Facultad de Farmacia y Nutrición - Tesis Doctorales y Tesinas - 2010-2019
Permanent URI for this collectionhttps://hdl.handle.net/10171/42547
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- Optimización de la terapia antiemética en pacientes oncológicos con tumores sólidos atendidos en el Hospital de día de la Clínica Universidad de Navarra(Universidad de Navarra, 2022-01-21) García-del-Barrio, M.A. (M.A.); Aldaz, A. (Azucena); Martin-Algarra, S. (Salvador)Optimization of antiemetic therapy in cancer patients receiving ambulatory chemotherapy at the University of Navarra Clinic María Ángeles García del Barrio. College of Pharmacy. University of Navarra. 2015 Chemotherapy-induced nausea and vomiting (CINV) is a major concern of antineoplastic treatment because of its high incidence, the patients¿ fear of experiencing them and clinicians¿ difficulty in assessing it properly, mainly in the delayed phase (days 2 to 5). The availability of new antiemetic drugs and the update of the Antiemesis Guidelines, has made imperative a review of the institutional protocols employed to prevent these effects. To analyze and promote changes, we have to establish the real efficacy of the protocol actually used. A prospective recruitment of 157 ambulatory patients showed a global incidence of emesis (nausea and/or vomiting-NV) of 28%. Only 11% of the patients suffered from vomiting; nausea was the major symptom (27%). Twenty one patients (13%) had NV in the first 24 hours after treatment and 43 (27%) at the delayed phase. The majority of them (98%) had received prophylaxis before chemotherapy, while health professionals underestimated the risk during days 2 to 5, with 22% of the patients without antiemetics. The apparition of acute symptoms was a main prognostic factor for delayed emesis, increasing the risk of NV at that period (OR 23). The emetogenicity level of the antineoplastic agents was relevant, with the highly emetogenic chemotherapy (HEC) as the principal cause of symptoms. The most implicated cytostatics were cisplatin, anthracycline-cyclophosphamide combination (AC) and irinotecan. Emetogenicity attributed to cisplatin was dose-depended and the patients who receive ≥ 50 mg/m² had more incidence of CINV. Irinotecan proved to be more emetogenic than its usual classification as moderate indicates. The results about AC combination were in consonance with its actual classification on the Antiemetic Guidelines as HEC. Some prognosis factors that remained at the multivariable regression model for emesis were: diagnosis of esophageal-gastric cancer, AC or irinotecan employment, patients¿ expectations regarding emesis ≥3, CINV antecedents and neoadjuvant intention of treatment. Patients¿ expectations of emesis were a good parameter to assess the impact of subjective factors, since it was related to others as individual susceptibility for emesis, insomnia, anxiety-depression level or NV related to meals. Seventy per cent of the patients with CINV felt this influenced their quality of life (iQoL) and nausea was the main symptom implicated (74% vs 50% cause by vomiting). The duration of the symptoms was relevant and the patients who had CINV for 2 days or more, demonstrated an increased risk of iQoL (OR 30). When nausea grade was ≥2, the probability for the patients to see affected their daily life activities was greater. Adverse events reported by the patients included fatigue, constipation, somnolence, insomnia and nervousness. Fatigue was probably related to the disease and the effect of chemotherapy treatment; constipation was linked to 5HT3-antagonist employ and insomnia-nervousness was an effect of corticosteroid therapy. With the results obtained it has been possible to establish some improvement proposals on antiemetic therapy.
