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Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 464-475). Available also in a digital version from Dissertation Abstracts.

Indiana University-Purdue University Indianapolis (IUPUI) / Polypharmacy leads to increased risk of drug-drug interactions (DDI’s). In this dissertation, we create a database for quantifying fraction of metabolism (fm) of CYP450 isozymes for FDA approved drugs. A reproducible data collection protocol was developed to extract key information from publicly available in vitro selective CYP enzyme inhibition studies. The fm was then estimated from the curated data. Then, proposed a random control selection approach for nested case-control design for electronical health records (HER) and electronical medical records (EMR) databases. By relaxing the matching by case’s index time restriction, random control dramatically reduces the computational burden compared with traditional control selection approaches. Using the Observational Medical Outcomes Partnership gold standard and an EMR database, random control is demonstrated to have better performances as well. Finally, combining epidemiological studies and pharmacokinetic modeling with fm database, we detected and evaluated high-dimensional drug-drug interactions among thirty high frequency drugs. Multi-drug combinations that increased risk of myopathy were identified in the FAERS and EMR databases by a mixture drug-count response model (MDCM) model. Twenty-eight 3-way and 43 4-way DDI’s increased ratio of area under plasma concentration–time curve (AUCR) >2-fold and had significant myopathy risk in both databases. The predicted AUCR of omeprazole in the presence of fluconazole and clonidine was 9.35; and increased risk of myopathy was 6.41 (LFDR = 0.002) in FAERS and 18.46 (LFDR = 0.005) in EMR. We demonstrate that combining health record informatics and pharmacokinetic modeling is a powerful translational approach to detect high-dimensional DDI’s. / 2 years

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12918号 / 論医博第2093号 / 新制||医||1009(附属図書館) / 32128 / (主査)教授 羽賀 博典, 教授 中川 一路, 教授 上杉 志成 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Numerous studies have demonstrated the impact of organic cation (OCTs; SLC22 family) and anion transporters (OATs; SLC22 family) on the efficacy and safety of clinically important therapeutics. To be specific, OCTs and OATs have been identified as determinants for uptake into and secretion from enterocytes, hepatocytes and renal proximal tubular cells, and are frequent sites of drug-drug interaction (DDI). In addition, OCTs expressed in brain are components of the low-affinity, high capacity clearance pathway (uptake-2) for biogenic monoamine neurotransmitters. As a result, OCTs may represent novel targets for mood disorders. The inhibitory effects of several therapeutic agents, designed drugs and novel compounds were assessed on the function of OCTs/Octs and OATs/Oats. Among these compounds, the anthraquinone rhein showed significant inhibition on hOATs. While the antituberculosis drug ethambutol, the herbal products matrine and oxymatrine, synthetic cathinones, and all quinazoline and guanidine compounds produced significant inhibition on hOCT activity with most IC50 values in the micro- and even nanomolar ranges. Considering the clinically relevant unbound concentrations in biofluids, significant DDI potentials were found for rhein, ethambutol, matrine, oxymatrine and several synthetic cathinones affecting enterocytes, hepatocytes and/or proximal tubules. As hOCT2 and hOCT3 may participate in modulating neurotransmitter homeostasis in the CNS, these findings also suggested that the CNS pharmacological effects of synthetic cathinones, quinazoline and guanidine compounds might be due to their inhibitory effects on OCTs; although their impact may be limited solely to clearance of these compounds. Based upon their in vitro OCT/Oct inhibition profiles, three lead quinazoline and guanidine compounds were chosen for in vivo studies. Potent antidepressant-like effects of one lead hOCT-interacting compound (KEO-099) were re-confirmed in the tail suspension test. While in vivo results of the two newly identified hOCT-interacting lead compounds were somewhat less clear. Finally, homology modeling and docking studies for hOCT3 identified key amino acid residues that might be involved in interaction between hOCT3 and small molecules. Subsequent experiments confirmed a competitive mode of interaction between MPP+ and lead compounds on hOCT3. Thus, preliminary analysis indicates our hOCT3 homology model can be used to support rational drug design and high-throughput screening of novel hOCT substrates/inhibitors.

