Fernandez-Cooke E.,Hospital Universitario 12 Of Octubre
Antiviral therapy | Year: 2016
BACKGROUND: Licensing data for paediatric dosing is often sparse and subsequent studies may result in changes to recommended doses. We measured the extent and consequences of off-label antiretroviral (ARV) use in an HIV-infected paediatric cohort.METHODS: In this multicentre cohort study involving 318 HIV-infected children and adolescents from the Madrid Cohort, all off-label prescriptions from March 1988 to March 2012 were recorded from the clinical records. The reasons for prescribing ARV off-label, the side effects and the consequences of incorrect dosing of ARVs are discussed.RESULTS: Among the 318 patients of the cohort, 221 (69%) received off-label ARVs according to EMA licensing at the time of prescription, representing 23% (540) of the 2,353 prescribed ARVs. The main reason for starting an off-label drug was treatment failure. Adverse events led to treatment discontinuation in 12% of the prescriptions. Problems taking the drug led to withdrawal in 5%, more likely when formulation was not suitable for age (P<0.05). Up to 10% were overdosed and 10% underdosed, defined as 25% above or below the current recommended dose, respectively. Treatment failure occurred significantly more frequently among underdosed compared to overdosed patients (50% versus 26%; P<0.05).CONCLUSIONS: Off-label use of ARVs was common in our HIV-1 paediatric patients. Adverse events were common but rarely led to withdrawal. Suitable formulation is important in younger children. Pharmacokinetic studies are needed as frequent incorrect dosing may occur when prescribing off-label and underdosing may lead to treatment failure.
Praga M.,Hospital Universitario 12 Of Octubre |
Gonzalez E.,Hospital Universitario 12 Of Octubre
Kidney International | Year: 2010
Acute interstitial nephritis (AIN) represents a frequent cause of acute kidney injury, accounting for 15-27% of renal biopsies performed because of this condition. By and large, drug-induced AIN is currently the commonest etiology of AIN, with antimicrobials and nonsteroidal anti-inflammatory drugs being the most frequent offending agents. Pathogenesis is based on an immunologic reaction against endogenous nephritogenic antigens or exogenous antigens processed by tubular cells, with cell-mediated immunity having a major pathogenic role. The characteristic interstitial infiltrates, mostly composed of lymphocytes, macrophages, eosinophils, and plasma cells, experience a rapid transformation into areas of interstitial fibrosis. A significant proportion of AIN has nowadays an oligosymptomatic presentation, although the presence of specific extrarenal symptoms such as fever, skin rash, arthralgias, and peripheral eosinophilia has an important role to orientate clinical diagnosis. Identification and removal of the offending drug are the mainstay of the treatment, but recent studies strongly suggest that early steroid administration (within 7 days after diagnosis) improves the recovery of renal function, decreasing the risk of chronic renal impairment. Delayed steroid treatment, when interstitial fibrosis has taken place, would have a less pronounced or nule therapeutic benefit. © 2010 International Society of Nephrology.
Castaneda C.A.,Instituto Nacional Enfermedades Neoplasicas |
Cortes-Funes H.,Hospital Universitario 12 Of Octubre |
Gomez H.L.,Instituto Nacional Enfermedades Neoplasicas |
Ciruelos E.M.,Hospital Universitario 12 Of Octubre
Cancer and Metastasis Reviews | Year: 2010
The phosphatidyl inositol 3-kinase (PI3K)/Akt pathway mediates the effects of a variety of extracellular signals in a number of cellular processes including cell growth, proliferation, and survival. The alteration of integrants of this pathway through mutation of its coding genes increases the activation status of the signaling and can thus lead to cellular transformation. The frequent dysregulation of the PI3K/Akt pathway in breast cancer (BC) and the mediation of this pathway in different processes characteristically implicated in tumorigenesis have attracted the interest of this pathway in BC; however, a more comprehensive understanding of the signaling intricacies is necessary to develop clinical applications of the modulation of this pathway in this pathology. We review a series of experiments examining the contribution of alteration of integrants of this signaling network to human BC and we make an update of the information about the effect of the modulation of this pathway in this cancer. © Springer Science+Business Media, LLC 2010.
