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PubMed1984

High-performance liquid chromatographic determination of sulfinpyrazone and its metabolites in plasma.

A specific sensitive reversed-phase high-performance liquid chromatographic method for simultaneous determination of sulfinpyrazone (Anturane) and five of its metabolites (p-hydroxy-sulfinpyrazone, p-hydroxy-sulfone, sulfone, p-hydroxy-sulfide, and sulfide) in plasma is described. The compounds were extracted from plasma, back-extracted, re-extracted and separated on a 10-micron muBondapak C18 column using 10 mmol/l orthophosphoric acid-acetonitrile-ethanol as the mobile phase. Phenylbutazone was used as internal standard, which was totally separated from all other compounds. The lower limit of sensitivity for sulfinpyrazone, sulfone, p-hydroxy-sulfide and sulfide is 30 ng/ml, and 100 ng/ml for p-hydroxy-sulfinpyrazone and p-hydroxy-sulfone. Concentrations of sulfinpyrazone between 0.5 and 25 micrograms/ml were measured with an average coefficient of variation of 5.1%. Examples of application of this assay are given.

Animals↗

PubMed1980

[Sulfinpyrazone in the prevention of sudden death after myocardial infarction (author's transl)].

The results of the Anturane Reinfarction Trial, a randomized, double-blind, multicenter clinical trial, represent the data on 1558 patients who received either sulfinpyrazone or placebo for an average of 16 months, starting 25 to 35 days after a documented myocardial infarction. All but one of the 106 deaths at 24 months were cardiac. In the sulfinpyrazone group the reduction in cardiac mortality 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 to a reduction in sudden death during the second through seventh month after infarction, when there were 24 sudden deaths in the placebo group and only six in the sulfinpyrazone group - a sulfinpyrazone - induced 74 per cent reduction in the calculated mortality rate (P = 0,003).

Adult↗

PubMed1980

[Effects of sulfinpyrazone on early ventricular fibrillation and 2d-phase arrhythmias in acute myocardial infarction (author's transl)].

Clinical and experimental studies indicate that ventricular arrhythmias, mainly ventricular fibrillation, are responsible for sudden cardiac death. A recent double-blind multicenter trial ("Anturane Reinfarction Trial") showed that the incidence of sudden cardiac death was reduced in Sulfinpyrazone-treated patients after acute myocardial infarction compared with the placebo group, although the rate of reinfarctions was not diminished. We investigated the efficacy of Sulfinpyrazone on the reduction and prevention of ventricular arrhythmias and primary ventricular fibrillation, utilizing a standardized experimental canine preparation. At normal therapeutic and at high cumulative doses of the drug, a reduction in ventricular arrhythmias within the first 24 hours after coronary occlusion could not be observed. Sulfinpyrazone failed also to alter the ventricular vulnerability to fibrillation in the very early myocardial infarction period. Furthermore, haemodynamics, contractility and oxygen consumption of the heart were not changed. These experimental findings show that the reduction in sudden cardiac deaths in Sulfinpyrazone-treated patients cannot be attributed to antiarrhythmic effects of the drug. Further research is needed to delineate the mechanism of action of Sulfinpyrazone as reported by the Anturane Reinfarction Trial Research Group.

Animals↗

PubMed1981

Induction of drug metabolizing enzymes by sulfinpyrazone.

A previous interaction study of sulfinpyrazone (Anturano) suggested that it induced microsomal drug metabolizing enzymes in the liver. To verify this finding the effect of sulfinpyrazone 800 mg per day for four weeks was investigated in ten healthy volunteers. Both the therapeutic actions of sulfinpyrazone, the uricosuric and the antiaggregating effects, were demonstrated (p less than 0.05). The influence on the microsomal drug metabolizing system in the liver was demonstrated by an increase in serum-gamma-glutamyl transpeptidase from 15.1 to 23.3 U/l (p greater than 0.05), a significant increase in the urinary excretion of d-glucaric acid (29.6 to 77.9 microMol/24 h, p less than 0.05) and an increase in antipyrine clearance from 50.3 ml/min to 83.9 ml/min (p less than 0.05). The possibility of enhancement of drug metabolism during treatment with sulfinpyrazone in combination with other drugs should be kept in mind.

