Zugl.: Bochum, Universiẗat, Diss., 2008.

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.

Made available in DSpace on 2014-06-11T19:22:13Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-02-20Bitstream added on 2014-06-13T20:09:08Z : No. of bitstreams: 1 batista_aap_me_botfm.pdf: 794304 bytes, checksum: fa2b18e42c88a75109fcc5e19ee952ff (MD5) / O presente trabalho teve como objetivo investigar os efeitos do parecoxibe, um antiinflamatório inibidor específico da COX-2, no intestino delgado e cólon do rato, pela medida da força de ruptura e avaliação morfológica intestinal. Foram utilizados 52 ratos distribuídos aleatoriamente, em um grupo controle constituído de 27 ratos que receberam solução fisiológica a 0,9% por via intramuscular (IM), na pata traseira direita em dose única diária por 4 dias; e em um grupo tratado, constituído por 24 ratos que receberam parecoxibe, na dose de 0,66 mg/ Kg de peso corpóreo, por via IM, na pata traseira direita, em dose única diária durante 4 dias. Todos os ratos foram sacrificados no 7o dia após início das injeções. No sacrifício foram retirados segmentos de intestino delgado e cólon de l 2 cm de extensão, para análise da força de ruptura e estudo microscópico. Os animais do grupo controle não apresentaram alterações no intestino delgado e cólon. Os fragmentos de cólon dos ratos tratados com parecoxibe tiveram a força de ruptura diminuída quando comparados com os do grupo controle. Na avaliação morfológica, o cólon dos ratos tratados com parecoxibe, mostrava-se com diminuição do número de glândulas caliciformes e com maior atividade mitótica do epitélio glandular. Assim, nas condições desse estudo experimental, concluímos que o parecoxibe diminui a força de ruptura e altera a morfologia do cólon. / Histological and mechanical alterations induced by parecoxib, a COX - 2 specific inhibitor non steroidal antiinflamatory, were studied. Fifty two rats were randomly assigned to 2 experimental groups: the first group with 27 rats, treated with saline 0,9% administrated IM for 4 days; the second group with 24 rats, treated with parecoxib, in a dose of 0,66 mg/kg of body weight IM for 4 days. All rats were sacrificed on day 7 of the follow-up. In the sacrifice day, segments of small intestine and colon were used to analyse breaking strength and histology. There were no histological and mechanical alterations in the first group. Colon segments from the rats treated with parecoxib had less breaking strength compared with control group. On histological evaluation, colon of rats from the second group showed less caliciform glands and bigger mitotic activity in glandular epithelium. We conclude that parecoxib decrease breaking strength and causes histological alterations in colon.

Resumo: O presente trabalho teve como objetivo investigar os efeitos do parecoxibe, um antiinflamatório inibidor específico da COX-2, no intestino delgado e cólon do rato, pela medida da força de ruptura e avaliação morfológica intestinal. Foram utilizados 52 ratos distribuídos aleatoriamente, em um grupo controle constituído de 27 ratos que receberam solução fisiológica a 0,9% por via intramuscular (IM), na pata traseira direita em dose única diária por 4 dias; e em um grupo tratado, constituído por 24 ratos que receberam parecoxibe, na dose de 0,66 mg/ Kg de peso corpóreo, por via IM, na pata traseira direita, em dose única diária durante 4 dias. Todos os ratos foram sacrificados no 7o dia após início das injeções. No sacrifício foram retirados segmentos de intestino delgado e cólon de l 2 cm de extensão, para análise da força de ruptura e estudo microscópico. Os animais do grupo controle não apresentaram alterações no intestino delgado e cólon. Os fragmentos de cólon dos ratos tratados com parecoxibe tiveram a força de ruptura diminuída quando comparados com os do grupo controle. Na avaliação morfológica, o cólon dos ratos tratados com parecoxibe, mostrava-se com diminuição do número de glândulas caliciformes e com maior atividade mitótica do epitélio glandular. Assim, nas condições desse estudo experimental, concluímos que o parecoxibe diminui a força de ruptura e altera a morfologia do cólon. / Abstract: Histological and mechanical alterations induced by parecoxib, a COX - 2 specific inhibitor non steroidal antiinflamatory, were studied. Fifty two rats were randomly assigned to 2 experimental groups: the first group with 27 rats, treated with saline 0,9% administrated IM for 4 days; the second group with 24 rats, treated with parecoxib, in a dose of 0,66 mg/kg of body weight IM for 4 days. All rats were sacrificed on day 7 of the follow-up. In the sacrifice day, segments of small intestine and colon were used to analyse breaking strength and histology. There were no histological and mechanical alterations in the first group. Colon segments from the rats treated with parecoxib had less breaking strength compared with control group. On histological evaluation, colon of rats from the second group showed less caliciform glands and bigger mitotic activity in glandular epithelium. We conclude that parecoxib decrease breaking strength and causes histological alterations in colon. / Orientador: Luis Eduardo Naresse / Coorientador: Oswaldo Melo da Rocha / Banca: Luis Eduardo Naresse / Banca: Shoiti Kobayasi / Banca: Luiz Roberto Montalar Verderesse / Mestre

