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PubMed1978

Vessel injury and atherosclerosis.

Repeated endothelial injury causes lipid-rich lesion in animals on a normal diet. In severely thrombocytopenic animals these lesions do not form or are markedly inhibited. The occurrence of lipid in some experimental designs is related to continued or repeated deposition of thrombus. Lipid deposition occurs in areas where endothelium is repeatedly removed and regrows. Repeated deposition of thrombus may bring about changes in the metabolism of the neo-intima which favor lipid deposition.

Animals↗
PubMed1983

Effect of single and multiple doses of sulphinpyrazone on antipyrine metabolism and urinary excretion of 6-beta-hydroxycortisol.

Sulphinpyrazone decreases the plasma clearance of tolbutamide and S-warfarin and increases the clearance of R-warfarin, theophylline and antipyrine. In order to determine whether sulphinpyrazone is an inducer or inhibitor or both of oxidative drug metabolism, antipyrine and its metabolites as well as 6-beta-hydroxycortisol were measured in urine before, 24 h and after 23 days of chronic administration of sulphinpyrazone (4 X 200 mg/day). During chronic treatment sulphinpyrazone increased the ratio of 6-beta-hydroxycortisol to the 17-hydroxycorticosteroids by 70% (p less than 0.02). The renal clearance of the main oxidative metabolites of antipyrine (4-hydroxyantipyrine, 3-hydroxymethylantipyrine and norantipyrine) were increased after sulphinpyrazone (p less than 0.02). Except for norantipyrine, no change in total excretion of antipyrine and its metabolites occurred after 24 h or after 23 days. It is concluded that sulphinpyrazone induces the enzymes which metabolize antipyrine and cortisol.

Adult↗
PubMed1982

The effect of sulphinpyrazone on oxidative drug metabolism in man: inhibition of tolbutamide elimination.

The effect of sulphinpyrazone on tolbutamide elimination was investigated in 6 healthy male volunteers. Co-administration of sulphinpyrazone (200 mg, 6 hourly) reduced mean plasma tolbutamide clearance by 40% and prolonged mean tolbutamide half-life by 80%. Twenty four hours after the cessation of a one week period of chronic sulphinpyrazone therapy tolbutamide plasma clearance (30% reduction) and half-life (19% prolongation) were still significantly different to control values, even though sulphinpyrazone could not be detected in the plasma of any of the subjects at this time. In vitro studies of the plasma protein binding of tolbutamide demonstrated concentration dependent binding but displacement of tolbutamide by sulphinpyrazone in vitro only became apparent at high concentrations of added sulphinpyrazone. Although the concentration dependence of tolbutamide protein binding demonstrated in vitro was also observed in the subject plasma samples, the magnitude of this effect was small. It is concluded that sulphinpyrazone and its metabolite(s) decrease the plasma clearance of tolbutamide by inhibition of oxidative metabolism.

Adult↗
PubMed1982

Interaction of sulphinpyrazone with warfarin.

The effect of sulphinpyrazone administration on the anticoagulant response was investigated in five patients receiving long-term treatment with warfarin. Sulphinpyrazone caused a rapid increase in prothrombin (PT) ratio in all five patients and warfarin dose had to be reduced by a mean of 46% to maintain the PT ratio in the therapeutic range. PT ratio and daily warfarin requirement returned to previous levels when sulphinpyrazone was ceased. Warfarin protein binding was not altered during sulphinpyrazone administration and sulphinpyrazone added to plasma in vitro did not increase warfarin free fraction. The average racemic plasma warfarin concentration over a dosage interval when adjusted for warfarin dose was not altered by sulphinpyrazone administration. The most likely mechanism for this drug interaction is a stereoselective effect of sulphinpyrazone on the metabolism of the warfarin enantiomers.

Aged↗
PubMed1980

Drug trials in myocardial infarction. Lessons to be learned from the Anturane Reinfarction Trial.

Drug intervention trials in myocardial infarction are unlikely to prove an effect unless planning takes into consideration: (1) the multiple causes for cardiac mortality after myocardial infarction, and the likelihood that the drug being tested is unlikely to affect all of these causes; (2) the different mortality rates at different periods following the qualifying infarct; (3) the contribution of each cause to the total mortality encountered during each period; and (4) the elimination of the various dilution factors which plague those trials based only on an intention to treat rather than on the efficacy of the drug when administered properly to eligible patients. Prospective studies should be designed with these points in mind. Otherwise one will be confronted with the usual criticisms and scepticism associated with a retrospective analysis. In this regard, the Anturane Reinfarction Trial represents an advance in trial design, and the lessons to be learned from it provide a basis for further improvements.

