Dans le milieu clinique des soins intensifs, l’induction du coma médicamenteux (i.e. iatrogénique) par les sédatifs et les analgésiques est souvent associée à une augmentation significative du délirium. De plus, l’utilisation de sédatifs et d’analgésiques comme le fentanyl et le midazolam sans interruption et sans ajustement aux besoins du patient augmentent la durée de séjour, les coûts et la mortalité. Le but de cette étude était d’explorer les facteurs de variabilité pouvant influencer la survenue du coma iatrogénique et du délirium tel que : les facteurs génétiques/sociodémographiques et la co-administration de médicaments substrats ou inhibiteurs de CYP3A4/3A5 ou de la glycoproteine P. L’étude prospective à visée observationnelle a été effectuée à l’unité de soins intensifs de l’hôpital Maisonneuve-Rosemont avec 53 patients perfusés avec fentanyl ou midazolam. La faisabilité du modèle pharmacocinétique du fentanyl a été mise en évidence à partir des échantillons sanguins des patients et était compatible avec les données cliniques. Cette étude montre donc que contrairement au profil génomique de CYP3A5 (p value = 0,521) et MDR1 (p value = 0,828), les effets des interactions médicamenteuses entre les inhibiteurs CYP3A4/CYP3A5 et fentanyl/midazolam représentent un facteur de risque pour le coma iatrogénique (p value = 0,014). Ces effets peuvent être facilement identifiés et sont prévisibles; résultats qui seront utiles aux praticiens – intensivistes dans le choix d’une thérapie pharmacologique appropriée pour prévenir les complications morbides comme le coma iatrogénique et le délirium. / When sedatives such as midazolam or opiate analgesics such as fentanyl administered to critically ill patients and medication-induced coma occurs, increased delirium is observed. In addition, there is an increase in the length of stay in ICU, in costs and mortality. The purpose of this study was to explore the factors of variability affecting the incidence of iatrogenic coma and delirium: genetics/socio demographics factors, co-administration of substrates/inhibitors of CYP3A4/3A5 or P-gp. We performed a prospective cohort observational study of 53 hospitalized patients treated with fentanyl or/and midazolam in the intensive care unit of the Maisonneuve-Rosemont hospital The feasibility of pharmacokinetics modeling using blood samples from critically ill patients was demonstrated and was compatible with clinical data. This study suggests that contrary to genomic variants in the CYP3A5 (p value = 0,521) and MDR1 (p value = 0,828) genes, the effect of drugs and drugs interactions between inhibitors of CYP3A4/3A5 and fentanyl/ midazolam constitutes the main risk factor for iatrogenic coma (p value - 0,014). These effects are easily identifiable and predictable, and are very important for intensive care workers to make the appropriate choice of medication in order to prevent morbid complications such as iatrogenic coma and delirium.

No description available.

No description available.