Adult↗

PubMed1983

Plasma levels of sulfinpyrazone and of two of its metabolites after a single dose and during the steady state.

The pharmacokinetics of sulfinpyrazone, and the plasma levels of its sulfide and sulfone metabolites, have been determined after a single oral dose (400 mg) and during steady-state conditions (4 x 200 mg daily for 6 days) in healthy female volunteers. The plasma half-lives of sulfinpyrazone, the sulfone and the sulfide were 3.7, 3.2 and 14.7 h, respectively, during steady-state. After a single dose and during steady state conditions the half-lives of sulfinpyrazone and the sulfone did not differ significantly. The trough plasma levels of the sulfide metabolite exceeded those of the parent compound in four of the six volunteers on the last day of the study. The data suggest that in man the most likely candidate for the prolonged inhibition of platelet aggregation observed after treatment with sulfinpyrazone is its sulfide metabolite, because of its prolonged elimination.

Adult↗

PubMed1982

Sulfinpyrazone decreases epinephrine-induced platelet aggregation after myocardial infarction.

Platelet studies were performed during a controlled double-blind randomized clinical trial of sulfinpyrazone (Anturane Reinfarction Trial) in 41 patients who had recent myocardial infarction. Aggregation of platelet-rich plasma by thrombin (0.185, 0.246 U/ml), collagen, adenosine diphosphate, and adrenaline (0.23, 0.46, and 0.91 microgram/ml) was estimated after a 12 hour fast including abstinence from drugs and cigarette smoking. The tests were carried out 2 weeks after myocardial infarction and 6, 12, and 24 months later. At the last visit, washed platelet suspensions were also tested for aggregation to thrombin (0.03, 0.015 U/ml) +/- epinephrine (0.55 microgram/ml) and their production of malonyldialdehyde was estimated. A significant (p less than 0.02) reduction (50%) of the aggregation response of platelet-rich plasma to epinephrine was found in the group treated with sulfinpyrazone (n = 21) as compared with the placebo group (n = 20). Also, adrenaline evoked a milder (p less than 0.01) potentiation of aggregation by thrombin of the washed platelet suspensions in the sulfinpyrazone versus the placebo group. Other assays including platelet coagulant activity were not useful in discriminating between the 2 groups. It is concluded that sulfinpyrazone (200 mg 4 times daily) normalizes the platelet response to epinephrine; a relation with the drug-reported reduction of sudden death after myocardial infarction is suggested.

Clinical Trials as Topic↗

PubMed1981

Reduction in the severity of myocardial infarction by sulfinpyrazone.

The effect of sulfinpyrazone (Anturane) on the extent of myocardial lesions caused by coronary ligation or isoproterenol, 5 mg/kg subcutaneously, was determined in the rat. Treatment was with sulfinpyrazone, 15 mg/kg twice daily for 5 days before the cardiac insult, or 21 days after the insult, or both. Pretreatment with sulfinpyrazone reduced isoproterenol-induced lesions by 42%. Treatment after isoproterenol had no significant effect. With coronary ligation, treatment before or after operation significantly reduced the size of infarct, pretreatment by 42%, post-treatment by 33%. The results provide evidence that sulfinpyrazone may have a clinically useful protective effect in individuals at risk of cardiac ischemia, as suggested in the Anturane Reinfarction Trial.

Animals↗

PubMed1987

The effect of sulfinpyrazone on the disposition of pseudoracemic phenprocoumon in humans.

