Introduktion: Knäartros är en degenerativ och låggradig inflammationssjukdom, som ungefär 22,9 % av alla över 40 år lider av. Det drabbar oftare kvinnor än män, och risken ökar vid bland annat fetma samt tidigare ledskador. Vid artros sker en skada på osteoblaster, kondrocyter och synoviocyter som stimulerar frisättning av tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) samt matrixnedbrytande enzymer. Detta resulterar i smärta, ledsvullnad och degenerering av leden. Diagnos ställs genom klinisk undersökning med hjälp av exempelvis American College of Rheumatology (ACR)-kriterier. Detta kompletteras ofta med radiologisk undersökning och ibland används ett självskattningsformulär som exempelvis Western Ontario and McMaster Universities Arthritis Index (WOMAC). I WOMAC innebär en minskning av värdet en förbättring av den kliniska parametern. Artros behandlas till en början med non-steroidal anti-inflammatory drugs (NSAID)-preparat och paracetamol, mot inflammation och smärta. Curcuma longa (C. longa) även kallat gurkmeja har använts vid matlagning och traditionell medicin i nära 2500 år. Den mest aktiva enheten i C. longa är polyfenolen curcumin som utvinns från dess rhizomer. Den har visat sig vara bland annat anti-inflammatorisk och antioxidantisk, båda dessa egenskaper är viktiga vid behandling av knäartros. Curcumins biotillgänglighet är låg, men det utförs och har utförts studier för att finna formuleringar som höjer biotillgängligheten. På så vis kan effekten förbättras. Verkningsmekanismen för curcumin är inte helt klarlagd men tidigare studier tyder på att den exempelvis kan minska oxidativ stress och minska koncentrationerna av inflammatoriska biomarkörer som TNF-α, IL-1β och IL-6. Syfte: Om curcumin kan användas som ett substitut till standardbehandlingen med NSAID-preparat och paracetamol som inflammationshämmande och smärtlindrande, vid behandling av knäartros. Metod: Detta examensarbete är en litteraturstudie, sökningarna utfördes i databasen PubMed och Linnéuniversitetets Onesearch. Totalt valdes fem studier ut med kriterierna att studien skulle vara max 10 år, vara en klinisk studie samt att den primära utfallsvariabeln skulle involvera förändringar i WOMAC. Resultat: I fyra av studierna blev resultatet en statistisk signifikant minskning i kategorin WOMAC-fysisk funktion. I tre av studierna blev det en statistiskt signifikant minskning i WOMAC-smärta och i två av studierna blev det en statistiskt signifikant minskning i WOMAC-stelhet. I tre av studier minskade användningen av akutläkemedel i form av NSAID eller paracetamol varav en studie hade en statistiskt signifikant minskning jämfört med kontrollgruppen. Slutsats: Resultaten tyder på att curcumin kan vara effektiv som behandling vid knäartros. Den har visat sig ha både anti-inflammatoriska egenskaper och en smärtstillande effektt vilket tyder på att det skulle kunna vara möjligt att använda som substitut till NSAID och paracetamol. För att kunna fastställa att curcumin är en säker och effektiv behandling finns ett behov av fler och större studier.

