Thesis (M.S.)--University of Michigan, 1996. / Includes bibliographical references.

Thesis (Ph.D.)--University of Florida, 2004. / Typescript. Title from title page of source document. Document formatted into pages; contains 136 pages. Includes Vita. Includes bibliographical references.

Orientador: Gilberto de Nucci / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-11T00:01:00Z (GMT). No. of bitstreams: 1 Gil_AnaCeciliaMontes_D.pdf: 1050627 bytes, checksum: 72f41a4bdcddba6633b8b082cc0ee0a0 (MD5) Previous issue date: 2007 / Resumo: No presente trabalho, foram avaliados os efeitos farmacológicos do Aspirinato de atenolol (AA T) uma potencial pró-droga mútua resultado da combinação química entre ácido acetilsalicílico (AAS) e atenolo!. As propriedades do AA T como droga antitrombótica foram avaliadas na inibição da agregação plaquetária estimulada in vitro e na inibição da produção de tromboxano estimulada ex-vivo em sangue de animais tratados. Por outro lado, o AA T foi avaliado como droga anti-hipertensiva no modelo de hipertensão induzida pela inibição crônica da síntese de NO em ratos, e seus efeitos como antagonista dos adrenoceptores 13 foram avaliados na resposta cronotrópica ao isoproterenol em átrios isolados. Foi determinada a estabilidade metabólica em diferentes frações subcelulares hepáticas, plasma e soluções tampão de diferente pH, assim como seu perfil farmacocinético após administração endovenosa. Também foram avaliadas as propriedades ulcerogênicas gástricas e o potencial mutag'ênico através do Teste de Ames. Os resultados mostraram na avaliação do efeito antiplaquetário, que o AA T não inibiu a agregação plaquetária induzida pelo ácido araquidônico em nenhuma das concentrações testadas e apesar d~ ini~ir significativamente a produção de tromboxano estimulada ex-vivo em rat6s e na maior dose testada em camundongos, este efeito inibitório foi menor quando comparado com o AAS. O acoplamento com AAS, na molécula de AAT, suprimiu os efeitos do atenolol como antagonista dos adrenoceptores 13. Igualmente, o AA T não reduziu a freqüência cardíaca e pressão arterial após tratamento oral crônico de ratos hipertensos, estes resultados indicaram que não houve liberação de atenolol desde a molécula de AA T. Na avaliação da estabilidade metabólica e farmacocinética, observamos que o AA T seguiu uma rápida e completa hidrólise no grupo orto-acetila, gerando salicilato de atenolol (SA T), este produto foi formado quando o AA T foi submetido à hidrólise plasmática (T% 7,6 min) e aquosa (T% 56,5; 24,9 e 6,4 nos pH 2,5; 7,4 e 9.4 respectivamente) metabolização hepática e também após administração endovenosa em cães. o salicilato de atenolol formado a partir do AA T nas frações subcelulares hepáticas foi metabolizado apenas na fração microssomal gerando dois metabólitos hidroxilados em posições diferentes na molécula, a formação destes metabólitos foi dependente do tempo e paralela à cinética de desaparecimento do SAT. Após administração endovenosa, concentrações de AA T não foram detectadas em plasma. Atenolol e ácido salicílico (AS), foram liberados a partir da molécula de SAT (após clivagem da ligação éster benzoato) em concentrações significativamente menores às concentrações obtidas nos grupos tratados com AAS ou atenoloL A ASC0-24h calculada para o AS no grupo tratado com AA T correspondeu ao 0,71% da área calculada para o grupo que recebeu AAS. Similarmente, a ASC0-24h do atenolol no grupo tratado com AA T correspondeu a 1,44% da área calculada para ~ grupo tratado com atenolol. O AA T e seu principal metabólito SA T, não apresentaram propriedades mutagênicas, obtendo-se resultados negativos no Teste de Ames. O AA T produziu lesões na mucosa gástrica significativamente menores às observadas com o AAS após administração oral aguda e crônica durante 4 semanas. Devido às relevantes diferenças obtidas entre o AA T, AAS ou atenolol na caracterização farmacológica e farmacocinética, concluímos que o AA T não atua como pró-droga mútua de AAS e atenolol, e modificações futuras na molécula devem ser consideradas com a finalidade de desenvolver aspirinatos cardioativos com potencial efeito farmacológico / : In this study, we evaluated the pharmacologica/ effects of Atenolol Aspirinate (A TA) a potential mutual prodrug that resulted of the chemical combination between Acetyl Salicylic Acid (ASA) and atenolo!. The properties of ATA as anthithrombotic drug were evaluated on the inhibition of in vitro stimulated platelet aggregation and on the inhibiton of ex-vivo stimulated thromboxane production in blood from treated animais. Additionally, A TA was evaluated as an antihypertensive drug on the hypertension induced by chronic inhibition of NO in rats, its effects as antagonist of f3 adrenoceptors were evaluated in the chronotropic response to isoproterenol in isolated atria. The metabolic stability was determined in different hepatic subcellular fractions, plasma and buffer solutions as well as its pharmacokinetic profile after intravenous administration. The gastric ulcerogenic properties and mutagenic potencial, using the Ames test, were toa evaluated. In the evaluation of the antiplatelet effect, our results showed that ATA had no effect on arachidonic acid induced platelet aggregation. Although it inhibited significantly the ex-vivo stimulated thromboxane production in rats and in the highest tested dose in mice, ATA showed lower inhibitory effect than ASA. The coupling with ASA, in the ATA mOlecule, abolished the atenolol effects as antagonist of f3 adrenoceptors. In the sa~e"way, ATA had no effect reducing the heart rate and blood pressure after chropic oral treatment of hypertensive rats, these results showed that atenolol was not liberated from ATA molecule. In the evaluation of the metabolic stability and pharmacokinetics, we observed that ATA followed a rapid and complete hydrolysis at the o-acetyl group, generating atenolol salicylate (A T8), this product was formed when ATA was submitted to plasma hydro/ysis (T% 7;6 min) and aqueous hydrolysis (T% 56,5; 24,9 and 6,4 at pH 2,5; 7,4 and 9.4 respectively), hepatic metabolization and after intravenous administration to dogs. ATA was biotransformed to A TS in ali hepatic subcellular fractions, then A TS was metabolized only in the microsomal fraction generating two hydroxylated metabolites, whose formation was time dependent and parallel to the kinetics of A TS consumption. After intravenous administration, concentrations of A TS instead ATA were found in plasma dog samples, SA and atenolol were originated from cleavage of A TS molecule at the benzoate ester linkage, generating concentration levels to a lesser extent than levels found after treatment with an equimolar dose of the drugs ',nóiviõua / Doutorado / Doutor em Farmacologia

