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PubMed1987

Effective antiplatelet drug concentrations in experimental arterial thromboembolism.

Although drugs that modify platelet function have been widely studied as antithrombotic agents in experimental and clinical studies, there is limited information regarding the relationship between in vivo drug blood concentrations and antithrombotic efficacy. This study compared the pharmacokinetics of three antiplatelet agents with their antithrombotic effects in an experimental model of arterial thromboembolism in baboons. Thrombus formation was measured as steady-state platelet utilization induced by thrombogenic arteriovenous cannulae. The drugs studied were aspirin, dipyridamole and sulfinpyrazone. Aspirin was administered in daily doses of 20 mg/kg, dipyridamole in daily doses of 2.5 and 10 mg/kg, and sulfinpyrazone in daily doses of 20 and 100 mg/kg; each drug was given in two equal doses per day. Multiple blood samples were collected for drug analysis after steady-state had been reached. The average concentrations of dipyridamole at steady-state were 26 +/- 15 and 79 +/- 69 ng/ml after 2.5 and 10 mg/kg/day. These concentrations were associated with 28 and 87% inhibition of cannula platelet consumption, respectively. The average steady-state concentrations of acetylsalicylic and salicylic acids were 0.67 +/- 0.80 and 3.76 +/- 2.60 micrograms/ml, respectively, after 20 mg/kg/day. Aspirin had no effect on platelet consumption. Average concentrations of sulfinpyrazone were 1.05 +/- 0.45 and 12.25 +/- 5.73 micrograms/ml after 20 and 100 mg/kg/day, with significant concentrations of the sulfide metabolite. These concentrations were associated with 23 and 85% inhibition of platelet consumption, respectively. No significant pharmacokinetic interactions were observed after concurrent administration of aspirin and dipyridamole or sulfinpyrazone. As the experimental model used involves thrombus formation on an artificial surface, it is likely that these results are most relevant to patients with arterial prosthetic devices.

Animals↗

PubMedDate not supplied

Ascorbate transport in pig coronary artery smooth muscle: Na(+) removal and oxidative stress increase loss of accumulated cellular ascorbate.

Pig deendothelialized coronary artery rings and smooth muscle cells cultured from them accumulated ascorbate from medium containing Na(+). The accumulated material was determined to be ascorbate using high-performance liquid chromatography. We further characterized ascorbate uptake in the cultured cells. The data fitted best with a Hill coefficient of 1 for ascorbate (K(asc) = 22 +/- 2 microM) and 2 for Na(+) (K(Na) = 84 +/- 10 mM). The anion transport inhibitors sulfinpyrazone and 4,4'-diisothiocyanatostilbene-2,2'-disulfonate (DIDS) inhibited the uptake. Transferring cultured cells loaded with (14)C-ascorbate into an ascorbate-free solution resulted in a biphasic loss of radioactivity - an initial sulfinpyrazone-insensitive faster phase and a late sulfinpyrazone-sensitive slower phase. Transferring loaded cells into a Na(+)-free medium increased the loss in the initial phase in a sulfinpyrazone-sensitive manner, suggesting that the ascorbate transporter is bidirectional. Including peroxide or superoxide in the solution increased the loss of radioactivity. Thus, ascorbate accumulated in coronary artery smooth muscle cells by a Na(+)-dependent transporter was lost in an ascorbate-free solution, and the loss was increased by removing Na(+) from the medium or by oxidative stress.

Actins↗

PubMed1991

Antiplatelet therapy in the prevention of stroke.

