PubMed · 12107917
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J C García-Pagán. 2002. [TIPSS].. https://pubmed.ncbi.nlm.nih.gov/12107917/
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BACKGROUND: Site-specific validation of the activated partial thromboplastin time (aPTT) therapeutic range is required to ensure administration of the optimal dose of unfractionated heparin. Therapeutic ranges of 1.5 to 2.5 times the control value are subtherapeutic for most modern aPTT reagents. PURPOSE: To audit the appropriateness of aPTT monitoring in clinical trials comparing unfractionated heparin and low-molecular-weight heparin in patients with venous thromboembolism. DATA SOURCES: Search of PubMed database from 1984 to 2001. STUDY SELECTION: Randomized, controlled trials that compared unfractionated and low-molecular-weight heparin for the treatment of venous thromboembolism. DATA EXTRACTION: Use of unvalidated and potentially suboptimal therapeutic ranges for aPTT in patients assigned to receive unfractionated heparin. DATA SYNTHESIS: Fifteen studies met inclusion criteria. Only 3 studies used a validated aPTT therapeutic range, and 11 studies used a range that included aPTT values 1.5 times the control value. Ten studies reported unfractionated heparin doses, and 7 of these documented a reduction to less than 30 000 U/d in response to aPTT results. CONCLUSIONS: Most studies monitored unfractionated heparin inappropriately. This shortcoming could be responsible for the reduced efficacy of unfractionated heparin in clinical trials.
Benzothiophene-anthranilamide 1 (3-chloro-N-[2-[[(4-fluorophenyl)amino]carbonyl]-4-methylphenyl]benzo[b]thiophene-2-carboxamide) was discovered by high throughput screening to be a highly potent and selective non-amidine inhibitor of human factor Xa with a K(i) of 15+/-4nM. Compound 1 is a selective inhibitor of human factor Xa as suggested by the K(i)((app)) determined for nine other human serine proteases and bovine trypsin. The activity of reconstituted human prothrombinase complex was inhibited by compound 1 when assayed in physiological concentrations of the substrate prothrombin. However, 27-fold higher inhibitor concentrations were needed to achieve the same level of inhibition than were required for the inhibition of free factor Xa, due in part to non-specific binding of the inhibitor to phospholipid under the assay conditions. Failure to demonstrate enzymatic cleavage of compound 1 suggests that compound 1 is solely an inhibitor rather than a substrate for factor Xa. The inhibition of factor Xa by compound 1 was reversible upon dilution of the enzyme/inhibitor mixture. Analyses of the inhibition mechanism with Dixon, Cornish-Bowden, and Lineweaver-Burk plots showed that compound 1 is a linear mixed-type inhibitor with 5-fold higher affinity for free factor Xa than the factor Xa/substrate complex. The linear mixed-type inhibition suggests that compound 1 binds to the active site region of factor Xa, but its binding cannot be fully displaced by the substrate S2222 (1:1 mixture of N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide and N-benzoyl-Ile-Glu(gamma-OMe)-Gly-Arg-p-nitroanilide hydrochloride). Thus, the inhibition mechanism for compound 1 is novel compared to most serine protease inhibitors including amidine-containing factor Xa inhibitors, which rely on binding to the S1 pocket of the enzyme active site. Compound 1 represents an attractive, novel structural template for further development of efficacious, safe, and potentially orally active human factor Xa inhibitors.