Strategie formulative per la veicolazione nasale di farmaci

Microparticelle a base di complessi polielettrolitici di Chitosano/Pectina per il rilascio nasale di Tacrina cloridrato. Lo scopo di questo studio è stata la ricerca di nuove formulazioni solide per la somministrazione nasale di Tacrina cloridrato allo scopo di ridurre l’eccessivo effetto di primo passaggio epatico ed aumentarne la biodisponibilità a livello del Sistema Nervoso Centrale. La Tacrina è stata incapsulata in microparticelle mucoadesive a base di complessi elettrolitici di chitosano e pectina. Le microparticelle sono state preparate mediante due diversi approcci tecnologici (spray-drying e spray-drying/liofilizzazione) e analizzate in termini di caratteristiche dimensionali, morfologiche e chimico-fisiche. Nanoparticelle di Chitosano reticolate con Sodio Cromoglicato per il trattamento della rinite allergica. Il Sodio Cromoglicato è uno dei farmaci utilizzati per il trattamento della rinite allergica. Come noto, la clearance mucociliare provoca una rapida rimozione dei farmaci in soluzione dalla cavità nasale, aumentando così il numero di somministrazioni giornaliere e, di conseguenza, riducendo la compliance del paziente. Per ovviare a tale problema, si è pensato di includere il sodio cromoglicato in nanoparticelle di chitosano, un polimero capace di aderire alla mucosa nasale, prolungare il contatto della formulazione con il sito di applicazione e ridurre il numero di somministrazioni giornaliere. Le nanoparticelle ottenute sono state caratterizzate in termini di dimensioni, resa, efficienza di incapsulazione e caricamento del farmaco, potenziale zeta e caratteristiche mucoadesive. Analisi quantitativa di Budesonide amorfa tramite calorimetria a scansione differenziale. È stato sviluppato un nuovo metodo quantitativo allo stato solido basato sulla Calorimetria a Scansione Differenziale (DSC) in grado di quantificare in modo selettivo e accurato la quantità di Budesonide amorfa presente in una miscela solida. Durante lo sviluppo del metodo sono stati affrontati problemi relativi alla convalida di metodi analitici su campioni solidi quali la miscelazione di polveri solide per la preparazione di miscele standard e il calcolo della precisione.

Hepatic arterial infusion enhances DOTATOC radiopeptide therapy in patients with neuroendocrine liver metastases

Intravenously administered radiolabeled peptides targeting somatostatin receptors are used for the treatment of unresectable gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Recently, we demonstrated a high first-pass effect during intra-arterial (i.a.) administration of positron emission tomography (PET) labeled (68)Ga-DOTA(0)-d-Phe(1)-Tyr(3)-octreotide (DOTATOC). In this pilot study, we investigated the therapeutic effectiveness of arterial administered DOTATOC, labeled with the therapeutic β emitters (90)Y and (177)Lu. (90)Y- and/or (177)Lu-DOTATOC were infused into the hepatic artery of 15 patients with liver metastases arising from GEP-NETs. Response was assessed using DOTATOC-PET, multiphase contrast enhanced computed tomography, magnetic resonance imaging, and the serum tumor marker chromogranin A. Pharmacokinetic data of the arterial approach were assessed using (111)In-DOTATOC scans. With the treatment regime of this pilot study, complete remission was achieved in one (7%) patient and partial remission was observed in eight (53%) patients, six patients were classified as stable (40%; response evaluation criteria in solid tumors criteria). The concomitant decrease of elevated serum tumor marker confirmed the radiologic response. Median time to progression was not reached within a mean follow-up period of 20 months. Receptor saturation and redistribution effects were identified as limiting factors for i.a. DOTATOC therapy. The high rate of objective radiologic response in NET patients treated with arterial infusion of (90)Y-/(177)Lu-DOTATOC compares favorably with systemic chemotherapy and intravenous radiopeptide therapy. While i.a. DOTATOC therapy is only applicable to patients with tumors of limited anatomic distribution, the results of this pilot study are a promising development in the treatment of GEP-NET and warrants further investigation of this novel approach.