No description available.

Background: There is a high incidence of moderate to severe postoperative pain in patients undergoing neurosurgery. Post-craniotomy headache (PCH) remains undertreated due to the cautious use of opioids in this surgical population. Various alternative analgesics such as acetaminophen and scalp blocks are widely utilized for the treatment of PCH, but this is often inadequate. Although a multimodal approach to the management of PCH may be effective in improved pain relief, only a limited number of randomized controlled trials have explored this. Aim: This study aims to investigate whether or not a multimodal analgesic regime, consisting of gabapentinoids and non-steroidal inflammatory drugs (NSAIDs) provides superior pain relief in patients undergoing elective craniotomy compared to the standard of care analgesia utilized at a local South African hospital. Methods: Twenty-seven patients, 18 years or older, scheduled for elective craniotomy for the management of their epilepsy were recruited into this clinical trial. Enrolled participants were randomized into one of two groups. The experimental group received oral 150mg pregabalin one hour before surgery, IV 40mg parecoxib at surgical closure, and oral 150mg pregabalin two hours after surgery. The control group received a matching placebo at these respective time points. Postoperatively, all patients received standard of care analgesia consisting of 24 hours IV paracetamol and additional analgesia as required (prn). Pain assessments using the numerical rating scale (NRS) and visual analogue scale (VAS) were performed at 1 hour, 8 hours, 24 hours, 48 hours and 72 hours postoperatively. Additional analgesia consumption, postoperative nausea and vomiting, as well as the incidence of any adverse events were captured. Results: Patients who received placebo showed an average trend of higher mean NRS pain scores compared to patients receiving pregabalin and parecoxib, although there was no significant difference (p = 0.218) in the maximum mean NRS pain scores between the experimental and control groups. However, patients who received pregabalin and parecoxib consumed significantly less dihydrocodeine than those who received placebo (p = 0.029). No significant differences were identified in use of other additional opioids and non-opioid analgesia during the first 24 postoperative hours. Conclusion: There is insufficient evidence to confirm that the perioperative use of pregabalin and parecoxib reduces PCH in patients undergoing elective craniotomy. The study medication did, however, result in a significant reduction in the use of postoperative dihydrocodeine, although it was also associated with higher rates of reported blurred vision and dizziness.

The duodenal mucosa is regularly exposed to acid, digestive enzymes and ingested noxious agents. It is thus critical to maintain a protective barrier to prevent the development of mucosal injury and inflammation, which are often observed in situations when barrier function is impaired. The rate of mucosal bicarbonate secretion, the regulation of epithelial paracellular permeability and motility are each key components of duodenal barrier function. The hormone melatonin is present in high levels in the gastrointestinal tract and it has been hypothesized that melatonin exerts protective properties. This thesis aims to investigate the impact of exogenous melatonin on the regulation of duodenal barrier function and motility in anesthetized rats in vivo. In addition, duodenal tissue was examined histologically and the expression levels of tight junction proteins and melatonin receptors were assessed with qRT-PCR. It was found that melatonin stimulated mucosal bicarbonate secretion and decreased basal paracellular permeability. Exposing the duodenal mucosa to the well-characterized barrier breaker ethanol increased mucosal bicarbonate secretion, paracellular permeability and motility. Omission of luminal Clˉ abolished, while pretreatment with a nicotinic receptor antagonist reduced, the ethanol-induced bicarbonate secretion suggesting that the secretory response to ethanol is meditated via Clˉ/HCO3ˉexchangers and enteric neural pathways. Melatonin reduced the ethanol-induced increases in paracellular permeability and motility either when injected intravenously or when administered in drinking water for two weeks. The actions of melatonin were abolished by the melatonin receptor antagonist luzindole and by nicotinic acetylcholine receptor inhibition. Two weeks oral administration of melatonin up-regulated the expression levels of melatonin receptors, down-regulated the expression of ZO-3 while the expression of ZO-1, ZO-2, claudin 2-4, occludin and myosin light chain kinase were unaffected. Superficial epithelial changes in a few villi were seen in response to ethanol exposure, an effect that was histologically unchanged by melatonin pretreatment. In conclusion, the results suggest that melatonin plays an important role in the neurohumoral regulation of gastrointestinal mucosal barrier function and motility via receptor- and enteric neural-dependent pathways in vivo in rats. Melatonin might be a candidate for treatment of barrier dysfunction in humans.