- Optimización de tratamientos con irinotecan y capecitabina en pacientes con cáncer colorrectar basada en técnicas de farmacocinética e inteligencia artificial(2020-03-16) Oyaga-Iriarte, E. (Esther); Sayar, O. (Onintza); Aldaz, A. (Azucena)Introduction: Colorectal cancer is the fourth cancer with the highest incidence and the second with the highest mortality rate, according to 2018 data. Adenocarcinoma is the fundamental form in which it occurs, occupying 90% of the cases. The drugs used to combat this disease are numerous and have narrow therapeutic ranges and strong adverse effects. Controlling plasma levels is essential to achieve optimal pharmacotherapy. Irinotecan and capecitabine have been the drugs analyzed in this work. These drugs are administered both in monotherapy and in combination, in schemes such as FOLFIRINOX or FOLFIRI for irinotecan and XELOX for capecitabine. Both drugs have an active metabolite responsible for the therapeutic action of the drug. These metabolites, in addition to the treatment effect, are responsible for a large part of the toxicities derived from the treatment, hence, their correct characterization is pharmacologically relevant. Hypothesis: The prevalence of colorectal cancer and the necessity to increase positive results in health generates the need to incorporate new tools, such as those included in the framework of artificial intelligence, which, together with other more classic ones such as pharmacokinetic and pharmacodynamic modeling, make it possible to facilitate optimal use of chemotherapy in routine care practice. Results: A compartmental pharmacokinetic model has been obtained for each of the drugs and their corresponding metabolites, making use of parametric and non-parametric methodologies. The precision indices of these models reach values of R2=0.964 for the case of irinotecan and R2=0.886 for capecitabine. Moreover, the capecitabine model has permitted to obtain optimal sampling times for this drug. On the other hand, models based on machine learning have been developed to predict irinotecan derived toxicities such as late diarrhea, leukopenia and neutropenia with success rates of 91, 76 and 75%, respectively. These models are based both on particular characteristics of each patient and on values of their pharmacokinetic parameters. Finally, the proposed models for irinotecan have been integrated in a software enabling their correct use in clinical practice. Conclusions: The kinetics of irinotecan and capecitabine and their corresponding metabolites have been correctly characterized, allowing an individualized adjustment of the concentrations over time of each of the patients. Moreover, in the case of irinotecan, the reconversion from the glucuronide metabolite to the active metabolite, due to enterohepatic reabsorption, has been characterized for the first time in the literature, which is a fundamental feature of this drug. The models based on artificial intelligence allow to correctly predict the possibility for a new patient to develop late diarrhea, leukopenia and neutropenia, by means of particular characteristics of that patient. A strong relationship between pharmacokinetic parameters and the studied toxicities for irinotecan has been demonstrated, for the areas under the plasma curves and the maximum concentrations of this drug are linked with the degree of toxicity. The developed software permits to apply the results obtained in this thesis in clinical practice.
- Antidepressant action of ketamine in two genetic models of impaired glutamate and melatonin function(2020-03-16) Belloch-Pérez, F. B. (Francisco de Borja); Puerta, E. (Elena); Tordera, R.M. (Rosa María)Major depression is a mental disorder characterized by extreme low mood and anhedonia. Facing major depression is an urgent social and medical need since it involves a lot of suffering in patients and their families or friends as well as an important socio-economic cost worldwide. Depression has been studied for many years the different hypothesis have important limitations including the latency time needed for antidepressants to start working, the great number of resistant patients and the enduring vulnerability of many patients to relapse. Those limitations drive the need to develop new strategies to treat this mental disorder. In recent years, one of the molecules that have opened this field is the NMDA antagonist ketamine that increases glutamate transmission in the PFC and trigger antidepressant effects within a few hours. At the preclinical level, most studies focused on identification of molecular mechanisms mediating the rapid antidepressant response of ketamine have been carried out in healthy mice. Here we have studied the effect of ketamine, comparatively to the classic antidepressant reboxetine, in two genetic models of impaired glutamate and melatonin function. The specific endophenotype of the VGLUT1+/- depression model has provided a better comprehension of the molecular mechanisms involved in antidepressant response or resistance to treatment. Specifically this model was resistant to the rapid antidepressant action of ketamine and it is suggested that the phosphorylation of the intracellular mediator eukaryote elongation factor 2 (p-eEF2) could be responsible for this resistance. Further stimulation of PFC VGLUT1 expression using the priming effect of a classic antidepressant or by recombinant adeno-associated virus (AAV) technology rescued the antidepressant action of ketamine. On the other hand, the melatonin receptor 2 deficient model (MT2-/- knock-out mice) showed impaired reward reactivity associated to circadian rhythm disruption and interestingly, both classic and the rapid-acting antidepressant ketamine were effective.