Aspirin (acetylsalicylic acid) is effective in reducing vascular outcome events in patients with atherosclerosis: a relative risk reduction of about 30% for stroke, 22% for stroke and death, and 15% for vascular mortality. It is probable that low and high dose aspirin are similar in efficacy. Complications are more frequent with high dose aspirin than with low doses. Four randomised trials evaluating sulfinpyrazone vs placebo, and 3 trials evaluating sulfinpyrazone vs aspirin, showed more cerebrovascular events in the sulfinpyrazone group than in the aspirin and placebo groups. One small trial comparing dipyridamole with placebo in patients with cerebrovascular disease found no difference between the 2 groups in outcome. No other studies have compared dipyridamole alone with placebo or aspirin. The European Stroke Prevention Study II is currently in progress and is comparing dipyridamole + aspirin, dipyridamole, aspirin, and placebo. In the first year, the Ticlopidine Aspirin Stroke Study (TASS) showed a 42% risk reduction for stroke and death using the efficacy analysis and a 47% risk reduction for stroke and stroke death. Ticlopidine was more effective than aspirin in reducing stroke in both males and females. Apart from a reversible severe neutropenia in 0.86% of patients, ticlopidine-related adverse effects were relatively benign and reversible. The Canadian-American Ticlopidine Study (CATS) compared ticlopidine with placebo in patients with completed major strokes. The cumulative event rates for the primary outcome events of stroke, myocardial infarction and vascular death, using the efficacy approach, show clear evidence of separation almost immediately after randomisation, consistent with a constant risk reduction of about 30% in the ticlopidine group. These data provide strong evidence that ticlopidine conveys a clinically important reduction in the risk of thromboembolic events in patients with a history of completed thromboembolic stroke. In conclusion, aspirin is effective in preventing atherothrombotic morbidity and mortality. It reduces the overall vascular event rate by about 25%. Sulfinpyrazone and dipyridamole appear to add nothing important over aspirin alone. Ticlopidine is more effective than aspirin in preventing stroke. The modest, reversible risk of neutropenia, affecting less than 1% of patients, makes the benefit: risk ratio a reasonable one.

Aspirin↗

PubMed1974

Platelet inhibition in the management of thrombosis.

The role of platelets in the initation of arterial thrombosis is clear. In venous thrombosis as well, platelets may in some circumstances play a significant role. For these reasons, and because of the complications and limitations of anticoagulant therapy, antithrombotic trials have been launched with several agents which inhibit platelet function. Regarding postoperative deep vein thrombosis, neither aspirin nor dipyridamole alone appears effective, although the combination offers promise. Results with dextrans are conflicting. In recurrent idiopathic deep vein thrombosis, sulfinpyrazone may be beneficial. On the arterial side, transient cerebral ischemic attacks may be favorably affected by either aspirin or sulfinpyrazone. Prevention of thromboembolism associated with prosthetic heart valves appears possible with combination warfarin-dipyridamole therapy, and the beneficial effect of sulfinpyrazone on shortened platelet survival in this group suggests that this agent may also be effective. Sulfinpyrazone may also be beneficial in preventing thrombosis in arteriovenous canulas. The issue which has attracted the greatest attention and about which no clear answer exists at present is whether antiplatelet agents can modify the course of acute myocardial infarction. Several trials with aspirin are currently underway, and it would be premature to recommend its use in this condition until the results of these trials are available, probably in 1975.

Aspirin↗

PubMed1982

[New aspects in the prophylaxis of myocardial reinfarction (author's transl)].

During the last 30 years several methods have been employed to reduce myocardial infarction and sudden death, rsp. The results with inhibitors of blood coagulation and platelet aggregation are somewhat controversial. Beta-receptor-blockers and sulfinpyrazone on the other hand have proven to be effective at least as far as reduction of sudden death is concerned. A multifactorial intervention program regarding rehabilitation has also been successful although this program may be difficult to use on a broader basis because of organization problems. The following concept may be followed: if there are no contraindications against beta-receptor-blockers and if the patients are younger than 65 years beta-receptor-blockers should be used because there are more studies with a larger number of patients are younger than 65 years beta-receptor-blockers should be used because there are more studies with a larger number of patients available providing their usefulness than for that of sulfinpyrazone. If there are additional indications for beta-receptor-blockers, as for instance hypertension the choice should be even easier. If there are on the other hand contraindications against beta-receptor-blockers or indications for a treatment with sulfinpyrazone such as hyperuricemia, sulfinpyrazone should be used. According to our knowledge such a treatment should be continued for a period of 5 months, a longer treatment seems not to be more promising.

Adrenergic beta-Antagonists↗

PubMed1982

Interruption of tumor-associated platelet consumption with platelet enzyme inhibitors.