Orientador: Eliana Marisa Ganem / Resumo: Introdução: O parecoxibe, um pró-fármaco hidrolisado à valdecoxibe, é um antagonista da COX-2 com intensa atividade anti-inflamatória e analgésica. Embora muitos estudos tenham sido realizados indicando a eficácia dos antagonistas da COX em aliviar o processo da dor, quase nada foi estudado sobre a toxicidade desses fármacos no neuroeixo. Objetivos: O objetivo desta pesquisa foi avaliar os efeitos que diferentes doses de parecoxibe, administrado pela via subaracnoidea, em punção única, determinariam sobre a medula espinal e as meninges de coelhos. Metodologia: Após aprovação pela Comissão de Ética no Uso de Animais, 30 coelhos adultos jovens, da raça grupo genético de Botucatu, com pesos entre 2510 g e 3560 g, fornecidos pelo Biotério da Faculdade de Medicina de Botucatu, foram randomizados em três grupos: grupo S – solução salina a 0,9%, grupo P4 – parecoxibe (dose: 4 mg) e grupo P8 – parecoxibe (dose: 8 mg). Após a anestesia intravenosa com xilazina e cetamina os animais foram submetidos à punção subaracnoidea guiada por ultrassom, com agulha de Quincke 25G, no espaço entre primeira e a segunda vértebras sacrais e realizada a injeção de uma das soluções previamente sorteadas em volume de 0,4 mL (10 µL por centímetro de medula espinal medida entre a base do crânio e o espaço lombossacral). Após a recuperação da anestesia e por 21 dias, os animais foram avaliados quanto à sensibilidade e à motricidade. Em seguida, foram sacrificados por decapitação e retiradas as porções lomb... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: Parecoxib, a pro-drug that is hydrolyzed to valdecoxib, is a COX-2 antagonist with strong anti-inflammatory and analgesic activity. Although many studies have demonstrated the efficacy of COX antagonists in relieving pain, almost nothing is known about the toxicity of these drugs when administered into the neuraxis. Objectives: The aim of this study was to evaluate the effects of a single injection of different doses of parecoxib into the subarachnoid space on the spinal cord and meninges of rabbits. Methods: After approval by the Ethics Committee on Animal Use, 30 young adult rabbits of the Botucatu genetic group weighing 2,510 to 3,560 g, were randomized into three groups: group S - 0.9% saline; group P4 – parecoxib (dose: 4 mg); group P8 – parecoxib (dose: 8 mg). After intravenous anesthesia with xylazine and ketamine, the animals underwent ultrasound-guided subarachnoid puncture with a Quincke 25G needle in the space between the first and second sacral vertebrae and the injection of one of the previously established solutions was performed in a volume of 0.4 mL (10 µL per cm of spinal cord measured from the skull base to the lumbosacral space). After recovery from anesthesia, the animals were evaluated regarding sensitivity and motor function for 21 days. After this period, the animals were sacrificed by decapitation and the lumbar and sacral portions of the spinal cord and the roots of the cauda equina were removed for histological examination by light micros... (Complete abstract click electronic access below) / Doutor

