the development of therapeutic strategies targeting human B lymphocytes or P2X7 receptors.
Assuntos
Linfócitos B/imunologia , Núcleo Celular/metabolismo , Fatores de Transcrição NFATC/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Trifosfato de Adenosina/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Criança , Gramicidina/farmacologia , Humanos , Ativação Linfocitária , Magnésio/metabolismo , Fármacos Neuromusculares Despolarizantes/farmacologia , Potássio/metabolismo , Transporte Proteico/efeitos dos fármacos , Receptor Cross-Talk , Valinomicina/farmacologiaRESUMO
BACKGROUND: Ruta graveolens L. (R. graveolens) is a medicinal plant employed in non-traditional medicines that has various therapeutic properties, including anthelmintic, and vasodilatory actions, among others. We evaluated the trachea-relaxant effects of hydroalcoholic extract of R. graveolens against potassium chloride (KCl)- and carbachol-induced contraction of rat tracheal rings in an isolated organ bath. RESULTS: The results showed that the airway smooth muscle contraction induced by the depolarizing agent (KCl) and cholinergic agonist (carbachol) was markedly reduced by R. graveolens in a concentration-dependent manner, with maximum values of 109 ± 7.9 % and 118 ± 2.6 %, respectively (changes in tension expressed as positive percentages of change in proportion to maximum contraction), at the concentration of 45 µg/mL (half-maximal inhibitory concentration IC50: 35.5 µg/mL and 27.8 µg/mL for KCl- and carbachol-induced contraction, respectively). Additionally, the presence of R. graveolens produced rightward parallel displacement of carbachol dose-response curves and reduced over 35 % of the maximum smooth muscle contraction. CONCLUSIONS: The hydroalcoholic extract of R. graveolens exhibited relaxant activity on rat tracheal rings. The results suggest that the trachea-relaxant effect is mediated by a non-competitive antagonistic mechanism. More detailed studies are needed to identify the target of the inhibition, and to determine more precisely the pharmacological mechanisms involved in the observed biological effects.
Assuntos
Animais , Ratos , Parassimpatolíticos/farmacologia , Traqueia/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ruta/química , Músculo Liso/efeitos dos fármacos , Fármacos Neuromusculares Despolarizantes/farmacologia , Cloreto de Potássio/farmacologia , Furocumarinas/análise , Quercetina/análise , Rutina/análise , Traqueia/cirurgia , Técnicas In Vitro , Carbacol/farmacologia , Extratos Vegetais/química , Cromatografia Líquida , Ratos Sprague-Dawley , Colinérgicos/farmacologia , Concentração Inibidora 50 , Componentes Aéreos da Planta/química , Contração Muscular/efeitos dos fármacos , Tono Muscular/efeitos dos fármacosRESUMO
We examined the contractile responsiveness of rat thoracic aortas under pressure overload after long-term suprarenal abdominal aortic coarctation (lt-Srac). Endothelium-dependent angiotensin II (ANG II) type 2 receptor (AT2R)-mediated depression of contractions to ANG II has been reported in short-term (1 week) pressure-overloaded rat aortas. Contractility was evaluated in the aortic rings of rats subjected to lt-Srac or sham surgery (Sham) for 8 weeks. ANG I and II levels and AT2R protein expression in the aortas of lt-Srac and Sham rats were also evaluated. lt-Srac attenuated the contractions of ANG II and phenylephrine in the aortas in an endothelium-independent manner. However, lt-Srac did not influence the transient contractions induced in endothelium-denuded aortic rings by ANG II, phenylephrine, or caffeine in Ca2+-free medium or the subsequent tonic constrictions induced by the addition of Ca2+ in the absence of agonists. Thus, the contractions induced by Ca2+ release from intracellular stores and Ca2+ influx through stored-operated channels were not inhibited in the aortas of lt-Srac rats. Potassium-elicited contractions in endothelium-denuded aortic rings of lt-Srac rats remained unaltered compared with control tissues. Consequently, the contractile depression observed in aortic tissues of lt-Srac rats cannot be explained by direct inhibition of voltage-operated Ca2+ channels. Interestingly, 12-O-tetradecanoylphorbol-13-acetate-induced contractions in endothelium-denuded aortic rings of lt-Srac rats were depressed in the presence but not in the absence of extracellular Ca2+. Neither levels of angiotensins nor of AT2R were modified in the aortas after lt-Srac. The results suggest that, in rat thoracic aortas, lt-Srac selectively inhibited protein kinase C-mediated activation of contraction that is dependent on extracellular Ca2+ entry.
