Febuxostat as a novel option to optimize thiopurines' metabolism in patients with inadequate metabolite levels.

PubMed

Doré, Maxime; Frenette, Anne Julie; Mansour, Anne-Marie; Troyanov, Yves; Bégin, Josiane

2014-05-01

To report the use of febuxostat in order to potentiate thiopurines' metabolism in a patient on azathioprine (AZA) therapy with low metabolite 6-thioguanine nucleotides (6-TGN) levels and elevated metabolite 6-methylmercaptopurine (6-MMP) levels. A 44-year-old woman with a history of anti-signal recognition particle necrotizing myopathy was treated with AZA-allopurinol combination therapy. When she developed an atypical drug-induced hypersensitivity syndrome, allopurinol was replaced by the new xanthine oxidase (XO) inhibitor febuxostat, at a daily dose of 40 mg. Febuxostat-AZA combination was successful with 6-TGN reaching therapeutic levels while 6-MMP levels remained low. After 5 months, she developed similar manifestations that she had presented on AZA-allopurinol combination. Febuxostat and AZA were then stopped. AZA and 6-MP are both inactive pro-drugs that undergo a complex metabolic transformation leading to active 6-TGN and potentially hepatotoxic 6-MMP. Some patients with unfavorable thiopurine metabolism might benefit from addition of XO inhibitor allopurinol in order to potentiate 6-TGN and reduce 6-MMP levels. It is likely that febuxostat, via its XO inhibition, would exhibit the same effect on thiopurines' metabolism. It has been shown that low dose of febuxostat was able to prevent hypermethylation and to potentiate 6-TGN levels in an AZA-treated patient. Thus, febuxostat could be useful in optimizing thiopurines' metabolism, but more data are needed before this practice can be recommended. The mechanisms by which febuxostat optimizes thiopurines' metabolism remain to be confirmed. Also, the optimal dose of febuxostat for this use remains to be determined.

Allopurinol therapy and cataractogenesis in humans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lerman, S.; Megaw, J.M.; Gardner, K.

1982-08-01

Long-term ingestion of allopurinol, an antihyperuricemic agent used to treat gout, may be related to the development of lens opacities in relatively young patients (second to fifth decades of life). Cataracts obtained from three patients taking allopurinol were subjected to high-resolution phosphorescence spectroscopy. The characteristic allopurinol triplet was demonstrated in all three cataracts. Identical spectra were obtained for normal human lenses incubated in media containing 10(-3)M allopurinol and exposed to 1.2 mW/cm2 ultraviolet radiation for 16 hours; control lenses (irradiated without allopurinol) showed no allopurinol triplets. Similar data were obtained for lenses from rats given one dose of allopurinol andmore » exposed to ultraviolet radiation overnight. These data provide evidence that allopurinol can be photobound in rat and human lenses and suggest its cataractogenic potential.« less

Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia.

PubMed

MacDonald, Thomas M; Ford, Ian; Nuki, George; Mackenzie, Isla S; De Caterina, Raffaele; Findlay, Evelyn; Hallas, Jesper; Hawkey, Christopher J; Ralston, Stuart; Walters, Matthew; Webster, John; McMurray, John; Perez Ruiz, Fernando; Jennings, Claudine G

2014-07-10

Gout affects 2.5% of the UK's adult population and is now the most common type of inflammatory arthritis. The long-term management of gout requires reduction of serum urate levels and this is most often achieved with use of xanthine oxidase inhibitors, such as allopurinol. Febuxostat is the first new xanthine oxidase inhibitor since allopurinol and was licensed for use in 2008. The European Medicines Agency requested a postlicensing cardiovascular safety study of febuxostat versus allopurinol, which has been named the Febuxostat versus Allopurinol Streamlined trial (FAST). FAST is a cardiovascular safety study using the prospective, randomised, open, blinded endpoint design. FAST is recruiting in the UK and Denmark. Recruited patients are aged over 60 years, prescribed allopurinol for symptomatic hyperuricaemia and have at least one additional cardiovascular risk factor. After an allopurinol lead-in phase where the dose of allopurinol is optimised to achieve European League against Rheumatism (EULAR) urate targets (serum urate <357 µmol/L), patients are randomised to either continue optimal dose allopurinol or to use febuxostat. Patients are followed-up for an average of 3 years. The primary endpoint is first occurrence of the Anti-Platelet Trialists' Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary endpoints are all cause mortality and hospitalisations for heart failure, unstable, new or worsening angina, coronary or cerebral revascularisation, transient ischaemic attack, non-fatal cardiac arrest, venous and peripheral arterial vascular thrombotic event and arrhythmia with no evidence of ischaemia. The primary analysis is a non-inferiority analysis with a non-inferiority upper limit for the HR for the primary outcome of 1.3. FAST (ISRCTN72443728) has ethical approval in the UK and Denmark, and results will be published in a peer reviewed journal. FAST is registered in the EU

The Effect of Lesinurad in Combination With Allopurinol on Serum Uric Acid Levels in Patients With Gout.

PubMed

Baumgartner, Scott; Yeh, Li-Tain; Shen, Zancong; Kerr, Bradley; Manhard, Kimberly; Quart, Barry

2018-05-07

The objective of the study was to evaluate the effect of lesinurad, a selective uric acid uptake inhibitor, alone and in combination with the xanthine oxidase inhibitor allopurinol, on serum uric acid and urinary urate excretion in patients with gout and hyperuricemia. A phase 1b, multicenter, open-label, multiple-dose study was carried out in patients with gout with serum uric acid ≥8 mg/dL following washout of urate-lowering therapy. Patients were treated with allopurinol 300 mg/day alone in week 1; lesinurad 400 or 600 mg/day was added in week 2, followed by lesinurad 400 or 600 mg/day alone in week 3. Serum uric acid and urine uric acid were evaluated each week. Safety was assessed throughout the study. Lesinurad 400 or 600 mg/day added to allopurinol 300 mg/day reduced serum uric acid by 60% and 72%, respectively, versus allopurinol alone (37%) or lesinurad 400 mg/day (44%) or 600 mg/day (47%) alone. A 100% response rate of serum uric acid <6 mg/dL was achieved by all combinations (serum uric acid <5 mg/dL by 50%-90%). Mean 24-hour urate excretion compared with baseline was -35% with allopurinol, +36% and +56.5% with lesinurad 400 mg/day and 600 mg/day, respectively, and -11.6% and -7.1% with the respective combination therapies. Treatments were well tolerated. In this phase 1 trial, lesinurad added to allopurinol resulted in greater serum uric acid reduction than did allopurinol or lesinurad monotherapy. © 2018, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Xanthine oxidase inhibitory activity of natural and hemisynthetic flavonoids from Gardenia oudiepe (Rubiaceae) in vitro and molecular docking studies.

PubMed

Santi, M D; Paulino Zunini, M; Vera, B; Bouzidi, C; Dumontet, V; Abin-Carriquiry, A; Grougnet, R; Ortega, M G

2018-01-01

Xanthine oxidase (XO), an enzyme widely distributed among mammalian tissues, is associated with the oxidation of xanthine and hypoxanthine to form uric acid. Reactive oxygen species are also released during this process, leading to oxidative damages and to the pathology called gout. Available treatments mainly based on allopurinol cause serious side effects. Natural products such as flavonoids may represent an alternative. Thus, a series of polymethoxyflavones isolated and hemisynthesized from the bud exudates of Gardenia oudiepe has been evaluated for in vitro XO inhibitory activity. Compounds 1, 2 and 3 were more active than the reference inhibitor, Allopurinol (IC 50  = 0.25 ± 0.004 μM) with IC 50 values of (0.004 ± 0.001) μM, (0.05 ± 0.01) μM and (0.09 ± 0.003) μM, respectively. Structure-activity relationships were established. Additionally, a molecular docking study using MOE™ tool was carried out to establish the binding mode of the most active flavones with the enzyme, showing important interactions with its catalytic residues. These promising results, suggest the use of these compounds as potential leads for the design and development of novel XO inhibitors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Allopurinol improves endothelial dysfunction in chronic heart failure.

PubMed

Farquharson, Colin A J; Butler, Robert; Hill, Alexander; Belch, Jill J F; Struthers, Allan D

2002-07-09

Increased oxidative stress in chronic heart failure is thought to contribute to endothelial dysfunction. Xanthine oxidase produces oxidative stress and therefore we examined whether allopurinol improved endothelial dysfunction in chronic heart failure. We performed a randomized, placebo-controlled, double-blind crossover study on 11 patients with New York Heart Association class II-III chronic heart failure, comparing 300 mg allopurinol daily (1 month) versus placebo. Endothelial function was assessed by standard forearm venous occlusion plethysmography with acetylcholine, nitroprusside, and verapamil. Plasma malondialdehyde levels were also compared to assess significant changes in oxidative stress. Allopurinol significantly increased the forearm blood flow response to acetylcholine (percentage change in forearm blood flow [mean+/-SEM]: 181+/-19% versus 120+/-22% allopurinol versus placebo; P=0.003). There were no significant differences in the forearm blood flow changes between the placebo and allopurinol treatment arms with regard to sodium nitroprusside or verapamil. Plasma malondialdehyde was significantly reduced with allopurinol treatment (346+/-128 nmol/L versus 461+/-101 nmol/L, allopurinol versus placebo; P=0.03), consistent with reduced oxidative stress with allopurinol therapy. We have shown that allopurinol improves endothelial dysfunction in chronic heart failure. This raises the distinct possibility that allopurinol might reduce cardiovascular events and even improve exercise capacity in chronic heart failure.

Up-titration of allopurinol in patients with gout.

PubMed

Jennings, Claudine G; Mackenzie, Isla S; Flynn, Rob; Ford, Ian; Nuki, George; De Caterina, Raffaele; Riches, Philip L; Ralston, Stuart H; MacDonald, Thomas M

2014-08-01

European League against Rheumatism (EULAR) gout management guidelines recommend achieving a target urate level <6.0 mg/dL (<357 µmol/L). Allopurinol is the most widely used urate-lowering therapy; however, many gout patients who are prescribed allopurinol do not have urate levels optimally controlled. The objective of this analysis was to review the efficacy and tolerability of allopurinol up-titration in achieving the EULAR target levels. The Febuxostat versus Allopurinol Streamlined Trial (FAST) is an ongoing multi-centre study comparing the cardiovascular safety of febuxostat and allopurinol (target recruitment: 5706 patients). Recruited patients were already taking allopurinol and the protocol required up-titration of daily allopurinol dose, in 100 mg increments, to achieve the EULAR urate target level prior to randomisation. We reviewed pre-randomisation data from the first 400 recruited and subsequently randomised FAST patients. Of 400 patients, 144 (36%) had urate levels ≥357 µmol/L at screening and required allopurinol up-titration. Higher urate levels were significantly associated with lower allopurinol dose, male sex, increased BMI, increased alcohol intake and diuretic use. Mean fall in urate levels after a single 100-mg dose increase was 71 µmol/L. The number of up-titrations required ranged from one to five (median = 1) with 65% of patients controlled after one 100-mg up-titration. Overall, 97% of up-titrated patients achieved target urate levels with median final allopurinol dose of 300 mg daily. Side effects and complications of up-titration were minimal. Overall, 36% of FAST patients were not at target urate levels and required up-titration. Allopurinol up-titration was effective in achieving urate target levels and was generally well tolerated by patients. Copyright © 2014 Elsevier Inc. All rights reserved.

Long-Term Inhibition of Xanthine Oxidase by Febuxostat Does Not Decrease Blood Pressure in Deoxycorticosterone Acetate (DOCA)-Salt Hypertensive Rats

PubMed Central

Szasz, Theodora; Davis, Robert Patrick; Garver, Hannah S.; Burnett, Robert J.; Fink, Gregory D.; Watts, Stephanie W.

2013-01-01

Xanthine oxidase and its products, uric acid and ROS, have been implicated in the pathogenesis of cardiovascular disease, such as hypertension. We have previously reported that allopurinol inhibition of XO does not alter the progression of deoxycorticosterone acetate (DOCA)-salt hypertension in rats. However other researchers have observed a reduction in blood pressure after allopurinol treatment in the same model. To resolve this controversy, in this study we used the newer and more effective XO inhibitor febuxostat, and hypothesized that a more complete XO blockade might impair hypertension development and its end-organ consequences. We used DOCA-salt hypertensive rats and administered vehicle (salt water) or febuxostat (orally, 5 mg/kg/day in salt water) in a short-term “reversal” experiment (2 weeks of treatment 3 weeks after DOCA-salt beginning) and a long-term “prevention” experiment (treatment throughout 4 weeks of DOCA-salt). We confirmed XO inhibition by febuxostat by measuring circulating and tissue levels of XO metabolites. We found an overall increase in hypoxanthine (XO substrate) and decrease in uric acid (XO product) levels following febuxostat treatment. However, despite a trend for reduced blood pressure in the last week of long-term febuxostat treatment, no statistically significant difference in hemodynamic parameters was observed in either study. Additionally, no change was observed in relative heart and kidney weight. Aortic media/lumen ratio was minimally improved by long-term febuxostat treatment. Additionally, febuxostat incubation in vitro did not modify contraction of aorta or vena cava to norepinephrine, angiotensin II or endothelin-1. We conclude that XO inhibition is insufficient to attenuate hypertension in the rat DOCA-salt model, although beneficial vascular effects are possible. PMID:23393607

Allopurinol and Cardiovascular Outcomes in Adults With Hypertension.

PubMed

MacIsaac, Rachael L; Salatzki, Janek; Higgins, Peter; Walters, Matthew R; Padmanabhan, Sandosh; Dominiczak, Anna F; Touyz, Rhian M; Dawson, Jesse

2016-03-01

Allopurinol lowers blood pressure in adolescents and has other vasoprotective effects. Whether similar benefits occur in older individuals remains unclear. We hypothesized that allopurinol is associated with improved cardiovascular outcomes in older adults with hypertension. Data from the United Kingdom Clinical Research Practice Datalink were used. Multivariate Cox-proportional hazard models were applied to estimate hazard ratios for stroke and cardiac events (defined as myocardial infarction or acute coronary syndrome) associated with allopurinol use over a 10-year period in adults aged >65 years with hypertension. A propensity-matched design was used to reduce potential for confounding. Allopurinol exposure was a time-dependent variable and was defined as any exposure and then as high (≥300 mg daily) or low-dose exposure. A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were studied. Allopurinol use was associated with a significantly lower risk of both stroke (hazard ratio, 0.50; 95% confidence interval, 0.32-0.80) and cardiac events (hazard ratio, 0.61; 95% confidence interval, 0.43-0.87) than nonexposed control patients. In exposed patients, high-dose treatment with allopurinol (n=1052) was associated with a significantly lower risk of both stroke (hazard ratio, 0.58; 95% confidence interval, 0.36-0.94) and cardiac events (hazard ratio, 0.65; 95% confidence interval, 0.46-0.93) than low-dose treatment (n=980). Allopurinol use is associated with lower rates of stroke and cardiac events in older adults with hypertension, particularly at higher doses. Prospective clinical trials are needed to evaluate whether allopurinol improves cardiovascular outcomes in adults with hypertension. © 2016 American Heart Association, Inc.

Uric acid and allopurinol aggravate absence epileptic activity in Wistar Albino Glaxo Rijswijk rats.

PubMed

Lakatos, Renáta Krisztina; Dobolyi, Árpád; Kovács, Zsolt

2018-05-01

Uric acid has a role in several physiological and pathophysiological processes. For example, uric acid may facilitate seizure generalization while reducing uric acid level may evoke anticonvulsant/antiepileptic effects. Allopurinol blocks the activity of xanthine oxidase, by which allopurinol inhibits catabolism of hypoxanthine to xanthine and uric acid and, as a consequence, decreases the level of uric acid. Although the modulation of serum uric acid level is a widely used strategy in the treatment of certain diseases, our knowledge regarding the effects of uric acid on epileptic activity is far from complete. Thus, the main aim of this study was the investigation of the effect of uric acid on absence epileptic seizures (spike-wave discharges: SWDs) in a model of human absence epilepsy, the Wistar Albino Glaxo/Rijswijk (WAG/Rij) rat. We investigated the influence of intraperitoneally (i.p.) injected uric acid (100 mg/kg and 200 mg/kg), allopurinol (50 mg/kg and 100 mg/kg), a cyclooxygenase 1 and 2 (COX-1 and COX-2) inhibitor indomethacin (10 mg/kg) and inosine (500 mg/kg) alone and the combined application of allopurinol (50 mg/kg) with uric acid (100 mg/kg) or inosine (500 mg/kg) as well as indomethacin (10 mg/kg) with uric acid (100 mg/kg) and inosine (500 mg/kg) with uric acid (100 mg/kg) on absence epileptic activity. We demonstrated that both uric acid and allopurinol alone significantly increased the number of SWDs whereas indomethacin abolished the uric acid-evoked increase in SWD number. Our results suggest that uric acid and allopurinol have proepileptic effects in WAG/Rij rats. Copyright © 2018 Elsevier B.V. All rights reserved.

Formulation development of allopurinol suppositories and injectables.

PubMed

Lee, D K; Wang, D P

1999-11-01

Allopurinol was formulated into injectable and suppository dosage forms. The injectable formulation was prepared by dissolving allopurinol in a cosolvent system consisting of dimethyl sulfoxide (DMSO) and propylene glycol (v/v = 50/50). The stability of allopurinol in the cosolvent system was studied under accelerated storage conditions, and results indicate first-order degradation kinetics with an activation energy of 24.3 kcal/mol. The development of suppository dosage forms was performed by formulating allopurinol with polyethylene glycol (PEG) mixtures of different molecular weights. In vitro release profiles of suppositories formulated with different polyethylene bases were obtained in the pH 7.4 buffer solution using the USP 23 paddle method at 100 rpm. Results indicate that the release rate of the suppository formulations containing PEG 1500/PEG 4000 at the ratio (w/w) of 2.5/10 to 10/2.5 appeared to be similar. However, the addition of sodium lauryl sulfate in the suppository decreased the release rate of allopurinol significantly. A future study to establish in vitro/in vivo correlation (iv/ivc) is suggested.

Diabetes and gout: efficacy and safety of febuxostat and allopurinol.

PubMed

Becker, M A; MacDonald, P A; Hunt, B J; Jackson, R L

2013-11-01

Assess influences of demographics and co-morbidities of gout patients with or without diabetes on safety and efficacy of urate-lowering agents. Post-hoc analysis of 312 diabetic and 1957 non-diabetic gout patients [baseline serum urate levels (sUA) ≥8.0 mg/dl] enrolled in a 6-month randomized controlled trial comparing urate-lowering efficacy (ULE) and safety of daily xanthine oxidase inhibitors (XOIs) febuxostat (40 mg or 80 mg) and allopurinol (200 mg or 300 mg). We compared baseline demographic, gout and co-morbid characteristics, ULE, and safety of XOI treatment in diabetic and non-diabetic gout patients. ULE was measured by the proportion of diabetic and non-diabetic patients in each treatment group achieving final visit sUA < 6.0 mg/dl. Safety was monitored throughout the trial. Diabetic gout patients were older, more frequently female, and had longer gout duration. Co-morbidities were more frequent among diabetic patients: cardiovascular disease; impaired renal function; hyperlipidemia; and obesity (body mass index >30 kg/m²) (p < 0.001 for all comparisons). Febuxostat 80 mg ULE exceeded that of febuxostat 40 mg or allopurinol (p < 0.050) at all levels of renal function, achieving sUA goal range in the majority of diabetic and non-diabetic patients. Diabetics and non-diabetics reported self-limiting diarrhoea and URIs as the most common adverse events. Despite higher co-morbidity rates in diabetic patients, febuxostat and allopurinol were safe in both groups at the doses tested. Febuxostat 80 mg achieved sUA <6.0 mg/dl more often than febuxostat 40 mg or allopurinol at commonly prescribed doses. © 2013 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Diabetes and gout: efficacy and safety of febuxostat and allopurinol

PubMed Central

Becker, M A; MacDonald, P A; Hunt, B J; Jackson, R L

2013-01-01

Aim Assess influences of demographics and co-morbidities of gout patients with or without diabetes on safety and efficacy of urate-lowering agents. Methods Post-hoc analysis of 312 diabetic and 1957 non-diabetic gout patients [baseline serum urate levels (sUA) ≥8.0 mg/dl] enrolled in a 6-month randomized controlled trial comparing urate-lowering efficacy (ULE) and safety of daily xanthine oxidase inhibitors (XOIs) febuxostat (40 mg or 80 mg) and allopurinol (200 mg or 300 mg). We compared baseline demographic, gout and co-morbid characteristics, ULE, and safety of XOI treatment in diabetic and non-diabetic gout patients. ULE was measured by the proportion of diabetic and non-diabetic patients in each treatment group achieving final visit sUA < 6.0 mg/dl. Safety was monitored throughout the trial. Results Diabetic gout patients were older, more frequently female, and had longer gout duration. Co-morbidities were more frequent among diabetic patients: cardiovascular disease; impaired renal function; hyperlipidemia; and obesity (body mass index >30 kg/m2) (p < 0.001 for all comparisons). Febuxostat 80 mg ULE exceeded that of febuxostat 40 mg or allopurinol (p < 0.050) at all levels of renal function, achieving sUA goal range in the majority of diabetic and non-diabetic patients. Diabetics and non-diabetics reported self-limiting diarrhoea and URIs as the most common adverse events. Conclusions Despite higher co-morbidity rates in diabetic patients, febuxostat and allopurinol were safe in both groups at the doses tested. Febuxostat 80 mg achieved sUA <6.0 mg/dl more often than febuxostat 40 mg or allopurinol at commonly prescribed doses. PMID:23683134

Cost-effectiveness of allopurinol and febuxostat for the management of gout.

PubMed

Jutkowitz, Eric; Choi, Hyon K; Pizzi, Laura T; Kuntz, Karen M

2014-11-04

Gout is the most common inflammatory arthritis in the United States. To evaluate the cost-effectiveness of urate-lowering treatment strategies for the management of gout. Markov model. Published literature and expert opinion. Patients for whom allopurinol or febuxostat is a suitable initial urate-lowering treatment. Lifetime. Health care payer. 5 urate-lowering treatment strategies were evaluated: no treatment; allopurinol- or febuxostat-only therapy; allopurinol-febuxostat sequential therapy; and febuxostat-allopurinol sequential therapy. Two dosing scenarios were investigated: fixed dose (80 mg of febuxostat daily, 0.80 success rate; 300 mg of allopurinol daily, 0.39 success rate) and dose escalation (≤120 mg of febuxostat daily, 0.82 success rate; ≤800 mg of allopurinol daily, 0.78 success rate). Discounted costs, discounted quality-adjusted life-years, and incremental cost-effectiveness ratios. In both dosing scenarios, allopurinol-only therapy was cost-saving. Dose-escalation allopurinol-febuxostat sequential therapy was more costly but more effective than dose-escalation allopurinol therapy, with an incremental cost-effectiveness ratio of $39 400 per quality-adjusted life-year. The relative rankings of treatments did not change. Our results were relatively sensitive to several potential variations of model assumptions; however, the cost-effectiveness ratios of dose escalation with allopurinol-febuxostat sequential therapy remained lower than the willingness-to-pay threshold of $109 000 per quality-adjusted life-year. Long-term outcome data for patients with gout, including medication adherence, are limited. Allopurinol single therapy is cost-saving compared with no treatment. Dose-escalation allopurinol-febuxostat sequential therapy is cost-effective compared with accepted willingness-to-pay thresholds. Agency for Healthcare Research and Quality.

Cost-effectiveness analysis of allopurinol versus febuxostat in chronic gout patients: a U.S. payer perspective.

PubMed

Gandhi, Pranav K; Gentry, William M; Ma, Qinli; Bottorff, Michael B

2015-02-01

Gout is a chronic inflammatory condition associated with poor urate metabolism. Xanthine oxidase inhibitors such as allopurinol and febuxostat are recommended to reduce uric acid levels and to prevent gout attacks in adult patients. Under budget-driven constraints, health care payers are faced with the broader challenge of assessing the economic value of these agents for formulary placement. However, the economic value of allopurinol versus febuxostat has not be assessed in patients with gout over a 5-year time period in the United States. To evaluate the cost-effectiveness of allopurinol versus febuxostat in adult patients with gout over a 5-year time period from a U.S. health care payer's perspective. A Markov model was developed to compare the total direct costs and success of serum uric acid (sUA) level reduction associated with allopurinol and febuxostat. Treatment success was defined as patient achievement of a sUA level less than  6 mg/dL (0.36 mmol/L) at 6 months. Event probabilities were based on published phase III randomized clinical trials and included long-term sequelae from open-label extension studies. A hypothetical cohort of 1,000 adult gout patients with sUA levels of ≥ 8 mg/dL (0.48 mmol/L) who had received either allopurinol 300 mg or febuxostat 80 mg at model entry transitioned among the 4 health states defined by treatment success, treatment failure and switch, treatment dropout, and death. The length of each Markov cycle was 6 months. Costs were gathered from the RED BOOK, Medicare fee schedules, Healthcare Cost and Utilization Project's Nationwide Inpatient Sample, and for a limited number of inputs, expert consultation. Direct costs included treatment drug costs, costs for prophylaxis drugs, diagnostic laboratory tests, and the treatment and management of acute gout flare. Resource utilization was based on clinical evidence and expert consultation. All costs were inflated to 2014 U.S. dollars and were discounted at 3% in the base case

Switching from allopurinol to febuxostat for the treatment of hyperuricemia and renal function in patients with chronic kidney disease.

PubMed

Tsuruta, Yuki; Mochizuki, Toshio; Moriyama, Takahito; Itabashi, Mitsuyo; Takei, Takashi; Tsuchiya, Ken; Nitta, Kosaku

2014-11-01

Hyperuricemia is a frequent complication of chronic kidney disease (CKD). Febuxostat is a novel xanthine oxidase inhibitor that is metabolized by many metabolic pathways in the kidney and the liver. We performed a 1-year cohort study of 73 hyperuricemic patients who had an estimated glomerular filtration rate (eGFR) below 45 ml/min and were being treated with urate-lowering therapy. In 51 patients, treatment was changed from allopurinol to febuxostat, and the other 22 patients were continued on allopurinol. The serum levels of uric acid (UA) level, creatinine, and other biochemical parameters were measured at baseline and after 3, 6, 9, and 12 months of treatment. The serum UA levels significantly decreased from 6.1 ± 1.0 to 5.7 ± 1.2 mg/dl in the febuxostat group and significantly increased from 6.2 ± 1.1 to 6.6 ± 1.1 mg/dl in the allopurinol group. The eGFR decreased 27.3 to 25.7 ml/min in the febuxostat group and from 26.1 to 19.9 ml/min in the allopurinol group. The switch from allopurinol to febuxostat was significantly associated with the changes in eGFR according to a multiple regression analysis (β = -0.22145, P < 0.05). Febuxostat reduced the serum UA levels and slowed the progression of renal disease in our CKD cohort in comparison with allopurinol.

Allopurinol Against Progression of Chronic Kidney Disease.

PubMed

Golmohammadi, Sima; Almasi, Afshin; Manouchehri, M; Omrani, Hamid Reza; Zandkarimi, Mohammad Reza

2017-07-01

Hyperuricemia is common in approximately 50% of patients with kidney failure due to decreased uric acid excretion, and it has been recently known as an independent factor in the progression of renal insufficiency. Allopurinol inhibits the production of uric acid. The aim of this study was to evaluate the effect of allopurinol on chronic kidney disease progression. In a clinical trial, patients with stages 3 and 4 of chronic kidney disease were divided into two groups to receive allopurinol, 100 mg, daily and placebo for 12 months. Patients' kidney function and serum uric acid levels were assessed at baseline and 3, 6, and 12 months after initial administration. Subgroups of patients with severe and mild glomerular filtration rate (GFR) impairment (GFR, 15 mL/min/1.73 m2 to 30 mL/min/1.73 m2 and 30 mL/min/1.73 m2 to 60 mL/min/1.73 m2, respectively), were compared between the groups. Serum uric acid levels decreased significantly during after 12 months of allopurinol administration (P = .004). In patients with severe GFR impairment, serum creatinine levels did not decrease significantly and there was no significant increase in GFR, but in those with mild GFR impairment, serum creatinine levels decreased and GFR increase significantly (P < .001) after administration of allopurinol. These effects were not observed in the control subgroups. Allopurinol may slow down stage 3 chronic kidney disease progression and could be administered with other effective medications for controlling the kidney disease.

The Effect of Allopurinol on Renal Function.

PubMed

Krishnamurthy, Aneesa; Lazaro, Deana; Stefanov, Dimitre G; Blumenthal, David; Gerber, Donald; Patel, Sheetal

2017-01-01

Hyperuricemia is associated with development of gout, hypertension, and renal disease. The impact of allopurinol, a urate-lowering therapy, on renal function is unclear, especially in patients with chronic kidney disease who are at higher risk of hypersensitivity reaction. The aim of this study was to determine the effect of allopurinol on kidney function in hyperuricemic male veterans. This is a retrospective cohort study using pharmacy, medical, and laboratory records of veterans enrolled at the Veterans Administration New York Harbor Healthcare System, Brooklyn campus. Fifty patients with hyperuricemia defined as a serum uric acid greater than 7 mg/dL (average of ~9 mg/dL), newly started on allopurinol for any reason, with evidence of treatment compliance, were matched by age, race, sex, and estimated glomerular filtration rate (EGFR) to 50 hyperuricemic control subjects. The retrospective cases were observed from October 2000 until November 2006, at which time there was a change in the laboratory analyzer, making further comparisons inappropriate. On average, patients treated with a mean 221 (SD, 96) mg/d dose of allopurinol achieved 11.9 mL/min higher GFR (95% confidence interval, 4.8-11.9 mg/d dose; P = 0.01) than did the control group. Treatment effect was found to depend on the initial EGFR, as indicated by the significant treatment by initial EGFR interaction (P = 0.004) and increased with a higher initial EGFR. The allopurinol-treated group had a 0.10 mg/dL lower final creatinine level (95% confidence interval, 0.003-0.20 mg/dL; P = 0.04) than did the control subjects, adjusted for initial creatinine and age. The average length of follow-up was 3.4 years. There were 5 mild adverse events in the treated cases. Treatment of hyperuricemic patients with allopurinol over an average of 3.4 years resulted in a significant improvement of kidney function in this male cohort from the Veterans Administration Healthcare System. Clinicians should consider this

Monochloramine produces reactive oxygen species in liver by converting xanthine dehydrogenase into xanthine oxidase.

PubMed

Sakuma, Satoru; Miyoshi, Emi; Sadatoku, Namiko; Fujita, Junko; Negoro, Miki; Arakawa, Yukio; Fujimoto, Yohko

2009-09-15

In the present study, we assessed the influence of monochloramine (NH(2)Cl) on the conversion of xanthine dehydrogenase (XD) into xanthine oxidase (XO) in rat liver in vitro. When incubated with the partially purified cytosolic fraction from rat liver, NH(2)Cl (2.5-20 microM) dose-dependently enhanced XO activity concomitant with a decrease in XD activity, implying that NH(2)Cl can convert XD into the reactive oxygen species (ROS) producing form XO. The NH(2)Cl (5 microM)-induced XD/XO interconversion in the rat liver cytosol was completely inhibited when added in combination with an inhibitor of NH(2)Cl methionine (25 microM). A sulfhydryl reducing agent, dithiothreitol at concentrations of 0.1, 1 and 5 mM also dose-dependently reversed the NH(2)Cl (5 microM)-induced XD/XO interconversion. These imply that NH(2)Cl itself acts on the XD/XO interconversion, and that this conversion occurs at the cysteine residues in XD. Furthermore, using the fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate, it was found that NH(2)Cl could increase ROS generation in the cytoplasm of rat primary hepatocyte cultures, and that this increase might be reversed by an XO inhibitor, allopurinol. These results suggest that NH(2)Cl has the potential to convert XD into XO in the liver, which in turn may induce the ROS generation in this region.

Design and Rationale for the Veterans Affairs "Cooperative Study Program 594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat" Trial.

PubMed

Timilsina, S; Brittan, K; O'Dell, J R; Brophy, M; Davis-Karim, A; Henrie, A M; Neogi, T; Newcomb, J; Palevsky, P M; Pillinger, M H; Pittman, D; Taylor, T H; Wu, H; Mikuls, T R

2018-05-01

Gout patients do not routinely achieve optimal outcomes related in part to suboptimal administration of urate lowering therapy (ULT) including first-line xanthine oxidase inhibitors allopurinol or febuxostat. Studies leading to the approval of febuxostat compared this agent to allopurinol in inappropriately low, fixed doses. We will compare allopurinol with febuxostat in gout using appropriately titrated doses of both agents and a "treat-to-target" strategy congruent with specialty guidelines. We have planned and initiated the Veterans Affairs (VA) Cooperative Study Program (CSP) 594, Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study. This large double-blind, non-inferiority trial will enroll 950 gout patients randomized to receive allopurinol or febuxostat. Patients will be followed for a total of 72 weeks encompassing 3 distinct 24-week study phases. During Phase I (0-24 weeks), participants will undergo gradual dose titration of ULT until achievement of serum uric acid (sUA) <6.0 mg/dL or <5.0 mg/dL if tophi are present. Dose escalation will not be allowed during final three study visits of Phase 2 (24-48 weeks) and during Phase 3 (48-72 weeks). The primary study outcome is the proportion of participants experiencing at least one gout flare during Phase 3. Subsequent to the 72-week study, participants will be followed passively for up to 10 years after the study to assess long-term health outcomes. With its completion, the VA Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study will demonstrate the central role of gradual ULT dose escalation and a treat-to-target strategy in gout management. Published by Elsevier Inc.

Implications of the cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular morbidities (CARES) trial and associated FDA public safety alert.

PubMed

Choi, Hyon; Neogi, Tuhina; Stamp, Lisa; Dalbeth, Nicola; Terkeltaub, Robert

2018-06-05

Recently, the FDA issued a public safety alert, responding to results of the now-published Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities (CARES) trial. CARES showed no significant difference between allopurinol and febuxostat in the primary composite endpoint of cardiovascular (CV) events in subjects with gout and established cardiovascular comorbidities at baseline. However, there was significantly increased risk of cardiac and all-cause mortality with febuxostat. Urate lowering therapy (ULT) is central to long-term management of gout, and xanthine oxidoreductase inhibitor (XOI) therapy is the consensus first line approach. Allopurinol is generally the first XOI employed, but febuxostat is an effective XOI option, and is commonly used when allopurinol is not tolerated. These data are further relevant since CV co-morbidities are common in gout. Here, we examine why the CARES trial was done, and discuss other, ongoing comparative studies of febuxostat and allopurinol whose results are awaited. We assess strengths and limitations of CARES, and appraise robustness and biologic plausibility of the results. CARES does not prove that febuxostat raises CV mortality risk, but suggests greater risk with febuxostat than allopurinol. CARES results do not support first line use of febuxostat ULT, and raise questions on febuxostat placement at various pharmacologic ULT decision tree branches. Alternatives to febuxostat that are frequently effective include allopurinol dose-escalation, and uricosuric therapy alone or combined with allopurinol. The FDA safety alert highlights the need for shared ULT medical decision with gout patients, including discussion of CV safety of febuxostat. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

An allopurinol-controlled, multicenter, randomized, double-blind, parallel between-group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia.

PubMed

Huang, Xinfang; Du, Hui; Gu, Jieruo; Zhao, Dongbao; Jiang, Lindi; Li, Xinfu; Zuo, Xiaoxia; Liu, Yi; Li, Zhanguo; Li, Xiangpei; Zhu, Ping; Li, Juan; Zhang, Zhiyi; Huang, Anbin; Zhang, Yuanchao; Bao, Chunde

2014-07-01

Febuxostat, a novel non-purine selective inhibitor of xanthine oxidase, has been identified as a potential alternative to allopurinol in patients with hyperuricemia. The purpose of this study was to compare the urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in Chinese gout patients with hyperuricemia. Gout patients (n = 512) with serum uric acid (sUA) concentrations of at least 8.0 mg/dL were randomized to receive daily febuxostat 40 mg or 80 mg or allopurinol 300 mg for 28 weeks. Prophylaxis against gout flares with meloxicam or colchicine was provided during weeks 1 through 8. The primary endpoint was the percentage of subjects achieving a sUA concentration of <6.0 mg/dL at the last three monthly measurements. The primary endpoint was reached in 44.77% of patients receiving 80 mg of febuxostat, 27.33% of those receiving 40 mg of febuxostat, and 23.84% of those receiving allopurinol. The UL efficacy in the febuxostat 80 mg group was higher than in the allopurinol (P < 0.0001) and febuxostat 40 mg (P = 0.0008) groups. The UL efficacy of the febuxostat 40 mg group was statistically non-inferior to that of the allopurinol group. No significant change in the number of tophi was observed during the final visit relative to baseline in each treatment group. The rate of gout flares requiring treatment from weeks 9 through 28 and the incidence of adverse events was similar among treatment groups. The UL efficacy of daily febuxostat 80 mg was greater than that of febuxostat 40 mg and allopurinol 300 mg, which exhibited comparable UL efficacy. Safety of febuxostat and allopurinol was comparable at the doses tested. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Allopurinol use in a New Zealand population: prevalence and adherence.

PubMed

Horsburgh, Simon; Norris, Pauline; Becket, Gordon; Arroll, Bruce; Crampton, Peter; Cumming, Jacqueline; Keown, Shirley; Herbison, Peter

2014-07-01

Allopurinol is effective for the control of gout and its long-term complications when taken consistently. There is evidence that adherence to allopurinol therapy varies across population groups. This may exacerbate differences in the burden of gout on population groups and needs to be accurately assessed. The aim of this study was to describe the prevalence of allopurinol use in a region of New Zealand using community pharmacy dispensing data and to examine the levels of suboptimal adherence in various population groups. Data from all community pharmacy dispensing databases in a New Zealand region were collected for a year covering 2005/2006 giving a near complete picture of dispensings to area residents. Prevalence of allopurinol use in the region by age, sex, ethnicity and socioeconomic position was calculated. Adherence was assessed using the medication possession ratio (MPR), with a MPR of 0.80 indicative of suboptimal adherence. Multiple logistic regression was used to explore variations in suboptimal adherence across population groups. A total of 953 people received allopurinol in the study year (prevalence 3%). Prevalence was higher in males (6%) than in females (1%) and Māori (5%) than non-Māori (3%). The overall MPR during the study was 0.88, with 161 (22%) of patients using allopurinol having suboptimal adherence. Non-Māori were 54% less likely to have suboptimal allopurinol adherence compared to Māori (95% CI 0.30-0.72, p = 0.001). These findings are consistent with those from other studies nationally and internationally and point to the important role for health professionals in improving patient adherence to an effective gout treatment.

Xanthine oxidoreductase and its inhibitors: relevance for gout.

PubMed

Day, Richard O; Kamel, Bishoy; Kannangara, Diluk R W; Williams, Kenneth M; Graham, Garry G

2016-12-01

Xanthine oxidoreductase (XOR) is the rate-limiting enzyme in purine catabolism and converts hypoxanthine to xanthine, and xanthine into uric acid. When concentrations of uric acid exceed its biochemical saturation point, crystals of uric acid, in the form of monosodium urate, emerge and can predispose an individual to gout, the commonest form of inflammatory arthritis in men aged over 40 years. XOR inhibitors are primarily used in the treatment of gout, reducing the formation of uric acid and thereby, preventing the formation of monosodium urate crystals. Allopurinol is established as first-line therapy for gout; a newer alternative, febuxostat, is used in patients unable to tolerate allopurinol. This review provides an overview of gout, a detailed analysis of the structure and function of XOR, discussion on the pharmacokinetics and pharmacodynamics of XOR inhibitors-allopurinol and febuxostat, and the relevance of XOR in common comorbidities of gout. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Allopurinol Resistance in Leishmania infantum from Dogs with Disease Relapse.

PubMed

Yasur-Landau, Daniel; Jaffe, Charles L; David, Lior; Baneth, Gad

2016-01-01

Visceral leishmaniasis caused by the protozoan Leishmania infantum is a zoonotic, life threatening parasitic disease. Domestic dogs are the main peridomestic reservoir, and allopurinol is the most frequently used drug for the control of infection, alone or in combination with other drugs. Resistance of Leishmania strains from dogs to allopurinol has not been described before in clinical studies. Following our observation of clinical disease relapse in dogs under allopurinol treatment, we tested susceptibility to allopurinol of L. infantum isolated from groups of dogs pre-treatment, treated in remission, and with disease relapse during treatment. Promastigote isolates obtained from four treated relapsed dogs (TR group) showed an average half maximal inhibitory concentration (IC50) of 996 μg/mL. A significantly lower IC50 (P = 0.01) was found for isolates from ten dogs before treatment (NT group, 200 μg/mL), as well as for five isolates obtained from treated dogs in remission (TA group, 268 μg/mL). Axenic amastigotes produced from isolates of the TR group also showed significantly higher (P = 0.002) IC50 compared to the NT group (1678 and 671 μg/mL, respectively). The lower sensitivity of intracellular amastigotes from the TR group relative to those from the NT group (P = 0.002) was confirmed using an infected macrophage model (6.3% and 20% growth inhibition, respectively at 300 μg/mL allopurinol). This is the first study to demonstrate allopurinol resistance in L. infantum and to associate it with disease relapse in the canine host. These findings are of concern as allopurinol is the main drug used for long term control of the disease in dogs, and resistant L. infantum strains may enhance uncontrolled transmission to humans and to other dogs.

Uric acid promotes vascular stiffness, maladaptive inflammatory responses and proteinuria in western diet fed mice.

PubMed

Aroor, Annayya R; Jia, Guanghong; Habibi, Javad; Sun, Zhe; Ramirez-Perez, Francisco I; Brady, Barron; Chen, Dongqing; Martinez-Lemus, Luis A; Manrique, Camila; Nistala, Ravi; Whaley-Connell, Adam T; Demarco, Vincent G; Meininger, Gerald A; Sowers, James R

2017-09-01

Aortic vascular stiffness has been implicated in the development of cardiovascular disease (CVD) and chronic kidney disease (CKD) in obese individuals. However, the mechanism promoting these adverse effects are unclear. In this context, promotion of obesity through consumption of a western diet (WD) high in fat and fructose leads to excess circulating uric acid. There is accumulating data implicating elevated uric acid in the promotion of CVD and CKD. Accordingly, we hypothesized that xanthine oxidase(XO) inhibition with allopurinol would prevent a rise in vascular stiffness and proteinuria in a translationally relevant model of WD-induced obesity. Four-week-old C57BL6/J male mice were fed a WD with excess fat (46%) and fructose (17.5%) with or without allopurinol (125mg/L in drinking water) for 16weeks. Aortic endothelial and extracellular matrix/vascular smooth muscle stiffness was evaluated by atomic force microscopy. Aortic XO activity, 3-nitrotyrosine (3-NT) and aortic endothelial sodium channel (EnNaC) expression were evaluated along with aortic expression of inflammatory markers. In the kidney, expression of toll like receptor 4 (TLR4) and fibronectin were assessed along with evaluation of proteinuria. XO inhibition significantly attenuated WD-induced increases in plasma uric acid, vascular XO activity and oxidative stress, in concert with reductions in proteinuria. Further, XO inhibition prevented WD-induced increases in aortic EnNaC expression and associated endothelial and subendothelial stiffness. XO inhibition also reduced vascular pro-inflammatory and maladaptive immune responses induced by consumption of a WD. XO inhibition also decreased WD-induced increases in renal TLR4 and fibronectin that associated proteinuria. Consumption of a WD leads to elevations in plasma uric acid, increased vascular XO activity, oxidative stress, vascular stiffness, and proteinuria all of which are attenuated with allopurinol administration. Copyright © 2017 Elsevier Inc

Allopurinol treatment and its effect on renal function in gout: a controlled study.

PubMed Central

Gibson, T; Rodgers, V; Potter, C; Simmonds, H A

1982-01-01

Fifty-nine patients with primary gout were treated with either a combination of colchicine and allopurinol or colchicine alone. Assessments of renal function over 2 years revealed a statistically significant fall of glomerular filtration rate an urine concentrating ability in those receiving only colchicine. The renal function of patients given allopurinol did not change. Treatment with allopurinol resulted ina significant reduction of ammonium excretion, a phenomenon which could not be readily explained. Urate clearance also declined during allopurinol treatment, and the impaired urate clearance associated with gout became more evident. The most important observation was that allopurinol retarded an apparent decline of renal function. Presumably this was achieved through its hypouricaemic effect and implies that the hyperuricaemia of gouty patients is deleterious to the kidneys. PMID:7039523

Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Williams, C. David; McGill, Mitchell R.; Lebofsky, Margitta

2014-02-01

Acetaminophen (APAP) overdose causes severe and occasionally fatal liver injury. Numerous drugs that attenuate APAP toxicity have been described. However these compounds frequently protect by cytochrome P450 inhibition, thereby preventing the initiating step of toxicity. We have previously shown that pretreatment with allopurinol can effectively protect against APAP toxicity, but the mechanism remains unclear. In the current study, C3HeB/FeJ mice were administered allopurinol 18 h or 1 h prior to an APAP overdose. Administration of allopurinol 18 h prior to APAP overdose resulted in an 88% reduction in liver injury (serum ALT) 6 h after APAP; however, 1 h pretreatmentmore » offered no protection. APAP-cysteine adducts and glutathione depletion kinetics were similar with or without allopurinol pretreatment. The phosphorylation and mitochondrial translocation of c-jun-N-terminal-kinase (JNK) have been implicated in the progression of APAP toxicity. In our study we showed equivalent early JNK activation (2 h) however late JNK activation (6 h) was attenuated in allopurinol treated mice, which suggests that later JNK activation is more critical for the toxicity. Additional mice were administered oxypurinol (primary metabolite of allopurinol) 18 h or 1 h pre-APAP, but neither treatment protected. This finding implicated an aldehyde oxidase (AO)-mediated metabolism of allopurinol, so mice were treated with hydralazine to inhibit AO prior to allopurinol/APAP administration, which eliminated the protective effects of allopurinol. We evaluated potential targets of AO-mediated preconditioning and found increased hepatic metallothionein 18 h post-allopurinol. These data show metabolism of allopurinol occurring independent of P450 isoenzymes preconditions the liver and renders the animal less susceptible to an APAP overdose. - Highlights: • 18 h allopurinol pretreatment protects against acetaminophen-induced liver injury. • 1 h allopurinol pretreatment does not protect

Risk of cutaneous adverse events with febuxostat treatment in patients with skin reaction to allopurinol. A retrospective, hospital-based study of 101 patients with consecutive allopurinol and febuxostat treatment.

PubMed

Bardin, Thomas; Chalès, Gérard; Pascart, Tristan; Flipo, René-Marc; Korng Ea, Hang; Roujeau, Jean-Claude; Delayen, Aurélie; Clerson, Pierre

2016-05-01

To investigate the cutaneous tolerance of febuxostat in gouty patients with skin intolerance to allopurinol. We identified all gouty patients who had sequentially received allopurinol and febuxostat in the rheumatology departments of 4 university hospitals in France and collected data from hospital files using a predefined protocol. Patients who had not visited the prescribing physician during at least 2 months after febuxostat prescription were excluded. The odds ratio (OR) for skin reaction to febuxostat in patients with a cutaneous reaction to allopurinol versus no reaction was calculated. For estimating the 95% confidence interval (95% CI), we used the usual Wald method and a bootstrap method. In total, 113 gouty patients had sequentially received allopurinol and febuxostat; 12 did not visit the prescribing physician after febuxostat prescription and were excluded. Among 101 patients (86 males, mean age 61±13.9 years), 2/22 (9.1%) with a history of cutaneous reactions to allopurinol showed skin reactions to febuxostat. Two of 79 patients (2.5%) without a skin reaction to allopurinol showed skin intolerance to febuxostat. The ORs were not statistically significant with the usual Wald method (3.85 [95% CI 0.51-29.04]) or bootstrap method (3.86 [95% CI 0.80-18.74]). The risk of skin reaction with febuxostat seems moderately increased in patients with a history of cutaneous adverse events with allopurinol. This moderate increase does not support the cross-reactivity of the two drugs. Copyright © 2015. Published by Elsevier SAS.

Allopurinol use in pregnancy in three women with inflammatory bowel disease: safety and outcomes: a case series

PubMed Central

2013-01-01

Background Allopurinol is a frequently prescribed drug. In inflammatory bowel disease patients who shunt thiopurine metabolism towards more toxic and less desirable pathways, allopurinol is proving to be an effective add on therapy with good resultant disease control and less treatment side effects. As many such patients are young, the potential for pregnant women to be exposed to allopurinol is increasing. The safety of allopurinol in pregnancy is not known however. Case presentation We report three cases of safe use of allopurinol in pregnancy for women with inflammatory bowel disease. This included 2 patients with ulcerative colitis and 1 patient with fistulising Crohn’s disease. Allopurinol was used throughout pregnancy in all patients. All 3 pregnancies resulted in normal healthy babies born at term by Caesarean section. Conclusion It is important to evaluate and document the safety of allopurinol during pregnancy, as it is finding new roles in young patients. These three cases add significantly to the very limited data on allopurinol use in pregnancy. We encourage reporting of all cases of allopurinol use in pregnant patients and suggest an allopurinol pregnancy registry to document drug exposures and outcomes. PMID:24345189

Allopurinol use in pregnancy in three women with inflammatory bowel disease: safety and outcomes: a case series.

PubMed

Fazal, Muhammad W; Doogue, Matt P; Leong, Rupert W; Bampton, Peter A; Andrews, Jane M

2013-12-17

Allopurinol is a frequently prescribed drug. In inflammatory bowel disease patients who shunt thiopurine metabolism towards more toxic and less desirable pathways, allopurinol is proving to be an effective add on therapy with good resultant disease control and less treatment side effects. As many such patients are young, the potential for pregnant women to be exposed to allopurinol is increasing. The safety of allopurinol in pregnancy is not known however. We report three cases of safe use of allopurinol in pregnancy for women with inflammatory bowel disease. This included 2 patients with ulcerative colitis and 1 patient with fistulising Crohn's disease. Allopurinol was used throughout pregnancy in all patients. All 3 pregnancies resulted in normal healthy babies born at term by Caesarean section. It is important to evaluate and document the safety of allopurinol during pregnancy, as it is finding new roles in young patients. These three cases add significantly to the very limited data on allopurinol use in pregnancy. We encourage reporting of all cases of allopurinol use in pregnant patients and suggest an allopurinol pregnancy registry to document drug exposures and outcomes.

Pathways of nitrogen assimilation in cowpea nodules studied using /sup 15/N/sub 2/ and allopurinol. [Vigna unguiculata L. Walp. cv Vita

DOE Office of Scientific and Technical Information (OSTI.GOV)

Atkins, C.A.; Storer, P.J.; Pate, J.S.

1988-01-01

In the presence of 0.5 millimolar allopurinol (4-hydroxypyrazolo (3,4-d)pyrimidine), an inhibitor of NAD:xanthine oxidoreductase (EC 1.2.3.2), intact attached nodules of cowpea (vigna unguiculata L. Walp. cv Vita 3) formed (/sup 15/N)xanthine from /sup 15/N/sub 2/ at rates equivalent to those of ureide synthesis, confirming the direct assimilation of fixed nitrogen into purines. Xanthine accumulated in nodules and was exported in increasing amounts in xylem of allopurinol-treated plants. Other intermediates of purine oxidation, de novo purine synthesis, and ammonia assimilation did not increase and, over the time course of experiments (4 hours), allopurinol had no effect on nitrogenase (EC 1.87.99.2) activity.more » Negligible /sup 15/N -labeling of asparagine from /sup 15/N/sub 2/ was observed, suggesting that the significant pool (up to 14 micromoles per gram of nodule fresh weight) of this amide in cowpea nodules was not formed directly from fixation but may have accumulated as a consequence of phloem delivery.« less

Long-term allopurinol use decreases the risk of prostate cancer in patients with gout: a population-based study.

PubMed

Shih, H-J; Kao, M-C; Tsai, P-S; Fan, Y-C; Huang, C-J

2017-09-01

Clinical observations indicated an increased risk of developing prostate cancer in gout patients. Chronic inflammation is postulated to be one crucial mechanism for prostate carcinogenesis. Allopurinol, a widely used antigout agent, possesses potent anti-inflammation capacity. We elucidated whether allopurinol decreases the risk of prostate cancer in gout patients. We analyzed data retrieved from Taiwan National Health Insurance Database between January 2000 and December 2012. Patients diagnosed with gout during the study period with no history of prostate cancer and who had never used allopurinol were selected. Four allopurinol use cohorts (that is, allopurinol use (>365 days), allopurinol use (181-365 days), allopurinol use (91-180 days) and allopurinol use (31-90 days)) and one cohort without using allopurinol (that is, allopurinol use (No)) were included. The study end point was the diagnosis of new-onset prostate cancer. Multivariable Cox proportional hazards regression and propensity score-adjusted Cox regression models were used to estimate the association between the risk of prostate cancer and allopurinol treatment in gout patients after adjusting for potential confounders. A total of 25 770 gout patients (aged between 40 and 100 years) were included. Multivariable Cox regression analyses revealed that the risk of developing prostate cancer in the allopurinol use (>365 days) cohort was significantly lower than the allopurinol use (No) cohort (adjusted hazard ratio (HR)=0.64, 95% confidence interval (CI)=0.45-0.9, P=0.011). After propensity score adjustment, the trend remained the same (adjusted HR=0.66, 95% CI=0.46-0.93, P=0.019). Long-term (more than 1 year) allopurinol use may associate with a decreased risk of prostate cancer in gout patients.

Randomized controlled trial of febuxostat versus allopurinol or placebo in individuals with higher urinary uric acid excretion and calcium stones.

PubMed

Goldfarb, David S; MacDonald, Patricia A; Gunawardhana, Lhanoo; Chefo, Solomon; McLean, Lachy

2013-11-01

Higher urinary uric acid excretion is a suspected risk factor for calcium oxalate stone formation. Febuxostat, a xanthine oxidoreductase inhibitor, is effective in lowering serum urate concentration and urinary uric acid excretion in healthy volunteers and people with gout. This work studied whether febuxostat, compared with allopurinol and placebo, would reduce 24-hour urinary uric acid excretion and prevent stone growth or new stone formation. In this 6-month, double-blind, multicenter, randomized controlled trial, hyperuricosuric participants with a recent history of calcium stones and one or more radio-opaque calcium stone ≥ 3 mm (as seen by multidetector computed tomography) received daily febuxostat at 80 mg, allopurinol at 300 mg, or placebo. The primary end point was percent change from baseline to month 6 in 24-hour urinary uric acid. Secondary end points included percent change from baseline to month 6 in size of index stone and change from baseline in the mean number of stones and 24-hour creatinine clearance. Of 99 enrolled participants, 86 participants completed the study. Febuxostat led to significantly greater reduction in 24-hour urinary uric acid (-58.6%) than either allopurinol (-36.4%; P=0.003) or placebo (-12.7%; P<0.001). Percent change from baseline in the size of the largest calcium stone was not different with febuxostat compared with allopurinol or placebo. There was no change in stone size, stone number, or renal function. No new safety concerns were noted for either drug. Febuxostat (80 mg) lowered 24-hour urinary uric acid significantly more than allopurinol (300 mg) in stone formers with higher urinary uric acid excretion after 6 months of treatment. There was no change in stone size or number over the 6-month period.

Achieving serum urate goal: a comparative effectiveness study between allopurinol and febuxostat.

PubMed

Hatoum, Hind; Khanna, Dinesh; Lin, Swu-Jane; Akhras, Kasem S; Shiozawa, Aki; Khanna, Puja

2014-03-01

Febuxostat is recommended as 1 of 2 first-line urate-lowering therapies (ULT) for treating gout in the 2012 American College of Rheumatology Guidelines. Several efficacy trials have compared febuxostat with allopurinol treatment, but real-world comparative data are limited. We compared effectiveness of the 2 agents in reaching serum urate (sUA) level goal (< 6 mg/dL) within 6 months (main endpoint), factors impacting the likelihood of reaching goal, and outcomes in allopurinol patients who were switched to febuxostat therapy after failing to reach sUA level goal. Data from the General Electric Electronic Medical Record database on adult patients with newly diagnosed gout, who had started treatment with allopurinol or febuxostat in 2009 or thereafter were analyzed. Descriptive statistics, bivariate analyses, and logistic regressions were used. Allopurinol (n = 17 199) and febuxostat (n = 1190) patients had a mean ± standard deviation (SD) age of 63.7 (± 13.37) years; most patients were men and white. Average daily medication doses (mg) in the first 6 months were 184.9 ± 96.7 and 48.4 ± 15.8 for allopurinol- and febuxostat-treated patients, respectively; 4.8% of allopurinol-treated patients switched to febuxostat, whereas 25.7% of febuxostat-treated patients switched to allopurinol. Febuxostat patients had lower estimated glomerular filtration rate levels, more diabetes mellitus, or tophi at baseline (P < 0.05) and 29.2% and 42.2% of patients in the allopurinol and febuxostat groups achieved goal sUA levels (P < 0.0001). Febuxostat was significantly more effective in patients reaching sUA goal (adjusted odds ratio, 1.73; 95% CI, 1.48-2.01). Older patients and women had greater likelihood of reaching sUA goal level; however, patients with higher Charlson Comorbidity Index scores, blacks, or those with estimated glomerular filtration rates between 15 to ≤ 60 mL/min had reduced likelihood of attaining goal (P < 0.05). Among allopurinol-treated patients who were

Efficacy and safety of febuxostat for prevention of tumor lysis syndrome in patients with malignant tumors receiving chemotherapy: a phase III, randomized, multi-center trial comparing febuxostat and allopurinol.

PubMed

Tamura, Kazuo; Kawai, Yasukazu; Kiguchi, Toru; Okamoto, Masataka; Kaneko, Masahiko; Maemondo, Makoto; Gemba, Kenichi; Fujimaki, Katsumichi; Kirito, Keita; Goto, Tetsuya; Fujisaki, Tomoaki; Takeda, Kenji; Nakajima, Akihiro; Ueda, Takanori

2016-10-01

Control of serum uric acid (sUA) levels is very important during chemotherapy in patients with malignant tumors, as the risks of tumor lysis syndrome (TLS) and renal events are increased with increasing levels of sUA. We investigated the efficacy and safety of febuxostat, a potent non-purine xanthine oxidase inhibitor, compared with allopurinol for prevention of hyperuricemia in patients with malignant tumors, including solid tumors, receiving chemotherapy in Japan. An allopurinol-controlled multicenter, open-label, randomized, parallel-group comparative study was carried out. Patients with malignant tumors receiving chemotherapy, who had an intermediate risk of TLS or a high risk of TLS and were not scheduled to be treated with rasburicase, were enrolled and then randomized to febuxostat (60 mg/day) or allopurinol (300 or 200 mg/day). All patients started to take the study drug 24 h before chemotherapy. The primary objective was to confirm the non-inferiority of febuxostat to allopurinol based on the area under the curve (AUC) of sUA for a 6-day treatment period. Forty-nine and 51 patients took febuxostat and allopurinol, respectively. sUA decreased over time after initiation of study treatment. The least squares mean difference of the AUC of sUA between the treatment groups was -33.61 mg h/dL, and the 95 % confidence interval was -70.67 to 3.45, demonstrating the non-inferiority of febuxostat to allopurinol. No differences were noted in safety outcomes between the treatment groups. Febuxostat demonstrated an efficacy and safety similar to allopurinol in patients with malignant tumors receiving chemotherapy. http://www.clinicaltrials.jp ; Identifier: JapicCTI-132398.

A Real-World Study of Switching From Allopurinol to Febuxostat in a Health Plan Database

PubMed Central

Altan, Aylin; Shiozawa, Aki; Bancroft, Tim; Singh, Jasvinder A.

2015-01-01

Objective The objective of this study was to assess the real-world comparative effectiveness of continuing on allopurinol versus switching to febuxostat. Methods In a retrospective claims data study of enrollees in health plans affiliated with Optum, we evaluated patients from February 1, 2009, to May 31, 2012, with a gout diagnosis, a pharmacy claim for allopurinol or febuxostat, and at least 1 serum uric acid (SUA) result available during the follow-up period. Univariate and multivariable-adjusted analyses (controlling for patient demographics and clinical factors) assessed the likelihood of SUA lowering and achievement of target SUA of less than 6.0 mg/dL or less than 5.0 mg/dL in allopurinol continuers versus febuxostat switchers. Results The final study population included 748 subjects who switched to febuxostat from allopurinol and 4795 continuing users of allopurinol. The most common doses of allopurinol were 300 mg/d or less in 95% of allopurinol continuers and 93% of febuxostat switchers (prior to switching); the most common dose of febuxostat was 40 mg/d, in 77% of febuxostat switchers (after switching). Compared with allopurinol continuers, febuxostat switchers had greater (1) mean preindex SUA, 8.0 mg/dL versus 6.6 mg/dL (P < 0.001); (2) likelihood of postindex SUA of less than 6.0 mg/dL, 62.2% versus 58.7% (P = 0.072); (3) likelihood of postindex SUA of less than 5.0 mg/dL, 38.9% versus 29.6% (P < 0.001); and (4) decrease in SUA, 1.8 (SD, 2.2) mg/dL versus 0.4 (SD, 1.7) mg/dL (P < 0.001). In multivariable-adjusted analyses, compared with allopurinol continuers, febuxostat switchers had significantly higher likelihood of achieving SUA of less than 6.0 mg/dL (40% higher) and SUA of less than 5.0 mg/dL (83% higher). Conclusions In this “real-world” setting, many patients with gout not surprisingly were not treated with maximum permitted doses of allopurinol. Patients switched to febuxostat were more likely to achieve target SUA levels than those

A Real-World Study of Switching From Allopurinol to Febuxostat in a Health Plan Database.

PubMed

Altan, Aylin; Shiozawa, Aki; Bancroft, Tim; Singh, Jasvinder A

2015-12-01

The objective of this study was to assess the real-world comparative effectiveness of continuing on allopurinol versus switching to febuxostat. In a retrospective claims data study of enrollees in health plans affiliated with Optum, we evaluated patients from February 1, 2009, to May 31, 2012, with a gout diagnosis, a pharmacy claim for allopurinol or febuxostat, and at least 1 serum uric acid (SUA) result available during the follow-up period. Univariate and multivariable-adjusted analyses (controlling for patient demographics and clinical factors) assessed the likelihood of SUA lowering and achievement of target SUA of less than 6.0 mg/dL or less than 5.0 mg/dL in allopurinol continuers versus febuxostat switchers. The final study population included 748 subjects who switched to febuxostat from allopurinol and 4795 continuing users of allopurinol. The most common doses of allopurinol were 300 mg/d or less in 95% of allopurinol continuers and 93% of febuxostat switchers (prior to switching); the most common dose of febuxostat was 40 mg/d, in 77% of febuxostat switchers (after switching). Compared with allopurinol continuers, febuxostat switchers had greater (1) mean preindex SUA, 8.0 mg/dL versus 6.6 mg/dL (P < 0.001); (2) likelihood of postindex SUA of less than 6.0 mg/dL, 62.2% versus 58.7% (P = 0.072); (3) likelihood of postindex SUA of less than 5.0 mg/dL, 38.9% versus 29.6% (P < 0.001); and (4) decrease in SUA, 1.8 (SD, 2.2) mg/dL versus 0.4 (SD, 1.7) mg/dL (P < 0.001). In multivariable-adjusted analyses, compared with allopurinol continuers, febuxostat switchers had significantly higher likelihood of achieving SUA of less than 6.0 mg/dL (40% higher) and SUA of less than 5.0 mg/dL (83% higher). In this "real-world" setting, many patients with gout not surprisingly were not treated with maximum permitted doses of allopurinol. Patients switched to febuxostat were more likely to achieve target SUA levels than those who continued on generally stable doses of

Allopurinol use and the risk of acute cardiovascular events in patients with gout and diabetes.

PubMed

Singh, Jasvinder A; Ramachandaran, Rekha; Yu, Shaohua; Curtis, Jeffrey R

2017-03-14

Few studies, if any, have examined cardiovascular outcomes in patients with diabetes and gout. Both diabetes and gout are risk factors for cardiovascular disease. The objective of this study was to examine the effect of allopurinol on the risk of incident acute cardiovascular events in patients with gout and diabetes. We used the 2007-2010 Multi-Payer Claims Database (MPCD) that linked health plan data from national commercial and governmental insurances, representing beneficiaries with United Healthcare, Medicare, or Medicaid coverage. In patients with gout and diabetes, we assessed the current allopurinol use, defined as a new filled prescription for allopurinol, as the main predictor of interest. Our outcome of interest was the occurrence of the first Incident hospitalized myocardial infarction (MI) or stroke (composite acute cardiovascular event), after which observations were censored. We employed multivariable-adjusted Cox proportional hazards models that simultaneously adjusted for patient demographics, cardiovascular risk factors and other medical comorbidities. We calculated hazard ratios [HR] (95% confidence intervals [CI]) for incident composite (MI or stroke) acute cardiovascular events. We performed sensitivity analyses that additionally adjusted for the presence of immune diseases and colchicine use, as potential confounders. There were 2,053,185 person days (5621.3 person years) of current allopurinol use and 1,671,583 person days (4576.5 person years) of prior allopurinol use. There were 158 incident MIs or strokes in current and 151 in prior allopurinol users, respectively. Compared to previous allopurinol users, current allopurinol users had significantly lower adjusted hazard of incident acute cardiovascular events (incident stroke or MI), with an HR of 0.67 (95% CI, 0.53, 0.84). Sensitivity analyses, additionally adjusted for immune diseases or colchicine use, confirmed this association. Current allopurinol use protected against the occurrence

Cost-effectiveness analysis of HLA-B*58: 01 genetic testing before initiation of allopurinol therapy to prevent allopurinol-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in a Malaysian population.

PubMed

Chong, Huey Yi; Lim, Yi Heng; Prawjaeng, Juthamas; Tassaneeyakul, Wichittra; Mohamed, Zahurin; Chaiyakunapruk, Nathorn

2018-02-01

Studies found a strong association between allopurinol-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and the HLA-B*58:01 allele. HLA-B*58:01 screening-guided therapy may mitigate the risk of allopurinol-induced SJS/TEN. This study aimed to evaluate the cost-effectiveness of HLA-B*58:01 screening before allopurinol therapy initiation compared with the current practice of no screening for Malaysian patients with chronic gout in whom a hypouricemic agent is indicated. This cost-effectiveness analysis adopted a societal perspective with a lifetime horizon. A decision tree model coupled with Markov models were developed to estimate the costs and outcomes, represented by quality-adjusted life years (QALYs) gained, of three treatment strategies: (a) current practice (allopurinol initiation without HLA-B*58:01 screening); (b) HLA-B*58:01 screening before allopurinol initiation; and (c) alternative treatment (probenecid) without HLA-B*58:01 screening. The model was populated with data from literature review, meta-analysis, and published government documents. Cost values were adjusted for the year 2016, with costs and health outcomes discounted at 3% per annum. A series of sensitivity analysis including probabilistic sensitivity analysis were carried out to determine the robustness of the findings. Both HLA-B*58:01 screening and probenecid prescribing were dominated by current practice. Compared with current practice, HLA-B*58:01 screening resulted in 0.252 QALYs loss per patient at an additional cost of USD 322, whereas probenecid prescribing resulted in 1.928 QALYs loss per patient at an additional cost of USD 2203. One SJS/TEN case would be avoided for every 556 patients screened. At the cost-effectiveness threshold of USD 8695 per QALY, the probability of current practice being the best choice is 99.9%, in contrast with 0.1 and 0% in HLA-B*58:01 screening and probenecid prescribing, respectively. This is because of the low incidence of

Inhibition properties of propolis extracts to some clinically important enzymes.

