Despite the fact that as many as 80-90% of patients with cancer pain can be effectively treated using pharmacological therapies and other advanced approaches, 31% to 85% of cancer patients in Taiwan still experience varying levels of pain. Pain is one of the symptoms that patients fear most; it overwhelms all aspects of patients' lives and creates a sense of uncertainly and hopelessness. Pain control is, therefore, a high priority in the treatment of cancer patients. Pharmacological therapy is the cornerstone of cancer pain management. With the current trend toward outpatient care, many patients are being required to assume greater responsibility for self-management of prescribed analgesics at home to deal with the variable and complex nature of cancer pain and side effects of opioids. Patients however, have misconceptions regarding analgesics and a series of difficulties when attempting to put a pain management regimen into practice. This research addressed the hypothesis that self-efficacy beliefs might play an important role in analgesic adherence and pain experience in Taiwanese outpatients with cancer. The purpose of this study was to develop a scale to measure the self-efficacy expectations relating to opioid-taking in Taiwanese outpatients with cancer. Another purpose was to explore how opioid-taking self-efficacy and beliefs about opioid analgesics contribute to patients' analgesic adherence and pain experience in Taiwanese outpatients with cancer. In the first stage semi-structured interviews were conducted to collect data from a purposeful sample (n=10) of oncology outpatients from two teaching hospitals in the Taipei area of Taiwan. The purpose of this phase was to identify behaviours and situational impediments associated with analgesic taking. Findings from this phase were used to develop a scale to measure opioid-taking self-efficacy. In the second stage a pilot test with a convenience sample (n=30) was conducted to test the validity and reliability of the new scale and to identify the feasibility of using the scale in a cross-sectional survey. In the third stage a cross-sectional survey was undertaken (n=92) to describe pain experiences, analgesic adherence, beliefs about opioid analgesics, and opioid-taking self-efficacy in Taiwanese outpatients with cancer and to explore how opioid-taking self-efficacy and beliefs about opioid analgesics contributed to analgesic adherence and pain experience. Results of this study highlight an important issue - under-treatment of cancer pain in this group of Taiwanese outpatients. As well, low adherence rates to opioid analgesics in cancer outpatients arose as an important issue in this study. A range of misconceptions about using opioids for pain was also common amongst the sample. Despite these misconceptions, patients reported being moderately confident in their ability to perform self-management behaviours related to their prescribed opioid-taking. Results of this research supported the notion that patients' self-efficacy in relation to taking their prescribed opioid regimen was a significant independent predictor of patients' adherence behaviour and pain relief, but not of pain severity. Beliefs about opioid analgesics were also an independent predictor of patients' adherence, but not of pain relief or pain severity. In addition, findings from this study provided support for the validity and reliability of the opioid-taking self-efficacy scale. Results suggested there is a need for systematic assessment of beliefs affecting patients' opioid adherence behaviours for cancer pain control, including perceived personal self-efficacy and beliefs about opioid analgesics. Educational programs that focus on overcoming patients' misconceptions (beliefs) about taking opioid analgesics may be particularly beneficial. In addition, this study advocates that conducting self-efficacy-enhancing interventions may improve medication adherence for patients and therefore pain relief. More research is needed to demonstrate the construct validity of the self-efficacy scale and to evaluate self-efficacy enhancing interventions in cancer pain management.

Ocotea puberula (Lauraceae) is a brazilian native tree, known in the South regions as canela guaicá or canela amarela. Its phytochemical composition includes several alkaloids of aporphinic type, some of them with biological activities already reported. Fruits collected in Curitiba, state of Paraná, were submitted to extraction and fractioning processes, allowing the isolation of an alkaloid identified as dicentrine, present as the majoritarian substance. In the present work we investigated the antinociceptive potential of the organic fractions obtained from O. puberula fruits extract and dicentrine (DCTN) isolated from the chloroform fraction (CF). Both CF and DCTN, given by oral route, were able to reduce the nociception induced by formalin and acetic acid with similar ID50, suggesting that the CF effect is due to the presence of DCTN. Hexanic (HF) or ethyl acetate (EAF) fractions had no antinociceptive effect. DCTN also presented antinociceptive effects in chronic models such as inflammatory (induced by intraplantar injection of Freund s complete adjuvant) and neuropathic (induced by partial sciatic nerve ligation), being able to reduce mechanical and cold hypersensitivity,with no changes in the response to heat. When evaluated against the thermo-receptors activation, DCTN administered either systemically (by oral route) or locally (by intraplantar route) reduced the nociception induced by cinnamaldehyde, a TRPA1 activator, but did not alter the response induced by capsaicin, a TRPV1 activator. The antinociceptive effect of DCTN was not affected by the pretreatment with antagonists of opioid, adrenergic or cannabinoid receptors, and neither by the pretreatment with an inhibitor of serotonin synthesis, suggesting that these descending mechanisms of pain control are not involved in the DCTN mechanism of action. On the other hand, DCTN was able to prevent the hypersensitivity induced by cAMP/PKA pathway activators, forskolin and PGE2, and it also reduced PKA activation, demonstrated by western blotting analysis, suggesting that DCTN may act by interaction with this signaling pathway. On the other hand, DCTN presented few or none action on the hypersensitivity induced by bradikinin or PMA, respectively, suggesting that the PLC/PKC pathway is not involved in DCTN antinociceptive action. Additionally, DCTN did not cause any sedative effect, neither alterations on