Assuntos
Animais , Masculino , Aorta Torácica/fisiopatologia , Coartação Aórtica/fisiopatologia , Cálcio/metabolismo , Endotélio Vascular/fisiologia , Músculo Liso Vascular/fisiopatologia , Proteína Quinase C/antagonistas & inibidores , Vasoconstrição/fisiologia , Angiotensina I/análise , Angiotensina II/análise , Aorta Torácica/lesões , Aorta Torácica/cirurgia , Western Blotting , Pressão Sanguínea/fisiologia , Cromatografia Líquida de Alta Pressão , Endotélio Vascular/lesões , Músculo Liso Vascular/metabolismo , Fármacos Neuromusculares Despolarizantes/farmacologia , Fenilefrina/farmacologia , Potássio/farmacologia , Proteína Quinase C/metabolismo , Radioimunoensaio , Ratos Wistar , /metabolismo , Vasoconstrição/efeitos dos fármacosRESUMO
We examined the contractile responsiveness of rat thoracic aortas under pressure overload after long-term suprarenal abdominal aortic coarctation (lt-Srac). Endothelium-dependent angiotensin II (ANG II) type 2 receptor (AT2R)-mediated depression of contractions to ANG II has been reported in short-term (1 week) pressure-overloaded rat aortas. Contractility was evaluated in the aortic rings of rats subjected to lt-Srac or sham surgery (Sham) for 8 weeks. ANG I and II levels and AT2R protein expression in the aortas of lt-Srac and Sham rats were also evaluated. lt-Srac attenuated the contractions of ANG II and phenylephrine in the aortas in an endothelium-independent manner. However, lt-Srac did not influence the transient contractions induced in endothelium-denuded aortic rings by ANG II, phenylephrine, or caffeine in Ca2+-free medium or the subsequent tonic constrictions induced by the addition of Ca2+ in the absence of agonists. Thus, the contractions induced by Ca2+ release from intracellular stores and Ca2+ influx through stored-operated channels were not inhibited in the aortas of lt-Srac rats. Potassium-elicited contractions in endothelium-denuded aortic rings of lt-Srac rats remained unaltered compared with control tissues. Consequently, the contractile depression observed in aortic tissues of lt-Srac rats cannot be explained by direct inhibition of voltage-operated Ca2+ channels. Interestingly, 12-O-tetradecanoylphorbol-13-acetate-induced contractions in endothelium-denuded aortic rings of lt-Srac rats were depressed in the presence but not in the absence of extracellular Ca2+. Neither levels of angiotensins nor of AT2R were modified in the aortas after lt-Srac. The results suggest that, in rat thoracic aortas, lt-Srac selectively inhibited protein kinase C-mediated activation of contraction that is dependent on extracellular Ca2+ entry.