Problem: There are a significant proportion of patients taking acetylcholinesterase inhibitors (ChEi) for cognitive dysfunction also taking medications with anticholinergic (ACh) properties that may counteract their effects. As the number of ACh medications, burden, increases so does the likelihood of an adverse outcome.Background: ACh medications are frequently used in the elderly population (Carnahan 2004) even those with dementia or AD (Roe et al., 2002; Giron et al., 2001; Altavela 2003; Gill et al., 2005; Kogut et al., 2005). Methods: Hospitalized patients > 65 years of age with dementia (AD, other dementias, or with inferred dementia based on ChEi or NMDA antagonist medication use) were studied using UHC clinical database. This document was created in Microsoft Word 2000. Results: Dementia patients on ChEi therapy were more likely to receive an ACh (chi-square 70.1, df=l, pConclusion: A person's age and mental health status along with their current drug regimen, such as ChEi therapy, need to be closely and carefully considered before deciding to use unnecessary ACh drugs in this population which can have detrimental effects.

Atualmente, é uma preocupação a exposição dos pacientes de unidade de terapia intensiva (UTI) a situações da prática clínica que colocam suas vidas em risco. Um agravante para essa exposição são os múltiplos agentes farmacológicos que esses pacientes recebem, aliado ao seu desequilíbrio fisiológico. Entre os principais problemas relacionados à utilização de medicamentos na UTI, estão as interações medicamentosas (IM), que quando não prevenidas ou tratadas prontamente podem provocar danos irreparáveis no paciente. Considerando que o conhecimento sobre IM é uma importante ferramenta para otimização no cuidado em enfermagem, desenvolveu-se este estudo com o propósito de analisar o conhecimento sobre interações medicamentosas de enfermeiros que atuam em unidades de terapia intensiva de adultos de três hospitais públicos de Goiânia - GO. Trata-se de um estudo descritivo, não experimental, com delineamento transversal. A população foi composta por 64 profissionais e a amostra constituiu-se de 51 enfermeiros que aceitaram participar do estudo. Para a coleta de dados construiu-se um instrumento com perguntas de múltipla escolha sobre IM. As alternativas desse instrumento foram extraídas da base de dados do MICROMEDEX® Healthcare Series (1974- 2009). Os dados foram organizados e analisados usando Microsoft Excel 2002. A faixa etária dos enfermeiros variou de 25 a 55 anos, com média de 38,9 anos. O tempo de atuação na enfermagem variou entre 2 e 31 anos, com média de 12 anos. Sobre a formação em farmacologia, 29 (56,9%) enfermeiros informaram ter tido uma formação regular na graduação e 49 (96,1%) expressaram necessidade de capacitação em farmacologia. Quanto ao conhecimento sobre interações medicamentosas na UTI, houve uma relação de acertos e erros praticamente de 50%. Os itens que alcançaram maior número de respostas corretas foram os que abordaram as interações relativas a medicamentos com ação sedativa e analgésica como o caso da dupla fentanila + morfina (86,3%). Os itens que apresentaram maior número de respostas incorretas foram os que abordaram medicamentos de ação antiinfecciosa e anti-hipertensiva. Quanto ao conhecimento do manejo clínico sobre IM, observou-se que metade dos profissionais responderam corretamente em mais de 50% dos itens se destacando, também, os medicamentos de ação sedativa e analgésica. Os resultados evidenciaram a necessidade de melhorar as práticas de cuidados na utilização de medicamentos e chamam a atenção para a importância de atualização dos enfermeiros a respeito dos medicamentos comumente administrados na UTI. Por sua vez, é necessário fornecer apoio aos profissionais para que busquem conhecimentos que sustente a qualidade da prática. Espera-se que as universidades e demais instituições de saúde se sensibilizem quanto à necessidade de difundir e promover um conhecimento farmacológico, adequado aos profissionais de enfermagem tendo em vista que a segurança do paciente na terapia medicamentosa deve ser uma prioridade no contexto da saúde. / Nowadays there is a hard concern on the exposition of intensive care unit (ICU) patients to situations on clinical practice which can put their lives in risk. An aggravating factor for this exhibition is the multiple pharmacological given to these patients, allied to their physiologic disturbs. Among the main troubles related to using drugs in ICU shot out drug interactions (DI). When not prevented or promptly treated, they can cause irreparable damage to the patients. As the knowledge on DI is an important tool for nurse optimizing care, this study was done aiming to analyze information which nurses have on DI in adult ICU in three public hospitals in