Institute Investigacion Sanitaria Of Navarra

Pamplona, Spain

Institute Investigacion Sanitaria Of Navarra

Pamplona, Spain
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Gonzalez-Fernandez Y.,University of Navarra | Gonzalez-Fernandez Y.,Institute Investigacion Sanitaria Of Navarra | Imbuluzqueta E.,University of Navarra | Imbuluzqueta E.,Institute Investigacion Sanitaria Of Navarra | And 4 more authors.
Current Pharmaceutical Design | Year: 2015

Osteosarcoma is the most frequent primary bone tumor in the pediatric age group. Its aggressive local growth pattern and its high propensity to metastasize, mainly to the lungs, give the disease an unfavorable prognosis that has situated this disease as one of the leading causes of pediatric cancer death. Current protocols for osteosarcoma treatment are based on neo-adjuvant (pre-operatory) chemotherapy followed by surgical resection of the tumor and a new phase of adjuvant chemotherapy. Despite the progress that these protocols have made in improving the outcome of the disease, the limited access of drugs to bone tumor and metastases, their indiscriminate distribution in the organism, the high required doses that cause intolerable toxicity and the development of multidrug resistance, still represent a major challenge. Nanotechnology has emerged as a new strategy to successfully address these problems by the development of nanoscaled drug carriers that present the ability to target the drug to the tumor cells, achieving high drug concentrations in the tumor area, while decreasing its presence in healthy tissues and therefore its potential systemic toxicity. This review summarizes the different lipid nanocarriers developed to deliver first and second-line anti-osteosarcoma drugs as well as emerging agents in the treatment of this disease. Moreover, it also discusses the potential of these nanocarriers for the treatment of osteosarcoma. © 2015 Bentham Science Publishers.

Pascual-Gil S.,University of Navarra | Pascual-Gil S.,Institute Investigacion Sanitaria Of Navarra | Simon-Yarza T.,University of Versailles | Garbayo E.,University of Navarra | And 5 more authors.
Journal of Controlled Release | Year: 2015

The growth factor neuregulin (NRG) is one of the most promising candidates in protein therapy as potential treatment for myocardial infarction (MI). In the last few years, biomaterial based delivery systems, such as polymeric microparticles (MPs) made of poly(lactic co glycolic acid) and polyethylene glycol (PLGA and PEG-PLGA MPs), have improved the efficacy of protein therapy in preclinical studies. However, no cardiac treatment based on MPs has yet been commercialized since this is a relatively new field and total characterization of polymeric MPs remains mandatory before they reach the clinical arena. Therefore, the objective of this study was to characterize the in vivo release, bioactivity and biodegradation of PLGA and PEG-PLGA MPs loaded with biotinylated NRG in a rat model of MI. The effect of PEGylation in the clearance of the particles from the cardiac tissue was also evaluated. Interestingly, MPs were detected in the cardiac tissue for up to 12 weeks after administration. In vivo release analysis showed that bNRG was released in a controlled manner throughout the twelve week study. Moreover, the biological cardiomyocyte receptor (ErbB4) for NRG was detected in its activated form only in those animals treated with bNRG loaded MPs. On the other hand, the PEGylation strategy was effective in diminishing phagocytosis of these MPs compared to noncoated MPs in the long term (12 weeks after injection). Taking all this together, we report new evidence in favor of the use of polymeric PLGA and PEG-PLGA MPs as delivery systems for treating MI, which could be soon included in clinical trials. © 2015 Elsevier B.V.