PubMed

Baltas, Nimet; Yildiz, Oktay; Kolayli, Sevgi

2016-01-01

The present study was conducted to envisage inhibition effects of propolis on the crucial enzymes, urease, xanthine oxidase (XO) and acetylcholinesterase (AChE). Some of the antioxidant properties of the propolis samples were determined using the total phenolic content (TPE) and total flavonoids in the eight different ethanolic propolis extracts (EPE) samples. Inhibition values of the enzymes were expressed as inhibition concentration (IC 50 ; mg/mL or μg/mL) causing 50% inhibition of the enzymes with donepezil, acetohydroxamic acid and allopurinol as reference inhibitors. All the propolis extracts exhibited variable inhibition effects on these enzymes, but the higher the phenolic contents the lower the inhibitions values (IC 50 = 0.074 to 1.560 mg/mL). IC 50 values of the P5 propolis sample having the highest TPE, obtained from Zonguldak, for AChE, urease and XO were 0.081 ± 0.009, 0.080 ± 0.006 and 0.074 ± 0.011 μg/mL, respectively. The EPE proved to be a good source of inhibitor agents that can be used as natural inhibitors to serve human health.

Lipid-derived free radical production in superantigen-induced interstitial pneumonia

PubMed Central

Miyakawa, Hisako; Mason, Ronald P.; Jiang, JinJie; Kadiiska, Maria B.

2009-01-01

We studied the free radical generation involved in the development of interstitial pneumonia (IP) in an animal model of autoimmune disease. We observed an electron spin resonance (ESR) spectrum of α-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) radical adducts detected in the lipid extract of lungs in autoimmune-prone mice after intratracheal instillation of staphylococcal enterotoxin B. The POBN adducts detected by ESR were paralleled by infiltration of macrophages and neutrophils in the bronchoalveolar lavage fluid. To further investigate the mechanism of free radical generation, mice were pretreated with the macrophage toxicant gadolinium chloride, which significantly suppressed the radical generation. Free radical generation was also decreased by pretreatment with the xanthine oxidase (XO) inhibitor allopurinol, the iron chelator Desferal, and the inducible nitric oxide synthase (iNOS) inhibitor 1400W. Histopathologically, these drugs significantly reduced both the cell infiltration to alveolar septal walls and the synthesis of pulmonary collagen fibers. Experiments with NADPH oxidase knockout mice showed that NADPH oxidase did not contribute to lipid radical generation. These results suggest that lipid-derived carbon-centered free radical production is important in the manifestation of IP and that a macrophage toxicant, an XO inhibitor, an iron chelator, and an iNOS inhibitor protect against both radical generation and the manifestation of IP. PMID:19376221

Allopurinol might improve response to azathioprine and 6-mercaptopurine by correcting an unfavorable metabolite ratio.

PubMed

Gardiner, Sharon J; Gearry, Richard B; Burt, Michael J; Chalmers-Watson, Teresa; Chapman, Bruce A; Ross, Alison G; Stedman, Catherine A M; Huelsen, Alexander; Barclay, Murray L

2011-01-01

Allopurinol potentiates azathioprine and 6-mercaptopurine (6-MP) by increasing 6-thioguanine nucleotide (6-TGN) metabolite concentrations. The outcome might also be improved by adding allopurinol in individuals who preferentially produce 6-methylmercaptopurine nucleotides (6-MMPN), rather than 6-TGN. The aim of the present study was to investigate the effect of allopurinol on concentrations of 6-MMPN and 6-TGN in individuals with a high ratio of these metabolites (>20), which is indicative of a poor thiopurine response. Sixteen individuals were identified who were taking azathioprine or 6-MP, and were commenced on allopurinol to improve a high 6-MMPN:TGN ratio. Metabolite concentrations were compared before and after commencing allopurinol, and markers of disease control were compared. The addition of 100-300 mg allopurinol daily and thiopurine dose reduction (17-50% of the original dose) resulted in a reduction of the median (and range) 6-MMPN concentration, from 11,643 (3,365-27,832) to 221 (55-844) pmol/8×10(8) red blood cells (RBC; P=0.0005), increased 6-TGN from 162 (125-300) to 332 (135-923) pmol/8×10(8) RBC (P=0.0005), and reduced the 6-MMPN:6-TGN ratio from 63 (12-199) to 1 (0.1-4.5) (P=0.0005). There was a significant reduction in steroid dose requirements at 12 months (P=0.04) and trends for improvement in other markers of disease control. One patient developed red cell aplasia that resolved upon stopping azathioprine and allopurinol. In those with a high 6-MMPN:6-TGN ratio (>20), response to thiopurine treatment might be improved by the addition of allopurinol, together with a reduced thiopurine dose and close hematological monitoring. © 2010 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Modelling the thermal conductivity of (U xTh 1-x)O 2 and (U xPu 1-x)O 2

DOE PAGES

Cooper, M. W. D.; Middleburgh, S. C.; Grimes, R. W.

2015-07-15

The degradation of thermal conductivity due to the non-uniform cation lattice of (U xTh 1-x)O 2 and (U xPu 1-x)O 2 solid solutions has been investigated by molecular dynamics, using the non-equilibrium method, from 300 to 2000 K. Degradation of thermal conductivity is predicted in (U xTh 1-x)O 2 and (U xPu 1-x)O 2 as compositions deviate from the pure end members: UO 2, PuO 2 and ThO 2. The reduction in thermal conductivity is most apparent at low temperatures where phonon-defect scattering dominates over phonon-phonon interactions. The effect is greater for (U xTh 1-x)O 2 than U xPu 1-x)Omore » 2 due to the greater mismatch in cation size. Parameters for an analytical expressions have been developed that describe the predicted thermal conductivities over the full temperature and compositional ranges. Finally, these expressions may be used in higher level fuel performance codes.« less

Stability of allopurinol and of five antineoplastics in suspension.

PubMed

Dressman, J B; Poust, R I

1983-04-01

The stability of allopurinol, azathioprine, chlorambucil, melphalan, mercaptopurine, and thioguanine each in an extemporaneously prepared suspension was studied. Tablets of each drug were crushed, mixed with a suspending agent, and brought to a final volume of 10, 15, or 20 ml with a 2:1 mixture of simple syrup and wild cherry syrup. Suspensions were prepared in the following concentrations: allopurinol (20 mg/ml), azathioprine (50 mg/ml), chlorambucil (2 mg/ml), melphalan (2 mg/ml), mercaptopurine (50 mg/ml), and thioguanine (40 mg/ml). Using high-performance liquid chromatography or ultraviolet scans, duplicate assays were performed on each suspension periodically during storage for up to 84 days at ambient room temperature or 5 degrees C. The time required for the suspensions to drop below 90% of labeled strength was used as an indicator of drug stability. Allopurinol and azathioprine were stable for at least 56 days at room temperature and at 5 degrees C. Chlorambucil decomposed rapidly at room temperature but was stable for seven days when stored at 5 degrees C. Melphalan suspensions did not meet the stated criteria for stability even at the time of initial assay. Mercaptopurine and thioguanine were stable for 14 and 84 days, respectively, at room temperature; at 5 degrees C, assay values dropped below those obtained at room temperature. In the suspension formulation tested, allopurinol, azathioprine, mercaptopurine, and thioguanine are stable for at least 14 days at room temperature; chlorambucil suspensions should be refrigerated and discarded after seven days. Melphalan decomposes too rapidly to make this suspension formulation feasible for extemporaneous compounding.

Vibrational spectra of Mg2KH(XO4)2·15H2O (X = P, As) containing dimer units [H(XO4)2

NASA Astrophysics Data System (ADS)

Stefov, V.; Koleva, V.; Najdoski, M.; Abdija, Z.; Cahil, A.; Šoptrajanov, B.

2017-08-01

Infrared and Raman spectra of Mg2KH(PO4)2·15H2O and Mg2KH(AsO4)2·15H2O and a series of their partially deuterated analogues were recorded and analyzed. Compounds of the type Mg2KH(XO4)2·15H2O (X = P, As) are little-known and a rare case of phosphate and arsenate salts containing dimer units [H(XO4)2] in the crystal structure. The analysis of their IR spectra (recorded at room and liquid nitrogen temperature) and Raman spectra showed that the spectral characteristics of the XO4 groups connected in a dimer through a proton are not consistent with the presence of X-O-H covalent linkage and C1 crystallographic symmetry of the XO4 groups. The observation of a singlet Raman band for the ν1(XO4) mode as well as the absence of substantial splitting of the ν3(XO4) modes and IR activation of the ν1(XO4) mode suggest that the dimer units [H(XO4)2] are most probably symmetric rather than non-symmetric ones. It was found that, in the vibrational spectra of Mg2KH(AsO4)2·15H2O, both ν1(AsО4) and ν3(AsО4) modes have practically the same wavenumber around 830 cm- 1. It was also established that the ν4(PО4) modes in the deuterated hydrogendiphosphate compound are strongly coupled, most probably with HDO and/or D2O librations. As a whole, the spectral picture of Mg2KH(XO4)2·15H2O (X = P, As) very much resembles that observed for the struvite type compounds with the formula KMgXO4·6H2O (X = P, As) which do not contain X-OH groups. This means that vibrations of the dimers [H(XO4)2] play a relatively small part in the general spectral appearance.

Allopurinol reduces B-type natriuretic peptide concentrations and haemoglobin but does not alter exercise capacity in chronic heart failure.

PubMed

Gavin, A D; Struthers, A D

2005-06-01

To study whether the effect of allopurinol on improvement of endothelial dysfunction in chronic heart failure (CHF) translates into improved exercise capacity and to examine whether allopurinol also improves B-type natriuretic peptide (BNP), the other important prognostic marker of CHF. Randomised, double blind, placebo controlled crossover trial. Teaching hospital. 50 patients with CHF (New York Heart Association functional classes II and III) were recruited. 50 patients with CHF were randomly assigned to three months' treatment with allopurinol (300 mg/day) or placebo. At two and three months into treatment, they underwent a modified Bruce exercise protocol and a six minute walk test. Blood was taken for BNP and haemoglobin analysis. Neither exercise test was altered by allopurinol. However, plasma BNP concentrations fell significantly (p = 0.035) with allopurinol (11.9 pmol/l) versus placebo (14.4 pmol/l). Haemoglobin concentrations also fell highly significantly with allopurinol (p = 0.001). An important negative finding is that despite high hopes for it, allopurinol had no effect on exercise capacity in CHF. On the other hand, allopurinol did reduce BNP, which is the best available surrogate marker for prognosis in CHF.

Allopurinol hypersensitivity: a systematic review of all published cases, 1950-2012.

PubMed

Ramasamy, Sheena N; Korb-Wells, Cameron S; Kannangara, Diluk R W; Smith, Myles W H; Wang, Nan; Roberts, Darren M; Graham, Garry G; Williams, Kenneth M; Day, Richard O

2013-10-01

Allopurinol is the primary therapy for the management of chronic gout. Utilization of allopurinol has increased in tandem with the growing prevalence of gout globally. This exposes more patients to the risk of allopurinol hypersensitivity (AH), a rare adverse reaction characterised by a spectrum of cutaneous reactions and systemic manifestations. Severe forms of AH have been associated with high mortality. The pathophysiology underlying this reaction remains unknown, but several risk factors have been proposed. The aim of this study was to review all published cases of AH documented in the literature in order to better understand the constellation of factors predisposing to this reaction, building on previous reviews by Lupton and Odom, Singer and Wallace and Arellano and Sacristan. A literature search was conducted in MEDLINE and EMBASE to identify relevant articles published between January 1950 and December 2012, with no language restrictions imposed. Articles that were included reported either allopurinol-induced cutaneous manifestations alone or satisfied the diagnostic criteria for AH as defined by Singer and Wallace. Nine hundred and one patients (overall AH cohort) were identified from 320 publications. Of these patients, 802 satisfied the Singer and Wallace criteria ('Singer and Wallace' cohort) while 99 patients had only mild cutaneous manifestations ('non-Singer and Wallace' cohort). Data were often incomplete; hence the results reported reflect the fractions of the subsets of the cohort where the data in question were available. In the overall AH cohort, 58 % (416/722) were male. The majority (73 %; 430/590) of patients were Asian. Renal impairment (48 %; 182/376) and hypertension (42 %; 160/376) were the most common chronic conditions; accordingly, diuretics (45 %; 114/252) and antihypertensives (39 %; 99/252) were the most prevalent concomitant medications. Allopurinol was prescribed for approved indications (chronic gout and chemoprophylaxis) in only

Febuxostat, an Inhibitor of Xanthine Oxidase, Suppresses Lipopolysaccharide-Induced MCP-1 Production via MAPK Phosphatase-1-Mediated Inactivation of JNK

PubMed Central

Nomura, Johji; Busso, Nathalie; Ives, Annette; Tsujimoto, Syunsuke; Tamura, Mizuho; So, Alexander; Yamanaka, Yoshihiro

2013-01-01

Excess reactive oxygen species (ROS) formation can trigger various pathological conditions such as inflammation, in which xanthine oxidase (XO) is one major enzymatic source of ROS. Although XO has been reported to play essential roles in inflammatory conditions, the molecular mechanisms underlying the involvement of XO in inflammatory pathways remain unclear. Febuxostat, a selective and potent inhibitor of XO, effectively inhibits not only the generation of uric acid but also the formation of ROS. In this study, therefore, we examined the effects of febuxostat on lipopolysaccharide (LPS)-mediated inflammatory responses. Here we show that febuxostat suppresses LPS-induced MCP-1 production and mRNA expression via activating MAPK phosphatase-1 (MKP-1) which, in turn, leads to dephosphorylation and inactivation of JNK in macrophages. Moreover, these effects of febuxostat are mediated by inhibiting XO-mediated intracellular ROS production. Taken together, our data suggest that XO mediates LPS-induced phosphorylation of JNK through ROS production and MKP-1 inactivation, leading to MCP-1 production in macrophages. These studies may bring new insights into the novel role of XO in regulating inflammatory process through MAPK phosphatase, and demonstrate the potential use of XO inhibitor in modulating the inflammatory processes. PMID:24086554

Vibrational spectra of Mg2KH(XO4)2·15H2O (X=P, As) containing dimer units [H(XO4)2].

PubMed

Stefov, V; Koleva, V; Najdoski, M; Abdija, Z; Cahil, A; Šoptrajanov, B

2017-08-05

Infrared and Raman spectra of Mg 2 KH(PO 4 ) 2 ·15H 2 O and Mg 2 KH(AsO 4 ) 2 ·15H 2 O and a series of their partially deuterated analogues were recorded and analyzed. Compounds of the type Mg 2 KH(XO 4 ) 2 ·15H 2 O (X=P, As) are little-known and a rare case of phosphate and arsenate salts containing dimer units [H(XO 4 ) 2 ] in the crystal structure. The analysis of their IR spectra (recorded at room and liquid nitrogen temperature) and Raman spectra showed that the spectral characteristics of the XO 4 groups connected in a dimer through a proton are not consistent with the presence of X-O-H covalent linkage and C 1 crystallographic symmetry of the XO 4 groups. The observation of a singlet Raman band for the ν 1 (XO 4 ) mode as well as the absence of substantial splitting of the ν 3 (XO 4 ) modes and IR activation of the ν 1 (XO 4 ) mode suggest that the dimer units [H(XO 4 ) 2 ] are most probably symmetric rather than non-symmetric ones. It was found that, in the vibrational spectra of Mg 2 KH(AsO 4 ) 2 ·15H 2 O, both ν 1 (AsО 4 ) and ν 3 (AsО 4 ) modes have practically the same wavenumber around 830cm -1 . It was also established that the ν 4 (PО 4 ) modes in the deuterated hydrogendiphosphate compound are strongly coupled, most probably with HDO and/or D 2 O librations. As a whole, the spectral picture of Mg 2 KH(XO 4 ) 2 ·15H 2 O (X=P, As) very much resembles that observed for the struvite type compounds with the formula KMgXO 4 ·6H 2 O (X=P, As) which do not contain X-OH groups. This means that vibrations of the dimers [H(XO 4 ) 2 ] play a relatively small part in the general spectral appearance. Copyright © 2017 Elsevier B.V. All rights reserved.

Lack of efficacy during the switch from brand to generic allopurinol.

PubMed

De Vuono, Antonio; Scicchitano, Francesca; Palleria, Caterina; Russo, Emilio; De Sarro, Giovambattista; Gallelli, Luca

2013-07-01

We report for the first time the lack of therapeutic effects after the switch from a brand formulation of allopurinol to a generic one. A 56-year-old man, with a 5 years history of well-treated gout arthropathy with allopurinol (Zyloric(®) 300 mg/die), developed acute gout arthropathy after the switch from the brand formulation of allopurinol to a generic one. Clinical evaluation and laboratory findings confirmed the diagnosis of acute gout arthropathy. Generic formulation of the drug was dismissed and Zyloric(®) was administered with an improvement of both clinical symptoms and laboratory findings. In conclusion, even if generic formulations are considered to have the same effects in comparison to the brand one, more data are necessaries in order to well define their effectiveness and rationale use. Copyright © 2013 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Impact of the HLA-B(*)58:01 Allele and Renal Impairment on Allopurinol-Induced Cutaneous Adverse Reactions.

PubMed

Ng, Chau Yee; Yeh, Yu-Ting; Wang, Chuang-Wei; Hung, Shuen-Iu; Yang, Chih-Hsun; Chang, Ya-Ching; Chang, Wan-Chun; Lin, Yu-Jr; Chang, Chee-Jen; Su, Shih-Chi; Fan, Wen-Lang; Chen, Der-Yuan; Wu, Yeong-Jian Jan; Tian, Ya-Chung; Hui, Rosaline Chung-Yee; Chung, Wen-Hung

2016-07-01

Allopurinol, a common drug for treating hyperuricemia, is associated with cutaneous adverse drug reactions ranging from mild maculopapular exanthema to life-threatening severe cutaneous adverse reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. We have previously reported that HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese, but the associations of the HLA-B*58:01 genotype in an allopurinol-induced hypersensitivity phenotype remain unclear. To investigate the comprehensive associations of HLA-B*58:01, we enrolled 146 patients with allopurinol-induced cutaneous adverse drug reactions (severe cutaneous adverse reactions, n = 106; maculopapular exanthema, n = 40) and 285 allopurinol-tolerant control subjects. Among these allopurinol-induced cutaneous adverse drug reactions, HLA-B*58:01 was strongly associated with severe cutaneous adverse reactions (odds ratio [OR] = 44.0; 95% confidence interval = 21.5-90.3; P = 2.6 × 10(-41)), and the association was correlated with disease severity (OR = 44.0 for severe cutaneous adverse reactions, OR = 8.5 for maculopapular exanthema). The gene dosage effect of HLA-B*58:01 also influenced the development of allopurinol-induced cutaneous adverse drug reactions (OR = 15.25 for HLA-B*58:01 heterozygotes and OR = 72.45 for homozygotes). Furthermore, coexistence of HLA-B*58:01 and renal impairment increased the risk and predictive accuracy of allopurinol-induced cutaneous adverse drug reactions (heterozygous HLA-B*58:01 and normal renal function: OR = 15.25, specificity = 82%; homozygous HLA-B*58:01 and severe renal impairment: OR = 1269.45, specificity = 100%). This HLA-B*58:01 correlation study suggests that patients with coexisting HLA-B*58:01 and renal impairment (especially estimated glomerular filtration rate < 30ml/minute/1.73 m(2)) should be cautious and avoid using

Clinical and health care use characteristics of patients newly prescribed allopurinol, febuxostat and colchicine for gout

PubMed Central

Kim, Seoyoung C.; Schmidt, Bernhard M.W.; Franklin, Jessica M.; Liu, Jun; Solomon, Daniel H.; Schneeweiss, Sebastian

2014-01-01

Background Gout is a common inflammatory arthritis with the increasing prevalence in the developed countries. It is well-known that many patients with gout have significant comorbidities and high health care utilization. Methods Using US insurance claims data (2009–2011), a population-based cohort study was conducted to describe clinical characteristics and health care utilization patterns in patients with gout newly prescribed allopurinol, febuxostat or colchicine. Results There were 25,051 allopurinol, 4,288 febuxostat and 6,238 colchicine initiators. Mean age was 53 years and 83%–87% were male. More than half of patients had hypertension and hyperlipidemia, 20% had diabetes and 10% cardiovascular disease. The mean uric acid level (mg/dl) was similar at baseline ranging from 8.1 to 8.5 across the groups. Compared to allopurinol or colchicine initiators, febuxostat initiators had more comorbidities and greater health care uses including outpatient, inpatient or emergency room visits, both at baseline and during the follow-up. Use of gout related drugs, such as opioids, steroids and non-steroidal anti-inflammatory drugs, was most common in febuxostat and least common in colchicine initiators. The median daily dose at both start and end of treatment was 300mg for allopurinol, 40mg for febuxostat, and 1.2mg for colchicine. The dosage of allopurinol and febuxostat was rarely increased during the follow-up. Conclusion Patients who started allopurinol, febuxostat or colchicine for gout generally had hyperuricemia and multiple comorbidities. Febuxostat initiators had more comorbidities and greater use of health care resources and gout-related drugs than other groups. Overall, the dosages of allopurinol or febuxostat remained unchanged over time. PMID:23861232

Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study).

PubMed

Friedman, A B; Brown, S J; Bampton, P; Barclay, M L; Chung, A; Macrae, F A; McKenzie, J; Reynolds, J; Gibson, P R; Hanauer, S B; Sparrow, M P

2018-04-01

Thiopurine hypermethylation towards 6-methylmercaptopurine (6MMP) instead of 6-thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation. To prospectively determine efficacy of allopurinol-thiopurine combination and to compare 2 doses of allopurinol. In a multicentre, double-blind trial, patients with clinically active or steroid-dependent IBD and thiopurine shunting were randomised to 50 or 100 mg/d allopurinol and 25% of their screening thiopurine dose, which was subsequently optimised, aiming for 6TGN of 260-500 pmol/8x10 8 RBCs. The primary endpoint was steroid-free clinical remission at 24 weeks. Of 73 patients, 39 (53% [95% CI 42-65]) achieved steroid-free remission, (54% with 50 mg/d and 53% with 100 mg/d). 81% were able to discontinue steroids. Therapeutic 6TGN levels were achieved in both groups. Final thiopurine doses were lower with 100 mg/d allopurinol (P < 0.005). 6MMP: 6TGN ratio decreased from mean 64 to 4 (P < 0.001), being higher with 50 mg/d (6 ± 1.83) than for 100 mg/d ([1 ± 0.16], P = 0.003). Three patients on 50 mg/d failed to sustain low ratios at 24 weeks. Toxicity was minimal; three patients on 50 mg/d allopurinol developed transient leukopenia. Alanine aminotransferase concentrations decreased (P < 0.001) similarly in both arms. Faecal calprotectin levels at study end were lower in patients who achieved the primary endpoint (median 171 [85-541] vs 821[110-5892] ug/g, P = 0.03). Low-dose allopurinol-thiopurine combination safely reverses shunting and optimises 6TGN with associated improvement in disease activity. 100 mg/d allopurinol is preferable due to greater metabolite profile stability and lower thiopurine dose without additional toxicity. © 2018 John Wiley & Sons Ltd.

Involvement of the pagR gene of pXO2 in anthrax pathogenesis

PubMed Central

Liang, Xudong; Zhang, Enmin; Zhang, Huijuan; Wei, Jianchun; Li, Wei; Zhu, Jin; Wang, Bingxiang; Dong, Shulin

2016-01-01

Anthrax is a disease caused by Bacillus anthracis. Specifically, the anthrax toxins and capsules encoded by the pXO1 and pXO2 plasmids, respectively, are the major virulence factors. We previously reported that the pXO1 plasmid was retained in the attenuated strain of B. anthracis vaccine strains even after subculturing at high temperatures. In the present study, we reinvestigate the attenuation mechanism of Pasteur II. Sequencing of pXO1 and pXO2 from Pasteur II strain revealed mutations in these plasmids as compared to the reference sequences. Two deletions on these plasmids, one each on pXO1 and pXO2, were confirmed to be unique to the Pasteur II strain as compared to the wild-type strains. Gene replacement with homologous recombination revealed that the mutation in the promoter region of the pagR gene on pXO2, but not the mutation on pXO1, contributes to lethal levels of toxin production. This result was further confirmed by RT-PCR, western blot, and animal toxicity assays. Taken together, our results signify that the attenuation of the Pasteur II vaccine strain is caused by a mutation in the pagR gene on its pXO2 plasmid. Moreover, these data suggest that pXO2 plasmid encoded proteins are involved in the virulence of B. anthracis. PMID:27363681

Dissolution assessment of allopurinol immediate release tablets by near infrared spectroscopy.

PubMed

Smetiško, Jelena; Miljanić, Snežana

2017-10-25

The purpose of this study was to develop a NIR spectroscopic method for assessment of drug dissolution from allopurinol immediate release tablets. Thirty three different batches of allopurinol immediate release tablets containing constant amount of the active ingredient, but varying in excipients content and physical properties were introduced in a PLS calibration model. Correlating allopurinol dissolution reference values measured by the routinely used UV/Vis method, with the data extracted from the NIR spectra, values of correlation coefficient, bias, slope, residual prediction determination and root mean square error of prediction (0.9632, 0.328%, 1.001, 3.58, 3.75%) were evaluated. The obtained values implied that the NIR diffuse reflectance spectroscopy could serve as a faster and simpler alternative to the conventional dissolution procedure, even for the tablets with a very fast dissolution rate (>85% in 15minutes). Apart from the possibility of prediction of the allopurinol dissolution rate, the other multivariate technique, PCA, provided additional data on the non-chemical characteristics of the product, which could not be obtained from the reference dissolution values. Analysis on an independent set of samples confirmed that a difference between the UV/Vis reference method and the proposed NIR method was not significant. According to the presented results, the proposed NIR method may be suitable for practical application in routine analysis and for continuously monitoring the product's chemical and physical properties responsible for expected quality. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparative effectiveness of allopurinol versus febuxostat for preventing incident renal disease in older adults: an analysis of Medicare claims data.

PubMed

Singh, Jasvinder A; Cleveland, John D

2017-10-01

To assess the comparative effectiveness of allopurinol versus febuxostat for preventing incident renal disease in elderly. In a retrospective cohort study using 2006-2012 Medicare claims data, we included patients newly treated with allopurinol or febuxostat (baseline period of 183 days without either medication). We used 5:1 propensity-matched Cox regression analyses to compare the HR of incident renal disease with allopurinol use (and dose) versus febuxostat (reference). Sensitivity analyses included multivariable-adjusted regression models. There were 31 465 new allopurinol or febuxostat treatment episodes in 26 443 patients; 8570 ended in incident renal disease. Crude rates of incident renal disease per 1000 person-years were 192 with allopurinol versus 338 with febuxostat. Crude rates of incident renal disease per 1000 person-years were lower with higher daily dose: allopurinol <200, 200-299 and ≥300 mg/day with 238, 176 and 155; and febuxostat 40 and 80 mg/day with 341 and 326, respectively. In propensity-matched analyses, compared with febuxostat, allopurinol use was associated with lower HR of incident renal disease, 0.61 (95% CI 0.49 to 0.77). Compared with febuxostat 40 mg/day, allopurinol doses <200, 200-299 and ≥300 mg/day were associated with lower HR of incident renal disease, 0.75 (95% CI 0.65 to 0.86), 0.61 (95% CI 0.52 to 0.73) and 0.48 (95% CI 0.41 to 0.55), respectively. Sensitivity analyses using multivariable-adjusted regression confirmed these findings. Allopurinol was associated with a lower risk of incident renal disease in elderly patients than febuxostat. Future studies need to examine the mechanism of this potential renal benefit of allopurinol. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Low-temperature photoluminescence in NixMg1-xO nanocrystals

NASA Astrophysics Data System (ADS)

Churmanov, V. N.; Gruzdev, N. B.; Sokolov, V. I.; Pustovarov, V. A.; Ivanov, V. Yu.; Mironova-Ulmane, N. A.

2015-03-01

A study of the photoluminescence and photoluminescence excitation spectra of NixMg1-xO nanocrystals, at low-temperatures. We examine the processes of concentration quenching and supposed mechanisms of energy migration in NixMg1-xO. It is shown that the edge energies of the charge-transfer transitions in NixMg1-xO (x = 0.008) and NiO are practically identical.

Chronic Allopurinol Treatment during the Last Trimester of Pregnancy in Sows: Effects on Low and Normal Birth Weight Offspring

PubMed Central

Gieling, Elise T.; Antonides, Alexandra; Fink-Gremmels, Johanna; ter Haar, Kim; Kuller, Wikke I.; Meijer, Ellen; Nordquist, Rebecca E.; Stouten, Jacomijn M.; Zeinstra, Elly; van der Staay, Franz Josef

2014-01-01

Low-birth-weight (LBW) children are born with several risk factors for disease, morbidity and neonatal mortality, even if carried to term. Placental insufficiency leading to hypoxemia and reduced nutritional supply is the main cause for LBW. Brain damage and poor neurological outcome can be the consequence. LBW after being carried to term gives better chances for survival, but these children are still at risk for poor health and the development of cognitive impairments. Preventive therapies are not yet available. We studied the risk/efficacy of chronic prenatal treatment with the anti-oxidative drug allopurinol, as putative preventive treatment in piglets. LBW piglets served as a natural model for LBW. A cognitive holeboard test was applied to study the learning and memory abilities of these allopurinol treated piglets after weaning. Preliminary analysis of the plasma concentrations in sows and their piglets suggested that a daily dose of 15 mg.kg−1 resulted in effective plasma concentration of allopurinol in piglets. No adverse effects of chronic allopurinol treatment were found on farrowing, birth weight, open field behavior, learning abilities, relative brain, hippocampus and spleen weights. LBW piglets showed increased anxiety levels in an open field test, but cognitive performance was not affected by allopurinol treatment. LBW animals treated with allopurinol showed the largest postnatal compensatory body weight gain. In contrast to a previous study, no differences in learning abilities were found between LBW and normal-birth-weight piglets. This discrepancy might be attributable to experimental differences. Our results indicate that chronic prenatal allopurinol treatment during the third trimester of pregnancy is safe, as no adverse side effects were observed. Compensatory weight gain of treated piglets is a positive indication for the chronic prenatal use of allopurinol in these animals. Further studies are needed to assess the possible preventive effects

Allopurinol Use during Pregnancy - Outcome of 31 Prospectively Ascertained Cases and a Phenotype Possibly Indicative for Teratogenicity

PubMed Central

Hoeltzenbein, Maria; Stieler, Katja; Panse, Mary; Wacker, Evelin; Schaefer, Christof

2013-01-01

Allopurinol is a purine analogue that inhibits xanthine oxidase. It is mainly used for the treatment of hyperuricemia in patients with gout or tumor lysis syndrome. Experience with allopurinol in pregnancy is scarce. In 2011, Kozenko et al. reported on a child with multiple malformations after maternal treatment with allopurinol throughout pregnancy. Possible teratogenicity of allopurinol was proposed due to the similarity of the pattern of malformations in children with mycophenolate embryopathy. A possible common mechanism of both drugs, i.e. disruption of purine synthesis, was discussed. We report on the outcome of 31 prospectively ascertained pregnancies with allopurinol exposure at least during first trimester. Pregnancy outcomes were 2 spontaneous abortions, 2 elective terminations of pregnancy and 27 live born children. The overall rate of major malformations (3.7%) and of spontaneous abortions (cumulative incidence 11%, 95%-CI 3–40) were both within the normal range. However, there was one child with severe malformations including microphthalmia, cleft lip and palate, renal hypoplasia, low-set ears, hearing deficit, bilateral cryptorchidism, and micropenis. The striking similarity of the anomalies in this child and the case described by Kozenko et al. might be considered as a signal for teratogenicity. Thus, we would recommend caution with allopurinol treatment in the first trimester, until further data are available. PMID:23840514

Reply to: Mounting evidence indicates that escalating doses of allopurinol are unnecessary for cardiovascular protection.

PubMed

Coburn, Brian W; Michaud, Kaleb; Bergman, Debra A; Mikuls, Ted R

2018-05-08

We thank Dr. Bredemeier for his comments regarding our manuscript on allopurinol dose escalation and mortality. He raises important evidence to consider in support of an interesting hypothesis that dose escalation may be unnecessary for allopurinol's cardiovascular (CV) protection and may actually be related to adverse CV outcomes. While we agree that evidence exists suggesting that low doses of allopurinol may be sufficient for CV protection, we believe that the studies cited highlight a number of areas where knowledge gaps remain which preclude any definitive conclusions about the effect of dose escalation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study

PubMed Central

Ko, Tai-Ming; Tsai, Chang-Youh; Chen, Shih-Yang; Chen, Kuo-Shu; Yu, Kuang-Hui; Chu, Chih-Sheng; Huang, Chung-Ming; Wang, Chrong-Reen; Weng, Chia-Tse; Yu, Chia-Li; Hsieh, Song-Chou; Tsai, Jer-Chia; Lai, Wen-Ter; Tsai, Wen-Chan; Yin, Guang-Dar; Ou, Tsan-Teng; Cheng, Kai-Hung; Yen, Jeng-Hsien; Liou, Teh-Ling; Lin, Tsung-Hsien; Chen, Der-Yuan; Hsiao, Pi-Jung; Weng, Meng-Yu; Chen, Yi-Ming; Chen, Chen-Hung; Liu, Ming-Fei; Yen, Hsueh-Wei; Lee, Jia-Jung; Kuo, Mei-Chuan; Wu, Chen-Ching; Hung, Shih-Yuan; Luo, Shue-Fen; Yang, Ya-Hui; Chuang, Hui-Ping; Chou, Yi-Chun; Liao, Hung-Ting; Wang, Chia-Wen; Huang, Chun-Lin; Chang, Chia-Shuo; Lee, Ming-Ta Michael; Chen, Pei; Wong, Chih-Shung; Chen, Chien-Hsiun; Wu, Jer-Yuarn; Chen, Yuan-Tsong

2015-01-01

Objective To evaluate the use of prospective screening for the HLA-B*58:01 allele to identify Taiwanese individuals at risk of severe cutaneous adverse reactions (SCARs) induced by allopurinol treatment. Design National prospective cohort study. Setting 15 medical centres in different regions of Taiwan, from July 2009 to August 2014. Participants 2926 people who had an indication for allopurinol treatment but had not taken allopurinol previously. Participants were excluded if they had undergone a bone marrow transplant, were not of Han Chinese descent, and had a history of allopurinol induced hypersensitivity. DNA purified from 2910 participants’ peripheral blood was used to assess the presence of HLA-B*58:01. Main outcome measures Incidence of allopurinol induced SCARs with and without screening. Results Participants who tested positive for HLA-B*58:01 (19.6%, n=571) were advised to avoid allopurinol, and were referred to an alternate drug treatment or advised to continue with their prestudy treatment. Participants who tested negative (80.4%, n=2339) were given allopurinol. Participants were interviewed once a week for two months to monitor symptoms. The historical incidence of allopurinol induced SCARs, estimated by the National Health Insurance research database of Taiwan, was used for comparison. Mild, transient rash without blisters developed in 97 (3%) participants during follow-up. None of the participants was admitted to hospital owing to adverse drug reactions. SCARs did not develop in any of the participants receiving allopurinol who screened negative for HLA-B*58:01. By contrast, seven cases of SCARs were expected, based on the estimated historical incidence of allopurinol induced SCARs nationwide (0.30% per year, 95% confidence interval 0.28% to 0.31%; P=0.0026; two side one sample binomial test). Conclusions Prospective screening of the HLA-B*58:01 allele, coupled with an alternative drug treatment for carriers, significantly decreased the incidence

Xanthine oxidase and the fetal cardiovascular defence to hypoxia in late gestation ovine pregnancy

PubMed Central

Kane, Andrew D; Hansell, Jeremy A; Herrera, Emilio A; Allison, Beth J; Niu, Youguo; Brain, Kirsty L; Kaandorp, Joepe J; Derks, Jan B; Giussani, Dino A

2014-01-01

Hypoxia is a common challenge to the fetus, promoting a physiological defence to redistribute blood flow towards the brain and away from peripheral circulations. During acute hypoxia, reactive oxygen species (ROS) interact with nitric oxide (NO) to provide an oxidant tone. This contributes to the mechanisms redistributing the fetal cardiac output, although the source of ROS is unknown. Here, we investigated whether ROS derived from xanthine oxidase (XO) contribute to the fetal peripheral vasoconstrictor response to hypoxia via interaction with NO-dependent mechanisms. Pregnant ewes and their fetuses were surgically prepared for long-term recording at 118 days of gestation (term approximately 145 days). After 5 days of recovery, mothers were infused i.v. for 30 min with either vehicle (n = 11), low dose (30 mg kg−1, n = 5) or high dose (150 mg kg−1, n = 9) allopurinol, or high dose allopurinol with fetal NO blockade (n = 6). Following allopurinol treatment, fetal hypoxia was induced by reducing maternal inspired O2 such that fetal basal decreased approximately by 50% for 30 min. Allopurinol inhibited the increase in fetal plasma uric acid and suppressed the fetal femoral vasoconstrictor, glycaemic and lactate acidaemic responses during hypoxia (all P < 0.05), effects that were restored to control levels with fetal NO blockade. The data provide evidence for the activation of fetal XO in vivo during hypoxia and for XO-derived ROS in contributing to the fetal peripheral vasoconstriction, part of the fetal defence to hypoxia. The data are of significance to the understanding of the physiological control of the fetal cardiovascular system during hypoxic stress. The findings are also of clinical relevance in the context of obstetric trials in which allopurinol is being administered to pregnant women when the fetus shows signs of hypoxic distress. PMID:24247986

Ameliorative Effect of Allopurinol on Vascular Complications of Insulin Resistance

PubMed Central

El-Bassossy, Hany M.; Elberry, Ahmed A.; Azhar, Ahmad; Ghareib, Salah A.; Alahdal, Abdulrahman M.

2015-01-01

The aim of the current study was to evaluate the possible protective effect of allopurinol (Allo) on experimentally induced insulin resistance (IR) and vascular complications. Rats were divided into four groups: control, IR, allopurinol-treated IR (IR-Allo), and allopurinol-treated control (Allo). IR was induced by adding fructose and high fat, high salt diet for 12 weeks. The results showed that Allo has alleviated the increased level of TNF-α and the systolic, diastolic, mean, and notch pressure observed in IR with no change in pulse pressure. In addition, Allo decreased the heart rate in the treated group compared to IR rats. On the other hand, it has no effect on increased levels of insulin, glucose, fructosamine, or body weight gain compared to IR group, while it increased significantly the insulin level and body weight without hyperglycemia in the control group. Moreover, Allo treatment ameliorated increased level of 4HNE, Ang II, and Ang R1. In conclusion, the results of the current study show that Allo has a protective effect on vascular complications of IR which may be attributed to the effect of Allo on decreasing the TNF-α, 4HNE, Ang II, and Ang R1 as well as increasing the level of insulin secretion. PMID:25785277

African American patients with gout: efficacy and safety of febuxostat vs allopurinol

PubMed Central

2012-01-01

Background African Americans are twice as likely as Caucasians to develop gout, but they are less likely to be treated with urate-lowering therapy (ULT). Furthermore, African Americans typically present with more comorbidities associated with gout, such as hypertension, obesity, and renal impairment. We determined the efficacy and safety of ULT with febuxostat or allopurinol in African American subjects with gout and associated comorbidities and in comparison to Caucasian gout subjects. Methods This is a secondary analysis of the 6-month Phase 3 CONFIRMS trial. Eligible gouty subjects with baseline serum urate (sUA) ≥ 8.0 mg/dL were randomized 1:1:1 to receive febuxostat 40 mg, febuxostat 80 mg, or allopurinol (300 mg or 200 mg depending on renal function) daily. All subjects received gout flare prophylaxis. Primary efficacy endpoint was the proportion of subjects in each treatment group with sUA < 6.0 mg/dL at the final visit. Additional endpoints included the proportion of subjects with mild or with moderate renal impairment who achieved a target sUA < 6.0 mg/dL at final visit. Adverse events (AEs) were recorded throughout the study. Results Of the 2,269 subjects enrolled, 10.0% were African American and 82.1% were Caucasian. African American subjects were mostly male (89.5%), obese (BMI ≥ 30 kg/m2; 67.1%), with mean baseline sUA of 9.8 mg/dL and mean duration of gout of 10.4 years. The proportions of African American subjects with a baseline history of diabetes, renal impairment, or cardiovascular disease were significantly higher compared to Caucasians (p < 0.001). ULT with febuxostat 80 mg was superior to both febuxostat 40 mg (p < 0.001) and allopurinol (p = 0.004). Febuxostat 40 mg was comparable in efficacy to allopurinol. Significantly more African American subjects with mild or moderate renal impairment achieved sUA < 6.0 mg/dL in the febuxostat 80 group than in either the febuxostat 40 mg or allopurinol group (p < 0.05). Efficacy rates in all

A randomized, placebo-controlled, preoperative trial of allopurinol in subjects with colorectal adenoma.

PubMed

Puntoni, Matteo; Branchi, Daniela; Argusti, Alessandra; Zanardi, Silvia; Crosta, Cristiano; Meroni, Emanuele; Munizzi, Francesco; Michetti, Paolo; Coccia, Gianni; De Roberto, Giuseppe; Bandelloni, Roberto; Turbino, Laura; Minetti, Egle; Mori, Marco; Salvi, Sandra; Boccardo, Simona; Gatteschi, Beatrice; Benelli, Roberto; Sonzogni, Angelica; DeCensi, Andrea

2013-02-01

Inflammation and oxidative stress play a crucial role in the development of colorectal cancer (CRC) and interference with these mechanisms represents a strategy in CRC chemoprevention. Allopurinol, a safe molecular scavenger largely used as antigout agent, has been shown to increase survival of patients with advanced CRC and to reduce CRC incidence in long-term gout users in epidemiologic studies. We conducted a randomized, double-blind, placebo-controlled preoperative trial in subjects with colorectal adenomatous polyps to assess the activity of allopurinol on biomarkers of colorectal carcinogenesis. After complete colonoscopy and biopsy of the index polyp, 73 subjects with colorectal adenomas were assigned to either placebo or one of two doses of allopurinol (100 mg or 300 mg) and treated for four weeks before polyp removal. Change of Ki-67 labeling index in adenomatous tissue was the primary endpoint. Secondary endpoints were the immunohistochemical (IHC) expression of NF-κB, β-catenin, topoisomerase-II-α, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) in adenomatous polyps and normal adjacent colonic tissue. Compared with placebo, Ki-67 levels were not significantly modulated by allopurinol, whereas β-catenin and NF-κB expression levels decreased significantly in adenomatous tissue, with a mean change from baseline of -10.6%, 95% confidence interval (CI), -20.5 to -0.7, and -8.1%, 95% CI, -22.7 to 6.5, respectively. NF-κB also decreased significantly in normal adjacent tissue (-16.4%; 95% CI, -29.0 to -3.8). No dose-response relationship was noted, except for NF-κB expression in normal tissue. Allopurinol can inhibit biomarkers of oxidative activation in colon adenomatous polyps and normal adjacent tissue. Further studies should define its potential chemopreventive activity.

Gout, allopurinol intake and clinical outcomes in the hospitalized multimorbid elderly.

PubMed

Franchi, Carlotta; Salerno, Francesco; Conca, Alessio; Djade, Codjo D; Tettamanti, Mauro; Pasina, Luca; Corrao, Salvatore; Marengoni, Alessandra; Marcucci, Maura; Mannucci, Pier Mannuccio; Nobili, Alessandro

2014-11-01

Increased serum uric acid has been considered a cardiovascular risk factor but no study has assessed its relation with hospital mortality or length of stay. On the basis of data obtained from a prospective registry, the prevalence of gout/hyperuricemia and its association with these and other clinical parameters was evaluated in an Italian cohort of elderly patients acutely admitted to internal medicine or geriatric wards. While the prevalence of gout was calculated by counting patients with this diagnosis hyperuricemia was inferred in patients taking allopurinol at hospital admission or discharge, on the assumption that this drug was only prescribed owing to the finding of high serum levels of uric acid. A series of clinical and demographic variables were evaluated for their association with gout/hyperuricemia. Of 1380 patients, 139 (10%) had a diagnosis of gout or were prescribed allopurinol. They had more co-morbidities (7.0 vs 5.6; P<0.0001) and consumed more drugs (6.8 vs 5.0; P<0.0001). The CIRS (co-morbidity index) was worse in these patients (OR 1.28 95% CI 1.15-1.41). Multivariable regression analysis showed that only renal and heart failures were independently associated with gout/allopurinol intake. Moreover, this combined event was associated with an increased risk of adverse events during hospitalization (OR 1.66, 95% CI 1.16-2.36), but not with the risk of re-hospitalization, length of hospital stay or death. Gout/allopurinol intake has a high prevalence in elderly patients acutely admitted to hospital and are associated with renal and cardiovascular diseases, an increased rate of adverse events and a high degree of drug consumption. In contrast, this finding did not affect the length of hospitalization nor hospital mortality. Copyright © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Allopurinol, benzbromarone and risk of coronary heart disease in gout patients: A population-based study.

PubMed

Lin, Hsiu-Chen; Daimon, Masao; Wang, Ching-Hung; Ho, Yi; Uang, Yow-Shieng; Chiang, Shuo-Ju; Wang, Li-Hsuan

2017-04-15

The effect of gout on the risk of developing coronary artery disease (CAD) is uncertain. Some studies have found that gout is a risk factor for acute myocardial infarction. This study examined the changes in risk of CAD in gout patients taking allopurinol and/or benzbromarone, and analyzed the dose-response relationship of both drugs with CAD incidence. The medical records of one million subjects from 2000 to 2011 were provided by the Taiwan National Health Insurance Research Database. Cox proportional hazard ratio was used to compare the risk of CAD in gout patients taking allopurinol or/and benzbromarone with those taking neither drug. Hazard ratios (HR) were adjusted for possible confounding factors, including age, gender, hypertension, hyperlipidemia, diabetes mellitus, chronic kidney disease, and relevant medications. Of 8047 gout patients, 1422 were treated with allopurinol (Group A), 4141 with benzbromarone (Group B), and 2484 with both drugs (Group A/B) during the follow-up period. Our results showed the incidence of CAD after adjusting for covariates for Group A, Group B, and Group A/B did not significantly differ from the comparison group. However, after adjustment for covariates in dose-response analyses, treatment with over 270 defined daily doses (DDDs) of allopurinol, and over 360 DDDs of benzbromarone, was associated with a significantly reduced risk of CAD. We found that the use of allopurinol and benzbromarone, whether alone or in combination, had a linear dose-response relationship between the numbers of defined daily doses and the risk of CAD, especially in higher DDDs. Copyright © 2017 Elsevier B.V. All rights reserved.

Pharmacokinetics and Metabolism of Allopurinol Riboside,

DTIC Science & Technology

1991-05-01

total bilirubin, alkaline phosphatase. uric acid , arnd was 28 years; the age range was from 18 to 48 years. chemical and microscopic urinalyses... uric acid , hy- tions, the mean retention times relative to N-acetlp- pIoxanthine, xanthine, allopurinol, oxypurinol, and al- aminophenol 128.5 + 1.5...there was a decrease in serum uric acid levels to less to 10%), and nilopurinol (0% to 2%), Oxvpudwl~i aixt than 4.2 mig/dl (normal level 4,2 to 8,8

Febuxostat for treating allopurinol-resistant hyperuricemia in patients with chronic kidney disease.

PubMed

Sakai, Yukinao; Otsuka, Tomoyuki; Ohno, Dai; Murasawa, Tsuneo; Sato, Naoki; Tsuruoka, Shuichi

2014-03-01

Availability of the novel xanthine oxidase inhibitor febuxostat, which has multiple excretion pathways, enables investigation of the significance of serum uric acid control on renal function in patients with chronic kidney disease (CKD). This was an exploratory, retrospective, observational study conducted at a single Japanese center. Serum uric acid concentrations and serum creatinine levels in the 6 months before and after the start of febuxostat treatment were collected for CKD patients switched from allopurinol after failing to achieve serum uric acid concentrations ≤6.0 mg/dL. Evaluable data were available for 60 patients, 67% of whom had advanced CKD (eGFR <30 mL/min/1.73 m2). Mean dose of febuxostat was 15.9 (± 8) mg/day. Mean serum uric acid concentration decreased from 8.4 (±1.4) mg/dL at baseline to 6.2 (±1.2) mg/dL at 6 months; 47.5% of patients achieved a level ≤6.0 mg/dL. The change from baseline in eGFR was positive at all time points during febuxostat treatment and the increase of 2.3 (±5.6) mL/min/1.73 m2 at 6 months was significant (p = 0.0027). Whereas the eGFR slope was negative during allopurinol treatment, it became positive after the switch to febuxostat. The change in eGFR slope before and after febuxostat treatment was significant for all patients (p < 0.01), for male patients (p < 0.05), and for patients with a baseline eGFR of <15 mL/min/1.73 m2 (p < 0.05). In patients with CKD, febuxostat reduces serum uric acid concentrations effectively and may suppress the progressive decline in renal function.

Allopurinol Medication Adherence as a Mediator of Optimal Outcomes in Gout Management.

PubMed

Coburn, Brian W; Bendlin, Kayli A; Sayles, Harlan; Meza, Jane; Russell, Cynthia L; Mikuls, Ted R

2017-09-01

Patient and provider factors, including allopurinol medication adherence, affect gout treatment outcomes. The aim of this study was to examine associations of patient and provider factors with optimal gout management. Linking longitudinal health and pharmacy dispensing records to questionnaire data, we assessed patient and provider factors among 612 patients with gout receiving allopurinol during a recent 1-year period. Associations of patient (medication adherence and patient activation) and provider factors (dose escalation, low-dose initiation, and anti-inflammatory prophylaxis) with serum urate (SU) goal achievement of less than 6.0 mg/dL were examined using multivariable logistic regression. Medication adherence was assessed as a mediator of these factors with goal achievement. A majority of patients (63%) were adherent, whereas a minority received dose escalation (31%). Medication adherence was associated with initiation of daily allopurinol doses of 100 mg/d or less (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.20-2.76). In adjusted models, adherence (OR, 2.35; 95% CI, 1.50-3.68) and dose escalation (OR, 2.48; 95% CI, 2.48-4.25) were strongly associated with SU goal attainment. Low starting allopurinol dose was positively associated with SU goal attainment (OR, 1.11; 95% CI, 1.02-1.20) indirectly through early adherence, but also had a negative direct association with SU goal attainment (OR, 0.21; 95% CI, 0.12-0.37). Medication adherence and low starting dose combined with dose escalation represent promising targets for future gout quality improvement efforts. Low starting dose is associated with better SU goal attainment through increased medication adherence, but may be beneficial only in settings where appropriate dose escalation is implemented.

A systematic review and meta-analysis on the safety and efficacy of febuxostat versus allopurinol in chronic gout.

PubMed

Faruque, Labib I; Ehteshami-Afshar, Arash; Wiebe, Natasha; Tjosvold, Lisa; Homik, Joanne; Tonelli, Marcello

2013-12-01

To evaluate the safety and efficacy of febuxostat compared to allopurinol for the treatment of chronic gout. We did a systematic review and meta-analysis of randomized and non-randomized controlled trials that compared oral febuxostat to oral allopurinol for treatment of chronic gout. Two reviewers independently selected studies, assessed study quality, and extracted data. Risk ratios (RR) were calculated with random effects and were reported with corresponding 95% confidence intervals (CI). From 1076 potentially relevant citations, 7 studies and 25 associated publications met inclusion criteria; 5 studies were ultimately included in the analysis. Febuxostat did not reduce the risk of gout flares compared with allopurinol (RR = 1.16, 95% CI = 1.03-1.30, I(2) = 44%). Overall, the risk of any adverse event was lower in febuxostat recipients compared to allopurinol (RR = 0.94, 95% CI = 0.90-0.99, I(2) = 13%). Patients receiving febuxostat were more likely to achieve a serum uric acid of <6 mg/dl than allopurinol recipients (RR = 1.56, 95% CI = 1.22-2.00, I(2) = 92%). Subgroup analysis did not indicate any significant difference between high- and low-dose febuxostat on the risk of gout flares. Although febuxostat was associated with higher likelihood of achieving a target serum uric acid level of <6 mg/dl, there was significant heterogeneity in the pooled results. There was no evidence that febuxostat is superior to allopurinol for clinically relevant outcomes. Given its higher cost, febuxostat should not be routinely used for chronic gout. Copyright © 2013 Elsevier Inc. All rights reserved.

Clinical and health care use characteristics of patients newly starting allopurinol, febuxostat, and colchicine for the treatment of gout.

PubMed

Kim, Seoyoung C; Schmidt, Bernhard M W; Franklin, Jessica M; Liu, Jun; Solomon, Daniel H; Schneeweiss, Sebastian

2013-12-01

Gout is a common form of inflammatory arthritis with an increasing prevalence in developed countries. It is well known that many patients with gout have significant comorbidities and high health care utilization. We aimed to describe the clinical characteristics and health care utilization patterns in patients with gout who were newly prescribed allopurinol, febuxostat, or colchicine. We used US insurance claims data (2009-2011) to conduct a population-based cohort study. There were 25,051 allopurinol, 4,288 febuxostat, and 6,238 colchicine initiators. The mean age was 53 years and 83-87% were men. More than one-half of the patients had hypertension and hyperlipidemia, 20% had diabetes mellitus, and 10% had cardiovascular disease. The mean uric acid level was similar across the groups at baseline, ranging from 8.1-8.5 mg/dl. Compared with allopurinol or colchicine initiators, febuxostat initiators had more comorbidities and greater health care utilization, including outpatient, inpatient, or emergency room visits, both at baseline and during followup. Use of gout-related drugs such as opioids, steroids, and nonsteroidal antiinflammatory drugs was most common in febuxostat initiators and least common in colchicine initiators. The median daily doses at both the start and end of treatment were 300 mg for allopurinol, 40 mg for febuxostat, and 1.2 mg for colchicine. The doses of allopurinol and febuxostat were rarely increased during followup. Patients who started allopurinol, febuxostat, or colchicine for gout generally had hyperuricemia and multiple comorbidities. Febuxostat initiators had more comorbidities and greater use of health care resources and gout-related drugs than the other groups. Overall, the doses of allopurinol or febuxostat remained unchanged over time. Copyright © 2013 by the American College of Rheumatology.

Allopurinol Reduces the Lethality Associated with Acute Renal Failure Induced by Crotalus durissus terrificus Snake Venom: Comparison with Probenecid

PubMed Central

Frezzatti, Rodrigo; Silveira, Paulo Flavio

2011-01-01

Background Acute renal failure is one of the most serious complications of envenoming resulting from Crotalus durissus terrificus bites. This study evaluated the relevance of hyperuricemia and oxidative stress and the effects of allopurinol and probenecid in renal dysfunction caused by direct nephrotoxicity of C. d. terrificus venom. Methodology/Principal Findings Hematocrit, protein, renal function and redox status were assessed in mice. High ratio of oxidized/reduced glutathione and hyperuricemia induced by C. d. terrificus venom were ameliorated by both, allopurinol or probenecid, but only allopurinol significantly reduced the lethality caused by C. d. terrificus venom. The effectiveness of probenecid is compromised probably because it promoted hypercreatinemia and hypocreatinuria and worsed the urinary hypo-osmolality in envenomed mice. In turn, the highest effectiveness of allopurinol might be due to its ability to diminish the intracellular formation of uric acid. Conclusions/Significance Data provide consistent evidences linking uric acid with the acute renal failure induced by C. d. terrificus venom, as well as that this envenoming in mice constitutes an attractive animal model suitable for studying the hyperuricemia and that the allopurinol deserves to be clinically evaluated as an approach complementary to anti-snake venom serotherapy. PMID:21909449

Randomized, allopurinol-controlled trial of the effects of dietary nucleotides and active hexose correlated compound in the treatment of canine leishmaniosis.

PubMed

Segarra, Sergi; Miró, Guadalupe; Montoya, Ana; Pardo-Marín, Luis; Boqué, Noemí; Ferrer, Lluis; Cerón, José

2017-05-30

First-line treatment for canine leishmaniosis (CanL) is N-methylglucamine antimoniate (MGA) combined with allopurinol. However, in some dogs allopurinol may induce hyperxanthinuria leading to urolithiasis. Moreover, allopurinol resistance has recently been described in Leishmania infantum isolates from treated dogs with a relapse of the disease. Alternative treatments are thus needed. Since the type of host immune response strongly influences CanL progression and prognosis, dogs could benefit from treatments targeted at modulating such response, such as nucleotides and active hexose correlated compound (AHCC). The aim of this study was to evaluate the effects of an oral combination of nucleotides and AHCC in dogs with clinical leishmaniosis. Sixty-nine dogs with naturally-occurring clinical leishmaniosis were included in this multicenter, open-label, positively-controlled clinical trial and randomized to receive 10mg/kg allopurinol PO BID (allopurinol group) or 17mg/kg AHCC plus 32mg/kg nucleotides PO SID (supplement group) for 180 days. All dogs were also given 50mg/kg MGA SC BID during the first 28 days. At the time points 0, 30, and 180 days of the trial, dogs underwent a clinical examination, and blood, urine, and bone marrow samples were submitted for analytical tests. Final data analyses (allopurinol group: n=29; supplement group: n=24) revealed a significant improvement in both groups in clinical scores and ELISA-determined antibody titers after treatment. However, the supplement group showed a significantly lower clinical score (P=0.005) and significantly higher antibody titers (P=0.032) after 180 days, compared to the allopurinol group. RT-PCR parasite loads were reduced in groups (mean±SD supplement: 0.38±0.56 vs 5.23±18.9; allopurinol: 0.45±1.47 vs 3.09±8.36 parasites/ng of DNA), but there were no significant differences over time or between groups. During the study, 12 dogs in the allopurinol group developed xanthinuria (41%) compared to no dogs (0

Exposure to cigarette smoke increases apoptosis in the rat gastric mucosa through a reactive oxygen species-mediated and p53-independent pathway.

PubMed

Wang, H; Ma, L; Li, Y; Cho, C H

2000-04-01

Cigarette smoking is a major risk factor for gastric cancer and peptic ulcer. The aim of our study was to investigate the relationship between exposure to cigarette smoke and apoptosis in the rat gastric mucosa and the mechanism involved. Rats were exposed to different concentrations of cigarette smoke (0, 2, and 4%) once daily for a different number of 1 h periods (1, 3, 6, and 9 d). Apoptosis was identified by the terminal deoxy-transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) method and caspase-3 activity. The mucosal xanthine oxidase (XO) activity and p53 level were also measured. The results showed that exposure to cigarette smoke produced a time- and concentration-dependent increase in apoptosis in the rat gastric mucosa that was accompanied by an increase in XO activity. The increased apoptosis and XO activity could be detected after even a single exposure. In contrast, the level of p53 was elevated only in the later stage of cigarette smoke exposure. The apoptotic effect could be blocked by pretreatment with an XO inhibitor (allopurinol, 20 mg/kg intraperitoneally) or a hydroxyl free radical scavenger (DMSO, 0.2%, 1 ml/kg intravenously). However, neither of these treatments had any effect on the p53 level of the mucosa. In summary, we conclude that exposure to cigarette smoke can increase apoptosis in the rat gastric mucosa through a reactive oxygen species- (ROS) mediated and a p53-independent pathway.

Study on the activity of non-purine xanthine oxidase inhibitor by 3D-QSAR modeling and molecular docking

NASA Astrophysics Data System (ADS)

Li, Peizhen; Tian, Yueli; Zhai, Honglin; Deng, Fangfang; Xie, Meihong; Zhang, Xiaoyun

2013-11-01

Non-purine derivatives have been shown to be promising novel drug candidates as xanthine oxidase inhibitors. Based on three-dimensional quantitative structure-activity relationship (3D-QSAR) methods including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), two 3D-QSAR models for a series of non-purine xanthine oxidase (XO) inhibitors were established, and their reliability was supported by statistical parameters. Combined 3D-QSAR modeling and the results of molecular docking between non-purine xanthine oxidase inhibitors and XO, the main factors that influenced activity of inhibitors were investigated, and the obtained results could explain known experimental facts. Furthermore, several new potential inhibitors with higher activity predicted were designed, which based on our analyses, and were supported by the simulation of molecular docking. This study provided some useful information for the development of non-purine xanthine oxidase inhibitors with novel structures.

Design and synthesis of novel 2-(indol-5-yl)thiazole derivatives as xanthine oxidase inhibitors.

PubMed

Song, Jeong Uk; Choi, Sung Pil; Kim, Tae Hun; Jung, Cheol-Kyu; Lee, Joo-Youn; Jung, Sang-Hun; Kim, Geun Tae

2015-03-15

Xanthine oxidase (XO) inhibitors have been widely used for the treatment of gout. Indole rings are frequently used as active scaffold in designing inhibitors for enzymes. Herein, we describe the structure-activity relationship for novel xanthine oxidase inhibitors based on indole scaffold. A series of novel tri-substituted 2-(indol-5-yl)thiazole derivatives were synthesized, and their in vitro inhibitory activities against xanthine oxidase and in vivo efficacy lowering uric acid level in blood were measured. Among them, 2-(3-cyano-2-isopropylindol-5-yl)-4-methylthiazole-5-carboxylic acid exhibits the most potent XO inhibitory activity (IC50 value: 3.5nM) and the excellent plasma uric acid lowering activity. Study of structure activity relationship indicated that hydrophobic moiety (e.g., isopropyl) at 1-position and electron withdrawing group (e.g., CN) at 3-position of indole ring and small hydrophobic group (CH3) at 4-position of the thiazole ring enhanced the XO inhibitory activity. Hydrophobic substitution such as isopropyl at 1-position of the indole moiety without any substitution at 2-position has an essential role for enhancing bioavailability and therefore for high in vivo efficacy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Structural insights into xenobiotic and inhibitor binding to human aldehyde oxidase.

PubMed

Coelho, Catarina; Foti, Alessandro; Hartmann, Tobias; Santos-Silva, Teresa; Leimkühler, Silke; Romão, Maria João

2015-10-01

Aldehyde oxidase (AOX) is a xanthine oxidase (XO)-related enzyme with emerging importance due to its role in the metabolism of drugs and xenobiotics. We report the first crystal structures of human AOX1, substrate free (2.6-Å resolution) and in complex with the substrate phthalazine and the inhibitor thioridazine (2.7-Å resolution). Analysis of the protein active site combined with steady-state kinetic studies highlight the unique features, including binding and substrate orientation at the active site, that characterize human AOX1 as an important drug-metabolizing enzyme. Structural analysis of the complex with the noncompetitive inhibitor thioridazine revealed a new, unexpected and fully occupied inhibitor-binding site that is structurally conserved among mammalian AOXs and XO. The new structural insights into the catalytic and inhibition mechanisms of human AOX that we now report will be of great value for the rational analysis of clinical drug interactions involving inhibition of AOX1 and for the prediction and design of AOX-stable putative drugs.

Characterizing Giant Exoplanets through Multiwavelength Transit Observations: XO-1 b

NASA Astrophysics Data System (ADS)

Cole, Jackson Lane; Gardner, Cristilyn N.; Garver, Bethany R.; Jarka, Kyla L.; Kar, Aman; McGough, Aylin M.; PeQueen, David J.; Rivera, Daniel Ivan; Kasper, David; Jang-Condell, Hannah; Kobulnicky, Henry; Dale, Daniel

2018-01-01

Multiwavelength observations of transiting exoplanets can reveal wavelength dependence of the observed transit depth (or a lack thereof), thereby allowing for thorough characterization of their atmospheres. In support of a larger project performing these characterizations of 12 transiting giant exoplanets through 66 nights of continuous observation at the 2.3 m Wyoming Infrared Observatory (WIRO), we report an updated ephemeris for transiting exoplanet XO- 1 b. We carried out an MCMC analysis on photometric data obtained using the standard broad bandpass Sloan filter system. Our data set for XO-1 b is the most limited of those contributing to the larger project, the target having only been successfully observed from the transit midpoint to the egress on one night with limited out-of-transit data available. Exoplanet XO-1 b is a planet transiting star XO-1 (GSC 02041-01657) of type G1 V with V = 11.19 McCullough et al. (2006). This work is supported by the National Science Foundation under REU grant AST 1560461.

Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout

PubMed Central

Perez-Ruiz, F; Alonso-Ruiz, A; Calabozo, M; Herrero-Beites, A; Garcia-Erauskin, G; Ruiz-Lucea, E

1998-01-01

OBJECTIVES—To study the efficacy of allopurinol and benzbromarone to reduce serum urate concentrations in patients with primary chronic gout.
METHODS—Prospective, parallel, open study of 86 consecutive male patients with primary chronic gout. Forty nine patients (26 normal excretors and 23 under excretors) were given allopurinol 300 mg/day and 37 under excretors benzbromarone 100 mg/day. After achieving steady plasma urate concentrations with such doses, treatment was then adjusted to obtain optimal plasmatic urate concentrations (under 6 mg/dl).
RESULTS—Patients receiving allopurinol 300 mg/day showed a mean reduction of plasmatic urate of 2.75 mg/dl (from 8.60 to 5.85 mg/dl) and 3.34 mg/dl (from 9.10 to 5.76 mg/dl) in normal excretors and under excretors respectively. Patients receiving benzbromarone 100 mg/day achieved a reduction of plasmatic urate of 5.04 mg/dl (from 8.58 to 3.54 mg/dl). Fifty three per cent of patients receiving allopurinol and 100% receiving benzbromarone achieved optimal plasma urate concentrations at such doses. The patients with poor results with allopurinol 300 mg/day achieved a proper plasma urate concentration with allopurinol 450 to 600 mg/day, the mean final dose being 372 mg/day. Renal fuction improved and no case of renal lithiasis was observed among benzbromarone treated patients, whose mean final dose was 76 mg/day.
CONCLUSION—Benzbromarone is very effective to control plasma urate concentrations at doses ranging from 50 to 100 mg/day. Uricosuric treatment is a suitable approach to the treatment of patients with gout who show underexcretion of urate.

 Keywords: gout; gout suppressants; allopurinol; benzbromarone PMID:9849314

Allopurinol Use During Maintenance Therapy for Acute Lymphoblastic Leukemia Avoids Mercaptopurine-related Hepatotoxicity.

PubMed

Giamanco, Nicole M; Cunningham, Bethany S; Klein, Laura S; Parekh, Dina S; Warwick, Anne B; Lieuw, Kenneth

2016-03-01

6-Mercaptopurine (6-MP) is the mainstay of treatment for acute lymphoblastic leukemia and lymphoblastic lymphoma. It is metabolized into the pharmacologically active, 6-thioguanine nucleotide (6-TGN), and 6-methyl mercaptopurine nucleotides (6-MMPN), which is associated with hepatotoxicity that jeopardizes antileukemic therapy. Allopurinol alters the metabolism of 6-MP to increase 6-TGN levels and decreases 6-methyl mercaptopurine nucleotides levels. We report 2 cases in which combination therapy of allopurinol with 6-MP was used successfully to avoid hepatotoxicity while delivering adequate 6-TGN levels. We suggest that this combination therapy can be used safely to change the metabolite production in patients who develop excessive hepatotoxicity.

