DOP076 A phase 2B, multicenter, randomized, placebo-controlled dose-ranging trial of peficitinab, an oral JAK inhibitor, in patients with moderately to severely active ulcerative colitis
Bruce E. SandsW. SandbornBrian G. FeaganGary R. LichtensteinH. ZhangPhilippe SzaparyJulían PanésSéverine VermeireChris O’BrienJesse DeweyZijiang YangJewel JohannsRichard StraußColleen Marano
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DOP075 -Table 1 Variable/unit/population Anti-TNF naive Anti-TNF non-responder PBO=16 FIL=57 PBO=28 FIL=71 Clinical remission (CDAI<150), %, ITT-NRI 13 60 29 37 100-points clinical response (CDAI improvement with ≥100 points), %, ITT-NRI 44 67 39 54 PRO2 score, mean change from baseline, ITT-LOCF (7×(mean daily number of liquid or very soft stools + 7×(mean daily abdominal pain score)) -19.8 -24.8 -13.2 -19.5 PRO2 remission (PRO2 ≤28), %, ITT-NRI 31 61 29 41 CDAI general well-being score, mean change from baseline, ITT-LOCF -0.78 -1.08 -0.58 -0.90Total IBDQ score, mean change from baseline, ITT-LOCF 19.7 40.8 16.3 28.2 Overall total histopathology score, mean change from baseline, ITT-LOCF -0.3 -3.9 -0.7 -3.2 Anti-TNF naive Anti-TNF non-responder PBO=9 FIL=39 PBO=18 FIL=54 Combined clinical-biological response, %, ITT-NRI (CDAI score <150 points and CRP decrease >50% and/or fecal calprotectin decraese >50% from baseline) 3 6 6 2 0 CDAI: Crohn's Disease Activity Index; ITT: Intent-to-treat; NRI: Non-responder imputation; LOCF: Last observation carried forward; IBDQ: Inflammatory Bowel Disease Questionnaire; ITT population = 172 patients (2 pts without post-baseline assessments).remained on stable doses until Week 10.Patients naïve to anti-TNF therapy as well as patients who were previously exposed to anti-TNF with no response or loss-of-response were included.Endpoints include clinical outcome (CDAI), patient-reported outcomes (PRO: CDAI and IBDQ), histopathology (D'Haens score) and combined clinical-biological response (CDAI and biomarkers).Results: Baseline characteristics were similar in FIL and PBO groups, including mean disease duration (8.3 years), mean CDAI score (293), mean CRP (15.6mg/L, 41%>10mg/L), oral corticosteroids (51%, mean daily dose 20.8 mg/day).42% of the patients were anti-TNF naïve, 58% were anti-TNF non-responder.Clinical remission (CDAI<150) was induced at Week 10 in 47% of FIL patients versus 23% on PBO (p=0.0077).CDAI remission and response were higher in the FIL group versus PBO irrespective of prior anti-TNF therapy.PRO measured by changes from baseline in PRO2 score and general well-being (CDAI component), as well as quality of life assessed by IBDQ improved more in both FIL subgroups compared to PBO.A combined clinicalbiological response endpoint confirmed these findings in the subgroup with elevated CRP or faecal calprotectin at baseline.Histopathology at Week 10 showed numerically greater effects after FIL treatment versus PBO for both subgroups (Table 1).FIL was safe and well tolerated.Similar incidences in SAEs, TEAEs leading to discontinuation and infections were observed in both anti-TNF subgroups, with a somewhat higher incidence of TEAEs in anti-TNF non-responders.Conclusions: Efficacy of filgotinib was shown in CD patients independently of their prior anti-TNF exposure, and was consistent across all endpoints.The safety profile was also similar.These data suggest a favourable risk/benefit profile, in both anti-TNF naives and anti-TNF non-responders.Keywords:
Dose-ranging study
Μελέτη της πολυπαραγοντικής αναλγησίας στο μετεγχειρητικό πόνο μετά από λαπαροσκοπική χολοκυστεκτομή
