Paracetamol är den aktiva substansen i ett flertal smärtstillande läkemedel. Paracetamol äräven ett vanligt ämne vid självmordsförsök, då en överdos kan leda till livshotandeleverskador. Laboratoriet Klinisk Kemi i Karlskrona hade för avsikt att införa ett nyttreagens för kvantitativ in vitro analys av p-paracetamol på instrumentet Alinity serie cifrån Abbott®. Detta på grund av att reagenset från Abbott® inte behövde kalibreras likaofta som tidigare reagens. Syftet med studien var därför att genomföra en metodverifieringav reagenset Abbotts® Acetaminophen på två Alinity serie ci instrument. För attgenomföra en metodverifiering behövdes reagensets repeterbarhet och riktighetkontrolleras, samt en metodjämförelse genomföras. Detta gjordes genom att analysera enhög och en låg kontroll 25 gånger på masterinstrumentet och 20 gånger påslavinstrumentet. Därefter analyserades samma kontroller 5 gånger över fem dagar påmasterinstrumentet, samt 35 patientprover på både referensmetoden och den nya metoden.Det resultat som erhölls var att samtliga inomserie- och mellanserieprecisioner hade envariationskoefficient inom de riktlinje som företaget angivit. Metodjämförelsen visade ettlinjärt förhållande mellan de båda reagensen med en korrelationskoefficient på 0,9999.Den slutsats som drogs var att det fanns en god repeterbarhet för både master- ochslavinstrument gällande samtliga kontrollnivåer för inomserieprecisionen. Vidare, förmellanserieprecisionen på masterinstrumentet gav även detta en god repeterbarhet för bådakontrollnivåerna. Metodjämförelsen gav ett linjärt samband mellan de två metoderna ochhade en låg bias mellan varandra. Metodverifieringen kunde därför godkännas och den nyametoden Abbotts® Acetaminophen (Abbott Diagnostics) kunde tas i bruk på Klinisk Kemii Karlskrona.

The research work described in this thesis, the environmentally friendly novel "Microwave Assisted Sub-Critical water (MASCW)" technology for particle engineering of active pharmaceutical ingredients and excipients was developed. The present novel technology MASCW process is described as green technology as water is used as the solvent medium and microwave energy as external source of heat energy for generation of a particle with different morphological and chemical properties. In MASCW process supersaturated solution of APIs is prepared by dissolving solute in water at high temperature and pressure conditions. Upon rapid and controlled cooling, based on the aqueous solubility of solute, solute/solvent concentration and dielectric constant of water rapid precipitation of API with narrow particle size distribution occurs. Using paracetamol (pca) as API moiety understanding of the mechanism of MASCW crystallisation process was investigated. The effect of different process and experimental parameters on crystallisation pathway and end product attributes were analysed. Correlation between the degree of supersaturation concentration of pca solution against temperature and pressure parameters was explained by generating binary phase diagram. Determination of polymorphic transformation pathway of pca from form I (stable) to form II metastable polymorphs in solution was analysed using Raman spectroscopy. The difference between conventional heating and subcritical treatment was explored by determining the change in the solvent dielectric constant and solubility of hydrophobic API molecule. Based on the process understanding results, this technology was further implemented to explore its application in generating phase pure stable and metastable cocrystal phase. Based on the solubility of API and cocrystal former congruent (CBZ/SAC, SMT/SAC, SMZ/SAC) and incongruent (CAF/4HBA) cocrystal pairs were selected. For the first time generation of anhydrous phase of CAF: 4HBA cocrystal in 1:1 stoichiometric ration was reported and generation of metastable cocrystal phase of CA CBZ: SAC form II was reported. The application of this technology was explored in generating phase pure metastable polymorph of paracetamol which retain higher compressibility and dissolution rate. The potential of MASCW micronisation process, theophylline is used as the model component to produce micro sized particles for pulmonary drug delivery system via dry powder inhaler (Foradil inhaler). The results demonstrate that the THF particles generated using MASCW process displayed greater aerodynamic performance compared to conventional spray-dried THF sample. In the final chapter, synthesis of inorganic biomaterial (nano crystalline hydroxyapatite) was reported for the first time and the prospects of combining API like ibuprofen (IBU) with a biologically active component like nano-crystalline hydroxyapatite (HA) through hydrogen bonding was mechanistically explained using X-ray diffractometer and spectroscopic techniques.

