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No. of bitstreams: 1 elaineduartemendesferreira.pdf: 2564205 bytes, checksum: 1b2251e5f6632134b32623071bf5c198 (MD5) Previous issue date: 2015-08-26 / O estudo teve como objeto o Itinerário Terapêutico de Pessoas em Terapia Renal Substitutiva com Doença de Base Hipertensão Arterial e/ou Diabetes Mellitus. Para alcançar o estudo desse objeto os seguintes objetivos foram definidos: Conhecer as percepções de pessoas hipertensas e/ou diabéticas que se encontram em Terapia Renal Substitutiva em relação ao seu próprio processo saúde-adoecimento, e as escolhas de tratamento propostas; identificar o fluxo assistencial às pessoas atendidas em um Centro de Terapia Renal Substitutiva nos três níveis de atenção; analisar o itinerário terapêutico de pessoas hipertensas e/ou diabéticas, portadoras de doença renal crônica, enquanto assistidas pela Terapia Renal de Substituição (TRS) em um serviço de nefrologia. Trata-se de uma pesquisa qualitativa, descritiva, O cenário do estudo foi um serviço de nefrologia localizado em uma cidade do interior da Zona da Mata Mineira, uma entidade que atende a este município e microrregião. Os participantes do estudo foram 20 pessoas em terapia renal substitutiva com doença de base hipertensão e/ou diabetes mellitus, sendo entrevistadas em seu horário de diálise. O período de realização das entrevistas foi de outubro de 2014 à janeiro de 2015. A coleta de dados foi feita utilizando-se de entrevistas semi-estruturadas e para análise dos dados elegeu-se a técnica de análise de conteúdo temático. A partir das narrativas construíram-se as seguintes categorias de discussão: 1) “A Descoberta Do Adoecimento”; 2)”Tecendo Saberes Sobre o Adoecimento” 3)“ O Sentido do Tratamento Renal Substitutivo” e 4)“Caminhos Percorridos em Busca de Tratamento: uma trajetória de (des) cuidado”. Os itinerários apresentados neste estudo descrevem trajetórias e escolhas individuais e singulares, mas que possuem uma forte convergência que expõem de forma clara as fragilidades dos serviços de saúde e profissionais que compõe a rede de assistência à saúde. Possibilitou a compreensão de itinerários que sofrem influências dos contextos de vida de cada pessoa, algo que normalmente vêm escapando aos serviços e profissionais de saúde. Evidencia a necessidade de fortalecer a atenção básica como a porta de entrada desses sujeitos no sentido de reduzir as vulnerabilidades para a Doença Renal Crônica. / The study had as its object the Itinerary Therapeutic of Peoples in Renal Replacement Therapy Based Disease arterial hypertension and / or diabetes mellitus. To achieve the object of this study the following objectives were defined: To know the perceptions of hypertensive and / or diabetic people who are on renal replacement therapy in relation to their own health-illness, and treatment choices proposals; identify the assistance flow to people attending a Renal Replacement Therapy Center in the three levels of care; analyze the therapeutic itinerary of hypertensive patients and / or diabetic, suffering from chronic kidney disease, while assisted by Renal Replacement Therapy (RRT) in a nephrology service. It is a qualitative, descriptive, the study setting was a nephrology service located in a town in Zona da Mata Mineira, an entity that serves this city and micro-region. Study participants were 20 people on renal replacement therapy with underlying disease hypertension and / or diabetes mellitus, being interviewed on his dialysis schedule. The interviews implementation period was from October 2014 to January 2015. Data collection was performed using semi-structured interviews and analysis of data elected to thematic content analysis technique. From the narratives built up the following discussion categories: 1) "The Discovery Of Illness"; 2) "Weaving Knowledge About Illness" 3) "The Renal Treatment Sense Substitute" and 4) "Paths taken in sewage search: a trajectory of (lack of) care." The itineraries presented in this study describe trajectories and individual and individual choices, but have a strong convergence that expose clearly the weaknesses of health and professionals who make up the health care network services. It enabled the understanding of itineraries that are influenced the life contexts of each person, something that usually come escaping services and health professionals. Highlights the need to strengthen primary care as the gateway of these subjects to reduce the vulnerabilities for Chronic Kidney Disease.

