The induction and inhibition of UDP-glycosyltransferases in Haemonchus contortus and their role in the metabolism of albendazole.

Albendazole (ABZ) is an anthelmintic frequently used to treat haemonchosis, a common parasitosis of ruminants caused by the gastrointestinal nematode Haemonchus contortus. This parasite is able to protect itself against ABZ via the formation of inactive ABZ-glycosides. The present study was designed to deepen the knowledge about the role of UDP-glycosyltransferases (UGTs) in ABZ glycosylation in H. contortus. The induction effect of phenobarbital, a classical inducer of UGTs, as well as ABZ and ABZ-sulphoxide (ABZSO, the main active metabolite of ABZ) on UGTs expression and UGT activity toward ABZ was studied ex vivo in isolated adult nematodes. The effect of three potential UGT inhibitors (5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine and sulfinpyrazone) on ABZ glycosylation was tested. Pre-incubation of nematodes with ABZ and ABZSO led to increased expression of several UGTs as well as ABZ-glycosides formation in subsequent treatment. Phenobarbital also induced UGTs expression, but did not affect ABZ biotransformation. In the nematode's subcellular fraction, sulfinpyrazone inhibited UGT activity toward ABZ, although no effect of other inhibitors was observed. The inhibitory potential of sulfinpyrazone on the formation of ABZ-glycosides was also proved ex vivo in living nematodes. The obtained results confirmed the role of UGTs in ABZ biotransformation in H. contortus adults and revealed sulfinpyrazone as a potent inhibitor of ABZ glycosylation in this parasite. The possible use of sulfinpyrazone with ABZ in combination therapy merits further research.

Uric acid lowering therapy: prescribing patterns in a large cohort of older adults.

BACKGROUND: Uric acid lowering therapy (UALT) is considered a chronic treatment for gout. Relatively little is known about adherence to UALT. METHODS: We assessed adherence with UALT over a 1-year study period among 9823 older adults enrolled in a pharmacy benefit program. Two adherence measures were calculated, the percentage of days covered (PDC) and the time until an extended break (at least 60 days) in treatment. A PDC <80% was considered poor adherence and its predictors were examined in multivariable logistic models. RESULTS: The mean (SD) PDC was 54% (36%) with 64% of patients considered poorly compliant over the study period. A total of 56% had experienced an extended break in UALT. Predictors of poor adherence included younger age (odds ratio (OR) 1.50, 95% CI 1.33-1.69 for ages 65-74 compared with 85 and above) and African-American race (OR 1.86, 95% CI 1.52-2.27 compared with Caucasian race). Most patients (93%) received their initial UALT prescription from a non-specialist and this also predicted poor adherence (OR 1.15, 95% CI 0.96-1.38 compared with rheumatologists or nephrologists). CONCLUSION: Adherence with UALT is poor. While uric acid levels were not measured in this study, poor adherence with UALT is likely to reduce attainment of goal uric acid levels.

The rising prevalence and incidence of gout in British Columbia, Canada: Population-based trends from 2000 to 2012.

OBJECTIVES: Gout is increasingly recognized as the most common form of inflammatory arthritis worldwide; however, no Canadian data on the disease burden of gout are available. We estimated the prevalence, incidence, prescription patterns, and comorbidity burden of gout in an entire Canadian province [British Columbia (BC)] over the last decade. METHODS: We utilized PopulationData BC, a province-wide database, to estimate temporal trends in the prevalence and incidence of gout from 2000 to 2012, as well as according to age category. Annual estimates were age-sex-standardized using 2012 as the reference. We also examined annual trends in prescription patterns of common gout medications and assessed the comorbidity burden among gout patients in 2012. RESULTS: The 2012 prevalence of gout was 3.8% among the overall population, and the incidence rate was 2.9 per 1000 person-years. Both gout prevalence and incidence increased substantially over the study period. This burden additionally increased according to age category, affecting over 8% of those ages 60-69 years in 2012. Approximately 22% of gout patients received a prescription for urate-lowering therapy (ULT), which remained stable over the study period, while colchicine and oral glucocorticoid use both increased modestly. By 2012, 72%, 52%, and 18% of prevalent gout patients had been diagnosed with hypertension, hyperlipidemia, and diabetes, respectively. CONCLUSIONS: The burden of gout in BC, Canada, is substantial, and both the prevalence and incidence have increased over the past decade, while prescription of ULT remains low. These data support the need to improve gout prevention and care.

Implications of preoperative administration of aspirin in patients undergoing coronary artery bypass grafting. Department of Veterans Affairs Cooperative Study on Antiplatelet Therapy.

