Interaction-based screening, Monte Carlo Bayesian inference-based de novo design and in vitro verification of adenine-binding peptide.

One of the main reasons for hyperuricemia is high purine intake. The primary strategy for treating hyperuricemia is blocking the purine metabolism enzyme. However, by binding the purine bases directly, we suggested a unique therapeutic strategy that might interfere with purine metabolism. There have been numerous reports of extensive interactions between proteins and purine bases. Adenine, constituting numerous protein co-factors, can interact with the adenine-binding motif. Using Bayesian Inference and Markov chain Monte Carlo sampling, we created a novel adenine-binding peptide Ile-Tyr-Val-Thr based on the structure of the adenine-binding motifs. Ile-Tyr-Val-Thr generates a semi-pocket that can clip the adenine within, as demonstrated by docking. Then, using thermodynamic techniques, the interaction between Ile-Tyr-Val-Thr and adenine was confirmed. The KD value is 1.50e-5 (ΔH = -20.2 kJ/mol and ΔG = -27.6 kJ/mol), indicating the high affinity. In brief, the adenine-binding peptide Ile-Tyr-Val-Thr may help lower uric acid level by blocking the absorption of food-derived adenine.

Soluble urate-induced effects on cytokine production in vitro - Assessment of methodologies and cell types.

BACKGROUND: Hyperuricemia has been shown to be an inducer of pro-inflammatory mediators by human primary monocytes. To study the deleterious effects of hyperuricemia, a reliable and stable in vitro model using soluble urate is needed. One recent report showed different urate-dissolving methods resulted in either pro-inflammatory or anti-inflammatory properties. The aim of this study was to compare the effect of two methods of dissolving urate on both primary human peripheral blood mononuclear cells (PBMCs) and THP-1 cells. The two methods tested were 'pre-warming' and 'dissolving with NaOH'. METHODS: Primary human PBMCs and THP-1 cells were exposed to urate solutions, prepared using the two methodologies: pre-warming and dissolving with NaOH. Afterwards, cells were stimulated with various stimuli, followed by the measurement of the inflammatory mediators IL-1ß, IL-6, IL-1Ra, TNF, IL-8, and MCP-1. RESULTS: In PBMCs, we observed an overall pro-inflammatory effect of urate, both in the pre-warming and the NaOH dissolving method. A similar pro-inflammatory effect was seen in THP-1 cells for both dissolving methods after restimulation. However, THP-1 cells exhibited pro-inflammatory profile with exposure to urate alone without restimulation. We did not find MSU crystals in our cellular assays. CONCLUSIONS: Overall, the urate dissolving methods do not have critical impact on its inflammatory properties. Soluble urate prepared using either of the two methods showed mostly pro-inflammatory effects on human primary PBMCs and monocytic cell line THP-1. However, human primary PBMCs and the THP-1 differ in their response to soluble urate without restimulation.

Assessment of the toxic effects of levetiracetam on biochemical, functional, and redox parameters of salivary glands in male Wistar rats.

Levetiracetam (LEV) is an anticonvulsant for epilepsy. The toxic effects of this medication in tissues have been associated with redox state imbalance, which can lead to salivary gland dysfunction. Therefore, the current work investigated the effects of LEV on the biochemical, functional, and redox parameters of the parotid and submandibular glands in rats. For this, male Wistar rats (Rattus norvegicus albinus) were randomly divided into 3 groups (n = 10/group): Control (0.9% saline solution), LEV100 (100 mg/kg), and LEV300 (300 mg/kg). After 21 consecutive days of intragastric gavage treatments, pilocarpine stimulated saliva secretion was collected for salivary biochemical analysis. The extracted salivary glands were utilized for histomorphometry and redox state analyses. Our results showed that LEV300 increased plasma hepatotoxicity markers and reduced salivary amylase activity and the acinar surface area of the parotid gland. Total oxidant capacity and oxidative damage to lipids and proteins were higher in the parotid gland, while total antioxidant capacity and uric acid levels were reduced in the submandibular gland of the LEV100 group compared to Control. On the other hand, total oxidant capacity, oxidative damage to lipids and proteins, total antioxidant capacity, and uric acid levels were lower in both salivary glands of the LEV300 group compared to Control. Superoxide dismutase and glutathione peroxidase activities were lower in the salivary glands of treated animals compared to Control. In conclusion our data suggest that treatment with LEV represents a potentially toxic agent, that contributes to drug-induced salivary gland dysfunction.

