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PubMed1976

Abnormalities of urinary sediment and renal failure following sulfinpyrazone therapy.

A patient with recurrent thrompophlebitis had sterile pyuria with white blood cell casts and transient, mild renal failure during therapy with sulfinpyrazone. These abnormalities resolved on cessation of therapy, but similar changes in the urinary sediment recurred during therapy with sulfinpyrazone. These abnormalities resolved on cessation of therapy, but similar changes in the urinary sediment recurred during a second course of sulfinpyrazone therapy.

Acute Kidney Injury↗

PubMed1979

Sulfinpyrazone kinetics after intravenous and oral administration.

Sulfinpyrazone kinetics has been investigated after intravenous and oral doses. They may be described by a 3-compartment open model. In the body about half the drug is in the plasma or in interstitial fluids, which equilibrated with plasma. Most of the rest is in an extravascular compartment, from which it easily diffuses back to the plasma. About 3% of the dose is still in the body after 24 hr and is located mainly in a deep compartment. After oral administration, sulfinpyrazone is quickly absorbed, largely from the stomach.

Administration, Oral↗

PubMed1982

Paired-ion high-performance liquid chromatographic assay for sulfinpyrazone in plasma.

A specific and sensitive liquid chromatographic method is reported for the assay of sulfinpyrazone in plasma utilizing ion pairing between the tetrabutylammonium cation and the sulfinpyrazone anion. The method is rapid in that conventional extraction procedures are avoided in favor of using disposable cartridges packed with an octade-cylsilane bonded phase as a means of separating the drug from plasma. The samples were chromatographed on a C18 reversed-phase column using a mobile phase consisting of 0.005 M tetrabutylammonium phosphate in methanol-water (56:44). The coefficient of variation obtained was 4.5% and the response was linear over a range of 0.2-80 micrograms/ml.

Chromatography, High Pressure Liquid↗

PubMed1998

Effects of sulfinpyrazone on retinal damage induced by experimental diabetes mellitus in rabbits.

The protective activity of the phenylbutazone derivative, sulfinpyrazone on retinal lesions has been assessed in rabbits with severe streptozotocin-induced diabetes. Sulfinpyrazone (8 mg kg-1 per day per os) was administered in diabetic animals in two different experimental procedures: for 135 days in a preventive approach (beginning on the day of initial hyperglicaemia); and for 30 days in a therapeutic approach (beginning on the day of appearance of severe retinal damage). The drug treatment made either with the preventive or the therapeutic approach reduced the incidence of serious retinal lesions and increased that of light lesions as assessed by a biomicroscopic method. Biochemical analyses showed that experimental diabetes was accompanied by sustained decrease in glucose and pyruvate and an increase of the lactate content in the retina. A decrease of alpha-ketoglutarate and citrate and an increase of succinate were also observed along with a decrease of ATP, ADP and an increase in AMP. Either the preventive or the therapeutic approach was followed by an increased pyruvate and ATP content and decreased lactate and AMP content in the retinal tissue. It is possible that this drug acts on the retinal tissue by inhibiting platelet aggregation and protecting vasal endothelium with the consequent suppression of the release of vasoactive substances that facilitate platelet adhesion.

Animals↗

PubMed1982

Potentiation of barbiturate- and halothane-induced hypnosis after probenecid or sulfinpyrazone pretreatment.

The uricosuric agent, probenecid, when administered prior to systemic administration of pentobarbital led to a decreased latency, to loss of righting reflex and to a potentiation of the duration of hypnosis. This potentiation was dose-related and doses of probenecid below 50 mg/kg (i.p.) were without effect. Pretreatment of rats with sulfinpyrazone, another uricosuric agent, yielded similar results. Pretreatment of animals with probenecid shortened the latency to onset of hypnosis induced by halothane (i.p.) and increased the duration of loss of righting reflex, 3-fold. Both sulfinpyrazone and probenecid, administered prior to 1.0% inhalation halothane exposure, shortened the latency to onset of hypnosis in doses as small as 10 mg/kg, much less than the doses required to affect significantly pentobarbital-induced hypnosis. The results, as yet, do not indicate a plausible mechanism of action, but do expose a potentially useful drug interaction which may be of clinical use.

