Thesis (Ph. D.)--West Virginia University, 2004. / Title from document title page. Document formatted into pages; contains xiii, 119 p. : ill. Vita. Includes abstract. Includes bibliographical references (p. 95-118).

Thesis (Ph. D.)--University of Texas at Austin, 2004. / Supervisors: Serrine S. Lau and Shawn B. Bratton. Vita. Includes bibliographical references.

Thesis (Ph. D.)--Michigan State University. Dept. of Biochemistry and Molecular Biology, 2007. / Title from PDF t.p. (viewed Aug. 17, 2009). Includes bibliographical references (p. 114-125). Also issued in print.

Thesis (M.S.)--West Virginia University, 2009. / Title from document title page. Document formatted into pages; contains viii, 61 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 39-52).

Thesis (M.S.)--West Virginia University, 2000. / Title from document title page. Document formatted into pages; contains viii, 58 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 42-56).

Thesis (doctoral)--Freie Universität Berlin, 1979.

Thesis (Ph. D.)--University of Texas at Austin, 2005. / Vita. Includes bibliographical references.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / 1,4-Cineol à um monoterpeno Ãter amplamente distribuido, o qual à um dos constituintes responsÃveis pelo odor do limÃo. O objetivo deste trabalho foi avaliar o efeito gastroprotetor de 1,4-Cineol (CIN 100 e 200 mg/Kg) nos modelos de lesÃo induzidas por etanol ou piroxicam em camundongos e, posteriormente, investigar os possÃveis mecanismos de aÃÃo farmacolÃgica envolvidos nesta aÃÃo. A administraÃÃo oral de 1,4-cineol 200 mg/Kg foi capaz de proteger a mucosa gÃstrica dos danos causados pelo etanol (0,2 ml/amimal, v.o). Esta gastroproteÃÃo foi tambÃm avaliada microscopicamente mostrando que CIN (200 mg/Kg, p.o.) diminuiu o edema na submucosa, o infiltrado inflamatÃrio e a hemorragia. 1,4-Cineol (100 e 200 mg/Kg, v.o.) tambÃm reduziu significantemente as lesÃes gÃstricas causadas pelo piroxicam (30 mg/Kg, s.c.). O mecanismo de gastroproteÃÃo de CIN foi examinado na dose de 200 mg/Kg no modelo de lesÃo gÃstrica induzida por etanol em camundongos. Nos animais prÃ-tratados com L-NAME (10 mg/Kg, i.p.), um inibidor da oxido nÃtrico sintetase, com glibenclamida (10 mg/Kg i.p.), uma substÃncia que bloqueia os canais de potÃssio ATP-dependente, ou com capsazepina (5 mg/Kg i.p.) um antagonista dos receptores vanilÃides TRPV-1, o efeito gastroprotetor de CIN nÃo foi significantemente inibido por estes mecanismos. Por outro lado, o efeito gastroprotetor de CIN foi revertido em animais prÃ-tratados com indometacina (10 mg/Kg v.o.), um inibidor nÃo seletivo da ciclooxigenase, demostrando que hà uma ativaÃÃo desta enzima no mecanismo de aÃÃo de CIN. Este trabalho avaliou tambÃm o mecanismo antioxidante de CIN como um agente gastroprotetor contra as lesÃes induzidas pelo etanol. Sob as nossas condiÃÃes experimentais, o modelo de induÃÃo pelo etanol causou mudanÃas nos sistema antioxidante da mucosa gÃstrica dos camundongos, como a diminuiÃÃo dos nÃveis de grupamentos sulfidrila (GSH) e da atividade da superÃxido dismutase (SOD), tambÃm mostrou um aumento da atividade da mieloperoxidade (MPO) e uma concentraÃÃo aumentada das espÃcies que reagem com o Ãcido tiobarbitÃrico (TBARS) como Ãndice de peroxidaÃÃo lipÃdica (LPO). 1.4-Cineol (200 mg/Kg, v.o.) no modelo de Ãlcera por etanol, nÃo interferiu na concentraÃÃo do GSH, mas permitiu a restauraÃÃo da atividade normal de SOD, nÃveis normais de LPO e de atividade da MPO. Estes dados sugerem que CIN 100 e 200 mg/Kg promovem gastroproteÃÃo contra lesÃes induzidas pelo etanol e/ou piroxicam em camundongos nos quais o mecanismo de aÃÃo incluem o envolvimento de prostaglandinas endÃgenas e uma potente atividade antioxidante. / 1,4-Cineole is a widely distributed monoterpene ether, which is one of the flavor constituents of lime juice. The aim of this work was to evaluate the gastroprotective effect of 1,4-Cineole (CIN 100 and 200 mg/Kg) on ethanol or piroxicam-induced lesions in mice and further investigate the possible pharmacological mechanisms involved in this action. The oral administration of 1,4-cineole 200 mg/kg was able to protect the gastric mucosa from ethanol injury (0.2 ml/animal, p.o.). This gastroprotection was also evaluated microscopically showing that CIN (200 mg/kg, p.o.) decreased the cell loss in the mucosa, submucosal edema, inflammatory infiltration and hemorrhage. 1,4-Cineole (100 and 200 mg/kg, p.o.) also reduced significantly the gastric lesions induced by piroxicam (30 mg/kg, s.c.). Gastroprotective mechanism of CIN was examined in the dose of 200 mg/kg, in the model of gastric lesions induced by ethanol in mice. In animals pretreated with L-NAME (10 mg/kg, i.p.), an inhibitor of nitric oxide synthase, or with glibenclamide (10 mg/kg, i.p.), a drug that blocks ATP-dependent potassium channels, or with capsazepine (5 mg/kg, i.p.), an antagonist of vanilloid receptor TRPV-1, the gastroprotective effect of CIN was not inhibited significantly, suggesting that the effect of CIN is not involved with this mechanisms. Otherwise, the gastroprotective effect of CIN (200 mg/kg, p.o.) was reverted in animals pretreated with indomethacin (10 mg/kg, p.o.), a nonselective inhibitor of cyclooxygenase, demonstrating that there is activation of these enzymes in the mechanism of action of CIN. This work also evaluated the antioxidant mechanism of CIN as gastroprotective agent against ethanol-induced lesions. Under our experimental conditions, the model of induction of ethanol injury caused changes in the antioxidant system of the gastric mucosa of mice as the decrease in the levels of sulfhydryl groups (GSH) and activity of superoxide dismutase (SOD), also showed increased activity of myeloperoxidase (MPO) and high concentration of species that react with thiobarbituric acid (TBARS) as index of lipid peroxidation (LPO). 1,4-Cineole (200 mg/kg, p.o.) in the model of ethanol did not interfere with the concentration of GSH, but allowed the restoration of normal SOD activity, normal levels of LPO and MPO activity. The data suggest that CIN 100 and 200 mg/kg promote gastroprotection against lesions induced by ethanol or piroxicam in mice whose mechanisms include the involvement of endogenous prostaglandins and potent antioxidant activity.