Introduction: Advances in modern medicine have enabled early detection of infective diagnosis through blood cultures and echocardiography, which have been standardized by the widely accepted Modified Duke Criteria and have enabled rapid administration of antibiotics. As a consequence, the well-discussed and often variable clinical findings have become less common and have relegated to minor criteria in diagnosis. Fever is the single most common presenting symptom, whereas more specific signs such as petechiae may be seen in only 20-40% of patients. Even more rare are the pathognomonic Janeway lesions, Roth spots, and Osler nodes. Here we present a case in which early diagnosis was established through minor criteria manifest upon physical exam, and we highlight the timely insight provided from physical exam. Case: A 29-year-old man was admitted to the hospital for altered mental status, fever, vomiting, diarrhea, and vertigo. His past medical history included IV drug abuse, thrombotic thrombocytopenia, Hepatitis C, and seizures. Upon admission, his encephalopathy progressed rapidly, and he was mechanically ventilated and started on hemodialysis. Blood cultures grew Methicillin sensitive Staphylococcus aureus and Elizabethkingia meningosepticum and susceptibilities were attained. Echocardiography showed 3.1 cm vegetation on the aortic valve. By the Modified Duke Criteria, the diagnosis of infective endocarditis was confirmed. Discussion: The increasing incidence of complex infective endocarditis—including polymicrobial infection as well as the increasing resistance to antibiotic therapy—poses challenges to the rapid assessment and treatment necessary to mitigate the multi-organ involvement and the devastating consequences of septic emboli. Developments in medical technology have expedited both the diagnosis and treatment of infective endocarditis, which has subsequently decreased the extent and frequency of classical signs. Nonetheless, this case illustrates the unavoidable vitality of the physical exam, because this patient’s quick and clear presentation enabled diagnosis solely through physical exam. Empiric antibiotic treatment was started promptly and subsequently adjusted based on culture and susceptibilities.

