The great amount of METH abuse all over the world causes enormous social and criminal justice problems. In the human brain the abuse of METH causes implications on both structures and functions given rise to acute as well as long term symptoms. In this essay the effects of METH abuse is described in the manner of the drug mechanism such as the impact on neurotransmitters, structural deficits with decreased and increased volumes and the implication on attention, memory, decision  making and emotions. Results from studies showing brain structural and cognitive impairments in METH abusers and in prenatal METH exposed children.

<p>The great amount of METH abuse all over the world causes enormous social and criminal justice problems. In the human brain the abuse of METH causes implications on both structures and functions given rise to acute as well as long term symptoms. In this essay the effects of METH abuse is described in the manner of the drug mechanism such as the impact on neurotransmitters, structural deficits with decreased and increased volumes and the implication on attention, memory, decision  making and emotions. Results from studies showing brain structural and cognitive impairments in METH abusers and in prenatal METH exposed children.</p>

En treballs anteriors del nostre grup de recerca es va demostrar que l’antagonista específic del receptor nicotínic α7, metillicaconitina (MLA), inhibia in vitro la producció d’espècies reactives d’oxigen (EROS) i protegia de la neurotoxicitat in vivo induïda per metamfetamina (METH) i per la 3,4-metilendioxi-N-metamfetamina (MDMA). En aquesta tesi, es descriu un nou mecanisme d’acció dels derivats amfetamínics. Mitjançant assajos de fixació de radiolligands, es va comprovar que ambdós derivats amfetamínics competien amb els radiolligands específics dels receptors nicotínics α7 ([3H]Metillicaconitina), i dels heteromèrics ([3H]Epibatidina), el que indicava que en les cèl•lules PC12, el nostre model experimental, i també en una preparació de cervell total de ratolí, aquestes substàncies interaccionaven directament amb els receptors nicotínics. L’MDMA mostrava més afinitat per ambdós subtipus de receptors. Està descrit que el tractament crònic amb nicotina provoca un augment en la densitat de receptors nicotínics tan in vivo com in vitro en cèl•lules PC12. Ambdós derivats amfetamínics van provocar una regulació a l’alça dels dos subtipus de receptors ja a les 6 hores de pretractament. A la vegada, in vivo, l’MDMA i la Nicotina van provocar la regulació a l’alça que va ser potenciada per la seva associació en determinades zones cerebrals on s’expressen cada subtipus de nAChR. De l’estudi dels mecanismes implicats en aquesta regulació a l’alça, mitjançant inhibidors a diferents nivells, es va concluir que, igual com passa amb la nicotina, es produeixen a nivell postraduccional. A nivell funcional, vam determinar que aquests derivats amfetamínics eren capaços d’activar els receptors nicotínics i, d’acord amb les hipòtesis de treballs anteriors, induir una entrada de calci i de sodi que podria estar implicada en els esdeveniments que comportarien la seva neurotoxicitat. Per una banda, l’MDMA i la METH es van comportar com agonistes parcials dels nAChR α7 induïnt un increment de Ca2+ citosòlic. Per altra banda, l’MDMA es va comportar com antagonista dels nAChR heteromèrics i la METH com agonista parcial induint l’entrada de Na+ de la mateixa manera, el qual explicaria diferències a nivell de dependència, ja que els nAChR α4β2 estan implicats en la via mesolímbica o de recompensa. Paral•lelament a l’increment de fixació de radiolligands, es va determinar que la preincubació