Twenty dogs with naturally occurring metastatic tumors were treated with anticoagulants (Warfarin) or platelet enzyme inhibitor drugs (dipyridamole, dipyridamole plus aspirin, RA233, sulfinpyrazone, or a combination of RA233 and sulfinpyrazone) to determine if tumor-related reductions in platelet survival and concentration could be reversed. Anticoagulation was ineffective, while platelet enzyme inhibitors were able to produce improvements in platelet survival. Of the 18 dogs with metastatic tumor treated with platelet enzyme inhibitors, only 5 (28%) showed a reduction in platelet survival during the first week of observation on therapy compared to their baseline survivals. This is significantly different than the decreases in platelet survivals observed in 8 of 10 untreated dogs (80%) with metastatic tumor observed for the same interval. Furthermore, 8 of the 18 treated dogs (44%) had platelet survivals within 2 standard deviations of normal, compared to only 1 of 10 untreated dogs. Of the 8 dogs with normal platelet survivals, 6 were treated with a combination of a phosphodiesterase inhibitor (RA233 or dipyridamole) and a cyclooxygenase inhibitor (sulfinpyrazone or aspirin). The combination of RA233 and sulfinpyrazone was the best drug program tested and resulted in normal platelet survivals in 63% and improved platelet counts in 75% of the animals treated. Thus, platelet enzyme inhibitors with different mechanisms of action may have a synergistic effect in reversing the abnormal platelet hemostasis found in a variety of spontaneously occurring canine neoplasms.

Animals↗

PubMed1988

Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: results of a Veterans Administration Cooperative Study.

To determine whether specific antiplatelet therapies improved vein graft patency after coronary artery bypass grafting (CABG) we compared (1) aspirin, 325 mg daily, (2) aspirin, 325 mg three times daily, (3) aspirin plus dipyridamole (325 mg and 75 mg, respectively, three times daily), (4) sulfinpyrazone (267 mg three times daily), and (5) placebo (three times daily). Therapy, except aspirin, was started 48 hr before CABG. When aspirin was a treatment, one 325 mg dose was given 12 hr before surgery and therapy was maintained thereafter according to the assigned regimen. Angiographic graft patency data were obtained within 60 days of surgery. Analysis of early graft patency in 555 patients (1781 grafts), revealed the following graft patency rates: aspirin daily, 93.5%; aspirin three times daily, 92.3%; aspirin and dipyridamole, 91.9%; and sulfinpyrazone, 90.2%. All aspirin-containing therapeutic regimens improved (p less than .05) graft patency compared with placebo (85.2%). Chest tube drainage measured within the first 35 hr after CABG revealed that the median loss with aspirin daily (965 ml), aspirin three times daily (1175 ml), and aspirin plus dipyridamole (1000 ml) exceeded (p less than .02) that with placebo (805 ml), while median loss with sulfinpyrazone (775 ml) did not. The reoperation rate was greater (p less than .01) in all the treatment groups that received aspirin (6.5%) compared with the two nonaspirin groups (1.7%). Overall operative mortality was 2.3%, without significant differences among treatment groups. Transient renal insufficiency occurred in 5.3% of patients taking sulfinpyrazone. Thus, early vein graft patency was improved after CABG with all aspirin-containing drug regimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Trials as Topic↗

PubMed1975

In vitro evaluation of inhibitors of platelet release and aggregation.

In order to determine which drugs would be most effective as inhibitors of platelet release and aggregation, in vitro release reactions and platelet aggregometry were used to evaluate aspirin, dipyridamole, sulfinpyrazone, flurbiprofen, low molecular weight dextran (dextran 40), prostaglandin E1 (PGE1), apyrase, and adenosine. Adenosine diphosphate-induced aggregation was most effectively inhibited by PGF1, sulfinpyrazone, and dipyridamole. The latter had to be used in large doses. Collagen and epinephrine-induced release and aggregation were inhibited by the same drugs as well as by aspirin and apyrase. Antihynocyte globulin (ATG)-induced release and aggregation could only be partially blocked by these agents. In vitro studies suggest that sulfinpyrazone is one of the most effective of platelet inhibitors currently available for clinical testing.