motor activity or body temperature, and although daily treatment caused a slight increase in liver relative weight, alterations on AST, ALT or γ-GT levels were not observed. Together, these results demonstrate that DCTN has an important antinociceptive effect in acute and chronic models of pain, mainly of inflammatory origin, and its mechanism of action seems to involve an interaction with TRPA1 channels and the cAMP/PKA signaling pathway. In this way, DCTN may be considered a potential candidate to further pre-clinical and even clinical investigations for development of analgesic drugs. / A Ocotea puberula (Lauraceae) é uma árvore nativa brasileira, conhecida nos estados da região sul por canela guaicá ou canela amarela, cuja composição fitoquímica inclui diversos alcaloides do tipo aporfínicos, alguns dos quais com atividades biológicas já demonstradas. Frutos coletados na região de Curitiba, Paraná, foram submetidos a processos de extração e fracionamento, permitindo isolar um alcaloide identificado como dicentrina, presente como componente majoritário. Neste trabalho, foi investigado o potencial antinociceptivo das frações orgânicas obtidas a partir do extrato dos frutos de O. puberula e da dicentrina (DCTN) isolada da fração clorofórmica (FC). Tanto a FC quanto a DCTN, administradas por via oral, foram capazes de reduzir a nocicepção induzida pela formalina e pelo ácido acético, com DI50 semelhantes, sugerindo que o efeito de FC seja devido à presença da DCTN. As frações hexânica (FH) e acetato de etila (FAE), por sua vez, não apresentaram efeito antinociceptivo. A DCTN também apresentou efeito antinociceptivo em modelos crônicos, tanto inflamatório (injeção intraplantar de Adjuvante Completo de Freund) quanto neuropático (ligadura parcial do nervo ciático), sendo capaz de reduzir a hipersensibilidade mecânica e ao frio, porém sem alterar a resposta ao calor. Quando avaliada frente à ativação de termo-receptores, a DCTN administrada tanto por via sistêmica (via oral) quanto local (via intraplantar) reduziu a nocicepção induzida pelo cinamaldeído, um ativador de canais TRPA1, mas não alterou a resposta induzida pela capsaicina, um ativador de canais TRPV1. O efeito antinociceptivo da DCTN não foi revertido pelo pré-tratamento com antagonistas de receptores opióides, adrenérgicos ou canabinóides e nem pelo prétratamento com um inibidor da síntese de serotonina, sugerindo que estes sistemas descendentes de controle da dor não estão envolvidos no mecanismo de ação da DCTN. Por outro lado, a DCTN foi capaz de prevenir a hipersensibilidade induzida pelos ativadores da via AMPc/PKA, forscolina e PGE2, e também foi capaz de reduzir a ativação da PKA, demonstrada por análise de western blotting, sugerindo que a DCTN possa agir por interação com essa via de sinalização. Por outro lado, a DCTN apresentou pouca ou nenhuma ação frente à hipersensibilidade mecânica induzida pela bradicinina ou pelo PMA, respectivamente, o que sugere que a via PLC/PKC não está envolvida no seu efeito antinociceptivo. A DCTN não causou efeitos sedativos, alteração motora ou alteração na temperatura corporal dos animais e, embora o tratamento diário durante 14 dias tenha aumentado o peso relativo do fígado, não foram observadas alterações nos níveis sanguíneos de AST, ALT ou γ-GT. Coletivamente, os dados deste trabalho demonstram que a DCTN apresenta um importante efeito antinociceptivo em modelos de dor agudos e crônicos, principalmente de cunho inflamatório, e seu mecanismo de ação parece envolver interação com canais TRPA1 e com a via de sinalização AMPc/PKA. Desta forma, a DCTN constitui-se como uma potencial candidata para a continuidade de estudos pré-clínicos aprofundados, e futuramente clínicos, visando o desenvolvimento de fármacos analgésicos.

Introdução: A literatura sugere que o medo da dependência de opióides é uma barreira para o alívio da dor, especialmente quando há suspeita de uso desses fármacos. No entanto, essa hipótese carece de testes empíricos. Objetivos: Comparar a conduta de profissionais de enfermagem na administração de analgésicos opióides e não opióides, quando há ou não suspeita de que o paciente seja usuário de drogas; identificar a prevalência de pacientes com suspeita de uso de drogas e conhecer as características dos pacientes que os profissionais de enfermagem consideram como sugestivas de uso de drogas. Método Estudo transversal com pacientes e profissionais de enfermagem (auxiliares e técnicos). Foram incluídos 507 pacientes com trauma ortopédico e prescrição de analgésico opióide, internados em quatro hospitais de Londrina, Paraná, entre fevereiro de 2011 a março de 2012, e 199 profissionais responsáveis pela administração de medicamentos a esses pacientes. Cada paciente recebeu a avaliação de três profissionais e considerou-se paciente suspeito aquele indicado por pelo menos um profissional. O desfechos principais foram a 1) quantidade administrada de analgésicos opióides e não opióides prescritos em regime se necessário e em horário fixo nas últimas 24 horas; 2) prevalência de pacientes suspeitos de uso de drogas; 3) condutas dos profissionais frente à solicitação do opióide; 4) Características dos pacientes que os profissionais consideram sugestivas de uso de drogas. Nas análises utilizaram-se os testes de Qui quadrado, Fisher e Mann-Whitney, e nível de significância de 5%. Resultados: A prevalência de pacientes suspeitos foi de 6,86%, maior em homens (p<0.036) e jovens (p<0,001). Os pacientes suspeitos receberam mais opióides se necessário (p=0,037) e até 30% da dose máxima possível, contra até 20% para os não suspeitos. A administração entre suspeitos e não suspeitos não diferiu quanto aos opióides prescritos em horário fixo, no entanto, deixou-se de administrar 10% da dose para ambos os grupos. Entre os profissionais entrevistados, 75,6% relataram que mantêm a analgesia com opióide, mesmo quando há suspeita de o paciente ser usuário de droga, mas 28,9% deles disseram tentar reduzir a dose nesses casos. As características dos pacientes mais frequentemente consideradas pelos profissionais como sugestivas de uso de drogas pertenciam à categoria consequências emocionais/físicas/sociais e sinais de abstinência (70,6%) e insistência pelo opióide (55,9%), mais do que a aparência pessoal (0,0%). Conclusão: A prevalência de suspeitos foi semelhante a estudos realizados em departamentos de emergência, sugerindo que os auxiliares e técnicos de enfermagem foram cuidadosos na estimativa de suspeição. Os resultados obtidos contrariam a