Conselho Nacional de Desenvolvimento Científico e Tecnológico / O objetivo deste trabalho é realizar uma avaliação econômica analisando o tratamento com atorvastatina e sinvastatina em comparação ao tratamento com placebo, no cenário do Sistema Único de Saúde (SUS), para subgrupos de pacientes classificados como alto risco de doença cardiovascular; avaliando se o custo adicional das estatinas em comparação ao tratamento placebo é justificado pelo ganho clínico esperado, em termos de redução de evento cardiovascular e redução de mortalidade. Utilizou-se o risco de eventos cardiovascular e a taxa de mortalidade como parâmetros de desfecho. Os dados epidemiológicos da doença e eficácia dos agentes terapêuticos foram obtidos de revisão e análise crítica da literatura. Um modelo analítico de decisão (Markov) foi desenhado para estimar a razão de custo-efetividade incremental da atorvastatina 10mg/dia e sinvastatina 40mg/dia em comparação ao placebo. A população analisada foi uma coorte hipotética composta por homens e mulheres, com idade média de 50 anos e com alto risco de doença cardiovascular. O modelo considera apenas custos médicos diretos, obtidos dos Sistemas de Informações Ambulatoriais e Hospitalares e Banco de Preços do Ministério da Saúde e de estudos de dados primários. A análise de custo-efetividade foi realizada através de planilha Excel, para o horizonte de tempo de 5 e 30 anos. O resultado revela que a atorvastatina 10mg/dia em comparação ao placebo tem maior custo e é mais efetiva, tanto no horizonte de tempo de 5 como no de 30 anos. A sinvastatina 40mg/dia mostrou ser uma estratégia de menor custo e maior efetividade, em comparação ao placebo, em ambos os horizontes de tempo analisados. O resultado da análise de impacto no orçamento demonstrou que o uso de sinvastatina 40mg/dia, em pacientes de alto risco de evento cardiovascular, representa minimização do custo anual em comparação ao uso de atorvastatina 10mg/dia. Observa-se que o tratamento com sinvastatina proporciona uma economia de, aproximadamente, 1,1 bilhão de reais em comparação ao tratamento com placebo. Em contrapartida, o tratamento dos pacientes com atorvastatina leva a um gasto adicional de cerca de 118,6 bilhões de reais em comparação ao tratamento com placebo. / The objective of this study is to perform an economic evaluation analyzing the treatment with atorvastatin and sinvastatin in comparison to placebo treatment, within the Brazilian Public Healthcare System (SUS) scenario, for patients with high risk of cardiovascular disease; analyzing if the additional cost related to statin treatment is justified by the clinical benefits expected, in terms of cardiovascular event and mortality reduction. Cardiovascular event risk and mortality risk were used as outcomes. Statin efficacy at LDL-c and cardiovascular events levels lowering data was obtained from a critical literature review. A decision analytic model was developed to perform a cost-effectiveness analysis comparing atorvastatin 10mg/day and sinvastatin 40mg/day to placebo treatment in patients with dyslipidemia in Brazil. The target population of this study was a hypothetic cohort of men and women with a mean age of 50 years old and high risk of cardiovascular disease. The model includes only direct costs obtained from Ambulatory and Hospital Information System and Price Database of Brazilian Ministry of Health. The comparative cost-effectiveness analysis itself was done through Excel spreadsheets covering a 5 or 30-years time horizon. The result shows that atorvastatin 10mg/day in comparison to placebo has higher cost with higher effectiveness in the time horizon of 5 and 30 years. The sinvastatin 40mg/day appears to be a strategy with lower cost and higher effectiveness in comparison to placebo, in both times horizon analyzed. The budget impact analysis shows that the use of sinvastatin 40mg/day, in patients with high risk of cardiovascular disease, leads to a cost minimization in comparison to the use of atorvastatin 10mg/day. The treatment with sinvastatin is responsible for an economy of, approximately, BRL1.1 billion in comparison to treatment with placebo. Otherwise, the treatment with atorvastatin leads to an additional cost of, approximately, BRL118.6 billions in comparison to the treatment with placebo.

