Depolymerization techniques
Either chemical or enzymatic depolymerization techniques or a combination of the two underlie the vast majority of analyses carried out on the structure and function of heparin and heparan sulfate (HS). Enzymatic
The enzymes traditionally used to digest heparin or HS are naturally produced by the soil bacterium Pedobacter heparinus (formerly named Flavobacterium heparinum). This bacterium is capable of using either heparin or HS as its sole carbon and nitrogen source. To do so, it produces a range of enzymes such as lyases, glucuronidases, sulfoesterases, and sulfamidases. The lyases have mainly been used in heparin/HS studies. The bacterium produces three lyases, heparinases I (EC 4.2.2.7), II (no EC number assigned) and III (EC 4.2.2.8) and each has distinct substrate specificities as detailed below. The lyases cleave heparin/HS by a beta elimination mechanism. This action generates an unsaturated double bond between C4 and C5 of the uronate residue. The C4-C5 unsaturated uronate is termed ΔUA or UA. It is a sensitive UV chromophore (max absorption at 232 nm) and allows the rate of an enzyme digest to be followed, as well as providing a convenient method for detecting the fragments produced by enzyme digestion. Chemical
Nitrous acid can be used to chemically depolymerize heparin/HS. Nitrous acid can be used at pH 1.5 or at a higher pH of 4. Under both conditions, nitrous acid effects deaminative cleavage of the chain. At both high (4) and low (1.5) pH, deaminative cleavage occurs between GlcNS-GlcA and GlcNS-IdoA, albeit at a slower rate at the higher pH.
The Quaid family subsequently sued the manufacturer, Baxter Healthcare Corp., and settled with the hospital for $750,000. Prior to the Quaid accident, six newborn babies at Methodist Hospital in Indianapolis, Indiana, were given an overdose. Three of the babies died after the mistake.In July 2008, another set of twins born at Christus Spohn Hospital South, in Corpus Christi, Texas, died after an accidentally administered overdose of the drug. The overdose was due to a mixing error at the hospital pharmacy and was unrelated to the products packaging or labeling. As of July 2008, the exact cause of the twins death was under investigation.In March 2010, a two-year-old transplant patient from Texas was given a lethal dose of heparin at the University of Nebraska Medical Center. The exact circumstances surrounding her death are still under investigation. Production
Pharmaceutical-grade heparin is derived from mucosal tissues of slaughtered meat animals such as porcine (pig) intestines or bovine (cattle) lungs. Advances to produce heparin synthetically have been made in 2003 and 2008. In 2011, a chemoenzymatic process of synthesizing low molecular weight heparins from simple disaccharides was reported. Research
As detailed in the table below, the potential is great for the development of heparin-like structures as drugs to treat a wide range of diseases, in addition to their current use as anticoagulants.