Assuntos
Aorta Torácica/fisiopatologia , Coartação Aórtica/fisiopatologia , Cálcio/metabolismo , Endotélio Vascular/fisiologia , Músculo Liso Vascular/fisiopatologia , Proteína Quinase C/antagonistas & inibidores , Vasoconstrição/fisiologia , Angiotensina I/análise , Angiotensina II/análise , Animais , Aorta Torácica/lesões , Aorta Torácica/cirurgia , Pressão Sanguínea/fisiologia , Western Blotting , Cromatografia Líquida de Alta Pressão , Endotélio Vascular/lesões , Masculino , Músculo Liso Vascular/metabolismo , Fármacos Neuromusculares Despolarizantes/farmacologia , Fenilefrina/farmacologia , Potássio/farmacologia , Proteína Quinase C/metabolismo , Radioimunoensaio , Ratos Wistar , Receptor Tipo 2 de Angiotensina/metabolismo , Vasoconstrição/efeitos dos fármacosRESUMO
This commentary addresses some of the diverse questions of current interest with regard to the health effects of air pollution, including exposure-response relationships, toxicity of inhaled particles and risks to health, multipollutant mixtures, traffic-related pollution, accountability research, and issues with susceptibility and vulnerability. It considers the challenges posed to researchers as they attempt to provide useful evidence for policy-makers relevant to these issues. This commentary accompanies papers giving the results from the ESCALA project, a multi-city study in Latin America that has an overall goal of providing policy-relevant results. While progress has been made in improving air quality, driven by epidemiological evidence that air pollution is adversely affecting public health, the research questions have become more subtle and challenging as levels of air pollution dropped. More research is still needed, but also novel methods and approaches to address these new questions.
Este comentario aborda algunos de los temas de interés actual en relación con los efectos de la contaminación del aire sobre la salud, tales como las relaciones exposición-respuesta, la toxicidad y riesgos para la salud de las partículas inhaladas, las mezclas de contaminantes múltiples, la contaminación relacionada con el tráfico, la investigación sobre responsabilidad, y los problemas de susceptibilidad y vulnerabilidad. Considera los retos que se presentan a los investigadores que intentan proporcionar evidencia para los responsables políticos en estas cuestiones. Este texto acompaña otros trabajos con resultados del proyecto ESCALA, un estudio en varias ciudades de América Latina que tiene como objetivo general proporcionar resultados relevantes para la política pública. Aunque ha habido avances para mejorar la calidad del aire, gracias a la evidencia epidemiológica de que la contaminación aérea está afectando negativamente a la salud pública, las preguntas de investigación se han vuelto más sutiles y difíciles a medida que los niveles de contaminación se reducen. Se necesita más investigación, pero también nuevos métodos y enfoques capaces de enfrentar estas preguntas.
Assuntos
Animais , Camundongos , Colina/análogos & derivados , Junção Neuromuscular/metabolismo , Neurotransmissores/metabolismo , Pró-Fármacos/metabolismo , Colina/metabolismo , Inibidores da Colinesterase/farmacologia , Edrofônio/farmacologia , Estimulação Elétrica , /farmacologia , Metilaminas/farmacologia , Camundongos Endogâmicos , Neostigmina/farmacologia , Fármacos Neuromusculares Despolarizantes/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Piperidinas/farmacologia , Rana pipiensRESUMO
Mutations in the butyrylcholinesterase gene can lead to a prolonged effect of the neuromuscular blocking agents, succinylcholine and mivacurium. If the anaesthesiologist is not aware of this condition, it may result in insufficient respiration after tracheal extubation. However, this can be avoided with the use of objective neuromuscular monitoring if used adequately. Three case reports of prolonged effect of succinylcholine or mivacurium were presented to illustrate the importance of neuromuscular monitoring during anaesthesia. In the first case, continuous intraoperative neuromuscular monitoring allowed a prolonged neuromuscular blockade to be discovered prior to tracheal extubation of the patient. The patient was extubated after successful reversal of the neuromuscular blockade. On the contrary, neuromuscular monitoring was not used during anaesthesia in the second patient; hence, the prolonged effect of the neuromuscular blocking agent was not discovered until after extubation. In the third patient, the lack of response to nerve stimulation was interpreted as a technical failure and the prolonged effect of succinylcholine was discovered when general anaesthesia was terminated. Both patients had insufficient respiration. They were therefore re-sedated, transferred to the intensive care unit and the tracheas were extubated after full recovery from neuromuscular blockade. We recommend the use of monitoring every time these agents are used, even with short-acting drugs like succinylcholine and mivacurium.