Submitted by Jean Medeiros (jeanletras@uepb.edu.br) on 2017-02-23T12:31:51Z No. of bitstreams: 1 PDF - Natan Emanuell de Sobral e Silva.pdf: 2512646 bytes, checksum: 803100d8d15d7d5d832f6862efe48740 (MD5) / Approved for entry into archive by Secta BC (secta.csu.bc@uepb.edu.br) on 2017-03-07T16:09:49Z (GMT) No. of bitstreams: 1 PDF - Natan Emanuell de Sobral e Silva.pdf: 2512646 bytes, checksum: 803100d8d15d7d5d832f6862efe48740 (MD5) / Made available in DSpace on 2017-03-07T16:09:49Z (GMT). No. of bitstreams: 1 PDF - Natan Emanuell de Sobral e Silva.pdf: 2512646 bytes, checksum: 803100d8d15d7d5d832f6862efe48740 (MD5) Previous issue date: 2015-08-28 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Chitosan is a polysaccharide derived from chitin has been arousing great interest in the tissue regeneration area, especially because of its biodegradability characteristics, biocompatibility and antimicrobial activity. It has also been frequently used in systems for controlled drug release, especially for the low aqueous solubility, such as simvastatin. Simvastatin, statin with hypolipidemic activity, in several studies have been show an interesting anti-inflammatory activity by an independent primary mechanism of action. However, those pharmaceutical forms in which this drug is available, unfeasible its use in cutaneous lesions. Therefore, the aim of this work was to develop and evaluate polymerics films for topical delivery of simvastatin. Chitosan, coming from two suppliers, was utilized to prepare films containing two concentrations of simvastatin (10 and 20 mg) for Sol-gel method. Fourier-transform infrared spectroscopy, X-ray diffraction and Thermal analysis were used to structural characterization. Additionally, in vitro release study using the Franz apparatus was realized. To in vivo testing, determination of residual wound area and total leukocyte count was conducted by analyzing statistically the data collected. In the infrared spectrum can be inferred that there were several intermolecular interactions between chitosan and simvastatin, while the X-ray diffraction and Thermal analysis, indicated the presence of the drug in amorphous form in the polymeric film. The films displayed similar release profiles, with its release governed by an anomalous transport, described in the Korsmeyer-Peppas model and in vivo evaluation of anti-inflammatory and wound healing activity, the groups receiving treatment with films with simvastatin 20 mg significantly reduced (p˂0.05) the leukocyte response and had the most efficient cicatrization that groups with white film and SALINA. Evidencing, the developed films are promising for the controlled administration of simvastatin topically in skin inflammation. / A quitosana é um polissacarídeo derivado da quitina que vem despertando grande interesse na área de regeneração tecidual, principalmente devido as suas características de biodegrabilidade, biocompatibilidade e atividade antimicrobiana. Também vem sendo bastante utilizada em sistemas para liberação controlada de fármacos, sobretudo para os de baixa solubilidade aquosa. A sinvastatina, estatina redutora de colesterol, tem exibido em diversos estudos uma interessante atividade anti-inflamatória por uma via independente do seu mecanismo de ação principal. Contudo, as formas farmacêuticas nas quais esse fármaco está disponibilizado no mercado inviabilizam seu uso em casos de lesões cutâneas. Desta forma, o objetivo deste trabalho foi desenvolver e avaliar filmes poliméricos para a liberação controlada de sinvastatina para uso tópico em eventos inflamatórios. A quitosana, proveniente de dois fornecedores, foi utilizada para preparar filmes brancos e filmes contendo duas concentrações de sinvastatina (10 e 20 mg) pelo método sol-gel. Para caracterização físico-química, técnicas como infravermelho com transformada de Fourier (FTIR), difração de raios-X (DRX) e análise térmica foram utilizadas. Além disso, foi realizado o estudo de liberação in vitro utilizando o aparato de Franz. Para o ensaio in vivo, foi realizada a determinação da área residual da ferida e contagem de leucócitos totais, analisando-se estatisticamente os dados obtidos. Nos resultados do FTIR pode-se inferir que ocorreram várias interações intermoleculares entre a quitosana e sinvastatina, enquanto a DRX e análise térmica indicaram a presença do fármaco na forma amorfa no retículo polimérico. Os filmes apresentaram perfis de liberação semelhantes, regidos por um transporte anômalo, descrito no modelo de Korsmeyer-Peppas e na avaliação in vivo da atividade anti-inflamatória e cicatrizante, os grupos que receberam o tratamento com filmes com 20 mg de sinvastatina reduziram significativamente (p˂0,05) a reposta leucocitária e apresentaram uma cicatrização mais eficiente que os grupos com o filme branco e SALINA. Evidenciando assim, que os filmes desenvolvidos são promissores para a administração controlada, via tópica de sinvastatina em inflamações cutâneas.

