title: Oversulfated chondroitin sulfate and OSCS-contaminated heparin cause dose- and route-dependent hemodynamic effects in the rat.
abstract: During 2007-2008, serious adverse events were reported following iv administration of certain batches of commercially available heparin in humans. Anaphylactoid reactions with acute hypotension were the hallmark of these cases. Subsequently, it was shown that a contaminant, oversulfated chondroitin sulfate (OSCS), was responsible for these adverse events. The present study was undertaken to further elucidate the risks related to OSCS-contaminated heparin preparations. Using an anesthetized rat hemodynamic model, marked diastolic blood pressure drops were induced with a single iv injection of a contaminated heparin (1000 IU/kg; 34% wt/wt OSCS). OSCS alone (0.8 and 20 mg/kg) or in combination (0.8-1.7 mg/kg) with uncontaminated heparin produced a similar hypotensive effect, whereas heparin spiked with 0.2 or 0.4 mg/kg OSCS produced no hemodynamic changes. In conscious rats, acute hypotensive effects were seen following single iv administration of OSCS-spiked heparin (1.7 or 3.0 mg/kg). Conversely, no hemodynamic effects were observed with same doses when administered sc. Pretreatment with a bradykinin-2 receptor antagonist (HOE140) fully abolished the hypotensive response after iv OSCS (1.7 mg/kg) administration, whereas pretreatment with the histamine (H1) receptor antagonist cetirizine did not. In vitro, OSCS (25 and 250 μg/ml) induced a robust, dose-related increase in kallikrein activity in rat and human plasma with a lower amplitude of response in dog and pig. The data suggest that the adverse events associated with OSCS-contaminated heparin are dependent upon the concentration of contaminant and its route of administration. Furthermore, the kallikrein-kinin system plays a pivotal role in the initiation of OSCS-related vascular effects.
authors: Department of Disposition, Safety and Animal Research, Sanofi-aventis R&D, Vitry-sur-Seine 94400 France.
authors: Alain
authors: A
authors: Corbier
authors: Nathalie
authors: N
authors: Le Berre
authors: David
authors: D
authors: Rampe
authors: Harry
authors: H
authors: Meng
authors: Martin
authors: M
authors: Lorenz
authors: Pascale
authors: P
authors: Vicat
authors: Sophie
authors: S
authors: Potdevin
authors: Michel
authors: M
authors: Doubovetzky
mesh_terms: D000707:Anaphylaxis / Q000139:chemically induced; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D002809:Chondroitin Sulfates / Q000008:administration & dosage* / Q000097:blood; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004340:Drug Contamination; D005260:Female; D006493:Heparin / Q000008:administration & dosage* / Q000097:blood; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D016234:Kallikrein-Kinin System / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine
chemical_list: C065679:icatibant; D006493:Heparin; D002809:Chondroitin Sulfates; D001920:Bradykinin