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Effect of cellulose derivatives on the characteristics and nasal application of vinpocetine-loaded polymeric micelles
No full textTrabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2024, Universidade de Lisboa, Faculdade de Farmácia.Este trabalho teve como objetivo o desenvolvimento e a otimização de um sistema de administração nasal utilizando micelas poliméricas carregadas com vinpocetina. A vinpocetina, um fármaco utilizado para melhorar a função cerebral particularmente em doenças neurodegenerativas como a do Alzheimer, enfrenta desafios relacionados com a sua fraca solubilidade em água e baixa biodisponibilidade. Foi avaliada a forma como diferentes derivados de celulose - especificamente hidroxipropilmetilcelulose (HPMC), carboximetilcelulose (CMC), metilcelulose (MC) e hidroxietilcelulose (HEC) - afetam as propriedades destas micelas e a sua aplicação na administração nasal. Estas formulações foram submetidas a um processo de secagem por aspersão, formando micelas com vinpocetina, que foram objeto de vários testes.
O produto obtido através do processo de secagem por aspersão foi caracterizado, determinando o tamanho das partículas e o teor do fármaco. As micelas foram também estudadas no estado líquido e, neste caso, foram determinados o seu tamanho, a distribuição, o potencial zeta, a eficiência de encapsulação e a solubilidade termodinâmica. Foram ainda efetuados estudos de aplicabilidade nasal in vitro, com estudos de libertação e permeação do fármaco.
A caraterização das partículas mostrou que as formulações com HEC e HPMC apresentavam as distribuições de tamanho de partículas mais uniformes. A eficiência de encapsulamento foi mais elevada com HEC a 0.5%, demonstrando um encapsulamento quase completo do fármaco. Já os estudos de libertação do fármaco in vitro indicaram que todas as formulações apresentaram uma libertação rápida nos primeiros 15-20 minutos, crucial para a administração nasal. Os testes de permeabilidade ao fármaco demonstraram ainda que concentrações mais baixas de HEC e HPMC proporcionaram uma permeabilidade superior, sugerindo uma janela de concentração eficaz entre 0.5% e 1.5%.
Estes resultados realçam o potencial dos derivados de celulose na otimização de micelas carregadas com vinpocetina para administração nasal. O estudo sugere que tais formulações podem ser desenvolvidas para melhorar a eficácia dos tratamentos em doenças neurodegenerativas.This study aimed the development and optimization of a nasal drug delivery system using vinpocetine-loaded polymeric micelles, improving bioavailability and solubility. Vinpocetine, a drug utilized to enhance brain function and cerebral blood circulation, particularly for conditions like neurodegenerative diseases such as Alzheimer’s Disease, dementia, faces challenges related to its poor water solubility and low bioavailability. The research investigates how different cellulose derivatives - specifically Hydroxypropyl-methylcellulose (HPMC), Carboxymethyl-cellulose (CMC), Methylcellulose (MC), and Hydroxyethyl-cellulose (HEC) - affect the properties of these polymeric micelles and their application in nasal drug delivery. These formulations were nano spray-dried, forming vinpocetine-loaded polymeric micelles, which were the subject of various tests.
The solid-state formulations were characterized, by determining the particle size and the drug content. The liquid state formulations were also analyzed and, in this case, the micelle size, micelle size distribution, zeta potential, encapsulation efficiency and thermodynamic solubility of each formulation were determined. In vitro nasal applicability studies were also done, with drug release and drug permeation studies. Solid-state characterization, including particle size determination via laser diffraction, showed that formulations with HEC and HPMC exhibited the most uniform particle size distributions. Encapsulation efficiency was highest with HEC at 0.5% w/v, demonstrating almost complete drug encapsulation. In vitro drug release studies indicated that all formulations showed rapid release within the first 15-20 minutes, crucial for nasal administration. Drug permeability tests further demonstrated that lower concentrations of HEC and HPMC provided optimal permeability, suggesting an effective concentration window between 0.5% and 1.5%.
These findings highlight the potential of cellulose derivatives in optimizing vinpocetine-loaded micelles for nasal delivery, supporting their viability for enhancing brain-targeted drug therapies. It was also crucial to determine the effect of these polymers on the nasal application, as they are commonly applied viscosity enhancers for liquid nasal dosage forms. The study suggests that such formulations could be further developed to improve the efficacy of treatments for neurodegenerative diseases
Validierung differenzieller Genexpression im duktalen Pankreaskarzinom
Get PDFValidierung differenzieller Genexpression von Anxa2, hk-10, MCM2, MCM7, MMP11 und TMPRSS4 auf Proteinebene im duktalen Pankreasadenokarzinom mit Hilfe der Immunhistochemie
Die Bedeutung der Chemokinrezeptoren CCR7 und CXCR4 sowie des CCR7-Liganden CCL21 für die Ausbreitung des duktalen Adenokarzinoms des Pankreas
Get PDFIn dieser Arbeit wurde ein Kollektiv von duktalen Adenokarzinomen des Pankreas hinsichtlich einer Expression der Chemokinrezeptoren CCR7 und CXCR4 sowie des CCR7-Liganden CCL21 untersucht. Es konnte ein Zusammenhang zwischen der lymphatischen Ausbreitung des Karzinoms und der CCR7-Expression sowie ein Zusammenhang zwischen der CXCR4-Expression und hohen klinischen Tumorstadien dargestellt werden. Weiterhin wird die Expression CCL21 in intra- und peritumoralen Lymphgefäßen sowie in entzündeten Pankreata hochreguliert
Optimierung eines orthotopen Pankreaskarzinommodells und seine Anwendung für anti-angiogene Therapieversuche
Get PDFGegenstand dieser Arbeit war die Optimierung bereits bestehender orthotoper Transplantationstechniken von Pankreaskarzinomzelllinien in Tiermodellen. Die optimierten präklinischen Mausmodelle wurden in einer Versuchserie eingesetzt, in die der Effekt einer anti-angiogenen (Endostatin) Behandlung, einer zytostatischen (Gemcitabin) Behandlung sowie die Kombination dieser Therapien untersucht wurde.
