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An animal model of nevirapine (NVP)-induced skin rash was used to test the hypothesis that sulfonation of 12-OH NVP, a metabolite of NVP proven essential for rash development, is the link between 12-OH NVP and the skin rash. Female Brown Norway (BN) rats were co-treated with NVP or 12-OH NVP and sulfation inhibitors dehydroepiandrosterone (DHEA) and salicylamide. Co-treatment with salicylamide markedly decreased formation of the sulfate conjugate but did not prevent development of the rash suggesting that the sulfate is not involved. However, it is not known whether the sulfate formation in the skin was affected. Co-treatments with DHEA decreased the sulfate formation and prevented the rash but also had other effects on NVP metabolism. This implies that the sulfate metabolite is responsible for the rash. Additional studies will be required to resolve these conflicting results.

An animal model of nevirapine (NVP)-induced skin rash was used to test the hypothesis that sulfonation of 12-OH NVP, a metabolite of NVP proven essential for rash development, is the link between 12-OH NVP and the skin rash. Female Brown Norway (BN) rats were co-treated with NVP or 12-OH NVP and sulfation inhibitors dehydroepiandrosterone (DHEA) and salicylamide. Co-treatment with salicylamide markedly decreased formation of the sulfate conjugate but did not prevent development of the rash suggesting that the sulfate is not involved. However, it is not known whether the sulfate formation in the skin was affected. Co-treatments with DHEA decreased the sulfate formation and prevented the rash but also had other effects on NVP metabolism. This implies that the sulfate metabolite is responsible for the rash. Additional studies will be required to resolve these conflicting results.

13-Cis-retinoic acid (13-cis-RA) is a synthetic retinoid and the active ingredient in the oral acne treatment Accutane. The medical literature has suggested that the use of 13-cis-RA for acne treatment can induce depression, but because acne itself can have a negative psychosocial impact on self esteem, whether or not 13-cis-RA can cause depression remains controversial. The purpose of this work was to examine whether chronic 13-cis-RA administration could induce depression-related behaviors in mice and to determine the impact 13-cis-RA has on regions of the brain thought to be associated with mood and depression. We found that chronic treatment of adolescent male mice with 13-cis-RA induced depression-related behaviors, as assessed by immobility in the tail suspension and forced swim tests. Although depression is a multifaceted disease in which many brain regions are involved, the regions that seem particularly vulnerable to the effects of 13-cis-RA are the serotonergic and hippocampal systems. In serotonergic cells in vitro, 13-cis-RA treatment increases protein levels of the serotonergic 5-HT[subscript 1A] autoreceptor and the serotonin reuptake transporter (SERT), two inhibitory components of serotonin (5-HT) signaling. In vivo, the median and dorsal raphe nuclei contain the main 5-HT producing cells. 13-Cis-RA uncoupled the functional connectivity of dorsal raphe nuclei from the hippocampal regions as measured by interregional correlations of cytochrome oxidase (CO) activity, a metabolic marker of neuronal activity. Decreased hippocampal neurogenesis is thought to occur in depression and is decreased by 13-cis-RA. 5-HT is also a known regulator of hippocampal neurogenesis. Uncoupling of the dorsal raphe nuclei from the regions of the hippocampus by 13-cis-RA treatment may be the cause of, or a result from, the decreased neurogenesis. Although retinoids are known regulators of apoptosis, the uncoupling of the dorsal raphe nuclei from the hippocampal regions was not due to serotonergic cell loss. Interestingly, 13-cis-RA treated animals with the lowest CO activity in the dentate gyrus have the highest immobility in the tail suspension and forced swim tests. Ultimately, the effects of 13-cis-RA on the serotonergic and hippocampal systems might be inducing depression-related behaviors. / text

With little research documenting elderly medication users’ beliefs and attitudes towards medication, the purpose of this study is to document how seniors experience medication use within the context of their daily lives. The study population was comprised of female and male seniors aged 65 and over who were recruited from the Parksville – Qualicum Beach and Nanaimo communities of eastern Vancouver Island, British Columbia. The findings of this research suggest that for seniors, medication use is a complex and emotionally charged experience. It is an experience filled with contradictions, in which seniors are forced to negotiate between diverse realms of information concerning medications, from the directives they receive from health care professionals, to the signals they receive from their bodies. It is an experience in which powerful conceptions of medications as prolongers of life often trump an individual’s overwhelming desire to stop taking those medications. This research is intended to expand our understandings of the perceptions, attitudes, and beliefs that inform Canadian seniors’ medication use practices. Furthermore, findings from this thesis will contribute to a collaborative investigation of seniors’ experiences with medication designed to address the increasing number of adverse drug reactions experienced by the elderly. / Graduate

