allopurinol and Diabetes-Mellitus--Type-1

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the western world. Current treatment methods, with better control of glycemia and blood pressure, including renin-angiotensin system blockade (RASB), appear to have slowed the DN progression rate but have not substantially decreased the annual incidence of new DN ESRD cases. Thus, new treatment targets are needed.. Higher levels of serum uric acid (UA) are associated with increased risk of the clinical manifestations of DN in persons with types 1 and 2 diabetes. Also, UA is a strong predictor of DN progression. Two small, short-term, proof-of-concept clinical trials in which a minority of the patients had diabetes suggested that reduction of UA with allopurinol could decrease the rate of glomerular filtration rate (GFR) loss in persons with chronic kidney disease (CKD). However, a definitive trial to check whether UA reduction can benefit DN progression has not been conducted as yet. Preventing Early Renal Loss in Diabetes (PERL) is an ongoing trial in persons with type 1 diabetes and early to moderate GFR reduction. This 3-year randomized placebo controlled trial in 530 subjects is to check whether UA reduction with allopurinol can slow the rate of GFR decline as determined by the plasma disappearance of iohexol. Key Message: If the results of the PERL trial are positive, initiation of UA reduction treatment while GFR is relatively well preserved could delay ESRD in DN by 8-10 years, that is, considerably longer than the period that has been demonstrated for RASB. This could have important implications for the treatment of DN in particular and of CKD in general.

Topics: Allopurinol; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Progression; Glomerular Filtration Rate; Gout Suppressants; Humans; Hyperuricemia; Risk Factors; Uric Acid

The pathogenesis of diabetic nephropathy is complex and still not fully elucidated. Uric acid has been associated with renal disease, even though hyperuricemia may be a marker of or by itself be responsible for microvascular disease in diabetes. In animal models, elevated level of uric acid can lead to arteriolopathy of preglomerular vessels, impaired autoregulation, glomerular hypertension, as well as endothelial dysfunction. Kidney damage in hyperuricemic rats is not dependent on blood pressure, and instead involves the renin-angiotensin system. In patients with diabetes, serum uric acid early in the course of diabetes is significantly, and independent of confounders, associated with later development of persistent macroalbuminuria. Therefore, uric acid may be a novel and important player in the pathogenesis of microvascular complications in diabetes. A dose-response relationship between serum uric acid and early decline in renal function has recently been demonstrated in patients with type-1 diabetes. Randomized controlled trials on drugs that lower uric acid need to be conducted to evaluate the causal relationship between serum uric acid and development and progression of diabetic kidney disease; in addition, large scale long-term treatment trials need to be performed, as they are still lacking.

Topics: Allopurinol; Animals; Antimetabolites; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Models, Animal; Humans; Rats; Uric Acid

Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease.. In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m. A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m. We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).

Topics: Adult; Aged; Allopurinol; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Enzyme Inhibitors; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Renin-Angiotensin System; Treatment Failure; Uric Acid; Xanthine Oxidase

Elevated serum urate levels are associated with progression of chronic kidney disease. Whether urate-lowering treatment with allopurinol can attenuate the decline of the estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease who are at risk for progression is not known.. In this randomized, controlled trial, we randomly assigned adults with stage 3 or 4 chronic kidney disease and no history of gout who had a urinary albumin:creatinine ratio of 265 or higher (with albumin measured in milligrams and creatinine in grams) or an eGFR decrease of at least 3.0 ml per minute per 1.73 m. Enrollment was stopped because of slow recruitment after 369 of 620 intended patients were randomly assigned to receive allopurinol (185 patients) or placebo (184 patients). Three patients per group withdrew immediately after randomization. The remaining 363 patients (mean eGFR, 31.7 ml per minute per 1.73 m. In patients with chronic kidney disease and a high risk of progression, urate-lowering treatment with allopurinol did not slow the decline in eGFR as compared with placebo. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; CKD-FIX Australian New Zealand Clinical Trials Registry number, ACTRN12611000791932.).