The perioperative consequences of preoperative aspirin administration were assessed in a large prospective cooperative study of 772 patients undergoing coronary artery bypass grafting. The 772 patients were randomized to receive either aspirin (325 mg once a day), aspirin (325 mg three times a day), aspirin plus dipyridamole (325 and 75 mg together three times a day) (aspirin group), sulfinpyrazone (267 mg three times a day) or placebo (nonaspirin group). The therapy, except in the aspirin group, was started 48 h before the operation. In all aspirin subgroups, one 325 mg aspirin dose was given 12 h before surgery and maintained thereafter according to the assigned regimen. Patients in the aspirin group had significantly more postoperative bleeding and received more packed blood cells and blood products than did patients in the nonaspirin group. Although total operative duration and cardiopulmonary bypass duration were not different, the interval between completion of cardiopulmonary bypass and wound closure was significantly longer (p = 0.035) in the aspirin group. Thirty-one (6.6%) of 471 patients in the aspirin group and 5 (1.7%) of 301 patients in the nonaspirin group also required reoperation for control of postoperative bleeding (p = 0.002). The site of bleeding found at reoperation was not different between the two groups. There was no difference in operative mortality rates, incidence of other bleeding complications or occurrence of other post-operative complications between the two groups. Thus, antiplatelet regimens involving preoperative initiation of aspirin therapy, which has been shown to improve graft patency, increase the risk of abnormal postoperative bleeding and the need for reoperation.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities of urinary sediment and renal failure following sulfinpyrazone therapy.

A patient with recurrent thrompophlebitis had sterile pyuria with white blood cell casts and transient, mild renal failure during therapy with sulfinpyrazone. These abnormalities resolved on cessation of therapy, but similar changes in the urinary sediment recurred during therapy with sulfinpyrazone. These abnormalities resolved on cessation of therapy, but similar changes in the urinary sediment recurred during a second course of sulfinpyrazone therapy.

Platelet-latelet-.

Two patients with thrombotic thrombocytopenic purpura were seen. Aspirin, dipyridamole, and sulfinpyrazone were administered to patient 1 after splenectomy, and administration of high-dose prednisone and methylprednisolone failed to induce remission. The platelet count rose, but the patient had a relapse when the dipyridamole dose was tapered. This condition responded to an increase of the drug, and the patient obtained a long-lasting remission. A splenectomy was not performed on patient 2, and all three platelet-inhibiting drugs, together with prednisone, were given. This resulted in a prompt remission that has been sustained for 29 weeks. Morphologic changes in the peripheral blood smear remained for several weeks after other features of the disease had resolved. Thus, in both cases, platelet-inhibiting drugs appeared to induce a remission.

Selection and results of antiplatelet therapy in the prevention of stroke and myocardial infarction.

Four antiplatelet drugs have been evaluated in cerebrovascular disease and in coronary heart disease--dipyridamole, clofibrate, sulfinpyrazone, and aspirin. There is no evidence that dipyridamole or clofibrate is beneficial in patients with stroke or myocardial infarction. Aspirin is effective in reducing stroke and death in patients with transient cerebral ischemia. Although aspirin has not been reported to significantly (statistically) reduce mortality or frequency of ischemic events in patients with acute myocardial infarction, five of six randomized trials showed a similar favorable trend. Sulfinpyrazone seems to be ineffective in the treatment of transient cerebral ischemia, but there is evidence that it decreases the incidence of sudden death in patients with myocardial infarction. In patients with prosthetic heart valves, the combined use of aspirin or dipyridamole with an oral anticoagulant is more effective in preventing systemic embolism than an oral anticoagulant alone.

Sulphinpyrazone reduces endocardial injury and mural thrombosis.

STUDY OBJECTIVE: The aim of the study was to investigate the effectiveness of sulphinpyrazone, a drug which stabilises endothelial cell membranes, in reducing endocardial injury and mural thrombosis produced by lactic acid in the left ventricle. DESIGN: The left ventricular endocardium of isolated beating rat hearts, perfused via the aorta with oxygenated Krebs-Henseleit buffer, was exposed for up to 4 h to additional lactic acid (pH 6.4), with and without sulphinpyrazone (100 ng x ml-1). After flushing with buffer, passage of 10 ml blood, and further flushing, the hearts were fixed by coronary perfusion and the endocardium examined by scanning electron microscopy. EXPERIMENTAL MATERIAL: Hearts from 48 male albino Wistar rats, weight 270-380 g, were used. MAIN RESULTS: Morphometric analysis of the surface of the papillary muscles showed that lactic acid caused membrane injury in endothelial cells, up to 30% of which exfoliated. However when sulphinpyrazone was present, endothelial cell damage was reduced and there was up to 75% reduction in the area of exposed basal lamina or connective tissue. This was associated with a corresponding reduction in the extent of platelet adhesion (79%) and thrombus formation (94%). CONCLUSIONS: The results show that sulphinpyrazone has the potential to reduce the risk of mural thrombosis following endocardial injury.

Antiplatelet therapy in thrombotic thrombocytopenic purpura.