Introduction Oral Non-steroidal anti-inflammatory drugs (NSAID) is an analgesia and is commonly used by people with osteoarthritis (OA). Oral NSAID is currently recommended as the second level of treatment for OA, and could be considered if physical activity, topical NSAID or paracetamol do not supply sufficient pain relief.   Aim To investigate how frequently oral NSAID is used in a sample of New Zealanders with OA and also to investigate the exposure to heightened risk of adverse events while using oral NSAID.   Method A cross-sectional survey was conducted to collect information about the use of oral NSAID by people with self-reported OA. The survey included 75 participants who were over the age of 45 with an average age of 70.6 years.   Results While having OA, 57,3% of the sample reported oral NSAID use. The results also show that 52% of the participants with cardiovascular (CV), gastrointestinal (GI) or renal comorbidities used oral NSAID, and 17,3% of them also combined that NSAID with medication for their comorbidity. Concerning the heightened risks of adverse events, 21% of the participants did acquire the analgesia over the counter (OTC), and 76,6% stated that they were over the age of 65.    Conclusion A majority of the participants in the study with self-reported OA take NSAID as an analgesia. Also, the study shows that NSAID is commonly used among participants with co-morbidity, which is similar to figures presented in previous studies in the area. However, the small sample size limits its generalizability to a larger population. / Introduktion Orala icke-steroida antiinflammatoriska läkemedel (NSAID) är en grupp smärtstillande mediciner som är vanligt använt av personer mer artros. Orala NSAID-preparat rekommenderas idag som en andrahandsbehandling och kan övervägas om fysisk aktivitet, topikala NSAID-preparat eller paracetamol inte ger tillräcklig smärtlindrande effekt.   Syfte Att undersöka hur vanligt användandet av orala NSAID-preparat är i ett stickprov av personer med artros i Nya Zeeland samt att undersöka exponering av orala NSAID-preparat i subgrupper med ökad risk för biverkningar vid användande av orala NSAID-preparat.   Metod En tvärsnittsstudie genomfördes för att samla in information kring användning av orala NSAID-preparat av personer med självrapporterad artros. Studiepopulationen bestod av 75 personer över 45 års ålder med en medelålder på 70,6 år.   Resultat 57,3% av deltagarna använder orala NSAID-preparat som behandling för sin självrapporterad artros. Gällande subgrupper med ökad risk för biverkning av NSAID användning visar studien att 52% av deltagare med kardiovaskulära, gastrointestinala eller njurpåverkade sjukdomar använder orala NSAID-preparat och av dessa kombinerar 17,3% NSAID-preparaten med medicin för sin samsjuklighet. Av deltagarna som uppgav att de använder orala NSAID-preparat erhåller 21% av dessa NSAID-preparaten receptfritt över disk. Av deltagare som var 65 år eller äldre uppgav 76,6% att de använder orala NSAID-preparat för behandling av artros.   Slutsats En majoritet av deltagarna med självrapporterad artros tar orala NSAID-preparat i smärtstillande syfte för sin artros. Studien visar också att NSAID ofta används bland deltagare med samsjuklighet, vilket motsvarar presenterade siffror från tidigare studier inom området. Den lilla stickprovsstorleken begränsar emellertid studiens generaliserbahet gentemot en större population.