Topics: Aged; Allopurinol; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Progression; Double-Blind Method; Enzyme Inhibitors; Female; Glomerular Filtration Rate; Gout Suppressants; Humans; Male; Middle Aged; Renal Insufficiency, Chronic; Renin-Angiotensin System; Treatment Failure; Uric Acid; Xanthine Oxidase

Topics: Albuminuria; Allopurinol; Creatinine; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Renal Agents; Uric Acid

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

Celsior solution (CS), which has recently become available, that might theoretically offer a new means for improving graft preservation quality. The present prospective, randomized study was designed to evaluate the efficacy of CS compared with University of Wisconsin (UW) for pancreas allografts. Between January 2001 and January 2007, 88 patients underwent pancreatic transplantation, including the last 30 consecutive simultaneous pancreas kidney patients who were randomly assigned to either CS or UW. There was no case of graft thrombosis in either group. There were 2 cases of pancreatitis in the UW group compared with 1 in the CS group. No case of primary nonfunction occurred in either group. There were 2 cases of early duodenal stump fistulae in the CS group that required transplantectomy, whereas this complication was not observed in the UW group. Relaparotomy in the UW group was required in 3 cases due to infection and treated by close drainage that which, progressed to fatal sepsis in 1 patient. In the UW group with 6 months of follow-up, there were 12 patients insulin free. In the CS group, 6 patients underwent relaparotomy, 3 for transplantectomy and the others for intra-abdominal infection, which was fatal in 2 cases. In the CS group with 6 months of follow-up, there were 10 patients insulin free. Two patients died with functioning grafts. These results provided indirect evidence that CS solution is at least as safe as UW to mitigate postreperfusion graft edema and pancreatitis, as well as graft thrombosis.

Topics: Adenosine; Adult; Allopurinol; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disaccharides; Electrolytes; Female; Glutamates; Glutathione; Histidine; Humans; Insulin; Kidney Transplantation; Male; Mannitol; Middle Aged; Organ Preservation Solutions; Pancreas; Pancreas Transplantation; Raffinose; Reperfusion Injury; Safety; Young Adult

The aim of this work was to study the mechanism of free radical formation in type 1 diabetes and its possible prevention. We have found oxidation of blood glutathione and an increase in plasma lipoperoxide levels in both human type 1 diabetes and experimental diabetes. Peroxide production by mitochondria does not increase in diabetes. On the contrary, the activity of xanthine oxidase, a superoxide-generating enzyme, increases in liver and plasma of diabetic animals. The increase in plasma xanthine oxidase activity may be explained by the increase in the hepatic release of this enzyme, which is not due to nonspecific membrane damage: release of other hepatic enzymes, such as the amino transferases, does not increase in diabetes. Superoxide formation by aortic rings of rabbits increases significantly in diabetes. This is completely inhibited by allopurinol, an inhibitor of xanthine oxidase. Heparin, which releases xanthine oxidase from the vessel wall, also decreases superoxide formation by aortic rings of diabetic animals. Treatment with allopurinol decreases oxidative stress in type 1 diabetic patients: hemoglobin glycation, glutathione oxidation, and the increase in lipid peroxidation are prevented. These results may have clinical significance in the prevention of late-onset vascular complications of diabetes.

Topics: Allopurinol; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Double-Blind Method; Free Radical Scavengers; Free Radicals; Glutathione; Glutathione Disulfide; Heart; Humans; Kinetics; Lipid Peroxidation; Liver; Male; Malondialdehyde; Membrane Potentials; Mitochondria, Heart; Myocardium; Oxidative Stress; Rats; Rats, Wistar; Xanthine Oxidase

Topics: Adenosine; Allopurinol; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Glutathione; Humans; Hypertonic Solutions; Insulin; Kidney Failure, Chronic; Kidney Transplantation; Organ Preservation; Organ Preservation Solutions; Pancreas; Pancreas Transplantation; Postoperative Complications; Raffinose; Retrospective Studies; Thrombosis

