Sulphinpyrazone increases lymphocyte beta-adrenoceptors in man.
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Adult↗
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Effects of chronic metoprolol and sulphinpyrazone on human lymphocyte beta-adrenoceptors.
Multiple (100 mg twice daily for 21 days) but not single (100 mg) oral doses of metoprolol significantly reduced the number (Bmax) and the KD of beta-adrenoceptors on intact lymphocytes from nine healthy volunteers. Sulphinpyrazone (400 mg twice daily for 21 days) did not change lymphocyte beta-adrenoceptors and did not modify their reaction to chronic metoprolol. In vitro sulphinpyrazone (10-4M) increased [3H]-DHA specific binding on intact lymphocytes. This effect was not modified by metoprolol, sulphinpyrazone or the two combined. Metoprolol and sulphinpyrazone did not interact in the experimental model of beta-adrenoceptors on intact lymphocytes in conditions mimicking long-term treatment.
Adult↗
Plasma levels and pharmacokinetics of sulphinpyrazone in renal impairment during chronic treatment: a case report.
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Humans↗
Verapamil disposition--effects of sulphinpyrazone and cimetidine.
The effects of separate 7 day pretreatments with sulphinpyrazone (800 mg daily) and cimetidine (1 g daily) on the disposition of (+/-)-verapamil have been examined in eight healthy volunteers (four male, four female). Each subject received single oral (80 mg) and intravenous (0.15 mg/kg) doses of verapamil on different occasions before and after each pretreatment. Following sulphinpyrazone pretreatment, verapamil apparent oral plasma clearance (CLpo) increased from 4.27 to 13.77 l h-1 kg-1 (s.e. mean 0.51--ANOVA) (P less than 0.001); CL increased from 1.05 to 1.20 l h-1 kg-1 (s.e. mean 0.05) (P less than 0.05) and Fpo decreased from 27 to 10% administered dose (s.e. mean 2) (P less than 0.001). Vss and t1/2,z were unchanged. There was no sex difference for any dispositional parameter in the control phase, but the increase in CLpo following sulphinpyrazone pretreatment was more marked in males (4.04 to 17.33 l h-1 kg-1) than in females (4.49 to 10.21 l h-1 kg-1) (s.e. mean 0.72) (P less than 0.01). There was no significant change in any verapamil disposition parameter following cimetidine pretreatment. Verapamil unbound fraction in plasma was 0.157 (s.e. mean 0.001, n = 40). There was no alteration in verapamil plasma protein binding associated with increasing verapamil concentration (25-250 micrograms l-1) or addition of sulphinpyrazone (50-500 mg l-1) or cimetidine (0.5-5 mg l-1). The results suggest that sulphinpyrazone induces the metabolic clearance of (+/-)-verapamil with a sex difference in the response.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
The influence of red blood cells on the effects of aspirin or sulphinpyrazone on platelet adherence to damaged rabbit aorta.
The effects of acetylsalicylic acid (ASA; aspirin) or sulphinpyrazone (SP) on the adherence of washed rabbit platelets to the subendotheilial surface of an everted aorta mounted on a probe or to the subendothelial surface of a rabbit aorta attached to a perfusion apparatus were examined. ASA had no effect on platelet adherence to a damaged aorta perfused with a suspension of washed platelets in a medium containing 10% red blood cells (RBC); SP was slightly inhibitory at high concentration. When damaged rabbit aortae were everted on a probe and rotated in a suspension of washed platelets to which RBC were added to a packed cell volume of 10%, both ASA and SP inhibited platelet adherence to the damaged vessel wall. When the PCV was 40%, ASA was not inhibitory and SP reduced platelet adherence only at very high concentrations. It is therefore unlikely that, at the concentrations achieved in man, SP exerts an effect on platelet adherence. The different effects of ASA and SP on platelet survival do not appear attributable to their effects on platelet adherence.
Animals↗
Potentiation of anticoagulant response to warfarin by sulphinpyrazone: a double-blind study in patients with prosthetic heart valves.
