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.

Acute renal failure due to sulfinpyrazone.

A case of sulfinpyrazone-associated acute renal failure is reported. Sulfinpyrazone can cause reversible acute renal failure from acute tubular necrosis in patients with volume depletion. Brown tubular casts on urine microscopy and a fractional excretion of sodium greater than 1 are helpful in the diagnosis. Uric acid nephropathy and allergic interstitial nephritis should be included in the differential diagnosis of sulfinpyrazone-associated acute renal failure. Acute reduction of renal blood flow due to inhibition of renal prostaglandin synthesis and kallikrein activity by the drug is a possible mechanism. Treatment of sulfinpyrazone-induced acute tubular necrosis consists of intravascular hydration, supportive care, and withholding sulfinpyrazone. The patients at risk for acute renal failure due to sulfinpyrazone are those who have intravascular volume depletion as sensed by the kidneys.

Risks and benefits of drugs used in the management and prevention of gout.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are now commonly used for the treatment of acute gout, but caution is required in view of their adverse effects, especially in the elderly. Colchicine is still an effective acute agent, but care must be taken to monitor toxicity. Intra-articular glucocorticosteroid therapy is useful and very safe; oral steroids and corticotrophin (adrenocorticotrophic hormone) may have a small role in acute therapy and seem safe when used over short time spans. Low dose colchicine may have a cost and toxicity advantage over NSAIDs in the prophylaxis of gout when commencing therapy aimed at reducing elevated plasma urate concentrations. Allopurinol is more frequently used than uricosuric agents such as probenecid, and toxicity may be largely avoided by tailoring dosage schedules according to renal function.

Combined aspirin and sulfinpyrazone in the prevention of recurrent hemodialysis vascular access thrombosis.

We carried out a pilot study in 15 hemodialysis patients with recurrent vascular access thrombosis to examine whether the combination of low dose aspirin (85 mg once daily) and sulfinpyrazone (200 mg three times daily) is safe and effective in the prevention of vascular access thrombosis. Hemostatic measurements were performed prior to and after four weeks of starting the drug combination. Baseline values for fibrinopeptide A were elevated in all patients while those for platelet factor 4, fibrinogen, antithrombin III and protein C were generally within normal limits. A major reduction in the frequency of vascular access thrombosis from 0.114 per month to 0.04 per month was noted during combined drug treatment (p less than 0.001). Although in vitro platelet aggregation to various stimuli was markedly suppressed and platelet thromboxane B2 formation was almost completely inhibited in patients on aspirin/sulfinpyrazone, this was not associated with a significant further prolongation of the bleeding time. A relatively high rate of complications, particularly mild gastrointestinal bleeding, was noted in patients on aspirin/sulfinpyrazone that could not be predicted on the basis of pre-treatment hemostatic test results.

The consent form as a possible cause of side effects.

In a multicenter trial of aspirin or sulfinpyrazone in the treatment of unstable angina, we examined the possible importance to the outcome of mentioning potential side effects in the consent form. Inclusion, in two of the three centers, of a statement outlining possible gastrointestinal side effects resulted in a sixfold increase (P less than 0.001) in the number of subjects in these centers withdrawing from the study because of subjective, minor gastrointestinal symptoms. Major gastrointestinal complications such as peptic ulcer or bleeding as diagnosed by study physicians were similar in the three centers. Furthermore, no patient discontinued therapy because of subjective, nongastrointestinal side effects. Post hoc analysis suggests that the inclusion of gastrointestinal side effects in the consent form may have increased the likelihood of patients attributing gastrointestinal symptoms to drug therapy, leading to subsequent withdrawal from the study.

Impairment of renal function due to sulphinpyrazone after coronary artery bypass surgery: a prospective double-blind study.

In this randomized, double-blind, placebo-controlled trial the renal function was studied in 60 patients recovering from coronary artery bypass surgery treated with a daily dose of 800 mg sulphinpyrazone (SP) or 880 mg acetylsalicylic acid (ASA) or placebo. Serum creatinine level increased (p less than 0.05) during the first 2 days of SP treatment, but returned to its baseline level within 4 days under maintained therapy; during ASA and placebo therapy no significant changes occurred. Serum urea levels decreased (p less than 0.01) during ASA and placebo treatments as time from surgery subsided; the decrease of serum urea level was delayed in the SP group compared with the ASA and placebo groups. Urinary excretion of prostaglandin E2 (PGE2) was significantly decreased (p less than 0.01) during ASA treatment; in the SP group, urinary PGE2 excretion tended also to decrease during the first days of treatment, the decrease being significant only on the 4th day (p less than 0.01). The urinary excretion of kallikrein decreased significantly only in the SP group (p less than 0.01), while the changes in the ASA and placebo group were not significant. We suggest that the rapidly reversible acute renal impairment during SP therapy was probably due to a transient renal ischemia caused by a drug-related decrease in urinary kallikrein excretion rather than by renal prostaglandin inhibition.

Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial.

We performed a randomized, double-blind, placebo-controlled trial in 555 patients with unstable angina who were hospitalized in coronary care units. Patients received one of four possible treatment regimens: aspirin (325 mg four times daily), sulfinpyrazone (200 mg four times daily), both, or neither. They were entered into the trial within eight days of hospitalization and were treated and followed for up to two years (mean, 18 months). The incidence of cardiac death and nonfatal myocardial infarction, considered together, was 8.6 per cent in the groups given aspirin and 17.0 per cent in the other groups, representing a risk reduction with aspirin of 51 per cent (P = 0.008). The corresponding figures for either cardiac death alone or death from any cause were 3.0 per cent in the groups given aspirin and 11.7 per cent in the other groups, representing a risk reduction of 71 per cent (P = 0.004). Analysis by intention to treat yielded smaller risk reductions with aspirin of 30 per cent (P = 0.072), 56 per cent (P = 0.009), and 43 per cent (P = 0.035) for the outcomes of cardiac death or nonfatal acute myocardial infarction, cardiac death alone, and all deaths, respectively. There was no observed benefit of sulfinpyrazone for any outcome event, and there was no evidence of an interaction between sulfinpyrazone and aspirin. Considered together with the results of a previous clinical trial, these findings provide strong evidence for a beneficial effect of aspirin in patients with unstable angina.

Cyclosporine-associated lymphoproliferation, despite controlled cyclosporine blood concentrations, in a renal allograft recipient.

In a patient receiving sulfinpyrazone (Anturan, Geigy) an unusually high dose of cyclosporine (Cys) was required to maintain serum values in the range of 50-200 ng/ml. After eight months of 1300-1500 mg/day, the patient complained of increasing malaise and symptoms of cyclosporine side-effects. This clinical state was accompanied by splenomegaly and two monoclonal peaks in the gamma region on serum electrophoresis. Concomitantly, rising cytomegalovirus IgM titres, following by rising IgG titres, indicated a primary cytomegalovirus infection. This ominous biclonal proliferation markedly diminished during the subsequent six months, during which time the cyclosporine dose was minimised. He returned to good health, splenomegaly and monoclonal gamma globulin virtually disappearing. He remains well at 16 months post-transplantation.

[Acute interstitial nephritis and kidney failure requiring dialysis after sulfinpyrazone therapy]. / Akute interstitielle Nephritis und dialysepflichtige Niereninsuffizienz nach Sulfinpyrazon-Therapie.

We report a case of acute interstitial nephritis (AIN) after a six weeks' therapy with sulphinpyrazone (Anturane, Ciba-Geigy, Wien). The patient presented with acute renal failure requiring hemodialysis. He died from acute cardiac failure three days after admission. According to our available information, it seems to be the first case of histologically proven acute interstitial nephritis with renal failure requiring hemodialysis after sulphinpyrazone therapy. Our observation underlines the suggestions made by Butler (7) and Mayrhofer et al. (19): During sulphinpyrazone therapy, serum creatinine and urea concentrations should be controlled regularly; the drug must be discontinued immediately when renal function is worsening; and the drug should not be administered in patients with even slightly impaired renal function.

Gastrointestinal blood loss in patients undergoing maintenance dialysis.

Gastrointestinal blood loss was measured for 14 days in 19 patients treated by hemodialysis and in 2 patients treated by chronic ambulatory peritoneal dialysis. 51Cr was used as a marker for erythrocytes. Fecal blood loss was 5.0 +/- 3.3 ml/day in hemodialysis patients who were not taking drugs affecting thrombocyte aggregation and 4.6 +/- 4.3 ml/day in those receiving sulfinpyrazone. There was no relationship between the severity of anemia, duration of dialysis, dose of heparin, grade of uremic intoxication, or dose of aluminum hydroxide and amount of fecal blood loss. It is concluded that gastrointestinal blood loss is not a major determinant of anemia in chronic renal failure. However, sulfinpyrazone is preferable to acetylsalicylic acid for prevention of shunt thrombosis in uremic patients because of their propensity for gastrointestinal bleeding.

Decrease in renal function due to sulphinpyrazone treatment early after myocardial infarction.

Twenty-nine patients with recent myocardial infarction were randomly allocated to a placebo group (n = 14) and to a group (n = 15) who received sulphinpyrazone, 4 x 200 mg daily for 7 days. Renal function significantly and transiently deteriorated in the sulphinpyrazone group compared to the placebo group. In the sulphinpyrazone group the 24 hour-urinary prostaglandin E2 and kallikrein excretion were suppressed. These data suggest that the decrease in renal function caused by sulphinpyrazone early after myocardial infarction could be mediated by an inhibition of renal prostaglandin and/or kallikrein-kinin synthesis.