chiniofon and Dyslipidemias

To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP).. The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n= 28) or were treated with a placebo (n= 10).. In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60-5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h.. BAY 60-5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated.

Topics: Administration, Oral; Adult; Blood Pressure; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Dose-Response Relationship, Drug; Dyslipidemias; Electrocardiography; Heart Rate; Humans; Hydroxyquinolines; Male; Middle Aged; Single-Blind Method; Young Adult

8-Hydroxyquinoline when subjected to Duff reaction resulted in the formation of unexpected 7-methylaminomethylene-8-oxo-7, 8-dihydroquinoline-5-carbaldehyde 2, which existed in the keto-enamine form, in which the aromaticity of the relevant ring was disrupted, which upon subsequent treatment with various primary amines resulted in its nucleophilic substitution of aliphatic methyl amine. These interesting novel derivatives were evaluated in vitro for their antioxidant and in vivo for their antidyslipidemic and post-heparin lipolytic activities. Compound 6 was found to be most active antidyslipidemic and antioxidative agent in this series, respectively, and thus represent a new class of promising lead.

Topics: Amines; Animals; Antioxidants; Dyslipidemias; Fluorescence; Heparin; Hydroxyl Radical; Hydroxyquinolines; Lipid Metabolism; Male; Rats; Schiff Bases; Superoxides