Lifetime prevalence estimates of psychotropic medicine use as well as prevalence of DSM-IV prescription drug use disorders from the baseline investigation of the Early Developmental Stages of Psychopathology (EDSP) Study are presented. Use of prescription medication at some time in their life was reported by 27.4% of the respondents. Illicit use of prescription drugs, which means an intake without medical legitimation, was reported by 4.5% of the sample. The findings suggest that abuse of and dependence on prescription drugs, with most cases reporting polysubstance use, is quite rare in the 14- to 24-year-olds. DSM-IV abuse was more prevalent than dependence (0.5 vs. 0.3%). In general, women reported higher prevalence rates of prescription drug use, whereas men reported higher prevalence rates of prescription drug disorders. This result suggests that men have a higher risk to develop a substance-use-related disorder.

Delusions of parasitosis are a rare psychiatric disorder in which the patient has a fixed, false belief of being infested with parasites. The disorder is classified as primary if no cause is identified or secondary if associated with general organic conditions, psychiatric illnesses, and drugs (substance induced). Several medications have been reported in association with delusions of parasitosis, including anti-parkinsonian medications, ciprofloxacin, cetirizine, doxepin, and others. Delusions of parasitosis have not been previously reported to be associated with gabapentin use. We present the case of a patient who developed delusions of parasitosis after been initiated on gabapentin treatment for neuropathic pain and complete disappearance of symptoms after the medication was discontinued.

Selon l’Organisation Mondiale de la Santé (OMS), les agonistes du récepteur opioïde Mu (MOR) sont la première ligne de traitement pour le soulagement des douleurs aiguës modérées à sévères. Cependant, ces derniers induisent de nombreux effets indésirables, tels que la dépression respiratoire et la constipation, qui limitent leur utilisation pour une gestion appropriée de la douleur. Chacun des effets indésirables des agonistes du MOR est médié par des mécanismes cellulaires et moléculaires complexes. C’est pourquoi un nombre considérable de recherches précliniques ont été menées afin de découvrir des opioïdes qui induiraient moins d’effets indésirables. Plus particulièrement, de nombreuses études se sont concentrées sur le développement d’agonistes biaisés du MOR qui ont peu ou pas de recrutement de β-arrestine 2 et qui activent préférentiellement les protéines G. Néanmoins, ces recherches n’ont pas réussi à identifier des agonistes biaisés avec un profil amélioré d’effets indésirables en clinique. Nous proposons dans cette thèse que la caractérisation des similarités signalétiques des agonistes du MOR serait une bonne alternative à l’agonisme biaisé pour l’identification d’opioïdes avec des profils d’effets indésirables distincts. Pour ce faire, nous avons développé une méthode basée sur l’utilisation de l’apprentissage non supervisé par clustering pour classifier les ligands du MOR en des catégories pharmacodynamiques. Cette classification s’est faite à l'aide des paramètres qui caractérisaient une panoplie de voies de signalisation médiées par les protéines G et par les β-arrestines. Nous avons pu associer ces différentes catégories pharmacodynamiques avec différentes fréquences de rapport d’effets indésirables d’opioïdes cliniques au programme de pharmacovigilance de la FDA (Food and drug administration) tels que des effets respiratoires et gastro-intestinaux. Nous avons également montré que cette méthode peut être plus généralement appliquée à d’autres sous-types et types de récepteurs couplés aux protéines G (RCPG). L’efficacité et l’innocuité des agonistes du MOR pour le soulagement des douleurs chroniques non cancéreuses, telles que les douleurs neuropathiques, est un sujet controversé et plusieurs essais cliniques ne sont pas en faveur de leur utilisation. Or, la douleur neuropathique est une maladie fréquente qui est associée à une très pauvre qualité de vie du patient et pour laquelle seulement 30 à 40% des patients rapportent un soulagement adéquat de la douleur avec les traitements actuels. Dans les modèles précliniques, les cannabinoïdes sont capables de moduler des processus impliqués dans le développement des douleurs neuropathiques. Ceci les rend des candidats prometteurs pour le soulagement de ces douleurs en clinique. Néanmoins, peu de médicaments à base de cannabis sont présentement approuvés sur le marché pour un usage thérapeutique. Ces derniers sont régulés selon leur contenu en Δ9-tétrahydrocannabinol (THC) et cannabidiol (CBD) et il existe une présomption selon laquelle les quantités de THC et les ratio THC:CBD permettraient de décrire l’activité biologique du cannabis médical. Or, les extraits commerciaux peuvent contenir jusqu’à 23 phytocannabinoïdes