The multikinase inhibitor axitinib is a potent inhibitor of human CYP1A2

Eine potenzielle neue Standardtherapie für Patienten mit metastasiertem bzw. inoperablem GIST nach Imatinib-und Sunitinib-Versagen sieht Prof. Carsten Bokemeyer, Hamburg, in dem oralen Multikinase-Inhibitor Regorafenib. In der randomisierten Phase-III-Studie GRID wurde Regorafenib als Drittlinientherapie nach Imatinib- und Sunitinib-Versagen gegen best-supportiv-care verglichen und erreichte eine statistisch hoch signifikante Verlängerung der PFS, dem primären Studienendpunkt (4,8 vs. 0,9 Monaten; HR 0,27; p˂0,0001).

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Isolation and Structural Charaderization of a Potent Inhibitor of Coagulation Factor Xa from the Leech Haementeria ghilianii

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646610 ◽

1989 ◽

Vol 61 (03) ◽

pp. 437-441 ◽

Cited By ~ 28

Author(s):

Cindra Condra ◽

Elka Nutt ◽

Christopher J Petroski ◽

Ellen Simpson ◽

P A Friedman ◽

...

Keyword(s):

Molecular Weight ◽

Salivary Gland ◽

Amino Acid ◽

Amino Acid Sequence ◽

Western Blot ◽

Potent Inhibitor ◽

Factor Xa ◽

Coagulation Factor ◽

Sds Page ◽

Bovine Factor

SummaryThe present work reports the discovery and charactenzation of an anticoagulant protein in the salivary gland of the giant bloodsucking leech, H. ghilianii, which is a specific and potent inhibitor of coagulation factor Xa. The inhibitor, purified to homogeneity, displayed subnanomolar inhibition of bovine factor Xa and had a molecular weight of approximately 15,000 as deduced by denaturing SDS-PAGE. The amino acid sequence of the first 43 residues of the H. ghilianii derived inhibitor displayed a striking homology to antistasin, the recently described subnanomolar inhibitor of factor Xa isolated from the Mexican leech, H. officinalis. Antisera prepared to antistasin cross-reacted with the H. ghilianii protein in Western Blot analysis. These data indicate that the giant Amazonian leech, H. ghilianii, and the smaller Mexican leech, H. officinalrs, have similar proteins which disrupt the normal hemostatic clotting mechanisms in their mammalian host’s blood.

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A Thiazole Compound with Potential Antithrombotic Activity

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657156 ◽

1982 ◽

Vol 47 (02) ◽

pp. 173-176 ◽

Cited By ~ 14

Author(s):

E E Nishizawa ◽

A R Mendoza ◽

T Honohan ◽

K A Annis

Keyword(s):

Platelet Aggregation ◽

Potent Inhibitor ◽

Platelet Rich Plasma ◽

Development Program ◽

Antithrombotic Agent ◽

Antithrombotic Activity ◽

Thiazole Derivative ◽

Cyclooxygenase Activity ◽

Drug Development Program

SummaryA thiazole derivative, 4,5-bis(p-methoxyphenyl)-2-(trifluoromethyl)-thiazole was found to be a potent inhibitor of collagen-induced platelet aggregation, in vitro, using platelets from at least six species, including man. It was active in human platelet-rich plasma at a concentration of 1 ng/ml. While its antiplatelet activity was greater than that of flurbiprofen, its cyclooxygenase activity was equivalent to that of flurbiprofen. Also, compared to flurbiprofen, the thiazole had less anti-inflammatory activity in the hind-paw edema test. The thiazole derivative inhibited platelet aggregation following oral administration in five laboratory species. In the guinea pig it was active at 0.5 mg/kg. The LD50 in mice was greater than 1000 mg/kg (i.p.). This compound, which was designed through a systematic drug development program, may have high potential as an antithrombotic agent.

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Tridegin, a Novel Peptidic Inhibitor of Factor XIIIa from the Leech, Haementeria ghilianii, Enhances Fibrinolysis In Vitro

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656085 ◽

1997 ◽

Vol 77 (05) ◽

pp. 0959-0963 ◽

Cited By ~ 18

Author(s):

Lisa Seale ◽

Sarah Finney ◽

Roy T Sawyer ◽

Robert B Wallis

Keyword(s):

Potent Inhibitor ◽

Platelet Rich Plasma ◽

Factor Xiiia ◽

Cross Linking ◽

Fibrinolytic Enzymes ◽

Small Polypeptide ◽

Tissue Plasminogen ◽

Protein Cross Linking

SummaryTridegin is a potent inhibitor of factor Xllla from the leech, Haementeria ghilianii, which inhibits protein cross-linking. It modifies plasmin-mediated fibrin degradation as shown by the absence of D-dimer and approximately halves the time for fibrinolysis. Plasma clots formed in the presence of Tridegin lyse more rapidly when either streptokinase, tissue plasminogen activator or hementin is added 2 h after clot formation. The effect of Tridegin is markedly increased if clots are formed from platelet-rich plasma. Platelet-rich plasma clots are lysed much more slowly by the fibrinolytic enzymes used and if Tridegin is present, the rate of lysis returns almost to that of platelet- free clots. These studies indicate the important role of platelets in conferring resistance to commonly used fibrinolytic enzymes and suggest that protein cross-linking is an important step in this effect. Moreover they indicate that Tridegin, a small polypeptide, may have potential as an adjunct to thrombolytic therapy.

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Ridogrel Inhibits Systemic and Renal Formation of Thromboxane A2 and Antagonizes Platelet Thromboxane A2/Prostaglandin Endoperoxide Receptors upon Chronic Administration to Man

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656351 ◽

1992 ◽

Vol 68 (02) ◽

pp. 214-220 ◽

Cited By ~ 5

Author(s):

C Weber ◽

J R Beetens ◽

F Tegtmeier ◽

P Van Rooy ◽

E Vercammen ◽

...

Keyword(s):

Uric Acid ◽

Potent Inhibitor ◽

Ex Vivo ◽

Thromboxane A2 ◽

Chronic Administration ◽

Response Curves ◽

Clinically Significant ◽

Synthase Inhibitor ◽

The Right ◽

Steady State Plasma Level

SummaryThe effects of ridogrel, a dual thromboxane A2 (TXA2) synthase inhibitor and TXA2/prostaglandin (PG) endoperoxide receptor antagonist, on systemic and renal production of prostaglandins and on platelet TXA2/PG endoperoxide receptors was evaluated upon chronic administration (300 mg b. i. d. orally, for 8 and 29 days) to man. Such a medication with ridogrel inhibits the systemic as well as the renal production of TXA2 as measured by the urinary excretion of 2,3-dinor-TXB2 and TXB2 respectively without inducing significant changes in systemic or renal PGI2 production. Simultaneously with the latter effects, the production of TXB2 by spontaneously coagulated whole blood ex vivo is inhibited (>99%) while that of PGE2 and PGF2α is largely increased. Administration of ridogrel causes a three- to five-fold shift to the right of concentration-response curves for U46619 in eliciting platelet aggregation; no tachyphylaxis is observed after 29 days of treatment in this respect. Apart from a reduction of serum uric acid levels with a concomitant increase in urinary uric acid excretion during the first days of treatment, no clinically significant changes in hematological, biochemical, hemodynamic and coagulation parameters occur during the 8 days or 29 days study. The study demonstrates that ridogrel is a potent inhibitor of the systemic as well as renal TXA2 synthase and an antagonist of platelet TXA2/PG endoperoxide receptor in man, covering full activity during 24 h at steady-state plasma level conditions without tachyphylaxis during 29 days of medication. The compound is well tolerated, at least during 1 month of administration.

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