<p>The intention of the study is to evaluate the risk of artemisinin in early pregnancy through the use of a qualitative research approach, with a focus on rural women in Babati District, Manyara Region, Tanzania.</p><p>Artemisinin-Based Combination Therapy (ACT) is the most effective and recommended antimalarial treatment at the present. Artemisinin compounds are extracted from <em>Artemisia annua</em><em>, </em>a plant which has been used as an herbal medical treatment in China for 2000 years.</p><p>Except few side-effects, there have not been any reports on medical problems due to artemisinin intake during pregnancy. On the other hand, artemisinin tested on animals have revealed that complications such as death of embryos are possible during pregnancy, why more research is needed concerning artemisinin safety in first trimester of pregnancy.</p><p>However, evaluating the risk of artemisinin in pregnancy is referred as complex, when numerous factors could contribute to e.g. fetal loss, abnormalities, or wrong medication. Cultural and economical aspects have to be considered when designing a monitoring system, to enable effective registration of drug quality and drug intake, and follow-up study of mother and child. Accessibility, affordability, possibility and knowledge, are other significant related aspects that have to be managed to eliminate the risk of artemisinin in early pregnancy.</p><p> </p><p><strong></strong></p><p> </p><p> </p>

The intention of the study is to evaluate the risk of artemisinin in early pregnancy through the use of a qualitative research approach, with a focus on rural women in Babati District, Manyara Region, Tanzania. Artemisinin-Based Combination Therapy (ACT) is the most effective and recommended antimalarial treatment at the present. Artemisinin compounds are extracted from Artemisia annua, a plant which has been used as an herbal medical treatment in China for 2000 years. Except few side-effects, there have not been any reports on medical problems due to artemisinin intake during pregnancy. On the other hand, artemisinin tested on animals have revealed that complications such as death of embryos are possible during pregnancy, why more research is needed concerning artemisinin safety in first trimester of pregnancy. However, evaluating the risk of artemisinin in pregnancy is referred as complex, when numerous factors could contribute to e.g. fetal loss, abnormalities, or wrong medication. Cultural and economical aspects have to be considered when designing a monitoring system, to enable effective registration of drug quality and drug intake, and follow-up study of mother and child. Accessibility, affordability, possibility and knowledge, are other significant related aspects that have to be managed to eliminate the risk of artemisinin in early pregnancy.

Doctor Scientiae / Achieving blood pressure and glycaemic treatment targets remain a major public health challenge in individuals with hypertension and diabetes mellitus (DM). This research project was, therefore, designed to investigate the socio-demographic, clinical and genetic factors associated with blood pressure and glycaemic control among indigenous South African adult patients. The main aims of the project were as follows: (1) To assess the prevalence and socio-demographic factors associated with uncontrolled hypertension, in individuals receiving chronic care in primary healthcare facilities, based in the rural areas of Mkhondo Municipality (Study 1). (2) To investigate the association of nineteen single nucleotide polymorphisms (SNPs) with blood pressure control among adult patients treated with hydrochlorothiazide (Study 2). (3) To assess the level of association between twelve SNPs with uncontrolled blood pressure for adult patients treated with amlodipine (Study 3). (4) To examine the association of five SNPs in selected genes (ABO, VEGFA, BDKRB2, NOS3 and ADRB2) with blood pressure response to enalapril treatment, and further assess interaction patterns that influence blood pressure response (Study 4). (5) To determine the prevalence of poor glycaemic control and its influencing factors among adult patients from Mkhondo Municipality attending chronic care for DM (Study 5). (6) To evaluate the level of association between polymorphisms found in the SLC22A1, SP1, PRPF31, NBEA, SCNN1B, CPA6 and CAPN10 genes, and glycaemic response to metformin and Sulphonylureas (SU) combination therapy among South African adults with DM. Also, to investigate interaction patterns that influence glycaemic control in response to metformin and SU combination therapy (Study 6).