FABRICATION AND OPTOELECTRONIC PROPERTIES OF MgxZn1-xO ULTRATHIN FILMS BY LANGMUIR-BLODGETT TECHNOLOGY

NASA Astrophysics Data System (ADS)

Tang, Dongyan; Feng, Qian; Jiang, Enying; He, Baozhu

2012-08-01

By transferring MgxZn1-xO sol and stearic acid onto a hydrophilic silicon wafer or glass plate, the Langmuir-Blodgett (LB) multilayers of MgxZn1-xO (x:0, 0.2, 0.4) were deposited. After calcinations at 350°C for 0.5 h and at 500°C for 3 h, MgxZn1-xO ultrathin films were fabricated. The optimized parameters for monolayer formation and multilayer deposition were determined by the surface pressure-surface (Π-A) area and the transfer coefficient, respectively. The expended areas of stearic acid with MgxZn1-xO sols under Π-A isotherms inferred the interaction of stearic acid with MgxZn1-xO sols during the formation of monolayer at air-water interface. X-ray diffraction (XRD) was used to determine the crystal structures of MgxZn1-xO nanoparticles and ultrathin films. The surface morphologies of MgxZn1-xO ultrathin films were observed by scanning probe microscopy (AFM). And the optoelectronic properties of MgxZn1-xO were detected and discussed based on photoluminescence (PL) spectra.

High-performance liquid chromatography coupled with post-column dual-bioactivity assay for simultaneous screening of xanthine oxidase inhibitors and free radical scavengers from complex mixture.

PubMed

Li, D Q; Zhao, J; Li, S P

2014-06-06

Xanthine oxidase (XO) can catalyze hypoxanthine and xanthine to generate uric acid and reactive oxygen species (ROS), including superoxide anion radical (O₂(•-)) and hydrogen peroxide. XO inhibitors and free radical scavengers are beneficial to the treatment of gout and many related diseases. In the present study, an on-line high-performance liquid chromatography (HPLC) coupled with post-column dual-bioactivity assay was established and successfully applied to simultaneously screening of XO inhibitors and free radical scavengers from a complex mixture, Oroxylum indicum extract. The integrated system of HPLC separation, bioactivity screening and mass spectrometry identification was proved to be simple and effective for rapid and sensitive screening of individual bioactive compounds in complex mixtures. Copyright © 2014 Elsevier B.V. All rights reserved.

Xanthine Oxidase Inhibition with Febuxostat Attenuates Systolic Overload-induced Left Ventricular Hypertrophy and Dysfunction in Mice

PubMed Central

Xu, Xin; Hu, Xinli; Lu, Zhongbing; Zhang, Ping; Zhao, Lin; Wessale, Jerry L.; Bache, Robert J.; Chen, Yingjie

2008-01-01

The purine analog xanthine oxidase (XO) inhibitors (XOIs), allopurinol and oxypurinol, have been reported to protect against heart failure secondary to myocardial infarction or rapid ventricular pacing. Since these agents might influence other aspects of purine metabolism that could influence their effect, this study examined the effect of the non-purine XOI, febuxostat, on pressure overload-induced left ventricular (LV) hypertrophy and dysfunction. Transverse aortic constriction (TAC) in mice caused LV hypertrophy and dysfunction as well as increased myocardial nitrotyrosine at 8 days. TAC also caused increased phosphorylated Akt (p-AktSer473), p42/44 extracellular signal-regulated kinase (p-ErkThr202/Tyr204) and mammalian target of rapamycin (mTOR) (p-mTORSer2488). XO inhibition with febuxostat (5mg/kg/day by gavage for 8 days) beginning ~60 minutes after TAC attenuated the TAC-induced LV hypertrophy and dysfunction. Febuxostat blunted the TAC-induced increases in nitrotyrosine (indicating reduced myocardial oxidative stress), p-ErkThr202/Tyr204 and p-mTORSer2488, with no effect on total Erk or total mTOR. Febuxostat had no effect on myocardial p-AktSer473 or total Akt. The results suggest that XO inhibition with febuxostat reduced oxidative stress in the pressure overloaded LV, thereby diminishing the activation of pathways that result in pathologic hypertrophy and contractile dysfunction. PMID:18995179

Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study).

PubMed

Bardin, Thomas; Keenan, Robert T; Khanna, Puja P; Kopicko, Jeff; Fung, Maple; Bhakta, Nihar; Adler, Scott; Storgard, Chris; Baumgartner, Scott; So, Alexander

2017-05-01

Determine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial. Patients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6.0 mg/dL (<357 µmol/L) (month 6). Key secondary end points were mean gout flare rate requiring treatment (months 7 through 12) and proportions of patients with complete resolution of one or more target tophi (month 12). Safety assessments included adverse events and laboratory data. Patients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p<0.0001 both lesinurad+allopurinol groups). In key secondary end points, there were no statistically significant treatment-group differences favouring lesinurad. Lesinurad was generally well tolerated; the 200 mg dose had a safety profile comparable with allopurinol-alone therapy. Renal-related adverse events occurred in 5.9% of lesinurad 200 mg+allopurinol, 15.0% of lesinurad 400 mg+allopurinol and 4.9% of allopurinol-alone groups, with serum creatinine elevation of ≥1.5× baseline in 5.9%, 15.0% and 3.4%, respectively. Serious treatment-emergent adverse events occurred in 4.4% of lesinurad 200 mg+allopurinol, in 9.5% of lesinurad 400 mg+allopurinol and in 3.9% of allopurinol-alone groups, respectively. Lesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200 mg was generally

Association of HLA-B*5801 allele and allopurinol-induced stevens johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis

PubMed Central

2011-01-01

Background Despite some studies suggesting a possible association between human leukocyte antigen, HLA-B*5801 and allopurinol induced Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), the evidence of association and its magnitude remain inconclusive. This study aims to systematically review and meta-analyze the association between HLA-B*5801 allele and allopurinol-induced SJS/TEN. Methods A comprehensive search was performed in databases including MEDLINE, Pre-MEDLINE, Cochrane Library, EMBASE, International Pharmaceutical Abstracts (IPA), CINAHL, PsychInfo, the WHO International, Clinical Trial Registry, and ClinicalTrial.gov from their inceptions to June 2011. Only studies investigating association between HLA-B*5801 with allopurinol-induced SJS/TEN were included. All studies were extracted by two independent authors. The primary analysis was the carrier frequency of HLA-B*5801 comparison between allopurinol-induced SJS/TEN cases and each comparative group. The pooled odds ratios were calculated using a random effect model. Results A total of 4 studies with 55 SJS/TEN cases and 678 matched-controls (allopurinol-tolerant control) was identified, while 5 studies with 69 SJS/TEN cases and 3378 population-controls (general population) were found. SJS/TEN cases were found to be significantly associated with HLA-B*5801 allele in both groups of studies with matched-control (OR 96.60, 95%CI 24.49-381.00, p < 0.001) and population-control (OR 79.28, 95%CI 41.51-151.35, p < 0.001). Subgroup analysis for Asian and Non-Asian population yielded similar findings. Conclusion We found a strong and significant association between HLA-B*5801 and allopurinol-induced SJS/TEN. Therefore, HLA-B*5801 allele screening may be considered in patients who will be treated with allopurinol. PMID:21906289

Hydroxychavicol: a potent xanthine oxidase inhibitor obtained from the leaves of betel, Piper betle.

PubMed

Murata, Kazuya; Nakao, Kikuyo; Hirata, Noriko; Namba, Kensuke; Nomi, Takao; Kitamura, Yoshihisa; Moriyama, Kenzo; Shintani, Takahiro; Iinuma, Munekazu; Matsuda, Hideaki

2009-07-01

The screening of Piperaceous plants for xanthine oxidase inhibitory activity revealed that the extract of the leaves of Piper betle possesses potent activity. Activity-guided purification led us to obtain hydroxychavicol as an active principle. Hydroxychavicol is a more potent xanthine oxidase inhibitor than allopurinol, which is clinically used for the treatment of hyperuricemia.

Clinical study on treatment of hyperuricaemia by retention enema of Chinese herbal medicine combined with allopurinol.

PubMed

Chen, Qian; Ma, Li; Akebaier, Wupu

2009-12-01

To study the effect of retention enema of Chinese herbal medicine combined with allopurinol in treating hyperuricaemia (HUE). Seventy-eight patients with HUE were assigned to two: groups, the 40 patients in the treated group were treated with retention enema of Chinese herbal medicine combined with oral intake of allopurinol, and the 38 patients in the control group were treated with allopurinol alone. The therapeutic course for all was 6 weeks. The clinical efficacy, changes of symptoms, blood levels of uric acid and lipids, renal function, and 24 h urinary micro-albumin were observed. The total effective rate was: 92.5% in the treated group, which was significantly higher than that in the control group (68.4%, P<0.05). After treatment, the score of symptoms in the treated group decreased from 9.43+/-1.15 scores to 3.25+/-0.85 scores, significantly lower than that in the control group (9.75+/-1.43 scores vs 9.25+/-0.82 scores, P<0.01). Moreover, the post-treatment improvements in blood uric acid, blood lipids, renal function and 24h urinary micro-albumin in the treated group were all better than those in the control group (P<0.05 or P<0.01). Retention enema with: Chinese herbal medicine combined with allopurinol could obviously reduce the uric acid level in blood, improve patients' renal function and lipid metabolism, and alleviate the clinical symptoms in patients with HUE.

Multicentre, prospective, randomised, open-label, blinded end point trial of the efficacy of allopurinol therapy in improving cardiovascular outcomes in patients with ischaemic heart disease: protocol of the ALL-HEART study.

PubMed

Mackenzie, Isla S; Ford, Ian; Walker, Andrew; Hawkey, Chris; Begg, Alan; Avery, Anthony; Taggar, Jaspal; Wei, Li; Struthers, Allan D; MacDonald, Thomas M

2016-09-08

Ischaemic heart disease (IHD) is one of the most common causes of death in the UK and treatment of patients with IHD costs the National Health System (NHS) billions of pounds each year. Allopurinol is a xanthine oxidase inhibitor used to prevent gout that also has several positive effects on the cardiovascular system. The ALL-HEART study aims to determine whether allopurinol improves cardiovascular outcomes in patients with IHD. The ALL-HEART study is a multicentre, controlled, prospective, randomised, open-label blinded end point (PROBE) trial of allopurinol (up to 600 mg daily) versus no treatment in a 1:1 ratio, added to usual care, in 5215 patients aged 60 years and over with IHD. Patients are followed up by electronic record linkage and annual questionnaires for an average of 4 years. The primary outcome is the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes include all-cause mortality, quality of life and cost-effectiveness of allopurinol. The study will end when 631 adjudicated primary outcomes have occurred. The study is powered at 80% to detect a 20% reduction in the primary end point for the intervention. Patient recruitment to the ALL-HEART study started in February 2014. The study received ethical approval from the East of Scotland Research Ethics Service (EoSRES) REC 2 (13/ES/0104). The study is event-driven and results are expected after 2019. Results will be reported in peer-reviewed journals and at scientific meetings. Results will also be disseminated to guideline committees, NHS organisations and patient groups. 32017426, pre-results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Two brothers with skewed thiopurine metabolism in ulcerative colitis treated successfully with allopurinol and mercaptopurine dose reduction.

PubMed

Hoentjen, Frank; Hanauer, Stephen B; de Boer, Nanne K; Rubin, David T

2012-01-01

Thiopurine therapy effectively maintains remission in inflammatory bowel disease. However, many patients are unable to achieve optimum benefits from azathioprine or 6-mercaptopurine because of undesirable metabolism related to high thiopurine methyltransferase (TPMT) activity characterized by hepatic transaminitis secondary to increased 6-methylmercaptopurine (6-MMP) production and reduced levels of therapeutic 6-thioguanine nucleotide (6-TGN). Allopurinol can optimize this skewed metabolism. We discuss two brothers who were both diagnosed with ulcerative colitis (UC). Their disease remained active despite oral and topical mesalamines. Steroids followed by 6-mercaptopurine (MP) were unsuccessfully introduced for both patients and both were found to have high 6-MMP and low 6-TGN levels, despite normal TMPT enzyme activity, accompanied by transaminitis. Allopurinol was introduced in combination with MP dose reduction. For both brothers addition of allopurinol was associated with successful remission and optimized MP metabolites. These siblings with active UC illustrate that skewed thiopurine metabolism may occur despite normal TPMT enzyme activity and can lead to adverse events in the absence of disease control. We confirm previous data showing that addition of allopurinol can reverse this skewed metabolism, and reduce both hepatotoxicity and disease activity, but we now also introduce the concept of a family history of preferential MP metabolism as a clue to effective management for other family members.

The xanthine oxidase inhibitor febuxostat suppresses development of nonalcoholic steatohepatitis in a rodent model.

PubMed

Nakatsu, Yusuke; Seno, Yasuyuki; Kushiyama, Akifumi; Sakoda, Hideyuki; Fujishiro, Midori; Katasako, Aya; Mori, Keiichi; Matsunaga, Yasuka; Fukushima, Toshiaki; Kanaoka, Ryuhei; Yamamotoya, Takeshi; Kamata, Hideaki; Asano, Tomoichiro

2015-07-01

Xanthine oxidase (XO) is an enzyme involved in the production of uric acid (UA) from purine nucleotides. Numerous recent studies have revealed the likelihood of metabolic syndrome including nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH) to be related to hyperuricemia. However, it remains unclear whether elevated serum UA during the development of NAFLD or NASH is a cause or a consequence of these diseases. In this study, the XO inhibitor febuxostat was administered to two types of NASH model mice. Febuxostat exerted a strong protective effect against NASH development induced by a high-fat diet containing trans fatty acid (HFDT). In contrast, methionine choline-deficient-diet-induced NASH development not accompanied by hyperuricemia showed no UA normalization, suggesting that the ameliorating effect of febuxostat occurs via the normalization of hyperuricemia itself and/or accompanying molecular mechanism(s) such as oxidative stress. In the HFDT-fed mice, hyperuricemia, elevated alanine aminotransferase, and increased Tunnel-positive cells in the liver were normalized by febuxostat administration. In addition, upregulation of fatty acid oxidation-related genes, fibrotic change, and increases in collagen deposition, inflammatory cytokine expressions, and lipid peroxidation in the HFDT-fed mice were also normalized by febuxostat administration. Taken together, these observations indicate that administration of febuxostat has a protective effect against HFDT-induced NASH development, suggesting the importance of XO in its pathogenesis. Thus XO inhibitors are potentially potent therapies for patients with NASH, particularly that associated with hyperuricemia. Copyright © 2015 the American Physiological Society.

Hydroxylated chalcones with dual properties: xanthine oxidase inhibitors and radical scavengers

PubMed Central

Hofmann, Emily; Webster, Jonathan; Do, Thuy; Kline, Reid; Snider, Lindsey; Hauser, Quintin; Higginbottom, Grace; Campbell, Austin; Ma, Lili; Paula, Stefan

2016-01-01

In this study, we evaluated the abilities of a series of chalcones to inhibit the activity of the enzyme xanthine oxidase (XO) and to scavenge radicals. 20 mono- and polyhydroxylated chalcone derivatives were synthesized by Claisen-Schmidt condensation reactions and then tested for inhibitory potency against XO, a known generator of reactive oxygen species (ROS). In parallel, the ability of the synthesized chalcones to scavenge a stable radical was determined. Structure-activity relationship analysis in conjunction with molecular docking indicated that the most active XO inhibitors carried a minimum of three hydroxyl groups. Moreover, the most effective radical scavengers had two neighboring hydroxyl groups on at least one of the two phenyl rings. Since it has been proposed previously that XO inhibition and radical scavenging could be useful properties for reduction of ROS-levels in tissue, we determined the chalcones’ effects to rescue neurons subjected to ROS-induced stress created by the addition of β-amyloid peptide. Best protection was provided by chalcones that combined good inhibitory potency with high radical scavenging ability in a single molecule, an observation that points to a potential therapeutic value of this compound class. PMID:26762836

Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery patients with chronic kidney disease (NU-FLASH trial for CKD).

PubMed

Sezai, Akira; Soma, Masayoshi; Nakata, Kin-ichi; Osaka, Shunji; Ishii, Yusuke; Yaoita, Hiroko; Hata, Hiroaki; Shiono, Motomi

2015-10-01

The NU-FLASH trial demonstrated that febuxostat was more effective for hyperuricemia than allopurinol. This time, we compared these medications in patients with chronic kidney disease (CKD) from the NU-FLASH trial. In the NU-FLASH trial, 141 cardiac surgery patients with hyperuricemia were randomized to a febuxostat group or an allopurinol group. This study analyzed 109 patients with an estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m(2), and also analyzed 87 patients with stage 3 CKD. The primary endpoint was the serum uric acid level. Secondary endpoints included serum creatinine, urinary albumin, cystatin-C, oxidized low-density lipoprotein, eicosapentaenoic acid/arachidonic acid ratio, total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, and high-sensitivity C-reactive protein. Among patients with an eGFR≤60 mL/min/1.73 m(2), uric acid levels were significantly lower in the febuxostat group than the allopurinol group from 1 month of treatment onward. The serum creatinine, urinary albumin, cystatin-C, oxidized low-density lipoprotein, eicosapentaenoic acid/arachidonic acid ratio, and high-sensitivity C-reactive protein were also significantly lower in the febuxostat group. Similar results were obtained in the patients with stage 3 CKD. In cardiac surgery patients with renal dysfunction, febuxostat reduced uric acid earlier than allopurinol, had a stronger renoprotective effect than allopurinol, and also had superior antioxidant and anti-inflammatory effects. Copyright © 2015. Published by Elsevier Ltd.

Comparative effectiveness of urate lowering with febuxostat versus allopurinol in gout: analyses from large U.S. managed care cohort.

PubMed

Singh, Jasvinder A; Akhras, Kasem S; Shiozawa, Aki

2015-05-12

To assess the comparative effectiveness of febuxostat and allopurinol in reducing serum urate (sUA) levels in a real-world U.S. managed care setting. This retrospective study utilized 2009 to 2012 medical and pharmacy claims and laboratory data from a large U.S. commercial and Medicare Advantage health plan. Study patients had at least one medical claim with a diagnosis of gout, at least one filled prescription for febuxostat or allopurinol and at least one sUA measurement post-index prescription. Reduction in sUA was examined using propensity score-matched cohorts, matched on patient demographics (gender, age), baseline sUA, comorbidities, geographic region and insurance type. The study sample included 2,015 patients taking febuxostat and 14,025 taking allopurinol. At baseline, febuxostat users had a higher Quan-Charlson comorbidity score (0.78 vs. 0.53; P <0.001), but similar age and gender distribution. Mean (standard deviation (SD)) sUA level following propensity score matching among treatment-naïve febuxostat vs. allopurinol users (n = 873 each) were: pre-index sUA, 8.86 (SD, 1.79) vs. 8.72 (SD, 1.63; P = 0.20); and post-index sUA, 6.53 (SD, 2.01) vs. 6.71 (SD, 1.70; P = 0.04), respectively. A higher proportion of febuxostat users attained sUA goals of <6.0 mg/dl (56.9% vs. 44.8%; P <0.001) and <5.0 mg/dl (35.5% vs. 19.2%; P <0.001), respectively. Time to achieve sUA goals of <6.0 mg/dl (346 vs. 397 days; P <0.001) and <5.0 mg/dl was shorter in febuxostat vs. allopurinol users (431 vs. 478 days; P <0.001), respectively. Similar observations were made for overall propensity score-matched cohorts that included both treatment-naïve and current users (n = 1,932 each). Febuxostat was more effective than allopurinol at the currently used doses (40 mg/day for febuxostat in 83% users and 300 mg/day or lower for allopurinol in 97% users) in lowering sUA in gout patients as demonstrated by post-index mean sUA level, the likelihood of and the

Protective effects of amifostine and cyclooxygenase-1 inhibitor against normal human epidermal keratinocyte toxicity induced by methotrexate and 5-fluorouracil.

PubMed

Maiguma, Takayoshi; Kaji, Hiroaki; Makino, Kazutaka; Teshima, Daisuke

2009-07-01

Our study aimed to find more effective protective agents against mucosa toxicity induced by methotrexate and 5-fluorouracil. We focused on the relationship between oral mucositis and keratinocyte injury and examined methotrexate and 5-fluorouracil-induced cytotoxicity in normal human epidermal keratinocyte cell lines. Cell viability and superoxide radical activity were measured based on converting WST-1 (4-[3-(4-indophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzen disulfonate) to a water-soluble formazan dye. DNA synthesis by 5-bromo-2'-deoxyuridine incorporation was measured as an indirect parameter of cell proliferation. Allopurinol and amifostine were used as the radical scavengers. l-glutamine was used as a mucosa-protective agent. A cyclooxygenase inhibitor interrupting the production of hydroxyl radicals in the arachidonic acid cascade was also examined. 5-fluorouracil and methotrexate caused cytotoxicity due to the activation of intracellular superoxide radicals specifically on normal human epidermal keratinocytes. From the electron spin resonance study, it was found that allopurinol was a superoxide radical scavenger, while amifostine was hydroxyl radical scavenger. Allopurinol showed no effect on the cytotoxicity due to 5-fluorouracil and methotrexate. The cell injury induced by methotrexate was restored by amifostine. However, the cell injury induced by 5-fluorouracil was markedly recovered by a selective cyclooxygenase-1 inhibitor compared to amifostine. It was suggested that amifostine and cyclooxygenase-1 inhibitor could be useful protective agents against methotrexate and 5-fluorouracil chemotherapeutic toxicity. Additionally, this in vitro cell injury model using normal human epidermal keratinocytes may be useful for understanding the pathophysiology of oral mucositis induced by chemotherapeutic agents.

Mechanism of action and interactions between xanthine oxidase inhibitors derived from natural sources of chlorogenic and ferulic acids.

PubMed

Gawlik-Dziki, Urszula; Dziki, Dariusz; Świeca, Michał; Nowak, Renata

2017-06-15

The aim of this study was to estimate the phenolic composition and xanthine oxidase (XO) inhibitory activity of green coffee beans (GCB) and wholemeal wheat flour (WF). Additionally, the type and strength of interaction (expressed as the combination index, CI) and mode of XO inhibition were analyzed. The major phenolic in GCB was 5-caffeoylquinic acid (39.92mg/g dw). The main phenolic acids in WF were trans- and cis-ferulic acids (257 and 165.57mg/100g dw, respectively). Both ferulic and chlorogenic acids individually inhibited XO, and for their combination moderate synergism was found. Buffer extractable compounds from GCB and WF demonstrated slight synergism (CI=0.92), while potentially bioaccessible and bioavailable compounds acted synergistically (CI=0.43 and 0.54, respectively). Buffer-extractable and potentially bioavailable phytochemicals from GCB acted uncompetitively, whereas potentially bioaccessible compounds acted as noncompetitive XO inhibitors. The addition of 3-5% of GCB to wheat bread significantly increased XO-inhibitory activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Safety and efficacy of oral febuxostat for treatment of HLA-B*5801-negative gout: a randomized, open-label, multicentre, allopurinol-controlled study

PubMed Central

Yu, K-H; Lai, J-H; Hsu, P-N; Chen, D-Y; Chen, C-J; Lin, H-Y

2016-01-01

Objectives: This phase IIIB study compared the efficacy and safety of febuxostat and allopurinol in gout patients with or without tophi who were HLA-B*5801 negative. Method: Eligible patients were randomized to a febuxostat group (80 mg QD) or an allopurinol group (300 mg QD). Following an initial 2-week washout period, over the next 12 weeks we made five measurements of serum urate levels along with assessments of adverse events (AEs). Results: Forty-three out of 152 screened subjects (28.3%) were ineligible either because of the presence of the HLA-B*5801 allele or for various other reasons. The febuxostat group (n = 54) and the allopurinol group (n = 55) had no significant differences in demographic or baseline characteristics. From week 2 to week 12, the febuxostat group had a significantly lower serum urate level than the allopurinol group (p ≤ 0.001 for all comparisons) and significantly more patients with serum urate levels less than 6.0 mg/dL. The serum urate levels of the febuxostat group declined by more than 40% from week 2 to week 12 and this decrease was greater than that in the allopurinol group (~30%). The two groups were similar in terms of AEs. Conclusions: Febuxostat was more effective than allopurinol in reducing the serum urate levels of Han Chinese patients with gout or tophaceous gout who were HLA-B*5801 negative, without causing any serious skin reactions. Febuxostat should be considered for treatment of Han Chinese patients with gout who are HLA-B*5801 negative. PMID:26771445

Safety and efficacy of oral febuxostat for treatment of HLA-B*5801-negative gout: a randomized, open-label, multicentre, allopurinol-controlled study.

PubMed

Yu, K-H; Lai, J-H; Hsu, P-N; Chen, D-Y; Chen, C-J; Lin, H-Y

2016-07-01

This phase IIIB study compared the efficacy and safety of febuxostat and allopurinol in gout patients with or without tophi who were HLA-B*5801 negative. Eligible patients were randomized to a febuxostat group (80 mg QD) or an allopurinol group (300 mg QD). Following an initial 2-week washout period, over the next 12 weeks we made five measurements of serum urate levels along with assessments of adverse events (AEs). Forty-three out of 152 screened subjects (28.3%) were ineligible either because of the presence of the HLA-B*5801 allele or for various other reasons. The febuxostat group (n = 54) and the allopurinol group (n = 55) had no significant differences in demographic or baseline characteristics. From week 2 to week 12, the febuxostat group had a significantly lower serum urate level than the allopurinol group (p ≤ 0.001 for all comparisons) and significantly more patients with serum urate levels less than 6.0 mg/dL. The serum urate levels of the febuxostat group declined by more than 40% from week 2 to week 12 and this decrease was greater than that in the allopurinol group (~30%). The two groups were similar in terms of AEs. Febuxostat was more effective than allopurinol in reducing the serum urate levels of Han Chinese patients with gout or tophaceous gout who were HLA-B*5801 negative, without causing any serious skin reactions. Febuxostat should be considered for treatment of Han Chinese patients with gout who are HLA-B*5801 negative.

Febuxostat, a novel xanthine oxidoreductase inhibitor, improves hypertension and endothelial dysfunction in spontaneously hypertensive rats.

PubMed

Shirakura, Takashi; Nomura, Johji; Matsui, Chieko; Kobayashi, Tsunefumi; Tamura, Mizuho; Masuzaki, Hiroaki

2016-08-01

Xanthine oxidase (XO) is an enzyme responsible for the production of uric acid. XO produces considerable amount of oxidative stress throughout the body. To date, however, its pathophysiologic role in hypertension and endothelial dysfunction still remains controversial. To explore the possible involvement of XO-derived oxidative stress in the pathophysiology of vascular dysfunction, by use of a selective XO inhibitor, febuxostat, we investigated the impact of pharmacological inhibition of XO on hypertension and vascular endothelial dysfunction in spontaneously hypertensive rats (SHRs). Sixteen-week-old SHR and normotensive Wistar-Kyoto (WKY) rats were treated with tap water (control) or water containing febuxostat (3 mg/kg/day) for 6 weeks. Systolic blood pressure (SBP) in febuxostat-treated SHR (220 ± 3 mmHg) was significantly (P < 0.05) decreased compared with the control SHR (236 ± 4 mmHg) while SBP in febuxostat-treated WKY was constant. Acetylcholine-induced endothelium-dependent relaxation in aortas from febuxostat-treated SHR was significantly (P < 0.05) improved compared with the control SHR, whereas relaxation in response to sodium nitroprusside was not changed. Vascular XO activity and tissue nitrotyrosine level, a representative indicator of local oxidative stress, were considerably elevated in the control SHR compared with the control WKY, and this increment was abolished by febuxostat. Our results suggest that exaggerated XO activity and resultant increase in oxidative stress in this experimental model contribute to the hypertension and endothelial dysfunction, thereby supporting a notion that pharmacological inhibition of XO is valuable not only for hyperuricemia but also for treating hypertension and related endothelial dysfunction in human clinics.

Four-week effects of allopurinol and febuxostat treatments on blood pressure and serum creatinine level in gouty men.

PubMed

Kim, Hyun Ah; Seo, Young-Il; Song, Yeong W

2014-08-01

The aim of this study was to observe the effects of uric acid lowering therapy (UALT), febuxostat and allopurinol, on blood pressure (BP) and serum creatinine level. Post-hoc data were derived from a phase-III, randomised, double-blind, 4-week trial of male gouty patients that compared the safety and efficacy of febuxostat and allopurinol in adults with gout. The subjects were randomly assigned to one of five groups, 35-37 in each group (febuxostat: 40, 80, 120 mg/d; allopurinol: 300 mg/d; control group: placebo). Blood pressure and serum creatinine level were measured at baseline and at weeks 2 and 4. Diastolic BP and creatinine level had decreased significantly in the UALT groups compared to the control group at week 4. Diastolic BP had decreased significantly in the allopurinol group and serum creatinine level had decreased significantly in the febuxostat groups at week 4. After adjusting for confounding variables, serum uric acid changes were found to be significantly correlated with changes in serum creatinine level but were not associated with changes in systolic or diastolic BP. UALT in gouty subjects significantly decreased diastolic BP and serum creatinine level. Changes in uric acid were significantly correlated with those in serum creatinine level, suggesting the feasibility of renal function improvement through UALT in gouty men.

Singlet Excited States of Cl and Br Molecules: New Theories Applied to the -XO and -XO2 (X=C1 and Br) Chromophores

NASA Technical Reports Server (NTRS)

Lee, Timothy J.; Srinivasan, Parthiban; Head-Gordon, Martin; Huo, Winifred (Technical Monitor)

1998-01-01

Electronic excitation energies are determined using single-reference based theories derived from response equations involving perturbation theory and coupled-cluster theory. These methods are applied to the singlet manifold of excited electronic states of the HClO, HBrO, HOClO, HOBrO, HClO2, and HBrO2 molecules. The reliability of the various perturbation theory approaches is assessed by comparison to the linear-response singles and doubles coupled-cluster (LRCCSD) method. The excitation energies for the Y-XO compounds are compared and contrasted for Y=H and HO, and X=Cl and Br. A similar comparison is performed for the H-XO2 compounds.

Xanthine oxidase inhibiting effects of noni (Morinda citrifolia) fruit juice.

PubMed

Palu, Afa; Deng, Shixin; West, Brett; Jensen, Jarakae

2009-12-01

Morinda citrifolia L. (noni), family Rubiaceae, has been used in Polynesia for over 2000 years for its reputed health benefits, one of which is its therapeutic effects on gout (langa e hokotanga hui). However, its healing mechanism has not been elucidated. This study showed that in an in vitro bioassay that Tahitian Noni Juice (TNJ) inhibited xanthine oxidase (XO) concentration dependently. Concentrations of 1, 5 and 10 mg/mL of TNJ inhibited XO by 11%, 113% and 148%, respectively, with an IC50 of 3.8 mg compared with an IC50 of 2.4 microm for allopurinol. Noni fruit juice concentrate (NFJC) also inhibited XO concentration dependently. Concentrations of 1 and 5 mg/mL NFJC inhibited XO in vitro by 184% and 159%, respectively. A 0.1 mg/mL methanol extract (NFJME) from the fractionation of noni fruit puree inhibited XO by 64%. It was elucidated that the noni fruit juice inhibitory effect on XO enzymes is the mechanism by which noni ameliorates gout and gout-like diseases. Further, the results also support the traditional usage of noni in the treatment of gout. Copyright (c) 2009 John Wiley & Sons, Ltd.

A phase 3, multicenter, randomized, allopurinol-controlled study assessing the safety and efficacy of oral febuxostat in Chinese gout patients with hyperuricemia.

PubMed

Xu, Shaoyong; Liu, Xiangyang; Ming, Jie; Chen, Shenren; Wang, Yangang; Liu, Xiumei; Liu, Hong; Peng, Yongde; Wang, Jianqin; Lin, Jinying; Ji, Haiwang; Liu, Bin; Lu, Ying; Liu, Peng; Zhang, Yonghong; Ji, Qiuhe

2015-07-01

To compare the efficiency and safety of febuxostat with those of allopurinol in Chinese patients with gout and hyperuricemia. The trial which was conducted at 13 centers in China during 2011-2013 included a 2-week run-in and a 24-week treatment period. A total of 504 eligible participants with gout and with serum urate ≥ 480 μmol/L were randomly assigned 1 : 1 : 1 to febuxostat 40 mg/day, febuxostat 80 mg/day and allopurinol 300 mg/day groups. The primary efficacy endpoint was the percentage of subjects whose last three serum urate levels were < 360 μmol/L. The primary efficacy endpoint was reached by 33.5% of subjects taking febuxostat 80 mg/day, 22.5% of those taking febuxostat 40 mg/day and 17.0% of those taking allopurinol 300 mg/day (P < 0.001 for the comparison between febuxostat 80 mg/day and allopurinol 300 mg/day groups; P = 0.216 for the comparison between febuxostat 40 mg/day and allopurinol 300 mg/day groups). The incidence of gout flare was relatively high in each group during the first 8 weeks and gradually decreased thereafter. There was no statistically significant difference between the three groups (P > 0.05). The incidence of adverse events was similar in the three treatment groups. The most frequent treatment-related adverse events were liver function test abnormalities. Febuxostat 80 mg/day had superior urate-lowering efficacy to that of febuxostat 40 mg/day or allopurinol 300 mg/day, which was comparable in Chinese gout patients with hyperuricemia. Febuxostat, at a daily dose of 40 or 80 mg, was safe and well tolerated. © 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study.

PubMed

Maahs, David M; Caramori, Luiza; Cherney, David Z I; Galecki, Andrzej T; Gao, Chuanyun; Jalal, Diana; Perkins, Bruce A; Pop-Busui, Rodica; Rossing, Peter; Mauer, Michael; Doria, Alessandro

2013-08-01

Diabetic kidney disease causes significant morbidity and mortality among people with type 1 diabetes (T1D). Intensive glucose and blood pressure control have thus far failed to adequately curb this problem and therefore a major need for novel treatment approaches exists. Multiple observations link serum uric acid levels to kidney disease development and progression in diabetes and strongly argue that uric acid lowering should be tested as one such novel intervention. A pilot of such a trial, using allopurinol, is currently being conducted by the Preventing Early Renal Function Loss (PERL) Consortium. Although the PERL trial targets T1D individuals at highest risk of kidney function decline, the use of allopurinol as a renoprotective agent may also be relevant to a larger segment of the population with diabetes. As allopurinol is inexpensive and safe, it could be cost-effective even for relatively low-risk patients, pending the completion of appropriate trials at earlier stages.

Febuxostat pretreatment attenuates myocardial ischemia/reperfusion injury via mitochondrial apoptosis.

PubMed

Wang, Shulin; Li, Yunpeng; Song, Xudong; Wang, Xianbao; Zhao, Cong; Chen, Aihua; Yang, Pingzhen

2015-07-02

Febuxostat is a selective inhibitor of xanthine oxidase (XO). XO is a critical source of reactive oxygen species (ROS) during myocardial ischemia/reperfusion (I/R) injury. Inhibition of XO is therapeutically effective in I/R injury. Evidence suggests that febuxostat exerts antioxidant effects by directly scavenging ROS. The present study was performed to investigate the effects of febuxostat on myocardial I/R injury and its underlying mechanisms. We utilized an in vivo mouse model of myocardial I/R injury and an in vitro neonatal rat cardiomyocyte (NRC) model of hypoxia/reoxygenation (H/R) injury. Mice were randomized into five groups: Sham, I/R (I/R + Vehicle), I/R + FEB (I/R + febuxostat), AL + I/R (I/R + allopurinol) and FEB (febuxostat), respectively. The I/R + FEB mice were pretreated with febuxostat (5 mg/kg; i.p.) 24 and 1 h prior to I/R. NRCs received febuxostat (1 and 10 µM) at 24 and 1 h before exposure to hypoxia for 3 h followed by reoxygenation for 3 h. Cardiac function, myocardial infarct size, serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH), and myocardial apoptotic index (AI) were measured in order to ascertain the effects of febuxostat on myocardial I/R injury. Hypoxia/reperfusion (H/R) injury in NRCs was examined using MTT, LDH leakage assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The underlying mechanisms were determined by measuring ROS production, mitochondrial membrane potential (ΔΨm), and expression of cytochrome c, cleaved caspases as well as Bcl-2 protein levels. Myocardial I/R led to an elevation in the myocardial infarct size, serum levels of CK and LDH, cell death and AI. Furthermore, I/R reduced cardiac function. These changes were significantly attenuated by pretreatment with febuxostat and allopurinol, especially by febuxostat. Febuxostat also protected the mitochondrial structure following myocardial I/R, inhibited H/R-induced ROS generation, stabilized the �

Efficacy of Combined Therapy with Liposome-Encapsulated Meglumine Antimoniate and Allopurinol in Treatment of Canine Visceral Leishmaniasis

PubMed Central

da Silva, Sydnei M.; Amorim, Izabela F. G.; Ribeiro, Raul R.; Azevedo, Erly G.; Demicheli, Cynthia; Melo, Maria N.; Tafuri, Wagner L.; Gontijo, Nelder F.; Michalick, Marilene S. M.

2012-01-01

An innovative liposomal formulation of meglumine antimoniate (LMA) was recently reported to promote both long-term parasite suppression and reduction of infectivity to sand flies in dogs with visceral leishmaniasis. However, 5 months after treatment, parasites were still found in the bone marrow of all treated dogs. In order to improve treatment with LMA, the present study aimed to evaluate its efficacy in combination with allopurinol. Mongrel dogs naturally infected with Leishmania infantum were treated with six doses of LMA (6.5 mg Sb/kg of body weight/dose) given at 4-day intervals, plus allopurinol (20 mg/kg/24 h per os) for 140 days. Comparison was made with groups treated with LMA, allopurinol, empty liposomes plus allopurinol, empty liposomes, and saline. Dogs remained without treatment from day 140 to 200 after the start of treatment. The drug combination promoted both clinical improvement of dogs and significant reduction in the parasitic load in bone marrow and spleen on days 140 and 200 compared to these parameters in the pretreatment period. This is in contrast with the other protocols, which did not result in significant reduction of the bone marrow parasite load on day 200. Strikingly, the combined treatment, in contrast to the other regimens, induced negative quantitative PCR (qPCR) results in the liver of 100% of the dogs. Both xenodiagnosis and skin parasite determination by qPCR indicated that the drug combination was effective in blocking the transmission of skin parasites to sand flies. Based on all of the parasitological tests performed on day 200, 50% of the animals that received the combined treatment were considered cured. PMID:22411610

A study comparing the safety and efficacy of febuxostat, allopurinol, and benzbromarone in Chinese gout patients: a retrospective cohort study
.

PubMed

Zhou, Qiao; Su, Jiang; Zhou, Ting; Tian, Juan; Chen, Xixi; Zhu, Jing

2017-02-01

To evaluate and compare the safety and efficacy of three urate lowering agents: febuxostat, allopurinol, and benzbromarone, when used to treat Chinese gout patients. A total of 120 patients treated in our department from November 2011 to December 2014 were randomly selected and divided into four groups: febuxostat (40 mg per day), febuxostat (80 mg per day), allopurinol (100 mg, 3 × per day) or benzbromarone (50 mg per day), (n = 30 patients/group). The serum uric acid (UA) concentrations of the patients in each group were recorded and compared from week 2 through week 24 after the treatments, and all adverse events were evaluated to determine the safety of the various treatment regimens. Treatment with febuxostat (40 mg) significantly reduced serum UA levels to those achieved with allopurinol or benzbromarone treatment. The treatment with febuxostat (80 mg) produced the best therapeutic effect and achieved the targeted UA level as early as week 2. However, the total number of patients experiencing adverse events was significantly higher in the febuxostat 80-mg group. The incidences of abnormal liver function, hyperlipidemia, and gout flare were higher in both febuxostat treatment groups. The allopurinol group had a higher incidence of hypersensitivity, and the benzbromarone group had a higher incidence of renal dysfunction. Chinese patients treated with the 40-mg dose of febuxostat experienced a treatment effect and total rate of adverse events similar to those produced by allopurinol or benzbromarone. To achieve a better therapeutic effect, the dose of febuxostat can be elevated to 80 mg per day; however, patients receiving the higher dose must be closely monitored for signs of liver dysfunction. Febuxostat is an alternative treatment for Chinese gout patients who are at a much higher risk for severe cutaneous adverse reactions as well as for patients with a history of kidney stones.
.

Resonant Raman scattering study of BexZn1-xO thin films grown on sapphire by molecular beam epitaxy

NASA Astrophysics Data System (ADS)

Wang, Yu-Chao; Su, Long-Xing; Zhao, Yu; Liu, Jian-Feng; Shen, Zheng-Chuan; Feng, Yu-Hua; Wu, Tian-Zhun; Tang, Zi-Kang

2017-07-01

Resonance Raman spectra of BexZn1-xO alloy materials were studied using 325 nm Laser. The research showed that the Raman spectra of BexZn1-xO alloys presents a dual-mode vibration. Compare BexZn1-xO alloy with ZnO single crystal, the A1 (LO) phonon vibration mode of BexZn1-xO alloy moved to the larger wave number direction. The position of A1 (LO) phonon vibration modes of Be0.08Zn0.92O and Be0.12Zn0.88O was 580 cm-1 and 582 cm-1, respectively. In addition, the temperature-dependent Raman spectroscopy was employed for Be0.12Zn0.88O, and the phonon mode frequency shift with temperature was studied in detail. Finally, the stability of the polar and nonpolar BexZn1-xO alloy materials was studied using resonance Raman spectroscopy. The results showed that the A1 (LO) phonon mode frequency of polar BexZn1-xO alloy remained in the same position, while the nonpolar BexZn1-xO alloys moved nearly 3.5 cm-1 to larger direction after being placed in the air for two years. The reason may be that the stability of the nonpolar BexZn1-xO alloy is relatively poor upon interaction with molecule such as H2O, O2 in the air.

An updated patent review: xanthine oxidase inhibitors for the treatment of hyperuricemia and gout (2011-2015).

PubMed

Ojha, Ritu; Singh, Jagjeet; Ojha, Anu; Singh, Harbinder; Sharma, Sahil; Nepali, Kunal

2017-03-01

Xanthine oxidase (XO) is a versatile molybdoflavoprotein, widely distributed, occurring in milk, kidney, lung, heart, and vascular endothelium. Catalysis by XO to produce uric acid and reactive oxygen species leads to many diseases. Anti hyperuricemic therapy by xanthine oxidase inhibitors has been mainly employed for the treatment of gout. Area covered: This review covers the patent literature (2011-2015) and also presents the interesting strategies/rational approaches employed for the design of xanthine oxidase inhibitors reported recently. Expert opinion: Recent literature indicates that various non purine scaffolds have been extensively investigated for xanthine oxidase inhibition. The significant potential endowed by heteroaryl based compounds, in particularly fused heterocycles clearly highlights their clinical promise and the need for detailed investigation. Studies by various research groups have also revealed that the flavone framework is open for isosteric replacements and structural modifications for yielding potent non purine xanthine oxidase inhibitors. In addition, various plant extracts recently reported to possess significant xanthine oxidase inhibitory potential presents enough promise to initiate a screening program for the identification of other plant extracts and phytoconstituents possessing inhibitory potential towards the enzyme.

Ultraviolet photodetector based on Mg{sub x}Zn{sub 1-x}O films using plasma-enhanced atomic layer deposition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Yu-Chang; Lee, Hsin-Ying, E-mail: hylee@ee.ncku.edu.tw; Lee, Ching-Ting

2016-01-15

A plasma-enhanced atomic layer deposition (PE-ALD) system was used to deposit magnesium zinc oxide (Mg{sub x}Zn{sub 1−x}O) films with various Mg content (x). The Mg{sub x}Zn{sub 1-x}O films were applied to metal–semiconductor–metal ultraviolet (UV) photodetectors (MSM-UPDs) as an active layer. The Mg content in the Mg{sub x}Zn{sub 1-x}O films was modulated by adjusting the ZnO–MgO cycle ratios to 15:1, 12:1, and 9:1. Correspondingly, the Mg content in the Mg{sub x}Zn{sub 1-x}O films characterized using an energy dispersive spectrometer was 0.10, 0.13, and 0.16, respectively. The optical bandgap of the Mg{sub x}Zn{sub 1-x}O films increased from 3.56 to 3.66 eV withmore » an increase in Mg content from 0.10 to 0.16. The peak position of photoresponsivity for the Mg{sub x}Zn{sub 1-x}O MSM-UPDs was also shifted from 350 to 340 nm. The UV-visible rejection ratios of the Mg{sub x}Zn{sub 1-x}O MSM-UPDs were higher than 3 orders of magnitude. In addition, excellent detectivity and noise equivalent power for the Mg{sub x}Zn{sub 1-x}O MSM-UPDs were observed at a bias voltage of 5 V. The high performance of the Mg{sub x}Zn{sub 1-x}O MSM-UPDs was achieved by PE-ALD at a low temperature.« less

LiNixCo1-xO2 Cell Grown by Pulsed Laser Deposition

NASA Astrophysics Data System (ADS)

Rao, M. C.; Ravindranadh, K.; Begum, Sk. Muntaz; Nirmala, G.

2011-07-01

Thin films of LiNixCo1-xO2 were prepared by pulsed laser deposition technique. Two important deposition parameters such as substrate temperature and oxygen partial pressure during the thin film deposition were controlled. The electrochemical measurements were carried out on Li//LiNixCo1-xO2 cells with a lithium metal foil as anode and LiNixCo1-xO2 film as cathode of 1.5 cm2 active area using a Teflon home-made cell hardware. Electrochemical titration was made by charging and discharging the cells using the galvanostatic mode of a Mac-Pile single 608 electrochemical analyzer system in the potential range between 2.0 and 4.1 V. Specific capacity as high as 220 mC/cm2 μm was measured for the film grown at 700 °C.

XO-2b: A HOT JUPITER WITH A VARIABLE HOST STAR THAT POTENTIALLY AFFECTS ITS MEASURED TRANSIT DEPTH

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zellem, Robert T.; Griffith, Caitlin A.; Pearson, Kyle A.

The transiting hot Jupiter XO-2b is an ideal target for multi-object photometry and spectroscopy as it has a relatively bright (V-mag = 11.25) K0V host star (XO-2N) and a large planet-to-star contrast ratio (R{sub p}/R{sub s} ≈ 0.015). It also has a nearby (31.″21) binary stellar companion (XO-2S) of nearly the same brightness (V-mag = 11.20) and spectral type (G9V), allowing for the characterization and removal of shared systematic errors (e.g., airmass brightness variations). We have therefore conducted a multiyear (2012–2015) study of XO-2b with the University of Arizona’s 61″ (1.55 m) Kuiper Telescope and Mont4k CCD in the Besselmore » U and Harris B photometric passbands to measure its Rayleigh scattering slope to place upper limits on the pressure-dependent radius at, e.g., 10 bar. Such measurements are needed to constrain its derived molecular abundances from primary transit observations. We have also been monitoring XO-2N since the 2013–2014 winter season with Tennessee State University’s Celestron-14 (0.36 m) automated imaging telescope to investigate stellar variability, which could affect XO-2b’s transit depth. Our observations indicate that XO-2N is variable, potentially due to cool star spots, with a peak-to-peak amplitude of 0.0049 ± 0.0007 R-mag and a period of 29.89 ± 0.16 days for the 2013–2014 observing season and a peak-to-peak amplitude of 0.0035 ± 0.0007 R-mag and 27.34 ± 0.21 day period for the 2014–2015 observing season. Because of the likely influence of XO-2N’s variability on the derivation of XO-2b’s transit depth, we cannot bin multiple nights of data to decrease our uncertainties, preventing us from constraining its gas abundances. This study demonstrates that long-term monitoring programs of exoplanet host stars are crucial for understanding host star variability.« less

Investigation of novel inverted NiO@NixCo1-xO core-shell nanoparticles

NASA Astrophysics Data System (ADS)

Hasan, Samiul; Mayanovic, R. A.; Benamara, Mourad

2018-05-01

Inverse core-shell nanoparticles, comprised of an antiferromagnetic (AFM) core covered by a ferromagnetic (FM) or ferrimagnetic (FiM) shell, are of current interest due to their different potential application and due to the tunability of their magnetic properties. The antiferromagnetic nature of NiO and high Néel temperature (523 K) makes this material well suited for inverse core-shell nanoparticle applications. Our primary objective in this project has been to synthesize and characterize inverted core-shell nanoparticles (CSNs) comprised of a NiO (AFM) core and a shell consisting of a NixCo1-xO (FiM) compound. The synthesis of the CSNs was made using a two-step process. The NiO nanoparticles were synthesized using a chemical reaction method. Subsequently, the NiO nanoparticles were used to grow the NiO@NixCo1-xO CSNs using our hydrothermal nano-phase epitaxy method. XRD structural characterization shows that the NiO@NixCo1-xO CSNs have the rock salt cubic crystal structure. SEM-EDS data indicates the presence of Co in the CSNs. Magnetic measurements show that the CSNs exhibit AFM/FiM characteristics with a small coercivity field of 30 Oe at 5 K. The field cooled vs zero field cooled hysteresis loop measurements show a magnetization axis shift which is attributed to the exchange bias effect between the AFM NiO core and an FiM NixCo1-xO shell of the CSNs. Our ab initio based calculations of the NixCo1-xO rock salt structure confirm a weak FiM character and a charge transfer insulator property of the compound.

Previous Dosage of Allopurinol Is a Strong Determinant of Febuxostat Efficacy.

PubMed

Koide, Hiroyoshi; Hira, Daiki; Tsujimoto, Masayuki; Katsube, Yurie; Minegaki, Tetsuya; Uzu, Takashi; Ikeda, Yoshito; Morita, Shin-Ya; Nishiguchi, Kohshi; Terada, Tomohiro

2017-01-01

Febuxostat has currently played pivotal role in the treatment of hyperuricemia, but there is little comprehensive information for the determinants of individual difference in efficacy of febuxostat. Therefore, the present study, a retrospective investigation, was carried out to analyze the effects of patient characteristics on the efficacy of febuxostat. A total of 225 patients who were continuously prescribed the same dose of febuxostat for 8-12 weeks from the initial therapy were enrolled in the present study. The data, including patient information and laboratory data, were collected from electronic medical records. Serum urate lowering effects of febuxostat were evaluated by calculating the change in serum urate level at baseline and at 8-12 weeks after starting febuxostat. The multiple regression analysis showed the change in serum urate level was significantly lower in male patients and in those with a lower baseline serum urate level, higher previous dose of allopurinol, lower dose of febuxostat and lower body surface area-unadjusted estimated glomerular filtration rate. Concomitantly administered drugs did not show a significantly influence on the efficacy of febuxostat. In conclusion, it should be noted that the serum urate lowering efficacy of febuxostat may decrease in patients with a higher previous dose of allopurinol, renal impairment or male patients. The basic findings of the present study are believed to contribute to the proper use of febuxostat.

Albumin microparticles as the carriers for allopurinol and applicable for the treatment of ischemic stroke

NASA Astrophysics Data System (ADS)

Aganyants, Hovsep Alexandr; Nikohosyan, Gayane; Danielyan, Kristine Edgar

2016-11-01

Albumin nanoparticles are already used for the treatment of the cancer. In our current work, it is presented the technique for the preparation of small-size 1- to 5-micron particles coated with the allopurinol. We propose that this combination of the compounds might be useful for the ischemic stroke treatment as the agent preventing formation of the brain edema, reactive oxygen species, and initiation of cells regeneration. Glutaraldehyde was used for the polymerization of albumin. Determination of the particle size was performed by the light as well as phase contrast microscopies and analyzed by Pixcavator 6.0 and Image Tool programs. Modification and establishment of iodine-based method served as the base for quantification of bound with the particles and free allopurinol. As a consequence of the experiments, the best formulation of glutaraldehyde ratio and albumin quantity as well as conditions for the formation of the smallest sized spheroid-shaped particles were found for the further in vivo application.

Structure-based design and biological evaluation of novel 2-(indol-2-yl) thiazole derivatives as xanthine oxidase inhibitors.

PubMed

Song, Jeong Uk; Jang, Jae Wan; Kim, Tae Hun; Park, Heuisul; Park, Wan Su; Jung, Sang-Hun; Kim, Geun Tae

2016-02-01

Inhibition of xanthine oxidase (XO) has obviously been a central concept for controlling hyperuricemia, which causes serious and painful inflammatory arthritis disease such as gout. We discovered a series of novel 2-(indol-2-yl)thiazole derivatives as XO inhibitors at the level of nanomolar activity. Structure-guided design using molecular modeling program (Accelrys Software program) provided an excellent basis for optimization of 2-(indol-2-yl)thiazole compounds. Structure-activity relationship indicated that hydrophobic alkoxy group (isopropoxy, cyclopentoxy) at 5-position and hydrogen binding acceptor (NO2, CN) at 7-position of indole ring appear as critical functional groups. Among the compounds, 2-(7-nitro-5-isopropoxy-indol-2-yl)-4-methylthiazole-5-carboxylic acid (9m) exhibits the most potent XO inhibitory activity (IC50 value: 5.1 nM) and the excellent uric acid lowering activity in potassium oxonate induced hyperuricemic rat model. Copyright © 2016. Published by Elsevier Ltd.

Facile synthesis of Cu/Cu{sub x}O nanoarchitectures with adjustable phase composition for effective NO{sub x} gas sensor at room temperature

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Lixue; Li, Li; Yang, Ying

2013-10-15

Graphical abstract: The Cu/Cu{sub x}O nanoarchitectures with 30–70 nm hollow nanospheres reduced by 3 mmol NaBH{sub 4} exhibits excellent gas-sensing property to low-concentration NO{sub x} gas at room temperature. - Highlights: • The Cu/Cu{sub x}O nanoarchitectures with hollow nanospheres are successfully synthesized. • The method is used for preparing the with Cu/Cu{sub x}O adjustable phase composition. • The C3 sample exhibites excellent gas-sensing propertie to NO{sub x} at room temperation. • The Cu/Cu{sub x}O nanoarchitectures have significant for application of gas sensor. - Abstract: The Cu/Cu{sub x}O nanoarchitectures with 30–70 nm hollow nanospheres are successfully synthesized by a facile wetmore » chemical method. The synthesized products have been studied by X-ray powder diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and thermo gravimetric-differential scanning calorimetry (TG-DSC) analysis. The Cu/Cu{sub x}O sensors based on the nanoarchitectures are used to detect the NO{sub x} at room temperature. The results demonstrate that the obtained Cu/Cu{sub x}O nanoarchitectures reduced by 3 mmol NaBH{sub 4} exhibits excellent gas-sensing properties: low detection limit of 0.97 ppm, relatively high sensitivity, short response time, broad linear range and high selectivity. The reasons for gas-sensing activity enhancement on Cu/Cu{sub x}O nanoarchitectures are discussed. The Cu/Cu{sub x}O nanocrystalline with the hierarchical pores structure and tunable compositions have significant for application of gas sensor.« less

Low-dose thiopurine with allopurinol co-therapy overcomes thiopurine intolerance and allows thiopurine continuation in inflammatory bowel disease.

PubMed

Vasudevan, Abhinav; Beswick, Lauren; Friedman, Antony B; Moltzen, Alicia; Haridy, James; Raghunath, Ajay; Sparrow, Miles; van Langenberg, Daniel

2018-02-10

To assess the utility and tolerability of thiopurine-allopurinol co-therapy in inflammatory bowel disease (IBD) patients with intolerance to thiopurine monotherapy. A retrospective observational study assessed cases of thiopurine intolerance then switched to thiopurine allopurinol co-therapy between 2011 and 2015 at two centres. Indications for switch, dosing and subsequent clinical outcomes (including thiopurine persistence) were recorded. Of 767 patients on thiopurines for IBD, 89 (12%) were switched to co-therapy for intolerance. 64/89 (72%) had Crohn's disease, 38 (43%) were males, median age at switch was 40y (range 17-78), median IBD duration 6y (0-29). Median follow-up was 1.9y (0-5). Reasons for switching to co-therapy included fatigue (37%), hepatotoxicity (23%), nausea (23%), arthralgia (10%), headache (12%) and hypersensitivity reaction (4%). Overall, 66 (74%) patients remained on co-therapy until most recent review and achieved a clinical response. High rates of overcoming intolerance (62-100%) occurred with co-therapy for all reasons above, although fatigue was less amenable to switching than non-fatigue indications (62% vs 91%, p = <0.001). Of 34 patients not escalated to biologics with endoscopic data, 15 were in remission (44%) at most recent review. Low-dose thiopurine combined with allopurinol appears safe and effective in overcoming intolerances to thiopurine monotherapy in many cases. Copyright © 2018. Published by Elsevier Ltd.

A comparative study of efficacy and safety of febuxostat and allopurinol in pyrazinamide-induced hyperuricemic tubercular patients.

PubMed

Pichholiya, Meenu; Yadav, Arvind Kumar; Luhadia, S K; Tahashildar, Jameela; Aseri, M L

2016-01-01

To compare the efficacy and safety of febuxostat and allopurinol in pyrazinamide (PZA)-induced hyperuricemia in patients taking antitubercular therapy (ATT). This randomized controlled study was conducted at a tertiary care teaching institute of Rajasthan in all the sputum-positive tubercular patients aged between 18 and 65 years of either sex. Serum uric acid level was monitored at 0 th , 2 nd , 4 th , 6 th , and 8 th week of ATT. Patients whose uric acid level was found to be increased at 2 nd week were finally recruited in the study. Ninety patients who developed hyperuricemia due to ATT were divided randomly into three groups (Group A - febuxostat, Group B - allopurinol, and Group C - control) of thirty patients each. Mean serum uric acid levels were calculated at all the weeks in all the groups, and serum uric acid levels were compared by applying student's t -test and ANOVA. Mean serum uric acid level decreased from 10.698 mg/dl (at 2 nd week) to 7.846 mg/dl (at 8 th week) in Group A and from 11.34 mg/dl (at 2 nd week) to 7.280 mg/dl (at 8 th week) in Group B. Numbers of adverse events encountered across both the treatment groups were same with both the drugs. Allopurinol and febuxostat were equally efficacious in lowering PZA induced raised serum uric acid level in tubercular patients, and it was possible to continue ATT without withdrawing PZA.

Low-temperature sintered Li2(MnxTi1-x)O3 microwave dielectric ceramics with adjustable τf

NASA Astrophysics Data System (ADS)

Liu, Cheng; Zhang, Huaiwu; Su, Hua; Li, Jie; Liao, Yulong; Jia, Lijun; Li, Yuanxun

2017-12-01

B2O3-Bi2O3-SiO2-ZnO (BBSZ) glass-modified Li2(MnxTi1-x)O3 ceramics were fabricated via a solid-state reaction route. Pure phase and dense crystal morphology were obtained at 900∘C. Suitable amount of Mn4+-ion substitution could adjust the τf value of the Li2(MnxTi1-x)O3 system to near zero. Among all of the Li2(MnxTi1-x)O3 samples, the sample with x = 0.9 (marked as BL9 in this paper) possessed good microwave dielectric properties: 𝜀r = 18, Q × f = 14,056 GHz (9.58 GHz) and τf = (+)2.43 ppm/∘C. It is suggested that the Li2(MnxTi1-x)O3 ceramic with BBSZ glass is a suitable low-temperature co-fired ceramic (LTCC) candidate for microwave applications.

Allopurinol

MedlinePlus

... is used to treat gout, high levels of uric acid in the body caused by certain cancer medications, ... inhibitors. It works by reducing the production of uric acid in the body. High levels of uric acid ...

Traditional Uighur Medicine Karapxa decoction, inhibits liver xanthine oxidase and reduces serum uric acid concentrations in hyperuricemic mice and scavenges free radicals in vitro.

PubMed

Amat, Nurmuhammat; Umar, Anwar; Hoxur, Parida; Anaydulla, Mihrigul; Imam, Guzalnur; Aziz, Ranagul; Upur, Halmurat; Kijjoa, Anake; Moore, Nicholas

2015-04-25

Karapxa decoction (KD) is a Traditional Uighur Medicine used for hepatitis, cholecystitis, gastralgia, oedema, gout and arthralgia. Because of its purported effect in gout, its effects were tested in hyperuricemic mice models induced by yeast extract paste or potassium oxonate, as well as its capacity to scavenge free radicals in vitro. Hyperuricemia was induced in mice by yeast extract paste or potassium oxonate. KD was given orally for 14 days at 200, 400 and 800 mg/kg/day, with Allopurinol 10 mg/kg/day as positive control. Serum uric acid (UA), and liver xanthine oxidase activity (XO) were measured. Scavenging activity of KD on 1, 1-diphenyl-2-picrylhydrazyl radicals (DPP•), nitric oxide (•NO), superoxide (O2•-), efficiency against lipid peroxidation, and XO inhibition were determined in vitro. KD inhibited liver XO activity and reduced serum uric acid in hyperuricemic mice. KD also showed noticeable antioxidant activity, scavenging free radicals (DPP•, •NO and O2•-). It was effective against lipid peroxidation and inhibited XO in vitro. This study supports the traditional use of Karapxa decoction to treat hyperuricemia and gout.

Electrical properties of solid-solution SrZrxTi1-xO3 grown epitaxially on Ge by molecular beam epitaxy

NASA Astrophysics Data System (ADS)

Moghadam, Reza; Ahmadi, Kamyar; Xiao, Z.-Y.; Hong, Xia; Ngai, Joseph

The epitaxial growth of crystalline oxides on semiconductors enables new functionalities to be introduced to semiconductor devices. In particular, dielectric and ferroelectric oxides grown epitaxially on semiconductors provide a pathway to realize ultra-low power logic and memory devices. Here we present electrical characterization of solid-solution SrZrxTi1-xO3 grown epitaxially on Ge through oxide molecular beam epitaxy. SrZrxTi1-xO3 is of particular interest since the band offset with respect to the semiconductor can be tuned through Zr content x. We will present current-voltage, capacitance-voltage and piezoforce microscopy characterization of SrZrxTi1-xO3 -Ge heterojunctions. In particular, we will discuss how the electrical characteristics of SrZrxTi1-xO3 -Ge heterojunctions evolve with respect to composition, annealing and film thickness.

A comparative study of efficacy and safety of febuxostat and allopurinol in pyrazinamide-induced hyperuricemic tubercular patients

PubMed Central

Pichholiya, Meenu; Yadav, Arvind Kumar; Luhadia, S. K.; Tahashildar, Jameela; Aseri, M. L.

2016-01-01

Objectives: To compare the efficacy and safety of febuxostat and allopurinol in pyrazinamide (PZA)-induced hyperuricemia in patients taking antitubercular therapy (ATT). Methods: This randomized controlled study was conducted at a tertiary care teaching institute of Rajasthan in all the sputum-positive tubercular patients aged between 18 and 65 years of either sex. Serum uric acid level was monitored at 0th, 2nd, 4th, 6th, and 8th week of ATT. Patients whose uric acid level was found to be increased at 2nd week were finally recruited in the study. Ninety patients who developed hyperuricemia due to ATT were divided randomly into three groups (Group A - febuxostat, Group B - allopurinol, and Group C - control) of thirty patients each. Mean serum uric acid levels were calculated at all the weeks in all the groups, and serum uric acid levels were compared by applying student's t-test and ANOVA. Results: Mean serum uric acid level decreased from 10.698 mg/dl (at 2nd week) to 7.846 mg/dl (at 8th week) in Group A and from 11.34 mg/dl (at 2nd week) to 7.280 mg/dl (at 8th week) in Group B. Numbers of adverse events encountered across both the treatment groups were same with both the drugs. Conclusion: Allopurinol and febuxostat were equally efficacious in lowering PZA induced raised serum uric acid level in tubercular patients, and it was possible to continue ATT without withdrawing PZA. PMID:27721537

Dissimilar distribution of Trypanosoma cruzi clones in humans after chemotherapy with allopurinol and itraconazole.

PubMed

Coronado, Ximena; Zulantay, Inés; Rozas, Marlene; Apt, Werner; Sánchez, Gittith; Rodríguez, Jorge; Ortiz, Sylvia; Solari, Aldo

2006-07-01

The aim of this work was to study the distribution of Trypanosoma cruzi clones after treatment failure with itraconazole or allopurinol in infected humans. Blood samples from treated and untreated individuals were used to detect T. cruzi by PCR assays and were confirmed by hybridization tests using total kinetoplast DNA as a universal probe. Also, xenodiagnosis (XD) tests were performed with Triatoma infestans fed from the same group of patients. We performed Southern-blot analyses of PCR products from blood or XD samples using a panel of four genotype-specific probes: corresponding to T. cruzi clones TcI, TcIIb, TcIId and TcIIe. The membranes were hybridized with radiolabelled probes and exposed in a Personal Molecular Imager. When comparing the presence of T. cruzi clones in the allopurinol-treated group with the non-treated group significant differences were only observed for XD samples. Clone TcI was present in 9/13 (69.2%) of the XD samples of the treated group, but only in 8/27 (29.6%) in the non-treated group (P = 0.0178). When the itraconazole-treated group and the control group were compared, significant differences were found in both the blood and XD samples. In blood, the clone TcIIb was detected in 6/17 (35.5%) of the treated group and in 18/27 (66.7%) of the non-treated group (P = 0.0207). When XD samples were analysed, the clone TcI was observed in 14/17 (82.3%) of the itraconazole-treated group but only in 8/27 (29.6%) of the control group (P = 0.0006), which suggests resistance of this clone to itraconazole. We detected a dissimilar distribution of T. cruzi clones in treated and untreated groups of patients. The presence of TcI increased in patients treated with allopurinol and itraconazole, whereas the presence of TcIIb decreased in itraconazole-treated patients. The type of T. cruzi clone that prevails suggests that TcI is resistant to both drugs and that TcIIb is susceptible to itraconazole.

Allopurinol attenuates rhabdomyolysis-associated acute kidney injury: Renal and muscular protection.

PubMed

Gois, Pedro H F; Canale, Daniele; Volpini, Rildo A; Ferreira, Daniela; Veras, Mariana M; Andrade-Oliveira, Vinicius; Câmara, Niels O S; Shimizu, Maria H M; Seguro, Antonio C

2016-12-01

Acute kidney injury (AKI) is the most severe complication of rhabdomyolysis. Allopurinol (Allo), a xanthine oxidase inhibitor, has been in the spotlight in the last decade due to new therapeutic applications related to its potent antioxidant effect. The aim of this study was to evaluate the efficacy of Allo in the prevention and treatment of rhabdomyolysis-associated AKI. Male Wistar rats were divided into five groups: saline control group; prophylactic Allo (300mg/L of drinking water, 7 days); glycerol (50%, 5ml/kg, IM); prophylactic Allo + glycerol; and therapeutic Allo (50mg/Kg, IV, 30min after glycerol injection) + glycerol. Glycerol-injected rats showed markedly reduced glomerular filtration rate associated with renal vasoconstriction, renal tubular damage, increased oxidative stress, apoptosis and inflammation. Allo ameliorated all these alterations. We found 8-isoprostane-PGF 2a (F2-IsoP) as a main factor involved in the oxidative stress-mediated renal vasoconstriction following rhabdomyolysis. Allo reduced F2-IsoP renal expression and restored renal blood flow. Allo also reduced oxidative stress in the damaged muscle, attenuated muscle lesion/inflammation and accelerated muscular recovery. Moreover, we showed new insights into the pathogenesis of rhabdomyolysis-associated AKI, whereas Allo treatment reduced renal inflammation by decreasing renal tissue uric acid levels and consequently inhibiting the inflammasome cascade. Allo treatment attenuates renal dysfunction in a model of rhabdomyolysis-associated AKI by reducing oxidative stress (systemic, renal and muscular), apoptosis and inflammation. This may represent a new therapeutic approach for rhabdomyolysis-associated AKI - a new use for an old and widely available medication. Copyright © 2016 Elsevier Inc. All rights reserved.

Stability of acetazolamide, allopurinol, azathioprine, clonazepam, and flucytosine in extemporaneously compounded oral liquids.