nÃo hà / A mucosite oral (MO) à um efeito colateral freqÃente e dose limitante da terapia do cÃncer, caracterizada por intensa reaÃÃo inflamatÃria na mucosa e formaÃÃo de Ãlceras na cavidade orofarÃngea. O objetivo deste trabalho foi avaliar o efeito da atorvastatina (ATV), droga utilizada para reduzir os nÃveis sÃricos de colesterol e que tem atividade antiinflamatÃria, na mucosite oral induzida por 5-fluorouracil (5-FU) em hamsters Golden Sirian. A mucosite oral foi induzida pela administraÃÃo intraperitoneal (i.p.) de 5-FU no 1 e 2 dias do experimento (60 e 40 mg/kg, respectivamente), com subseqÃentes escoriaÃÃes na mucosa jugal, no quarto dia. Os animais foram tratados intraperitonealmente (i.p.) com ATV 1, 5 ou 10 mg/kg ou salina ou salina/etanol 5% vol/vol 30 minutos antes de cada injeÃÃo do 5-FU e diariamente por 5 ou 10 dias. Os animais foram sacrificados no 5 ou 10 dia e amostras de mucosa jugal e dos principais ÃrgÃos vitais foram coletados para anÃlise histopatolÃgica. A determinaÃÃo dos nÃveis de TNF-α, IL-1β, nitrito, grupos sulfidrilas nÃo proteicos (NP-SH), ensaio da mieloperoxidase (MPO), imunohistoquÃmica para TNF-α, Ãxido nÃtrico sintase induzida (iNOS), NF-KB-p50, NF-kB-p50 NLS (sequÃncia de localizaÃÃo nuclear) e a expressÃo do NF-kB-p50 por Western Blot foram outros parÃmetros avaliados em amostras coletadas da mucosa jugal dos animais. O sangue foi coletado para leucograma, anÃlise dos parÃmetros bioquÃmicos e anÃlise da bacteremia. Atorvastatina nas doses de 1 e 5 mg/kg reduziu o dano na mucosa e a inflamaÃÃo, bem como os nÃveis de citocinas, nitrito e a atividade da MPO no 5 e 10 dia da MO. Ademais, atorvastatina 1 e 5 mg/Kg diminuiu a marcaÃÃo imunohistoquÃmica para TNF-α, NOSi, NF-kB-p50, NF-kB-p50 NLS, bem como a expressÃo do NF-kB-p50 na mucosa jugal dos hamsters submetidos a MO, no 5 dia. ATV 1 mg/Kg aumentou os nÃveis de NP-SH na mucosa jugal dos animais, quando comparado com os grupos 5-FU no 10 dia da MO. A associaÃÃo de ATV 5 mg/Kg e 5-FU diminuiu a taxa de sobrevida, amplificou a leucopenia dos animais, aumentou os nÃveis sÃricos de transaminases e causou lesÃo hepÃtica. NÃs tambÃm detectamos a presenÃa de bacilos Gram negativos no sangue de 100% dos animais tratados com ATV 5mg/Kg + 5-FU. Esses resultados sugerem que a atorvastatina previne o dano na mucosa oral e a inflamaÃÃo associada com MO induzida por 5-FU, entretanto a combinaÃÃo de altas doses de ATV com 5-FU induz hepatotoxicidade, amplificaÃÃo da leucopenia e bacteremia, que merecem atenÃÃo e futuros estudos em humanos. / Oral mucositis (OM) is a frequent side effect and dose-limiting of cancer therapy, characterized by intense inflammatory mucosal reaction and formation of ulcers in oropharyngeal cavity. The aim of this study was to evaluate the effect of atorvastatin (ATV) â cholesterol lowering drug with anti-inflammatory activity - in oral mucositis induced by 5-fluorouracil (5-FU) in Golden Sirian hamsters. Oral mucositis was induced by intraperitoneal (i.p.) administration of 5-FU in the first and second days of experiment (60 and 40 mg/kg i.p., respectively), with subsequent excoriations of the cheek pouch mucosa on the fourth day. The animals were treated by intraperitoneal route (i.p.) with ATV 1, 5 or 10 mg/kg or saline or saline and 5% vol/vol ethanol 30 min before 5-FU injection and daily for 5 or 10 days. The animals were sacrificed on the 5th or 10th day and samples of cheek pouches and major vital organs were removed for histopathological analysis. The determination of TNF-α, IL-1β, nitrite, non-protein sulfhydryl group (NP-SH) levels, myeloperoxidase (MPO) assay, immunohistochemistry for