literatura, pois indicaram que os suspeitos de serem usuários de droga receberam mais analgésicos opióides. Assumindo-se a premissa de que os profissionais identificaram corretamente os usuários de drogas, pode-se explicar o maior recebimento de opióide pelos suspeitos, pelas características comportamentais e emocionais: maior inquietude, insistência verbal e talvez menor alívio da dor, pois usuários de droga podem desenvolver tolerância. A administração de analgésicos, especialmente em esquema se necessário, é uma decisão importante da enfermagem que pode contribuir para o alívio da dor, daí a importância de entender as motivações que influenciam os profissionais nessa decisão. / Introduction: The literature suggests that the fear of getting addicted to opiods can be a barrier to adequate pain relief, especially when there is a suspicious of drug use. However, this hypothesis needs to be tested empirically. Objectives: Compare the conduct of nursing professionals in administering analgesics when there is the suspicion that the patient is a drug user; identify the prevalence of patients with the suspicious of drugs use and knowing the characteristics of patients that nursing professionals consider as indicators of drug use. Method: Transversal study with patients and nursing professionals (aides and technicians). The study included 507 patients with orthopedics trauma to whom opiod analgesics were prescribed. They were admitted to four hospitals in Londrina, Paraná, Brazil, between February 2011 and 2012. Patients were seen by 199 professionals responsible for administering the medications. Each patient was evaluated by three professionals regarding drug use suspicion. The patient was classified as suspect when indicated by at least one of these professionals. The evaluation included 1) amount of opioid analgesics prescribed under the if necessary regime and at fixed times; 2) prevalence of patients being suspected of drug use and 3) professionals conduct when dealing with opioid prescriptions in the last 24 hours. The analysis used Chi Square, Fisher and Mann- Whitney tests at 5% of level of significance. Results: The prevalence of suspect patients was 6.86%, greater in men (p<0.036) and young people (p<0,001). When comparing the group of suspects with the group of non-suspects, the suspect patients received more opioids under the if needed regime (p=0.037) and up to 30% of the possible maximum dosage against 20% for the non suspects. There was no difference between suspects and non suspects regarding the administration of opioid analgesics prescribed as if necessary; however, 10% of the dosage was not administered to both groups. Among the interviewed nursing aides and technicians, 75,6% reported that they maintain analgesia with opioid even when there was a suspicion that the patient is a drug user; however, 28,9% said they tried to reduce the dosage in these cases. The patients characteristics most often considered by professionals as suggestive of drug use belonged to the emotional/physical/social consequences and withdrawal signs category (70,6%) and insistence by the opioid (55,9%), more than personal appearance (0,0%). Conclusion: The prevalence of suspects was similar to studies performed in emergency departments, suggesting that nursing aides and technicians were careful in estimating suspicion. The results contradict those mentioned in the literature, since they indicate that drug users suspects received more opioid analgesics. By accepting the assumption that nursing aides and technicians have identified illicit drug users correctly, the greater number of opioid administration by the suspects can be explained based on the behavioral and emotional characteristics of this group: greater restlessness, verbal insistence and perhaps less pain relief, since drug users may develop tolerance to certain drugs. Whether or not to administer analgesics, especially those with the if necessary regime, is an important decision for the nursing staff, since they can contribute to an adequate pain relief, thus the importance of understanding the motivations that lead professionals to take this decision.

Dissertação(mestrado) - Universidade Federal do Rio Grande, Programa de Pós-Graduação em Enfermagem, Escola de Enfermagem, 2006. / Submitted by eloisa silva (eloisa1_silva@yahoo.com.br) on 2012-11-09T16:14:25Z No. of bitstreams: 1 alexander.pdf: 756246 bytes, checksum: 88ceec500d6a04e9af9fa8b3904c3119 (MD5) / Approved for entry into archive by Bruna Vieira(bruninha_vieira@ibest.com.br) on 2012-11-13T17:43:39Z (GMT) No. of bitstreams: 1 alexander.pdf: 756246 bytes, checksum: 88ceec500d6a04e9af9fa8b3904c3119 (MD5) / Made available in DSpace on 2012-11-13T17:43:39Z (GMT). No. of bitstreams: 1 alexander.pdf: 756246 bytes, checksum: 88ceec500d6a04e9af9fa8b3904c3119 (MD5) Previous issue date: 2006 / As plantas têm sido, desde a antiguidade, um recurso terapêutico ao alcance da civilização humana. O conhecimento popular acerca das plantas, repassado através de gerações, possibilita a identificação de fontes naturais de compostos químicos importantes para a obtenção de novos fármacos. No município do Rio Grande, RS, a Brugmansia suaveolens, popularmente conhecida como “trombeteira” ou “cartucheira”, é uma planta utilizada como droga psicoativa e que teve evidenciada, em 2004, importante atividade analgésica através de estudos realizados na Fundação Universidade Federal do Rio Grande- FURG. O presente trabalho teve por objetivo investigar o mecanismo pela qual se processa a referida atividade, utilizando-se para isso modelos farmacológicos de nocicepção e de comportamento em camundongos. Observou-se, através dos testes das contorções abdominais induzidas pelo ácido acético e da placa quente, importante atividade antinociceptiva no extrato aquoso das flores de Brugmansia suaveolens (EABs), quando administrado nas doses de 100 e 300 mg/kg via intraperitoneal, reforçando os resultados obtidos em trabalho anterior (PARKER, 2004). No entanto, tal atividade antinociceptiva, quando investigada no teste da placa quente, foi significativamente reduzida pelo pré tratamento dos animais com naloxona (antagonista dos receptores opióides), principalmente quando a dose do extrato testada foi de 300 mg/kg. Tal inibição da atividade do extrato não foi evidenciada em relação ao pré-tratamento dos animais com naloxona no teste das contorções abdominais. Quanto à participação do óxido nítrico no mecanismo da antinocicepção, o pré-tratamento com L-NAME (inibidor da óxido nítrico