Plano D.,University of Navarra | Plano D.,Institute Investigacion Sanitaria Of Navarra | Alcolea V.,University of Navarra | Alcolea V.,Institute Investigacion Sanitaria Of Navarra | And 3 more authors.
Expert Opinion on Therapeutic Patents | Year: 2017

Introduction: Colorectal cancer (CRC) is the fourth most common cancer worldwide. Targeted therapy drugs (TTDs) are a valid treatment, epithelial growth factor receptor (EGFR) inhibitors being one of the most commonly used for CRC patients. However, this treatment is only useful for patients with wild-type KRAS (wtKRAS) and is effective only on about 40 to 60% of this subset due to the high plasticity of ErbB network. Areas covered: The invention proposes the use of ErbB protein levels and ErbB receptor dimer formation as biomarkers for selecting, predicting and monitoring CRC patients showing sensitivity to the action of EGFR inhibitors to benefit from the combination therapy of EGFR and HER2 inhibitors. The in vitro data on Lim1215 cells suggest the over-activation of HER3 signaling pathway in response to the use of EGFR inhibitors on monotherapy; the use of HER2 or HER3 or MEK inhibitors in combination with EGFR inhibitors reversed this activation. Expert opinion: To assess the clinical applicability of this invention, further studies are needed since the conclusions are derived solely based on the data obtained from only one CRC cell line (Lim1215). Furthermore, other biofactors/mutations should be considered to assure the potential benefits of the combination therapies proposed. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Wen M.M.,Pharos University in Alexandria | El-Salamouni N.S.,Pharos University in Alexandria | El-Refaie W.M.,Pharos University in Alexandria | Hazzah H.A.,Pharos University in Alexandria | And 7 more authors.
Journal of Controlled Release | Year: 2017

Alzheimer's disease (AD) is a neurodegenerative disease with high prevalence in the rapidly growing elderly population in the developing world. The currently FDA approved drugs for the management of symptomatology of AD are marketed mainly as conventional oral medications. Due to their gastrointestinal side effects and lack of brain targeting, these drugs and dosage regiments hinder patient compliance and lead to treatment discontinuation. Nanotechnology-based drug delivery systems (NTDDS) administered by different routes can be considered as promising tools to improve patient compliance and achieve better therapeutic outcomes. Despite extensive research, literature screening revealed that clinical activities involving NTDDS application in research for AD are lagging compared to NTDDS for other diseases such as cancers. The industrial perspectives, processability, and cost/benefit ratio of using NTDDS for AD treatment are usually overlooked. Moreover, active and passive immunization against AD are by far the mostly studied alternative AD therapies because conventional oral drug therapy is not yielding satisfactorily results. NTDDS of approved drugs appear promising to transform this research from ‘paper to clinic’ and raise hope for AD sufferers and their caretakers. This review summarizes the recent studies conducted on NTDDS for AD treatment, with a primary focus on the industrial perspectives and processability. Additionally, it highlights the ongoing clinical trials for AD management. © 2016 Elsevier B.V.

Diaz-Herraez P.,University of Navarra | Diaz-Herraez P.,Institute Investigacion Sanitaria Of Navarra | Saludas L.,University of Navarra | Saludas L.,Institute Investigacion Sanitaria Of Navarra | And 11 more authors.
Journal of Controlled Release | Year: 2017

Tissue engineering is a promising strategy to promote heart regeneration after a myocardial infarction (MI). In this study, we investigated the reparative potential of a system that combines adipose-derived stem cells (ADSCs) with microparticles (MPs) loaded with neuregulin (NRG), named ADSC-NRG-MPs, on a rat MI model. First, cells were attached to the surface of MPs encapsulating NRG and coated with a 1:1 mixture of collagen and poly-D-lysine. One week after in vivo administration, the system favored the shift of macrophage expression from a pro-inflammatory to a regenerative phenotype. At long-term, the adhesion of ADSCs to MPs resulted in an increased cell engraftment, with cells being detectable in the tissue up to three months. In consonance, better tissue repair was observed in the animals treated with cells attached to MPs, which presented thicker left ventricles than the animals treated with ADSCs alone. Moreover, the presence of NRG in the system promoted a more complete regeneration, reducing the infarct size and stimulating cardiomyocyte proliferation. Regarding vasculogenesis, the presence of ADSCs and NRG-MPs alone stimulated vessel formation when compared to the control group, but the combination of both induced the largest vasculogenic effect, promoting the formation of both arterioles and capillaries. Importantly, only when ADSCs were administered adhered to MPs, they were incorporated into newly formed vessels. Collectively, these findings demonstrate that the combination of ADSCs, MPs and NRG favored a synergy for inducing a greater and more complete improvement in heart regeneration and provided strong evidence to move forward with preclinical studies with this strategy. © 2017 Elsevier B.V.

