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.

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.

Adherence with urate-lowering therapies for the treatment of gout.

INTRODUCTION: Adherence to urate-lowering drugs (ULDs) has not been well evaluated among those with gout. Our aim was to assess the level and determinants of non-adherence with ULDs prescribed for gout. METHODS: We identified persons using two integrated delivery systems aged 18 years or older with a diagnosis of gout who initiated use of allopurinol, probenecid or sulfinpyrazone from 1 January 2000 to 30 June 2006. Non-adherence was measured using the medication possession ratio (MPR) over the first year of therapy and defined as an MPR < 0.8. Descriptive statistics were calculated and logistic regression was used to estimate the strength of the association between patient characteristics and non-adherence. RESULTS: A total of 4,166 gout patients initiated ULDs; 97% received allopurinol. Median MPR for any ULD use was 0.68 (interquartile range (IQR) 0.64). Over half of the patients (56%) were non-adherent (MPR < 0.8). In adjusted analyses, predictors of poor adherence included younger age (odds ratio (OR) 2.43, 95% confidence interval (CI) 1.86 to 3.18 for ages <45 and OR 1.44, 95% CI 1.08 to 1.93 for ages 45 to 49), fewer comorbid conditions (OR 1.46, 95% CI 1.20 to 1.77), no provider visits for gout prior to urate-lowering drug initiation (OR 1.28, 95% CI 1.05 to 1.55), and use of non-steroidal anti-inflammatory drugs in the year prior to urate-lowering drug initiation (OR 1.15, 95% CI 1.00 to 1.31). CONCLUSIONS: Non-adherence amongst gout patients initiating ULDs is exceedingly common, particularly in younger patients with less comorbidity and no provider visits for gout prior to ULD initiation. Providers should be aware of the magnitude of non-adherence with ULDs.

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.

Antithrombotic therapy in patients with saphenous vein and internal mammary artery bypass grafts.

Aspirin (325 and 900 mg/d) is effective for a period of 1 year in reducing the frequency of saphenous vein bypass graft occlusion when begun 1 day before operation or on the day of operation. Aspirin in combination with dipyridamole is not more effective than aspirin alone in the prevention of saphenous vein graft occlusion. Bleeding is higher among patients treated with aspirin (325 mg/d) than among controls if aspirin is started 1 day before operation. Bleeding in one trial was greater than controls if aspirin (300 mg/d) was started the day of operation, and in one trial there was no difference when aspirin (325 mg/d) was started the day of operation. Ticlopidine (500 mg/d), started 2 days after operation, was effective in maintaining graft patency. Oral anticoagulants were inconsistent in the maintenance of saphenous vein graft patency. The continued use of aspirin for 2 additional years after an initial year of aspirin therapy for the prevention of saphenous vein bypass graft occlusion showed no additional long-term benefit on graft patency at the end of the third year. Antithrombotic agents given to patients with internal mammary artery bypass grafts showed no benefit in comparison to placebo because patency on placebo was high.

Effects of sulfinpyrazone on retinal damage induced by experimental diabetes mellitus in rabbits.

The protective activity of the phenylbutazone derivative, sulfinpyrazone on retinal lesions has been assessed in rabbits with severe streptozotocin-induced diabetes. Sulfinpyrazone (8 mg kg-1 per day per os) was administered in diabetic animals in two different experimental procedures: for 135 days in a preventive approach (beginning on the day of initial hyperglicaemia); and for 30 days in a therapeutic approach (beginning on the day of appearance of severe retinal damage). The drug treatment made either with the preventive or the therapeutic approach reduced the incidence of serious retinal lesions and increased that of light lesions as assessed by a biomicroscopic method. Biochemical analyses showed that experimental diabetes was accompanied by sustained decrease in glucose and pyruvate and an increase of the lactate content in the retina. A decrease of alpha-ketoglutarate and citrate and an increase of succinate were also observed along with a decrease of ATP, ADP and an increase in AMP. Either the preventive or the therapeutic approach was followed by an increased pyruvate and ATP content and decreased lactate and AMP content in the retinal tissue. It is possible that this drug acts on the retinal tissue by inhibiting platelet aggregation and protecting vasal endothelium with the consequent suppression of the release of vasoactive substances that facilitate platelet adhesion.

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.

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.