- Emulsions as delivery systems of unsaturated lipids: oxidative stability and applications(2020-01-31) Poyato, C. (Candelaria); Astiasarán, I. (Iciar); Ansorena-Artieda, D. (Diana)The formulation of healthier and functional foods sometimes implies the incorporation of bioactive compounds, and therefore the design and development of technological strategies to facilitate an adequate integration of the new substances into the final product. In the present work, the formulation of emulsions as new delivery systems was proposed, aiming to obtain complex and stable ingredients for food applications. In this sense, the use of hydrophilic polymers (carrageenan) allowed to obtain both multiple emulsions and gelled emulsions for food use, and able to deliver unsaturated fatty acids in the formulation of healthier foods. Furthermore, the incorporation of antioxidant plant extracts (Melissa officinalis, Fucus vesiculosus and Lavandula latifolia) were used to increase the oxidative stability of the emulsion systems studied in this work (conventional, multiple and gelled emulsions). Among the systems studied, a gelled emulsion was selected to be used as fat replacer in fresh and cooked meat products, resulting in technologically feasible and sensory acceptable products. Moreover, the reformulated meat products showed a healthier lipid profile, lower fat and cholesterol content and lower energy value. These nutritional characteristics allowed to establish, in some of the developed formulations, nutrition and health claims according to the current European legislation.
- Novel tissue engineering strategies based on the combination of the polymeric devices and adult stem cells for cardiac repair(2020-01-30) Díaz-Herráez, P. (Paula); Blanco-Prieto, M.J. (María José); Garbayo, E; Garbayo, E. (Elisa)Cardiovascular diseases (CVD) are the leading cause of death worldwide. Among them, myocardial infarction (MI) is the main CVDs, causing 7.4 million deaths each year. The current therapies for MI are palliative rather than regenerative. Since that, the tissue engineering (TE) strategy has grown investigators attention. With the aim of improving heart repair after MI, we have developed two TE strategies. The first strategy was the use of poly(lactic co-glycolic acid) (PLGA) microparticles (MPs) containing neuregulin (NRG), as support for attaching adipose-derived stem cells (ADSC): ADSC-NRG-MP. The second strategy was the combination of two different polymeric devices, MPs and hydrogels. The MPs loaded with NRG were embedded together with the ADSCs in hydrogels composed of different ratios of dextran (Dex) and hyaluronic acid (HA). Our hypothesis was that the developed systems would increase cell survival and would activate different pathways to favor heart regeneration. The ADSC-NRG-MP induced a more pronounced regeneration of the infarcted heart in a rat MI model (reduction in infarct size, higher left ventricle thickness and vasculogenesis). Also the employment of MPs as support for the ADSC, favored a long-term survival of the cells once in the tissue, being detectable three months after their administration. Moreover, among the hydrogels developed, the 50:50 Dex:HA hydrogel embedding 1 mg of NRG-MP and 500,000 ADSC showed to present the best characteristics (adequate stiffness for heart administration, prolonged gelation time to allow its injectability and degradation rate to allow cell survival). To conclude, the two strategies developed have shown to be promising candidates for heart repair after a MI.