The effect of sulfinpyrazone on the pharmacokinetics and disposition of the enantiomers of pseudoracemic phenprocoumon was assessed by analyzing serial plasma, urine, and fecal samples for parent drug and metabolites by GC/MS. Essentially all of the administered dose could be accounted for either as parent drug, known metabolites, or their conjugates. Phenprocoumon and the 7-hydroxymetabolite represented the major materials recovered. All drug-related materials excreted into the urine were extensively conjugated. Sulfinpyrazone treatment did not affect the hypoprothrombinemia produced by phenprocoumon nor did it significantly alter the plasma elimination kinetics of the individual (R)- and (S)-enantiomers. However, an apparent increased free fraction of both enantiomers in plasma and inhibition of 7-hydroxylation of (S)-phenprocoumon were observed in the presence of sulfinpyrazone. The results of this study are contrasted with those of a previous study on the interaction between sulfinpyrazone and the structurally similar coumarin anticoagulant warfarin.

4-Hydroxycoumarins↗

PubMed1982

[Sulfinpyrazone-associated renal failure (author's transl)].

Three patients developed renal failure a few days after onset of sulfinpyrazone administration. In two the renal dysfunction was reversible, while the third died of a second myocardial infarction. The clinical picture of renal failure was uncharacteristic. It is recommended that renal function be tested two to four days after starting sulfinpyrazone, and to discontinue the drug immediately if there is a rise in blood urea nitrogen and creatinine. Since in two of the patients the creatinine values were elevated before sulfinpyrazone had been administered, it is clear that even minor pointers to impaired renal function should be considered as contraindications to the use of sulfinpyrazone.

Acute Kidney Injury↗

PubMed1978

Sulfinpyrazone in the prevention of cardiac death after myocardial infarction. The Anturane Reinfarction Trial.

The Anturane Reinfarction Trial is a randomized, double-blind, multicenter clinical trial comparing sulfinpyrazone (200 mg four times a day) and placebo in the prevention of cardiac mortality among patients with a recent documented myocardial infarction. Results represent data accumulated on 1475 cligible patients entered 25 to 35 days after myocardial infarction and followed for an average of 8.4 months. The data reflect excellent randomization, compliance with therapy and tolerance of the drug. All 69 deaths were a cardiovascular nature (68 cardiac and one cerebrovascular). For cardiac deaths, the annual death rate was 9.5 per cent in the placebo group and 4.9 per cent in the sulfinpyrazone group, representing an observed reduction of 48.5 per cent (P = 0.018). The annual sudden-cardiac-death rate was 6.3 per cent for the placebo and 2.7 per cent for the sulfinpyrazone group, representing a 57.2 per cent reduction in sudden-cardiac-death rate (P = 0.015). Sulfinpyrazone appears to be effective in reducing cardiac deaths during the first year after myocardial infarction.

Aged↗

PubMed1984

Warfarin-sulfinpyrazone interaction on binding to human serum albumin.

Sulfinpyrazone displacement of warfarin from human serum albumin was studied in-vitro. At low sulfinpyrazone concentrations one molecule of warfarin is displaced on binding by one molecule of sulfinpyrazone. Clinical plasma concentrations of sulfinpyrazone are, however, too low to cause significant displacement.

Binding, Competitive↗

PubMed1993

The effect of sulfinpyrazone on treadmill exercise-induced angina pectoris.

Suspecting that platelet thromboemboli could play a role in the pathogenesis of myocardial ischemia, we have done a random-order, double-blind, crossover study of the effect of the platelet-active drug sulfinpyrazone on treadmill exercise-induced angina pectoris in 30 men with coronary artery disease. The mean duration of exercise before onset of angina was 43 s longer after taking sulfinpyrazone than before and 11 s shorter after taking placebo than before. Analysis of variance for crossover design showed that the mean difference between the values obtained before and after sulfinpyrazone was significantly different (p < 0.01) from the mean difference between the values before and after placebo. Sulfinpyrazone had no effect on the mean heart rate-blood pressure product at onset of angina, change in ST segment during exercise, or preexercise platelet aggregate ratio and bleeding time. Exercise until angina occurred did not affect the platelet aggregate ratio.