Submitted by Michele Mologni (mologni@unoeste.br) on 2018-09-27T19:11:36Z No. of bitstreams: 1 André Casanova de Oliveira.pdf: 871298 bytes, checksum: 1a18f35c00a5d4e07f5e4dff3f267e48 (MD5) / Made available in DSpace on 2018-09-27T19:11:36Z (GMT). No. of bitstreams: 1 André Casanova de Oliveira.pdf: 871298 bytes, checksum: 1a18f35c00a5d4e07f5e4dff3f267e48 (MD5) Previous issue date: 2017-08-28 / . / .

A hipertensão arterial sistêmica (HAS) pós-transplante é frequente e está associada com aumento da morbimortalidade cardiovascular e subsequente disfunção do enxerto, sendo relatada como consequência ao uso de imunossupressores, especialmente os inibidores da calcineurina. Este estudo pretende avaliar o impacto da hipertensão arterial sobre a rigidez arterial calculada utilizando o índice ambulatorial de rigidez arterial (IARA) como desfecho substituto obtido pela monitorização ambulatorial da pressão arterial (MAPA) em pacientes transplantados de coração. Trata-se de um estudo prospectivo, observacional, analítico, com grupo controle, realizado no Hospital de Messejana Dr. Carlos Alberto Studart Gomes, hospital público do estado do Ceará, especializado em doenças cardiopulmonares e de referência em transplante de coração. Foram selecionados pacientes adultos transplantados do coração, os quais passaram por exames clínicos e complementares, e um grupo controle com pacientes não transplantados hipertensos. Todos foram submetidos a MAPA e obtenção do IARA com o objetivo de estimar o risco de rigidez arterial. Foram realizados testes estatísticos de significância e regressão logística para controle de confundimento. A média de idade dos transplantados foi de 55 anos, contra 48 dos não transplantados. A hipertensão prévia foi mais frequente em não transplantados, mas diabetes e doença arterial coronariana foram mais frequentes em transplantados. A média diastólica dos transplantados (82) é significativamente maior que a dos não transplantados (74) e o descenso sistólico é praticamente inexistente em pacientes transplantados (-0,18) que no grupo-controle (9,45). A condição de transplantado do paciente não é determinante de rigidez arterial, mas a hipertensão arterial sistólica na primeira avaliação, a média sistólica em 24h, a média diastólica em 24h, o descenso sistólico, o descenso diastólico e o IARA (parâmetros da MAPA) o são. Este estudo encontrou que num grupo de transplantados de coração adultos, a hipertensão arterial sistêmica está independentemente associada com a rigidez arterial estimada pelo IARA, que é um novo método, não invasivo, de fácil execução e de baixo custo. A evidência demonstrada por este estudo pode auxiliar no direcionamento de tratamento dos pacientes transplantados, contribuindo com melhoria do prognóstico / Hypertension post cardiac transplant is frequent and is associated with increased cardiovascular morbidity and mortality and graft dysfunction, being reported because of the use of immunosuppressant, especially the calcineurin inhibitors. This study aims to evaluate the impact of hypertension on the arterial stiffness calculated using the IARA as surrogate outcome obtained by the Home Blood Pressure Monitoring in heart transplanted patients. This is an observational study, analytical, with the control group, in Heart and Lung Messejana´s Hospital, a public institution in the State of Ceará, which is specialized in cardiopulmonary diseases and especially in heart transplant, with adult patients cardiac transplanted, which underwent clinical and complementary exams, from which were obtained the IARA. Statistical significance tests and logistic regression to control for confounding were performed. The average age of transplanted was 55 years, against 48 of the non-transplanted. Hypertension was more frequent in prior not transplanted, but diabetes and coronary artery disease were more frequent in transplanted. The average diastolic of transplanted (82) is significantly higher than the non-transplanted (74) and decrease systolic is virtually nonexistent in transplant patients (-0.18) than in the control group (9.45). The condition of the transplanted patient is not determinant of arterial stiffness (p = 0.105), but are the systolic hypertension in the first evaluation, the average systolic, diastolic average in 12:0 am 12:0 am, systolic, diastolic descent and the IARA (parameters of the HBPM). This study showed that in a group of adult cardiac transplanted, hypertension is independently associated with arterial stiffness estimated by IARA, which is a new method, non-invasive, easy to perform and inexpensive. The evidence demonstrated by this study may assist in treatment of transplanted patients, contributing to improving the prognosis