Stereoselective biotransformation of ketamine in equine liver and lung microsomes

Stereoselectivity has to be considered for pharmacodynamic and pharmacokinetic features of ketamine. Stereoselective biotransformation of ketamine was investigated in equine microsomes in vitro. Concentration curves were constructed over time, and enzyme activity was determined for different substrate concentrations using equine liver and lung microsomes. The concentrations of R/S-ketamine and R/S-norketamine were determined by enantioselective capillary electrophoresis. A two-phase model based on Hill kinetics was used to analyze the biotransformation of R/S-ketamine into R/S-norketamine and, in a second step, into R/S-downstream metabolites. In liver and lung microsomes, levels of R-ketamine exceeded those of S-ketamine at all time points and S-norketamine exceeded R-norketamine at time points below the maximum concentration. In liver and lung microsomes, significant differences in the enzyme velocity (V(max)) were observed between S- and R-norketamine formation and between V(max) of S-norketamine formation when S-ketamine was compared to S-ketamine of the racemate. Our investigations in microsomal reactions in vitro suggest that stereoselective ketamine biotransformation in horses occurs in the liver and the lung with a slower elimination of S-ketamine in the presence of R-ketamine. Scaling of the in vitro parameters to liver and lung organ clearances provided an excellent fit with previously published in vivo data and confirmed a lung first-pass effect.

Intravenous mesenchymal stem cell therapy for traumatic brain injury.

OBJECT: Cell therapy has shown preclinical promise in the treatment of many diseases, and its application is being translated to the clinical arena. Intravenous mesenchymal stem cell (MSC) therapy has been shown to improve functional recovery after traumatic brain injury (TBI). Herein, the authors report on their attempts to reproduce such observations, including detailed characterizations of the MSC population, non-bromodeoxyuridine-based cell labeling, macroscopic and microscopic cell tracking, quantification of cells traversing the pulmonary microvasculature, and well-validated measurement of motor and cognitive function recovery. METHODS: Rat MSCs were isolated, expanded in vitro, immunophenotyped, and labeled. Four million MSCs were intravenously infused into Sprague-Dawley rats 24 hours after receiving a moderate, unilateral controlled cortical impact TBI. Infrared macroscopic cell tracking was used to identify cell distribution. Immunohistochemical analysis of brain and lung tissues 48 hours and 2 weeks postinfusion revealed transplanted cells in these locations, and these cells were quantified. Intraarterial blood sampling and flow cytometry were used to quantify the number of transplanted cells reaching the arterial circulation. Motor and cognitive behavioral testing was performed to evaluate functional recovery. RESULTS: At 48 hours post-MSC infusion, the majority of cells were localized to the lungs. Between 1.5 and 3.7% of the infused cells were estimated to traverse the lungs and reach the arterial circulation, 0.295% reached the carotid artery, and a very small percentage reached the cerebral parenchyma (0.0005%) and remained there. Almost no cells were identified in the brain tissue at 2 weeks postinfusion. No motor or cognitive functional improvements in recovery were identified. CONCLUSIONS: The intravenous infusion of MSCs appeared neither to result in significant acute or prolonged cerebral engraftment of cells nor to modify the recovery of motor or cognitive function. Less than 4% of the infused cells were likely to traverse the pulmonary microvasculature and reach the arterial circulation, a phenomenon termed the "pulmonary first-pass effect," which may limit the efficacy of this therapeutic approach. The data in this study contradict the findings of previous reports and highlight the potential shortcomings of acute, single-dose, intravenous MSC therapy for TBI.

