Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis

T Hohlfeld, N Zimmermann, A-A Weber, G Jessen, H Weber, K Schrör, H-D Höltje, R Ebel

Research output: Contribution to journalArticle

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Abstract

Background: Anti-inflammatory analgesics, including ibuprofen and naproxen, are known to interfere with the antiplatelet effect of aspirin, presumably as a result of a drug–drug interaction at the level of platelet cyclooxygenase-1 (COX-1).

Objective: We studied whether dipyrone, which has recently been reported to inhibit COX isoforms by a mechanism different from conventional non-steroidal anti-inflammatory drugs (NSAIDs), also interferes with the antiplatelet effect of aspirin.

Methods: Arachidonic acid- and collagen-induced aggregation, as well as thromboxane formation, were measured in human platelet-rich plasma. Platelet P-selectin expression was determined by flow cytometry and cell-free COX enzyme activity was quantified by luminol-enhanced luminescence of human platelet microsomes. In addition, computerized docking was performed based on the crystal structure of COX-1.

Results: 4-Methylaminoantipyrine (MAA), the active metabolite of dipyrone, largely attenuated or even completely abolished the inhibition of arachidonic acid-induced platelet aggregation, thromboxane formation and P-selectin expression by aspirin. Similar results were obtained for other pyrazolinones, as well as for the conventional NSAIDs ibuprofen and naproxen. Moreover, MAA attenuated the effect of aspirin on COX activity of platelet microsomes, suggesting a competition with aspirin at the COX-1 enzyme. This was confirmed by docking studies, which revealed that MAA forms a strong hydrogen bond with serine 530 within the COX-1, thereby preventing enzyme acetylation by aspirin.

Conclusion: This study demonstrates for the first time that dipyrone and other pyrazolinones have a high potential to attenuate or prevent the antiplatelet effect of aspirin. This should be considered if pyrazolinone analgesics are administered to patients with cardiovascular disease requiring antiplatelet aspirin therapy.
Original languageEnglish
Pages (from-to)166-173
Number of pages8
JournalJournal of Thrombosis and Haemostasis
Volume6
Issue number1
Early online date17 Oct 2007
DOIs
Publication statusPublished - Jan 2008

Fingerprint

Thromboxanes
Aspirin
Analgesics
Blood Platelets
Cyclooxygenase 1
Dipyrone
Naproxen
P-Selectin
Ibuprofen
Microsomes
Arachidonic Acid
Anti-Inflammatory Agents
Enzymes
Luminol
Platelet-Rich Plasma
Non-Steroidal Anti-Inflammatory Agents
Acetylation
Luminescence
Platelet Aggregation
Pharmaceutical Preparations

Keywords

  • aspirin
  • cyclooxygenase
  • dipyrone
  • drug interaction
  • platelets
  • pyrazolinone analgesics

Cite this

Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis. / Hohlfeld, T; Zimmermann, N; Weber, A-A; Jessen, G; Weber, H; Schrör, K; Höltje, H-D; Ebel, R.

In: Journal of Thrombosis and Haemostasis, Vol. 6, No. 1, 01.2008, p. 166-173.

Research output: Contribution to journalArticle

Hohlfeld, T ; Zimmermann, N ; Weber, A-A ; Jessen, G ; Weber, H ; Schrör, K ; Höltje, H-D ; Ebel, R. / Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis. In: Journal of Thrombosis and Haemostasis. 2008 ; Vol. 6, No. 1. pp. 166-173.
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T1 - Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis

AU - Hohlfeld, T

AU - Zimmermann, N

AU - Weber, A-A

AU - Jessen, G

AU - Weber, H

AU - Schrör, K

AU - Höltje, H-D

AU - Ebel, R

PY - 2008/1

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N2 - Background: Anti-inflammatory analgesics, including ibuprofen and naproxen, are known to interfere with the antiplatelet effect of aspirin, presumably as a result of a drug–drug interaction at the level of platelet cyclooxygenase-1 (COX-1). Objective: We studied whether dipyrone, which has recently been reported to inhibit COX isoforms by a mechanism different from conventional non-steroidal anti-inflammatory drugs (NSAIDs), also interferes with the antiplatelet effect of aspirin. Methods: Arachidonic acid- and collagen-induced aggregation, as well as thromboxane formation, were measured in human platelet-rich plasma. Platelet P-selectin expression was determined by flow cytometry and cell-free COX enzyme activity was quantified by luminol-enhanced luminescence of human platelet microsomes. In addition, computerized docking was performed based on the crystal structure of COX-1. Results: 4-Methylaminoantipyrine (MAA), the active metabolite of dipyrone, largely attenuated or even completely abolished the inhibition of arachidonic acid-induced platelet aggregation, thromboxane formation and P-selectin expression by aspirin. Similar results were obtained for other pyrazolinones, as well as for the conventional NSAIDs ibuprofen and naproxen. Moreover, MAA attenuated the effect of aspirin on COX activity of platelet microsomes, suggesting a competition with aspirin at the COX-1 enzyme. This was confirmed by docking studies, which revealed that MAA forms a strong hydrogen bond with serine 530 within the COX-1, thereby preventing enzyme acetylation by aspirin. Conclusion: This study demonstrates for the first time that dipyrone and other pyrazolinones have a high potential to attenuate or prevent the antiplatelet effect of aspirin. This should be considered if pyrazolinone analgesics are administered to patients with cardiovascular disease requiring antiplatelet aspirin therapy.

AB - Background: Anti-inflammatory analgesics, including ibuprofen and naproxen, are known to interfere with the antiplatelet effect of aspirin, presumably as a result of a drug–drug interaction at the level of platelet cyclooxygenase-1 (COX-1). Objective: We studied whether dipyrone, which has recently been reported to inhibit COX isoforms by a mechanism different from conventional non-steroidal anti-inflammatory drugs (NSAIDs), also interferes with the antiplatelet effect of aspirin. Methods: Arachidonic acid- and collagen-induced aggregation, as well as thromboxane formation, were measured in human platelet-rich plasma. Platelet P-selectin expression was determined by flow cytometry and cell-free COX enzyme activity was quantified by luminol-enhanced luminescence of human platelet microsomes. In addition, computerized docking was performed based on the crystal structure of COX-1. Results: 4-Methylaminoantipyrine (MAA), the active metabolite of dipyrone, largely attenuated or even completely abolished the inhibition of arachidonic acid-induced platelet aggregation, thromboxane formation and P-selectin expression by aspirin. Similar results were obtained for other pyrazolinones, as well as for the conventional NSAIDs ibuprofen and naproxen. Moreover, MAA attenuated the effect of aspirin on COX activity of platelet microsomes, suggesting a competition with aspirin at the COX-1 enzyme. This was confirmed by docking studies, which revealed that MAA forms a strong hydrogen bond with serine 530 within the COX-1, thereby preventing enzyme acetylation by aspirin. Conclusion: This study demonstrates for the first time that dipyrone and other pyrazolinones have a high potential to attenuate or prevent the antiplatelet effect of aspirin. This should be considered if pyrazolinone analgesics are administered to patients with cardiovascular disease requiring antiplatelet aspirin therapy.

KW - aspirin

KW - cyclooxygenase

KW - dipyrone

KW - drug interaction

KW - platelets

KW - pyrazolinone analgesics

U2 - 10.1111/j.1538-7836.2007.02800.x

DO - 10.1111/j.1538-7836.2007.02800.x

M3 - Article

VL - 6

SP - 166

EP - 173

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

SN - 1538-7933

IS - 1

ER -