et de nombreux autres composés chimiques. La description de ces derniers uniquement en termes de contenus en THC et en CBD ne prend pas en considération les interactions potentielles qui peuvent arriver entre les multiples autres composants et qui peuvent aboutir à des effets cliniques différents. Nous avons donc testé dans cette thèse s’il y avait réellement une équivalence entre l’activité biologique d’un extrait de cannabis et des traitements cannabinoïdes avec des contenus en THC et/ou en CBD équivalents Nous avons démontré que les réponses analgésiques du THC et du CBD seuls, d’une combinaison THC:CBD (1 :1) et d’un extrait de cannabis de chémotype II (avec un ratio THC:CBD ≈ 1 :1) ne sont pas équivalentes dans un modèle de neuropathie diabétique chez les rats. Aux hautes doses testées, l’extrait était plus efficace à soulager la douleur que la combinaison THC:CBD (1 :1) qui, elle-même, était plus efficace que le THC et le CBD seuls. De plus, ces différents traitements engageaient les cibles moléculaires du système endocannabinoïde CB1 (récepteur cannabinoïde 1), CB2 (récepteur cannabinoïde 2) et TRPV1 de façon distincte. Ensemble ces résultats suggèrent qu’une équivalence au niveau des contenus en THC et des ratios THC:CBD ne se traduit pas par une équivalence d’activité biologique telle que l’analgésie. Dans son ensemble, cette thèse propose dans un premier temps une méthode basée sur la classification pharmacodynamique de ligands de RCPG qui pourrait être utile pour l’identification de nouveaux candidats opioïdes avec un profil d’effets indésirables amélioré. Dans un second temps, nous avons démontré que les cannabinoïdes induisent des effets analgésiques à travers différentes cibles pharmacodynamiques et que ces dernières étaient engagées de façon distincte par les différents traitements. Notre intention future est de décrire in vitro les profils signalétiques des cannabinoïdes sur ces différentes cibles et d'utiliser notre outil de classification pharmacodynamique afin de corréler ces réponses signalétiques avec leurs effets analgésiques et indésirables in vivo. Ces travaux fournissent des éléments pertinents pour le développement rationnel d’analgésiques plus efficaces et mieux tolérés en clinique. / According to the World Health Organization (WHO), Mu opioid receptor agonists (MOR) are the first line of treatment for the relief of moderate to severe acute pain. However, they induce numerous adverse effects, such as respiratory depression and constipation, which limit their use for appropriate pain management. Each of the adverse effects of MOR agonists is mediated by complex cellular and molecular mechanisms. As a result, a considerable amount of preclinical research has been conducted to discover opioids that would induce fewer adverse effects. Specifically, many studies have focused on developing biased MOR agonists that have little or no β-arrestin 2 recruitment and preferentially activate G proteins. Despite these investigations, efforts to identify biased agonists with an improved adverse event profile in the clinic have been unsuccessful. In this thesis, we propose that characterizing the signaling similarities of MOR agonists would be a good alternative to biased agonism for identifying opioids with distinct adverse effect profiles. To this end, we developed a method based on the use of unsupervised clustering learning to classify MOR ligands into pharmacodynamic categories. This classification was done using parameters that characterized a panoply of G protein- and β-arrestin-mediated signaling pathways. We were able to associate these different pharmacodynamic categories with different frequencies of clinical opioid adverse event reported to the FDA pharmacovigilance program such as respiratory and gastrointestinal effects. We have also shown that this method can be more generally applied to other subtypes and types of G protein-coupled receptors (GPCRs). The efficacy and safety of MOR agonists for the relief of chronic non-cancer pain, such as neuropathic pain, is a controversial topic and several clinical trials do not support their use. Neuropathic pain is a common condition that is associated with very poor patient quality of life and for which only 30-40% of patients report adequate pain relief with current treatments. In preclinical models, cannabinoids are able to modulate processes involved in the development of neuropathic pain. This makes them promising candidates for the relief of such pain in the clinic. However, few cannabis-based medications are currently approved for therapeutic use. For safety reasons, these are regulated according to their Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) content under the presumption that THC amounts and THC:CBD ratios would adequately describe the biological activity of medical cannabis. Commercial extracts of medical cannabis may contain up to 23 phytocannabinoids and many other chemical