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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↗
PubMed1982

Binding of sulfinpyrazone and its metabolites in human serum and in solutions of human serum albumin.

The binding of sulfinpyrazone its sulfone metabolite and its sulfide metabolite to serum protein was studied by equilibrium dialysis. At 20 micrograms/ml 99.1% of the parent compound was bound in serum, whereas 99.8% of the sulfide and 98.3% of the sulfone were bound at this concentration. The binding of the three compounds were studied in diluted serum and in solutions of human serum albumin (HSA). There was no evidence of binding to proteins other than albumin. The association constants to primary and secondary binding sites and the number of binding sites were calculated. For the sulfide a lower K1-value in serum (0.76 . 10(6)M-1) than in the HSA solution (1.8 . 10(6)M-1) indicated the possible presence of a competitively bound substance in serum. In undiluted serum no displacing effect of the sulfide on sulfinpyrazone binding was found when both compounds were present in a concentration of 20 micrograms/ml, but in a HSA solution a pronounced sulfide induced displacement of the sulfinpyrazone from its primary binding site was shown. Acetylation of HSA depressed the binding of sulfinpyrazone but in undiluted serum there was no other effect on sulfinpyrazone binding by the addition of acetylsalicylic acid than could be explained by the displacing effect of salicylic acid. At concentrations of 20 micrograms/ml of sulfinpyrazone and above 50 micrograms/ml of the displacing agent significant displacement was demonstrated with phenylbutazone, tolbutamide and salicylic acid.

Acetylation↗
PubMed1982

Effect of salicylate on the fate of [14C]sulfinpyrazone in the rat.

The effect of acetylsalicylic acid (ASA, 100 mg/kg, po) on the fate of [14C]sulfinpyrazone (50 mg/kg, ip) was studied in male Wistar rats. ASA increased the rate of elimination of [14C]sulfinpyrazone-derived radioactivity from the blood during the first 5 h following drug administration. A tissue distribution study at 4 h showed that ASA increased the concentration of radioactivity in the gastrointestinal tract (GIT) and decreased it in the blood, heart, lung, and testis. ASA had little or no effect on the urinary and fecal excretion of sulfinpyrazone metabolites. Biliary elimination of radioactivity was increased from 54.2 +/- 4.7 to 69.6 +/- 1.2% of the dose in the 0- to 5-h period by salicylate (SAL), a major in vivo metabolite of ASA. Bile flow rate was also increased by SAL. An in vitro protein binding study showed that SAL displaced sulfinpyrazone from its binding sites. The results suggested that, in the rat, SAL enhanced the rate of sulfinpyrazone elimination by a combination of its choleretic action and displacement of bound sulfinpyrazone from plasma proteins.

Animals↗
PubMed1982

Stereoselective interaction of sulfinpyrazone with racemic warfarin and its separated enantiomorphs in man.

Although serious hemorrhage during therapeutic coadministration of sulfinpyrazone and racemic warfarin occurs, no prospective studies have been done. In this study, single oral doses of racemic warfarin, 1.5 mg/kg, were administered to six normal subjects with and without oral sulfinpyrazone, 400 mg daily. Both the hypoprothrombinemia (p less than 0.001) and the plasma warfarin concentrations (p less than 0.05) were significantly augmented. To determine if this interaction was stereoselective, the experiments were repeated in the same subjects with R-and S-warfarin enantiomorphs. S-warfarin with sulfinpyrazone caused a highly significant augmentation of both the hypoprothrombinemia (p less than 0.001) and the plasma warfarin concentrations (p less than 0.001). R-warfarin with sulfinpyrazone did not significantly change the hypoprothrombinemia but significantly (p less than 0.05) reduced warfarin concentrations. Thus, sulfinpyrazone augmented the hypoprothrombinemia of racemic warfarin stereoselectively by reduced metabolic clearance of S-warfarin. Sulfinpyrazone and racemic warfarin are most dangerous when either drug is added to a stabilized regimen of the other drug.