Myocardial infarction (MI), often referred to as a heart attack, is a serious health issue in the United States. There is a well-documented link between MI and major depressive disorder (MDD), with a high incidence of MDD occurring after an MI. Overlapping pathologies have been observed within the hippocampus of the brain in animal models of MI and depression. These observations suggest that pathobiological cross-talk between the heart and brain could have a role in the etiology of MDD that occurs after an MI. Spinal cord stimulation (SCS) has previously been shown to have both cardioprotective and neuroprotective effects post-MI, and hence may protect individuals from developing depression post-MI. In this study, we examined the potential biochemical mechanisms that might underlie the neuroprotective actions of SCS following MI. Brain tissues were obtained from three groups of canines: sham-operated animals, animals subjected to experimental myocardial infarction/mitral regurgitation (MI/MR), and animals subjected to MI/MR that were simultaneously administered SCS. The whole hippocampus and hippocampal dentate gyrus were dissected from frozen brains. Quantitative endpoint-PCR and RT-qPCR techniques were employed to measure select biochemical mediators of neuroprotection, i.e. adenosine A2A receptor, ghrelin, and ghrelin receptor expression in hippocampal samples. SCS induced a significant decrease in A2A receptor expression and a dramatic increase in ghrelin expression in MI/MR canines as compared to the MI/MR group without SCS. These findings suggest that adenosine receptors and ghrelin may play a biochemical role in SCS-induced neuroprotection of the hippocampus. Understanding the neuroprotective actions of SCS has the potential to aid the development of new treatments or preventative measures for depression following a heart attack.

Stroke is a leading cause of serious long-term disability in the United States. The neurological insult following a stroke may leave the survivor with a chronic illness encompassing a lifetime of recovery. Recovery for the stroke survivor entails more than the return of function. A synopsis of the literature indicates that there are three domains of stroke recovery: physical, psychological, and social. There are six categories that comprise the three domains: cognition, function, health perception, self-concept, relationships, and role change. Stroke is a multifaceted and complex disease. Individual aspects of stroke recovery do not occur in isolation and cannot be separated from one another. In the future, studies involving the integration of the domains of stroke recovery are needed to understand the interactive processes that support recovery.

No description available.

Cardiovascular diseases (CVDs) are the leading causes of death globally. Recent studies show that CVDs are one of the major causes of morbidity and mortality in people living with HIV/AIDS (PLWHA). HIV symptoms arise as our body tries to fight off the virus but as our immune system weakens as CD4 T cells are targeted. As these T cells diminish in quantity, it leaves the body susceptible to other infections, which is why ARV drug treatment is used. NRTIs are common drug treatments for these viruses as they inhibit the enzyme reverse transcriptase. Unfortunately, these NRTIs are known to cause dilated cardiomyopathy, while protease inhibitors are known to cause increased cardiovascular mortality and heart failure. Treatment of these side effects is crucial since millions of people are on these ARV drug treatments. Therefore, we analyzed RNA sequencing data of neonatal ventricular cardiomyocytes treated with ARV's to determine the regulatory pathway of upregulated/downregulated genes associated with the ARV treatment. It was seen that many of the upregulated genes such as PSEN and PSENEN2 were mitophagy control genes, and most of the downregulated genes were from complexes I-IV of the oxidative phosphorylation chain. Based on the genomic data, we hypothesized that increasing the expression of these downregulated genes could potentially reduce mitochondrial dysfunction and bring back the functionality of the complexes. Research has shown that rapamycin treatment can potentially reduce the effects of mitochondrial dysfunction, and tests were conducted to see how much expression changed. Another indicator of mitochondrial dysfunction is the detection of ROS, and this project aims to see how rapamycin will affect the presence of these ROS.

No description available.

University of Macau / Faculty of Science and Technology / Department of Electrical and Electronics Engineering