Metabonomics bildet das Ende der Omics-Kaskade und stellt eine top-down-Strategie zur Erfassung und Interpretation des Metaboloms, d. h. der Gesamtheit aller niedermolekularen Metaboliten in einem intakten Organismus, dar. Ziel der Technik ist es, mittels geeigneter ungerichteter Screeningverfahren in nicht-invasiv zu gewinnenden biologischen Proben wie Urin oder Blut charakteristische Metabolitenprofile zu bestimmen. Im Kontext des Metabonomics wurde in Anlehnung an den Geno- bzw. Phänotyp hierfür der Begriff „Metabotyp“ geprägt. Durch biostatistische Methoden, die auf Mustererkennung (pattern recognition) basieren, können Signaturen gegenübergestellt und auf diesem Weg gruppenspezifische Metaboliten, d. h. Biomarker bzw. Metabolitenmuster, extrahiert werden. Metabonomics kann folglich als Fusion klassischer bioanalytischer und biostatistischer Verfahren aufgefasst werden. Seit der Einführung im Jahr 1999 hat sich das Konzept des Metabonomics in mehrere Richtungen weiterentwickelt. So gab es Bestrebungen, die Technik, die ursprünglich zur Prädiktion von toxischen Effekten bei der Arzneistoffentwicklung etabliert wurde, auf Fragestellungen zu übertragen, die den Menschen im Mittelpunkt haben. Neben präklinischen Anwendungen verfolgt man mit Metabonomics zunehmend das Ziel, einer personalisierten Medizin und Ernährung einen Schritt näher zu kommen. Da sich die ursprünglich eingesetzte NMR-Technik als zu unempfindlich und die resultierenden Metabolitenprofile als zu anfällig gegenüber biologischen und analytischen Einflussgrößen (Confoundern) erwiesen haben, wurde parallel auf sensitivere Verfahren wie die Massenspektrometrie gesetzt. Insbesondere die Kopplung mit der Hochdruckflüssigchromatographie erwies sich hierbei für das Metabolitenscreening als geeignet. Schnell wurde allerdings klar, dass aus den klassischen full scan/TOF-Methoden Datensätze resultierten, die häufig zu komplex waren, um mit nachgeschalteten chemometrischen Verfahren die „Spreu vom Weizen trennen“ zu können. Da sich Metabolitendatenbanken bisher noch im Aufbau befinden, ist die Identifizierung der Marker mit zusätzlichen Schwierigkeiten verbunden und bedarf aufwändiger analytischer Verfahren. Eine Strategie stellt daher die Beschränkung auf ein Metabolitensubset dar. Indem man sich auf Metabolitenklassen fokussiert, die einen Bezug zum untersuchten Mechanismus haben, können die Erfolgsaussichten bei der Identifizierung charakteristischer Biomarker deutlich erhöht werden. Aufgrund zahlreicher exogener und endogener Faktoren (Arzneistoffe, Industriechemikalien, Nahrungsbestandteile, Tabakrauchbestandteile, Produkte der Lipidperoxidation etc.) ist der menschliche Organismus stets einer Vielzahl an elektrophilen Verbindungen ausgesetzt. Oxidative Schädigungen an Strukturen wie der DNA, Proteinen und Lipiden werden mit einer Reihe von Krankheitsbildern in Zusammenhang gebracht, darunter Parkinson, Alzheimer, Krebs und Volkskrankheiten wie Arteriosklerose, Allergien und koronare Herzerkrankungen. Mit dem Glutathionsystem verfügt der Körper über einen wirksamen Detoxifizierungsmechanismus. Das Tripeptid Glutathion reagiert als Nukleophil mit den exogen oder endogen gebildeten elektrophilen Intermediaten. Endprodukte sind Merkaptursäuren (N-Acetyl-L-Cystein-Addukte) bzw. deren Sulfoxide, die in erster Linie mit dem Urin ausgeschieden werden. Folglich besteht zwischen diesen Merkaptursäurederivaten und der elektrophilen Belastung eines Organismus ein direkter Zusammenhang. Vor diesem Hintergrund war es das Ziel der Arbeit, einen nicht-invasiven Metabonomicsansatz zur Anwendung am Menschen zu entwickeln. Durch die Fokussierung des Metabolitenscreenings