thromboxane-b2 and Intermittent-Claudication

Cilostazol improves walking distance in peripheral arterial disease (PAD) patients. The study objectives were to assess the effects of cilostazol on walking distance, followed by the additional assessment of cilostazol on exercise-induced ischaemia-reperfusion injury in such patients.. PAD patients were prospectively recruited to a double-blinded, placebo-controlled trial. Patients were randomised to receive either cilostazol 100mg or placebo twice a day. The primary end-point was an improvement in walking distance. Secondary end-points included the assessment of oxygen-derived free-radical generation, antioxidant consumption and other markers of the inflammatory cascade. Initial and absolute claudication distances (ICDs and ACDs, respectively) were measured on a treadmill. Inflammatory response was assessed before and 30 min post-exercise by measuring lipid hydroperoxide, ascorbate, alpha-tocopherol, beta-carotene, P-selectin, intracellular and vascular cell-adhesion molecules (I-CAM and V-CAM), thromboxane B(2) (TXB(2)), interleukin-6, interleukin-10, high-sensitive C-reactive protein (hsCRP), albumin-creatinine ratio (ACR) and urinary levels of p75TNF receptor. All tests were performed at baseline and 6 and 24 weeks.. One hundred and six PAD patients (of whom 73 were males) were recruited and successfully randomised from December 2004 to January 2006. Patients who received cilostazol demonstrated a more significant improvement in the mean percentage change from baseline in ACD (77.2% vs. 26.6% at 6 weeks, p=0.026 and 161.7% vs. 79.0% at 24 weeks, p=0.048) as compared to the placebo. Cilostazol reduced lipid hydroperoxide levels compared to a placebo-related increase before and after exercise (6 weeks: pre-exercise: -11.8% vs. +5.8%, p=0.003 and post-exercise: -12.3% vs. +13.9%, p=0.007 and 24 weeks: pre-exercise -15.5% vs. +12.0%, p=0.025 and post-exercise: -9.2% vs. +1.9%, p=0.028). beta-Carotene levels were significantly increased in the cilostazol group, compared to placebo, before exercise at 6 and 24 weeks (6 weeks: 34.5% vs. -7.4%, p=0.028; 24 weeks: 34.3% vs. 17.7%, p=0.048). Cilostazol also significantly reduced P-selectin, I-CAM and V-CAM levels at 24 weeks as compared to baseline (p<0.05). There was no difference between treatment groups for ascorbate, alpha-tocopherol, interleukin-6 and -10, hsCRP and p75TNF receptor levels.. Cilostazol significantly improves ACD, in addition to attenuating exercise-induced ischaemia-reperfusion injury, in PAD patients.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; alpha-Tocopherol; Ascorbate Oxidase; beta Carotene; C-Reactive Protein; Cilostazol; Creatinine; Double-Blind Method; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-10; Interleukin-6; Intermittent Claudication; Lipid Peroxides; Male; Middle Aged; P-Selectin; Prospective Studies; Receptors, Tumor Necrosis Factor; Reperfusion Injury; Tetrazoles; Thromboxane B2; Vascular Cell Adhesion Molecule-1; Vasodilator Agents; Walking

We evaluated the effectiveness of indobufen administration in reducing neutrophil activation in a clinical model of ischemia-reperfusion. Thirty stable patients with intermittent claudication due to occlusive peripheral arterial disease of the leg were randomly assigned to two groups. Patients in group I were treated with indobufen [200 mg orally twice daily (p.o. b.i.d.) for a week]; patients in group II received a placebo. Both groups of patients were submitted to standardized treadmill exercise until onset of claudication. Plasma levels of thromboxane B2 (TxB2) and 6-keto-prostaglandin F1alpha(6-k-PGF1alpha) neutrophil filterability, and neutrophil activation (by nitro-blue tetrazolium test) were assessed in blood samples from the femoral vein draining the ischemic leg. The values were obtained at rest and 5, 30, and 60 min after onset of claudication. Urinary albumin excretion was measured at rest and 1 h after onset of claudication. Plasma levels of TxB2 and 6-k-PGF1alpha increased significantly in the placebo group 5 min after onset of claudication, whereas only a slight nonsignificant increase was observed in the indobufen-treated group at the same timepoint.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Arterial Occlusive Diseases; Cyclooxygenase Inhibitors; Humans; Intermittent Claudication; Isoindoles; Lactic Acid; Middle Aged; Neutrophil Activation; Phenylbutyrates; Platelet Aggregation Inhibitors; Thromboxane B2