Adult↗
PubMed1987

Effects of sulfinpyrazone and its metabolite G25671 on platelet activation and desensitization and on bronchoconstriction induced by the prostaglandin endoperoxide analog U46619.

Sulfinpyrazone (100 microM) and its thioether metabolite G25671 (50 microM) suppressed arachidonic acid-induced platelet aggregation, thromboxane (Tx) B2 formation and ATP release. Platelet activation by the endoperoxide analog U46619 also was prevented by sulfinpyrazone or G25671 (0.3-1 mM). Previous studies have shown that human platelets pre-exposed to arachidonic acid or to U46619 and then washed and resuspended failed to respond to a second challenge by both arachidonic acid and U46619; desensitization by arachidonic acid and U46619 occurred at a site sensitive to endoperoxides/Tx receptor antagonists; and the desensitizing effects of U46619 were direct, whereas those of arachidonic acid were mediated by a cyclooxygenase-dependent metabolite. We now demonstrate that the presence of sulfinpyrazone or G25671 during platelet exposure to arachidonic acid or U46619 prevented desensitization. We also studied the threshold aggregating concentration of arachidonic acid and U46619 in healthy subjects before and after treatment with sulfinpyrazone and we found a good correlation between ex vivo and in vitro findings. We finally examined the actions of sulfinpyrazone and G25671 on the bronchoconstriction in vivo and parenchymal lung strip contraction in vitro induced by U46619. Neither drug had any preventive effect. Our results demonstrate that sulfinpyrazone and its metabolite G25671 are not only cyclooxygenase inhibitors but can also act as endoperoxide/Tx antagonists and indicate clearly that antagonism of U46619 by both drugs is selective for platelets.

Arachidonic Acid↗
PubMed1981

[Antinatriuretic effect of sulfinpyrazone].

Clinical observations suggest that sulfinpyrazone (Anturan) may lead to edema formation in borderline compensated cardiac insufficiency. Since the drug is increasingly used in secondary prophylaxis of sudden death after myocardial infarction, a trial was designed to confirm or to refute the suspicion that sulfinpyrazone may interfere with natriuresis. In two experimental series, 18 volunteers were given a sodium load of 5 g or 6 g and natriuresis was first measured at hourly intervals for 4 hours and thereafter for an additional 4-hour period. The experiment was repeated with a single dose of 400 mg sulfinpyrazone given with the sodium load. In the first, non-randomized trial (n = 8) 71.2 +/- 20.7 (SD) mval Na was excreted within 8 hours without, and 41.2 +/- 20.6 mval with sulfinpyrazone (p less than 0.05). In the second, randomized trial (n = 10), sodium excretion fell from 74.2 +/- 38.0 mval/8 h in the control experiment to 43.5 +/- 20.6 mval/8 h after sulfinpyrazone (-42%; p less than 0.05). Excretion of potassium and creatinine remained unchanged. It is concluded that sulfinpyrazone does indeed interfere with normal renal sodium excretion and that the phenomenon may be relevant in patients with borderline compensated myocardial insufficiency. The design of the trial provides a relatively easy way to obtain valuable information on the clinically relevant antinatriuretic side effects of many drugs, particularly that of non-steroidal antiinflammatory agents.

Adult↗
PubMed1981

Comparative interaction of sulfinpyrazone and phenylbutazone with racemic warfarin: alteration in vivo of free fraction of plasma warfarin.