L'hypertension artérielle pulmonaire (HTAP) est une maladie rare caractérisée par une augmentation de la pression artérielle pulmonaire moyenne liée à un important remodelage de la paroi vasculaire obstruant progressivement les petites artères pulmonaires. Le récepteur NMDA (NMDAR) est un récepteur au glutamate jouant un rôle crucial dans la transmission synaptique neuronale. Il est aussi présent dans des cellules périphériques, notamment les cellules vasculaires aortiques et cérébrales, et participe à leur prolifération. De plus, le NMDAR contribue à la prolifération des cellules cancéreuses. Puisque dans l'HTAP, les cellules vasculaires pulmonaires présentent un phénotype cancer-like, hyperprolifératif et résistant à l'apoptose, nous avons émis l'hypothèse selon laquelle les NMDARs vasculaires pulmonaires pourraient contribuer au remodelage vasculaire et conduire à l'HTAP. Nous avons montré que les cellules vasculaires pulmonaires expriment physiologiquement les principaux éléments d'une communication glutamatergique fonctionnelle via le NMDAR. Dans l'HTAP, le glutamate s'accumule dans les vaisseaux remodelés et l'endothéline-1, un acteur majeur du remodelage vasculaire, induit la libération du glutamate par les cellules musculaires lisses. Le NMDAR est mobilisé dans les cellules vasculaires et sa fonction pourrait être altérée en raison d'un déséquilibre dans le ratio d'expression de ses sous-unités. L'activation du NMDAR contribue à la prolifération des cellules vasculaires pulmonaires et à l'angiogenèse, éléments clés de la physiopathologie de l'HTAP. Des études réalisées sur des souris n'exprimant pas les NMDARs vasculaires ou utilisant des antagonistes du NMDAR mettent en évidence le rôle du NMDAR dans l'hypertension pulmonaire expérimentale. Ces résultats suggèrent que le NMDAR est un nouvel acteur du remodelage vasculaire et qu'il représente une nouvelle cible thérapeutique de l'HTAP. Ils apportent également de nouveaux éléments alimentant l'analogie entre le système vasculaire et le système nerveux. / Pulmonary arterial hypertension (PAH) is a rare disease characterized by an increase in the mean pulmonary arterial pressure, due to a deep vascular remodeling leading to the progressive obstruction of the small pulmonary arteries. The NMDA receptor (NMDAR) is a glutamate receptor playing a crucial role in the neuronal synaptic communication. It is also present in peripheral cells, including aortic and cerebral vascular cells, and promotes their proliferation. Moreover, NMDAR contributes to proliferation of cancer cells. As pulmonary vascular cells exhibit a cancer-like hyperproliferative and apoptotic-resistant phenotype in PAH, we hypothesized that the activation of pulmonary vascular NMDARs may contribute to the vascular remodeling leading to PAH. We found that pulmonary vascular cells express the main features of a functional synaptic-like glutamatergic communication through NMDARs. In PAH, glutamate accumulates in pulmonary arteries, and endothelin-1, a major actor of the PAH-associated vascular remodeling, triggers glutamate release from smooth muscle cells. Furthermore, the NMDAR is mobilized and its function may be altered due to an unbalanced expression ratio of the NMDAR subunits. Moreover, NMDAR activation contributes to vascular cell proliferation and angiogenesis, key features of PAH pathophysiology. Finally, studies with NMDAR antagonists and vascular NMDAR-knockout mice showed that vascular NMDARs are involved in pulmonary hypertension. These results suggest that NMDAR is a new actor of the vascular remodeling and could represent a new therapeutic target in PAH. They also bring new pieces to the vascular/nervous parallels.

