Acetylsalicylic acid therapy: influence of metformin use and other variables on urinary 11-dehydrothromboxane B2 levels.

BACKGROUND: The effect of acetylsalicylic acid (ASA) may be measured through the analysis of urinary concentrations of 11-dehydrothromboxane B2 (11-dhTXB2), a metabolite of thromboxane A2, which is a potent platelet aggregant agent. It has been suggested that metformin (an oral antidiabetic drug) could improve oxidative stress and control platelet activation in type 2 diabetic patients, potentially reducing cardiovascular risk. We determined the concentrations of urinary 11-dhTXB2 in type 2 diabetic patients taking ASA and its concentrations with metformin use and several other clinical variables (hypertension, age, gender, smoking, body mass index, insulin and statin use), considering a reduction of at least 75% in the concentrations of this marker as a target, compared to results before ASA intake. METHODS: Urinary concentrations of 11-dhTXB2 of 81 type 2 diabetic patients were measured before and at 15 days taking 100 mg of aspirin daily. RESULTS: Most patients who presented a reduction of 11-dhTXB2 above 75% were under metformin use. This reduction was achieved in 51.5% of patients taking this drug, against 20.0% in the patients who were not (p=0.027). The analysis of the other variables did not show a significant difference. The use of metformin appears to play a role in the reduction of 11-dhTXB2 concentrations in type 2 diabetic patients. CONCLUSION: According to previous reports, hyperglycemia control seems to be a determinant factor for the success of ASA therapy, given the influence of metformin in the reduction of 11-dhTXB2 concentrations.

Urinary 11-dehydro thromboxane B2 levels in type 2 diabetic patients before and during aspirin intake.

BACKGROUND: Diabetic patients commonly present an increased risk for cardiovascular events, for which aspirin is the most frequently used medication for primary prevention. Urinary 11-dehydro thromboxane (11-dhTXB2) concentrations assess the effect of aspirin on platelets and identify patients who are at risk of cardiovascular events. The present study investigated whether or not type 2 diabetic patients who took a daily dose of 100mg of aspirin had a significant reduction in urinary 11-dhTXB2 concentrations and whether these results were associated with clinical and laboratory variables. METHODS: Eighty-one type 2 diabetic patients were enrolled in the study. Laboratory tests included the determination of lipidic profile, glycated hemoglobin, platelets count, molecular analysis for both GPIIbIIIa and COX-1 polymorphisms, and urinary 11-dhTXB2. RESULTS: Patients' median value for urinary 11-dhTXB2 before aspirin intake was 179 pg/mg of creatinine. After 15days taking aspirin, the patients presented median of 51 pg/mg of creatinine, thus revealing a significant difference between medians (p=0.00). A reduction of 95% in urinary 11-dhTXB2 concentrations could only be identified in 4 patients (5%). A BMI of ≥ 26 presented a significant association with a reduction of urinary 11-dhTXB2 concentrations (p=0.010), as shown by the multiple logistic regression model. Other clinical and laboratory variables showed no association. CONCLUSIONS: Regardless of the mechanisms related to aspirin non-responsiveness, most patients enrolled in the present study also presented a reduced or minimal response to low-dose aspirin therapy, thereby indicating a clear variability related to aspirin effectiveness. Moreover, BMI appears to be independently associated to the reduction of urinary 11-dhTXB2 concentrations in type 2 diabetic patients taking aspirin.

Increased lipid peroxidation correlates with platelet activation but not with markers of endothelial cell and blood coagulation activation in patients with antiphospholipid antibodies.

Recent studies have shown that patients with antiphospholipid antibodies (aPL) have increased lipid peroxidation. We evaluated the urinary excretion of 11-dehydro thromboxane B2 (11-DH-TXB(2) and isoprostane F(2alpha)III (IPF(2alpha)III), reflecting platelet activation and lipid peroxidation in vivo, and plasma soluble markers of endothelial cell, platelet and blood coagulation activation: soluble vascular cell adhesion molecule-1 (sVCAM-1), P- and E-selectin (sPsel and sEsel), F1 + 2 fragment of prothrombin (F1 + 2), thrombin-antithrombin complexes (TAT) and D-Dimer (DD). We studied 79 patients with aPL (47 with previous thrombosis), 45 healthy volunteers (normal controls, NC), 12 patients with systemic lupus erythematosus (SLE) without aPL and a thrombosis control group (TCG) without thrombophilia (n = 16). Urinary levels (mean, range) of eicosanoids and isoeicosanoids were significantly increased in 39 patients with aPL compared with 25 NC, 11-DH-TXB(2) 164.0 ng/mmol creatinine (9.5-1162.8) versus 43.4 ng/mmol creatinine (4.2-87.6), P < 0.001; IPF(2alpha)III 56.9 pg/mg creatinine (5.5-388.7) versus 27.0 pg/mg creatinine (4.6-87.6), P = 0.03. Both metabolites were significantly correlated (rho = 0.49, P = 0.014), but none correlated with any clinical manifestation or antibody profile. The aPL group presented increased levels of sPsel, sEsel, sVCAM-1, TAT, F1 + 2 and DD, but any soluble marker correlated with IPF2alphaIII. Urinary 11-DH-TXB(2) correlated with sPsel (rho = 0.39, P = 0.04). Compared with SLE controls, the SLE group with aPL had higher levels of F1 + 2. Plasma levels of F1 + 2 and DD were significantly increased and a trend to higher sPsel was found in aPL patients with thrombosis compared with the TCG. Platelet activation, lipid peroxidation and blood coagulation activation seem to be important in the pathophysiology of antiphospholipid syndrome.