Contexte – Les cancers de la prostate, du sein, et colorectaux sont parmi les cancers les plus fréquents dans les pays développés, et, même si plusieurs facteurs de risque sont aujourd’hui bien établis pour ces cancers, leur étiologie reste encore largement à expliquer. L’inflammation chronique est fortement suspectée de jouer un rôle dans la survenue de ces cancers et la présence, dans les tissus tumoraux, d’infiltrats inflammatoires localisés pouvant être considérés comme des lésions précancéreuses, contribue à renforcer l’hypothèse d’un lien possible entre inflammation chronique et cancers. Dans ce contexte, de nombreuses études épidémiologiques se sont intéressées au rôle des Anti-Inflammatoires Non Stéroïdiens (AINS) dans les cancers. En effet, les médicaments ayant des propriétés anti-inflammatoires comme les AINS, dont l’aspirine, et les anti-inflammatoires inhibiteurs sélectifs de la cyclo-oxygénase 2 (COX-2), pourraient diminuer le risque de survenue de ces cancers.Objectifs – L’objectif général de cette thèse a été d’étudier le rôle de la consommation d’AINS, dont l’aspirine, les AINS usuels et les inhibiteurs sélectifs de la COX-2 dans la survenue des cancers de la prostate, du sein et colorectaux.Population et méthodes – Ce travail s’est appuyé sur les données de l’Echantillon Généraliste des Bénéficiaires (EGB) de l’Assurance Maladie pour les trois cancers d’intérêt et sur les données d’une étude cas-témoins réalisée en population générale dans le département de l’Hérault (EPICAP) pour le cancer de la prostate. Pour les données de l’EGB, une cohorte fixe de 426 410 personnes présentes au 1er janvier 2007 a permis d’identifier les cas incidents entre 2008 et 2012 à partir de différents algorithmes. L’exposition aux AINS a été identifiée à partir du 1er janvier 2005 jusqu’à la date de fin d’observation : date de survenue du cancer, date de décès ou date de censure fixée au 31 décembre 2012. Un temps de latence d’au moins un an a été défini entre l’exposition aux AINS et la survenue du cancer d’intérêt. Pour les données d’EPICAP, 819 cas incidents de cancer de la prostate et 879 témoins de population générale, de même âge en moyenne que les cas, ont été interrogés en face-à-face, à l’aide d’un questionnaire standardisé, notamment sur leur consommation d’AINS.Résultats – A partir de la cohorte issue de l’EGB, des résultats préliminaires montraient une augmentation du risque de cancer de la prostate (RR=1,30 [1,17-1,46]) et du sein (RR=1,29 [1,14-1,46]) chez les patients exposés aux AINS et une absence d’association pour les cancers colorectaux (RR=0,92 [0,82-1,05]). En revanche, une association négative était observée pour les cancers de la prostate (RR=0,85 [0,74-0,96]) et colorectaux (RR=0,77 [0,66-0,90]) lorsque le temps de latence considéré était de six ans. L’étude EPICAP a montré que la consommation d’AINS était associée négativement au cancer de la prostate (OR=0,77 [0,61-0,98]). Cette association était plus prononcée pour une fréquence de consommation quotidienne (OR=0,75 [0,33-0,92]) ou d’une consommation pluriquotidienne (OR=0,38 [0,18-0,79]), et pour une durée entre 5 à 10 ans (OR=0,55 [0,33-0,92]). L’association était renforcée pour une molécule ayant une activité anti-COX-2 préférentielle (OR=0,48 [0,28-0,79]). Enfin, une association négative était également observée pour les cancers de la prostate de haut grade (Gleason score =7 (4+3) ou GS>7) avec un OR de 0,62 [0,41-0,95].Conclusion – L’ensemble de ce travail de thèse a montré que la consommation d’AINS semblait être associée négativement à la survenue du cancer de la prostate et aux cancers colorectaux. Pour le cancer de la prostate cette thèse s’est appuyée sur deux bases de données et deux méthodologies différentes, permettant d’appréhender les limites et les forces de chacune. / Background – Prostate, breast, and colorectal cancers are among the most common cancers in developed countries. Many risk factors have been identified over the years but could explain only a part of the new cases. Chronic inflammation is highly suspected to play a role in the carcinogenesis of those cancers and the presence of inflammatory infiltrate in tumoral tissue, considered as precancerous lesions, reinforced this hypothesis. In this context, several epidemiological studies have investigated the potential role of Non-steroidal anti-inflammatory drugs (NSAIDs) in cancer occurrence. Indeed, NSAIDs such as aspirin and non-aspirin NSAIDS including selective inhibitors of cyclo-oxygenase 2 (COX-2) may decrease the incidence of those cancers.Objectives – The main objective of the thesis was to investigate the role of NSAIDs use including aspirin, non-aspirin NSAIDs and selective inhibitors of COX-2 in the occurrence of prostate, breast and colorectal cancers.Population and methods – This work was based on the General Sample of health insurance Beneficiaries (EGB) for the three localizations of cancer and on the data of a population-based case-control study carried out in the département of Herault (EPICAP) for prostate cancer. In the EGB study, a cohort of 426 410 persons present in the database in January 1st, 2007 allowed to identify incident cases between 2008 and 2012 based on different algorithms. Exposure to NSAIDs was determined from January 1st, 2005 until the end of the follow up defined as either cancer incident date, date of death, or censure date fixed as December 31st, 2012. A latency of at least one year between the beginning of exposure to NSAIDs and the cancer occurrence was taken into account. For the EPICAP study, 819 incident prostate cancer cases and 879 population-based controls, frequently matched by age to the cases, were face-to-face interviewed using a standardized questionnaire, specifically on their NSAIDs use.Results – From the EGB cohort, preliminary results showed a positive association between all NSAIDs use and prostate or breast cancer occurrence (RR=1,30 [1,17-1,46], RR=1,29 [1,14-1,46], respectively), while no association was found with colorectal cancer occurrence (RR=0,92 [0,82-1,05]). These associations became negative associations when a latency of six years was taken into account in prostate and colorectal cancer (RR=0,85[0,74-0,96], RR=0,77 [0,66-0,90], respectively). In the EPICAP study, NSAIDs use was negatively associated with prostate cancer (OR=0,77 [0,61-0,98]). This association was more pronounced with daily intake (OR=0,75 [0,33-0,92]) or more than once a day (OR=0,38 [0,18-0,79]), and for a duration of five to ten years (OR=0,55 [0,33-0,92]). The negative association was reinforced for preferential anti-COX-2 NSAIDs (OR=0,48 [0,28-0,79]), and for patient with high grade prostate cancer (Gleason score, GS=7 (4+3) or GS>7 : OR=0,62 [0,41-0,95]).Conclusion – This work showed that NSAIDs use was negatively to prostate and colorectal cancer occurrence. For prostate cancer, this thesis was based on two different databases (a medical and administrative database and a case-control study) and used two different methodologies, allowing comparison about strengths and limits of both.

No description available.

