Institute of Pharmacology and Therapeutics


Institute of Pharmacology and Therapeutics

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Loureiro A.I.,BIAL Portela and Ca S.A. | Fernandes-Lopes C.,BIAL Portela and Ca S.A. | Bonifacio M.J.,BIAL Portela and Ca S.A. | Wright L.C.,BIAL Portela and Ca S.A. | And 2 more authors.
Drug Metabolism and Disposition | Year: 2013

Etamicastat [(R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1H- imidazole-2(3H)-thione hydrochloride] is a reversible dopamine-β- hydroxylase inhibitor that decreases norepinephrine levels in sympathetically innervated tissues. After in vivo administration, N-acetylation of etamicastat was found to be a main metabolic pathway. The purpose of the current study was to characterize the N-acetylation of etamicastat by N-acetyltransferases (NAT1 and NAT2) and evaluate potential species differences in etamicastat N-acetylation using a sensitive and specific liquid chromatography-mass spectrometry assay. Marked differences in etamicastat N-acetylation were observed among the laboratory species and humans. After oral administration, the rat, hamster, and human subjects presented the highest rates of etamicastat N-acetylation, whereas almost no acetylation was observed in the mouse, rabbit, minipig, and monkey and no acetylation was observed in the dog. In in vitro studies, rats and humans showed similar acetylation rates, whereas no acetylation was detected in the dog. Studies performed with human recombinant NAT1 4 and NAT2 4 enzymes revealed that both were able to conjugate etamicastat, although at different rates. NAT1 had lower affinity compared with NAT2 (K m, 124.8 ± 9.031 μM and 17.14 ± 3.577 μM, respectively). A significant correlation (r2 = 0.65, P < 0.05) was observed in a comparison of etamicastat N-acetylation by human single-donor enzymes and sulfamethazine, a selective substrate to NAT2. No correlation was observed with p-aminosalicylic acid, a NAT1 selective substrate. In conclusion, these results suggest that NAT2 and, to a lesser extent, NAT1 contribute to etamicastat N-acetylation. Furthermore, the high interspecies and intraspecies differences in N-acetylation should be taken into consideration when evaluating the in vivo bioavailability of etamicastat. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.

Burisch J.,Copenhagen University | Pedersen N.,Copenhagen University | Cukovic-Cavka S.,University of Zagreb | Turk N.,University of Zagreb | And 48 more authors.
Inflammatory Bowel Diseases | Year: 2014

Background: The EpiCom cohort is a prospective, population-based, inception cohort of inflammatory bowel disease (IBD) patients from 31 European centers covering a background population of 10.1 million. The aim of this study was to assess the 1-year outcome in the EpiCom cohort. Methods: Patients were followed-up every third month during the first 12 (±3) months, and clinical data, demographics, disease activity, medical therapy, surgery, cancers, and deaths were collected and entered in a Web-based database ( Results: In total, 1367 patients were included in the 1-year follow-up. In western Europe, 65 Crohn's disease (CD) (16%), 20 ulcerative colitis (UC) (4%), and 4 IBD unclassified (4%) patients underwent surgery, and in eastern Europe, 12 CD (12%) and 2 UC (1%) patients underwent surgery. Eightyone CD (20%), 80 UC (14%), and 13 (9%) IBD unclassified patients were hospitalized in western Europe compared with 17 CD (16%) and 12 UC (8%) patients in eastern Europe. The cumulative probability of receiving immunomodulators was 57% for CD in western (median time to treatment 2 months) and 44% (1 month) in eastern Europe, and 21% (5 months) and 5% (6 months) for biological therapy, respectively. For UC patients, the cumulative probability was 22% (4 months) and 15% (3 months) for immunomodulators and 6% (3 months) and 1% (12 months) for biological therapy, respectively in the western and eastern Europe. Discussion: In this cohort, immunological therapy was initiated within the first months of disease. Surgery and hospitalization rates did not differ between patients from eastern and western Europe, although more western European patients received biological agents and were comparable to previous population-based inception cohorts. Copyright © 2013 Crohn's & Colitis Foundation of America, Inc.

Burisch J.,Copenhagen University | Vardi H.,Ben - Gurion University of the Negev | Pedersen N.,Copenhagen University | Brinar M.,University of Zagreb | And 51 more authors.
Inflammatory Bowel Diseases | Year: 2015

Background: No direct comparison of health care cost in patients with inflammatory bowel disease across the European continent exists. The aim of this study was to assess the costs of investigations and treatment for diagnostics and during the first year after diagnosis in Europe. Methods: The EpiCom cohort is a prospective population-based inception cohort of unselected inflammatory bowel disease patients from 31 Western and Eastern European centers. Patients were followed every third month from diagnosis, and clinical data regarding treatment and investigations were collected. Costs were calculated in euros (€) using the Danish Health Costs Register. Results: One thousand three hundred sixty-seven patients were followed, 710 with ulcerative colitis, 509 with Crohn's disease, and 148 with inflammatory bowel disease unclassified. Total expenditure for the cohort was €5,408,174 (investigations: €2,042,990 [38%], surgery: €1,427,648 [26%], biologicals: €781,089 [14%], and standard treatment: €1,156,520 [22%)]). Mean crude expenditure per patient in Western Europe (Eastern Europe) with Crohn's disease: investigations €1803 (€2160) (P = 0.44), surgery €11,489 (€13,973) (P = 0.14), standard treatment €1027 (€824) (P = 0.51), and biologicals €7376 (€8307) (P = 0.31). Mean crude expenditure per patient in Western Europe (Eastern Europe) with ulcerative colitis: investigations €1189 (€1518) (P < 0.01), surgery €18,414 (€12,395) (P = 0.18), standard treatment €896 (€798) (P < 0.05), and biologicals €5681 (€72) (P = 0.51). Conclusions: In this population-based unselected cohort, costs during the first year of disease were mainly incurred by investigative procedures and surgeries. However, biologicals accounted for >15% of costs. Long-term follow-up of the cohort is needed to assess the cost-effectiveness of biological agents. © 2014 Crohn's & Colitis Foundation of America, Inc.