Angina Pectoris↗

PubMed1975

Effects of clofibrate and sulfinpyrazone on platelet survival time in coronary artery disease.

Platelet survival time was measured (autologous labelling with 51chromium) in 68 men with coronary artery disease (CAD). Survival was shortened slightly (3.2 +/- 0.04 days; mean +/- SEM) as compared to normal (3.7 +/- 0.04 days; N = 18; P less than 0.001), and 60% had shortened survival (less than 3.3 days). Thirty-seven had hyperlipoproteinemia (36 with Type IV and one with Type III) and platelet survival was shortened (3.1 +/- 0.10 days) and significantly different from survival of men with normal lipoproteins (3.3 +/- 0,12 days; P less than 0.05). Twenty-two with shortened platelet survival and CAD received either clofibrate or sulfinpyrazone. Clofibrate prolonged platelet survival (2.6 +/- 0.09 to 3.4 +/- 0,14 days; P less than 0.001) and ten of 12 had prolongation of survival. Sulfinpyrazone increased survival (2.8 +/- 0.12 to 3.6 +/- 0.21; P less than 0.001) and nine of ten had prolognation of platelet survival. Clofibrate lowered serum cholesterol and tryglyceride but alteration in lipids did not correlate with alteration of survival. Sulfinpyrazone did not alter lipids. Data suggest that survival is shortened in CAD and that clofibrate and sulfinpyrazone alter survival. Platelet suppressant agents may prove beneficial in reducing the extent and complications of atherosclerotic arterial injury.

Adult↗

PubMed1981

Effect of sulfinpyrazone on ventricular fibrillation during acute myocardial ischemia.

In patients treated with sulfinpyrazone, an apparent reduction in the incidence of sudden death and presumed ventricular fibrillation has been reported. Using an intact animal model without microcirculatory thrombosis, we studied the effects of sulfinpyrazone on ischemic myocardium in 58 anesthetized dogs divided into three groups: control untreated (n =24), group 1 (n = 16), treated daily with 300 mg of sulfinpyrazone for 7 days, and group 2 (n = 18), treated daily with 300 mg of sulfinpyrazone for 7 days but omitting treatment on day 8. Although consistent hemodynamic differences were not apparent, the degree of injury determined by ECG mapping was significantly lower in group 1. The incidence of fibrillation was 54% for control and 0% in group 1. Group 2 had a 44% incidence, suggesting a limited duration of action. The apparent absence of microcirculatory thrombosis in this model suggests other mechanisms of action. A significantly smaller increase in tissue water and Na+ and smaller loss of K+ in group 1 may have contributed to the lower incidence of fibrillation, perhaps through selective prostaglandin inhibition.

Acute Disease↗

PubMedDate not supplied

Effect of sulfinpyrazone on platelet survival time in patients with transient cerebral ischemic attacks.

Platelet suppressant drugs have been suggested as beneficial for patients with transient cerebral ischemic attacks and these drugs have been shown to lengthen shortened platelet survival time. In the present study platelet survival time (autologous labeling with 51Chromium) was measured in 25 patients with transient cerebral ischemia involving a carotid distribution. Platelet survival was shortened in all patients (2.5 +/- 0.10 days; AVE t 1/2 +/- SEM; Normal 3.7 +/- 0.04 days P less than 0.001). Sulfinpyrazone increased platelet survival in 9 of 19 (47%) of patients (2.4 +/- 0.10 to 2.8 +/- 0.16 days; P less than 0.01). Of the 19 treated with sulfinpyrazone, 10 had a marked reduction in the frequency of transient ischemic episodes and an increased in platelet survival (2.6 +/- 0.16 to 3.1 +/- 0.22 days; P less than 0.01) was observed in all patients. Three patients had no benefit from sulfinpyrazone and alteration of platelet survival did not occur. Results suggest that platelet survival is shortened in patients with transient cerebral ischemia, that sulfinpyrazone increases platelet curvival and may decrease the frequency of ischemic episodes, and that there may be a relationship between clinical benefit and alteration of platelet survival time.