Sulfinpyrazone and phenylbutazone cause stereoselective alterations in the metabolic clearance of racemic warfarin in man. To determine if these drugs additionally displace warfarin from its binding sites in vivo free fractions of plasma warfarin were measured by equilibrium dialysis. Single doses of racemic warfarin, 1.5 mg/kgb.wt., were administered to eight normal humans. Six subjects received 300 mg orally of phenybutazone daily, beginning 3 days before warfarin and continuing throughout hypoprothrombinemia. Six subjects in separate experiments received 400 mg orally of sulfinpyrazone daily by the same schedule. Free warfarin of every subject's plasma was measure by equilibrium dialysis; trace amounts of [14C] racemic warfarin were added to each sample. The free fraction increased from 1.09% for warfarin alone to 1.46% (34%) during concurrent phenylbutazone (P less than .001). Free warfarin was unaltered by sulfinpyrazone, 1.08%. As the lack of effect of sulfinpyrazone on free warfarin enantiomorphs, the experiments were repeated with them. Sulfinpyrazone had no significant effect on the free fraction of either S-warfarin or R-warfarin. Sulfinpyrazone augmented the hypoprothrombinemia of racemic warfarin by steroselectively altering its metabolic clearance;phenylbutazone additionally displaced albumin-bound warfarin.

Adolescent↗
PubMed1977

Effects of sulfinpyrazone on platelet prostaglandin synthesis and platelet release of serotonin.

Sulfinpyrazone added to PRP inhibited the release of serotonin induced by collagen. The inhibitory effect depended strongly on the strength of the collagen stimulus. Serotonin release was also inhibited (up to 73%) in PRP prepared from subjects who had ingested the drug. This is the first demonstration of a direct effect of a sulfinpyrazone in vivo on in vitro tests of platelet function. Prostaglandin synthesis was studied with lysates of washed platelets, arachidonic acid-14C, and silicic acid chromatography to isolate a reaction product which was tentatively identified as thromboxane B2. Platelet prostaglandin synthesis was shown to be strongly inhibited by sulfinpyrazone. Inhibition was competitive with respect to substrate. It is proposed that effects of sulfinpyrazone on platelet function may be due to inhibition of prostaglandin synthesis. The competitive nature of sulfinpyrazone inhibition may explain why sulfinpyrazone is a strong inhibitor of the release reaction under conditions of dilute collagent stimulation but is weak in the presence of stronger stimuli. In comparing the potency of inhibitors of platelet prostaglandin synthesis the nature of inhibition must be considered. Competitive inhibitors may be incorrectly regarded as weak if studied only at high substrate concentration.

Blood Platelets↗
PubMed1975

Biotransformation and pharmacokinetics of sulfinpyrazone (Anturan) in man.

The absorption, biotransformation and elimination of sulfinpyrazone, 1,2-diphenyl-3,5-dioxo-4-(2'-phenylsufinylethyl)-pyrazolidine, have been studied by administration of single 200 mg oral doses of a 14C-labelled preparation to two male volunteers. Absorption from the gastro-intestinal tract was rapid and complete and the plasma concentration of unchanged drug reached maximum values of 22.67 and 13.04 mug/ml, respectively, after 1 - 2 hours. The elimination half-life in the two subjects, calculated from the decline between 3 and 8 hours, was 2.7 and 2.2 hours. The integrated concentration of unchanged sulfinpyrazone in plasma, estimated from the area under the concentration curves (AUC), was almost as high as that of total 14C-substances, so the proportion of metabolized drug in plasma was low. In no case did the AUC of the three specifically determined metabolites. i.e. the sulphone G 31 442, the "para-hydroxy"=compound G 32 642 and the "4-hydroxy"- compound GP 52 097, exceed 4% of the sulfinpyrazone value. More than 95% of whole blood radioactivity was confined to plasma. The oral dose was rapidly and completely excreted, since within 4 days more than 95% was recovered, 85% from urine and 10% from faeces. A large proportion of the dose was excreted as unchanged drug in the two volunteers: 51 and 54% of total urinary radioactivity was present as sulfinpyrazone; 8.2 and 8.8% was present as "para-hydroxy"-metabolite, 2.7 and 3.0% as sulphone-metabolite, and 0.6 and 0.8% as "4-hydroxy"-metabolite. About 30% of urinary radioactivity consisted of highly polar metabolites. Spectroscopy of them showed that they were the C-beta-glucuronides of sulfinpyrazone (28%) and the corresponding sulfone (2%). In these metabolites the C(4) of the pyrazolidine ring was directly attached to glucuronic acid, and thus they represent a new type of biosynthetic conjugate.

