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At least 19 recordsLinked to original sources
PubMed2001

Metabolism of sulfinpyrazone sulfide and sulfinpyrazone by human liver microsomes and cDNA-expressed cytochrome P450s.

Human liver microsomes catalyze the oxidation of sulfinpyrazone sulfide (SPZS) to a variable mixture of sulfinpyrazone (SPZ) enantiomers and two minor phenolic metabolites. In one, the thiophenyl ring is hydroxylated, whereas in the second an N-phenyl ring is hydroxylated. SPZ is further oxidized to sulfinpyrazone sulfone (SPZO) and a minor polar metabolite that also has an N-phenyl ring hydroxylated. Determination of the metabolism of SPZ and SPZS under modified incubation conditions of prior heat treatment, higher pH, and the presence of detergent indicated that the formation of SPZ was cytochrome P450 (P450)- but not flavin monooxygenase-dependent. Specific P450 inhibitors (sulfaphenazole, quinidine sulfate, coumarin, diethyldithiocarbamic acid, troleandomycin, and furafylline) and specific cDNA-expressed P450s were used to identify the major isoforms responsible for the oxidation of SPZS to SPZ and SPZ to SPZO. Both P450 2C9 and P450 3A4 were responsible for the oxidation of SPZS to SPZ, whereas P450 3A4 alone catalyzed the further oxidation of SPZ to SPZO. SPZS was found to be metabolized by P450 2C9 to SPZ with a high degree of enantiomeric selectivity (9:1) and a K(m) comparable with its previously determined K(i) for inhibition of the P450 2C9-dependent 7-hydroxylation of (S)-warfarin (WARF). In contrast, the P450 3A4-catalyzed oxidation of SPZS to SPZ proceeded with the same enantioselectivity but to a much lesser degree (58:42). These results provide evidence that the metabolism of both (S)-WARF and SPZS is mediated by a common enzyme, P450 2C9, which is central to understanding the WARF-SPZ interaction and SPZS-mediated drug interactions in general.

Chromatography, High Pressure Liquid↗
PubMed2000

Sulfinpyrazone reduces cyclosporine levels: a new drug interaction in heart transplant recipients.

BACKGROUND: Management of cyclosporine (CsA)-associated hyperuricemia in heart transplantation (HT) is difficult. Because of the myelotoxicity of combined allopurinol and azathioprine, we tested sulfinpyrazone. METHODS: We studied 120 HT recipients (109 men; mean age at HT, 52+/-10 years). All had received allopurinol for at least 6 months, which was stopped for 1 month before initiation of sulfinpyrazone. Mean follow-up from HT to onset of sulfinpyrazone (200 mg/day) was 59+/-41 months. We stopped the drug after 6+/-2 months. We compared CsA level and daily dose, serum creatinine, blood urea, and uric acid at onset and before interruption of sulfinpyrazone and, as control, in the last 6 months of allopurinol. RESULTS: Mean uricemia decreased with allopurinol (0.58+/-0.12 vs. 0.41+/-0.07 mmol/liter, p = 0.0001) as well as with sulfinpyrazone (0.51+/-0.13 vs. 0.40+/-0.12 mmol/liter, p = 0.0001). Mean creatinine increased (171+/-42 and 164+/-35 micromol/liter, p = 0.01) with allopurinol, whereas it tended to decrease with sulfinpyrazone (160+/-35 and 154+/-48 micromol/liter, p = NS). Mean urea did not change with allopurinol (14+/-5 vs. 15+/-7 mmol/liter, p = NS), but fell with sulfinpyrazone (14.01+/-5 vs. 12.60 +/-5 mmol/liter, p = 0.0004). Mean CsA levels were constant with allopurinol (193+/-73 vs. 188+/-65 ng/ml, p = NS), although CsA dose was slightly reduced (2.7+/-0.8 vs. 2.6+/-0.8 mg/kg/day, p = 0.007). Conversely, CsA levels dropped with sulfinpyrazone (183+/-89 vs. 121 +/-63 ng/ml, p = 0.0001) despite an increase in CsA daily dose (2.6 +/-0.9 vs. 2.8+/-0.9 mg/kg/day, p = 0.0001). Two subjects were treated for acute rejection. We observed no other side effects. In HT recipients sulfinpyrazone, as an alternative to allopurinol, is effective in achieving metabolic control of hyperuricemia. However, this drug reduced CsA levels, thus the risk of rejection is present.