PubMed

Allen, L V; Erickson, M A

1996-08-15

The stability of drugs commonly prescribed for use in oral liquid dosage forms but not commercially available as such was studied. Acetazolamide 25 mg/mL, allopurinol 20 mg/mL, azathioprine 50 mg/mL, clonazepam 0.1 mg/mL, and flucytosine 10 mg/mL were prepared in 1:1 mixture of Ora-Sweet and Ora-Plus (Paddock Laboratories), a 1:1 mixture of Ora-Sweet SF and Ora-Plus (Paddock Laboratories), and cherry syrup and placed in polyethylene terephthalate bottles. The sources of the drugs were capsules and tablets. Six bottles were prepared per liquid; three were stored at 5 degrees C and three at 25 degrees C, all in the dark. A sample was removed from each bottle initially and at intervals up to 60 days and analyzed for drug concentration by stability-indicating high-performance liquid chromatography. At least 94% of the initial drug concentration was retained in all the oral liquids for up to 60 days. There were no substantial changes in the appearance or odor of the liquids, or in the pH. Acetazolamide 25 mg/mL, allopurinol 20 mg/mL, azathioprine 50 mg/mL, clonazepam 0.1 mg/mL, and flucytosine 10 mg/mL were stable for up to 60 days at 5 and 25 degrees C in three extemporaneously compounded oral liquids.

9-Benzoyl 9-deazaguanines as potent xanthine oxidase inhibitors.

PubMed

Rodrigues, Marili V N; Barbosa, Alexandre F; da Silva, Júlia F; dos Santos, Deborah A; Vanzolini, Kenia L; de Moraes, Marcela C; Corrêa, Arlene G; Cass, Quezia B

2016-01-15

A novel potent xanthine oxidase inhibitor, 3-nitrobenzoyl 9-deazaguanine (LSPN451), was selected from a series of 10 synthetic derivatives. The enzymatic assays were carried out using an on-flow bidimensional liquid chromatography (2D LC) system, which allowed the screening¸ the measurement of the kinetic inhibition constant and the characterization of the inhibition mode. This compound showed a non-competitive inhibition mechanism with more affinity for the enzyme-substrate complex than for the free enzyme, and inhibition constant of 55.1±9.80 nM, about thirty times more potent than allopurinol. Further details of synthesis and enzymatic studies are presented herein. Copyright © 2015 Elsevier Ltd. All rights reserved.

The GAPS programme with HARPS-N at TNG. X. Differential abundances in the XO-2 planet-hosting binary

NASA Astrophysics Data System (ADS)

Biazzo, K.; Gratton, R.; Desidera, S.; Lucatello, S.; Sozzetti, A.; Bonomo, A. S.; Damasso, M.; Gandolfi, D.; Affer, L.; Boccato, C.; Borsa, F.; Claudi, R.; Cosentino, R.; Covino, E.; Knapic, C.; Lanza, A. F.; Maldonado, J.; Marzari, F.; Micela, G.; Molaro, P.; Pagano, I.; Pedani, M.; Pillitteri, I.; Piotto, G.; Poretti, E.; Rainer, M.; Santos, N. C.; Scandariato, G.; Zanmar Sanchez, R.

2015-11-01

Binary stars hosting exoplanets are a unique laboratory where chemical tagging can be performed to measure the elemental abundances of both stellar components with high accuracy, with the aim to investigate the formation of planets and their subsequent evolution. Here, we present a high-precision differential abundance analysis of the XO-2 wide stellar binary based on high-resolution HARPS-N at TNG spectra. Both components are very similar K-dwarfs and host planets. Since they formed presumably within the same molecular cloud, we expect that they possess the same initial elemental abundances. We investigated whether planets can cause some chemical imprints in the stellar atmospheric abundances. We measure abundances of 25 elements for both stars with a range of condensation temperature TC = 40-1741 K, achieving typical precisions of ~0.07 dex. The northern component shows abundances in all elements higher by +0.067 ± 0.032 dex on average, with a mean difference of +0.078 dex for elements with TC > 800 K. The significance of the XO-2N abundance difference relative to XO-2S is at the 2σ level for almost all elements. We discuss that this result might be interpreted as the signature of the ingestion of material by XO-2N or depletion in XO-2S that is due to locking of heavy elements by the planetary companions. We estimate a mass of several tens of M⊕ in heavy elements. The difference in abundances between XO-2N and XO-2S shows a positive correlation with the condensation temperatures of the elements, with a slope of (4.7 ± 0.9) × 10-5 dex K-1, which could mean that both components have not formed terrestrial planets, but first experienced the accretion of rocky core interior to the subsequent giant planets. Based on observations made with the Italian Telescopio Nazionale Galileo (TNG), operated on the island of La Palma by the INAF - Fundación Galileo Galilei at the Roche de los Muchachos Observatory of the Instituto de Astrofísica de Canarias (IAC) in the

Raman scattering in HfxZr1-xO2 nanoparticles

NASA Astrophysics Data System (ADS)

Robinson, Richard D.; Tang, Jing; Steigerwald, Michael L.; Brus, Louis E.; Herman, Irving P.

2005-03-01

Raman spectroscopy demonstrates that ˜5nm dimension HfxZr1-xO2 nanocrystals prepared by a nonhydrolytic sol-gel synthesis method are solid solutions of hafnia and zirconia, with no discernable segregation within the individual nanoparticles. Zirconia-rich particles are tetragonal and ensembles of hafnia-rich particles show mixed tetragonal/monoclinic phases. Sintering at 1200 °C produces larger particles (20-30 nm) that are monoclinic. A simple lattice dynamics model with composition-averaged cation mass and scaled force constants is used to understand how the Raman mode frequencies vary with composition in the tetragonal HfxZr1-xO2 nanoparticles. Background luminescence from these particles is minimized after oxygen treatment, suggesting possible oxygen defects in the as-prepared particles. Raman scattering is also used to estimate composition and the relative fractions of tetragonal and monoclinic phases. In some regimes there are mixed phases, and Raman analysis suggests that in these regimes the tetragonal phase particles are relatively rich in zirconium and the monoclinic phase particles are relatively rich in hafnium.

A novel drug management system in the Febuxostat versus Allopurinol Streamlined Trial: A description of a pharmacy system designed to supply medications directly to patients within a prospective multicenter randomised clinical trial.

PubMed

Rogers, Amy; Flynn, Robert Wv; McDonnell, Patrick; Mackenzie, Isla S; MacDonald, Thomas M

2016-12-01

Trials of investigational medicinal products are required to adhere to strict guidelines with regard to the handling and supply of medication. Information technology offers opportunities to approach clinical trial methodology in new ways. This report summarises a novel pharmacy system designed to supply trial medications directly to patients by post in the Febuxostat versus Allopurinol Streamlined Trial. A bespoke web-based software package was designed to facilitate the direct supply of trial medications to Febuxostat versus Allopurinol Streamlined Trial participants from a pharmacy based in the Medicines Monitoring Unit, University of Dundee. To date, 65,467 packs of medication have been dispensed using the system to 3978 patients. Up to 238 packs per day have been dispensed. The Medicines Monitoring Unit Febuxostat versus Allopurinol Streamlined Trial drug management system is an effective method of administering the complex drug supply requirements of a large-scale clinical trial with advantages over existing arrangements. A low rate of loss to follow-up in the Febuxostat versus Allopurinol Streamlined Trial may be attributable to the drug management system. © The Author(s) 2016.

Scalable ferroelectric MOS capacitors comprised of single crystalline SrZrxTi1-xO3 on Ge.

NASA Astrophysics Data System (ADS)

Moghadam, Reza; Xiao, Z.-Y.; Ahmadi-Majlan, K.; Grimley, E.; Ong, P. V.; Lebeau, J. M.; Chambers, S. A.; Hong, X.; Sushko, P.; Ngai, J. H.

The epitaxial growth of multifunctional oxides on semiconductors has opened a pathway to introduce new functionalities to semiconductor device technologies. In particular, ferroelectric materials integrated on semiconductors could lead to field-effect devices that require very little power to operate, or that possess both logic and memory functionalities. The development of metal-oxide-semiconductor (MOS) capacitors in which the polarization of a ferroelectric gate is coupled to the surface potential of a semiconducting channel is essential in order to realize such field-effect devices. Here we demonstrate that scalable, ferroelectric MOS capacitors can be realized using single crystalline SrZrxTi1-xO3 (x = 0.7) that has been epitaxially grown on Ge. Single crystalline SrZrxTi1-xO3 exhibits characteristics that are ideal for a ferroelectric gate material, namely, a type-I band offset with respect to Ge, large coercive fields and polarization that can be enhanced with electric field. The latter characteristic stems from the relaxor nature of SrZrxTi1-xO3. These properties enable MOS capacitors with 5 nm thick SrZrxTi1-xO3 layers to exhibit a nearly 2 V wide hysteretic window in the capacitance-voltage characteristics. The realization of ferroelectric MOS capacitors with technologically relevant gate thicknesses opens the pathway to practical field effect devices. NSF DMR 1508530.

Horizontal transfer of chromosomal markers mediated by the large conjugative plasmid pXO16 from Bacillus thuringiensis serovar israelensis.

PubMed

Makart, Lionel; Commans, Florian; Gillis, Annika; Mahillon, Jacques

2017-05-01

pXO16, a large plasmid originating from Bacillus thuringiensis serovar israelensis, displays unique conjugation capacities: besides efficient self-transfer, it is able to mobilize and retro-mobilize non-conjugative plasmids, including those missing an oriT and/or a mob gene, also known as "non-mobilizable" plasmids. In this paper, another peculiar transfer property of pXO16 is described. This element is indeed able to transfer chromosomal loci at frequencies of ca. 10 -5 -10 -6 transconjugants/donor cell. Whereas most other chromosomal transfer systems occur via the integration of the conjugative elements into the chromosome prior to its transfer, pXO16 appears to transfer the chromosomal markers in the absence of physical integration, but rather through a "donation-type" mobilization. Copyright © 2017 Elsevier Inc. All rights reserved.

PROBING THE TERMINATOR REGION ATMOSPHERE OF THE HOT-JUPITER XO-1b WITH TRANSMISSION SPECTROSCOPY

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tinetti, G.; Deroo, P.; Swain, M. R.

2010-04-01

We report here the first infrared spectrum of the hot-Jupiter XO-1b. The observations were obtained with the NICMOS instrument on board the Hubble Space Telescope during a primary eclipse of the XO-1 system. Near photon-noise-limited spectroscopy between 1.2 and 1.8 {mu}m allows us to determine the main composition of this hot-Jupiter's planetary atmosphere with good precision. This is the third hot-Jupiter's atmosphere for which spectroscopic data are available in the near-IR. The spectrum shows the presence of water vapor (H{sub 2}O), methane (CH{sub 4}), and carbon dioxide (CO{sub 2}), and suggests the possible presence of carbon monoxide (CO). We showmore » that the published IRAC secondary transit emission photometric data are compatible with the atmospheric composition at the terminator determined from the NICMOS spectrum, with a range of possible mixing ratios and thermal profiles; additional emission spectroscopy data are needed to reduce the degeneracy of the possible solutions. Finally, we note the similarity between the 1.2-1.8 {mu}m transmission spectra of XO-1b and HD 209458b, suggesting that in addition to having similar stellar/orbital and planetary parameters the two systems may also have a similar exoplanetary atmospheric composition.« less

Accurate solid solution range of BiMnxFe3-xO6 and low temperature magnetism

NASA Astrophysics Data System (ADS)

Jiang, Pengfei; Yue, Mufei; Cong, Rihong; Gao, Wenliang; Yang, Tao

2017-11-01

BiMnxFe3-xO6 (x = 1) represents a new type of oxide structure containing Bi3+ and competing magnetic super-exchanges. In literature, multiple magnetic states were realized at low temperatures in BiMnFe2O6, and the hypothetical parent compounds (BiMn3O6, BiFe3O6) were predicted to be different in magnetism. Herein, we performed a careful study on the syntheses of BiMnxFe3-xO6 at ambient pressure, and the solid solution range was determined to be 0.9 ≤ x ≤ 1.3 by Rietveld refinements on high-quality powder X-ray diffraction data. Due to the very similar cationic size of Mn3+ and Fe3+, and possibly the structural rigidity, there was no significant structure change in the whole range of solid solution. The magnetic behavior of BiMnxFe3-xO6 (x = 1.2, 1.22, 1.26, 1.28 and 1.3) was generally similar to BiMnFe2O6, while the relative higher concentration of Mn3+ led to the decreasing of the antiferromagnetic ordering temperature.

Synthesis, Characterization, and Gas-Sensing Properties of Mesoporous Nanocrystalline Sn(x)Ti(1-x)O2.

PubMed

Zhong, Cheng; Lin, Zhidong; Guo, Fei; Wang, Xuehua

2015-06-01

A nanocomposite mesoporous material composed by SnO2 and TiO2 with the size of -5-9 nm were prepared via a facile wet-chemical approach combining with an annealing process. The microstructure of obtained Sn(x)Ti(1-x)O2 powders were characterized by X-ray diffraction, X-ray Photo-electronic Spectroscopy, scanning electron microscope, transmission electron microscope and nitrogen adsorption-desorption experiment. The gas sensing performances to several gases of the mesoporous material were studied. The sensors of Sn(x)Ti(1-x)O2 (ST10, with 9.1% Ti) exhibited very high responses to volatile organic compounds at 160 degrees C. The order of the responses to volatile gases based on ST10 was ethanol > formaldehyde > acetone > toluene > benzene > methane. Sensor based on ST10 displays a highest sensitivity to hydrogen at 200 degrees C. Sensor responses to H2 at 200 degrees C have been measured and analyzed in a wide concentration range from 5 to 2000 ppm. The solid solution Sn(x)Ti(1-x)O2 can be served as a potential gas-sensing material for a broad range of future sensor applications.

Genomic sequencing of uric acid metabolizing and clearing genes in relationship to xanthine oxidase inhibitor dose.

PubMed

Carroll, Matthew B; Smith, Derek M; Shaak, Thomas L

2017-03-01

It remains unclear why the dose of xanthine oxidase inhibitors (XOI) allopurinol or febuxostat varies among patients though they reach similar serum uric acid (SUA) goal. We pursued genomic sequencing of XOI metabolism and clearance genes to identify single-nucleotide polymorphisms (SNPs) relate to differences in XOI dose. Subjects with a diagnosis of Gout based on the 1977 American College of Rheumatology Classification Criteria for the disorder, who were on stable doses of a XOI, and who were at their goal SUA level, were enrolled. The primary outcome was relationship between SNPs in any of these genes to XOI dose. The secondary outcome was relationship between SNPs and change in pre- and post-treatment SUA. We enrolled 100 subjects. The average patient age was 68.6 ± 10.6 years old. Over 80% were men and 77% were Caucasian. One SNP was associated with a higher XOI dose: rs75995567 (p = 0.031). Two SNPs were associated with 300 mg daily of allopurinol: rs11678615 (p = 0.022) and rs3731722 on Aldehyde Oxidase (AO) (His1297Arg) (p = 0.001). Two SNPs were associated with a lower dose of allopurinol: rs1884725 (p = 0.033) and rs34650714 (p = 0.006). For the secondary outcome, rs13415401 was the only SNP related to a smaller mean SUA change. Ten SNPs were identified with a larger change in SUA. Though multiple SNPs were identified in the primary and secondary outcomes of this study, rs3731722 is known to alter catalytic function for some aldehyde oxidase substrates.

A prospective evaluation of the impact of allopurinol in pediatric and adult IBD patients with preferential metabolism of 6-mercaptopurine to 6-methylmercaptopurine.

PubMed

Gerich, Mark E; Quiros, J Antonio; Marcin, James P; Tennyson, Linda; Henthorn, Maria; Prindiville, Thomas P

2010-11-01

6-mercaptopurine (6-MP) is used for the induction and maintenance of remission of inflammatory bowel disease (IBD). 6-MP is converted into 6-methylmercaptopurine (6-MMP) or 6-thioguanine nucleotides (6-TGN) intracellularly. Treatment response in IBD patients correlates with 6-TGN levels. This study prospectively evaluated the effect of allopurinol on 6-MP metabolites in adult and pediatric IBD patients. Additionally, we quantified the prevalence of preferential metabolism towards 6-MMP through a retrospective analysis of IBD patients. Twenty patients (10 adult; 10 pediatric) with evidence of preferential metabolism towards 6-MMP, (6-TGN<250 pmol/8×10⁸ RBCs and 6-MMP>5000 pmol/8×10⁸ RBCs) were prospectively treated with allopurinol 100 mg daily and up to 100 mg of 6-MP. 6-MP dose was adjusted after a 3-week metabolite measurement. The median dose of 6-MP for adults decreased from 100mg daily (range: 37.5-150 mg) to 25mg daily (range: 12.5-50 mg). The median dose of 6-MP for pediatric patients decreased from 50 mg (range: 25-50 mg) to 10.7 mg (range: 10.7 to 21.4 mg). Mean 6-TGN levels in all subjects increased from 197.4 (± 59) to 284.8 (± 107) pmol/8×10⁸ RBCs (p=0.0005). Mean 6-MMP levels in all subjects decreased from a mean of 7719.8 (± 4716) to 404.8 (± 332) pmol/8×10⁸ RBCs (p=0.0004). There were no complications associated with allopurinol therapy. Eighty-eight (30.9%) of 285 IBD patients had evidence of preferential metabolism towards 6-MMP. The proportion of preferential metabolism was equal in adults and pediatric patients. Our results indicate that the addition of allopurinol safely shifts metabolite production in both adult and pediatric IBD patients and that there is a high prevalence of preferential metabolism towards 6-MMP among IBD patients. Published by Elsevier B.V.

Bi2MoxW1-xO6 solid solutions with tunable band structure and enhanced visible-light photocatalytic activities

NASA Astrophysics Data System (ADS)

Li, Wenqi; Ding, Xingeng; Wu, Huating; Yang, Hui

2018-07-01

Semiconductor photocatalysis is an effective green way to combat water pollution. For the first time, this study reports a novel method to develop Bi2MoxW1-xO6 solid solution with microsphere structure through anion-exchange method. All Bi2MoxW1-xO6 samples exhibit an Aurivillius-type crystal structure without any secondary phase, confirming that in complete solid solutions as the value of x increases, the band gap energy of Bi2MoxW1-xO6 solid solutions decreases, while the optical absorption edge moves to longer wavelength. The Raman spectra research shows an increase in orthorhombic distortion with progressive replacement of W sites in Bi2WO6 with Mo6+ ions. Compared to Bi2MoO6 and Bi2WO6 samples, Bi2Mo0.4W0.6O6 sample displayed best photocatalytic activity and cycling stability for degradation of RhB dye. The enhanced photocatalytic activity of Bi2Mo0.4W0.6O6 sample can be synergetically linked to hierarchical hollow structure, enhanced light absorbance, and high carrier-separation efficiency. Additionally, the hollow Bi2MoxW1-xO6 microspheres formation can be attributed to the Kirkendall effect.

Extracts, Anthocyanins and Procyanidins from Aronia melanocarpa as Radical Scavengers and Enzyme Inhibitors

PubMed Central

Bräunlich, Marie; Slimestad, Rune; Wangensteen, Helle; Brede, Cato; Malterud, Karl E.; Barsett, Hilde

2013-01-01

Extracts, subfractions, isolated anthocyanins and isolated procyanidins B2, B5 and C1 from the berries and bark of Aronia melanocarpa were investigated for their antioxidant and enzyme inhibitory activities. Four different bioassays were used, namely scavenging of the diphenylpicrylhydrazyl (DPPH) radical, inhibition of 15-lipoxygenase (15-LO), inhibition of xanthine oxidase (XO) and inhibition of α-glucosidase. Among the anthocyanins, cyanidin 3-arabinoside possessed the strongest and cyanidin 3-xyloside the weakest radical scavenging and enzyme inhibitory activity. These effects seem to be influenced by the sugar units linked to the anthocyanidin. Subfractions enriched in procyanidins were found to be potent α-glucosidase inhibitors; they possessed high radical scavenging properties, strong inhibitory activity towards 15-LO and moderate inhibitory activity towards XO. Trimeric procyanidin C1 showed higher activity in the biological assays compared to the dimeric procyanidins B2 and B5. This study suggests that different polyphenolic compounds of A. melanocarpa can have beneficial effects in reducing blood glucose levels due to inhibition of α-glucosidase and may have a potential to alleviate oxidative stress. PMID:23459328

Extracts, anthocyanins and procyanidins from Aronia melanocarpa as radical scavengers and enzyme inhibitors.

PubMed

Bräunlich, Marie; Slimestad, Rune; Wangensteen, Helle; Brede, Cato; Malterud, Karl E; Barsett, Hilde

2013-03-04

Extracts, subfractions, isolated anthocyanins and isolated procyanidins B2, B5 and C1 from the berries and bark of Aronia melanocarpa were investigated for their antioxidant and enzyme inhibitory activities. Four different bioassays were used, namely scavenging of the diphenylpicrylhydrazyl (DPPH) radical, inhibition of 15-lipoxygenase (15-LO), inhibition of xanthine oxidase (XO) and inhibition of α-glucosidase. Among the anthocyanins, cyanidin 3-arabinoside possessed the strongest and cyanidin 3-xyloside the weakest radical scavenging and enzyme inhibitory activity. These effects seem to be influenced by the sugar units linked to the anthocyanidin. Subfractions enriched in procyanidins were found to be potent α-glucosidase inhibitors; they possessed high radical scavenging properties, strong inhibitory activity towards 15-LO and moderate inhibitory activity towards XO. Trimeric procyanidin C1 showed higher activity in the biological assays compared to the dimeric procyanidins B2 and B5. This study suggests that different polyphenolic compounds of A. melanocarpa can have beneficial effects in reducing blood glucose levels due to inhibition of α-glucosidase and may have a potential to alleviate oxidative stress.

Ripk3 promotes ER stress-induced necroptosis in cardiac IR injury: A mechanism involving calcium overload/XO/ROS/mPTP pathway.

PubMed

Zhu, Pingjun; Hu, Shunying; Jin, Qinhua; Li, Dandan; Tian, Feng; Toan, Sam; Li, Yang; Zhou, Hao; Chen, Yundai

2018-06-01

Receptor-interacting protein 3 (Ripk3)-mediated necroptosis contributes to cardiac ischaemia-reperfusion (IR) injury through poorly defined mechanisms. Our results demonstrated that Ripk3 was strongly upregulated in murine hearts subjected to IR injury and cardiomyocytes treated with LPS and H 2 O 2 . The higher level of Ripk3 was positively correlated to the infarction area expansion, cardiac dysfunction and augmented cardiomyocytes necroptosis. Function study further illustrated that upregulated Ripk3 evoked the endoplasmic reticulum (ER) stress, which was accompanied with an increase in intracellular Ca 2+ level ([Ca 2+ ]c) and xanthine oxidase (XO) expression. Activated XO raised cellular reactive oxygen species (ROS) that mediated the mitochondrial permeability transition pore (mPTP) opening and cardiomyocytes necroptosis. By comparison, genetic ablation of Ripk3 abrogated the ER stress and thus blocked the [Ca 2+ ]c overload-XO-ROS-mPTP pathways, favouring a pro-survival state that ultimately resulted in the inhibition of cardiomyocytes necroptosis in the setting of cardiac IR injury. In summary, the present study helps to elucidate how necroptosis is mediated by ER stress, via the calcium overload /XO/ROS/mPTP opening axis. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Amperometric biosensor based on prussian blue and nafion modified screen-printed electrode for screening of potential xanthine oxidase inhibitors from medicinal plants.

PubMed

El Harrad, Loubna; Amine, Aziz

2016-04-01

A simple and sensitive amperometric biosensor was developed for the screening of potential xanthine oxidase inhibitors from medicinal plants. This biosensor was prepared by immobilization of xanthine oxidase on the surface of prussian blue modified screen-printed electrodes using nafion and glutaraldehyde. The developed biosensor showed a linear amperometric response at an applied potential of +0.05 V toward the detection of hypoxanthine from 5 μM to 45 μM with a detection limit of 0.4 μM (S/N=3) and its sensitivity was found to be 600 mA M(-1) cm(-2). In addition, the biosensor exhibited a good storage stability. The inhibition of xanthine oxidase by allopurinol was studied under the optimized conditions. The linear range of allopurinol concentration is obtained up to 2.5 μM with an estimated 50% of inhibitionI50=1.8 μM. The developed biosensor was successfully applied to the screening of xanthine oxidase inhibitors from 13 medicinal plants belonging to different families. Indeed, Moroccan people traditionally use these plants as infusion for the treatment of gout and its related symptoms. For this purpose, water extracts obtained from the infusion of these plants were used for the experiments. In this work, 13 extracts were assayed and several of them demonstrated xanthine oxidase inhibitory effect, with an inhibition greater than 50% compared to spectrophotometry measurements that only few extracts showed an inhibition greater than 50%. Copyright © 2016 Elsevier Inc. All rights reserved.

Effective work function engineering for a TiN/XO(X = La, Zr, Al)/SiO{sub 2} stack structures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Dongjin, E-mail: dongjin0710.lee@samsung.com; Lee, Jieun; Jung, Kyoungho

In this study, we demonstrated that work function engineering is possible over a wide range (+200 mV to −430 mV) in a TiN/XO (X = La, Zr, or Al)/SiO{sub 2} stack structures. From ab initio simulations, we selected the optimal material for the work function engineering. The work function engineering mechanism was described by metal diffusion into the TiN film and silicate formation in the TiN/SiO{sub 2} interface. The metal doping and the silicate formation were confirmed by transmission electron microscopy and energy dispersive spectroscopy line profiling, respectively. In addition, the amount of doped metal in the TiN film depended on the thickness ofmore » the insertion layer XO. From the work function engineering technique, which can control a variety of threshold voltages (Vth), an improvement in transistors with different V{sub th} values in the TiN/XO/SiO{sub 2} stack structures is expected.« less

In vitro xanthine oxidase inhibitory and in vivo hypouricemic activity of herbal coded formulation (Gouticin).

PubMed

Akram, Muhammad; Usmanghani, Khan; Ahmed, Iqbal; Azhar, Iqbal; Hamid, Abdul

2014-05-01

Currently, natural products have been used in treating gouty arthritis and are recognized as xanthine oxidase inhibitors. Current study was designed to evaluate in vitro xanthine oxidase inhibitory potential of Gouticin and its ingredients extracts and in vivo hypouricemic activity of gouticin tablet 500 mg twice daily. Ethanol extracts of Gouticin and its ingredients were evaluated in vitro, at 200, 100, 50, 25 μ g/ml concentrations for xanthine oxidase inhibitory activity. IC(50) values of Gouticin and its ingredients were estimated. Further, in vivo therapeutic effect of Gouticin was investigated in comparison with allopathic medicine (Allopurinol) to treat gout. Total patients were 200 that were divided into test and control group. Herbal coded medicine (Gouticin) was given to test group and allopathic medicine allopurinol was administered to control group. In vitro, Gouticin has the highest percent inhibition at 96% followed by Allopurinol with 93% inhibition. In vivo study, mean serum uric acid level of patients was 4.62 mg/dl and 5.21mg/dl by use of Gouticin and Allopurinol at end of therapy. The study showed that herbal coded formulation gouticin and its ingredients are potential sources of natural xanthine oxidase inhibitors. Gouticin 500 mg twice daily is more effective than the allopurinol 300mg once daily in the management of gout.

Efficacy and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase for the treatment of hyperuricemia in kidney transplant recipients.

PubMed

Tojimbara, T; Nakajima, I; Yashima, J; Fuchinoue, S; Teraoka, S

2014-01-01

Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia. In this study, we evaluated the efficacy and safety of febuxostat for the management of hyperuricemia in renal transplant recipients. Between June 2012 and January 2013, a total of 22 renal transplant recipients (56 ± 10 years old) with hyperuricemia were enrolled in this study. All patients underwent de novo kidney transplantation, except for 1 patient, who received a second kidney transplant. Ten patients receiving allopurinol and 3 patients receiving benzbromarone were converted to febuxostat at doses of 10-20 mg/d. In the remaining 9 patients, who did not have a history of other urate-lowering medications, febuxostat was initiated at a dose of 10 mg/d. Uric acid levels after initiation of febuxostat were significantly lower than before treatment (5.7 ± 0.7 mg/mL vs 8.0 ± 0.8 mg/mL; P < .001). At last follow-up visit, 16 of the 22 patients (73%) achieved uric acid levels of ≤ 6.0 mg/dL, despite the low dosage of febuxostat. All patients were maintained on febuxostat without serious adverse events, except for 1 patient, who discontinued febuxostat because of numbness in the arms. Low-dose febuxostat is a promising alternative to allopurinol or benzbromarone for the treatment of hyperuricemia in kidney transplant recipients. The long-term urate-lowering efficacy and safety of febuxostat with regard to renal function in kidney transplant recipients with hyperuricemia requires further investigation. Copyright © 2014 Elsevier Inc. All rights reserved.

Structures and electron affinity of XO30,-, XOF40,- and XO2F20,- (X = P, As, Sb, Bi): a theoretical study of novel superhalogen formulae and exceptions of superhalogen formulae

NASA Astrophysics Data System (ADS)

Yang, Yi-Fan; Cui, Zhong-Hua; Ding, Yi-Hong

2015-03-01

Most superhalogen species are in the form of oxides or halides. To enrich the family of superhalogen species, herein, we investigated the structures and electron affinity (EA) values of higher group 15 elements (X = P, As, Sb, Bi) oxyfluoride species XO30,-, XOF40,- and XO2F20,-, at the CCSD(T)/aug-cc-pVTZ-pp & aug-cc-pVTZ //B3LYP/aug-cc-pVTZ-pp & aug-cc-pVTZ levels (aug-cc-pVTZ-pp for X = Sb and Bi). Some oxyfluoride species, i.e., PO2F20,-, AsO2F20,-, SbO2F20,-, POF40,-, AsOF40,-, SbOF40,- and BiOF40,-, were found to possess higher EA (VDE: 5.0-6.2 eV; ADE: 4.5-5.5 eV) than halogens (F: 3.4 eV; Cl: 3.6 eV). Thus, we recommended that the oxyfluorides in the form of XO2F20,- and XOF40,- should be considered as potential superhalogens, which have not been considered previously. Surprisingly, we showed that BiO3 and BiO2F2, in superhalogen formulae, possess a high vertical detachment energy (VDE) yet a low adiabatic detachment energy (ADE). This is in marked contrast to the previously reported superhalogens, which generally contain both the high VDE and high ADE values. It is the first report about exceptions of superhalogen formulae. These findings revealed that for the analogous main-group compounds with the same structural formula, the difference in the metallic property of the core element could lead to the significant difference in the ground structures of either the anionic or neutral structures, which would result in the much differed superhalogen features.

A theoretical study on the electronic structure of Au-XO(0,-1,+1) (X=C, N, and O) complexes: effect of an external electric field.

PubMed

Tielens, Frederik; Gracia, Lourdes; Polo, Victor; Andrés, Juan

2007-12-20

A theoretical study on the nature of Au-XO(0,-1,+1) (X=C, N, O) interaction is carried out in order to provide a better understanding on the adsorption process of XO molecules on Au surfaces or Au-supported surfaces. The effect of the total charge as well as the presence of an external electric field on the formation processes of the Au-XO complex are analyzed and discussed using DFT (B3LYP) and high-level ab initio (CCSD(T)//MP2) methods employing a 6-311+G(3df) basis set for X and O atoms and Stuttgart pseudopotentials for Au atom. The presence of an electric field can increase the binding of O2 molecule to Au while weakening the formation of the Au-CO complex. These behaviors are discussed in the context of adsorption or deadsorption of these molecules on Au clusters. The formation of the Au-XO complex, the effect of addition/removal of one electron, and the role of the electric field are rationalized by studying the nature of the bonding interactions by means of the electron localization function (ELF) analysis. The net interaction between Au and XO fragments is governed by the interplay of three factors: (i) the amount of charge transfer from Au to XO, (ii) the sharing of the lone pair from X atom by the Au core (V(X, Au) basin), and (iii) the role of the lone pair of Au (V(Au) basin) mainly formed by 6s electrons. The total charge of the system and the applied electric field determine the population and orientation of the V(Au) basin and, subsequently, the degree of repulsion with the V(X, Au) basin.

FLORENCE: a randomized, double-blind, phase III pivotal study of febuxostat versus allopurinol for the prevention of tumor lysis syndrome (TLS) in patients with hematologic malignancies at intermediate to high TLS risk.

PubMed

Spina, M; Nagy, Z; Ribera, J M; Federico, M; Aurer, I; Jordan, K; Borsaru, G; Pristupa, A S; Bosi, A; Grosicki, S; Glushko, N L; Ristic, D; Jakucs, J; Montesinos, P; Mayer, J; Rego, E M; Baldini, S; Scartoni, S; Capriati, A; Maggi, C A; Simonelli, C

2015-10-01

Serum uric acid (sUA) control is of key relevance in tumor lysis syndrome (TLS) prevention as it correlates with both TLS and renal event risk. We sought to determine whether febuxostat fixed dose achieves a better sUA control than allopurinol while preserving renal function in TLS prevention. Patients with hematologic malignancies at intermediate to high TLS risk grade were randomized to receive febuxostat or allopurinol, starting 2 days before induction chemotherapy, for 7-9 days. Study treatment was blinded, whereas daily dose (low/standard/high containing allopurinol 200/300/600 mg, respectively, or fixed febuxostat 120 mg) depended on the investigator's choice. The co-primary end points, sUA area under curve (AUC sUA1-8) and serum creatinine change, were assessed from baseline to day 8 and analyzed through analysis of covariance with two-sided overall significance level of 5%. Secondary end points included treatment responder rate, laboratory and clinical TLS incidence and safety. A total of 346 patients (82.1% intermediate TLS risk; 82.7% assigned to standard dose) were randomized. Mean AUC sUA1-8 was 514.0 ± 225.71 versus 708.0 ± 234.42 mgxh/dl (P < 0.0001) in favor of febuxostat. Mean serum creatinine change was -0.83 ± 26.98% and -4.92 ± 16.70% for febuxostat and allopurinol, respectively (P = 0.0903). No differences among secondary efficacy end points were detected. Drug-related adverse events occurred in 6.4% of patients in both arms. In the largest adult trial carried out in TLS prevention, febuxostat achieved a significant superior sUA control with one fixed dose in comparison to allopurinol with comparable renal function preservation and safety profile. NCT01724528. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Cost-effectiveness analysis of genotyping for HLA-B*5801 and an enhanced safety program in gout patients starting allopurinol in Singapore.

PubMed

Dong, Di; Tan-Koi, Wei-Chuen; Teng, Gim Gee; Finkelstein, Eric; Sung, Cynthia

2015-11-01

Allopurinol is an efficacious urate-lowering therapy (ULT), but is associated with rare serious adverse drug reactions of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), with higher risk among HLA-B*5801 carriers. We assessed the cost-effectiveness of HLA-B*5801 testing, an enhanced safety program or strategies with both components. The analysis adopted a health systems perspective and considered Singaporean patients with chronic gout, over a lifetime horizon, using allopurinol or probenecid. The model incorporated SJS/TEN and gout treatment outcomes, allele frequencies, drug prices and other medical costs. Based on cost-effectiveness threshold of US$50,000 per quality-adjusted life year, HLA-B*5801-guided ULT selection or enhanced safety program was not cost effective. Avoidance of ULTs was the least preferred strategy as uncontrolled gout leads to lower quality-adjusted life years and higher costs. The analysis underscores the need for biomarkers with higher positive predictive value for SJS/TEN, less expensive genetic tests or safety programs, or more effective gout drugs. .

Structural characterization of LiCrxMn2-xO4 via a simple reflux technique

NASA Astrophysics Data System (ADS)

Purwaningsih, Dyah; Roto, Roto; Sutrisno, Hari; Purwanto, Agus

2017-03-01

LiCrxMn2-xO4 (x=0; 0.02; 0.04; 0.06; 0.08, 0.10) have been successfully synthesized via a facile and simple reflux technique. The SEM-EDS data confirm the presence of Cr, Mn and O elements in the products, while the XRD pattern suggests that the materials have well-developed cubic crystals. Direct method was applied to extract structural parameters of LiCrxMn2-xO4 using the Fullprof and Oscail software in WinPlotr package program. Materials were refined in the crystal system, and space group of structures Fd3m phase were then identified. The lattice parameters decrease with the decrease in Cr content. The highest Li-O bond length was found for LiCr0.10Mn1.90O4. It was observed that there is no significant change in particle size as Cr content increased.

GTC OSIRIS transiting exoplanet atmospheric survey: detection of sodium in XO-2b from differential long-slit spectroscopy

NASA Astrophysics Data System (ADS)

Sing, D. K.; Huitson, C. M.; Lopez-Morales, M.; Pont, F.; Désert, J.-M.; Ehrenreich, D.; Wilson, P. A.; Ballester, G. E.; Fortney, J. J.; Lecavelier des Etangs, A.; Vidal-Madjar, A.

2012-10-01

We present two transits of the hot-Jupiter exoplanet XO-2b using the Gran Telescopio Canarias (GTC). The time series observations were performed using long-slit spectroscopy of XO-2 and a nearby reference star with the Optical System for Imaging and low Resolution Integrated Spectroscopy (OSIRIS) instrument, enabling differential spectrophotometric transit light curves capable of measuring the exoplanet's transmission spectrum. Two optical low-resolution grisms were used to cover the optical wavelength range from 3800 to 9300 Å. We find that sub-mmag-level slit losses between the target and reference star prevent full optical transmission spectra from being constructed, limiting our analysis to differential absorption depths over ˜1000 Å regions. Wider long slits or multi-object grism spectroscopy with wide masks will likely prove effective in minimizing the observed slit-loss trends. During both transits, we detect significant absorption in the planetary atmosphere of XO-2b using a 50-Å bandpass centred on the Na I doublet, with absorption depths of Δ(Rpl/R★)2 = 0.049 ± 0.017 per cent using the R500R grism and 0.047 ± 0.011 per cent using the R500B grism (combined 5.2σ significance from both transits). The sodium feature is unresolved in our low-resolution spectra, with detailed modelling also likely ruling out significant line-wing absorption over an ˜800 Å region surrounding the doublet. Combined with narrow-band photometric measurements, XO-2b is the first hot Jupiter with evidence for both sodium and potassium present in the planet's atmosphere. Based on observations made with the Gran Telescopio Canarias (GTC), installed in the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofísica de Canarias, in the island of La Palma, and part of the large European Southern Observatory (ESO) programme 182.C-2018.

Methane oxidation on Pd–Ceria: A DFT study of the mechanism over PdxCe1-xO2, Pd, and PdO

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mayernick, Adam D.; Janik, Michael J.

2011-02-14

Palladium/ceria exhibits unique catalytic activity for hydrocarbon oxidation; however, the chemical and structural properties of active sites on the palladium–ceria surface are difficult to characterize. Strong interactions between palladium and the ceria support stabilize oxidized Pdδ+ species, which may contribute to the significant activity of Pd/ceria for methane oxidation. We present a density functional theory (DFT + U) investigation into methane oxidation over Pd/ceria and quantify the activity of the Pd xCe 1-xO 2(1 1 1) mixed oxide surface in comparison with the PdO(1 0 0) and Pd(1 1 1) surfaces. The methane activation barrier is lowest over the Pdmore » xCe 1-xO 2(1 1 1) surface, even lower than over the Pd(1 1 1) surface or low coordinated stepped or kinked Pd sites. Subsequent reaction steps in complete oxidation, including product desorption and vacancy refilling, are considered to substantiate that methane activation remains the rate-limiting step despite the low barrier over Pd xCe 1-xO 2(1 1 1). The low barrier over the Pd xCe 1-xO 2(1 1 1) surface demonstrates that mixed ceria-noble metal oxides offer the potential for improved hydrocarbon oxidation performance with respect to dispersed noble metal particles on ceria.« less

More allopurinol is needed to get gout patients < 0.36 mmol/l: a gout audit in the form of a before-after trial.

PubMed

Arroll, Bruce; Bennett, Merran; Dalbeth, Nicola; Hettiarachchi, Dilanka; Ben, Cribben; Shelling, Ginnie

2009-12-01

To establish a benchmark for gout control using the proportion of patients with serum uric acid (SUA) < 0.36 mmol/L, assess patients' understanding of their preventive medication and trial a mail and phone intervention to improve gout control. Patients clinically diagnosed with gout and baseline SUAs were identified in two South Auckland practices. A mail and phone intervention was introduced aimed at improving the control of gout. Intervention #1 took place in one practice over three months. Intervention #2 occurred in the other practice four to 16 months following baseline. No significant change in SUA from intervention #1 after three months. The second intervention by mail and phone resulted in improvement in SUA levels with a greater proportion of those with SUA < 0.36 mmol/L and the difference in means statistically significant (p = 0.039 two-tailed paired t-test). Benchmarking for usual care was established at 38-43% SUA < 0.36 level. It was possible to increase from 38% to 50%. Issues relating to gout identified included lack of understanding of the need for long-term allopurinol and diagnosis and management for patients for whom English is not their first language. 1. Community workers who speak Pacific languages may assist GPs in communicating to non-English speaking patients. 2. Alternative diagnoses should be considered in symptomatic patients with prolonged normouricaemia. 3. GPs should gradually introduce allopurinol after acute gout attacks, emphasising importance of prophylaxis. 4. A campaign to inform patients about benefits of allopurinol should be considered. 5. A simple one keystroke audit is needed for gout audit and benchmarking. 6. GP guidelines for gout diagnosis and management should be available.

Refining Parameters of the XO-5 Planetary System with High-Precision Transit Photometry

NASA Astrophysics Data System (ADS)

Maciejewski, G.; Seeliger, M.; Adam, Ch.; Raetz, St.; Neuhäuser, R.

2011-03-01

Studies of transiting extrasolar planets provide unique opportunity to get to know the internal structure of those worlds. The transiting exoplanet XO-5 b was found to have an anomalously high Safronov number and surface gravity. Our aim was to refine parameters of this intriguing system and search for signs of transit timing variations. We gathered high-precision light curves for two transits of XO-5 b. Assuming three different limb darkening laws, we found the best-fitting model and redetermined parameters of the system, including planet-to-star radius ratio, impact parameter and central time of transits. Error estimates were derived by the prayer bead method and Monte Carlo simulations. Although system's parameters obtained by us were found to agree with previous studies within one sigma, the planet was found to be notable smaller with the radius of 1.03+0.06-0.05 Jupiter radii. Our results confirm the high Safronov number and surface gravity of the planet. With two new mid-transit times, the ephemeris was refined to BJDTDB=(2454485.66842±0.00028)+(4.1877537±0.000017)E. No significant transit timing variation was detected.

Febuxostat for the treatment of gout.

PubMed

Bridgeman, Mary Barna; Chavez, Benjamin

2015-02-01

Gout is a rheumatologic condition associated with elevated serum uric acid levels and deposition of monosodium urate crystals in joints and soft tissues. The xanthine oxidase inhibitor, allopurinol, has historically been the principle agent utilized for reducing elevated uric acid levels and treating underlying cause of gout symptoms; the availability of febuxostat, a newer non-purine selective xanthine oxidase inhibitor, represents an alternative therapy for those patients with contraindications or intolerance to allopurinol. This article reviews the published literature on the pharmacologic characteristics and clinical safety and efficacy data on the use of febuxostat in the treatment of gout. A literature search of MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations Databases (1996-November 2014) was conducted utilizing the key words 'febuxostat', 'allopurinol', and 'gout'. All published articles regarding febuxostat were evaluated. References of selected articles, data from poster presentations, and abstract publications were additionally reviewed. Febuxostat has shown benefit with respect to symptomatic relief and uric acid level reduction. The safety profile of this agent makes it an ideal alternative in those patients with contraindications to or who are intolerant of allopurinol.

Investigations on structural and electrical parameters of p-Si/ MgxZn1-xO thin film heterojunction diodes grown by RF magnetron sputtering technique

NASA Astrophysics Data System (ADS)

Singh, Satyendra Kumar; Hazra, Purnima

2018-05-01

This work reports fabrication and characterization of p-Si/ MgxZn1-xO thin film heterojunction diodes grown by RF magnetron sputtering technique. In this work, ZnO powder was mixed with MgO powder at per their weight percentage from 0 to 10% to prepare MgxZn1-xO target. The microstructural, surface morphological and optical properties of as-deposited p-Si/MgxZn1-xO heterostructure thin films have been studied using X-ray Diffraction, atomic force microscopy and variable angle ellipsometer. XRD spectra exhibit that undoped ZnO thin films has preferred crystal orientation in (002) plane. However, with increase in Mg-doping, ZnO (101) crystal plane is enhanced progressively due to phase segregation, even though preferred growth orientation of ZnO crystals is still towards (002) plane. The electrical characteristics of Si/ MgxZn1-xO heterojunction diodes with large area Al/Ti ohmic contacts are evaluated using semiconductor parameter analyzer. With rectification ratio of 27894, reverse saturation current of 20.5 nA and barrier height of 0.724 eV, Si/Mg0.5Zn0.95O thin film heterojunction diode is believed to have potential to be used in wider bandgap nanoelectronic device applications.

Use of allopurinol in children with acute lymphoblastic leukemia to reduce skewed thiopurine metabolism.

PubMed

Brackett, Julienne; Schafer, Eric S; Leung, Daniel H; Bernhardt, M Brooke

2014-06-01

Mercaptopurine (6-MP), a critical component of acute lymphoblastic leukemia (ALL) therapy, is metabolized to 6-thioguanine (6-TGN) which is responsible for its anti-leukemic effect, and to 6-methylmercaptopurine nucleotides (6-MMPN/6-MMP) which can be hepatotoxic. Some patients preferentially metabolize 6-MP to 6-MMPN which may increase the risk of liver injury, reduce serum levels of 6-TGN and potentially increase the risk of relapse. The addition of allopurinol to oral 6-MP has been shown to optimize metabolism towards 6-TGN in patients with inflammatory bowel disease (IBD); however, this use has not been reported in patients undergoing treatment for ALL. © 2013 Wiley Periodicals, Inc.

Enhanced dielectric and piezoelectric responses in Zn 1 -xMg xO thin films near the phase separation boundary

DOE PAGES

Kang, Xiaoyu; Shetty, Smitha; Garten, Lauren; ...

2017-01-23

Dielectric and piezoelectric properties for Zn 1-xMg xO (ZMO) thin films are reported as a function of MgO composition up to and including the phase separation region. Zn 1-xMg xO (0.25 ≤ x ≤ 0.5) thin films with c-axis textures were deposited by pulsed laser deposition on platinized sapphire substrates. The films were phase pure wurtzite for MgO concentrations up to 40%; above that limit, a second phase with rocksalt structure evolves with strong {100} texture. With increasing MgO concentration, the out-of-plane ( d33,f) and in-plane ( e31,f) piezoelectric coefficients increase by 360% and 290%, respectively. The increase in piezoelectricmore » coefficients is accompanied by a 35% increase in relative permittivity. Loss tangent values fall monotonically with increasing MgO concentration, reaching a minimum of 0.001 for x ≥ 0.30, at which point the band gap is reported to be 4 eV. As a result, the enhanced piezoelectric response, the large band gap, and the low dielectric loss make Zn 1-xMg xO an interesting candidate for thin film piezoelectric devices, and demonstrate that compositional phase transformations provide opportunities for property engineering.« less

Ripk3 regulates cardiac microvascular reperfusion injury: The role of IP3R-dependent calcium overload, XO-mediated oxidative stress and F-action/filopodia-based cellular migration.

PubMed

Zhou, Hao; Wang, Jin; Zhu, Pingjun; Hu, Shunying; Ren, Jun

2018-05-01

Ripk3-mediated cellular apoptosis is a major contributor to the pathogenesis of myocardial ischemia reperfusion (IR) injury. However, the mechanisms by which Ripk3 influences microvascular homeostasis and endothelial apoptosis are not completely understood. In this study, loss of Ripk3 inhibited endothelial apoptosis, alleviated luminal swelling, maintained microvasculature patency, reduced the expression of adhesion molecules and limited the myocardial inflammatory response. In vitro, Ripk3 deficiency protected endothelial cells from apoptosis and migratory arrest induced by HR injury. Mechanistically, Ripk3 had the ability to migrate onto the endoplasmic reticulum (ER), leading to ER damage, as evidenced by increased IP3R and XO expression. The higher IP3R content was associated with cellular calcium overload, and increased XO expression was involved in cellular oxidative injury. Furthermore, IP3R-mediated calcium overload and XO-dependent oxidative damage were able to initiate cellular apoptosis. More importantly, IP3R and XO also caused F-actin degradation into G-actin via post-transcriptional modification of cofilin, impairing the formation of the filopodia and limiting the migratory response of endothelial cells. Altogether, our data confirmed that Ripk3 was involved in microvascular IR injury via regulation of IP3R-mediated calcium overload, XO-dependent oxidative damage and filopodia-related cellular migration, ultimately leading to endothelial apoptosis and migratory inhibition. These findings provide a potential target for treating cardiac microcirculatory IR injury. Copyright © 2018 Elsevier Inc. All rights reserved.

Surface compositions of atomic layer deposited Zn{sub 1−x}Mg{sub x}O thin films studied using Auger electron spectroscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xie, Ting; Romero, Danilo; Gomez, Romel D., E-mail: rdgomez@umd.edu

2015-09-15

In this paper, the authors present Auger electron spectroscopy (AES) studies of Zn{sub 1−x}Mg{sub x}O (ZMO) films grown via interrupted atomic-layer deposition (ALD) techniques. The ZMO films were fabricated by alternating ALD deposition of ZnO and MgO layers up to 1000 cycles. Zn{sub 1−x}Mg{sub x}O films with progressively decreasing Mg/Zn ratios (Mg/Zn = 1/1, 1/2, 1/3, 1/4, 1/5, 1/6, 1/9, and 2/8, 3/12, 4/16, and 5/20) were fabricated for this study. The AES results exhibit an abrupt drop of Mg composition on the ZMO surface when the Mg/Zn < 1/3. Additionally, the surface composition ratios of O to Mg, O to Zn, and Mgmore » to Zn were estimated with known Auger sensitivity factors. The results indicate that Mg ions diffuse into the bulk, forming Zn{sub 1−x}Mg{sub x}O alloys.« less

Magnetic and hyperthermia properties of CoxFe3-xO4 nanoparticles synthesized via cation exchange

NASA Astrophysics Data System (ADS)

Mohapatra, Jeotikanta; Xing, Meiying; Liu, J. Ping

2018-05-01

We demonstrate magnetic and hyperthermia properties of CoxFe3-xO4 (x = 0, 0.1, 0.3 and 0.5) nanoparticles synthesized via a simple cation exchange reaction of ˜12 nm Fe3O4 nanoparticles. The substitution of Fe cations with Co2+ ions leads to enhanced magnetocrystalline anisotropy and coercivity of the pristine superparamagnetic Fe3O4 nanoparticles. Hyperthermia measurement shows that by controlling the Co content (x = 0 to 0.5) in CoxFe3-xO4 nanoparticles, their specific absorption rate (SAR) can be greatly improved from 132 to 534 W/g. The strong enhancement in SAR value is attributed to the increased anisotropy and coercivity. Moreover, with the increase of ac magnetic field from 184 to 491 Oe, the SAR values of Fe3O4 and Co0.5Fe2.5O4 nanoparticles increase from 81 to 132 W/g and 220 to 534 W/g, respectively.

Mounting evidence indicates that escalating doses of allopurinol are unnecessary for cardiovascular protection: Comment on Coburn et al.

PubMed

Bredemeier, Markus

2018-05-09

We read with interest the study by Coburn et al. (1), a methodologically sound propensity-score matched cohort study evaluating the effect of dose escalation of allopurinol on cardiovascular (CV) and overall mortality. The results indicate that increasing doses carry a higher risk of mortality, but the authors comment that failure in achieving doses up to 600 mg may have contributed to the absence of protective effect. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Efficient up-conversion in Yb:Er:NaT(XO4)2 thermal nanoprobes. Imaging of their distribution in a perfused mouse

PubMed Central

Serrano, María Dolores; Han, Xiumei; Cascales, Concepción; Cantero, Marta; Montoliu, Lluís; Arza, Elvira; Caiolfa, Valeria R.; Zamai, Moreno

2017-01-01

Yb and Er codoped NaT(XO4)2 (T = Y, La, Gd, Lu and X = Mo, W) disordered oxides show a green (Er3+ related) up-conversion (UC) efficiency comparable to that of Yb:Er:β-NaYF4 compound and unless 3 times larger UC ratiometric thermal sensitivity. The similar UC efficiency of Yb:Er doped NaT(XO4)2 and β-NaYF4 compounds allowed testing equal subcutaneous depths of ex-vivo chicken tissue in both cases. This extraordinary behavior for NaT(XO4)2 oxides with large cutoff phonon energy (ħω≈ 920 cm-1) is ascribed to 4F9/2 electron population recycling to higher energy 4G11/2 level by a phonon assisted transition. Crystalline nanoparticles of Yb:Er:NaLu(MoO4)2 have been synthesized by sol-gel with sizes most commonly in the 50–80 nm range, showing a relatively small reduction of the UC efficiency with regards to bulk materials. Fluorescence lifetime and multiphoton imaging microscopies show that these nanoparticles can be efficiently distributed to all body organs of a perfused mouse. PMID:28542327

A role for xanthine oxidase in the control of fetal cardiovascular function in late gestation sheep

PubMed Central

Herrera, E A; Kane, A D; Hansell, J A; Thakor, A S; Allison, B J; Niu, Y; Giussani, D A

2012-01-01

Virtually nothing is known about the effects on fetal physiology of xanthine oxidase inhibition. This is despite maternal treatment with the xanthine oxidase inhibitor allopurinol being considered in human complicated pregnancy to protect the infant's brain from excessive generation of ROS. We investigated the in vivo effects of maternal treatment with allopurinol on fetal cardiovascular function in ovine pregnancy in late gestation. Under anaesthesia, pregnant ewes and their singleton fetus were instrumented with vascular catheters and flow probes around an umbilical and a fetal femoral artery at 118 ± 1 dGA (days of gestational age; term ca. 145 days). Five days later, mothers were infused i.v. with either vehicle (n= 11) or allopurinol (n= 10). Fetal cardiovascular function was stimulated with increasing bolus doses of phenylephrine (PE) following maternal vehicle or allopurinol. The effects of maternal allopurinol on maternal and fetal cardiovascular function were also investigated following fetal NO blockade (n= 6) or fetal β1-adrenergic antagonism (n= 7). Maternal allopurinol led to significant increases in fetal heart rate, umbilical blood flow and umbilical vascular conductance, effects abolished by fetal β1-adrenergic antagonism but not by fetal NO blockade. Maternal allopurinol impaired fetal α1-adrenergic pressor and femoral vasopressor responses and enhanced the gain of the fetal cardiac baroreflex. These effects of maternal allopurinol were restored to control levels during fetal NO blockade. Maternal treatment with allopurinol induced maternal hypotension, tachycardia and acid–base disturbance. We conclude that maternal treatment with allopurinol alters in vivo maternal, umbilical and fetal vascular function via mechanisms involving NO and β1-adrenergic stimulation. The evidence suggests that the use of allopurinol in clinical practice should be approached with caution. PMID:22331413

Xanthine Oxidase Mediates Axonal and Myelin Loss in a Murine Model of Multiple Sclerosis

PubMed Central

Okuno, Tatsusada; Takata, Kazushiro; Koda, Toru; Tada, Satoru; Shirakura, Takashi; Fujimura, Harutoshi; Mochizuki, Hideki; Sakoda, Saburo; Nakatsuji, Yuji

2013-01-01

Objectives Oxidative stress plays an important role in the pathogenesis of multiple sclerosis (MS). Though reactive oxygen species (ROS) are produced by various mechanisms, xanthine oxidase (XO) is a major enzyme generating ROS in the context of inflammation. The objectives of this study were to investigate the involvement of XO in the pathogenesis of MS and to develop a potent new therapy for MS based on the inhibition of ROS. Methods XO were assessed in a model of MS: experimental autoimmune encephalomyelitis (EAE). The contribution of XO-generated ROS to the pathogenesis of EAE was assessed by treating EAE mice with a novel XO inhibitor, febuxostat. The efficacy of febuxostat was also examined in in vitro studies. Results We showed for the first time that the expression and the activity of XO were increased dramatically within the central nervous system of EAE mice as compared to naïve mice. Furthermore, prophylactic administration of febuxostat, a XO inhibitor, markedly reduced the clinical signs of EAE. Both in vivo and in vitro studies showed infiltrating macrophages and microglia as the major sources of excess XO production, and febuxostat significantly suppressed ROS generation from these cells. Inflammatory cellular infiltration and glial activation in the spinal cord of EAE mice were inhibited by the treatment with febuxostat. Importantly, therapeutic efficacy was observed not only in mice with relapsing-remitting EAE but also in mice with secondary progressive EAE by preventing axonal loss and demyelination. Conclusion These results highlight the implication of XO in EAE pathogenesis and suggest XO as a target for MS treatment and febuxostat as a promising therapeutic option for MS neuropathology. PMID:23951137

Simultaneous electrical transport and Raman spectroscopic measurements on individual nanowires of WxV1 - xO2

NASA Astrophysics Data System (ADS)

Wu, Tai-Lung; Whittaker, Luisa; Patridge, C. J.; Banerjee, S.; Sambandamurthy, G.

2011-03-01

Vanadium oxide is a well-know material to study the metal-insulator transition (MIT) in correlated electron systems. Upon heating to about 340 K, VO2 undergoes orders of magnitude drop in resistance from an insulating phase (I) to a metallic phase (M) and accompanies a lattice structural phase transition from a low-temperature monoclinical phase (M1) to a high-temperature tetragonal phase (R). We present results from combined electrical transport and Raman spectroscopic measurements to discern the effects of doping in controllably tuning the MIT in individual nanowires of single crystal WxV1 - xO2 . The MIT temperature (Tc) in our WxV1 - xO2 nanowires can be tuned through a wide range from 280 to 330 K by controlling the dopant concentration. The M-I transition can also driven electrically in these nanowires. Our simultaneous measurement of electrical transport and Raman spectroscopic measurement help us understand the role of structural transition in affecting the macroscopic electrical transition in individual wires.

Flower-like morphology of blue and greenish-gray ZnCoxAl2-xO4 nanopigments

NASA Astrophysics Data System (ADS)

Wahba, Adel Maher; Imam, N. G.; Mohamed, Mohamed Bakr

2016-02-01

In the present work, ZnCoxAl2 - xO4 (x = 0.00-1.50) nanosized pigments were synthesized for the first time by citrate-precursor autocombustion method and heat treatment at 900 °C. In this new nanopigment system the vacancies participate in the spinel structure since the divalent cobalt ions substitute the trivalent Al ions. Structural, microstructural and optical properties were investigated using XRD, FTIR, TEM, HRSEM, XRF, and PL techniques. XRD and FTIR spectra proved the formation of a pure cubic spinel phase. Size of the synthesized nano-crystals ranges from 15 to 60 nm, which is further confirmed with TEM micrographs. HRSEM confirms the microporous nature with flower-like morphology of the prepared nanopigments. Cation distribution has been suggested for the whole samples that matches quite well with XRD and IR experimental data. PL results show that the ZnCoxAl2 - xO4 pigments have good potential for use as a yellow-orange phosphor for displays and/or white light-emitting diodes.

High-rate deposition of LiNb 1- xTa xO 3 films by thermal plasma spray CVD

NASA Astrophysics Data System (ADS)

Majima, T.; Yamamoto, H.; Kulinich, S. A.; Terashima, K.

2000-12-01

LiNb 1- xTa xO 3 films were prepared by a thermal plasma spray CVD method using liquid source materials. Preferentially (0 0 1)-oriented LiNb 1- xTa xO 3 films with satisfactory in-plane and out-of-plane alignment were fabricated on sapphire (0 0 1) substrates. The full-width at half-maximum (FWHM) of the (0 0 6) rocking curve could achieve 0.12°, which was comparable with those of LiNbO 3 and LiTaO 3 films prepared by other conventional vapor-phase deposition methods. The deposition rate was up to 0.07 μm/min, which was 5-40 times faster than those for most other conventional vapor-phase deposition methods. From inductively coupled plasma atomic emission spectroscopy analysis, x values of these films were estimated to be 0.36-0.49.

The effect of some medications given to CKD patients on vitamin D levels.

PubMed

Yuste, Claudia; Quiroga, Borja; de Vinuesa, Soledad García; Goicoechea, Maria Angeles; Barraca, Daniel; Verdalles, Ursula; Luño, Jose

2015-01-01

Vitamin D deficiency and polypharmacy is a common problem over chronic kidney disease (CKD) population. To assess the clinical and analytical characteristics of CKD patients with 25-OH-D3 deficiency (<15 ng/mL), including the possible role of associated drugs. A single center observational review of 137 incident patients referred to our outpatient clinic with different stages of CKD and 25-OH-D3<15ng/mL (male gender 53.3%, mean age 70.8 [±16.1] years, mean GFR (MDRD-4) 43.6 [±25.5] ml/min/1.73 m²). 25-OH-D3 levels were collected in spring. Clinical and biochemical data and associated medications were recorded. Mean 25-OH-D3 levels were 8.23 [±4.03] ng/ml. Eighty-eight patients (64.7%) had 3 or more concomitant drugs. Only 7 patients (5.1%) were not receiving any medication. Patients were divided in three groups according the therapies into none (n=26), RAS inhibitors or allopurinol (n=81), and RAS inhibitors plus allopurinol (n=30); with the aim to study the influence of statin therapy. Patients under renin angiotensin (RAS) inhibitors or Allopurinol treatment presented significantly higher 25-OH-D3 levels (p=0.001 and p=0.01 respectively), however patients with Statins treatment had lower 25-OH-D3 level (p=0.039). Personal history of diabetes, cardiovascular events or other therapies did not modify 25-OH-D3 levels, adjusted by age and eGFR. CKD patients with vitamin D deficiency who received RAS inhibitors or Allopurinol treatment had higher 25-OH-D3 levels, however those with statins treatment had lower vitamin D levels. Randomized controlled trials are required to confirm these findings. Copyright © 2015. Published by Elsevier España, S.L.U.

Synthesis and characterization of lithium aluminum-doped spinel (LiAl xMn 2- xO 4) for lithium secondary battery

NASA Astrophysics Data System (ADS)

Lee, Yun-Sung; Kumada, Naoki; Yoshio, Masaki

LiAl xMn 2- xO 4 has been synthesized using various aluminum starting materials, such as Al(NO 3) 3, Al(OH) 3, AlF 3 and Al 2O 3 at 600-800°C for 20 h in air or oxygen atmosphere. A melt-impregnation method was used to synthesize Al-doped spinel with good battery performance in this research. The Al-doped content and the intensity ratio of (3 1 1)/(4 0 0) peaks can be important parameters in synthesizing Al-doped spinel which satisfies the requirements of high discharge capacity and good cycleability at the same time. The decrease in Mn 3+ ion by Al substitution induces a high average oxidation state of Mn ion in the LiAl xMn 2- xO 4 material. The electrochemical behavior of all samples was studied in Li/LiPF 6-EC/DMC (1:2 by volume)/LiAl xMn 2- xO 4 cells. Especially, the initial and last discharge capacity of LiAl 0.09Mn 1.97O 4 using LiOH, Mn 3O 4 and Al(OH) 3 complex were 128.7 and 115.5 mAh/g after 100 cycles. The Al substitution in LiMn 2O 4 was an excellent method of enhancing the cycleability of stoichiometric spinel during electrochemical cycling.

Cost effectiveness analysis of HLA-B*58:01 genotyping prior to initiation of allopurinol for gout.

PubMed

Plumpton, Catrin O; Alfirevic, Ana; Pirmohamed, Munir; Hughes, Dyfrig A

2017-10-01

To determine whether prospective testing for HLA-B*58:01, as a strategy to prevent serious adverse reactions to allopurinol in patients with gout, is cost-effective from the perspective of the National Health Service in the UK. A systematic review and meta-analysis for the association of HLA-B*58:01 with cutaneous and hypersensitivity adverse drug reactions informed a decision analytic and Markov model to estimate lifetime costs and outcomes associated with testing vs standard care (with febuxostat prescribed for patients who test positive). Scenario analyses assessed alternative treatment assumptions and patient populations. The number of patients needed to test to prevent one case of adverse drug reaction was 11 286 (95% central range (CR): 2573, 53 594). Cost and quality-adjusted life-year (QALY) gains were small, £103 (95% CR: £98, £106) and 0.0023 (95% CR: -0.0006, 0.0055), respectively, resulting in an incremental cost-effectiveness ratio (ICER) of £44 954 per QALY gained. The probability of testing being cost-effective at a threshold of £30 000 per QALY was 0.25. Reduced costs of testing or febuxostat resulted in an ICER below £30 000 per QALY gained. The ICER for patients with chronic renal insufficiency was £38 478 per QALY gained. Routine testing for HLA-B*58:01 in order to reduce the incidence of adverse drug reactions in patients being prescribed allopurinol for gout is unlikely to be cost-effective in the UK; however testing is expected to become cost-effective with reductions in the cost of genotyping, and with the future availability of cheaper, generic febuxostat. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

WARM SPITZER OBSERVATIONS OF THREE HOT EXOPLANETS: XO-4b, HAT-P-6b, AND HAT-P-8b

DOE Office of Scientific and Technical Information (OSTI.GOV)

Todorov, Kamen O.; Deming, Drake; Knutson, Heather A.

2012-02-10

We analyze Warm Spitzer/Infrared Array Camera observations of the secondary eclipses of three planets, XO-4b, HAT-P-6b, and HAT-P-8b. We measure secondary eclipse amplitudes at 3.6 {mu}m and 4.5 {mu}m for each target. XO-4b exhibits a stronger eclipse depth at 4.5 {mu}m than at 3.6 {mu}m, which is consistent with the presence of a temperature inversion. HAT-P-8b shows a stronger eclipse amplitude at 3.6 {mu}m and is best described by models without a temperature inversion. The eclipse depths of HAT-P-6b can be fitted with models with a small or no temperature inversion. We consider our results in the context of amore » postulated relationship between stellar activity and temperature inversion and a relationship between irradiation level and planet dayside temperature, as discussed by Knutson et al. and Cowan and Agol, respectively. Our results are consistent with these hypotheses, but do not significantly strengthen them. To measure accurate secondary eclipse central phases, we require accurate ephemerides. We obtain primary transit observations and supplement them with publicly available observations to update the orbital ephemerides of the three planets. Based on the secondary eclipse timing, we set upper boundaries for ecos ({omega}) for HAT-P-6b, HAT-P-8b, and XO-4b and find that the values are consistent with circular orbits.« less

Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells.

PubMed

Wang, Guansong; Qian, Pin; Jackson, Fannie R; Qian, Guisheng; Wu, Guangyu

2008-01-01

Xanthine dehydrogenase/oxidase (XDH/XO) is associated with various pathological conditions related to the endothelial injury. However, the molecular mechanism underlying the activation of XDH/XO by hypoxia remains largely unknown. In this report, we determined whether the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) signaling pathway is involved in hypoxia-induced activation of XDH/XO in primary cultures of lung microvascular endothelial cells (LMVEC). We found that hypoxia significantly increased interleukin 6 (IL6) production in a time-dependent manner in LMVEC. Hypoxia also markedly augmented phosphorylation/activation of JAKs (JAK1, JAK2 and JAK3) and the JAK downstream effectors STATs (STAT3 and STAT5). Hypoxia-induced activation of STAT3 was blocked by IL6 antibodies, the JAK inhibitor AG490 and the suppressor of cytokine signaling 3 (SOCS3), implying that hypoxia-promoted IL6 secretion activates the JAK/STAT pathway in LMVEC. Phosphorylation and DNA-binding activity of STAT3 were also inhibited by the p38 MAPK inhibitor SB203580 and the phosphatidylinositol 3-kinase inhibitor LY294002, suggesting that multiple signaling pathways involved in STAT activation by hypoxia. Importantly, hypoxia promoted XDH/XO activation in LMVEC, which was markedly reversed by inhibiting the JAK-STAT pathway using IL6 antibodies, AG490 and SOCS3. These data demonstrated that JAKs, STATs and XDH/XO were sequentially activated by hypoxia. These data provide the first evidence indicating that the JAK-STAT pathway is involved in hypoxia-mediated XDH/XO activation in LMVEC.