compounds. Describing these products only in terms of THC and CBD content does not take into consideration the potential interactions that may occur between these multiple components and that may result in different clinical effects. We therefore tested in this thesis whether there was really an equivalence between the biological activity of a cannabis extract and cannabinoid treatments with equivalent THC and/or CBD contents. We demonstrated that the analgesic responses of pure THC and CBD, a THC:CBD (1:1) combination, and a chemotype II cannabis extract (with a THC:CBD ratio ≈ 1:1) were not equivalent in a rat model of diabetic neuropathy. At the high doses tested, the extract was more efficacious than the THC:CBD (1:1) combination which, in turn, was more efficacious than pure THC and CBD. Furthermore, these different treatments engaged the molecular targets of the endocannabinoid system CB1 (cannabinoid receptor 1), CB2 (cannabinoid receptor 2), and TRPV1 in distinct ways. Together, these results suggest that equivalence in THC content and THC:CBD ratios does not translate into equivalence in biological activity such as analgesia. Overall, this thesis firstly proposes a pharmacodynamic-based method of GPCR ligand classification that could be useful for the identification of new opioid candidates with an improved adverse effect profile. Secondly, we demonstrated that cannabinoids produced their analgesic effects via different pharmacodynamic targets and that these targets were distinctively engaged by the different treatments. Our future intention is to describe the in vitro signaling profiles of cannabinoids at these different targets, and to use our pharmacodynamic clustering tool to correlate these signaling responses with their in vivo their analgesic and adverse effects. This work provides relevant insights for the rational development of more effective and better tolerated analgesics in the clinic.

La douleur chronique est une maladie fréquente et grave qui, pour de nombreuses personnes, ne peut pas être entièrement traitée avec les choix thérapeutiques actuels. Des agonistes des récepteurs opioïdes delta (DORs) ont été proposés comme interventions thérapeutiques pour ces maladies. Des recherches précliniques ont montré que l'activation des DOR produit des effets anti-hyperalgiques et antidépresseurs avec moins d'effets secondaires associés aux analgésiques opioïdes disponibles sur le plan clinique. Cependant, de nombreux agonistes DOR induisent une tolérance analgésique, entravant ainsi leur développement en tant que médicaments. Les travaux de cette thèse visent à mieux comprendre les causes cellulaires et moléculaires de la tolérance ainsi que ce qui rend certains agonistes plus résistants à la tolérance que d'autres. Dans le premier projet, nous nous sommes concentrés sur la superactivation de l'adénylyl cyclase induite par un ligand, un modèle de réponse adaptative médiée par les isoformes de l'adénylyl cyclase (AC). La superactivation de l'adénylyl cyclase (SA) a été associée à l’hyperalgésie, la tolérance analgésique et à des symptômes de sevrage. Ainsi, nous étions curieux de voir si les profils de signalisation cellulaire créés pour la découverte de médicaments pouvaient nous fournir des informations sur la capacité d'un ligand à induire la SA. Pour répondre à cette question, nous avons généré des profils de signalisation complets pour six agonistes différents du DORs (Met-enképhaline, deltorphine II, DPDPE, SNC-80, ARM390 et TIPP) tout en surveillant 12 différents résultats de signalisation avec des biocapteurs à base de BRET. L'analyse des profils de signalisation a montré une sélectivité fonctionnelle remarquable parmi les ligands étudiés. Ensuite, nous avons pu classer les agonistes DOR en fonction de la similarité de leurs profils en utilisant l'approche que nous avons adaptée de notre laboratoire. Nous avons par la suite démontré que, à l'exception de TIPP, dont la réponse SA était Ca2+-indépendante, les catégories de médicaments résultant du regroupement sont corrélées avec la capacité du ligand à provoquer une SA. Une investigation plus approfondie des mécanismes a révélé que Gαi/o était essentiel tant pour la SA déclenchée par TIPP que par Met-Enkepkaline, mais les mécanismes en aval étaient assez distincts pour ces ligands. Ensemble, nos résultats indiquent que les mécanismes sous-jacents à la tolérance cellulaire induite par les agonistes DOR sont spécifiques au ligand. Dans le deuxième projet, nous nous sommes principalement intéressés aux mécanismes de tolérance aux agonistes DOR qui peuvent être en partie expliqués par la désensibilisation et la régulation négative des récepteurs. Il a été établi que, les ligands qui induisent le recyclage du récepteur après l'internalisation ont été trouvés pour fournir une analgésie de longue durée. Par conséquent, les expériences menées dans cette étude ont été menées pour révéler davantage les déterminants moléculaires