Assuntos
Butirilcolinesterase/deficiência , Isoquinolinas/efeitos adversos , Erros Inatos do Metabolismo/diagnóstico , Bloqueio Neuromuscular , Fármacos Neuromusculares Despolarizantes/efeitos adversos , Monitoração Neuromuscular , Fármacos Neuromusculares não Despolarizantes/efeitos adversos , Succinilcolina/efeitos adversos , Acelerometria/métodos , Idoso , Antídotos/uso terapêutico , Apneia , Apendicite , Butirilcolinesterase/genética , Butirilcolinesterase/metabolismo , Butirilcolinesterase/fisiologia , Colecistectomia Laparoscópica , Análise Mutacional de DNA , Feminino , Fraturas do Colo Femoral/cirurgia , Genótipo , Humanos , Hipnóticos e Sedativos/uso terapêutico , Isoquinolinas/farmacocinética , Isoquinolinas/farmacologia , Laparoscopia , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Pessoa de Meia-Idade , Mivacúrio , Neostigmina/uso terapêutico , Fármacos Neuromusculares Despolarizantes/farmacocinética , Fármacos Neuromusculares Despolarizantes/farmacologia , Fármacos Neuromusculares não Despolarizantes/farmacocinética , Fármacos Neuromusculares não Despolarizantes/farmacologia , Respiração Artificial , Paralisia Respiratória/induzido quimicamente , Paralisia Respiratória/prevenção & controle , Paralisia Respiratória/terapia , Succinilcolina/farmacocinética , Succinilcolina/farmacologia , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Neuromodulation is used to restore neural function in disorders that stem from an imbalance in the activity of specific neural networks when they prove refractory to pharmacological therapy. The Kir2.1 gene contributes to stabilizing the resting potential below the threshold of activation of voltage-gated sodium channels and action potentials. Therefore, the delivery of the Kir2.1 gene to neuronal cells could reduce the probability of action potential generation, inhibiting excessive neural activity. OBJECTIVE: To address the hypothesis that overexpression of the inwardly rectifying potassium channel 2.1 (Kir2.1) gene could inhibit motor neuron activity and therefore be therapeutically used in gene-based neuromodulation. METHODS: To induce expression of Kir2.1, the inducible RheoSwitch promoter was used and controlled by ligand. In vivo gene expression was accomplished by an adenoviral vector to deliver unilaterally into the lumbar spinal cord of rats. RESULTS: Behavioral assays demonstrated that neuromuscular inhibition was exclusive to rats that received the ligand. Histological analysis also showed evidence of some motor neuron loss in these animals. Behavioral effects of Kir2.1 expression were completely reversible, arguing that the behavioral effect did not result from motor neuron death. CONCLUSION: Delivery of the gene for Kir2.1 inhibits neurons by resisting depolarization to the action potential threshold. Regulated neuronal expression of Kir2.1 may provide an elegant means for neuromodulation in a selected neuronal population.
Assuntos
Regulação da Expressão Gênica , Técnicas de Transferência de Genes , Neurônios/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização/biossíntese , Medula Espinal/fisiologia , Animais , Linhagem Celular Tumoral , Regulação da Expressão Gênica/fisiologia , Humanos , Fármacos Neuromusculares Despolarizantes/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Distribuição Aleatória , Ratos , Medula Espinal/citologiaRESUMO
Recent case-controlled clinical studies show that bronchioalveolar carcinomas (BAC) are correlated with smoking. Nicotine, the addictive component of cigarettes, accelerates cell proliferation through nicotinic acetylcholine receptors (nAChR). In this study, we show that human BACs produce acetylcholine (ACh) and contain several cholinergic factors including acetylcholinesterase (AChE), choline acetyltransferase (ChAT), choline transporter 1 (CHT1, SLC5A7), vesicular acetylcholine transporter (VAChT, SLC18A3), and nACh receptors (AChRs, CHRNAs). Nicotine increased the production of ACh in human BACs, and ACh acts as a growth factor for these cells. Nicotine-induced ACh production was mediated by α7-, α3ß2-, and ß3-nAChRs, ChAT and VAChT pathways. We observed that nicotine upregulated ChAT and VAChT. Therefore, we conjectured that VAChT antagonists, such as vesamicol, may suppress the growth of human BACs. Vesamicol induced potent apoptosis of human BACs in cell culture and nude mice models. Vesamicol did not have any effect on EGF or insulin-like growth factor-II-induced growth of human BACs. siRNA-mediated attenuation of VAChT reversed the apoptotic activity of vesamicol. We also observed that vesamicol inhibited Akt phosphorylation during cell death and that overexpression of constitutively active Akt reversed the apoptotic activity of vesamicol. Taken together, our results suggested that disruption of nicotine-induced cholinergic signaling by agents such as vesamicol may have applications in BAC therapy.