Avaliação da permeabilidade de fármacos antirretrovirais por meio de modelo ex vivo com emprego de segmentos da mucosa bucal de suínos

A via de administração oral é a forma favorita de administração de fármacos em função das vantagens que apresenta, dentre elas destacam-se: a adesão do paciente, conveniência e praticidade. Em função disto, a maioria dos medicamentos comercializados encontra-se disponível na forma farmacêutica de administração oral, entretanto, o sucesso de um tratamento medicamentoso por esta via requer que a absorção gastrointestinal do fármaco seja suficiente para assegurar a sua disponibilidade no local de ação (VOLPE, 2010). No entanto, a absorção do fármaco no trato gastrointestinal é complexa e pode ser influenciada por vários fatores, os quais têm impacto sobre a dissolução, solubilidade e permeabilidade do fármaco. Com o intuito de aumentar a biodisponibilidade de fármacos, que possuem absorção dificultada pela via oral, a via de administração pela mucosa bucal vem sendo uma alternativa na atualidade farmacêutica. Esta mucosa é um tecido não queratinizado, altamente vascularizado e apresenta poucas enzimas metabolizadoras. Tais características possibilitam boa absorção de fármacos sem que ocorra a metabolização pré-sistêmica, ou efeito de primeira passagem, somando-se ao fato desta apresentar fácil acessibilidade para a administração de fármacos (VRIES, M. E et al., 1991; NIELSEN, H. M &RASSING, M. R, 1999). Nesse sentido, o presente trabalho teve como objetivo avaliar a permeabilidade dos fármacos antirretrovirais (lamivudina e estavudina) por meio de modelo ex vivo em segmentos da mucosa bucal de suínos, com emprego de câmaras de difusão do tipo células de Franz. Para avaliação da permeabilidade bucal dos fármacos antirretrovirais, lamivudina e estavudina, e dos marcadores para transporte transcelular (metoprolol) e paracelular (fluoresceína sódica), empregou-se método ex-vivo, em células de Franz, com segmento de mucosa bucal de suíno ( a 37ºC, meio Ringer- Krebs- HEPES, pH 7,4), e Franz posterior análise das concentrações das substâncias permeadas (fármacos e marcadores) por cromatografia líquida de alta eficiência. Os resultados obtidos, por meio do protocolo desenvolvido, demonstram que o transporte através da via paracelular (marcador fluoresceína) foi mais expressivo que o transporte transcelular (marcador metoprolol), o que provavelmente se deve ao fato dos espaços intercelulares da mucosa bucal serem mais frouxos do que aqueles observados na mucosa intestinal (junções íntimas). Quanto à lamivudina e estavudina, os resultados de permeabilidade indicaram que estes fármacos permearam por mecanismo semelhante ao do metoprolol, isto é, por via transcelular.

Développement et utilisation de modèles in vitro et de données précliniques pour augmenter la prédictibilité de la perméabilité et du métabolisme intestinal chez l'humain

Tout médicament administré par la voie orale doit être absorbé sans être métabolisé par l’intestin et le foie pour atteindre la circulation systémique. Malgré son impact majeur sur l’effet de premier passage de plusieurs médicaments, le métabolisme intestinal est souvent négligé comparativement au métabolisme hépatique. L’objectif de ces travaux de maîtrise est donc d’utiliser, caractériser et développer différents outils in vitro et in vivo pour mieux comprendre et prédire l’impact du métabolisme intestinal sur l’effet de premier passage des médicaments comparé au métabolisme hépatique. Pour se faire, différents substrats d’enzymes du métabolisme ont été incubés dans des microsomes intestinaux et hépatiques et des différences entre la vitesse de métabolisme et les métabolites produits ont été démontrés. Afin de mieux comprendre l’impact de ces différences in vivo, des études mécanistiques chez des animaux canulés et traités avec des inhibiteurs enzymatiques ont été conduites avec le substrat métoprolol. Ces études ont démontré l’impact du métabolisme intestinal sur le premier passage du métoprolol. De plus, elles ont révélé l’effet sur la vidange gastrique du 1-aminobenzotriazole, un inhibiteur des cytochromes p450, évitant ainsi une mauvaise utilisation de cet outil dans le futur. Ces travaux de maîtrise ont permis d’améliorer les connaissances des différents outils in vitro et in vivo pour étudier le métabolisme intestinal tout en permettant de mieux comprendre les différences entre le rôle de l’intestin et du foie sur l’effet de premier passage.