Allopurinol↗
PubMed1985

Dose-related cardiac electrophysiologic effects of sulfinpyrazone.

To test the hypothesis that sulfinpyrazone exerts cardiac electrophysiologic effects, the drug was intravenously injected into 20 subjects during invasive electrophysiologic testing. Sulfinpyrazone was given intravenously as a bolus and by infusion to achieve two different and stable serum levels. The 20 subjects who were treated with drug were assigned to either a low- (N = 10) or high- (N = 10) dose regimen. The resultant four serum levels of sulfinpyrazone were 102 +/- 45, 199 +/- 75, 278 +/- 57, and 352 +/- 77 X 10(-3) mumol (means +/- SD). Electrophysiologic measurements were made during a baseline electrophysiologic study and at each of the sulfinpyrazone levels and at equivalent times in an untreated control group (N = 11). Two electrophysiologic measurements differed when measured at the highest level of sulfinpyrazone and in control subjects: increased HV interval in sinus rhythm and shortened atrial functional refractory period in sinus rhythm (only for those values below the median). Serum levels of sulfinpyrazone correlated with increased sinoatrial conduction time (only for those values above the median; r = 0.64) and with shortened atrial functional refractory periods (r = 0.37). The latter was stronger (r = 0.67) when only values below the median were included in analysis. Shortening of atrial functional refractory period correlated with serum sulfinpyrazone levels during atrial pacing at fixed cycle lengths of 600 and 500 msec. Serum levels of sulfinpyrazone did not correlate with changes in HV interval. HV intervals did not increase in subjects receiving sulfinpyrazone during atrial pacing and, therefore, the effect on HV interval in sinus rhythm is felt to be spurious.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Plasma levels and effects of sulfinpyrazone in patients requiring chronic hemodialysis.

Sulfinpyrazone (Anturane), which inhibits platelet synthesis of prostaglandins and platelet release of serotonin, was given to patients with chronic renal failure requiring hemodialysis. Patients were mateched in double-blind fashion to receive either placebo or sulfinpyrazone at 200 mg orally three times a day. Peak plasma levels of sulfinpyrazone after the first 200-mg dose ranged from 6.7 to 11.4 micrograms/ml (mean : 8.7 micrograms/ml). The plasma concentration showed a monoexponential disappearance pattern with an apparent half-life of 4 hours. At steady state, sulfinpyrazone peak plasma levels were 10.7 to 30.1 micrograms/ml. Residual plasma levels 12 hours after a final dose while in steady state were 3.7 and 4.3 micrograms/ml. Sulfinpyrazone protected against falls of platelet counts normally encountered during hemodialysis. Sulfinpyrazone blocked the increased platelet aggregability and the platelet uptake and release of serotonin normally seen following dialysis. Sulfinpyrazone prevented the consumption of antithyrombin III which is normally seen with hemodialysis, without having changed the anticoagulant efficacy of heparin. Sulfinpyrazone can be given to patients with chronic renal failure. It prevents platelet consumption during hemodialysis and protects against the decrement of antithyrombin III normally seen during hemodialysis.

Blood Coagulation↗
PubMedDate not supplied

Effect of sulfinpyrazone on ventricular arrhythmia, prostaglandin synthesis, and catecholamine release following coronary artery occlusion in the cat.