The effect of Sulphinpyrazone on the anticoagulant response to Warfarin was evaluated by a double-blind study in 11 patients with prosthetic heart valves. Six patients received Warfarin and Sulphinpyrazone and 5 Warfarin and placebo. Sulphinpyrazone potentiated the anticoagulant effect of Warfarin. Patients receiving Sulphinpyrazone needed about half the amount of Warfarin as compared to the control group. There were four bleeding episodes in the Sulphinpyrazone group and one episode in the control group. It was difficult to regulate the dose of Warfarin in patients also receiving Sulphinpyrazone.
Adult↗
Acute non-oliguric renal failure secondary to sulphinpyrazone overdose.
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Acute Kidney Injury↗
Anti platelet agents for strokes and myocardial infarction: a critical appraisal of recent clinical trials.
Attempts at prevention of arterial thrombosis with platelet inhibitors have been the subject of a number of major trials in recent years. These trials were prompted by earlier observations that aspirin takers seemed to fare better after acute myocardial infarction and were further stimulated by the recent growth of knowledge about the role of vascular and platelet prostaglandins. The trials have sought to establish that aspirin (ASA), sulphinpyrazone and dipyridamole may prevent thrombosis in the form of recurrence of transient ischaemic attack (TIA) and stroke or reduce the recurrence rate and mortality after acute myocardial infarction. No single trial has provided conclusive evidence although there is a strong suggestion of some benefit from ASA. With further understanding of PG metabolism and the effects of inhibitors new approaches are likely to emerge in the near future.
Aspirin↗
Does sulphinpyrazone reduce haemolysis from prosthetic heart valves?
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Aged↗
Electrophysiological and mechanical effects of sulphinpyrazone on isolated rat atria.
Clinical trials suggest that sulphinpyrazone reduces the incidence of sudden death in patients having suffered a myocardial infarction. To investigate possible direct antiarrhythmic properties of sulphinpyrazone, we carried out experiments on spontaneously beating and electrically stimulated isolated rat atrial preparations. Dose-response curves for electrophysiological and mechanical effects of sulphinpyrazone were obtained. Increasing doses of sulphinpyrazone decreased the spontaneous atrial frequency, prolonged the sinus node recovery time after overdrive pacing, slightly increased the electrical threshold for excitation and decreased the contractile force. Although the mechanism by which sulphinpyrazone may reduce the incidence of sudden cardiac death is still not settled, the present study demonstrates direct electrophysiological and mechanical effects of the drug at high concentrations.
Animals↗
Effects of sulphinpyrazone and aspirin on prostaglandin I2 (prostacyclin) synthesis by endothelial cells.
Synthesis of prostaglandin I2, (PGI2, prostacyclin) by vascular endothelium (assayed by the ability of cultured endothelial cells to inhibit platelet aggregation) was inhibited by aspirin. At 100 mumol/l aspirin completely blocked measurable PGI2 production, but endothelial cells had substantially recovered their ability to synthesize PGI2 24 h after removal of the drug. In contrast, the effect of 1 mmol/l aspirin was still evident 24 h after drug withdrawal. Sulphinpyrazone also inhibited PGI2 synthesis, but was about 100 fold less potent than aspirin, and the effect of the drug was lost within 24 h of its addition, even when endothelial cells were left in contact with the drug during this period.
Aspirin↗
Haemodynamic effects of sulphinpyrazone in experimental myocardial ischaemia.
The effect of sulphinpyrazone (30 mg/kg i.v.) on heart rate, blood pressure and ventricular arrhythmias was studied in open-chested anaesthetized dogs during sequential 10 min occlusions of the left anterior descending coronary artery. An increased duration of occlusion without ventricular fibrillation and reduction in epicardial activation delay in the central ischaemic region were observed after intravenous sulphinpyrazone (n = 7). These effects were associated with a progressive and significant reduction in intrinsic heart rate (up to 15 beats/min) but no change in blood pressure. These findings suggest that heart rate changes alone may account for the observed protective effect of sulphinpyrazone against early ventricular fibrillation during acute experimental myocardial ischaemia.