Linear predicted two-pass hexagonal algorithm with parallel implementation for motion estimation

This paper presents a paralleled Two-Pass Hexagonal (TPA) algorithm constituted by Linear Hashtable Motion Estimation Algorithm (LHMEA) and Hexagonal Search (HEXBS) for motion estimation. In the TPA., Motion Vectors (MV) are generated from the first-pass LHMEA and are used as predictors for second-pass HEXBS motion estimation, which only searches a small number of Macroblocks (MBs). We introduced hashtable into video processing and completed parallel implementation. We propose and evaluate parallel implementations of the LHMEA of TPA on clusters of workstations for real time video compression. It discusses how parallel video coding on load balanced multiprocessor systems can help, especially on motion estimation. The effect of load balancing for improved performance is discussed. The performance or the algorithm is evaluated by using standard video sequences and the results are compared to current algorithms.

Paralelled Two-Pass Hexagonal algorithm for motion estimation

This paper presents a paralleled Two-Pass Hexagonal (TPA) algorithm constituted by Linear Hashtable Motion Estimation Algorithm (LHMEA) and Hexagonal Search (HEXBS) for motion estimation. In the TPA, Motion Vectors (MV) are generated from the first-pass LHMEA and are used as predictors for second-pass HEXBS motion estimation, which only searches a small number of Macroblocks (MBs). We introduced hashtable into video processing and completed parallel implementation. We propose and evaluate parallel implementations of the LHMEA of TPA on clusters of workstations for real time video compression. It discusses how parallel video coding on load balanced multiprocessor systems can help, especially on motion estimation. The effect of load balancing for improved performance is discussed. The performance of the algorithm is evaluated by using standard video sequences and the results are compared to current algorithms.

Two-pass hexagonal algorithm with parallel implementation for video coding

This paper presents a paralleled Two-Pass Hexagonal (TPA) algorithm constituted by Linear Hashtable Motion Estimation Algorithm (LHMEA) and Hexagonal Search (HEXBS) for motion estimation. In the TPA, Motion Vectors (MV) are generated from the first-pass LHMEA and are used as predictors for second-pass HEXBS motion estimation, which only searches a small number of Macroblocks (MBs). We introduced hashtable into video processing and completed parallel implementation. We propose and evaluate parallel implementations of the LHMEA of TPA on clusters of workstations for real time video compression. It discusses how parallel video coding on load balanced multiprocessor systems can help, especially on motion estimation. The effect of load balancing for improved performance is discussed. The performance of the algorithm is evaluated by using standard video sequences and the results are compared to current algorithms.

