Apesar do recente conhecimento do papel anti-inflamatório e anti-nociceptivo do H2S na artrite induzida por carragenina (CGN) em rato, os mecanismos envolvidos ainda não são conhecidos. Tampouco se sabe se compostos híbridos antiinflamatórios não esteroides (AINEs) doadores de H2S possuem vantagens farmacológicas adicionais quando comparados aos doadores de H2S clássicos. Apesar de H2S exercer um efeito anti-nociceptivo em modelos de inflamação e dor aguda, pouco se sabe sobre o papel deste gás na dor crônica. Neste estudo investigou-se os mecanismos do H2S no modelo de sinovite e participação desse gás na dor crônica. Verificou-se que os canais de K+ATP, canais de Ca2+ tipo L ou receptores TRPV1 não estão envolvidos no mecanismo protetor do H2S na sinovite, diminuição da IL-1b e aumento da IL-10 e não houve diferença em relação a participação das enzimas oxidantes GPx e GR. Ainda, o tratamento agudo com o doador de H2S não reverteu o desconforto do teste do Rota Rod e alodinia térmica. / Despite recent knowledge of the anti-inflammatory and anti-nociceptive role of H2S in the carrageenin-induced arthritis (CGN) in rats, the mechanisms involved are not yet known. Nor is it known whether hybrid compounds antiinflammatory drugs (NSAIDs) H2S donors have additional pharmacological advantages when compared to classical H2S donors. Although H2S exert an anti-nociceptive effect in models of inflammation and acute pain, little is known about the role of this gas in chronic pain . In this study we investigated the protective mechanisms of H2S in the model of synovitis and chronic pain . It was found that the K+ATP channel, L type Ca2+ channel or TRPV1 receptors are not involved in the protective mechanism of H2S in synovitis , decreased IL-1b and increased IL-10 and there was no difference in the participation of oxidant enzymes GPx and GR . Still, the acute treatment with H2S donor did not reverse the discomfort of the Rota Rod test and thermal allodynia.

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are currently widely used as fever and pain relief in patients with arthritis and other inflammatory symptoms. NSAIDs effect by inhibiting cyclooxygenase-1 (COX-1) and/or cyclooxygenase-2 (COX-2). COX isozymes (COXs) are key enzymes in the biosynthesis of prostaglandin H2 (PGH2) from arachidonic acid (AA). It is now clear that prostaglandin E2 (PGE2), one of the downstream products of PGH2, is the main mediator in both chronic and acute inflammation. Microsomal prostaglandin E synthase (mPGES-1) is the terminal enzyme of COX-2 in the PGE2 biosynthesis pathway. Different from other two constitutively expressed PGE2 synthase (PGES), mPGES-2 and cPGES, mPGES-1 is induced by pro-inflammatory stimuli and responsible for the production of PGE2 related to inflammation, fever and pain. For these reasons, selective inhibition of mPGES-1 is expected to suppress inflammation induced PGE2 production and, therefore, will exert anti-inflammatory activity while avoid the side effects of COXs inhibitors, such as gastrointestinal (GI) toxicity, and cardiovascular events. A combination of computational and experimental approaches was used to discovery mPGES-1 inhibitors with new scaffolds. The methods used include molecular docking, molecular dynamic simulation, molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculation, and in vitro activity assays. Our large-scale structure-based virtual screening was performed on compounds in the NCI libraries, containing a total of ~260,000 compounds. 7 compounds have been determined for their IC50 values (about 300 nM to 8000 nM). What’s more, these new inhibitors of mPGES-1 identified from virtual screening did not shown significant inhibition against COX isozymes even at substantially high concentrations (e.g. 100 µM). Rational methodology for drug design and organic synthesis were applied to generate three series of mPGES-1 inhibitors with different scaffolds. In total, about 200 compounds were synthesized and tested for their in vitro inhibition against human mPGES-1. Compounds with high potency against human mPGES-1 were further screened for their inhibition against mouse mPGES-1 and selectivity of human mPGES-1 over COXs. Several compounds were identified as submicromolar inhibitors against human mPGES-1 with high selectivity over COXs. In general, we have successfully identified a library of compounds as potent mPGES-1 inhibitors without significant inhibition against COXs. Structure information and in vitro activity evaluation data generated from the virtual screening and the library of compounds will be used to guide future design and synthesis of the mPGES-1 inhibitors.