L’hypertension artérielle pulmonaire (HTAP) est une maladie mortelle caractérisée par un important remodelage vasculaire, principalement dû à l’hyperprolifération et à la résistance à l’apoptose des cellules du muscle lisse de l’artère pulmonaire (CML-AP). Récemment il a été montré que les CML-AP présentent un remodelage du métabolisme énergétique, avec une régulation négative de l’oxidation phosphorylante associée à une activation de la voie glycolytique, qui semble contribuer à leur phénotype particulier. La désacétylase sirtuine1 (SIRT1) est un important modulateur du métabolisme énergétique, notamment via son activation de peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), régulateur clé de la biogenèse mitochondriale. Dans cette étude, nous montrons pour la première fois que la prolifération des CML-AP de rat et humaines est caractérisée par une réduction de l’activité de SIRT1, et est augmentée suite à l’inhibition pharmacologique ou la sous-expression spécifique de SIRT1. De plus, suite à hypoxie chronique, des souris génétiquement déficientes en SIRT1 présentent un remodelage vasculaire plus important que celui observé chez les souris contrôles, ce qui est associé à une augmentation accentuée de l’hypertrophie et de la pression systolique du ventricule droit. Au contraire, l’activation pharmacologique de SIRT1 inhibe fortement la prolifération des CML-AP, et est associée à l’activation de la biogenèse mitochondriale. L’ensemble de ces résultats suggère que l'inactivation de SIRT1 joue un rôle causal dans l’hyperprolifération des CML-AP et cette enzyme pourrait être une nouvelle cible thérapeutique prometteuse pour le traitement de l’HTAP. / Pulmonary arterial hypertension (PAH) is a lethal disease characterized by an intensive vascular remodelling, mainly due to hyper-proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs). Recently it has been found that PASMCs, similarly to cancer cells, demonstrate a shift in energy metabolism from oxidative phosphorylation towards glycolysis thus contributing to their particular phenotype. The deacetylase sirtuin1 (SIRT1) is an important modulator of energy metabolism, particularly via its activation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), the master regulator of mitochondrial biogenesis. Here we show for the first time that rat and human PASMC proliferation is characterised by a diminution of SIRT1 activity, and is potentiated by SIRT1 pharmacological inhibition or specific downregulation. Moreover, after chronic hypoxia exposure, SIRT1 KO mice display a more intense vascular remodelling compared to their control littermates and this is associated with an exacerbated increase in right ventricle systolic pressure and hypertrophy. Conversely, pharmacological SIRT1 activation strongly inhibits PASMC proliferation, and is associated with the activation of mitochondrial biogenesis. In general, the data obtained show that SIRT1 inactivation plays a causative role in PASMC proliferation and this enzyme could be a promising therapeutic target for PAH treatment.

L’hypertension artérielle pulmonaire (HTAP) est une maladie rare définie par une augmentation de la pression artérielle pulmonaire moyenne due à un remodelage progressif des artérioles pulmonaires, menant à une défaillance du ventricule cardiaque droit. Le remodelage vasculaire est la conséquence d’une dysfonction endothéliale conduisant à une hyperprolifération et à un défaut d’apoptose des cellules vasculaires pulmonaires. Le récepteur NMDA (NMDAR), un récepteur au glutamate connu pour son rôle dans la plasticité neuronale et la transmission synaptique, a été récemment identifié comme acteur de ce remodelage vasculaire. Cependant, le sous-type de NMDAR impliqué n’est pas connu. Le développement de traitements potentiels ciblant le NMDAR nécessite de mieux comprendre quelles sous-unités du récepteur sont mobilisées dans la maladie. Dans la mesure où la sous-unité GluN2A est impliquée dans la survie des neurones et la sous-unité GluN2B dans leur mort, nous avons fait l’hypothèse que la composition des NMDARs vasculaires pulmonaires devait être dérégulée dans l’HTAP. Par conséquent, cette thèse a pour objectifs i) d’étudier la composition du NMDAR dans l’HTAP, ii) d’en identifier les conséquences fonctionnelles, et iii) d’explorer son intégration au sein de la physiopathologie de l’HTAP.Nous avons montré que l’expression de la sous-unité GluN2B est réduite dans les artères pulmonaires des patients HTAP comparés à des sujets non-HTAP, malgré l’augmentation de l’expression de la sous-unité obligatoire GluN1, suggérant une commutation de l’expression des NMDARs de type GluN2B vers d’autres sous-types. Nous avons également montré que les NMDARs de type GluN2B sont rapidement