INFLAMMATION AND CARDIOVASCULAR DISEASES: VALSARTAN PHARMACOKINETICS AND PHARMACODYNAMICS IN RHEUMATOID ARTHRITIS

HOME
Search 2003 Abstracts

011

INFLAMMATION AND CARDIOVASCULAR DISEASES: VALSARTAN PHARMACOKINETICS AND PHARMACODYNAMICS IN RHEUMATOID ARTHRITIS

N Daneshtalab, AS Russell, RZ Lewanczuk, F Jamali

Edmonton, Alberta

Inflammatory conditions decrease cardiovascular response to b-adrenergic and calcium channel blockers despite increased levels of the drugs due to downregulation of the receptors during inflammation by inflammatory mediators such as C-reactive protein (CRP), nitric oxide (NO) and tumor necrosis factor (TNFa). The purpose of this investigation was to determine whether downregulation is also evident in angiotensin II type 1 receptors (AT₁R) during varying inflammatory states.

METHODS: A total of 38 normotensive subjects were recruited for the human study and divided into 3 groups according to the severity of disease; 14 patients had acute arthritis, 12 patients had rheumatoid arthritis in remission and 12 served as control subjects. An AT₁R antagonist valsartan (160 mg) was given to all the subjects and blood samples were taken for at 0, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 8, and 12 hours for pharmacokinetic (PK) analysis. Thirteen cardiovascular parameters including systolic, diastolic and mean arterial pressure were determined at the time of blood sample measurement for pharmacodynamic (PD) analysis. The degree of inflammation was measured using inflammatory markers such as tissue swelling, TNFa, NO and CRP at the time of blood sampling. An HPLC method was used for the PK analysis of valsartan.

RESULTS: The levels of inflammatory mediators were significantly higher in patients with acute arthritis as compared with arthritis in remission and control subjects. The PK parameters area under the concentration vs. time curve (AUC), oral clearance (Cl/F), terminal half-life (t_1/2) and maximum concentration (C_max) were determined to be not significantly different between the 3 groups. Similar results were observed when the area under the % effect versus time curve (AUEC) and the maximum effect from baseline (E_max) were determined for the 13 cardiovascular parameters.

CONCLUSION: Neither the PK nor the PD of valsartan was altered with severity of rheumatoid arthritis. This is clinically significant, as it indicates valsartan as an alternative antihypertensive agent to b blockers or calcium channel blockers for patients who have inflammatory diseases such as angina, myocardial infarction and rheumatoid arthritis.