Orientador: Leonardo Fernandes Fraceto / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-26T03:20:07Z (GMT). No. of bitstreams: 1 Baratelli_Diego_M.pdf: 5417308 bytes, checksum: 04980cc029526e213ff664b425962296 (MD5) Previous issue date: 2014 / Resumo: O controle da dor em diferentes procedimentos clínicos é de extrema importância, logo a descoberta dos anestésicos locais (ALs), caracterizados pela capacidade de diminuir a dor sem a perda da consciência representou um grande avanço para a clínica médica. O anestésico local ideal deve apresentar ação anestésica duradoura e baixa toxicidade. Devido aos avanços da nanotecnologia, gerou-se a possibilidade de associar os ALs com sistemas nanoparticulados poliméricos (SNPs), que agem como transportadores, aumentando assim a eficácia terapêutica daqueles. O presente trabalho teve como objetivo o desenvolvimento de nanocápsulas poliméricas como sistema carreador conjunto para dois ALs amplamente usados na clínica, a prilocaína (PLC) e a lidocaína (LDC) visando melhorar as propriedades terapêuticas destes ALs, pela liberação sustentada, de forma a diminuir os efeitos indesejáveis como a alergenicidade e toxicidade. Desta forma, no presente estudo foram preparadas nanocápsulas (NC) compostas por três diferentes polímeros (PCL) poli-epsilon-caprolactona, (PLGA) poli-lactídeo-co-glicolídeo e (PHBV) poli-hidroxibutirato-co-hidroxivalerato, baseadas na metodologia de emulsificação/evaporação do solvente. A caracterização destes sistemas foi feita através da medida de diâmetro médio das partículas, polidispersão, potencial zeta, pH, eficiência de encapsulação e avaliação do perfil de liberação. Os resultados mostraram que as nanopartículas apresentaram diâmetro médio de 375 a 580 nm com valores de polidispersão abaixo de 0,25; o potencial zeta variou de - 5,4 a - 25,1 mV e o pH entre 3,5 e 8,5. A eficiência de encapsulação dos ALs foi superior a 50% para a PLC e 75% para a LDC. Os ensaios de liberação in vitro mostraram que em todas as formulações a PLC é liberada mais rapidamente que a LDC. Os resultados para os diferentes polímeros mostraram que o perfil de liberação (horas) para a PLC de ~ 2,0; 4,0; 4,5; 5,5 e para LDC de 4,5; 6,0; 8,0; 9,5 seguindo a ordem PLGA>PCL>PCLmistura>PHBV, devido às diferentes características dos polímeros e interações intermoleculares entre os ALs e a matriz polimérica. A análise matemática dos perfis de liberação mostrou que os ALs são liberados por transporte do tipo caso II (difusão e relaxamento da cadeia polimérica). Os resultados obtidos neste trabalho indicou que sistemas carreadores poliméricos de PLC e LDC constituem uma alternativa promissora para futuras aplicações no tratamento da dor / Abstract: In different clinical procedures pain control is of extreme important, so that the discovery of local anesthetics (LAs), characterized by the ability to reduce pain without loss of consciousness represented a major breakthrough in medicine. An ideal local anesthetic agent should have long duration and low toxicity. Advances in nanotechnology allowed the combined use of Las with polymeric nanoparticle systems (SNPs), which act as carriers to increase the therapeutic efficacy of anesthetics. This study aimed the development of polymeric nanocapsules as carrier systems for two LAs widely used in the clinics: prilocaine (PLC) and lidocaine (LDC). To improve these LAs, we wanted to prolong their release profile to reduce side effects, such as allergenicity and toxicity. Thus, in this study were have prepared nanocapsules (NC) using three different kind of polymers: poly-epsilon-caprolactone (PCL), poly-lactide-co-glycolide (PLGA) and polyhydroxybutyrate-co-hydroxyvalerate (PHBV) based on the emulsification/solvent evaporation methodology, The characterization of these systems was considerate by measuring the diameter, polydispersion, zeta potential, pH, encapsulation efficiency of the LAs and investigation of the in release profile. Results demonstrated that the nanoparticles had a mean diameter of 375 to 580 nm with values of polydispersity below 0.25; the zeta potential ranged from - 5.4 to - 25.1 mV and the pH between 3.5 and 8.5. The encapsulation efficiency of LAs were above 50% for PLC and 75% for the LDC. The in vitro release assays showed that PLC was released faster than LDC. in all formulations The results for the different polymers showed the following release profile order PLGA>PCL>PHBV, due to the differences in the polymers proprieties and intermolecular interactions of LAs and the polymeric matrixes. Mathematical analysis of the release profiles showed that LAs are released by type II transport. The results obtained in this work indicated polymeric carrier systems of PLC and LDC could be a promising alternative for future applications in the treatment of pain / Mestrado / Bioquimica / Mestre em Biologia Funcional e Molecular