Retentiojärjestelmän optimointi kartonkikoneella

Diplomityössä tutkittiin kartonkikoneen retentiojärjestelmää ja eri mahdollisuuksia retention ja vedenpoiston tehostamiseen. Tavoitteena oli parantaa etenkin runkokerroksen retentiota ja vedenpoistoa. Työssä testattiin kilpailevan kemikaalitoimittajan mikropartikkelia kartonkikoneella. Lisäksi runkokerroksessa testattiin retentiotärkkelyksen vaikutus kartongin palstaumislujuuteen, suoritettiin käytössä olevan mikropartikkelin annostuksen optimointi sekä testattiin alunan käyttöä retentioainesysteemin tehoaineena. Kirjallisuusosassa tarkasteltiin pinta- ja kolloidikemian perusteita, retentioainejärjestelmiä ja niissä käytettäviä kemikaaleja sekä retentioaineilla tehtävään flokkaukseen vaikuttavia tekijöitä. Laboratoriokokeilla tutkittiin kokeellisessa osassa eri mikropartikkelijärjestelmien toimivuutta kartonkikoneen eri kerroksien massoilla. Toimivimmaksi osoittautuneella mikropartikkelilla suoritettiin pilot-koeajo runkokerroksen massalla. Lisäksi suoritettiin toinen pilot-koeajo, jossa tutkittiin mikropartikkelin vaikutuksia saostuman aiheuttajana. Pilot-koeajoissa saavutettiin samat retentiotasot kuin referenssisysteemillä lähes puolet pienemmällä kemikaalin kulutuksella. Kartongin laatuominaisuuksista huokoisuus, formaatio ja AKD-liiman retentio muuttuivat viiraretention mukaan. Saostumakoeajossa ei todettu retentioaineen vaikuttavan saostumien syntyyn. Täyden mittakaavan koeajossa tarkoituksena oli testata kilpailevan mikropartikkelin toimivuus kartonkikoneella. Koeajossa etsittiin optimaalinen mikropartikkelin annostus eri kerroksiin. Pintakerroksen tuhkaretentio nousi hiukan ja vedenpoisto parani. Runko- ja taustakerroksessa saavutettiin samat retentiotasot sekä vedenpoistot. Samat retentiotasot saavutettiin n. 25 % pienemmällä mikropartikkelin kulutuksella. Kartongin laatuominaisuuksista seurattiin palstautumislujuutta, formaatiota ja AKD-liiman retentoitumista. Kartongin palstautumislujuus heikkeni. Vastaavasti runko- ja taustakerroksen AKD-liiman retentio oli hiukan korkeampi koeajetulla mikropartikkelilla. Formaatiossa ei tapahtunut merkittäviä muutoksia. Jatkokokeet tehtiin kartonkikoneen runkokerroksessa. Kokeissa todettiin retentiotärkkelyksen vaikuttavan kartongin palstautumislujuuteen. Käytössä olevan mikropartikkelin annostelun optimointikokeissa ei saavutettu parannusta retentioon eikä vedenpoistoon. Mikropartikkelilla saavutetaan tietty retentiotaso, jonka jälkeen sillä ei ole enää vaikutusta retentiotasoon. Alunan annostelukokeissa ei alle yksi kg/t annosmäärällä ole vaikutusta retentioon ja vedenpoistoon.

Three Essays on International Trade and the Labor Market

The thesis is made of three independent chapters interested in the impact of globalization on workers in industrialized countries. The dissertation is especially focused on identifying the causal impact of international trade on workers' mobility, wages, and employment with both a short- and medium-term perspective. The first paper explores the relation between intra-industry trade (IIT) expansion and associated worker flows, taking the latter as an indicator of labor-market adjustment costs. Being the first study to combine theoretical simulations and a novel identification strategy, we find that both theoretical and empirical analyses are consistent with the "smooth adjustment hypothesis", according to which IIT expansion is less disruptive than inter-industry trade expansion. The study therefore lends support to the use of IIT indices as first-pass proxies for the adjustment effects of trade expansion. The second chapter contrasts the impact of increased import competition coming from China and the European Union (EU) on workers in the United Kingdom over a 15-year period. The most salient findings show that increased imports from China had significantly negative effects on workers' earnings, wages and employment. In contrast, larger imports from the EU are associated with positive worker-level outcomes, which is largely explained by the fact that increased imports from the EU were mostly offset by increased same-industry exports to the EU. Besides, we find that increased imports from China exert additional pressure on workers through spillovers to employment and wages in downstream industries. Finally, the last chapter is focused on the impact of exposure to trade and real exchange rate shocks on wages for Swiss manufacturing workers. A particular attention is made to consistently estimate the causal effect in using a two-step gravity-type identification strategy. The study shows that the impact of trade and exchange rate movements is concentrated among high-skilled workers almost exclusively.