amb MDMA indueix un increment en la resposta per activació de receptors nicotínics, demostrant que l’ MDMA també indueix regulació a l’alça funcional. Alhora, es va observar que la preincubació de les cèl•lules durant 24 hores amb MDMA dona lloc a un increment perllongat dels nivells basals de Ca2+, el qual indica que l’MDMA inhibeix la desensibilització dels receptors i fa que entri calci durant un temps més llarg. Aquesta entrada persistent podria estar implicada en fenòmens de neurotoxicitat ja que va seguida de l’activació de vies dependents de calci com la calpaïna i la caspasa-3. / During the last years, our emphasis has focused in the study of the neurotoxic effects of MDMA and methamphetamine (METH) on central nervous system and their pharmacological prevention. It has been demonstrated that these amphetamine derivatives produce oxygen species (ROS) in an in vitro model of synaptosomes. In previous works, we demonstrated that blockade of alpha7 nicotinic receptors with methyllycaconitine (MLA) prevented ROS production induced by MDMA and METH, consequently the alpha7 receptor would be involved in the neurotoxicity induced by these drugs. Studies at molecular level, using radioligand binding assays, showed the interaction of METH and MDMA with homomeric alpha7 nAChR and heteromeric subtypes of nicotinic receptors, such as aplha4 beta2. In addition, we investigated the effects of pretreatment with METH and MDMA on nAChR densities. We used PC 12 cells as an experimental model due to the fact other authors have similarly utilised them to evaluate the neurotoxicity of amphetamines. Moreover, they not only express nAChR, including the alpha7 subtype, but also provide an in vitro model for the up-regulation of nAChR, which occurs in vivo following chronic exposure to nicotine. In recent works, we demonstrated in vitro that Ca2+ chelation with EGTA prevented the production of reactive oxygen species (ROS) to a similar extent as nAChR blockade. This indicates that calcium influx, probably through alpha7 nAChR, is a key step in this process. Consequently, one of the objectives of this work was to use a fluorimetric method to investigate the effect of MDMA on Ca2+ and Na+ levels in cultured PC12 cells and the involvement of different nAChR subtypes and other cell pathways related to Ca2+ mobilization. In addition, we used electrophysiology in transfected Xenopus oocytes to corroborate the effects on alpha7 and alpha4 beta2 nAChR. Moreover, pretreatment with MDMA induced functional upregulation by potentiating the effects of specific nAChR agonists or whether it provoked a persistent Ca2+ increase, leading to calpain, caspase 3, NFκB, GSK-3 and Cyt C activation, which was involved in toxicity.

Between 2003 and 2007, concerns about the illegal drug crystal methamphetamine (meth) increased dramatically in British Columbia despite research data that indicated usage rates were low among the general youth and adult populations. This dissertation draws on the insights of social constructionist theories that challenge the assumption that social problems are the natural outcome of ‘society’s ills,’ and explores the claims-making activities including public policy, that construct a ‘social problem’ like meth. This project draws on semi-structured interviews with members of citizen groups, policy-makers in the B.C. provincial government, representatives from health authorities and community-based services. It also includes textual analysis of key public policy and other documents. My analysis explores the narratives of illicit drug use that emerged from this data. The findings indicate that public policy officials and citizen groups