- Regulación del transportador de glutamato 1 (VGLUT1) en situaciones de resistencia a insulina: Implicación en la enfermedad de Alzheimer(2019-12-02) Rodríguez-Perdigón, M. (Manuel); Ramirez, M.J. (María Javier); Solas, M. (Maite)-In AD postmortem brain samples central insulin resistance was observed, as reflected by decreased expression of insulin receptor (IR) mRNA and reduced pAKT and pERK2 protein levels. -High fat diet induced insulin resistance model showed both peripheral (assessed by high levels of peripheral ketone bodies and high HOMA index) as well as central insulin resistance (assessed by decreased expression of IR, IRS-1 and pAKT and high levels of ketone bodies). -Both in postmortem human brains of AD and in an experimental model of insulin resistance, the glutamatergic terminal marker VGLUT1 expression was diminished. -Treatment with ketone bodies decreased glutamate release in primary cell cultures in a concentration dependent manner. These results suggest that elevated levels of ketone bodies associated with an insulin resistance situation promotes decreases in VGLUT1 expression and glutamate release, contributing to the glutamatergic deficits observed in AD. -In AD brain samples, increased JNK activity associated with alterations in insulin signaling was observed. In an experimental model of insulin resistance, the specific JNK inhibitor (D-JNKi-1) reversed the central alterations in insulin signaling markers as well as the decreases in VGLUT1 levels. -In high β-amyloid peptide level models, such as Tg2576 mice primary cell culture or wild type mice primary cell cultures treated with Aβ1-42, decreased VGLUT1 expression and reduced glutamate release was observed. In human AD brain cortex samples, it has been also observed a decrease in VGLUT1 expression which correlated statistically with increased levels of Aβ1-42 and senile plaques. This decrease in VGLUT1 expression did not correlate with cognitive decline, measured by MMSE. -In Tg2576 mice, an experimental AD model characterized by amyloid pathology, a decrease in VGLUT1 levels at 8 months of age was observed that is not accompanied by cognitive impairment in the Morris water maze task. These results suggest that initially the loss of glutamatergic terminals does not appear to be decisive for the development of cognitive deficits in AD. Aβ administration in VGLUT1 +/- mice caused an increased microglial and astrocytic reactivity (using Iba1 and GFAP markers respectively) in the hippocampus. These data suggest that VGLUT1 terminals loss may increase the vulnerability to subsequent hippocampal insults. -Diet supplementation with lipoic acid reversed the cognitive deficits associated to the experimental model of insulin resistance, decreased the expression of peripheral (HOMA index and insulin levels) and increased central insulin resistance markers (pIR, pAKT, pERK), reversed increased levels of ketone bodies (in plasma and hippocampus) and increased expression of VGLUT1. Therefore, it is proposed that lipoic acid may be a potential treatment to reverse the insulin resistance and altered expression of VGLUT1 that could underlie in AD pathogenesis. -The results obtained the present study support the idea that in a situation of insulin resistance, metabolism shifts to the production of ketone bodies and acting on VGLUT1 could enhance the glutamatergic deficit in AD. Insulin resistance could be related to the action of Aβ on the insulin receptor. Although initially this glutamatergic impairment does not seem to be directly related to cognitive decline in AD, the decreased expression of VGLUT1 could facilitate other pathological mechanisms, such as neuroinflammation, and it is this complex combination of factors which could lead to the cognitive deficits associated to AD.
- Towards model-based personalised medicine in oncology: Using biomarkers to predict clinical outcome(2019-11-25) Buil-Bruña, N (Núria); Troconiz, I.F. (Iñaki F.); Lopez-Picazo, J.M. (José M.)The use of personalised medicine in oncology is gaining recognition as a way of enabling individualised tailored-treatment. Circulating biomarkers have been proposed to provide early indications of treatment and thus to support individualised disease monitoring. The field of pharmacometrics is a potentially useful discipline here which focuses on obtaining quantitative mathematical and statistical models of the different physiological processes from drug administration to measurement of drug exposure, biomarker response and clinical outcome. In this thesis we show two different examples of the use of circulating biomarkers and pharmacometric tools to facilitate personalised medicine. The first section proposes a model-based framework to identify at risk patients early supporting therefore personalised medicine in small cell lung cancer patients. This framework is based on a semi-mechanistic pharmacodynamic model integrating lactate dehydrogenase and neuron specific enolase from routinely collected data. The second section focuses on the use of pharmacometrics to support drug development. We pooled data from four clinical trials to develop a model to describe the pharmacokinetics of Lanreotide Autogel® in patients with gastroenteropancreatic neuroendocrine tumours. We then expanded that model to establish the link between exposure, the dynamics of the circulating biomarker Chromogranin A and the clinical outcome. The use of circulating biomarkers within semi-mechanistic population models provides a better understanding of the relationship between drug exposure, biomarker dynamics and clinical outcome and allows to classify patients according to their disease and responses offering therefore the possibility to individualise therapy strategy and disease monitoring.