auf die Effekt-, Dosis- und Suszeptibilitätsmarkerklasse der Merkaptursäuren sollten hierbei die Erfolgsaussichten im Hinblick auf die Identifizierung potentieller Biomarker für diverse toxikologische sowie medizinische Endpunkte erhöht werden. / Metabonomics forms the end of the omics-cascade and represents a top-down strategy for the interpretation of the metabolome, i. e. all the low molecular weight metabolites in an intact organism. The aim of the approach is to analyse characteristic metabolite profiles by suitable untargeted screening methods in biological samples like urine or blood that can be obtained in a non-invasive manner. In the context of metabonomics, the term “metabotype” was defined according to the geno- and phenotype, respectively. Biostatistical methods based on pattern recognition techniques allow comparing metabolic signatures and extracting group specific metabolites and biomarkers. Therefore, metabonomics can be regarded as the fusion of bioanalytical and biostatistical techniques. Since its introduction in 1999, the concept of metabonomics has permanently gained importance in many fields of scientific research. One aim was to transfer the methodology, which was originally established to predict toxic effects in drug development processes, to human issues. Apart from preclinical questions, metabonomics is increasingly applied in the area of personalised medicine and nutrition. As the NMR technique used by pioneers of the field was too insensitive and the resulting metabolite profiles were too susceptible to biological and analytical confounders, more sensitive techniques like mass spectrometry were more and more applied. Especially mass spectrometry in combination with high performance liquid chromatography showed great promise for the screening of metabolites. However, after a very short time, it was clear that the data sets resulting from full scan/TOF-methods were too complex to “separate the wheat from the chaff” with chemometric procedures. Metabolite databases are still under construction, and therefore marker identification is challenging and requires complex analytical techniques. Thus, one strategy is to concentrate on a certain metabolite subset. The focus on a metabolite class with a close relation to the mechanism under investigation can considerably increase the prospects of success in the biomarker identification process. Due to a variety of exogenous and endogenous factors (drugs, industrial chemicals, food ingredients, and tobacco smoke) the human organism is steadily confronted with a multitude of electrophilic compounds. Oxidative damage of the DNA, proteins, and lipids is associated with the development of diseases like Parkinson’s, Alzheimer’s, cancer and widespread diseases like arteriosclerosis, allergies and coronary heart diseases. With the glutathione system the human organism is equipped with an efficient detoxification mechanism. The tripeptide glutathione reacts as nucleophile with exogenously and endogenously formed electrophilic intermediates. End products are mercapturic acids (N-acetyl-L-cysteine-adducts) and respective sulfoxides that are predominantly excreted with urine. Therefore, there is a close relationship between these mercapturic acid patterns and the electrophilic burden of an organism. In this context, the aim of this thesis was to develop a non-invasive human metabonomics approach that focuses the metabolite screening on the effect, dose and susceptibility marker class of the mercapturic acids. Thus, the prospects of success regarding the identification of potential biomarkers for various toxicological and pathological endpoints should be increased.

