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        Testing the suitability of a structured substance database for pharmacovigilance purposes: an exploratory study about the role of structural alerts and reactive metabolites in drug toxicity

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        Onderzoeksproject eindverslag Helen Gatling.pdf (1.946Mb)
        Publication date
        2022
        Author
        Gatling, Helen
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        Summary
        The GSRS database was developed by the Global Ingredient Archival System (GINAS) initiative and contains the molecular structure, classification information and metabolites of compounds used in human and animal medicinal, food, tobacco, and cosmetic products. Using GSRS, five sub-studies were performed each investigating a pre-selected SA-ADR relationship. For four sub-studies, the SAADR relationship was described in former studies. For the fifth sub-study, a newly discovered potential SA-ADR relationship was investigated. For each study, a GSRS search was performed, and it was extracted if a specific drug-ADR combination was reported disproportionally in VigiLyze, the global database for Individual Case Safety Reports of the WHO, and in addition the summary of product characteristics (SmPC) was checked. First it was shown that the GSRS database could indeed be queried to find relevant structures containing a number of pre-selected SAs. It was also shown that, based on a specific RM, GSRS contained sufficient information to highlight drugs that formed similar RMs or contained parts of the RM in their original structure. Thirdly, the possibilities of searching for drugs containing structural varieties within one drug class were investigated and this showed the mediating effects of a substituent on the occurrence of ADRs. This analysis showed the potential usability of the GSRS for future PV research. Additionally, it was demonstrated that GSRS could be used to find drugs with diverse therapeutic indications containing a pre-selected SA. Looking at the SmPCs and reporting rate for the results, 2 signs of the involvement of this SA in the development of Steven-Johnson syndrome and methemoglobinemia were displayed. Finally, a possible relationship between a SA that was discovered by looking at the reason behind the retraction of two fluoroquinolones and the ADR QT prolongation was described. The drugs containing the SA showed, with one exception, a high reporting rate for QT prolongation, whereas drugs that did not contain the SA did not. Implications This study shows that the GSRS database is a suitable tool for identifying drugs containing a SA. It can help PV research by finding structurally related drugs in pre- and postmarketing stages.
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        https://studenttheses.uu.nl/handle/20.500.12932/43084
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