Animals↗
Mechanisms of Forssman-induced bronchospasm and their inhibition.
1 The bronchospasm induced in the guinea-pig by the injection of Forssman antiserum was biphasic in nature in both the sublethal and the lethal reaction. 2 The development of both phases of the bronchospasm in the sublethal reaction was dependent upon the presence of the intact complement system and circulating platelets. In the lethal reaction the phase II bronchospasm did not appear to depend on these factors. 3 The compounds used in this study inhibited phase I bronchospasm of the sublethal reaction in the order, methysergide greater than indomethacin greater than aspirin = sulphinpyrazone and phase II in the order, indomethacin greater than sulphinpyrazone greater than aspirin. Methysergide was inactive. 4 Aspirin, indomethacin and sodium salicylate all prevented the inhibitory action of sulphinpyrazone in reducing the phase II bronchospasm of the sublethal reaction in the order, indomethacin greater than sodium salicylate greater than aspirin, when the drugs were administered prior to sulphinpyrazone. 5 The inhibitory action of aspirin on the sulphinpyrazone effect could be prevented by administering sulphinpyrazone before aspirin. All drug-induced inhibitions of sulphinpyrazone by aspirin, indomethacin and sodium salicylate were dose-dependent.
Animals↗
A direct protective effect of sulphinpyrazone on ischaemic and reperfused rat hearts.
Initiation of 60 min ischaemia to rat isolated hearts produced a depression in developed tension and heart rate. Subsequent reperfusion caused a greatly exacerbated creatine phosphokinase (CPK) efflux and limited functional recovery. Sulphinpyrazone (100 ng ml-1 and 1 microgram ml-1) significantly reduced CPK release, particularly after reperfusion, the lower concentration being more effective. A reduction in the mechanical depression during ischaemia and enhanced recovery after reperfusion were seen only with 100 ng ml-1 sulphinpyrazone. Heart rate and coronary perfusion pressure were unaffected by drug treatment. The reduction in reperfusion-induced CPK efflux by 100 ng ml-1 sulphinpyrazone was maximal when the drug was present throughout the perfusion period although some protection was evident when sulphinpyrazone was present either during ischaemia or reperfusion only. An enhanced recovery in contractility was seen only when the drug was present throughout all phases of perfusion. It is suggested that sulphinpyrazone exerts a direct protective effect on the heart particularly during reperfusion. The degree of protection is critically dependent on the concentration of sulphinpyrazone.
Animals↗
Alteration of monocrotaline pyrrole-induced cardiopulmonary effects in rats by hydrallazine, dexamethasone or sulphinpyrazone.
The effects of intraperitoneal hydrallazine, dexamethasone, or sulphinpyrazone on the toxicity of monocrotaline pyrrole (MCTP) were examined in rats 14 days after injection of MCTP (5 mg kg-1, i.v.). MCTP alone caused increases in lung weight, and of both lactate dehydrogenase activity and protein concentration in bronchopulmonary lavage fluid. Right ventricular hypertrophy also occurred. Hydrallazine (3 mg kg-1, daily), a vasodilator and platelet prostaglandin synthesis inhibitor, reduced the degree of right ventricular hypertrophy and the elevation in the concentration of protein in lavage fluid. Dexamethasone (27 micrograms kg-1, daily), an anti-inflammatory agent and inhibitor of phospholipase, also reduced the right ventricular hypertrophy and the increased protein concentration in lavage fluid caused by MCTP. Sulphinpyrazone (100 mg kg-1, twice daily), an inhibitor of platelet prostaglandin biosynthesis, prevented right ventricular hypertrophy in the MCTP treated rats without affecting any of the indices of lung injury. These results provide further support for the hypothesis that platelets and vasoconstrictor agents play a role in the development of MCTP-induced pulmonary hypertension.
Animals↗
A protective effect of sulphinpyrazone against coronary occlusion-induced shortening of myocardial refractory periods in the rat.