Assessment of the influence on left ventricle by potassium oxonate and hypoxanthine-induced chronic hyperuricemia.

Cellular cytoplasmic xanthine oxidase (XO)-mediated uric acid synthesis and extracellular excess uric acid exposure are both causes of cardiomyocytic injury under the condition of hyperuricemia (HUA). Potassium oxonate suppresses uric acid degradation to increase extracellular concentration, while hypoxanthine is the catalytic substrate of XO. We aimed to observe cardiac damage in a chronic HUA mouse model induced by potassium oxonate and hypoxanthine. The mouse model was established by the co-administration of potassium oxonate and hypoxanthine for eight weeks. Then, left ventricular parameters were examined by echocardiographic evaluation, and the heart tissues were harvested for further histopathological analysis. The results showed that plasma uric acid was persistently elevated in the model mice, which demonstrated the stable establishment of chronic HUA. The left ventricular anterior wall was significantly thickened in the model group compared with the blank control group. After the end of modeling, the left ventricular anterior wall thickness of the hyperuricemic mice increased compared with that of blank group. The histological analysis showed and myocardial structure disorganization in the model group compared with the blank control. The above cardiac impairment changes could be attenuated by allopurinol pretreatment. This study systematically assessed cardiac damage in a chronic HUA mouse model. In addition, it provides useful information for future HUA-associated heart injury mechanism investigation and therapeutic treatment evaluation.

Assessment of redox state and biochemical parameters of salivary glands in streptozotocin-induced diabetic male rats treated with mate tea (Ilex paraguariensis).

OBJECTIVE: The study aimed to assess the effects of mate tea [Ilex paraguariensis] on the redox state and biochemical parameters of salivary glands in diabetic male rats. DESIGN: Twenty-four male Wistar rats (3 months old) were randomly divided into groups (n = 8 per group): control rats that received water (C); diabetic rats that received water (D); diabetic rats treated with mate tea (DMT). The treated streptozotocin-induced diabetic rats were given mate tea powder by intragastric gavage at a dose of 20 mg/kg daily for 28 days. Content of total protein, amylase, oxidative lipid damage, measured as thiobarbituric acid reactive substances (TBARs), oxidative protein damage, measured as protein carbonyl, total antioxidant capacity, uric acid, reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were examined by the spectrophotometric method in the parotid and submandibular glands. RESULTS: The D group showed lower total protein, amylase, TBARs, protein carbonyl, total antioxidant capacity, GSH, uric acid, and GPx than the C group in both salivary glands, as well as higher SOD and CAT activities. The DMT group showed higher total protein, amylase, total antioxidant capacity, GSH, uric acid, and GPx than the D group in both salivary glands. Moreover, mate tea increased SOD in the parotid gland and CAT in the submandibular gland of diabetic rats but did not influence TBARs and protein carbonyl in either salivary gland compared to D group. CONCLUSION: Mate tea increased tissue protein synthesis and improved antioxidant defenses in the salivary glands of streptozotocin-induced diabetic male rats.

Assessment of the efficacy of hemodialysis on uric acid clearance in a sub-Saharan African population at the end stage kidney disease.