sintase) bem como o pré-tratamento com azul de metileno (inibidor da guanilato ciclase) não foram capazes de reverter o efeito antinociceptivo do EABs. Na investigação do envolvimento do sistema nervoso central no mecanismo antinociceptivo do EABs, foi realizado o teste da indução do sono em camundongos, onde os animais tratados somente com água e pentobarbital (barbitúrico) permaneceram acordados. Já os animais tratados com EABs e pentobarbital apresentaram um elevado índice de indução ao sono, sugerindo assim uma possível participação da via central. Na avaliação da participação do sistema gabaérgico na resposta antinociceptiva produzida pelo EABs, os animais, quando pré-tratados com flumazenil(antagonista competitivo dos benzodiazepínicos) no modelo das contorções abdominais, apresentaram significativa redução no índice de antinocicepção. Em síntese, o mecanismo antinociceptivo presente no extrato aquoso das flores de Brugmansia suaveolens parece estar atuando através dos sistemas opióide e gabaérgico. / Plants have been a therapeutic resource within reach of human civilization since antiquity. The popular knowledge concerning the plants, reviewed through generations, makes possible the identification of natural sources of important chemical compositions for the obtaining of 'new drugs. In the municipal district of Rio Grande, RS, Brugmansia suaveolens, popularly known as "trombeteira" or "cartucheira", is a plant used as psicoative drug and it was evidenced, in 2006, an important analgesic activity through studies accomplished in the Fundação Universidade Federal do Rio Grande - FURG. The present work aimed at investigating the mechanism through which is processed the referred activity, using pharmacological nociception and behavior models in mice. It was observed, through tests of abdominal constrictions induced by the acetic acid, and the hot plate one, an important antinociceptive activity in the aqueous extract of Brugmansia suaveolens flowers (EABs), when managed in doses of 100 and 300 mg/kg through intraperitoneal. It reinforced the results obtained in previous work (Parker, 2004). However, such antinociceptive activity was significantly reduced for the prior treatment of the animals with naloxone (antagonist of the opioids receptors) when investigated in the hot plate test, mainly when the tested extract dose was 30mg/kg. The same was not evidenced in relation to the prior treatment of the animals with naloxone in the abdominal constrictions test. In relation to the participation of Nitric Oxid (NO) in the mechanism of the antinociception, the prior treatment with L-NAME (inhibitor of NO synthase) as well as the prior treatment with methylene blue (antagonist of guanylate cyclase) were not capable to revert the antinociceptive effect of EABs. In the investigation of the central nervous system involvement in the antinociceptive mechanism of EABs, the sleep test induction was carried out in mice, where only the animals treated with water and pentobarbital (barbiturate) stayed awake. The animals treated with EABs and pentobarbital presented a high induction index to the sleep, suggesting a possible participation of the central way. In the valuation of the gabaergic system participation in the antinociceptive response produced by EABs, the animals, when prior treated with flumazenil (competitive antagonist of the benzodiazepinics) in the model of abdominal constrictions, presented significant reduction in the antinociception index. In summary, the antinociceptive mechanism present in the aqueous extract of the flowers of Brugmansia suaveolens seems to be acting through the opioid and gabaergic systems. / Las plantas han sido, desde la antiguedad, un recurso terapêutico al alcance de la civilización humana. El conocimiento popular acerca de las plantas, repasado através de las generaciones, posibilita la identificación de fuentes naturales de compuestos químicos importantes para la obtención de nuevos fármacos. En el município de Rio Grande, R.S a Brugmansia suaveolens, popularmente conocida como “tompetera” o “cartuchera”, es una planta utilizada como droga psicoativa y que tuvo evidenciado, em 2004, importante actividad analgésica através de los estúdios realizados em la Fundação Universidade Federal do Rio Grande - FURG. El presente trabajo tuvo por objetivo investigar el mecanismo por el cual se procesa la referida actividad, se utilizando para esto modelos farmacológicos de nocicepción y de comportamiento en ratones. Se observo, através de los testes de las contorciones abdominales inducidas por el ácido acético y de la placa caliente, importante actividad antinociceptiva en el extrato acuoso de las flores de Brugmansia suaveolens (EABs), cuando administrado em dosis de 100 y 300 mg/kg vía intraperitonial, reforzando los resultados obtenidos en trabajo anterior (PARKER, 2004). Sin embargo, tal actividad antinociceptiva, cuando investigada em la placa caliente, fué significativamente reducida por el pre tratamiento de los animales com naloxona (antagonista de los receptores opióides), principalmente cuando la dosis del extracto fué de 300 mg/kg. Tal inhibición de la actividad del extrato no fué evidenciada em relación al pre tratamiento de los animales con naloxona en el teste de las contorciones abdominales. Cuanto a la participación del óxido nítrico en el mecanismo de la antinocicepción, el pre tratamiento con L-NAME (inhibidor de la sintase del óxido nítrico) así como em el tratamiento con azul de metileno (inhibidor de la ciclase guanilato) no fueron capaces de reverter el efecto antinociceptivo do EABs. En la investigación del envolvimiento del sistema nervioso central em el mecanismo antinociceptivo del EABs, fué realizado el teste de la inducción al sueño en ratones, donde los animales tratados solamente con água y pentobarbital (barbitúrico) permanecieron despiertos. Ya los animales tratados con EABs y pentobarbital apresentaron un elevado índice de indución al sueño, sugeriendo así una posible participación de la via central. En la avaliación de la participación del sistema gabaergico en la respuesta antinociceptiva producida por EABs, los animales, cuando pre tratados com flumazenil (antagonista competitivo de los benzodiazepínicos) en el modelo de las contorciones abdominales, apresentaron significativa redución del índice de antinocicepción. En síntesis, el mecanismo antinociceptivo presente en el extrato acuoso de las flores de Brugmansia suaveolens parece estar actuando através de los sistemas opióide y gabaérico.