The duodenal epithelium is regularly exposed to HCl, digestive enzymes, bacteria and toxins, and sometimes also to ethanol and drugs. The imbalance of aggressive factors in the intestinal lumen and mucosal barrier function increases the risk of tissue injury and inflammation. The key components of the duodenal barrier function include mucosal permeability, bicarbonate transport and the secretion or absorption of fluids. This thesis aims to elucidate the role of melatonin, neuropeptide S (NPS) and short chain fatty acids (SCFAs) in the regulation of intestinal mucosal barrier function and motility in the anesthetized rat in vivo and in tissues of human origin in vitro. Melatonin was found to reduce ethanol-induced increases in paracellular permeability and motility by a neural pathway within the enteric nervous system involving nicotinic receptors. In response to luminal exposure of ethanol, signs of mild mucosal edema and beginning of desquamation were observed in a few villi only, an effect that was not influenced by melatonin. Melatonin did not modify increases in paracellular permeability in response to luminal acid. NPS decreased basal and ethanol-induced increases in duodenal motility as well as bethanechol stimulated colonic motility in a dose-dependent manner. Furthermore, NPS was shown to inhibit basal duodenal bicarbonate secretion, stimulate mucosal fluid absorption and increase mucosal paracellular permeability. In response to luminal exposure of acid, NPS increased bicarbonate secretion and mucosal paracellular permeability. All effects induced by the administration of NPS were dependent on nitrergic pathways. In rats, administration of NPS increased the tissue protein levels of the inflammatory biomarkers IL-1β and CXCL1. Immunohistochemistry showed that NPS was localized at myenteric nerve cell bodies and fibers, while NPSR1 and nNOS were only confined to the myenteric nerve cell bodies. Perfusing the duodenal segment with the SCFAs acetate or propionate reduced the duodenal mucosal paracellular permeability, decreased transepithelial net fluid secretion and increased bicarbonate secretion. An i.v. infusion of SCFAs reduces mucosal paracellular permeability without any effects on mucosal net fluid flux. However, it significantly decreased bicarbonate secretion. Luminal SCFAs changed the duodenal motility pattern from fasting to feeding motility while i.v. SCFAs was without effect on motility. The systemic administration of glucagon-like peptide-2 (GLP-2) induced increases in mucosal bicarbonate secretion and fluid absorption. An i.v. GLP-2 infusion during a luminal perfusion of SCFAs significantly reduced the duodenal motility. In conclusion, the results in the present thesis show that melatonin, NPS and SCFAs influence the neurohumoral regulation of intestinal mucosal barrier function and motility. Aberrant signaling in response to melatonin, NPS and to luminal fatty acids might be involved in the symptom or the onset of disease related to intestinal dysfunction in humans. / <p>Research funders and strategic development areas:</p><p>- Bengt Ihre Foundation (grant SLS-177521)</p><p>- Socialstyrelsen(grant SLS-176671)</p><p>- Erik, Karin, and Gösta Selanders Foundation</p><p>- Emil and Ragna Börjesson Foundation</p><p>- Uppsala University </p><p>- Ministry of Education of Malaysia</p><p>- Universiti Malaysia Sabah, Malaysia</p>

Abdominal surgery inhibits gastrointestinal motility, a phenomenon referred to as postoperative ileus. Since the postoperative ileus disturbs duodenal physiology it is important to minimize the side effects of this condition. Recent experiments in our laboratory show that treatment of anaesthetised rats with parecoxib, a selective cyclooxygenase-2 inhibitor, prevents duodenal postoperative ileus, increases duodenal mucosal bicarbonate secretion and improves other functions as well. One aim of the thesis was to investigate whether removal of luminal chloride affect the parecoxib- and the vasoactive intestinal peptide (VIP)-induced stimulation of duodenal mucosal bicarbonate secretion. The proximal duodenum of anaesthetised Dark Agouti rats was perfused with isotonic solutions containing zero or low Cl- and the effect on luminal alkalinisation determined. The basal as well as the parecoxib-induced increase in alkalinisation, but not that stimulated by VIP, were markedly reduced in the absence of luminal Cl-. One important function of the duodenum is to adjust luminal osmolality towards that in the blood. It is believed that the adjustment of osmolality in the duodenum is achieved by osmosis and diffusion of electrolytes along their concentration gradients and that these processes occur predominately paracellularly. Another aim of the thesis was to examine whether prevention of postoperative ileus affects the duodenal response to luminal hypertonicity. The proximal duodenum of anaesthetised Dark Agouti and Sprague-Dawley rats were perfused with hypertonic solutions of different composition and osmolality and the effects on duodenal motility, alkaline secretion, transepithelial fluid flux, mucosal permeability and the adjustment of luminal osmolality were determined in absence and presence of parecoxib. It is concluded that COX-2 inhibition increases duodenal mucosal bicarbonate secretion by stimulating apical Cl-/HCO3- exchange in duodenocytes. Furthermore, pretreatment of anaesthetised rats with parecoxib improves a number of duodenal functions in both rat strains that contribute to improve the ability to adjust luminal osmolality. The choice of rat strain is another important feature to consider when interpreting the results because the DA strain was more responsive to luminal hypertonicity than the SD strain. Finally, several evidences are provided to suggest that the adjustment of luminal osmolality in the rat duodenum is a regulated process.