- 4 - Abstract The aim of this study was to carry out phytoextraction experiments using corn plants (Zea mays) and determine the phytoextraction efficiency for specific non-steroidal anti- inflammatory drugs and carbamazepine and their combinations. After 10 days of growth, a nutrient solution containing ibuprofene, naproxene, diclofenac and carbamazepine in concentrations ranging from 5 to 10 mg/L was added to hydrophonically cultivated plants. Nutrient solution samples were taken every 24 hours and the samples were then analysed using a HPLC/DAD system. At the end of the experiment, the experimental plants and roots were analysed for extractable residua using HPLC/DAD + FLD. The greatest phytoextraction efficiency was found for ibuprofene. The second and third most effective extraction was observed for naproxene and diclofenac, depending on the evaluation criteria. The lowest phytoextraction efficiency was observed for carbamazepine. With multi-component experiments, lower phytoextraction efficiency was found out for all substances with the exception of ibuprofene in combination with diclofenac and carbamazepine. The toxic impact of ibuprofene on plant transport mechanisms was also proven. The extractable residua analysis confirmed the ibuprofene's toxicity on plant transport mechanisms and also the...

Os antiinflamatórios não esteroidais (AINEs) constituem um grupo de medicamentos de uso rotineiro na terapêutica clínica, principalmente no tratamento do processo inflamatório e doloroso. O efeito colateral mais comum constatado pelo seu uso é a irritação da mucosa gástrica. A atividade ulcerogênica dos AINEs tem variabilidade diária, uma vez que quando administrados à noite, são melhor tolerados que durante o dia. Tal observação chama a atenção para a possível ação do hormônio pineal, melatonina, sintetizado no período de escuro, tanto por animais de hábitos noturnos como diurnos. No presente estudo foram investigados os efeitos da administração de melatonina sobre a atividade antiinflamatória e lesão gástrica induzida pelo piroxicam e o efeito da melatonina e do piroxicam sobre a síntese de PGE2 pela mucosa gástrica, testando esse hormônio nos seguintes modelos: edema de pata de rato induzido por carragenina, lesão da mucosa gástrica induzida pelo piroxicam e determinação da síntese de PGE2 por enzima-imunoensaio (EIA). A administração intragástrica de melatonina não alterou o efeito aniinflamatório do piroxicam, mas inibiu o efeito colateral ulcerogênico. O efeito antiulcerogênico da melatonina foi observado após administração intragástrica, mas não após a administração subcutânea. As diferenças observadas entre as duas vias de de administração sugere um efeito local desse hormônio sobre a mucosa gástrica. O efeito antiulcerogênico da mealtonina intragástrica esta relacionada à prevenção da inibição da produção der PGE2 da mucosa gástrica pelo piroxicam. A pinealectomia aumentou o efeito ulcerogênico da adminstração noturna de piroxicam. Mesmo utilizando fenilbutazona, que é um AINEs ulcerogenicamente mais potente, no período da manhã, quando o efeito ulcerogênico dos AINEs parece ser acentuado, a melatonina administrada intragastricamente promoveu proteção da mucosa gástrica. Por outro lado, a melatonina administrada intragastricamente não interferiu com ulceração induzida pelo estresse, sugerindo que o efeito antiulcerogênico da melatonina está relacionado mais especificamente com fatores importantes na patogênese da lesão gástrica induzida pelos AINEs (piroxicam e fenilbutazona) em ratos, prevenindo a inibição da síntese de PGE2 da mucosa gástrica induzida pelo piroxicam, sem afetar a ação antiinflamatória. / Non-steroidal antiinflammatory drugs are, the most frequently consumed drugs worlwide. They also cause gastrointestinal adverse effects, like gastric ulceration and bleedig. Several reports indicate that, both antiinflammatory effect and the susceptibility to mucosal damage produced by NSAIDs in rats and humans show a circadian variation. Nighttime administration of NSAIDs is better tolerated than morning administration in human and rats. Melatonin, the principal hormone of the pineal gland is secreted at night both in nocturnal and diurnal animals. The purpose of this experiment was to study the effect of melatonin on the antiinflammatory action and gastric mucosal damage induced by piroxicam and the effect of melatonin and piroxicam on the gastric mucosal prostaglandin E2 (PGE2) synthesis. Intragastric administration of melatonin significantly attenuated the gastric lesions induced by piroxicam, but, did not entiinflammatory action accessed by measuring paw edema after carrageenin adminstration. Melatonin anti-ulcerogenic effect was observed after intragastric, but not subcutaneus administration. The differences observed between the two administration routes point to a local effect of the hormone on the stomach mucosa. Pinealectomy increases the ulcerogenic effect of nocturnal administred piroxicam. The anti-ulcerogenic effect of intragastric melatonin was related to prevention of the inhibition of gastric mucosal PGE2 production induced by piroxicam. Indeed, intragastric administration of melatonin protect the gastric mucosa damage induced by effect on stress-induced gastric ulceration. These data suggest that melatonin may attenuate the severity of NSAID-induced gastric mucosal lesions in rats by preventing NSAID-induced inhibition of mucosal PGE2 production whithout affecting th anti-inflamamtory action.