Lipoxygenases (LOXs), cytochromes P450 (CYPs) and cyclooxygenases (COXs) catalyze peroxidation of unsaturated fatty acids. In humans they convert arachidonic acid into a variety of eicosanoids, which play a role in all inflammatory responses, cardiovascular and kidney diseases, Alzheimer's, cancer and other ailments. Blocking one pathway can prompt the body to switch to the available alternatives. In contrast to CYP and COX, LOX has a non-heme iron co-factor. Several LOXs are produced or stress-induced in the human body. They share the same mechanism, but differ in sequence causing catalysis on the same substrate to be regio- and stereospecific. The action of 15-LOXs could be pro- or anti-inflammatory, and pro- or anti-carcinogenic. Depending on the dose, LOXs inhibitors can induce or inhibit other oxygenases. Inhibition of these enzymes presents a great challenge in solving the problem of how to control their action and treat diseases, without causing severe side effects and maintaining/restoring a delicate equilibrium between them. Research on CYPs and COXs is more advanced, while studies of LOXs are lagging behind. This article presents a brief review about LOX structures and inhibition, their involvement in human diseases, and their interplay with other oxidoreductases.

No description available.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24478号 / 医博第4920号 / 新制||医||1062(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山本 洋介, 教授 近藤 尚己, 教授 柳田 素子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Stroke is a devastating neurological disease with limited treatment opportunities. Recent advances in understanding the underlying pathogenesis of cerebral ischemia support the involvement of multiple biochemical pathways in the development of the ischemic injury. The work reported in this thesis was undertaken to investigate the hypothesis that fenamate NSAIDs have neuroprotective properties against ischemic stroke and to explore the underlying mechanisms for any efficacy. Fenamates are non-selective inhibitors of cyclooxygenases. In addition, fenamates are antagonists of non-selective cation channels, subtype-selective modulators of GABA A receptors, weak inhibitors of glutamate receptors and activators of some potassium channels, all potentially important in the pathogenesis of ischemic stroke. Mefenamic acid, a prototype fenamate, administered by intracerebroventricular (ICV) infusion, reduced the ischemic brain damage and edema volume in the middle cerebral artery occlusion model in male rats. Consistent with these results, systemic administration of mefenamic acid, by multiple intravenous injections, also reduced the ischemic damage and edema volume measured by morphometric analysis and as a function of brain water content. These are the first set of experiments to demonstrate a significant neuroprotective effect of a fenamate against an in vivo model of ischemic stroke. In vitro , mefenamic acid was also shown to reduce glutamate-evoked cell death ( excitotoxicity ) in a concentration-dependent manner in cultured embryonic rat hippocampal neurons. Similarly, selected other fenamates also reduced excitotoxicity in the rank order (from highest): mefenamic acid > flufenamic acid ≥ meclofenamic acid > niflumic acid supporting the idea that this is a drug class action. Three pharmacological properties of fenamates, cyclooxygenase inhibition, GABA A receptor modulation and potassium channel activation were investigated as the potential mechanism(s) for the neuroprotective effects of mefenamic acid against excitotoxicity. The experimental results suggest that these are not the primary mechanisms for neuroprotective effects of mefenamic acid against glutamate-evoked cell death. Collectively, these data support the hypothesis that fenamate NSAIDs are neuroprotective against experimental models of cerebral ischemia and suggest they should be further investigated as potential pharmacological treatments for stroke.

No description available.

This study aimed to investigate athletes’ hypothetical use of non-steroidal anti-inflammatory drugs (NSAIDs), a behavior similar to doping, and its association with doping attitudes, competitive anxiety and situational opportunity. One hundred twenty-two sport science students completed an online survey assessing biographical information, doping attitudes, and competitive anxiety. Students’ intention to use analgesics was measured via two discussed.

