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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.

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Master of Science / Department of Clinical Sciences / Elizabeth Davis / Differences in pharmacokinetics and drug disposition exist between young and adult animals which become especially important for drugs with a narrow therapeutic index. While the pharmacokinetics and plasma concentrations of intravenous lidocaine have been studied in adult horses, determination of the disposition in foals is necessary before appropriate clinical use can be determined. This study examined the disposition of intravenous lidocaine in healthy (phase I) and hospitalized (phase II) foals. Phase I consisted of 6 healthy 4-10 week old foals administered a 6-hour intravenous lidocaine infusion. Phase II consisted of 8 hospitalized foals (2-136 days old) administered intravenous lidocaine. A bolus (1.3 mg/kg) of lidocaine was administered intravenously to all foals followed by a 50 µg/kg/min infusion. Plasma lidocaine and monoethylglycinexylidide (MEGX) concentrations were determined. In phase I, plasma lidocaine concentrations remained below the suggested adult target range of 1-2 µg/mL with MEGX concentrations approximately half that of the parent drug. Total body clearance of lidocaine was 72.2 ± 7.8 mL/min/kg, elimination half-life (t₁/₂) was 26.3 ± 3.7 min, peak concentration (C[subscript]m[subscript]a[subscript]x) was 0.79 ± 0.07 µg/mL, and the volume of distribution (V[subscript]d) was 1.8 ± 0.4 L/kg. The C[subscript]m[subscript]a[subscript]x for MEGX was 0.36 ± 0.11 µg/mL, t₁/₂ was 60 ± 6 min and time to peak concentration (T[subscript]m[subscript]a[subscript]x) was 279.6 ± 90.3 min. In phase II, the severely compromised foals that were eventually euthanized had the largest fluctuations in plasma lidocaine and MEGX concentrations; foals that were discharged from the hospital had plasma concentrations below the target adult range similar to foals in phase I. In conclusion, despite low plasma lidocaine concentrations, the clinical benefits observed in foals may be due to the presence of metabolites. Further research in a larger population of unhealthy foals is required before comprehensive dosing recommendations can be made.

Purpose: The purpose of this study is to examine the pain response experienced by children undergoing simple tooth extractions using 2% Lidocaine injection versus Oraqix topical anesthetic gel. Methods: This study is being conducted at VCU pediatric dentistry clinic. The sample size will consist of 15 children ages 7-12 undergoing a simple extraction procedure. Each participant is randomly assigned to one of two groups, the lidocaine injection group or the Oraqix topical group. The pain level will be measured at four key events during the procedure. The first event will evaluate the pain at baseline. The second event will measure pain during the anesthetic injection or Oraqix topical gel application. The third event will record the response after the tooth has been extracted and the final event will evaluate pain five minutes post operatively. The children are asked to rate their pain using the Facial Pain Scale after all four events. The dentist and an independent observer watching a video of the extraction will also examine and rate the pain responses of each child at each of the four events. Results: The first two participants received lidocaine injection and experienced some pain upon injection. This pain was supported by what the dentist rated as well. One child felt pain on extraction and the other felt nothing. The dentist rated both children as feeling pain. The Oraqix child felt nothing upon application but felt pain during the extraction and post-operatively. The dentist rated the child as feeling nothing during the entire procedure. Conclusions: It appears that the lidocaine injection group’s pain rating matches the pain rating given by the dentist. The Oraqix patient experienced no pain upon application, but did feel pain upon extraction and five minutes post-op. The dentist’s rating contradicted this by rating the child as feeling no pain through the entire procedure. This study is limited by the number of participants and needs more patients to further evaluate other children’s pain responses.