Adult↗
PubMed1985

The effect of sulfinpyrazone on platelet deposition on Dacron vascular grafts in man.

To determine if sulfinpyrazone inhibits platelet deposition on chronically implanted (greater than 9 months) Dacron aortic bifurcation grafts in man, we performed indium-111 platelet imaging over 24 to 96 hours after labeled platelet injection in 10 males with grafts before and during sulfinpyrazone therapy (200 mg four times daily). Platelet accumulation was quantitated by a graft/blood ratio that compared indium-111 platelet image activity in the graft to platelet activity in well-counted whole blood. In addition, independent visual analysis compared platelet accumulation in the graft area to adjacent native arteries. By quantitative evaluation, sulfinpyrazone did not decrease the graft/blood ratio compared to baseline at 24 hours (3.2 +/- 0.4 vs 3.3 +/- 0.5, mean +/- SEM), 48 hours (4.6 +/- 0.6 vs 4.6 +/- 0.9) , 72 hours (6.8 +/- 0.8 vs 6.7 +/- 1.3), or 96 hours (9.7 +/- 1.6 vs 9.7 +/- 1.6) after labeled platelet injection. Visual interpretation also revealed no decrease in deposition in any patient during sulfinpyrazone therapy. We conclude that sulfinpyrazone does not inhibit platelet deposition on chronically implanted Dacron arterial graft surfaces in man. The techniques described provide a useful method of evaluating antithrombotic drug effects in patients with intravascular prosthetic materials.

Aged↗
PubMed1984

Inhibition of human platelet cyclo-oxygenase activity by sulfinpyrazone and three of its metabolites.

Sulfinpyrazone and three of its major metabolites were compared in vitro for their inhibitory effect on human platelet cyclo-oxygenase activity. Sulfinpyrazone appeared to be about 15-20 times less potent than its sulfide metabolite (G25671) and 6-7 times less potent than the other two compounds, the sulfone metabolite (G31442) and p-hydroxysulfide (G33378). All four compounds were apparently competitive inhibitors of platelet cyclo-oxygenase activity. Comparison of the potency of sulfinpyrazone and its metabolites, as determined in the present study and the plasma levels previously measured in man, indicates that sulfinpyrazone and G33378 were not potent enough to be effective in man. G31442 showed inhibitory potency slightly lower than its corresponding plasma levels, whereas G25671 was effective at concentrations well below those found in human plasma. This study supports the hypothesis that sulfinpyrazone metabolites (in particular the sulfide) rather than the drug itself affect platelet function when administered therapeutically.

Arachidonic Acid↗
PubMed1981

The inactivation of prostaglandin E2 is decreased by dipyridamole and sulfinpyrazone in isolated rat lungs.

The inactivation of prostaglandin E2 (PGE2) was decreased in the pulmonary circulation of isolated rat lungs, when either dipyridamole or sulfinpyrazone was infused into the pulmonary artery at the concentration of 20 microM. After pulmonary injection of 7.1 nmoles of 14C-PGE2 the amount of 15-oxo-metabolites of PGE2 in the effluent was 3.91 +/- 0.19 nmoles from control lungs and 2.05 +/- 0.19 nmoles (2P less than 0.001) in that from 20 microM dipyridamole treated lungs. The corresponding values for control and 20 microM sulfinpyrazone lungs were 4.11 +/- 0.25 and 3.03 +/- 0.14 nmoles (2P less than 0.01), respectively. The amounts of unmetabolized PGE2 were correspondingly increased in the effluents from dipyridamole and sulfinpyrazone (20 microM) lungs. Neither dipyridamole nor sulfinpyrazone had at concentration of 2 microM any significant effect on the amount of 15-oxo-metabolites in the effluent, although the amount of unmetabolized PGE2 was slightly increased in 2 microM sulfinpyrazone experiments.

Animals↗
PubMed1979

The effect of sulfinpyrazone on morphological changes in the coronary vasculature induced by prolonged unpredictable stress in the rat.