Before the regulation of opium as a “narcotic” in Sweden in 1923, opium was not regulated for its intoxicating properties and was freely available. But not in any kind of shop. Opium was legally available only through the pharmacies. This thesis explores how this free availability of a narcotic was understood by its traders, the pharmacists. The title of this thesis – The Value of Poison – indicates how opium could be conceptualized both as a safe, everyday remedy essential to keep freely available and as a drug of intoxication. As a poison it could be articulated as a matter of primarily pharmacological, not moral or medical, concern. This also gave the pharmacists, with their special knowledge of pharmaka (drugs, poisons), an autonomous space of knowledge free from the ever more intruding “medical gaze”. But, in order to articulate this kind of understanding of opium, another kind of knowledge was needed to be acknowledged: that of the user. In this articulation a “sensus communis” was tied in with a broader cultural knowledge of drugs. Problems with opium were focused on the danger of acute poisoning, not recreational intoxication. Concepts that could have problematized this kind of use were rearticulated as problems either of illegitimate trade, unregulated markets and advertising or of draconian regulation by greedy or sloppy doctors. These rather opposite elements were made equivalent through the articulation of ignorance in both cases, thus further emphasizing the special knowledge of the pharmacist. The thesis locates a process of contradiction that contributes to the eventual diminishing of the discourse of poison towards the end of the period. The pharmaceutical knowledge that guaranteed the discourse was based on a “pharmaceutical gaze” on pharmaka. It pierced through the drug to identify its constituent parts. In this process it was promised that the different effects of opium would be separated. “Narcotic” could be a by-product, to be discarded or controlled, without dispensing of other therapeutic effects. With this ever deeper knowledge of opium, knowledge in the pharmacies was made insufficient for the full understanding or opium, and so too was that of the traditional user. The era of opium as a poison was over. / Före den första särlagstiftningen om narkotika i Sverige 1923 reglerades inte opiumets rusgivande egenskaper. Drogen var fritt tillgänglig i handeln. Men inte i vilken butik som helst. Opium kunde bara köpas lagligt på landets apotek. Den här avhandlingen undersöker hur denna fria tillgänglighet av narkotika förstods av droghandlarna själva, apotekarna. Titeln pekar på hur opium på en och samma gång kunde tänkas som en säker husmedicin vars tillgänglighet var avgörande för folkhälsan och som en rusgivande drog. Som ”gift” artikulerades det som en i första hand farmakologisk angelägenhet, inte en moralisk eller medicinsk. När de talade på detta sätt upprättade apotekarna, genom sin särskilda kunskap om farmaka, ett eget rum för sitt vetande, fritt från läkarnas allt mer genomträngande ”kliniska blick”. Men för att kunna artikulera denna förståelse av opium krävdes också att en annan typ av kunskap vidkändes: brukarens. Genom denna artikulation knöts brukarnas ”sensus communis” samman med en bredare kulturell kunskap om droger. De av opiumets problem som lyftes fram handlade om akut förgiftning, inte rekreationellt rusbruk. De begrepp som hade varit möjliga att användas för att problematisera denna senare form av bruk reartikulerades: antingen förpassades de till den olagliga handeln, de oreglerade marknaderna och reklamen, eller också till de drakoniska regleringarna som giriga och slarviga läkare stod bakom. Apotekarna artikulerade dessa båda helt motstående element som ekvivalenta genom en brist på kunskap, vilket i sin tur ytterligare stärkte deras egen kunskapsmakt. Avhandlingen lokaliserar även en processande motsägelse som sker när giftets diskurs tynar bort vid slutet av den undersökta perioden. Den farmaceutiska kunskap som underbyggde diskursen vilade på en ”farmaceutisk blick” på farmaka. Denna genomborrade drogämnet för att avslöja dess beståndsdelar. Genom denna process utlovades att opiumets olika effekter skulle kunna skiljas från varandra. ”Narkotikan” kunde ses som en bieffekt, som kunde kastas åt sidan eller kontrolleras separat, utan att opiumets kvarvarande terapeutiska effekter minskade. Denna allt djupare kunskap medförde att de enskilda apotekarnas eget vetande på apoteken inte räckte till för att fullt ut förstå opium, och därmed bröts även samartikulationen med brukarnas kunskap. Tidseran när opium var ett gift tog därmed slut under mellankrigsperioden.