et transitoirement recrutés à la membrane des cellules musculaires lisses (CMLs) en réponse à un facteur de croissance, le PDGF, par l’intermédiaire des Src family kinases (SFKs). En utilisant un inhibiteur spécifique des NMDARs de type GluN2B, nous avons observé qu’ils réduisaient la prolifération et la migration dépendantes du PDGF, indiquant une boucle de rétrocontrôle négatif. Ces résultats suggèrent une signalisation croisée entre le PDGFR-β, les SFKs et les NMDARs de type GluN2B. Ainsi le déficit en NMDARs de type GluN2B chez les patients HTAP pourrait potentialiser la réponse proliférative et migratoire au PDGF, une voie suractivée dans l’HTAP. De plus, nous avons montré que les NMDARs de type GluN2A sont recrutés de façon prolongée à la membrane des CMLs lors d’une stimulation par le PDGF. Néanmoins, le rôle précis des récepteurs de type GluN2A dans l’HTAP reste à découvrir. Pour approfondir le rôle du NMDAR dans la physiopathologie de l’HTAP, nous avons mené une étude bio-informatique complémentaire afin de modéliser les voies de signalisation impliquant le NMDAR dans l’HTAP. Nous avons construit et connecté en réseau les bases de connaissance sur les acteurs de l’HTAP d’une part, et les voies de signalisation impliquant le NMDAR dans le système nerveux central d’autre part. Nous avons montré que ces réseaux positionnent le NMDAR au cœur de nombreuses voies de signalisation caractéristiques de l’HTAP, dont celle du PDGFR-β.Ainsi, nous avons montré que l’expression membranaire des récepteurs de type GluN2A et GluN2B est dérégulée dans l’HTAP, orientant probablement la réponse au glutamate dépendante du PDGF vers les récepteurs de type GluN2A. Les conséquences d’un tel déséquilibre sont l’augmentation de la prolifération et de la migration des CMLs vasculaires pulmonaires. De plus le manque de récepteurs de type GluN2B est une caractéristique physiopathologique nouvelle dans l’HTAP et dans la compréhension du mode d’action des NMDARs périphériques en général. Enfin, le NMDAR semble être un acteur central dans la physiopathologie de l’HTAP, interagissant avec de nombreuses voies de signalisation impliquées dans la maladie, suggérant de nouvelles pistes pour avancer dans la compréhension des mécanismes physiopathologiques de l’HTAP. / Pulmonary arterial hypertension (PAH) is a rare disease defined by an increase in mean pulmonary arterial pressure due to progressive obstruction of the small pulmonary arteries, leading to right heart failure and death. The vascular remodeling is a consequence of complex and multiple patho-mechanisms, including endothelial cells dysfunction and hyperproliferation of smooth muscle cells in the pulmonary vascular wall. The N-methyl-D-aspartate receptor (NMDAR), a glutamate receptor, has been recently identified as playing an active role in this vascular remodeling. It has been shown that in pulmonary arteries of PAH patients, NMDAR is overexpressed and overactivated and is involved in the proliferation and resistance to apoptosis of pulmonary vascular cells. However, the NMDAR subtype involved in this process remains unknown. The development of potential treatments targeting the NMDAR requires a better understanding of its subunit involvement in the disease. Since the GluN2A subunit is involved in the survival of neurons and the GluN2B subunit in their death, we hypothesized that the pulmonary vascular NMDAR subunit composition could be dysregulated in PAH. Therefore, in this thesis study we aimed to: i) study the composition of NMDAR in PAH, ii) explore its functional consequences in the pathophysiology of PAH, and iii) uncover its integration in the pathophysiology of PAH.We showed that the expression of the GluN2B subunit is reduced in the pulmonary arteries of PAH patients compared to non-PAH subjects. This occurs despite the overall increased expression of the obligatory GluN1 subunit, suggesting a switch from GluN2B-type receptors to, at least, another GluN2-type receptor. We also showed that in the presence of PDGF-BB, there is an immediate increase in the levels of phosphorylated Src family kinases (SFKs), associated to an increase in phosphorylated GluN2B (the active form) that were relocated to the cell membrane, suggesting the cross-talk between PDGF, SFKs and NMDAR. To validate the pathway, we inhibited the activation of PDGFR-β or SFKs, and in both cases the phosphorylation of GluN2B after PDGF stimulation was aborted. To assess the functional importance of this pathway, proliferation and “wound healing” tests were performed. The results clearly showed that selective inhibition of GluN2B, in the presence of PDGF, significantly increased both migration and proliferation of PASMCs. These results suggest that the lack of GluN2B-type receptors