Ciruelos Gil E.M.,Hospital Universitario 12 Of Octubre
Cancer Treatment Reviews | Year: 2014
Approximately 70-75% of breast cancers express the estrogen receptor (ER), indicating a level of dependence on estrogen for growth. Endocrine therapy is an important class of target-directed therapy that blocks the growth-promoting effects of estrogen via ER. Although endocrine therapy continues to be the cornerstone of effective treatment of ER-positive (ER+) breast cancer, many patients with advanced ER+ breast cancer encounter de novo or acquired resistance and require more aggressive treatment such as chemotherapy. Novel approaches are needed to augment the benefit of existing endocrine therapies by prolonging time to disease progression, preventing or overcoming resistance, and delaying the use of chemotherapy.The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is a key intracellular signaling system that drives cellular growth and survival; hyperactivation of this pathway is implicated in the tumorigenesis of ER+ breast cancer and in resistance to endocrine therapy. Moreover, preclinical and clinical evidence show that PI3K/AKT/mTOR pathway inhibition can augment the benefit of endocrine therapy in ER+ breast cancer, from the first-line setting and beyond.This article will review the fundamental role of the PI3K/AKT/mTOR pathway in driving ER+ breast tumors, and its inherent interdependence with ER signaling. In addition, ongoing strategies to combine PI3K/AKT/mTOR pathway inhibitors with endocrine therapy for improved clinical outcomes, and methods to identify patient populations that would benefit most from inhibition of the PI3K/AKT/mTOR pathway, will be evaluated. © 2014 Elsevier Ltd.
Gil Borlado M.C.,Hospital Universitario 12 Of Octubre
PloS one | Year: 2010
In recent years clinical evidence has emphasized the importance of the mtDNA genetic background that hosts a primary pathogenic mutation in the clinical expression of mitochondrial disorders, but little experimental confirmation has been provided. We have analyzed the pathogenic role of a novel homoplasmic mutation (m.15533 A>G) in the cytochrome b (MT-CYB) gene in a patient presenting with lactic acidosis, seizures, mild mental delay, and behaviour abnormalities. Spectrophotometric analyses of the respiratory chain enzyme activities were performed in different tissues, the whole muscle mitochondrial DNA of the patient was sequenced, and the novel mutation was confirmed by PCR-RFLP. Transmitochondrial cybrids were constructed to confirm the pathogenicity of the mutation, and assembly/stability studies were carried out in fibroblasts and cybrids by means of mitochondrial translation inhibition in combination with blue native gel electrophoresis. Biochemical analyses revealed a decrease in respiratory chain complex III activity in patient's skeletal muscle, and a combined enzyme defect of complexes III and IV in fibroblasts. Mutant transmitochondrial cybrids restored normal enzyme activities and steady-state protein levels, the mutation was mildly conserved along evolution, and the proband's mother and maternal aunt, both clinically unaffected, also harboured the homoplasmic mutation. These data suggested a nuclear genetic origin of the disease. However, by forcing the de novo functioning of the OXPHOS system, a severe delay in the biogenesis of the respiratory chain complexes was observed in the mutants, which demonstrated a direct functional effect of the mitochondrial genetic background. Our results point to possible pitfalls in the detection of pathogenic mitochondrial mutations, and highlight the role of the genetic mtDNA background in the development of mitochondrial disorders.
Diaz Guzman J.,Hospital Universitario 12 Of Octubre
Neurologia | Year: 2012
Approximately one in four ischemic strokes is of cardioembolic origin. Non-valvular atrial fibrillation accounts for 50% of these cases, followed by myocardial infarction, intraventricular thrombus, valvular heart disease and a miscellany of causes. The incidence of embolic heart disease in the population could be about 30 cases per 100,000 inhabitants per year, and its prevalence between 5 and 10 cases per 1,000 persons aged 65 years or older. Hospital mortality is high, and 5-year survival is only one out of every five patients. The recurrence rate of this type of stroke is about 12% at 3 months, higher than that of non-cardioembolic stroke. The severity of cardioembolic strokes and the resulting disability are greater than with non-cardioembolic stroke. Age, a history of stroke or transient ischemic attack, hypertension, diabetes and heart failure play a role in stroke with atrial fibrillation as additional risk factors for future embolisms. Stroke rates can reach over 20% per year and therefore the prevention and treatment of these events are of paramount importance. © 2012 Sociedad Española de Neurología.