Copaifera langsdorffii Desf. é conhecida popularmente como \"copaíba\", sendo encontrada nas regiões norte e nordeste do Brasil. Nesta tese reportam-se o estudo fitoquímico das folhas de C. langsdorffii, por meio do fracionamento de seu extrato hidroalcoólico, o isolamento e a purificação de seus metabólitos secundários majoritários, a biotransformação do epóxido do ácido caurenóico, bem como a avaliação das atividades analgésica e anti-inflamatória do extrato e compostos isolados. Para avaliação do perfil cromatográfico, o extrato hidroalcoólico das folhas (Cop) foi particionado em hexano, diclorometano, acetato de etila, n-butanol e água. Com o uso de filtração em gel, Cromatografia Contra Corrente e CLAE preparativa foram isolados os compostos quercetina-3-O-?-L-ramnopiranosídeo (quercitrina), canferol-3-O-?-L-ramnopiranosídeo (afzelina), bem como os ácidos 4\',4\'\'-dimetóxi-4,5-di-O-galoilquínico e 4-(4\'\'-metóxi galoil)-3,5-di-O-galoilquínico. O ácido caurenóico e o caurenol foram isolados em coluna de gel de sílica a partir da fração em acetato de etila. O ácido caurenóico foi submetido a epoxidação com ácido 3-cloroperbenzóico e foi submetido à biotransformação pelo fungo Beauveria sulfurenscens em meio sintético. A biotransformação do epóxido do ácido caurenóico forneceu o ácido 7?,17-diidroxi-ent-caur-15-en-19-oico, até então desconhecido, bem como o ácido 7?,17-diidroxi-16?-ent-cauran-19-oico, o ácido 7?,17-diidroxi-16?-ent-cauran-19-oico, o ácido 9?,16?,17-triidroxi-ent-cauran-19-oico e o ácido 16?,17-diidroxi-ent-cauran-19-óico. Cop e caurenol reduziram a inflamação induzida por ácido acético com máxima inibição de 40,3 e 53,6%, respectivamente. Na segunda fase do ensaio de formalina foi observada redução de 54,5 e 64,6%, respectivamente. A resposta inflamatória observada por carragenina e dextrana mostrou máxima redução de 52,3 e 43,6% para Cop e de 64,3 e 80% para caurenol, respectivamente. Cop e caurenol reduziram a produção de NO estimulada por LPS e aumentaram a liberação de TNF-?, mas não modularam a expressão de IL-6 e IL-10. Portanto, caurenol está envolvido na atividade antiedematogênica do extrato. Já a quercitrina e a afzelina não foram ativas nos protocolos utilizados. Cop e caurenol não alteraram a primeira fase do ensaio de formalina, a latência em placa quente, o desempenho motor dos animais e a migração celular. Concluiu-se que Cop e caurenol possuem atividade antiedematogênica atuando em sítios periféricos, contudo essa propriedade não está associada com a regulação da migração celular, TNF-?, IL-6 e IL-10. / Copaifera langsdorffii Desf., known as \"copaiba\", is found in the northern and northeastern of Brazil. This thesis reports the phytochemical study of C. langsdorffii leaves, through its hydroalcoholic extract (Cop) fractionation, isolation and purification of its major secondary metabolites, the biotransformation of kaurenoic acid epoxide, as well the evaluation of the analgesic and anti-inflammatory activities of the extract and isolated compounds. For the evaluation of the chromatographic profile, the extract was partitioned into hexane, dichloromethane, ethyl acetate, n-butanol and water fractions. With the use of gel filtration chromatography, counter current chromatography and preparative HPLC, quercetin-3-O-?-L-rhamnopyranoside (quercitrin), kaempferol-3-O-?-L-rhamnopyranoside (afzelin), 4\'- 4\'\'-dimethoxy-4 ,5-di-O-galloylquinic acid and 4-(4-methoxy galloyl\'\')-3,5-di-O-galloylquinic were isolated. The epoxidation of kaurenoic acid was performed with 3-chloroperbenzoic acid and it was submitted to biotransformation by the fungus Beauveria sulfurenscens in synthetic medium. Biotransformation of kaurenoic acid epoxide furnished the unknown compound 7?,17-dihydroxy-ent-kaur-15-en-19-oic acid and the compounds 7?,17-dihydroxy-16?-ent-kauran-19-oic acid, 7?,17-dihydroxy-16?