Desarrollo y validación de métodos analíticos para la cuantificación de antifúngicos triazólicos en muestras preclínicas y clínicas

El tratamiento de las micosis sistémicas es uno de los principales retos a día de hoy en el manejo de la patología infecciosa. En los últimos años el arsenal terapéutico antifúngico para el tratamiento de la infección fúngica invasora ha experimentado una importante mejora. La aparición y comercialización de nuevas moléculas con mayor actividad y menos toxicidad han modificado el tratamiento y el pronóstico de la infección fúngica. A pesar de ello, esta patología continúa siendo un problema médico de gran importancia debido a la elevada mortalidad/morbilidad asociada en algunos grupos de pacientes inmunodeprimidos y, en menor medida, en individuos inmunocompetentes. Son varios los factores que condicionan la evolución de los pacientes con estas infecciones como son el estado inmunológico, las características del patógeno (principalmente la susceptibilidad a los antifúngicos), el tiempo trascurrido desde el establecimiento de la infección hasta el diagnóstico, así como un uso efectivo y seguro del fármaco. Los triazoles sistémicos forman parte de este arsenal terapéutico. Los antifúngicos del grupo de los triazoles se han convertido en fármacos de primera línea para el tratamiento y profilaxis de muchas micosis sistémicas. Este grupo muestra importantes peculiaridades farmacocinéticas y en consecuencia una misma dosis administrada a diferentes pacientes puede dar como resultado concentraciones muy distintas, tanto plasmáticas como tisulares, lo que hace que estos agentes sean firmes candidatos a la monitorización terapéutica. La individualización de la terapia mediante la determinación de las concentraciones sanguíneas (monitorización) implica una mejora de la respuesta al tratamiento, una prevención de las reacciones adversas, un mejor manejo de las interacciones medicamentosas y en consecuencia un ahorro en costes derivados de tratamientos y dosificaciones inadecuados. El objetivo de la monitorización es, por tanto, aumentar la probabilidad de éxito terapéutico minimizando la toxicidad. Los estudios farmacocinéticos/farmacodinámicos en las diferentes poblaciones de pacientes tratan de definir la relación entre la dosis administrada y el éxito o fracaso de una terapia, con el objetivo de definir un parámetro farmacocinético/farmacodinámico que ayude a predecir el éxito terapéutico..

Desarrollo y validación de métodos analíticos para la cuantificación de antifúngicos triazólicos en muestras preclínicas y clínicas

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Microbiología II, leída el 05-02-2016El tratamiento de las micosis sistémicas es uno de los principales retos a día de hoy en el manejo de la patología infecciosa. En los últimos años el arsenal terapéutico antifúngico para el tratamiento de la infección fúngica invasora ha experimentado una importante mejora. La aparición y comercialización de nuevas moléculas con mayor actividad y menos toxicidad han modificado el tratamiento y el pronóstico de la infección fúngica. A pesar de ello, esta patología continúa siendo un problema médico de gran importancia debido a la elevada mortalidad/morbilidad asociada en algunos grupos de pacientes inmunodeprimidos y, en menor medida, en individuos inmunocompetentes. Son varios los factores que condicionan la evolución de los pacientes con estas infecciones como son el estado inmunológico, las características del patógeno (principalmente la susceptibilidad a los antifúngicos), el tiempo trascurrido desde el establecimiento de la infección hasta el diagnóstico, así como un uso efectivo y seguro del fármaco. Los triazoles sistémicos forman parte de este arsenal terapéutico. Los antifúngicos del grupo de los triazoles se han convertido en fármacos de primera línea para el tratamiento y profilaxis de muchas micosis sistémicas. Este grupo muestra importantes peculiaridades farmacocinéticas y en consecuencia una misma dosis administrada a diferentes pacientes puede dar como resultado concentraciones muy distintas, tanto plasmáticas como tisulares, lo que hace que estos agentes sean firmes candidatos a la monitorización terapéutica. La individualización de la terapia mediante la determinación de las concentraciones sanguíneas (monitorización) implica una mejora de la respuesta al tratamiento, una prevención de las reacciones adversas, un mejor manejo de las interacciones medicamentosas y en consecuencia un ahorro en costes derivados de tratamientos y dosificaciones inadecuados. El objetivo de la monitorización es, por tanto, aumentar la probabilidad de éxito terapéutico minimizando la toxicidad. Los estudios farmacocinéticos/farmacodinámicos en las diferentes poblaciones de pacientes tratan de definir la relación entre la dosis administrada y el éxito o fracaso de una terapia, con el objetivo de definir un parámetro farmacocinético/farmacodinámico que ayude a predecir el éxito terapéutico...Invasive fungal infections are currently one of the most important issues in infectious diseases. In recent years, therapeutic arsenal has been increased and development of broad spectrum drugs with higher activity and lower toxicity has improved the management and prognosis of invasive fungal diseases. This infectious disease is still a very major clinical problem due to its high mortality and morbility rates. It is almost always associated to inmunocompromissed patients and, in lower frequency, to inmunocompetent patients. Evolution and prognosis of fungal infections are associated to other factors as inmunological status, pathogen features, time between the set up of infection and diagnosis and a rational use of the antifungal drugs. They kill the fungal cell due to the growth inhibition of the fungus cell wall. Triazole agents are first line agents in treatment and prophylaxis of systemic fungal infections. Due to their especial pharmacokinetic features, therapeutic drug monitoring (TDM) can be recommended in order to ensure blood and tissue concentrations. TDM implies an improvement in response to treatment, decreased in frequency of adverse events and drud-drug interactions. Therefore, there is a save in costś treatments and in adverse events. The final target of TDM is the optimisation of the antifungal therapy. Pharmacokinetic/pharmacodinamic studies are essential to define pharmacokinetic parameters to optimize and follow up the efficacy of the antifungal treatment. These studies should be done in different populations (healthy and patients populations) in order to define the best pharmacokinetic parameter which defines the exposure to the drug and helps the clinician to manage the infection in a better manner...Depto. de Microbiología y ParasitologíaFac. de FarmaciaTRUEunpu