Adult↗

PubMedDate not supplied

Influence of cimetidine, sulfinpyrazone, and cigarette smoking on theobromine metabolism in man.

Theobromine metabolism and clearance were investigated at steady-state under chronic oral dosing conditions in eight healthy volunteers, four of whom were cigarette smokers. The subjects were studied before and after separate 1 week pretreatments with cimetidine (1 g/day) and sulfinpyrazone (800 mg/day). Theobromine plasma clearance (ClTB) was 33% higher in smokers than in non-smokers due to induction of all metabolic pathways (3-demethylation, 7-demethylation, and formation of 6-amino-5-(N-methylformylamino)-1-methyluracil (AMMU]. 7-Demethylation was induced by cigarette smoking to a greater extent than the other pathways. Cimetidine pretreatment inhibited theobromine 3-demethylation and AMMU formation resulting in a 27% decrease in ClTB in the combined smoker/nonsmoker group. The 7-demethylation pathway was unaffected by cimetidine. In contrast, sulfinpyrazone pretreatment increased ClTB by 50% in the whole group by approximately equal induction of each metabolic pathway. The extent of induction due to sulfinpyrazone was 2.4-fold greater in nonsmokers than in smokers. When compared with previous data relating to theophylline, the results suggest that theobromine 3-demethylation is mediated by the same form(s) of cytochrome P-450 involved in theophylline demethylation, while a second form(s) of cytochrome P-450 is involved in theobromine 7-demethylation and theophylline 8-hydroxylation. In addition, since AMMU formation was inhibited by cimetidine and induced by cigarette smoking and sulfinpyrazone, it would appear that the conversion of theobromine to AMMU is also mediated by cytochrome P-450.

Adult↗

PubMed1983

[Interaction of sulfinpyrazone (Anturan) and glibenclamide (Euglucon) in type II diabetic patients].

In a randomised double blind study on 19 with glibenclamide well controlled diabetics of type II the possible interaction between sulfinpyrazone (Anturan) and glibenclamide was studied with the help of the artificial endocrine pancreas. The trial substance in a dose of 800 mg/die or placebo were used over a period of 70 days. During the trial period and at the end of it there were no significant differences in the sulfinpyrazone group as compared to the placebo group concerning the metabolic control of the diabetic condition. It is therefore justified to assume that there exists no interaction between sulfinpyrazone and glibenclamide in this regard. The dosage of sulfinpyrazone used in this trial was well tolerated by all patients and no side effects were observed.

Adult↗

PubMedDate not supplied

Electromicroscopic observations on small vessels in animals treated with sulfinpyrazone and placebo following vascular microsurgery.

To evaluate the antithrombotic effect of sulfinpyrazone on blood vessels (1-2 mm diameter) injured by microsurgical procedures, twenty male rabbits were chosen at random to receive sulfinpyrazone (10 mg/kg/die) or placebo three days prior to and on the morning of vascular microsurgery, which consisted of a complete transverse section, or a longitudinal section 1 cm long, of the femoral artery and vein, followed by interrupted suture. Scanning electron microscopy revealed consistently less fibrin and blood cell adhesion to the endothelial areas adjacent to the surgical trauma in the animals treated with sulfinpyrazone than in those treated with placebo. Our results agree with those reported in the literature, demonstrating the antithrombotic effects of sulfinpyrazone at the level of the vascular endothelium injured by various kinds of trauma and are sufficiently encouraging to justify testing this drug in the prevention of vascular thrombosis following microsurgical procedures in man.

Animals↗