Thesis(M.S.)--Auburn University, 2006. / Abstract. Vita. Includes bibliographic references.

Computational methods such as Molecular Dynamics (MD) simulations and Molecular Mechanics generalized Born surface area solvation (MM-GBSA) binding affinity calculations have been utilized to determine the binding modes and final binding affinities of small molecules that are known to interact with the heart sodium channel NaV1.5. Lidocaine, ranolazine, and flecainide are FDA approved arrhythmia drugs that are prescribed to patients in the event of heart disease. Here, we demonstrate the likely binding preferences and modes of action of all molecules with NaV1.5, the stability of the systems, and overall final binding affinities of the small molecules with the protein. To gain insights into the mechanisms of heart disease treatments, the MM-GBSA method was utilized to estimate the binding free energies of each molecule and pose to NaV1.5. The evaluation of the binding of small molecules to NaV1.5 contributes to enhancing our understanding of the underlying processes involved in heart disease treatments. The MM-GBSA approach provides a valuable tool for predicting and analyzing binding affinities, which can aid in the design and optimization of potential therapeutic compounds targeting NaV1.5.

No description available.

Previous studies in our laboratory have indicated that anesthetic block of neural activity at discrete sites within the limbic system, including the lateral hypothalamus and anterior cingulum bundle, causes a significant long-lasting analgesia during the formalin test. In this experiment, the local anesthetic lidocaine was microinjected into the dentate region of the hippocampus, an important limbic structure presumed to subserve the affective-motivational aspects of pain. The dentate gyrus is strategically situated at a point of convergence of widespread polysensory cortical input to the hippocampus, to allow modulation of cortical signals before they diverge into numerous limbic circuits. The results indicate that anesthetic block of the anterior region of the dentate gyrus produces analgesia in the rat during the formalin test. The analgesia produced by this procedure became apparent 30 minutes after regional block contralateral to the site of injury and persisted for the duration of the test period. These data provide further evidence that limbic forebrain structures are involved in pain and analgesia.

Thesis (Ph.D.) - James Cook University, 2003. / Typescript (photocopy) Bibliography: leaves 170-238.

Made available in DSpace on 2014-06-11T19:31:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2002-08-14Bitstream added on 2014-06-13T20:47:25Z : No. of bitstreams: 1 peiro_jr_dr_jabo.pdf: 1256820 bytes, checksum: ef439522328684a352aaeec5533665d3 (MD5) / A endotoxemia é a maior causa de mortalidade em eqüinos. O desencadeamento da endotoxemia clínica nos eqüinos é freqüente em decorrência da elevada sensibilidade desta espécie aos lipopolissacarídeos (LPS) da membrana externa de bactérias Gram-negativas liberados para a circulação durante o processo de choque séptico. Em resposta a esta agressão, o organismo libera substâncias pró-inflamatórias, as citocinas, na corrente circulatória. Dentre estas, o fator de necrose tumoral (TNF) tem sido implicado como a principal citocina no desencadeamento do quadro endotoxêmico dos eqüinos, sendo encontrados níveis elevados desta citocina, tanto séricos como peritoneais, em eqüinos com cólica. Os anestésicos locais, com o grupamento amídico em sua estrutura molecular, têm exibido ação inibitória sobre a resposta inflamatória por bloqueio da resposta funcional da atividade dos polimorfonucleares na liberação das citocinas. A lidocaína tem sido utilizada com sucesso, como anestésico local, na prevenção da vasoconstrição mesentérica durante o choque endotóxico em cães, assegurando proteção a esta agressão e demonstrando ser efetiva no tratamento de processos inflamatórios localizados no intestino delgado quando aplicada topicamente na serosa, ou na forma de bolus seguida de infusão contínua para o tratamento do ileus adinâmico. O principal objetivo deste ensaio foi estudar os efeitos da infusão contínua de lidocaína, sobre a resposta clínica, laboratorial e na resposta inflamatória, avaliados através da produção do TNF alfa, antes e após a injeção intraperitoneal de LPS em eqüinos, e avaliar a segurança desta dose de lidocaína neste modelo experimental. Com base nos achados clínicos e laboratoriais deste estudo, concluiu-se que a utilização da lidocaína após a administração do LPS foi mais efetiva na inibição da produção... / Endotoxemia is the major cause of mortality in horses. The onset of signs of endotoxemia in horses occurs frequently due to their sensitivity to the release of lipopolysaccharides (LPS) of the outer membranes of gram negative bacteria during the septic shock. In response, the host releases proinflammatory cytokines into the bloodstream. Tumor necrosis factor-a is an important cytokine released during the onset of endotoxemia and increased levels of TNF can be found in peritoneal fluid as in serum of colicky horses. Amide local anaesthetics have shown to inhibit polymorphonuclear release of cytokines. Lidocaine has also been shown to be an effective method for treating small intestine inflammatory conditions when injected as an intravenous bolus followed by continuous infusion or acting as a prokinetic drug during postoperative ileus. The main goal of this study was to evaluate the effects of lidocaine continuous infusion on clinical, laboratory responses and inflammatory response, in terms of TNF-alpha activity, before and after intraperitoneal injection of lypopolisaccharides in horses. Based on the clinical and laboratory findings in this study, we concluded that lidocaine administered after LPS was more effective in inhibiting TNF-alpha activity, although it was not able to avoid the increasing of inflammatory cells in the peritoneal fluid.