held different perspectives about what kind of problem meth posed, as well as about the appropriate programs and policies government should use to respond to this drug. To problematize meth, citizen group members drew on long-standing emotionally driven claims informed by law enforcement and media, to shape meth as a uniquely addictive and dangerous agent with the potential to ensnare innocent victims from all walks of life. Public policy officials, on the other hand, insisted that governmental responses to meth must be similar to other prohibited substances, and should be evidence-based to avoid the influence of politics. These evidence-based responses, however, were shaped by values-based frameworks emerging from the marriage between neo-liberal ideas about governing and what Foucault calls ‘governmentality’. The twin pressures of public outrage, and this marriage of ideologies, shaped a hybrid of governmental approaches to the meth ‘problem’ that illustrated the complex and contradictory forces at work inside state institutions and between state institutions and non-governmental actors. Citizen groups pressured government using claims that bypassed scientific ‘evidence’ about drug use, in favour of frightening assertions about the need to protect children from the supposedly uniquely dangerous effects of this drug. These claims were used to gain support from politicians, resulting in new funding and program initiatives such as the Crystal Meth Secretariat that took as axiomatic a criminalized approach to drug use that excluded harm reduction measures. These claims depended upon and highlighted law enforcement and media based claims about meth and illicit drug use. But in neither case did official government responses, or crystal meth groups scrutinize or challenge the health and social inequities that shape illicit drug use. Rather both governmental and citizen group responses focused on change at the individual level eschewing sociological insights about the social conditions that shape illicit drug use and its harms. / Graduate / 2013-04-24

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AbstractSyfte. Att: beskriva sjuksköterskors erfarenheter av att arbeta i glesbygd med jour på distans.Bakgrund. Jour på distans innebär att sjuksköterskor, med stöd av läkare på di-stans, omhändertar patienter med olika slags akuta symtom. Frånvaron av nationella studier, rörande sjuksköterskors erfarenhet av jour på distans i kombination med behovet av att hitta nya sätt att bedriva vård i glesbygd, borde medföra ett intresse för studien.Design: Deskriptiv intervjustudie med kvalitativ ansats.Metod. Intervjuer genomfördes med 9 sjuksköterskor, vilka arbetar vid 2 olika häl-socentraler belägna i nordligaste delen av Sverige. Intervjuerna genomfördes våren 2017. Materialet analyserades med kvalitativ innehållsanalys.Resultat. Analysen resulterade i de 4 kategorierna rollutveckling, fördelar för pati-enten, stöd samt osäkerhet. Sjuksköterskor beskriver sig ha ett arbete som på olika sätt medför rollutveckling. Fördelar för patinten framställs bestå av exempelvis mins-kat behov av resor samt möjlighet att få snabb bedömning utan att alltid behöva åka till sjukhus. Kategorin stöd belyser betydelsen av tillit från läkare och fungerande teknik. Sista kategorin påvisar att vissa situationer medför känslor av osäkerhet hos sjuksköterskan, som exempelvis när läkare har dålig kunskap om jour på distans.Slutsats. Resultatet påvisar att jour på distans, sett ur sjuksköterskornas perspektiv, är ett bra sätt att tillvarata befintlig personal och teknik i syfte att tillhandahålla vård under jourtid i glest befolkade områden. Arbete med jour på distans kräver sjukskö-terskor med god kunskap och erfarenhet och studien påvisar även betydelsen av ut-bildning samt stöd från läkaren.