Topics: Allopurinol; Diabetes Mellitus, Type 1; Gout; Gout Suppressants; Humans; Kidney; Uric Acid

Topics: Allopurinol; Diabetes Mellitus, Type 1; Gout Suppressants; Humans; Hyperuricemia; Kidney; Renal Insufficiency, Chronic; Uric Acid

Topics: Allopurinol; Diabetes Mellitus, Type 1; Disease Progression; Gout Suppressants; Humans; Renal Insufficiency, Chronic; Uric Acid

Topics: Allopurinol; Diabetes Mellitus, Type 1; Disease Progression; Gout; Humans; Kidney; Renal Insufficiency, Chronic; Uric Acid

Topics: Allopurinol; Diabetes Mellitus, Type 1; Gout Suppressants; Humans; Renal Insufficiency, Chronic; Uric Acid

Topics: Allopurinol; Diabetes Mellitus, Type 1; Gout Suppressants; Humans; Renal Insufficiency, Chronic; Uric Acid

Topics: Allopurinol; Diabetes Mellitus, Type 1; Gout Suppressants; Humans; Renal Insufficiency, Chronic; Uric Acid

Topics: Allopurinol; Diabetes Mellitus, Type 1; Gout Suppressants; Humans; Renal Insufficiency, Chronic; Uric Acid

Topics: Allopurinol; Diabetes Mellitus, Type 1; Gout Suppressants; Humans; Renal Insufficiency, Chronic; Uric Acid

The dynamics of cytopathic hypoxia markers in patients with acute pancreatitis (AP) biliary etiology (BE), depending on the presence of concomitant diabetes mellitus (DM), which is an independent factor of premorbid severity increase and increase in the degree of operational and anesthetic risk. Markers of cytopathic hypoxia use as methods for early diagnosis of acute liver failure (ALF) and monitoring the effectiveness of its correction promising. In terms of cytopathic hypoxia may be at the stage of laboratory diagnostics to distinguish between destructive and non-destructive forms APBE, and for markers of endothelial dysfunction--destructive forms on the area and depth of destruction of the pancreas.

Topics: Adenosine Deaminase; Adult; Aged; Arginine; Biomarkers; Case-Control Studies; Common Bile Duct; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hypoxia; Liver; Liver Failure, Acute; Male; Middle Aged; Pancreas; Pancreatitis, Acute Necrotizing; Severity of Illness Index; Xanthine Dehydrogenase; Xanthine Oxidase

Thioredoxin-interacting protein (TXNIP), a regulator of cellular oxidative stress, has been associated with activation of NOD-like receptor 3 (NLRP3) inflammasome, inflammation and lipid metabolism, suggesting it has a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) in diabetes. In this study we investigated whether TXNIP is involved in type 1 diabetes-associated NAFLD and whether antioxidants, quercetin and allopurinol, alleviate NAFLD by targeting TXNIP.. Diabetes was induced in male Sprague-Dawley rats by a single i.p. injection of 55 mg · kg⁻¹ streptozotocin. Quercetin and allopurinol were given p.o. to diabetic rats for 7 weeks. Hepatic function, oxidative stress, inflammation and lipid levels were determined. Rat BRL-3A and human HepG2 cells were exposed to high glucose (30 mM) in the presence and absence of antioxidants, TXNIP siRNA transfection or caspase-1 inhibitor, Ac-YVAD-CMK.. Quercetin and allopurinol significantly inhibited the TXNIP overexpression, activation of NLRP3 inflammasome, down-regulation of PPARα and up-regulation of sterol regulatory element binding protein-1c (SREBP-1c), SREBP-2, fatty acid synthase and liver X receptor α, as well as elevation of ROS and IL-1β in diabetic rat liver. These effects were confirmed in hepatocytes in vitro and it was further shown that TXNIP down-regulation contributed to the suppression of NLRP3 inflammasome activation, inflammation and changes in PPARα and SREBPs.. Inhibition of hepatic TXNIP by quercetin and allopurinol contributes to the reduction in liver inflammation and lipid accumulation under hyperglycaemic conditions. The targeting of hepatic TXNIP by quercetin and allopurinol may have therapeutic implications for prevention of type 1 diabetes-associated NAFLD.