Orientadores: Eneida de Paula, Michelle Franz Montan Braga Leite / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-21T07:56:47Z (GMT). No. of bitstreams: 1 Sobral_VivianeRobertaVieira_M.pdf: 3065834 bytes, checksum: 821d44f8c5c07441498c0b9a0426b822 (MD5) Previous issue date: 2012 / Resumo: Benzocaína (BZC) é um anestésico local do tipo éster usado principalmente em formulações de uso tópico, dérmico ou em mucosas. Em estudos anteriores de nosso laboratório, a interação da BZC com lipossomas convencionais compostos de fosfatidilcolina de ovo, colesterol e alfa-tocoferol foi caracterizada. No entanto, estudos recentes têm demonstrado que lipossomas elásticos, preparados com adição de um tensoativo, apresentam vantagens em relação aos convencionais, pois conseguem atravessar de maneira mais eficiente o estrato córneo. O objetivo deste trabalho foi avaliar e caracterizar, sob o aspecto físico-químico e farmacêutico, diferentes formulações em gel de benzocaína: BZC a 10% e 20%, BZC a 10% encapsulada em lipossomas convencionais (LC) ou lipossomas elásticos (LE) e formulação comercial (contendo BZC a 20%). A quantificação do teor de benzocaína nas formulações foi realizada através de cromatografia líquida de alta eficiência e validada segundo o Guia de Validação de Métodos Analíticos e Bioanalíticos (Brasil, 2003). Em estudos de estabilidade acelerada (Brasil, 2005) foram avaliados: peroxidação lipídica, pH, teor e comportamento reológico das formulações. As formulações recém-preparadas foram avaliadas também quanto à citotoxicidade, liberação e permeação in vitro. Todas as formulações mostraram-se estáveis por até 6 meses, com pequenas variações de pH e teor; a peroxidação lipídica aumentou ao final deste período, porém a quantidade de peróxidos formados não ultrapassou 1% do total de lipídios presentes na formulação.... Observação: O resumo, na íntegra, poderá ser visualizado no texto completo da tese digital / Abstract: Benzocaine (BZC) is an ester type local anesthetic mainly used in topical formulations for either dermal or mucosa. In previous studies from our laboratory, the interaction of BZC with conventional liposomes composed of egg phosphatidylcholine, cholesterol and alpha-tocopherol was characterized. However, recent studies have demonstrated that elastic liposomes prepared with the addition of a surfactant, show advantages over conventional vesicles, as they can effectively cross the stratum corneum. The objective of this study was to evaluate and characterize the physicochemical and pharmaceutical aspects of different gel formulations of BZC: 10% and 20% of BZC, 10% BZC encapsulated into conventional (CL) or elastic liposomes (EL) and commercial formulation (containing 20% BZC). The quantification of BZC in the formulations was performed by high performance liquid chromatography (HPLC) and validated according to the Guide for Validation of Analytical and Bioanalytical Methods (Brazil, 2003). Accelerated stability studies (Brazil, 2005) were used to evaluate lipid peroxidation, pH, and rheological behavior of the formulations. The freshly prepared formulations were submitted to cytotoxicity and in vitro release tests. All formulations were stable up to 6 months, with minor variations in pH and content of BZC; although the lipid peroxidation increased at the end of that period, the amount of peroxides produced was less than 1% of the total lipids in the formulation. ... Note: The complete abstract is available with the full electronic digital thesis or dissertations / Mestrado / Bioquimica / Mestre em Biologia Funcional e Molecular