As one of the most common medications, it is reasonable to assume that the adverse effects from nonsteroidal anti-inflammatory drugs (NSAIDs) are well understood. While this is the case for NSAID-induced gastropathy, NSAID-induced enteropathy is often clinically overlooked and has a pathogenesis that is incompletely understood. The goal of this study was to determine how alterations in the microbiota impact NSAID-induced intestinal injury. Initial studies explore how gastric acid secretion suppression substantially decreases Bifidobacteria in the small intestine, and emphasize how replenishment of these bacteria results in an amelioration of NSAID-induced enteropathy. Follow-up studies involved pretreating rats with specific bacteria that have conferred protection in other models of small intestinal injury. We examined the role that acetate may play in reducing the damage by evaluating bacteria that had an acetate production gene knocked out via homologous recombination. Protection levels were similar between wildtype and knockout bacteria, and it did not appear that acetate had a key role in damage reduction. Moreover, we found that changes in intestinal damage were dependent not only on the strain of bacteria used but also on the NSAID administered. None of the bacterial pretreatments tested protected against indomethacin- or diclofenac-induced small intestinal injury, and pretreatment with one specific bacterial strain resulted in a significant worsening of damage. To gain further insight as to the potential role of the microbiota in exacerbation of injury, we conducted studies using single antibiotics and antibiotic cocktails. No single antibiotic treatment conferred protection against naproxen-induced small intestinal injury, but an antibiotic cocktail decreased damage scores by ~46%. Furthermore we explored the effects of L-lactic acid supplementation of drinking water but this was unable to reduce naproxen-induced intestinal damage. Collectively, the work presented in this thesis provides novel insights on the relationship between alterations in the microbiota and susceptibility to NSAID-induced enteropathy. / Dissertation / Doctor of Philosophy (Medical Science)

Colorectal carcinoma is an important, feasible and attractive target for chemoprevention because a) it is a major cause of mortality in the United States and in other developed countries worldwide, b) there is a high mortality associated with advanced disease, c) there is a well described molecular carcinogenesis pathway and d) recent advances in molecular genetics will improve the ability to identify high-risk subjects. Epidemiological data, colonoscopic screening and advances in molecular genetics has made possible the identification and selection of subjects at increased risk of developing colorectal cancer. Due to this new information it may be possible to impede malignant cellular transformation with drugs. Such intervention with relatively simple maneuvers, such as a low daily dose of aspirin, can potentially reduce mortality from colorectal cancer. Prospective trials need to confirm experimental and epidemiological data supporting the efficacy of aspirin and other NSAID as chemopreventive agents before they can be used in the general population at risk. To use cancer chemopreventives effectively and safely in an asymptomatic population, the risks should be minimized and the benefits maximized by determination of optimal dose, schedule and chemopreventive mechanism of the NSAID. By linking the putative mechanism of drug action to effect endpoints, we expect to know whether the chemopreventive intervention is likely to be effective in a given individual.

No description available.

Introduction Aspirin has been associated with a reduction in mortality in patients diagnosed with colorectal cancer (CRC). A possible mechanism for this is related to the programmed cell death 1 (PD-1) immune checkpoint pathway. Aspirin may have a synergistic effect with PD-1 inhibitors via inhibition of prostaglandin E2 (PGE2) production, which can reverse the ability of tumor cells to evade the immune system. This appears to be strongest in cancers that express PI3 kinase (PI3K) signaling activity, which aspirin downregulates. However, the benefit of pre-diagnosis aspirin use on CRC overall survival (OS) and cancer-specific survival is still controversial, and most studies have been performed in racially homogenous populations. Our study examines the effect of pre-diagnosis aspirin therapy on OS in a racially diverse group of patients with CRC. Methods This is a retrospective chart review of 782 patients diagnosed with CRC from January 2007 to December 2020. Kaplan-Meier curve was created to study the association of aspirin exposure compared to no exposure on OS. In addition, univariate and multivariate binary logistic regression analyses were done to investigate potential predictors of survival. Results Of the 782 patients with CRC, 55.1% were males, 22.2% whites, 58.5% Asians, and 17.7% Pacific-Islanders. Moreover, 38.4% of the patients had a history of aspirin use, 79% of them used it for more than one year. There were more patients with hypertension (HTN), hyperlipidemia (HLD), diabetes mellitus (DM), and chronic kidney disease (CKD) among those with a history of aspirin use. There was no difference in one, three, and five-year OS among aspirin users compared to non-users, p-value = 0.63. Age, grade, and stage were potential predictors of worsened OS. However, treatment with chemotherapy and CKD were potential predictors of worsened OS on univariate analysis only. No significant association was noticed with gender, tumor location, or other associated comorbidities. Conclusion The effect of pre-diagnosis aspirin use on CRC survival is not clear. In this retrospective analysis of a racially diverse population of CRC patients, we found that aspirin use was not associated with improved OS. Therefore, physicians should be careful about using aspirin as adjuvant therapy in CRC patients until high-quality prospective data are available, given the potential associated complications.