Submitted by Cássio da Cruz Nogueira (cassionogueirakk@gmail.com) on 2017-01-31T12:12:07Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_SinteseCapacidadeAntioxidante.pdf: 1936790 bytes, checksum: c31289c3ccac51d2352de37d23f858b6 (MD5) / Approved for entry into archive by Edisangela Bastos (edisangela@ufpa.br) on 2017-02-01T12:18:40Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_SinteseCapacidadeAntioxidante.pdf: 1936790 bytes, checksum: c31289c3ccac51d2352de37d23f858b6 (MD5) / Made available in DSpace on 2017-02-01T12:18:40Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_SinteseCapacidadeAntioxidante.pdf: 1936790 bytes, checksum: c31289c3ccac51d2352de37d23f858b6 (MD5) Previous issue date: 2014 / A prostaglandina endoperóxido-sintase (PGES) e o citocromo P-450 são enzimas chaves em humanos, responsáveis pelos efeitos analgésicos e toxicidade do acetaminofen, respectivamente. O acetaminofen (ACP) ou paracetamol é um fármaco analgésica e antipirética de venda livre, amplamente utilizado e parece ser seguro, se utilizada em doses terapêuticas normais, mas altas doses de ACP produzem lesão hepática e/ou renal em seres humanos e em animais de experimentação. Até o momento, os projetos de desenvolvimento de novos derivados paracetamol tiveram pouco impacto na aplicação clínica de um derivado mais seguro do ACP. Assim, neste trabalho uma série de derivados de ACP baseados na analogia entre chalconas e hidrazonas foi investigada usando cálculos de química quântica no nível de teoria DFT/B3LYP, com o conjunto de base 6- 31G*. O HOMO, IP, BDEOH e contribuição da densidade de spin para a oxidação inicial de um eléctron ou um átomo de hidrogênio a partir de abstração do grupo hidroxila fenólica foi relacionada com a reatividade do radical tirosil produzindo N-acetil-p-benzosemiquinona imina (NAPSQI). A segunda abstração de hidrogênio foi relacionada com a reação química entre o grupo amida e o radical hidroxil formando N-acetil-p-benzoquinona imina (NAPQI). Os valores mais baixos de BDEOH foram relacionados com os valores mais elevados de extinção do radical tirosil e a estabilidade está relacionada com a densidade de spin para as abstrações iniciais do elétron ou hidrogênio. Os valores mais elevados de BDENH foram relacionados com a formação de NAPQI e os baixos valores de LUMO com a reatividade de NAPQI como sistema Michael. Os resultados mostraram que alguns análogos podem ser uma boa estratégia para o desenvolvimento de fármacos mais seguros como compostos analgésicos. Os compostos foram sintetizados e suas propriedades antioxidantes foram estimadas utilizando o método de química teórica. Alguns compostos podem ser bons antioxidantes. Um mecanismo de interação entre os derivados de hidrazonas e a PGES foi proposto usando propriedades moleculares. / The prostaglandin-endoperoxide synthase (PGES) and cytochrome P-450 are key enzymes in human, which are responsible for analgesic effect and toxicity of acetaminophen, respectively. Acetaminophen or paracetamol is a widely used over-the-counter analgesic and antipyretic drug and appears to be safe if used in normal therapeutic doses, but large doses of ACP produce hepatic and/or renal injury in humans and in experimental animals. At moment, the design of new acetaminophen derivatives has few impacts for its clinical applications of safe acetaminophen derivative. Thus, in this work a series of acetaminophen derivatives based on chalcone and hydrazone analogy was been investigated using quantum chemical calculations at the DFT/B3LYP theory level, with the 6-31G* basis sets. The HOMO, IP, BDEOH, and spin density contribution for the oxidation of an initial electron or hydrogen atom abstraction from the phenolic hydroxyl group was related with the quenching reactivity of tyrosyl radical to give N-acetyl-p-benzosemiquinone imine (NAPSQI). The second hydrogen abstraction was related with the chemistry reaction between amide group and hydroxyl radical to give N-acetyl-p-benzoquinone imine (NAPQI). The lowest BDEOH values were related with higher quenching values of the tyrosyl radical and the stability was related with the spin density for the initial electron or hydrogen abstractions. The highest BDENH values were related with small NAPQI formation and LUMO values with reactivity of NAPQI-like Michael system. Our results showed that some analogous may be a good strategy for safer drug design of analgesic compounds. The compounds were synthesized and their antioxidant property was estimated using theoretical methods. Some compounds can be good antioxidant. A proposed mechanism for the interaction between hydrazone derivatives and PGES was realized using molecular properties.