Orientador: Eneida de Paula / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-21T20:38:17Z (GMT). No. of bitstreams: 1 Vieira_AnaLaisNascimento_M.pdf: 1761666 bytes, checksum: 7180ab65e3505754f86cafe1a14f9b0d (MD5) Previous issue date: 2012 / Resumo: Os anestésicos locais (AL) são fármacos utilizados para o tratamento, alívio ou eliminação da dor crônica ou aguda. Muitas pesquisas têm sido desenvolvidas com a finalidade de prolongar sua duração de ação e reduzir sua toxicidade sistêmica, através do uso de diferentes carreadores, como lipossomas e ciclodextrinas. Essas novas formulações possibilitam a liberação sustentada do ativo no local de ação, prolongando o efeito anestésico, além de evitar picos de concentração plasmática, reduzindo sua toxicidade. A ropivacaína (RVC) é um AL de longa duração de ação, que é sintetizado na forma do estereoisômero S, de menor toxicidade para o sistema nervoso central e cardíaco. Estudos anteriores de nosso laboratório demonstraram a complexação da RVC em hidroxipropil-betaciclodextrina (HP-?CD) (de Araujo et al., 2008b). Neste trabalho objetivamos: i) desenvolver uma formulação contendo complexo de inclusão de RVC em HP-?CD na razão molar de 1:1 e posteriormente, encapsulado em lipossomas de fosfatidilcolina de ovo (EPC) contendo 1 mol%de ?-tocoferol, ii) caracterizar esta nova formulação anestésica, comparando-a com as preparações comerciais deste fármaco, quanto à estabilidade e liberação sustentada do anestésico. Os lipossomas unilamelares grandes (LUV) compostos por fosfatidilcolina de ovo e ?- tocoferol (1,0: 0,01 - razão molar) foram preparados por extrusão, em pH 7,0. A formulação lipossomal foi caracterizada quanto à eficiência de encapsulação com a obtenção de valores de porcentagem de encapsulação da RVC de 33,0±2,4 % e coeficiente de partição de 102,1. Ensaios de Ressonância Magnética Nuclear com variação de campo magnético (diffusion ordered spectroscopy, DOSY) demonstraram a interação molecular da RVC tanto com a ciclodextrina (constante de associação, Ka RVC: HP-?CD = 128 M-1) quanto com os lipossomas (Ka LUV: RVC = 22 M-1). No sistema de duplo carreamento (LUV: RVC: HP-?CD) a constante de associação foi maior que nos sistemas binários RVC: HP-?CD e LUV: RVC (2,6 e 1,7 vezes, respectivamente) indicando que este novo sistema de liberação sustentada é capaz de aumentar ainda mais a quantidade de ropivacaína carreada. O tamanho dos lipossomas (220,2±20,3 nm) e o potencial zeta (-31,7±1,4 Mv) não se alteraram com a adição do anestésico. As formulações foram acompanhadas por 60 dias, em termos de peroxidação lipídico e tamanho das vesículas: os níveis de peroxidação mostraram-se baixos (menor que 1% do total de lipídios da formulação) e as vesículas tiveram um comportamento estável em relação ao tamanho por até 30 dias de armazenamento a 4oC. Ensaios de liberação in vitro, demonstraram menor velocidade de liberação da RVC quando na forma de complexo de inclusão em ciclodextrinas e encapsulada nos lipossomas, em relação à RVC livre. Testes de toxicidade in vitro, em culturas de células de fibroblastos 3T3 revelaram que a RVC livre induz morte celular de maneira concentração dependente; efeito este que foi parcialmente revertido com incubação das células com o sistema de duplo carreamento LUV: RVC: HP-?CD, indicando menor potencial tóxico para a formulação proposta. Ensaios de bloqueio sensorial in vivo (teste de pressão na pata, em camundongo) mostraram uma ação analgésica prolongada da RVC encapsulada no sistema de duplo carreamento (até 300 min. para 0,25% LUV: RVC: HP-?CD), quando comparado ao fármaco livre (180 min.) e sistema binário LUV: RVC (240 min.). Em geral, o efeito da analgesia para o sistema de duplo carreamento proposto foi cerca de 1,6 vezes maior em relação ao fármaco livre e 1,3 vezes maior em relação ao sistema lipossomal binário. Os resultados obtidos contribuem com a investigação, pesquisa e caracterização de formas farmacêuticas de liberação sustentada e demonstram regulação da cinética de liberação da RVC quando do uso conjugado desses dois carreadores (lipossoma de EPC e HP-?CD) em sistema de liberação sustentada de anestésico local, abrindo perspectivas para justificar o uso clínico / Abstract: Local anesthetics (LA) are medicines used for the treatment, alleviation or elimination of acute or chronic pain. Many studies