It was confirmed that prolonged unpredictable stress in the rat induces morphological change in the coronary microcirculation. These changes include dilation in venules, deposits staining positive with PAS in the venules due to platelet aggregation and a breakdown of the endothelial lining in arterioles. Sulfinpyrazone is reported to prevent platelet agglutination, and shows effectiveness in the clinic in preventing re-infarction following infarction. Accordingly rats were exposed to the stress regimen for 50 days, and groups were treated with sulfinpyrazone, either prophylactically (receive drug for 50 days) or therapeutically (receive drug Day 30 to Day 50). The morphology of the hearts of treated animals were compared with those of placebo treated controls. It was demonstrated that therapeutic sulfinpyrazone did not prevent (p less than 0.01), but reduced the incidence of morphological change in the coronary microcirculation. Prophylactic sulfinpyrazone had a distinct protective effect (p less than 0.001). It was demonstrated that the plasma corticosterone levels in both drug groups did not fall to the level found in control groups. The results are discussed in terms of a glucocorticoid-sulfinpyrazone interaction preventing prostaglandin release which will prevent platelet aggregation. It is possible that the interaction relates to maintaining the integrity of the microcirculatory endothelial cells, thus preventing the local release of inflammatory substances.

Animals↗
PubMed1986

The warfarin-sulfinpyrazone interaction: stereochemical considerations.

To allow the simultaneous evaluation of the interaction between sulfinpyrazone and each enantiomer of racemic warfarin, pseudoracemic warfarin (1:1 12C-R(+) and 13C-S(-)warfarin) was given to six normal subjects both before and during oral sulfinpyrazone dosing. Serial blood and urine samples were analyzed for unchanged warfarin and its metabolic products by GC/MS. A mass balance of an oral dose of pseudoracemic warfarin, containing a tracer quantity of 14C-warfarin, was carried out in one of the subjects by monitoring 14C levels in urine and feces for 15 days. Concomitant sulfinpyrazone dosing markedly increased hypoprothrombinemia, decreased clearance of (S)-warfarin, and increased clearance of (R)-warfarin. Sulfinpyrazone also decreased the urinary excretion of warfarin-related products but increased their fecal excretion by an equivalent amount. Virtually all of the administered warfarin dose could be accounted for either as unchanged drug or known metabolites. Pharmacokinetic analysis of the data suggests the following: At least four distinct enzymes (two oxidases and two reductases) are involved in the metabolism of warfarin. Sulfinpyrazone increases the hypoprothrombinemia caused by warfarin primarily by inhibition of the cytochrome P-450-mediated oxidation of (S)-warfarin, the biologically more potent enantiomer. The increased clearance of (R)-warfarin results not from induction, but from its selective displacement from plasma protein binding sites.

Administration, Oral↗
PubMed2000

Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export.

The multidrug resistance proteins MRP1 and MRP2 are members of the same subfamily of ATP-binding cassette transporters. Besides organic molecules conjugated to negatively charged ligands, these proteins also transport cytotoxic drugs for which no negatively charged conjugates are known to exist. In polarized MDCKII cells, MRP1 routes to the lateral plasma membrane, and MRP2 to the apical plasma membrane. In these cells MRP1 transports daunorubicin, and MRP2 vinblastine; both transporters export reduced glutathione (GSH) into the medium. We demonstrate that glutathione transport in MDCKII-MRP1 cells is inhibited by the inhibitors of organic anion transporters sulfinpyrazone, indomethacin, probenecid and benzbromarone. In MDCKII-MRP2 cells, GSH export is stimulated by low concentrations of sulfinpyrazone or indomethacin, whereas export is inhibited down to control levels at high concentrations. We find that unmodified sulfinpyrazone is a substrate for MRP2, also at concentrations where GSH export is inhibited. We also show that GSH export in MDCKII-MRP2 cells increases in the presence of vinblastine, and that the stoichiometry between drug and GSH exported is between two and three. Our data indicate that transport of sulfinpyrazone and vinblastine is associated with GSH export. However, at high sulfinpyrazone concentrations this compound is transported without GSH. Models of MRP action are discussed that could explain these results.