Topics: Allopurinol; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Carrier Proteins; Cell Cycle Proteins; Cell Line; Diabetes Mellitus, Type 1; Dietary Supplements; Fatty Liver; Gene Silencing; Humans; Inflammasomes; Lipid Metabolism; Liver; Male; Molecular Targeted Therapy; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Quercetin; Random Allocation; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

Reactive oxygen species (ROS) have been widely implicated in the pathogenesis of diabetes and more recently in mitochondrial alterations in skeletal muscle of diabetic mice. However, so far the exact sources of ROS in skeletal muscle have remained elusive. Aiming at better understanding the causes of mitochondrial alterations in diabetic muscle, we designed this study to characterize the sites of ROS production in skeletal muscle of streptozotocin (STZ)-induced diabetic mice. Hyperglycemic STZ mice showed increased markers of systemic and muscular oxidative stress, as evidenced by increased circulating H(2)O(2) and muscle carbonylated protein levels. Interestingly, insulin treatment reduced hyperglycemia and improved systemic and muscular oxidative stress in STZ mice. We demonstrated that increased oxidative stress in muscle of STZ mice is associated with an increase of xanthine oxidase (XO) expression and activity and is mediated by an induction of H(2)O(2) production by both mitochondria and XO. Finally, treatment of STZ mice, as well as high-fat and high-sucrose diet-fed mice, with oxypurinol reduced markers of systemic and muscular oxidative stress and prevented structural and functional mitochondrial alterations, confirming the in vivo relevance of XO in ROS production in diabetic mice. These data indicate that mitochondria and XO are the major sources of hyperglycemia-induced ROS production in skeletal muscle and that the inhibition of XO reduces oxidative stress and improves mitochondrial alterations in diabetic muscle.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diet; Enzyme Inhibitors; Hydrogen Peroxide; Hyperglycemia; Insulin; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Mitochondria, Muscle; Muscle, Skeletal; Oxidative Stress; Oxypurinol; Protein Carbonylation; Reverse Transcriptase Polymerase Chain Reaction; RNA; Xanthine Oxidase

The aims of this study were to study the influence of the duration of diabetes, the role of endothelial-derived vasodilators, and the role of phosphodiesterase (PDE) isoform activity in the early changes in vascular reactivity of aortic rings from diabetic rats. Diabetes mellitus was induced in female rats by intravenous streptozotocin (85 mg/kg). Two or 4 wk later, thoracic aortic rings from control and diabetic rats were isolated, and vascular responses to acetylcholine (ACh), S-nitroso-N-acetylpenicillamine (SNAP) [nitric oxide (NO) donor], DMPPO (PDE5 inhibitor), and phenylephrine (PE) were obtained in the presence and absence of endothelium or other drugs. PDE isoform activity was also measured. At 2 wk, responses to ACh and DMPPO were enhanced, whereas those to PE were attenuated in diabetic rats relative to controls. Indomethacin and SQ-29548 (a thromboxane A(2) receptor antagonist), but not N(G)-nitro-L-arginine methyl ester, corrected these differences. The responses to SNAP, and cAMP and cGMP hydrolytic activities, were similar in the two groups. In contrast, at 4 wk, ACh, DMPPO, and PE produced similar responses in the two groups: N(G)-nitro-L-arginine methyl ester rendered the response to PE lower in the diabetic group, and this was corrected by indomethacin, but not SQ-29548, treatment. The response to SNAP was greater in the diabetic group, and this was corrected by DMPPO. Activity of all PDEs was decreased at 4 wk. We conclude that, at 2 wk, there is modulation of thromboxane A(2) production, but no change in the NO system or PDE isoform activities. At 4 wk, a reduction in NO activity is superimposed; at this stage, PDE activity is reduced, together with increased production of vasodilating prostaglandins, possibly as a compensatory mechanism to maintain normal vascular reactivity.

