2020 American College of Rheumatology Guideline for the Management of Gout.

OBJECTIVE: To provide guidance for the management of gout, including indications for and optimal use of urate-lowering therapy (ULT), treatment of gout flares, and lifestyle and other medication recommendations. METHODS: Fifty-seven population, intervention, comparator, and outcomes questions were developed, followed by a systematic literature review, including network meta-analyses with ratings of the available evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and patient input. A group consensus process was used to compose the final recommendations and grade their strength as strong or conditional. RESULTS: Forty-two recommendations (including 16 strong recommendations) were generated. Strong recommendations included initiation of ULT for all patients with tophaceous gout, radiographic damage due to gout, or frequent gout flares; allopurinol as the preferred first-line ULT, including for those with moderate-to-severe chronic kidney disease (CKD; stage >3); using a low starting dose of allopurinol (≤100 mg/day, and lower in CKD) or febuxostat (<40 mg/day); and a treat-to-target management strategy with ULT dose titration guided by serial serum urate (SU) measurements, with an SU target of <6 mg/dl. When initiating ULT, concomitant antiinflammatory prophylaxis therapy for a duration of at least 3-6 months was strongly recommended. For management of gout flares, colchicine, nonsteroidal antiinflammatory drugs, or glucocorticoids (oral, intraarticular, or intramuscular) were strongly recommended. CONCLUSION: Using GRADE methodology and informed by a consensus process based on evidence from the current literature and patient preferences, this guideline provides direction for clinicians and patients making decisions on the management of gout.

UHPLC-fluorescence method for the determination of trace levels of hydrazine in allopurinol and its formulations: Validation using total-error concept.

The present approach poses an interesting way to quantify residues of the genotoxic impurity hydrazine in allopurinol and its pharmaceutical formulations using ultra high performance liquid chromatography coupled to fluorescence detection. Hydrazine was pre-column derivatized through a unique chemistry with o-phthalaldehyde under acidic conditions. Using highly acidic mobile phase the derivative exhibits a strong fluorescence intensity. Derivatization and chromatographic parameters were thoroughly investigated. The validation of the developed method has been carried out in the range of 10 to 200% of the target concentration limit of the analyte using the accuracy profiles as a graphical decision-making tool. The ß-expectation tolerance intervals did not exceed the acceptance criteria of ±20% which means that 95% of future results will be included in the defined bias limits. The variation of the relative bias ranged between -6.0 and 0.5% and the RSD values for repeatability and intermediate precision were lower than 6.9% in all cases. The limit of detection (LOD) and the lower limit of quantification (LLOQ) were satisfactory and found to be 0.3 ng mL-1 (corresponding to 0.03 µg g-1 in solid sample). Experimental designs were constructed to study the robustness of the instrumental method and the derivatization procedure. The developed method has been successfully applied for the analysis of hydrazine in allopurinol API batches and tablets indicating that this methodology could be adopted from QC laboratories.

Effects of allopurinol and febuxostat on cardiovascular mortality in elderly heart failure patients.

Hyperuricemia is an emerging risk factor for the development of heart failure (HF) and is associated with a worsen prognosis of the disease. The effect of urate lowering drugs (ULT) and, in particular, the xanthine oxidase inhibitor in patients with HF is controversial. The aim of the study is to compare the effects of treatment with two different xanthine oxidase inhibitors (allopurinol or febuxostat) on cardiovascular mortality in elderly patients with chronic HF in a setting of clinical practice. In this observational trial, 255 elderly patients affected by chronic HF and treated with ULT on top of optimal medical treatment for HF. The sample included only outpatients with mild-to-moderate HF mainly secondary to chronic arterial hypertension or coronary artery disease and not previously hospitalized for HF. Patient treated with febuxostat (N. 120) and allopurinol (N. 135) were balanced for most of the baseline variables. In particular age, NYHA class distribution, drug treatment and renal function were comparable at the baseline and during the observation in both groups (p > 0.05). After a mean follow-up period of 5.1 years, the cumulative cardiovascular survival was 0.96 (95% CI 0.93-0.99) in febuxostat-treated patients and 0.89 (95% CI 0.84-0.93) in those treated with allopurinol. The between group difference, adjusted for the main confounding risk factors, was statistically significant (p = 0.04). Our study results suggest that possibility that febuxostat, a selective XO inhibitor, may favorably affect cardiovascular mortality in comparison with allopurinol in elderly patients with mild-to-moderate HF. This preliminary observation deserves further evaluation in the next future.

