allopurinol and Intermittent-Claudication

Patients with peripheral arterial disease (PAD) are limited by intermittent claudication in the distance they can walk. Allopurinol has been shown in coronary arterial disease to prolong exercise before angina occurs, likely by prevention of oxygen wastage in tissues and reduction of harmful oxidative stress.. In this study we evaluated whether allopurinol could prolong the time to development of leg pain in participants with PAD. In a double-blind, randomized controlled clinical trial participants were randomized to receive either allopurinol 300 mg twice daily or placebo for 6 months. The primary outcome was change in exercise capacity on treadmill testing at 6 months. Secondary outcomes were 6-minute walking distance, Walking Impairment Questionnaire, SF-36 questionnaire, flow-mediated dilatation, and oxidized low-density lipoprotein. Outcome measures were repeated midstudy and at the end of study. The mean age of the 50 participants was 68.4 ± 1.2 years with 39 of 50 (78%) male.. Five participants withdrew during the study (2 active, 3 placebo). There was a significant reduction in uric acid levels in those who received active treatment of 52.1% (P < 0.001), but no significant change in either the pain-free or the maximum walking distance. Other measures of exercise capacity, blood vessel function, and the participants' own assessment of their health and walking ability also did not change during the course of the study.. Although allopurinol has been shown to be of benefit in a number of other diseases, in this study there was no evidence of any improvement after treatment in patients with PAD.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Dose-Response Relationship, Drug; Double-Blind Method; Exercise Test; Exercise Tolerance; Female; Follow-Up Studies; Free Radical Scavengers; Humans; Intermittent Claudication; Male; Middle Aged; Peripheral Arterial Disease; Retrospective Studies; Surveys and Questionnaires; Treatment Outcome; Walking

Oxygen-derived free radicals have been implicated as contributors to the development of lower limb oedema observed after femoropopliteal bypass grafting. This study investigates the occurrence of free radical-induced lipid peroxidation after this operation and the possible effects of allopurinol (xanthine oxidase inhibitor) in reducing free radical injury in order to minimise lower leg oedema. Twenty-nine patients undergoing femoropopliteal bypass surgery were randomised in a double blind fashion into two groups; those in one were given allopurinol 200 mg orally (n = 15) at 24 h and 2 h preoperatively and again at 24 h postoperatively, while those in the second group received a placebo (n = 14). Daily lower limb volume was calculated to assess swelling. Blood samples were taken from the femoral vein for measurements of malondialdehyde (MDA), an end product of lipid peroxidation, before the application of the femoral artery clamp, just prior to and immediately after clamp release, and at 20 minute intervals thereafter for 1 hour. The increase in lower limb volume in the placebo group was almost twice (8.9 +/- 1.6%) that of the allopurinol group (4.6 +/- 1%; p = 0.02). Six out of the 14 patients receiving placebo suffered swelling of 10% or more of original lower limb volume in comparison to only one out of 15 in those given allopurinol (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Allopurinol; Blood Vessel Prosthesis; Double-Blind Method; Edema; Femoral Artery; Free Radical Scavengers; Humans; Intermittent Claudication; Leg; Lipid Peroxidation; Malondialdehyde; Popliteal Artery; Postoperative Complications

Topics: Allopurinol; Exercise Tolerance; Female; Humans; Intermittent Claudication; Male; Walking

We previously showed oxidative damage and edema within skeletal muscle after contractile claudication. To investigate the sources of this oxidative damage in the gastrocnemius muscle, we administered allopurinol (Allo, to inhibit xanthine oxidase) and cyclophosphamide (Cyclo, to deplete neutrophils) before inducing contractile claudication in male Sprague Dawley rats. Contractile claudication (ligated stimulated, LS) caused a significant increase in xanthine oxidase activity [sham ligated stimulated (SS) = 2.57 +/- 0.07; LS = 3.22 +/- 0.07] and neutrophil infiltration (SS = 0.47 +/- 0.03; LS = 0.91 +/- 0.10) compared with controls (SS), and this was associated with increased lipid peroxidation, protein oxidation, muscle damage, and edema. Pretreatment with Allo attenuated the increase in xanthine oxidase activity and attenuated lipid hydroperoxides (control LS = 12.85 +/- 0.50; Allo LS = 9.96 +/- 0.71), muscle damage, and neutrophil infiltration (control LS = 0.91 +/- 0.10; Allo LS = 0.61 +/- 0.07). This latter finding suggests that xanthine oxidase-derived oxidants are chemotactic to neutrophils. Pretreatment with Cyclo reduced neutrophil infiltration (control LS = 0.91 +/- 0.10; Cyclo LS = 0.55 +/- 0.02) and attenuated lipid peroxidation (control LS = 12.85 +/- 0.50; Cyclo LS = 6.462 +/- 0.62), protein oxidation (control LS = 2.59 +/- 0.47; Cyclo LS = 1.77 +/- 0.60), muscle damage, and edema. Together, these data indicate that contractile claudication causes an increase in xanthine oxidase activity and neutrophils in muscle and that inhibition of these oxidant sources protects against oxidative stress, muscle damage, and edema.

Topics: Animals; Intermittent Claudication; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Muscle Contraction; Muscle Proteins; Muscle, Skeletal; Neutrophil Activation; Neutrophils; Oxidation-Reduction; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley; Xanthine Oxidase

The purpose of this study was to determine the extent and sources of oxidative stress within skeletal muscle following an acute bout of contractile claudication. Twenty-four hours after unilateral ligation of the femoral artery, rat hind limbs were stimulated in vivo for 30 min, and force production measured. One-hour post-stimulation, animals were sacrificed and soleus and gastrocnemius muscles removed. There was significant reduction in force in the control limb (sham ligated/stimulated (SS)), while force in the ligated limb (ligated/stimulated (LS)) was reduced by 72%. There was an increase in skeletal muscle lipid hydroperoxides (53 and 47%) and protein carbonyls (57 and 54%) in the soleus and gastrocnemius muscles, respectively, and the muscle wet/dry weight ratio was increased in the gastrocnemius muscles. Total glutathione (GHS) was reduced, while xanthine oxidase (XO) activity and neutrophil levels were increased, in LS compared to SS in both soleus and gastrocnemius muscles. These data suggest that an acute bout of contractile claudication causes significant oxidative damage and edema to skeletal muscle. This is associated with both an increase in the activity of the radical-producing enzyme xanthine oxidase and an increase in activated neutrophils.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Glutathione; Intermittent Claudication; Male; Muscle Contraction; Muscle, Skeletal; Neutrophils; Oxidative Stress; Physical Conditioning, Animal; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Xanthine Oxidase

Xanthine oxidase activity in blood from the ipsilateral femoral vein, and the relationship between xanthine oxidase production and the products of lipid peroxidation, were studied before operation and for 60 min following release of clamps after successful revascularization in two groups of patients with claudication or critical ischaemia. Before revascularization, detectable levels of xanthine oxidase were found only in patients with critical ischaemia. Clamping during bypass surgery led to release of xanthine oxidase in claudicants, but this activity reduced after 60 min. There was no evidence of lipid peroxidation during this time. Xanthine oxidase activity in brachial vein blood was higher than in femoral vein blood in patients with critical ischaemia before revascularization.

Topics: Adult; Aged; Aged, 80 and over; Constriction; Female; Femoral Vein; Humans; Intermittent Claudication; Ischemia; Leg; Male; Middle Aged; Reperfusion; Xanthine Oxidase