- Protein nanoparticles for oral delivery of bioactives(2019-11-25) Peñalva, R. (Rebeca); Esparza, I. (Irene); Irache, J.M. (Juan Manuel)Food grade proteins can be considered as adequate materials for the preparation of nanoparticles and microparticles. They offer several advantages such as their digestibility, low price and good capability to interact with a wide variety of compounds and nutrients. The aim of this work was to prepare, characterize and evaluate casein and zein nanoparticles for the oral delivery of bioactives. In this order, casein and zein nanoparticles were prepared by a coacervation and desolvation process respectively, followed by purification, concentration and finally dried by spray-drying. The resulting nanoparticles displayed a mean size between 150-300 nm with negative zeta potential. Biodistribution studies in rats showed mucopenetrating abilities for casein nanoparticles and mucus-adhesion properties for zein ones in the proximal jejunum of the rats. Folic acid, resveratrol and quercetin were selected as bioactives and encapsulated into both kind of nanoparticles with encapsulation efficiencies between 50-80%. Casein and zein nanoparticles containing folic acid, resveratrol or quercetin orally administered to male wistar rats displayed in all cases higher drug levels in plasma for at least 24 hours, with longer residence time for zein nanoparticles. This resulted in an increase in the oral bioavailability of the bioactives up to 30-70%. Moreover, the combination of these casein and zein nanoparticles encapsulating quercetin with a P-gP inhibitor, such as 2-hydroxypropyl-b-cyclodextrin (HP-β-CD), was a more effective strategy to increase the oral bioavailability of the active. Besides, the developed zein nanoparticles containing quercetin and resveratrol were evaluated in a LPS endotoxic mice model. Results showed that animals pre-treated with nanoparticles were able to diminish the endotoxic symptoms induced in mice by the intraperitoneal administration of LPS compared to the flavonoids on daily basics. In addition, serum TNF-α also significantly decreased in those animals receiving quercetin encapsulated in zein nanoparticles combined with HP-β-CD. In conclusion, these casein and zein nanocarriers appear to be promising systems for the increase the oral bioavailability of different bioactives.
- Propuesta de un protocolo de cribado virtual para el diseño de nuevos inhibidores de Fosfodiesterasa 5 en el tratamiento de las enfermedades neurodegenerativas(2019-11-25) Viñolas-Puig, A. (Aleix); Font-Arellano, B. (Belén)Alzheimer's disease stands out for her high and increasing morbidity, mortality and social impact. In this pathology has been observed an interruption of the mechanism to save long-term memory. This interruption has demonstrated related to the overexpression of phosphodiesterase 5 (PDE5). The aim of this research is the development of a virtual screening protocol to identify new selective PDE5 inhibitors. The auxiliary target is to enlarge the scope of this protocol to assist the design of a selective PDE2, PDE3, PDE4 and PDE9 inhibitors. To approach this goal crystal structures of PDEs have been studied and it s been detected in their active site 5 sub-regions and 6 principal residues to join molecules to the target. Molecular models for the target are been prepared with MOE and AutoDockTools software and the molecular models for ligands are been prepared with Hyperchem and AutoDockTools software. Docking protocol has been validated through their application over PDE substrates and products and cocrystalized reference PDE inhibitor ligands. After analysis of the binding mode of PDE3, PDE4 and PDE5 inhibitors, there are proposed pharmacophoric models of the inhibitors. These results don t allow preparing a good discernment method by virtual screening. It s been improved Docking protocol and it s been applied to different sets of PDE inhibitors. It s been calculated the affinity energy against whole active site and the affinity against their sub-regions and principal residues interactions. Analysing interaction energy results it s been proposed an initial method of discernment selective PDE5 inhibitors. This method is been evaluated as selective, but poor specific. This method is been improved by the identification of a complete energy profile using residues, sub-regions and total binding affinity against all PDEs studied using inverse docking increasing their specificity. The same protocol is been applied to build the initial and improved methods to identify PDE2, PDE3, PDE4 and PDE9 inhibitors. These methods are been applied to in house PDE inhibitors and it s been selected different molecules as hits for their future development as new selective PDE inhibitors.