in PAH may potentiate SMC proliferative and migratory response to PDGF, a well-known overactivated pathway in PAH. In addition, we showed that GluN2A-type NMDARs arerecruited to the SMC membrane following PDGF stimulation, but the precise role of GluN2A-type NMDARs in PAH remains elusive. To further explore the crosstalk between the NMDAR and the PDGF receptor (PDGFR) pathways, we conducted a complementary bioinformatics study. To provide a model of the NMDAR signaling pathways in PAH we constructed and connected comprehensive knowledge bases of the actors involved in PAH on one hand and the signaling pathways involving NMDAR within the central nervous system on the other hand. Within these networks the NMDAR was revealed as a central downstream effector of the hallmark signaling pathways of PAH, including that of PDGFR.These results indicate that the membrane expression of GluN2A-type and GluN2B-type receptors is dysregulated in PAH, presumably switching the PDGF-dependent glutamate response towards GluN2A-type receptors. The consequences of such imbalance are the increased proliferation and migration of pulmonary vascular SMCs. Moreover, the lack of GluN2B-type NMDARs is a new feature in the pathophysiology of PAH and in the understanding of peripheral NMDA receptors in general. Besides, the NMDAR seems to be a central effector in PAH, interacting with multiple hallmark pathways of the disease, suggesting new tracks to further understanding the pathophysiology of PAH.

En Perú el gasto de bolsillo es el principal financiamiento de los servicios de salud (MINSA, 2018), siendo la botica el principal punto de contacto. Lima Metropolitana tiene un 22.5% de la población con hipertensión arterial (INEI, 2019), 5.1% con diabetes (INEI, 2019) y 33% con triglicéridos y colesterol total elevados (INS, 2020), quienes requieren tratamiento con medicamentos y el uso de dispositivos médicos. Adicionalmente, el volumen de ventas del 2020 de medicamentos creció entre 2% y 3%, y el canal online aumentó un 42%, mostrando un importante cambio en las tendencias de compra (Gestión.pe, 2021). Una Botica digital con entrega por delivery mejoraría el acceso a medicamentos y dispositivos médicos requeridos para estas enfermedades; los pacientes podrían solicitar su tratamiento desde la comodidad de su hogar, recibiéndolos de manera oportuna y mejorando la adherencia al tratamiento, evitando las complicaciones de las distancias, tiempos de traslados y riesgos de acudir personalmente. Lima moderna tiene más población de los niveles socioeconómicos A, B y C, quienes mayormente compran productos por internet (APEIM, 2020). Pharma Place, presenta una estrategia de enfoque debido a la especialización de los productos, la venta por canal digital y la entrega por delivery. Dentro de las ventajas competitivas se consideran la innovación tecnológica y ser la primera botica digital especializada en Lima. La inversión requerida es S/ 325,000.00 los cuales serán financiados por los socios y entidades bancarias, el análisis de factibilidad financiera muestra un VAN de S/ 329,491.90 y TIR de 46.10% en un escenario conservador. / In Peru, the health out-of-pocket spending is the main financing for health services (MINSA, 2018), with the drugstore being the main point of contact. Metropolitan Lima has 22.5% of the population with arterial hypertension (INEI, 2019), 5.1% with diabetes (INEI, 2019) and 33% with high triglycerides and total cholesterol (INS, 2020), who require drug treatment and the use of medical devices. Additionally, the 2020 sales volume of medicines grew between 2% and 3%, and the online channel increased by 42%, showing an important change in purchasing trends (Gestión.pe, 2021). A digital drugstore with the supply by delivery would improve access to medicines and medical devices required for these diseases; patients could request their treatment from the comfort of their home, receiving them in a timely manner and improving adherence to treatment; thus avoiding the complications of distances, travel times and risks of going in person. Modern Lima has a larger population of socioeconomic levels A, B and C, who mostly purchase products through the internet. Pharma Place presents a focus strategy due to the specialization of the products and the sale through the digital channel; the main competitive advantages are technological innovation and being the first specialized digital drugstore in Lima. The required investment is S/ 325,000.00 which will be financed by the associates and banks; the financial feasibility analysis shows an NPV of S/ 329,491.90 and IRR of 46.10% in a conservative scenario. / Trabajo de investigación