Le paracétamol est un analgésique parmi les plus consommés dans le monde. Les synthèses actuelles de cette molécule induisent la formation de quantités non-négligeables de sels ou de produits secondaires non valorisables. En plus d'induire de faibles économies d'atomes, la présence de ces déchets engendre des surcoûts importants pour la synthèse du paracétamol dus aux lourds traitements des réactions. Les objectifs de la thèse étaient à la fois de proposer une synthèse plus respectueuse de l'environnement mais également économiquement viable. En ce sens, deux synthèses du paracétamol ont été étudiées. La première synthèse étudiée concerne la réduction sélective du nitrobenzène en p-aminophénol, l'intermédiaire clé du paracétamol. Cette synthèse nécessite typiquement une quantité importante d'acide sulfurique qui est corrosif et engendre la formation de sels (sulfate d'ammonium) importante. Un catalyseur acide recyclable à base d'oxyde de niobium a été utilisé et associé à l'acide sulfurique. Ainsi les sélectivités en aminophénol de 74 % sans catalyseur de niobium ont été améliorées à 82 % en présence de ce catalyseur. En outre, la quantité d'acide sulfurique a été réduite au minimum sans pertes significatives de sélectivité. La deuxième synthèse est la substitution de l'hydroquinone par l'acétate d'ammonium en milieu acide acétique. Cette synthèse innovante s'est révélée être particulièrement performante car elle induit la formation du paracétamol en une étape en partant d'un produit disponible en grande quantité, avec de très bons rendements et sélectivités. De plus, un test à large échelle a permis de montrer que le paracétamol produit est facilement récupérable par précipitation et l'acide acétique récupérable par distillation. Enfin, la réaction a été testée avec succès à d'autres polyhydroxybenzènes et aux naphtols / Paracetamol is an analgesic among the most consumed in the world. Currents syntheses of paracetamol induce a quantity of salts and non-reusable by-products. These wastes lead to both a low atom economy and a high process cost due to the work-ups. The main objectives of this thesis were to propose eco-friendly and competitive synthesis of paracetamol. Two syntheses have been studied. The first one was the selective reduction of nitrobenzene to p-aminophenol, the key intermediate of paracetamol. This synthesis requires a large amount of sulphuric acid which is corrosive and induces salts formation. A reusable niobium oxide-based catalyst has been associated with sulphuric acid. This association gave better selectivities to aminophenol (82%) compare to sulphuric acid alone (74%). Moreover, the quantity of sulphuric acid has been minimized without significant loss of selectivities. The second synthesis study was the hydroquinone substitution to paracetamol with ammonium acetate in acid acetic. This new synthesis is very powerful due to the one-step synthesis of paracetamol from bulk quantity available products, with very good conversion and selectivity. Moreover, a large scale synthesis has been tested which demonstrates that paracetamol and acetic acid were easily recovered by precipitation and distillation, respectively. The reaction has been successfully extended to other polyhydroxybenzenes and naphtols

El text del capítol 4 ha estat retirat seguint instruccions de l’autorai, en existir participació d’empreses, existir conveni de confidencialidad o existeix la possibilitat de generar patents / El texto del capítulo 4 ha sido retirado siguiendo instrucciones de la autora, al existir participación de empresas, convenio de confidencialidad o la posibilidad de generar patentes. / The text of chapter 4 has been withdrawn on the instructions of the author, as there is participation of undertakings, confidentiality agreement or the ability to generate patent / OBJETIVO: Conocer el método de administración intermitente de un fármaco endovenoso en un servicio de urgencias (SU) y si la retención de fármaco en el equipo de sueroterapia, una vez finalizada la perfusión, repercute sobre la respuesta clínica. MÉTODO: Estudio prospectivo, observacional y descriptivo en una primera fase. En una segunda fase ha sido intervencionista y analítico. Fase 1: análisis de la técnica de perfusión y su repercusión en la respuesta terapéutica sobre el paciente. Fase 2: análisis de la técnica de perfusión intermitente tras acción docente de mejora dirigida al personal de enfermería y su repercusión en la respuesta terapéutica sobre el paciente. Fármaco analizado: Paracetamol 1 g/ev. Variables: edad, sexo, peso, minutos de perfusión, volumen residual post-perfusión en los equipos, escala de dolor y/o temperatura basal (15’, 60’ y 4 horas), concentración plasmática de paracetamol a las 4 horas. Población de estudio: Individuos de ambos sexos mayores de 15 años de edad que acuden al SU y que se les prescribe paracetamol 1 g/ev. RESULTADOS: Se incluye 119 pacientes, 60 durante la 1ª fase y 59 en la 2ª fase. Ninguna perfusión considerada administrada en su totalidad había sido purgada durante la fase 1. El tiempo de administración de la perfusión fue de 25,7 ± 10,9 minutos. La omisión de purga conllevó un volumen residual medio retenido en