have been carried out aiming to prolong LA duration of action and to reduce their systemic toxicity by the use of carrier systems such as liposomes and cyclodextrins. Such formulations allow the sustained release of the LA at the site of action, prolonging the anesthetic effect and avoiding peak plasma concentrations, thus reducing LA toxicity. Ropivacaine (RVC) is a long acting LA, synthesized in the S enantiomer form which is less toxic to the Central nervous and cardiac systems. Previous work from our lab has shown the complexation of RVC in hydroxipropyl-beta-cyclodextrin (HP-?CD) (de Araujo et al., 2008b). The present work aimed: i) the development of a formulation containing RVC in HP-?CD inclusion complex in a 1:1 mole % ratio and subsequently encapsulated into egg phosphatidylcholine plus 1 mol% ?-tocopherol liposomes; ii) the characterization of that formulation, comparing it with commercial preparations of RVC, regarding the stability and sustained release of the anesthetic. Large unilamellar liposomes (LUV) composed of egg phosphatidylcholine and ?-tocopherol (1,0:0,01 mol %) was prepared by extrusion, at pH 7.0. The liposomal formulation was characterized with respect to encapsulation efficiency (33.0±2.4%) corresponding to partition coefficient of 102.1. Nuclear magnetic resonance (diffusion ordered spectroscopy, DOSY) experiments clearly demonstrated the molecular interaction between RVC and the HP-?CD (association constant, Ka RVC:HP-?CD = 128 M-1) and liposomes (Ka LUV:RVC = 22 M-1). In the ternary system LUV:RVC:HP-?CD) a stronger association was detected (Ka = 2.6 and 1.7 x higher than in the binary RVC:HP-?CD e LUV:RVC systems, respectively), pointing out the increased RVC loading capacity of the new drug-delivery system. The size of the vesicles (220.2± 20.3 nm), and zeta potential of the liposomes (-31.7±1.4 Mv) were not changed by the incorporation of the anesthetic. The formulations were followed by 60 days in terms of lipid peroxidation and size of vesicles: peroxidation were shown to be low (less than 1% of total lipids in the formulation) and the vesicles remained stable in relation to their size up to 30 days of storage at 4°C. Release kinetics experiments revealed a decrease in the release of RVC when in the inclusion complex with HP-?CD and when encapsulated into the liposomes, relatively to free RVC, Citotoxicity assays in vitro, over cultures of 3T3 fibroblast cells showed that RVC was able to induce cell death in a concentration dependent manner and that this effect was partially reverted if cells were incubated with double-loading LUV:RVC:HP-?CD system. In vivo sensory block experiments (paw withdraw threshold to pressure in rats) showed a prolonged anesthetic effect for RVC in the ternary system (300 min) in comparison to free RVC (180min) and binary system LUV:RVC (240min). In general, pain relief effect of the double-loading system was longed about 1.6 times than that of free RVC and 1.3 times when compared to the liposomal binary system. The results obtained were important in the research, study and characterization of controlled release dosage forms and show changes on the release kinetics of RVC following the combined use of two carriers (EPC liposomes and HP-?CD) in a delivery system among its future use in clinical practice / Mestrado / Bioquimica / Mestre em Biologia Funcional e Molecular

Abstract The rationale for automatically monitoring anesthetic drug effects on the central nervous system (CNS) is to improve possibilities to gain objective information on a patient's state and to adjust the medication individually. Although monitors have shown their usefulness in practice, there are still a number of unclear issues, especially with respect to the scientific foundations and validity of CNS monitoring techniques, and in monitoring the light hypnotic levels. Current monitors are, for example, often based on heuristics and ad hoc solutions. However, a quantitative index for anesthetic drug effect should have a sound relationship with observations and with the selected control variable. The research objectives are: (1) to explore propofol anesthetic related neurophysiological phenomena that can be applied in the automatic assessment of CNS suppression; (2) to develop a valid