Synthesis and characterization of mesoporous and hollow-mesoporous MxFe3-xO4 (M=Mg, Mn, Fe, Co, Ni, Cu, Zn) microspheres for microwave-triggered controllable drug delivery

NASA Astrophysics Data System (ADS)

Chen, Ping; Cui, Bin; Bu, Yumei; Yang, Zhenfeng; Wang, Yaoyu

2017-12-01

Spinel ferrites can be used in magnetic targeting and microwave heating and can therefore be used for targeted and controllable drug delivery. We used the cetyltrimethylammonium bromide-assisted solvothermal method to synthesize a series of spinel ferrites (MxFe3-xO4, M=Mg, Mn, Fe, Co, Ni, Cu, Zn) with a mesoporous or hollow-mesoporous structure suitable for direct drug loading and the particle diameters ranging from 200 to 350 nm. We investigated the effects of M2+ cation on the morphology and properties of these products by analyzing their transmission electron microscopy images, mesoporous properties, magnetic properties, and microwave responses. We chose hollow-mesoporous MxFe3-xO4 (M=Fe, Co, Zn) nanoparticles, which had better overall properties, for the drug VP16 (etoposide) loading and microwave-controlled release. The CoxFe3-xO4 and Fe3O4 particles trapped 61.5 and 64.8%, respectively, of the VP16, which were higher than that (60.4%) of ZnxFe3-xO4. Controllable drug release by these simple magnetic nanocarriers can be achieved by microwave irradiation, and VP16-loaded CoxFe3-xO4 released the most VP16 molecules (more than 50% after 1 h and 69.1% after 6 h) under microwave irradiation. Our results confirm the favorable drug loading and microwave-controlled delivery by these ferrites, and lay a theoretical foundation to promote clinical application of the targeted controllable drug delivery system. [Figure not available: see fulltext.

Investigation of the interaction between benzaldehyde thiosemicarbazone compounds and xanthine oxidase

NASA Astrophysics Data System (ADS)

Li, Mengrong; Yu, Yanying; Liu, Jing; Chen, Zelu; Cao, Shuwen

2018-05-01

A series of substituted benzaldehyde thiosemicarbazide compounds (1-7) were synthesized as xanthine oxidase (XO) inhibitors, and the interactions between substituted benzaldehyde thiosemicarbazide compounds (1-7) and XO were studied by ultraviolet spectroscopy, fluorescence spectroscopy, and molecular docking. It was found that the hydrogen bond and hydrophobicity were the main interactions between substituted benzaldehyde thiosemicarbazide compounds and XO, and introducing sbnd OH at the para position of the benzene ring and a Ph- or Me-group at the amino terminal of compound 4 increased the modifier's inhibitory activity. The results suggest that the newly introduced benzene ring interacted with the hydrophobic cavity of XO by means of the π-π stacking force between the newly introduced benzene ring and the aromatic amino acid residues, such as the Phe residue, which greatly increased the modifier's inhibitory activity. We conclude that introducing the Ph-group at the amino terminal of compound 4 and the sbnd OH group at the para position of the benzene ring was a good route to obtain novel XO inhibitors. Fluorescence spectroscopy assisted by 8-anilino-1-naphthalenesulfonic acid fluorescence probing and molecular docking were helpful for achieving a preliminary and relatively clear understanding of the interactions between target compounds and XO, which deserve further study.

Hydrogen peroxide (H/sub 2/O/sub 2/) stimulates the active transport of 5-hydroxytryptamine (5-HT) into platelets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bosin, T.R.

1986-03-01

Platelets function in a variety of physiological and pathological processes which may be altered by oxidant injury. One such process is the active transport 5-HT, which is an important mechanism in the control of circulating 5-HT levels. Exposure of mouse platelets (10/sup 8//ml) to H/sub 2/O/sub 2/ caused a time-dependent and dose-dependent increase in 5-HT (10/sup -7/M) uptake. The uptake 4 and 10 min following H/sub 2/O/sub 2/ (50 ..mu..M) was 228% and 145% of control values, respectively. Fluoxetine (10/sup -6/M) blocked all 5-HT uptake and catalase (1500 U/ml) blocked the H/sub 2/O/sub 2/-stimulated uptake. Enzymatically produced H/sub 2/O/sub 2/more » (glucose/glucose oxidase) and xanthine (X)/xanthine oxidase (XO) generated oxygen radicals produced quantitatively and qualitatively similar results. The stimulatory response of platelets to X/XO generated oxidants was unaffected by superoxide dismutase (250 U/ml) but, was inhibited using heat-denatured XO, allopurinol (0.5 mM) and catalase; fluoxetine inhibited all 5-HT uptake. Platelets exposed to X/XO in the presence of chelated (EDTA, 100 ..mu..M) or unchelated FeSO/sub 4/, FeNH/sub 4/(SO/sub 4/)/sub 2/ or CuCl (50 ..mu..M) did not have altered 5-HT uptake. These data indicate that brief exposure of platelets to physiological levels of H/sub 2/O/sub 2/ results in marked, reversible stimulation of active 5-HT uptake which may represent a homeostatic defense mechanism when H/sub 2/O/sub 2/ is elevated in the platelet microenvironment.« less

Use of allopurinol with low-dose 6-mercaptopurine in inflammatory bowel disease to achieve optimal active metabolite levels: A review of four cases and the literature

PubMed Central

Witte, Todd N; Ginsberg, Allen L

2008-01-01

BACKGROUND: At least one-third of patients with inflammatory bowel disease do not respond or are intolerant to therapy with 6-mercaptopurine (6-MP). A subgroup fails to attain optimal levels of 6-thioguanine nucleotide (6-TGN) and instead shunts to 6-methylmercaptopurine nucleotide (6-MMPN). PATIENTS AND METHODS: A retrospective chart review was conducted, and four patients are described who had been previously unable to achieve optimal 6-TGN metabolite levels until allopurinol was added to their treatment. RESULTS: All four patients achieved optimal 6-TGN levels and undetectable 6-MMPN with a mean 6-MP dose of 0.49 mg/kg. Three achieved steroid-free clinical remission. Two of those three patients had normalization of liver enzymes; one patient had baseline normal liver enzymes despite an initial 6-MMPN level of 27,369 pmol/8×108 red blood cells. Two patients experienced reversible leukopenia. CONCLUSIONS: Combination allopurinol and low-dose 6-MP is an effective means to achieve optimal metabolite levels and steroid-free clinical remission in previously refractory patients. Caution is advised. PMID:18299738

Febuxostat: a review of its use in the treatment of hyperuricaemia in patients with gout.

PubMed

Frampton, James E

2015-03-01

Febuxostat (Adenuric(®), Uloric(®), Feburic(®)) is an orally-active, potent, non-purine, selective xanthine oxidase inhibitor. In the EU, it is indicated in adults for the treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred. Unlike allopurinol, the prototypical xanthine oxidase inhibitor that is the cornerstone therapy for chronic gout, febuxostat does not require dosage adjustment in patients with mild or moderate renal impairment. In randomized, double-blind studies, 6-12 months' treatment with febuxostat at dosages approved for use in the EU (80 and 120 mg/day) was significantly more effective in lowering serum uric acid (sUA) levels in patients with hyperuricaemia and gout than allopurinol at dosages commonly prescribed in practice (100-300 mg/day); febuxostat demonstrated greater urate-lowering efficacy than allopurinol in patients with renal impairment. In open-label extension studies, 3-5 years' treatment with febuxostat maintained a target sUA level of <6.0 mg/dL in most patients; sustained reduction in sUA level was associated with near elimination of gout flares and improved tophus status. Febuxostat therapy was generally well tolerated during clinical development; frequently reported adverse events included liver function abnormalities, diarrhoea and rash. Cardiovascular (CV) events were the most common serious adverse events; the comparative safety of febuxostat and allopurinol is being examined further in large, ongoing trials in patients with gout who already have, or are at risk of developing, CV disease. In conclusion, febuxostat is a well established antihyperuricaemic agent that provides an effective alternative to allopurinol for the management of chronic gout.

Pharmacophore modeling, molecular docking and molecular dynamics studies on natural products database to discover novel skeleton as non-purine xanthine oxidase inhibitors.

PubMed

Peng, Jiale; Li, Yaping; Zhou, Yeheng; Zhang, Li; Liu, Xingyong; Zuo, Zhili

2018-05-29

Gout is a common inflammatory arthritis caused by the deposition of urate crystals within joints. It is increasingly in prevalence during the past few decades as shown by the epidemiological survey results. Xanthine oxidase (XO) is a key enzyme to transfer hypoxanthine and xanthine to uric acid, whose overproduction leads to gout. Therefore, inhibiting the activity of xanthine oxidase is an important way to reduce the production of urate. In the study, in order to identify the potential natural products targeting XO, pharmacophore modeling was employed to filter databases. Here, two methods, pharmacophore based on ligand and pharmacophore based on receptor-ligand, were constructed by Discovery Studio. Then GOLD was used to refine the potential compounds with higher fitness scores. Finally, molecular docking and dynamics simulations were employed to analyze the interactions between compounds and protein. The best hypothesis was set as a 3D query to screen database, returning 785 and 297 compounds respectively. A merged set of the above 1082 molecules was subjected to molecular docking, which returned 144 hits with high-fitness scores. These molecules were clustered in four main kinds depending on different backbones. What is more, molecular docking showed that the representative compounds established key interactions with the amino acid residues in the protein, and the RMSD and RMSF of molecular dynamics results showed that these compounds can stabilize the protein. The information represented in the study confirmed previous reports. And it may assist to discover and design new backbones as potential XO inhibitors based on natural products.

Identification of crypto- and neochlorogenic lactones as potent xanthine oxidase inhibitors in roasted coffee beans.

PubMed

Honda, Sari; Miura, Yukari; Masuda, Akiko; Masuda, Toshiya

2014-01-01

Xanthine oxidase (XO) inhibitory activity has been found in boiling water extracts from roasted coffee beans. Therefore, assay-guided purification of the extracts was performed using size-exclusion column chromatography, and subsequently with reversed phase HPLC to afford lactone derivatives of chlorogenic acids. Among the tested lactones, crypto- and neochlorogenic lactones showed potent XO inhibitory activities compared with three major chlorogenic acids found in coffee beans. These XO inhibitory lactones may ameliorate gout and hyperuricemia in humans who drink coffee.

N-Acetylcysteine and Allopurinol Confer Synergy in Attenuating Myocardial Ischemia Injury via Restoring HIF-1α/HO-1 Signaling in Diabetic Rats

PubMed Central

Mao, Xiaowen; Wang, Tingting; Liu, Yanan; Irwin, Michael G.; Ou, Jing-song; Liao, Xiao-long; Gao, Xia; Xu, Yuan; Ng, Kwok F. J.; Vanhoutte, Paul M.; Xia, Zhengyuan

2013-01-01

Objectives To determine whether or not the antioxidants N-acetylcysteine (NAC) and allopurinol (ALP) confer synergistic cardioprotection against myocardial ischemia/reperfusion (MI/R) injury by stabilizing hypoxia inducible factor 1α (HIF-1α)/heme oxygenase 1 (HO-1) signaling in diabetic myocardium. Methods Control or diabetic [streptozotocin (STZ)-induced] Sprague Dawley rats received vehicle or NAC, ALP or their combination for four weeks starting one week after STZ injection. The animals were then subjected to thirty minutes of coronary artery occlusion followed by two hours reperfusion in the absence or presence of the selective HO-1 inhibitor, tin protoporphyrin-IX (SnPP-IX) or the HIF-1α inhibitor 2-Methoxyestradiol (2ME2). Cardiomyocytes exposed to high glucose were subjected to hypoxia/re-oxygenation in the presence or absence of HIF-1α and HO-1 achieved by gene knock-down with related siRNAs. Results Myocardial and plasma levels of 15-F2t-isoprostane, an index of oxidative stress, were significantly increased in diabetic rats while cardiac HO-1 protein and activity were reduced; this was accompanied with reduced cardiac protein levels of HIF-1α, and increased post-ischemic myocardial infarct size and cellular injury. NAC and ALP given alone and in particular their combination normalized cardiac levels of HO-1 and HIF-1α protein expression and prevented the increase in 15-F2t-isoprostane, resulting in significantly attenuated post-ischemic myocardial infarction. NAC and ALP also attenuated high glucose-induced post-hypoxic cardiomyocyte death in vitro. However, all the above protective effects of NAC and ALP were cancelled either by inhibition of HO-1 or HIF-1α with SnPP-IX and 2ME2 in vivo or by HO-1 or HIF-1α gene knock-down in vitro. Conclusion NAC and ALP confer synergistic cardioprotection in diabetes via restoration of cardiac HIF-1α and HO-1 signaling. PMID:23874823

Structural and magnetic properties of non-stoichiometric Fe1-xO thin films

NASA Astrophysics Data System (ADS)

Muhammed Shameem P., V.; Mekala, Laxman; Kumar, M. Senthil

2018-04-01

The Fe1-xO thin films of various iron deficiencies (x) have been grown at ambient temperature by reactive dc magnetron sputtering technique and their structural and magnetic properties are studied. The structural study shows that the films are polycrystalline. As the iron content (1-x) varies from 0.924 to 0.855 a clear consistent change in the preferential orientation of the grains from [111] to the [200] direction is observed. The magnetization measurements show the possible existence of small superparamagnetic defect clusters at 300 K and large spinel-type defect clusters below the Neel temperature.

Febuxostat for the chronic management of hyperuricemia in patients with gout.

PubMed

Chinchilla, Sandra Pamela; Urionaguena, Irati; Perez-Ruiz, Fernando

2016-01-01

Febuxostat is a non-purine, selective inhibitor of both isoforms of xanthine oxido-reductase (XOR), and a major alternative to the scarce number of urate-lowering medications available in the last decades. Its inhibition of XOR is more potent than allopurinol in a mg to mg comparison, what is associated to achievement of serum urate target more frequently than allopurinol at doses tested in clinical trials, especially in patients with the highest baseline serum urate levels. Its pharmacokinetics is not greatly dependent on renal clearance, contrary to allopurinol, what may be an advantage in patients with chronic kidney disease. Several trials are further evaluating both the cardiovascular safety of febuxostat and its possible beneficial effect on renal function preservation. Still scarce, but clinically interesting, evidence on its use in transplant patients has been recently released.

Validation of a pXO2-A PCR Assay To Explore Diversity among Italian Isolates of Bacillus anthracis Strains Closely Related to the Live, Attenuated Carbosap Vaccine

PubMed Central

Muscillo, M.; La Rosa, G.; Sali, M.; De Carolis, E.; Adone, R.; Ciuchini, F.; Fasanella, A.

2005-01-01

Several circulating Bacillus anthracis strains isolated in Italy and belonging to the A1.a cluster, genotype 3 (A1.a-3) are genotypically indistinguishable from Carbosap, a live attenuated vaccine strain, containing both pXO1 and pXO2 plasmids. The genotype was assessed by using eight-locus multilocus variable-number tandem repeat analysis. We describe here the use of a ninth locus able to explore variability among strains that have the same genotype. It is important to be able to genotype the wild isolate of B. anthracis strains from outbreaks of anthrax in areas where Carbosap vaccination of cattle and sheep is common practice. A total of 27 representative field strains isolated in Italy and four vaccinal strains, namely, Carbosap, Sterne, Pasteur I, and Pasteur II, were characterized by a ninth marker, called pXO2-A. Twenty-three field strains were genotype 3 and therefore identical to Carbosap. The marker was in the pXO2 plasmid and is based on the polymorphism of the already-known VX2-3 locus. Detection was obtained by PCR with fluorescence-labeled forward primers in order to produce appropriate fragments for capillary electrophoresis with an ABI 310 genetic analyzer. Genetic relationships showed heterogeneity in all of the examined samples. Interestingly, with respect to genotype 3, samples grouped into eight different subtypes, A to H, and the subtype G, had only two samples indistinguishable from Carbosap. The results of the present study confirm the validity of a hierarchical progressive protocol for discrimination among closely related isolates. PMID:16145138

Characterization of thin films of the solid electrolyte Li(x)Mg(1-2x)Al(2+x)O4 (x = 0, 0.05, 0.15, 0.25).

PubMed

Put, Brecht; Vereecken, Philippe M; Mees, Maarten J; Rosciano, Fabio; Radu, Iuliana P; Stesmans, Andre

2015-11-21

RF-sputtered thin films of spinel Li(x)Mg(1-2x)Al(2+x)O4 were investigated for use as solid electrolyte. The usage of this material can enable the fabrication of a lattice matched battery stack, which is predicted to lead to superior battery performance. Spinel Li(x)Mg(1-2x)Al(2+x)O4 thin films, with stoichiometry (x) ranging between 0 and 0.25, were formed after a crystallization anneal as shown by X-ray diffraction and transmission electron microscopy. The stoichiometry of the films was evaluated by elastic recoil detection and Rutherford backscattering and found to be slightly aluminum rich. The excellent electronic insulation properties were confirmed by both current-voltage measurements as well as by copper plating tests. The electrochemical stability window of the material was probed using cyclic voltammetry. Lithium plating and stripping was observed together with the formation of a Li-Pt alloy, indicating that Li-ions passed through the film. This observation contradicted with impedance measurements at open circuit potential, which showed no apparent Li-ion conductivity of the film. Impedance spectroscopy as a function of potential showed the occurrence of Li-ion intercalation into the Li(x)Mg(1-2x)Al(2+x)O4 layers. When incorporating Li-ions in the material the ionic conductivity can be increased by 3 orders of magnitude. Therefore it is anticipated that the response of Li(x)Mg(1-2x)Al(2+x)O4 is more adequate for a buffer layer than as the solid electrolyte.

Metabolism of 2-phenylethylamine to phenylacetic acid, via the intermediate phenylacetaldehyde, by freshly prepared and cryopreserved guinea pig liver slices.

PubMed

Panoutsopoulos, Georgios I

2004-01-01

2-Phenylethylamine is an endogenous amine, which acts as a neuromodulator of dopaminergic responses. Exogenous 2-phenylethylamine is found in certain foodstuffs and may cause toxic side-effects in susceptible individuals. The present investigation examined the metabolism of 2-phenylethylamine to phenylacetic acid, via phenylacetaldehyde, in freshly prepared and cryopreserved liver slices. Additionally, it compared the relative contribution of aldehyde oxidase, xanthine oxidase and aldehyde dehydrogenase by using specific inhibitors for each oxidizing enzyme. In freshly prepared and cryopreserved liver slices, phenylacetic acid was the main metabolite of 2-phenylethalamine. In freshly prepared liver slices, phenylacetic acid was completely inhibited by disulfiram (inhibitor of aldehyde dehydrogenase), whereas isovanillin (inhibitor of aldehyde oxidase) inhibited acid formation to a lesser extent and allopurinol (inhibitor of xanthine oxidase) had no effect. In cryopreserved liver slices, isovanillin inhibited phenylacetic acid by 85%, whereas disulfiram inhibited acid formation to a lesser extent and allopurinol had no effect. In liver slices, 2-phenylethylamine is rapidly oxidized to phenylacetic acid, via phenylacetaldehyde, by aldehyde dehydrogenase and aldehyde oxidase with no contribution from xanthine oxidase.

In vitro study of 6-mercaptopurine oxidation catalysed by aldehyde oxidase and xanthine oxidase.

PubMed

Rashidi, Mohammad-Reza; Beedham, Christine; Smith, John S; Davaran, Soodabeh

2007-08-01

In spite of over 40 years of clinical use of 6-mercaptopurine, many aspects of complex pharmacology and metabolism of this drug remain unclear. It is thought that 6-mercaptopurine is oxidized to 6-thiouric acid through 6-thioxanthine or 8-oxo-6-mercaptopurine by one of two molybdenum hydroxylases, xanthine oxidase (XO), however, the role of other molybdenum hydroxylase, aldehyde oxidase (AO), in the oxidation of 6-mercaptopurine and possible interactions of AO substrates and inhibitors has not been investigated in more details. In the present study, the role of AO and XO in the oxidation of 6- mercaptopurine has been investigated. 6-mercaptopurine was incubated with bovine milk xanthine oxidase or partially purified guinea pig liver molybdenum hydroxylase fractions in the absence and presence of XO and AO inhibitor/substrates, and the reactions were monitored by spectrophotometric and HPLC methods. According to the results obtained from the inhibition studies, it is more likely that 6- mercaptopurine is oxidized to 6-thiouric acid via 6-thioxanthine rather than 8-oxo-6-mercaptopurine. The first step which is the rate limiting step is catalyzed solely by XO, whereas both XO and AO are involved in the oxidation of 6-thioxanthine to 6-thiouric acid.

Plasmid Capture by the Bacillus thuringiensis Conjugative Plasmid pXO16▿

PubMed Central

Timmery, Sophie; Modrie, Pauline; Minet, Olivier; Mahillon, Jacques

2009-01-01

Conjugation, mobilization, and retromobilization are three related mechanisms of horizontal gene transfer in bacteria. They have been extensively studied in gram-negative species, where retromobilization, the capture of DNA from a recipient by a donor cell, was shown to result from two successive steps: the transfer of the conjugative plasmid from the donor to the recipient followed by the retrotransfer of the mobilizable plasmid to the donor. This successive model was established for gram-negative bacteria but was lacking experimental data from the gram-positive counterparts. In the present work, the mobilization and retromobilization abilities of the conjugative plasmid pXO16 from Bacillus thuringiensis subsp. israelensis were studied using the mobilizable plasmids pUB110 and pE194 and the “nonmobilizable” element pC194 lacking the mob and oriT features (all from Staphylococcus aureus). Experimental data suggested a successive model, since different retromobilization frequencies were observed between the small plasmids. More importantly, retromobilization was shown to be delayed by 50 and 150 min for pUB110 and pE194, respectively, compared to pXO16 conjugation. Natural liquid foods (cow milk, soy milk, and rice milk) were used to evaluate the putative ecological impact of these transfers. In cow and soy milk, conjugation, mobilization, and retromobilization were shown to occur at frequencies of 8.0 × 10−1, 1.0 × 10−2, and 1.2 × 10−4 transconjugants per recipient, respectively. These data are comparable to those obtained with LB medium and about 10-fold lower than in the case of rice milk. Taken together, these results emphasize the potential role of plasmid capture played by B. thuringiensis in natural environments. PMID:19181805

Susceptibility of Helicobacter pylori to simethicone and other non-antibiotic drugs.

PubMed

Ansorg, R; von Recklinghausen, G; Heintschel von Heinegg, E

1996-01-01

The antifoaming agent simethicone (Lefax), the protease inhibitor gabexate mesilate (FOY), the antimycotic ketoconazole, and the hydroxyl scavangers dimethylsulphoxide (DMSO) and allopurinol were investigated for growth inhibition of Helicobacter pylori and representative strains of other bacterial species. H. pylori were selectively inhibited by 64-128 mg/L of simethicone, 64-128 mg/L gabexate mesilate, and 16-64 mg/L ketoconazole. Dimethylsulphoxide and allopurinol showed no antibacterial effect at concentrations used therapeutically. It is concluded that gabexate mesilate, ketoconazole and, particularly, simethicone are candidates for treatment of H. pylori infection.

Stability of Cd 1–xZn xO yS 1–y Quaternary Alloys Assessed with First-Principles Calculations

DOE PAGES

Varley, Joel B.; He, Xiaoqing; Rockett, Angus; ...

2017-02-08

One route to decreasing the absorption in CdS buffer layers in Cu(In,Ga)Se 2 and Cu 2ZnSn(S,Se) 4 thin-film photovoltaics is by alloying. Here we use first-principles calculations based on hybrid functionals to assess the energetics and stability of quaternary Cd, Zn, O, and S (Cd 1–xZn xO yS 1–y) alloys within a regular solution model. Our results identify that full miscibility of most Cd 1–xZn xO yS 1–y compositions and even binaries like Zn(O,S) is outside typical photovoltaic processing conditions. Finally, the results suggest that the tendency for phase separation of the oxysulfides may drive the nucleation of other phasesmore » such as sulfates that have been increasingly observed in oxygenated CdS and ZnS.« less

Stability of Cd 1–xZn xO yS 1–y Quaternary Alloys Assessed with First-Principles Calculations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Varley, Joel B.; He, Xiaoqing; Rockett, Angus

One route to decreasing the absorption in CdS buffer layers in Cu(In,Ga)Se 2 and Cu 2ZnSn(S,Se) 4 thin-film photovoltaics is by alloying. Here we use first-principles calculations based on hybrid functionals to assess the energetics and stability of quaternary Cd, Zn, O, and S (Cd 1–xZn xO yS 1–y) alloys within a regular solution model. Our results identify that full miscibility of most Cd 1–xZn xO yS 1–y compositions and even binaries like Zn(O,S) is outside typical photovoltaic processing conditions. Finally, the results suggest that the tendency for phase separation of the oxysulfides may drive the nucleation of other phasesmore » such as sulfates that have been increasingly observed in oxygenated CdS and ZnS.« less

New process of preparation, X-ray characterisation, structure and vibrational studies of a solid solution LiTiOAs 1-xP xO 4 (0⩽ x⩽1)

NASA Astrophysics Data System (ADS)

Chakir, M.; El Jazouli, A.; Chaminade, J. P.; Bouree, F.; de Waal, D.

2006-01-01

LiTiOAs 1-xP xO 4 (0⩽ x⩽1) compounds have been prepared using solutions of Li, Ti, As and P elements as starting products. Selected compositions have been investigated by powder X-ray or neutrons diffraction analysis, Raman and infrared spectroscopy. The structure of LiTiOAs 1-xP xO 4 ( x=0, 0.5 and 1) samples determined by Rietveld analysis is orthorhombic with Pnma space group. It is formed by a 3D network of TiO 6 octahedra and XO 4 ( X=As 1-xP x) tetrahedra where octahedral cavities are occupied by lithium atoms. TiO 6 octahedra are linked together by corners and form infinite chains along a-axis. Ti atoms are displaced from the centre of octahedral units in alternating short (1.700-1.709 Å) and long (2.301-2.275 Å) Ti-O bonds. Raman and infrared studies confirm the existence of Ti-O-Ti chains. Thermal stability of LiTiOAsO 4 has been reported.

Going One-to-One in Urban Schools: An Evaluation of the XO Champions Initiative in Project LIFT Elementary Schools

ERIC Educational Resources Information Center

Beaver, Jessica K.; Englander, Katie; Leow, Christine; Barnes, Marvin

2015-01-01

Beginning in spring 2013, students in seven elementary schools throughout the Project LIFT zone in Charlotte, North Carolina began to receive XO laptops provided by the organization One Laptop Per Child (OLPC) for use both within their classroom and at home. This report details Research for Action's (RFA) mixed-method evaluation of the first year…

C60 and U ion irradiation of Gd 2Ti xZr 2-xO 7 pyrochlore

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Jiaming; Toulemonde, Marcel; Lang, Maik

2015-08-01

Gd 2Ti xZr 2-xO 7 (x = 0 to 2) pyrochlore was irradiated by 30 MeV C 60 clusters, which provide an extremely high ionizing energy density. Here, high-resolution transmission electron microscopy revealed a complex ion-track structure in Gd 2Ti 2O 7 and Gd 2TiZrO 7, consisting of an amorphous core and a shell of a disordered, defect-fluorite structure.

The effect of antioxidants on ozone-induced airway hyperresponsiveness in dogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matsui, S.; Jones, G.L.; Woolley, M.J.

1991-12-01

The role of oxygen radicals in causing ozone-induced airway hyperresponsiveness in dogs was examined by pretreating dogs with allopurinol and/or deferoxamine mesylate (desferal), which are inhibitors of oxygen radical generation, before ozone inhalation. Acetylcholine airway responsiveness was measured before and after either air or ozone inhalation (3 ppm for 20 min) on 5 experimental days separated by at least 2 wk. On each day, the dogs were pretreated intravenously with allopurinol (50 mg/kg) followed by inhaled desferal (1,000 mg inhalation) or with allopurinol followed by the diluent for desferal or with the diluent for allopurinol and desferal or with bothmore » diluents. The effect of ozone on acetylcholine airway responsiveness was expressed as the differences in the log-transformed preozone-postozone acetylcholine provocative concentrations. When dogs received both diluents or either treatment alone, ozone inhalation caused airway hyperresponsiveness. The mean log differences for the preozone-postozone acetylcholine provocative concentration were 0.804 (SEM, 0.17) for both diluents, 0.524 (SEM, 0.16) for allopurinol alone, and 0.407 (SEM, 0.22) for desferal alone. However, the combination of allopurinol and desferal significantly inhibited the development of ozone-induced airway hyperresponsiveness, the log difference being 0.195 (SEM, 0.11) (p less than 0.05), without inhibiting ozone-induced neutrophil influx into the airways. The results suggest that the production of oxygen radicals is important in the pathogenesis of ozone-induced airway hyperresponsiveness.« less

Local surrounding of Mn in LaMn 1-xCo xO 3 compounds by means of EXAFS on Mn-K

NASA Astrophysics Data System (ADS)

Procházka, Vít; Sikora, Marcin; Kapusta, Czeslaw; Štěpánková, Helena; Chlan, Vojtěch; Knížek, Karel; Jirák, Zdeněk

2010-05-01

A systematic study of LaMn 1-xCo xO 3 perovskite series by means of X-ray absorption spectroscopy in the extended X-ray absorption fine structure (EXAFS) range of the K-absorption edge of Mn is reported. The Mn-K edge absorption measurements in the EXAFS region were performed to study the local surrounding of Mn ions. Polycrystalline powder samples of LaMn 1-xCo xO 3 ( x=0, 0.02; 0.2; 0.4; 0.5; 0.6; 0.8) prepared by solid-state reaction were used. The EXAFS spectra were analyzed with the FEFF8 computer program. The Mn-O distances of Mn to the nearest oxygen surroundings were evaluated for the samples in the series and compared with the Co-O distances obtained by EXAFS in V. Procházka et al., JMMM 310 (2007) 197 and with results of X-ray powder diffraction in C. Autret, J. Phys. Condens. Matter 17 (2005) 1601.

Novel red phosphors KBaEu(XO4)3 (X = Mo, W) show high color purity and high thermostability from a disordered chained structure.

PubMed

Wang, G Q; Gong, X H; Chen, Y J; Huang, J H; Lin, Y F; Luo, Z D; Huang, Y D

2017-05-23

Two novel red phosphors KBaEu(XO 4 ) 3 (X = Mo, W) have been synthesized by high-temperature solid-state reactions and the crystal structures were determined for the first time. Single-crystal X-ray diffraction data reveal that their space groups are C2/c. The crystalline structure is constituted of K/BaO 8 distorted square antiprisms and distorted EuO 8 polyhedra which form chains lying along the c-axis and two kinds of distorted XO 4 tetrahedra. This high disorder of K/Ba which might lower the crystal field symmetry around Eu 3+ results in the high purity of red emission around 615 nm originating from 5 D 0 → 7 F 2 transition under near-ultraviolet (NUV) excitation. With increasing temperature, the luminescence of KBaEu(XO 4 ) 3 (X = Mo, W) phosphors decreases almost linearly with subtle alteration for the CIE coordinate. As the temperature reaches 550 K, the red emission intensity decreases to 37.3% and 50.7% of that at 300 K for KBaEu(MoO 4 ) 3 and KBaEu(WO 4 ) 3 , respectively. The analysis of the decay curves of the 5 D 0 → 7 F 2 emission at variable temperatures indicates the weak cross relaxation and non-radiative energy transfer between Eu 3+ ions. These results demonstrate that the investigated phosphors are attractive for application in high power NUV excited white LEDs.

Wuestite (Fe/1-x/O) - A review of its defect structure and physical properties

NASA Technical Reports Server (NTRS)

Hazen, R. M.; Jeanloz, R.

1984-01-01

Such complexities of the Wustite structure as nonstoichiometry, ferric iron variable site distribution, long and short range ordering, and exsolution, yield complex physical properties. Magnesiowustite, a phase which has been suggested to occur in the earth's lower mantle, is also expected to exhibit many of these complexities. Geophysical models including the properties of (Mg, Fe)O should accordingly take into account the uncertainties associated with the synthesis and measurement of iron-rich oxides. Given the variability of the Fe(1-x)O structure, it is important that future researchers define the structural state and extent of exsolution of their samples.

Allopurinol attenuates acute kidney injury following Bothrops jararaca envenomation

PubMed Central

Martines, Monique Silva; Ferreira, Daniela; Volpini, Rildo; Canale, Daniele; Malaque, Ceila; Crajoinas, Renato; Girardi, Adriana Castello Costa; Massola Shimizu, Maria Heloisa; Seguro, Antonio Carlos

2017-01-01

Snakebites have been recognized as a neglected public health problem in several tropical and subtropical countries. Bothrops snakebites frequently complicate with acute kidney injury (AKI) with relevant morbidity and mortality. To date, the only treatment available for Bothrops envenomation is the intravenous administration of antivenom despite its several limitations. Therefore, the study of novel therapies in Bothrops envenomation is compelling. The aim of this study was to evaluate the protective effect of Allopurinol (Allo) in an experimental model of Bothrops jararaca venom (BJ)-associated AKI. Five groups of Wistar rats were studied: Sham, Allo, BJ, BJ+Allo, BJ+ipAllo. BJ (0.25 mg/kg) was intravenously injected during 40’. Saline at same dose and infusion rate was administered to Sham and Allo groups. Allo and BJ+Allo groups received Allo (300 mg/L) in the drinking water 7 days prior to Saline or BJ infusion respectively. BJ+ipAllo rats received intraperitoneal Allo (25 mg/Kg) 40’ after BJ infusion. BJ rats showed markedly reduced glomerular filtration rate (GFR, inulin clearance) associated with intense renal vasoconstriction, hemolysis, hemoglobinuria, reduced glutathione and increased systemic and renal markers of nitro-oxidative stress (Nitrotyrosine). Allo ameliorated GFR, renal blood flow (RBF), renal vascular resistance and arterial lactate levels. In addition, Allo was associated with increased serum glutathione as well as reduced levels of plasma and renal Nitrotyrosine. Our data show that Allo attenuated BJ-associated AKI, reduced oxidative stress, improved renal hemodynamics and organ perfusion. It might represent a novel adjuvant approach for Bothrops envenomation, a new use for an old and widely available drug. PMID:29155815

Enhanced magnetization in VxFe3-xO4 nanoparticles

NASA Astrophysics Data System (ADS)

Pool, V. L.; Kleb, M. T.; Chorney, C. L.; Arenholz, E.; Idzerda, Y. U.

2015-12-01

Nanoparticles of VxFe3-xO4 with up to 33% vanadium doping (x=0 to 1) and a 9 nm diameter are investigated in order to determine the site preference of the vanadium and the magnetic behavior of the nanoparticles. The iron and vanadium L23-edge X-ray absorption spectroscopy (XAS) and X-ray magnetic circular dichroism (MCD) spectra are used to identify that vanadium initially substitutes into the tetrahedral iron site as V3+ and that the average iron moment is observed to increase with vanadium concentration up to 12.5% (x=.375). When the vanadium incorporation exceeds 12.5%, the XAS and MCD show that the vanadium begins substituting as V2+ in the octahedral coordination. This coincides with a rapid reduction of the average moment to zero by 25% (x=.75). The frequency-dependent alternating-current magnetic susceptibility (ACMS) displays a substantial increase in blocking temperature with vanadium concentration and indicated substantial variation in the strength of inter-particle interactions.

Xanthine Oxidase Inhibition by Febuxostat Attenuates Experimental Atherosclerosis in Mice

PubMed Central

Nomura, Johji; Busso, Nathalie; Ives, Annette; Matsui, Chieko; Tsujimoto, Syunsuke; Shirakura, Takashi; Tamura, Mizuho; Kobayashi, Tsunefumi; So, Alexander; Yamanaka, Yoshihiro

2014-01-01

Atherosclerosis is a chronic inflammatory disease due to lipid deposition in the arterial wall. Multiple mechanisms participate in the inflammatory process, including oxidative stress. Xanthine oxidase (XO) is a major source of reactive oxygen species (ROS) and has been linked to the pathogenesis of atherosclerosis, but the underlying mechanisms remain unclear. Here, we show enhanced XO expression in macrophages in the atherosclerotic plaque and in aortic endothelial cells in ApoE−/− mice, and that febuxostat, a highly potent XO inhibitor, suppressed plaque formation, reduced arterial ROS levels and improved endothelial dysfunction in ApoE−/− mice without affecting plasma cholesterol levels. In vitro, febuxostat inhibited cholesterol crystal-induced ROS formation and inflammatory cytokine release in murine macrophages. These results demonstrate that in the atherosclerotic plaque, XO-mediated ROS formation is pro-inflammatory and XO-inhibition by febuxostat is a potential therapy for atherosclerosis. PMID:24686534

Management of hyperuricemia in gout: focus on febuxostat

PubMed Central

Reinders, Mattheus K; Jansen, Tim L Th A

2010-01-01

Gout is the most common inflammatory arthritis in an elderly population, and can be diagnosed with absolute certainty by polarization microscopy. However, diagnosis may be challenging because atypical presentations are more common in the elderly. Management of hyperuricemia in the elderly with gout requires special consideration because of co-medication, contra-indications, and risk of adverse reactions. Urate-lowering agents include allopurinol and uricosuric agents. These also must be used sensibly in the elderly, especially when renal function impairment is present. However, if used at the lowest dose that maintains the serum urate level below 5.0 to 6.0 mg/dL (0.30 to 0.36 mmol/L), the excess urate in the body will eventually be eliminated, acute flares will no longer occur, and tophi will resolve. Febuxostat, a new xanthine oxidase inhibitor, is welcomed, as few alternatives for allopurinol are available. Its pharmacokinetics and pharmacodynamics are not significantly altered in patients with moderate renal function or hepatic impairment. Its antihyperuricemic efficacy at 80 to 120 mg/day is better than “standard dosage” allopurinol (300 mg/day). Long-term safety data and efficacy data on tophus diminishment and reduction of gout flares have recently become available. Febuxostat may provide an important option in patients unable to use allopurinol, or refractory to allopurinol. PMID:20169038

Antioxidant, anti-inflammatory, and enzyme inhibitory activity of natural plant flavonoids and their synthesized derivatives.

PubMed

Nile, Shivraj Hariram; Keum, Young Soo; Nile, Arti Shivraj; Jalde, Shivkumar S; Patel, Rahul V

2018-01-01

The synthesized flavonoid derivatives were examined for their antioxidant, anti-inflammatory, xanthine oxidase (XO), urease inhibitory activity, and cytotoxicity. Except few, all the flavonoids under this study showed significant antioxidant activity (45.6%-85.5%, 32.6%-70.6%, and 24.9%-65.5% inhibition by DPPH, ferric reducing/antioxidant power, and oxygen radical absorption capacity assays) with promising TNF-α inhibitory activity (42%-73% at 10 μM) and IL-6 inhibitory activity (54%-81% at 10 μM) compared with that of control dexamethasone. The flavonoids luteolin, apigenin, diosmetin, chrysin, O 3Ꞌ , O 7 -dihexyl diosmetin, O 4Ꞌ , O 7 -dihexyl apigenin, and O 7 -hexyl chrysin, showed an inhibition with IC 50 values (4.5-8.1 μg/mL), more than allopurinol (8.5 μg/mL) at 5 μM against XO and showing more than 50% inhibition at a final concentration (5 mM) with an IC 50 value of ranging from 4.8 to 7.2 (μg/mL) in comparison with the positive control thiourea (5.8 μg/mL) for urease inhibition. Thus, the flavonoid derivatives may be considered as potential antioxidant and antigout agents. © 2017 Wiley Periodicals, Inc.

Modifying Optical Properties of ZnO Films by Forming Zn[subscript 1-x] Co[subscript x]O Solid Solutions via Spray Pyrolysis

ERIC Educational Resources Information Center

Bentley, Anne K.; Weaver, Gabriela C.; Russell, Cianan B.; Fornes, William L.; Choi, Kyoung-Shin; Shih, Susan M.

2007-01-01

A simple and cost-effective experiment for the development and characterization of semiconductors using Uv-vis spectroscopy is described. The study shows that the optical properties of ZnO films can be easily modified by forming Zn[subscript 1-x] Co[subscript x]O solid solutions via spray pyrolysis.

Structural and electromagnetic properties of NiAlxFe2-xO4/SiO2 nanocomposite films deposited using a sol-gel spin-coating method

NASA Astrophysics Data System (ADS)

Wang, Li; Li, Xuejian; Li, Ji; Liu, Mei; Xu, Shichong; Li, Haibo

2017-12-01

NiAlxFe2-xO4/SiO2 (0 ≤ x ≤ 1.0) nanocomposite films deposited on Si(1 0 0) substrates were prepared by a sol-gel spin-coating method. The influences of Al3+ content and annealing temperature on the structural and electromagnetic properties of the nanocomposite films were investigated. The results indicated that NiAlxFe2-xO4 in the nanocomposite films crystallized after annealing at 1073 K and above. When the doping content x increased from 0 to 1.0, the lattice constants and the average crystallite sizes of the NiAlxFe2-xO4 nanoparticles decreased. The saturation magnetization and coercivity of the films were inversely proportional to the Al3+ content. The maximum value of saturation magnetization (361.6 emu/cm3) and the minimum value of coercivity (18.6 kA/m) were obtained for x of 0.2. When the annealing temperature increased from 1073 to 1473 K, the lattice constant and the average crystallite size of the NiAl0.2Fe1.8O4 nanoparticles increased from 0.8322 to 0.8349 nm and 4 to 28 nm, respectively, and the saturation magnetization and coercivity of the films increased from 214.8 to 464.5 emu/cm3 and 8.2 to 26.9 kA/m, respectively. Moreover, the DC resistivity of the films increased with increasing Al3+ content and annealing temperature.

Design, synthesis and biological evaluation of novel xanthine oxidase inhibitors bearing a 2-arylbenzo[b]furan scaffold.

PubMed

Tang, Hong-Jin; Li, Wei; Zhou, Mei; Peng, Li-Ying; Wang, Jin-Xin; Li, Jia-Huang; Chen, Jun

2018-05-10

Xanthine oxidase, which catalyzes the oxidative reaction of hypoxanthine and xanthine into uric acid, is a key enzyme to the pathogenesis of hyperuricemia and gout. In this study, for the purpose of discovering novel xanthine oxidase (XO) inhibitors, a series of 2-arylbenzo[b]furan derivatives (3a-3d, 4a-4o and 6a-6d) were designed and synthesized. All these compounds were evaluated their xanthine oxidase inhibitory and antioxidant activities by using in vitro enzymatic assay and cellular model. The results showed that a majority of the designed compounds exhibited potent xanthine oxidase inhibitory effects and antioxidant activities, and compound 4a emerged as the most potent xanthine oxidase inhibitor (IC 50  = 4.45 μM). Steady-state kinetic measurements of the inhibitor 4a with the bovine milk xanthine oxidase indicated a mixed type inhibition with 3.52 μM K i and 13.14 μM K is , respectively. The structure-activity relationship analyses have also been presented. Compound 4a exhibited the potent hypouricemic effect in the potassium oxonate-induced hyperuricemic mice model. A molecular docking study of compound 4a was performed to gain an insight into its binding mode with xanthine oxidase. These results highlight the identification of a new class of xanthine oxidase inhibitors that have potential to be more efficacious in treatment of gout. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Investigation of the Structural Stability of Ion-Implanted Gd 2Ti 2-xSn xO 7 Pyrochlore-Type Oxides by Glancing Angle X-ray Absorption Spectroscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aluri, Esther Rani; Hayes, John R.; Walker, James D.S.

2016-03-24

Rare-earth titanate and stannate pyrochlore-type oxides have been investigated in the past for the sequestration of nuclear waste elements because of their resistance to radiation-induced structural damage. In order to enhance this property, it is necessary to understand the effect of radioactive decay of the incorporated actinide elements on the local chemical environment. In this study, Gd 2Ti 2–xSn xO 7 materials have been implanted with Au– ions to simulate radiation-induced structural damage. Glancing angle X-ray absorption near-edge spectroscopy (GA-XANES), glancing angle X-ray absorption fine structure (GA-EXAFS) analysis, and powder X-ray diffraction have been used to investigate changes in themore » local coordination environment of the metal atoms in the damaged surface layer. Examination of GA-XANES/EXAFS spectra from the implanted Gd 2Ti 2–xSn xO 7 materials collected at various glancing angles allowed for an investigation of how the local coordination environment around the absorbing atoms changed at different depths in the damaged surface layer. This study has shown the usefulness of GA-XANES to the examination of ion-implanted materials and has suggested that Gd 2Ti 2–xSn xO 7 becomes more susceptible to ion-beam-induced structural damage with increasing Sn concentration.« less

Time-dependent alterations in serum NO concentration after oral administration of l-arginine, l-NAME, and allopurinol in intestinal ischemia/reperfusion

PubMed Central

Yanni, Amalia E; Margaritis, Eleutherios; Liarakos, Nikolaos; Pantopoulou, Alkisti; Poulakou, Maria; Kostakis, Maria; Perrea, Despoina; Kostakis, Alkis

2008-01-01

Objective To study the effect of oral administration of a nitric oxide (NO) donor l-arginine (l-Arg), a NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME) and an inhibitor of xanthine oxidase, allopurinol (Allo), on serum NO concentration and catalase activity after intestinal ischemia/reperfusion (I/R) in rats. Methods Male Wistar rats received per os l-Arg (800 mg/kg) or l-NAME (50 mg/kg) or Allo (100 mg/kg) 24 hrs, 12 hrs and 1 hr before underwent 1 hr occlusion of superior mesenteric artery followed by 1 hr of reperfusion (l-Arg(IR1), l-NAME(IR1) and Allo(IR1) respectively) or 1 hr occlusion followed by 8 hrs of reperfusion (l-Arg(IR8), l-NAME(IR8) and Allo(IR8) respectively). There was one group underwent 1 hr occlusion (I), a group underwent 1 hr occlusion followed by 1 hr reperfusion (IR1), a group subjected to 1 hr occlusion followed by 8 hrs of reperfusion (IR8) and a last group that served as control (C). Serum NO concentration and catalase activity were measured. Results After 1 hr of reperfusion serum NO concentration was elevated in IR1 and l-Arg(IR1) groups compared with group C but not in l-NAME(IR1) and Allo(IR1) group. Catalase activity was enhanced in l-NAME(IR1) group. Interestingly, serum NO concentration was increased after 8 hrs of reperfusion in all groups (IR8, l-Arg(IR8), l-NAME(IR8) and Allo(IR8)) compared with control while catalase activity did not show significant difference in any group. Conclusions The results of the present study show that NO concentration is elevated in serum after intestinal I/R and the elevation sustained after administration of l-Arg but not after administration of l-NAME or Allo after 1 hr reperfusion. However, after 8 hrs of reperfusion NO concentration was increased in all groups studied, focusing attention on its possible important role in a complicated situation such as intestinal I/R that involves intestine and other organs. Serum catalase activity does not seem to be affected by per os

Comparative study on cubic and tetragonal CexZr1-xO2 supported MoO3-catalysts for sulfur-resistant methanation

NASA Astrophysics Data System (ADS)

Liu, Zhaopeng; Xu, Yan; Cheng, Jiaming; Wang, Weihan; Wang, Baowei; Li, Zhenhua; Ma, Xinbin

2018-03-01

In this paper, two kinds of CexZr1-xO2 solid solution carriers with different Ce/Zr ratio were prepared by one-step co-precipitation method: the cubic Ce0.8Zr0.2O2 and the tetragonal Ce0.2Zr0.8O2 support. The MoO3/Ce0.8Zr0.2O2 and MoO3/Ce0.2Zr0.8O2 catalysts were prepared by incipient wetness impregnation method for comparative study on sulfur-resistant methanation reaction. The N2 adsorption/desorption, X-ray diffraction (XRD), Raman spectroscopy (RS), X-ray photoelectron (XPS), transmission electron microscopy (TEM), temperature-programmed reduction by hydrogen (H2-TPR) were undertaken to characterize the physico-chemical properties of the samples. The results indicated that the prepared MoO3/CexZr1-xO2 catalysts have a mesoporous structure with high surface area and uniform pore size distribution, achieving good MoO3 dispersion on CexZr1-xO2 supports. As for the catalytic performance of sulfur-resistant methanation, the cubic MoO3/Ce0.8Zr0.2O2 exhibited better than the tetragonal MoO3/Ce0.2Zr0.8O2 catalyst at reaction temperature 400 °C and 450 °C. CO conversion on the cubic MoO3/Ce0.8Zr0.2O2 catalyst was 50.1% at 400 °C and 75.5% at 450 °C, which is respectively 7% and 20% higher than that on the tetragonal MoO3/Ce0.2Zr0.8O2 catalyst. These were mainly attributed to higher content of active MoS2 on the surface of catalyst, the enhanced oxygen mobility, increased Mo-species dispersion as well as the excellent reducibility resulted from the increased amount of the reducible Ce3+ on the cubic MoO3/Ce0.8Zr0.2O2 catalyst.

Pulsed laser deposited BexZn1-xO1-ySy quaternary alloy films: structure, composition, and band gap bowing

NASA Astrophysics Data System (ADS)

Zhang, Wuzhong; Xu, Maji; Zhang, Mi; Cheng, Hailing; Li, Mingkai; Zhang, Qingfeng; Lu, Yinmei; Chen, Jingwen; Chen, Changqing; He, Yunbin

2018-03-01

In this work, c-axis preferentially oriented BexZn1-xO1-ySy (BeZnOS) quaternary alloy films were prepared successfully on c-plane sapphire by pulsed laser deposition for the first time. By appropriate adjustment of O2 pressure during the deposition, the grown films exhibited a single-phase hexagonal structure and good crystalline quality. The solid solubility of S in BexZn1-xO1-ySy quaternary alloy was significantly expanded (y ≤ 0.17 or y ≥ 0.35) as a result of simultaneous substitution of cation Zn2+ by smaller Be2+ and anion O2- by bigger S2-. Besides, due to the introduction of BeO with a wide band gap, BeZnOS quaternary films exhibited wider band gaps than the ternary ZnOS films with similar S contents. As the O2 pressure increased from 0.05 Pa to 6 Pa, the band gap of BeZnOS displayed an interesting bowing behavior. The variation range of the band gap was between 3.55 eV and 3.10 eV. The BeZnOS films with a wide band gap show potential applications in fabricating optoelectronic devices such as UV-detectors.

Evolution of competing magnetic order in the J eff=1/2 insulating state of Sr 2Ir 1-xRu xO 4

DOE PAGES

Calder, Stuart A.; Kim, Jong-Woo; Cao, Guixin; ...

2015-10-27

We investigate the magnetic properties of the series Sr 2Ir 1-xRu xO 4 with neutron, resonant x-ray and magnetization measurements. The results indicate an evolution and coexistence of magnetic structures via a spin flop transition from ab-plane to c-axis collinear order as the 5d Ir4 + ions are replaced with an increasing concentration of 4d Ru4 + ions. The magnetic structures within the ordered regime of the phase diagram (x<0.3) are reported. Despite the changes in magnetic structure no alteration of the J eff=1/2 ground state is observed. This behavior of Sr 2Ir 1-xRu xO 4 is consistent with electronicmore » phase separation and diverges from a standard scenario of hole doping. The role of lattice alterations with doping on the magnetic and insulating behavior is considered. Our results presented here provide insight into the magnetic insulating states in strong spin-orbit coupled materials and the role perturbations play in altering the behavior.« less

Structure-Based Rational Design of Novel Inhibitors Against Fructose-1,6-Bisphosphate Aldolase from Candida albicans.

PubMed

Han, Xinya; Zhu, Xiuyun; Hong, Zongqin; Wei, Lin; Ren, Yanliang; Wan, Fen; Zhu, Shuaihua; Peng, Hao; Guo, Li; Rao, Li; Feng, Lingling; Wan, Jian

2017-06-26

Class II fructose-1,6-bisphosphate aldolases (FBA-II) are attractive new targets for the discovery of drugs to combat invasive fungal infection, because they are absent in animals and higher plants. Although several FBA-II inhibitors have been reported, none of these inhibitors exhibit antifungal effect so far. In this study, several novel inhibitors of FBA-II from C. albicans (Ca-FBA-II) with potent antifungal effects were rationally designed by jointly using a specific protocols of molecular docking-based virtual screening, accurate binding-conformation evaluation strategy, synthesis and enzymatic assays. The enzymatic assays reveal that the compounds 3c, 3e-g, 3j and 3k exhibit high inhibitory activity against Ca-FBA-II (IC 50 < 10 μM), and the most potential inhibitor is 3g, with IC 50 value of 2.7 μM. Importantly, the compounds 3f, 3g, and 3l possess not only high inhibitions against Ca-FBA-II, but also moderate antifungal activities against C. glabrata (MIC 80 = 4-64 μg/mL). The compounds 3g, 3l, and 3k in combination with fluconazole (8 μg/mL) displayed significantly synergistic antifungal activities (MIC 80 < 0.0625 μg/mL) against resistant Candida strains, which are resistant to azoles drugs. The probable binding modes between 3g and the active site of Ca-FBA-II have been proposed by using the DOX (docking, ONIOM, and XO) strategy. To our knowledge, no FBA-II inhibitors with antifungal activities against wild type and resistant strains from Candida were reported previously. The positive results suggest that the strategy adopted in this study are a promising method for the discovery of novel drugs against azole-resistant fungal pathogens in the future.

Ionic configuration of copper ferrimanganites Cu 0.5Mn xFe 2.5- xO 4

NASA Astrophysics Data System (ADS)

Lenglet, M.; Kasperek, J.; Hannoyer, B.; Lopitaux, J.; d'Huysser, A.; Tellier, J. C.

1992-06-01

Mössbauer spectrometry, neutron diffraction, XANES, and XPS have led to the determination of the cation distributions of the system Cu 0.5Mn xFe 2.5- xO 4 (0≤ x≤1.5). The three cations are present in both tetrahedral and octahedral sites, and the relative number of Fe ions on A- and B-sites remains nearly constant in the whole range of x. It appears that for x≤0.5 manganese is divalent and copper is in its two oxidation states. For x>0.5 copper and iron are respectively divalent and trivalent; the manganese is in +2 and +3 oxydation states.

INFRARED TRANSMISSION SPECTROSCOPY OF THE EXOPLANETS HD 209458b AND XO-1b USING THE WIDE FIELD CAMERA-3 ON THE HUBBLE SPACE TELESCOPE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deming, Drake; Wilkins, Ashlee; McCullough, Peter

Exoplanetary transmission spectroscopy in the near-infrared using the Hubble Space Telescope (HST) NICMOS is currently ambiguous because different observational groups claim different results from the same data, depending on their analysis methodologies. Spatial scanning with HST/WFC3 provides an opportunity to resolve this ambiguity. We here report WFC3 spectroscopy of the giant planets HD 209458b and XO-1b in transit, using spatial scanning mode for maximum photon-collecting efficiency. We introduce an analysis technique that derives the exoplanetary transmission spectrum without the necessity of explicitly decorrelating instrumental effects, and achieves nearly photon-limited precision even at the high flux levels collected in spatial scanmore » mode. Our errors are within 6% (XO-1) and 26% (HD 209458b) of the photon-limit at a resolving power of {lambda}/{delta}{lambda} {approx} 70, and are better than 0.01% per spectral channel. Both planets exhibit water absorption of approximately 200 ppm at the water peak near 1.38 {mu}m. Our result for XO-1b contradicts the much larger absorption derived from NICMOS spectroscopy. The weak water absorption we measure for HD 209458b is reminiscent of the weakness of sodium absorption in the first transmission spectroscopy of an exoplanet atmosphere by Charbonneau et al. Model atmospheres having uniformly distributed extra opacity of 0.012 cm{sup 2} g{sup -1} account approximately for both our water measurement and the sodium absorption. Our results for HD 209458b support the picture advocated by Pont et al. in which weak molecular absorptions are superposed on a transmission spectrum that is dominated by continuous opacity due to haze and/or dust. However, the extra opacity needed for HD 209458b is grayer than for HD 189733b, with a weaker Rayleigh component.« less

Infrared Transmission Spectroscopy of the Exoplanets HD 209458b and XO-1b Using the Wide Field Camera-3 on the Hubble Space Telescope

NASA Astrophysics Data System (ADS)

Deming, Drake; Wilkins, Ashlee; McCullough, Peter; Burrows, Adam; Fortney, Jonathan J.; Agol, Eric; Dobbs-Dixon, Ian; Madhusudhan, Nikku; Crouzet, Nicolas; Desert, Jean-Michel; Gilliland, Ronald L.; Haynes, Korey; Knutson, Heather A.; Line, Michael; Magic, Zazralt; Mandell, Avi M.; Ranjan, Sukrit; Charbonneau, David; Clampin, Mark; Seager, Sara; Showman, Adam P.

2013-09-01

Exoplanetary transmission spectroscopy in the near-infrared using the Hubble Space Telescope (HST) NICMOS is currently ambiguous because different observational groups claim different results from the same data, depending on their analysis methodologies. Spatial scanning with HST/WFC3 provides an opportunity to resolve this ambiguity. We here report WFC3 spectroscopy of the giant planets HD 209458b and XO-1b in transit, using spatial scanning mode for maximum photon-collecting efficiency. We introduce an analysis technique that derives the exoplanetary transmission spectrum without the necessity of explicitly decorrelating instrumental effects, and achieves nearly photon-limited precision even at the high flux levels collected in spatial scan mode. Our errors are within 6% (XO-1) and 26% (HD 209458b) of the photon-limit at a resolving power of λ/δλ ~ 70, and are better than 0.01% per spectral channel. Both planets exhibit water absorption of approximately 200 ppm at the water peak near 1.38 μm. Our result for XO-1b contradicts the much larger absorption derived from NICMOS spectroscopy. The weak water absorption we measure for HD 209458b is reminiscent of the weakness of sodium absorption in the first transmission spectroscopy of an exoplanet atmosphere by Charbonneau et al. Model atmospheres having uniformly distributed extra opacity of 0.012 cm2 g-1 account approximately for both our water measurement and the sodium absorption. Our results for HD 209458b support the picture advocated by Pont et al. in which weak molecular absorptions are superposed on a transmission spectrum that is dominated by continuous opacity due to haze and/or dust. However, the extra opacity needed for HD 209458b is grayer than for HD 189733b, with a weaker Rayleigh component.

Rap Phosphatase of Virulence Plasmid pXO1 Inhibits Bacillus anthracis Sporulation†

PubMed Central

Bongiorni, Cristina; Stoessel, Ricarda; Shoemaker, Dorinda; Perego, Marta

2006-01-01

This study shows that the Bacillus anthracis pXO1 virulence plasmid carries a Rap-Phr system, BXA0205, which regulates sporulation initiation in this organism. The BXA0205Rap protein was shown to dephosphorylate the Spo0F response regulator intermediate of the phosphorelay signal transduction system that regulates the initiation of the developmental pathway in response to environmental, metabolic, and cell cycle signals. The activity of the Rap protein was shown to be inhibited by the carboxy-terminal pentapeptide generated through an export-import processing pathway from the associated BXA0205Phr protein. Deregulation of the Rap activity by either overexpression or lack of the Phr pentapeptide resulted in severe inhibition of sporulation. Five additional Rap-Phr encoding systems were identified on the chromosome of B. anthracis, one of which, BA3790-3791, also affected sporulation initiation. The results suggest that the plasmid-borne Rap-Phr system may provide a selective advantage to the virulence of B. anthracis. PMID:16385039

Rap phosphatase of virulence plasmid pXO1 inhibits Bacillus anthracis sporulation.

PubMed

Bongiorni, Cristina; Stoessel, Ricarda; Shoemaker, Dorinda; Perego, Marta

2006-01-01

This study shows that the Bacillus anthracis pXO1 virulence plasmid carries a Rap-Phr system, BXA0205, which regulates sporulation initiation in this organism. The BXA0205Rap protein was shown to dephosphorylate the Spo0F response regulator intermediate of the phosphorelay signal transduction system that regulates the initiation of the developmental pathway in response to environmental, metabolic, and cell cycle signals. The activity of the Rap protein was shown to be inhibited by the carboxy-terminal pentapeptide generated through an export-import processing pathway from the associated BXA0205Phr protein. Deregulation of the Rap activity by either overexpression or lack of the Phr pentapeptide resulted in severe inhibition of sporulation. Five additional Rap-Phr encoding systems were identified on the chromosome of B. anthracis, one of which, BA3790-3791, also affected sporulation initiation. The results suggest that the plasmid-borne Rap-Phr system may provide a selective advantage to the virulence of B. anthracis.

Improving the sodium storage capacity of tunnel structured NaxFexTi2-xO4 (x = 1, 0.9 & 0.8) anode materials by tuning sodium deficiency

NASA Astrophysics Data System (ADS)

Bhange, Deu S.; Ali, Ghulam; Kim, Ji-Young; Chung, Kyung Yoon; Nam, Kyung-Wan

2017-10-01

Due to their abundance and environmentally benign nature, iron and titanium present as the most attractive potential elements for use in rechargeable sodium-ion batteries (SIBs). Accordingly, two structurally different Fe and Ti based compounds, stoichiometric NaFeTiO4 and sodium deficient NaxFexTi2-xO4 (where x = 0.9, and 0.8), are explored as anode materials for SIBs. Their structure and sodium storage capacity are systematically investigated by using combined structural and electrochemical analysis. Rietveld refinement analysis reveals that the sodium deficiency leads to the structural transformation from a single-tunnel structure (NaFeTiO4) to a zigzag-type double-tunnel structure (Na0.9Fe0.9Ti1.1O4 and Na0.8Fe0.8Ti1.2O4). The series of sodium deficient compounds bears systematic sodium ion vacancies in their structure up to 20%. Sodium deficiency in the NaxFexTi2-xO4 logically provides additional space for accommodating the excess sodium ions as such the NaxFexTi2-xO4 compounds with higher level of sodium deficiency show higher specific capacities than the stoichiometric NaFeTiO4. All the compounds exhibited very good electrochemical cycling stability, with minimal capacity loss during cycling. The present approach is a model example of improvement in the sodium storage capacity of the anode materials by tuning the chemical composition, and could facilitate the performance improvement of known or new electrode materials for SIBs.

Development of a bacterial screen for novel hypoxanthine-guanine phosphoribosyltransferase substrates.

PubMed

Shivashankar, K; Subbayya, I N; Balaram, H

2001-10-01

The lack of de novo purine biosynthesis in many parasitic protozoans makes the enzymes in the salvage of purines attractive chemotherapeutic targets. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is a key enzyme for purine salvage and bacterial complementation screens for HGPRT inhibitors are known. The low KMS for purine bases makes purine analogs unattractive as competitive inhibitors for this enzyme. Despite the availability of many crystal structures of HGPRTs, it is only recently that selective inhibitors of the enzyme have been developed. Therefore, novel purine analogs which act as substrates for the HGPRT reaction and thereby inhibit downstream enzymes or get incorporated into the nucleotide pool are an attractive altenative for drug design. We have used a combination of two E. coli strains Sphi606 (ara, deltapro-gpt-lac, thi, hpt) and Sphi609 (ara, deltapro-gpt-lac, thi, hpt, pup, purH,J, strA) to identify inhibitors and substrates of HGPRT. E. coli Sphi609 is deficient in both de novo synthesis as well as salvage enzymes of purine nucleotide synthesis, while E. coli Sphi606 is deficient in salvage enzymes only. Hence, expression of functional HGPRTs in E. coli Sphi606 grown in minimal medium makes it susceptible to HGPRT substrates, which inhibit downstream processes. Growth of E. coli Sphi609 in minimal medium can be made conditional for the expression of a functional HGPRT and this growth would be susceptible to both HGPRT substrate analogs and inhibitors. A substance that strictly acts as an inhibitor will affect growth of transformed E. coli Sphi609 only. For this purpose, we compared the human and P. falciparum enzymes with known HGPRT substrate analogs. Our data with 6-mercaptopurine, 6-thioguanine and allopurinol show that these compounds act by being substrates for HGPRT. Our results with allopurinol suggest that it is a better substrate for P. falciparum HGXPRT than the human enzyme. Therefore, species-specific substrates can be tested

Evaluation of Pharmacokinetic Interactions Between Lesinurad, a New Selective Urate Reabsorption Inhibitor, and CYP Enzyme Substrates Sildenafil, Amlodipine, Tolbutamide, and Repaglinide.

PubMed

Gillen, Michael; Yang, Chun; Wilson, David; Valdez, Shakti; Lee, Caroline; Kerr, Bradley; Shen, Zancong

2017-07-01

Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. In vitro assays indicate that lesinurad is an inducer of CYPs in the order CYP3A > CYP2C8 > CYP2C9 > CYP2C19 > CYP2B6 and an inhibitor of CYP2C8 and CYP2C9. To investigate the drug interaction potential of lesinurad, clinical drug interaction studies were conducted. Open-label studies in volunteers investigated the effects of single-/multiple-dose lesinurad on the pharmacokinetics of sildenafil and amlodipine (CYP3A4 induction), tolbutamide (CYP2C9 inhibition/induction), and repaglinide (CYP2C8 inhibition/induction). There was no apparent induction of CYP2C8 and CYP2C9 following repeated lesinurad administration, although no inhibition of CYP2C9 and modest inhibition of CYP2C8 were observed following single-dose lesinurad. Consistent with in vitro observations, lesinurad (200 mg once daily) was an inducer of CYP3A based on the effects on sildenafil exposure. Sildenafil exposure decreased by approximately 34% for C max and AUC when administered with multiple-dose lesinurad 200 mg and allopurinol 300 mg, relative to sildenafil alone. During lesinurad therapy, the possibility of reduced efficacy of concomitant drugs that are CYP3A substrates should be considered and their efficacy monitored because of induction of CYP3A by lesinurad. © 2017, The American College of Clinical Pharmacology.

The Effect of Using XO Computers on Students' Mathematics and Reading Abilities: Evidences from Learning Achievement Tests Conducted in Primary Education Schools in Mongolia

ERIC Educational Resources Information Center

Yamaguchi, Shinobu; Sukhbaatar, Javzan; Takada, Jun-ichi; Dayan-Ochir, Khishigbuyan

2014-01-01

In 2008, Mongolia took part in One Laptop per Child (OLPC) project. Since that time, over 10,000 students in grades 2-5 in 43 primary education schools are using XO computers. This paper presents the findings of a study conducted in 2012 to evaluate the impact of the OLPC initiatives on students' literacy and math skills. This study covered 14…

The Crystal Structure of TAL Effector PthXo1 Bound to Its DNA Target

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mak, Amanda Nga-Sze; Bradley, Philip; Cernadas, Raul A.

2012-02-10

DNA recognition by TAL effectors is mediated by tandem repeats, each 33 to 35 residues in length, that specify nucleotides via unique repeat-variable diresidues (RVDs). The crystal structure of PthXo1 bound to its DNA target was determined by high-throughput computational structure prediction and validated by heavy-atom derivatization. Each repeat forms a left-handed, two-helix bundle that presents an RVD-containing loop to the DNA. The repeats self-associate to form a right-handed superhelix wrapped around the DNA major groove. The first RVD residue forms a stabilizing contact with the protein backbone, while the second makes a base-specific contact to the DNA sense strand.more » Two degenerate amino-terminal repeats also interact with the DNA. Containing several RVDs and noncanonical associations, the structure illustrates the basis of TAL effector-DNA recognition.« less

Febuxostat hypersensitivity: another cause of DRESS syndrome in chronic kidney disease?