Clinical Trials as Topic↗
PubMed1983

Sulphinpyrazone and renal function following myocardial infarction.

The effects of sulphinpyrazone 800 mg daily on renal excretory function were studied in a double-blind placebo-controlled randomised trial of incremental and full doses of the drug in 28 patients with plasma urea concentration less than 10 mmol/l in the period 2-28 days following uncomplicated acute myocardial infarction. Sulphinpyrazone in both dosage regimens increased uric acid excretion and lowered plasma urate concentration. There was no evidence that the drug reduced glomerular filtration rate or damaged the renal tubules. These results suggest that sulphinpyrazone in the doses used in this study is not contraindicated in patients early after acute myocardial infarction even though they may have a moderate rise in the blood urea.

Adult↗
PubMed1986

Renal clearance of sulphinpyrazone in man.

Six healthy young volunteers received a single dose of sulphinpyrazone 200 mg p.o. Plasma concentration and urinary excretion rate curves showed large intersubject variation for sulphinpyrazone and its metabolites. The sulphide metabolite could only be detected in plasma and not before 3-7 h after ingestion. The total recovery in urine of all compounds varied from 30-56% of the dose. In two subjects the mean residence time of sulphinpyrazone was twice as long as in the other subjects (10.4 h compared with 4.6 h), but the area under the plasma concentration-time curve was comparable to that in the others (mean: 3.0 mg X ml-1 X min), indicating that drug absorption was quantitatively similar but delayed. The renal clearance of sulphinpyrazone varied from 14-40 ml X min-1 (mean: 28 ml X min-1). In view of the very high plasma protein binding of sulphinpyrazone, active tubular secretion is the predominant mechanism in its renal clearance. The same holds for the sulphone metabolite, which has a mean renal clearance of 24 ml X min-1, and even more for the p-hydroxysulphinpyrazone metabolite, which has a renal clearance of 118 ml X min-1. No unambiguous evidence was found in favour of concentration-dependent renal clearance of sulphinpyrazone or its metabolites over the concentration range studied. The renal clearance, especially of sulphinpyrazone, appeared to be dependent on urine pH and not on urine flow rate.

Adult↗
PubMed1986

Interference by sulphinpyrazone with the antihypertensive effects of oxprenolol.

The interfering effect of sulphinpyrazone, a uricosuric agent which reduces the activity of cyclo-oxygenase, with the antihypertensive activity of oxprenolol, a non-cardioselective beta-blocker with sympathomimetic activity, has been evaluated. Ten patients with primary arterial hypertension of mild to moderate degree entered a randomized double-blind cross-over study versus placebo. They were given oxprenolol + placebo or oxprenolol + sulphinpyrazone for 15 days, and then the treatments were crossed-over for a further 15 days. Oxprenolol significantly reduced blood pressure (161 +/- 3/101 +/- 1 vs 149 +/- 4/96 +/- 2 mmHg) and heart rate (72 +/- 3 vs 66 +/- 3 beats/min). During administration of the combination with sulphinpyrazone the blood pressure increased to its pretreatment level (156 +/- 5/101 +/- 2 mmHg). The effect of oxprenolol on heart rate was not influenced by the combined treatment (67 +/- 6 beats/min). The results may be explained by 1) sulphinpyrazone-induced inhibition of prostaglandin synthesis, which could interfere with the antihypertensive activity of oxprenolol, or 2) sulphinpyrazone-induced acceleration of the metabolism of oxprenolol.

Adult↗
PubMed1985

Pharmacokinetics of sulphinpyrazone and its major metabolites after a single dose and during chronic treatment.