Topics: Acetylcholine; Allopurinol; Animals; Aorta, Thoracic; Blood Glucose; Cyclic Nucleotide Phosphodiesterases, Type 1; Cyclic Nucleotide Phosphodiesterases, Type 2; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Endothelium, Vascular; Female; Nitric Oxide Donors; Phenylephrine; Phosphoric Diester Hydrolases; Rats; Rats, Sprague-Dawley; S-Nitroso-N-Acetylpenicillamine; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Islet transplantation has recently emerged as an effective therapy and potential cure for type 1 diabetes mellitus. Recent reports show that the two-layer method (TLM), which employs oxygenated perfluorochemical (PFC) and University of Wisconsin (UW) solution, is superior to simple cold storage in UW for pancreas preservation in islet transplantation. Moreover, we recently reported that islet yield was significantly higher in the ET-Kyoto solution with ulinastatin (MK)/PFC preservation solution compared with the UW/PFC preservation solution in the porcine model and that the advantages of MK solution are trypsin inhibition and less collagenase inhibition. In this study, we compared ulinastatin with another trypsin inhibitor, Pefabloc, in preservation solution for islet isolation. Islet yield before purification was higher in the MK/PFC group compared with the ET-Kyoto with Pefabloc (PK)/PFC group. The stimulation index was higher for the MK/PFC group than for the PK/PFC group. These data suggest that ET-Kyoto with ulinastatin was the better combination for pancreas preservation than ET-Kyoto with Pefabloc. Based on these data, we now use ET-Kyoto solution with ulinastatin for clinical islet transplantation.

Topics: Adenosine; Allopurinol; Animals; Cell Separation; Diabetes Mellitus, Type 1; Fluorocarbons; Gluconates; Glutathione; Glycoproteins; Hydroxyethyl Starch Derivatives; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Organ Preservation; Organ Preservation Solutions; Phosphates; Raffinose; Sulfones; Swine; Trehalose; Trypsin Inhibitors

NADH dehydrogenase subunit 2, encoded by the mtDNA, has been associated with resistance to autoimmune type I diabetes (T1D) in a case control study. Recently, we confirmed a role for the mouse ortholog of the protective allele (mt-Nd2(a)) in resistance to T1D using genetic analysis of outcrosses between T1D-resistant ALR and T1D-susceptible NOD mice. We sought to determine the mechanism of disease protection by elucidating whether mt-Nd2(a) affects basal mitochondrial function or mitochondrial function in the presence of oxidative stress. Two lines of reciprocal conplastic mouse strains were generated: one with ALR nuclear DNA and NOD mtDNA (ALR.mt(NOD)) and the reciprocal with NOD nuclear DNA and ALR mtDNA (NOD.mt(ALR)). Basal mitochondrial respiration, transmembrane potential, and electron transport system enzymatic activities showed no difference among the strains. However, ALR.mt(NOD) mitochondria supported by either complex I or complex II substrates produced significantly more reactive oxygen species when compared with both parental strains, NOD.mt(ALR) or C57BL/6 controls. Nitric oxide inhibited respiration to a similar extent for mitochondria from the five strains due to competitive antagonism with molecular oxygen at complex IV. Superoxide and hydrogen peroxide generated by xanthine oxidase did not significantly decrease complex I function. The protein nitrating agents peroxynitrite or nitrogen dioxide radicals significantly decreased complex I function but with no significant difference among the five strains. In summary, mt-Nd2(a) does not confer elevated resistance to oxidative stress; however, it plays a critical role in the control of the mitochondrial reactive oxygen species production.