Adenosine↗

PubMed1993

In vivo responses of mouse blood cells to platelet-activating factor (PAF): role of the mediators of anaphylaxis.

Intravenous injection of platelet-activating factor (PAF) (0.36 mumol/kg b.w.) in mice induced severe hemoconcentration, leucopenia, thrombocytopenia and finally the death of 85% of the tested animals. Combined inhibition of histamine and serotonin by promethazine and chlorpromazine, 6.24 and 3.12 mg/kg b.w. subcutaneously, protected the mice from PAF in part, reducing the death rate to 43%. These drugs did not protect the mice against the PAF-induced hemoconcentration, leucopenia and thrombocytopenia. Sulfinpyrazone (100 mg/kg b.w.) intravenously was the most effective both in protecting mice from PAF-induced death, reducing the death rate to 17%, and from thrombocytopenia, although hemoconcentration persisted. These results indicated that an important component of the PAF-induced systemic effects is mediated by reactions which can be inhibited by sulfinpyrazone. Furthermore, PAF-induced thrombocytopenia is not a direct PAF effect since it can be inhibited by sulfinpyrazone.

Anaphylaxis↗

PubMed1984

Effect of antiplatelet therapy on restenosis after experimental angioplasty.

Restenosis is recognized as a common complication of PTCA and can limit the long-term benefit of this procedure. To study the effect of antiplatelet agents in preventing restenosis, 25 New Zealand rabbits had bilateral iliac stenoses created by balloon deendothelialization and a 2% cholesterol diet for 6 weeks. After angiographic delineation of the iliac atherosclerosis, successful angioplasty was performed in all rabbits, with an average increase in luminal diameter of 0.9 mm (81%). Seven rabbits received aspirin (32 mg/day) plus dipyridamole (25 mg/day) and 9 received sulfinpyrazone (100 mg/day); 9 were given no antiplatelet drugs and served as controls. After 4 weeks of drug therapy and a continued atherogenic diet, angiography was repeated and the rabbits were killed for histologic examination. The angiographic luminal diameter was similar for these groups both before and immediately after angioplasty. However, the luminal diameter 4 weeks later was significantly larger in both the aspirin plus dipyridamole and the sulfinpyrazone groups compared with the control rabbits (1.3 +/- 0.6 and 1.8 +/- 0.5 mm vs 0.7 +/- 0.6 mm, respectively, p less than 0.05). Histologic examination revealed intraluminal clot in 4 of 9 control rabbits and in none of the drug-treated rabbits. Also, less intimal thickening was evident. In conclusion, aspirin plus dipyridamole and sulfinpyrazone inhibited angiographic restenosis after transluminal angioplasty in this experimental model. These findings support the use of antiplatelet agents in clinical angioplasty and suggest that platelet aggregation at the angioplasty site may promote restenosis.

Angioplasty, Balloon↗

PubMed1983

Determinants of the pharmacokinetics of antithrombotic drugs.

This review describes a variety of factors which determine the pharmacokinetics of antithrombotic drugs, viz., elimination by hepatic and/or renal clearance, plasma protein binding and drug disposition in the geriatric population. An understanding of biotransformation of acetylsalicylic acid and sulfinpyrazone is critical to understanding their usefulness as antithrombotic agents. Acetylsalicylic acid is rapidly hydrolysed to salicylic acid in the body and the latter may be eliminated by five different routes. Two of the biotransformation processes involving salicylic acid are readily saturable. For this reason, salicylate concentration increases more than proportionately with an increase in dose. Acetylsalicylic acid, but not salicylic acid, acetylates cyclo-oxygenase resulting in its inactivation. It is important in pharmacokinetic studies to measure plasma levels of both acetylsalicylic acid and salicylic acid. Biotransformation of sulfinpyrazone involves oxidation to the sulfone and reduction to the sulfide. The sulfide has marked antiplatelet activity. Dipyridamole undergoes hepatic biotransformation to a monoglucuronide which is eliminated by biliary and fecal excretion. Sulfinpyrazone, dipyridamole and salicylic acid are highly bound to plasma proteins. Since binding diminishes with age, one must expect therapeutic and toxic effects at lower plasma drug concentrations in the geriatric population. Other factors to be considered in the geriatric group are altered distribution, diminished glomerular filtration rate, and diminished oxidative biotransformation.