甲基安非他命是一種被廣泛濫用的非法神經興奮劑，而且使用之後常伴隨著精神疾病的發生，動物研究也顯示，施打甲基安非他命所引起的神經毒性不僅會造成多巴胺神經元及血清素神經元的損傷，也引起認知功能和社交行為的缺失，同時對於產生迷幻作用的5-HT2A受體作用劑的行為反應增強。N,N,N-trimethylglycine (TMG)和N,N-dimethylglycine (DMG)是甘胺酸的甲基化衍生物，由於這兩種藥物具有治療神經系統疾病的潛力，因此本研究的目的為評估TMG及DMG是否可以預防或改善小鼠在甲基安非他命的暴露下所導致的行為缺失包括新位置辨識測試，新物體辨識測試，社交行為互動測試以及使用5-HT2A受體作用劑DOI 誘導小鼠頭部抽搐(head twitch )的行為。實驗方式為腹腔注射給予雄性ICR小鼠甲基安非他命，一天注射四劑（4 × 5mg/kg），每劑間隔兩小時。實驗一，小鼠在暴露甲基安非他命，先確認行為改變後，給予腹腔注射TMG及DMG (10或30 mg/kg)連續七天，評估TMG及DMG的治療效果。實驗二在施打每劑甲基安非他命30分鐘前給予TMG及DMG (100 mg/kg)，七天後進行行為評估，實驗三，評估TMG及DMG個別及混合劑量的治療效果，小鼠給予甲基安非他命之後，先確認行為改變，再給予腹腔注射TMG及DMG (20、5+5或是10+10 mg/kg) 連續七天，七天後進行行為測試。實驗四，檢測TMG及DMG的治療效果是否藉由活化NMDA受體glycine binding site，小鼠給予甲基安非他命七天之後，腹腔注射TMG及DMG (20 mg/kg)並在給予TMG及DMG前30分鐘給予glycine binding site 拮抗劑7-chlorokynurenic acid (7-CK) (1 mg/kg)，連續給藥七天，七天後進行行為評估。實驗結果發現連續給予七天TMG及DMG在個別劑量及混合劑量中都能夠恢復甲基安非他命所造成的認知功能缺損，社交退縮和降低由DOI 誘導小鼠頭部抽搐行為表現，以及在紋狀體中酪氨酸羥化酶的蛋白質表達減少情況。而前給予7-CK則阻斷TMG及DMG對甲基安非他命所造成的認知功能缺損，社交退縮的改善作用，但是對TMG及DMG對DOI 誘導小鼠頭部抽搐的行為的改善作用影響較小，顯示TMG及DMG可能都是經由活化NMDA 受體的glycine binding site改善甲基安非他命所造成的認知功能缺損，社交退縮，這些發現表示，TMG及DMG具有治療甲基安非他命成癮者所造成的精神分裂等異常症狀的潛力。 / Methamphetamine (METH) is a widely abused illicit psychostimulant. METH use is commonly associated with psychosis. A neurotoxic regimen of METH, which damages the dopaminergic and serotonergic neurons, causes cognitive dysfunction, social interaction deficits, and supersensitivity to hallucinogen in mice. N,N,N-trimethylglycine (TMG) and N,N-dimethylglycine (DMG) are methyl derivatives of amino acid glycine and naturally occur as intermediate metabolites in choline-to-glycine metabolism. Growing evidence shows that both compounds have potential to treat some neurological disorders. The aim of this study was to examine the protective and therapeutic effects of TMG and DMG on METH-induced behavioral aberrations. The novel location recognition test (NLRT), the novel objective recognition test (NORT), the social interaction and the hallucinogenic 2, 5-dimethoxy-4-iodoamphetamine (DOI)-induced head twitch response were evaluated. Male ICR mice received one day drug treatment with four injections of METH (4 × 5 mg/kg, i.p.) or saline at 2h interval. First, TMG or DMG (10 or 30 mg/kg, i.p.) were separately administered once daily for seven consecutive days after the behavioral impairment was confirmed in METH-treated mice. Seven days after final injection of TMG and DMG, the behavioral tests were monitored. Secondly, the preveting effects of TMG and DMG were examined by TMG and DMG (100 mg/kg, i.p.) pretreatment, 30 min prior to each dose of METH. Third, the lower dose (20 mg/kg) and combined effects of TMG and DMG (5+5 or 10+10 mg/kg i.p.) were evaluated. Fourth, in order to determine if the improving effects of TMG and DMG are mediated by NMDA receptor glycine binding site, the glycine binding site antagonist 7-CK (1 mg/kg, i.p.) was administered 30 min prior to each dose of TMG and DMG (20 mg/kg, i.p.), TMG and DMG dose-dependently improved, but not prevented the METH-induced cognition deficits, social withdrawal and hypersensitivity to hallucinogen with additional effect. Pretreatment of 7-CK, reversed the improving effects of TMG and DMG on behavioral deficits after METH exposure, yet had minor effect on hypersensitivity to hallucinogen. These results demonstrate that TMG and DMG might activate the glycine binding site of NMDA receptor to improve METH-induced cognition deficits and social withdrawal. TMG and DMG may be the novel therapeutic agents for psychiatric disorders related to METH abuse.