[ES] Los tratamientos en los que se utilizan Polímeros Terapéuticos ofrecen numerosas ventajas en comparación con los tratamientos convencionales y otros enfoques de nanomedicina. Entre estas ventajas se puede destacar la especificidad para cruzar ciertas barreras biológicas y su capacidad de acumulación pasiva en tumores. Además, la conjugación de fármacos a polímeros ofrece ventajas adicionales tales como una farmacocinética mejorada, multivalencia, co-entrega de fármacos en la proporción deseada y liberación/activación específica en el sitio de acción requerido a través de la aplicación de enlaces polímero-fármaco que responden a estímulos fisiológicos. Uno de los tipos más importantes de polímeros que se utiliza para la administración de fármacos pertenecen a los polielectrolitos polipeptídicos. Su uso se debe principalmente, a su biocompatibilidad, biodegradabilidad, multivalencia y versatilidad estructural, así como a la plasticidad sintética en la modificación de cadenas laterales. La aplicación conjunta de ciencia de polielectrolitos con otras ramas de la química es muy prometedora; sin embargo, aún permanece en un estadío temparano en su desarrollo. Esto es debido a que, el control del autoensamblaje de polielectrolitos sigue siendo una tarea complicada y la investigación en esta área puede resultar muy laboriosa a la hora de encontrar sistemas biocompatibles más avanzados con un único perfil de acción y por supuesto, se abre un nuevo campo de estudio sobre las nuevas propiedades desconocidas de estos. Este tema es novedoso por la posibilidad de realizar diferentes estudios de combinación de polielectrolitos con residuos supramoleculares y representa el estudio de nuevas arquitecturas potencialmente mas complicadas. En la presente tesis doctoral se estudiarán el desarrollo de sistemas de administración de fármacos basados en polielectrolitos supramoleculares con un alto grado de control sobre las propiedades fisicoquímicas, centrándose principalmente en el control de la forma y el tamaño. Se han estudiado en profundidad varias familias de poliglutamatos de forma estrella con núcleos de diferente hidrofobicidad para determinar cómo la estructura del núcleo y la longitud de la cadena de polielectrolitos afectan el mecanismo de autoensamblaje. Una vez que se definieron estas correlaciones, se seleccionaron los candidatos más prometedores para la preparación de dos sistemas de transportede fármacos que consisten en partículas esféricas o en forma de cilindro. Finalmente, también se realizó la conjugación de varios fármacos (fasudil y dinaciclib) como agentes únicos o en combinación a través de diferentes enlaces biodegradables. Las propiedades fisicoquímicas y la actividad in vitro de los conjugados se estudiaron en profundidad y actualmente se están llevando a cabo experimentos in vivo en un modelo de cáncer de mama metastásico triple negativo ortotópico preclínicamente relevante, con los conjugados previamente seleccionados. / [CAT] Els tractaments en els quals s'utilitzen Polímers Terapèutics ofereixen nombrosos avantatges en comparació amb els tractaments convencionals i altres enfocaments amb nanomedicina. Entre aquests avantatges es pot destacar l'especificitat per creuar certes barreres biològiques i la seva capacitat d'acumulació passiva en tumors. A més, la conjugació de fàrmacs a polímers ofereix avantatges addicionals com ara una farmacocinètica millorada, multivalència, co-lliurament de fàrmacs en la proporció desitjada i alliberament / activació específica en el lloc d'acció requerit a través de l'aplicació d'enllaços polímer-fàrmac que responen a estímuls fisiològics. Un dels tipus més importants de polímers que s'utilitza per a l'administració de fàrmacs pertanyen als polielectròlits polipeptídics. El seu ús es deu principalment, ala seua biocompatibilitat, biodegradabilitat, multivalència i versatilitat estructural, així com a la plasticitat sintètica en la modificació de cadenes laterals. L'aplicació conjunta de ciència de polielectròlits amb altres branques de la química és molt prometedora; però, encara roman en un estadi primerenc en el seu desenvolupament. Això és degut al fet que, el control de l'autoensamblatge de