Guada M.,University of Navarra | Guada M.,Institute Investigacion Sanitaria Of Navarra | Lasa-Saracibar B.,University of Navarra | Lana H.,University of Navarra | And 3 more authors.
International Journal of Pharmaceutics | Year: 2016

In the present work, the feasibility of cyclosporine A lipid nanoparticles (CsA LN) for oral administration was investigated. Three CsA LN formulations were developed using Precirol as lipid matrix, one stabilized with Tween® 80 (Tw) and the other two with mixtures of phosphatidylcholine or Pluronic® F127 with taurocholate (Lec:TC and PL:TC, respectively). The physical characteristics of the LN were studied under gastrointestinal pH and their integrity was found to be dependent on the stabilizers. The in vitro intestinal permeability was assessed with a human colon adenocarcinoma cell model and in vivo pharmacokinetic and biodistribution studies were performed in Balb/c mice using Sandimmune Neoral® as reference. In vitro results showed the highest CsA permeability with the LN containing Lec:TC. In contrast, the best in vivo performance was achieved from the LN containing Tw. The bioavailability of CsA was matched and even enhanced with Precirol nanoparticles. This study suggests the suitability of LN as promising vehicles for CsA oral delivery. © 2016 Elsevier B.V. All rights reserved.

Marques-Rocha J.L.,Federal University of Viçosa | Samblas M.,University of Navarra | Milagro F.I.,University of Navarra | Milagro F.I.,Charles III University of Madrid | And 7 more authors.
FASEB Journal | Year: 2015

Chronic inflammation is involved in the onset and development of many diseases, including obesity, atherosclerosis, type 2 diabetes, osteoarthritis, autoimmune and degenerative diseases, asthma, periodontitis, and cirrhosis. The inflammation process is mediated by chemokines, cytokines, and different inflammatory cells. Although the molecules and mechanisms that regulate this primary defense mechanism are not fully understood, recent findings offer a putative role of noncoding RNAs, especially microRNAs (miR-NAs), in the progression and management of the inflammatory response. These noncoding RNAs are crucial for the stability and maintenance of gene expression patterns that characterize some cell types, tissues, and biologic responses. Several miRNAs, such as miR-126, miR-132, miR-146, miR-155, and miR-221, have emerged as important transcriptional regulators of some inflammation-related mediators. Additionally, little is known about the involvement of long noncoding RNAs, long intergenic noncoding RNAs, and circular RNAs in inflammation-mediated processes and the homeostatic imbalance associated with metabolic disorders. These noncoding RNAs are emerging as biomarkers with diagnosis value, in prognosis protocols, or in the personalized treatment of inflammation-related alterations. In this context, this review summarizes findings in the field, highlighting those noncoding RNAs that regulate inflammation, with emphasis on recognized mediators such as TNF-α, IL-1, IL-6, IL-18, intercellular adhesion molecule 1, VCAM-1, and plasminogen activator inhibitor 1. The down-regulation or antagonism of the noncoding RNAs and the administration of exogenous miRNAs could be, in the near future, a promising therapeutic strategy in the treatment of inflammation-related diseases. © FASEB.