Biotransformation↗

PubMed1984

Determinants of acetaminophen metabolism: effect of inducers and inhibitors of drug metabolism on acetaminophen's metabolic pathways.

Acetaminophen metabolism and clearance after a single 1 gm oral dose of the drug was investigated in 12 healthy men, six of whom were cigarette smokers, and in six men who were receiving anticonvulsant drugs for epilepsy. The 12 healthy subjects were studied before and after 1 wk of pretreatment with cimetidine (1 gm/day) or sulfinpyrazone (800 mg/day). There was no significant difference in acetaminophen clearance (ClAP) between nonsmokers and smokers; cimetidine pretreatment had no effect on ClAP. Neither cigarette smoking nor cimetidine pretreatment had a significant effect on any of the metabolic pathways of acetaminophen. In contrast, sulfinpyrazone pretreatment increased ClAP by 23% (from 5.70 +/- 0.21 to 7.00 +/- 0.39 ml/min/kg) and ClAP was 46% greater in the epileptic subjects who received anticonvulsant drugs than in the control group (8.32 +/- 0.45 and 5.70 +/- 0.21 ml/ml/kg). In both cases the increase in ClAP was a result of induction of acetaminophen glucuronidation and oxidation; clearance of the glucuronic acid conjugate was 26% and 59% greater and clearance of the glutathione-derived conjugates (reflecting the activity of the oxidative pathway) was 43% and 60% greater in the groups given sulfinpyrazone and anticonvulsants, respectively.

Acetaminophen↗

PubMedDate not supplied

Effect of prostaglandin synthesis inhibition and sympathectomy on ouabain-induced arrhythmia in cats.

The purpose of this study was to examine the importance of endogenous prostaglandins (PGs) and sympathectomy on the arrhythmogenic action of ouabain. Cats, anesthetized with dial-urethane, were infused intravenously with ouabain continuously. The dose of ouabain necessary to produce arrhythmia (AR), ventricular tachycardia (VT), and death was determined. Pretreatment with sulfinpyrazone at 100 mg kg-1 i.v. 1 h before glycoside infusion was used to inhibit PG synthesis. Removal of endogenous PGs with sulfinpyrazone reduced the cardiotoxic dose of ouabain. Sympathetic influences were removed by: (a) destroying sympathetic nerve terminals with 6-hydroxydopamine (6-OHDA); (b) depleting nerve terminal catecholamines with reserpine; or (c) preventing catecholamine release from the nerve terminal with bretylium. Reduction of sympathetic influences with reserpine or bretylium increased the cardiotoxic dose of ouabain; whereas removal of nerve terminals with 6-OHDA did not alter the toxic dose of ouabain from that found in control animals. When endogenous PG synthesis was inhibited with sulfinpyrazone the protective effects of reserpine and bretylium were eliminated. These results suggest that endogenous PGs protect against the arrhythmogenic action of ouabain, not only by interfering with catecholamine influences at the sympathetic nerve terminal, but also by a mechanism independent of sympathetic inhibition. Furthermore, the protective action of agents which diminishes the cardiotoxic action of ouabain by interfering with sympathetic influences is lost when endogenous PGs are removed. Finally, 6-OHDA, which destroys the sympathetic nerve terminals, removes both the arrhythmic influence of the catecholamine as well as the protective influence of the PG, resulting in no net change in the cardiotoxic dose of this glycoside.

Animals↗

PubMed1983

Platelet tests and antiplatelet drugs in coronary artery disease.

This study was designed to clarify discrepancies in the literature concerning platelet survival time and beta-thromboglobulin (beta TG) levels in patients with coronary artery disease (CAD) and the effect of platelet-suppressant drugs on these tests. Platelet survival time and plasma beta TG levels were determined in 48 patients with angiographically documented CAD. The effect of sulfinpyrazone or aspirin/dipyridamole on these measurements was investigated in a double-blind, crossover trial that included a placebo phase. In patients with CAD, the mean plasma beta TG concentration was significantly elevated, but the mean platelet survival time was not significantly different from that in controls. Treatment with sulfinpyrazone or aspirin/dipyridamole did not produce changes in platelet survival time or plasma beta TG concentration that were significantly different from the values during the placebo phase. This study demonstrates that compared with the spontaneous variation in platelet survival time or beta TG concentration, there was no measureable effect of sulfinpyrazone or aspirin/dipyridamole on the results of the tests.