PubMed

Paschou, E; Gavriilaki, E; Papaioannou, G; Tsompanakou, A; Kalaitzoglou, A; Sabanis, N

2016-11-01

Febuxostat is a xanthine oxidase inhibitor that during the last years has successfully replaced allopurinol treatment in patients with chronic kidney disease (CKD) and hyperuricemia. Several adverse events have been observed during therapy with febuxostat. DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome induced by febuxostat has been poorly described, mainly in patient with CKD who previously developed allopurinol hypersensitivity syndrome. DRESS syndrome is characterized by manifold cutaneous reactions and systemic disorders with potential devastating consequences. The underlying pathogenetic mechanisms remain unidentified, though immune responses are often complicated. P-i concept can partially explain the phenomenon. The role of renal insufficiency appears to be crucial and further investigation is required. The present article describes the case of a CKD patient that developed febuxostat-related DRESS syndrome.

Unanticipated spin gap measured in the frustrated quasi-FCC d3 double perovskites La2 LiXO6 (X = Ru, Os)

NASA Astrophysics Data System (ADS)

Maharaj, Dalini D.; Sala, Gabriele; Marjerrison, Casey A.; Greedan, John; Gaulin, Bruce; Stone, Matthew

There is much current interest in the influence of strong spin-orbit (SO) interactions on exotic ground state selection in new 4d and 5d magnets, particularly involving 4d5 Ir. Here we consider double perovskites of the form A2 BB'O6 which are based on heavy 4d or 5d magnetic ions, where the SO interaction is expected to be significant as it increases as ~Z4 . The double perovskite structure can accommodate a variety of magnetic ions on the B' site, providing a playground for systematic studies of the exotic ground states stabilized by strong SO coupling. Here, we report inelastic neutron scattering (INS) measurements conducted on the frustrated monoclinic magnets, La2LiXO6 (X = Ru, Os), wherein the magnetic moments decorate a quasi face-centered-cubic lattice. Our results show the development of a spin gap in the spin excitation spectrum of size ΔOs = 8 meV and ΔRu = 2.5meV concomitant with TN, which is unexpected for orbitally quenched d3 systems. We liken these results to INS results obtained for Ba2YXO6 and La2NaXO6, which were also shown to exhibit spin gaps that correlate with TN. We shall discuss trends observed in these three d3 double perovskite families which correlate strong SO coupling, spin gap and TN.

Synchrotron radiation x-ray photoelectron spectroscopy study on the interface chemistry of high-k PrxAl2-xO3 (x=0-2) dielectrics on TiN for dynamic random access memory applications

NASA Astrophysics Data System (ADS)

Schroeder, T.; Lupina, G.; Sohal, R.; Lippert, G.; Wenger, Ch.; Seifarth, O.; Tallarida, M.; Schmeisser, D.

2007-07-01

Engineered dielectrics combined with compatible metal electrodes are important materials science approaches to scale three-dimensional trench dynamic random access memory (DRAM) cells. Highly insulating dielectrics with high dielectric constants were engineered in this study on TiN metal electrodes by partly substituting Al in the wide band gap insulator Al2O3 by Pr cations. High quality PrAlO3 metal-insulator-metal capacitors were processed with a dielectric constant of 19, three times higher than in the case of Al2O3 reference cells. As a parasitic low dielectric constant interface layer between PrAlO3 and TiN limits the total performance gain, a systematic nondestructive synchrotron x-ray photoelectron spectroscopy study on the interface chemistry of PrxAl2-xO3 (x =0-2) dielectrics on TiN layers was applied to unveil its chemical origin. The interface layer results from the decreasing chemical reactivity of PrxAl2-xO3 dielectrics with increasing Pr content x to reduce native Ti oxide compounds present on unprotected TiN films. Accordingly, PrAlO3 based DRAM capacitors require strict control of the surface chemistry of the TiN electrode, a parameter furthermore of importance to engineer the band offsets of PrxAl2-xO3/TiN heterojunctions.

Ecstasy induces reactive oxygen species, kidney water absorption and rhabdomyolysis in normal rats. Effect of N-acetylcysteine and Allopurinol in oxidative stress and muscle fiber damage

PubMed Central

de Bragança, Ana C.; Moreau, Regina L. M.; de Brito, Thales; Shimizu, Maria H. M.; Canale, Daniele; de Jesus, Denise A.; Silva, Ana M. G.; Gois, Pedro H.; Seguro, Antonio C.

2017-01-01

Background Ecstasy (Ec) use produces hyperthermia, excessive sweating, intense thirst, an inappropriate antidiuretic hormone secretion (SIADH) and a multisystemic toxicity due to oxidative stress (OS). Intense thirst induces high intake of pure water, which associated with SIADH, usually develops into acute hyponatremia (Hn). As Hn is induced rapidly, experiments to check if Ec acted directly on the Inner Medullary Collecting Ducts (IMCD) of rats were conducted. Rhabdomyolysis and OS were also studied because Ec is known to induce Reactive Oxygen Species (ROS) and tissue damage. To decrease OS, the antioxidant inhibitors N-acetylcysteine (NAC) and Allopurinol (Allo) were used. Methods Rats were maintained on a lithium (Li) diet to block the Vasopressin action before Ec innoculation. AQP2 (Aquaporin 2), ENaC (Epitheliun Sodium Channel) and NKCC2 (Sodium, Potassium, 2 Chloride) expression were determined by Western Blot in isolated IMCDs. The TBARS (thiobarbituric acid reactive substances) and GSH (reduced form of Glutathione) were determined in the Ec group (6 rats injected with Ec-10mg/kg), in Ec+NAC groups (NAC 100mg/Kg/bw i.p.) and in Allo+Ec groups (Allo 50mg/Kg/i.p.). Results Enhanced AQP2 expression revealed that Ec increased water transporter expression, decreased by Li diet, but the expression of the tubular transporters did not change. The Ec, Ec+NAC and Allo+Ec results showed that Ec increased TBARS and decreased GSH, showing evidence of ROS occurrence, which was protected by NAC and Allo. Rhabdomyolysis was only protected by Allo. Conclusion Results showed that Ec induced an increase in AQP2 expression, evidencing another mechanism that might contribute to cause rapid hyponatremia. In addition, they showed that NAC and Allo protected against OS, but only Allo decreased rhabdomyolysis and hyperthermia. PMID:28678861

Reactive oxygen species are involved in regulating alpha1-adrenoceptor-activated vascular smooth muscle contraction.

PubMed

Tsai, Ming-Ho; Jiang, Meei Jyh

2010-08-23

Reactive oxygen species (ROS) were shown to mediate aberrant contractility in hypertension, yet the physiological roles of ROS in vascular smooth muscle contraction have remained elusive. This study aimed to examine whether ROS regulate alpha1-adrenoceptor-activated contraction by altering myosin phosphatase activities. Using endothelium-denuded rat tail artery (RTA) strips, effects of anti-oxidants on isometric force, ROS production, phosphorylation of the 20-kDa myosin light chain (MLC20), and myosin phosphatase stimulated by alpha1-adrenoceptor agonist phenylephrine were examined. An antioxidant, N-acetyl-L-cysteine (NAC), and two NADPH oxidase inhibitors, apocynin and VAS2870, dose-dependently inhibited contraction activated by phenylephrine. Phenylephrine stimulated superoxide anion production that was diminished by the pretreatment of apocynin, VAS2870, superoxide scavenger tiron or mitochondria inhibitor rotenone, but not by xanthine oxidase inhibitor allopurinol or cyclooxygenase inhibitor indomethacin. Concurrently, NADPH oxidase activity in RTA homogenates increased within 1 min upon phenylephrine stimulation, sustained for 10 min, and was abolished by the co-treatment with apocynin, but not allopurinol or rotenone. Phenylephrine-induced MLC20 phosphorylation was dose-dependently decreased by apocynin. Furthermore, apocynin inhibited phenylephrine-stimulated RhoA translocation to plasma membrane and phosphorylation of both myosin phosphatase regulatory subunit MYPT1Thr855 and myosin phosphatase inhibitor CPI-17Thr38. ROS, probably derived from NADPH oxidase and mitochondria, partially regulate alpha1-adrenoceptor-activated smooth muscle contraction by altering myosin phosphatase-mediated MLC20 phosphorylation through both RhoA/Rho kinase- and CPI-17-dependent pathways.

Stripe-like nanoscale structural phase separation in superconducting BaPb 1-xBi xO 3

DOE PAGES

Giraldo-Gallo, P.; Zhang, Y.; Parra, C.; ...

2015-09-16

The phase diagram of BaPb 1-xBi xO 3 exhibits a superconducting “dome” in the proximity of a charge density wave phase. For the superconducting compositions, the material coexists as two structural polymorphs. Here we show, via high resolution transmission electron microscopy, that the structural dimorphism is accommodated in the form of partially disordered nanoscale stripes. Identification of the morphology of the nanoscale structural phase separation enables determination of the associated length scales, which we compare to the Ginzburg-Landau coherence length. Thus, we find that the maximum T c occurs when the superconducting coherence length matches the width of the partiallymore » disordered stripes, implying a connection between the structural phase separation and the shape of the superconducting dome.« less

Structural and magnetic phase transitions in EuTi 1-xNb xO 3

DOE PAGES

Li, Ling; Morris, James R.; Koehler, Michael R.; ...

2015-07-30

Here, we investigate the structural and magnetic phase transitions in EuTi 1-xNb xO 3 (0≤x≤0.3) with synchrotron powder x-ray diffraction, resonant ultrasound spectroscopy, and magnetization measurements. Upon Nb doping, the Pmmore » $$\\bar{3}$$m ↔ I4/mcm structural transition shifts to higher temperatures and the room temperature lattice parameter increases while the magnitude of the octahedral tilting decreases. In addition, Nb substitution for Ti destabilizes the antiferromagnetic ground state of the parent compound and long-range ferromagnetic order is observed in the samples with x≥0.1. Moreover, the structural transition in pure and doped compounds is marked by a dramatic step-like softening of the elastic moduli near T S, which resembles that of SrTiO 3 and can be adequately modeled using the Landau free energy model employing the same coupling between strain and octahedral tilting order parameter as previously used to model SrTiO 3.« less

Multiferroic properties of microwave sintered PbFe12-xO19-δ

NASA Astrophysics Data System (ADS)

Prathap, S.; Madhuri, W.

2017-05-01

The effect of iron deficiency on the structural, electrical, ferroelectric and magnetic properties of nano PbFe12-xO19-δ (where x=0.0, 0.25, 0.50, 0.75, 1.0) hexaferrites prepared by sol-gel auto combustion and processed by microwaves are investigated. X-ray analysis confirms single phase magneto-plumbite phase formation. The surface morphology is studied from Field Emission Scanning Electron Microscope. Further, optical properties are investigated using Fourier Transform Infrared spectra and UV-visible spectra. AC electrical conductivity is estimated as a function of temperature and frequency in the range of room temperature (RT) to 500 °C and 100 Hz to 5MHz. AC electrical conduction analysis shows that conduction is mainly due to small polaron hopping mechanism. The variation of polarization with applied electric field exhibits hysteresis loop confirming the ferroelectric nature. The initial permeability studies with varying temperature reveals that the Curie transition temperature for the present series is around 400 °C. Variation of initial permeability with frequency ranging from 100 to 5 MHz shows a constant value (except for x=0.0) opening avenues for high frequency applications.

Ferromagnetic resonance study of the non-stoichiometric double perovskite Sr2Fe1+xMo1-xO6

NASA Astrophysics Data System (ADS)

Medina, J. De La Torre; Piraux, L.; Soto, T. E.; Morales, R.; Navarro, O.

2018-02-01

In this work we report a ferromagnetic resonance study on the magnetic properties of double perovskite compounds fab-ricated by solid state reaction. Based on a mean field approach, along with morphological considerations, we accurately determined the saturation magnetization of the non-stoichiometric double perovskite Sr2Fe1+xMo1-xO6. Our approach has revealed a direct in-fluence of composition on the overall magnetic behavior of these materials, providing complementary experimental evidence that corroborates previous theoretical findings. The understanding of the influence of composition is of paramount importance for the design of ferromagnetic oxides with tunable magnetic and magneto-transport behavior.

Composition effect in luminescence properties of Y(NbxTa1-x)O4 mixed crystals

NASA Astrophysics Data System (ADS)

Spassky, D.; Vasil'ev, A.; Vielhauer, S.; Sidletskiy, O.; Voloshyna, O.; Belsky, A.

2018-06-01

The luminescence properties of Y(NbxTa1-x)O4 mixed crystals were studied. Local structure modifications arise due to the inhomogeneous distribution of the substitutional ions in the mixed crystal and can be traced using the luminescence spectroscopy. In particular, it is shown that the intensity of exciton emission under interband VUV excitation increases for intermediate values of x with the maximum at x = 0.4 relatively to the intensity observed in the constituents of the mixed crystals - YTaO4 and YNbO4. From the luminescence excitation spectra it follows that the probability of exciton creation from the separated e-h pairs increases for intermediate values of x as well. Using numerical simulation it is shown that the effect is connected with the variation of the thermalization length of hot electrons and holes, which is minimal at x = 0.4.

Monodisperse NixFe3-xO4 nanospheres: Metal-ion-steered size/composition control mechanism, static magnetic and enhanced microwave absorbing properties

NASA Astrophysics Data System (ADS)

Jiang, Kedan; Liu, Yun; Pan, Yefei; Wang, Ru; Hu, Panbing; He, Rujia; Zhang, Lingli; Tong, Guoxiu

2017-05-01

An easy metal-ion-steered solvothermal method was developed for the one-step synthesis of monodisperse, uniform NixFe3-xO4 polycrystalline nanospheres with tunable sphere diameter (40-400 nm) and composition (0 ≤ x ≤ 0.245) via changing just Ni2+/Fe3+ molar ratio (γ). With g increased from 0:1 to 2:1, sphere diameter gradually decreased and crystal size exhibited an inversed U-shaped change tendency, followed by increased Ni/Fe atom ratio from 0% to 0.0888%. An in situ-reduction, coordination-precipitation transformation mechanism was proposed to interpret the metal-ion-steered growth. Size- and composition-dependent static magnetic and microwave absorbing properties were systematically investigated. Saturation magnetization declines with g in a Boltzmann model due to the changes of crystal size, sphere diameter, and Ni content. The coercivity reaches a maximum at γ = 0.75:1 because of the critical size of Fe3O4 single domain (25 nm). Studies on microwave absorption reveal that 150-400 nm Fe3O4 nanospheres mainly obey the quarter-wavelength cancellation model with the single-band absorption; 40-135 nm NixFe3-xO4 nanospheres (0 ≤ x ≤ 0.245) obey the one and three quarter-wavelength cancellation model with the multi-band absorption. 150 nm Fe3O4 nanospheres exhibit the optimal EM wave-absorbing property with an absorbing band of 8.94 GHz and the maximum RL of -50.11 dB.

The effect of PO 4 doping on the luminescent properties of Sr 3-3zEu 2zV 2-xP xO 8

NASA Astrophysics Data System (ADS)

Cao, S.; Ma, Y. Q.; Yang, K.; Zhu, W. L.; Yin, W. J.; Zheng, G. H.; Wu, M. Z.; Sun, Z. Q.

2010-07-01

The luminescent properties of Sr 3V 2-xP xO 8 (0 ⩽ x ⩽ 2), Eu 3+ doped Sr 2.7Eu 0.2V 2-yP yO 8 (0 ⩽ y ⩽ 2) and Sr 3-3zEu 2zV 0.8P 1.2O 8 (0 < z ⩽ 0.3) have been investigated. For the Sr 3V 2-xP xO 8 (0 ⩽ x ⩽ 2) samples, the VO43- activation and emission intensity reaches the strongest as x = 1.6. For the Sr 2.7Eu 0.2V 2-yP yO 8 (0 ⩽ y ⩽ 2) samples, an appropriate amount of phosphorus doping enhances the Eu 3+ emission with the strongest emission occurring at y = 1.2. For the Sr 3-3zEu 2zV 0.8P 1.2O 8 (0 < z ⩽ 0.3) sample with the phosphorus content fixed at 1.2, it exhibits the most intense emission as Eu 3+ concentration reaches at z = 0.2. Our results indicate that the introduction of the PO43- plays an important role in the photoluminescence properties of the studied samples and the relevant mechanism has been discussed.

Influence of the K+ ions and the superstoichiometric manganese on structure defects, magneto-transport and dielectric properties of magnetoresistive La0.7Ca0.3-xKxMn1+xO3-δ ceramic

NASA Astrophysics Data System (ADS)

Liedienov, N. A.; Pashchenko, A. V.; Pashchenko, V. P.; Prokopenko, V. K.; Tatarchuk, D. D.; Revenko, Yu. F.; Turchenko, V. A.; Burchovetskii, V. V.; Sycheva, V. Ya.; Sil'cheva, A. G.; Didenko, Yu. V.; Levchenko, G. G.

2017-09-01

The structure, its defects, nanostructural clustering and functional properties of the La0.7Ca0.3-xKxMn1+xO3-δ ceramic with x = 0-0.3 have been investigated by x-ray diffraction, thermogravimetric, SEM, resistance, magnetic, magnetoresistance and dielectric spectroscopy methods. We establish that the lattice parameter of the cubic structure increases when the Ca2+ ions are substituted with ions of K+. We show that the real perovskite structure contains different valence states of manganese MnA2 +,MnB3 + and MnB4 + in A- and B-positions, as well as vacancy type point defects, in the form of anionic V(a) and cationic V(c) vacancies. The increase in the content of the superstoichiometric manganese is connected to the nanostructured clustering process. We find that K+ and superstoichiometric manganese cause the increase in relative permittivity ɛ' and dielectric loss tangent angle tg δ. The experimental phase diagram of the magnetic state has been constructed and allows determining the composition of the magnetoresistant La0.7Ca0.3-xKxMn1+xO3-δ ceramics with set magnetotransport properties. The optimal La0.7Ca0.3-xKxMn1+xO3-δ composition showing the highest magnetoresistance effect at room temperature has been determined by comparing the functional properties of lanthanum-calcium, lanthanum-strontium and lanthanum-calcium-potassium manganites.

In Vitro Oxidative Metabolism of 6-Mercaptopurine in Human Liver: Insights into the Role of the Molybdoflavoenzymes Aldehyde Oxidase, Xanthine Oxidase, and Xanthine Dehydrogenase

PubMed Central

Choughule, Kanika V.; Barnaba, Carlo; Joswig-Jones, Carolyn A.

2014-01-01

Anticancer agent 6-mercaptopurine (6MP) has been in use since 1953 for the treatment of childhood acute lymphoblastic leukemia (ALL) and inflammatory bowel disease. Despite being available for 60 years, several aspects of 6MP drug metabolism and pharmacokinetics in humans are unknown. Molybdoflavoenzymes such as aldehyde oxidase (AO) and xanthine oxidase (XO) have previously been implicated in the metabolism of this drug. In this study, we investigated the in vitro metabolism of 6MP to 6-thiouric acid (6TUA) in pooled human liver cytosol. We discovered that 6MP is metabolized to 6TUA through sequential metabolism via the 6-thioxanthine (6TX) intermediate. The role of human AO and XO in the metabolism of 6MP was established using the specific inhibitors raloxifene and febuxostat. Both AO and XO were involved in the metabolism of the 6TX intermediate, whereas only XO was responsible for the conversion of 6TX to 6TUA. These findings were further confirmed using purified human AO and Escherichia coli lysate containing expressed recombinant human XO. Xanthine dehydrogenase (XDH), which belongs to the family of xanthine oxidoreductases and preferentially reduces nicotinamide adenine dinucleotide (NAD+), was shown to contribute to the overall production of the 6TX intermediate as well as the final product 6TUA in the presence of NAD+ in human liver cytosol. In conclusion, we present evidence that three enzymes, AO, XO, and XDH, contribute to the production of 6TX intermediate, whereas only XO and XDH are involved in the conversion of 6TX to 6TUA in pooled HLC. PMID:24824603

In vitro oxidative metabolism of 6-mercaptopurine in human liver: insights into the role of the molybdoflavoenzymes aldehyde oxidase, xanthine oxidase, and xanthine dehydrogenase.

PubMed

Choughule, Kanika V; Barnaba, Carlo; Joswig-Jones, Carolyn A; Jones, Jeffrey P

2014-08-01

Anticancer agent 6-mercaptopurine (6MP) has been in use since 1953 for the treatment of childhood acute lymphoblastic leukemia (ALL) and inflammatory bowel disease. Despite being available for 60 years, several aspects of 6MP drug metabolism and pharmacokinetics in humans are unknown. Molybdoflavoenzymes such as aldehyde oxidase (AO) and xanthine oxidase (XO) have previously been implicated in the metabolism of this drug. In this study, we investigated the in vitro metabolism of 6MP to 6-thiouric acid (6TUA) in pooled human liver cytosol. We discovered that 6MP is metabolized to 6TUA through sequential metabolism via the 6-thioxanthine (6TX) intermediate. The role of human AO and XO in the metabolism of 6MP was established using the specific inhibitors raloxifene and febuxostat. Both AO and XO were involved in the metabolism of the 6TX intermediate, whereas only XO was responsible for the conversion of 6TX to 6TUA. These findings were further confirmed using purified human AO and Escherichia coli lysate containing expressed recombinant human XO. Xanthine dehydrogenase (XDH), which belongs to the family of xanthine oxidoreductases and preferentially reduces nicotinamide adenine dinucleotide (NAD(+)), was shown to contribute to the overall production of the 6TX intermediate as well as the final product 6TUA in the presence of NAD(+) in human liver cytosol. In conclusion, we present evidence that three enzymes, AO, XO, and XDH, contribute to the production of 6TX intermediate, whereas only XO and XDH are involved in the conversion of 6TX to 6TUA in pooled HLC. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Growth of ternary CdxZn1-xO thin films in oxygen ambient using pulsed laser deposition

NASA Astrophysics Data System (ADS)

Sharma, Sugandha; Saini, Basant; Kaur, Ravinder; Gupta, Vinay; Tomar, Monika; Kapoor, Avinashi

2018-05-01

This study reports the growth of cadmium alloyed zinc (CdxZn1-xO) oxide thin films using pulsed laser deposition. The films are deposited on Corning glass substrates at different oxygen pressures of 5, 20, and 40 mTorr. High resolution X-ray diffraction studies reveal mixed phase (hexagonal and cubic) for films deposited at 20 and 40 mTorr, while a cubic phase for film deposited at 5 mTorr pressure. Optical transmittance studies indicate red-shifting of transmission edge as oxygen pressure decreases to 5 mTorr from 20 mTorr, hinting at a possible increase in cadmium content in thin films. Minimum band gap energy is obtained at growth pressure of 5 mTorr. Resistivity measurements have been performed using Hall effect measurement set up at 298 K.

Raman effect in multiferroic Bi5Fe1+xTi3-xO15 solid solutions: A temperature study

NASA Astrophysics Data System (ADS)

Rodríguez Aranda, Ma. Del Carmen; Rodríguez-Vázquez, Ángel G.; Salazar-Kuri, Ulises; Mendoza, María Eugenia; Navarro-Contreras, Hugo R.

2018-02-01

In this work, a Raman study of powder samples of multiferroic Bi5Fe1+xTi3-xO15 solid solutions and Bi6Fe2Ti3O18 as a function of temperature from 27 °C (room temperature) to 850 °C is presented. The values of x (i.e., the Fe composition) for the solid solutions were 1.0, 1.1, 1.3, and 1.4. The temperature coefficients of eight phonon frequencies were determined for all the samples. The large observed phonon broadenings with increasing temperature precluded the observation of several of the phonon bands above defined temperatures in the range of 200-700 °C depending on the sample. These phonon broadenings were explained on the basis of the Klemens model, which considers that the broadenings are due to the thermal expansion of the lattice with a major contribution in terms of magnitude from anharmonic phonon-phonon interactions. However, some evidence for the presence of several of the phonons persisted up to 800-850 °C. These solid solutions are expected to exhibit a ferroelectric-paraelectric phase transition at 742 to 750 °C and a ferromagnetic-antiferromagnetic transition at 426 °C. We also observed changes in the slopes of the temperature dependence of the phonon frequencies for the lines at 228 cm-1 for Bi5FeTi3O15 and 330 cm-1 for Bi6Fe2Ti3O18 at temperatures of 247 °C and 347 °C, respectively. No similar temperature-frequency slope changes indicative of possible phase transitions were observed for any of the phonon lines of the other three Bi5Fe1+xTi3-xO15 solid solutions examined.

Design, synthesis, and molecular docking studies of N-(9,10-anthraquinone-2-carbonyl)amino acid derivatives as xanthine oxidase inhibitors.

PubMed

Zhang, Ting-Jian; Li, Song-Ye; Yuan, Wei-Yan; Zhang, Yi; Meng, Fan-Hao

2018-04-01

A series of N-(9,10-anthraquinone-2-carbonyl)amino acid derivatives (1a-j) was designed and synthesized as novel xanthine oxidase inhibitors. Among them, the L/D-phenylalanine derivatives (1d and 1i) and the L/D-tryptophan derivatives (1e and 1j) were effective with micromolar level potency. In particular, the L-phenylalanine derivative 1d (IC 50  = 3.0 μm) and the D-phenylalanine derivative 1i (IC 50  = 2.9 μm) presented the highest potency and were both more potent than the positive control allopurinol (IC 50  = 8.1 μm). Preliminary SAR analysis pointed that an aromatic amino acid fragment, for example, phenylalanine or tryptophan, was essential for the inhibition; the D-amino acid derivative presented equal or greater potency compared to its L-enantiomer; and the 9,10-anthraquinone moiety was welcome for the inhibition. Molecular simulations provided rational binding models for compounds 1d and 1i in the xanthine oxidase active pocket. As a result, compounds 1d and 1i could be promising lead compounds for further investigation. © 2017 John Wiley & Sons A/S.

LiAl xCo 1- xO 2 as 4 V cathodes for lithium ion batteries

NASA Astrophysics Data System (ADS)

Huang, Haitao; Rao, G. V. Subba; Chowdari, B. V. R.

Nominal LiAl xCo 1- xO 2 with x ranging from 0.1 to 0.3 was prepared by heating mixture of Al(OH) 3, Co 3O 4 and LiOH at 750°C in air. The effect of substitution of non-transition metal, Al, in LiCoO 2 is investigated as a 4 V cathode for lithium ion. X-ray diffraction (XRD) indicates formation of a single phase (R3¯m) within this range of substitution. When cycled between 4.5 and 2.5 V vs. Li/Li + at a current density of 1 mA cm -2, the LiAl 0.15Co 0.85O 2 cathode exhibits reversible capacity of 160 mA h g -1 initially. XRD of the cathode made at the end of 10 cycles reveals no significant change on host structure.

Guava leaves polyphenolics-rich extract inhibits vital enzymes implicated in gout and hypertension in vitro.

PubMed

Irondi, Emmanuel Anyachukwu; Agboola, Samson Olalekan; Oboh, Ganiyu; Boligon, Aline Augusti; Athayde, Margareth Linde; Shode, Francis O

2016-01-01

Elevated uric acid level, an index of gout resulting from the over-activity of xanthine oxidase (XO), increases the risk of developing hypertension. However, research has shown that plant-derived inhibitors of XO and angiotensin 1-converting enzyme (ACE), two enzymes implicated in gout and hypertension, respectively, can prevent or ameliorate both diseases, without noticeable side effects. Hence, this study characterized the polyphenolics composition of guava leaves extract and evaluated its inhibitory effect on XO and ACE in vitro. The polyphenolics (flavonoids and phenolic acids) were characterized using high-performance liquid chromatography (HPLC) coupled with diode array detection (DAD). The XO, ACE, and Fe(2+)-induced lipid peroxidation inhibitory activities, and free radicals (2,2-diphenylpicrylhydrazyl [DPPH]* and 2,2´-azino-bis-3-ethylbenzthiazoline-6-sulphonic [ABTS]*(+)) scavenging activities of the extract were determined using spectrophotometric methods. Flavonoids were present in the extract in the order of quercetin > kaempferol > catechin > quercitrin > rutin > luteolin > epicatechin; while phenolic acids were in the order of caffeic acid > chlorogenic acid > gallic acids. The extract effectively inhibited XO, ACE and Fe(2+)-induced lipid peroxidation in a dose-dependent manner; having half-maximal inhibitory concentrations (IC50) of 38.24 ± 2.32 μg/mL, 21.06 ± 2.04 μg/mL and 27.52 ± 1.72 μg/mL against XO, ACE and Fe(2+)-induced lipid peroxidation, respectively. The extract also strongly scavenged DPPH* and ABTS*(+). Guava leaves extract could serve as functional food for managing gout and hypertension and attenuating the oxidative stress associated with both diseases.

Nanocrystalline Ce 1- xY xO 2- x/2 (0≤ x≤0.35) Oxides via Carbonate Precipitation: Synthesis and Characterization

NASA Astrophysics Data System (ADS)

Li, Ji-Guang; Ikegami, Takayasu; Wang, Yarong; Mori, Toshiyuki

2002-10-01

A novel carbonate (co)precipitation method, employing nitrates as the starting salts and ammonium carbonate as the precipitant, has been used to synthesize nanocrystalline CeO 2 and Ce 1- xY xO 2- x/2 ( x≤0.35) solid-solutions. The resultant powders are characterized by elemental analysis, differential thermal analysis/thermogravimetry (DTA/TG), X-ray diffractometry (XRD), Brunauer-Emmett-Teller (BET) analysis, and high-resolution scanning electron microscopy (HRSEM). Due to the direct formation of carbonate solid-solutions during precipitation, Ce 1- xY xO 2- x/2 solid-solution oxides are formed directly during calcination at a very low temperature of ˜300°C for 2 h. The thus-produced oxide nanopowders are essentially non-agglomerated, as revealed by BET in conjunction with XRD analysis. The solubility of YO 1.5 in CeO 2 is determined via XRD to be somewhere in the range from 27 to 35 mol%, from which a Y 2O 3-related type-C phase appears in the final product. Y 3+-doping promotes the formation of spherical nanoparticles, retards thermal decomposition of the precursors, and suppresses significantly crystallite coarsening of the oxides during calcination. The activation energy for crystallite coarsening increases gradually from 68.7 kJ mol -1 for pure CeO 2 to 138.6 kJ mol -1 for CeO 2 doped with 35 mol% YO 1.5. The dopant effects on crystallite coarsening is elaborated from the view point of solid-state chemistry.

Structure symmetry determination and magnetic evolution in Sr 2Ir 1–xRh xO 4

DOE PAGES

Ye, Feng; Wang, Xiaoping; Hoffmann, Christina; ...

2015-11-23

We use single-crystal neutron diffraction to determine the crystal structure symmetry and to study the magnetic evolution in the rhodium doped iridates Sr 2Ir 1–xRh xO 4 (0 ≤ x ≤ 0.16). Throughout this doping range, the crystal structure retains a tetragonal symmetry (space group I4 1/a) with two distinct magnetic Ir sites in the unit cell forming staggered IrO 6 rotation. Upon Rh doping, the magnetic order is suppressed and the magnetic moment of Ir4+ is reduced from 0.21 μ B/Ir for x = 0 to 0.18 μ B/Ir for x = 0.12. As a result, the magnetic structuremore » at x = 0.12 is different from that of the parent compound while the moments remain in the basal plane.« less

Structural and electrochemical properties of La 0.8Sr 0.2Ga 1-xFe xO 3

NASA Astrophysics Data System (ADS)

Mori, Kazuhiro; Onodera, Yohei; Kiyanagi, Ryoji; Richardson, James W.; Itoh, Keiji; Sugiyama, Masaaki; Kamiyama, Takashi; Fukunaga, Toshiharu

2009-02-01

Mixed ionic-electronic conductor of Fe doped lanthanum gallate, La 0.8Sr 0.2Ga 1-xFe xO 3, has been studied by the dc four-probe method and the neutron powder diffraction. In the electrical conductivity measurement at RT, insulator-metal transition-like phenomenon was observed at around x˜0.35; this suggests an existence of the percolation limit for the electronic conductivity. Simultaneously, a bond length between O atoms, lO-O, in a MO 6 octahedron (M dbnd Ga 1-xFe x) drastically expands over x˜0.4, according to the result of crystal structure refinement based on the hexagonal phase. Such a drastic expansion in the lO-O would induce the decrease in the oxygen ionic conductivity.

(3+1)D superspace structural determination of two new modulated composite phases: Sr 1+ x(Cu xMn 1- x)O 3; x=3/11 and x=0.3244

NASA Astrophysics Data System (ADS)

El Abed, Ahmed; Gaudin, Etienne; zur Loye, Hans-Conrad; Darriet, Jacques

2003-01-01

We report the structure determination of two new phases belonging to the A 1+ x(A' xB 1- x)O 3 family of oxides with A=Sr, A'=Cu, and B=Mn, where x=3/11 and x=0.3244, corresponding to a commensurate and incommensurate composite structure, respectively. These two compounds are the first examples of oxides belonging to the Sr 1+ x(Cu xMn 1- x)O 3 family. Their structures were solved in the (3+1) dimensional superspace formalism as modulated composite structures with two subsystems [(Cu,Mn)O 3] and [Sr]. The superspace group used to solve the structures is R 3¯m(00γ)0s . The first phase ( x=3/11), corresponding to the chemical formula Sr 14Cu 3Mn 8O 33, was obtained as a single crystal with unit cell parameters of a=9.6025(3) Å and c1=2.5660(8) Å ( q=7/11 c1∗, Z=3), where c1 is the lattice parameter corresponding to the c-axis of the trigonal subsystem [(Cu,Mn)O 3]. The second phase ( x=0.3244(1)), is a polycrystalline sample with unit cell parameters of a=9.5933(7) and c1=2.5933(3) ( q=0.6622 c1∗, Z=3). In both structures, one dimensional chains run along the c-axis which contain octahedra and trigonal prisms occupied by manganese and copper atoms, respectively. The refinement results show that in both cases copper occupies the rectangular faces of the trigonal prism while manganese occupies the octahedral sites. The magnetic measurements of the polycrystalline phase (Sr 1+ x(Cu xMn 1- x)O 3, x=0.3244(2)) and the Curie constant obtained from the high temperature susceptibility are in agreement with a spin state configuration of S=3/2 for Mn 4+ and S=1/2 for Cu 2+.

High-pressure phase transitions of Fe 3-xTi xO 4 solid solution up to 60 GPa correlated with electronic spin transition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamanaka, Takamitsu; Kyono, Atsushi; Nakamoto, Yuki

2013-06-12

The structural phase transition of the titanomagnetite (Fe 3–xTi xO 4) solid solution under pressures up to 60 GPa has been clarified by single-crystal and powder diffraction studies using synchrotron radiation and a diamond-anvil cell. Present Rietveld structure refinements of the solid solution prove that the prefered cation distribution is based on the crystal field preference rather than the magnetic spin ordering in the solid solution. The Ti-rich phases in 0.734 ≤ x ≤1.0 undergo a phase transformation from the cubic spinel of Fd3m to the tetragonal spinel structure of I4 1/amd with c/a < 1.0. The transition is drivenmore » by a Jahn-Teller effect of IVFe 2+ (3d 6) on the tetrahedral site. The c/a < 1 ratio is induced by lifting of the degeneracy of the e orbitals by raising the d x2-y2 orbital below the energy of the d z2 orbital. The distortion characterized by c/a < 1 is more pronounced with increasing Ti content in the Fe 3–xTi xO 4 solid solutions and with increasing pressure. An X-ray emission experiment of Fe 2TiO 4 at high pressures confirms the spin transition of FeKβ from high spin to intermediate spin (IS) state. The high spin (HS)-to-low spin (LS) transition starts at 14 GPa and the IS state gradually increases with compression. The VIFe 2+ in the octahedral site is more prone for the HS-to-LS transition, compared with Fe 2+ in the fourfold- or eightfold-coordinated site. The transition to the orthorhombic post-spinel structure with space group Cmcm has been confirmed in the whole compositional range of Fe 3–xTi xO 4. The transition pressure decreases from 25 GPa (x = 0.0) to 15 GPa (x = 1.0) with increasing Ti content. There are two cation sites in the orthorhombic phase: M1 and M2 sites of eightfold and sixfold coordination, respectively. Fe 2+ and Ti 4+ are disordered on the M2 site. This structural change is accelerated at higher pressures due to the spin transition of Fe 2+ in the octahedral site. This is because the ionic radius

Guava leaves polyphenolics-rich extract inhibits vital enzymes implicated in gout and hypertension in vitro

PubMed Central

Irondi, Emmanuel Anyachukwu; Agboola, Samson Olalekan; Oboh, Ganiyu; Boligon, Aline Augusti; Athayde, Margareth Linde; Shode, Francis O.

2016-01-01

Background/Aim: Elevated uric acid level, an index of gout resulting from the over-activity of xanthine oxidase (XO), increases the risk of developing hypertension. However, research has shown that plant-derived inhibitors of XO and angiotensin 1-converting enzyme (ACE), two enzymes implicated in gout and hypertension, respectively, can prevent or ameliorate both diseases, without noticeable side effects. Hence, this study characterized the polyphenolics composition of guava leaves extract and evaluated its inhibitory effect on XO and ACE in vitro. Materials and Methods: The polyphenolics (flavonoids and phenolic acids) were characterized using high-performance liquid chromatography (HPLC) coupled with diode array detection (DAD). The XO, ACE, and Fe2+-induced lipid peroxidation inhibitory activities, and free radicals (2,2-diphenylpicrylhydrazyl [DPPH]* and 2,2´-azino-bis-3-ethylbenzthiazoline-6-sulphonic [ABTS]*+) scavenging activities of the extract were determined using spectrophotometric methods. Results: Flavonoids were present in the extract in the order of quercetin > kaempferol > catechin > quercitrin > rutin > luteolin > epicatechin; while phenolic acids were in the order of caffeic acid > chlorogenic acid > gallic acids. The extract effectively inhibited XO, ACE and Fe2+-induced lipid peroxidation in a dose-dependent manner; having half-maximal inhibitory concentrations (IC50) of 38.24 ± 2.32 μg/mL, 21.06 ± 2.04 μg/mL and 27.52 ± 1.72 μg/mL against XO, ACE and Fe2+-induced lipid peroxidation, respectively. The extract also strongly scavenged DPPH* and ABTS*+. Conclusion: Guava leaves extract could serve as functional food for managing gout and hypertension and attenuating the oxidative stress associated with both diseases. PMID:27104032

Structural and optical properties of magnetron sputtered MgxZn1-xO thin films

NASA Astrophysics Data System (ADS)

Kumar, Sanjeev; Gupte, Vinay; Sreenivas, K.

2006-04-01

MgxZn1-xO (MZO) thin films prepared by an rf magnetron sputtering technique are reported. The films were grown at room temperature and at relatively low rf power of 50 W. MZO thin films were found to possess preferred c-axis orientation and exhibited hexagonal wurtzite structure of ZnO up to a Mg concentration of 42 mol%. A small variation in the c-axis lattice parameter of around 0.3% was observed with increasing Mg composition, showing the complete solubility of Mg in ZnO. The band gap of the MZO films in the wurtzite phase varied linearly with the Mg concentration and a maximum band gap ~4.19 eV was achieved at x = 0.42. The refractive indices of the MgO films were found to decrease with increasing Mg content. The observed optical dispersion data are in agreement with the single oscillator model. A photoluminescence study revealed a blue shift in the near band edge emission peak with increasing Mg content in the MZO films. The results show the potential of MZO films in various opto-electronic applications.

X-ray diffraction and Raman investigations of thickness dependent stress effects on Pb(ZrxTi1-x)O3 thin films

NASA Astrophysics Data System (ADS)

Lappalainen, Jyrki; Lantto, Vilho; Frantti, Johannes; Hiltunen, Jussi

2006-06-01

Microstructure, film orientation, and optical transmission spectra of polycrystalline Nd-modified Pb(ZrxTi1-x)O3 films were studied as a function of film thickness. Pulsed laser deposition was used for the fabrication of films with thickness from 80to465nm on single-crystal MgO(100) substrates. Raman spectroscopy, x-ray diffraction, and spectrophotometry measurements were utilized in the film characterization. With the decreasing film thickness, films first oriented with c axis perpendicular to film surface, and then, after some critical thickness, changed to a-axis orientation. At the same time, compressive stress increased up to 1.3GPa and a clear blueshift of the optical absorption edge was found in transmission spectra.

Azathioprine with Allopurinol: Lower Deoxythioguanosine in DNA and Transcriptome Changes Indicate Mechanistic Differences to Azathioprine Alone.

PubMed

Coulthard, Sally A; Berry, Phil; McGarrity, Sarah; McLaughlin, Simon; Ansari, Azhar; Redfern, Christopher P F

2017-06-01

Use of azathioprine (AZA) for inflammatory bowel disease is limited by side effects or poor efficacy. Combining low-dose azathioprine with allopurinol (LDAA) bypasses side effects, improves efficacy, and may be appropriate as first-line therapy. We test the hypothesis that standard-dose azathioprine (AZA) and LDAA treatments work by similar mechanisms, using incorporation of the metabolite deoxythioguanosine into patient DNA, white-blood cell counts, and transcriptome analysis as biological markers of drug effect. DNA was extracted from peripheral whole-blood from patients with IBD treated with AZA or LDAA, and analyzed for DNA-incorporated deoxythioguanosine. Measurement of red-blood cell thiopurine metabolites was part of usual clinical practice, and pre- and on-treatment (12 wk) blood samples were used for transcriptome analysis. There were no differences in reduction of white-cell counts between the 2 treatment groups, but patients on LDAA had lower DNA-incorporated deoxythioguanosine than those on AZA; for both groups, incorporated deoxythioguanosine was lower in patients on thiopurines for 24 weeks or more (maintenance of remission) compared to patients treated for less than 24 weeks (achievement of remission). Patients on LDAA had higher levels of red-blood cell thioguanine nucleotides than those on AZA, but there was no correlation between these or their methylated metabolites, and incorporated deoxythioguanosine. Transcriptome analysis suggested down-regulation of immune responses consistent with effective immunosuppression in patients receiving LDAA, with evidence for different mechanisms of action between the 2 therapies. LDAA is biologically effective despite lower deoxythioguanosine incorporation into DNA, and has different mechanisms of action compared to standard-dose azathioprine.

Magnetic studies on Layered solid solution Lix(Ni0.4Mn0.6)2-xO2

NASA Astrophysics Data System (ADS)

Nakao, K.; Nakamura, T.; Yamada, Y.; Koshiba, N.

2011-05-01

Lix(Ni0.4Mn0.6)2-xO2 (1.09<=x<=1.23) were prepared by the solid-state reaction using LiOH and coprecipitated mixed hydroxide as raw materials. All the compounds have a layered rock-salt structure, and the cation mixing degree (Ni2+ occupancy in the Li-layer) decreases with an increase in x. From the low-temperature magnetic measurement, they all have negative Weiss temperature and spontaneous magnetization, that is, they are ferromagnetic materials. Both the Curie temperature and the spontaneous magnetization at 4.2K decrease with an increase in x. These magnetic variations are attributed to the lowering of the cation mixing degree: the magnetic interaction network turns to two-dimensional one with the loss of the inert-layer coupling. These situations may be considered semi-quantitatively using the ferromagnetic cluster model. Additionally, the cation mixing degree has an influence on their electrochemical properties such as cycle fading and rate capability.

Improvement of Sol-Gel Derived PbZrxTi1-xO3 Film Properties Using Thermal Press Treatment

NASA Astrophysics Data System (ADS)

Kaneda, Toshihiko; Kim, Joo-Nam; Tokumitsu, Eisuke; Shimoda, Tatsuya

2010-09-01

A thermal press treatment was introduced in the sol-gel process of PbZrxTi1-xO3 (PZT) thin films for the first time and the crystalline and electrical characteristics of the PZT films were investigated. The thermal press treatment was applied to the amorphous PZT gel film before crystallization annealing. It is found that the crystalline orientation and grain size of the PZT film fabricated with the thermal press treatment are different from those of the film fabricated by the conventional sol-gel process without the thermal press treatment, even though the crystallization conditions are exactly the same. It is demonstrated that the electrical properties, especially leakage current density and breakdown field, are significantly improved for the PZT film fabricated with the thermal press treatment. Furthermore, we also demonstrate that the fatigue property is improved by introducing the thermal press treatment.

Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress

NASA Technical Reports Server (NTRS)

McNally, J. Scott; Davis, Michael E.; Giddens, Don P.; Saha, Aniket; Hwang, Jinah; Dikalov, Sergey; Jo, Hanjoong; Harrison, David G.

2003-01-01

Oscillatory shear stress occurs at sites of the circulation that are vulnerable to atherosclerosis. Because oxidative stress contributes to atherosclerosis, we sought to determine whether oscillatory shear stress increases endothelial production of reactive oxygen species and to define the enzymes responsible for this phenomenon. Bovine aortic endothelial cells were exposed to static, laminar (15 dyn/cm2), and oscillatory shear stress (+/-15 dyn/cm2). Oscillatory shear increased superoxide (O2.-) production by more than threefold over static and laminar conditions as detected using electron spin resonance (ESR). This increase in O2*- was inhibited by oxypurinol and culture of endothelial cells with tungsten but not by inhibitors of other enzymatic sources. Oxypurinol also prevented H2O2 production in response to oscillatory shear stress as measured by dichlorofluorescin diacetate and Amplex Red fluorescence. Xanthine-dependent O2*- production was increased in homogenates of endothelial cells exposed to oscillatory shear stress. This was associated with decreased xanthine dehydrogenase (XDH) protein levels and enzymatic activity resulting in an elevated ratio of xanthine oxidase (XO) to XDH. We also studied endothelial cells lacking the p47phox subunit of the NAD(P)H oxidase. These cells exhibited dramatically depressed O2*- production and had minimal XO protein and activity. Transfection of these cells with p47phox restored XO protein levels. Finally, in bovine aortic endothelial cells, prolonged inhibition of the NAD(P)H oxidase with apocynin decreased XO protein levels and prevented endothelial cell stimulation of O2*- production in response to oscillatory shear stress. These data suggest that the NAD(P)H oxidase maintains endothelial cell XO levels and that XO is responsible for increased reactive oxygen species production in response to oscillatory shear stress.

Effect of Ni doping on structural and optical properties of Zn{sub 1−x}Ni{sub x}O nanopowder synthesized via low cost sono-chemical method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Singh, Budhendra, E-mail: bksingh@ua.pt; Kaushal, Ajay, E-mail: ajay.kaushal@ua.pt; Bdikin, Igor

2015-10-15

Highlights: • Pure and Ni doped ZnO nanopowders were synthesized by low cost sonochemical method. • The optical properties of Zn{sub 1−x}Ni{sub x}O nanopowders can be tuned by varying Ni content. • The results reveal the solubility limit of Ni into ZnO matrix as below 8%. - Abstract: Zn{sub 1−x}Ni{sub x}O nanopowders with different Ni contents of x = 0.0, 0.04 and 0.08 were synthesized via cost effective sonochemical reaction method. X-ray diffraction (XRD) pattern reveals pure wurtzite phase of prepared nanostructures with no additional impurity peaks. The morphology and dimensions of nanoparticles were investigated using scanning electron microscope (SEM).more » A sharp and strong peak for first order optical mode for wurtzite zinc oxide (ZnO) structure was observed at ∼438 cm{sup −1} in Raman spectra. The calculated optical band gap (E{sub g}) from UV–vis transmission data was found to decrease with increase in Ni content. The observed red shift in E{sub g} with increasing Ni content in ZnO nanopowders were in agreement with band gap behaviours found in their photoluminescence (PL) spectra. The synthesised ZnO nanopowders with controlled band gap on Ni doping reveals their potential for use in various electronic and optical device applications. The results were discussed in detail.« less

Effect of Manganese Addition on the Structure, Magnetic Properties and Microwave Absorption of La0.8Ba0.2MnxFe½(1-x)Ti½(1-x)O3

NASA Astrophysics Data System (ADS)

Adi, W. A.; Indro, M. N.; Kusumastuti, A. A.

2017-03-01

We have carried out modification of La0.8Ba0.2MnxFe½(1-x)Ti½(1-x)O3 (x = 0.1 - 0.8) magnetic materials by wet milling method. Raw materials of La2O3, BaCO3, Fe2O3, TiO2 and MnCO3 were mixed according to stoichiometry calculation for each composition. The mixture was milled for 5 hours and then sintered at 1000 °C for 5 hours. The refinement results by X-ray diffraction pattern shows that the increasing Mn composition enhances the mass fraction of La0.8Ba0.2MnxFe½(1-x)Ti½(1-x)O3 phase which has the same structure as LaMnO3. For x = 0.8 a single phase of LaMnO3 was formed. The single phase has a crystal monoclinic crystal structure with space group of I 1 2 / a 1, with lattice parameters given by a = 5.519(5) Å, b = 5.5537(5) Å and c = 7.8176(9) Å, α = γ = 90o and β = 90.345(6)o, V = 239.64(3) Å3, ρ = 6.463 gr.cm-3, wRp = 5.96, and χ2 (chi-squared) = 1.17. The hysteresis curve shows that the sample with composition x = 0.8 produces ferromagnetic behaviour at room temperature. The ferromagnetic properties arise due to the mixed valence of Mn3+ and Mn4+ ions through a double exchange mechanism. The results of the microwave absorption indicated that there was a broadening of absorption peak frequency at 9.9 GHz. The reflection loss (RL) increases with the increasing of LaMnO3 phase. For x = 0.8 we have the best of RL where the microwave absorption was calculated reaching 95% at the highest peak frequency with a thickness of 1.5 mm. Thus we have been successful in creating a single phase of La0.8Ba0.2MnxFe½(1-x)Ti½(1-x)O3 with application as a microwave absorber.

Low Temperature Synthesis, Chemical and Electrochemical Characterization of LiNi(x)Co(1-x)O2 (0 less than x less than 1)

NASA Technical Reports Server (NTRS)

Nanjundaswamy, K. S.; Standlee, D.; Kelly, C. O.; Whiteley, R. V., Jr.

1997-01-01

A new method of synthesis for the solid solution cathode materials LiNi(x)Co(1-x)O2 (0 less than x less than 1) involving enhanced reactions at temperatures less than or equal to 700 deg. C, between metal oxy-hydroxide precursors MOOH (M = Ni, Co) and Li-salts (Li2CO3, LiOH, and LiNO3) has been investigated. The effects of synthesis conditions and sources of Li, on phase purity, microstructure, and theoretical electrochemical capacity (total M(3+) content) are characterized by powder X-ray diffraction analysis, scanning electron microscopy, chemical analysis and room temperature magnetic susceptibility. An attempt has been made to correlate the electrochemical properties with the synthesis conditions and microstructure.

Influence of Y doping concentration on the properties of nanostructured MxZn1-xO (M=Y) thin film deposited by nebulizer spray pyrolysis technique

NASA Astrophysics Data System (ADS)

Mariappan, R.; Ponnuswamy, V.; Chandra Bose, A.; Suresh, R.; Ragavendar, M.

2014-09-01

Yttrium doped Zinc Oxide (YxZn1-xO) thin films deposited at a substrate temperature 400 °C. The effect of substrate temperature on the structural, surface morphology, compositional, optical and electrical properties of YxZn1-xO thin films was studied. X-ray diffraction studies show that all films are polycrystalline in nature with hexagonal crystal structure having highly textured (002) plane parallel to the surface of the substrate. The structural parameters, such as lattice constants (a and c), crystallite size (D), dislocation density (δ), microstrain (σ) and texture coefficient were calculated for different yttrium doping concentrations (x). High resolution scanning electron microscopy measurements reveal that the surface morphology of the films change from platelet like grains to hexagonal structure with grain size increase due to the yttrium doping. Energy dispersive spectroscopy confirms the presence of Y, Zn and O elements in the films prepared. Optical studies showed that all samples have a strong optical transmittance higher than 70% in the visible range. A slight shift of the absorption edge towards the large wavelengths was observed as the Y doping concentration increased. This result shows that the band gap is slightly decreased from 3.10 to 2.05 eV with increase of the yttrium doping concentrations (up to 7.5%) and then slightly increased. Room temperature PL measurements were done and the band-to-band emission energies of films were determined and reported. The complex impedance of the 10%Y doped ZnO film shows two distinguished semicircles and the diameter of the arcs got decreased in diameter as the temperature increases from 70 to 175 °C.

Direct measurement of electrocaloric effect in lead-free Ba(SnxTi1-x)O3 ceramics

NASA Astrophysics Data System (ADS)

Sanlialp, Mehmet; Luo, Zhengdong; Shvartsman, Vladimir V.; Wei, Xianzhu; Liu, Yang; Dkhil, Brahim; Lupascu, Doru C.

2017-10-01

In this study, we report on investigation of the electrocaloric (EC) effect in lead-free Ba(SnxTi1-x)O3 (BSnT) ceramics with compositions in the range of 0.08 ≤ x ≤ 0.15 by the direct measurement method using a differential scanning calorimeter. The maximum EC temperature change, ΔTEC-max = 0.63 K under an electric field of 2 kV/mm, was observed for the composition with x = 0.11 at ˜44 °C around the multiphase coexistence region. We observed that the EC effect also peaks at transitions between ferroelectric phases of different symmetries. Comparison with the results of indirect EC measurements from our previous work shows that the indirect approach provides reasonable estimations of the magnitude of the largest EC temperature changes and EC strength. However, it fails to describe correctly temperature dependences of the EC effect for the compositions showing relaxor-like behaviour (x = 0.14 and 0.15) because of their non-ergodic nature. Our study provides strong evidence supporting that looking for multiphase ferroelectric materials can be very useful to optimize EC performance.

Bismuth chalcogenide compounds Bi 2 × 3 (X=O, S, Se): Applications in electrochemical energy storage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ni, Jiangfeng; Bi, Xuanxuan; Jiang, Yu

2017-04-01

Bismuth chalcogenides Bi2×3 (X=O, S, Se) represent a unique type of materials in diverse polymorphs and configurations. Multiple intrinsic features of Bi2×3 such as narrow bandgap, ion conductivity, and environmental friendliness, have render them attractive materials for a wide array of energy applications. In particular, their rich structural voids and the alloying capability of Bi enable the chalcogenides to be alternative electrodes for energy storage such as hydrogen (H), lithium (Li), sodium (Na) storage and supercapacitors. However, the low conductivity and poor electrochemical cycling are two key challenges for the practical utilization of Bi2×3 electrodes. Great efforts have been devotedmore » to mitigate these challenges and remarkable progresses have been achieved, mainly taking profit of nanotechnology and material compositing engineering. In this short review, we summarize state-of-the-art research advances in the rational design of diverse Bi2×3 electrodes and their electrochemical energy storage performance for H, Li, and Na and supercapacitors. We also highlight the key technical issues at present and provide insights for the future development of bismuth based materials in electrochemical energy storage devices.« less

A Dual Role for the Bacillus anthracis Master Virulence Regulator AtxA: Control of Sporulation and Anthrax Toxin Production.

PubMed

Dale, Jennifer L; Raynor, Malik J; Ty, Maureen C; Hadjifrangiskou, Maria; Koehler, Theresa M

2018-01-01

Bacillus anthracis is an endemic soil bacterium that exhibits two different lifestyles. In the soil environment, B. anthracis undergoes a cycle of saprophytic growth, sporulation, and germination. In mammalian hosts, the pathogenic lifestyle of B. anthracis is spore germination followed by vegetative cell replication, but cells do not sporulate. During infection, and in specific culture conditions, transcription of the structural genes for the anthrax toxin proteins and the biosynthetic operon for capsule synthesis is positively controlled by the regulatory protein AtxA. A critical role for the atxA gene in B. anthracis virulence has been established. Here we report an inverse relationship between toxin production and sporulation that is linked to AtxA levels. During culture in conditions favoring sporulation, B. anthracis produces little to no AtxA. When B. anthracis is cultured in conditions favoring toxin gene expression, AtxA is expressed at relatively high levels and sporulation rate and efficiency are reduced. We found that a mutation within the atxA promoter region resulting in AtxA over-expression leads to a marked sporulation defect. The sporulation phenotype of the mutant is dependent upon pXO2-0075 , an atxA -regulated open reading frame located on virulence plasmid pXO2. The predicted amino acid sequence of the pXO2-0075 protein has similarity to the sensor domain of sporulation sensor histidine kinases. It was shown previously that pXO2-0075 overexpression suppresses sporulation. We have designated pXO2-0075 " skiA " for "sporulation kinase inhibitor." Our results indicate that in addition to serving as a positive regulator of virulence gene expression, AtxA modulates B. anthracis development.

Transition métal—isolant dans V 1-xMn xO 2-2xF 2x (0 < x ≤ 0, 10)étude des propriétés structurales, magnétiques, etélectriques

NASA Astrophysics Data System (ADS)

Akroune, A.; Casalot, A.

1987-05-01

V 1- xMn xO 2-2 xF 2 x samples (0 < x ≤ 0, 10) have been prepared by solid state reaction in sealed platinium tubes. The metal ⇄ insulator transition occurs at a quickly decreasing temperatures as MnF 2 increases. The crystallographic, magnetic, transport properties, and DTA have been determined and discussed.

Differential involvement of various sources of reactive oxygen species in thyroxin-induced hemodynamic changes and contractile dysfunction of the heart and diaphragm muscles

PubMed Central

Elnakish, Mohammad T.; Schultz, Eric J.; Gearinger, Rachel L.; Saad, Nancy S.; Rastogi, Neha; Ahmed, Amany A.E.; Mohler, Peter J.; Janssen, Paul M.L.

2015-01-01

Thyroid hormones are key regulators of basal metabolic state and oxidative metabolism. Hyperthyroidism has been reported to cause significant alterations in hemodynamics, and in cardiac and diaphragm muscle function, all of which have been linked to increased oxidative stress. However, the definite source of increased reactive oxygen species (ROS) in each of these phenotypes is still unknown. The goal of the current study was to test the hypothesis that thyroxin (T4) may produce distinct hemodynamic, cardiac, and diaphragm muscle abnormalities by differentially affecting various sources of ROS. Wild-type and T4 mice with and without 2-week treatments with allopurinol (xanthine oxidase inhibitor), apocynin (NADPH oxidase inhibitor), L-NIO (nitric oxide synthase inhibitor), or MitoTEMPO (mitochondria-targeted antioxidant) were studied. Blood pressure and echocardiography were noninvasively evaluated, followed by ex vivo assessments of isolated heart and diaphragm muscle functions. Treatment with L-NIO attenuated the T4-induced hypertension in mice. However, apocynin improved the left-ventricular (LV) dysfunction without preventing the cardiac hypertrophy in these mice. Both allopurinol and MitoTEMPO reduced the T4-induced fatigability of the diaphragm muscles. In conclusion, we show here for the first time that T4 exerts differential effects on various sources of ROS to induce distinct cardiovascular and skeletal muscle phenotypes. Additionally, we find that T4-induced LV dysfunction is independent of cardiac hypertrophy and NADPH oxidase is a key player in this process. Furthermore, we prove the significance of both xanthine oxidase and mitochondrial ROS pathways in T4-induced fatigability of diaphragm muscles. Finally, we confirm the importance of the nitric oxide pathway in T4-induced hypertension. PMID:25795514

Studies on redox H 2-CO 2 cycle on CoCr xFe 2- xO 4

NASA Astrophysics Data System (ADS)

Ma, Ling Juan; Chen, Lin Shen; Chen, Song Ying

2009-01-01

Completely reduced CoCr xFe 2-xO 4 can be used to decompose CO 2. It was found that for pure CoFe 2O 4 there is no FeO formation in the first step while there is formation in the second step. For CoCr 0.08Fe 2-0.08O 4, there is no FeO formed in all the oxidation process, because of effect of Cr 3+. Pure CoFe 2O 4 was destroyed at the first reaction cycle of H 2 reduction and CO 2 oxidation, while doped Cr 3+ spinel CoCr 0.08Fe 1.92O 4 showed good stability. The results from H 2-TG, CO 2-TG and XRD show that the addition of Cr 3+ to CoFe 2O 4 can inhibit the increasing of crystallite size and the sintering of alloy. Most importantly, the CoCr 0.08Fe 1.92O 4 can be used to decompose CO 2 repeatedly, implying that it is a potential catalyst for dealing with the CO 2 as a 'green house effect' gas.

Structural and optical characterization of ZnO/Mg(x)Zn(1-x)O multiple quantum wells based random laser diodes.

PubMed

Jiang, Qike; Zheng, He; Wang, Jianbo; Long, Hao; Fang, Guojia

2012-12-01

Two kinds of laser diodes (LDs) comprised of ZnO/Mg(x)Zn(1-x)O (ZnO/MZO) multiple quantum wells (MQWs) grown on GaN (MQWs/GaN) and Si (MQWs/Si) substrates, respectively, have been constructed. The LD with MQWs/GaN exhibits ultraviolet random lasing under electrical excitation, while that with MQWs/Si does not. In the MQWs/Si, ZnO/MZO MQWs consist of nanoscaled crystallites, and the MZO layers undergo a phase separation of cubic MgO and hexagonal ZnO. Moreover, the Mg atom predominantly locates in the MZO layers along with a significant aggregation at the ZnO/MZO interfaces; in sharp contrast, the ZnO/MZO MQWs in the MQWs/GaN show a well-crystallized structure with epitaxial relationships among GaN, MZO, and ZnO. Notably, Mg is observed to diffuse into the ZnO well layers. The structure-optical property relationship of these two LDs is further discussed.

Continuum Excitation and Pseudospin Wave in Quantum Spin-Liquid and Quadrupole Ordered States of Tb2+xTi2-xO7+y

NASA Astrophysics Data System (ADS)

Kadowaki, Hiroaki; Wakita, Mika; Fåk, Björn; Ollivier, Jacques; Ohira-Kawamura, Seiko; Nakajima, Kenji; Takatsu, Hiroshi; Tamai, Mototake

2018-06-01

The ground states of the frustrated pyrochlore oxide Tb2+xTi2-xO7+y have been studied by inelastic neutron scattering experiments. Three single-crystal samples are investigated; one shows no phase transition (x = -0.007 < xc ˜ -0.0025), being a putative quantum spin-liquid (QSL), and the other two (x = 0.000,0.003) show electric quadrupole ordering (QO) below Tc ˜ 0.5 K. The QSL sample shows continuum excitation spectra with an energy scale 0.1 meV as well as energy-resolution-limited (nominally) elastic scattering. As x is increased, pseudospin wave of the QO state emerges from this continuum excitation, which agrees with that of powder samples and consequently verifies good x control for the present single crystal samples.

A Dual Role for the Bacillus anthracis Master Virulence Regulator AtxA: Control of Sporulation and Anthrax Toxin Production

PubMed Central

Dale, Jennifer L.; Raynor, Malik J.; Ty, Maureen C.; Hadjifrangiskou, Maria; Koehler, Theresa M.

2018-01-01

Bacillus anthracis is an endemic soil bacterium that exhibits two different lifestyles. In the soil environment, B. anthracis undergoes a cycle of saprophytic growth, sporulation, and germination. In mammalian hosts, the pathogenic lifestyle of B. anthracis is spore germination followed by vegetative cell replication, but cells do not sporulate. During infection, and in specific culture conditions, transcription of the structural genes for the anthrax toxin proteins and the biosynthetic operon for capsule synthesis is positively controlled by the regulatory protein AtxA. A critical role for the atxA gene in B. anthracis virulence has been established. Here we report an inverse relationship between toxin production and sporulation that is linked to AtxA levels. During culture in conditions favoring sporulation, B. anthracis produces little to no AtxA. When B. anthracis is cultured in conditions favoring toxin gene expression, AtxA is expressed at relatively high levels and sporulation rate and efficiency are reduced. We found that a mutation within the atxA promoter region resulting in AtxA over-expression leads to a marked sporulation defect. The sporulation phenotype of the mutant is dependent upon pXO2-0075, an atxA-regulated open reading frame located on virulence plasmid pXO2. The predicted amino acid sequence of the pXO2-0075 protein has similarity to the sensor domain of sporulation sensor histidine kinases. It was shown previously that pXO2-0075 overexpression suppresses sporulation. We have designated pXO2-0075 “skiA” for “sporulation kinase inhibitor.” Our results indicate that in addition to serving as a positive regulator of virulence gene expression, AtxA modulates B. anthracis development. PMID:29599764

Cardiovascular effects of urate-lowering therapies in patients with chronic gout: a systematic review and meta-analysis.

PubMed

Zhang, Tony; Pope, Janet E

2017-07-01

To determine if urate-lowering treatment (ULT) in gout can reduce cardiovascular (CV) outcomes. Randomized trials were searched for treatment with ULT in gout. Eligible trials had to report CV safety of a ULT. Potential medications included allopurinol, febuxostat, pegloticase, rasburicase, probenecid, benzbromarone, sulphinpyrazone, losartan, fenofibrate and sodium-glucose linked transporter 2 inhibitors. A total of 3084 citations were found, with 642 duplicates. After the primary screen, 35 studies were selected for review. Several trials did not report CV events. Six were not randomized controlled trials (RCTs). Four studies reported no events in either intervention arm while the other four had 40 events in the febuxostat group ( n = 3631) and 5 in allopurinol group ( n = 1154). Overall, the pooled analysis did not show a significant difference between the two [febuxostat vs allopurinol: relative risk (RR) 1.69 (95% CI 0.54, 5.34), P = 0.37]. CV events did not decrease over time. Comparing shorter studies (<52 weeks) to longer ones did not reveal any statistical differences. However, in long-term studies with febuxostat vs allopurinol, results were nearly significant, with more CVE occurring with febuxostat treatment. Comparing any ULT to placebo (eight studies, n = 2221 patients) did not demonstrate a significant difference in non-Anti-Platelet Trialists' Collaboration events [any ULT vs placebo: RR 1.47 (95% CI 0.49, 4.40), P = 0.49] or all-cause mortality [any ULT vs placebo: RR 1.45 (95% CI 0.35, 5.77), P = 0.60]. RCT data do not suggest differences in CV events among ULTs in gout. Trials had few events despite high-risk patients being enrolled and may have been too short to show CV reduction by controlling inflammatory attacks and lowering uric acid. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Average and local atomic-scale structure in BaZrxTi(1-x)O3 (x = 0. 10, 0.20, 0.40) ceramics by high-energy x-ray diffraction and Raman spectroscopy.

PubMed

Buscaglia, Vincenzo; Tripathi, Saurabh; Petkov, Valeri; Dapiaggi, Monica; Deluca, Marco; Gajović, Andreja; Ren, Yang

2014-02-12

High-resolution x-ray diffraction (XRD), Raman spectroscopy and total scattering XRD coupled to atomic pair distribution function (PDF) analysis studies of the atomic-scale structure of archetypal BaZrxTi(1-x)O3 (x = 0.10, 0.20, 0.40) ceramics are presented over a wide temperature range (100-450 K). For x = 0.1 and 0.2 the results reveal, well above the Curie temperature, the presence of Ti-rich polar clusters which are precursors of a long-range ferroelectric order observed below TC. Polar nanoregions (PNRs) and relaxor behaviour are observed over the whole temperature range for x = 0.4. Irrespective of ceramic composition, the polar clusters are due to locally correlated off-centre displacement of Zr/Ti cations compatible with local rhombohedral symmetry. Formation of Zr-rich clusters is indicated by Raman spectroscopy for all compositions. Considering the isovalent substitution of Ti with Zr in BaZrxTi1-xO3, the mechanism of formation and growth of the PNRs is not due to charge ordering and random fields, but rather to a reduction of the local strain promoted by the large difference in ion size between Zr(4+) and Ti(4+). As a result, non-polar or weakly polar Zr-rich clusters and polar Ti-rich clusters are randomly distributed in a paraelectric lattice and the long-range ferroelectric order is disrupted with increasing Zr concentration.

