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Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects

Marta L. Capone, PhD^_*,, Maria G. Sciulli, PhD^_*,, Stefania Tacconelli, PhD^_*,, Marilena Grana, MD^_*,, Emanuela Ricciotti, PharmD^_*,, Giulia Renda, MD^_*,, Patrizia Di Gregorio, MD, Gabriele Merciaro and Paola Patrignani, PhD^_*,,_*

^_* Department of Medicine and Center of Excellence on Aging, School of Medicine, "G. d’Annunzio" University, Chieti, Italy
"G. d’Annunzio" University Foundation, Ce.S.I., Chieti, Italy
SS Annunziata Hospital, Chieti, Italy.

Manuscript received October 22, 2004; revised manuscript received December 17, 2004, accepted January 4, 2005.

^_* Reprint requests and correspondence: Dr. Paola Patrignani, Dipartimento di Medicina e Scienze dell’Invecchiamento, Università "G. d’Annunzio," Via dei Vestini 31, 66013 Chieti, Italy. (Email: ppatrignani{at}unich.it).

OBJECTIVES: We investigated the occurrence of pharmacodynamic interaction between low-dose aspirin and naproxen.

BACKGROUND: The uncertainty of cardioprotection by naproxen has encouraged its combination with aspirin in patients with arthritis and cardiovascular disease.

METHODS: The incubation of washed platelets with naproxen for 5 min before the addition of aspirin reduced the irreversible inhibition of thromboxane (TX)B₂ production by aspirin. The pharmacodynamic interaction between the two drugs was then investigated in four healthy volunteers who received aspirin (100 mg daily) for 6 days and then the combination of aspirin and naproxen for further 6 days: aspirin 2 h before naproxen (500 mg, twice-daily dosing). After 14 days of washout, naproxen was given 2 h before aspirin for further 6 days.

RESULTS: The inhibition of serum TXB₂ production (index of platelet cyclooxygenase [COX]-1 activity) and platelet aggregation ex vivo and urinary 11-dehydro-TXB₂ levels (index of TXB₂ biosynthesis in vivo) by aspirin alone (99 ± 0.2%, 95 ± 0.6%, and 81 ± 4%, respectively) was not significantly altered by the co-administration of naproxen, given either 2 h after aspirin or in reverse order. In a second study, the concurrent administration of a single dose of aspirin and naproxen did not affect platelet TXB₂ production and aggregation at 1 h after dosing, when aspirin alone causes maximal inhibitory effect. Moreover, the rapid recovery of platelet COX-1 activity and function supports the occurrence of a pharmacodynamic interaction between naproxen and aspirin.

CONCLUSIONS: Naproxen interfered with the inhibitory effect of aspirin on platelet COX-1 activity and function. This pharmacodynamic interaction might undermine the sustained inhibition of platelet COX-1 that is necessary for aspirin’s cardioprotective effects.

Abbreviations and Acronyms   AA = arachidonic acid   BID = twice-daily dosing   CI = confidence interval   COX = cyclooxygenase   IC50 = concentrations required to inhibit 50% of enzyme activity   NANSAIDs = nonaspirin nonsteroidal anti-inflammatory drugs   NSAIDs = nonsteroidal anti-inflammatory drugs   PG = prostaglandin   TX = thromboxane

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