Publications

Quantitative consequences of the pharmacological model of oral anticoagulant action, explored through computer simulation
A.D. Corlan, I. Corlan, C. Constantinescu. Terapeutica, Farmacologie si Toxicologie Clinica 2003, 7(3), 39-54.

ABSTRACT: There is, yet, no satisfactory method to control the therapeutic response to oral anticoagulants. Anually, over 6% of chronically anticoagulated patients suffer a major bleeding event, including almost 1% who die as a consequence of the therapy. The anticoagulation level is maintained within therapeutic limits, overall, only for 60% of time.

Many recent studies present quantitative results of isolated aspects of the pharmacokinetics and phamacodynamics of oral anticoagulants. The simulation system (usable with a browser at warfarissimo.corlan.net) presented in this paper integrates results on the absorbtion and distribution of the R and S enantiomers of warfarin and acenocoumarol, genetical varieties of their elimination due to mutations of the cytochrome P-450 2C9 gene, the effect on vitamin-K-2,3-epoxide reductase and quantitative changes in the methabolism of vitamin K, the effect of reduced vitamin-KH₂ on the synthesis of factors II, VII, IX and X, protein C and protein S, the effect of their changed synthesis and elimination on the INR.

With this simulator we explore the effect of various regimens of anticoagulant administration on the INR, as a function of genetical and constitutional parameters. We reproduced the effect on INR as seen in most patients. The reduction of CYP2C9 activity led to a detectable change in the S-/R-warfarin ratio, as reported in the literature. The use of a variabile daily dose of acenocoumarol, such as a 2-2-2-2-1 scheme or the administration at a random hour each day led to a 200% increase in the range of the INR compared to regimens with a fixed dose at the same hour daily.

[Terapeutica] [postprint (PDF), in Romanian]

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