Σκοπός:Ο βασικός σκοπός της μελέτης ήταν να ελεγχθεί αν ο συνδυασμός γκαμπαπεντίνης (600mg 4ώρες προεγχειρητικά, 600mg 24ώρες μετά), κεταμίνης (0.3mg/kg πριν την αναισθησία), λορνοξικάμης (8mg πριν την αναισθησία και 8mg/12ώρες) και τοπικής έγχυσης ροπιβακαΐνης (5ml 7.5% στα σημεία εισόδου των trocar) έχει καλύτερη αναλγητική δράση σε σχέση με το καθένα από αυτά τα φάρμακα ξεχωριστά τις πρώτες 24 ώρες μετά από λαπαροσκοπική χολοκυστεκτομή. Δευτερεύων σκοπός ήταν να εξετασθεί αν αυτός συνδυασμός έχει λιγότερες επιπλοκές σχετιζόμενες με την κατανάλωση οπιοειδών.Μέθοδος:Διεξήχθη μία ελεγχόμενη τυχαιοποιημένη μελέτη σε 2 νοσηλευτικά κέντρα. 148 ασθενείς ηλικίας 18-70 ετών κατανεμήθηκαν τυχαία σε 6 ομάδες (28 σε κάθε ομάδα) με τη χρήση λογισμικού: A (γκαμπαπεντίνη/κεταμίνη/λορνοξικάμη/ροπιβακαΐνη), B (γκαμπαπεντίνη/placebo/placebo/placebo), Γ (placebo/κεταμίνη/placebo/placebo), Δ (placebo/placebo/λορνοξικάμη/placebo), E (placebo/placebo/placebo/ροπιβακαΐνη) και ΣΤ (placebo/placebo/placebo/placebo). Μόνο ο κύριος ερευνητής γνώριζε την ομάδα κάθε ασθενούς και παρείχε τα φάρμακα και τα εικονικά φάρμακα σε καλυμμένες προγεμισμένες σύριγγες. Η κύρια έκβαση της μελέτης ήταν η 24ωρη κατανάλωση μορφίνης. Δευτερεύουσες εκβάσεις ήταν η συχνότητα των σχετιζόμενων με τα οπιοειδή επιπλοκών (ναυτία, έμετος, καταστολή, κνησμός και δυσκολία ούρησης).Αποτελέσματα:Μόνο οι ομάδες Α (6.4mg), B (9.46mg) και Δ (9.36mg) είχαν χαμηλότερη κατανάλωση μορφίνης σε σχέση με την ομάδα ελέγχου (20.29mg) (p<0.001, p=0.01 και p=0.008 αντίστοιχα). Η ομάδα Α δε διέφερε από τις ομάδες Β και Δ (p=0.92, p=0.93). Υπήρξε διαφορά μόνο στα επεισόδια ναυτίας και μόνο μεταξύ των ομάδων Α (n=5) και της ομάδας ελέγχου (n=12) (p=0.018). Συμπεράσματα:Ο συνδυασμός γκαμπαπεντίνης, κεταμίνης, λορνοξικάμης, και τοπικής έγχυσης ροπιβακαΐνης δεν έχει ισχυρότερη αναλγητική δράση σε σχέση με μόνη την γκαμπαπεντίνη ή τη λορνοξικάμη μετά από λαπαροσκοπική χολοκυστεκτομή. Ο συνδυασμός μειώνει μόνο τη συχνότητα της μετεγχειρητικής ναυτίας αλλά απαιτούνται μεγαλύτερες μελέτες για την εξαγωγή ασφαλών συμπερασμάτων.
Placebo group
Placebo response
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Combined Signature of the Fecal Microbiome and Plasma Metabolome in Patients with Ulcerative Colitis
BACKGROUND Ulcerative colitis is a chronic, idiopathic inflammatory disease that destroys the colon structure. Nevertheless, the exact pathogenesis is not clear and needs to be fully elucidated. MATERIAL AND METHODS Stool and plasma samples were used for 16S ribosomal RNA sequencing and liquid chromatography mass spectrometry, respectively. In addition, we detected the level of trimethylamine N-oxide. Finally, we performed Pearson correlation analysis between the microbiome and the metabolome. RESULTS Twenty-three active ulcerative colitis, 25 inactive ulcerative colitis, and 30 control cases were included. Thirty-four significantly different metabolites were found between the active ulcerative colitis and control groups, 38 were found between the inactive ulcerative colitis and control groups, and only 1 was found between the active ulcerative colitis and inactive ulcerative colitis groups. The plasma trimethylamine N-oxide level of the inactive ulcerative colitis and active ulcerative colitis groups was significantly higher than that of the control group. Moreover, we identified significant changes in 24, 18, and 12 bacterial genera for active ulcerative colitis-control, inactive ulcerative colitis-control, and active ulcerative colitis-inactive ulcerative colitis, respectively. Cross-correlation indicated an association between sphingosine 1-phosphate and Roseburia, Klebsiella, and Escherichia-Shigella. Through the pathway analysis, we found sphingolipid metabolism was one of the most significantly increased pathways. CONCLUSIONS Although levels of trimethylamine N-oxide were higher in ulcerative colitis patients, they did not achieve statistical significance in active ulcerative colitis and inactive ulcerative colitis groups. Sphingosine 1-phosphate was increased in ulcerative colitis patients and there were several microbiota associated with it. Although further study is still needed, sphingosine 1-phosphate will probably become a new target for treatment of ulcerative colitis.