Assuntos
Acetilcolina/metabolismo , Adenocarcinoma Bronquioloalveolar/tratamento farmacológico , Apoptose/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Piperidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Adenocarcinoma Bronquioloalveolar/metabolismo , Adenocarcinoma Bronquioloalveolar/patologia , Animais , Western Blotting , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , Fármacos Neuromusculares Despolarizantes/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Proteínas Vesiculares de Transporte de Acetilcolina/antagonistas & inibidores , Proteínas Vesiculares de Transporte de Acetilcolina/genética , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Humanos , Bloqueadores Neuromusculares/farmacologia , Bloqueio Neuromuscular/métodos , Fármacos Neuromusculares Despolarizantes/farmacologia , Músculo Esquelético , Junção Neuromuscular , Período de Recuperação da Anestesia , Bloqueadores Neuromusculares/antagonistas & inibidores , Fármacos Neuromusculares Despolarizantes/antagonistas & inibidores , gama-Ciclodextrinas/farmacologiaRESUMO
Neurite outgrowth is a fundamental step in establishing proper neuronal connections in the developing central nervous system. Dynamic control of outgrowth has been attributed to changes in growth cone Ca2+ levels in response to extracellular cues. Here we have investigated a possible role for Ca2+ permeable kainate (KA) receptors in regulating neurite outgrowth of nociceptive-like dorsal root ganglion (DRG) neurons. To identify KA receptor subunits likely to be involved, we used quantitative RT-PCR on acutely dissociated DRG and dorsal horn neurons. DRG neurons expressed more GluK1, particularly the GluK1b spice variant, than dorsal horn neurons. Conversely, dorsal horn neurons expressed more GluK2, particularly GluK2a, than DRG neurons. Further, an RNA editing assay indicated that the majority of GluK1 and GluK2 mRNA transcripts in DRG were unedited. Imaging Ca2+ transients following application of a KA receptor agonist to DRG and dorsal horn co-cultures revealed increases in intracellular Ca2+ in the growth cones of DRG neurons. In the majority of cases, this increase in Ca2+ was partly or completely blocked by Joro spider toxin (JSTX), an antagonist for Ca2+-permeable AMPA and KA receptors. Treatment of DRG/dorsal horn co-cultures with KA for 18 hours suppressed neurite outgrowth while application of the rapidly desensitizing KA receptor agonist SYM 2081, the competitive AMPA/KA receptor antagonist, CNQX, and JSTX or philanthotoxin enhanced neurite outgrowth and prevented KA effects on neurite outgrowth. Thus, Ca2+ entry through KA receptors at the growth cone of DRG neurons may be an important regulator of neurite outgrowth.