TNF-α, induced nitric oxide synthase (iNOS), NF-kB-p50, NF-kB-p50 NLS and the expression of NF-kB-p50 by Western Blot were other parameters evaluated in the samples collected from the oral mucosa of animals. Blood was collected for a leukogram, analysis of biochemical parameters and analysis of bacteremia. Atorvastatin at doses of 1 and 5 mg/kg reduced mucosal damage and inflammation, as well as the levels of cytokines, nitrite, and myeloperoxidase activity on the 5th and 10th day of OM. Moreover, ATV 1 and 5 mg/kg decreased the immunohistochemical staining for TNF-α, iNOS, NF-kB-p50, NF-kB-p50 NLS and expression of NF-kB-p50 of the cheek pouch mucosa on the 5th day of OM. ATV at 1 mg/kg increased cheek pouch NP-SH when compared to 5-FU groups on the 10th day of OM. The association of ATV 5 mg/kg and 5-FU decreased the survival rate, amplified the leukopenia of animals, increased transaminase serum levels and caused liver lesions. We also detected the presence of Gram negative bacillus in the blood of 100% of the animals treated with ATV 5 mg/kg + 5-FU. These results suggest that atorvastatin prevent mucosal damage and inflammation associated with 5-FU-induced OM, but the association of a higher dose of ATV with 5-FU induced hepatotoxicity, amplified leucopenia and bacteremia, which deserves attention and further research in humans.

A obesidade é um estado inflamatório crônico. As estatinas têm efeito antiinflamatório e podem afetar a homeostase glicêmica. Estudos, nesse sentido são contraditórios e pouco se sabe sobre os mecanismos moleculares envolvidos. Este estudo verificou em animais obesos por glutamato monossódico (MSG) que além de apresentaram resistência à insulina in vivo, o tecido adiposo branco (TAB) desses animais mostrou aumento de infiltração de macrófagos, fosforilação de IKK-a/b, expressão de mRNA de TNF-a and IL-6, e redução de mRNA e proteína de GLUT4. O tratamento com atorvastatina por 4 semanas restabeleceu a sensibilidade à insulina in vivo, reduziu a inflamação e restabeleceu a expressão de GLUT4 no TAB dos animais obesos. Adicionalmente, esse trabalho encontrou sítios de ligação de NF-kB no promotor do gene GLUT4, sugerindo ligação entre resistência à insulina e inflamação. Em conclusão, a obesidade induzida por MSG em camundongos acompanha-se de resistência à insulina in vivo e atividade inflamatória crônica no tecido adiposo, com prejuízo da expressão de GLUT4. A atorvastatina melhorou esses aspectos, sugerindo que essa estatina tenha efeitos antiinflamatórios que podem melhorar a resistência à insulina na obesidade. / Obesity is a chronic inflammatory state. Statins have anti-inflammatory effects and may affect glucose homeostasis; therefore, few are known about the molecular mechanisms. Considering that inflammation contributes to insulin resistance, the aim of the present study was to investigate if atorvastatin treatment has anti-inflammatory, and consequently insulin sensitization action in white adipose tissue (WAT) of obese mice. WAT of insulin-resistant obese mice showed increased macrophage infiltration, IKK-a and IKK-b phosphorylation, TNF-a and IL-6 mRNA expression and decreased GLUT4 mRNA and protein expression. Atorvastatin restored whole-body insulin sensitivity, decreased macrophage infiltration and normalized IKK-a/b phosphorylation, TNF-a, IL-6 and GLUT4 mRNA and GLUT4 protein to control levels. Moreover, NF-kB binding sites were found in GLUT4 gene promoter, pointing out an association between insulin resistance and inflammation. Together, atorvastatin anti-inflammatory effects on WAT may be important to its local and whole-body insulin sensitization effects.