UW is superior to Celsior and HTK in the protection of human liver endothelial cells against preservation injury.

Celsior solution (CS), a new preservation solution in thoracic organ transplantation, was evaluated for its efficacy in cold preservation of human liver endothelial cells (HLEC) and was compared to University of Wisconsin solution (UW) and histidine-tryptophan-ketoglutarate solution (HTK, Custodiol). HLEC cultures were preserved at 4 degrees C in CS, UW, and HTK, for 2, 6, 12, 24, and 48 hours, with 6 hours of reperfusion. Levels of lactate dehydrogenase (LDH), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and adenosine 5'-triphosphate (ATP) were measured after each interval of ischemia and the respective phase of reperfusion. Preservation injury of HLEC as measured by LDH release, intracellular ATP level, and MTT reduction were overall significantly (P > CS > HTK.

Preservation of rat livers by cold storage: a comparison between the University of Wisconsin solution and Hypothermosol.

OBJECTIVES: The University of Wisconsin solution (UW) is the gold standard for cold storage (CS) of donor livers. However, UW contains the colloid Hydroxyethyl starch (HES), which may cause perfusion deficits due to its high viscosity. Recently, a new CS preservation solution, Hypothermosol (HTS), was introduced which contains the less viscous colloid Dextran. The aim of this study was to assess HTS as a cold storage solution for preservation of the liver. METHODS: In an isolated perfused rat liver model, hepatocellular damage was assessed after 24 hours of CS. Liver enzymes were measured during reperfusion with Krebs-Henseleit Buffer. Bile was collected during reperfusion as a parameter of liver function. RESULTS: CS using HTS showed a significant decrease of ALT and LDH levels (as compared to UW) at all time points during reperfusion. For LDH these results where most pronounced at t=10 min (84 +/- 7.09 vs 113 +/- 7.57: p < 0.05) and t=30 min (149.2 +/- 9.68 vs 194 +/-6.52: p< 0.05). Regarding liver function, more bile was produced after 24 hours CS in HTS, but this did not reach statistical significancy. CONCLUSIONS: Cold storage preservation of rat livers using Hypothermosol results in equal or even better preservation as compared to cold storage using UW.

Comparison of Celsior and UW solution in experimental pancreas preservation.

BACKGROUND: The University of Wisconsin solution (UW) is the gold standard for pancreas preservation. Celsior (CEL) was formulated specifically for heart preservation. Recently, experimental and clinical experience has been reported on the application of CEL to abdominal organs. In this animal study, pancreas preservation with CEL was compared with that in UW solution. PATIENTS AND MATERIALS: Heterotopic, allogeneic pancreaticoduodenal transplantation was performed in female Göttingen Minipigs (n = 12 donors, n = 12 recipients). The grafts were flushed and stored for 6 h at 4 degrees C in UW or CEL. The recipients were randomized into two groups receiving either UW (n = 6)- or CEL (n = 6)-preserved grafts with a follow-up of 5 days. Blood flow (laser Doppler), partial oxygen tension, histological changes, endothelin-1 (plasma, immunohistochemistry), lipase, amylase, trypsinogen activation peptide, and C-reactive protein (CRP) were measured. RESULTS: Partial oxygen tension was lower in the CEL group (P < 0.05). However, blood flow did not differ between UW- and CEL-preserved organs. The histomorphologic analysis of the pancreatic grafts revealed significantly less edema in the UW-preserved organs. Serum levels of amylase, lipase, CRP, and TAP taken from the central venous blood were comparable in the two groups, except for higher amylase values 36 h after reperfusion in the CEL group compared to the UW group (P < 0.05). Likewise, TAP taken from the portal venous effluent of the graft was found to be higher in the CEL group than in UW (P < 0.05). Endothelin-1 serum levels rose significantly during reperfusion without differences between the two groups. ET-1 immunohistochemistry revealed increased local ET-1 during reperfusion in all grafts. However, the ET-1 immunostaining in the CEL group was more pronounced than that in the UW group (P < 0.05). CONCLUSIONS: Our results suggest that CEL solution is not as effective in preventing pancreatic ischemia/reperfusion damage as the standard UW solution in experimental pancreas transplantation. Increased ET-1 immunostaining and reduced p(ti)O(2) in the CEL group indicate increased microcirculatory damage in the CEL group.