No description available.

Le traitement de la douleur après chirurgie cardiaque avec sternotomie reste à ce jour un défi pour le clinicien. Chez ces patients à risque, une prise en charge non adaptée de la douleur peut altérer la réhabilitation postopératoire et majorer les complications métaboliques, immunologiques, cardiovasculaires, respiratoires, ou psychiques de la chirurgie. L’objectif de ce travail de recherche clinique en chirurgie cardiaque était : 1) d’évaluer les effets analgésiques d’une anesthésie locorégionale continue par un bloc bi-latéro-sternal (bloc BLS) par perfusion continue de ropivacaïne,2) d’évaluer l’effet du bloc BLS sur la durée de séjour en réanimation et morbidité postopératoire, chez les patients présentant un risque respiratoire accru, 3) d’évaluer l’effet analgésique d’un antiinflammatoire non stéroïdien (AINS) de référence, le kétoprofène, à une posologie conventionnelle et des posologies réduites. Les deux techniques étaient appliquées pendant les 48 heures suivant la chirurgie cardiaque.Testé (contre placebo) sur une population standard, le bloc BLS continu diminue de 41% la douleur à la mobilisation (dynamique), diminue la douleur au repos et la consommation de morphine (d’environ 40%). Il permet une reprise plus précoce de l’alimentation et du traitement per os, une mobilisation plus précoce et une plus grande satisfaction des patients. En revanche, il ne permet pas une amélioration des paramètres respiratoires (spirométrie et gaz du sang artériel). Testé (contre une prise en charge standard) sur une population à risque respiratoire accru, contrairement aux attentes, il ne réduit pas la durée de séjour en réanimation et à l’hôpital, mais il a des effets bénéfiques sur la douleur dynamique, la satisfaction des patients, l’incidence de nausées/vomissements et de troubles neurologiques de type confusionnel. Un bénéfice en termes médico-économique est suggéré par une analyse secondaire. Testé (contre placebo) sur une population à faible risque, l’utilisation du kétoprofène en plein dose permet de réduire la douleur dynamique et au repos, sans augmentation des effets indésirables rénaux et hémorragiques, habituellement craints avec les AINS. Bien que les arguments manquent pour pouvoir utiliser des posologies réduites, le kétoprofène peut néanmoins être conseillé chez ce type de patients, alors qu’il est à ce jour insuffisamment prescrit. L’étude de protocoles d’administration utilisant des posologies réduites potentialisées par une dose de charge est suggérée. / The treatment of pain after cardiac surgery with sternotomy remains to this day a challenge for the clinician. In these frail patients, non-appropriated pain treatment can alter the postoperative rehabilitation and increase metabolic, immunologic, cardiovascular, respiratory, and psychological postoperative complications. The goal of this clinical research was to evaluate:- the analgesic effects of bi-latero-sternal (BLS) block by a continuous infusion of ropivacaine, - the effect of the BLS block on the length of stay in intensive care and postoperative morbidity in patients with increased respiratory risk,- evaluate the analgesic effect of ketoprofen, the standard non-steroidal anti-inflammatory drug (NSAID), at a conventional and reduced dosages.The two techniques were applied during the 48 hours following cardiac surgery.Tested (against placebo) on a standard population, the BLS continuous block decreased pain at mobilisation (dynamic pain) by 41%, decreased pain at rest, and morphine consumption (by 40%). It allowed an earlier postoperative first dietary and oral medication intake, earlier mobilisation and a greater patients’ satisfaction. On the other hand, it did not show any significant improvement of respiratory parameters (spirometry and arterial blood gases).Tested against a standard treatment in patients with increased respiratory risk, the BLS block did not reduce the length of stay in intensive care and in hospital, but it had beneficial effects on dynamic pain, patients’ satisfaction, the incidence of nausea/vomiting and of postoperative delirium. A benefit in economics terms is suggested by a secondary analysis.Tested against placebo in a low-risk population, the use of ketoprofen in full dose regimen, reduced pain at mobilisation and at rest, without increasing renal adverse effects or bleeding (as it could be feared with NSAIDs). We missed to demonstrate the ketoprofen efficacy at reduced doses. Ketoprofen may be recommended on a low-risk population, while it is insufficiently prescribed so far. The study of protocols using a reduced dosage potentiated by a loading dose is suggested.