With the emergence of novel and more effective drug therapies, increased importance is being placed upon the methods by which these drugs are being delivered to the body. In conventional drug delivery systems, there is very little control over the release of drug. The effective concentration at the target site can be achieved by intermittent administration of grossly excessive doses, which, often results in constantly, unpredictable variations in plasma concentrations, with the risk of reaching levels below or above the therapeutic range leading to marked side effects. A plethora of formulation strategies mainly based on polymeric/lipid nanoparticles, are described in literature. Even though these systems are therapeutically advantageous in comparison to conventional systems, they remain insensitive to the changing metabolic states of the body although the symptoms of most metabolic diseases follow a rhythmic pattern.A more appropriate and effective approach of managing some of these conditions lies in the chronotherapy. This approach allows for pulsed or self-regulated drug delivery which is adjusted to the staging of biological rhythms, since the onset of certain diseases exhibits strong circadian temporal dependence. In order to reach the objective of mimicking the biophysical and biochemical processes of pathological states, many innovations in material design for drug delivery systems (DDS) that are able to release the therapeutic payload-on-demand were done to release the therapeutic agent only when it is required, according to the physiological need. The development of multidisciplinary research teams has brought huge advantages in the design, fabrication and utilization of such smart systems, especially in the pharmaceutical field. Interestingly, numerous smart polymeric materials exhibit a response to a specific stimulus. A step further, the elaboration of purpose-built monomers can give rise to compounds with tunable sensitivities or multi-stimuli responsiveness. These smart polymers demonstrate an active responsiveness to environmental (or external) signals and change their physicochemical properties as designed (e.g. conformation, solubility, shape, charge or size). As far as the stimuli are concerned, they consist of physical (e.g. temperature, ultrasound, light, electricity, magnetic or mechanical stress), chemical (e.g. pH, ionic strength) and biological signals (e.g. enzymes, biomolecules). Due to the intrapersonal variabilities which may make internal stimuli hazardous, externally controlled systems rely on externally applied stimuli that are produced by stimuli-generating devices, which results in pulsed drug delivery. This type of delivery may be rapid and allows a transient release of a determined amount of drug within a short period of time immediately after a pre-determined off-release period. A novel strategy for the formation of multi-stimuli responsive materials endowed with pH, magnetic and light sensitivity was achieved. The approach relied on the incorporation of magnetic tetrahalogenoferrate(III) anions along a polymeric backbone based on poly(2-(N,N-dimethylamino) ethyl meth-acrylate) (PDMAEMA). Starting from the same PDMAEMA, quaternized pending amine groups with various halide derivatives gave rise to magnetic materials after anion metathesis. Measuring the magnetic susceptibility of these materials exhibited that the magnetic susceptibility increased as the substituted group size decreased (become smaller) which was apparently related to the steric hindrance around the ionic pendants. Additionally, a good correlation between the magnetic susceptibility and ferric content was found. Additional experimental and theoretical Raman analyses allowed the determination of the nature of the magnetic species constituting the materials. This strategy further offers the opportunity to tailor the magnetic response through partial ammonium salt formation. In order to merge the magnetic properties of ferric-based materials with another stimuli-responsive functionality, random copolymers containing DMAEMA (D) with diazobenzene (A) unit were prepared. So, three copolymers PDA were synthesized (with targeted D/A ratios 4/6 (PDA4), 6/4 (PDA6) and 8/2 (PDA8)). Meanwhile, different degrees of amine quaternization (10, 50 and 100 %) were applied, which led to the following polymeric salts PDAX/Y where X = 4, 6, 8 (referring to the percentage of the DMAEMA unit) and Y = 10, 50 and 100 (referring to the percentage of quaternized amine groups). Finally, the aforementioned materials were converted into magnetic polymers by anion exchange. As a result, magnetic responses correlated well with amount of iron oxide in these compounds and the amount of ionic pending groups along the backbone. Moreover, the remaining tertiary amines conferred pH sensitivity to