In a multi-center, double-blind, placebo-controlled trial in claudicating patients with peripheral atherosclerosis, the effects of 1 year of treatment with ketanserin (20 mg t.i.d. for 1 month, 40 mg t.i.d. thereafter; n = 63 patients) or placebo (n = 84 patients) on platelet function (aggregation in P.R.P. by 5-HT 5 x 10(-6) M, ADP 1 to 5 x 10(-6) M, collagen 2 micrograms/ml; platelet 5-HT content; plasma beta TG- and PF4-levels; serum TXB2) were analyzed. Before treatment, claudicating patients (n = 173) displayed an higher reactivity of platelets to 5-HT and signs of platelet activation/release in vivo (higher plasma beta TG-PF4, lower platelet 5-HT content and decreased platelet aggregation by ADP, collagen) in comparison with healthy controls (n = 50). After 1 year of treatment with ketanserin, but not with placebo, platelet aggregation induced by 5-HT (slope -41.1%) and platelet 5-HT content (-23.7%) were significantly reduced. PF4 and beta TG were significantly higher than their pre-medication values in the two trial groups. The other platelet function tests were not significantly modified by the treatment. Only the small subgroup of patients with initially elevated plasma beta TG levels (greater than 20 ng/ml) also scrutinized for hidden NSAID consumption or technical bias (exclusion of data with serum TXB2 less than or equal to 10000 pg/100 microliters and/or plasma PF4 greater than 10 ng/ml) had significantly lower plasma beta TG levels (-22.7%) than the pre-medication values after treatment with ketanserin, but not with placebo. The present study confirms that ketanserin affects some platelet functions, during long-term administration in claudicating patients with atherosclerosis.

Topics: beta-Thromboglobulin; Calcium; Clinical Trials as Topic; Double-Blind Method; Humans; Intermittent Claudication; Ketanserin; Multicenter Studies as Topic; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Serotonin; Thromboxane B2

Percutaneous transluminal angioplasty is an acute, local stimulus to platelets which activation is regarded as an important factor for a later restenosis. The balance between the production of prostacyclin and thromboxane A2 is of (patho)physiological importance due to their opposite actions on vascular tone and platelet reactivity. In this study we investigated the influence of percutaneous transluminal angioplasty of the peripheral arteries on prostacyclin and thromboxane A2 productions in vivo by measuring the excretions of their urinary index metabolites, 2,3-dinor-6-ketoprostaglandin F1 alpha and 11-dehydrothromboxane B2, respectively, in 10 patients. We found a twofold increase in thromboxane A2, but no significant change in prostacyclin, production after peripheral transluminal angioplasty which shifted prostacyclin/thromboxane A2 balance to the direction of thromboxane A2 formation. This gives theoretical support to the use of thromboxane A2 synthase inhibitors and receptor antagonists as well as prostacyclin analogues in combination with peripheral percutaneous transluminal angioplasty to prevent thrombosis and restenosis.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aged, 80 and over; Angiography; Angioplasty, Balloon; Arteries; Female; Humans; Intermittent Claudication; Male; Middle Aged; Thromboxane A2; Thromboxane B2

It has been postulated that ischaemia-reperfusion occurs in intermittent claudication resulting in neutrophil activation and release of soluble mediators, increasing systemic vascular permeability and enhancing atherogenesis.. We measured neutrophil deformability, plasma thromboxane levels, and urinary microalbumin excretion in 30 male claudicants, and 10 age- and sex-matched controls, before and after exercise to maximum walking distance. Blood was taken from an antecubital vein.. There was an increase in urinary microalbumin excretion after exercise in claudicants. Statistically significant increases in the median and 90th percentile transit times (markers of neutrophil deformability) for isolated neutrophils from blood drawn 5 min after exercise in the claudicants were observed with no change in control subjects. Plasma thromboxane concentrations in claudicants increased within 10 min post-exercise. Plasma concentrations in controls were significantly lower throughout the study period. In the claudicant group, a positive correlation between the percentage change in the median transit time for neutrophils, and the percentage change in plasma thromboxane at 60 min post-exercise was found.. The results lend further support to the concept of ischaemia-reperfusion events in patients with intermittent claudication, leading to a systemic increase in vascular permeability as a result of endothelial injury or dysfunction (a crucial step in atherogenesis), associated with thromboxane production and neutrophil activation. We suggest that the above changes may contribute to the increased mortality seen in such patients.