Thesis (Ph. D.)--University of Texas at Austin, 2008. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--Michigan State University. Dept. of Pharmacology and Toxicology, 2008. / Title from PDF t.p. (viewed on July 23, 2009) Includes bibliographical references (p. 278-302). Also issued in print.

Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2007. / Title from first page of PDF file (viewed May 29, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 57-65).

Adverse drug reactions (ADRs) are a pervasive complication in the realm of pharmacotherapy. At the root of ADRs lies interindividual variability in drug response, which can range from allergic reactions, to genetic variability, to any factors that influence the pharmacokinetics of a drug. Nonalcoholic steatohepatitis (NASH) is the late-stage of non-alcoholic fatty liver disease (NAFLD), characterized by fat deposition, oxidative stress, inflammation, and fibrosis. Over the last several years, alterations in drug metabolizing enzymes and transporters have been broadly characterized through NAFLD progression. Multidrug resistance-associated protein 2 (MRP2) is a canalicular efflux transporter that directs the biliary elimination of a wide variety of xenobiotics and metabolites. In NASH, MRP2 is mislocalized away from the canalicular membrane in a post-translational event. The mechanism and extent of this mislocalization has yet to be elucidated. While transporter misregulation has been shown to influence the disposition of a variety of substrates, the direct impact of MRP2 mislocalization on its overall transport capacity, and pharmacologic consequence of this change, is unknown. The purpose of this study was to elucidate the mechanism behind, and functional consequence of, MRP2/Mrp2 mislocalization in NASH, predominantly using the rodent methionine-and-choline-deficient (MCD) dietary model.To identify the mechanism of MRP2/Mrp2 mislocalization, a comparison of the activation status of various mediators of MRP2/Mrp2 retrieval was conducted between healthy and NASH livers. Results in rat samples and human NASH samples indicate that activation changes of these mediators, including radixin, PKCα, PKCδ, and PKA, are consistent with a shift toward active retrieval of MRP2/Mrp2 from the membrane, and some evidence of impaired membrane insertion is also present. Measurement of Mrp2 transport capacity was completed using pemetrexed, a novel Mrp2 probe substrate. Comparison of biliary excretion of pemetrexed between wild-type and Mrp2^(-/-) rats shows a 100% decrease, confirming that it relies upon Mrp2 for biliary excretion. NASH rats exhibited a 60% decrease in pemetrexed levels in the bile compared to their control counterparts, indicating that Mrp2 transport capacity is severely impaired in NASH rats. Finally, to ascertain the pharmacologic consequence of impaired Mrp2 transport, a study was conducted measuring the effects of the active morphine glucuronide on control and NASH rats. NASH rats exhibited a decreased biliary excretion, and increased systemic retention, of M3G. While they did also exhibit increased antinociception of M6G, the definitive impact of altered disposition on pharmacologic response was masked due to the interference of an MCD dietary effect on antinociception. Overall, the data reported herein identify active membrane retrieval as a mechanism of MRP2/Mrp2 mislocalization in NASH, and that mislocalization results in a 60% decrease in overall Mrp2 transport capacity. This decrease significantly hinders biliary excretion of Mrp2 substrates, and may result in ADRs by contributing to interindividual variability in drug response.