Introdução: Este estudo prospectivo, randomizado, duplo-cego investigou, em valvopatas, alterações hemodinâmicas durante o tratamento odontológico com o uso do anestésico local contendo adrenalina e sem a mesma. Métodos: O estudo foi conduzido na Unidade de Odontologia do Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (Brasil 2004-2005). Os pacientes foram alocados em dois grupos através de tabela de números aleatórios: LSA (lidocaína a 2% sem adrenalina, n= 31, 42.2 ± 10.3 anos) e LCA (lidocaína a 2% com adrenalina 1:100.000, n= 28, 40.3 ± 10.9 anos). O volume anestésico foi registrado. Um monitor multiparamétrico DIXTAL (São Paulo- Brasil) registrou os valores da pressão arterial sistêmica, freqüência cardíaca, saturação de oxigênio e traçado eletrocardiográfico. Registrou-se também o volume anestésico aplicado em cada procedimento realizado. Resultados: 22 homens e 37 mulheres foram incluídos. Valores da pressão arterial sistêmica, freqüência cardíaca e saturação de oxigênio, antes, durante e após administração da anestesia local não mostraram diferenças estatísticas entre os dois grupos (P > 0.05). Arritmias observadas em alguns pacientes antes do início do tratamento odontológico não sofreram alterações de morfologia ou gravidade após injeção anestésica. Relatos de dor durante a realização do procedimento odontológico foram mais freqüentes no grupo LSA com conseqüente aumento no volume de anestésico local administrado. Conclusão: lidocaína 2% com adrenalina 1:100.000 mostrou maior eficácia anestésica em comparação com a lidocaína 2% sem adrenalina sem causar alterações hemodinâmicas em pacientes portadores de valvopatias. / Introduction: This prospective, randomized double-blinded study investigated hemodynamic changes in valvular cardiac patients during dental treatment with the use of a local anesthesia containing epinephrine. Methods: The study was conducted in the Dental Department of the Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (Brazil 2004- 2005). Patients were allocated into two groups through an aleatory numbered table: PL (plain 2% lidocaine, n= 31) and LE (2% lidocaine with 1:100.000 epinephrine, n= 28). The anesthetic amount was registered. DIXTAL monitor (São Paulo- Brazil) captured blood pressure, heart rate, oxygenation and electrocardiogram records. Results: 22 men and 37 women were included (LE age 40.3 ± 10.9 and PL age 42.2 ± 10.3). Blood pressure, heart rate and pulse oximetry values before, during and after local anesthesia injection did not show any difference between the two groups (P > 0.05). Any arrhythmias observed in some patients prior to dental anesthesia did not suffer alterations of shape or gravity after it. Complains of pain during dental procedure were more often in the PL group with a higher amount of local anesthesia needed. Conclusion: 2% lidocaine with epinephrine 1:100.000 showed a superior anesthetic efficiency without leading to hemodynamics changes in patients with cardiac valvular compromise.

O jejum prolongado, utilizado como preparação para a gastroscopia em equinos, não proporciona um completo esvaziamento gástrico. Para avaliar a eficácia da lavagem gástrica e de três procinéticos na preparação para o exame gastroscópico, foram utilizados seis equinos adultos, sem alterações clínicas, que passaram por quatro horas de jejum e quatro protocolos: G1- lavagem gástrica; G2- betanecol (0,04mg/kg VO); G3- metoclopramida (0,12mg/kg SC) e G4- lidocaína (1,3mg/kg IV). Após a lavagem ou administração de uma das medicações (duas horas após o betanecol ou uma hora após as demais) foi realizada a gastroscopia. As avaliações foram feitas por um profissional que conhecia o grupo experimental dos equinos (P1) e outro que desconhecia a informação (P2), sem diferença estatística entre suas avaliações. Em todos os exames foi observado conteúdo gástrico, com predominância de conteúdo líquido no G1 e de sólido a misto nos demais. Para o P1, a média de visualização da mucosa aglandular foi 95,0±0,0% no G1, 74,1±17,4% no G2, 88,3±4,0% no G3 e 90,0±6,3% no G4, com diferença estatística entre G1 e G2 e entre G2 e G4. Para a mucosa glandular, a média de visualização foi de 45,8±8,6% no G1, 29,1±10,6% no G2, 31,6±10,3% no G3 e 34,1±9,1% no G4, com diferença estatística entre G1 e G2. Na classificação geral, o melhor exame foi o do G1 e o pior o do G2. Conclui-se que a lavagem gástrica pode ser usada como preparação para o exame gastroscópico em equinos. De acordo com o protocolo testado, o betanecol é o menos indicado para esta finalidade. Embora sejam necessários mais estudos, o uso de procinéticos antes do exame gastroscópico em equinos mostra-se promissor, com resultados semelhantes aos observados com períodos de jejum mais prolongados. / Prolonged fasting in horses (12 - 24 hours), as a preparation for gastroscopy, does not permit complete gastric emptying. Six healthy adult horses were used to evaluate the efficacy of gastric lavage and the use of three prokinetics. Horses with held from feed for four hours were submitted to four protocols: G1 - gastric lavage; G2 - bethanechol (0,04mg/kg PO); G3 - metoclopramide (0,12mg/kg SC) and G4 - lidocaine (1,3mg/kg IV). Gastroscopy was performed: immediately (G1); two hours following admnistration (G2); one hour following administration (G3 and G4). To reduce bias gastric examination was conducted by two professionals: the first (P1), aware of the protocol and the second (P2) was kept blind. No significant difference was seen between them. Gastric content was predominantly liquid in G1 and solid or mixed in the other three groups. The average observation of the aglandular mucosa of P1 was: 95,0±0,0% for G1, 74,1±17,4% for G2, 88,3±4,0% for G3 and 90,0±6,3% for G4. Significant difference was observed between G1 and G2 and between G2 and G4. Observation of the glandular mucosa was: 45,8±8,6% for G1, 29,1±10,6% for G2, 31,6±10,3% for G3 and 34,1±9,1% for G4. Groups G1 and G2 were significantly different. Considering all classification criteria, G1 and G2 protocols permitted respectively the best and worst evaluations. It was concluded that gastric lavage is indicated for preparing horses for gastroscopy, the bethanechol protocol here tested is the least indicated. Although more studies are necessary, the use of prokinectics prior to gastroscopy in horses seems promising, producing results similar to those observed in long fasting periods.