Tumor lysis syndrome.

Tumor lysis syndrome (TLS) is a constellation of metabolic disturbances observed in tumors with high cell turnover. It is associated with significant morbidity and mortality. TLS is characterized by the increased release of intracellular contents (uric acid, potassium, phosphorus) into the extracellular compartment, which can overwhelm the body's capacity for clearance. TLS is usually caused by response to chemotherapy; however, it may also occur spontaneously. Because uric acid, potassium, and phosphorus are excreted primarily by the kidneys, TLS can lead to hyperuricemia, hyperkalemia, and hyperphosphatemia with accompanying renal compromise. The pathophysiology of TLS-associated acute renal failure is probably multifactorial. Potential etiologies include intravascular volume depletion, urinary precipitation of nucleic acid metabolites and calcium phosphate, and malignancy-associated nephrotoxins. Despite prophylactic therapy with allopurinol and volume repletion, patients may still develop TLS with acute renal failure. While reducing the risk of uric acid precipitation, allopurinol and alkalinization increase the risk of xanthine and calcium phosphate crystals, respectively. Aggressive hydration might lead to volume overload, specifically in older patients. Novel approaches in the management of TLS include the use of urate oxidase, which can provide effective treatment with an acceptable safety profile.

Improved preservation solutions for organ storage: a dynamic study of hepatic metabolism.

BACKGROUND: Organ cold storage times may be extended by modifications to organ preservation solutions. METHODS: Three preservation solutions were investigated for their ability to maintain viable hepatic bioenergetics in stored pig livers: modified University of Wisconsin (mUW); mUW+adenosine (1.34 g/L), and mUW+ iloprost (10(-8)mol/L), a prostacyclin analogue. Using human liver retrieval and storage techniques, pig livers were stored on ice for either 2 or 16 hr, after which phosphorus-31 spectra were collected every 2 min during the period of cold ischemia and hypothermic reperfusion (HtR). During HtR, metabolite concentration changes associated with phosphomonoesters, inorganic phosphate, gamma-nucleotide triphosphate (NTP), and beta-NTP were measured for all solutions. RESULTS: After a 2-hr storage, beta-NTP regeneration in mUW+iloprost produced +57.7% (P<0.01) more beta-NTP, at a faster initial rate of +66.3% (P<0.001), compared with mUW, and mUW+adenosine regenerated +35.6% (P<0.05) more beta-NTP, compared with mUW. Storage for 16 hr did not slow the rates of regeneration, and the total NTP produced during the course of the experiment remained unchanged for the respective preservation solutions. Cessation of HtR invoked a net accumulation of nucleotide diphosphate, indicating differential kinetics of adenine nucleotide hydrolysis. CONCLUSION: This large animal model study suggests significant improvements to human organ preservation solutions using prostacyclin analogues and adenosine with respect to hepatic bioenergetics.

Evaluation of preservation conditions and various solutions for small bowel preservation.

The aim of the study was to delineate the most optimal preservation conditions for small bowel grafts. Established preservation solutions such as EuroCollins, University of Wisconsin, histidine-tryptophane-ketoglutarate-Brettschneider, phosphate-buffered sucrose (PBS 140), and 3 new solutions--extracellular fluid (ECF), lactobionate fructose, and a modified lactobionate fructose solution--were compared with saline to determine the most optimal solution for the intestine. Recipient survival, standard histology, and glutaminase activity were used to assess the degree of injury encountered after 12 hr of preservation followed by transplantation. To evaluate the various preservation conditions, ECF was used at pH 6.8 (original ECF). Grafts were preserved most optimally when a vascular washout after the cold storage period was omitted and when topical rewarming of the graft with 37 degrees C saline before reperfusion was performed. Graft survival was not significantly different after preservation with any solution tested (50-83%). Highest graft survival (83%) was achieved with lactobionate fructose and PBS140. Histologic evaluation 20 min after reperfusion revealed minor differences between most groups; a slight advantage was observed for PBS140-preserved grafts. Mucosal glutaminase activity of PBS140-preserved grafts was significantly higher 20 min after reperfusion compared with any other solution evaluated, indicating a superior graft function. These data indicate that different preservation conditions have a great impact on postoperative graft survival and that PBS140 might be preferable to any of the other preservation solutions tested.