nÃo hà / A farmacovigilÃncia à a ciÃncia relativa à detecÃÃo, avaliaÃÃo, compreensÃo e prevenÃÃo de reaÃÃes adversas ou quaisquer outros possÃveis problemas relacionados a medicamentos. No Brasil, a farmacovigilÃncia encontra-se em desenvolvimento. Ainda nÃo està completamente disseminada a cultura da notificaÃÃo espontÃnea, principalmente na oncologia, onde a ocorrÃncia de reaÃÃo adversa passa muitas vezes despercebida por ser considerada como um evento esperado, e, portanto, sem importÃncia significativa. Este estudo avaliou as aÃÃes de farmacovigilÃncia desenvolvidas numa instituiÃÃo hospitalar da cidade de Teresina-PI, atravÃs da monitorizaÃÃo de pacientes portadores de cÃncer de mama submetidos à terapia antineoplÃsica com o regime de combinaÃÃo FEC. Para isso, foi realizada uma investigaÃÃo baseada em uma revisÃo dos prontuÃrios desses pacientes para detectar o registro: de reaÃÃes adversas decorrentes da quimioterapia antineoplÃsica vigente e da distinÃÃo das mesmas, segundo os graus de severidade estabelecidos pelo National Cancer Institute (NCI); de intercorrÃncias clÃnicas devido à RAM ocorridas durante a terapia e de possÃveis alteraÃÃes no plano do tratamento protocolado (atrasos na realizaÃÃo dos ciclos de quimioterapia ou suspensÃo temporÃria da terapia, reduÃÃes das doses preconizadas) relacionadas com reaÃÃes adversas. De todas as reaÃÃes adversas observadas durante a investigaÃÃo, 2,07% foram registradas em nÃo conformidade com a terminologia qualitativa adotada pelo NCI e 15,06% nÃo foram graduadas quanto à severidade; alÃm disso, 100% das RAMs nÃo foram notificadas à autoridade sanitÃria competente (ANVISA) e nÃo existe um banco de dados institucional com essas reaÃÃes adversas. Foram ainda identificadas 17 (70,83%) intervenÃÃes clÃnicas devido à RAM realizadas em nÃvel ambulatorial e 7 (29,17%) intervenÃÃes clÃnicas devido à RAM que exigiram a hospitalizaÃÃo do paciente; atrasos ou suspensÃo temporÃria da realizaÃÃo dos ciclos de quimioterapia, com 8,70% decorrentes de causas clÃnicas, entre estas reaÃÃes adversas; e 8 (5,84%) casos de reduÃÃo das doses protocoladas devido à presenÃa e severidade de reaÃÃes adversas. Conclui-se que as aÃÃes de farmacovigilÃncia da instituiÃÃo hospitalar ainda sÃo incipientes, com falhas organizacionais que diminuem a confiabilidade das informaÃÃes registradas; alÃm disso, houve a comprovaÃÃo da importÃncia da farmacovigilÃncia em oncologia, onde a toxicidade dos fÃrmacos utilizados pode ser considerada fator limitante primÃrio para uma prÃtica terapÃutica ideal. / Pharmacovigilance is the science concerning the detection, assessment, understanding and prevention of adverse reactions or any other possible drug-related problems. In Brazil, pharmacovigilance is in the developmental stage. The culture of spontaneous reporting not yet fully spread, especially in oncology, where the occurrence of adverse reaction is often unnoticed because it is considered as an expected event, and therefore immaterial. This study evaluated the pharmacovigilance actions carried out at a hospital in the city of Teresina, PI, through the monitoring of patients with breast cancer undergoing anticancer therapy with the FEC protocol. An investigation was undertaken based on a review of the medical records of these patients to detect the registry: of adverse reactions resulting from cancer chemotherapy and the distinction of them according to the degrees of severity established by the National Cancer Institute (NCI); of clinical interventions due to ADR that occurred during therapy and possible changes in the plan of treatment protocol (delays in the achievement of cycles of chemotherapy or temporary suspension of therapy, reductions in the recommended doses) related with adverse reactions. Of all the adverse reactions observed during the investigation, 2,07% were not registered in accordance with the terminology adopted by NCI qualitative and 15,06% were not graded as to severity. In addition, 100% of ADRs were not reported to the recognized health authority (ANVISA) and there is not an institutional database with these adverse reactions. There were also 17 identified (70,83%) clinical interventions due to ADR performed on an outpatient basid and 7 (29,17%) clinical interventions due to ADR that required hospitalization of the patient; delays or temporary suspension of achievement of cycles of chemotherapy with 8,70% due to clinical causes among these adverse reactions; and 8 (5,84%) cases of dose reduction due to the presence and severity of adverse reactions. It is concluded that the pharmacovigilance actions of the hospital are still preliminary, with organizational flaws that reduce the reliability of the information recorded. In addition, there was evidence of the importance of pharmacovigilance in oncology, where the toxicity of drugs used may be considered a limiting factor necessary for an ideal therapeutic practice.