title: Antithrombotic effect of chikusetsusaponin IVa isolated from Ilex paraguariensis (Maté).
abstract: The triterpene chikusetsusaponin IVa was isolated from the fruit of Ilex paraguariensis. Using biochemical and pharmacological methods, we demonstrated that chikusetsusaponin IVa (1) prolongs the recalcification time, prothrombin time, activated partial thromboplastin time, and thrombin time of normal human plasma in a dose-dependent manner, (2) inhibits the amidolytic activity of thrombin and factor Xa upon synthetic substrates S2238 and S2222, (3) inhibits thrombin-induced fibrinogen clotting (50% inhibition concentration, 199.4 ± 9.1 μM), and (4) inhibits thrombin- and collagen-induced platelet aggregation. The results also indicate that chikusetsusaponin IVa preferentially inhibits thrombin in a competitive manner (K(i)=219.6 μM). Furthermore, when administered intravenously to rats, chikusetsusaponin IVa inhibited thrombus formation in a stasis model of venous thrombosis, although it did not induce a significant bleeding effect. Chikusetsusaponin IVa also prolonged the ex vivo activated partial thromboplastin time. Altogether, these data suggest that chikusetsusaponin IVa exerts antithrombotic effects, including minor hemorrhagic events. This appears to be important for the development of new therapeutic agents.
authors.affiliation: Faculty of Pharmacy, Federal University of Rio Grande do Sul , Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Tabitha
authors.initials: T
authors.lastname: Dahmer
authors.forename: Markus
authors.initials: M
authors.lastname: Berger
authors.forename: Adriana Gregory
authors.initials: AG
authors.lastname: Barlette
authors.forename: José
authors.initials: J
authors.lastname: Reck
authors.forename: Jéferson
authors.initials: J
authors.lastname: Segalin
authors.forename: Simone
authors.initials: S
authors.lastname: Verza
authors.forename: George González
authors.initials: GG
authors.lastname: Ortega
authors.forename: Simone Cristina Baggio
authors.initials: SC
authors.lastname: Gnoatto
authors.forename: Jorge Almeida
authors.initials: JA
authors.lastname: Guimarães
authors.forename: Hugo
authors.initials: H
authors.lastname: Verli
authors.forename: Grace
authors.initials: G
authors.lastname: Gosmann
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D030019:Ilex paraguariensis / Q000737:chemistry*; D016014:Linear Models; D008297:Male; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010314:Partial Thromboplastin Time; D010936:Plant Extracts / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012503:Saponins / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism; D013918:Thrombin Time
chemical_list: D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D010936:Plant Extracts; D010975:Platelet Aggregation Inhibitors; D012503:Saponins; C098580:chikusetsu saponin IVa; D009828:Oleanolic Acid; D013917:Thrombin; D015951:Factor Xa