-ent-kauran-19-oic acid, 9?, 16?,17-trihydroxy-ent-kauran-19-oic acid and 16?,17-dihydroxy-19-ent-kauran-oic acid. Cop and kaurenol reduced the inflammation induced by acetic acid in mice with a maximal inhibition of 40.3 and 53.6%, respectively. The second phase in the formalin test in mice showed maximal reduction of 54.5 and 64.6%, respectively. The inflammatory responses induced by both carrageenan and dextran in rats showed maximal reduction of 52.3 and 43.6 % for Cop, as well as 64.3% and 80.0% for kaurenol, respectively. Cop and kaurenol reduced the NO production stimulated by LPS in a dose-dependent manner, and increased the release of TNF-?, but did not regulate IL-6 and IL-10. Therefore, kaurenol is involved in the extract antiedematogenic activity of the extract, whereas quercitrin and afzelin were not active in the used protocols. Cop and kaurenol did not alter the formalin first phase, hot-plate latency, motor performance or cell migration. The obtained results show that C. langsdorffi extract and kaurenol possess antiedematogenic properties acting on peripheral sites, but these properties are not associated with cell migration, TNF-?, IL-6 or IL-10 regulation.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Polyamines (putrescine, spermidine and spermine) are important endogenous regulators of ion channels, such as vanilloid (TRPV1), glutamatergic (NMDA or AMPA/kainate) and acid-sensitive (ASIC) receptors. In the present study, it was investigated the possible nociceptive effect induced by polyamines and the mechanisms involved in this nociception in vivo and in vitro. The subcutaneous (s.c.) injection of capsaicin, spermine, spermidine or putrescine produced nociception with ED50 of 0.16 (0.07-0.39) nmol/paw, 0.4 (0.2-0.7) μmol/paw, 0.3 (0.1-0.9) μmol/paw and 3.2 (0.9-11.5) μmol/paw, respectively. The antagonists of NMDA (MK801, 1 nmol/paw), AMPA/kainate (DNQX, 1 nmol/paw) or ASIC receptors (amiloride, 100 nmol/paw) failed to reduce the spermine-trigged nociception. However, the TRPV1 antagonists capsazepine or SB366791 (1 nmol/paw) reduced spermine-induced nociception, with inhibition of 81±10 and 68±9%, respectively. The previous desensitization with resiniferatoxin (RTX) largely reduced the spermine-induced nociception and TRPV1 expression in the sciatic nerve, with reductions of 82±9% and 67±11%, respectively. Furthermore, the combination of spermine (100 nmol/paw) and RTX (0.005 fmol/paw), in doses which alone were not capable of inducing nociception, produced nociceptive behaviors. Moreover, different concentrations of spermine (3-300 μM) enhanced the specific binding of [3H]-RTX to TRPV1 receptor. Altogether, polyamines produce spontaneous nociceptive effect through the stimulation of TRPV1, but not of ionotropic glutamate or ASIC receptors. / As poliaminas (putrescina, espermidina e espermina) são importantes reguladores endógenos de canais iônicos como o receptor vaniloide (TRPV1), os receptores glutamatérgicos (NMDA ou AMPA/cainato) e o canal iônico sensível ao ácido (ASIC). No presente estudo, investigou-se o possível efeito nociceptivo induzido por poliaminas e o mecanismo envolvido nesta nocicepção in vivo e in vitro. A injeção subcutânea (s.c.) de capsaicina, espermina, espermidina e putrescina produziram nocicepção com DE50 de 0,16 (0,07-0,39) nmol/pata, 0,4 (0,2-0,7) μmol/pata, 0,3 (0,1-0,9) μmol/pata e 3,2 (0,9-11,5) μmol/pata, respectivamente. Os antagonistas dos receptores NMDA (MK801, 1 nmol/pata), AMPA/cainato (DNQX, 1 nmol/pata) ou ASIC (amiloride, 100 nmol/pata) não reduziram a nocicepção induzida por espermina. Porém, os antagonistas do receptor TRPV1 capsazepina (1 nmol/pata) e SB366791 (10 nmol/pata) reduziram a nocicepção induzida por espermina, com inibições de 81±10 e 68±9%, respectivamente. A dessensibilização prévia com resiniferatoxina (RTX) reduziu a nocicepção induzida por espermina e a expressão de TRPV1 no nervo ciático, com reduções de 82±9% e 67±11%, respectivamente. Além disso, a combinação de espermina (1 nmol/pata) e RTX (0,005 fmol/pata), em doses que separadamente não são eficientes em induzir nocicepção, produziu comportamento nociceptivo. Finalmente, diferentes concentrações de espermina (3-300 μM) aumentaram a ligação específica de [3H]-RTX ao receptor TRPV1. Assim, os resultados demonstram que poliaminas produzem efeito nociceptivo espontâneo através da estimulação de receptor TRPV1, mas não de receptores glutamatérgicos ionotrópicos ou canal iônico sensível a ácido.