Xanthine-oxidase inhibitors and statins in chronic heart failure: effects on vascular and functional parameters.

PubMed

Greig, Douglas; Alcaino, Hernan; Castro, Pablo F; Garcia, Lorena; Verdejo, Hugo E; Navarro, Mario; López, Rafael; Mellado, Rosemarie; Tapia, Fabiola; Gabrielli, Luigi A; Nogerol, Camilo; Chiong, Mario; Godoy, Ivan; Lavandero, Sergio

2011-04-01

Increased oxidative stress in heart failure (HF) leads to inflammation and endothelial dysfunction (ED). Both statins and allopurinol have known anti-oxidant properties, but their utility in HF has not been fully assessed. This investigation was a prospective, double-blind, double-dummy study, performed between March 2007 and June 2009. Seventy-four HF patients, with New York Heart Association (NYHA) Class II or III status and left ventricular ejection fraction (LVEF) <40%, were included. Patients received placebo during 4 weeks and were then randomized to receive 4 weeks of either atorvastatin 20 mg/day plus placebo (ATV+PLA group) or atorvastatin 20 mg/day orally plus allopurinol 300 mg/day orally (ATV+ALLO group). Malondialdehyde (MDA), extracellular superoxide dismutase (ecSOD) activity and uric acid (UA) levels, among others, were determined at baseline and after 4 weeks of treatment. ED was assessed by flow-dependent endothelial-mediated vasodilation (FDD), and functional capacity by 6-minute walk test (6MWT). Thirty-two patients were randomized to ATV+PLA and 38 to ATV+ALLO. Mean age was 59 ± 2 years, 82% were male, and 22% had an ischemic etiology. Hypertension was present in 60% and diabetes in 15% of those studied. No significant differences were observed between baseline measurements and after placebo. After 4 weeks of treatment, both groups showed a significant decrease on MDA (0.9 ± 0.1 to 0.8 ± 0.1 and 1.0 ± 0.5 to 0.9 ± 0.1 μmol/liter, p = 0.88), UA (7.4 ± 0.4 to 6.8 ± 0.3 and 7.2 ± 0.4 to 5.0 ± 0.3 mg/dl, p < 0.01) and FDD (3.9 ± 0.2% to 5.6 ± 0.4% and 4.6 ± 0.3% to 7.1 ± 0.5%, p = 0.07) with increased ecSOD activity (109 ± 11 to 173 ± 13 and 98 ± 10 to 202 ± 16, U/ml/min, p = 0.41) and improved 6MWT (447 ± 18 to 487 ± 19 and 438 ± 17 to 481 ± 21 m, p = 0.83), with all values for ATV+PLA and ATV+ALLO, respectively; p-values are for comparison between groups after treatment. Short-term ATV treatment in heart failure (HF

Investigations of optical and thermoelectric response of direct band gap Ca3XO (X = Si, Ge) anti-perovskites stabilized in cubic and orthorhombic phases

NASA Astrophysics Data System (ADS)

Mahmood, Q.; Ashraf, A.; Hassan, M.

2018-02-01

We predict the phase dependent electronic properties for elaborating the optical and thermoelectric behaviors of both cubic (Pm-3m) and orthorhombic (Pbnm) Ca3XO (X = Si, Ge) antiperovskites using first-principles density functional theory (DFT) computations. The mBJ functional is employed for computing the most accurate electronic characteristics. A direct band gap semiconducting nature has been found appearing due to hybridization between O and Si/Ge p-states. The calculated band gaps lying in the infrared energy region suggest that the studied anti-perovskites can absorb visible and ultraviolet energy revealing potential optoelectronics device applications. Moreover, the important thermoelectric parameters are computed for illustrating the potential thermoelectric applications. Hence, the studied anti-perovskites can simultaneously exhibit various flexible material properties, which reveal their worth for the devices demonstrating versatile characteristics.

Discovering Anti-platelet Drug Combinations with an Integrated Model of Activator-Inhibitor Relationships, Activator-Activator Synergies and Inhibitor-Inhibitor Synergies

PubMed Central

Lombardi, Federica; Golla, Kalyan; Fitzpatrick, Darren J.; Casey, Fergal P.; Moran, Niamh; Shields, Denis C.

2015-01-01

Identifying effective therapeutic drug combinations that modulate complex signaling pathways in platelets is central to the advancement of effective anti-thrombotic therapies. However, there is no systems model of the platelet that predicts responses to different inhibitor combinations. We developed an approach which goes beyond current inhibitor-inhibitor combination screening to efficiently consider other signaling aspects that may give insights into the behaviour of the platelet as a system. We investigated combinations of platelet inhibitors and activators. We evaluated three distinct strands of information, namely: activator-inhibitor combination screens (testing a panel of inhibitors against a panel of activators); inhibitor-inhibitor synergy screens; and activator-activator synergy screens. We demonstrated how these analyses may be efficiently performed, both experimentally and computationally, to identify particular combinations of most interest. Robust tests of activator-activator synergy and of inhibitor-inhibitor synergy required combinations to show significant excesses over the double doses of each component. Modeling identified multiple effects of an inhibitor of the P2Y12 ADP receptor, and complementarity between inhibitor-inhibitor synergy effects and activator-inhibitor combination effects. This approach accelerates the mapping of combination effects of compounds to develop combinations that may be therapeutically beneficial. We integrated the three information sources into a unified model that predicted the benefits of a triple drug combination targeting ADP, thromboxane and thrombin signaling. PMID:25875950

The thermal conductivity of mixed fuel U xPu 1-xO 2: molecular dynamics simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Xiang-Yang; Cooper, Michael William Donald; Stanek, Christopher Richard

2015-10-16

Mixed oxides (MOX), in the context of nuclear fuels, are a mixture of the oxides of heavy actinide elements such as uranium, plutonium and thorium. The interest in the UO 2-PuO 2 system arises from the fact that these oxides are used both in fast breeder reactors (FBRs) as well as in pressurized water reactors (PWRs). The thermal conductivity of UO 2 fuel is an important material property that affects fuel performance since it is the key parameter determining the temperature distribution in the fuel, thus governing, e.g., dimensional changes due to thermal expansion, fission gas release rates, etc. Formore » this reason it is important to understand the thermal conductivity of MOX fuel and how it differs from UO 2. Here, molecular dynamics (MD) simulations are carried out to determine quantitatively, the effect of mixing on the thermal conductivity of U xPu 1-xO 2, as a function of PuO 2 concentrations, for a range of temperatures, 300 – 1500 K. The results will be used to develop enhanced continuum thermal conductivity models for MARMOT and BISON by INL. These models express the thermal conductivity as a function of microstructure state-variables, thus enabling thermal conductivity models with closer connection to the physical state of the fuel.« less

Gram scale synthesis of Fe/Fe xO y core–shell nanoparticles and their incorporation into matrix-free superparamagnetic nanocomposites

DOE PAGES

Watt, John Daniel; Bleier, Grant C.; Romero, Zachary William; ...

2018-05-15

In this paper, significant reductions recently seen in the size of wide-bandgap power electronics have not been accompanied by a relative decrease in the size of the corresponding magnetic components. To achieve this, a new generation of materials with high magnetic saturation and permeability are needed. Here, we develop gram-scale syntheses of superparamagnetic Fe/Fe xO y core–shell nanoparticles and incorporate them as the magnetic component in a strongly magnetic nanocomposite. Nanocomposites are typically formed by the organization of nanoparticles within a polymeric matrix. However, this approach can lead to high organic fractions and phase separation; reducing the performance of themore » resulting material. Here, we form aminated nanoparticles that are then cross-linked using epoxy chemistry. The result is a magnetic nanoparticle component that is covalently linked and well separated. By using this ‘matrix-free’ approach, we can substantially increase the magnetic nanoparticle fraction, while still maintaining good separation, leading to a superparamagnetic nanocomposite with strong magnetic properties.« less

Gram scale synthesis of Fe/Fe xO y core–shell nanoparticles and their incorporation into matrix-free superparamagnetic nanocomposites

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watt, John Daniel; Bleier, Grant C.; Romero, Zachary William

In this paper, significant reductions recently seen in the size of wide-bandgap power electronics have not been accompanied by a relative decrease in the size of the corresponding magnetic components. To achieve this, a new generation of materials with high magnetic saturation and permeability are needed. Here, we develop gram-scale syntheses of superparamagnetic Fe/Fe xO y core–shell nanoparticles and incorporate them as the magnetic component in a strongly magnetic nanocomposite. Nanocomposites are typically formed by the organization of nanoparticles within a polymeric matrix. However, this approach can lead to high organic fractions and phase separation; reducing the performance of themore » resulting material. Here, we form aminated nanoparticles that are then cross-linked using epoxy chemistry. The result is a magnetic nanoparticle component that is covalently linked and well separated. By using this ‘matrix-free’ approach, we can substantially increase the magnetic nanoparticle fraction, while still maintaining good separation, leading to a superparamagnetic nanocomposite with strong magnetic properties.« less

Honey as an apitherapic product: its inhibitory effect on urease and xanthine oxidase.

PubMed

Sahin, Huseyin

2016-01-01

The aim of this study was to evaluate new natural inhibitor sources for the enzymes urease and xanthine oxidase (XO). Chestnut, oak and polyfloral honey extracts were used to determine inhibition effects of both enzymes. In addition to investigate inhibition, the antioxidant capacities of these honeys were determined using total phenolic content (TPC), ferric reducing antioxidant power (FRAP), and DPPH radical scavenging activity assays. Due to their high phenolic content, chestnut and oak honeys are found to be a powerful source for inhibition of both enzymes. Especially, oak honeys were efficient for urease inhibition with 0.012-0.021 g/mL IC50 values, and also chestnut honeys were powerful for XO inhibition with 0.028-0.039 g/mL IC50 values. Regular daily consumption of these honeys can prevent gastric ulcers deriving from Helicobacter pylori and pathological disorders mediated by reactive oxygen species.

Coprecipitation of nickel zinc malonate: A facile and reproducible synthesis route for Ni{sub 1−x}Zn{sub x}O nanoparticles and Ni{sub 1−x}Zn{sub x}O/ZnO nanocomposites via pyrolysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lontio Fomekong, Roussin, E-mail: lonforou@yahoo.fr; Institut de la Matière Condensée et des Nanosciences, Université Catholique de Louvain, Croix du Sud 1, 1348 Louvain-La-Neuve; Kenfack Tsobnang, Patrice

2015-10-15

Nanoparticles of Ni{sub 1−x}Zn{sub x}O and Ni{sub 1−x}Zn{sub x}O/ZnO, which can be good candidates for selective gas sensors, were successfully obtained via a two-step synthetic route, in which the nickel zinc malonate precursor was first synthesized by co-precipitation from an aqueous solution, followed by pyrolysis in air at a relatively low temperature (~500 °C). The precursor was characterized by ICP-AES, FTIR and TG and the results indicate the molecular structure of the precursor to be compatible with Ni{sub 1−x}Zn{sub x}(OOCCH{sub 2}COO)·2H{sub 2}O. The decomposition product, characterized using various techniques (FTIR, XRD, ToF-SIMS, SEM, TEM and XPS), was established to bemore » a doped nickel oxide (Ni{sub 1−x}Zn{sub x}O for 0.01≤x≤0.1) and a composite material (Ni{sub 1−x}Zn{sub x}O/ZnO for 0.2≤x≤0.5). To elucidate the form in which the Zn is present in the NiO structure, three analytical techniques were employed: ToF-SIMS, XRD and XPS. While ToF SIMS provided a direct evidence of the presence of Zn in the NiO crystal structure, XRD showed that Zn actually substitutes Ni in the structure and XPS is a bit more specific by indicating that the Zn is present in the form of Zn{sup 2+} ions. - Highlights: • Coprecipitation synthesis of nickel zinc malonate single bath precursor was achieved. • The as synthesized precursors are an homogeneous mixture of nickel and zinc malonate. • XRD, ToF-SIMS, XPS, SEM and TEM was used to characterized decomposition products. • Ni{sub 1−x}Zn{sub x}O nanoparticles (0.01≤x≤0.1) formed after pyrolysis (~500 °C) of precursor. • Ni{sub 1−x}Zn{sub x}O/ZnO nanocomposite (0.2≤x≤0.5) formed after pyrolysis at 500 °C of precursor.« less

A causal role for uric acid in fructose-induced metabolic syndrome.

PubMed

Nakagawa, Takahiko; Hu, Hanbo; Zharikov, Sergey; Tuttle, Katherine R; Short, Robert A; Glushakova, Olena; Ouyang, Xiaosen; Feig, Daniel I; Block, Edward R; Herrera-Acosta, Jaime; Patel, Jawaharlal M; Johnson, Richard J

2006-03-01

The worldwide epidemic of metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake (in the form of table sugar and high-fructose corn syrup). Fructose raises uric acid, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in metabolic syndrome. Four sets of experiments were performed. First, pair-feeding studies showed that fructose, and not dextrose, induced features (hyperinsulinemia, hypertriglyceridemia, and hyperuricemia) of metabolic syndrome. Second, in rats receiving a high-fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) was able to prevent or reverse features of metabolic syndrome. In particular, the administration of allopurinol prophylactically prevented fructose-induced hyperinsulinemia (272.3 vs.160.8 pmol/l, P < 0.05), systolic hypertension (142 vs. 133 mmHg, P < 0.05), hypertriglyceridemia (233.7 vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05) at 8 wk. Neither allopurinol nor benzbromarone affected dietary intake of control diet in rats. Finally, uric acid dose dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. These data provide the first evidence that uric acid may be a cause of metabolic syndrome, possibly due to its ability to inhibit endothelial function. Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid.

Aggravation by paroxetine, a selective serotonin reuptake inhibitor, of antral lesions generated by nonsteroidal anti-inflammatory drugs in rats.

PubMed

Takeuchi, Koji; Tanaka, Akiko; Nukui, Kazuo; Kojo, Azusa; Gyenge, Melinda; Amagase, Kikuko

2011-09-01

Recent clinical studies have suggested a risk of adverse gastric reactions from the concomitant use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) with nonsteroidal anti-inflammatory drugs (NSAIDs). We examined the adverse effects of SSRIs on antral lesions produced by indomethacin in rats. Rats fasted for 24 h were refed for 1 h, then administered indomethacin (30 mg/kg s.c.) 1 h after the refeeding and killed 6 h later. Paroxetine (1-10 mg/kg) was given orally 30 min before indomethacin. Indomethacin caused antral lesions in refed rats. Paroxetine dose-dependently aggravated these lesions, despite provoking no damage by itself. Similar results were obtained when other NSAIDs such as diclofenac, flurbiprofen, and loxoprofen were coadministered with paroxetine or when indomethacin was coadministered with other antidepressants such as fluvoxamine and milnacipran, but not imipramine or maprotiline. Exogenous 5-HT also worsened the indomethacin-induced antral damage, whereas the aggravating effect of paroxetine was attenuated by ondansetron, a selective 5-HT(3) antagonist, but not antagonists for other 5-HT receptor subtypes. Indomethacin plus paroxetine had no effect on gastric secretion but significantly decreased mucosal superoxide dismutase (SOD) activity as well as GSH content. The antral damage induced by indomethacin plus paroxetine was significantly prevented by antisecretory (acid or pepsin) agents and mucosal protective agents as well as SOD and allopurinol. These results suggest that SSRIs aggravate NSAID-induced antral lesions, probably via the activation of 5HT(3) receptors, and the mechanism of aggravation may involve the corrosive action of acid/pepsin as well as an impaired antioxidative system.

Thyroid function in 36 dogs with leishmaniosis due to Leishmania infantum before and during treatment with allopurinol with or without meglumine antimonate.

PubMed

Saridomichelakis, Manolis N; Xenoulis, Panagiotis G; Chatzis, Manolis K; Kasabalis, Dimitris; Steiner, Jörg M; Suchodolski, Jan S; Petanides, Theodoros

2013-10-18

Hypothyroidism may predispose to the development of canine leishmaniosis or it may appear during the course of the latter due to infiltration and destruction of the thyroid gland by infected macrophages. The main purpose of this study was to evaluate thyroid function through measurement of serum total thyroxin (tT₄), free thyroxin (fT₄), and canine thyroid stimulating hormone (cTSH) concentrations in 36 dogs with leishmaniosis, before and after 2 and 4 weeks of treatment with allopurinol with or without meglumine antimonate. Before treatment 27/36 (75%) dogs had serum tT₄ concentrations below the lower limit of the reference interval but only 2 of them had concurrently serum fT₄ concentrations below the lower limit of the reference interval and none had increased serum cTSH concentrations. During treatment there were no significant changes in serum tT₄ or fT₄ concentrations, whereas a significant increase in serum cTSH was observed. Two dogs had decreased serum tT₄ and fT₄ but normal cTSH concentrations before treatment and two other dogs had decreased serum tT₄ and increased cTSH, but normal fT₄ concentrations during the treatment period. Although hypothyroidism could not be definitively excluded in these dogs it is considered unlikely based on their overall hormonal profile, clinical presentation, and response to treatment. Therefore, hypothyroidism does not appear to be an important predisposing disease or a frequent complication of canine leishmaniosis. Copyright © 2013 Elsevier B.V. All rights reserved.

Plasma surface modification of rigid contact lenses decreases bacterial adhesion.

PubMed

Wang, Yingming; Qian, Xuefeng; Zhang, Xiaofeng; Xia, Wei; Zhong, Lei; Sun, Zhengtai; Xia, Jing

2013-11-01

Contact lens safety is an important topic in clinical studies. Corneal infections usually occur because of the use of bacteria-carrying contact lenses. The current study investigated the impact of plasma surface modification on bacterial adherence to rigid contact lenses made of fluorosilicone acrylate materials. Boston XO and XO2 contact lenses were modified using plasma technology (XO-P and XO2-P groups). Untreated lenses were used as controls. Plasma-treated and control lenses were incubated in solutions containing Staphylococcus aureus or Pseudomonas aeruginosa. MTT colorimetry, colony-forming unit counting method, and scanning electron microscopy were used to measure bacterial adhesion. MTT colorimetry measurements showed that the optical density (OD) values of XO-P and XO2-P were significantly lower than those of XO and XO2, respectively, after incubation with S. aureus (P < 0.01). The OD value of XO-P was also much lower than that of XO after incubation with P. aeruginosa (P < 0.01). Colony-forming unit counting revealed that a significantly lower number of bacterial colonies attached to the XO-P versus XO lenses and to the XO2-P versus XO2 lenses incubated with S. aureus (P < 0.01). Fewer bacterial colonies attached to the XO-P versus XO lenses incubated with P. aeruginosa (P < 0.01). Further, scanning electron microscopy suggested different bacterial adhesion morphology on plasma-treated versus control lenses. Plasma surface modification can significantly decrease bacterial adhesion to fluorosilicone acrylate contact lenses. This study provides important evidence of a unique benefit of plasma technology in contact lens surface modification.

N-Acetylcysteine and Allopurinol Synergistically Enhance Cardiac Adiponectin Content and Reduce Myocardial Reperfusion Injury in Diabetic Rats

PubMed Central

Wang, Tingting; Qiao, Shigang; Lei, Shaoqing; Liu, Yanan; Ng, Kwok F. J.; Xu, Aimin; Lam, Karen S. L.; Irwin, Michael G.; Xia, Zhengyuan

2011-01-01

Background Hyperglycemia-induced oxidative stress plays a central role in the development of diabetic myocardial complications. Adiponectin (APN), an adipokine with anti-diabetic and anti-ischemic effects, is decreased in diabetes. It is unknown whether or not antioxidant treatment with N-acetylcysteine (NAC) and/or allopurinol (ALP) can attenuate APN deficiency and myocardial ischemia reperfusion (MI/R) injury in the early stage of diabetes. Methodology/Principal Findings Control or streptozotocin (STZ)-induced diabetic rats were either untreated (C, D) or treated with NAC (1.5 g/kg/day) or ALP (100 mg/kg/day) or their combination for four weeks starting one week after STZ injection. Plasma and cardiac biochemical parameters were measured after the completion of treatment, and the rats were subjected to MI/R by occluding the left anterior descending artery for 30 min followed by 2 h reperfusion. Plasma and cardiac APN levels were decreased in diabetic rats accompanied by decreased cardiac APN receptor 2 (AdipoR2), reduced phosphorylation of Akt, signal transducer and activator of transcription 3 (STAT3) and endothelial nitric oxide synthase (eNOS) but increased IL-6 and TNF-α (all P<0.05 vs. C). NAC but not ALP increased cardiac APN concentrations and AdipoR2 expression in diabetic rats. ALP enhanced the effects of NAC in restoring cardiac AdipoR2 and phosphorylation of Akt, STAT3 and eNOS in diabetic rats. Further, NAC and ALP, respectively, decreased postischemic myocardial infarct size and creatinine kinase-MB (CK-MB) release in diabetic rats, while their combination conferred synergistic protective effects. In addition, exposure of cultured rat cardiomyocytes to high glucose resulted in significant reduction of cardiomyocyte APN concentration and AdipoR2 protein expression. APN supplementation restored high glucose induced AdipoR2 reduction in cardiomyocytes. Conclusions/Significance NAC and ALP synergistically restore myocardial APN and AdipoR2 mediated e

Design of Semiconducting Tetrahedral Mn 1-xZn xO Alloys and Their Application to Solar Water Splitting

DOE PAGES

Peng, Haowei; Ndione, Paul F.; Ginley, David S.; ...

2015-03-18

Transition metal oxides play important roles as contact and electrode materials, but their use as active layers in solar energy conversion requires achieving semiconducting properties akin to those of conventional semiconductors like Si or GaAs. In particular, efficient bipolar carrier transport is a challenge in these materials. Based on the prediction that a tetrahedral polymorph of MnO should have such desirable semiconducting properties, and the possibility to overcome thermodynamic solubility limits by nonequilibrium thin-film growth, we exploit both structure-property and composition-structure relationships to design and realize novel wurtzite-structure Mn 1₋xZn xO alloys. At Zn compositions above x≈0.3, thin films ofmore » these alloys assume the tetrahedral wurtzite structure instead of the octahedral rocksalt structure of MnO, thereby enabling semiconductor properties that are unique among transition metal oxides, i.e., a band gap within the visible spectrum, a band-transport mechanism for both electron and hole carriers, electron doping, and a band lineup suitable for solar hydrogen generation. In conclusion, a proof of principle is provided by initial photo-electrocatalytic device measurements, corroborating, in particular, the predicted favorable hole-transport properties of these alloys.« less

Constraints on the atmospheric circulation and variability of the eccentric hot Jupiter XO-3b

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wong, Ian; Knutson, Heather A.; Cowan, Nicolas B.

We report secondary eclipse photometry of the hot Jupiter XO-3b in the 4.5 μm band taken with the Infrared Array Camera on the Spitzer Space Telescope. We measure individual eclipse depths and center of eclipse times for a total of 12 secondary eclipses. We fit these data simultaneously with two transits observed in the same band in order to obtain a global best-fit secondary eclipse depth of 0.1580% ± 0.0036% and a center of eclipse phase of 0.67004 ± 0.00013. We assess the relative magnitude of variations in the dayside brightness of the planet by measuring the size of themore » residuals during ingress and egress from fitting the combined eclipse light curve with a uniform disk model and place an upper limit of 0.05%. The new secondary eclipse observations extend the total baseline from one and a half years to nearly three years, allowing us to place an upper limit on the periastron precession rate of 2.9 × 10{sup –3} deg day{sup –1}— the tightest constraint to date on the periastron precession rate of a hot Jupiter. We use the new transit observations to calculate improved estimates for the system properties, including an updated orbital ephemeris. We also use the large number of secondary eclipses to obtain the most stringent limits to date on the orbit-to-orbit variability of an eccentric hot Jupiter and demonstrate the consistency of multiple-epoch Spitzer observations.« less

Investigation of Cr substitution in Co ferrite (CoCrxFe2-xO4) using Mossbauer spectroscopy

NASA Astrophysics Data System (ADS)

Krieble, K.; Lo, C. C. H.; Melikhov, Y.; Snyder, J. E.

2006-04-01

Substitution of other metals for Fe in cobalt ferrite has been proposed as a method to tailor the magnetic and magnetoelastic properties for sensor and actuator applications [H. Zheng et al., Science 303, 661 (2004)]. However, to understand the effect of Cr substitution, one needs atomic-level information on the local environments and interactions of the transition-metal ions. In this study, Mossbauer spectroscopy was used to investigate the local environments of the Fe atoms in these materials. A series of five powder samples with compositions CoCrxFe2-xO4 (x=0.0 to 0.8) was investigated using transmission geometry. Results show two distinct six-line hyperfine patterns, indicating Fe in A and B spinel sites. Increasing Cr concentration is seen to decrease the hyperfine field strength for both A and B sites, as well as increasing the width of those distributions. Results for Cr substitution show generally similar behavior to a prior study using Mn; however, Cr substitution has more pronounced effects: the hyperfine fields decrease and distribution widths increase at greater rates for Cr substitution, and the differences between A and B site behavior are more pronounced. Results are consistent with a model in which Cr has an even stronger B-site preference than Mn, and displaces more of the Co from the B to the A sites.

Thermochemistry of rare earth doped uranium oxides LnxU1-xO2-0.5x+y (Ln = La, Y, Nd)

NASA Astrophysics Data System (ADS)

Zhang, Lei; Navrotsky, Alexandra

2015-10-01

Lanthanum, yttrium, and neodymium doped uranium dioxide samples in the fluorite structure have been synthesized, characterized in terms of metal ratio and oxygen content, and their enthalpies of formation measured by high temperature oxide melt solution calorimetry. For oxides doped with 10-50 mol % rare earth (Ln) cations, the formation enthalpies from constituent oxides (LnO1.5, UO2 and UO3 in a reaction not involving oxidation or reduction) become increasingly exothermic with increasing rare earth content, while showing no significant dependence on the varying uranium oxidation state. The oxidation enthalpy of LnxU1-xO2-0.5x+y is similar to that of UO2 to UO3 for all three rare earth doped systems. Though this may suggest that the oxidized uranium in these systems is energetically similar to that in the hexavalent state, thermochemical data alone can not constrain whether the uranium is present as U5+, U6+, or a mixture of oxidation states. The formation enthalpies from elements calculated from the calorimetric data are generally consistent with those from free energy measurements.

Long-term Safety and Efficacy of Low-dose Azathioprine and Allopurinol Cotherapy in Inflammatory Bowel Disease: A Large Observational Study.

PubMed

Pavlidis, Polychronis; Stamoulos, Panagiotis; Abdulrehman, Answar; Kerr, Patrick; Bull, Claire; Duley, John; Ansari, Azhar

2016-07-01

Low-dose azathioprine with allopurinol (LDAA) has been proposed as a potent therapy in inflammatory bowel disease (IBD) with the benefit of overcoming side effects regularly associated with thiopurine monotherapy and poor responses. Concerns regarding safety remain, while a layer of complexity has been added by the trend toward treatment directed by red cell thioguanine nucleotide (TGN) profiling. We report on the clinical efficacy and safety of LDAA use in IBD undirected by metabolite profiling. Observational study of clinical practice from a single IBD center. Patient outcomes were defined clinically based on established activity scores and corticosteroid withdrawal. Red cell TGN was monitored only for suspected nonadherence. Overall, 113/164 (69%) patients with Crohn's disease and 83/136 (61%) patients with ulcerative/unclassified colitis had a clinical response by the end of follow-up (median 19 months), while 85 (52%) patients with Crohn's disease and 74 (54%) patients with ulcerative/unclassified colitis were in clinical remission. Clinical response was seen in 45/57 (79%) patients with Crohn's disease and 34/53 (64%) patients with ulcerative/unclassified colitis who were thiopurine naive, had active IBD, and received LDAA as the first line immunomodulator, while in 35 (61%) and 28 (53%), respectively, remission was achieved. LDAA was stopped in 20/300 (7%) patients because of side effects, all of which resolved on drug cessation. This is the largest cohort supporting the favorable safety profile and high efficacy of LDAA in IBD. It presents 2 advances in therapy: prescribing LDAA for thiopurine-naive patients, and bypassing TGN monitoring in favor of clinical monitoring (blood counts, etc.), which will make it more accessible for clinics without access to TGN assays.

Preferential inhibition of xanthine oxidase by 2-amino-6-hydroxy-8-mercaptopurine and 2-amino-6-purine thiol

PubMed Central

Kalra, Sukirti; Jena, Gopabandhu; Tikoo, Kulbhushan; Mukhopadhyay, Anup Kumar

2007-01-01

Background The anticancer drug, 6-mercaptopurine (6MP) is subjected to metabolic clearance through xanthine oxidase (XOD) mediated hydroxylation, producing 6-thiouric acid (6TUA), which is excreted in urine. This reduces the effective amount of drug available for therapeutic efficacy. Co-administration of allopurinol, a suicide inhibitor of XOD, which blocks the hydroxylation of 6MP inadvertently enhances the 6MP blood level, counters this reduction. However, allopurinol also blocks the hydroxylation of hypoxanthine, xanthine (released from dead cancer cells) leading to their accumulation in the body causing biochemical complications such as xanthine nephropathy. This necessitates the use of a preferential XOD inhibitor that selectively inhibits 6MP transformation, but leaves xanthine metabolism unaffected. Results Here, we have characterized two such unique inhibitors namely, 2-amino-6-hydroxy-8-mercaptopurine (AHMP) and 2-amino-6-purinethiol (APT) on the basis of IC50 values, residual activity in bi-substrate simulative reaction and the kinetic parameters like Km, Ki, kcat. The IC50 values of AHMP for xanthine and 6MP as substrate are 17.71 ± 0.29 μM and 0.54 ± 0.01 μM, respectively and the IC50 values of APT for xanthine and 6MP as substrates are 16.38 ± 0.21 μM and 2.57 ± 0.08 μM, respectively. The Ki values of XOD using AHMP as inhibitor with xanthine and 6MP as substrate are 5.78 ± 0.48 μM and 0.96 ± 0.01 μM, respectively. The Ki values of XOD using APT as inhibitor with xanthine and 6MP as substrate are 6.61 ± 0.28 μM and 1.30 ± 0.09 μM. The corresponding Km values of XOD using xanthine and 6MP as substrate are 2.65 ± 0.02 μM and 6.01 ± 0.03 μM, respectively. The results suggest that the efficiency of substrate binding to XOD and its subsequent catalytic hydroxylation is much superior for xanthine in comparison to 6MP. In addition, the efficiency of the inhibitor binding to XOD is much more superior when 6MP is the substrate instead of

Preferential inhibition of xanthine oxidase by 2-amino-6-hydroxy-8-mercaptopurine and 2-amino-6-purine thiol.

PubMed

Kalra, Sukirti; Jena, Gopabandhu; Tikoo, Kulbhushan; Mukhopadhyay, Anup Kumar

2007-05-18

The anticancer drug, 6-mercaptopurine (6MP) is subjected to metabolic clearance through xanthine oxidase (XOD) mediated hydroxylation, producing 6-thiouric acid (6TUA), which is excreted in urine. This reduces the effective amount of drug available for therapeutic efficacy. Co-administration of allopurinol, a suicide inhibitor of XOD, which blocks the hydroxylation of 6MP inadvertently enhances the 6MP blood level, counters this reduction. However, allopurinol also blocks the hydroxylation of hypoxanthine, xanthine (released from dead cancer cells) leading to their accumulation in the body causing biochemical complications such as xanthine nephropathy. This necessitates the use of a preferential XOD inhibitor that selectively inhibits 6MP transformation, but leaves xanthine metabolism unaffected. Here, we have characterized two such unique inhibitors namely, 2-amino-6-hydroxy-8-mercaptopurine (AHMP) and 2-amino-6-purinethiol (APT) on the basis of IC50 values, residual activity in bi-substrate simulative reaction and the kinetic parameters like Km, Ki, kcat. The IC50 values of AHMP for xanthine and 6MP as substrate are 17.71 +/- 0.29 microM and 0.54 +/- 0.01 microM, respectively and the IC50 values of APT for xanthine and 6MP as substrates are 16.38 +/- 0.21 microM and 2.57 +/- 0.08 microM, respectively. The Ki values of XOD using AHMP as inhibitor with xanthine and 6MP as substrate are 5.78 +/- 0.48 microM and 0.96 +/- 0.01 microM, respectively. The Ki values of XOD using APT as inhibitor with xanthine and 6MP as substrate are 6.61 +/- 0.28 microM and 1.30 +/- 0.09 microM. The corresponding Km values of XOD using xanthine and 6MP as substrate are 2.65 +/- 0.02 microM and 6.01 +/- 0.03 microM, respectively. The results suggest that the efficiency of substrate binding to XOD and its subsequent catalytic hydroxylation is much superior for xanthine in comparison to 6MP. In addition, the efficiency of the inhibitor binding to XOD is much more superior when 6MP is the

Investigation of magnetic ordering and cation distribution in the spinel ferrites CrxFe3-xO4 (0.0≤x≤1.0)

NASA Astrophysics Data System (ADS)

Tang, G. D.; Han, Q. J.; Xu, J.; Ji, D. H.; Qi, W. H.; Li, Z. Z.; Shang, Z. F.; Zhang, X. Y.

2014-04-01

Ferrite powder samples of CrxFe3-xO4 (0.0≤x≤1.0) were prepared by chemical co-precipitation, and calcined in a tube furnace with argon-flow at 1723 K for 2 h. X-ray diffraction patterns indicated that all the samples had an (A)[B]2O4 single phase cubic spinel structure with a Fd3barm space group. Magnetic measurements indicated that the magnetization of the samples decreased with the Cr doping level. A new model for the magnetic ordering in these samples was employed to explain the dependence of the magnetization and cation distribution on the Cr doping level; namely, taking into consideration constraints arising from Hund's rules and from the spin direction of the itinerant 3d electrons, the directions of the Cr2+ and Cr3+ cation magnetic moments were taken to lie antiparallel to the moments of the Fe cations within the same sub-lattice (A or B sub-lattice).

Newer treatments of psoriasis regarding IL-23 inhibitors, phosphodiesterase 4 inhibitors, and Janus kinase inhibitors.

PubMed

Wcisło-Dziadecka, Dominika; Zbiciak-Nylec, Martyna; Brzezińska-Wcisło, Ligia; Bebenek, Katarzyna; Kaźmierczak, Agata

2017-11-01

The rapid progress of genetic engineering furthermore opens up new prospects in the therapy of this difficult-to-treat disease. IL-23 inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and Janus kinase (JAK) inhibitors are currently encouraging further research. Two drugs which are IL-23 inhibitors are now in phase III of clinical trials. The aim of the action of both drugs is selective IL-23 inhibition by targeting the p19 subunit. Guselkumab is a fully human monoclonal antibody. Tildrakizumab is a humanized monoclonal antibody, which also belongs to IgG class and is targeted to subunit p19 of interleukin 23 (IL-23). Phosphodiesterase inhibitors exert an anti-inflammatory action and their most common group is the PDE4 family. PDE4 inhibits cAMP, which reduces the inflammatory response of the pathway of Th helper lymphocytes, Th17, and type 1 interferon which modulates the production of anti-inflammatory cytokines such as IL-10 interleukins. The Janus kinase (JAK) signaling pathway plays an important role in the immunopathogenesis of psoriasis. Tofacitinib suppresses the expression of IL-23, IL-17A, IL-17F, and IL-22 receptors during the stimulation of lymphocytes. Ruxolitinib is a selective inhibitor of JAK1 and JAK2 kinases and the JAK-STAT signaling pathway. This article is a review of the aforementioned drugs as described in the latest available literature. © 2017 Wiley Periodicals, Inc.

Dependence of e31,f on polar axis texture for tetragonal Pb(Zrx,Ti1-x)O3 thin films

NASA Astrophysics Data System (ADS)

Yeager, Charles B.; Ehara, Yoshitaka; Oshima, Naoya; Funakubo, Hiroshi; Trolier-McKinstry, Susan

2014-09-01

It was shown by Ouyang et al. [Appl. Phys. Lett. 86, 152901 (2005)] that the piezoelectric e31,f coefficient is largest parallel to the spontaneous polarization in tetragonal PbZrxTi1-xO3 (PZT) films. However, the expected piezoelectric data are typically calculated from phenomenological constants derived from data on ceramic PZT. In this work, the dependence of e31,f on c-axis texture fraction, f001, for {001}PZT thin films was measured by growing films with systematically changed f001 using CaF2, MgO, SrTiO3, and Si substrates. An approximately linear increase in e31,f with f001 was observed for compositions up to 43 mol. % Zr, and 100% c-domain properties were extrapolated. It was demonstrated that c-axis PZT films can achieve e31,f exceeding -12 C/m2 for many tetragonal compositions. The energy harvesting figure of merit, e31,f2/ɛr, for c-axis PZT films surpassed 0.8 C2/m4. This is larger than the figure of merit of gradient-free PZT films grown on Si substrates by a factor of four.

Investigation of conduction and relaxation phenomena in BaZrxTi1-xO3 (x=0.05) by impedance spectroscopy

NASA Astrophysics Data System (ADS)

Mahajan, Sandeep; Haridas, Divya; Ali, S. T.; Munirathnam, N. R.; Sreenivas, K.; Thakur, O. P.; Prakash, Chandra

2014-10-01

In present study we have prepared ferroelectric BaZrxTi1-xO3 (x=0.05) ceramic by conventional solid state reaction route and studied its electrical properties as a function of temperature and frequency. X-ray diffraction (XRD) analysis shows single-phase formation of the compound with orthorhombic crystal structure at room temperature. Impedance and electric modulus spectroscopy analysis in the frequency range of 40 Hz-1 MHz at high temperature (200-600 °C) suggests two relaxation processes with different time constant are involved which are attributed to bulk and grain boundary effects. Frequency dependent dielectric plot at different temperature shows normal variation with frequency while dielectric loss (tanδ) peak was found to obey an Arrhenius law with activation energy of 1.02 eV. The frequency-dependent AC conductivity data were also analyzed in a wide temperature range. In present work we have studied the role of grain and grain boundaries on the electrical behaviour of Zr-doped BaTiO3 and their dependence on temperature and frequency by complex impedance and modulus spectroscopy (CIS) technique in a wide frequency (40 Hz-1 MHz) and high temperature range.

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

PubMed

Mitri, Ghaith; Wittbrodt, Eric T; Turpin, Robin S; Tidwell, Beni A; Schulman, Kathy L

2016-04-01

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. 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. 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. 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

Superoxide from NADPH oxidase upregulates type 5 phosphodiesterase in human vascular smooth muscle cells: inhibition with iloprost and NONOate.

PubMed

Muzaffar, S; Shukla, N; Bond, M; Sala-Newby, G B; Newby, A C; Angelini, G D; Jeremy, J Y

2008-11-01

To determine whether there is an association between vascular NADPH oxidase (NOX), superoxide, the small GTPase Rac(1) and PDE type 5 (PDE5) in human vascular smooth muscle cell (hVSMCs). hVSMCs were incubated with xanthine-xanthine oxidase (X-XO; a superoxide generating system) or the thromboxane A(2) analogue, U46619 (+/-superoxide dismutase (SOD) or apocynin) for 16 h. The expression of PDE5 and NOX-1 was assessed using Western blotting and superoxide measured. The role of Rac(1) in superoxide generation was assessed by overexpressing either the dominant-negative or constitutively active Rac isoforms. The effects of iloprost, DETA-NONOate and the Rho-kinase inhibitor, Y27632, on PDE5 and NOX-1 expression were also studied. Following 16 h incubation, U46619 and X-XO promoted the expression of PDE5 and NOX-1, an effect blocked by SOD or apocynin when co-incubated over the same time course. X-XO and U46619 both promoted the formation of superoxide. Overexpression of dominant-negative Rac(1) or addition of iloprost, DETA-NONOate or Y27632 completely blocked both superoxide release and PDE5 protein expression and activity. These data demonstrate that superoxide derived from NOX upregulates the expression of PDE5 in human VSMCs. As PDE5 hydrolyses cyclic GMP, this effect may blunt the vasculoprotective actions of NO.

Fabrication of Co0.5Ni0.5CrxFe2-xO4 materials via sol-gel method and their characterizations

NASA Astrophysics Data System (ADS)

Kadam, R. H.; Birajdar, A. P.; Alone, Suresh T.; Shirsath, Sagar E.

2013-02-01

Co0.5Ni0.5CrxFe2-xO4 nanoparticles have been designed by the sol-gel auto combustion method, using nitrates of the respective metal ions, and citric acid as the starting materials. The process takes only a few minutes to obtain as-received Cr-substituted Co-Ni ferrite powders. X-ray diffraction (XRD), vibrational sample magnetometer (VSM), transmission electron microscopy (TEM) are utilized in order to study the effect of variation in the Cr3+ substitution and its impact on particle size, lattice constant, specific surface area, cation distribution and magnetic properties. Lattice parameter, particle size found to decrease with increasing Cr3+ content, whereas specific surface area showed increasing trend with the Cr3+ substitution. Cation distribution indicates that the Cr, Co and Ni ions show preference toward octahedral [B] site, whereas Fe occupies both tetrahedral (A) and octahedral [B] sites. Saturation magnetization (MS) decreased from 65.1 to 40.6 emu/g with the increase in Cr3+ substitution. However, Coercivity increased from 198 to 365 Oe with the Cr3+ substitution.

Chemical control of orbital polarization in artificially structured transition-metal oxides: La2NiXO6 (X=B,Al,Ga,In) from first principles

NASA Astrophysics Data System (ADS)

Han, M. J.; Marianetti, C. A.; Millis, A. J.

2010-10-01

The application of modern layer-by-layer growth techniques to transition-metal oxide materials raises the possibility of creating new classes of materials with rationally designed correlated electron properties. An important step toward this goal is the demonstration that electronic structure can be controlled by atomic composition. In compounds with partially occupied transition-metal d shells, one important aspect of the electronic structure is the relative occupancy of different d orbitals. Previous work has established that strain and quantum confinement can be used to influence orbital occupancy. In this paper we demonstrate a different modality for orbital control in transition-metal oxide heterostructures, using density-functional band calculations supplemented by a tight-binding analysis to show that the choice of nontransition-metal counterion X in transition-metal oxide heterostructures composed of alternating LaNiO3 and LaXO3 units strongly affects orbital occupancy, changing the magnitude and in some cases the sign of the orbital polarization.

Discovery of natural mouse serum derived HIV-1 entry inhibitor(s).

PubMed

Wei, M; Chen, Y; Xi, J; Ru, S; Ji, M; Zhang, D; Fang, Q; Tang, B

Among rationally designed human immunodeficiency virus 1 (HIV-1) inhibitors, diverse natural factors have showed as potent anti-HIV activity in human blood. We have discovered that the boiled supernatant of healthy mouse serum could suppress HIV-1 entry, and exhibited reduced inhibitory activity after trypsin digestion. Further analysis demonstrated that only the fraction containing 10-25 K proteins could inhibit HIV-1 mediated cell-cell fusion. These results suggest that the 10-25 K protein(s) is novel natural HIV-1 entry inhibitor(s). Our findings provide important information about novel natural HIV entry inhibitors in mouse serum.

Structural, magnetic and hyperfine characterization of ZnxFe3-xO4 nanoparticles prepared by sol-gel approach via inorganic precursors

NASA Astrophysics Data System (ADS)

Kotsikau, Dzmitry; Pankov, Vladimir; Petrova, Elena; Natarov, Valentin; Filimonov, Dmitry; Pokholok, Konstantin

2018-03-01

Structural characteristics and magnetic properties of ZnxFe3-xO4 (where x = 0; 0.09; 0.18; 0.45; 1) nanoparticles were studied with X-ray diffraction (XRD), transmission electron microscopy (TEM), infrared spectroscopy (IR) and vibrating sample magnetometry (VSM). Oxidation of Fe2+ ions, redistribution of Zn2+ and Fe3+ ions between octahedral and tetrahedral sites, and the formation of cation vacancies in spinel-type cubic structure of the obtained ZnxFe3-x-y□yO4 substitutional solid solutions were revealed by 57Fe Mössbauer spectroscopy. The nanoparticles synthesized via a modified sol-gel method using inorganic precursors have a size of 4-10 nm, single-phase composition, superparamagnetic behavior at room temperature (300 K) and a relatively hydrophilic surface to form stable aqueous suspensions. The maximum magnetization of 59 emu/g at 300 K corresponds to Zn0.18Fe2.82O4 composition. The listed features make the materials promising candidates for various biological and medical applications such as contrast-enhanced magnetic resonance imaging, hyperthermia of pathological tissues, controlled drug release, and separation of nucleic acids.

Cost-effectiveness of febuxostat in chronic gout.

PubMed

Beard, Stephen M; von Scheele, Birgitta G; Nuki, George; Pearson, Isobel V

2014-06-01

Our objective was to evaluate data on the cost-effectiveness of febuxostat compared with standard clinical practice with allopurinol in patients with gout that was presented to the Scottish Medicines Consortium (SMC) in 2010. A Markov health-state model estimated the direct health-related costs and clinical benefits expressed as quality-adjusted life-years (QALYs). Adults with chronic gout and established hyperuricaemia received treatment sequences of daily doses of allopurinol 300 mg alone or allopurinol 300 mg followed by febuxostat 80 mg/120 mg. The proportion of patients achieving the target serum uric acid (sUA) level of less than 6 mg/dl (0.36 mmol/l) was linked to the utility per sUA level to generate an incremental cost-effectiveness ratio (ICER). Second-line therapy with febuxostat 80 mg/120 mg versus with allopurinol alone resulted in an ICER of £3,578 per QALY over a 5-year time horizon. Additional univariate analyses showed that ICER values were robust and ranged from £2,550 to £7,165 per QALY when different parameters (e.g., low- and high-dose allopurinol titrations and variations in treatment-induced flare rates) were varied. Febuxostat reduces sUA below the European League Against Rheumatism target of 0.36 mmol/l (6 mg/dl) in significantly more patients with gout than allopurinol in its most frequently prescribed dose of 300 mg per day. The SMC accepted febuxostat as cost-effective as a suitable second-line option for urate-lowering therapy for the treatment of patients with chronic hyperuricaemia in conditions where urate deposition has already occurred (including a history or presence of tophus and/or gouty arthritis) when treatment with allopurinol was inadequate, not tolerated, or contraindicated.

DOE Office of Scientific and Technical Information (OSTI.GOV)

French, Jarrod B.; Ealick, Steven E.

The stereospecific oxidative degradation of uric acid to (S)-allantoin was recently shown to proceed via three enzymatic steps. The final conversion is a decarboxylation of the unstable intermediate 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU) and is catalyzed by OHCU decarboxylase. Here we present the structures of Klebsiella pneumoniae OHCU decarboxylase in unliganded form and with bound allantoin. These structures provide evidence that ligand binding organizes the active site residues for catalysis. Modeling of the substrate and intermediates provides additional support for this hypothesis. In addition we characterize the steady state kinetics of this enzyme and report the first OHCU decarboxylase inhibitor, allopurinol, a structuralmore » isomer of hypoxanthine. This molecule is a competitive inhibitor of K. pneumoniae OHCU decarboxylase with a K{sub i} of 30 {+-} 2 {micro}m. Circular dichroism measurements confirm structural observations that this inhibitor disrupts the necessary organization of the active site. Our structural and biochemical studies also provide further insights into the mechanism of catalysis of OHCU decarboxylation.« less

Polyoxometalates from heteropoly "brown" precursors. A new structural class of mixed valence heteropolytungstates, [(XO4)W3IVW17VIO 62Hx]n-

USGS Publications Warehouse

Dickman, M.H.; Ozeki, T.; Evans, H.T.; Rong, C.; Jameson, G.B.; Pope, M.T.

2000-01-01

Reduction of the ??-Keggin anion [Xn+O4W12O36][8-n]- (X = H22+, B3+, Si4+) by six electrons results in the known tungsten "brown" species [Xn+O4(H2O)3WIV3WVI9O33][8-n]- in which three W atoms have been reduced from WVI to WIV, forming a metal-metal bonded triad. The WIV atoms have terminal water coordinated in place of terminal oxo groups. Additional tungstate can condense onto these water molecules in aqueous solution between pH = 4 and 6.5 to form the species reported here, [(XO4)WIV3WVI17O 62Hx]y-. The boron derivative (X = B3+) is more stable than the metatungstate (X = H22+), both of which have been characterized by elemental analysis, 183W NMR and X-ray crystal structure analysis. Eight additional tungstate groups condense in the form of a partial Keggin structure containing two triads and one dyad which is rotated 60?? relative to a hypothetical ??-isomer. ?? The Royal Society of Chemistry 2000.

Synthesis of BaTiO3 and Ba(ZrxTi1-X)O3 by using the soft combustion method

NASA Astrophysics Data System (ADS)

Ahmad, Atiqah; Razak, Khairunisak Abdul

2017-07-01

In this work, barium titanate, BaTiO3 (BT) and Zr doped BT, BaZrxTi1-xO3 (BZT) with powders were successfully produced using the soft combustion method. Barium nitrate and titanium (IV) isopropoxide were used as the starting materials while zirconium (IV) oxynitrate hydrate as the doping precursors, and glycine as the combustion agent. The produced powders were pressed into 12 mm diameter pellets by using 150 MPa cold press. The effect of Zr dopant in BT was studied with molar ratio of x = 0.00, 0.03, 0.05, 0.08 and 0.10. The phase presence was identified using X-ray diffractometer. Morphology of powders and sintered pellets was observed using a scanning electron microscope. Density of the sintered pellets was measured by using Archimedes' principle, while dielectric properties were analysed by using an LCR meter. Pure perovskite BT and BZT structure were obtained after sintering at 1400 °C for 5 h. BZT with x = 0.03 has grain size of 3.9 µm and shows the highest dielectric constant of 525, compared to undoped BT that has the average grain size of 4.2 µm with dielectric constant 223. The results is in agreement with microstructure observation and density of the sample.

Photoelectrochemical and theoretical investigations of spinel type ferrites (MxFe3-xO4) for water splitting: a mini-review

NASA Astrophysics Data System (ADS)

Taffa, Dereje H.; Dillert, Ralf; Ulpe, Anna C.; Bauerfeind, Katharina C. L.; Bredow, Thomas; Bahnemann, Detlef W.; Wark, Michael

2017-01-01

Solar-assisted water splitting using photoelectrochemical cells (PECs) is one of the promising pathways for the production of hydrogen for renewable energy storage. The nature of the semiconductor material is the primary factor that controls the overall energy conversion efficiency. Finding semiconductor materials with appropriate semiconducting properties (stability, efficient charge separation and transport, abundant, visible light absorption) is still a challenge for developing materials for solar water splitting. Owing to the suitable bandgap for visible light harvesting and the abundance of iron-based oxide semiconductors, they are promising candidates for PECs and have received much research attention. Spinel ferrites are subclasses of iron oxides derived from the classical magnetite (FeIIFe2IIIO4) in which the FeII is replaced by one (some cases two) additional divalent metals. They are generally denoted as MxFe3-xO4 (M=Ca, Mg, Zn, Co, Ni, Mn, and so on) and mostly crystallize in spinel or inverse spinel structures. In this mini review, we present the current state of research in spinel ferrites as photoelectrode materials for PECs application. Strategies to improve energy conversion efficiency (nanostructuring, surface modification, and heterostructuring) will be presented. Furthermore, theoretical findings related to the electronic structure, bandgap, and magnetic properties will be presented and compared with experimental results.

Xanthine oxido-reductase activity in ischemic human and rat intestine.

PubMed

Bianciardi, Paola; Scorza, Roberto; Ghilardi, Giorgio; Samaja, Michele

2004-09-01

We measured time course and extent of xanthine dehydrogenase (XD) to xanthine oxidase (XO) conversion in ischemic human and rat intestine. To model normothermic no-flow ischemia, we incubated fresh biopsies for 0, 2, 4, 8 and 16h. At t = 0h, XO was less in humans than in rats (P < 0.0004), while XD was essentially the same (P = NS). After 16h incubation at 37 degrees C, there was no appreciable XD-to-XO conversion and no change in neither XO nor XD activity in human intestine. In contrast, the rat intestine had XO/(XO + XD) ratio doubled in the first 2h and then maintained that value until t = 16 h. In conclusion, no XO-to-XD conversion was appreciable after 16 h no-flow normothermic ischemia in human intestine; in contrast, XO activity in rats increased sharply after the onset of ischemia. An immunohistochemical labelling study shows that, whereas XO + XD expression in liver tissue is localised in both hepatocytes and endothelial cells, in the intestine that expression is mostly localised in epithelial cells. We conclude that XO may be considered as a major source of reactive oxygen species in rats but not in humans.

Composition and hydrophilicity control of Mn-doped ferrite (MnxFe3-xO4) nanoparticles induced by polyol differentiation.

PubMed

Vamvakidis, Kosmas; Katsikini, Maria; Vourlias, George; Angelakeris, Mavroeidis; Paloura, Eleni C; Dendrinou-Samara, Catherine

2015-03-28

Manganese doped ferrite (MnxFe3-xO4) nanoparticles with x = 0.29-0.77 were prepared under solvothermal conditions in the presence solely of a polyol using the trivalent manganese and iron acetylacetonates as precursors. In this facile approach, a variety of polyols such as polyethylene glycol (PEG 8000), tetraethylene glycol (TEG), propylene glycol (PG) and a mixture of TEG and PG (1 : 1) were utilized in a triple role as a solvent, a reducing agent and a surface-functionalizing agent. The composition of the fine cubic-spinel structures was found to be related to the reductive ability of each polyol, while determination of structural characteristics plus the inversion parameter (i = 0.18-0.38) were provided by X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) spectroscopy at both the Fe and Mn K-edges. The saturation magnetization increased up to 80 emu g(-1) when x = 0.35 and i = 0.22. In addition, the as-prepared nanocrystals coated with PEG, PG and PG&TEG showed excellent colloidal stability in water, while the TEG-coated particles were not water dispersible and converted to hydrophilic when were extra PEGylated. Measurements of the (1)H NMR relaxation in water were carried out and the nanoprobes were evaluated as potential contrast agents.

Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study

PubMed Central

Schlesinger, Naomi; Mysler, Eduardo; Lin, Hsiao-Yi; De Meulemeester, Marc; Rovensky, Jozef; Arulmani, Udayasankar; Balfour, Alison; Krammer, Gerhard; Sallstig, Peter; So, Alexander

2011-01-01

Objective This study assessed the efficacy and safety of canakinumab, a fully human anti-interleukin 1β monoclonal antibody, for prophylaxis against acute gouty arthritis flares in patients initiating urate-lowering treatment. Methods In this double-blind, double-dummy, dose-ranging study, 432 patients with gouty arthritis initiating allopurinol treatment were randomised 1:1:1:1:1:1:2 to receive: a single dose of canakinumab, 25, 50, 100, 200, or 300 mg subcutaneously; 4×4-weekly doses of canakinumab (50+50+25+25 mg subcutaneously); or daily colchicine 0.5 mg orally for 16 weeks. Patients recorded details of flares in diaries. The study aimed to determine the canakinumab dose having equivalent efficacy to colchicine 0.5 mg at 16 weeks. Results A dose-response for canakinumab was not apparent with any of the four predefined dose-response models. The estimated canakinumab dose with equivalent efficacy to colchicine was below the range of doses tested. At 16 weeks, there was a 62% to 72% reduction in the mean number of flares per patient for canakinumab doses ≥50 mg versus colchicine based on a negative binomial model (rate ratio: 0.28–0.38, p≤0.0083), and the percentage of patients experiencing ≥1 flare was significantly lower for all canakinumab doses (15% to 27%) versus colchicine (44%, p<0.05). There was a 64% to 72% reduction in the risk of experiencing ≥1 flare for canakinumab doses ≥50 mg versus colchicine at 16 weeks (hazard ratio (HR): 0.28–0.36, p≤0.05). The incidence of adverse events was similar across treatment groups. Conclusions Single canakinumab doses ≥50 mg or four 4-weekly doses provided superior prophylaxis against flares compared with daily colchicine 0.5 mg. PMID:21540198

Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jin, Hyeon-Ok; Hong, Sung-Eun; Kim, Chang Soon

2015-08-15

Despite excellent initial clinical responses of non-small cell lung cancer (NSCLC) patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), many patients eventually develop resistance. According to a recent report, vacuolar H + ATPase (vATPase) is overexpressed and is associated with chemotherapy drug resistance in NSCLC. We investigated the combined effects of EGFR TKIs and vATPase inhibitors and their underlying mechanisms in the regulation of NSCLC cell death. We found that combined treatment with EGFR TKIs (erlotinib, gefitinib, or lapatinib) and vATPase inhibitors (bafilomycin A1 or concanamycin A) enhanced synergistic cell death compared to treatments with each drugmore » alone. Treatment with bafilomycin A1 or concanamycin A led to the induction of Bnip3 expression in an Hif-1α dependent manner. Knock-down of Hif-1α or Bnip3 by siRNA further enhanced cell death induced by bafilomycin A1, suggesting that Hif-1α/Bnip3 induction promoted resistance to cell death induced by the vATPase inhibitors. EGFR TKIs suppressed Hif-1α and Bnip3 expression induced by the vATPase inhibitors, suggesting that they enhanced the sensitivity of the cells to these inhibitors by decreasing Hif-1α/Bnip3 expression. Taken together, we conclude that EGFR TKIs enhance the sensitivity of NSCLC cells to vATPase inhibitors by decreasing Hif-1α/Bnip3 expression. We suggest that combined treatment with EGFR TKIs and vATPase inhibitors is potentially effective for the treatment of NSCLC. - Highlights: • Co-treatment with EGFR TKIs and vATPase inhibitors induces synergistic cell death • EGFR TKIs enhance cell sensitivity to vATPase inhibitors via Hif-1α downregulation • Co-treatment of these inhibitors is potentially effective for the treatment of NSCLC.« less

ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors.

PubMed

Halasi, Marianna; Wang, Ming; Chavan, Tanmay S; Gaponenko, Vadim; Hay, Nissim; Gartel, Andrei L

2013-09-01

NAC (N-acetyl-L-cysteine) is commonly used to identify and test ROS (reactive oxygen species) inducers, and to inhibit ROS. In the present study, we identified inhibition of proteasome inhibitors as a novel activity of NAC. Both NAC and catalase, another known scavenger of ROS, similarly inhibited ROS levels and apoptosis associated with H₂O₂. However, only NAC, and not catalase or another ROS scavenger Trolox, was able to prevent effects linked to proteasome inhibition, such as protein stabilization, apoptosis and accumulation of ubiquitin conjugates. These observations suggest that NAC has a dual activity as an inhibitor of ROS and proteasome inhibitors. Recently, NAC was used as a ROS inhibitor to functionally characterize a novel anticancer compound, piperlongumine, leading to its description as a ROS inducer. In contrast, our own experiments showed that this compound depicts features of proteasome inhibitors including suppression of FOXM1 (Forkhead box protein M1), stabilization of cellular proteins, induction of ROS-independent apoptosis and enhanced accumulation of ubiquitin conjugates. In addition, NAC, but not catalase or Trolox, interfered with the activity of piperlongumine, further supporting that piperlongumine is a proteasome inhibitor. Most importantly, we showed that NAC, but not other ROS scavengers, directly binds to proteasome inhibitors. To our knowledge, NAC is the first known compound that directly interacts with and antagonizes the activity of proteasome inhibitors. Taken together, the findings of the present study suggest that, as a result of the dual nature of NAC, data interpretation might not be straightforward when NAC is utilized as an antioxidant to demonstrate ROS involvement in drug-induced apoptosis.

Structural and magnetic characterization of mixed valence Co(II, III)xZn1-xO epitaxial thin films

NASA Astrophysics Data System (ADS)

Negi, D. S.; Loukya, B.; Dileep, K.; Sahu, R.; Shetty, S.; Kumar, N.; Ghatak, J.; Pachauri, N.; Gupta, A.; Datta, R.

2014-03-01

In this article, we report on the Co atom incorporation, secondary phase formation and composition-dependent magnetic and optical properties of mixed valence Co(II, III)xZn1-xO epitaxial thin films grown by pulsed laser deposition. The intended total Co concentration is varied between ~6-60 at.% with relatively higher concentration of +3 over +2 charge state. Mixed valence Co(II, III) shows high solubility in ZnO (up to 38 at.%) and ferromagnetism is observed in samples with total Co incorporation of ~29 and 38 at.%. Electron diffraction pattern and high resolution transmission electron microscopy images reveal single crystalline nature of the thin films with wurtzite structure. Co oxide interlayer, with both rock salt and spinel structure, are observed to be formed between the substrate and wurtzite film for total Co concentration at ~17 at.% and above. Magnetization shows composition dependence with a saturation moment value of ~93 emu cm-3 and a coercive field of ~285 Oe observed for ~38 at.% Co:ZnO films. Ferromagnetism was not observed for films with Co concentration 17 and 9 at.%. The Co oxide interlayer does not show any ferromagnetism. All the films are n-type with carrier concentration ~1019 cm-3. The observed magnetism is probably resulting from direct antiferromagntic exchange interaction between Co2+ and Co3+ ions favored by heavy Co alloying giving rise to ferrimagnetism in the system.

Polyphenol oxidase inhibitor(s) from German cockroach (Blattella germanica) extract

USDA-ARS?s Scientific Manuscript database

An extract from German cockroach appears effective in inhibiting browning on apples and potatoes. Successful identification of inhibitor(s) of PPO from German cockroach would be useful to the fruit and vegetable segments of the food industry, due to the losses they incur from enzymatic browning. Ide...

Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema.

PubMed

Brown, Nancy J; Byiers, Stuart; Carr, David; Maldonado, Mario; Warner, Barbara Ann

2009-09-01

Dipeptidyl peptidase-IV (DPP-IV) inhibitors decrease degradation of the incretins. DPP-IV inhibitors also decrease degradation of peptides, such as substance P, that may be involved in the pathogenesis of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. This study tested the hypothesis that DPP-IV inhibition affects risk of clinical angioedema, by comparing the incidence of angioedema in patients treated with the DPP-IV inhibitor vildagliptin versus those treated with comparator in Phase III randomized clinical trials. Prospectively defined angioedema-related events were adjudicated in a blinded fashion by an internal medicine adjudication committee and expert reviewer. Concurrent ACE inhibitor or angiotensin receptor blocker exposure was ascertained from case report forms. Study drug exposure was ascertained from unblinded data from phase III studies. Odds ratios and 95% confidence intervals comparing angioedema risk in vildagliptin-treated and comparator-treated patients were calculated for the overall population and for patients taking ACE inhibitors or angiotensin receptor blockers, using both an analysis of pooled data and a meta-analysis (Peto method). Overall, there was no association between vildagliptin use and angioedema. Among individuals taking an ACE inhibitor, however, vildagliptin use was associated with an increased risk of angioedema (14 confirmed cases among 2754 vildagliptin users versus 1 case among 1819 comparator users: odds ratio 4.57 [95% confidence interval 1.57 to 13.28]) in the meta-analysis. Vildagliptin use may be associated with increased risk of angioedema among patients taking ACE inhibitors, although absolute risk is small. Physicians confronted with angioedema in a patient taking an ACE inhibitor and DPP-IV inhibitor should consider this possible drug-drug interaction.

Effects of Parsley (Petroselinum crispum) and its Flavonol Constituents, Kaempferol and Quercetin, on Serum Uric Acid Levels, Biomarkers of Oxidative Stress and Liver Xanthine Oxidoreductase Aactivity inOxonate-Induced Hyperuricemic Rats.

PubMed

Haidari, Fatemeh; Keshavarz, Seid Ali; Mohammad Shahi, Majid; Mahboob, Soltan-Ali; Rashidi, Mohammad-Reza

2011-01-01

Increased serum uric acid is known to be a major risk related to the development of several oxidative stress diseases. The aim of this study was to investigate the effect of parsley, quercetin and kaempferol on serum uric acid levels, liver xanthine oxidoreductase activity and two non-invasive biomarkers of oxidative stress (total antioxidant capacity and malondialdehyde concentration) in normal and oxonate-induced hyperuricemic rats. A total of 60 male Wistar rats were randomly divided into ten equal groups; including 5 normal groups (vehicle, parsley, quercetin, kaempferol and allopurinol) and 5 hyperuricemic groups (vehicle, parsley, quercetin, kaempferol and allopurinol). Parsley (5 g/Kg), quercetin (5 mg/Kg), kaempferol (5 mg/Kg) and allopurinol (5 mg/Kg) were administrated to the corresponding groups by oral gavage once a day for 2 weeks. The results showed that parsley and its flavonol did not cause any significant reduction in the serum uric acid levels in normal rats, but significantly reduced the serum uric acid levels of hyperuricemic rats in a time-dependent manner. All treatments significantly inhibited liver xanthine oxidoreductase activity. Parsley, kaempferol and quercetin treatment led also to a significant increase in total antioxidant capacity and decrease in malondialdehyde concentration in hyperuricemic rats. Although the hypouricemic effect of allopurinol was much higher than that of parsley and its flavonol constituents, it could not significantly change oxidative stress biomarkers. These features of parsley and its flavonols make them as a possible alternative for allopurinol, or at least in combination therapy to minimize the side effects of allopurinol to treat hyperuricemia and oxidative stress diseases.

Effects of Parsley (Petroselinum crispum) and its Flavonol Constituents, Kaempferol and Quercetin, on Serum Uric Acid Levels, Biomarkers of Oxidative Stress and Liver Xanthine Oxidoreductase Aactivity inOxonate-Induced Hyperuricemic Rats

PubMed Central

Haidari, Fatemeh; Keshavarz, Seid Ali; Mohammad Shahi, Majid; Mahboob, Soltan-Ali; Rashidi, Mohammad-Reza

2011-01-01

Increased serum uric acid is known to be a major risk related to the development of several oxidative stress diseases. The aim of this study was to investigate the effect of parsley, quercetin and kaempferol on serum uric acid levels, liver xanthine oxidoreductase activity and two non-invasive biomarkers of oxidative stress (total antioxidant capacity and malondialdehyde concentration) in normal and oxonate-induced hyperuricemic rats. A total of 60 male Wistar rats were randomly divided into ten equal groups; including 5 normal groups (vehicle, parsley, quercetin, kaempferol and allopurinol) and 5 hyperuricemic groups (vehicle, parsley, quercetin, kaempferol and allopurinol). Parsley (5 g/Kg), quercetin (5 mg/Kg), kaempferol (5 mg/Kg) and allopurinol (5 mg/Kg) were administrated to the corresponding groups by oral gavage once a day for 2 weeks. The results showed that parsley and its flavonol did not cause any significant reduction in the serum uric acid levels in normal rats, but significantly reduced the serum uric acid levels of hyperuricemic rats in a time-dependent manner. All treatments significantly inhibited liver xanthine oxidoreductase activity. Parsley, kaempferol and quercetin treatment led also to a significant increase in total antioxidant capacity and decrease in malondialdehyde concentration in hyperuricemic rats. Although the hypouricemic effect of allopurinol was much higher than that of parsley and its flavonol constituents, it could not significantly change oxidative stress biomarkers. These features of parsley and its flavonols make them as a possible alternative for allopurinol, or at least in combination therapy to minimize the side effects of allopurinol to treat hyperuricemia and oxidative stress diseases. PMID:24250417

Removal of inhibitor(s) of the polymerase chain reaction from formalin fixed, paraffin wax embedded tissues.