Clinical indications for therapeutic drug monitoring of antifungal agents. In the way for optimizing the treatment of fungal infection

[ES] La monitorización de fármacos se ha consolidado en los últimos años como una herramienta útil, y en algunos casos esencial, en el manejo de las enfermedades infecciosas. En las infecciones fúngicas, la posibilidad de monitorizar las concentraciones sanguíneas de los antifúngicos ha supuesto un valor añadido en el manejo de esta patología infecciosa. Las especiales características farmacocinéticas de estos fármacos y de sus formulaciones dificultan el correcto empleo que asegure su eficacia y minimice su toxicidad. La monitorización de las concentraciones plasmáticas puede mejorar la utilización de estos agentes antiinfecciosos, así como facilitar el manejo de las interacciones medicamentosas, la patología y los efectos adversos teniendo como consecuencia un ahorro en costes derivados de tratamientos y dosificaciones inadecuadas. En estarevisión se evalúa el papel de la monitorización clínica de los antifúngicos que están actualmente disponibles en la práctica clínica, con una dedicación casi exclusiva a los compuestas azólicos. [EN] Therapeutic drug monitoring as a tool in the management of infectious diseases has been introduced in therapy with anti-infective agents for years. Nowadays, it has taken importance in the management of fungal diseases due to the appearance of new antifungal drugs such as new-generation azoles. These azoles have pharmacokinetic characteristics that hinder a proper use to ensure efficacy and minimize toxicity. Monitoring of serum concentrations may help in the better use of these anti-infective agents, as well as in a better management of drug interactions, infectious disease and adverse effects. It has resulted in saving costs of treatment and in avoiding inadequate dosages. This review will attempt to clarify the role of the antifungal agents Therapeutic Drug Monitoring, highlighting the role of azole compounds.S

Multicentre Surveillance of Candida Species from Blood Cultures during the SARS-CoV-2 Pandemic in Southern Europe (CANCoVEU Project)

Introduction: Surveillance of Candida species isolates from blood cultures (BCs) in Europe is considered fragmented, unable to allow the definition of targets of antifungal stewardship recommendations especially during the SARS-CoV-2 pandemic. Methods: We performed a multicentric retrospective study including all consecutive BC Candida isolates from six Southern European tertiary hospitals (1st January 2020 to 31st December 2021). Etiology, antifungal susceptibility patterns, and clinical setting were analyzed and compared. Results: C. albicans was the dominant species (45.1%), while C. auris was undetected. Candida species positive BC events increased significantly in COVID-19 ICUs in 2021 but decreased in other ICUs. Resistance to azole increased significantly and remained very high in C. albicans (fluconazole from 0.7% to 4.5%, p = 0.03) and C. parapsilosis complex (fluconazole up to 24.5% and voriconazole up to 8.9%), respectively. Resistance to caspofungin was remarkable in C. tropicalis (10%) and C. krusei (20%), while resistance to at least one echinocandin increased in 2021, especially in C. parapsilosis complex (from 0.8% to 5.1%, p = 0.05). Although no significant differences were observed over the study period, fluconazole and echinocandin resistance increased in COVID-19 ICUs by up to 14% and 5.8%, respectively, but remained undetected in non-intensive COVID-19 wards. Conclusions: Antifungal stewardship activities aimed at monitoring resistance to echinocandin in C. tropicalis and C. krusei, and against the spread of fluconazole resistant C. parapsilosis complex isolates are highly desirable. In COVID-19 patients, antifungal resistance was mostly present when the illness had a critical course.publishersversionpublishe