the polymers whereas the diazobenzene units ensured light responsiveness through the well-established trans-to-cis isomerization.In order to functionalize these materials in the pharmaceutical field, an intelligent delivery system was prepared. Firstly, an attempt to formulate riboflavin-5’-phosphate sodium (RPS) loaded on PDA8 microspheres was made using double emulsion evaporation method. Meanwhile, prednisolone (PRD) microspheres were prepared using s/o/w emulsion technique. Subsequently, coating systems of cochineal red tablets were developed. These tablets were coated with polymer solution (using each of three types of copolymers: PDA8, PDA6, and PDA4) until the desired percentage of the coating was achieved (10, 15, and 20 % w/w). The cumulative release profiles of cochineal red tablets coated with PDA8, PDA6, and PDA4 showed a pH-sensitive release behavior. The release in the neutral media (pH ≈ 7.0) was very slow (less than 3 % after one hour). Then, after changing the pH to 1.2, an increase in the release of cochineal was observed. Furthermore, the cumulative release of cochineal red was at the highest value for the PDA8 and the lowest for PDA4 depending on the percentage of PDMAEMA moieties. Moreover, by increasing the percentage of the coating from (10, 15 to 20 % w/w), the cumulative release of cochineal decreased. Therefore, the copolymer PDAX can be used for controlling the release of drug by changing the pH value.Finally, the cochineal tablets coated with PDA6 (10 %) showed features of light sensitivity. The release of cochineal red from coated tablets was only due to the switching in the conformational trans/cis isomerization of azobenzene moieties upon irradiation, which was confirmed by comparing the release of coated tablets with uncoated tablets upon irradiation. / Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie) / info:eu-repo/semantics/nonPublished

Le travail de thèse porte sur la synthèse de nouveaux monomères photopolymérisables issus de la biomasse, l’étude de leur photopolymérisation et la caractérisation des matériaux qui en résultent. Les monomères formulés ont été testés dans un procédé d’impression de caractères Braille.Les monomères ont été élaborés en deux étapes en utilisant un chemin réactionnel simple, économique et respectueux de l’environnement. La première étape a consisté à faire réagir des dérivés du glycérol (carbonate de glycérol ou glycidol) avec des acides gras. Dans un deuxième temps, les [alpha]-monoglycérides obtenus ont été fonctionnalisés en vue de les rendre photopolymérisables. Les différents monomères obtenus porteurs de fonctions (méth)acrylate et/ou époxy ont été photopolymérisés en quelques secondes en présence d’un photoamorceur. Les cinétiques de photopolymérisation ont été suivies par spectrométrie IR-TF en mode ATR et différents paramètres tels que la quantité et la nature du photoamorceur, l’intensité d’irradiation et la température ont été optimisés. Les différents matériaux obtenus après photoréticulation ont été caractérisés afin de mettre en évidence leurs principales physico-chimiques. Des relations structure – propriétés ont ainsi été établies.Enfin, une formulation photopolymérisable présentant une viscosité compatible avec le procédé d’impression Braille a été élaborée par ajout de silice nanométrique. Les points Braille obtenus présentent des caractéristiques proches de ceux réalisés par le partenaire industriel. / The work of the PhD deals with the synthesis of polymerizable monomers derived from biomass, the study of their photopolymerization and the characterization of the resulting materials. The formulated monomers were tested in a printing method of Braille characters.The monomers were prepared in a two-steps reaction that is simple, economic and environmentally friendly. The first step comprised a reaction between glycerol derivatives (glycerol carbonate or glycidol) and fatty acids. In the second step, the obtained [alpha]-monoglycerides were functionalized to obtain photopolymerizable monomers. The different obtained monomers that bear (meth)acrylate and/or epoxy groups were photopolymerized in a few seconds in the presence of photoinitiator.The photopolymerization kinetics were followed by FT-IR spectroscopy in ATR mode, and various parameters such as the amount and the nature of the photoinitiator, the irradiation intensity and the temperature were optimized. The different photocured materials were characterized to highlight their main physicochemical properties. Structure-properties relations were then established.Finally, a photopolymerizable formulation having a viscosity compatible with the printing process of Braille characters was developed by adding nanometric silice. The obtained Braille characters exhibited features close those carried out by the industrial partner.