The presence of platelet-fibrin microthrombotic occlusions in the arterioles and capillaries of involved tissues of patients with TTP has suggested a role for platelet aggregation in this disorder. Inhibitors of platelet aggregation have been reported to produce resolution of thrombocytopenia and clinical improvement in many instances. Failure of such agents to produce a clinical effect has been attributed to inadequate dose-duration, severity and extent of end organ/vascular involvement, long-term or secondary effects of the etiologic principal leading to patient deterioration and/or demise. On the other hand, the parallel use of several treatment modalities that themselves may produce clinical effect confounds the interpretation that anti-platelet agents alone may have been responsible for clinical improvement. Nonetheless, complete remission has been reported in a number of TTP patients when the combination ASA/dipyridamole was used alone or together with plasmapheresis, splenectomy, and/or other antiplatelet agents. The evidence for a beneficial clinical effect would seem strongest for the use of this combination early in the course of the disease. More limited and less conclusive has been the experience with sulfinpyrazone, with ticlopidine, and with intravenous PGI2 infusions in TTP. Reports of clear-cut benefit with each of these agents have been rare. Finally, serial dextran infusions have apparently produced amelioration of the clinical syndrome in certain individuals. Assessment of benefit of dextran infusions from retrospective series has been limited by antecedent use of splenectomy. The use of red cell and plasma infusions during splenectomy has been argued to provide some benefit. However, it is likely that dextran can produce definite responses in certain patients. Unfortunately, therapeutic efficacy has been judged from such anecdotal reports and retrospective series. No prospective controlled trials of any of these approaches are available.

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.

Increased platelet aggregability in young patients with stroke. Diagnosis and therapy.

Four patients ages 20 to 38 years had repeated cerebrovascular occlusions. Three of the four patients had vascular headaches (classical migraine in two) for some years before their first occlusive event occurred. When first seen at the time of their major cerebrovascular occlusion, all had evidence of plasma hyper-coagulability, and two of the women were receiving birth control pills. Many months later, while off the "pill" and on warfarin sodium (Coumadin) therapy, two women and one man continued to have new cerebrovascular symptoms. For the first time, their platelet aggregability was tested to several biological substances known to come in contact with platelets in vivo. At this time, all four patients were found to have platelet hyperaggregability. The three symptomatic patients also had a shortened platelet survival time. Long-term management of these patients with chronic platelet aggregability and chronic plasma hyper-coagulability is described.

Does platelet antiaggregant therapy lessen the severity of stroke?

Data from the Aspirin in Transient Ischemic Attack (AITIA) study, an ongoing study of two platelet antiaggregant drugs, and other published therapeutic trials were reviewed to determine whether the severity of stroke is reduced in patients taking platelet antiaggregants. Data from three of four studies suggest that strokes in treated patients are less severe than those in untreated patients. Further studies evaluating platelet antiaggregant therapy should include assessment of the severity as well as the incidence of stroke.

Changing concepts of pathophysiology, prognosis, and therapy in acute myocardial infarction.

Recent research findings regarding the pathophysiology of acute myocardial infarction, newer concepts of treatment, and better means of identifying high- and low-risk patients after acute myocardial infarction are presented, along with practical clinical considerations.

Platelets, carotids, and coronaries. Critique on antithrombotic role of antiplatelet agents, exercise, and certain diets.

"Antiplatelet" drugs and certain life styles seem to have an "antithrombotic" effect that may help protect against stroke and heart attack. This review of the experience with aspirin, dipyridamole, and sulfinpyrazone offers new interpretations of some of the major clinical trials, suggests guidelines for use of antiplatelet drugs, and integrates novel observations on diet and exercise into the "thromboxane-prostacyclin balance" hypothesis. It is argued that the Canadian stroke study showed that aspirin protects men with transient ischemic attacks from coronary death as well as from stroke, that type II errors may have been made in some clinical trials, that aspirin protects women as well as men, that aspirin benefits patients who have had a heart attack, that the effect of aspirin in angina varies with the type of angina, that the dose of aspirin used may not be critical, that guidelines for use of dipyridamole and sulfinpyrazone are still inconclusive, and that exercise and fish oil supplements may be "antithrombotic."

Pathogenesis and prevention of graft arteriosclerosis in an experimental heart transplant model.

Accelerated graft arteriosclerosis is a major cause of death in human heart transplantation. Despite many investigations, the pathogenesis of this disease remains undetermined and its control inadequate. In this study using a rat heart transplant model and cyclosporin A, a new immunosuppressant, acute rejection was prevented but arteriosclerotic-like vessel disease still developed consistently as early as 20 days postoperatively. The combination of cyclosporin A and dipyridamole prevented the development of this vessel disease in transplanted hearts at 20 and 50 days postoperatively. Sulfinpyrazone and cyclosporin A reduced but did not prevent the disease. These findings suggest that immunologically induced graft arteriosclerosis can be prevented in transplanted rat hearts by the combination of cyclosporin A and dipyridamole.