We examined if inhibition of endogenous prostaglandin (PG) synthesis reduced the severity of ventricular arrhythmia and the incidence of ventricular fibrillation (VF) following occlusion of the left anterior descending coronary artery (LAD) in anesthetized cats. We also determined whether the PGs were interacting in a facilitory manner with the sympathetic nervous system to produce arrhythmia and VF after LAD occlusion. Sulfinpyrazone, an inhibitor of cyclo-oxygenase enzyme, or vehicle was administered intravenously to cats 1 h before LAD occlusion. Sulfinpyrazone completely (p less than 0.001) inhibited the release of 6-keto-PGF1 alpha into the great cardiac vein following LAD occlusion. Sulfinpyrazone (100 mg/kg) significantly (p less than 0.001) reduced the amount of ventricular arrhythmia and the incidence of VF (p less than 0.05) in the 1st h after LAD occlusion. In addition to 6-keto-PGF1 alpha sulfinpyrazone also (p less than 0.001) inhibited the increase in plasma norepinephrine from the heart due to sympathetic nervous system stimulation following LAD occlusion. Since sulfinpyrazone was ineffective in increasing the dose of digoxin required to produce arrhythmia and death, sulfinpyrazone apparently did not depress cardiac excitability. Finally, the extent of infarction resulting from LAD occlusion was not different in sulfinpyrazone-treated animals compared with control. These data indicate that sulfinpyrazone, by inhibiting endogenous PG synthesis in the heart following LAD occlusion, may prevent a facilitory interaction between PGs and the sympathetic nervous system that contributes, in part, to the development of ventricular arrhythmia and VF normally associated with this event.

Animals↗
PubMed1985

Effects of sulfinpyrazone on renal function and prostaglandin formation in man.

Sulfinpyrazone (800 mg/day for 6 days) significantly reduced the excretion of the main urinary prostaglandin E metabolite by 54% in 6 healthy female volunteers. While sulfinpyrazone did not affect inulin clearance, clearances of creatinine and PAH were significantly diminished by 18.0 and 44.7%, respectively. In the anaesthetized dog sulfinpyrazone decreased PAH clearance and PAH extraction concomitantly without affecting renal blood flow. These results show that clearances of creatinine and PAH do not reliably reflect glomerular filtration and renal perfusion, respectively, during sulfinpyrazone administration. Whereas sodium balance and body weight were not significantly different between the first control period and sulfinpyrazone administration, net sodium excretion significantly increased from 121.6 +/- 5.4 mEq/day during sulfinpyrazone treatment to 139.3 +/- 6.6 mEq/day during the following control period, while body weight significantly decreased indicating modest sodium retention during drug administration. Plasma renin activity, vascular sensitivity to angiotensin II, and urinary excretion of the enzymes N-acetylglucosaminidase and alanineaminopeptidase were not affected by sulfinpyrazone administration. In summary, sulfinpyrazone caused a decrease of total body prostaglandin E formation in healthy female volunteers together with a moderate sodium retention. Despite inhibition of prostaglandin synthesis, glomerular filtration rate, plasma renin activity, or pressor effects of angiotensin II were not altered.

Adult↗
PubMed1981

Preservation of platelets during extracorporeal circulation in sheep. A comparison between aspirin and sulfinpyrazone.

We studied the effect of aspirin and sulfinpyrazone on changes in platelet count, thromboxane B2 production, and pulmonary vascular resistance following the onset of veno-venous membrane oxygenator perfusion in sheep. Perfusion under identical circumstances was performed in three groups of animals, with one group serving as controls, one group receiving pretreatment with 1.5 grams of sulfinpyrazone iv, and one group receiving pretreatment with aspirin 50 mg/kg, iv. Both aspirin and sulfinpyrazone eliminated the rise in thromboxane B2 and the increase in pulmonary vascular resistance seen in control animals. Platelet preservation was improved significantly with sulfinpyrazone pretreatment, but not affected by aspirin. We conclude that sulfinpyrazone and aspirin have different mechanisms of action as far as platelet preservation during extracorporeal perfusion is concerned. The major difference may be sulfinpyrazone's ability to reduce platelet adhesion to the membrane surface. Since both aspirin and sulfinpyrazone eliminated the pulmonary vascular-response, but only sulfinpyrazone preserved platelets, it is apparent that the pulmonary vascular response is more closely related to thromboxane synthesis than to platelet disappearance.