- Role of cardiotrophin-1 on adipocyte liposysis and adipokine production, intestinal sugar uptake and the regulation of circadians clocks(2019-11-21) López-Yoldi, M. (Miguel); Moreno-Aliaga, M. J. (María Jesús); Bustos, M. (Matilde)In the last years, several studies have pointed out that CT-1 might play a key role in the regulation of body weight and fat and glucose metabolism, with potential applications for treatment of obesity and insulin resistance. In the present work, we demonstrated that CT-1 stimulates lipolysis in vitro and in vivo through the activation of the main lipases and lipid droplet associated proteins. CT-1 treatment stimulated basal glycerol and free fatty acid release in a concentration and time-dependent manner in 3T3-L1 adipocytes. This lipolytic action of CT-1 is mainly mediated by activation of HSL through the PKA pathway. In ob/ob mice, acute rCT-1 treatment also promoted PKA-mediated phosphorylation of perilipin and HSL at Ser660 and Ser563, and increased ATGL content in adipose tissue. Our results suggest that the ability of CT-1 to regulate the activity of the main lipases underlies the lipolytic action of this cytokine in vitro and in vivo, and could contribute to CT-1 antiobesity effects. In addition we observed that CT-1 inhibits the production of adipocyte-secreted hormones implicated in obesity and insulin resistance with pro-inflammatory properties such as leptin, resistin and visfatin in cultured adipocytes, whereas promotes the gene expression and secretion of apelin. Moreover, acute CT-1 administration to obese mice reduced leptin and resistin expression in WAT. Thus, the present study demonstrates the ability of rCT-1 to modulate the production of adipokines in vitro and in vivo, suggesting that the regulation of the secretory function of adipocytes could be also involved in the metabolic actions of this cytokine. Furthermore, the present investigation has revealed the ability of CT-1 to inhibit intestinal sugar absorption in vitro and in vivo. Mechanistic studies performed in Caco-2 cells showed that the reduction of α-Methyl-D-glucoside uptake induced by CT-1 is accompanied by the downregulation of the expression of the SGLT-1 co-transporter at the apical membrane of the cells. These effects of CT-1 on intestinal sugar absorption could contribute to the hypoglycemic and anti-obesity properties of this cytokine. Finally, the present study aimed to characterize the potential role of CT-1 in the regulation of metabolic rhythms. Interestingly, the circadian rhythmicity of oxygen consumption rate (VO2) was totally disrupted in old CT-1 deficient (CT-1-/-) obese mice (12 months). Moreover, the lack of CT-1 also induced remarkable alterations in Bmal1 and Cry mRNA levels in young CT-1 null mice, which become also evident for Clock and Per2 in CT-1-/- 12-month-old mice. Moreover, treatment with CT-1 attenuated the drop in adipose Clock mRNA observed in ob/ob mice. Furthermore, in humans the 24-h profile of CT-1 plasma levels showed daytime variations characterized by a pronounced rise during the night period (from 2:00 to 8:00 am), with the acrophase at 8:00 am. Interestingly, the circadian rhythmicity of CT-1 observed in normal weight subjects was lost in overweight/obese individuals. All these observations suggest a potential role of CT-1 as a peripheral regulator of metabolic circadian rhythms.