A Double-Blind, Placebo-Controlled, Parallel, Randomized Study to Evaluate the Efficacy and Safety of 3 Oral Dose Levels of TMI-005 in Subjects With Active Rheumatoid Arthritis on a Background of Methotrexate

The primary objective of this clinical research study is to compare the efficacy and the safety of 3 dose levels of oral TMI-005 in comparison with placebo in subjects with active Rheumatoid Arthritis (RA) who have been receiving stable doses of Methotrexate (MTX).

Start Date-

Sponsor / Collaborator

Wyeth AB

EUCTR2004-002215-80-HU

/ Not yet recruitingPhase 2

A Double-Blind, Parallel, Randomized Extension Trial to Evaluate Safety and Efficacy of TMI-005 (Apratastat) in Subjects with Rheumatoid Arthritis on Methotrexate Who Have Completed Protocol 3140A1-200-WW

Start Date20 Jul 2005

Sponsor / Collaborator-

EUCTR2004-000012-13-CZ

/ Not yet recruitingPhase 2

A Double-Blind, Placebo-Controlled, Parallel, Randomized Study To Evaluate The Efficacy And Safety Of 3 Oral Dose Levels Of TMI-005 In Subjects With Active Rheumatoid Arthritis On A Background Of Methotrexate

Start Date26 Oct 2004

Sponsor / Collaborator-

100 Clinical Results associated with MMPs x ADAM17

100 Translational Medicine associated with MMPs x ADAM17

0 Patents (Medical) associated with MMPs x ADAM17

286

Literatures (Medical) associated with MMPs x ADAM17

01 Nov 2024·Biochemistry (Moscow)

Role of MMP-2 and MMP-9 in the Relationship between Inflammation, Fibrosis, and Apoptosis during Progression of Non-Alcoholic Fatty Liver Disease and Diagnostic Significance of Plasma Levels of Their Active Forms

Article

Author: Topchieva, Lyudmila V ; Kurbatova, Irina V ; Dudanova, Olga P ; Shipovskaya, Anastasia A

MMP-2 and MMP-9 play an important role in pathogenesis of chronic liver diseases, participating in the processes of inflammation and fibrosis. Their role in progression of non-alcoholic fatty liver disease (NAFLD) is poorly understood. Analysis of MMP-2, -9 levels in the blood plasma of patients with different forms of NAFLD [liver steatosis (LS) and non-alcoholic steatohepatitis (NASH) of weak (-WA), moderate (MA), high (-HA) activity without pronounced fibrosis] was performed. Correlations between the levels of MMP-2, -9 and mRNA of the genes MMP2, MMP9, ADAM17, NLRP3, caspase 3 activity in peripheral blood leukocytes (PBL), TNFα, IL-6, sIL-6R, cytokeratin-18 fragments in plasma were assessed. In steatosis, the levels of MMP2 gene mRNA in PBL and MMP-2 in plasma are lower than in the control, and expression of the NLRP3 gene in PBL is increased relative to other groups. In the NASH-WA, the level of MMP-9 is higher than in the control, in LS, and in NASH-MA, which could be associated with activation of inflammation during transformation of LS into NASH. The plasma level of MMP-9 over 389.50 pg/ml has been shown to be diagnostically significant for identification of NASH-WA among the patients with steatosis (AUC ROC = 0.818, 95% CI = 0.689-0.948, p < 0.001). In NAFLD, the level of MMP-9 could be associated not only with inflammation, but also with apoptosis. ADAM17 probably plays a certain role in this regard. In the advanced NASH, hepatocyte apoptosis is increased, the level of caspase 3 activity in PBL is increased, the level of MMP-9 in the blood is reduced to the level of the control and LS. In the NASH-HA, the level of mRNA of the ADAM17 gene in PBL is increased compared to the control, NASH-WA, and NASH-MA. Thus, MMP-2 and MMP-9 are involved in pathogenesis of NAFLD already at the early stages and their level in blood could be associated with the presence and severity of inflammation in the liver parenchyma.

01 Sep 2024·Journal of Applied Physiology

Chronic intermittent hypoxia facilitates the development of angiotensin II-induced abdominal aortic aneurysm in male mice

Article

Author: Sharma, Neekun ; Morales-Quinones, Mariana ; Manrique-Acevedo, Camila ; Gozal, David ; Chen, Shiyou ; Soares, Rogerio N. ; Martinez-Lemus, Luis A. ; Chandrasekar, Bysani ; Higashi, Yusuke ; Khalyfa, Abdelnaby ; Cai, Dunpeng ; Padilla, Jaume

IH facilitates Ang II-induced abdominal aortic diameter expansion and AAA development in C57BL/6J male mice. IH upregulates the expression of specific MMPs such as MMP8, MMP12, and ADAM17. IH directly suppresses RECK expression and increases MMPs activity in SMCs. Human AAA tissues exhibit a downregulation of RECK and an upregulation of ADAM17 and MMPs.

01 Jan 2024·Liver International

FXR agonists INT‐787 and OCA increase RECK and inhibit liver steatosis and inflammation in diet‐induced ob/ob mouse model of NASH

Article

Author: Croce, Anna C ; Cadamuro, Massimiliano ; Vairetti, Mariapia ; Cagna, Marta ; Adorini, Luciano ; Di Pasqua, Laura G ; Fabris, Luca ; Palladini, Giuseppina ; Ferrigno, Andrea ; Perlini, Stefano

AbstractBackground and AimsWe have previously shown in a model of hepatic ischaemia/reperfusion injury that the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) restores reversion‐inducing‐cysteine‐rich protein with Kazal motifs (RECK), an inverse modulator of metalloproteases (MMPs) and inhibitor of the sheddases ADAM10 and ADAM17 involved in inflammation and fibrogenesis. Here, the effects of FXR agonists OCA and INT‐787 on hepatic levels of RECK, MMPs, ADAM10 and ADAM17 were compared in a diet‐induced ob/ob mouse model of non‐alcoholic steatohepatitis (NASH).MethodsLep ob/ob NASH mice fed a high‐fat diet (HFD) or control diet (CD) for 9 weeks (wks) were treated with OCA or INT‐787 0.05% dosed via HFD admixture (30 mg/kg/day) or HFD for further 12 wks. Serum alanine transaminase (ALT) and inflammatory cytokines, liver RECK, MMP‐2 and MMP‐9 activity as well as ADAM10, ADAM17, collagen deposition (Sirius red), hepatic stellate cell activation (α‐SMA) and pCK+ reactive biliary cells were quantified.ResultsOnly INT‐787 significantly reduced serum ALT, IL‐1β and TGF‐β. A downregulation of RECK expression and protein levels observed in HFD groups (at 9 and 21 wks) was counteracted by both OCA and INT‐787. HFD induced a significant increase in liver MMP‐2 and MMP‐9; OCA administration reduced both MMP‐2 and MMP‐9 while INT‐787 markedly reduced MMP‐2 expression. OCA and INT‐787 reduced both ADAM10 and ADAM17 expression and number of pCK+ cells. INT‐787 was superior to OCA in decreasing collagen deposition and α‐SMA levels.ConclusionINT‐787 is superior to OCA in controlling specific cell types and clinically relevant anti‐inflammatory and antifibrotic molecular mechanisms in NASH.

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