Anti-inflammatory drugs are a widely used class of therapeutic agents, but the use of non-steroidal anti-inflammatory drugs (NSAID) is hampered by their gastrointestinal side-effects. Recent reports that cyclooxygenase-2 inhibitors may cause cardiovascular events underline the importance of identifying new therapeutic strategies for the treatment of inflammation. One such target could be agents modifying the endogenous cannabinoid (endocannabinoid) system, since there is evidence that this system plays a role in our natural defence against inflammation. The levels of the endocannabinoid anandamide (arachidonoyl ethanolamide, AEA) are low under normal conditions, and stand under strict regulatory control of synthesising and degrading enzymes. Fatty acid amide hydrolase (FAAH) is the main enzyme degrading AEA, hydrolysing it to ethanolamine and arachidonic acid. The focus of this thesis lies in exploring the pharmacology of FAAH to evaluate its possibilities as a target for new anti-inflammatory drugs. In Papers I and II, the effects of the ambient pH on the properties of FAAH were investigated, since tissue pH is known to decrease under inflammatory conditions. In homogenates, it was found that the activity of FAAH decreased as the assay pH was decreased, consistent with the known pH profile of the enzyme. More importantly, the sensitivity of the enzyme to inhibition by FAAH inhibitors changed. In particular, the sensitivity of the enzyme to inhibition by the NSAID ibuprofen increased seventeen-fold as the assay pH decreased from 8.37 to 5.28. A similar pattern was found using intact C6 glioma cells when the extracellular, but not the intracellular pH was reduced. Thus, at an extracellular pH value of 6.2, (R)-ibuprofen, (S)-flurbiprofen and (R,S)-flurbiprofen inhibited the metabolism of AEA with IC50 values of 26, 14 and 15 µM, respectively. These values are in theory reachable upon normal dosing of the compounds. In Paper III, the effect of the selective FAAH inhibitor URB597 and the NSAID indomethacin were investigated in vivo upon the oedema response to carrageenan administration in the paw of anaesthetised mice. Both compounds reduced the oedema in a manner completely blocked by the CB2 receptor antagonist SR144528. In Paper IV, the effect of inflammation upon endocannabinoid synthesis was investigated in mice. Lipopolysaccharide-induced pulmonary inflammation was found not to affect the release of AEA to any obvious extent, and did not change the activities of the AEA synthesising enzymes N-acyl transferase or N-acyl phosphatidylethanolamine phospholipase D, or of FAAH in lung tissue. The results of this thesis would suggest that FAAH inhibitors can produce anti-inflammatory effects, and that the endocannabinoid system contributes to the actions of the NSAID indomethacin in the carrageenan model of inflammation, but that an increased endocannabinoid synthesis (a prerequisite for FAAH inhibition as a therapeutic strategy) is not an obligatory response to an inflammatory stimulus.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Die vorliegende Arbeit überprüft vergleichend die Wirksamkeit der NSAID Flunixin und Ketoprofen in der unterstützenden Therapie bei Rindern nach Schwergeburten auf hämatologische und klinisch-chemische Parameter. Sie fokussiert sich dabei auf Parameter, welche für die Einschätzung einer endotoxämischen Belastung von Relevanz sind. Besondere Bedeutung kommt hierbei dem Haptoglobin und dem CRP zu, da bislang keine Untersuchungen zum Einfluss von NSAID auf Akute-Phase-Proteine beim Rind vorliegen.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Acute synovitis and capsulitis are common articular problems and can contribute to the development of a degenerative process due to the release of enzymes and inflammatory mediators. The indicated treatment for synovitis and capsulitis is based on anti-inflammatory drugs. An experimental synovitis model was used in ponies to evaluate the effect of parecoxib, a selective ciclo-oxygenase 2 anti-inflammatory drug. Cardiac (FC) and respiratory frequency (FR) and rectal temperature (T) were determined. The ponies also had their stride length (CP), carpal joint angle at rest (AR), angle of maximum flexion (AFM), joint circumference (CA), carpal effusion degree (GE) and lameness degree (GC) evaluated. The analysis of the synovial fluid included cytology, protein, mucin precipitation quality and viscosity. After synovitis induction with Freund s complete adjuvant, three ponies were treated with 0,55mg/kg/day IV parecoxib, and three received sterile 0,9% saline solution (IV) for five days. Clinical and synovial fluid parameters were evaluated before synovitis induction, immediately before treatment and 12, 24, 48, 96 and 120 hours after the first treatment. Induced synovitis findings were similar to natural occurring ones. Repeated artrocentesis increased