PubMed | University of Granada, Hospital Infantil Universitario Nino Jesus, University of Zaragoza, University of Navarra and 2 more.
Type: Journal Article | Journal: International journal of obesity (2005) | Year: 2016

The aims of this study were to identify the cognitive and behavioral predictors of dropping out and to estimate the attrition rate during different phases of an intervention program to treat overweight and obesity in adolescents. Overweight/obese adolescents (n=156, aged: 13-16 years; 71 male and 85 female subjects) were included in a multicomponent (diet, physical activity and psychological support) family-based group treatment program. At baseline and after 2 months (intensive phase) and 13 months (extensive phase) of follow-up, we measured adolescents cognitive and behavioral dimensions, together with the parents perception of their childs behavior. Of the 156 adolescents selected, 112 completed the full program (drop-out rate of 28.2%). The risk of dropping out during the extensive phase increased by 20% for each unit increase in the adolescents social insecurity score (odds ratio=1.20, 95% confidence interval=1.07-1.34, P=0.002). The adolescents who had a high interoceptive awareness showed a significant decrease of 13.0% in the probability of dropping out (odds ratio=0.87, 95% confidence interval=0.77-0.99, P=0.040). Adolescents social insecurity was the main predictor of drop-out in a multicomponent family-group-based obesity treatment program. To reduce attrition rates in these programs, the individuals social insecurity level needs to be reduced, whereas the familys awareness of eating-related behavior needs adjustment.

Martinez-Lopez J.,Hospital Universitario 12 Of Octubre | Paiva B.,Institute Investigacion Sanitaria Of Navarra | Lopez-Anglada L.,Hospital Universitario 12 Of Octubre | Mateos M.-V.,Hospital Universitario Of Salamanca Instituto Of Investigacion Biomedica Of Salamanca | And 16 more authors.
Blood | Year: 2015

Stringent complete response (sCR) criteria are used in multiple myeloma as a deeper response category compared with CR, but prospective validation is lacking, it is not always clear how evaluation of clonality is performed, and is it not known what the relative clinical influence is of the serum free light chain ratio (sFLCr) and bone marrow (BM) clonality to define more sCR. To clarify this controversy, we focused on 94 patients that reached CR, of which 69 (73%) also fulfilled the sCR criteria. Patients with sCR displayed slightly longer time to progression (median, 62 vs 53 months, respectively; P = .31). On analyzing this contribution to the prognosis of sFLCr or clonality, it was found that the sFLCr does not identify patients in CR at distinct risk; by contrast, low-sensitive multiparametric flow cytometry (MFC) immunophenotyping (2 colors), which is equivalent to immunohistochemistry, identifies a small number of patients (5 cases) with high residual tumor burden and dismal outcome; nevertheless, using traditional 4-color MFC, persistent clonal BM disease was detectable in 36% of patients, who, compared with minimal residual disease-negative cases, had a significantly inferior outcome. These results show that the current definition of sCR should be revised. © 2015 by The American Society of Hematology.

Garcia-Rueda N.,University of Navarra | Garcia-Rueda N.,Institute Investigacion Sanitaria Of Navarra | Carvajal Valcarcel A.,University of Navarra | Carvajal Valcarcel A.,Institute Investigacion Sanitaria Of Navarra | And 4 more authors.
European Journal of Cancer Care | Year: 2016

The aim of the study was to understand the experience of people living with advanced-stage cancer through literature. The search included The Cochrane Library, PubMed, PsycInfo, CINAHL and Cuiden. Thirteen studies were included. A qualitative meta-synthesis was conducted. One thread emerged from the thematic synthesis: the desire to live as normally as possible, despite being aware of the proximity of death. Three themes also emerged: “a process that is unique” with its four sub-themes; “support network” and “health context,” each of them having two sub-themes. This study concludes that living with advanced-stage cancer is a unique and complex process which has both positive and negative aspects. The review provides a comprehensive view of the experience, which considers the importance of the support network and the health context in which the person lives. In this study, “normalcy” is the adjustment to the new reality and living as closely as possible to the way one lived before the disease, while developing a new relationship with being finite and death. A better understanding of the experience of living with advanced-stage cancer will help health professionals to identify the needs of the patients in order to plan individual, high-quality care. © 2016 John Wiley & Sons Ltd

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