el sistema de perfusión de 12,6 ± 2,9 ml, alcanzándo una concentración plasmática media de paracetamol de 4,3 ± 5,0 μg/ml, frente a los 5,27 ± 4,42 μg/ml en los casos en los que sí se realizó purga (fase 2). La relación entre concentración de fármaco y la mejoría del dolor se mostró estadísticamente significativa en la medición del mismo a las 4 horas (p = 0,05). El efecto antitérmico no estuvo relacionado con el volumen residual obtenido. CONCLUSIONES: El volumen residual es considerable en los equipos de perfusión y puede tener una repercusión en la respuesta clínica y terapéutica. Consideramos que la práctica de una purga del equipo de sueroterapia es una medida necesaria y debe considerarse su implantación y realización rutinaria. / OBJECTIVES: To determine whether acetaminophen is retained inside intravenous infusion bottles and lives after intermittent administration of fluids in the emergency department and whether such retention has an effect on outcomes. METHODS: Prospective, observational study in the first phase, followed by a second phase to analyze the effect of technical instruction and intervention. In the first phase, the completeness of intravenous administration of medication and the patient’s response to therapy were recorded. In the second phase, after instruction to improve the staff’s technical performance of intravenous infusion of medication, completeness of administration and patient response were again recorded. The medication studied was acetaminophen (1 g) infused through an intravenous line. Variables recorded were age, sex, weight, duration of infusion, residual volume left in the intravenous infusion equipment, score on a pain scale and/or temperature (at 15 minutes, 1 hour, and 4 hours), and plasma concentration of acetaminophen at 4 hours. The study population consisted of male and female emergency department patients aged 15 years or older who were prescribed 1 g of intravenous Acetaminophen. RESULTS: A total of 119 patients were enrolled; 60 were studied in the first phase and 59 in the second. In the first phase, the infusion equipment failed to draim completely in all cases. Intravenous administration took a mean (SD) of 25.7 (10.9) minutes during this phase and omission of a flush maneuver at the end led to leaving a mean residual volume of 12.65 (2.95) mL in the system. The mean plasma concentration of acetaminophen in the first phase (no instruction to flush the line) was 4.28 (5.04) micrograms/mL; in the second phase, after the staff had been instructed to flush the system, the mean plasma concentration was 5,27 (4,42) micrograms/mL. We observed a statistically significant relation between drug plasma concentration and pain relief at 4 hours (P=.05), but no correlation between temperature and residual volume in the equipment. CONCLUSIONS: Considerable volume is left inside intravenous infusion systems, and loss of infusion may affect clinical response and therapy. We believe routine flusing of intravenous infusion system is essential.

La premisa de partida de esta Tesis Doctoral es que la Unidad de Toxicologia Clinica (UTC) del Hospital Universitari Son Dureta(HUSD), entendida como instrumento funcional y vertebrador de los profesionales de diferentes Servicios hospitalarios con interés profesional en el ámbito de la Toxicología, puede actuar como elemento generador de las condiciones favorables para desarrollar métodos y estrategias orientadas a la mejora global del proceso asistencial del paciente intoxicado. En dicha Unidad, el Registro de Intoxicados es el instrumento principal para estructurar, planificar, monitorizar y evaluar los trabajos realizados tanto en el campo asistencial como en el docente e investigador. La segunda premisa es que la participación del analista clínico como miembro activo de la UTC no se limita a intervenir en la identificación, cuantificación y confirmación de los productos tóxicos y sus metabolitos en muestras biológicas, en la interpretación toxico-cinética del resultado analítico obtenido y en el asesoramiento de la solicitud de pruebas analíticas, sino que también participa en todas las fases del proceso de atención al intoxicado. Atendiendo a estas premisas, las hipótesis que se formulan en este trabajo son las siguientes: 1. El registro de pacientes intoxicados con especial atención en sus aspectos analíticos, es una herramienta válida para aportar conocimiento sobre la realidad epidemiológica de nuestro entorno y sobre la utilización de los recursos analíticos, tanto los específicamente toxicológicos como los meramente complementarios. 2. El conocimiento que posee el médico asistencial sobre la utilidad, condicionamientos y limitaciones de algunas determinaciones analíticas utilizadas en el intoxicado agudo, concretamente sobre las pruebas de cribado de drogas de abuso en orina, es limitado y susceptible de mejora. 3. En la intoxicación por paracetamol, es posible mejorar el tratamiento del paciente mediante el diseño y la utilización de herramientas simples basadas en parámetros farmacocinéticos del paracetamol. Los objetivos generales que se propone alcanzar esta Tesis Doctoral son los siguientes: 1. Adecuar racionalmente la cartera de servicios del laboratorio de la UTC del HUSD/HUSE en base al conocimiento obtenido con los resultados del registro de los pacientes intoxicados agudos, para poder ofrecer una respuesta analítica toxicológica específica adecuada a los tóxicos más prevalentes en nuestra área asistencial. 