Clinical trials in thrombosis: secondary prevention of myocardial infarction.

Numerous in vivo and in vitro experiments, investigating the inhibition of platelet aggregation and the prevention of experimentally-induced thrombosis, suggest that anti-platelet drugs, such as aspirin or the combination of aspirin, and dipyridamole or sulfinpyrazone, may be effective anti-thrombotic agents in man. Since 1971, seven randomized prospective trials and two case-control studies have been referenced in the literature or are currently being conducted, which evaluate the effects of aspirin, sulfinpyrazone, or dipyridamole in combination with aspirin in the secondary prevention of myocardial infarction. A critical review of these trials indicates a range of evidence from no difference to a favorable trend that anti-platelet drugs may serve as anti-thrombotic agents in man. To date, a definitive answer concerning the therapeutic effects of these drugs in the secondary prevention of coronary heart disease is not available.

Inhibition of spontaneous platelet aggregation by sulfinpyrazone.

In a randomized double-blind crossover study in 16 patients with enhanced in vitro spontaneous platelet aggregation, sulfinpyrazone proved to be effective in normalizing platelet aggregability within 4 days after initiation of therapy.

Transcoronary platelet thromboxane A2 formation without platelet trapping in patients with coronary stenosis-effect of sulphinpyrazone treatment.

Platelet count, and plasma thromboxane B2 (TXB2) and circulating platelet aggregates (CPA) were determined in the coronary sinus (CS), aortic bulb (AO) and cubital vein (V) in 21 patients with stable angina and in 6 control subjects before and after atrial pacing (AP). TXB2 measurements were repeated before and after AP in 6 of the 21 angina patients after 15 days' sulphinpyrazone treatment. Platelet count and CPA ratio were similar in angina patients and controls at all three sampling sites and were unchanged at AP peak. In the controls, basal TXB2 values in CS, AO and V were not significantly different and were unchanged at AP peak. In the angina patients compared with the controls, basal TXB2 values in the AO, CS and V were not significantly different whereas the CS/AO TBX2 ratio was significantly higher; at AP-induced ischaemia, CS TXB2 was significantly increased and the CS/AO TXB2 ratio was increased. A weak but significant direct correlation was found between CS/AO TXB2 ratio and coronary score. Sulphinpyrazone treatment reduced CS TXB2 levels at rest and after AP, but not the ischaemic threshold at AP.

In vivo platelet activation following myocardial infarction and acute coronary ischaemia.

Forty-seven patients presenting with acute chest pain had in vivo platelet activity assessed by measuring plasma levels of the platelet-specific protein beta thromboglobulin (BTG), and by screening for the presence of circulating platelet aggregates. Nineteen patients with transmural myocardial infarction (MI), 21 patients with acute coronary ischaemia (CI), and 7 patients with non-cardiac chest pain (NCCP) were investigated in a serial study and compared with a normal control group. The means of all BTG determinations in the MI (34, +/- SD = 21-57) and CI (33, +/- SD = 19-57) groups were significantly higher than those in the NCCP group (24, +/- SD equal 17-34; p less than 0.01) and normal subjects (22,5 +/- SD = 14-37; p less than 0.001). There was no difference in BTG between those with MI or CI, nor between the NCCP group and normal subjects. Raised numbers of circulating platelet aggregates could not be detected in either MI or CI. The mean BTG levels in both MI and CI patients were significantly raised, compared to normal subjects, on the first day of admission to hospital and remained so on each of the subsequent nine days. Neither heparin plus warfarin nor sulphinpyrazone had any significant effect in lowering BTG levels. 15/40 patients (37.5%) following MI and CI had repeatedly raised BTG levels throughout the study period, and it is suggested that these patients represent an "at risk" group that may benefit from anti-platelet therapy in secondary prevention studies.

Platelet and coagulation function in patients with abnormal cardiac valves treated with sulphinpyrazone.

Eight patients on warfarin with rheumatic heart disease and prosthetic cardiac valves were selected for study on the basis of persistently elevated plasma beta-thromboglobulin (beta-tg) and platelet factor 4 (PF4) concentrations. Platelet mean lifespan and fibrinogen half life were short, and positively correlated, and both were inversely related to the plasma concentration of the platelet specific proteins. Antithrombin III (ATIII) levels were also reduced. Treatment with sulphinpyrazone resulted in lengthening of both platelet and fibrinogen survival, a rise in ATIII but no change in the beta tg or PF4 concentrations. It is concluded that patients with abnormal cardiac valves and raised plasma levels of beta tg or PF4 have, despite warfarin, a consumption coagulopathy that can be inhibited by sulphinpyrazone.