Sterols play many important roles in physiology, including maintaining cell membrane integrity, and producing vitamin D and steroid hormones. Recent studies implicate sterol metabolism in the host innate immune response. Previous work, based on transcriptional profiling studies of mouse cytomegalovirus (MCMV) infection of primary bone-marrow-derived macrophages (BMDM, MΦ), uncovered a previously uncharacterized role of interferon in regulating the cholesterol pathway. Notably, Toll-like receptor (TLR) induced interferon modulates the suppression of SREBP2 (Sterol Regulatory Element-Binding Protein 2) activation, the master transcription factor for sterol biosynthesis. This finding resulted in the downregulation of the sterol biosynthesis pathway. However, how interferon is molecularly linked to sterol metabolism, and what part of the pathway mediates the antiviral effect remains unknown. The central hypothesis of the thesis is that the antiviral effect of interferon is in part mediated by secondary sterol metabolites and the dependency of viral replication on the host mevalonate branch of the sterol biosynthesis pathway. To test this hypothesis, my studies have examined the components of the host sterol pathway and their respective roles in influencing viral replication. Paradigmatically, I used MCMV and BMDM to explore the host- metabolic-virus interactions. Specifically, my findings address the question of how MCMV replication depends on the sterol biosynthesis pathway, and how the pathway is modulated by interferon as an antiviral response. In Chapter 2, the importance of the sterol biosynthesis pathway for viral replication was investigated using a combination of gene silencing and pharmacological inhibitors. These studies demonstrated that resistance to viral infection through suppressing the cholesterol pathway is not due to a requirement of the virus for cholesterol itself, but instead involves the mevalonate-isoprenoid arm of the pathway. This branch of the pathway chemically links lipids to specific host proteins (protein prenylation). These results suggest a new role for the mevalonate arm during viral infection. In Chapter 3, I examined what part of the sterol pathway mediates the antiviral effects. Oxysterols are natural modulators of sterol biosynthesis, and are produced by the oxidation of cholesterol by the enzyme cholesterol hydroxylase. Oxysterol suppression of SREBP2 activation leads to transcriptional repression of the sterol biosynthesis pathway. Additionally, oxysterols also modulate cholesterol homeostasis through cholesterol efflux. My studies led to identifing cholesterol-25-hydroxylase (Ch25h) as an interferon-stimulated gene (ISG). CH25H oxidizes cholesterol to produce a soluble oxysterol metabolite, 25-hydroxycholesterol (25-HC). Treatment of cells with 25-HC resulted in antiviral effects against MCMV and MHV-68. 25-HC was found to have no effects on MCMV entry into the host cell, but rather mediated inhibition of viral gene transcription. In addition, 25-HC-specific antiviral effect partially involved the suppression of the isoprenoid pathway, rather than cholesterol efflux. This work uncovered a physiological role for 25-HC as a sterol-lipid effector of an innate immune pathway. The antiviral activity of 25-HC in a lipid replete condition was found to occur at a concentration higher than the concentration required to inhibit SREBP2 activation. This implies that the antiviral effects of 25-HC is independent of SREBP2 in sterol replete conditions. Conversely, the antiviral action of 25-HC was signifi enhanced in cells under sterol-depleted conditions, suggesting that the antiviral effect of 25- HC is likely mediated through multiple processes involving SREBP2 dependent and independent mechanisms. These sterol dependent and independent mechanisms are examined in Chapter 4, using pathway expression