Topics: Alleles; Animals; Diabetes Mellitus, Type 1; Electron Transport; Electron Transport Complex I; Free Radical Scavengers; Inbreeding; Membrane Potential, Mitochondrial; Mice; Mice, Inbred NOD; Mitochondria, Liver; Mitochondrial Proteins; Nitric Oxide; Oxidative Stress; Oxygen Consumption; Protein Subunits; Reactive Oxygen Species; Species Specificity; Xanthine Oxidase

We investigated the effects of nicotinamide (NA) supplementation of the processing medium during islet isolation. One hundred and two human pancreata were processed for clinical transplantation after preservation either in the University of Wisconsin (UW) or using the two-layer method (TLM). Pancreata were then divided into four groups and retrospectively analyzed. Group I: UW preservation followed by processing without NA, Group II: UW preservation and processing with NA, Group III: TLM preservation without NA, Group IV: TLM preservation with NA. We observed a significant increase in islet yield in Group II (4343+/-348 IEQ/g) [mean+/-SEM], compared to Group I (2789+/-348 IEQ/g) (p=0.005). Similarly, a significant increase in islet yield was observed when NA was used in the processing of organs preserved with TLM (Group IV: 5538+/-413 vs. Group III: 3500+/-629; p=0.02). Furthermore islet yield was higher in Group IV than in Group II (p<0.05). The percentages of preparations that qualified for transplantation were 25, 47, 45, 69% in Groups I, II, III, IV, respectively. Addition of NA to the processing medium significantly improved islet yields in both the UW and TLM preservation protocols, allowing for a higher percentage of islet preparations to qualify for clinical transplantation.

Topics: Adenosine; Adult; Allopurinol; Cell Separation; Diabetes Mellitus, Type 1; Glutathione; Humans; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Middle Aged; Niacinamide; Organ Preservation; Organ Preservation Solutions; Pancreas; Raffinose; Retrospective Studies

The use of Celsior solution for organ preservation has not been thoroughly studied in pancreas transplantation. The aim of this study was to compare University of Wisconsin and Celsior solutions for preservation of pancreas grafts.. From March 1995 to December 2005, 72 patients with type 1 diabetes underwent pancreas transplantation. There were 42 men and 30 women, with a mean age at transplantation of 38.1 +/- 7.5 years (range: 27 to 55 years), and a mean duration of diabetes of 22.5 +/- 6.6 years. Recipients were classified into two groups according to the preservation solution: (A) Celsior (n = 28, 38.9%) and (B) Wisconsin (n = 44, 61.1%).. The donor and recipient characteristics were similar in both groups. There were five cases of venous thrombosis in the Wisconsin group and two in the Celsior group (P = NS). The venous drainage technique in the former group was portocaval in 19 patients and portoiliac in 25; in the Celsior group, portocaval in 23 patients and portoiliac in five (P = .001). Enteric drainage was used in 19 patients from the Celsior group and 17 patients from the Wisconsin group (P = .01). Actuarial 2-year graft survival was 74.6% in the Wisconsin group and 77.4% in the Celsior group (P = NS).. No differences were observed in venous thrombosis between the two groups. The lower rate of venous thrombosis with the portocaval technique was related to the type of venous drainage rather than the type of preservation solution. Celsior solution may be considered as good as Wisconsin solution for pancreas transplantation.

Topics: Adenosine; Adolescent; Adult; Allopurinol; Diabetes Mellitus, Type 1; Disaccharides; Drainage; Electrolytes; Female; Glutamates; Glutathione; Histidine; Humans; Insulin; Male; Mannitol; Middle Aged; Organ Preservation; Organ Preservation Solutions; Pancreas; Pancreas Transplantation; Portacaval Shunt, Surgical; Raffinose; Retrospective Studies; Tissue Donors

Islet transplantation, though still in the experimental phase, is a therapeutic option that has opened new expectations for the control of diabetes mellitus. Initial results are encouraging for the significant advantages compared with whole pancreas transplantation for selected patients with type 1 diabetes mellitus, with or without kidney failure. However, the success of transplantation, both at centers with more experience and others with less, is limited by the difficulty in obtaining a suitable number of donors and by laboratory isolation techniques. Significant advances require changes in donor selection, perfusion, oxygenation, and transfer of the pancreas, and in the process of isolation, purification, and culture in the laboratory. Of the 32 pancreases sent to the islet isolation laboratory from different hospitals in Andalusia, a viable percentage of islets was finally available in 19. However, in only 4 (18%) procedures were the preparations considered optimal for implantation in 2 recipients.