Animals↗

PubMed1982

Effect of sulfinpyrazone upon antithrombin III and platelet factor 4 in chronic renal failure.

Despite the suppressive effects of uremia upon platelet function, patients with chronic renal failure are at increased risk for thrombotic diseases. This increased risk is linked to lowered concentrations of antithrombin III (AT III) and increased platelet release in vivo, as indicated by increased plasma concentrations of platelet factor 4 (PF4). Sulfinpyrazone, a drug capable of reducing the frequency of thrombotic events in uremic patients, allows return toward normal of the AT III while reducing to normal the plasma concentration of PF4. Thus, suppression of platelet function by sulfinpyrazone appears to reduce in vivo clotting, and thus reduces consumption of AT III.

Adult↗

PubMed1979

Interference by sulfinpyrazone and salicylate of aspirin inhibition of platelet cyclooxygenase activity.

The irreversible effect of acetylsalicylic acid on platelet cyclooxygenase activity is inhibited by salicylate and by sulfinpyrazone. Since acetylsalicylate is rapidly hydrolysed in plasma to salicylate which has a relatively prolonged half life in plasma, it is possible that persistant elevation of plasma salicylate may interfere with the efficacy of subsequent doses of aspirin. Sulfinpyrazone is sometimes used in combination with aspirin, and could interfere with the efficacy of aspirin on platelets. This theoretical possibility would be more likely to occur at lower doses of aspirin.

Aspirin↗

PubMed1981

Protective effect of sulfinpyrazone against catecholamine metabolite adrenochrome-induced arrhythmias.

Single intravenous injection of adrenochrome (10 to 50 mg/kg body weight), an oxidation product of catecholamines, has been shown to induce arrhythmias and cause death in anesthetized rats in a dose-dependent manner. Sulfinpyrazone, which is an inhibitor of platelet aggregation, was found to protect animals from these adrenochrome effects. It is suggested that sudden death due to arrhythmias in patients following the first attack of myocardial infarction of during other stressful situations may be linked to the formation of adrenochrome from abnormally high catecholamine levels in blood. Furthermore, results presented here also suggest that the reduction in the mortality rate of patients on sulfinpyrazone therapy may involve an antiarrhythmic property of the drug.

Adrenochrome↗

PubMed1983

Potentiation of morphine analgesia after pretreatment with probenecid or sulfinpyrazone.

Pretreatment with uricosuric agents probenecid or sulfinpyrazone potentiate the analgesic effects of morphine sulfate as ascertained using the phenylquinone (PQ)-induced writhing test. Doses of either uricosuric agent at 50 mg/kg had no effect on the number of PQ-induced writhes in test animals while potentiating the analgesic effects of morphine. High doses of probenecid or sulfinpyrazone alone did produce decreases in PQ-induced writing. Probenecid (50 mg/kg) did not alter hot water tail flick latency nor did it influence morphine analgesia. Attempts to uncover the underlying mechanisms in the uricosuric agent plus morphine attenuation of PQ-induced writhing were directed towards a possible displacement of morphine from plasma binding sites. However, administration of N-methyl-H3-morphine and estimation of plasma and brain morphine concentrations indicate no differences in the uricosuric drug pretreated groups compared to controls. The conflicting results in the PQ writhing test vs. hot water tail flick might indicate a false positive response in the former test. On the other hand this might be indicative of differing analgesic mechanisms for different types of pain. If the latter is true, this drug interaction may prove clinically useful.

Analgesia↗

PubMed1978

A randomized trial of aspirin and sulfinpyrazone in threatened stroke.

