[Show abstract][Hide abstract] ABSTRACT: In late 2007 and early 2008, a cluster of adverse events in patients receiving Heparin Sodium Injection occurred in the United States and in some countries in Europe. The adverse events were reported as being "allergic type" reactions, chiefly characterized by acute hypotension, nausea, and shortness of breath. The root cause of the cluster of adverse events was determined to be a contamination of the heparin by oversulfated chondroitin sulfate. The isolation and structure determination of this contaminant was accomplished by an FDA-led consortium of academic and government laboratories and independently by Baxter Healthcare, whose vial products were first identified in the USA as being associated with the adverse events. Oversulfated chondroitin sulfate was shown to produce acute hypotension in animal models, demonstrating that it was most likely the causative agent responsible for certain of the reported adverse events in patients receiving the contaminated heparin products.
Full-text · Article · Jan 2012 · Handbook of experimental pharmacology
[Show abstract][Hide abstract] ABSTRACT: From late December 2007 to February 2008, the number of adverse responses to heparin infusions rose noticeably above baseline levels in North America, ultimately resulting in a widespread recall of all heparin vial products made by Baxter Healthcare. Using various analytical techniques and the de novo synthesis of a fully sulfated chondroitin sulfate (FSCS) derivative, the authors have confirmed the identity of the contaminant as an oversulfated chondroitin sulfate (OSCS) and have also defined the heterogeneity and concentration of this contaminant in various lots of heparin. Using both contaminated heparin products and the synthetically produced derivative, the authors have shown that the OSCS produces a dose-dependent hypotension in both pigs and rats and that the response in rats can be abrogated with bradyzide, a rodent-selective B(2) bradykinin receptor antagonist. The no observed effect level (NOEL) for this contaminant appears to be approximately 1 mg/kg, corresponding to a contamination level in finished lots of heparin of approximately 3%. Using human plasma, the OSCS derivative was shown to activate kallikrein. These data provide insight into the etiology of the adverse events, particularly refractory hypotension, observed in patients who were exposed to heparin contaminated with OSCS.
Full-text · Article · Feb 2010 · The Journal of Clinical Pharmacology