Topics: Adult; Aged; Albuminuria; Humans; Intermittent Claudication; Male; Middle Aged; Neutrophil Activation; Physical Exertion; Thromboxane B2; Walking

The effect of 5 min treadmill exercise was investigated in claudicant patients and healthy controls; systemic neutrophil count, plasma thromboxane and von Willebrand's factor (a marker for endothelial injury) were measured. Median (interquartile range (i.q.r.)) resting neutrophil count was 5.6 (5.2-6.0) x 10(6) cells l-1 in claudicants and 2.8 (2.6-3.2) x 10(6) l-1 in controls (P < 0.05); this increased in those with claudication to 7.1 (6.2-7.7) x 10(6) l-1 immediately after exercise (P < 0.05). The resting plasma thromboxane level was 32.1 (25.0-60.0) pg ml-1 in claudicants and rose to 135.0 (104.0-141.3) pg ml-1 15 min after exercise, compared with a rise from 25.0 (22.0-33.5) to 55.5 (33.0-67.0) pg ml-1 in controls (P < 0.05). The resting serum von Willebrand's factor level was 127 (110-135) units dl-1 in claudicants compared with 60 (48-71) units dl-1 in controls; this difference persisted after exercise (P < 0.01). In patients with claudication, the level of von Willebrand's factor increased to 150 (140-156) units dl-1 60 min after exercise (P < 0.05). Free radical scavenging capacity was also investigated by measuring the plasma antioxidant activity of glutathione peroxidase and its essential non-metal cofactor selenium. Scavenging capacity was lower in claudicant patients whose median (i.q.r.) glutathione peroxidase activity (change in absorbance per min per ml plasma) was 2.84 (2.39-3.61) versus 3.24 (3.06-3.79) in controls (P < 0.05). Similarly, plasma concentrations of selenium were lower in claudicants at a median (i.q.r.) of 75.0 (58.0-81.0) micrograms l-1 compared with 88.0 (75.0-92.5) micrograms l-1 in controls (P < 0.05). Exercise in claudicant patients leads to neutrophilia and thromboxane production with subsequent endothelial injury. The antioxidant activity of glutathione peroxidase is reduced in patients with claudication and may allow the unopposed action of free radicals to damage endothelium.

Topics: Aged; Exercise Test; Female; Glutathione Peroxidase; Humans; Intermittent Claudication; Leukocyte Count; Male; Middle Aged; Neutrophil Activation; Neutrophils; Physical Exertion; Platelet Activation; Thromboxane B2; von Willebrand Factor

Platelet activation, with subsequent formation of thromboxane A2 (TxA2), is thought to play a role in the development of arterial occlusion. In patients with severe atherosclerosis of the lower limbs, characterized by leg ulcers and rest pain, the basal formation of TxA2 and prostacyclin (PGI2) is increased. Corresponding data in patients with more moderate atherosclerosis of the lower limbs have not been reported. Since the capacity to physical exercise is not blunted in such patients proper evaluation of their TxA2-PGI2 synthesis should comprise not only assessment of the basal formation, but also TxA2/PGI2 biosynthesis during conditions of elevated cardiovascular activity. To address this, we analysed these eicosanoids in patients with a history of intermittent claudication. Urinary dinor-metabolites of TxB2 and PGI2 (Tx-M and PGI-M, respectively) were estimated by gas chromatography/negative ion-chemical ionization mass spectrometry in samples collected prior to, during and immediately after 20 min of severe treadmill exertion. The basal excretion of Tx-M was 105 +/- 26 pg/mg creatinine. It was not changed during exercise, but increased to 176 +/- 48 pg/mg creatinine (P less than 0.05) during the recovery. The basal excretion of PGI-M was 142 +/- 25 pg/mg creatinine. The PGI-M response to exercise varied from no change at all to a 30-fold increase, without any obvious correlation to experienced leg pain, walking distance or other recorded variables. During the recovery period the outflow of PGI-M was significantly higher than at rest (482 +/- 145 pg/mg creatinine; P less than 0.01). We conclude that in patients with intermittent claudication due to atherosclerosis (1) platelet activation does not occur during the course of the exercise, and (2) vascular prostacyclin formation can be dissociated from of TxA2 synthesis. The observed increase in PGI-M in some of the patients is suggested to reflect tissue ischaemia induced by the lack of adequate hyperaemia during exercise.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Female; Humans; Intermittent Claudication; Male; Middle Aged; Physical Exertion; Thromboxane B2