Effects of mannoprotein E1 in liquid diet on inflammatory response and TLR5 expression in the gut of rats infected by Salmonella typhimurium

<p>Abstract</p> <p>Background</p> <p>Mannoproteins are yeast cell wall componend, and rich in mannose. The use of foods rich in mannose as carbohydrate, could have a bioprotective effect against entrobacteria intestinal infection. Nothing is known about mannoproteins' activity in inflammatory bowel processes induced by entrobacteria.</p> <p>This study investigates the effects of mannoprotein administration via a liquid diet on inflammatory response and TLR5 expression during intestinal tissue injury in a rat model of infection with <it>Salmonella typhimurium</it>.</p> <p>Methods</p> <p>Adult Wistar male rats were divided into three groups: control, and mannoprotein E₁at 10 or 15%. Animals were fed with a liquid diet supplemented or not with mannoprotein E₁. Groups were infected by intragastrical administration of <it>S. typhimurium</it>. 24 h post-inoculation samples of spleen, ileum and liver were collected for microbiological studies. Gut samples were processed to determine levels of proinflammatory cytokines (mRNA) and TLR5 (mRNA and protein) by quantitative PCR and Western-blot, and the number of proliferative and apoptotic cells determined by immunohistochemistry.</p> <p>Results</p> <p>Ininfected levels of proinflammatory cytokines and TLR5 were higher in untreated controls than in the animals receiving mannoprotein. Proliferation was similar in both groups, whereas apoptosis was higher in controls. Curiosly, the mannoprotein effect was dose dependent.</p> <p>Conclusions</p> <p>Mannoprotein administration in a liquid diet seems to protect intestinal tissue against <it>S. typhimurium </it>infection. This protection seems to expressed as a lower pro-inflammatory response and TLR5 downregulation in gut epithelium, as well as by an inhibition of apoptosis. Nevertheless, the molecular mechanism by which mannoprotein is able to regulate these responses remain unclear. These results could open up new avenues in the use of mannoproteins as prebiotics in the therapeutic strategy for treatment of inflammatory gut processes induced by microbia.</p

Measurement of the t-channel single top quark production cross section in pp collisions at √s =7 TeV

Peer reviewe

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass

Severe early onset preeclampsia: short and long term clinical, psychosocial and biochemical aspects

Preeclampsia is a pregnancy specific disorder commonly defined as de novo hypertension and proteinuria after 20 weeks gestational age. It occurs in approximately 3-5% of pregnancies and it is still a major cause of both foetal and maternal morbidity and mortality worldwide1. As extensive research has not yet elucidated the aetiology of preeclampsia, there are no rational preventive or therapeutic interventions available. The only rational treatment is delivery, which benefits the mother but is not in the interest of the foetus, if remote from term. Early onset preeclampsia (<32 weeks’ gestational age) occurs in less than 1% of pregnancies. It is, however often associated with maternal morbidity as the risk of progression to severe maternal disease is inversely related with gestational age at onset2. Resulting prematurity is therefore the main cause of neonatal mortality and morbidity in patients with severe preeclampsia3. Although the discussion is ongoing, perinatal survival is suggested to be increased in patients with preterm preeclampsia by expectant, non-interventional management. This temporising treatment option to lengthen pregnancy includes the use of antihypertensive medication to control hypertension, magnesium sulphate to prevent eclampsia and corticosteroids to enhance foetal lung maturity4. With optimal maternal haemodynamic status and reassuring foetal condition this results on average in an extension of 2 weeks. Prolongation of these pregnancies is a great challenge for clinicians to balance between potential maternal risks on one the eve hand and possible foetal benefits on the other. Clinical controversies regarding prolongation of preterm preeclamptic pregnancies still exist – also taking into account that preeclampsia is the leading cause of maternal mortality in the Netherlands5 - a debate which is even more pronounced in very preterm pregnancies with questionable foetal viability6-9. Do maternal risks of prolongation of these very early pregnancies outweigh the chances of neonatal survival? Counselling of women with very early onset preeclampsia not only comprises of knowledge of the outcome of those particular pregnancies, but also knowledge of outcomes of future pregnancies of these women is of major clinical importance. This thesis opens with a review of the literature on identifiable risk factors of preeclampsia