Anion Transport Proteins↗
PubMed1982

Sulfinpyrazone: an antiarrhythmic drug?

To determine whether a direct antiarrhythmic effect could explain the claimed beneficial effect of sulfinpyrazone on the sudden death rate in postmyocardial infarction patients, we performed a double-blind, randomized trial in 20 patients with impulse-formation and conduction defects. The patients were studied by intracardiac electrocardiography and programmed stimulation before and after an intravenous bolus injection of either 500 mg sulfinpyrazone or a placebo. We found no consistent clinical or statistical effects of sulfinpyrazone on sinus rate, sinus node recovery time, sinoatrial conduction time, conduction intervals during spontaneous cardiac activity and atrial pacing. Wenckebach point and refractory periods of the atrium, AV node, His Purkinje system and right ventricle. We conclude that sulfinpyrazone has no clinical electrophysiological effects comparable with those of known antiarrhythmic agents and that a direct antiarrhythmic action is an unlikely explanation for the reduction of sudden death in postinfarction patients treated with this drug. Antiarrhythmic activity by an indirect mechanism, related to the antiplatelet properties of the drug, or by metabolites of sulfinpyrazone, remains a possibility requiring further investigation.

Arrhythmias, Cardiac↗
PubMed1977

Sulfinpyrazone and postoperative deep vein thrombosis.

Small doses of subcutaneous heparin and infusions of dextran both reduce the incidence of fatal pulmonary embolism after elective general surgery. But both methods have disadvantages. Therefore, the protection against deep vein thrombosis afforded by sulfinpyrazone, a drug which can be taken by mouth as well as by injection, was assessed in a prospective study of 119 patients undergoing elective general or urological surgery. The prophylactic administration of sulfinpyrazone was compared with the effects of small doses of sodium heparin and infusions of dextran-70. The 125I-fibrinogen test was carried out in all patients during their hospitalization. Deep vein thrombosis was diagnosed in 13 of 30 patients (43%) who received sulfinpyrazone, in 9 of 29 (31%) receiving dextran-70 and in 2 of 22 (9%) having subcutaneous heparin. The difference between the sulfinpyrazone and heparin groups was statistically significant (p less than 0.01). Sulfinpyrazone in the dose used in this trial was not effective in reducing the incidence of deep vein thrombosis during elective general surgery.

Administration, Oral↗
PubMed1981

Effects of sulfinpyrazone, aspirin and propranolol on the isoproterenol-induced myocardial necrosis.

Prophylactic effects of sulfinpyrazone (100 mg/Kg), aspirin (5 mg/Kg, 50 mg/Kg), and propranolol (2 mg/Kg, 10 mg/Kg) on myocardial necrosis and hypertrophy induced by isoproterenol were examined. Drugs were administered to rats daily by gavage for a period of 2 weeks and after that isoproterenol (40 mg/Kg) was injected subcutaneously. The control group received gavage of water and isoproterenol injection. The "no infarct" group received gavage of water and saline injection. Premedication of sulfinpyrazone and propranolol significantly preserved myocardial CK activity and decreased cardiac hypertrophy compared with control group (24 hours after isoproterenol injection) while aspirin did not have such effects. Myocardial cyclic AMP concentration significantly increased 30 min after isoproterenol injection in control and all the premedicated rats compared with the "no infarct" rats. The increment of cyclic AMP was not suppressed by sulfinpyrazone and propranolol during this period. Plasma levels of prostaglandins were significantly suppressed by the administration of sulfinpyrazone and 50 mg/Kg of aspirin, and were not suppressed by 5 mg/Kg of aspirin. It was concluded that premedication of sulfinpyrazone and propranolol reduce cardiac necrosis and hypertrophy induced by isoproterenol, but aspirin did not have such cardioprotective effects.

Animals↗