Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia.

Plasma cholesterol and other lipoproteins play a significant role in the development of atherosclerosis and subsequent coronary heart disease (CHD). This 1 year study was designed to confirm the efficacy and safety of atorvastatin (Lipitor) compared to pravastatin, a marketed agent for low density lipoprotein cholesterol (LDL-C) reduction in hypercholesterolemic patients. Patients were recruited at 26 centers in six European countries. After a 6 week placebo baseline phase, patients were randomized to receive atorvastatin 10 mg or pravastatin 20 mg daily. The dose could be doubled at week 16, if LDL-C levels remained > or = 3.4 mmol/l (135 mg/dl). Atorvastatin significantly lowered LDL-C from baseline by 35% compared with 23% for pravastatin (P < 0.05). A total of 72% of atorvastatin patients attained the LDL-C target level of < 3.4 mmol/l, compared to 26% of pravastatin patients. Atorvastatin also significantly reduced TC, TG and apo B (P < 0.05). Safety was assessed by recording adverse events and measuring clinical laboratory parameters. The adverse event profile was similar for both treatment groups and neither treatment caused clinically relevant laboratory abnormalities. Atorvastatin 10 and 20 mg once daily is superior to pravastatin 20 and 40 mg once daily in treating patients with hypercholesterolemia.

An original intragastric delivery system for oral administration of solid formulations to fully conscious rats: its application to oxodipine studies.

The purpose of this paper is to describe an original intragastric delivery system for powders to conscious rats. This system is an administration cannula composed of a simple polypropylene tube, long enough to reach the stomach and an adapted metallic stem in the lumen of the tube. A finite dose of powder, set on the free extremity of the cannuly, is expulsed into the stomach. This delivery system is applied to study oxodipine absorption from oral solid forms containing appropriate vehicles. Different test formulations were administered to rats: solution by I.V. (1 mg/kg) and P.O. (2mg/kg) routes, and oral dry powders (2 ng/kg). Blood samples were collected until 12 hours post-dose. Oxodipine plasma levels are measured by a HPLC method. Results indicated that the rate and extent of absorption can be modulated by the administration of oxodipine in different formulations. The formulations studied can be classified as a function of the vehicles added to the solid formulation. In fact, the limiting factor of absorption in rats is the in vivo dissolution rate. Absolute bioavailability can be modulated by different formulations. The apparent elimination half-life was dependent on the dissolution rate of oxodipine from formulations.

Metabolism rate of oxodipine in rats and humans: comparison of in vivo and in vitro data.

The in vitro metabolism of oxodipine was studied with rat and human hepatic and intestinal microsomes. Rat liver, human liver and intestine were able to metabolize oxodipine in vitro to the main metabolites found in vivo, namely pyridine and deesterified derivatives; rat intestine did not produce any detectable metabolite. The Kms were found to be in the range of 30 to 60 microM. Human in vitro intestinal metabolism was negligible compared to that of liver and, taking into account the dose administered, it was predicted that the intestinal first-pass effect would also be negligible in vivo. The use of in vitro kinetic constants enabled us to evaluate the amount of oxodipine metabolized and to compare it to values found in vivo. Both results were on the same order of magnitude, indicating that it might be possible to evaluate the in vivo metabolism from in vitro data. Finally, we clearly showed, by substrate inhibition and immunoinhibition, that oxodipine was metabolized by the cytochrome P4503A subfamily both in intestine and in liver.