sous-jacents au recyclage du récepteur et sur la manière dont l'interaction agoniste-récepteur pourrait produire des modèles distincts de régulation des récepteurs. Nous avons évalué l'activation de l'agoniste et la désensibilisation du signal DOR-Gαi1. Nos données ont rapporté que le DPDPE était pratiquement sans effet sur la désensibilisation de l'activation de Gαi1, tandis que la désensibilisation par la deltorphine II était plus importante que celle induite par le DPDPE mais moins que celle induite par l'ARM390 et le SNC-80. Ensuite, nous avons établi que les DORs stimulés par le DPDPE se recyclaient de manière plus efficace que ceux activés par la deltorphine II. De plus, nous fournissons des preuves phénoménologiques que des interventions similaires ont des effets distincts sur le recyclage évoqué par chaque ligand. En particulier, la truncation du DOR ou la surexpression de βarr2 avaient des effets différentiels sur le recyclage par le DPDPE et la deltorphine II. Il est admis que les mécanismes sous-jacents à ces différences restent à être pleinement décrits, mais la phénoménologie de nos observations soutient l'idée que le DPDPE et la deltorphine II mettent en œuvre des processus de recyclage distincts. / Chronic pain is a common and severe disease that, for many people, cannot be fully treated with current therapeutic choices. Agonists of the delta opioid receptor (DOR) have been proposed as therapeutic interventions for this illness. Preclinical research has shown that DORs produce antihyperalgesic and antidepressant-like effects with fewer side effects than the ones associated with clinically available opioid analgesics. However, numerous DOR agonists induce analgesic tolerance, hampering their development as medications. Thus, further investigations are needed to understand the mechanisms underlying the tolerance associated with chronic opioid use. This thesis aimed to further understand the cellular and molecular mechanisms that causes tolerance as well as what makes some agonists more resistant to tolerance than others. In the first project, we focused on ligand-induced cyclase superactivation (SA), a pattern of adaptive response mediated by adenylyl cyclase (AC) isoforms. Cyclase SA has been associated with hyperalgesia, analgesic tolerance, and withdrawal symptoms. Therefore, we were curious to assess weather cell-based signalling profiles created for drug discovery could provide us with information on the ability of a ligand to induce cyclase SA. To address this question, we generated comprehensive signalling profiles for six different DOR agonists (Met-enkephalin, deltorphin II, DPDPE, SNC-80 and ARM390) while monitoring 12 different signalling outcomes with BRET-based biosensors. Analysis of the signalling profiles showed remarkable functional selectivity among the investigated ligands. Next, we were able to classify DOR agonists based on the similarity of their profiles using the approach we adapted from our lab. We subsequently demonstrated that except for TIPP, whose SA response was Ca2+-independent, the drug categories resulting from clustering are correlated with ligand capacity to cause SA. Further investigation of the mechanisms revealed that Gαi/o was essential for both TIPP and Met-Enkepkalin-driven cyclase SA. However, downstream mechanisms were quite distinct for these two ligands. Altogether, our findings indicate that mechanisms underlying cellular tolerance induced by DOR agonists are ligand-specific. In the second project, we were primarily concerned with the mechanisms of tolerance to DOR agonists that may be, in part, explained the receptor desensitization and downregulation. Obviously, ligands that induce receptor recycling after internalization have been found to provide long-lasting analgesia. Therefore, the objectives of the experiments in this project were to assess the molecular determinants affecting receptor recycling and how agonist-receptor interaction can result in different patterns of receptor regulation. We assessed agonist inducing activation and desensitization of DOR-Gαi1 signal. Our data showed that DPDPE was efficient in activating the receptor without noticeable desensitization effect. On the other hand, deltorphin II exerted a significant desensitization effect. However, this effect was low when compared to ARM390 and SNC-80. Then, we established that DORs stimulated by DPDPE recycle more efficiently than those activated by deltorphin II. We also provided phenomenological evidence on receptor recycling elicited by each ligand. In particular, DOR truncation or the overexpression of βarr2 had differential effects on receptor recycling by DPDPE and deltorphin II. While our data shed light on the mechanism underlying these differences, further investigation is needed for the mechanism to be fully elucidated. Admittedly, our observations support the notion that DPDPE and deltorphin II engage distinct recycling processes.

