allopurinol and Diabetic-Neuropathies

We evaluated the effects of a combination triple antioxidant therapy on measures of cardiovascular autonomic neuropathy (CAN) and myocardial blood flow (MBF) in patients with type 1 diabetes.. This was a randomised, parallel, placebo-controlled trial. Participants were allocated to interventions by sequentially numbered, opaque, sealed envelopes provided to the research pharmacist. All participants and examiners were masked to treatment allocation. Participants were evaluated by cardiovascular autonomic reflex testing, positron emission tomography with [(11)C]meta-hydroxyephedrine ([(11)C]HED) and [(13)N]ammonia, and adenosine stress testing. Markers of oxidative stress included 24 h urinary F2-isoprostanes. Diabetic peripheral neuropathy (DPN) was evaluated by symptoms, signs, electrophysiology and intra-epidermal nerve fibre density. Randomised participants included 44 eligible adults with type 1 diabetes and mild-to-moderate CAN, who were aged 46 ± 11 years and had HbA1c 58 ± 5 mmol/mol (7.5 ± 1.0%), with no evidence of ischaemic heart disease. Participants underwent a 24-month intervention, consisting of antioxidant treatment with allopurinol, α-lipoic acid and nicotinamide, or placebo. The main outcome was change in the global [(11)C]HED retention index (RI) at 24 months in participants on the active drug compared with those on placebo.. We analysed data from 44 participants (22 per group). After adjusting for age, sex and in-trial HbA1c, the antioxidant regimen was associated with a slight, but significant worsening of the global [(11)C]HED left ventricle RI (-0.010 [95% CI -0.020, -0.001] p = 0.045) compared with placebo. There were no significant differences at follow-up between antioxidant treatment and placebo in the global MBF, coronary flow reserve, or in measures of DPN and markers of oxidative stress. The majority of adverse events were of mild-to-moderate severity and did not differ between groups. In this cohort of type 1 diabetes patients with mild-to-moderate CAN, a combination antioxidant treatment regimen did not prevent progression of CAN, had no beneficial effects on myocardial perfusion or DPN, and may have been detrimental. However, a larger study is necessary to assess the underlying causes of these findings.

Topics: Adolescent; Adult; Aged; Allopurinol; Antioxidants; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Female; Humans; Male; Middle Aged; Myocardium; Niacinamide; Regional Blood Flow; Young Adult

This study investigated the relationship between serum xanthine oxidase (XOD) activity and the occurrence of diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus (T2DM) patients. Serum XOD activity, ischemia-modified albumin (IMA), uric acid (UA), albumin, glycated hemoglobin (HbA1c), advanced glycation end products (AGE), total free thiols, atherogenic index of plasma (AIP), and body mass index (BMI) were measured in 80 T2DM patients (29 with and 51 without DPN), and 30 nondiabetic control subjects. Duration of diabetes, hypertension, medication, and microalbuminuria was recorded. Serum XOD activities in controls, non-DPN, and DPN were 5.7 ± 2.4 U/L, 20.3 ± 8.6 U/L, and 27.5 ± 10.6 U/L (

Topics: Aged; Biomarkers; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Hypertension; Logistic Models; Male; Middle Aged; Multivariate Analysis; Serum Albumin; Serum Albumin, Human; Sulfhydryl Compounds; Time Factors; Uric Acid; Xanthine Oxidase

The objective of the present study was to investigate the possible neuroprotective effect of resveratrol against streptozotocin-induced hyperglycaemia in the rat brain and medulla spinalis. Thirty adult male Wistar rats were divided into three groups as follows: control group, streptozotocin-induced diabetic-untreated group, and streptozotocin-induced diabetic resveratrol-treated group. Diabetes was induced by a single injection of streptozotocin (STZ) (60 mg/kg body weight). Three days after streptozotocin injection, resveratrol (10 mg/kg) was injected intraperiteonally daily over 6 weeks to the rats in the treatment group. Six weeks later, seven rats from each group were killed and the brain stem and cervical spinal cord were removed. The hippocampus, cortex, cerebellum, brain stem and spinal cord were dissected for biochemical studies (lipid peroxidation measuring malondialdehyde [MDA], xanthine oxidase [XO], nitric oxide [NO] and glutathione). MDA, XO and NO levels in hippocampus, cortex, cerebellum, brain stem and spinal cord in the streptozotocin-induced diabetic-untreated group increased significantly. Treatment with resveratrol significantly reduced MDA, XO and NO production and increased glutathione levels when compared to the streptozotocin-induced diabetic-untreated group. This study demonstrates that resveratrol is a potent neuroprotective agent against diabetic oxidative damage.

Topics: Animals; Central Nervous System Diseases; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Free Radical Scavengers; Glutathione; Hyperglycemia; Lipid Peroxidation; Male; Malondialdehyde; Medulla Oblongata; Neuroprotective Agents; Nitric Oxide; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Spinal Cord; Stilbenes; Vasodilator Agents; Xanthine Oxidase

Several putative sources of reactive oxygen species could potentially contribute to diabetic neuropathy and vasculopathy. The aim was to assess the involvement of elevated xanthine oxidase activity. After 6 weeks of streptozotocin-diabetes, groups of rats were given 2 weeks of high-dose allopurinol treatment (50 and 250 mg/kg) to gauge the effect of maximal blockade of xanthine oxidase. In the final experiments, rats were subjected to sensory testing and, under butabarbital anaesthesia, measurements were made on nerve conduction velocities and neural tissue blood flow estimated by hydrogen clearance microelectrode polarography. Further groups were used to study detailed responses of the isolated mesenteric vascular bed after 4 weeks of diabetes and allopurinol (150 mg/kg) treatment. Diabetes caused 20% and 14% reduction in motor and sensory conduction velocity, which were 78% and 81% corrected by allopurinol treatment respectively, both doses giving similar results. Diabetic rats showed tactile allodynia and thermal hyperalgesia, which were completely corrected by allopurinol, whereas mechanical hyperalgesia was only 45% ameliorated. Sciatic nerve and superior cervical ganglion blood flow was halved by diabetes and allopurinol corrected this by approximately 63%. Mesenteric endothelium-dependent vascular responses to acetylcholine, which depend upon nitric oxide and endothelium derived hyperpolarizing factor, were attenuated by diabetes. Allopurinol treatment gave approximately 50% protection for both components. Thus, xanthine oxidase is an important source of reactive oxygen species that contributes to neurovascular dysfunction in experimental diabetes. Inhibition of xanthine oxidase could be a potential therapeutic approach to diabetic neuropathy and vasculopathy.

Topics: Acetylcholine; Allopurinol; Animals; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Disease Models, Animal; Enzyme Inhibitors; Ganglia, Autonomic; Hyperalgesia; Male; Mesenteric Artery, Superior; Neural Conduction; Pain; Polarography; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Regional Blood Flow; Sciatic Nerve; Xanthine Oxidase