polielectròlits segueix sent una tasca complicada i la investigació en aquesta àrea pot resultar molt laboriosa a l'hora de trobar sistemes biocompatibles més avançats amb un únic perfil d'acció i per descomptat, s'obre un nou camp d'estudi sobre les noves propietats desconegudes d'aquests. Aquest tema és nou j que ofereix la possibilitat de realitzar diferents estudis de combinació de polielectròlits amb residus supramoleculars i representa l'estudi de noves arquitectures potencialment més complicades. En la present tesi doctoral s'estudiaran el desenvolupament de sistemes d'administració de fàrmacs basats en polielectròlits supramoleculars amb un alt grau de control sobre les propietats fisicoquímiques, centrant-se principalment en el control de la forma i la mida. S'han estudiat en profunditat diverses famílies de poliglutamatos de forma estrella amb nuclis de diferent hidrofobicitat per determinar com l'estructura delnucli i la longitud de la cadena de polielectròlits afecten el mecanisme de autoensamblatge. Una vegada que es van definir aquestes correlacions, es van seleccionar els candidats més prometedors per a la preparació de dos sistemes de transport de fàrmacs que consisteixen en partícules esfèriques o en forma de cilindre. Finalment, també es va realitzar la conjugació de diversos fàrmacs (fasudil i dinaciclib) com a agents únics o en combinació a través de diferents enllaços biodegradables. Les propietats fisicoquímiques i l'activitat in vitro dels conjugats es van estudiar en profunditat i actualment s'estan duent a terme experiments in vivo en un model ortotòpic de càncer de mama metastàtic triple negatiu preclínicament rellevant, amb els conjugats prèviament seleccionats. / [EN] Treatments based on polymer therapeutics offer numerous advantages when compared to conventional treatments and other nanomedicine approaches. These include passive tumor accumulation and the ability to cross specific biological barriers. Furthermore, polymer conjugation of drugs offers additional advantages such as improved pharmacokinetics, multivalency, co-delivery of drugs at the desired ratio, and specific release/activation at the required site of action via the application of polymer-drug linkers that respond to physiological stimuli. One of the most important types of polymers suitable for drug delivery belong to polypeptide polyelectrolytes, mainly due to their biocompatibility and synthetic plasticity of side chain modification. The merging of polyelectrolyte science with other branches of chemistry seems very promising; however, it still remains in an embryonic state. While the control of polyelectrolyte self-assembly remains a complicated task, research in this area may provide more advanced biocompatible systems with unique profiles of action and new materials with yet unknown properties. The combination of polyelectrolytes with supramolecular moieties represents an especially interesting research topic, with the potential to derived more complicated architectures. This thesis is focused on the development of supramolecular-polyelectrolyte-based drug delivery systems with high degree of control over physicochemical properties, focusing mainly on shape and size. Several families of star-polyglutamates with cores of different hydrophobicity have been studied in depth in order to determine how the core structure and polyelectrolyte chain length affect self-assembly mechanism. Once these correlations were defined, the most promising candidates were selected for preparation of two drug delivery systems consisting of either spherical or rod-like particles. Finally, conjugation of several drugs (fasudil and dinaciclib) as single agents or in combination through different responsive linkers were also performed; physicochemical properties and in vitro activity of the conjugates were studied in depth and in vivo experiments with selected conjugates are currently ongoing in a preclinically relevant orthotopic Triple Negative Metastatic Breast Cancer Model. / Zagorodko, O. (2020). CONFORMATIONALLY SWITCHABLE POLYGLUTAMATES AS A PROSPECTIVE MATERIAL FOR POLYMER THERAPEUTICS DESIGN [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/146228 / TESIS