Avanços terapêuticos em cardiologia: parte 4. Antiplaquetários em cardiologia / Terapeutic advances in cardiology: Part 4. Antiplatelets in cardiology

Os autores fazem uma revisäo dos antiagregantes plaquetários disponíveis. Chamam a atençäo que a hirudina é inibidora da trombina, o verapamil é antagonista da adrenalina, o ridogrel e o ômega 3 bloqueiam os endoperóxidos bem como a sulfinpirazona, a aspirina, dipiridamol e ticlopidina. Existem antiagregantes com açäo do fator de ativaçäo plaquetária como a ginkgo-biloba e o diltiazem. Fazem uma revisäo das indicaçöes clínicas destas drogas à luz dos conhecimentos atuais

Influence of antiplatelet drugs on occlusion of arteriovenous fistula in uraemic patients.

A long-standing arteriovenous (A-V) fistula may develop thrombotic complications. In 20 patients on intermittent peritoneal dialysis (IPD) arteriovenous fistula was made surgically. We evaluated the efficacy of three antiplatelet drugs: Ibustrin (Group A), sulphinpyrazone (Group B) and alpha-tocopherol (Group C) in preventing thrombotic occlusion of A-V fistulas. Results of the trial indicate that the three drugs significantly reduce spontaneous platelet aggregation and ADP induced aggregation. The heparin neutralizing activity was significantly increased during treatment. Significant prolongation of bleeding time was observed only in Groups B and C. In patients receiving antiplatelet drugs no occlusion of A-V fistulas was observed. In the control group such complications occurred in 3 of the 20 patients. Our results indicate that antiplatelet drugs by inhibiting the platelet function may prevent thrombotic occlusions of A-V fistulas in IPD patients.

[Platelet antiaggregants in the treatment of arterial thrombosis]. / Gli antiaggreganti piastrinici nel trattamento delle trombosi arteriose.

The paper contains a critical review of the major clinical controlled trials which have been carried out on the use of platelet anti-aggregating agents in the prophylactic treatment of arterial thrombosis. The drugs studied to date include aspirin, sulphinpyrazone, dipyridamole and ticlopidine. These drugs have been used in primary infarction prophylaxis and secondary prophylaxis of arterial thrombosis at a cardiac (reinfarction, instable angina, valvular prosthesis, aortocoronary bypass, coronary angioplasty), cerebral (TIA, ictus) and peripheral (obliterating arteriopathy, thromboendarterectomy, arteriovenous shunt) level. The most frequently studied end-points are non-fatal reinfarction, cardiovascular mortality (fatal reinfarction, sudden death, fatal ictus), non-fatal ictus, vascular re-occlusion after arterio-lesive surgery, and some clinico-radiographical parameters at a peripheral level. The best results, which are statistically significant, have been obtained in the prophylaxis of instable angina and re-occlusion following aortocoronary by-pass; results obtained in cerebrovascular disease and peripheral obliterating arteriopathy are less statistically significant but equally successful and worthy of attention, especially in the case of ticlopidine which showed a greater number of advantages than aspirin. Positive but statistically not reliable findings were reported regarding the secondary prophylaxis of reinfarction, whereas non-significant data were reported for secondary prophylaxis of reocclusion of coronary angioplasty, thromboendarterectomy and arterio-venous shunt, and for the primary prophylaxis of reinfarction. The Author confirms that the clinical trials carried out for the long-term prophylaxis of still asymptomatic subjects are the only way of evaluating the clinical efficacy of a platelet anti-aggregating agent; the results of these trials must however be carefully and critically assessed from a clinical and statistical point of view and at all events can only act as a guideline for the doctor; the latter continues to be solely responsible for the choice of the drug and he must be aware of possible collateral effects and the risk/benefit ratio as well as the personal characteristics of the patient.

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.

Aspirin in transient ischemic attacks and minor stroke: a meta-analysis.

An overview analysis of seven randomized controlled trials testing the effectiveness of aspirin in the treatment of patients with transient ischemic attacks and minor strokes was performed. A total of 6409 patients from the seven trials was entered in the analysis; 2182 patients received only aspirin; 1598 patients received an aspirin-combination regimen with either sulfinpyrazone or dipyridamole; and 2629 subjects received a placebo. Aspirin alone produced an 18% decrease in all strokes and cardiovascular deaths. The pooling of studies examining aspirin-combination regimens and the larger grouping of studies of aspirin and aspirin-combination regimens led to more striking results. Indeed, significant risk reductions were observed for three of the four outcomes, namely, total deaths, total strokes, and total strokes and cardiovascular deaths, with odds ratios ranging from 0.59 to 0.78. Suggestive, albeit more modest, results were obtained when examining the impact of these regimens on total cardiovascular mortality. The same tendencies have also been observed in three previously published meta-analyses.