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PubMed1983

Mechanisms of action of sulphinpyrazone.

Sulphinpyrazone normalises the shortened platelet survival associated with gout or artificial heart valves and has shown benefit in secondary prevention of myocardial infarction. The compound is metabolised in all species but in variable amounts to a sulphide metabolite which is a potent cyclo-oxygenase inhibitor. At the plasma concentration found in man, the metabolic inhibits prostaglandin synthesis-dependent platelet behaviour and this is therefore the likely mechanism of action of sulphinpyrazone. The compound has some additional effects which may be important.

Animals↗
PubMed1985

Differential inhibition of platelet thromboxane and lung prostacyclin production by sulphinpyrazone, acetylsalicylic acid and indomethacin by human tissues in vitro.

To compare the inhibition of human platelet and lung cyclo-oxygenases by sulphinpyrazone (SP), acetylsalicylic acid (ASA) and indomethacin, we investigated their effects on platelet thromboxane A2 (TxA2) production during spontaneous clotting and on prostacyclin (PGI2) and TxA2 productions of superfused minced human lung. The synthesis of proaggregatory, vasoconstricting TxA2 and antiaggregatory, vasodilating PGI2 were evaluated by measuring the concentration of their stable metabolites thromboxane B2 (TxB2) and 6-keto-prostaglandin F1 alpha respectively, by radioimmunoassays. The basal platelet TxB2 production was 241.0 +/- 56.3 ng/ml (mean +/- SEM, n = 12). The concentrations needed for 50% inhibition of this production (IC50) were 41.3 mumol/l for sulphinpyrazone, 6.3 mumol/1 for ASA and 0.094 mumol/l for indomethacin. The lung generated 23.8 +/- 5.5 ng/g/min (mean +/- SEM, n = 6) of 6-keto-PGF1 alpha and 8.5 +/- 1.8 ng/g/min of TxB2. The IC50 values for pulmonary 6-keto-PGF1 alpha and TxB2 productions were 530.0 mumol/l for SP, 370.0 mumol/l for ASA and 50.0 mumol/l for indomethacin. Thus pulmonary cyclo-oxygenase, presumably originating from endothelial cells, was 13, 59, and 532 times more resistant to these prostaglandin synthesis inhibitors (PGI's) than platelet cyclo-oxygenase. These data suggest that there are considerable differences in the concentration ranges of various PGI's by which the PGI2/TxA2 balance can be shifted to a dominance of PGI2.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Prolongation of platelet survival in hypercholesterolaemic rabbits by CGS 12970 (3-methyl-2-(3-pyridyl)-1 indoleoctanoic acid) and dazoxiben.

In rabbits receiving a normal laboratory diet the platelet half-life was 40.4 +/- 2.5h (mean +/- S.D., n = 35). In animals fed the cholesterol-enriched diet for 12 weeks the platelet half-life was reduced to 31.6 +/- 3.6h (mean +/- S.D., n = 35). Treatment of cholesterol-fed animals with a single daily dose of CGS 12970 (a long acting inhibitor of thromboxane synthase) normalised the platelet half-life. Single daily doses of the relatively shorter acting thromboxane synthase inhibitors (CGS 13080 and dazoxiben) failed to correct the reduced platelet survival. However, twice daily dosing with dazoxiben was effective. The cyclooxygenase inhibitors, aspirin and sulphinpyrazone, failed to correct the reduced platelet survival.

Animals↗
PubMed1984

Prostaglandin endoperoxides and thromboxane A2 in thrombus formation in the hamster cheek pouch in vivo.

Electrical stimulation in the presence of ADP of arterioles of the hamster cheek pouch caused endothelial damage and white thrombus formation. The thrombus formation was inhibited by cyclo-oxygenase inhibitors aspirin and sulphinpyrazone and its thioether derivative G 25671. Thromboxane synthetase inhibitors N-(7-carboxyheptyl) imidazole and butylimidazole failed to inhibit thrombus formation, although in the same doses both compounds inhibited serum levels of thromboxane. These results indicate that thromboxane is not important in thrombus formation in the hamster, but that prostaglandin endoperoxides are more significant. However, it is possible that the inhibition of white thrombus formation by aspirin, sulphinpyrazone and G 25671 may be mediated by a different mechanism altogether.

Animals↗
PubMed1982

Overview of recent clinical and methodological advances from clinical trials of cardiovascular disease.