Os opióides de curta duração e de alta potencia analgésica, como o fentanil, embora amplamente utilizados em cães, ainda são pouco empregados pela via epidural nesta espécie. O presente estudo teve como objetivo avaliar a associação do anestésico local lidocaína à morfina ou à combinação morfina-fentanil, pela via epidural. Foram analisados os efeitos cardiovasculares, respiratórios bem como a analgesia pós-operatória, em cães submetidos a cirurgia de joelho. Para tanto, 24 animais da espécie canina foram aleatoriamente divididos em 2 grupos. Todos os animais receberam acepromazina (0,05 mg/kg), foram induzidos com propofol (5 mg/kg) e mantidos em anestesia inalatória. Os animais do GRUPO I foram tratados com lidocaína (5mg/kg) associada a morfina (0,1mg/kg) e os animais do GRUPO II receberam, pela via epidural, a combinação lidocaína-morfina-fentanil, sendo este último na dose de 2µ/kg. Parâmetros como frequência cardíaca, respiratória, pressão arterial (sistólica, média e diastólica) foram mensurados, bem como pH e gases sanguíneos. Para a avaliação da analgesia foram utilizadas a escala Analógica-visual (EAV), a escala proposta por Lascelles, 1994 e a termoalgimetria. Amostras de sangue foram coletadas para posterior dosagem de cortisol e Interleucina-06. O período de avaliação imediata foi de 06 horas após a cirurgia, sendo os animais reavaliados no período de 24 horas após o procedimento. No tocante aos parâmetros cardiorrespiratórios os grupos se comportaram de maneira muito semelhante. Entretanto, pode-se observar que os animais tratados com a combinação lidocaína-fentanil-morfina apresentaram menor escore de dor quando avaliados pelas escalas do estudo no período pós-operatório. De fato verificou-se diferença significativa nos escores da EAV (p <0,05) nos tempos T180 e T360; na escala de Lascelles obteve-se diferença estatística nos tempos T180, T360 e T24h e na termoalgimetria houve diferença estatística nos tempos T180, T360 e T24h. A analgesia de resgate foi necessária em 3 animais do Grupo II, enquanto no Grupo I a necessidade desta medicação foi observada em 6 animais. Pode-se concluir, com os resultados obtidos, que a associação do fentanil no protocolo de anestesia epidural, promoveu adequada analgesia perioperatória, além de produzir um efeito sinérgico-residual, o que melhorou a analgesia pós-operatória, diminuindo a necessidade de analgesia de resgate. / Short duration opioids and high potency analgesics such as fentanyl, although widely used in dogs are seldom used for epidural anesthesia in this species. This study aimed to evaluate the association of lidocaine with morphine or morphine-fentanyl combination, epidurally. 24 dogs were randomly divided into two groups. All animals received acepromazine intramuscularlly (0.05 mg / kg), were induced with propofol (5 mg / kg) and maintained under inhalation anesthesia. The animals in group I were treated with lidocaine (5 mg / kg) combined with morphine (0.1 mg / kg) epidurally and the animals of group II received epidurally, the combination lidocaine-morphine-fentanyl, the latter at the dose of 2µ/kg. Parameters such as heart and respiratory rate, blood pressure (systolic, mean and diastolic), blood gases and pH were measured. For the assessment of analgesia were used visual-analogue scale (VAS), the scale proposed by Lascelles and thermoalgimetry. Blood samples were collected for later determination of cortisol and interleukin-06. The evaluation period was 06 hours after surgery, the animals were re-evaluated within 24 hours after the procedure. Except the cardiorespiratory parameters, the groups were similarly. However, was observed that animals treated with the combination lidocaine-fentanyl-morphine had lower pain scores in the postoperative period. In fact there were significant differences in VAS scores (p <0.05) at times T180 and T360; in Lascelles scores at times T180, T360 and T24h and there were no statistical diferences in thermoalgimetry at times T180, T360 and T24h. The rescue analgesia was required in three animals in Group II, and six animals in Group I. It can be concluded that the combination of fentanyl in epidural anesthesia protocol, promoted adequate perioperative analgesia, producing synergistic and residual effects, which improved postoperative analgesia.