BACKGROUND: Uricemia dramatically rises with the stage of chronic kidney disease (CKD) and correlates with its mortality. Hemodialysis (HD) being the most used treatment at the end stage in sub-Saharan Africa, we sought to evaluate its efficacy on the clearance of uric acid (UAc) when used alone and twice per week. METHODS: A cross-sectional study of all consenting patients with CKD stage 5 recruited at random during HD sessions in a reference Centre in Cameroon from January to April 2017. We collected socio-demographic data, relevant clinical information, HD related variables, and measured serum uric acid (SUA) levels before and after the dialysis to assess the uric acid clearance. A clearance between 65 and 80% and above 80% was considered as low and good efficacy of HD respectively. Statistical analysis was performed using SPSS version 21.0. Factors associated with HD efficacy were assessed using Fisher's exact test and are presented with their odds ratios (OR) and 95% confidence levels. RESULTS: One hundred four patients (53 females) were included. The mean age was 49.9 ± 13.3 years. Hypertension (25%) and chronic glomerulonephritis (16%) were the main suspected etiologies of CKD. The median time on renal replacement therapy by HD was 3 years [1; 6]. The prevalence of hyperuricemia was 81.9%. The means of SUA levels were 78.8 ± 13.8 mg/L and 26.4 ± 6.6 mg/L respectively before and after dialysis. Mean SUA clearance was 66% ± 10%. The efficacy of HD on UAc was moderate in 92 (63.9%) and good in 2 (1.4%) patients. Excess weight (OR 0.4 [0.2; 0.9]) and Kt/Vurea < 1.2 (OR 0.1 [0.04; 0.2]) significantly reduces the efficacy of HD. CONCLUSION: HD used alone for 2 sessions per week has a moderate efficacy on uric acid clearance in CKD. Therefore, we should improve the Kt/V (> 1.2), and combine HD to uric acid lowering drugs and diet modifications to increase its efficacy.

Understanding and perceptions of gout: an interdisciplinary assessment among patients, physicians and pharmacists in Italy.

The objective was to assess knowledge and therapeutic approaches to the management of gout among healthcare professionals and people with/without gout, in Italy. This was a cross-sectional internet-based survey targeting general practitioners (GPs), specialists, pharmacists, and people with/without gout. Between December 2017 and March 2018, participants completed questionnaires on epidemiology, cause/risk factors, therapy objectives and management/treatment strategies to improve outcomes. Overall, 3184 people completed the survey: 699 GPs, 426 specialists, 655 pharmacists and 1404 subjects from the general population: 126 (9.0%) with and 1278 (91.0%) without gout. Notably, less than half of GPs, specialists and people without gout confirmed the published 1% prevalence of gout in Italy. Lifestyle was acknowledged as the main risk factor for gout by nearly 50% of specialists and GPs, while only 13.8% and 12.4%, respectively, considered the role of genetic factors. Uric acid overproduction was deemed as the cause of gout by 60% of GPs and specialists, whereas insufficient excretion by only 30%. Fewer than half of patients were aware that gout permanently damages joints, and even fewer of the renal and cardiovascular implications (19.4% and 12%, respectively); moreover, most people without gout replied that their doctor had never talked with them about uric acid and its correlation with gout development. Finally, GPs were divided on uric acid target levels (48.3% said <6 mg/dL and 18.9% <7 mg/dL). Despite major advances in the knowledge of physiopathological mechanisms of gout, the results of our survey highlight the many treatment and knowledge gaps in its management. Cooperation between multidisciplinary teams is required to break down barriers and ensure optimal treatment with effective and innovative agents of this ever-increasing debilitating condition.

Reactivity of salivary uric acid in response to social evaluative stress in African Americans.

High uric acid (UA) is associated with hypertension and cardiovascular disease (CVD), both of which occur disproportionately among African Americans. High UA also predicts greater blood pressure reactivity responses to acute social stress. However, whether UA itself shows reactivity in response to stress is unknown. We evaluated salivary uric acid (sUA) and blood pressure reactivity in response to acute social stress. Healthy African Americans (N = 103; 32 % male; M age = 31.36 years), completed the Trier Social Stress Test. sUA and blood pressure measurements were taken before, during and after the stressor task. sUA showed significant reactivity and recovery, especially among older African Americans. Total sUA activation was also associated with systolic and diastolic blood pressure total activation. Findings illuminate that acute stress may be a way in which UA is implicated in hypertension and CVD, suggesting a critical need to explore UA reactivity as a novel parameter of the acute stress response.

The value of fixed rasburicase dosing versus weight-based dosing in the treatment and prevention of tumor lysis syndrome.