The use of hair and oral fluid for drugs of abuse testing has increased over the last years. For this reason, the assurance that results provided using these matrices are reliable and error-free is needed. The objective of this thesis is to develop tools to assess the quality of results provided by laboratories analysing drugs of abuse in hair and in oral fluid and to evaluate the effect on the quality of results of different actions carried out. For this reason, intercomparison exercises have been organized and some studies have been performed to develop appropriate quality control materials. Regarding the analysis of drugs of abuse in hair, nine different intercomparison exercises have been organized. The evaluation of qualitative and quantitative results reported by laboratories together with the study of the methodology used, has led to know the quality of the results, to identify the sources of error and to know the corrective actions that should be developed. Concerning the quality control material, these exercises have enabled to know the influence on the results of the type of hair used to perform the analysis. Concerning the analysis of drugs of abuse in oral fluid, a method has been developed to identify and quantify 6-monoacetyl morphine, morphine, codeine, cocaine and benzoylecgonine in oral fluid samples. On the other hand, stability studies of the main drugs of abuse in oral fluid have been done to establish the optimal preparation, transport and storage conditions, and finally, two intercomparison exercises have been conducted to know the performance of analytical laboratories when analysing drugs of abuse in oral fluid and to know the stability of some drugs of abuse in two commercial collection devices. / La creixent utilització del cabell i del fluid oral per a l’anàlisi de drogues d’abús, ha portat a la necessitat d’assegurar que els resultats obtinguts utilitzant aquestes matrius són fiables i lliures d’error. L’objectiu d’aquesta tesi és desenvolupar eines que permetin avaluar la qualitat dels resultats dels laboratoris que analitzen drogues d’abús en cabell i en fluid oral i avaluar l’efecte de diferents accions sobre la qualitat final dels resultats. Per això s’han organitzat exercicis interlaboratori i s’han realitzat estudis per desenvolupar material d’assaig adequat. Pel que fa a l’anàlisi de drogues d’abús en cabell, s’han realitzat nou exercicis interlaboratori. A través de l’avaluació dels resultats qualitatius i quantitatius informats pels laboratoris i mitjançant l’estudi de la metodologia emprada, ha estat possible conèixer la qualitat dels resultats obtinguts, detectar les fonts d’error i conèixer quines mesures correctives caldria desenvolupar. Pel que fa al material d’assaig, aquests exercicis han permès conèixer la influència que té, en els resultats, el tipus de cabell del qual es parteix per realitzar l’anàlisi. Pel que fa a l’anàlisi de drogues d’abús en fluid oral, s’ha desenvolupat i validat un mètode analític que ha permès identificar i quantificar 6-monoacetil morfina, morfina, codeïna, cocaïna i benzoïlecgonina en mostres de fluid oral. Per altra banda, s’han realitzat estudis d’estabilitat de les principals drogues en fluid oral que han permès establir les condicions òptimes de preparació, transport i conservació del material d’assaig i, per últim, s’han realitzat dos exercicis interlaboratori que han permès conèixer la qualitat dels resultats analítics obtinguts pels laboratoris i també l’estabilitat de les drogues en dos dispositius de recollida comercials.

In forensic chemistry, a quicker and more accurate analysis of a sample is always being pursued. Speedy analyses allow the analyst to provide quick turn-around times and potentially decrease back-logs that are known to be a problem in the field. Accurate analyses are paramount with the futures and lives of the accused potentially on the line. One of the most common methods of analysis in forensic chemistry laboratories is gas chromatography, chosen for the relative speed and efficiency afforded by this method. Two major routes were attempted to further improve on gas chromatography applications in forensic chemistry.<br> The first route was to decrease separation times for analysis of ignitable liquid residues by using micro-bore wall coated open-tubular columns. Micro-bore columns are much shorter and have higher separation efficiencies than the standard columns used in forensic chemistry, allowing for faster analysis times while maintaining the expected peak separation. Typical separation times for fire debris samples are between thirty minutes and one hour, the micro-bore columns were able to achieve equivalent performance in three minutes. The reduction in analysis time was demonstrated by analysis of ignitable liquid residues from simulated fire debris exemplars.<br> The second route looked at a relatively new detector for gas chromatography known as a vacuum ultraviolet (VUV) spectrophotometer. The VUV detector uses traditional UV and far-ultraviolet light to probe the pi and sigma bonds of the gas phase analytes as well as Rydberg traditions to produce spectra that are nearly unique to a compound. Thus far, the only spectra that were not discernable were from enantiomers, otherwise even diastereomers have been differentiated. The specificity attained with the VUV detector has achieved differentiation of compounds that mass spectrometry, the most common detection method for chromatography in forensic chemistry labs, has difficulty distinguishing. This specificity has been demonstrated herein by analyzing various classes of drugs of abuse and applicability to “real world” samples has been demonstrated by analysis of de-identified seized samples.<br>