Burisch J.,Copenhagen University | Pedersen N.,Copenhagen University | Cukovic-Cavka S.,University of Zagreb | Brinar M.,University of Zagreb | And 51 more authors.
Gut | Year: 2014

Objective: The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe. The reasons for these changes remain unknown. The aim of this study was to investigate whether an East-West gradient in the incidence of IBD in Europe exists. Design: A prospective, uniformly diagnosed, population based inception cohort of IBD patients in 31 centres from 14 Western and eight Eastern European countries covering a total background population of approximately 10.1 million people was created. One-third of the centres had previous experience with inception cohorts. Patients were entered into a low cost, web based epidemiological database, making participation possible regardless of socioeconomic status and prior experience. Results: 1515 patients aged 15 years or older were included, of whom 535 (35%) were diagnosed with Crohn's disease (CD), 813 (54%) with ulcerative colitis (UC) and 167 (11%) with IBD unclassified (IBDU). The overall incidence rate ratios in all Western European centres were 1.9 (95% CI 1.5 to 2.4) for CD and 2.1 (95% CI 1.8 to 2.6) for UC compared with Eastern European centres. The median crude annual incidence rates per 100 000 in 2010 for CD were 6.5 (range 0-10.7) in Western European centres and 3.1 (range 0.4-11.5) in Eastern European centres, for UC 10.8 (range 2.9-31.5) and 4.1 (range 2.4-10.3), respectively, and for IBDU 1.9 (range 0-39.4) and 0 (range 0-1.2), respectively. In Western Europe, 92% of CD, 78% of UC and 74% of IBDU patients had a colonoscopy performed as the diagnostic procedure compared with 90%, 100% and 96%, respectively, in Eastern Europe. 8% of CD and 1% of UC patients in both regions underwent surgery within the first 3 months of the onset of disease. 7% of CD patients and 3% of UC patients from Western Europe received biological treatment as rescue therapy. Of all European CD patients, 20% received only 5-aminosalicylates as induction therapy. Conclusions: An East-West gradient in IBD incidence exists in Europe. Among this inception cohort-including indolent and aggressive cases-international guidelines for diagnosis and initial treatment are not being followed uniformly by physicians.

Soares J.-B.,Hospital of Braga | Marinho A.S.,Hospital of Braga | Marinho A.S.,University of Minho | Fernandes D.,Hospital of Braga | And 8 more authors.
European Journal of Gastroenterology and Hepatology | Year: 2015

Background/aims Structural equation modeling (SEM) is a very popular data-analytic technique for the evaluation of customer satisfaction. We aimed to measure the overall satisfaction of inflammatory bowel disease (IBD) patients with healthcare in Portugal and to define its main determinants using SEM. Patients and methods The study included three steps: (i) specification of a patient satisfaction model that included the following dimensions: Image, Expectations, Facilities, Admission process, Assistant staff, Nursing staff, Medical staff, Treatment, Inpatient care, Outpatient care, Overall quality, Overall satisfaction, and Loyalty; (ii) sample survey from 2000 patients, members of the Portuguese Association of the IBD; and (iii) estimation of the satisfaction model using partial least squares (XLSTAT-PLSPM). Results We received 498 (25%) valid questionnaires from 324 (66%) patients with Crohn's disease and 162 (33%) patients with ulcerative colitis. Our model provided a substantial explanation for Overall satisfaction (R 2 =0.82). The mean index of overall satisfaction was 74.4 (0-100 scale). The main determinants of Overall satisfaction were the Image (β=0.26), Outpatient care (β=0.23), and Overall quality (β=0.21), whose mean indices were 83, 75, and 81, respectively. Facilities and Inpatient care were the variables with a significant impact on Overall satisfaction and the worst mean indices. Conclusion SEM is useful for the evaluation of IBD patient satisfaction. The Overall satisfaction of IBD patients with healthcare in Portugal is good, but to increase it, IBD services need to focus on the improvement of Outpatient care, Facilities, and Inpatient care. Our model could be a matrix for a global model of IBD patient satisfaction. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Albuquerque A.,Hospital Of Sao Joao | Magro F.,Hospital Of Sao Joao | Magro F.,Institute of Pharmacology and Therapeutics | Magro F.,University of Porto | And 7 more authors.
European Journal of Gastroenterology and Hepatology | Year: 2011

Metastatic cutaneous Crohn's disease is one of the most uncommon cutaneous extraintestinal manifestations. The face is the rarest location, with only eight cases described in the literature. We report a rare case of a young man with Crohn's disease and two granulomatous lesions on the face in a nodular form. To the best of our knowledge, this is the first report of metastatic Crohn's disease of the forehead with the features of nodules. A review of the literature concerning metastatic Crohn's disease is also provided. © 2011 Wolters Kluwer Health | Lippincott Williams &Wilkins.

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