The pharmacokinetics of sulphinpyrazone and its major metabolites (sulfide, sulfone, p-hydroxysulfone and p-hydroxy-sulphinpyrazone) were investigated in 9 volunteers after a single oral dose as well as after chronic treatment for 23 days. Chronic administration of sulphinpyrazone, in comparison with a single oral dose, led to significant changes in plasma AUC (115.86 to 42.90 mg/l . h), in renal clearance (1.06 to 1.80 l/h), in hepatic intrinsic clearance (319.0 to 598.0 l/h), and in the unbound fraction in plasma 1.15 to 1.69%) and in tissue (2.73 to 1.31%). The volume of distribution changed from 20.24 to 52.04 l. The steady state concentrations predicted from the single dose were significantly higher than the values found after chronic treatment. The results suggest that sulphinpyrazone induces its own metabolism. The metabolism of the sulfone, p-hydroxysulfone and the p-hydroxy-sulphinpyrazone to further degradation products was also induced. Chronic treatment with sulphinpyrazone reduced the plasma AUC of the sulfide and caused a decrease in its elimination half-life (20.9 to 14.3 h). Since considerable amounts of the sulfide are formed in the G.I. tract, it is suggested that besides the induction of metabolism, bacteria which reduce sulphinpyrazone to the sulfide may also be responsible for the observed pharmacokinetic changes.

Adult↗
PubMed1978

Effect of sulphinpyrazone (Anturan) on uric acid excretion and plasma uric acid concentration in healthy volunteers.

Investigations in six healthy volunteers given single oral doses of sulphinpyrazone (Anturan) showed that the drug had a potent uricosuric effect, even if the concentration of uric acid in the plasma was normal. In the dose range tested of 50 to 800 mg the increase in uric acid excretion was dose-related. It reached a maximum within 2 h and was still detectable 6--8 h after the drug was taken. There was a corresponding dose-related reduction in the plasma concentration of uric acid, which reached its lowest level after 8--10 h. The administration of 300 mg twice daily for four days to a further five healthy volunteers reduced plasma uric acid from 5.06 to 1.8 mg%. The findings indicate that, even if plasma uric acid levels are unknown, it would be advisable to avoid the risk of formation of urinary calculi by administering sulphinpyrazone in gradually increasing doses, ensuring adequate fluid intake and alkalinizing the urine during the first few days of treatment.

Humans↗
PubMed1982

Pharmacological properties of PAF-acether in the guinea-pig: platelet-dependent and independent reactions.

The in vivo effects of PAF-acether in the guniea-pig are reviewed, particularly with respect to bronchoconstriction and to platelets, the former being suppressed when the latter are depleted. Bronchoconstriction by PAF-acether is not inhibited by aspirin, and when the latter was associated to mepyramine and to methysergide, bronchoconstriction was blocked, whereas thrombocytopenia persisted. Our results indicated that platelets collected from aspirin--mepyramine--methysergide-treated animals are less reactive for PAF-acether than control platelets, with respect to secretion of ATP, but aggregated fully. Secretion and aggregation are thus dissociable, the former being involved with bronchoconstriction. Results obtained with sulphinpyrazone and with reserpine are also discussed, and lead to the concept that platelet may release a presently unknown mediator when stimulated with PAF-acether.

Animals↗
PubMed1990

The effect of sulphinpyrazone and alpha-tocopherol on platelet activation and function in haemodialysed patients.

In 30 patients on chronic haemodialysis treatment the platelet activity and function were studied before and during antiplatelet therapy with alpha-tocopherol and sulphinpyrazone. In both kinds of treatment a significant decrease of ADP-induced and spontaneous aggregation was observed. Sulphinpyrazone exerts an inhibitory effect not only on platelet aggregation but also on platelet factor 3 and provokes a significant prolongation of the bleeding time.

Adult↗
PubMed1992

Influence of antiplatelet drugs on occlusion of arteriovenous fistula in uraemic patients.

A long-standing arteriovenous (A-V) fistula may develop thrombotic complications. In 20 patients on intermittent peritoneal dialysis (IPD) arteriovenous fistula was made surgically. We evaluated the efficacy of three antiplatelet drugs: Ibustrin (Group A), sulphinpyrazone (Group B) and alpha-tocopherol (Group C) in preventing thrombotic occlusion of A-V fistulas. Results of the trial indicate that the three drugs significantly reduce spontaneous platelet aggregation and ADP induced aggregation. The heparin neutralizing activity was significantly increased during treatment. Significant prolongation of bleeding time was observed only in Groups B and C. In patients receiving antiplatelet drugs no occlusion of A-V fistulas was observed. In the control group such complications occurred in 3 of the 20 patients. Our results indicate that antiplatelet drugs by inhibiting the platelet function may prevent thrombotic occlusions of A-V fistulas in IPD patients.

Arteriovenous Shunt, Surgical↗