Assuntos
Cálcio/metabolismo , Gânglios Espinais/citologia , Regulação da Expressão Gênica/fisiologia , Neuritos/fisiologia , Receptores de Ácido Caínico/metabolismo , Células Receptoras Sensoriais/citologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Adenosina Desaminase/metabolismo , Análise de Variância , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Proteína GAP-43/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamatos/farmacologia , Cones de Crescimento/efeitos dos fármacos , Cones de Crescimento/fisiologia , Ácido Caínico/análogos & derivados , Ácido Caínico/farmacologia , Proteínas de Membrana/metabolismo , Neuritos/efeitos dos fármacos , Fármacos Neuromusculares Despolarizantes/farmacologia , Edição de RNA/fisiologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Ácido Caínico/genética , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Venenos de Aranha/farmacologia , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismo , Receptor de GluK2 CainatoRESUMO
INTRODUCTION: Malignant hyperthermia (MH) is a potentially lethal anesthetic complication characterized by muscle hypermetabolism and generalized rigor. The exact mechanism of succinylcholine as an MH trigger cannot be examined in existing in vitro models. Therefore, a novel in vivo model was used to examine the metabolic response to succinylcholine. METHODS: With institutional review board approval, 6 MH susceptible (MHS) and 6 MH non-susceptible (MHN) pigs were anesthetized with hemodynamic and systemic metabolic monitoring. Microdialysis catheters were placed intramuscularly. After equilibration, succinylcholine, halothane, and Ringer solution were injected. Lactate was measured in the dialysate and statistically analyzed by Mann-Whitney U-test (significance level P < 0.05). RESULTS: Hemodynamic and systemic metabolic parameters were not different between the groups throughout the experiment. In the MHS pigs, halothane induced a significant increase of lactate. In MHN pigs, no substance induced a reaction. CONCLUSIONS: Halothane, but not succinylcholine, induced a hypermetabolic reaction in this model. Therefore, the role of succinylcholine as an MH trigger remains questionable.
Assuntos
Hipertermia Maligna/etiologia , Músculo Esquelético/efeitos dos fármacos , Fármacos Neuromusculares Despolarizantes/farmacologia , Junção Neuromuscular/efeitos dos fármacos , Succinilcolina/farmacologia , Animais , Suscetibilidade a Doenças , Feminino , Hemodinâmica/efeitos dos fármacos , Masculino , Hipertermia Maligna/genética , Hipertermia Maligna/metabolismo , Músculo Esquelético/metabolismo , Junção Neuromuscular/metabolismo , SuínosRESUMO
Emergency airway management is associated with a high complication rate. Evaluating the patient prior to airway management is important to identify patients with increased risk of failed airways. Pre-oxygenation of critically ill patients is less effective in comparison to less sick patients. Induction agents are often required, but most induction agents are associated with hypotension during emergency intubation. Use of muscle relaxants is controversial for emergency intubation, but they are commonly used in the emergency department. Supervision of emergency airway management by attending physicians significantly decreases complications. Standardized algorithms may increase the success of emergency intubation. Attention should be paid to cardiopulmonary stability in the immediate post-intubation period.
Assuntos
Intubação Intratraqueal , Algoritmos , Serviços Médicos de Emergência , Etomidato/farmacologia , Humanos , Hipnóticos e Sedativos/farmacologia , Intubação Intratraqueal/efeitos adversos , Ketamina/farmacologia , Máscaras Laríngeas , Laringoscopia , Fármacos Neuromusculares Despolarizantes/farmacologia , Propofol/farmacologia , Succinilcolina/farmacologiaRESUMO
The amount of neurotransmitter released from a presynaptic terminal is the product of the quantal content (number of vesicles) and the presynaptic quantal size (QSpre, amount of transmitter per vesicle). QSpre varies with synaptic use, but its regulation is poorly understood. The motor nerve terminals at the neuromuscular junction (NMJ) contain TGF-beta receptors. We present evidence that TGF-beta2 regulates QSpre at the NMJ. Application of TGF-beta2 to the rat diaphragm NMJ increased the postsynaptic response to both spontaneous and evoked release of acetylcholine, whereas antibodies to TGF-beta2 or its receptor had the converse effect. L-vesamicol and bafilomycin blocked the actions of TGF-beta2, indicating that TGF-beta2 acts by altering the extent of vesicular filling. Recordings of the postsynaptic currents from the diaphragm were consistent with TGF-beta2 having this presynaptic action and a lesser postsynaptic effect on input resistance. TGF-beta2 also decreased quantal content by an atropine-sensitive pathway, indicating that this change is secondary to cholinergic feedback on vesicular release. Consequently, the net actions of TGF-beta2 at the NMJ were to amplify the postsynaptic effects of spontaneous transmission and to diminish the number of vesicles used per evoked stimulus, without diminishing the amount of acetylcholine released.