Animals↗
PubMed1981

Species differences in the disposition and metabolism of sulfinpyrazone.

1. The disposition and metabolism of sulfinpyrazone have been studied in rats, guinea-pigs, rabbits, dogs, rhesus monkeys and miniature swine after intravenous administration of 100 mg/kg of 14C-labelled drug. 2. In all species, the integrated plasma concentration (AUC, 0-24 h) of total radioactivity was almost completely covered by the sum of the AUC-values of unchanged sulfinpyrazone and six metabolites, i.e. the sulphide, the sulphone, p-hydroxy-sulfinpyrazone, the p-hydroxy-sulphide, the p-hydroxy-sulphone and 4-hydroxy-sulfinpyrazone. 3. Comparison of the plasma level profiles of unchanged sulfinpyrazone and the metabolites revealed pronounced differences between the species. Unchanged sulfinpyrazone was the most prominent compound in plasma of rats, dogs, monkeys and swine, whereas the sulphide metabolite predominated in guinea-pigs. In plasma of rabbits, these two compounds were found in similar amounts. 4. Species with predominant renal excretion of the 14C dose, i.e. rabbits, dogs and monkeys, eliminated sulfinpyrazone to a high extent unchanged. The renal excretion of the sulphide metabolite was low in all species. 5. Species differences in the biotransformation of sulfinpyrazone explain previously observed differences in inhibitory effect on platelet aggregation. This effect is intensive and long-lasting in species showing high plasma concentrations of the sulphide metabolite.

Animals↗
PubMed1995

Inhibition of (S)-warfarin metabolism by sulfinpyrazone and its metabolites.

Sulfinpyrazone markedly potentiates the anticoagulant effect of warfarin. The increased clotting time is accompanied by a marked decrease in the clearance of (S)-warfarin by virtue of a decrease in the P4502C9-catalyzed formation clearance to its major and inactive metabolite (S)-7-hydroxywarfarin. These data suggested that the mechanism of the drug interaction might be mediated through the inhibition of the catalytic activity of P4502C9 by sulfinpyrazone. However, initial human liver microsomal studies indicated that the in vitro Ki, for inhibition of (S)-7-hydroxywarfarin formation by sulfinpyrazone is at least 25-fold higher than the therapeutic concentration of sulfinpyrazone in vivo. This result implied that other inhibitors probably contribute to the interaction. Kinetic studies conducted on sulfinpyrazone and two major metabolites, sulfinpyrazone sulfide and sulfinpyrazone sulfone, in microsomes prepared from three human livers give mean Ki's of 230 microM, 17 microM, and 73 microM respectively. Because sulfinpyrazone and its sulfide metabolite attain comparable plasma concentrations during the course of therapy, our inhibition results suggest that the sulfide metabolite is likely to be the primary species responsible for the inhibition of P4502C9-catalyzed formation of (S)-7-hydroxywarfarin and the decrease in (S)-warfarin clearance in vivo.

Drug Synergism↗
PubMed1982

Effects of sulfinpyrazone on early graft closure after myocardial revascularization.