protein in the synovial fluid, but did not modify the other evaluated parameters of the healthy joints. Synovial fluid parameters were not affected by parecoxib treatment. Protein amount and total leukocyte count increased and remained high up to 120 hours of the beginning of treatment, and the viscosity and mucin precipitation quality decreased in synovitis induced joints. The intra-articular injection of Freund s complete adjuvant induced a moderate to serious synovitis. Significant increases in T, FC, GC and GE and reduction of AFM and CP occurred in the synovitis control group. Treated ponies showed GC reduction, maintenance of the AFM, CP, T and FC and attenuation of GE. Although the used dosage of parecoxib had no effect on evaluated synovial fluid parameters, analgesic, antipyretic and anti-inflammatory effects were observed. / Sinovite e capsulite agudas são problemas comuns em algumas articulações e podem resultar em um processo degenerativo pela liberação de enzimas e mediadores inflamatórios. O tratamento recomendado nestes casos são os antiinflamatórios não esteroidais (AINEs). Com o objetivo de avaliar o efeito do parecoxib, um AINE seletivo para cicloxigenase 2 injetável, foi usado um modelo experimental de sinovite em pôneis. No exame clínico geral foi determinada a freqüência cardíaca (FC) e respiratória (FR) e a temperatura retal (T). No exame clínico específico foram avaliados o comprimento do passo (CP), ângulo do membro em repouso (AR), ângulo de flexão máxima (AFM), circunferência articular (CA), grau de efusão carpal (GE) e grau de claudicação (GC). A análise do líquido sinovial foi realizada através da citologia, concentração de proteína, qualidade do precipitado da mucina e viscosidade. Cinco dias após indução da sinovite com adjuvante completo de Freund, três pôneis foram tratados com 0,55mg/kg/dia de parecoxib (IV) e três receberam solução fisiológica estéril 0,9% (IV) por cinco dias. A avaliação dos parâmetros clínicos gerais e específicos, e das características celulares e bioquímicas do fluido sinovial foi realizada antes da indução de sinovite, imediatamente antes do tratamento e 12, 24, 48, 72, 96 e 120 horas após início do tratamento. A sinovite induzida neste experimento foi semelhante a uma sinovite naturalmente ocorrida. A artrocentese repetida, apesar de contribuir para o aumento da proteína no fluido sinovial, não modificou significativamente os outros parâmetros avaliados das articulações sadias. O tratamento com parecoxib não influenciou significativamente os parâmetros do líquido sinvovial, pois a quantidade de proteína e de leucócitos totais aumentou, e a qualidade da viscosidade e da precipitação da mucina diminuiu com a indução da sinovite, permanecendo sem alteração até 120 horas após o início do tratamento. A injeção intra-articular com adjuvante completo de Freund, induziu uma sinovite de intensidade moderada a grave. Ocorreram aumentos significativos na T, FC, GC e GE e diminuição do AFM e CP no grupo controle. Já os pôneis tratados com parecoxib apresentaram diminuição do GC, manutenção do AFM, CP, T e FC e atenuação do GE articular. Portanto, embora o parecoxib, na dose utilizada, não tenha apresentado efeito sobre os parâmetros do líquido sinovial das articulações com sinovite, sua ação antipirética, antiinflamatória e analgésica foi documentada.

No description available.

Icke-steroida antiinflammatoriska läkemedel (NSAID) är ett samlingsnamn för olika antipyretiska, analgetiska och antiinflammatoriska läkemedel och är bland de mest använda läkemedlen i världen. Dock kan användning av NSAID leda till magsår. I denna litteraturstudie undersöks effekten av PPI respektive H2RA vid behandling och förebyggande av NSAID-inducerat magsår. Med hjälp av databasen PubMed valdes fem kliniska studier ut. De rapporterade resultaten analyserades noga och sammanställdes. Resultatet i de olika studierna tyder på att PPI är 5 till 15 % mer effektiv än H2RA med avseende på effekt vid behandling av NSAID-inducerat magsår och att PPI är 10 % mer effektiv än H2RA med avseende på effekt vid förebyggandet av NSAID-inducerat magsår. / Non-steroidal anti-inflammatory drug (NSAID) is a collective name for various antipyretic, analgesic and anti-inflammatory drugs and are among the most used drugs in the world. However, the use of NSAIDs can lead to gastric ulcers. In this literature study, the effects of PPI and H2RA, respectively, in the treatment and prevention of NSAID-induced gastric ulcer are studied. Five clinical studies were selected using the PubMed database. The reported results were carefully analyzed and compiled. The results in the different studies indicate that PPI is 5 to 15% more effective than H2RA in terms of efficacy in the treatment of NSAID-induced gastric ulcer and that PPI is 10% more effective than H2RA in terms of efficacy in the prevention of NSAID-induced gastric ulcer.