Im ersten Teil der Arbeit wurde die klassische Inokulationsmethode der Zellen in das Pankreas (Tumorzellen in Kulturmedium) weiterentwickelt, da sich oft artifizielle Metastasen in der Bauchdecke und im Peritoneum nach dieser Inokulationstechnik ausbildeten und somit die Auswertung von Tumorwachstum und spontaner Metastasierung erschwert haben. Zwischen den zwei untersuchten Implantationstechniken, der orthotopen Implantation von subkutan gezüchteten Tumorfragmenten und der Inokulation von Tumorzellen in Matrigel, wurde der zweiten Methode Vorzug gegeben, da zum einen die Anzahl der eingebrachten Tumorzellen besser zu kontrollieren war und zum anderen die Pankreaszelllinien im organspezifischen Umgebungsmilieu wuchsen, wodurch eine bessere Vergleichbarkeit und Übertragbarkeit zum humanen Pankreaskarzinom bestand.
Bei der orthotopen Inokulation mittels Matrigel zeigten sich im Vergleich mit der ursprünglichen Methode weniger und kleinere artifizielle Bauchdeckenmetastasen bei gleich gebliebener hundertprozentiger Tumorangehrate, so dass mit der neu etablierten Inokulationstechnik mit Matrigel eine wesentliche Verbesserung des Tumormodells hinsichtlich der Tumorprogression und klinischer Relevanz erreicht wurde.
Im zweiten Teil der Arbeit wurde eine anti-angiogene Behandlungsversuchserie mit Endostatin und Gemcitabin mit Hilfe der etablierten Mausmodelle durchgeführt. Die Hemmung der Tumorangiogenese stellt eine wichtige Therapieoption dar, die mittlerweile Einzug in den klinischen Alltag gefunden hat.
In unserer Versuchsserie zeigte Endostatin als Monotherapie nach 14 Behandlungstagen einen hemmenden Effekt auf das Tumorwachstum, der allerdings zum Endpunkt der Serie (28 Tage) nicht mehr zu beobachten war. Unter der Gemcitabin- und Kombinationstherapie kam es zu keiner Größenzunahme oder Metastasierung der Tumore. Die Unterschiede zwischen den Therapieerfolgen mit der Gemcitabin-Monotherapie und Kombinationstherapie waren nicht signifikant, allerdings war die Kombinationstherapie nach vierwöchiger Behandlung tendenziell erfolgreicher.
Die immunhistochemische Untersuchung der Gefäßdichte wies eine Reduzierung der Gefäßdichte sowohl in den durch Endostatin als auch durch Gemcitabin behandelten Gruppen auf, zeigte aber keinen synergistischen Effekt in der Kombination beider Substanzen. Parallel mit der Verringerung der Gefäßdichte, nahm ebenfalls in allen Gruppen, mit Ausnahme der mit Endostatin behandelten Gruppe am Ende der Versuchsreihe, die Proliferationsrate der Tumorzellen ab.
Zusammenfassend kann festgestellt werden, dass Endostatin allein kurzfristig das Tumorwachstum hemmt und tendenziell in Kombination mit Gemcitabin einen additiven Effekt auf das Tumorwachstum ausübt. Das Ergebnis bestätigt prinzipiell das therapeutische Potenzial einer Kombination aus einer anti-angiogenen Substanz und einem Zytostatikum im Pankreaskarzinom, indem die verschiedenen Wirkmechanismen auf unterschiedliche Zellpopulationen im Tumor ausgeübt werden
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Hyperplasia to neoplasia sequence of duodenal and pancreatic neuroendocrine diseases and pseudohyperplasia of the PP-cells in the pancreas.
Get PDFHyperplastic changes of the neuroendocrine cell system may have the potential to evolve into neoplastic diseases. This is particularly the case in the setting of genetically determined and hereditary neuroendocrine tumor syndromes such as MEN1. The review discusses the MEN1-associated hyperplasia-neoplasia sequence in the development of gastrinomas in the duodenum and glucagon-producing tumors in the pancreas. It also presents other newly described diseases (e.g., glucagon cell adenomatosis and insulinomatosis) in which the tumors are (or most likely) also preceded by islet cell hyperplasia. Finally, the pseudohyperplasia of PP-rich islets in the pancreatic head is defined as a physiologic condition clearly differing from other hyperplastic-neoplastic neuroendocrine diseases
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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