Metabolome
Gut microbiome
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Many studies have been conducted for the role of Ahara (~dietary habits), Vihara (~abnormal Physical activity) and Manas (~Psychological factors) and their association with pathogenesis of Ulcerative colitis, which is a subtype of inflammatory bowel disease, which pursue a protracted relapsing and remitting course, usually extending over years. The causes of relapsing of ulcerative colitis are not known. Dietary factors have been associated in the pathogenesis of ulcerative colitis as well as associated with an increased risk of relapse of ulcerative colitis. Here, we have reviewed the probable mechanisms of the role of diet and its association with pathogenesis of Ulcerative colitis (UC). In Ayurveda, on the basis of signs and symptoms ulcerative colitis can be best compared with Raktatisara. This article is an attempt to do critical review and put a light on the role of diet, faulty lifestyle and Psychological factors in occurrence and progression of Ulcerative colitis (UC), and try to explain Etiopathogenesis of Raktatisara in relation to ulcerative colitis by going through Ayurvedic texts, Google Scholar, PubMed journals etc.
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Objective To observe the levels of plasma P-selection(P-sel) and in patients with ulcerative colitis and to study the clinical significance of them. Methods the concentrations of P-sel in 18 patients with active ulcerative colitis and 13 relief ulcerative colitis were determined with ELISA method. Results The results shown that the levels of P-sel in active ulcerative colitis patients were markedly elevated and were correlated with the severity of the disease. But the levels of P-sel in relief ulcerative colitis patients have no difference with normal controls. Conclusion It is suggested that the occurrence and development of ulcerative colitis may be related to the increase of plasma P-sel. Measurement of levels of plasma P-sel and might therefore provide a tool for monitoring the clinical course and for gaiding the treatment of ulcerative colitis.
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The aim of the study was to assess the efficacy and safety of RAD1901, an oral estrogen receptor ligand, for the treatment of moderate-to-severe vasomotor symptoms of menopause.This was a randomized, placebo-controlled, double-blind, dose-ranging, proof-of-concept trial. Postmenopausal women with a minimum of 7 moderate-to-severe, diary-reported hot flashes per day, or 50 per week, were randomized to one of five blinded dose groups (0 [placebo], 10, 25, 50, or 100 mg RAD1901 daily for 28 d). Efficacy endpoints included frequency and severity of hot flashes over 4 weeks of treatment.One hundred participants were randomized across the five treatment regimens. The frequency of moderate-to-severe hot flashes decreased in all groups over the treatment period (mean percent change from baseline at 4 wk, -54.1%, -77.2%, -51.8%, -53.8%, and -67.0% for placebo, 10, 25, 50, and 100 mg groups). The response in the 10 mg group was significantly different from placebo at 4 weeks (P = 0.024). No other dose group was significantly different from placebo. There were no statistically significant differences in severity of hot flashes between placebo and any dose group. Treatment was well tolerated; most treatment-emergent adverse events were mild to moderate in severity.Daily treatment with 10 mg RAD1901 over 4 weeks resulted in a statistically significant reduction in the frequency of moderate-to-severe hot flashes compared with placebo, with an acceptable safety profile. Further clinical trials are warranted to investigate RAD1901's utility as a potential treatment for vasomotor symptoms.
