Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. G A FitzGerald, … , J A Lawson, A R Brash J Clin Invest. 1983;71(3):676-688. https://doi.org/10.1172/JCI110814. Research Article To assess the pharmacologic effects of aspirin on endogenous prostacyclin and thromboxane biosynthesis, 2,3-dinor-6- keto PGF1 alpha (PGI-M) and 2,3-dinor-thromboxane B2 (Tx-M) were measured in urine by mass spectrometry during continuing administration of aspirin. To define the relationship of aspirin intake to endogenous prostacyclin biosynthesis, sequential urines were initially collected in individuals prior to, during, and subsequent to administration of aspirin. Despite inter- and intra-individual variations, PGI-M excretion was significantly reduced by aspirin. However, full mass spectral identification confirmed continuing prostacyclin biosynthesis during aspirin therapy. Recovery of prostacyclin biosynthesis was incomplete 5 d after drug administration was discontinued. To relate aspirin intake to indices of thromboxane biosynthesis and platelet function, volunteers received 20 mg aspirin daily followed by 2,600 mg aspirin daily, each dose for 7 d in sequential weeks. Increasing aspirin dosage inhibited Tx-M excretion from 70 to 98% of pretreatment control values; platelet TxB2 formation from 4.9 to 0.5% and further inhibited platelet function. An extended study was performed to relate aspirin intake to both thromboxane and prostacyclin generation over a wide range of doses. Aspirin, in the range of 20 to 325 mg/d, resulted in a dose-dependent decline in both Tx-M and PGI-M excretion. At doses of 325-2,600 mg/d Tx-M excretion ranged from 5 to 3% of control values while PGI-M remained at 37-23% of control. 3 d […] Find the latest version: https://jci.me/110814/pdf Endogenous Biosynthesis of Prostacyclin and Thromboxane and Platelet Function during Chronic Administration of Aspirin in Man GARRET A. FITZGERALD, JOHN A. OATES, JACEK HAWIGER, RICHARD L. MAAS, L. JACKSON ROBERTS II, JOHN A. LAWSON, and ALAN R. BRASH, Divisions of Clinical Pharmacology and Thrombosis and Hemostasis, Departments of Medicine and Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 A B S T R A C T To assess the pharmacologic effects of tion over a wide range of doses. Aspirin, in the range aspirin on endogenous prostacyclin and thromboxane of 20 to 325 mg/d, resulted in a dose-dependent de- biosynthesis, 2,3-dinor-6-keto PGFia (PGI-M) and 2,3- cline in both Tx-M and PGI-M excretion. At doses of dinor-thromboxane B2 (Tx-M) were measured in urine 325-2,600 mg/d Tx-M excretion ranged from 5 to by mass spectrometry during continuing administra- 3% of control values while PGI-M remained at 37-23% tion of aspirin. To define the relationship of aspirin of control. 3 d after the last dose of aspirin (2,600 mg/ intake to endogenous prostacyclin biosynthesis, se- d) mean Tx-M excretion had returned to 85% of con- quential urines were initially collected in individuals trol, whereas mean PGI-M remained at 40% of pre- prior to, during, and subsequent to administration of dosing values. Although the platelet aggregation re- aspirin. Despite inter- and intra-individual variations, sponse (Tmax) to ADP ex vivo was inhibited during PGI-M excretion was significantly reduced by aspirin. administration of the lower doses of aspirin the ag- However, full mass spectral identification confirmed gregation response returned to control values during continuing prostacyclin biosynthesis during aspirin the final two weeks of aspirin administration (1,300 therapy. Recovery of prostacyclin biosynthesis was in- and 2,600 mg aspirin/d) despite continued inhibition complete 5 d after drug administration was discontin- of thromboxane biosynthesis. ued. To relate aspirin intake to indices of thromboxane These results suggest that although chronic admin- biosynthesis and platelet function, volunteers received istration of aspirin results in inhibition of endogenous 20 mg aspirin daily followed by 2,600 mg aspirin daily, thromboxane and prostacyclin biosynthesis over a wide each dose for 7 d in sequential weeks. Increasing as- dose range, inhibition of thromboxane biosynthesis is pirin dosage inhibited Tx-M excretion from 70 to 98% more selective at 20 than at 2,600 mg aspirin/d. How- of pretreatment control values; platelet TxB2 forma- ever, despite this, inhibition of platelet function is not tion from 4.9 to 0.5% and further inhibited platelet maximal at the lower aspirin dosage. Doses of aspirin function. in excess of 80 mg/d resulted in substantial inhibition An extended study was performed to relate aspirin of endogenous prostacyclin biosynthesis. Thus, it is intake to both thromboxane and prostacyclin genera- unlikely that any dose of aspirin can maximally inhibit thromboxane generation without also reducing endog- Portions of this work were presented at the 54th Session enous prostacyclin biosynthesis. These results also in- of the American Heart Association, 16-19 October 1981 Dallas, TX, at the National Meeting of the American Society dicate that