Pharmacodynamic effects of the Low Molecular Weight Heparin (LMWH) tinzaparin in obese, hemodialysis, healthy human subjects on plasma tissue factor pathway inhibitor and nitric oxide

Abstract number: P1855

Mousa S.

Albany College of Pharmacy & PRI at Albany, USA

Background  

Heparin and its improved version LMWH are known to have poly pharmacological actions at various levels. Earlier studies focused on the anti-Xa and anti-IIa pharmacodynamic for the different LMWH. This current investigation examined the effects of tinzaparin beyond its anti-Xa and anti-IIa.

Objectives  

Effects of the LMWH tinzaparin on plasma levels of tissue factor pathway inhibitor (TFPI) and nitric oxide (NO) were compared in obese, hemodialysis subjects, and normal healthy subjects.

Design and methods  

Obese (n = 13) and hemodialysis (n = 12) patients received a single 75 IU kg^-1 SC injection of tinzaparin. Normal healthy subjects (n = 32) received single SC tinzaparin dose regimens. Blood samples were obtained pre- and post administration of tinzaparin and at different intervals over 24 h and assayed for total TFPI and NO stable metabolites (nitrates and nitrites) plasma levels using a specific immunoassay and calorimetric methods.

Results  

Mean maximum plasma TFPI levels approached 150–230 ng mL^-1 at the 0.8 h and up to 5 h post-tinzaparin dose compared to basal TFPI levels of 35–90 ng mL^-1. Plasma TFPI levels were still about 2-fold above basal levels at 12 h and fell to basal levels at 16 h after tinzaparin dose. Basal plasma levels of NO, but not TFPI, were significantly lower (P < 0.01) in obese patients compared to controls. Haemodialysis patients showed a slightly higher basal TFPI and NO compared to controls. Similar TFPI and NO pharmacodynamic profiles for tinzaparin at 75 anti-Xa IU kg^-1 were demonstrated in hemodialysis and obese patients. Plasma NO (nitrate + nitrite) showed a lag time of about 5–6 h post-tinzaparin followed by a steady increase with a peak at 12–15 h and slow decline with a significant residual levels of NO at 24 h in obese, hemodialysis and healthy subjects.

Conclusion  

TFPI plasma levels following a single subcutaneous administration of 75 IU kg^-1 tinzaparin yields about a 3-fold increase in obese or hemodialysis subjects. A similar profile of plasma NO increase was shown in all groups. Data suggests a normal responsiveness of vascular endothelial cells and other cellular compartments to tinzaparin with regard to the pharmacodynamic profiles of plasma TFPI and NO in obese and hemodialysis subjects as compared to healthy human subjects.