The effect of sulfinpyrazone on the incidence of early postoperative closure of saphenous vein bypass grafts was compared with placebo in a prospective randomized study of 255 eligible patients. Treatment with sulfinpyrazone (800 mg/day) was started 24 hours after operation in 130 patients; 125 patients received placebo. Graft blood flow was measured at operation in 96 percent of all patients. Graft angiography was performed between the 7th and 14th postoperative days. There was no significant difference between the two groups in graft blood flow, number and diameter of the grafted arteries, left ventricular filling pressure or ejection fraction. During the study 73 patients (41 on sulfinpyrazone, 32 on placebo therapy) were excluded because graft angiography was contraindicated or because of concomitant use of anticoagulant or antiplatelet drugs. The incidence rate of early graft closure in the remaining 182 patients (43.1 grafts) was 3.8 percent (8 or 212) in the sulfinpyrazone group and 9.1 percent (20 of 219) in the placebo group (p less than 0.025). The incidence of graft closure for the sulfinpyrazone and placebo groups classified according to the recipient coronary arteries was: (1) left anterior descending artery; 3 of 98 versus 11 of 111; p less than 0.05; (2) left circumflex coronary artery: 3 of 50 versus 5 of 43; difference not significant; (3) right coronary artery: 2 of 64 versus 4 of 65; difference not significant. The incidence of closure in grafts with a flow of less than 30 ml/min did not differ significantly in the sulfinpyrazone and placebo groups (4 of 26 versus 6 of 22). These results suggest that sulfinpyrazone reduces the incidence of early graft closure in grafts with a flow rate greater than 30 ml/min.

Constriction, Pathologic↗
PubMed1980

Sulfinpyrazone in the prevention of sudden death after myocardial infarction.

We report the results of a randomized double-blind, multicenter trial comparing sulfinpyrazone (200 mg four times a day) and a placebo in the prevention of cardiac mortality among 1558 patients followed for an average of 16 months, beginning 25 to 35 days after a documented myocardial infarction. All but one of the 106 deaths in the group were cardiac; 59 were sudden. The reduction in cardiac mortality at 24 months in the sulfinpyrazone group was 32 per cent (P = 0.058), and the reduction in sudden death was 43 per cent (P = 0.041). The benefit of sulfinpyrazone was attributable entirely to a reduction in sudden death during the second through seventh months after infarction, when there were 35 cardiac deaths in the placebo group and 17 in the sulfinpyrazone group (P = 0.021); of these deaths, 24 in the placebo group and six in the sulfinpyrazone group were sudden cardiac deaths -- a sulfinpyrazone-induced 74 per cent reduction in the calculated mortality rate (P = 0.003). We conclude that sulfinpyrazone prevents sudden cardiac death during the high-risk period shortly after an acute myocardial infarction, but that there is no further apparent effect beyond the seventh month after infarction.

Aged↗
PubMed1983

Effect of sulfinpyrazone on homocysteine-induced endothelial injury and arteriosclerosis in baboons.

The effect of sulfinpyrazone on endothelial injury induced by homocysteine has been studied both in vitro, using cultured human umbilical vein endothelial cells, and in vivo, using a primate model of homocysteine-induced arteriosclerosis. Oral sulfinpyrazone (250 mumol/kg body weight per day in three divided doses) in eight chronically homocystinemic baboons (0.14 +/- 0.04 mM plasma homocystine) decreased the extent of aortic endothelial injury as measured morphometrically by silver staining techniques, compared with six untreated comparably homocystinemic animals (denuded surface averaged 0.5% with range 0-2.1 vs 7.7 +/- 1.6%, respectively; P less than 0.001). Sulfinpyrazone therapy to homocystinemic baboons also normalized platelet survival and turnover measurements (5.1 +/- 0.4 days and 70,000 +/- 11,000 platelets/microliter per day vs. 2.8 +/- 0.6 days and 179,000 +/- 19,000 platelets/microliter per day in untreated homocystinemic controls; P less than 0.001). Sulfinpyrazone therapy also reduced the size and frequency of homocysteine-induced intimal lesion formation (P less than 0.001). Although sulfinpyrazone reduced the amount of specific 51Cr release from cultured human umbilical vein endothelial cells induced by 10 mM homocysteine after 24 hours of co-incubation, no effect was observed in assays of endothelial cell detachment when sulfinpyrazone (10(-5) M) or its thioether metabolite were pre- or co-incubated during 24 hours with homocysteine (2.5-10 mM). These data suggest that sulfinpyrazone may protect endothelial cells from injury in vivo by some apparently indirect mechanism.

Animals↗
PubMed1984

Role of the gut flora in the reduction of sulfinpyrazone in humans.