Anti-beta2 glycoprotein I antibodies and platelet activation in patients with antiphospholipid antibodies: association with increased excretion of platelet-derived thromboxane urinary metabolites.

Platelet activation may contribute to the increased risk of thrombotic complications in patients with antiphospholipid antibodies (aPL). The increased urinary excretion of 11-dehydro-thromboxane B2 (11-DH-TXB2) reported in patients with lupus anticoagulant (LA) and/or anticardiolipin antibodies (aCL) reflects in vivo platelet activation. However the majority of autoimmune aPL are directed to beta2 glycoprotein I (beta2GPI) or prothrombin (II). We investigated the relationship of these antibodies with 11-DH-TXB2 urinary excretion in 34 patients with aPL. The urinary 11-DH-TXB2 was measured by EIA after extraction on octadecyl columns and purification on silica gel columns, which was validated by thin-layer chromatography/EIA procedure. A significantly increased excretion of 11-DH-TXB2 was found in aPL patients as compared to 18 normal controls (p <0.01). But no differences were seen in the excretion of 11-DH-TXB2 between patients with or without LA, or aCL. The number of patients with anti-II antibodies was too small to draw any conclusion. In contrast, patients with anti-beta2GPI antibodies IgG at moderate/high titre (group A, n = 14) had higher levels of urinary 11-DH-TXB2 than those at low titre or negative (group B, n = 20) (p = 0.01). The group A of patients presented an increase in 11-DH-TXB2 compared to controls (p <0.001), but no statistically significant difference was found between patients from the group B and normal controls. A correlation between levels of urinary 11-DH-TXB2 and titre of antibodies was only found for anti-beta2GPI-IgG (r(s) = 0.51, p <0.005). Our data show that the observed platelet activation in aPL patients is related to the presence of antibodies reacting with beta2GPI.

[Metabolic changes in arachidonic acid during aspirin desensitization]. / Cambios metabólicos del ácido araquidónico en la desensibilización a la aspirina.

Aspirin sensitivity occurs in 10% of all asthmatics patients. In this subset of asthmatics, nasal congestion and bronchospasm occurs between 30-180 minutes after ingestion of aspirin. Following a respiratory reaction to aspirin, all patients can be desensitized to aspirin by repetitively introducing small and then larger doses of aspirin until the asthmatic subject can ingest 650 mg of aspirin without adverse effect. The mechanism of aspirin sensitivity are incompletely understood. And the reasons why ASA desensitization occurs universally are unknown. In this study, known ASA sensitive and control insensitive asthmatics were challenged with ASA. Urine was collected before, during induced bronchospasm, and after ingestion of 650 mg of ASA when the adverse effect (ie., acute desensitization) had subsided. Excretion levels of cyclo-oxygenase and lipoxygenase products in the urine were determined.

Contribution of platelet thromboxane production to enhanced urinary excretion and glomerular production of thromboxane and to the pathogenesis of albuminuria in the streptozotocin-diabetic rat.

Previous studies have demonstrated that urinary thromboxane B2 (TXB2) excretion (UTXB2) and glomerular production of TXB2 are enhanced in experimental diabetes and that selective inhibitors of TX synthesis prevent or delay the development of albuminuria. The present study was conducted to examine the contribution of platelet TXB2 production to the enhancement of UTXB2 and glomerular TXB2 production and to the pathogenesis of albuminuria in the partially insulin-treated moderately hyperglycemic (blood glucose, 200 to 400 mg/dL) streptozotocin-diabetic rat (SDR). Treatment of control rats or of SDR with diabetes of 5 months' duration with antiplatelet serum for 4 consecutive days reduced circulating platelet counts and serum TXB2 generation, an index of platelet cyclooxygenase activity, by 80% or greater, but reduced UTXB2 excretion by only 30%. UTXB2 and glomerular production of TXB2 of thrombocytopenic SDR remained markedly elevated compared with corresponding values from age-matched thrombocytopenic or platelet-replete, nondiabetic controls. Similarly, treatment of rats for 180 days with a dose of aspirin (ASA), which selectively inhibited platelet versus renal cyclooxygenase activity, reduced UTXB2 of both SDR and controls by 25% to 35%. The absolute reductions in UTXB2 induced by either ASA or thrombocytopenia in SDR were significantly greater than the absolute decrements in corresponding controls, suggesting that increased platelet TXB2 production in SDR may contribute to the enhanced UTXB2. However, as in the thrombocytopenic SDR, UTXB2 and glomerular production of TXB2 of SDR treated with ASA remained clearly above corresponding control values. Moreover, chronic ASA treatment failed to prevent the development of albuminuria in SDR.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of urinary albumin excretion in diabetic rats by 4'(imidazol-1-yl) acetophenone, a selective inhibitor of thromboxane synthesis.