BACKGROUND: Rasburicase is a recombinant urate oxidase enzyme used for the treatment and prevention of tumor lysis syndrome. Our objective was to assess the efficacy of indication-based, low-dose rasburicase administration compared to the Food and Drug Administration-approved weight-based dosing. METHODS: This was a retrospective cohort study utilizing data from a tertiary medical center including patients admitted from 2012 to 2016, who received at least one dose of rasburicase. The primary outcome was achieving a uric acid level less than 7.5 mg/dl after a single dose of rasburicase in the preprotocol (Food and Drug Administration-approved weight-based dosing) and postprotocol (indication-based, low-dose) groups. Secondary outcomes included the change in uric acid levels between the pre- and postprotocol groups, adherence to the new institutional protocol, need for repeat rasburicase doses, and a cost analysis. RESULTS: Sixty-four patients received at least one dose of rasburicase between 1 January 2012 and 1 December 2016. Twenty-seven (79.4%) doses in the preprotocol group and 28 (82.4%) doses in the postprotocol group successfully achieved a uric acid level less than 7.5 mg/dl after a single dose of rasburicase (p=1.000). The average total monthly cost of rasburicase was reduced by 59.9% after adoption of the new protocol. CONCLUSIONS: Indication-based, low-dose rasburicase displayed significantly more value when compared to weight-based dosing as shown by achieving cost savings without compromising clinical efficacy.

Monosodium urate burden assessed with dual-energy computed tomography predicts the risk of flares in gout: a 12-month observational study : MSU burden and risk of gout flare.

BACKGROUND: Predicting the risk of flares in patients with gout is a challenge and the link between urate burden and the risk of gout flare is unclear. The objective of this study was to determine if the extent of monosodium urate (MSU) burden measured with dual-energy computed tomography (DECT) and ultrasonography (US) is predictive of the risk of gout flares. METHODS: This prospective observational study recruited patients with gout to undergo MSU burden assessment with DECT (volume of deposits) and US (double contour sign) scans of the knees and feet. Patients attended follow-up visits at 3, 6 and 12 months. Patients having presented with at least one flare at 6 months were compared to those who did not flare. Odds ratios (ORs) (95% confidence interval) for the risk of flare were calculated. RESULTS: Overall, 64/78 patients included attended at least one follow-up visit. In bivariate analysis, the number of joints with the double contour sign was not associated with the risk of flare (p = 0.67). Multivariate analysis retained a unique variable: DECT MSU volume of the feet. For each 1 cm3 increase in DECT MSU volume in foot deposits, the risk of flare increased 2.03-fold during the first 6 months after initial assessment (OR 2.03 (1.15-4.38)). The threshold volume best discriminating patients with and without flare was 0.81 cm3 (specificity 61%, sensitivity 77%). CONCLUSIONS: This is the first study showing that the extent of MSU burden measured with DECT but not US is predictive of the risk of flares.

Assessment of Uric Acid Level in the Saliva of Patients with Oral Lichen Planus.

OBJECTIVE: The aim of this study was to evaluate the level of uric acid (UA) in saliva, which is considered to be an antioxidant defense biomarker against oxidative stress in patients with oral lichen planus (OLP). SUBJECTS AND METHODS: In this case-control study, 25 OLP patients were included. The reticular form of OLP was verified by a clinical examination with Wickham striae, and other types (erosive, atrophic, ulcerative) were confirmed by histopathological assessment. Thirty healthy individuals matched for age and gender were selected as the control group. In both groups, the Navazesh technique was used to collect the unstimulated saliva. Then, the amount of UA was measured using a Cobas Mira autoanalyzer with a wavelength of 546 nm. The Student t test was used to analyze the data assuming a significance level at <0.05. RESULTS: Of the 25 patients, the most common type of OLP was erosive (n = 11, 44%), and the most common site of OLP was seen as bilateral in the buccal mucosa (n = 12, 48%). The mean level of salivary UA was significantly lower in the patients with OLP (2.10 ± 0.19 mg/dL) in comparison with the control group (4.80 ± 0.29 mg/dL; p < 0.001). CONCLUSION: In this study, OLP was associated with a decrease in UA levels in the saliva. Salivary UA as a biomarker could be used for monitoring and treating OLP.

A Clinical and Economic Comparison of Rasburicase and Allopurinol in the Treatment of Patients With Clinical or Laboratory Tumor Lysis Syndrome.