Topics: Adenosine; Allopurinol; Diabetes Mellitus, Type 1; Glutathione; Humans; Insulin; Islets of Langerhans Transplantation; Organ Preservation Solutions; Pancreas; Patient Selection; Raffinose; Spain; Tissue and Organ Procurement; Tissue Donors

Topics: Allopurinol; Diabetes Mellitus, Type 1; Drug Hypersensitivity; Enzyme Inhibitors; Female; Humans; Hypertension; Middle Aged; Pancreatic Diseases

A new treatment regimen was tested on patients with incurable diffuse cutaneous leshmaniasis (DCL) infected with Leishmania mexicana mexicana in Mexico. Two patients with advanced stages of the disease were treated with polychemotherapy (pentamidine and allopurinol) combined with recombinant human interferon-gamma (rIFN-gamma). For determination of the best medication, parasites isolated from patient lesions were exposed to available drugs both as promastigotes and as intracellular amastigotes. A synergistic effect was observed in vitro for the combination of pentamidine and allopurinol. Both patients were treated and recovered rapidly, but one of them developed insulin-dependent type I diabetes because of pentamidine toxicity. The complication was controlled and both patients were discharged with an apparent parasitologic cure, but after 3 months the two patients began to relapse. Our results suggest that allopurinol-pentamidine polychemotherapy, involving reduced dosage of pentamidine, combined with rIFN-gamma is an alternative for DCL patients infected with L. m. mexicana.

Topics: Adult; Allopurinol; Animals; Antiprotozoal Agents; Combined Modality Therapy; Diabetes Mellitus, Type 1; Drug Synergism; Humans; Interferon-gamma; Leishmania mexicana; Leishmaniasis, Diffuse Cutaneous; Mexico; Pentamidine; Recombinant Proteins

Alterations of vascular smooth muscle function have been implicated in the development of vascular complications and circulatory dysfunction in diabetes. However, little is known about changes in smooth muscle contractility and the intracellular mechanisms contributing to altered responsiveness of blood vessels of diabetic patients. Therefore, smooth muscle and endothelial cell function were assessed in 20 patients with diabetes and compared with 41 age-matched control subjects. In rings from uterine arteries, smooth muscle sensitivity to K+, norepinephrine (NE), and phenylephrine (PE) was enhanced by 1.4-, 2.3-, and 9.7-fold, respectively, and endothelium-dependent relaxation was reduced by 64% in diabetic patients, as compared with control subjects. In addition, in freshly isolated smooth muscle cells from diabetic patients, an increased perinuclear Ca2+ signaling to K+ (30 mmol/l >73%; 60 mmol/l >68%) and NE (300 nmol/l >86%; 10 micromol/l >67%) was found. In contrast, subplasmalemmal Ca2+ response, which favors smooth muscle relaxation caused by activation of Ca2+-activated K+ channels, was reduced by 38% in diabetic patients as compared with control subjects, indicating a significant change in the subcellular Ca2+ distribution in vascular smooth muscle cells in diabetic patients. In contrast to the altered Ca2+ signaling found in freshly isolated cells from diabetic patients, in cultured smooth muscle cells isolated from control subjects and diabetic patients, no difference in the intracellular Ca2+ signaling to stimulation with either K+ or NE was found. Furthermore, production of superoxide anion (*O2-) in intact and endothelium-denuded arteries from diabetic patients was increased by 150 and 136%, respectively. Incubation of freshly isolated smooth muscle cells from control subjects with the *O2- -generating system xanthine oxidase/hypoxanthine mimicked the effect of diabetic patients on subcellular Ca2+ distribution in a superoxide dismutase-sensitive manner. We conclude that in diabetic subjects, smooth muscle reactivity is increased because of changes in subcellular Ca2+ distribution on cell activation. Increased *O2- production may play a crucial role in the alteration of smooth muscle function.