Five hundred and eighty-five patients with threatened stroke were followed in a randomized clinical trial for an average of 26 months to determine whether aspirin or sulfinpyrazone, singly or in combination, influence the subsequent occurrence of continuing transient ischemic attacks, stroke or death. Eighty-five subjects went on to stroke, and 42 died. Aspirin reduced the risk of continuing ischemic attacks, stroke or death by 19 per cent (P less than 0.05) and also reduced risk for the "harder," more important events of stroke or death by 31 percent (P less than 0.05), but this effect was sex-dependent: among men, the risk reduction for stroke or death was 48 per cent (P less than 0.005), whereas no significant trend was observed among women. For sulfinpyrazone, no risk reduction of ischemic attacks was observed, and the 10 per cent risk reduction of stroke or death was not statistically significant. No overall synergism or antagonism was observed between the two drugs. We conclude that aspirin is an efficacious drug for men with threatened stroke.

Aspirin↗

PubMedDate not supplied

Vasodilator effects of sulfinpyrazone in dogs.

The hemodynamic effects of sulfinpyrazone were investigated in 12 anesthetized dogs. Bolus injections into a coronary artery (1--500 mg) and a femoral artery (10--300 mg) and intravenous infusions (10 and 20 mg/min up to 500 mg) were given. After intracoronary injection, coronary dilatation occurred for over 20 min without major changes in cardiac muscle function. Femoral vasodilatation was also induced by local injection. Slow intravenous infusion resulted in inconsistent changes of coronary blood flow. However, in one instance, coronary dilatation was observed at a plasma level of 27.8 microgram/ml, which is comparable with that reached in man after standard oral dosage. Thus, sulfinpyrazone has coronary vasodilator effects which may have relevance to patient therapy.

Animals↗

PubMed1981

In vivo platelet hyperactivity and factor VIII related antigen increase long after myocardial infarction. A controlled effect of sulfinpyrazone.

In the Anturane Reinfarction Italian Study the trend of some specific and quantitative haemostatic parameters is being investigated in different series of patients balanced for sulfinpyrazone and placebo. In a series of young male patients who had had myocardial infarction 6 months previously, it has been shown that the placebo treatment subsample presented shortened platelet production time (PPT), increased levels of plasma beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4), and increased factor VIII related antigen (VIII:RAg) compared with a matched control group. A close correlation between plasma concentration of VIII:RAg and PPT was evidenced in the same treatment subsample. The sulfinpyrazone treatment subsample presented normalized PPT accompanied by reduction of VIII:RAg but not of beta-TG or PF4 levels.

Adult↗

PubMed1984

Sulfinpyrazone increases the number of beta-adrenoceptors on intact human lymphocytes.

Sulfinpyrazone increased the number of beta-adrenoceptors (+ 17-40%) on intact human lymphocytes at concentrations ranging from 10(-5) to 2 X 10(-4) M. It affected the Bmax (187 +/- 6 and 142 +/- 5 fmol mg-1 protein respectively with and without sulfinpyrazone, P less than 0.001) but did not influence KD (4.4 +/- 0.3 and 4.6 +/- 0.7 nM with and without the drug). This effect was observed on either washed or unwashed lymphocyte membrane preparations. These findings have several pharmacological and therapeutic implications.

Cell Membrane↗

PubMed2006

Sulfinpyrazone C-glucuronidation is catalyzed selectively by human UDP-glucuronosyltransferase 1A9.