2. Medir la importancia que los facultativos que atienden a los intoxicados otorgan al laboratorio en el proceso diagnóstico y terapéutico y valorar sus conocimientos sobre algunos aspectos básicos de determinadas pruebas de laboratorio. 3. Establecer si mediante el cociente entre dos determinaciones de paracetamol en suero es posible predecir el riesgo de hepatotoxicidad y si la determinación de paracetamol en orina en la población pediátrica es útil para detectar la ingesta de este fármaco. Estudiados los resultados obtenidos con los materiales y métodos utilizados en esta Tesis como conclusiones de la misma se destaca en primer lugar que el estudio de los datos del registro ha conseguido conocer la realidad de la epidemiologia de la intoxicación en nuestro entorno geográfico lo que ha permitido dirigir los objetivos del laboratorio a la consecución de los medios, tanto instrumentales como humanos, capaces de mejorar sustancialmente la respuesta a las necesidades clínicas evidenciadas, incrementado la capacidad de detección y/o cuantificación analítica de los tóxicos presentes en nuestra muestra, tanto la del grupo TOP 50 como la del grupo TOP DRUGS. Asimismo, las encuestas realizadas han permitido valorar objetivamente el grado de conocimiento que poseen los clínicos que atienden a enfermos intoxicados sobre diferentes aspectos relativos a la toxicología analítica, y se han obtenido orientaciones que han facilitado conocer con una base objetiva lo que se espera del laboratorio, y cómo valora el clínico solicitante al laboratorio y los resultados analíticos suministrados. En relación a la intoxicación por Paracetamol, la estimación de la semivida del PCT en los casos en que no es posible aplicar el nomograma de Rumack-Mattew, posibilita obtener de manera rápida y fácil una información objetiva útil que permite valorar la adecuación o no de instaurar el tratamiento específico, y que aporta un dato complementario útil en la valoración pronostica de la intoxicación por PCT. Asimismo la determinación de PCT en orina ha mostrado ser una herramienta útil para descartar una ingesta de PCT en las 24 horas previas, por lo que resulta adecuada su inclusión en el algoritmo de actuación del paciente pediátrico con sospecha de intoxicación aguda por PCT. Como conclusión final, se indica que la creación, el mantenimiento y el desarrollo de la UTC en nuestro Hospital ha sido el instrumento funcional vertebrador y generador de las condiciones necesarias para el desarrollo de trabajos e investigaciones en el campo de la Toxicología Clínica, actuando como elemento aglutinador de los profesionales de diferentes Servicios hospitalarios con interés en el ámbito de la Toxicología Clínica. / Title: Analytical input to the process of patient care intoxicated. Experience in the Clinical Toxicology Unit of Hospital Universitari Son Dureta. Author: Bartomeu Castanyer Puig The overall objectives of this thesis are: 1. Rationally adjust the service portfolio of Unit of Clinical Toxicology (UTC) of Hospital Universitari Son Dureta (HUSD), based on the knowledge gained from the results of registration of acute poisoned patients, to provide adequate specific toxicological analytical response to toxicants more prevalent in our area care. 2. Measuring the importance that physicians who care for intoxicated give the laboratory in diagnostic and therapeutic process and assess their knowledge of some basic aspects of certain lab tests. 3. Set if the quotient between two determinations of serum paracetamol is possible to predict the risk of hepatotoxicity, and if the determination of paracetamol in urine in the pediatric population is useful for detecting the intake in the previous 24 hours The conclusions of this thesis, studied the results obtained with the materials and methods used, emphasizes first that the study of log data has gotten to know the reality of the epidemiology of poisoning in our geographic area which has allowed direct laboratory objectives the achievement of the means capable of responding to the clinical needs evidenced. Furthermore, surveys have assessed objectively the degree of knowledge possessed by different clinical aspects of analytical toxicology, and orientations have been obtained which have facilitated an objective basis to know what is expected of the laboratory, and how to assess the applicant to the clinical laboratory and analytical results provided. Regarding paracetamol poisoning, the estimated half-life of PCT in cases where it is not possible to apply the Rumack-Matthew nomogram, allows to obtain quickly and easily objective information that provides a useful complementary data in the prognostic assessment of intoxication. Also PCT determination in urine has proved a useful tool to rule out an intake of PCT in the previous 24 hours, making it suitable for inclusion in the action algorithm of pediatric patients with suspicion of acute PCT intake.