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Dose-ranging study
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Objective To investigate action and significance of serum nitric oxide(NO) in patients with ulcerative colitis.Methods Levels of serum NO in active stage of 33 patients with ulcerative colitis and 40 healthy controls were detected.Results Levels of serum NO in patients with ulcerative colitis were significantly high and related to severe degrees of the disease (P0.05).Conclusion Immune dysfunction exists in patients with ulcerative colitis, There are relationship between higher levels of serum NO and ulcerative colitis pathogenesis and elevation of serum NO level may be as an indicator of ulcerative colitis.
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Objective:To investigate the action of TNF-a,IL-6 and sIL-2R in the mechanism of ulcerative colitis.Methods:Bi-antibody radioimmune methods and ELISA methods were used to analysis the samples in TNF-a,IL-6 and sIL-2R of 25 cases with active ulcerative colitis.30 normal persons were assigned as the contrast group.The data of cytokines(TNF-a,IL-6,sIL-2R)among contrast group,the active and catabolic phases of ulcerative colitis were compared.That in catabolic phases of ulcerative colitis was also compared with that in contrast group,the difference were compared among slight,moderate and severe groups,The relativity among the serum level in TNF-a,IL-6 of active ulcerative colitis had been observed.Results:The level of serum TNF-a,IL-6 and sIL-2R in active ulcerative colitis was much more higher than catabolic ulcerative colitis and contrast group(P0.05).The level had no significant difference between catabolic ulcerative colitis and contrast group(P0.005).The level in severe group is higher than that in moderate and slight group(P0.05).Serum cytokines,TNF-a and IL-6 are positively related to active ulcerative colitis.(r=0.8476,P0.05).Conclusion:There is a severe disorders of cellular immunity in the patients with active ulcerative colitis.TNF-a,IL-6,sIL-2R etc play the very important roles in the genesis and development of ulcerative colitis.The serum level of the above cytokines not only reflected the development of ulcerative colitis but also could be used as biological index of the effect and estimate the prognosis.
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This paper discusses the treatment of ulcerative colitis with Traditional Chinese Medicine, and expounds the specific pathogenesis of ulcerative colitis. In addition, we put forward the application of some new technologies and methods for the scientific research on the treatment of ulcerative colitis, and summarizes the research hotspots of ulcerative colitis, hoping to provide reference for other scholars to study ulcerative colitis. Keywords: Chinese traditional; ulcerative colitis; techniques and methods; medicine treatment.
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Ulcerative colitis is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. The pathogenesis is multifactorial, involving genetic predisposition, epithelial barrier defects, deregulated immune responses, and environmental factors. Patients with ulcerative colitis have mucosal inflammation starting in the rectum that can extend continuously to proximal segments of the colon. Ulcerative colitis usually present with bloody diarrhoea and is diagnosed by colonoscopy and histological findings. Treatment for ulcerative colitis include 5-aminosalicylic acid drugs, steroids, and immune-suppressant. The therapeutic armamentarium for ulcerative colitis is expanding. A total of 60 respondents were interviewed and were investigated for ulcerative colitis. A predesigned and pretested was used to collect the information about the participants. For the research survey method was used for the collection of data. Results shows that mostly 70 (%) respondents were aware of ulcerative colitis and 30 (%) respondents were not aware of ulcerative colitis. In conclusion that studies ulcerative colitis.
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Genetic predisposition
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Objective To observe the severity correlation of TNF-α、IL-6 and IL-8 levels in plasma in patients with ulcerative colitis and investigate mechanism of ulcerative colitis.Methods TNF-α,IL-6 and IL-8 levels in plasma were measured with ELISA methods in 56 patients with ulcerative colitis and 20 normal persons as a control group.The active and catabolic phases of ulcerative colitis were compared and the difference were compared among slight,moderate and sever groups.Results The level of serum TNF-α,IL-6 and IL-8 in active ulcerative colitis was much more higher than catabolic ulcerative colitis and contrast group(P0.05).The level had no significant differences between catabolic ulcerative colitis and contrast group(P0.05).The level in severe group was higher than that in moderate and slight group(P0.05).Conclusions There is a sever disorders of cellular immunity in the patients with active ulcerative colitis.TNF-α,IL-6 and IL-8 play the very important roles in the genesis and development of ulcerative colitis.The measurement of TNF-α,IL-6 and IL-8 levels in plasma may contribute to predict the severity of ulcerative colitis.
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