The family Nyctaginaceae consist of approximately 30 genus and 14 species. In Brazil, 10 genus and 70 species are found. The genus Mirabilis belongs this family and can be found spread worldwide. This plant popularly known as maravilha or bonina and it is used in folk medicine to treat infection, inflammation and pain. The plant was collected in March 2006 in Santa Maria (RS). Ethanolic extract (70%) was made by maceration and fractionated using organic solvents with increasing polarity (hexanic, dichloromethane, ethyl acetate and butanolic). Through qualitative chemical analysis it was found in greater quantity alkaloids, amino groups, sterols and/or triterpenoids, hidroxiantraquinones, anthocyanic pigments, volatile acids and phenols. In relation to the antimicrobial activity, the best response was obtained for the fraction dichloromethane from stem and the ethyl acetate from leaves for S. aureus and the fraction ethyl acetate from stem and leaves for S. cerevisiae. The higher concentration of phenolic compounds was found in the ethyl acetate fraction from leaves (7,45 mg/g drug). Through the method of DPPH, all samples showed antioxidant activity by TLC and by spectrophotometry. Ethyl acetate and butanolic fractions from leaves showed excellent antioxidant activity with IC50 of 20,40 μg/ml and 25,41 μg/ml, respectively. The highest content of quercetin was found in the leaves extract (0,19%). The ethyl acetate fraction produced analgesic activity reaching 82.8±7.9% inhibition in the writhing test. The hexanic fraction from leaves expressed the best toxicity front of Artemia (LC50 = 1.27 μg/ml) / A família Nyctaginaceae compreende aproximadamente 30 gêneros e 400 espécies. No Brasil são encontrados 10 gêneros e 70 espécies. O gênero Mirabilis está inserido nesta família e encontra-se amplamente distribuído por todo o mundo. Conhecida popularmente como bonina ou maravilha, é utilizada na medicina popular para o tratamento de infecções, inflamações e dores. A planta foi coletada em março de 2006 no município de Santa Maria (RS). O extrato bruto em etanol (70%) foi preparado por maceração e fracionado com solventes orgânicos de polaridade crescente (hexano, diclorometano, acetato de etila e butanol). Através da análise química qualitativa foram encontrados em maior quantidade heterosídeos antociânicos, alcalóides, amino-grupos, ácidos voláteis, esteróides e/ou triterpenos, hidroxiantraquinonas, e fenóis. Quanto à atividade antimicrobiana, as melhores respostas obtidas foram para a fração diclorometano do caule e folhas frente a S. aureus e a fração acetato de etila do caule e das folhas frente a S. cerevisiae. A maior concentração de compostos fenólicos foi encontrada na fração acetato de etila das folhas (7,45 mg/g de droga). Através do método do DPPH, todas as amostras mostraram atividade antioxidante por CCD e pelo método espectrofotométrico, sendo que as frações acetato de etila e butanólica das folhas demonstraram excelente atividade antioxidante com CI50 de 20,40 μg/ml e 25,41 μg/ml, respectivamente. O maior teor de quercetina foi encontrado no extrato das folhas (0,19%). A fração acetato de etila apresentou a maior atividade analgésica (I% = 82.8) no teste de contorções abdominais. A fração hexânica das folhas expressou a melhor toxicidade frente a Artemia salina (CL50=1,27 μg/ml).

The diploma thesis if focused on the study of bioactive hydrogél and nanofiber wound dressings composed of natural biopolymers, which were functionalized by active compounds in the form of analgesic, antibiotics and enzymes. Hydrogél wound dressings were constituted from alginate and chitosan and nanofibers were created from polyhydroxybutyrate. The following 7 active compounds were selected to be added to the wound dressings: ampicillin, streptomycin, ibuprofen, papain, bromelain, collagenase and trypsin. In the theoretical part the structure of the skin and types of wound injuries were described. This part also talks about types of wound dressing and their applications, as well as treatment of skin wounds using enzymes and compounds with analgesic and antimicrobial properties. In addition, this section describes safety assays, in particular cytotoxicity assays on human cells. At the beginning of the experimental part, the process of preparation of hydrogél wound dressing was optimised. Subsequently, the dressings were enriched with active compounds and the rate of gradual releasing of the substances into model environment was monitored. In the case of enzymes, their proteolytic activity was also tested after their incorporation to the wound dressings. Furthermore, the prepared bioactive wound dressings were analyzed for possible cytotoxic effect on human keratinocytes. Finally, the wound dressing with combined content of active substances was created and also characterized for the rate of substance release, proteolytic activity and cytotoxicity. Antimicrobial activity of this wound dressings, against two selected strains of microorganisms: Escherichia coli and Staphylococcus epidermidis, was also evaluated.

Le paracétamol est sujet à controverse depuis sa découverte. Que ce soit son mécanisme d’action, ses effets indésirables ou son efficacité, de nombreuses études ont été réalisées et parfois se contredisent. Parfois critiqué pour son efficacité limitée, il n’a pourtant rien à envier aux autres antalgiques : il soulage les douleurs faibles à modérées sans effets indésirables aux doses thérapeutiques. Cela en fait un médicament de premier recours chez la femme enceinte, le nourrisson et l’enfant. D’après un rapport de l’ANSM, sur les 30 substances actives les plus vendues en France en 2013 (montant total 1,15 milliard de boîtes), le paracétamol domine très largement (plus de 500 millions de boîtes). C'est l’antalgique et l’antipyrétique le plus consommé au monde. La pharmacopée des antalgiques est vieillissante, l’évolution de l’arsenal thérapeutique depuis 50 ans est limitée. Ce constat amène à réévaluer les stratégies de recherche. Maintenant, notre intérêt serait de comprendre les mécanismes et les cibles de ces antalgiques afin de développer des analogues plus affins tout en limitant leurs effets indésirables. Basée cette stratégie, le paracétamol est un parfait candidat. En effet, son mécanisme d’action n’est pas parfaitement connu mais son efficacité n’est plus à prouver. L’objectif de ces travaux est d’élucider le mystère qui entoure son mécanisme d’action et de découvrir ses cibles. Les dernières études redéfinissent le paracétamol comme un précurseur métabolique à l’origine d’un dérivé lipidique actif, nommé AM404. Ce dernier serait synthétisé dans certaines régions cérébrales exprimant l’enzyme FAAH capable de catalyser cette réaction. Le mécanisme