Topics: Arteries; Calcium; Cells, Cultured; Diabetes Mellitus, Type 1; Female; Humans; Hypoxanthine; In Vitro Techniques; Muscle, Smooth, Vascular; Norepinephrine; Oxygen; Phenylephrine; Potassium Chloride; Signal Transduction; Uterus; Vasoconstriction; Vasoconstrictor Agents; Xanthine Oxidase

Topics: Adenosine; Allopurinol; Animals; Blood Glucose; Diabetes Mellitus, Type 1; Glucose; Glutathione; Insulin; Mannitol; Organ Preservation; Organ Preservation Solutions; Pancreas; Pancreas Transplantation; Pancreatectomy; Potassium Chloride; Procaine; Raffinose; Swine

Topics: Adenosine; Adult; Allopurinol; Amylases; Blood Glucose; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Duodenum; Glutathione; Histocompatibility Testing; Humans; Insulin; Kidney Failure, Chronic; Kidney Transplantation; Male; Organ Preservation; Organ Preservation Solutions; Pancreas Transplantation; Raffinose; Solutions; Spleen; Thrombosis; Tomography, X-Ray Computed; Transplantation, Homologous

Topics: Adenosine; Adult; Allopurinol; Blood Glucose; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Glutathione; Humans; Immunosuppression Therapy; Insulin; Kidney Transplantation; Middle Aged; Organ Preservation; Organ Preservation Solutions; Pancreas Transplantation; Raffinose; Solutions; Tissue Donors; Urinary Bladder

We tested the hypothesis that free radicals play a role in the selective destruction of pancreatic beta-cells in BB/Wor rats. Diabetes-prone BB rats of both sexes and 40 days of age were divided into three groups. The control group was fed ad libitum Purina rat chow powder, while the experimental group was fed ad libitum the rat chow powder blended with a mixture of four known free radical scavengers: allopurinol, mercaptopropionylglycine, dimethylthiourea and Vitamin E. A third group was pair-fed 10 g chow powder/rat/day, since in earlier experiments we observed that rats on the experimental diet consumed only about 10 g/rat/day. All rats were studied up to age 120 days. Body weight and food intake were measured daily. Urine was tested for glucose beginning at age 60 days. When glucosuria appeared, blood glucose and urinary ketones were measured. Body weight gain in the experimental and pair-fed groups was similar, but lower than the control group. Life table analysis of the data showed a decreased and a delayed onset of diabetes in the rats fed free radical scavengers. Thus, the results of this study demonstrated that calorie restriction and the related impaired growth did not affect the incidence of diabetes in the BB rat. In addition, the results suggested a role for free radicals in the spontaneous destruction of pancreatic beta-cells in the BB rat.

Topics: Allopurinol; Animals; Body Weight; Diabetes Mellitus, Type 1; Diet; Female; Free Radical Scavengers; Male; Rats; Rats, Inbred BB; Thiourea; Tiopronin; Vitamin E; Weight Gain

Topics: Adenosine; Allopurinol; Cell Separation; Colony Count, Microbial; Diabetes Mellitus, Type 1; Drug Contamination; Glutathione; Humans; Insulin; Islets of Langerhans Transplantation; Organ Preservation Solutions; Pancreatic Neoplasms; Postoperative Complications; Pseudomonas; Raffinose; Solutions; Staphylococcus

Topics: Adenosine; Adult; Allopurinol; Cold Temperature; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glutathione; Humans; Insulin; Kidney Transplantation; Male; Organ Preservation; Organ Preservation Solutions; Pancreas Transplantation; Raffinose; Retrospective Studies; Solutions; Transplantation, Homologous