Abstract 874: MLN1202, a Novel CCR2 Antagonist, Decreases C-reactive protein in Patients at Risk for Atherosclerotic Cardiovascular Disease in a Double Blind Placebo Controlled study

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
M. Davidson ◽  
J. Lekstrom-Himes ◽  
J. Gilbert ◽  
D. Donaldson ◽  
Y. Lee ◽  
...  

Background: Macrophages play a central role in atherosclerotic plaque formation. The CC chemokine receptor 2 (CCR2), expressed on the surface of circulating monocytes, and its ligand MCP-1 (CCL2), are present in atherosclerotic plaques and may play a critical part in endothelial monocyte recruitment and activation. MLN1202 is a humanized monoclonal antibody with high specificity to CCR2, which interrupts MCP-1 binding to CCR2. MLN1202 is being developed for the treatment of immune mediated diseases. Hypothesis: We tested the hypothesis that MLN1202 significantly influences disease activity in patients at risk for ASCVD as measured by a reduction in circulating levels of high sensitivity C-reactive protein (hsCRP), an established biomarker of inflammation. Trial Design: In this double-blind placebo controlled study patients with at least 2 or more risk factors for ASCVD, no history or symptoms of ASCVD disease, and circulating levels of hsCRP > 3mg/L, were randomized 1:1 to receive a single infusion of 10 mg/kg MLN1202 (n 56) or placebo (n = 56). Subjects with hypercholesterolemia on stable doses of lipid-lowering agents were included. Circulating levels of hsCRP were determined every 2 weeks, and clinical examination performed every 4 weeks for 16 weeks following treatment. Results and Conclusion: Patients were recruited from nine centers in the US. The study population had a mean age of 60.9 years and included subjects with hypertension (59%), hypercholesterolemia (70%), significant smoking history (28%), and type 2 diabetes (16%). At screening the median value CRP was 6.8 mg/L with interquartile range from 4.7–9.3 mg/L. PK/PD results showed that the plasma level of MLN1202 required for > 90% receptor saturation was maintained for 6 to 8 weeks. A between-group difference in reduction of hsCRP was statistically significant from week 4 through week 8 following dosing. The maximum difference in absolute median reduction was observed at week 8 and it was 1.6 mg/L (p = 0.0275; Wilcoxon); the observed median percent reduction of hsCRP was 24.2% for MLN1202 group versus 2.5% increase for placebo group at 8 weeks (p = 0.0089; Wilcoxon). These data indicate that blockade of CCR2 reduces a biomarker related to inflammation in patients at risk for ASCVD.

2008 ◽  
Vol 22 (2) ◽  
pp. 150-157 ◽  
Author(s):  
Roland von Känel ◽  
Brigitte M. Kudielka ◽  
Petra Metzenthin ◽  
Susanne Helfricht ◽  
Daniel Preckel ◽  
...  

CHEST Journal ◽  
2020 ◽  
Vol 158 (2) ◽  
pp. 637-645 ◽  
Author(s):  
Steven D. Nathan ◽  
Kevin.R. Flaherty ◽  
Marilyn.K. Glassberg ◽  
Ganesh Raghu ◽  
Jeffrey Swigris ◽  
...  

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Evan A Stein ◽  
Rebecca Bakker-Arkenma ◽  
Margaret M McShane ◽  
Mina P Sooch ◽  
Charles L Bisgaier

Background: It is well established that inflammation plays a key role the progression of atherosclerosis and that serum high sensitivity c-reactive protein (hsCRP), may be a good marker of the degree of underlying vascular inflammation. Thus hsCRP has been recognized as a predictor of cardiovascular risk and lipid lowering drugs, such as statins, which also result in a reduction of hsCRP may be more likely to reduce cardiovascular events. Gemcabene is an inhibitor of hepatic cholesterol, triglyceride, and apoC-III synthesis resulting in decreased assembly of VLDL and enhances the systemic clearance of VLDL and its subsequently production of remodeled lipoproteins including LDL. Study Design and Results: In an 8-week double blind randomized, placebo-controlled, dose-ranging, efficacy and safety Phase 2 study, gemcabene 300, 600 and 900 mg/day administered as monotherapy or in combination with atorvastatin 10, 20 and 80 mg/day resulted in a significant and dose dependent reduction of LDL-C (Study 4141001). A secondary objective of this study was to evaluate the modulation of hsCRP by gemcabene. Of 277 patients randomized, 250 (90%) completed the study. Baseline mean LDL-C was 174.7mg/dL, and median hsCRP = 2.5 mg/L. The median % reduction in hsCRP with Gemcabene 300, 600 and 900 mg monotherapy was 25.8%, 41.5% and 35.3% respectively compared with 9.4% for placebo. The rank-transformed data showed significant difference favoring gemcabene over placebo in the 600 and 900 mg groups (p=0.0070 and p =0.0018, respectively). Co-administration of 300, 600, and 900 mg gemcabene with atorvastatin aggregated over the dose range showed decreases in hsCRP beyond atorvastatin monotherapy (which ranged from 27-41%) by an additional 16% (p=0.0237), 23% (p=0.0017) and 28% (p=0.0001), respectively. Conclusions: Gemcabene significantly lowered hsCRP alone and on top of statins in hypercholesterolemic patients.


2015 ◽  
Vol 100 (3) ◽  
pp. 394-401 ◽  
Author(s):  
EunJin Ahn ◽  
Hyun Kang ◽  
Geun Joo Choi ◽  
Yong Hee Park ◽  
So Young Yang ◽  
...  

A perioperative intravenous lidocaine infusion has been reported to decrease postoperative pain. The goal of this study was to evaluate the effectiveness of intravenous lidocaine in reducing postoperative pain for laparoscopic colectomy patients. Fifty-five patients scheduled for an elective laparoscopic colectomy were randomly assigned to 2 groups. Group L received an intravenous bolus injection of lidocaine 1.5 mg/kg before intubation, followed by 2 mg/kg/h continuous infusion during the operation. Group C received the same dosage of saline at the same time. Postoperative pain was assessed at 2, 4, 8, 12, 24, and 48 hours after surgery by using the visual analog scale (VAS). Fentanyl consumption by patient-controlled plus investigator-controlled rescue administration and the total number of button pushes were measured at 2, 4, 8, 12, 24, and 48 hours after surgery. In addition, C-reactive protein (CRP) levels were checked on the operation day and postoperative days 1, 2, 3, and 5. VAS scores were significantly lower in group L than group C until 24 hours after surgery. Fentanyl consumption was lower in group L than group C until 12 hours after surgery. Moreover, additional fentanyl injections and the total number of button pushes appeared to be lower in group L than group C (P < 0.05). The CRP level tended to be lower in group L than group C, especially on postoperative day1 and 2 and appeared to be statistically significant. The satisfaction score was higher in group L than group C (P = 0.024). Intravenous lidocaine infusion during an operation reduces pain after a laparoscopic colectomy.


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