BACKGROUND: The aim of the study was to compare reductions in uric acid (UA), length of stay (LOS), and hospitalization costs in patients with tumor lysis syndrome (TLS) treated with rasburicase or allopurinol. PATIENTS AND METHODS: This retrospective study of administrative data included hospitalized pediatric and adult patients who had clinical or laboratory TLS and received rasburicase or allopurinol. Each rasburicase-treated patient was propensity score-matched with 4 allopurinol-treated patients. Mean changes in UA within ≤ 2 days of treatment initiation were determined. Economic outcomes included mean number of days in the intensive care unit (ICU), total LOS, costs/hospitalization, and costs/percentage change in UA. RESULTS: Twenty-six rasburicase-treated patients were matched with 104 allopurinol-treated patients. Reduction in plasma UA was 5.3 mg/dL greater for patients treated with rasburicase than for patients treated with allopurinol (P < .0001). Length of ICU stay was 2.5 days less for patients treated with rasburicase than for patients treated with allopurinol (P < .0001), and total LOS was 5 days less for patients treated with rasburicase than for patients treated with allopurinol (P = .02). Total costs per patient were $20,038 lower for patients treated with rasburicase than for patients treated with allopurinol (P < .02). Cost per percentage UA reduction was also lower for patients treated with rasburicase versus patients treated with allopurinol ($3899 vs. $16,894; P < .001). CONCLUSION: In this analysis of TLS patients who received care in real-world settings, rasburicase versus allopurinol was significantly more effective in treating hyperuricemia and was associated with significantly shorter ICU and overall hospital stays and lower total inpatient costs.

Cost Comparison of Urate-Lowering Therapies in Patients with Gout and Moderate-to-Severe Chronic Kidney Disease.

BACKGROUND: Patients with chronic kidney disease (CKD) are at increased risk for developing gout and having refractory disease. Gout flare prevention relies heavily on urate-lowering therapies such as allopurinol and febuxostat, but clinical decision making in patients with moderate-to-severe CKD is complicated by significant comorbidity and the scarcity of real-world cost-effectiveness studies. OBJECTIVE: To compare total and disease-specific health care expenditures by line of therapy in allopurinol and febuxostat initiators after diagnosis with gout and moderate-to-severe CKD. METHODS: A retrospective observational cohort study was conducted to compare mean monthly health care cost (in 2012 U.S. dollars) among gout patients with CKD (stage 3 or 4) who initiated allopurinol or febuxostat. The primary outcome was total mean monthly health care expenditures, and the secondary outcome was disease-specific (gout, diabetes, renal, and cardiovascular disease [CVD]) expenditures. Gout patients (ICD-9-CM 274.xx) aged ≥ 18 years with concurrent CKD (stage 3 or 4) were selected from the MarketScan databases (January 2009-June 2012) upon allopurinol or febuxostat initiation. Patients were followed until disenrollment, discontinuation of the qualifying study agent, or use of the alternate study agent. Patients initiating allopurinol were subsequently propensity score-matched (1:1) to patients initiating febuxostat. Five generalized linear models (GLMs) were developed, each controlling for propensity score, to identify the incremental costs (vs. allopurinol) associated with febuxostat initiation in first-line (without prior allopurinol exposure) and second-line (with prior allopurinol exposure) settings. RESULTS: Propensity score matching yielded 2 cohorts, each with 1,486 patients (64.6% male, mean [SD] age 67.4 [12.8] years). Post-match, 74.6% of patients had stage 3 CKD; 82.9% had CVD; and 42.1% had diabetes. The post-match sample was well balanced on numerous comorbidities and medication exposures with the following exception: 50.0% of febuxostat initiators were treated in the second-line setting; that is, they had baseline exposure to allopurinol, whereas only 4.2% of allopurinol initiators had baseline exposure to febuxostat. Unadjusted mean monthly cost was $1,490 allopurinol and $1,525 febuxostat (P = 0.809). GLM results suggest that first-line febuxostat users incurred significantly (P = 0.009) lower cost than allopurinol users ($1,299 vs. $1,487), whereas second-line febuxostat initiators incurred significantly (P = 0.001) higher cost ($1,751 vs. $1,487). Febuxostat initiators in both settings had significantly (P < 0.001) higher gout-specific cost, due to higher febuxostat acquisition cost. Increased gout-specific cost in the first-line febuxostat cohort was offset by significantly (P < 0.001) lower CVD ($288 vs. $459) and renal-related cost ($86 vs. $216). There were no significant differences in either renal or CVD costs (adjusted) between allopurinol initiators treated almost exclusively in the first-line setting and second-line febuxostat patients. CONCLUSIONS: Gout patients with concurrent CKD, initiating treatment with febuxostat in a first-line setting, incurred significantly less total cost than patients initiating allopurinol during the first exposure to each agent. Conversely, patients treated with second-line febuxostat following allopurinol incurred significantly higher total cost than patients initiating allopurinol. There was no significant difference in total cost between the agents across line of therapy. Although study findings suggest the potential for CVD and renal-related savings to offset febuxostat's higher acquisition cost in gout patients with moderate-to-severe CKD, this is the first such retrospective evaluation. Future research is warranted to both demonstrate the durability of study findings and to better elucidate the mechanism by which associated cost offsets occur. DISCLOSURES: No outside funding supported this study. Turpin is an employee of Takeda Pharmaceuticals U.S.A. Mitri and Wittbrodt were employees of Takeda Pharmaceuticals U.S.A. at the time of this study. Tidwell and Schulman are employees of Outcomes Research Solutions, consultants to Takeda Pharmaceuticals U.S.A. All authors contributed to the design of the study and to the writing and review of the manuscript. All authors read and approved the final manuscript. Tidwell and Schulman collected the data, and all authors participated in data interpretation.