Pulmonary arterial hypertension (PAH) is a rare, devastating disease with no cure. Current treatment consists of a cocktail of vasodilators which relieve symptoms of PAH but do not treat the cause. Thus, there is a need for novel drugs that target the underlying pathological causes of PAH. PAH is a multi-factorial, but one key contributor is the pro-inflammatory cytokine IL-6 which stimulates pro-inflammatory and pro-angiogenic signalling mediated by the JAK/STAT pathway. One way in which IL-6 signalling via JAK/STAT is inhibited is via SOCS3 in a type of negative feedback loop whereby IL-6 induces transcription of SOCS3, which then attenuates further JAK/STAT signalling. SOCS3 can also be induced by cAMP. This is interesting as prostanoids, a type of drug used in the treatment of PAH due to its vasodilator effects and the only type to show any efficacy improving the life expectancy of PAH patients, acts by mobilising cAMP. Thus, prostanoid stimulation of cAMP could potentially limit IL-6 signalling via the induction of SOCS3. This is a novel mechanism of prostanoids which has not previously been considered. This study investigated the capability of prostanoids to limit the pro-inflammatory/pro-angiogenic effects of IL-6 that enable PAH to develop. Initial experiments confirmed that vascular endothelial cells responded to prostanoids which increased SOCS3 and limited IL-6 signalling activity. Further experiments utilising SOCS3 KO endothelial cell models demonstrated prostanoid inhibition of IL-6 signalling was due in part to SOCS3. In conclusion, this project has confirmed that prostanoids do limit the pro-inflammatory effects induced by IL-6 and that this is in part due to SOCS3. Although the exact mechanism is yet to be discovered, it will be beneficial in the treatment of PAH as it provides currently unexploited drug targets which can be considered for future PAH therapies. / British Heart Foundation

Pulmonary Arterial Hypertension (PAH) is a rare incurable condition affecting both the cardiac and respiratory systems. Patients living with PAH face the burden of both intensive medication regimens and debilitating disease symptoms. This study’s primary aim was to identify patients’ medication-taking behaviours and beliefs using a framework derived from the extended health belief model (EHBM), and to use this information to deliver personalised interventions to improve medication-taking behaviours. A mixed-methodology longitudinal study design recorded patients’ parameters over a 12-month period. Thirteen participants from Northern Ireland completed the study. The results showed that the level of high-adherence to PAH medicines, as assessed using the MARS questionnaire was 80%, but this value differed when assessed via pill counting and interview data. There was a trend to improvement in observed and predicted medication adherence over the study duration. Participants’ beliefs showed a non-statistical increase in the specific-necessity beliefs and a reduction in general-overuse belief. This study added to the EHBM new constructs of trust and support in being able to better predict nonadherent behaviours. Key medication-taking themes were self-confidence, perceived ranking of medicines, uncertainty and knowledge. This study developed important learning that can be applied to future research on behavioural health studies. / Heart Trust Fund; Actelion Pharmaceuticals

Background: Fingolimod is the first oral immunomodulatory therapy approved for highly active relapsing remitting multiple sclerosis. Based on the distribution pattern of fingolimod interacting sphingosine-1-phosphat receptors in organism including immune system and cardiovascular system clinical monitoring of patients and evaluation of adverse events are recommended. Despite extensive data on cardiovascular safety, experience with fingolimod in patients with concomitant cardiological disease, especially within the pulmonary circulation, is rare. Case presentation: We report the case of a 46-year-old woman presented with relapsing remitting multiple sclerosis and severe idiopathic pulmonary arterial hypertension. Fingolimod was initiated because of disease activity of multiple sclerosis with two relapses and gadolinium-enhancing lesions in MRI. The patient demonstrated stable disease course of idiopathic pulmonary arterial hypertension when fingolimod was started. Fingolimod therapy did not alter or even worsen the pulmonary or cardiovascular conditions during first dose application as well as follow up of nine months. Conclusion: In this report, we present the first case of fingolimod treatment in a patient with highly active multiple sclerosis and severe idiopathic pulmonary arterial hypertension. We suggest an interdisciplinary approach with detailed cardiopulmonary monitoring for safety in such patients.