Adult↗

PubMed1984

The effects of antithrombotic drugs in patients with left ventricular thrombi: assessment with indium-111 platelet imaging and two-dimensional echocardiography.

Patients with left ventricular thrombi not caused by recent myocardial infarction were prospectively studied by indium-111 platelet imaging and two-dimensional echocardiography to determine the reproducibility of these techniques and the short-term effects of sulfinpyrazone (200 mg four times daily), aspirin (325 mg three times daily) plus dipyridamole (75 mg three times daily), and full-dose warfarin. At baseline, all patients underwent indium-111 platelet imaging and echocardiography, and the results were positive for thrombus. In six patients on no antithrombotic drug therapy, repeat platelet scans and echocardiographic studies at 6.0 +/- 3.3 weeks remained positive and were unchanged. In seven patients studied on sulfinpyrazone, three platelet scans became negative, two became equivocal, and two were unchanged; the presence and size of thrombus was constant by echocardiography in all seven patients. Of the six patients studied on aspirin plus dipyridamole, one platelet scan became negative, those of three became equivocal, and two were unchanged; all echocardiographic findings remained positive, but one patient had decreased thrombus size. Among four warfarin-treated patients, three had resolution of platelet deposition and one was unchanged; by echocardiography, thrombus resolved in one patient, was decreased in size in one, and was unchanged in two. We conclude that, in the absence of antithrombotic drug therapy, platelet imaging and echocardiographic findings are stable in patients with left ventricular thrombi not caused by recent myocardial infarction. Sulfinpyrazone, aspirin plus dipyridamole, and warfarin all interrupt platelet deposition in some patients with chronic left ventricular thrombi.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1979

[Antiplatelet drugs (author's transl)].

Acetyl salicylic acid, sulfinpyrazone, dipyridamole, hydroxychloroquine, ticlopidine, clofibrate, nicergoline are the most used antiplatelet drugs. A. S. A. and sulfinpyrazone have been tested in several large scale clinical trials. A. S. A. seems beneficial in the prevention of cerebral ischemia for patients, specially men who have previously had a transient cerebral ischemic attack. Sulfinpyrazone appears to be effective in reducing cardiac deaths during the first year after myocardial infarction.

Aspirin↗

PubMed1983

Failure of sulphinpyrazone to affect platelet survival in patients with rheumatic heart valvular disease: a double blind study using 75Se-methionine labeled platelets.

We have investigated platelet survival time in 18 patients suffering from valvular heart disease. Platelet survival was performed using the 75Se-methionine method modified by us. Nine of our eighteen patients underwent surgery for heart valve replacement. Platelet survival time was performed before treatment and six months afterwards with placebo or sulfinpyrazone in a double blind study. Before treatment and surgery, platelet survival time was significantly reduced in patients with a history of embolism (P less than 0.0048). In patients receiving valve replacement, platelet survival time was shortened both in the sulfinpyrazone and placebo groups six months after surgery. Of the nine patients not receiving prostheses and with a thrombotic history, treatment with placebo and sulfinpyrazone resulted in improved platelet survival times.

Adult↗

PubMed1980

Summary of design features: clinical trials of platelet-active drugs in cerebrovascular disease.

Two randomized, double-blind clinical trials in cerebrovascular disease are described. The Controlled trial of Aspirin in Cerebral Ischemia compared aspirin (650 mg twice daily) with placebo in medically and surgically treated groups of patients who had experienced transient ischemic attacks. The Randomized Trial of Aspirin and Sulfinpyrazone in Threatened Stroke compared aspirin (325 mg four times daily), sulfinpyrazone (200 mg four times daily) and aspirin plus sulfinpyrazone with placebo in patients with transient cerebral ischemia.

Aspirin↗