The antiarrhythmic actions of prostaglandins were first investigated using arrhythmias associated with cardiac ischemia in the dog and the rat. These studies were followed by investigations of the possible mechanisms of action, using rat heart tissue in intact, isolated, and cell culture preparations. Preliminary experiments in the dog revealed that prostaglandins E₂ and F₁α markedly reduced the number of premature ventricular contractions occurring within the first 25 minutes following coronary artery ligation. Prostaglandin E₂ or F₁α did not markedly alter the cardiovascular response to occlusion, making it unlikely that modulation of autonomic reflexes is a central factor in their antiarrhythmic action. Coronary ligation in the rat was used to compare the antiarrhythmic effectiveness of prostaglandins, lidocaine, and quinidine. Prostaglandins E₂, F₂β and quinidine were found to be the most effective against arrhythmias occurring within the first 25 minutes following occlusion, reducing the number of PVCs by 40 to 50 per cent. The number of flutter episodes and the number of animals dying from arrhythmias was also markedly decreased by prostaglandins E₂ and F₂β and by quinidine. Prostaglandins F₁α and A₂, and lidocaine had lesser effects. Prostaglandins had only minor effects on blood pressure or heart rate, which were not related to their antiarrhythmic activity. No significant differences were found in the infarct size with prostaglandin treatment. The effects of prostaglandins E₂, A₂ and F₂β, quinidine, and lidocaine were tested in in situ rat heart on electrically-induced flutter threshold and maximum following frequency. Flutter threshold was not changed by any of the prostaglandins tested, although lidocaine increased and quinidine decreased it. Prostaglandins caused a dose-dependent change in maximum following frequency which was usually less than 10 per cent of control. Lidocaine produced a marked increase and quinidine a marked decrease in maximum following frequency. The slight depressive action of prostaglandins does not correlate with their antidysrhythmic actions. Prostaglandins of the E, A, and F series were found to have only minimal effects on rate and force in isolated rat hearts. However, both PGE₂ and PGF₂β, delayed the loss of contractile force with time at 10⁻⁷ M. All prostaglandins tested markedly increased coronary flow rate at 10⁻⁵ M. The effects on the beating behavior of cultured rat heart cells of fourteen prostaglandins of the A, B, D., E, and F series were investigated in cultured rat heart cells. With the exception of PGF₂α, which produced a chronotropic response, prostaglandins had limited direct action in cultured rat heart cells. The effects of ouabain, calcium, potassium, dinitrophenol, and Cyanea toxin, together with prostaglandins, lidocaine, and quinidine on cultured rat heart cells were also investigated. Ouabain and calcium increased rate and fibrillatory movements, while potassium and dinitrophenol slowed rate and decreased rhythmic beating. Cyanea toxin produced a characteristic series of arrhythmogenic changes which were also used to test for antiarrhythmic activity in cultured heart cells. Lidocaine and quinidine were effective only against cellular arrhythmias caused by high calcium concentration, and prostaglandins were effective only against dinitrophenol-induced arrhythmias, indicating that there is no over-all "protective" effect of prostaglandins in cell culture. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Unknown

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