Goiania- GO, Brazil. It is a descriptive not experimental cross-sectional study. Population was formed by 64 professionals and the sample had 51 nurses who agreed to participate on it. Data collection used an instrument with multiple choice questions on DI. The instrument alternatives were picked up on MICROMEDEX® Healthcare Series (1974- 2009) database. These data were organized and analyzed by Microsoft Excel 2002. The participants ages ranged from 25 to 55 years, mean 38.9 years. The nursing working time ranged from 2 to 31 years, mean 12 years. Concerning to formation in pharmacology, 29 (56,9%) of the nurses informed that they had a regular formation on Graduation Course and 49 (96,1%) expressed need for training in pharmacology. There was a ratio of hits and misses nearly 50% on ICU DI. The items that reached most correct answers were those related to interactions due to sedative and analgesic drugs, as the pair fentanil + morphine (86,3%). Questions that showed most incorrect answers were related to anti infection and anti hypertension drugs. Concerning to clinical manage on DI, 50% of the professionals answered correctly more than 50% of the questions. Sedative and analgesic drugs stood out. The results showed the need of improving care practices on using drugs and they claim attention to the importance of training nurses on drugs commonly administrated on ICU. It is also necessary to support the professionals in order they can look for knowledge that give quality on the practice. One hopes that the universities and other institutions may be touched by the need of spreading and improving a nurse pharmacological knowledge aiming the patient insurance on drug therapy as a priority in health context.

Atualmente, é uma preocupação a exposição dos pacientes de unidade de terapia intensiva (UTI) a situações da prática clínica que colocam suas vidas em risco. Um agravante para essa exposição são os múltiplos agentes farmacológicos que esses pacientes recebem, aliado ao seu desequilíbrio fisiológico. Entre os principais problemas relacionados à utilização de medicamentos na UTI, estão as interações medicamentosas (IM), que quando não prevenidas ou tratadas prontamente podem provocar danos irreparáveis no paciente. Considerando que o conhecimento sobre IM é uma importante ferramenta para otimização no cuidado em enfermagem, desenvolveu-se este estudo com o propósito de analisar o conhecimento sobre interações medicamentosas de enfermeiros que atuam em unidades de terapia intensiva de adultos de três hospitais públicos de Goiânia - GO. Trata-se de um estudo descritivo, não experimental, com delineamento transversal. A população foi composta por 64 profissionais e a amostra constituiu-se de 51 enfermeiros que aceitaram participar do estudo. Para a coleta de dados construiu-se um instrumento com perguntas de múltipla escolha sobre IM. As alternativas desse instrumento foram extraídas da base de dados do MICROMEDEX® Healthcare Series (1974- 2009). Os dados foram organizados e analisados usando Microsoft Excel 2002. A faixa etária dos enfermeiros variou de 25 a 55 anos, com média de 38,9 anos. O tempo de atuação na enfermagem variou entre 2 e 31 anos, com média de 12 anos. Sobre a formação em farmacologia, 29 (56,9%) enfermeiros informaram ter tido uma formação regular na graduação e 49 (96,1%) expressaram necessidade de capacitação em farmacologia. Quanto ao conhecimento sobre interações medicamentosas na UTI, houve uma relação de acertos e erros praticamente de 50%. Os itens que alcançaram maior número de respostas corretas foram os que abordaram as interações relativas a medicamentos com ação sedativa e analgésica como o caso da dupla fentanila + morfina (86,3%). Os itens que apresentaram maior número de respostas incorretas foram os que abordaram medicamentos de ação antiinfecciosa e anti-hipertensiva. Quanto ao conhecimento do manejo clínico sobre IM, observou-se que metade dos profissionais responderam corretamente em mais de 50% dos itens se destacando, também, os medicamentos de ação sedativa e analgésica. Os resultados evidenciaram a necessidade de melhorar as práticas de cuidados na utilização de medicamentos e chamam a atenção para a importância de atualização dos enfermeiros a respeito dos medicamentos comumente administrados na UTI. Por sua vez, é necessário fornecer apoio aos profissionais para que busquem conhecimentos que sustente a qualidade da prática. Espera-se que as universidades e demais instituições de saúde se sensibilizem quanto à necessidade de difundir e promover um conhecimento farmacológico, adequado aos profissionais de enfermagem tendo em vista que a segurança do paciente na terapia medicamentosa deve ser uma prioridade no contexto da saúde. / Nowadays there is a hard concern on the exposition of intensive care unit (ICU) patients to