control variable for this purpose; (3) by means of digital signal processing and mathematical modeling, to design and to evaluate the performance of an index that correlates with the control variable. This dissertation introduces potentially useful neurophysiological phenomena, such as changes in phase synchronization between different EEG channels due to anesthesia, and painful stimulus evoked responses during the burst suppression. Furthermore, it refines the progression of the time-frequency patterns during the induction of anesthesia and shows their relation to the instant of unresponsiveness. The presented spontaneous and evoked EEG phenomena provide complementary information about the CNS functional suppression. Most significantly, the dissertation proposes a continuous and observation based control variable (r scale) and the means to predict its values by using EEG data. The definition of the scale provides a basis for anticipating the instant of the loss of consciousness. Additionally, the phase synchronization index as an indicator of drug effect is introduced. The approximate entropy descriptor performance is evaluated and optimised with a non-stationary signal recorded during the induction of anesthesia. The results open up opportunities to improve the preciseness, scientific validity and the interpretation of information on the anesthetic effects on CNS, and therefore, to increase the reliability of the anesthesia monitoring. Further work is needed to extend and verify the results in deep anesthesia.

Bakgrund Barn som genomgår vaccination enligt allmänt vaccinationsprogram upplever smärta under injektioner. Smärtlindrande metoder som bedövningskräm och sötningsmedel finns, men används inte rutinmässigt. Detta utgör ett onödigt lidande för dessa barn. Syfte Syftet är att undersöka om bedövningskräm alternativt sötningsmedel, ensamt eller i kombination med andra interventioner, kan minska smärtresponsen hos barn mellan 0–6 år i samband med vaccination enligt allmänt vaccinationsprogram. Metod För att besvara studiens syfte gjordes en deskriptiv litteraturöversikt med kvantitativ ansats. Artiklar med RCT som metod kvalitetsgranskades, analyserades och syntetiserades till ett resultat. Resultat Resultatet visar att bedövningskräm respektive sötningsmedel minskar smärtresponsen hos barn som vaccineras enligt allmänt vaccinationsprogram. Bedövningskräm i kombination med amning var ännu mer effektivt än att använda antingen bara bedövningskräm eller bara amning. Vid jämförelse av sötningsmedel och amning pekar forskningen i olika riktningar. Slutsats Resultatet från denna litteraturöversikt visade att bedövningskräm och sötningsmedel kunde minska smärtresponsen hos barn vid rutinmässiga vaccinationer. Även amning kunde minska smärtan, och en kombination av bedövningskräm och amning minskade smärtan ytterligare. Andra interventioner som kunde minska smärtan var fysiskt tröstande metoder, kylspray ochatt suga på napp eller finger. Resultatet skulle kunna leda till ett ökat användande av dessasmärtlindrande metoder på BVC. / Background Children undergoing vaccination according to general immunization programs experience pain during injections. Analgesic methods such as anesthetic cream and sweetening agents are available but are not used routinely. This is an unnecessary suffering for these children. Aim The aim is to investigate whether anesthetic cream or sweetening agents, alone or in combination with other interventions, can reduce pain response in children between 0-6 years of age, during vaccination according to general immunization programs. Method To answer the purpose of the study, a descriptive literature review was done with a quantitative approach. Articles with RCT as a method were quality reviewed, analyzed and synthesized to a result. Results The results show that anesthetic cream and sweetener respectively reduce the pain response in children during vaccination according to general immunization programs. Anesthetic cream in combination with breastfeeding was even more effective than using either just anesthetic cream or just breastfeeding. When comparing sweeteners and breastfeeding, research points in different directions. Conclusion The results from this literature review showed that anesthetic cream and sweeteners could reduce the pain response in children during routine vaccinations. Breastfeeding could also reduce the pain, and a combination of anesthetic cream and breastfeeding could further reduce the pain. Other interventions that could reduce the pain were physically comforting methods, cooling spray and sucking on a pacifier or finger. The result could lead to an increased use of these painrelief methods at childcare centers.