Factores asociados a fenómeno de no reflujo coronario en pacientes adultos llevados a angioplastia

Introducción: La disminución de flujo en los vasos coronarios sin presencia de oclusión, es conocido como fenómeno de no reflujo, se observa después de la reperfusión, su presentación oscila entre el 5% y el 50% dependiendo de la población y de los criterios diagnósticos, dicho suceso es de mal pronóstico, aumenta el riesgo de morir en los primeros 30 días posterior a la angioplastia (RR 2,1 p 0,038), y se relaciona con falla cardiaca y arritmias, por eso al identificar los factores a los cuales se asocia, se podrán implementar terapias preventivas. Metodología: Estudio de casos y controles pareado por médico que valoró el evento, para garantizar que no existieron variaciones inter observador, con una razón 1:4 (18:72), realizado para identificar factores asociados a la presencia de no reflujo en pacientes llevados a angioplastia, entre noviembre de 2010 y mayo de 2014, en la Clínica San Rafael de Bogotá, D.C. Resultados: La frecuencia del no reflujo fue del 2.89%. El Infarto Agudo de Miocardio con elevación del ST (IAMCEST) fue la única variable que mostró una asociación estadísticamente significativa con este suceso, valor de p 0,002, OR 8,7, IC 95% (2,0 – 36,7). Discusión: El fenómeno de no reflujo en esta población se comportó de manera similar a lo descrito en la literatura, siendo el IAMCEST un factor fuertemente asociado.

A novel two pass hexagonal search algorithm for motion estimation

This paper presents a novel two-pass algorithm constituted by Linear Hashtable Motion Estimation Algorithm (LHMEA) and Hexagonal Search (HEXBS). compensation. for block base motion On the basis of research from previous algorithms, especially an on-the-edge motion estimation algorithm called hexagonal search (HEXBS), we propose the LHMEA and the Two-Pass Algorithm (TPA). We introduce hashtable into video compression. In this paper we employ LHMEA for the first-pass search in all the Macroblocks (MB) in the picture. Motion Vectors (MV) are then generated from the first-pass and are used as predictors for second-pass HEXBS motion estimation, which only searches a small number of MBs. The evaluation of the algorithm considers the three important metrics being time, compression rate and PSNR. The performance of the algorithm is evaluated by using standard video sequences and the results are compared to current algorithms. Experimental results show that the proposed algorithm can offer the same compression rate as the Full Search. LHMEA with TPA has significant improvement on HEXBS and shows a direction for improving other fast motion estimation algorithms, for example Diamond Search.

Two-Pass Hexagonal algorithm with improved Hashtable structure for motion estimation

This paper presents an improved Two-Pass Hexagonal (TPA) algorithm constituted by Linear Hashtable Motion Estimation Algorithm (LHMEA) and Hexagonal Search (HEXBS) for motion estimation. In the TPA, Motion Vectors (MV) are generated from the first-pass LHMEA and are used as predictors for second-pass HEXBS motion estimation, which only searches a small number of Macroblocks (MBs). The hashtable structure of LHMEA is improved compared to the original TPA and LHMEA. The evaluation of the algorithm considers the three important metrics being processing time, compression rate and PSNR. The performance of the algorithm is evaluated by using standard video sequences and the results are compared to current algorithms.

Improved two-pass hexagonal algorithm with parallel implementation for video coding - art. no. 60630J

This paper presents an improved parallel Two-Pass Hexagonal (TPA) algorithm constituted by Linear Hashtable Motion Estimation Algorithm (LHMEA) and Hexagonal Search (HEXBS) for motion estimation. Motion Vectors (MV) are generated from the first-pass LHMEA and used as predictors for second-pass HEXBS motion estimation, which only searches a small number of Macroblocks (MBs). We used bashtable into video processing and completed parallel implementation. The hashtable structure of LHMEA is improved compared to the original TPA and LHMEA. We propose and evaluate parallel implementations of the LHMEA of TPA on clusters of workstations for real time video compression. The implementation contains spatial and temporal approaches. The performance of the algorithm is evaluated by using standard video sequences and the results are compared to current algorithms.