profiling and pharmacological synergy studies. These studies showed that 25-HC suppression of the isoprenoid synthetic pathway is crucial in controlling infection, but also highlighted that other 25-HC dependent antiviral mechanisms are likely to exist. The inhibition of the mevalonate-isoprenoid arm by statins and 25-HC clearly demonstrated that MCMV replication dependents on protein prenylation. Chapter 5 investigation showed that either chemical inhibition of geranylgeranylation of host proteins or limiting mevalonate production led to restriction of MCMV replication. Importantly, through a series of systematic loss of function siRNA screenings demonstrated that specific host RabGTPases mediating vesicular transport pathways play vital roles in the replication and the assembly of the virus. This finding provides new mechanistic insights in to the dependency of cytomegalovirus replication on the host cell trafficking pathways and lays the groundwork for further definition of this important aspect of host-viral interactions. In summary, the overall findings of this research support the original hypothesis, by highlighting the importance of the host mevalonate-isoprenoid pathway, and provide further definition of the mechanisms and components linking sterol metabolism with interferon mediated antiviral effect.

Bakgrund: Av de kroniska sjukdomarna i världen orsakar hjärt-kärlsjukdomarna 17,5 miljoner dödsfall per år. Läkemedel som används för prevention mot hjärt-kärlsjukdomar är bl.a. statiner. Enligt Socialstyrelsen hämtade 455 716 patienter ut läkemedel från läkemedelsgruppen statiner från apoteken år 2011. Mellan åren 1988-2012 har Swedis (biverkningsdatabas) fått inrapporterat 24 biverkningsrapporter relaterat till statiner och neurologiska biverkningar som berör syftet i studien (perifer neuropati, polyneuropati, neuropati). Syfte: Studiens syfte var att sammanställa vetenskapliga publikationer rörande statiners direkta påverkan på perifera nervsystemet och eventuella förklaring till uppkomsten av neuropati. Resultat: De teorier som finns om hur statinbehandling kan ge neuropati säger att statiner, som ger en störd kolesterolsyntes, leder till rubbning i kolesterolrika neuronala membran. Även en minskad syntes av coenzymet ubiquinon ses, vilket påverkar mitokondriernas respiratoriska kedja och stör energiflödet till olika neuron. Statinbehandling har vidare visats öka risken att utveckla perifer neuropati. En ökad risk syns vid högre doser än rekommenderade samt vid långtidsbehandling. Statinbehandling vid diabetesrelaterad neuropati har däremot visats förbättra överledningshastigheten i motornerver med 5 % (P<0,05). Statinbehandling hos diabetes mellitus (DM) typ 2 patienter har visats ha en skyddande effekt från att utveckla perifer neuropati. Slutsats: Behandling med statiner ökar i takt med att vår tids folksjukdom, hjärt-kärlsjukdom, ökar. När behandling med statiner ökar, rapporteras samtidigt en bredare biverkningsprofil. Med statinbehandling ökar troligen risken för att utveckla neuropati speciellt vid användning av högre doser än rekommenderade samt vid långtidsbehandling. Däremot får statinbehandlade patienter med DM typ 2 en bättre nervöverledningsförmåga och ett skydd mot att utveckla perifer neuropati. En patientgrupp som därför troligen har god nytta av statinbehandling är DM typ 2-patienter. Att använda statiner till andra patientgrupper kanske istället kan leda till neuropati. Således kan skillnader mellan patientgrupper föreligga. Fler studier krävs dock för att bekräfta dessa resultat. / Background: Cardiovascular disease is one of the chronic diseases that afflict the world with 17.5 million deaths per year, in particular coronary heart disease and stroke. The National Board in Sweden reported for 2011 that 464 847 patients collected drugs from the pharmacies that affect the serum lipid levels. The most