Background: Bupivacaine is an amide type local anesthetic which is widely used for epidural anesthesia and nerve blockade in patients. However, local administration of bupivacaine could cause neuron injury showing transient neurologic symptoms. α-Lipoic acid (LA) was shown to protect nerve cells from substance-induced injury. We hypothesized that LA administration could attenuate bupivacaine-induced neurotoxicity. Methods: To evaluate our hypothesis, we treated mouse neuroblastoma N2a cells with LA 30 min before the cells were exposed to bupivacaine. We evaluated cellular injury by examination of cell viability, morphology changes, nuclear condensation, and Annexin V staining. We also examined the levels of intracellular reactive oxygen species (ROS) and activation of PI3K/Akt signaling pathway. In a separate experiment, we determined the effect of Akt inhibition on cell viability in the presence of LA and bupivacaine. Results: Bupivacaine treatment significantly induced cell injury as evidenced by decreased cell viability, increased nuclear condensation and Annexin V staining. Administration of LA significantly attenuated bupivacaine-induced cell injury. In addition, LA treatment increased the levels of phospho-Akt and phospho-GSK3β and attenuated bupivacaine decreased the levels of ROS. More significantly, pharmacological inhibition of Akt abolished the LA-induced protection from bupivacaine-caused cell injury. Conclusions: Our findings suggest that pretreatment of neuroblastoma cells with LA protected neural cells from bupivacaine-induced injury. The mechanisms involve activation of the PI3K/Akt signaling pathway.

Indiana University-Purdue University Indianapolis (IUPUI) / Voltage-gated sodium channels (VGSCs) are transmembrane proteins responsible for the initiation of action potentials in excitable tissues by selectively allowing Na+ to flow through the cell membrane. VGSC subtype Nav1.7 is highly expressed in nociceptive (pain-sensing) neurons. It has recently been shown that individuals lacking the Nav1.7 subtype do not experience pain but otherwise function normally. In addition, dysfunction of Nav1.7 caused by point mutations in the channel is involved in two inherited pain disorders, primary erythromelalgia (PE) and paroxysmal extreme pain disorder (PEPD). This indicates Nav1.7 is a very important component in nociception. The aims of this dissertation were to 1) investigate if the antipsychotic drug, trifluoperazine (TFP), could modulate Nav1.7 current; 2) examine changes in Nav1.7 properties produced by the PE mutation N395K including sensitivity to the local anesthetic (LA), lidocaine; and 3) determine how different inactivated conformations of Nav1.7 affect lidocaine inhibition on the channel using PEPD mutations (I1461T and T1464I) that alter transitions between the different inactivated configurations of Nav1.7. Standard whole-cell electrophysiology was used to determine electrophysiological and pharmacological changes in WT and mutant sodium currents. Results from this dissertation demonstrate 1) TFP inhibits Nav1.7 channels through the LA interaction site; 2) the N395K mutation alters electrophysiological properties of Nav1.7 and decreases channel sensitivity to the local anesthetic lidocaine; and 3) lidocaine stabilizes Nav1.7 in a configuration that decreases transition to the slow inactivated state of the channel. Overall, this dissertation answers important questions regarding the pharmacology of Nav1.7 and provides insight into the changes in Nav1.7 channel properties caused by point mutations that may contribute to abnormal pain sensations. The results of this dissertation on the function and pharmacology of the Nav1.7 channel are crucial to the understanding of pain pathophysiology and will provide insight for the advancement of pain management therapies.