The research addressed in this thesis focuses on monitoring and characterization of pharmaceutical compounds by laser backscattering. In particular, this study covers two topics: (1) the determination of naproxen sodium solubility in water, and its phase transition; and (2) comparisons of batch and laminar flow tubular crystallizers for the production of paracetamol (acetaminophen) and D-mannitol. Using a Lasentec™ Focused Beam Reflectance Measurement (FBRM) device, the solubility of naproxen sodium in aqueous solutions was determined over a temperature range from 15.2 to 39.7 ℃ With the determination of the solubilities of two pseudopolymorphs, anhydrous and dihydrated naproxen sodium, the phase transition point between these two forms of the pharmaceutical compound was determined to occur at 30.3 ℃ Enthalpy of solution and metastable zone widths were also determined for the experimental conditions. Crystallizations of paracetamol and D-mannitol were performed in a batch crystallizer and in a laminar flow tubular crystallizer (LFTC) system. In the latter system, supersaturation was generated rapidly in the solution being transported through a temperature-controlled tube and recovered in a batch vessel where product crystals were grown to equilibration. Because of the rapid rate at which supersaturation was generated in the LFTC, the resulting crystals were of smaller mean size than those obtained from batch crystallizations. The total time required for crystallization was significantly less with the LFTC than with the batch unit. Additionally, the rapid cooling in the LFTC led to the formation of two different polymorphs of paracetamol, Forms I and II.

Several sophisticated techniques to study in vivo GI transit and regional absorption of pharmaceuticals are available and increasingly used. Examples of such methods are Magnetic Marker Monitoring (MMM) and local drug administration with remotely operated capsules. Another approach is the paracetamol and sulfapyridine double marker method which utilizes observed plasma concentrations of the two substances as markers for GI transit. Common for all of these methods is that they generate multiple types of observations e.g. tablet GI position, drug release and plasma concentrations of one or more substances. This thesis is based on the hypothesis that application of mechanistic nonlinear mixed-effect models could facilitate a better understanding of the interrelationship between such variables and result improved predictions of the processes involved in oral absorption. Mechanistic modeling approaches have been developed for application to data from MMM studies, paracetamol and sulfapyridine double marker studies and for linking in vitro and in vivo drug release. Models for integrating information about tablet GI transit, in vivo drug release and drug plasma concentrations measured in MMM studies was outlined and utilized to describe drug release and absorption properties along the GI tract for felodipine and the investigational drug AZD0837. A mechanistic link between in vitro and in vivo drug release was established by estimation of the mechanical stress in different regions of the GI tract in a unit equivalent to rotation speed in the in vitro experimental setup. The effect of atropine and erythromycin on gastric emptying and small intestinal transit was characterized with a semi-mechanistic model applied to double marker studies in fed and fasting dogs. The work with modeling of in vivo drug absorption has highlighted the need for, and led to, further development of mixed-effect modeling methodology with respect to model diagnostics and the handling of censored observations.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.