Plasma and Liver Lipidomics Response to an Intervention of Rimonabant in ApoE*3Leiden.CETP Transgenic Mice

Background: Lipids are known to play crucial roles in the development of life-style related risk factors such as obesity, dyslipoproteinemia, hypertension and diabetes. The first selective cannabinoid-1 receptor blocker rimonabant, an anorectic anti-obesity drug, was frequently used in conjunction with diet and exercise for patients with a body mass index greater than 30 kg/m2 with associated risk factors such as type II diabetes and dyslipidaemia in the past. Less is known about the impact of this drug on the regulation of lipid metabolism in plasma and liver in the early stage of obesity. Methodology/Principal Findings: We designed a four-week parallel controlled intervention on apolipoprotein E3 Leiden cholesteryl ester transfer protein (ApoE&z.ast;3Leiden.CETP) transgenic mice with mild overweight and hypercholesterolemia. A liquid chromatography-linear ion trap-Fourier transform ion cyclotron resonance-mass spectrometric approach was employed to investigate plasma and liver lipid responses to the rimonabant intervention. Rimonabant was found to induce a significant body weight loss (9.4%, p<0.05) and a significant plasma total cholesterol reduction (24%, p<0.05). Six plasma and three liver lipids in ApoE&z.ast;3Leiden.CETP transgenic mice were detected to most significantly respond to rimonabant treatment. Distinct lipid patterns between the mice were observed for both plasma and liver samples in rimonabant treatment vs. non-treated controls. This study successfully applied, for the first time, systems biology based lipidomics approaches to evaluate treatment effects of rimonabant in the early stage of obesity. Conclusion: The effects of rimonabant on lipid metabolism and body weight reduction in the early stage obesity were shown to be moderate in ApoE&z.ast;3Leiden.CETP mice on high-fat diet. © 2011 Hu et al

Effect of rosuvastatin versus atorvastatin treatment on paraoxonase-1 activity in men with established cardiovascular disease and a low HDL-cholesterol

Objective: Paraoxonase-1 (PON-1) is a highdensity lipoprotein (HDL) associated enzyme involved in the protective mechanisms of HDL. Our aim was to compare the effect of treatment with rosuvastatin and atorvastatin on serum PON-1 activity. Methods: We performed a prespecif ied prospective study in 68 patients, part of a larger, multicentre randomized study - RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport). Patients aged 40-80 years, all men, with established cardiovascular disease and high-density lipoprotein cholesterol (HDL-C) <1.0 mmol/L (<40 mg/dL) entered a 6-week dietary run-in period before receiving treatment with rosuvastatin 10 mg or atorvastatin 20 mg daily for 6 weeks. Doses were increased after 6 weeks to rosuvastatin 20 mg or atorvastatin 40 mg and after 12 weeks to rosuvastatin 40 mg or atorvastatin 80 mg daily. Serum PON-1 activity and lipid profile were determined at baseline, 6 and 18 weeks. Results: After 18 weeks, the rosuvastatin arm showed a significant increase of PON-1 activity (6.39 U/L, p = 0.02) whereas this was not observed in the atorvastatin arm (1.84U/L, p = 0.77). The difference between groups did not reach significance (p = 0.11). Both rosuvastatin and atorvastatin resulted in significant (p = 0.0001) and similar increases in HDL-C after 6 weeks [0.06mmol/L (2.32 mg/dL) vs. 0.05 mmol/L (1.93 mg/dL] and after 18 weeks [0.10 mmol/L (3.87 mg/dL) vs. 0.10 mmol/L (3.87 mg/dL)]. Conclusions: Rosuvastatin treatment resulted in a significant increment of serum PON-1 activity with increasing dose while this was not observed with atorvastatin

Asymmetric dimethylarginine (ADMA) levels display a morning peak in patients with acute myocardial infarction

Vascular Biology and Interventio

Treatment of internuclear ophthalmoparesis in multiple sclerosis with fampridine: A randomized double-blind, placebo-controlled cross-over trial