Indiana University-Purdue University Indianapolis (IUPUI) / The cardiac voltage-gated sodium channel α subunit Nav1.5 generates the cardiac sodium current, which is essential for the initiation and propagation of the cardiac action potentials. Mutations of SCN5A, the gene that encodes Nav1.5, have been well documented to cause long-QT syndrome (LQTs) by disrupting channel inactivation and increasing late sodium current. Previous studies have revealed the importance of the intracellular loop region between transmembrane domain III and IV of sodium channel α subunit in regulating the fast inactivation. A recent clinical case study reported an infant patient with LQTs carrying a phenylalanine (F) deletion at amino acid 1486 of the Nav1.5 channel. This study reported that the patient showed severe cardiac arrhythmia reflected as LQTs and subsequent ventricular tachycardia, which was refractory to antiarrhythmic drug lidocaine treatment. Therefore, it was hypothesized that the deletion of F1486 on Nav1.5 would substantially alter electrophysiological properties of the channel and reduce the potency of lidocaine on sodium channel. Using HEK293 cells and neonatal rat cardiomyocytes, the F1486del channel was functionally characterized by whole-cell patch clamp techniques. Studies revealed that the deletion of F1486 causes a combination of changes including a loss-of-function alteration reflected as a substantial reduction of peak current density and a number of gain-of-function alterations including reduced channel inactivation, substantial augmentation of late sodium current, and an increase in ramp current. In addition, lidocaine sensitivity was dramatically reduced. By contrast, the voltage for half maximal activation (V1/2) and the time constant for channel deactivation for the F1486del channel were identical to the wild type channels. Using neonatal rat cardiomyocytes, we were able to study the functional consequence of F1484del on action potential duration (APD). Cardiomyocytes expressing F1486del channel have substantial APD prolongation and prominent spontaneous early afterdepolarizations, which likely underlie the subsequent LQTs in the patient. Taken together, despite the reduction in peak current density, the substantial gain-of-function changes are sufficient to cause the APD prolongation, which is a prominent characteristic of LQTs. These findings provide knowledge for understanding the relationships between sodium channel structure, pharmacology and the physiological consequence of sodium channel mutations that underlie LQT3.

The perioperative use of regional anesthesia and local anesthetics is part of almost every anesthesiologist’s daily clinical practice. Retrospective analyses and results from experimental studies pointed towards a potential beneficial effect of the local anesthetics regarding outcome—i.e., overall and/or recurrence-free survival—in patients undergoing cancer surgery. The perioperative period, where the anesthesiologist is responsible for the patients, might be crucial for the further course of the disease, as circulating tumor cells (shed from the primary tumor into the patient’s bloodstream) might form new micro-metastases independent of complete tumor removal. Due to their strong anti-inflammatory properties, local anesthetics might have a certain impact on these circulating tumor cells, either via direct or indirect measures, for example via blunting the inflammatory stress response as induced by the surgical stimulus. This narrative review highlights the foundation of these principles, features recent experimental and clinical data and provides an outlook regarding current and potential future research activities.

No description available.