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PubMed2004

Effect of a selective CYP2C9 inhibitor on the pharmacokinetics of nateglinide in healthy subjects.

PURPOSE: The objective of the study was to determine the effect of a potent and selective CYP2C9 inhibitor, sulfinpyrazone (Anturane), on the pharmacokinetics of nateglinide (Starlix), a novel antidiabetic drug which is primarily (approximately 70%) metabolized via CYP2C9. METHODS: This was a randomized, open-label, two-period, crossover study in 18 healthy volunteers. Nateglinide was administered as a single 120-mg oral dose alone (reference) on day 1 or in combination with sulfinpyrazone (test) on day 7, following twice-daily 200-mg oral doses (i.e., 400 mg/day) of sulfinpyrazone for 7 days. Pharmacokinetic parameters of nateglinide were determined following the administration of nateglinide alone, and when administered in combination with sulfinpyrazone. Plasma nateglinide concentrations were determined using a validated high-performance liquid chromatography method. RESULTS: The administration of nateglinide in combination with sulfinpyrazone resulted in approximately 28% higher mean AUC of nateglinide (90% CI for test-reference ratio: 1.20-1.39) with no differences in mean peak plasma concentration (Cmax; 90% CI test-reference ratio: 0.86-1.12) compared with nateglinide-alone treatment. The time to reach Cmax (tmax) and the elimination half-life of nateglinide were similar between the two treatments. Both treatments were safe and well tolerated. CONCLUSIONS: Sulfinpyrazone increased the mean exposure of nateglinide by 28% when both drugs were administered in combination. Nateglinide, given as a single dose or co-administered with multiple doses of sulfinpyrazone, was safe and well tolerated in healthy subjects.

Adolescent↗
PubMed1979

Platelet suppressant therapy in patients with prosthetic cardiac valves. Relationship of clinical effectiveness to alteration of platelet survival time.

Platelet survival time (SURV) has correlated with thromboembolism in patients with prosthetic cardiac valves. Sulfinpyrazone increases SURV. SURV (autologous labeling with 51Chromium) was measured in 126 patients who had aortic or mitral valve replacement. These patients were followed prospectively. Ninety-four with shortened SURV received sulfinpyrazone; 32 with normal SURV were not treated with platelet suppressants. Eighty-seven patients were anticoagulated with warfarin--67 with shortened SURV and 20 with normal SURV. Eleven patients have had thromboembolism, and all had shortened SURV (2.4 +/- 0.08 days; average half-time +/- SEM; normal 3.7 +/- 0.03 days; n = 26) none had an increase of SURV with sulfinpyrazone (2.3 +/- 0.09 days). Of 83 patients with shortened SURV who did not have embolism, sulfinpyrazone increased SURV in 59 (71%) 2.6 +/- 0.05 to 2.9 +/- 0.06 days). Of 35 patients with shortened SURV who failed to increase SURV with sulfinpyrazone, 11 (31%) had embolism; none of 59 (0%) with an increase of SURV with sulfinpyrazone had thromboembolism. These results suggest that patients with thromboembolism after prosthetic cardiac valve replacement have shortened SURV and that patients treated with slufinpyrazone who have thromboembolism do not have an increased SURV.

Aortic Valve↗
PubMed1973

Evidence for a postsecretory reabsorptive site for uric acid in man.

The effects of administration of drug combinations on uric acid excretion were studied in order to test the hypothesis that a portion of renal tubular reabsorption of uric acid occurs distal to the uric acid secretory site. Oral administration of pyrazinamide (3 g) during probenecid uricosuria (probenecid 500 mg every 6 h) decreased urate excretion from 463 mug/min following probenecid medication alone to 135 mug/min following probenecid plus pyrazinamide (P < 0.01). When a greater uricosuric effect was induced with a 2 g oral dose of probenecid, the decrement in urate excretion which followed pyrazinamide administration (3 g) was more pronounced (2,528 mug/min following probenecid alone, 574 mug/min following probenecid plus pyrazinamide). Results were similar when an 800 mg oral dose of sulfinpyrazone was given in place of probenecid (1,885 mug/min following sulfinpyrazone alone, 475 mug/min following sulfinpyrazone plus pyrazinamide). Thus, apparent urate secretion (measured as the decrease in excretion of urinary uric acid resulting from pyrazinamide administration) appeared to vary, depending upon the degree of inhibition of reabsorption produced by probenecid or sulfinpyrazone. When small doses of aspirin were administered in place of pyrazinamide to produce secretory inhibition, the results were similar. Neither probenecid nor pyrazinamide significantly altered urate excretion when administered to patients with serum salicylate levels above 14 mg/100 ml. These results are interpreted as suggesting that renal tubular reabsorption of uric acid occurs at least in part at a postsecretory site and that a portion of secreted urate is reabsorbed. During maximum probenecid- or sulfinpyrazone-induced uricosuria, inhibition of urate secretion with either pyrazinamide or low doses of aspirin resulted in a decrease in uric acid excretion which exceeded total urinary uric acid during control periods by two- to fourfold. This suggests that renal tubular secretion of urate may greatly exceed uric acid excretion and that a large fraction of secreted urate is reabsorbed. The pyrazinamide suppression test underestimates urate secretion. Uricosuria induced by some drugs, including probenecid, sulfinpyrazone, and iodinated radioopaque dyes, appears to represent, at least in part, inhibition of postsecretory urate reabsorption.