The hearts of anaesthetized, artificially ventilated rats were exposed, and the left coronary artery occluded. The diastolic threshold voltage for stimulation (DTV), the duration of the bipolar electrogram (DBE) and the functional refractory period (FRP) of the ischaemic area were measured at minute intervals for an hour after occlusion. Coronary occlusion caused a rise in DTV, a prolongation of the DBE and a biphasic change in the FRP, with an initial prolongation phase (1-4 min) followed by a decline to below pre-occlusion values (5-15 min). Episodes of ventricular tachyarrhythmia (VT) were most frequent during the period 5-15 min after the onset of occlusion of the coronary artery. This coincided with the period when FRP was minimal and the difference between DBE and FRP was maximal. Pretreatment of rats with sulphinpyrazone (2.5-40 mg kg-1) or indomethacin (5-20 mg kg-1) protected against the episodes of coronary occlusion-induced VT and against the associated decline in FRP of the ischaemic muscle. Sulphinpyrazone was more effective than indomethacin in this respect and a combination of the two drugs was approximately as effective as sulphinpyrazone alone. It was concluded that sulphinpyrazone protects rats against coronary occlusion-induced episodes of VT by reducing the risk of ventricular action potential re-entry. This effect is probably due to protection against the ischaemia-induced shortening of the myocardial FRP.
Action Potentials↗
Electrical changes produced by injury to the rat myocardium in vitro and the protective effects of certain antiarrhythmic drugs.
Glass microelectrodes were used to record intracellular electrical activity from rat isolated and superfused atrial myocardium during external electrical stimulation. After 2 h in normal oxygenated physiological salt solution the muscle was exposed for 30 min to a superfusate simulating the composition of extracellular fluid during myocardial ischaemia (SI). This fluid contained lactate (20 mM), a raised potassium concentration (7 mM), no glucose and a pH lowered to 6.4, and was gassed with N2 in place of O2 (hypoxia). During SI the diastolic threshold voltage for stimulation increased, the speed of action potential conduction between the right and left atria slowed, and both the effective and functional refractory periods of the right atrium shortened, as did the duration of the right atrial action potential. The only component of SI which separately caused electrical changes similar to those of the full simulation was hypoxia. Addition to the superfusate of verapamil (0.5 micrograms ml-1), sulphinpyrazone (1-20 micrograms ml-1) or indomethacin (10-20 micrograms ml-1) attenuated many of the SI-induced electrical changes, although indomethacin was much less effective than the other two drugs. Lowering the calcium concentration of the superfusate from 2 mM to 0.5 mM protected against the SI-induced electrical changes that were inhibitable with sulphinpyrazone and verapamil.
Animals↗
Continuous fluorimetric assessment of the changes in cytoplasmic calcium concentration during exposure of rat isolated myocardium to conditions of simulated ischaemia.
1. The cytoplasmic calcium concentration ([Ca]c) of rat isolated atrial myocardium was assessed with the dye indo-1. Dye-loaded atria were superfused with physiological salt solution and excited with radiation at 360 nm, while epifluorescence emissions were collected simultaneously at 400 nm and 500 nm. The ratio of these emissions was used as a measure of [Ca]c. 2. Dye-loaded atria showed a phasic rise and fall in [Ca]c with each applied electrical pacing stimulus. The amplitudes of systolic increments in tension and [Ca]c were augmented by the presence of isoprenaline. 3. Atria superfused with a solution the composition of which resembled that found extracellularly in regions of ischaemia rapidly lost systolic increments in tension and [Ca]c, while end-diastolic [Ca]c and tension gradually rose. 4. The presence of lactate (20 mM) or flufenamate (5 microM) in the superfusate during simulated ischaemia aggravated the rises in both end-diastolic tension and end-diastolic [Ca]c. Inclusion in the superfusate of sulphinpyrazone (50 microM) or glucose (20 mM) protected against some of the deleterious effects of lactate seen during simulated ischaemia.
Animals↗