The uricosuric agent sulfinpyrazone (SFZ) is metabolized via C-glucuronidation, an uncommon metabolic pathway, in humans. The present study aimed to characterize SFZ glucuronidation by human liver microsomes (HLMs) and identify the hepatic forms of UDP-glucuronosyltransferase responsible for this pathway. Incubations of SFZ with HLMs formed a single glucuronide that was resistant to beta-glucuronidase and acid hydrolysis, consistent with formation of a C-glucuronide. Mass spectral analysis confirmed the identity of the metabolite as SFZ glucuronide (sulfinpyrazone beta-D-glucuronide; SFZG). SFZ C-glucuronidation by HLMs exhibited Michaelis-Menten kinetics, with mean (+/- S.D.) Km and Vmax values of 51 +/- 21 microM and 2.6 +/- 0.6 pmol/min . mg, respectively. Fifteen recombinant human UDP-glucuronosyltransferases (UGTs), expressed in HEK293 cells, were screened for their capacity to catalyze SFZ C-glucuronidation. Of the hepatically expressed enzymes, only UGT1A9 formed SFZG. UGTs 1A7 and 1A10, which are expressed in the gastrointestinal tract, also metabolized SFZ, but rates of metabolism were low compared with UGT1A9. SFZ glucuronidation by UGT1A9 exhibited "weak" negative cooperative kinetics, which was modeled by the Hill equation (S50 16 microM). The data indicate that UGT1A9 is the enzyme responsible for hepatic SFZ C-glucuronidation and that SFZ may be used as a substrate "probe" for UGT1A9 activity in HLMs.

Catalysis↗

PubMed1976

Antithrombotic effects of sulfinpyrazone in animals: influence on fibrinolysis and sodium arachidonate-induced pulmonary embolism.

It has been shown that sulfinpyrazone stimulates fibrinolytic activity in various in vitro and in vivo test systems. In rats with kaolin-induced paw oedema this compound is able to restore the markedly prolonged euglobulin clot lysis time in an oral dose of 30 mg/kg, whereas salicylate and dipyridamole are somewhat less active in this respect. Beside these effects, sulfinpyrazone protects rabbits from arachidonate-induced sudden death after a single oral dose of 10-30 mg/kg.

Animals↗

PubMed1979

A controlled study of the effect of sulfinpyrazone on platelet survival and on platelet-bound 14C-serotonin release in patients with previous myocardial infarction.

Preliminary data obtained in the ambit of Anturan Reinfarction Italian Study (ARIS) show that, in postmyocardial infarction, reduced platelet survival time occurred in hyperbetalipoproteinemic patients treated with placebo, but not in the group of patients treated with sulfinpyrazone (interaction between treatment and lipemic level is at p approximately equal to 0.1). The sulfinpyrazone effect on platelet survival is probably related to the release reaction inhibition as suggested by our ex vivo results on platelet-bound 14C-serotonin release.

Adult↗

PubMed1978

Comparison of antithrombotic activity of heparin, ASA, sulfinpyrazone and VK 744 in a rat model of arterial thrombosis.

Rat carotid arteries were injured electrically (350 V, 2 mA DC for 5 min) before and after the intravenous administration of heparin (1,000 U/kg), VK 744 (25, 50, 100 mg/kg) ASA (100, 200 mg/kg) and sulfinpyrazone (50, 100, 150, 200 mg/kg). Thrombus growth was quantified by recording arterial temperature change distal to the injury. Heparin completely blocked thrombus formation in most experiments. All other agents exhibited antithrombotic activity with sulfinpyrazone being most potent. None was as effective as heparin. This model may be a useful tool for screening antithrombotic drugs.

Animals↗

PubMed1979

Effects of acetylsalicylic acid, sulfinpyrazone and dipyridamole on platelet adhesion and aggregation in flowing native and anticoagulated blood.

The interaction of rabbit platelets with subendothelium of rabbit aorta was investigated under controlled blood flow conditions. Platelet adhesion and thrombus formation were compared after perfusion of native blood and of blood anticoagulated with citrate, heparin or heparin plus citrate. 15 mM citrate in plasma caused significant reduction of aggregation, thrombus volume and thrombus height; adhesion was concomitantly increased. Heparin (500 U/kg) had no significant effect on adhesion and thrombus dimensions. Treatment of rabbits with acetylsalicylic acid or sulfinpyrazone caused a significant reduction of thrombus volume and thrombus height in the presence of citrate. However, no significant effects were observed in native or heparinized blood. It is concluded that low citrate concentrations: (1) inhibit thrombus growth; (2) enhance thrombus breakdown; (3) therefore increase adhesion, and (4) strongly enhance a possible inhibitory effect of acetylsalicylic acid and sulfinpyrazone on thrombus growth.

Animals↗