collected drugs were statins standing for 455 716. The rare side effects (1/10 000) affecting the CNS (central nervous system) and the PNS (peripheral nervous system) were headache, parastesies, dizziness, peripheral neuropathy and polyneuropathy. Between the years of 1988 to 2012, the Swedis (a database of side effects) reported 258 adverse reactions related to statins and neurological side effects. Within the neurological side effect reports there were three groups related to the purpose in this study; peripheral neuropathy (2), polyneuropathy (10) and neuropathy (12). Objective: The purpose of this study was to collate scientific publications regarding the direct effects of the statins on the peripheral nervous system. It was also to present a possible explanation for the onset of neuropathy. Results: The theories concerning development of neuropathy with statin therapy includes a disturbed cholesterol synthesis, leading to disruption of cholesterol-rich neuronal membrane. Also, a decreased synthesis of ubiquinone coenzymes, which affect the electron transport of the mitochondrial respiratory chain, was shown. This in turn disturbs the flow production of energy (ATP) in the various neurons. Electrophysiological measurements were performed in many studies that showed changes in both sensory and motor nerves after treatment with statins. Statin therapy was shown to increase the risk of developing peripheral neuropathy. An increased risk was seen at higher doses than recommended, and in long term treatment. Statin treatment of diabetic neuropathy was shown to improve nerve conduction velocity in motor nerves with 5% (P <0.05). Statin therapy in type 2 DM (diabetes mellitus) patients was shown to have a protective effect from developing peripheral neuropathy. Larebs database in the Netherlands reports that the reporting odds ratios (ROR) were 3.7. The WHO reports that ROR was 2.86. Conclusion: Change of the nerve membrane in conjunction with a reduced cholesterol synthesis alters membrane composition thus function. A reduced cholesterol synthesis also seems to disturb the mitochondrial respiratory chain due to decreased levels of the coenzyme Q10, which in turn can cause neuropathy. Statin therapy increases the risk of developing neuropathy, especially when using higher than recommended doses and in long-term treatment. In contrast, statin-treated patients with DM type 2 got a better nerve conduction and protection against the development of peripheral neuropathy. A group of patients who probably therefore have good benefit of statin therapy is the DM type 2 patients. The use of statins to other groups of patients might instead cause neuropathy. More studies are needed to confirm the results. The frequency of reported adverse event reports involving statins and neuropathy is higher than other reported side effects.

Huntington’s disease (HD) is a heritable, neurodegenerative disorder characterized by motor, cognitive, and psychiatric disturbances. An unstable CAG expansion within the gene normally encoding for the Huntingtin protein is responsible. The expanded mutant form of Huntingtin and the putative protein co-factor Rhes interact and cause cell death within the striatum. We hypothesized chronic treatment with simvastatin, a cholesterol lowering drug, would disrupt the biosynthetical pathway which gives both Rhes and its target cells binding sites and render Rhes inactive. Healthy and HD mice were treated with simvastatin or a vehicle. Animals’ motor behavior was assessed with three separate tests over the first four months of life. No significant differences were found between the HD groups; however, the HD treated animals’ performance on the rotarod test, at month 4, was intermediate between healthy mice and HD vehicle treated mice. The results hint at simvastatin’s therapeutic potential, but are interpreted cautiously.