Thromboxane contributes to the regulation of glomerular hemodynamics in experimental models of diabetes and has been implicated as mediator in some models of glomerular injury. In the present study we examined urinary albumin, protein, and thromboxane B2 (TXB2) excretion during the 170 days after induction of diabetes by injection of streptozotocin in insulin-treated moderately hyperglycemic (200 to 400 mg/dl glucose) rats (SDRs). The effects of a thromboxane synthesis inhibitor, 4'-(imidazol-1-yl)acetophenone (TXI) (100 mg/kg/day) on these parameters were also assessed. Urinary TXB2 and albumin excretion in SDRs was not different from that in normal rats between 7 and 90 days but were three times higher than normal in SDRs at 125 and 170 days after induction of diabetes. In SDRs, urinary protein excretion was higher than in controls at 170 days but not at earlier time points. Inulin clearance (CIn) of SDRs was significantly higher than control values at 7 and 90 days and was not influenced by TXI during this period. At 170 days CIn was not significantly different in SDRs and normal rats. By contrast, albumin clearance (CAIb) and fractional CAIb were elevated in SDRs when compared with those values in normal rats. Treatment of SDRs with TXI for 170 days completely prevented the rise in urinary TXB2, albumin, and protein excretion, as well as the rise in fractional CAIb, but did not alter prostaglandin E2 (PGE2) excretion. TXI also increased CIn in SDRs to levels that were significantly higher than normal at 170 days. TXI had no significant effect on urinary PGE2, TXB2, albumin, or protein excretion or on CIn in normal rats and did not influence blood pressure or blood glucose in normal rats or SDRs. The results suggest a role for thromboxane in the mediation of albuminuria in the SDR.

[Immunoreactive urinary thromboxane B2 in experimental mesenteric thrombosis in dogs]. / Tromboxano B2 urinario inmunorreactivo en trombosis mesentérica experimental en perros.

Thromboxane B2 (TxB2) the stable metabolite of thromboxane A2 may be released as a response to ischemia. With the aim of investigating its role as an early diagnostic test in mesenteric thrombosis, immunoreactive TxB2 was measured in urine aliquotes in six sham operated dogs, nine dogs subjected to superior mesenteric artery ligation, and twelve dogs with superior mesenteric vein ligation. One hour urine volumes were collected before surgery and during the eight hours after the experimental procedures, and urinary osmolarities were also determined in each sample. Basal TxB2 levels were comparable in all groups. Although all groups showed a significant and rapid (one hour) increase in TxB2 as a response to surgery, in the controls it returned to normal after six hours, whereas in the rest a continuously increased production persisted throughout the study period. There was no difference in t-test comparisons depending on the sort of thrombosis. In spite of the urinary dilution induced during the study, a persistent increase in TxB2 excretion was found. We conclude that urinary TxB2 levels could prove useful in the early diagnosis of mesenteric ischemia.

Urinary thromboxane B2 as an indicator of acute rejection in lung allotransplantation.

The behavior of urinary thromboxane B2 (TXB2) during acute rejection of lung allotransplants was evaluated. Unmatched mongrel dogs were submitted to a left lung orthotopic allotransplantation (groups I and II), or a sham operation (group III). All animals had an initial significant elevation of TXB2 excretion due to surgical trauma; however, in sham-operated animals (group III) this elevation returned to basal levels after 3 days. All transplanted animals (groups I and II) had persistent TXB2 elevation with 2 important peaks on postop days 5 and 9. The elevated TXB2 excretion persisted in spite of immunosuppressive treatment with azathioprine and prednisone (group II). Rejection was followed by means of an objective grading system applied to chest roentgenograms taken on all animals. It was found that TXB2 levels correlated directly with the grade of radiographic changes seen, thus indicating degree of rejection. TXB2 can be useful as a noninvasive indicator for surveillance of lung allograft rejection.

Systemic production of prostacyclin and thromboxane A2 does not correlate with patency of the ductus arteriosus in very low birth weight infants.

Urinary excretion of prostacyclin and thromboxane metabolites (2,3-dinor-6-ketoprostaglandin F1 alpha, thromboxane B2, and 2,3-dinor-thromboxane B2) as indices of systemic biosynthesis was prospectively determined in nine premature infants during the first 10 days of life, by gas chromatography-mass spectrometry. The patients ranged in gestational age from 27 to 29 weeks and in birth weight from 720 to 980 gm. Four infants developed symptomatic patent ductus arteriosus (PDA). Excretion of all metabolites exceeded adult values on the basis of body surface area at birth, reached a maximum on the fourth day of life, was related to urine output, and did not distinguish patients with and without symptomatic PDA. We conclude that neither circulating prostacyclin nor thromboxane A2 contribute significantly to the pathophysiology of symptomatic PDA in very low birth weight infants.