Over the last decade, three species of Gyps vultures on the Asian subcontinent have declined dramatically in population numbers, some as much as 97 to 99%. Although the initial cause was believed to be infectious, it was later shown to be due to an inadvertent exposure to diclofenac via the food chain. In order to protect the remaining wild vultures, diclofenac needed to be removed from the food chain. Unfortunately the Indian government was reluctant to ban diclofenac until an alternate veterinary non-steroidal anti-inflammatory drug (NSAID) that was both safe in vultures and effective in cattle could be identified. Although meloxicam was tentatively identified as this drug, toxicity testing still needed to be undertaken. Using a previously validated model, two studies were undertaken to determine the acute toxic effect of diclofenac in vulture as well as to ascertain if the drug had the potential to accumulate. In the first study, meloxicam in formulation was shown to be safe as a single oral dose up to 2mg/kg in African White Backed-Vultures (Gyps africanus). To further demonstrate the safety of food borne meloxicam, vultures were exposed to meat rich in meloxicam residues, with once again no signs of toxicity being evident. In the second study the drugs ability to accumulate was evaluated pharmacokinetically in Cape Griffon Vultures (Gyps corprotheres). From this study meloxicam was shown to have a very short half-life of elimination, making it unlikely that the drug could be a cumulative toxin. This was subsequently confirmed clinically by the absence of toxicity in birds receiving repeated doses of meloxicam. Although meloxicam was shown to be adequately safe, the safety of other veterinary NSAIDs still required elucidation. While further testing in vultures would have been possible, the small population size of the various vulture species made this unethical. Therefore a surrogate species needed to be identified. With the domestic chicken (Gallus domesticus) being commonly available, attempts were made to validate the chicken as a model. Although the dosed chickens did show similar toxicity patterns from clinical pathology to histopathology, a major problem was their higher tolerance making it impossible to use them as a surrogate. It was, however, concluded that the domestic chicken may be used in mechanistic studies in an attempt to establish an in vitro model. From the mechanistic studies both diclofenac and meloxicam were directly toxic to chicken and vulture renal tubular epithelial cells following 48h of incubation. It was later shown that this toxicity was associated with an increased production of reactive oxygen species (ROS), which could be temporarily ameliorated by pre-incubation with uric acid due to its anti-oxidant activity. When cultures were incubated with either drug for only two hours, meloxicam showed no toxicity in contrast to the cellular toxicity present for diclofenac. In both cases no increase in ROS production was evident. In addition diclofenac influenced the excretion of uric acid by interfering with p-amino-hippuric acid channels. The effect on uric acid excretion persisted after the removal of the diclofenac. It was therefore concluded that vulture susceptibility to diclofenac results from a combination of an increase in cellular ROS, a depletion of intracellular uric acid concentration and most importantly the drug’s long half-life in the vulture. Unfortunately the importance of the drug’s half-life in the toxicodynamics makes it unlikely that in vitro testing will be possible. / Thesis (PhD (Paraclinical Sciences))--University of Pretoria, 2007. / Paraclinical Sciences / unrestricted

NSAIDs depress prostaglandins synthesis through inhibition of COX-1 that is involved in maintaining cell integrity and COX-2 that, although presents particularly in the kidneys, is overexpressed in response to inflammation. Both the beneficial and side effects of NSAIDs are, therefore, through their inhibition of COX enzymes. Introduction of COX-2-selective inhibitors has improved the safety profile of the drugs with regard to their most common side effect which occurs at the gastrointestinal level but has not rendered them less cardio-nephrotoxic. Renal side effects of NSAIDs are rare, sometimes transient and often reversible upon drug withdrawal. The incident rate and the severity of the renal side effect, however, increase in patients with risk factors such as those with diabetes, heart failure, renal dysfunction and in the elderly. The side effects range from electrolyte retention and reduce glomerular filtration to nephritic syndrome and chronic renal failure. These effects are shared among NSAIDs with evidence of dose and exposure dependency. There is no known predictor for the nephrotoxicity. However, a relationship has been found between high plasma concentration and the renal adverse effect of NSAIDs. The usefulness of therapeutic drug monitoring in patients with risk factors needs to be explored.