Peak plasma concentrations of sulfinpyrazone occurred about 2 h after administration of a single oral dose (200 mg tablet) to 11 normal volunteers. In contrast, the peak concentrations of the active sulfide metabolite occurred 15 h after dosing. Concurrent oral administration of metoclopramide with sulfinpyrazone resulted in a 4-fold decrease in the time to peak sulfide concentrations and a 3-fold increase in the amounts formed. A slow release formulation showed a low, variable bioavailability, but the proportion of sulfide was 3-fold higher based on the ratio of the area under the plasma concentration-time curve of the sulfide to that of the parent compound. Intravenous administration of sulfinpyrazone demonstrated that the tablets had a high bioavailability (about 90%), and the time to peak plasma concentration of the sulfide and the amount formed were similar to those seen after oral administration. Patients who had undergone surgical removal of the distal part of the intestine had normal plasma concentrations of sulfinpyrazone, but negligible amounts of the sulfide, after oral administration of sulfinpyrazone. The ileostomy effluent of such patients showed little ability to reduce sulfinpyrazone in vitro, in contrast to the extensive reduction detected with normal feces. These data demonstrate that the hind gut microflora are the principal and possibly the only site of reduction of sulfinpyrazone to its active sulfide metabolite in humans.

Administration, Oral↗
PubMed1982

Effects of sulfinpyrazone on ventricular vulnerability in the normal and the ischemic heart.

The effects of sulfinpyrazone were studied in 33 chloralose-anesthetized dogs. Ventricular fibrillation thresholds, mid diastolic thresholds and duration of the effective refractory period were determined in the normal heart after intravenous administration of sulfinpyrazone, 30 mg/kg body weight. The drug significantly raised the ventricular fibrillation threshold by 24 percent and the mid diastolic threshold by 36 percent and prolonged the effective refractory period by seven percent. The influence of sulfinpyrazone during acute myocardial ischemia was evaluated before and during a 10 minute occlusion of the left anterior descending coronary artery and after abrupt release of the occlusion. Although the drug afforded significant protection during coronary occlusion, it had no effect on the ventricular fibrillation threshold after reperfusion. Because potent cardiocardiac reflexes are elicited during ischemia, the influence of sulfinpyrazone on the ventricular fibrillation threshold was studied during norepinephrine infusion. Sulfinpyrazone attenuated the reduction of the ventricular fibrillation threshold during sympathetic humoral stimulation. Its effect was additive to beta adrenergic blockade with practolol and membrane stabilization with lidocaine. This investigation suggests that sulfinpyrazone exerts significant effects on ventricular vulnerability of both the normal and the ischemic myocardium. Further studies are needed to elucidate its precise mechanism of action.

Animals↗
PubMed1981

The metabolism of prostaglandin E2 is decreased by sulfinpyrazone in isolated hamster lungs.

The metabolism of prostaglandin E2 (PGE2) was decreased in isolated male hamster lungs, when sulfinpyrazone was infused into the pulmonary circulation. After pulmonary injection of 20 nmol of 14C-PGE2 the amount of 15-keto-metabolites of PGE2 was in the effluent from control lungs 4.0 +/- 0.5 nmol (mean +/- SEM) and in those from 20 mu M and 100 mu M sulfinpyrazone treated lungs 1.9 +/- 0.2 nmol (2P Less Than 0.01 compared to the control) and 1.7 +/- 0.4 nmol (2P Less Than 0.01), respectively. The amount of unmetabolized PGE2 was correspondingly increased in the effluent by sulfinpyrazone. The rate of efflux of the radioactivity from the lungs was increased by sulfinpyrazone. After injection of 10 nmol of 14C-PGE2 into the pulmonary circulation half of the injected radioactivity appeared in the effluent in 30 +/- 4 sec in control and in 15 +/- 0.7 sec (2P Less Than 0.01) in 20 mu M sulfinpyrazone experiments. Sulfinpyrazone had no effect on the activity of 15-hydroxyprostaglandin dehydrogenase in the 100.000 g supernatant fraction of homogenized hamster lungs. Thus the decreased metabolism of PGE2 in the pulmonary circulation of hamster lungs is obviously not due to the inhibition of 15-hydroxyprostaglandin dehydrogenase. A more likely explanation seems to be the decreased uptake of PGE2 into the lung cells.