situations on clinical practice which can put their lives in risk. An aggravating factor for this exhibition is the multiple pharmacological given to these patients, allied to their physiologic disturbs. Among the main troubles related to using drugs in ICU shot out drug interactions (DI). When not prevented or promptly treated, they can cause irreparable damage to the patients. As the knowledge on DI is an important tool for nurse optimizing care, this study was done aiming to analyze information which nurses have on DI in adult ICU in three public hospitals in Goiania- GO, Brazil. It is a descriptive not experimental cross-sectional study. Population was formed by 64 professionals and the sample had 51 nurses who agreed to participate on it. Data collection used an instrument with multiple choice questions on DI. The instrument alternatives were picked up on MICROMEDEX® Healthcare Series (1974- 2009) database. These data were organized and analyzed by Microsoft Excel 2002. The participants ages ranged from 25 to 55 years, mean 38.9 years. The nursing working time ranged from 2 to 31 years, mean 12 years. Concerning to formation in pharmacology, 29 (56,9%) of the nurses informed that they had a regular formation on Graduation Course and 49 (96,1%) expressed need for training in pharmacology. There was a ratio of hits and misses nearly 50% on ICU DI. The items that reached most correct answers were those related to interactions due to sedative and analgesic drugs, as the pair fentanil + morphine (86,3%). Questions that showed most incorrect answers were related to anti infection and anti hypertension drugs. Concerning to clinical manage on DI, 50% of the professionals answered correctly more than 50% of the questions. Sedative and analgesic drugs stood out. The results showed the need of improving care practices on using drugs and they claim attention to the importance of training nurses on drugs commonly administrated on ICU. It is also necessary to support the professionals in order they can look for knowledge that give quality on the practice. One hopes that the universities and other institutions may be touched by the need of spreading and improving a nurse pharmacological knowledge aiming the patient insurance on drug therapy as a priority in health context.

The research presented in this thesis addressed knowledge gaps for three medicinal plant taxa, Souroubea spp. (Marcgraviaceae) and Platanus (Platanaceae) as well as Echinacea spp. (Asteraceae). The primary pharmacological mechanism of Souroubea sympetala and Platanus occidentalis were well established, with pentacyclic triterpenes identified as major active principles. My results indicate that major triterpenoids, and crude plant extracts, selectively inhibited monoacyglycerol lipase (MAGL) activity but not fatty acid amide hydrolase (FAAH) activity. These data suggest a possible secondary anxiolytic mechanism of action through the endocannabinoid system (ECS). My study of herb-drug interactions of Souroubea and Plantanus products showed some potential risk when combined with a classic benzodiazepine class drug, diazepam, and I proposed a mechanism through in vitro CYP450 enzyme inhibition. The pharmacokinetic study revealed the difficulty of detecting betulinic acid in animal blood. To support the development a commercial botanical composed of these medicinal plants, an extraction method and a highly sensitive and selectivity HPLC-APCI-MS based quantification method was successfully developed and validated. Part II of this thesis focused on the impact of phytochemical variation and hepatic metabolism on the ECS activity of Echinacea spp. and explored the potential for new applications of Echinacea spp. as a natural health product. My research indicated that considerable variability in the content of phenolic and alkylamide (AKA) compounds reflected similar variability in in vitro bioactivity at ECS-related pharmacological targets. Following biochemometric analysis, several phenolic compounds and AKAs in Echinacea spp. were found to be significant independent variables determining FAAH inhibition and CB receptor activation. Hepatic metabolism was also found to affect the FAAH inhibition of AKA, as increased FAAH inhibitory effects were observed after CYP450-mediated metabolism of both individual AKAs and crude extracts of E angustifolia and E. purpurea, suggesting a “pro-drug” mechanism. Dose dependent activities were observed with oral administration of both E angustifolia and E. purpurea root extract in rat paw model of inflammation and pain. Further tests indicated these activities can be partially blocked by co-administration of CB1 and CB2 receptor antagonists AM251 and AM630, respectively. This evidence suggests activity for peripheral pain was at least partially mediated through the ECS.