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Platinum-based chemotherapies are effective agents in the treatment of a wide variety of human cancers. However, patients with recurrent disease can become resistant to platinum-based chemotherapy, leading to low overall survival rates. Activating transcription factor 3 (ATF3) is a stress-inducible gene that is a regulator of cisplatin-induced cytotoxicity. ATF3 protein expression was upregulated after cytotoxic doses of cisplatin treatment in a panel of cell lines. A chromatin immunoprecipitation assay showed that upon treatment with cisplatin, ATF3 directly bound to the CHOP gene promoter and this correlated with an increase in CHOP protein expression. In a 1200 compound library screen performed on cancer cell lines, disulfiram, a dithiocarbamate drug, was identified as an enhancer of the cytotoxic effects of cisplatin. This increased cytotoxic action was likely due to disulfiram and cisplatin’s ability to induce ATF3 independently through two separate mechanisms, namely the MAPK and integrated stress pathways. Furthermore, ATF3 protein and mRNA levels were variable amongst human ovarian and lung cancer tissues, suggesting the potential for basal expression of ATF3 to be predictive of cisplatin treatment response. Thus, understanding ATF3’s role in cisplatin-induced cytotoxicity will lead to novel therapeutic approaches that could improve this drug’s efficacy.

Platinum-based chemotherapies are effective agents in the treatment of a wide variety of human cancers. However, patients with recurrent disease can become resistant to platinum-based chemotherapy, leading to low overall survival rates. Activating transcription factor 3 (ATF3) is a stress-inducible gene that is a regulator of cisplatin-induced cytotoxicity. ATF3 protein expression was upregulated after cytotoxic doses of cisplatin treatment in a panel of cell lines. A chromatin immunoprecipitation assay showed that upon treatment with cisplatin, ATF3 directly bound to the CHOP gene promoter and this correlated with an increase in CHOP protein expression. In a 1200 compound library screen performed on cancer cell lines, disulfiram, a dithiocarbamate drug, was identified as an enhancer of the cytotoxic effects of cisplatin. This increased cytotoxic action was likely due to disulfiram and cisplatin’s ability to induce ATF3 independently through two separate mechanisms, namely the MAPK and integrated stress pathways. Furthermore, ATF3 protein and mRNA levels were variable amongst human ovarian and lung cancer tissues, suggesting the potential for basal expression of ATF3 to be predictive of cisplatin treatment response. Thus, understanding ATF3’s role in cisplatin-induced cytotoxicity will lead to novel therapeutic approaches that could improve this drug’s efficacy.

Platinum-based chemotherapies are effective agents in the treatment of a wide variety of human cancers. However, patients with recurrent disease can become resistant to platinum-based chemotherapy, leading to low overall survival rates. Activating transcription factor 3 (ATF3) is a stress-inducible gene that is a regulator of cisplatin-induced cytotoxicity. ATF3 protein expression was upregulated after cytotoxic doses of cisplatin treatment in a panel of cell lines. A chromatin immunoprecipitation assay showed that upon treatment with cisplatin, ATF3 directly bound to the CHOP gene promoter and this correlated with an increase in CHOP protein expression. In a 1200 compound library screen performed on cancer cell lines, disulfiram, a dithiocarbamate drug, was identified as an enhancer of the cytotoxic effects of cisplatin. This increased cytotoxic action was likely due to disulfiram and cisplatin’s ability to induce ATF3 independently through two separate mechanisms, namely the MAPK and integrated stress pathways. Furthermore, ATF3 protein and mRNA levels were variable amongst human ovarian and lung cancer tissues, suggesting the potential for basal expression of ATF3 to be predictive of cisplatin treatment response. Thus, understanding ATF3’s role in cisplatin-induced cytotoxicity will lead to novel therapeutic approaches that could improve this drug’s efficacy.

Platinum-based chemotherapies are effective agents in the treatment of a wide variety of human cancers. However, patients with recurrent disease can become resistant to platinum-based chemotherapy, leading to low overall survival rates. Activating transcription factor 3 (ATF3) is a stress-inducible gene that is a regulator of cisplatin-induced cytotoxicity. ATF3 protein expression was upregulated after cytotoxic doses of cisplatin treatment in a panel of cell lines. A chromatin immunoprecipitation assay showed that upon treatment with cisplatin, ATF3 directly bound to the CHOP gene promoter and this correlated with an increase in CHOP protein expression. In a 1200 compound library screen performed on cancer cell lines, disulfiram, a dithiocarbamate drug, was identified as an enhancer of the cytotoxic effects of cisplatin. This increased cytotoxic action was likely due to disulfiram and cisplatin’s ability to induce ATF3 independently through two separate mechanisms, namely the MAPK and integrated stress pathways. Furthermore, ATF3 protein and mRNA levels were variable amongst human ovarian and lung cancer tissues, suggesting the potential for basal expression of ATF3 to be predictive of cisplatin treatment response. Thus, understanding ATF3’s role in cisplatin-induced cytotoxicity will lead to novel therapeutic approaches that could improve this drug’s efficacy.

Invasive fungal infections (IFIs) are associated with considerable morbidity and mortality among high-risk individuals. Outcomes for IFI historically have been suboptimal and associated with a high mortality rate, hence global prophylaxis strategies have been applied to at-risk populations. Among certain populations, fluconazole prophylaxis has reduced systemic and superficial infections caused by Candida species. Newer azoles are currently being evaluated as prophylaxis and have the potential to provide protection against mould pathogens that are more troublesome to treat once they occur. Global prophylaxis strategies have the shortcoming of subjecting patients to therapy that ultimately will not need it. Targeted prophylaxis has the advantage of treating only patients at highest risk using some parameter of greater host susceptibility. Prophylaxis strategies are most suitable in patients at the highest risk for IFI. For patient groups whose risk is somewhat lower or when suspicion of IFI occurs in patients receiving prophylaxis, empirical antifungal therapy is often employed following a predefined period of fever. Again this approach subjects many non-infected patients to unnecessary and toxic therapy. A more refined approach such as presumptive or pre-emptive therapy whereby treatment is only initiated upon positive identification of a surrogate marker of infection in combination with clinical and radiological signs will subject fewer patients to toxic and expensive treatments.