Aim: To examine whether the velocity of saccadic eye movements in internuclear ophthalmoparesis (INO) improves with fampridine treatment in patients with multiple sclerosis (MS). Methods: Randomized, double-blind, placebo-controlled, cross-over trial with fampridine in patients with MS and INO. Horizontal saccades were recorded at baseline and at multiple time points post-dose. Main outcome measures were the change of peak velocity versional dysconjugacy index (PV-VDI) and first-pass amplitude VDI (FPA-VDI). Both parameters were compared between fampridine and placebo using a mixed model analysis of variance taking patients as their own control. Pharmacokinetics was determined by serial blood sampling. Results: Thirteen patients had a bilateral and 10 had a unilateral INO. One patient had an INO of abduction (posterior INO of Lutz) and was excluded. Fampridine significantly reduced both PV-VDI (−17.4%, 95% CI: −22.4%, −12.1%; P < 0.0001) and FPA-VDI (−12.5%, 95% CI: −18.9%, −5.5%; P < 0.01). Pharmacokinetics demonstrated that testing coincided with the average t max at 2.08 hours (SD 45 minutes). The main adverse event reported after administration of fampridine was dizziness (61%). Conclusion: Fampridine improves saccadic eye movements due to INO in MS. Treatment response to fampridine may gauge patient selection for inclusion to remyelination strategies in MS using saccadic eye movements as primary outcome measure

Seladelpar for the treatment of primary biliary cholangitis: Experience with 26 cirrhotic patients

Background and aims: Primary biliary cholangitis (PBC) is a progressive liver disease that leads to cirrhosis. Seladelpar, a selective PPAR delta agonist, demonstrates potent anti-cholestatic and anti-inflammatory activity in PBC. We evaluated the efficacy and safety of seladelpar in PBC patients with clinically diagnosed compensated cirrhosis. Method: PBC patients were enrolled into an ongoing, randomized, open-label Phase 2 study (EudraCT 2016-002996-91) and evaluated for the effect of oral seladelpar 5 and 10 mg. Eligible patients had inadequate response (alkaline phosphatase [AP] ≥ 1.67 × upper limit of normal (ULN)) or an intolerance to ursodiol and a total bilirubin ≤ 2 mg/dL. Cirrhosis was diagnosed using liver biopsy, imaging tests, or liver elastography. After 12 weeks, patients on 5 mg were dose-escalated to 10 mg when the AP threshold was not met (5/10 mg group). The primary outcome was AP % change from baseline. Secondary outcome measures included AP responder analyses (\u3c 1.67xULN), changes in hepatic function, inflammatory markers, and pruritus using the visual analogue scale (VAS). Safety analysis included adverse events and laboratory parameters. Results: 119 patients were exposed to at least one dose of seladelpar, 26 of whom had compensated cirrhosis (5/10 mg n = 15 and 10 mg n = 11). Analysis was performed with a July 2018 data cut. At this time 15 of 26 cirrhotic patients received seladelpar for 3 months, 13 of 26 for 6 months, and 8 of 26 for 1 year. In cirrhotic patients, the baseline values for the 5/10 and 10 mg groups were: mean AP-277 U/L and 309 U/L, median total bilirubin-0.73 mg/dL and 0.80 mg/dL, median ALT-32 U/L and 50 U/L, and median VAS 20 and 37, respectively. Mean decreases in AP (%) were –25% and –39% at 3 months, –24% and –41% at 6 months, and –36% and –43% at 1 year in the 5/10 mg and 10 mg groups, respectively. After 1 year, all patients in 5/10 mg and 3 of 5 patients in 10 mg had Ap\u3c 1.67 × ULN; the median decreases in ALT (%) were –31% and –50%, and the median absolute changes in pruritus VAS were 0 and –25 in 5/10 mg and 10 mg groups, respectively. Three patients with cirrhosis experienced an SAE, all unrelated to seladelpar. Total bilirubin, platelets, albumin, and INR remained stable. No liver decompensation events were observed. Conclusion: In PBC patients with compensated cirrhosis, seladelpar was shown to be safe and well tolerated and demonstrated anti-cholestatic and anti-inflammatory effects