Dokument: Insight into interactions between aspirin and non-steriodal anti-inflammatory drugs
| Titel: | Insight into interactions between aspirin and non-steriodal anti-inflammatory drugs | |||||||
| Weiterer Titel: | Insight into interactions between aspirin and non-steriodal anti-inflammatory drugs | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=31205 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20141030-090611-1 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Aaruni Saxena [Autor] | |||||||
| Dateien: |
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| Stichwörter: | drug interaction, aspirin, NSAIDs | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | This thesis studies the interaction of aspirin (acetylsalicylic acid, ASA) and nonsteroidal antiinflammatory drugs (NSAIDs) in human blood platelets. ASA is widely used all around the globe to prevent atherothrombotic events. Multi-morbid patients suffering from cardiovascular and rheumatological disorders including rheumatoid arthritis or osteoarthritis need a comedication of ASA with NSAID drugs. Hence, potential NSAID/ASA drug interactions, possibly affecting the
cardioprotective effect of ASA, are of great interest. The present research aimed to determine which NSAIDs would decrease the anti-platelet activity of ASA. Using arachidonic acid-induced platelet aggregation and thromboxane formation108 in platelet rich plasma from healthy donors, the effect of NSAIDs on the antiplatelet activity of ASA was studied experimentally. It turned out that celecoxib, dipyrone, fenoprofen, flufenamic acid, ibuprofen, methylaminoantipyrin, mefenamic acid, nabumetone, naproxen, nimesulide, NS-398, oxaprozin, phenazone, piroxicam, propylphenazone, sulindac sulfide and tolmetin clearly decreased the antiplatelet activity of ASA. In contrast, acetaminophen, diclofenac, flurbiprofen, indomethacin and ketoprofen did not decrease the antiplatelet activity of ASA. The data was further used to design a QSAR model which showed that the IC50 and selectivity of NSAID towards COX-1 might predict the effect of NSAID on the antiplatelet activity of ASA. Further investigation aimed to identify the reasons for the interference of NSAIDs with the antiplatelet activity of ASA by molecular docking studies, which were performed for all NSAIDs on COX-I protein (PDB ID: 1CQE). Docking studies suggested that NSAIDs, forming hydrogen bonds with Ser 530, Arg 120, Tyr 385 and some other amino acids in the COX-I hydrophobic channel, play role in determining whether a particular NSAID might decrease the antiplatelet activity of ASA or not. NSAIDs which decreased the antiplatelet activity of ASA in the in vitro experiments mostly showed one or more hydrogen bond interactions with Ser 530, Tyr 385 or Arg 120. Less or no hydrogen bond interactions were seen in docking studies of NSAIDs which did not decrease the antiplatelet activity of ASA in the in vitro experiments. Therefore, hydrogen bond interactions with Ser 530 and Tyr 385 were found to be most relevant for NSAIDs effects on the antiplatelet activity of ASA.This thesis studies the interaction of aspirin (acetylsalicylic acid, ASA) and nonsteroidal antiinflammatory drugs (NSAIDs) in human blood platelets. ASA is widely used all around the globe to prevent atherothrombotic events. Multi-morbid patients suffering from cardiovascular and rheumatological disorders including rheumatoid arthritis or osteoarthritis need a comedication of ASA with NSAID drugs. Hence, potential NSAID/ASA drug interactions, possibly affecting the cardioprotective effect of ASA, are of great interest. The present research aimed to determine which NSAIDs would decrease the anti-platelet activity of ASA. Using arachidonic acid-induced platelet aggregation and thromboxane formation108 in platelet rich plasma from healthy donors, the effect of NSAIDs on the antiplatelet activity of ASA was studied experimentally. It turned out that celecoxib, dipyrone, fenoprofen, flufenamic acid, ibuprofen, methylaminoantipyrin, mefenamic acid, nabumetone, naproxen, nimesulide, NS-398, oxaprozin, phenazone, piroxicam, propylphenazone, sulindac sulfide and tolmetin clearly decreased the antiplatelet activity of ASA. In contrast, acetaminophen, diclofenac, flurbiprofen, indomethacin and ketoprofen did not decrease the antiplatelet activity of ASA. The data was further used to design a QSAR model which showed that the IC50 and selectivity of NSAID towards COX-1 might predict the effect of NSAID on the antiplatelet activity of ASA. Further investigation aimed to identify the reasons for the interference of NSAIDs with the antiplatelet activity of ASA by molecular docking studies, which were performed for all NSAIDs on COX-I protein (PDB ID: 1CQE). Docking studies suggested that NSAIDs, forming hydrogen bonds with Ser 530, Arg 120, Tyr 385 and some other amino acids in the COX-I hydrophobic channel, play role in determining whether a particular NSAID might decrease the antiplatelet activity of ASA or not. NSAIDs which decreased the antiplatelet activity of ASA in the in vitro experiments mostly showed one or more hydrogen bond interactions with Ser 530, Tyr 385 or Arg 120. Less or no hydrogen bond interactions were seen in docking studies of NSAIDs which did not decrease the antiplatelet activity of ASA in the in vitro experiments. Therefore, hydrogen bond interactions with Ser 530 and Tyr 385 were found to be most relevant for NSAIDs effects on the antiplatelet activity of ASA. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät » Institute » Institut für Pharmakologie und Klinische Pharmakologie | |||||||
| Dokument erstellt am: | 30.10.2014 | |||||||
| Dateien geändert am: | 30.10.2014 | |||||||
| Datum der Promotion: | 22.10.2014 |