alors mis en jeu montre que le paracétamol, via l’AM404, activerait les récepteurs TRPV1 centraux et indirectement les récepteurs CB1 pour renforcer un mécanisme central d’atténuation de la douleur via les voies descendantes sérotoninergiques. Cependant, le noyau cérébral concerné et le mécanisme cellulaire mis en jeu demeurent inconnus. Des données comportementales associées à une étude d’imagerie fonctionnelle ont levé le voile sur plusieurs régions cérébrales potentiellement impliquées dans l’action du paracétamol, notamment la substance grise périaqueducale. Cette dernière a suscité notre intérêt, car ce noyau exprime à la fois la triade FAAH/TRPV1/CB1, mais aussi est un carrefour des voies descendantes sérotoninergiques. Une activation dans la substance grise périaqueducale des récepteurs TRPV1 et CB1 est à même de produire un effet antinociceptif dépendant de ces contrôles descendants. Ces travaux de thèse ont conduit à conforter que l’action antalgique du paracétamol implique un mécanisme supra-spinal dépendant de l’enzyme FAAH en condition pathologique. Plus précisément, nous avons étudié le rôle de la triade FAAH/TRPV1/CB1 au niveau de la SGPA. Nous avons découvert que le paracétamol interagissait avec une voie de signalisation cellulaire mGLUR5-PLC-DAGL responsable de la production de l’endocannabinoïde 2-AG. Ce mécanisme pourrait à la fois expliquer l’étroite collaboration existant entre les récepteurs TRPV1 et CB1 dans l’effet antalgique du paracétamol et le renforcement des voies descendantes sérotoninergiques. Le paracétamol est donc un promédicament dont l’action cérébrale recruterait un ensemble de systèmes complexes pour médier son effet antalgique. Ce mécanisme séduisant ouvre la piste à de nouveaux antalgiques toujours plus efficaces avec des effets indésirables moindres, à l’image du paracétamol. / Paracetamol is since its discovery controversial. Whether with respect to the mechanism of action, its side effects or effectiveness, many studies have been performed, at times contradictory. Sometimes criticized for its limited effectiveness, it has nothing to envy in contrast to other analgesics whose effectiveness are often associated with side effects. Paracetamol has proven itself to relieve low to moderate pain without side effects at therapeutic doses. This makes it drug of choice for pregnant women, infants and children. According to a report by the ANSM of the 30 top-selling active substances in France in 2013, with a total of 1.15 billion boxes, paracetamol largely dominates this ranking as its sales are over 500 million boxes. Thus it has become the analgesic and antipyretic most consumed in the world. Today, the pharmacopoeia of analgesics is outdated; evolution of the therapeutic arsenal for 50 years is limited with few major discoveries reported. This observation leads to the need to reassess research strategies to innovate new and more effective molecules. Until now, the aim was to focus on a few molecules with high therapeutic potential in order to optimize their effectiveness without understanding their mechanisms. Now our interest is to understand the mechanisms and targets of these analgesics in order to develop more comparable molecules while limiting their adverse effects. Based on this strategy, paracetamol is a perfect candidate. Indeed, its mechanism of action is not fully known, but its effectiveness is proven. The aim of this work is to elucidate the mystery surrounding its mechanism of action and discover its targets. The latest studies redefine paracetamol as a metabolic precursor to the origin of an active lipid derivative, called AM404. The latter is synthesized in certain regions of the brain expressing the FAAH enzyme capable of catalyzing this reaction. The mechanism thus put into play shows that paracetamol, via AM404, activates TRPV1 receptors and the central CB1 receptors indirectly to reinforce a central mechanism of pain relief via serotonergic descending pathways. However, the cerebral area concerned and the cellular mechanism involved remain unknown. Behavioral data associated with a functional imaging study unveiled several brain regions potentially involved in the action of paracetamol, including the periaqueductal gray matter. The latter sparked our interest for two reasons: one because it expresses the core triad FAAH/TRPV1/CB1; and two it also represents a crossroad of descending serotonergic pathways. Activation in the periaqueductal gray matter of the TRPV1 and CB1 receptors is adapted to produce an antinociceptive effect dependent on these descendant control systems. This work of this thesis has led to re-affirm that the analgesic action induced by paracetamol involves a supra-spinal mechanism dependent on the FAAH enzyme in pathological conditions. Specifically, we investigated the role of the triad FAAH/TRPV1/CB1 in the periaqueductal gray matter. We found that paracetamol interacted with the cell signaling pathway mGluR5-PLC-DAGL responsible for production of the endocannabinoid 2-AG. This mechanism can explain both the close collaboration between the TRPV1 and CB1 receptors in the analgesic effect of paracetamol and the reinforcing of serotonergic descending pathways. Paracetamol is thus a prodrug whose cerebral action involves a set of complex systems to mediate its analgesic effect. This attractive mechanism opens the track to new painkillers ever more effective with fewer side effects, reflected paracetamol mechanism.

Electrostimulatory forms of therapy can reduce angina that arises from activation of cardiac nociceptive afferent fibers during transient ischemia. This study sought to determine the effects of electrical stimulation of left thoracic vagal afferents (C8-T1 level) on the release of putative nociceptive [substance P (SP)] and analgesic [dynorphin (Dyn)] peptides in the dorsal horn at the T4 spinal level during coronary artery occlusion in urethane-anesthetized Sprague-Dawley rats. Release of Dyn and SP was measured by using antibody-coated microprobes. While Dyn and SP had a basal release, occlusion of the left anterior descending coronary artery only affected SP release, causing an increase from lamina I-VII. Left vagal stimulation increased Dyn release, inhibited basal SP release, and blunted the coronary artery occlusion-induced release of SP. Dyn release reflected activation of descending pathways in the thoracic spinal cord, because vagal afferent stimulation still increased the release of Dyn after bilateral dorsal rhizotomy of T2-T5. These results indicate that electrostimulatory therapy, using vagal afferent excitation, may induce analgesia, in part, via inhibition of the release of SP in the spinal cord, possibly through a Dyn-mediated neuronal interaction.