Animals↗
PubMed1982

The effect of sulfinpyrazone on the response to sympathetic nervous system stimulation.

The purpose of this study was to determine if sulfinpyrazone has a direct action on sympathetic nerve endings to prevent release of the transmitter. Pre-synaptic and post-synaptic events as well as direct sympathetic nervous system stimulation were tested in 15 alpha-chloralose anesthetized cats before and 1 hour after sulfinpyrazone (100 mg . kg-1, i.v.). Heart rate response to cardiac accelerator nerve stimulation or to increasing doses of isoproterenol was not significantly depressed by sulfinpyrazone. In addition, no alteration in the reflex activation of the sympathetic nervous system in response to histamine was observed following sulfinpyrazone. Both norepinephrine and epinephrine levels were similar to those levels reported previously by Smith and Robinson for (7) untreated cats. We conclude sulfinpyrazone has no direct depressing effect on the sympathetic nerve endings and that this mechanism cannot explain the reported beneficial effect of sulfinpyrazone on coronary occlusion induced arrhythmias.

Animals↗
PubMed1985

Cyclooxygenase inhibition, platelet function, and metabolite formation during chronic sulfinpyrazone dosing.

The inhibitory effects of sulfinpyrazone are more marked ex vivo than in vitro, suggesting biotransformation to potentially active metabolites such as the sulfide and sulfone metabolites. As a platelet inhibitor, the sulfide metabolite is 10 times as potent as the parent and because of its long t1/2, the former may lead to cumulative inhibition of platelet function in vivo during chronic sulfinpyrazone dosing. In our study, healthy subjects received sulfinpyrazone, 200 mg four times a day, for 6 days. Plasma levels of the sulfide metabolite rose slightly from 2.1 +/- 0.8 micrograms/ml 12 hr after the fourth dose to 2.8 +/- 0.8 microgram/ml 12 hr after the twenty-fourth dose. This was associated with increasing inhibition of ex vivo platelet aggregation induced by platelet-activating factor during the dosing period, but inhibition of arachidonic acid-induced aggregation did not increase cumulatively during dosing and collagen-induced aggregation was not inhibited. Inhibition of platelet aggregation was no longer evident 24 hr after the final dose of sulfinpyrazone. The effects of sulfinpyrazone on cyclooxygenase activity were assessed by measurement of thromboxane B2 production by thrombin-stimulated platelets ex vivo and urinary excretion of the major prostacyclin metabolite 2,3-dinor-6-keto-PGF1 alpha. During sulfinpyrazone dosing, thromboxane formation and prostacyclin biosynthesis were correspondingly lowered 50% to 60%. The extent of this depression was of the same order on days 2 and 5 of dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1998

Acute renal failure due to sulfinpyrazone.

A case of sulfinpyrazone-associated acute renal failure is reported. Sulfinpyrazone can cause reversible acute renal failure from acute tubular necrosis in patients with volume depletion. Brown tubular casts on urine microscopy and a fractional excretion of sodium greater than 1 are helpful in the diagnosis. Uric acid nephropathy and allergic interstitial nephritis should be included in the differential diagnosis of sulfinpyrazone-associated acute renal failure. Acute reduction of renal blood flow due to inhibition of renal prostaglandin synthesis and kallikrein activity by the drug is a possible mechanism. Treatment of sulfinpyrazone-induced acute tubular necrosis consists of intravascular hydration, supportive care, and withholding sulfinpyrazone. The patients at risk for acute renal failure due to sulfinpyrazone are those who have intravascular volume depletion as sensed by the kidneys.

Acute Kidney Injury↗