A cross-sectional internet-based patient survey of the management strategies for gout.

BACKGROUND: Almost half of the patients with gout are not prescribed urate-lowering therapy (ULT) by their health care provider and >50 % use complementary and alternative therapies. Diet modification is popular among gout patients due to known associations of certain foods with gout flares. The interplay of the use of dietary supplements, diet modification, and ULT adherence in gout patients is not known. Despite the recent interest in diet and supplements, there are limited data on their use. Our objective was to assess ULT use and adherence and patient preference for non-pharmacological interventions by patients with gout, using a cross-sectional survey. METHODS: People who self-reported physician-diagnosed gout during their visit to a gout website ( http://gouteducation.org ) were invited to participate in a brief anonymous cross-sectional Internet survey between 08/11/2014 to 04/14/2015 about the management of their gout. The survey queried ULT prescription, ULT adherence, the use of non-pharmacological interventions (cherry extract, diet modification) and the likelihood of making a lifelong diet modification for gout management. RESULTS: A total of 499 respondents with a mean age 56.3 years were included; 74% were males and 74% were White. Of these, 57% (285/499) participants were prescribed a ULT for gout, of whom 88% (251/285) were currently taking ULT. Of those using ULT, 78% (97/251) reported ULT adherence >80%. Gender, race, and age were not significantly associated with the likelihood of receiving a ULT prescription or ULT adherence >80%. Fifty-six percent of patients with gout preferred ULT as a lifelong treatment for gout, 24% preferred cherry extract and 16% preferred diet modification (4% preferred none). Men had significantly lower odds of preferring ULT as the lifelong treatment choice for gout vs. other choices (p = 0.03). We found that 38.3% participants were highly motivated to make a lifelong dietary modification to improve their gout (score of 9-10 on a 0-10 likelihood scale). Older age was significantly associated with high level of willingness to modify diet (p = 0.02). CONCLUSION: We found that only 57% of gout patients reported being prescribed ULT. 40% of gout patients preferred non- pharmacological interventions such as cherry extract and diet modification for gout management. The latter finding requires further investigation.

An update on metabolic assessment in patients with urinary lithiasis.

