Analysis of pharmaceutical heparins and potential contaminants using 1H-NMR and PAGE

Zhang, Zhenqing; Li, Boyangzi; Suwan, Jiraporn; Zhang, Fuming; Wang, Zhenyu; Liu, Haiying; Mulloy, Barbara; Linhardt, Robert J.

doi:10.1002/jps.21729

Cited by 75 publications

(70 citation statements)

References 33 publications

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“…Conversely, the GAG waste contains heparin and DS. PAGE has been shown to be able to resolve individual components of GAG mixtures (11). From this initial analysis, it is clear that undersulfated polysaccharide components are largely removed early in the heparin purification process, with DS being removed throughout the purification process.…”

Section: Resultsmentioning

confidence: 99%

“…Various compendia standardsetting organizations across the globe, including the United States Pharmacopeia and the European Pharmacopeia, have proposed implementation of tests, based on defined biochemical assays, NMR spectroscopy and capillary electrophoresis (CE)/high performance liquid chromatography (HPLC), to measure specific structural and charge properties of heparin (10). Reexamination of historical lots of pharmaceutical heparin, prepared since 1941, using these types of methods, suggest a surprising level of purity and structural consistency (11).…”

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confidence: 99%

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Orthogonal analytical approaches to detect potential contaminants in heparin

Guerrini

Zhang

Shriver

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Heparin is a widely used anticoagulant and antithrombotic agent. Recently, a contaminant, oversulfated chondroitin sulfate (OSCS), was discovered within heparin preparations. The presence of OSCS within heparin likely led to clinical manifestations, most prevalently, hypotension and abdominal pain leading to the deaths of several dozens of patients. Given the biological effects of OSCS, one continuing item of concern is the ability for existing methods to identify other persulfonated polysaccharide compounds that would also have anticoagulant activity and would likely elicit a similar activation of the contact system. To complete a more extensive analysis of the ability for NMR and capillary electrophoresis (CE) to capture a broader array of potential contaminants within heparin, we completed a systematic study of NMR, both mono-and bidimensional, and CE to detect both various components of sidestream heparin and their persulfonated derivatives. We show that given the complexity of heparin samples, and the requirement to ensure their purity and safety, use of orthogonal analytical techniques is effective at detecting an array of potential contaminants that could be present.anticoagulant ͉ capillary electrophoresis ͉ contamination ͉ NMR ͉ oversulfated chondroitin

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Orthogonal analytical approaches to detect potential contaminants in heparin

Guerrini

Zhang

Shriver

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, it detects not only oversulfated GAGs but also other possible contaminants in heparin. 23 Some contaminated heparin lots (e.g. G1, G2, and G3) produced higher UV absorbance compared to authentic heparin (Fig.…”

Section: Discussionmentioning

confidence: 93%

Identification of Chemically Sulfated/desulfated Glycosaminoglycans in Contaminated Heparins and Development of a Simple Assay for the Detection of Most Contaminants in Heparin

Pan

Qian²,

Zhou³

et al. 2010

Glycobiology Insights

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Contaminated heparin was linked to at least 149 deaths and hundreds of adverse reactions. Published report indicates that heparin contaminants were a natural impurity, dermatan sulfate, and a contaminant, oversulfated chondroitin sulfate (OSCS). OSCS was assumed to derive from animal cartilage. By analyzing 26 contaminated heparin lots from different sources, our data indicate that the heparin contaminants were chemically sulfated or chemically sulfated/desulfated glycosaminoglycans (GAGs) consisting of heparan sulfate, chondroitin sulfate, and dermatan sulfate based on monosaccharide quantification, CE, heparin lyase digestion, and liquid chromatography/mass spectrometry analysis. Since currently recommended heparin quality control assays had failed to detect certain heparin contaminants, a simple method that detects most contaminants in heparin was developed. This assay detects specific heparin structures that most contaminants cannot mimic and can be performed in any laboratory equipped with an UV spectrometer.

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“…Furthermore, other analytical approaches that are able to detect OSCS in Hep preparations, such as polyacrylamide gel electrophoresis [5,11], coagulation assay prothrombin time [12][13][14], UV spectroscopy scanning [15] and Inc-PolyH assay [16] have been published. Overall, specific and sensitive analytical techniques are required for the detection of very low percentages of several possible contaminants fairly similar as regards structure and physico-chemical properties such as charge density and molecular mass.…”

Section: Introductionmentioning

confidence: 99%