Absorption↗
PubMed1979

[Action mechanism and clinical indications for thrombocyte aggregation inhibitors].

The mechanisms of action of three most commonly used antiplatelet agents (aspirin, sulfinpyrazone, dipyridamole) are briefly discussed. Aspirin inhibits the prostaglandin synthetase of platelets irreversibly and thereby blocks the production of prostaglandin endoperoxides and thromboxane A2, which stimulate platelet aggregation. A daily aspirin dose of 200--300 mg is sufficient to achieve this effect. Sulfinpyrazone appears to interfere with the adhesion of platelets to subendothelial structures and atherosclerotic plaques. Dipyridamole increases cyclic AMP in platelets and thus reduces platelet response to aggregating agents. A few of the satisfactorily performed studies on the clinical effectiveness of antiplatelet agents are mentioned. Sulfinpyrazone treatment of patients with myocardial infarction (Killip--classification I and II), starting 25--35 days after the acute myocardial infarction, reduces cardiac mortality and incidence of sudden death for a period of two years. The efficacy of aspirin treatment in coronary artery disease is not yet definitely established. In patients with transient ischemic attacks, particularly males with appropriate carotid lesions, aspirin therapy reduces the frequency of transient ischemic attacks and possibly the incidence of stroke and death. Sulfinpyrazone is ineffective in these patients. Sulfinpyrazone and aspirin are of value in the prevention of thrombosis in straight arterio-venous shunts. Aspirin reduces the frequency of deep venous thrombosis after total hip replacement in males but not in females. In patients with recurrent venous thrombosis, sulfinpyrazone treatment is effective in preventing thrombosis.

Anticoagulants↗
PubMed1980

The anturane reinfarction trial.

The Anturane Reinfarction Trial evaluated the effect of sulfinpyrazone (Anturane) (200 mg four times a day) vs placebo on cardiac mortality rates among patients recently recovered from an acute myocardial infarction. This study involved 1558 eligible patients who were observed for an average period of 16 months (maximum 2 years). The trial differed from studies on other platelet-active drugs in that it was designed as a clinical efficacy study rather than an "intent-to-treat" trial, and all patients were entered within a very narrow window, i.e., 25-35 days after infarction, which allowed for the drug to be evaluated against the natural history of mortality after an acute myocardial infarction. At the end of the trial, there were 105 analyzable cardiac deaths among eligible patients. 62 in the placebo group and 43 in the sulfinpyrazone group; this represented a reduction in mortality rate by sulfinpyrazone of 32% and was of borderline statistical significance (p = 0.044-0.058 using three methods of analysis). This reduction was attributable primarily to a significant reduction in sudden death (37 in the placebo group vs 22 in the sulfinpyrazone group, sudden death mortality reduction of 43%, p = 0.023-0.041). Interpretation of the data by time period and cause revealed that the effect of sulfinpyrazone was restricted to the prevention of sudden death during the high-risk period for this event, i.e., the first 6 months after trial entry (24 in the placebo group vs six in the sulfinpyrazone group, sudden death mortality reduction of 74%, p = 0.001-0.003).

Aspirin↗
PubMed1984

Differential inhibition of neutrophil superoxide generation by nonsteroidal antiinflammatory drugs.

In order to further characterize the effects of nonsteroidal antiinflammatory drugs on neutrophil superoxide (O2-) generation, human neutrophils were incubated in the presence of sulfinpyrazone, phenylbutazone, and indomethacin prior to exposure to a variety of oxidative stimuli. Stimuli used included the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP, 5.0 X 10(-7) M), NaF (20 mM), phorbol myristate acetate (PMA, 3.2 X 10(-7) M), and opsonized zymosan (250 micrograms/ml). Superoxide release induced by FMLP was inhibited by all three drugs with half-maximal inhibition (KI50) at 2.5, 30, and 120 microM for sulfinpyrazone, phenylbutazone, and indomethacin, respectively. This inhibition was not due to drug interference with the assay system since comparable inhibition was not observed in a cell-free O2- -generating system. The neutrophil's response to NaF was blunted by sulfinpyrazone (KI50 = 400 microM) and phenylbutazone (KI50 = 65 microM), but was unaffected by indomethacin. A similar inhibitory pattern was observed when zymosan was used as the oxidative stimulus. Sulfinpyrazone and phenylbutazone inhibited the response to zymosan (KI50s of 425 and 32 microM, respectively), whereas indomethacin augmented it. PMA stimulation evoked O2- production which was inhibited by phenylbutazone (KI50 = 350 microM) but not by sulfinpyrazone or indomethacin in concentrations up to 1 mM. The results support the hypothesis that the enzyme system responsible for neutrophil O2- generation can be activated by more than one mechanism. The results also emphasize the need to evaluate pharmacologic modulation of neutrophil responses in light of the stimulus used to evoke the response.

Anti-Inflammatory Agents↗