PMID- 19617248
OWN - NLM
STAT- MEDLINE
DCOM- 20091001
LR  - 20131121
IS  - 1076-0296 (Print)
IS  - 1076-0296 (Linking)
VI  - 15
IP  - 4
DP  - 2009 Jul-Aug
TI  - Isolation and characterization of contaminants in recalled unfractionated heparin 
      and low-molecular-weight heparin.
PG  - 395-401
LID - 10.1177/1076029609338710 [doi]
AB  - Recently, a contaminant was found in some clinically used unfractionated heparin 
      (UFH) preparations. Administration of this UFH was associated with an increased 
      risk of developing a wide range of adverse effects including death. To further 
      investigate the chemical profile of the contaminant, contaminated batches of UFH 
      were treated by exhaustive nitrous acid depolymerization followed by methanol 
      precipitation to remove heparin oligosaccharides. Because contaminated heparins 
      may have been used as starting material in the production of low-molecular-weight 
      heparins (LMWHs), a similar procedure was carried out using an experimental batch 
      of enoxaparin prepared from contaminated heparin. While high-pressure liquid 
      chromatography (HPLC) analysis of contaminated heparin did not distinguish the 
      presence of the contaminant, it could readily be observed as a high-molecular 
      weight shoulder in the elution profile of contaminated enoxaparin. Digesting 
      contaminated heparin with heparinase-I prior to HPLC analysis showed the presence 
      of a nondigestible component (15%-30% of the mixture). This contaminant was also 
      resistant to degradation by chondroitinases A, B, and C. Proton nuclear magnetic 
      resonance (NMR) indicated that the contaminant was oversulfated chondroitin 
      sulfate (OSCS). Size-exclusion chromatography indicated that the mean molecular 
      weight of the OSCS was 16.8 kD, comparable to that of a synthetic porcine 
      cartilage OSCS preparation that was used as a reference material (17.2 kD). While 
      varying degrees of high-molecular weight dermatan sulfate and other minor 
      impurities were detected, OSCS appeared to be the major contaminant in these 
      preparations. The process involved in the production of enoxaparin does not 
      significantly degrade OSCS.
FAU - Viskov, Christian
AU  - Viskov C
AD  - sanofi-aventis, 13 Quai Jules Guesde, Vitry sur Seine, France. 
      Christian.Viskov@sanofi-aventis.com
FAU - Bouley, E
AU  - Bouley E
FAU - Hubert, P
AU  - Hubert P
FAU - Martinez, Celine
AU  - Martinez C
FAU - Herman, F
AU  - Herman F
FAU - Jeske, Walter
AU  - Jeske W
FAU - Hoppensteadt, Debra
AU  - Hoppensteadt D
FAU - Walenga, Jeanine M
AU  - Walenga JM
FAU - Fareed, Jawed
AU  - Fareed J
LA  - eng
PT  - Journal Article
DEP - 20090717
PL  - United States
TA  - Clin Appl Thromb Hemost
JT  - Clinical and applied thrombosis/hemostasis : official journal of the 
      International Academy of Clinical and Applied Thrombosis/Hemostasis
JID - 9508125
RN  - 0 (Anticoagulants)
RN  - 0 (Enoxaparin)
RN  - 0 (Heparin, Low-Molecular-Weight)
RN  - 0 (Oligosaccharides)
RN  - 9007-28-7 (Chondroitin Sulfates)
RN  - EC 4.2.2.20 (Chondroitin ABC Lyase)
RN  - EC 4.2.2.7 (Heparin Lyase)
RN  - T2I5UM75DN (Nitrous Acid)
RN  - Y4S76JWI15 (Methanol)
SB  - IM
MH  - Animals
MH  - Anticoagulants/*analysis
MH  - Chondroitin ABC Lyase
MH  - Chondroitin Sulfates/chemistry/*isolation & purification
MH  - Chromatography, High Pressure Liquid
MH  - Drug Contamination
MH  - Enoxaparin/analysis
MH  - Heparin Lyase
MH  - Heparin, Low-Molecular-Weight/*analysis
MH  - Methanol
MH  - Molecular Weight
MH  - Nitrous Acid
MH  - *Nuclear Magnetic Resonance, Biomolecular
MH  - Oligosaccharides/chemistry/*isolation & purification
MH  - Sharks
MH  - Swine
EDAT- 2009/07/21 09:00
MHDA- 2009/10/02 06:00
CRDT- 2009/07/21 09:00
PHST- 2009/07/21 09:00 [entrez]
PHST- 2009/07/21 09:00 [pubmed]
PHST- 2009/10/02 06:00 [medline]
AID - 1076029609338710 [pii]
AID - 10.1177/1076029609338710 [doi]
PST - ppublish
SO  - Clin Appl Thromb Hemost. 2009 Jul-Aug;15(4):395-401. doi: 
      10.1177/1076029609338710. Epub 2009 Jul 17.