No / A significant number of people in the UK experience chronic pain, resulting in high levels of suffering and reduced quality of life. Management of chronic pain is complex, time consuming and not always successful. Good communication between patients and healthcare professionals is essential to ensure realistic treatment plans and outcomes can be negotiated. Accurate assessment is also key, and nurses play a fundamental role in ensuring patients with chronic pain receive the most appropriate care.

No / PURPOSE: Self-emulsifying systems (SES) emulsify spontaneously to produce fine oil-in-water emulsion when introduced into aqueous phase. The self-emulsification process plays an important role during formation of emulsion. The objective of current work was to understand and explore the inner structuration of SES through controlled hydration and further to study the influence of additive on the same which ultimately governs performance of final formulation in terms of droplet size. METHODS: Droplet size of final formulations containing structural analogues of ibuprofen was determined. Microstructural properties of intermediate hydrated regimes of SES were investigated using techniques such as small angle X-ray scattering, differential scanning calorimetry and rheology. RESULTS: The current work established inverse relationship between droplet size of the formulations containing structural analogues of ibuprofen and their Log P values. Microstructural analysis of intermediate hydrated regimes of the prepared samples showed formation of local lamellar structure. Structural analogues of ibuprofen significantly altered microstructure of lamellae which was well correlated with the droplet size of final formulations. In vitro drug release study showed increase in dissolution rate of lipophillic drugs when formulated as SES. CONCLUSION: The current work emphasizes the fact that tailor-made formulations can be prepared by controlling the properties of intermediate regimes.

Made available in DSpace on 2014-07-29T15:04:30Z (GMT). No. of bitstreams: 1 Luciano Ramos de Lima.pdf: 1365345 bytes, checksum: ef60ed7553c3b76d00042fe7e22ffcb3 (MD5) Previous issue date: 2009-06-16 / Postoperative pain is characterized as an acute pain, prevalent inside the hospital environment, commonly associated with tissue damage. This study had, as a general objective, the evaluation of post-operative pain in clients who have undergone to cardiac surgery by sternotomy, according to the occurrence, intensity (measured at rest and on deep inspiration), location and quality, 1st, 2nd and 3rd. This is a cohort, prospective study, developed in a general hospital in the countryside of the State of Goiás, in the period from January to August 2008. Pain intensity was measured by means of verbal numerical scale (0-10); quality was measured by the McGill Pain Questionnaire (MPQ-SF), the location was measured by body diagrams, and preoperative anxiety was measured via STAI (State/Trait Anxiety Inventory). Numerical vares were explored by descriptive measures of centrality (mean and median) and dispersion (minimum, maximum, standard deviation). The categorical variables were explored by simple absolute frequencies and percentages. The associations between variables were explored using non-parametric association tests, such as chi-square, Spearman coefficient, Kruskal-Wallis and Mann-Whitney with &#945; = 5%. 62 clients participated, 56.5% men, 67.7% white, 42% of socioeconomic class C and 72.6% married. The mean age was 54.8 years, SD = 12.1 years, and the predominant age group (29.0%) from 51 to 60 years. The prevalent surgery was valve surgery (46.8%), followed by myocardial revascularization (40.3%). The postoperative anxiety level was medium to 92.0% of the clients. Pain intensity at rest and deep inspiration had a decrease as days passed by, (p<0.05), being classified as mild-moderate (MD [median]=0,0-3,0; Q1 [quartile 1]=0,0-1,0; Q3 [quartile 3]=2,0-6,0; MAX [maximum]=8,0-10,0; MIN [minimum]=0,0-0,0) at rest and moderate-intense (MD=2,0-5,0; Q1=0,75-2,75; Q3=3,0-7,25; MAX=9,0-10,0; MIN=0,0-0,0) at deep inspiration. The chest region was the region in where there was the greatest pain occurrence in the 4 days of PO (40,3%-53,2%).The words which were most frequently chosen to describe postoperative pain were tiring/exhaustive (83,9%- 95,2%), painful (88,7%-91,9%), persistent (85,5%-87,1%) and splitting (72,6%- 82,3%). Splitting, was the one which received the greatest attribution (score 3) from the sensory-discriminative group, in numerical scale (0-3), both at POI as in the 1st and 2nd PO. The PRI (Pain Rating Index), results from the MPQ-SF, for the sensory group (PRI-S) , the affective group (PRI-A) and total (PRI-T) showed a reduction in the scores over the 4 days of PO (p<0.001). The correlation between the pain intensity and PRI scores in the 4 days of PO was positive and significant both for the PRI-S (0.52-0.34; p<0.001), and PRI-A (0.52-0.30; p<0.001) as to PRI-T (0.56-0.36; p<0.001). Postoperative pain at rest intensity was consistent to the one observed in other studies. However, postoperative pain at deep inspiration is still intense, being able to generate greatest losses in the clients early recovery. Even tough it isn t significantly associated to pain intensity, it is stressed that all the clients presented some degree of anxiety, a natural stimulus which can influence the endogenous pain modulation system, which may exacerbate the pain. In terms of quality, pain was described through words from the sensory and affective MPQ group, pointing to the multidimensionality of the painful experience. It is stressed the importance of the evaluation/measure and the postoperative pain systematic record as essential items to the adequate relief of this experience in the surgical environment. / A dor pós-operatória caracteriza-se como dor aguda, prevalente no âmbito hospitalar, comumente associada a um dano tecidual. Este estudo teve como objetivo geral avaliar a dor pós-operatória, em clientes submetidos a cirurgias cardíacas, por esternotomia, segundo a ocorrência, intensidade (mensurada ao repouso e à inspiração profunda), localização e qualidade, no POI, 1º, 2º e 3º PO. Trata-se de uma coorte, prospectiva, desenvolvida em um hospital geral do interior do Estado de Goiás, no período de janeiro a agosto 2008. A intensidade da dor foi medida por meio da Escala Numérica (0-10) verbal; a qualidade pelo Questionário de Dor de McGill (MPQ-SF); a localização por meio de diagramas corporais; e a ansiedade pré-operatória por meio do IDATE-estado. As variáveis numéricas foram exploradas pelas medidas descritivas de centralidade (média e mediana) e de dispersão (mínimo, máximo, desvio padrão) e as variáveis categóricas por freqüências simples absolutas e porcentuais. As associações entre as variáveis foram exploradas por meio de testes não paramétricos de associações como o quiquadrado, coeficiente de Spearman, Kruskal-Wallis e Mann-Whitney, com &#945;=5%. Participaram 62 pacientes, 56,5% do sexo masculino, 67,7% brancos, 42% da classe socioeconômica C e 72,6% casados. A média de idade foi de 54,8 anos; d.p.=12,1 anos, e a faixa etária predominante (29,0%) de 51 a 60 anos. A cirurgia prevalente foi a valvar (46,8%) seguida pela revascularização do miocárdio (40,3%). O nível de ansiedade pré-operatória foi médio para 92,0% dos clientes. A intensidade de dor ao repouso e à inspiração profunda declinou com o passar dos dias (p<0,05), sendo classificada como leve-moderada (MD=0,0-3,0; Q1=0,0-1,0; Q3=2,0-6,0; MAX=8,0-10,0; MIN=0,0-0,0) ao repouso e moderada-intensa, (MD=2,0- 5,0; Q1=0,75-2,75; Q3=3,0-7,25; MAX=9,0-10,0; MIN=0,0-0,0) à inspiração profunda. Os locais de maior ocorrência de dor, nos 4 dias PO, foi a região peitoral (40,3% a 53,2%). As palavras escolhidas com maior freqüência para descrever a dor pós-operatória foram cansativa/exaustiva (83,9% a 95,2%), doída (88,7% a 91,9%), enjoada (85,5% a 87,1%) e rachando (72,6% a 82,3%) sendo que rachando, do agrupamento sensitivo-discriminativo foi a que recebeu maior atribuição (escore 3), em escala numérica (0-3), tanto no POI como no 1º e 2º PO. O cálculo do PRI (Pain Rating Index), do MPQ-SF, para o agrupamento sensitivo (PRI-S), afetivo (PRI-A) e total (PRI-T) mostrou redução dos escores ao longo dos 4 dias PO (p<0,001). A correlação entre os escores de intensidade de dor e do PRI, nos 4 dias PO, foi positiva e significativa tanto para o PRI-S (0,52-0,34; p<0,001), PRI-A (0,52-0,30; p<0,001) como para o PRI-T (0,56-0,36; p<0,001). A dor pós-operatória ao repouso teve intensidade compatível com aquela observada em outros estudos, porém, à inspiração profunda ainda é intensa, podendo gerar maiores prejuízos na pronta recuperação dos clientes. Embora não associada significativamente à intensidade de dor, ressalta-se que todos os clientes apresentaram algum grau de ansiedade, estímulo natural que pode influenciar o sistema endógeno de modulação da dor, podendo exacerbar a dor. Qualitativamente a dor foi descrita por palavras do agrupamento sensitivo e afetivo do MPQ, apontando a multidimensionalidade da experiência dolorosa. Ressalta-se a importância da avaliação/mensuração e registro sistemático da dor pós-operatória, como quesitos fundamentais para a identificação precisa de complicações e a avaliação de intervenções para seu alívio.

La morphine demeure l'antalgique de référence pour le traitement de la douleur (nociception), mais elle est également responsable d‘effets secondaires importants. Des études ont montré que les animaux privés de canaux potassiques TREK-1 (TWIK-related K+channels) étaient plus sensibles à la douleur. Plus récemment, il a été démontré que le canal potassique TREK-1 joue un rôle crucial dans l'analgésie induite par la morphine chez les souris, alors qu'il n'est pas impliqué dans les effets secondaires (constipation, dépression respiratoire et dépendance). Ces résultats suggèrent que les canaux TREK-1 constituent des cibles d‘intérêt pour la conception de nouveaux antalgiques sans effets indésirables liés aux opioïdes. Des études antérieures au sein de notre laboratoire ont permis l'identification de quatre structures chefs de file, activatrices des canaux TREK-1, présentant une activité antalgique in vivo. La structure 3D du canal TREK-1 n‘étant pas élucidée au moment de nos travaux, nous avons décidé d'effectuer une optimisation basée sur une étude de relation structure-activité (RSA). Trente-six analogues ont été synthétisés par condensation de Knoevenagel et évalués pour leur effet antalgique (test de l‘acide acétique, test de la plaque chaude) et leur capacité à activer le canal TREK-1 (électrophysiologie). La capacité des substituants du noyau aromatique à établir des interactions de type liaison hydrogène ainsi que le volume de ces substituants ont une influence déterminante sur l'activité. Des résultats prometteurs ont émergé de cette étude RSA: 5 molécules présentent une très bonne activité antalgique (> 50% d'inhibition de la douleur, test de la plaque chaude) ainsi que d'une bonne activation de TREK-1 canaux (R ≥ 2 à 10 μM ou R ≥ 4 au-dessus de 20 μM). / Morphine remains the analgesic of reference for the treatment of pain (nociception), but it is also responsible for serious adverse effects. Research studies have shown that animals deprived of potassium channels TREK-1 (TWIK-related K+ channels) were over-sensitive to pain. More recently, it has been demonstrated that the TREK-1 potassium channel is a crucial contributor of morphine-induced analgesia in mice, while it is not involved in morphine-induced constipation, respiratory depression and dependence. These results suggest that the TREK-1 channels constitute targets of interest for the design of novel analgesics without opioid-like adverse effects. Previous studies within our consortium led to the identification of four lead structures as TREK-1 activators exhibiting analgesic activity in vivo.Since the 3D structure of TREK-1 was not available at the time, we decided to perform hit optimization by conventional structure-activity relationship (SAR) studies. Thirty six analogs were synthesized via Knoevenagel condensation and evaluated for their analgesic effect (writhing test, hot plate assay) and their ability to activate TREK-1 channel (electrophysiology). It turned out that the possibility to form hydrogen bonding interaction (aryl moiety) and the volume of substituents of the amide or ester has a crucial influence on activity. Promising results emerged from this SAR study: 5 molecules display a very good analgesic activity (> 50% inhibition of pain, hot plate assay) as well as a good activation of TREK-1 channels (R ≥ 2 at 10μM or R ≥ 4 above 20μM).

