| Pharmaceutical development of the novel arsenical based cancer therapeutic GSAO for Phase I clinical trial. | |
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MedLine Citation:
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PMID: 22286018 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The novel organoarsenical GSAO, 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid, has potential anti-angiogenic capability with application in cancer where tumour metastasis relies on neo-vascularisation. As GSAO arsenic is trivalent, the arsenoxide moiety reacts with appropriately spaced cysteine residues on adenine nucleotide translocase (ANT) mitochondrial membrane protein. Molecular oxidation of the arsenic to the pentavalent structure, as in the degradant GSAA (4-(N-(S-glutathionylacetyl)amino) phenylarsonic acid), prevents sulphydryl interaction and risks abolition of activity. We report here on formulation studies aiming to produce a parenteral product with the primary objective of restricting GSAA transformation from GSAO to protect maximal potency of the molecule. Successful anti-oxidant strategy primarily came from pH control. The presence of glycine was proposed to form a stabilising five-membered oxazarsolidinone ring with arsenoxide and this was investigated using potentiometric assays. We report on these tritration studies identifying a pK(a) of 8.2 associated with an As-OH, but not confirming ring presence. An original clinical trial pharmaceutical was successfully realised by lyophilisation of 50mg/mL GSAO in 100mM glycine solution, pH 7 to obtain a 48-month shelf life for the freeze-dried vials. The Phase I clinical study is ongoing in patients with solid tumours refractory to standard therapy. |
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Authors:
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M A Elliott; S J Ford; E Prasad; L J Dick; H Farmer; P J Hogg; G W Halbert |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-21 |
Journal Detail:
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Title: International journal of pharmaceutics Volume: - ISSN: 1873-3476 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-30 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7804127 Medline TA: Int J Pharm Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012. Published by Elsevier B.V. |
Affiliation:
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Research UK Formulation Unit, Strathclyde Institute for Pharmacy and Biomedical Sciences, Robertson Wing, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, Scotland, UK. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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