Concurrently controlled, randomized clinical trials play an important role in the validation of treatment and control measures of cardiovascular disease. As such trials have been carried to conclusion, a great deal has been learned not only about the treatment of the disease but also about the methodology of clinical trials. Seven recently completed clinical trials, the Coronary Drug Project, the Aspirin Myocardial Infarction Study, the Anturane Reinfarction Trial, the Hypertension Detection and Follow-Up Program and three drug trials of betablockers, are reviewed from the perspective of both their clinical and methodological significance.

Adrenergic beta-Antagonists↗
PubMed1995

Use of cumulative meta-analysis in the design, monitoring, and final analysis of a clinical trial: a case study.

From 1983 to 1987, the Department of Veterans Affairs (DVA) Cooperative Studies Program (CSP) conducted a multicenter clinical trial (CSP #207) to determine whether four different antiplatelet regimens compared to placebo could prevent the occlusion of grafts following coronary artery bypass surgery. The study showed that all of the active regimens tended to be better than placebo and that the three regimens containing aspirin were statistically significantly better. A cumulative meta-analysis of 12 trials performed shortly before the end of CSP #207 raised the issue as to whether the meta-analysis, if done earlier, would have changed the conduct of the trial. At the start of the planning period, one trail of size n = 37 had been published with a nonsignificant odds ratio (OR) of 0.74 (95% CI: 0.18, 3.12). At the time that CSP # 207 was approved by the DVA Cooperative Studies Evaluation Committee, two trials had been published (cumulative n = 150, OR = 0.44, 95% CI 0.19, 0.99). At the time patient intake started, five trials showed cumulative n = 769, OR = 0.42, 95% CI = 0.26, 0.68. Although the first 6-month CSP #207 progress report showed no treatment effect, by the time of the 12-month review by the Data Monitoring Board (DMB) a trend was developing in favor of active treatment. If the results of the meta-analysis had been available to the DMB at that time, conceivably the Board would have recommended stopping the placebo arm because of a convincing treatment effect based on the totality of the evidence. Cumulative meta-analysis could be useful as an adjunct in the planning, conduct, and final analysis of a clinical trial. It could also be used as one piece of evidence in the monitoring of the ongoing phase of a trial.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1989

Issues in planning and interpreting active control equivalence studies.

Active control equivalence studies, with the goal of demonstrating therapeutic equivalence between a new and an active control treatment, are becoming more widespread due to current therapies that reflect previous successes in the development of new treatments. Because ethical requirements preclude the use of a placebo or no-treatment control for internal study validation, certain methodologic issues arise in active control equivalence trials that require special attention. We emphasize a special feature of this alternative study design, namely, its reliance on an implicit "historical control assumption". To conclude that a new drug is efficacious on the basis of an active control equivalence study (ACES) requires a fundamental assumption that the active control drug would have performed better than a placebo, had a placebo been used in the trial. In designing an ACES, one needs some assurance that historical estimates of the active control drug's efficacy relative to placebo are applicable to the new experimental setting. Steps that can be taken to compile such evidence and to justify the use of an active control equivalence design are described. These issues are illustrated in the context of a planned study to evaluate the efficacy of a new drug for the prevention of stroke, using aspirin as an active control.

Adult↗
PubMed2003

Differential effects of glucose on dehydroascorbic acid transport and intracellular ascorbate accumulation in astrocytes and skeletal myocytes.

Skeletal muscle and brain are major sites of glucose transport and ascorbate (vitamin C) storage. Ascorbate is oxidized to dehydroascorbic acid (DHAA) when used as an enzyme cofactor or free radical scavenger. We evaluated the hypothesis that glucose regulates DHAA uptake and reduction to ascorbate (i.e., recycling) by skeletal muscle cells and cerebral astrocytes. DHAA uptake was inhibited partially by glucose added simultaneously with DHAA. Comparison of wild type L6 skeletal muscle cells with an L6-derived cell line (D23) deficient in facilitative hexose transporter isoform 3 (GLUT3), indicated that both GLUT3 and facilitative hexose transporter isoform 1 (GLUT1) mediate DHAA uptake. Preincubation of muscle cells with glucose inhibited the rates of glucose and DHAA uptake, and decreased the intracellular concentration of ascorbate derived from recycling of DHAA. In contrast, glucose preincubation did not depress GLUT1 protein and activity levels or DHAA recycling in astrocytes. These results establish that glucose downregulates subsequent recycling of DHAA by skeletal muscle cells but not astrocytes.

Animals↗