Orientador: Wilson Roberto Poi / Resumo: É proposta deste trabalho avaliar as propriedades da pasta de metronidazol a 10% e lidocaína a 2% em alvéolos dentários acometidos por alveolite, em 25 pacientes atendidos pelas disciplinas de Clínica Integrada e de Cirurgia e Traumatologia Buco-Maxilo-Facial da Faculdade de Odontologia de Araçatuba - Unesp. Os parâmetros estudados foram o controle da dor nos períodos de 1, 2 e 3 dias após a instituição do tratamento da alveolite diagnosticada. A terapêutica constou de anestesia local, cuidadosa limpeza cirúrgica e irrigação intra-alveolar com solução fisiológica, seguida da aplicação da pasta preenchendo todo o alvéolo. Com base nos resultados foi possível concluir que o emprego tópico da pasta proporcionou redução da dor e não proporcionou reações adversas locais e/ou sistêmicas ao material empregado fatos que indicam o seu uso como um medicamento eficaz sendo uma opção segura para o tratamento de feridas de extrações acometidas pela alveolite e dos desconfortos causados por esta patologia. / Abstract: It is proposal of this work to evaluate the properties of the ointment compounded by 10% metronidazole and 2% lidocaine in dental alveolus attacks for dry sockets, in 25 patients attended in discipline of Integrated Clinic and Surgery and Buco-Maxillo-Facial Traumatology of the Dentistry College of Araçatuba - Unesp. The studied parameter had been the control of pain, in the periods of 1, 2 and 3 days after the instituion of the treatment of the installed osteitis. The therapeutics were local anesthesia, careful surgery cleanness and alveolar irrigation with physiological solution, followed of the application of the ointment filling al the alveolus. Based on the results, it was possible to conclude that the topic use of ointment, produced positive results that recommend its use as an effective medice being a safe option on the treatment of wound extractions attacks harmed by dry socket and the discomforts caused for this pathology. / Mestre

The effect of inducing agents of cytochrome P-450 on the binding and metabolism of three local anaesthetic agents: lidocaine, mepivacaine and bupivacaine has been investigated. All three local anaesthetic agents bound to the type I binding site of cytochrome P-450, which is characteristic of substrate binding to cytochrome P-450, and stimulated the CO-inhibitable oxidation of NADPH. Lidocaine is shown to be metabolized by cytochrome P-450 to the products MEGX and acetaldehyde. The forms of cytochrome P-450 elevated with phenobarbital and/or pregnenolone-16α-carbonitrile were shown to play an important role in the binding of lidocaine to cytochrome P-450. Cytochrome P-448 did not appear to be involved in the binding of lidocaine to cytochrome P-450. These findings are supported by the ability of the inhibitors of cytochrome P-450 viz. metyrapone, SKF 525-A and CO:O₂ to inhibit binding of lidocaine to cytochrome P-450. No single form of cytochrome P-450 appears to preferentially metabolize lidocaine, but rather multiple forms of the enzyme appear to be involved in the metabolism of lidocaine. The phenobarbital inducible form of cytochrome P-450 appears to play a major role in the binding of mepivacaine to cytochrome P-450. Cytochrome P-450 in microsomes from rats pretreated with β-naphthoflavone and pregnenolone-16α-carbonitrile does not appear to have a significant role in the binding of mepivacaine to cytochrome P-450. All forms of cytochrome P-450 are involved in the metabolism of mepivacaine· to metabolic products as assessed by the oxidation of NADPH. However, the form of cytochrome P-450 induced by pretreatment of rats with phenobarbital may play a predominant role in the total metabolism of mepivacaine. Multiple forms of cytochrome P-450 appear to be involved in the binding and total metabolism of bupivacaine. As in the case of mepivacaine, the total metabolism of bupivacaine, as assessed by the oxidation of NADPH, may be predominantly catalyzed by the form of cytochrome P-450 found in microsomes from rats pretreated with phenobarbital. Partially purified cytochrome P-450 was found to bind lidocaine in a type I manner and, in the presence of the artificial electron donor H₂O₂, produce MEGX. This further supports the role of cytochrome P-450 in the in vitro metabolism of lidocaine. Hepatocytes were found to metabolize lidocaine to MEGX, indicating that lidocaine metabolism in vivo might well be mediated by cytochrome P-450.

No description available.

No description available.