Castellano D.,Hospital Universitario 12 Of Octubre
Cancer metastasis reviews | Year: 2012
Pharmacogenomics is the study of how variation in the genetic background affects an individual's response to a specific drug and/or its metabolism. Using knowledge about the genes which produce the enzymes that metabolize a specific drug, a physician may decide to raise or lower the dose, or even change to a different drug. Targeted therapy with tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors has led to a substantial improvement in the standard of care for patients with advanced or metastatic renal cell carcinoma (RCC). Although few studies have identified biomarkers that predict the response of targeted drugs in the treatment of metastatic RCC, some associations have been found. Several studies have identified genetic polymorphisms with implications in the pharmacokinetics and/or pharmacodynamics of TKIs and mTOR inhibitors and which are associated with a prolonged progression-free survival and/or overall survival in patients with metastatic RCC. Among the genes of interest, we should consider IL8, FGFR2, VEGFA, FLT4, and NR1I2. In this review, we discuss single nucleotide polymorphisms (SNPs) associated with outcome and toxicity following targeted therapies and provide recommendations for future trials to facilitate the use of SNPs in personalized therapy for this disease.
Barrientos A.,University of Miami |
Ugalde C.,Hospital Universitario 12 Of Octubre |
Ugalde C.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer
Cell Metabolism | Year: 2013
The mitochondrial respiratory chain is believed to dynamically arrange in suprastructures known as supercomplexes or respirasomes, though their function remains elusive. A recent study in Science (Lapuente-Brun et al., 2013) now reports that dynamic supercomplex assembly determines electron flux from different substrates through the respiratory chain. © 2013 Elsevier Inc.
Ruiz-Hurtado G.,Hospital Universitario 12 Of Octubre |
Ruilope L.M.,Hospital Universitario 12 Of Octubre
Nature Reviews Cardiology | Year: 2014
Cardiovascular and renal disease often have similar origins and shared risk factors. With the progression of chronic kidney disease (CKD), additional risk factors develop, contributing to the evolution of both diseases. Progression of CKD has been primarily investigated in patients with established diabetic nephropathy and severely increased albuminuria, in cohorts smaller than those necessary for studies of cardiovascular outcomes. Consequently, simultaneous cardiovascular and renal protection was not demonstrated clearly in these studies. Nevertheless, data from some clinical trials in the field of arterial hypertension have demonstrated that cardiovascular and renal protection can be attained using the same therapy. Further investigation on factors that promote rapid progression of cardiovascular disease and CKD should result in new therapies to improve the outcome of patients presenting with both diseases. © 2015 Macmillan Publishers Limited.
Hinojosa J.,Hospital Universitario 12 Of Octubre
Child's Nervous System | Year: 2012
Minimally invasive, endoscopic repair of metopic craniosynostosis has emerged as a potentially efficacious, safe, and aesthetically acceptable alternative to open procedures. Potential advantages of an early endoscopic approach to repair metopic craniosynostosis include a reduction in blood loss and consequent decreases in transfusion volumes, decreased hospital costs, shorter operative times, and limited duration of hospitalization. Other benefits of minimally invasive techniques would be avoidance of anaesthetic surgical scarring, decrease in postoperative swelling and discomfort, and lower rate of complications such as duramater tears, postoperative hyperthermia, or infection. However, a concern is usually raised about the achievements of the endoscopic techniques when compared to standard open approaches. The indications for endoscopic-assisted surgery in the treatment of trigonocephaly remain controversial and further series and follow-up of these patients are necessary to set up the role of these approaches. © 2012 Springer-Verlag.