recovery of endogenous prostacyclin bio- for Clinical Investigation, Washington, DC, 7-10 May 1982, synthesis is delayed following aspirin administration and at the 5th International Conference on Prostaglandins, and that the usual effects of aspirin on platelet function 18-21 May 1982, Florence, Italy. ex vivo may be obscured during chronic aspirin ad- Dr. FitzGerald is the recipient of a Faculty Development in man. Award from the Pharmaceutical Manufacturer's Association ministration Foundation. Dr. Oates is the Joe and Morris Werthan Professor of In- INTRODUCTION vestigative Medicine. Received for publication 8 October 1982 and in revised The use of aspirin as an analgesic, antiinflammatory, form 26 November 1982. and antipyretic agent has evolved empirically in ther- 676 J. Clin. Invest. © The American Society for Clinical Investigation, Inc. * 0021-9738/83/03/0676/13 $1.00 Volume 71 March 1983 676-688 apeutic practice. The more recent interest in aspirin mg four times per day. Full mass spectral analysis was per- as a platelet-inhibiting agent has derived from the formed on pooled urines obtained before and during aspirin administration to confirm continuing prostacyclin synthesis observation that aspirin prolonged the bleeding time during aspirin therapy. and inhibited platelet aggregation ex vivo (1). It is now In another investigation five different male volunteers appreciated that aspirin has several actions potentially (aged 28-33 yr; wt 78±7 kg) received aspirin in daily doses relevant to platelet function and that these may be of 20 and 2,600 mg (650 mg four times daily), each dose for 7 d, in successive weeks. Urine was obtained for determi- mutually antagonistic. Furthermore, the relative nation of 2,3-dinor-thromboxane B2 (Tx-M) and blood drawn prominence of these actions may be highly dependent for platelet function studies on the day prior to dosing and on the dose of aspirin administered. on the final day of each dosing period. Blood samples were Inhibition of human platelet aggregation ex vivo by obtained following an overnight (12-h) fast and were drawn aspirin is seen after doses as low as 20 mg daily (2). 1 h after the morning doses during the treatment period. In the final study, five different male volunteers received These low doses inhibit the cyclooxygenase enzyme of aspirin capsules in oral doses of 20, 40, 80, 160, 325, 650, the platelet and it is likely that this explains the ag- 1,300, and 2,600 mg daily. Each dose was given for 7 d and gregation defect. Aspirin irreversibly acetylates this ascending doses were administered in consecutive weeks. enzyme and thereby inhibits the capacity of the plate- Aspirin was administered as a single daily dose except the let to synthesize thromboxane A2, which can induce two highest doses, which were given as 650 mg twice per day and 650 mg four times per day. Highly motivated re- irreversible platelet aggregation (3). This is generally search workers were selected as volunteers to enhance com- regarded as a beneficial action of aspirin. However, pliance. Additionally, compliance was assessed by capsule the cyclooxygenase pathway in other tissues leads to count. 24 h collections of urine for prostacyclin and throm- the formation of prostaglandins that may themselves boxane metabolite determination were performed on the day prior to the first dose of aspirin, on the final day of each inhibit platelet activation. Recent attention has fo- dosage period and for the 3 d after the last dose of aspirin. cussed on prostacyclin, a vasodilator and potent in- Prostaglandin metabolites were adjusted to creatinine ex- hibitor of platelet aggregation formed in vascular en- cretion to reduce the possibility that incomplete collection dothelium (4). It has been suggested that tissue sen- of urine might have confounded the results. Urinary values sitivity to cyclooxygenase inhibition by aspirin is of creatinine did not significantly alter during the course of highly variable and thus aspirin may selectively alter any of the studies described. the capacity to synthesize endogenous prostaglandins (5, 6). Biochemical analyses Although the enzyme remains inhibited for the life- time of Quantification of Tx-M. Both Tx-M and PGI-M were exposed platelets, enzyme turnover permits measured by stable isotope dilution assay using gas chro- functional recovery in the vascular endothelium in matography-mass spectrometry. Briefly, the assay for Tx-M vitro (5). In addition, platelet cyclooxygenase may be required the addition of 100 ng of a combined tritium and more sensitive than the vascular enzyme to aspirin in- deuterium labeled internal standard to a 10% aliquot of a hibition in vitro (6), suggesting that it might be possible 24-h collection of urine. The urine was acidified to pH 3.2 and absorbed onto a column of Amberlite XAD-2 and the to achieve a dose-dependent, selective inhibition of metabolite eluted with ethanol.
Details
-
File Typepdf
-
Upload Time-
-
Content LanguagesEnglish
-
Upload UserAnonymous/Not logged-in
-
File Pages14 Page
-
File Size-