Background: Type 2 diabetes mellitus (T2DM) is a major health concern among Navajo Indians. Native Americans and Alaskan Natives (NA/AN) currently have the highest rates of T2DM in the United States (Indian Health Service, 2016). The rate of diabetes on the Navajo Indian reservation is 22% (Partnersinhealth.org, 2009). Major health concerns for patients with T2DM include cardiovascular complications. Treatment is essential to prevent high-risk complications such as, cardiovascular disease (CVD). Purpose: The purpose of this quality improvement project was to implement a clinical decision support tool (CDST) to increase primary care provider awareness of current American Diabetes Association (ADA) statin therapy guidelines. The first objective was to increase the prescription rates of statin medications by 10%. The second objective of this project was to increase the performance target rate by 10%. Setting: This project was implemented at the Gallup Indian Medical Center (GIMC) Family Medicine Clinic. GIMC is located in Gallup, New Mexico. Participants: Participants included primary care providers, six Medical Doctors, two Nurse Practitioners, and one Physician Assistant. Methods: An evidence based clinical support decision tool (CDST) was generated the ADA statin therapy guidelines. Participants were educated on these practice guidelines and the CDST. The CDST was implemented into the electronic health record (EHR) over a four-week period. The provider used the CDST as a point-of-care guide when prescribing statin therapy to those with T2DM. Results: There was a 0.5% increase in the GPRA performance rating at GIMC as well as a 10% increase in prescribed statin therapy medications. There were 253 newly prescribed statin medications during data collection. Conclusion: While this project did not result in significant improvement of statin therapy GPRA performance ratings, a new EHR tool that providers can use to improve patient care was implemented. One outcome was met, there was a 10% increase in statin medication prescriptions. Further studies and future PDSA cycles will be required for testing the effectiveness of CDSTs.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22005号 / 医博第4519号 / 新制||医||1038(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 平井 豊博, 教授 松原 和夫, 教授 萩原 正敏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Rheumatoid arthritis (RA) is a chronic inflammatory condition of unknown etiology for which there is no cure. It is one of the most disabling diseases and affects about 1% of the world‟s population. Recent developments in the field of molecular biology have resulted in the production of new drugs used in the treatment RA. Despite these advancements, achieving optimal disease control and prevention of disease progression is still difficult in many patients, leading to a continued search for treatment methods that will improve patient outcomes. Non-biologic forms of treatment that are still being investigated include the use of statins as an adjunct therapy due to their reported antiinflammatory effects. Some studies have shown that the use of statins in patients with RA help in reducing disease activity and swollen joint count in addition to lowering cardiovascular risk. As evidence continue to increase on the anti-inflammatory effect of statins, researchers have started investigating possible benefits that may result from the use of statins in treatment of RA, a chronic disease marked by high levels of systemic and local inflammation. This study investigated the anti-inflammatory effect of statins in rheumatoid arthritis patients with associated risks for cardiovascular disease, using simvastatin as the investigational product. Patients with moderately active RA despite being on maximum disease-modifying antirheumatic drugs (DMARDs) therapy and having associated risks for cardiovascular disease were screened for the study. Eligible patients were randomized into two groups, 1 and 2. Patients in group 1 received simvastatin treatment (20mg/day) for a period of 3 months in addition to their usual DMARDs after which they stopped simvastatin treatment and were followed up for a further 3 months off simvastatin treatment. Those in group 2 were allowed to continue on their usual DMARDs without simvastatin treatment for the first 3 months of the study after which they received 20mg/day simvastatin for a period of 3 months in addition to their usual DMARDs. The anti-inflammatory effect of simvastatin was assessed by monitoring the inflammatory variables; erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) and disease activity in the two groups at screening, at the crossover point and at end of the study. Disease activity was significantly reduced with simvastatin treatment in the two groups. The mean change in disease activity score with simvastatin treatment was 1.30 (p = 0.01) in group 1 and 1.74 (p = 0.01) in group 2. ESR was significantly reduced with simvastatin treatment in group 1 with a mean change of 19.0 (p = 0.005) and marginally reduced in group 2 with a mean change 26.0 (p = 0.09). There was no significant change in CRP with simvastatin treatment in the two groups. The mean change in CRP with simvastatin treatment was 7.0 (p = 0.24) in group 1 and 14.7 (p =0.20) in group 2. All the patients benefited from the lipid-lowering effect of simvastatin. These findings suggest that statins may have mild anti-inflammatory properties and will be good adjuvant in RA patients with associated risks for cardiovascular disease. / Dissertation (MSc)--University of Pretoria, 2013. / gm2014 / Pharmacology / unrestricted