PURPOSE: The objective of this study was to evaluate the prevalence of urinary metabolic abnormalities in patients with urolithiasis and their potential risk factors. METHODS: A total of 905 stone patients were evaluated in a prospective trial from February 2000 to January 2012. Inclusion criteria were as follows: history and/or imaging tests confirming at least 2 separate or concurrent stone episodes; creatinine clearance ≥ 60 mL/min; and negative proteinuria and urine culture. Metabolic study consisted of two 24-h urine collections separated by a period of 3 months for dosing Ca, P, uric acid, Na, K, Mg, oxalate, and citrate. Serum levels of Ca, P, uric acid, Na, K, Cl, Mg, creatinine, and glucose were assessed. Urinary pH and urinary acidification tests were also performed. RESULTS: A total of 735 patients were included, with a mean age of the 40 ± 1.0 year; 96.8 % of patients presented diagnosis of one or more urinary metabolic abnormalities. The most prevalent metabolic abnormalities were hypercalciuria (50.8 %), hypomagnesuria (50.1 %), hypocitraturia (35.4 %), and hyperuricosuria (30.7 %). Body weight was significantly higher in patients with hyperuricosuria (81.20 ± 15.67 kg vs. 70.17 ± 14.13 kg, respectively, p = 0.001). Urinary sodium was significantly higher in patients with hypercalciuria than without (246.97 ± 103.9 mEq/24 h vs. 200.31 ± 91.6 mEq/24 h, p = 0.001) and hyperuricosuria compared to without (283.24 ± 107.95 mEq/24 h vs. 198.57 ± 85.3 mEq/24 h, p = 0.001). CONCLUSION: Urinary metabolic disturbances were diagnosed in 96.8 % of patients in the study. These results warrant metabolic study and follow-up in patients with recurrent lithiasis in order to decrease recurrence rate through specific treatments, modification in alimentary, and behavioral habits.

Assessment of the role of multidrug resistance-associated proteins in MPTP neurotoxicity in mice.

GOALS: The available scientific data indicate that the pathomechanism of Parkinson's disease (PD) involves the accumulation of endogenous and exogenous toxic substances. The disruption of the proper functioning of certain transporters in the blood-brain barrier and in the blood-cerebrospinal fluid barrier in PD would accompany to that accumulation. Although there is an emerging role of the dysfunction of multidrug resistance-associated proteins (MRPs), members of ATP-b nding cassette (ABC) transporter superfamily, in neurodegenerative disorders, there is only a few available data as regards PD. So the aim of our study was the assessment of the role of certain MRPs (1 ,2, 4 and 5) in neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine METHODS: Following the intraperitoneal administration of silymarin (with MRP1, 2, 4 and 5 inhibitory effects), naringenin (with MRP1, 2 and 4 stimulatory effects), sulfinpyrazone (with MRP1, 4 and 5 inhibitory and MRP2 stimulatory effects) and allopurinol (with MRP4 stimulatory effect in doses of 100 mg/kg, 100 mg/kg, 100 mg/kg and 60 mg/kg, respectively, for one week before and after the administration of MPTP in C57B/6 mice in acute dosing regimen the striatal concentrations of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid has been measured using high-performance liquid chromatography. RESULTS: Although the results of these experiments showed that neither of these substances exerted significant influence on MPTP-induced striatal depletion of dopamine and its metabolites, naringenin exerted a slight prevention of dopamine decrease, while allopurinol considerably enhanced the MPTP-induced lethality in mice. The explanation of these findings would be that the stimulation of MRP1- and MRP2-mediated transport of glutathione conjugates of toxic substances may have slight beneficial effects, while stimulation of MRP4-mediated efflux of brain urate, which has an important antioxidant potency, may worsen the effects of oxidative stress.

Ultrasound imaging for the rheumatologist XXXVI. Sonographic assessment of the foot in gout patients.

OBJECTIVES: This study aims to investigate the relationship between clinical and US findings together with the prevalence and distribution of US findings indicative of monosodium urate (MSU) crystal deposition within the foot in patients with gout. METHODS: A total of 50 patients with gout attending the in-patient and the out-patient clinics of the Rheumatology Departments were prospectively enrolled in this multi-centre study. Multiplanar examination of the following 15 joints was performed: talo-navicular, navicular-cuneiform (medial, intermediate and lateral), calcaneo-cuboid, medial, intermediate and lateral cuneiform-metatarsal, cuboid-4th metatarsal, cuboid-5th metatarsal and all five metatarsophalangeal (MTP) joints. RESULTS: The following US findings were indicative of gout: enhancement of the superficial margin of the hyaline cartilage, intra-articular tophus, and extraarticular tophus. In 46 patients, a total of 1380 foot joints were investigated. In 1309 joints that were not clinically involved, US detected signs indicative of joint inflammation in 9% (121/1309). Talo-navicular joint and the first MTP joint were the joints in which the highest number of US findings were found at mid-foot and fore-foot, respectively. At MTP joint level, dorsal scans allowed the detection of a higher number of US findings indicative of joint inflammation, and MSU crystal deposits rather than on the volar plane. CONCLUSIONS: This study demonstrated that US detected a higher number of inflamed foot joints than clinical examination, and that the first MTP and the talo-navicular joints were the anatomic sites with the highest prevalence of US signs of MSU crystal aggregates.