Eficácia do anti-inflamatório não-esteroidal diclofenaco associado ou não ao opioide codeína para controle da dor, edema e trismo no modelo de extração bilateral de terceiros molares inferiores com alto grau de dificuldade O controle da dor e inflamação após cirurgias bucais é normalmente realizado através do uso de anti-inflamatórios não-esteroidais (AINEs); no entanto a combinação de opioides aos AINEs pode garantir uma melhor analgesia principalmente após cirurgias mais traumáticas. Apesar disso, poucos estudos têm comparado AINEs associados ou não aos opioides após cirurgias bucais e maxilofaciais. Este estudo cruzado, randomizado e duplo-cego comparou a eficácia clínica no controle da dor, edema e trismo pós-operatório em 46 voluntários que consumiram randomicamente os medicamentos diclofenaco sódico (50 mg) associado à codeína (50 mg) e apenas diclofenaco sódico (50 mg) após extrações dos dois terceiros molares em posições complexas como alto grau de dificuldade cirúrgica. Os voluntários enquanto em uso do diclofenaco associado à codeína relataram dor pós-operatória significativamente menor em vários momentos (90 minutos (p=0,043), 2 horas (p=0,014), 3 horas (p=0,001), 5 horas (p=0,010), 10 horas (p=0,005), 12 horas (p=0,006) e 24 horas (p=0,018)) dentro das primeiras 24 horas após a cirurgia e também consumiram significativamente menos (p=0,003) medicação de resgate (paracetamol) ao longo do estudo, comparados com os valores expressos pelos mesmos voluntários enquanto em uso do diclofenaco apenas. Em conclusão, o diclofenaco sódico associado à codeína foi mais eficaz no controle da dor pós-operatória, enquanto que o trismo e o edema não apresentaram diferenças quando comparado com o diclofenaco sem codeína. / Postoperative pain and inflammation after oral surgery is mostly managed using non steroidal anti-inflammatory drugs (NSAIDs); however, opioids combined with NSAIDs may improve pain management in patients especially after traumatic oral surgery. Despite this, few studies have compared NSAIDs with and without opioids after oral and maxillofacial surgery. This randomized double-blinded crossover study compared the clinical efficacy for managing postoperative pain in 46 volunteers consuming either sodium diclofenac (50 mg) plus codeine (50 mg) or only sodium diclofenac (50 mg) after invasive surgeries for extraction of both lower third molar surgeries in different appointments. Volunteers reported significantly less postoperative pain at various time points (90 minutes (p=0,043), 2 hours (p=0,014), 3 hours (p=0,001), 5 hours (p=0,010), 10 hours (p=0,005), 12 hours (p=0,006) e 24 hours (p=0,018)) within 24 hours after surgery and also consumed significantly less(p=0,003) rescue medication (acetaminophen) throughout the study while consuming diclofenac plus codeine when compared to only taking NSAIDs. In conclusion, despite no difference between inflammation aspects, oral sodium diclofenac with codeine was more effective for managing postoperative pain when compared to diclofenac without codeine.

Anti-inflamatórios não esteroidais (AINEs) são frequentemente utilizados para controlar a dor pós-operatória e inflamação em pacientes após a cirurgia oral e maxilofacial, mas eles são muitas vezes associados a problemas gastrointestinais. Recentemente, o AINE naproxeno foi introduzido no mercado em combinação com esomeprazol, um inibidor da bomba de prótons que reduz a formação de ácido do estômago, com o intuito de amenizar esses efeitos colaterais. Usando um design duplo-cego randomizado e cruzado, este estudo teve como objetivo avaliar, pela primeira vez, o controle da dor aguda pós-operatória em 46 pacientes que consumiram um comprimido de NE (naproxeno 500 mg + esomeprazol 20 mg) ou de naproxeno puro (500 mg) a cada 12 horas por 4 dias após a cirurgia dos dois terceiros molares inferiores em posições semelhantes, em dois momentos distintos. As pacientes do sexo feminino relataram significativamente mais dor em 1, 1,5, 2, 3 e 4 horas após a cirurgia e também consumiram sua primeira medicação de socorro (paracetamol) em um tempo significativamente menor quando consumiram NE em comparação com naproxeno puro (3,7 horas e 6,7 horas, respectivamente). Não foram encontradas diferenças significativas nos pacientes do sexo masculino entre cada grupo de pesquisa. Em conclusão, o naproxeno melhorou o manejo da dor aguda pós-operatória quando comparado ao NE em mulheres, embora, ao longo de todo o estudo, a dor foi considerada leve após o uso de ambos os medicamentos em homens e mulheres com escores de dor em média bem abaixo de 40 mm na EAV. / Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to manage postoperative pain and inflammation in patients after oral and maxillofacial surgery, yet they are often associated with gastrointestinal problems. Recently the NSAID naproxen was introduced in combination with esomeprazole, a proton pump inhibitor that reduces stomach acid formation, in an effort to assuage these side effects. Using a double-blinded randomized crossover design, this study aimed to evaluate, for the first time, acute postoperative pain management in 46 volunteers who consumed a tablet of either naproxen (500 mg) with esomeprazole (20 mg) (NE) or only naproxen (500 mg) every 12 hours for 4 days after extractions of the two lower third molars, in two different appointments. Female volunteers reported significantly more pain at 1, 1.5, 2, 3 and 4 hours after surgery and also consumed their first rescue medication (acetaminophen) at a time significantly earlier when consuming NE when compared to naproxen (3.7 hours and 6.7 hours, respectively). No significant differences were found in the males between each research group. In conclusion, naproxen improved acute postoperative pain management when compared to NE in women although, throughout the entire study, pain was mild after the use of both drugs in both men and women with pain scores on average well below 40 mm on the VAS.