This work is based on the current issue of increasing concentrations of pharmaceutical residues in various components of the environment. These new environmental contaminants continuously enter the environment. The most affected environmental component is the aquatic environment. This study is focused on the development and optimization of reliable analytical method, which can determine selected drugs in the aquatic environment (waste waters and surface waters) qualitatively and quantitatively. The target compounds were selected mainly from the group of non-steroidal anti-inflammatory drugs (NSAID): salicylic acid, acetylsalicylic acid, clofibric acid, ibuprofen, acetaminophen, caffeine, naproxen, mefenamic acid, ketoprofen and diclofenac. NSAIDs are one of the most used drugs in Czech Republic. For the final analysis of this study was used the comprehensive two-dimensional gas chromatography with mass spectrometric detection Time-of-Flight (GCxGC-TOF MS). It is a very sensitive and reliable analytical method for trace and ultra-trace analysis. Simultaneously, solid phase extraction (SPE) and derivatization are optimized in this work. Optimized analytical method including SPE, derivatization with MSTFA (N-methyl-N-(trimethylsilyl) trifluoroacetamide) and final analysis by GCxGC-TOF MS were applied successfully for the analysis of real samples. Samples of waste water were collected from the waste water treatment plant in Brno – Modřice and samples of surface water were collected from two river streams Svratka and Svitava in Moravian region. The range of concentrations of selected drug residues varied from one to tens of g/L in wastewater and from tens to hundreds of ng/L in surface waters. The degree of wastewater and surface waters contamination by drug residues is assessed in conclusions of the work. Simultaneously, spontaneous degradation of selected drugs in water and removal efficiency of the wastewater treatment plant is assessed in conclusions of the work. The developed method is usable for monitoring and environmental analysis of water ecosystems. It is usable not only for selected drugs, but even for other organic compounds with similar properties.

The incidence of postoperative nausea and vomiting (PONV) is unknown in neuraxial anesthesia for orthopedic surgery. The effect on PONV of adding gabapentin to an evidence-based antiemetic regimen as part of an opioid-sparing analgesic protocol is also unknown in this population. A retrospective analysis of all adults undergoing hip and knee arthroplasty and receiving neuraxial anesthesia in 2017 was conducted. The overall incidence of PONV was assessed. Additionally, PONV incidence was assessed for all combinations of gabapentin, dexamethasone, and/or ondansetron (in addition to propofol infusion) and compared with propofol alone. The PONV risk ratios were estimated, adjusting for age and PONV risk score. The overall incidence of PONV was 14.0%. The addition of gabapentin to propofol was associated with reduced PONV (multivariable risk ratio [mRR], 0.6; 95% CI, 0.4-1.0) vs propofol alone. Dexamethasone with propofol was associated with reduced PONV (mRR 0.6; 95% CI, 0.4-1.1) vs propofol alone, although not statistically significant. The addition of both gabapentin and dexamethasone to propofol was associated with stronger reduction in PONV (mRR 0.3; 95% CI, 0.1-0.7) vs propofol alone. Adding ondansetron to propofol showed little benefit. Gabapentin and dexamethasone are effective in reducing PONV in patients undergoing knee and hip arthroplasty with neuraxial anesthesia.