A new perspective on the pharmacoeconomics of colchicine.

BACKGROUND: Gout is a common inflammatory arthritis that affects ∼4% of the US population. Most patients with gout are >50 years of age and have multiple comorbidities. Gout is caused by the deposition of monosodium urate crystals in joints secondary to hyperuricemia. Gout typically presents as an acute painful inflammation (flare) involving one or more joint. Left untreated it can progress into a more chronic polyarthritis. Acute gout flare treatment options include colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), and corticosteroids. The safety and efficacy of colchicine, especially in the presence of comorbidity and potential contraindications, has only recently been systematically investigated. METHODS: Through the use of a systematic computer-based literature analysis, this pharmacoeconomic review evaluated costs, risks, and benefits of Colcrys (colchicine) compared with other treatments for gout in the US. RESULTS: Both colchicine and NSAIDs are historically associated with gastrointestinal (GI) adverse events (AEs). Colchicine has very low risk for AEs, even in patients with GI disorders; whereas, NSAIDS are contraindicated in patients with GI disorders, renal insufficiency, and heart failure. The monthly cost of treating 100 patients with Colcrys was $33,100 compared with $3000 for NSAIDs. However, hospitalization for GI complications (1.8%) and heart failure (1.9%) is common with NSAIDs and can increase the monthly cost of treating 100 patients with NSAIDs to $161,000, considering $15,000-20,000 per day of hospitalization. CONCLUSIONS: Considering high costs associated with treating patients with gout, it seems prudent to choose the treatment with greatest benefit, lowest cost, and least risk. Despite higher cost per dose, colchicine appears to be more cost effective for management of gout flares than NSAIDs.

[The current role of ultrasound in the assessment of crystal-related arthropathies]. / Il ruolo attuale dell'ecografia nelle artropatie da microcristalli.

Over last few years, the ultrasonography (US) generated an increasing popularity among rheumatologists due to excellent potentiality and numerous applications in rheumatology. Most of the published papers focus mainly to demonstrate the utility of US in early and chronic arthritis, short-term therapy monitoring and guidance for invasive procedures. Less attention has been paid to the potential of this technique in the field of crystal-related arthropathies. By virtue of the high resolution of "new generation" equipments, minimal crystal deposits can be detected even sometime when the radiography was negative. The aim of this paper was to present the principal findings in patients with crystal-related arthropathies.

Simultaneous electrochemical monitoring of metabolites related to the xanthine oxidase pathway using a grinded carbon electrode.

Using a mechanically grinded pyrolytic graphite electrode in edge orientation, a sensitive electrochemical method was developed for simultaneous determination of uric acid (UA), xanthine (XAN), hypoxanthine (HYP) (products of purine catabolism in human), allopurinol (ALO), and oxypurinol (OXY) (a drug used in treatment of purine catabolism disorders and its metabolite, respectively). It is demonstrated that differential pulse voltammetry in connection with this electrode can serve as a simple and efficient tool for monitoring transformation of purine catabolites (HYP --> XAN --> UA) catalyzed by xanthine oxidase (XO) as well as inhibition of this pathway by ALO being enzymatically converted to OXY. Our protocol is based on direct electrochemical measurement of oxidation peaks for each of the substances during in vitro reactions in a single detection step by the same electrode system. In addition, we show that the proposed electrochemical technique can be applied to parallel detection of metabolites involved in the XO pathway excreted in urine without any pretreatment of the clinical samples.