PubMed

An, S F; Fleming, K A

1991-11-01

A problem associated with use of the polymerase chain reaction to amplify specific DNA fragments from formalin fixed, paraffin wax embedded tissues is the not infrequent failure of amplification. One possible reason for this could be the presence of inhibitor(s), which interfere with the activity of the reaction. It has been shown that such inhibitor(s) exist when amplifying the human beta globin gene (which exists in human genomic DNA as a single copy gene) from routine clinical samples. A variety of methods to remove such inhibitor(s) were investigated. The results indicate that inhibitor(s) are removed by proteinase K digestion, followed by purification with phenol/chloroform, and centrifugation through a Centricon-30 membrane (30,000 molecular weight cut off). Other factors, including the length and concentration of the DNA sequence to be amplified, can also affect amplification.

Superoxide from NADPH oxidase upregulates type 5 phosphodiesterase in human vascular smooth muscle cells: inhibition with iloprost and NONOate

PubMed Central

Muzaffar, S; Shukla, N; Bond, M; Sala-Newby, G B; Newby, A C; Angelini, G D; Jeremy, J Y

2008-01-01

Background and purpose: To determine whether there is an association between vascular NADPH oxidase (NOX), superoxide, the small GTPase Rac1 and PDE type 5 (PDE5) in human vascular smooth muscle cell (hVSMCs). Experimental approach: hVSMCs were incubated with xanthine–xanthine oxidase (X-XO; a superoxide generating system) or the thromboxane A2 analogue, U46619 (±superoxide dismutase (SOD) or apocynin) for 16 h. The expression of PDE5 and NOX-1 was assessed using Western blotting and superoxide measured. The role of Rac1 in superoxide generation was assessed by overexpressing either the dominant-negative or constitutively active Rac isoforms. The effects of iloprost, DETA-NONOate and the Rho-kinase inhibitor, Y27632, on PDE5 and NOX-1 expression were also studied. Key results: Following 16 h incubation, U46619 and X-XO promoted the expression of PDE5 and NOX-1, an effect blocked by SOD or apocynin when co-incubated over the same time course. X-XO and U46619 both promoted the formation of superoxide. Overexpression of dominant-negative Rac1 or addition of iloprost, DETA-NONOate or Y27632 completely blocked both superoxide release and PDE5 protein expression and activity. Conclusions and implications: These data demonstrate that superoxide derived from NOX upregulates the expression of PDE5 in human VSMCs. As PDE5 hydrolyses cyclic GMP, this effect may blunt the vasculoprotective actions of NO. PMID:18660830

Formation of (FexMn(2-x))O3 solid solution and high sulfur capacity properties of Mn-based/M41 sorbents for hot coal gas desulfurization.

PubMed

Zhang, Y; Liu, B S; Zhang, F M; Zhang, Z F

2013-03-15

Several MCM-41 materials were synthesized at different conditions by hydrothermal procedure using cheap and easily available industrial water glass as silica source. Fe doped manganese-based oxide/MCM-41 sorbents were prepared by a sol-gel method. The effects of loadings of metal oxide, Fe/Mn molar ratios over MCM-41 and reaction temperature on the performance of sorbent for hot coal gas desulfurization were investigated. Various techniques such as BET, XRD, XPS, LRS and HRTEM were used to characterize the sorbents. The result indicated Fe(3+) ions could occupy a position of Mn(3+) in cubic lattice of Mn2O3 and the (FexMn2-x)O3 solid solution is mainly active phase of sorbent. Moreover, the result of nine successive sulfurization-regeneration cycles of sorbent showed high sulfur adsorption capacity and endurable stability of FeMn4Ox/MCM-41 for H2S removal. Copyright © 2013 Elsevier B.V. All rights reserved.

[ROLE OF SLC2A9 AND ABCG2 GENE POLYMORPHISMS IN ORIGIN OF HYPERURICEMIA AND GOUT].

PubMed

Fadieieva, A; Prystupa, L; Pogorelova, O; Kirichenko, N; Dudchenko, I

2016-03-01

The polymorphisms V253I, Q126X, Q141K of SLC2A9 and ABCG2 genes were characterized. GCA и GTC haplotypes of Q126X and Q141K variants can be predictors of gout. The relationship of these polymorphisms with hyperuricaemia according to gender, metabolic syndrome components, with the response to allopurinol was analyzed. It has been established that Q141K polymorphism can directly modulate BCRP-mediated allopurinol and oxypurinol efflux, the K allele is associated with a lower reduction in serum uric acid in response to allopurinol treatment.

Disulfide S-monoxides convert xanthine dehydrogenase into oxidase in rat liver cytosol more potently than their respective disulfides.

PubMed

Sakuma, Satoru; Fujita, Junko; Nakanishi, Masahiko; Wada, Shun-ich; Fujimoto, Yohko

2008-05-01

Xanthine oxidase (XO)/xanthine dehydrogenase (XD) oxidizes oxypurines to uric acid, with only the XO form producing reactive oxygen species. In the present study, the effects of cystamine S-monoxide and cystine S-monoxide (disulfide S-monoxides) on the conversion of XD to XO in rat liver were examined. A partially purified enzyme fraction from the rat liver was incubated with xanthine in the presence or absence of NAD+, and the uric acid formed was measured by HPLC. Under basal conditions, XO activity represented about 15% of the total XO plus XD activity. Cystamine S-monoxide and cystine S-monoxide converted XD into XO in a dose-dependent manner, and the concentrations required to increase XO activity by 50% were approximately 1 and 2 microM, respectively. Their respective thiols (cysteamine and cysteine) and disulfides (cystamine and cystine) up to 10 microM showed weak or no effects on the activities of XO and XD and their conversion. Experiments utilizing a sulfhydryl reducing reagent (dithiothreitol) and sulfhydryl modifiers (4,4'-dithiodipyridine and 1-fluoro-2,4-dinitrobenzene) indicated that disulfide S-monoxides-induced conversion of XD to XO occurs via disulfide bridge formation in XD, but not the modification of sulfhydryl groups. These results suggest that disulfide S-monoxides have the potential to increase the generation of reactive oxygen species through the conversion of XD to XO in liver.

Carboxylesterase inhibitors

PubMed Central

Hatfield, M. Jason; Potter, Philip M.

2011-01-01

Introduction Carboxylesterases play major roles in the hydrolysis of numerous therapeutically active compounds. This is, in part, due to the prevalence of the ester moiety in these small molecules. However, the impact these enzymes may play on drug stability and pharmacokinetics is rarely considered prior to molecule development. Therefore, the application of selective inhibitors of this class of proteins may have utility in modulating the metabolism, distribution and toxicity of agents that are subjected to enzyme hydrolysis. Areas covered This review details the development of all such compounds dating back to 1986, but principally focuses on the very recent identification of selective human carboxylesterases inhibitors. Expert opinion The implementation of carboxylesterase inhibitors may significantly revolutionize drug discovery. Such molecules may allow for improved efficacy of compounds inactivated by this class of enzymes and/or reduce the toxicity of agents that are activated by these proteins. Furthermore, since lack of carboxylesterase activity appears to have no obvious biological consequence, these compounds could be applied in combination with virtually any esterified drug. Therefore, inhibitors of these proteins may have utility in altering drug hydrolysis and distribution in vivo. The characteristics, chemical and biological properties, and potential uses of such agents, are discussed here. PMID:21609191

Febuxostat for hyperuricemia in patients with advanced chronic kidney disease.

PubMed

Akimoto, Tetsu; Morishita, Yoshiyuki; Ito, Chiharu; Iimura, Osamu; Tsunematsu, Sadao; Watanabe, Yuko; Kusano, Eiji; Nagata, Daisuke

2014-01-01

Febuxostat is a nonpurine xanthine oxidase (XO) inhibitor, which recently received marketing approval. However, information regarding the experience with this agent among advanced chronic kidney disease (CKD) patients is limited. In the current study, we investigated the effects of oral febuxostat in patients with advanced CKD with asymptomatic hyperuricemia. We demonstrated, for the first time, that not only the serum levels of uric acid (UA) but also those of 8-hydroxydeoxyguanosine, an oxidative stress marker, were significantly reduced after six months of febuxostat treatment, with no adverse events. These results encouraged us to pursue further investigations regarding the clinical impact of lowering the serum UA levels with febuxostat in advanced CKD patients in terms of concomitantly reducing oxidative stress via the blockade of XO. More detailed studies with a larger number of subjects and assessments of the effects of multiple factors affecting hyperuricemia, such as age, sex, and dietary habits, would shed light on the therapeutic challenges of treating asymptomatic hyperuricemia in patients with various stages of CKD.

Immunization studies with attenuated strains of Bacillus anthracis.

PubMed Central

Ivins, B E; Ezzell, J W; Jemski, J; Hedlund, K W; Ristroph, J D; Leppla, S H

1986-01-01

Live, attenuated strains of Bacillus anthracis lacking either the capsule plasmid pXO2, the toxin plasmid pXO1, or both were tested for their efficacy as vaccines against intravenous challenge with anthrax toxin in Fischer 344 rats and against aerosol or intramuscular challenge with virulent anthrax spores in Hartley guinea pigs. Animals immunized with toxigenic, nonencapsulated (pXO1+, pXO2-) strains survived toxin and spore challenge and demonstrated postimmunization antibody titers to the three components of anthrax toxin (protective antigen, lethal factor, and edema factor). Immunization with two nontoxigenic, encapsulated (pXO1-, pXO2+), Pasteur vaccine strains neither provided protection nor elicited titers to any of the toxin components. Therefore, to immunize successfully against anthrax toxin or spore challenge, attenuated, live strains of B. anthracis must produce the toxin components specified by the pXO1 plasmid. PMID:3084383

Clinical efficacy and safety of topiroxostat in Japanese hyperuricemic patients with or without gout: a randomized, double-blinded, controlled phase 2b study.

PubMed

Hosoya, Tatsuo; Sasaki, Tomomitsu; Ohashi, Tetsuo

2017-03-01

Topiroxostat, a selective xanthine oxidoreductase inhibitor, is used in Japan for the treatment of hyperuricemic patients with or without gout. In terms of the effectiveness of topiroxostat in lowering serum urate levels, the dose-response relationship has been evaluated; however, it remains to be verified. A randomized, multi-center, double-blinded study of topiroxostat was performed for Japanese hyperuricemic patients with or without gout. During the 16-week study, 157 Japanese hyperuricemic patients with or without gout were randomly assigned to receive a placebo, topiroxostat at 120 or 160 mg/day, or allopurinol at 200 mg/day. The primary endpoint of this study was to determine the lowering rate of serum uric acid levels compared to those of baseline at the end of administration. A dose-response relationship (regarding decreases in the serum urate levels) was confirmed for the placebo and topiroxostat at 120 and at 160 mg/day. Moreover, at the end of administration, the lowering rate of serum urate levels was determined to be -44.8% in the topiroxostat 160-mg/day group. No significant difference in the incidence of adverse events was observed among all groups, including the allopurinol group. The serum urate-lowering effect of topiroxostat was found to have a dose-response relationship in Japanese hyperuricemic patients with or without gout.

Potential Pharmacologic Treatments for Cystinuria and for Calcium Stones Associated with Hyperuricosuria

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goldfarb, David S.

Two new potential pharmacologic therapies for recurrent stone disease are described. The role of hyperuricosuria in promoting calcium stones is controversial with only some but not all epidemiologic studies demonstrating associations between increasing urinary uric acid excretion and calcium stone disease. The relationship is supported by the ability of uric acid to 'salt out' (or reduce the solubility of) calcium oxalate in vitro. A randomized, controlled trial of allopurinol in patients with hyperuricosuria and normocalciuria was also effective in preventing recurrent stones. Febuxostat, a nonpurine inhibitor of xanthine oxidase (also known as xanthine dehydrogenase or xanthine oxidoreductase) may have advantagesmore » over allopurinol and is being tested in a similar protocol, with the eventual goal of determining whether urate-lowering therapy prevents recurrent calcium stones. Treatments for cystinuria have advanced little in the past 30 years. Atomic force microscopy has been used recently to demonstrate that effective inhibition of cystine crystal growth is accomplished at low concentrations of L-cystine methyl ester and L-cystine dimethyl ester, structural analogs of cystine that provide steric inhibition of crystal growth. In vitro, L-cystine dimethyl ester had a significant inhibitory effect on crystal growth. The drug's safety and effectiveness will be tested in an Slc3a1 knockout mouse that serves as an animal model of cystinuria.« less

Metabolism of 2-phenylethylamine and phenylacetaldehyde by precision-cut guinea pig fresh liver slices.

PubMed

Panoutsopoulos, Georgios I; Kouretas, Demetrios; Gounaris, Elias G; Beedham, Christine

2004-01-01

2-Phenylethylamine is an endogenous constituent of human brain and is implicated in cerebral transmission. It is also found in certain foodstuffs and may cause toxic side-effects in susceptible individuals. Metabolism of 2-phenylethylamine to phenylacetaldehyde is catalyzed by monoamine oxidase and the oxidation of the reactive aldehyde to its acid derivative is catalyzed mainly by aldehyde dehydrogenase and perhaps aldehyde oxidase, with xanthine oxidase having minimal transformation. The present investigation examines the metabolism of 2-phenylethylamine to phenylacetaldehyde in liver slices and compares the relative contribution of aldehyde oxidase, xanthine oxidase and aldehyde dehydrogenase activity in the oxidation of phenylacetaldehyde with precision-cut fresh liver slices in the presence/absence of specific inhibitors of each enzyme. In liver slices, phenylacetaldehyde was rapidly converted to phenylacetic acid. Phenylacetic acid was the main metabolite of 2-phenylethylamine, via the intermediate phenylacetaldehyde. Phenylacetic acid formation was completely inhibited by disulfiram (specific inhibitor of aldehyde dehydrogenase), whereas isovanillin (specific inhibitor of aldehyde oxidase) inhibited acid formation to a lesser extent and allopurinol (specific inhibitor of xanthine oxidase) had little or no effect. Therefore, in liver slices, phenylacetaldehyde is rapidly oxidized by aldehyde dehydrogenase and aldehyde oxidase with little or no contribution from xanthine oxidase.

KIDFamMap: a database of kinase-inhibitor-disease family maps for kinase inhibitor selectivity and binding mechanisms

PubMed Central

Chiu, Yi-Yuan; Lin, Chih-Ta; Huang, Jhang-Wei; Hsu, Kai-Cheng; Tseng, Jen-Hu; You, Syuan-Ren; Yang, Jinn-Moon

2013-01-01

Kinases play central roles in signaling pathways and are promising therapeutic targets for many diseases. Designing selective kinase inhibitors is an emergent and challenging task, because kinases share an evolutionary conserved ATP-binding site. KIDFamMap (http://gemdock.life.nctu.edu.tw/KIDFamMap/) is the first database to explore kinase-inhibitor families (KIFs) and kinase-inhibitor-disease (KID) relationships for kinase inhibitor selectivity and mechanisms. This database includes 1208 KIFs, 962 KIDs, 55 603 kinase-inhibitor interactions (KIIs), 35 788 kinase inhibitors, 399 human protein kinases, 339 diseases and 638 disease allelic variants. Here, a KIF can be defined as follows: (i) the kinases in the KIF with significant sequence similarity, (ii) the inhibitors in the KIF with significant topology similarity and (iii) the KIIs in the KIF with significant interaction similarity. The KIIs within a KIF are often conserved on some consensus KIDFamMap anchors, which represent conserved interactions between the kinase subsites and consensus moieties of their inhibitors. Our experimental results reveal that the members of a KIF often possess similar inhibition profiles. The KIDFamMap anchors can reflect kinase conformations types, kinase functions and kinase inhibitor selectivity. We believe that KIDFamMap provides biological insights into kinase inhibitor selectivity and binding mechanisms. PMID:23193279

HIV-1 protease inhibitor mutations affect the development of HIV-1 resistance to the maturation inhibitor bevirimat.

PubMed

Fun, Axel; van Maarseveen, Noortje M; Pokorná, Jana; Maas, Renée Em; Schipper, Pauline J; Konvalinka, Jan; Nijhuis, Monique

2011-08-24

Maturation inhibitors are an experimental class of antiretrovirals that inhibit Human Immunodeficiency Virus (HIV) particle maturation, the structural rearrangement required to form infectious virus particles. This rearrangement is triggered by the ordered cleavage of the precursor Gag polyproteins into their functional counterparts by the viral enzyme protease. In contrast to protease inhibitors, maturation inhibitors impede particle maturation by targeting the substrate of protease (Gag) instead of the protease enzyme itself. Direct cross-resistance between protease and maturation inhibitors may seem unlikely, but the co-evolution of protease and its substrate, Gag, during protease inhibitor therapy, could potentially affect future maturation inhibitor therapy. Previous studies showed that there might also be an effect of protease inhibitor resistance mutations on the development of maturation inhibitor resistance, but the exact mechanism remains unclear. We used wild-type and protease inhibitor resistant viruses to determine the impact of protease inhibitor resistance mutations on the development of maturation inhibitor resistance. Our resistance selection studies demonstrated that the resistance profiles for the maturation inhibitor bevirimat are more diverse for viruses with a mutated protease compared to viruses with a wild-type protease. Viral replication did not appear to be a major factor during emergence of bevirimat resistance. In all in vitro selections, one of four mutations was selected: Gag V362I, A364V, S368N or V370A. The impact of these mutations on maturation inhibitor resistance and viral replication was analyzed in different protease backgrounds. The data suggest that the protease background affects development of HIV-1 resistance to bevirimat and the replication profiles of bevirimat-selected HIV-1. The protease-dependent bevirimat resistance and replication levels can be explained by differences in CA/p2 cleavage processing by the different

Natural product-based amyloid inhibitors.

PubMed

Velander, Paul; Wu, Ling; Henderson, Frances; Zhang, Shijun; Bevan, David R; Xu, Bin

2017-09-01

Many chronic human diseases, including multiple neurodegenerative diseases, are associated with deleterious protein aggregates, also called protein amyloids. One common therapeutic strategy is to develop protein aggregation inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. These plant- or microorganism-extracted compounds have shown significant therapeutic potential from in vitro studies as well as in vivo animal tests. Despite the technical challenges of intrinsic disordered or partially unfolded amyloid proteins that are less amenable to characterizations by structural biology, a significant amount of research has been performed, yielding biochemical and pharmacological insights into how inhibitors function. This review aims to summarize recent progress in natural product-based amyloid inhibitors and to analyze their mechanisms of inhibition in vitro. Major classes of natural product inhibitors and how they were identified are described. Our analyses comprehensively address the molecular interactions between the inhibitors and relevant amyloidogenic proteins. These interactions are delineated at molecular and atomic levels, which include covalent, non-covalent, and metal-mediated mechanisms. In vivo animal studies and clinical trials have been summarized as an extension. To enhance natural product bioavailability in vivo, emerging work using nanocarriers for delivery has also been described. Finally, issues and challenges as well as future development of such inhibitors are envisioned. Copyright © 2017 Elsevier Inc. All rights reserved.

Natural product-based amyloid inhibitors

PubMed Central

Velander, Paul; Wu, Ling; Henderson, Frances; Zhang, Shijun; Bevan, David R.; Xu, Bin

2018-01-01

Many chronic human diseases, including multiple neurodegenerative diseases, are associated with deleterious protein aggregates, also called protein amyloids. One common therapeutic strategy is to develop protein aggregation inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. These plant- or microorganism-extracted compounds have shown significant therapeutic potential from in vitro studies as well as in vivo animal tests. Despite the technical challenges of intrinsic disordered or partially unfolded amyloid proteins that are less amenable to characterizations by structural biology, a significant amount of research has been performed, yielding biochemical and pharmacological insights into how inhibitors function. This review aims to summarize recent progress in natural product-based amyloid inhibitors and to analyze their mechanisms of inhibition in vitro. Major classes of natural product inhibitors and how they were identified are described. Our analyses comprehensively address the molecular interactions between the inhibitors and relevant amyloidogenic proteins. These interactions are delineated at molecular and atomic levels, which include covalent, non-covalent, and metal-mediated mechanisms. In vivo animal studies and clinical trials have been summarized as an extension. To enhance natural product bioavailability in vivo, emerging work using nanocarriers for delivery has also been described. Finally, issues and challenges as well as future development of such inhibitors are envisioned. PMID:28390938

Amperometric biosensors based on deposition of gold and platinum nanoparticles on polyvinylferrocene modified electrode for xanthine detection.

PubMed

Baş, Salih Zeki; Gülce, Handan; Yıldız, Salih; Gülce, Ahmet

2011-12-15

In this study, new xanthine biosensors, XO/Au/PVF/Pt and XO/Pt/PVF/Pt, based on electroless deposition of gold(Au) and platinum(Pt) nanoparticles on polyvinylferrocene(PVF) coated Pt electrode for detection of xanthine were presented. The amperometric responses of the enzyme electrodes were measured at the constant potential, which was due to the electrooxidation of enzymatically produced H(2)O(2). Compared with XO/PVF/Pt electrode, XO/Au/PVF/Pt and XO/Pt/PVF/Pt exhibited excellent electrocatalytic activity towards the oxidation of the analyte. Effect of Au and Pt nanoparticles was investigated by monitoring the response currents at the different deposition times and the different concentrations of KAuCl(4) and PtBr(2). Under the optimal conditions, the calibration curves of XO/Au/PVF/Pt and XO/Pt/PVF/Pt were obtained over the range of 2.5 × 10(-3) to 0.56 mM and 2.0 × 10(-3) to 0.66 mM, respectively. The detection limits were 7.5 × 10(-4)mM for XO/Au/PVF/Pt and 6.0 × 10(-4)mM for XO/Pt/PVF/Pt. The effects of interferents, the operational and the storage stabilities of the biosensors and the applicabilities of the proposed biosensors to the drug samples analysis were also evaluated. Copyright © 2011 Elsevier B.V. All rights reserved.

Inhibition of chrysin on xanthine oxidase activity and its inhibition mechanism.

PubMed

Lin, Suyun; Zhang, Guowen; Liao, Yijing; Pan, Junhui

2015-11-01

Chrysin, a bioactive flavonoid, was investigated for its potential to inhibit the activity of xanthine oxidase (XO), a key enzyme catalyzing xanthine to uric acid and finally causing gout. The kinetic analysis showed that chrysin possessed a strong inhibition on XO ability in a reversible competitive manner with IC50 value of (1.26±0.04)×10(-6)molL(-1). The results of fluorescence titrations indicated that chrysin bound to XO with high affinity, and the interaction was predominately driven by hydrogen bonds and van der Waals forces. Analysis of circular dichroism demonstrated that chrysin induced the conformational change of XO with increases in α-helix and β-sheet and reductions in β-turn and random coil structures. Molecular simulation revealed that chrysin interacted with the amino acid residues Leu648, Phe649, Glu802, Leu873, Ser876, Glu879, Arg880, Phe1009, Thr1010, Val1011 and Phe1013 located within the active cavity of XO. The mechanism of chrysin on XO activity may be the insertion of chrysin into the active site occupying the catalytic center of XO to avoid the entrance of xanthine and causing conformational changes in XO. Furthermore, the interaction assays indicated that chrysin and its structural analog apigenin exhibited an additive effect on inhibition of XO. Copyright © 2015 Elsevier B.V. All rights reserved.

Nd: YAG laser irradiation effects on structural and magnetic properties of Ni1+xZrxFe2-2xO4 nanoparticles

NASA Astrophysics Data System (ADS)

Saraf, Tukaram S.; Kounsalye, Jitendra S.; Birajdar, Shankar D.; Shamkuwar, N. R.

2018-05-01

The effect of 112 mJ Nd: YAG laser irradiation on structural, morphological, infrared and magnetic properties of Ni1+xZrxFe2-2xO4 spinel ferrite nanoparticles has been systematically investigated in the present work. The sol-gel auto combustion synthesis method was successfully executed for the synthesis of the present system. All the samples were characterized by X-ray diffraction technique (XRD), scanning electron microscopy (SEM) and infrared spectroscopy (IR) technique. The magnetic properties of the present samples were measured by pulse field hysteresis loop technique. All the properties were measured for laser irradiated samples as well, to understand the effect of irradiation on the properties. The single-phase cubic spinel structure was confirmed by X-ray diffraction patterns of all samples and the disordered structure was observed for irradiated samples. The two principle absorption bands in IR spectra also confirm the formation of the spinel structure. Spherical and agglomerated morphology was observed for Zr4+ substituted nickel ferrite, whereas scratched morphology was observed for the irradiated samples. The grain size confirms the nanocrystalline nature, the crystallite size also evident the same. The magnetic parameters decreased after Zr4+ ion doping and strongly influenced by the irradiation.

SGLT2 inhibitors.

PubMed

Dardi, I; Kouvatsos, T; Jabbour, S A

2016-02-01

Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM. Copyright © 2015 Elsevier Inc. All rights reserved.

Combined treatment with MAO-A inhibitor and MAO-B inhibitor increases extracellular noradrenaline levels more than MAO-A inhibitor alone through increases in beta-phenylethylamine.

PubMed

Kitaichi, Yuji; Inoue, Takeshi; Nakagawa, Shin; Boku, Shuken; Izumi, Takeshi; Koyama, Tsukasa

2010-07-10

Monoamine oxidase inhibitors (MAO inhibitors) have been widely used as antidepressants. However, it remains unclear whether a difference exists between non-selective MAO inhibitors and selective MAO-A inhibitors in terms of their antidepressant effects. Using in vivo microdialysis methods, we measured extracellular noradrenaline and serotonin levels following administration of Ro 41-1049, a reversible MAO-A inhibitor and/or lazabemide, a reversible MAO-B inhibitor in the medial prefrontal cortex (mPFC) of rats. We examined the effect of local infusion of beta-phenylethylamine to the mPFC of rats on extracellular noradrenaline and serotonin levels. Furthermore, the concentrations of beta-phenylethylamine in the tissue of the mPFC after combined treatment with Ro 41-1049 and lazabemide were measured. The Ro 41-1049 alone and the combined treatment significantly increased extracellular noradrenaline levels compared with vehicle and lazabemide alone. Furthermore, the combined treatment increased noradrenaline levels significantly more than Ro 41-1049 alone did. The Ro 41-1049 alone and the combined treatment significantly increased extracellular serotonin levels compared with vehicle and lazabemide alone, but no difference in serotonin levels was found between the combined treatment group and the Ro 41-1049 group. Local infusion of low-dose beta-phenylethylamine increased extracellular noradrenaline levels, but not that of serotonin. Only the combined treatment significantly increased beta-phenylethylamine levels in tissues of the mPFC. Our results suggest that the combined treatment with a MAO-A inhibitor and a MAO-B inhibitor strengthens antidepressant effects because the combined treatment increases extracellular noradrenaline levels more than a MAO-A inhibitor alone through increases in beta-phenylethylamine. Copyright 2010 Elsevier B.V. All rights reserved.

Increased xanthine oxidase during labour--implications for oxidative stress.

PubMed

Many, A; Roberts, J M

1997-11-01

Xanthine dehydrogenase/oxidase (XDH/XO) produces uric acid. When in the oxidase form, this production is coupled with the generation of free radicals. Hypoxia-reperfusion enhances conversion of XDH to XO. Since the placenta is exposed to short periods of hypoxia reperfusion during labour, 17 placentae of pregnancy terminated by elective caesarean section and five placentae of pregnancies terminated by caesarean section during labour were examined for XDH/XO activity. It was found that XO activity was higher in the placentae of labouring women (P = 0.003), which suggests that labour enhances conversion of XDH to XO, facilitating free radical production.

Co0.6Zn0.4Cu0.2CdxFe1.8-xO4 (0.2 ⩽ x ⩽ 0.8) magnetic ferrite nano-particle: Synthesis, characterization and photo-catalytic degradation of methyl orange

NASA Astrophysics Data System (ADS)

Bhukal, Santosh; Bansal, S.; Singhal, Sonal

2014-02-01

Cd2+ ion substituted nano-crystalline cobalt-zinc ferrites having chemical formula Co0.6Zn0.4Cu0.2CdxFe1.8-xO4 (x = 0.2, 0.4, 0.6 and 0.8) have been prepared using sol-gel auto-combustion method. The X-ray diffraction analysis confirmed the crystalline structure and phase purity of all the prepared nano-ferrites. The lattice constant was found to vary linearly from 8.360 Å to 8.390 Å for cadmium ion concentration from 0.2 to 0.8 in accordance with Vegard's law. Ionic radii of tetrahedral site (rA) and octahedral site (rB) was found to increase with increase in the cadmium ion concentration because of larger size of Cd2+ ion (0.97 Å) as compared to that of Fe3+ ion (0.67 Å). Vibrating sample magnetometer (VSM) results revealed that the saturation magnetization, coercivity and anisotropy constant decrease with increase in the cadmium concentration. The distribution of cations among A and B sites of the lattice was estimated by the magnetic moments which were calculated from the magnetic data. Moreover resistivity was found to be decrease with increase in the cadmium concentration. There was increase in drift mobility with increase in temperature because of the enhanced mobility of charge carriers due to thermal activation. Co0.6Zn0.4Cu0.2CdxFe1.8-xO4 showed good catalytic activity towards methyl orange and easily recovered by magnetic separation after the reaction. The photo-catalytic degradation was enhanced as the concentration of cadmium ion increased from 0.2 to 0.8 may be due to decrease in band gap with increase in Cd2+ ion concentration.

BPA-toxicity via superoxide anion overload and a deficit in β-catenin signaling in human bone mesenchymal stem cells.

PubMed

Leem, Yea-Hyun; Oh, Seikwan; Kang, Hong-Je; Kim, Jung-Hwa; Yoon, Juno; Chang, Jae-Suk

2017-01-01

Bisphenol A (BPA), used in the manufacture of products based on polycarbonate plastics and epoxy resins, is well known as an endocrine-disrupting monomer. In the current study, BPA increased cytotoxicity in hBMSCs in a dose- and time-dependent manner, concomitantly with increased lipid peroxidation. Increased cell death in BPA-treated cells was markedly blocked by pretreatment with the superoxide dismutase mimetic MnTBAP and MnTMPyP, but not by catalase, glutathione, the glutathione peroxidase mimetic ebselen, the NOS inhibitor NAME, or the xanthine oxidase inhibitor allopurinol. Furthermore, the decline in nuclear β-catenin and cyclin D1 levels in hBMSCs exposed to BPA was reversed by MnTBAP treatment. Finally, treatment of hBMSCs with the GSK3β inhibitor LiCl 2 increased nuclear β-catenin levels and significantly attenuated cytotoxicity compared with BPA treatment. Our current results in hBMSCs exposed to BPA suggest that BPA causes a disturbance in β-catenin signaling via a superoxide anion overload. © 2016 The Authors Environmental Toxicology Published by Wiley Periodicals, Inc. Environ Toxicol 32: 344-352, 2017. © 2016 The Authors Environmental Toxicology Published by Wiley Periodicals, Inc.

Contribution of aldehyde oxidizing enzymes on the metabolism of 3,4-dimethoxy-2-phenylethylamine to 3,4-dimethoxyphenylacetic acid by guinea pig liver slices.

PubMed

Panoutsopoulos, Georgios I

2006-01-01

3,4-Dimethoxy-2-phenylethylamine is catalyzed to its aldehyde derivative by monoamine oxidase B, but the subsequent oxidation into the corresponding acid has not yet been studied. Oxidation of aromatic aldehydes is catalyzed mainly by aldehyde dehydrogenase and aldehyde oxidase. The present study examines the metabolism of 3,4-dimethoxy-2-phenylethylamine in vitro and in freshly prepared and cryopreserved guinea pig liver slices and the relative contribution of different aldehyde-oxidizing enzymes was estimated by pharmacological means. 3,4-Dimethoxy-2- phenylethylamine was converted into the corresponding aldehyde when incubated with monoamine oxidase and further oxidized into the acid when incubated with both, monoamine oxidase and aldehyde oxidase. In freshly prepared and cryopreserved liver slices, 3,4-dimethoxyphenylacetic acid was the main metabolite of 3,4-dimethoxy-2- phenylethylamine. 3,4-Dimethoxyphenylacetic acid formation was inhibited by 85% from disulfiram (aldehyde dehydrogenase inhibitor) and by 75-80% from isovanillin (aldehyde oxidase inhibitor), whereas allopurinol (xanthine oxidase inhibitor) inhibited acid formation by only 25-30%. 3,4- Dimethoxy-2-phenylethylamine is oxidized mainly to its acid, via 3,4-dimethoxyphenylacetaldehyde, by aldehyde dehydrogenase and aldehyde oxidase with a lower contribution from xanthine oxidase.

BPA‐toxicity via superoxide anion overload and a deficit in β‐catenin signaling in human bone mesenchymal stem cells

PubMed Central

Oh, Seikwan; Kang, Hong‐Je; Kim, Jung‐Hwa; Yoon, Juno

2016-01-01

ABSTRACT Bisphenol A (BPA), used in the manufacture of products based on polycarbonate plastics and epoxy resins, is well known as an endocrine‐disrupting monomer. In the current study, BPA increased cytotoxicity in hBMSCs in a dose‐ and time‐dependent manner, concomitantly with increased lipid peroxidation. Increased cell death in BPA‐treated cells was markedly blocked by pretreatment with the superoxide dismutase mimetic MnTBAP and MnTMPyP, but not by catalase, glutathione, the glutathione peroxidase mimetic ebselen, the NOS inhibitor NAME, or the xanthine oxidase inhibitor allopurinol. Furthermore, the decline in nuclear β‐catenin and cyclin D1 levels in hBMSCs exposed to BPA was reversed by MnTBAP treatment. Finally, treatment of hBMSCs with the GSK3β inhibitor LiCl2 increased nuclear β‐catenin levels and significantly attenuated cytotoxicity compared with BPA treatment. Our current results in hBMSCs exposed to BPA suggest that BPA causes a disturbance in β‐catenin signaling via a superoxide anion overload. © 2016 The Authors Environmental Toxicology Published by Wiley Periodicals, Inc. Environ Toxicol 32: 344–352, 2017. PMID:26822619

Magnetic properties evolution of the CoxFe3-xO4/SiO2 system due to advanced thermal treatment at 700 °C and 1000 °C

NASA Astrophysics Data System (ADS)

Dippong, Thomas; Levei, Erika Andrea; Tanaselia, Claudiu; Gabor, Mihai; Nasui, Mircea; Barbu Tudoran, Lucian; Borodi, Gheorghe

2016-07-01

The CoxFe3-xO4 (x=0.5-2.5) system embedded in the silica matrix was synthesised by sol-gel method using cobalt nitrate, iron nitrate, 1.4-butanediol and tetraethyl orthosilicate. Five different Co/Fe molar ratios in the presence of diol and one without diol were used for the synthesis. The obtained gels were subjected to thermal treatment at 700 °C and 1000 °C. The oxide species formed in the silica matrix, the optimum temperature for the CoFe2O4 phase formation, the evolution of nanocrystallites size and magnetic properties with the calcination temperature were studied. The formed oxide species were studied using X-ray diffraction, Fourier transformed infrared spectrometry, the Co/Fe molar ratio was confirmed using inductively coupled plasma optical emission spectrometry, the nanocrystallites size, shape and clustering was identified by transmission electron microscopy and scanning electron microscopy, while the formation of magnetic phases was investigated by hysteresis and magnetization derivatives measurements.

Oxypurinol - A novel marker for wastewater contamination of the aquatic environment.

PubMed

Funke, Jan; Prasse, Carsten; Lütke Eversloh, Christian; Ternes, Thomas A

2015-05-01

The anti-gout agent allopurinol is one of the most prescribed pharmaceuticals in Germany and is widely metabolized into oxypurinol (80%) as well as the corresponding riboside conjugates (10%) within the human body. To investigate the occurrence of allopurinol and oxypurinol in the urban water cycle an analytical method was developed based on solid phase extraction (SPE) and subsequent liquid chromatography electrospray-ionization tandem mass spectrometry (LC-MS/MS). In raw wastewater concentration levels of oxypurinol ranged up to 26.6 μg L(-1), whereas allopurinol was not detected at all. In wastewater treatment plant (WWTP) effluents, concentrations of allopurinol were allopurinol as well as the cleavage of allopurinol-9-riboside, which was confirmed by laboratory experiments with activated sludge taken from a municipal WWTP. Further tracking of oxypurinol in the urban water cycle revealed its presence in rivers and streams (up to 22.6 μg L(-1)), groundwater (up to 0.38 μg L(-1)) as well as in finished drinking water (up to 0.30 μg L(-1)). Due to the high biological stability and the almost ubiquitous presence in the urban water cycle at elevated concentrations, oxypurinol might be used as marker for domestic wastewater in the environment. This was confirmed by correlation analysis to other wastewater markers with strong correlations of the concentrations of oxypurinol and carbamazepine (r(2) = 0.89) as well as of oxypurinol and primidone (r(2) = 0.82). Copyright © 2015 Elsevier Ltd. All rights reserved.

GLUT9 influences uric acid concentration in patients with Lesch-Nyhan disease.

PubMed

Torres, Rosa J; Puig, Juan G

2018-06-01

Patients with deficient hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity present hyperuricemia and/or hyperuricosuria, with a variable degree of neurological manifestations. Hyperuricemia in HPRT deficiency is due to uric acid overproduction and is frequently treated with allopurinol. Renal uric acid excretion is sharply increased in these patients. In recent years, several renal tubular urate transporter single nucleotide polymorphisms (SNPs), including those of the GLUT9, ABCG2 and URAT1 genes, have been described that influence the renal handling of uric acid and modulate serum urate levels. In the present study, we analyzed whether GLUT9, ABCG2 and URAT1 gene SNPs are able to influence uric acid levels and allopurinol response in patients with HPRT deficiency. Three SNPs, URAT1 rs11231825, GLUT9 rs16890979 and ABCG2 rs2231142, previously associated in our population with hyperuricemia and gout, were analyzed in 27 patients with HPRT deficiency treated with allopurinol for at least 5 years. Patients with HPRT deficiency having allele A of rs16890979 in the GLUT9 gene present with a lower serum urate concentration at diagnosis, before allopurinol treatment is instituted, and need lower allopurinol doses to maintain serum urate levels between 268 and 446 μmol/L (4.5 and 7.5 mg/dL). No relationship between rs2231142 in the ABCG2 gene or rs11231825 in the URAT1 gene and serum urate levels or allopurinol response was found in our patients with HPRT deficiency. GLUT9 SNPs influence the renal handling of uric acid and modulate serum urate levels and the response to treatment in patients with uric acid overproduction due to HPRT deficiency. © 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Peptidase inhibitors in tick physiology.

PubMed

Parizi, L F; Ali, A; Tirloni, L; Oldiges, D P; Sabadin, G A; Coutinho, M L; Seixas, A; Logullo, C; Termignoni, C; DA Silva Vaz, I

2018-06-01

Peptidase inhibitors regulate a wide range of physiological processes involved in the interaction between hematophagous parasites and their hosts, including tissue remodeling, the immune response and blood coagulation. In tick physiology, peptidase inhibitors have a crucial role in adaptation to improve parasitism mechanisms, facilitating blood feeding by interfering with defense-related host peptidases. Recently, a larger number of studies on this topic led to the description of several new tick inhibitors displaying interesting novel features, for example a role in pathogen transmission to the host. A comprehensive review discussing these emerging concepts can therefore shed light on peptidase inhibitor functions, their relevance to tick physiology and their potential applications. Here, we summarize and examine the general characteristics, functional diversity and action of tick peptidase inhibitors with known physiological roles in the tick-host-pathogen interaction. © 2017 The Royal Entomological Society.

Inside HDAC with HDAC inhibitors.

PubMed

Bertrand, Philippe

2010-06-01

Histone deacetylase inhibitors are a large group of diverse molecules intrinsically able to inhibit cell proliferation in various cancer cell lines. Their apoptotic effects have been linked to the modulation in the expression of several regulatory tumor suppressor genes caused by the modified status of histone acetylation, a key event in chromatin remodelling. As the initial histone deacetylase activity of HDAC has been extended to other proteins, the possible other biological mechanisms modified by HDAC inhibitor treatments are still to be clarified. The need for HDAC isoform selective inhibitors is an important issue to serve this goal. This review discusses the approaches proposed by several research groups working on the synthesis of HDAC inhibitors, based on modelling studies and the way these findings were used to obtain new HDAC inhibitors with possible isoform selectivity. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

New scheme for cation distribution and electrical characterization of nanocrystalline aluminum doped magnesium ferrite MgAlxFe2-xO4

NASA Astrophysics Data System (ADS)

Zaki, H. M.; Al-Heniti, S.; Al Shehri, N.

2014-03-01

MgAlxFe2-xO4 (x=0.0 up to 1 step 0.2) was prepared using co-precipitation method. The value of lattice constant is found to decrease with increasing Al3+ concentration. The particle size of the samples calculated using the Sherrer formula was obtained in the range of 15-28 nm. The two main bands corresponding to tetrahedral and octahedral sites were observed to be around 600 cm-1 and 450 cm-1, respectively. These bands are shifted to high frequencies with more doping of Al3+ ions which may be attributed to the decrease in the mean radius of the tetrahedral and octahedral sites. The threshold frequency (νth) for the electronic transition decreases with increasing the Al3+content. The tetrahedral force constant (KT) increases continuously with Al3+ concentration.The bandwidth of the tetrahedral site is found to increase gradually with the Al3+ content. The validity of the proposed cation distribution is confirmed by considering the X-ray intensity ratios of diffraction lines sensitive to the tetrahedral and octahedral sites. DC conductivity measurements exhibited metallic and semiconductor-like behavior with temperature for all compositions. The decrease of Curie temperature with the increase of non-magnetic ions of aluminum indicates their preference to the octahedral sites as well and confirms the validity of the cation distribution.

Structural and electrical properties of Zn1.10CuxMn1.90-xO4 (0 ≤ x ≤ 0.15) for application in IR detectors

NASA Astrophysics Data System (ADS)

Kim, Kyeong-Min; Lee, Sung-Gap; Lee, Dong-Jin; Kwon, Min-Su

2017-05-01

In this study, Zn1.10CuxMn1.90-xO4 (0 ≤ x ≤ 0.15) systems were prepared through the conventional solid state reaction method. All specimens were sintered in air at 1200 °C for 12 h and cooled at a rate of 2 °C/min to 800 °C, subsequently quenching to room temperature. Structural investigations were carried out using X-ray diffraction patterns and energy dispersive spectrometry. For x ≥ 0.10, formation of a tetragonal phase with a Zn-rich Zn-Cu-Mn-O segregated second phase was observed. In the microstructure, the grain size increased from 5.10 μm to 9.68 μm with an increase in Cu content. The resistivity at room temperature, B-value, responsivity and detectivity of the Zn1.10Cu0.05Mn1.85O4 specimen were found to be 300.2 kΩ·cm, 4665, 0.025 V/W, and 2.12 ×104 cmHz1/2/W, respectively. [Figure not available: see fulltext.

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics

PubMed Central

Corsino, Patrick E.; Narayan, Satya

2015-01-01

Cyclin-dependent kinases (CDKs) have been considered promising drug targets for a number of years, but most CDK inhibitors have failed rigorous clinical testing. Recent studies demonstrating clear anticancer efficacy and reduced toxicity of CDK4/6 inhibitors such as palbociclib and multi-CDK inhibitors such as dinaciclib have rejuvenated the field. Favorable results with palbociclib and its recent U.S. Food and Drug Administration approval demonstrate that CDK inhibitors with narrow selectivity profiles can have clinical utility for therapy based on individual tumor genetics. A brief overview of results obtained with ATP-competitive inhibitors such as palbociclib and dinaciclib is presented, followed by a compilation of new avenues that have been pursued toward the development of novel, non–ATP-competitive CDK inhibitors. These creative ways to develop CDK inhibitors are presented along with crystal structures of these agents complexed with CDK2 to highlight differences in their binding sites and mechanisms of action. The recent successes of CDK inhibitors in the clinic, combined with the potential for structure-based routes to the development of non–ATP-competitive CDK inhibitors, and evidence that CDK inhibitors may have use in suppressing chromosomal instability and in synthetic lethal drug combinations inspire optimism that CDK inhibitors will become important weapons in the fight against cancer. PMID:26018905

Syk inhibitors.

PubMed

Chihara, Kazuyasu; Kimura, Yukihiro; Honjo, Chisato; Takeuchi, Kenji; Sada, Kiyonao

2013-01-01

Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in University of Fukui in 1991. Syk is most highly expressed by haemopoietic cells and known to play crucial roles in the signal transduction through various immunoreceptors of the adaptive immune response. However, recent reports demonstrate that Syk also mediates other biological functions, such as innate immune response, osteoclast maturation, platelet activation and cellular adhesion. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Because of its critical roles on the cellular functions, the development of Syk inhibitors for clinical use has been desired. Although many candidate compounds were produced, none of them had progressed to clinical trials. However, novel Syk inhibitors were finally developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure and function of Syk, and then the novel Syk inhibitors and their current status. In addition, we will introduce our research focused on the functions of Syk on Dectin-1-mediated mast cell activation.

Febuxostat ameliorates diabetic renal injury in a streptozotocin-induced diabetic rat model.

PubMed

Lee, Hong-Joo; Jeong, Kyung Hwan; Kim, Yang Gyun; Moon, Joo Young; Lee, Sang Ho; Ihm, Chun Gyoo; Sung, Ji Youn; Lee, Tae Won

2014-01-01

Oxidative stress and inflammation are known to play central roles in the development of diabetic nephropathy (DN). Febuxostat is a novel non-purine xanthine oxidase (XO)-specific inhibitor developed to treat hyperuricemia. In this study, we investigated whether febuxostat could ameliorate DN via renoprotective mechanisms such as alleviation of oxidative stress and anti-inflammatory actions. Male Sprague-Dawley rats were divided into three groups: a normal group, a diabetes group (DM group), and a febuxostat-treated diabetes group (DM+Fx group). We administered 5 mg/kg of febuxostat to experimental rats for 7 weeks and evaluated clinical and biochemical parameters and XO and xanthine dehydrogenase (XDH) activity in hepatic tissue. The degree of oxidative stress and extent of inflammation were evaluated from urine samples and renal tissue collected from each group. Diabetic rats (DM and DM+Fx groups) had higher blood glucose and kidney weight relative to body weight than normal rats. Albuminuria was significantly reduced in febuxostat-treated diabetic rats compared with untreated diabetic rats. Quantitative analysis showed that hepatic XO and XDH activities were higher in the DM groups, but decreased after treatment with febuxostat. Urinary 8-OHdG concentrations and renal cortical nitrotyrosine also indicated reduced oxidative stress in the DM+Fx group relative to the DM group. The number of ED-1-stained cells in the glomerulus and tubule of diabetic renal tissue decreased in febuxostat-treated diabetic rats relative to that of non-treated diabetic rats. Diabetic rats also expressed higher transcript levels of inflammatory genes (E-selectin and VCAM-1), an inflammation-induced enzyme (COX-2), and inflammatory mediators (ED-1 and NF-κB) than control rats; expression of these genes was significantly reduced by treatment with febuxostat. Febuxostat prevents diabetic renal injury such as albuminuria. This renoprotective effect appears to be due to attenuation of the

The effects of residual platelets in plasma on plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays.

PubMed

Pieters, Marlien; Barnard, Sunelle A; Loots, Du Toit; Rijken, Dingeman C

2017-01-01

Due to controversial evidence in the literature pertaining to the activity of plasminogen activator inhibitor-1 in platelets, we examined the effects of residual platelets present in plasma (a potential pre-analytical variable) on various plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays. Blood samples were collected from 151 individuals and centrifuged at 352 and 1500 g to obtain plasma with varying numbers of platelet. In a follow-up study, blood samples were collected from an additional 23 individuals, from whom platelet-poor (2000 g), platelet-containing (352 g) and platelet-rich plasma (200 g) were prepared and analysed as fresh-frozen and after five defrost-refreeze cycles (to determine the contribution of in vitro platelet degradation). Plasminogen activator inhibitor-1 activity, plasminogen activator inhibitor-1 antigen, tissue plasminogen activator/plasminogen activator inhibitor-1 complex, plasma clot lysis time, β-thromboglobulin and plasma platelet count were analysed. Platelet α-granule release (plasma β-thromboglobulin) showed a significant association with plasminogen activator inhibitor-1 antigen levels but weak associations with plasminogen activator inhibitor-1 activity and a functional marker of fibrinolysis, clot lysis time. Upon dividing the study population into quartiles based on β-thromboglobulin levels, plasminogen activator inhibitor-1 antigen increased significantly across the quartiles while plasminogen activator inhibitor-1 activity and clot lysis time tended to increase in the 4th quartile only. In the follow-up study, plasma plasminogen activator inhibitor-1 antigen was also significantly influenced by platelet count in a concentration-dependent manner. Plasma plasminogen activator inhibitor-1 antigen levels increased further after complete platelet degradation. Residual platelets in plasma significantly influence plasma plasminogen activator inhibitor-1 antigen levels mainly through release of

Purine nucleoside phosphorylase and xanthine oxidase activities in erythrocytes and plasma from marine, semiaquatic and terrestrial mammals.

PubMed

López-Cruz, Roberto I; Pérez-Milicua, Myrna Barjau; Crocker, Daniel E; Gaxiola-Robles, Ramón; Bernal-Vertiz, Jaime A; de la Rosa, Alejandro; Vázquez-Medina, José P; Zenteno-Savín, Tania

2014-05-01

Purine nucleoside phosphorylase (PNP) and xanthine oxidase (XO) are key enzymes involved in the purine salvage pathway. PNP metabolizes purine bases to synthetize purine nucleotides whereas XO catalyzes the oxidation of purines to uric acid. In humans, PNP activity is reported to be high in erythrocytes and XO activity to be low in plasma; however, XO activity increases after ischemic events. XO activity in plasma of northern elephant seals has been reported during prolonged fasting and rest and voluntary associated apneas. The objective of this study was to analyze circulating PNP and XO activities in marine mammals adapted to tolerate repeated cycles of ischemia/reperfusion associated with diving (bottlenose dolphin, northern elephant seal) in comparison with semiaquatic (river otter) and terrestrial mammals (human, pig). PNP activities in plasma and erythrocytes, as well as XO activity in plasma, from all species were quantified by spectrophotometry. No clear relationship in circulating PNP or XO activity could be established between marine, semiaquatic and terrestrial mammals. Erythrocytes from bottlenose dolphins and humans are highly permeable to nucleosides and glucose, intraerythrocyte PNP activity may be related to a release of purine nucleotides from the liver. High-energy costs will probably mean a higher ATP degradation rate in river otters, as compared to northern elephant seals or dolphins. Lower erythrocyte PNP activity and elevated plasma XO activity in northern elephant seal could be associated with fasting and/or sleep- and dive-associated apneas. Copyright © 2014 Elsevier Inc. All rights reserved.

Effects of antirheumatic gold compounds on the conversion of xanthine dehydrogenase to oxidase in rabbit liver cytosol in vitro.

PubMed

Sakuma, Satoru; Gotoh, Kyohko; Sadatoku, Namiko; Fujita, Tadashi; Fujimoto, Yohko

2004-07-23

Effects of auranofin (AUR), aurothioglucose (AuTG) and aurothiomalate (AuTM) on the conversion of xanthine dehydrogenase (XD) to oxidase (XO) in the cytosolic fraction from rabbit liver were examined. AUR had no effect on the conversion of XD to XO at concentrations up to 50 microM, whereas at concentrations ranging from 10 to 25 microM, AuTG and AuTM induced the conversion of XD to XO. The constituents of AuTG and AuTM, aurous ion (Au+), but not mercaptosuccinic acid and 1-thio-beta-D-glucose, converted XD to XO in a similar degree to AuTG and AuTM. This means that Au (I) moiety has an important role in the AuTG- and AuTM-induced conversion of XD to XO. Furthermore, N-acetyl-L-cysteine (NAC) and British anti-Lewisite (BAL) reconverted AuTG and AuTM-induced XO to XD, implying that clinical activity of NAC and BAL against toxic reactions of AuTG and AuTM is partially due to the XO reconversion. These results suggest that AuTG and AuTM have the potential to convert XD to its reactive oxygen species-generating form, XO, and that this effect may be correlated with cytotoxic actions of these drugs.

Synthesis of Lysine Methyltransferase Inhibitors

NASA Astrophysics Data System (ADS)

Ye, Tao; Hui, Chunngai

2015-07-01

Lysine methyltransferase which catalyze methylation of histone and nonhistone proteins, play a crucial role in diverse biological processes and has emerged as a promising target for the development of various human diseases, including cancer, inflammation, and psychiatric disorders. However, inhibiting Lysine methyltransferases selectively has presented many challenges to medicinal chemists. During the past decade, lysine methyltransferase inhibitors covering many different structural classes have been designed and developed. In this review, we describe the development of selective, small-molecule inhibitors of lysine methyltransferases with an emphasis on their discovery and chemical synthesis. We highlight the current state of lysine methyltransferase inhibitors and discuss future directions and opportunities for lysine methyltransferase inhibitor discovery.

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics.

PubMed

Law, Mary E; Corsino, Patrick E; Narayan, Satya; Law, Brian K

2015-11-01

Cyclin-dependent kinases (CDKs) have been considered promising drug targets for a number of years, but most CDK inhibitors have failed rigorous clinical testing. Recent studies demonstrating clear anticancer efficacy and reduced toxicity of CDK4/6 inhibitors such as palbociclib and multi-CDK inhibitors such as dinaciclib have rejuvenated the field. Favorable results with palbociclib and its recent U.S. Food and Drug Administration approval demonstrate that CDK inhibitors with narrow selectivity profiles can have clinical utility for therapy based on individual tumor genetics. A brief overview of results obtained with ATP-competitive inhibitors such as palbociclib and dinaciclib is presented, followed by a compilation of new avenues that have been pursued toward the development of novel, non-ATP-competitive CDK inhibitors. These creative ways to develop CDK inhibitors are presented along with crystal structures of these agents complexed with CDK2 to highlight differences in their binding sites and mechanisms of action. The recent successes of CDK inhibitors in the clinic, combined with the potential for structure-based routes to the development of non-ATP-competitive CDK inhibitors, and evidence that CDK inhibitors may have use in suppressing chromosomal instability and in synthetic lethal drug combinations inspire optimism that CDK inhibitors will become important weapons in the fight against cancer. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Nanostructured GdxZn1-xO thin films by nebulizer spray pyrolysis technique: Role of doping concentration on the structural and optical properties

NASA Astrophysics Data System (ADS)

Mariappan, R.; Ponnuswamy, V.; Suresh, P.; Suresh, R.; Ragavendar, M.

2013-07-01

Nanostructured GdxZn1-xO thin films with different Gd concentration from 0% to 10% deposited at 400 °C using the NSP technique. The films were characterized by structural, surface and optical properties, respectively. X-ray diffraction analysis shows that the Gd doped ZnO films have lattice parameters a = 3.2497 Å and c = 5.2018 Å with hexagonal structure and preferential orientation along (0 0 2) plane. The estimated values compare well with the standard values. When film thickness increases from 222 to 240 nm a high visible region transmittance (>70%) is observed. The optical band gap energy, optical constants (n and k), complex dielectric constants (ɛr and ɛi) and optical conductivities (σr and σi) were calculated from optical transmittance data. The optical band gap energy is 3.2 eV for pure ZnO film and 3.6 eV for Gd0.1Zn0.9O film. The PL studies confirm the presence of a strong UV emission peak at 399 nm. Besides, the UV emission of ZnO films decreases with the increase of Gd doping concentration correspondingly the ultra-violet emission is replaced by blue and green emissions.

Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents

PubMed Central

Ververis, Katherine; Hiong, Alison; Karagiannis, Tom C; Licciardi, Paul V

2013-01-01

Histone deacetylase (HDAC) inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents) as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza) and depsipeptide (romidepsin, Istodax). More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the advancement of these drugs, especially to facilitate the rational design of HDAC inhibitors that are effective as antineoplastic agents. This review will discuss the use of HDAC inhibitors as multitargeted therapies for malignancy. Further, we outline the pharmacology and mechanisms of action of HDAC inhibitors while

Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents.

PubMed

Ververis, Katherine; Hiong, Alison; Karagiannis, Tom C; Licciardi, Paul V

2013-01-01

Histone deacetylase (HDAC) inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents) as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza) and depsipeptide (romidepsin, Istodax). More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the advancement of these drugs, especially to facilitate the rational design of HDAC inhibitors that are effective as antineoplastic agents. This review will discuss the use of HDAC inhibitors as multitargeted therapies for malignancy. Further, we outline the pharmacology and mechanisms of action of HDAC inhibitors while

Phosphodiesterase 4 inhibitors.

PubMed

Zebda, Rema; Paller, Amy S

2018-03-01

Historically, drugs available for treating atopic dermatitis (AD) have been limited to topical corticosteroids and topical calcineurin inhibitors, with systemic immunosuppressants and phototherapy reserved for severe AD. Despite their efficacy and infrequent adverse events, phobia about the use of topical steroids and calcineurin inhibitors has limited their use. More targeted options with fewer systemic and cutaneous side effects are needed for treating AD. Phosphodiesterase 4 (PDE4) is involved in the regulation of proinflammatory cytokines via the degradation of cyclic adenosine monophosphate. PDE4 activity is increased in the inflammatory cells of patients with AD, leading to increased production of proinflammatory cytokines and chemokines. Targeting PDE4 reduces the production of these proinflammatory mediators in AD. Both topical and oral PDE4 inhibitors have a favorable safety profile. Crisaborole 2% ointment, a topical PDE4, is now US Food and Drug Administration-approved for children older than 2 years and adults in the treatment of AD. Crisaborole 2% ointment shows early and sustained improvement in disease severity and pruritus and other AD symptoms, with burning and/or stinging upon application as the only related adverse event. Other PDE4 inhibitors are currently in trials with promising efficacy and safety. Copyright © 2017. Published by Elsevier Inc.

The significance of the measurement of serum xanthine oxidase and oxidation markers in patients with acute organophosphorus pesticide poisoning.

PubMed

Zhang, J-W; Lv, G-C; Zhao, Y

2010-01-01

This study investigated whether xanthine oxidase (XO) plays an important role in the mechanism of toxicity of acute organophosphorus pesticide poisoning (AOPP). The serum activities of XO, superoxide dismutase (SOD), paraoxonase-1 (PON1), butyrylcholinesterase (BChE) and malondialdehyde (MDA) were compared in 49 patients with AOPP and 50 age- and gender-matched healthy controls. Serum XO and MDA activities were higher and the serum SOD, PON1 and BChE activities were lower in the AOPP patients compared with the controls. Pearson correlation analysis demonstrated a significant negative correlation between XO activity and the SOD, PON1 and BChE activities, but a significant positive correlation between XO activity and MDA. These results suggest that increased activity of XO and decreased antioxidant enzyme activity contribute to the development of oxidative injury in AOPP patients. Thus, effective antioxidant therapy may be a therapeutic option following AOPP.

Role of host xanthine oxidase in infection due to enteropathogenic and Shiga-toxigenic Escherichia coli.

PubMed

Crane, John K; Naeher, Tonniele M; Broome, Jacqueline E; Boedeker, Edgar C

2013-04-01

Xanthine oxidase (XO), also known as xanthine oxidoreductase, has long been considered an important host defense molecule in the intestine and in breastfed infants. Here, we present evidence that XO is released from and active in intestinal tissues and fluids in response to infection with enteropathogenic Escherichia coli (EPEC) and Shiga-toxigenic E. coli (STEC), also known as enterohemorrhagic E. coli (EHEC). XO is released into intestinal fluids in EPEC and STEC infection in a rabbit animal model. XO activity results in the generation of surprisingly high concentrations of uric acid in both cultured cell and animal models of infection. Hydrogen peroxide (H(2)O(2)) generated by XO activity triggered a chloride secretory response in intestinal cell monolayers within minutes but decreased transepithelial electrical resistance at 6 to 22 h. H(2)O(2) generated by XO activity was effective at killing laboratory strains of E. coli, commensal microbiotas, and anaerobes, but wild-type EPEC and STEC strains were 100 to 1,000 times more resistant to killing or growth inhibition by this pathway. Instead of killing pathogenic bacteria, physiologic concentrations of XO increased virulence by inducing the production of Shiga toxins from STEC strains. In vivo, exogenous XO plus the substrate hypoxanthine did not protect and instead worsened the outcome of STEC infection in the rabbit ligated intestinal loop model of infection. XO released during EPEC and STEC infection may serve as a virulence-inducing signal to the pathogen and not solely as a protective host defense.

Synthesis and crystal structures of new oxyapatites BiCa{sub 4-x}La{sub x}(VO{sub 4}){sub 3-x}(GeO{sub 4}){sub x}O, x=1-3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhuravlev, V.D., E-mail: zhvd@ihim.uran.ru; Tyutyunnik, A.P.; Zubkov, V.G.

2012-10-15

New germanate-vanadates with the general formula BiCa{sub 4-x}La{sub x}(VO{sub 4}){sub 3-x}(GeO{sub 4}){sub x}O, x=1-3, have been synthesized by the nitrate-citrate method and characterized. Structural refinement based on X-ray powder diffraction data showed that these compounds are isostructural with BiCa{sub 4}(VO{sub 4}){sub 3}O (space group P6{sub 3}/m (N 176), Z=2, a=9.8327-9.8755(3), and c=7.1203-7.2133(2) ). They may be viewed as continuous series of solid solutions where Ca{sup 2+} and V{sup 5+} cations in the crystal lattice of vanadate BiCa{sub 4}(VO{sub 4}){sub 3}O are replaced by La{sup 3+} and Ge{sup 4+} cations. In the process of substitution, the La{sup 3+} cations occupy mainlymore » the 4f lattice sites of the germanate-vanadate oxyapatites, but the filling of the 4f and 6h lattice sites in the germanate BiCaLa{sub 3}(GeO{sub 4}){sub 3} is equivalent. IR and Raman spectra were studied. The Raman spectra clearly show a two-mode behavior: the lines of GeO{sub 4} and VO{sub 4} are separated from each other, and the (V/Ge)O{sub 4} tetrahedra exhibit a quasi-independent behavior. - Graphical abstract: Schematic drawing of the BiCa{sub 3}La(VO{sub 4}){sub 2}(GeO{sub 4})O structure in projection on the ac plane. Green-V and Ge, red-Ca(1) and La(1), yellow-Ca(2), La(2) and Bi, dark-blue-O(1)-O(4), blue-O(5). Highlights: Black-Right-Pointing-Pointer The citrate synthesis of germanate-vanadate oxyapatites. Black-Right-Pointing-Pointer The synthesized compounds crystallize in the hexagonal symmetry. Black-Right-Pointing-Pointer A single series of solid solutions BiCa{sub 4-x}La{sub x}(VO{sub 4}){sub 3-x}(GeO{sub 4}){sub x}O, (x=0-3). Black-Right-Pointing-Pointer IR an Raman spectra of mixed crystals.« less

Impact of single anaerobic exercise on delayed activation of endothelial xanthine oxidase in men and women.

PubMed

Wiecek, Magdalena; Maciejczyk, Marcin; Szymura, Jadwiga; Kantorowicz, Malgorzata; Szygula, Zbigniew

2017-11-01

The aim of the study was to evaluate the activity of xanthine oxidase (XO) in the blood of men and women during the first hour following a single anaerobic exercise (AN-EX), and after 24 hours of recovery, and to determine whether the changes in XO activity in the blood after AN-EX are dependent on anaerobic performance. Ten men and ten women performed a single AN-EX. Blood was collected before and five times after completion of the AN-EX. The activity of XO was determined. In both groups, a significant (P < 0.05) increase in blood XO activity was found only 24 hours after the AN-EX. The increased activity of XO in men was significantly lower than in women (P < 0.05). Negative correlations were found between the increase in XO activity in the blood plasma 24 hours after the AN-EX and anaerobic power, the total work performed during the AN-EX and the power decrease. In the first hour after the single AN-EX, XO activity in the blood of women and men did not change, but after 24 hours of recovery, it was significantly higher compared to baseline levels in both sexes. Single AN-EX causes a smaller increase in XO activity in people with higher anaerobic performance.

Reversal of Acetylcholinesterase Inhibitor Toxicity In Vivo by Inhibitors of Choline Transport.

DTIC Science & Technology

1983-10-31

the increased interaction of acetylcholine with the receptor resulting from the inhibition of the enzyme acetylcholinesterase. . Acetylcholinesterase...competitive inhibitors of acetylcholine at the enzyme receptor. The second category, "reversible" cholinesterase inhibitors, form covalent bonds with the...method of Ellman et al. (46) was used to determine the acetyicholinesterase activity in mouse brain homogenates. Briefly, the enzyme activity was

Identification of fermentation inhibitors in wood hydrolyzates and removal of inhibitors by ion exchange and liquid-liquid extraction

NASA Astrophysics Data System (ADS)

Luo, Caidian

1998-12-01

Common methods employed in the ethanol production from biomass consist of chemical or enzymatic degradation of biomass into sugars and then fermentation of sugars into ethanol or other chemicals. However, some degradation products severely inhibit the fermentation processes and substantially reduce the efficiency of ethanol production. How to remove inhibitors from the reaction product mixture and increase the production efficiency are critical in the commercialization of any processes of energy from biomass. The present study has investigated anion exchange and liquid-liquid extraction as potential methods for inhibitor removal. An analytical method has been developed to identify the fermentation inhibitors in a hydrolyzate. The majority of inhibitors present in hybrid poplar hydrolyzate have positively been identified. Ion exchange with weak basic Dowex-MWA-1 resin has been proved to be an effective mean to remove fermentation inhibitors from hybrid poplar hydrolyzate and significantly increase the fermentation productivity. Extraction with n-butanol might be a preferred way to remove inhibitors from wood hydrolyzates and improve the fermentability of sugars in the hydrolyzates. n-Butanol also removes some glucose, mannose and xylose from the hydrolyzate. Inhibitor identification reveals that lignin and sugar degradation compounds including both aromatic and aliphatic aldehydes and carboxylic acids formed in hydrolysis, plus fatty acids and other components from wood extractives are major fermentation inhibitors in Sacchromyces cerevisiae fermentation. There are 35 components identified as fermentation inhibitors. Among them, 4-hydroxy benzoic acid, 3,4-dihydroxy benzoic acid, syringic acid, syringaldehyde, and ferulic acid are among the most abundant aromatic inhibitors in hybrid poplar hydrolyzate. The conversion of aldehyde groups into carboxylic acid groups in the nitric acid catalyzed hydrolysis reduces the toxicity of the hydrolyzate. A wide spectrum of

Influence of crystal structure on the Co{sup II} diffusion behavior in the Zn{sub 1-x}Co{sub x}O system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peiteado, M.; Makovec, D.; Villegas, M.

2008-09-15

The solid state interaction of the Zn{sub 1-x}Co{sub x}O nominal system is investigated by means of diffusion couples and analysis of co-precipitated samples. The formation of a homogeneous Co:ZnO solid solution is found to be determined by the crystal structure from which Co{sup II} ions diffuse into the wurtzite lattice. No diffusion is observed whenever the CoO rock-salt structure is formed from the Co{sup II} precursor. On the contrary, the diffusion from the Co{sub 3}O{sub 4} spinel phase is feasible but has a limited temperature range defined by the reduction at a high temperature of Co{sup III}-Co{sup II}, since thismore » process again leads to the formation of the rock-salt structure. However, when using a highly reactive and homogeneous co-precipitated starting powder, neither the spinel phase nor the rock-salt structure is formed, and a Co{sup II}:ZnO solid solution is obtained, which remains stable up to high temperatures. - Graphical abstract: Maximum diffusion distance for the ZnO-CoO{sub x} couple as a function of temperature. Dashed gray lines represent the temperature values at which the transformations between CoO and Co{sub 3}O{sub 4} compounds take place.« less

Quantitative analysis of phenolic metabolites from different parts of Angelica keiskei by HPLC-ESI MS/MS and their xanthine oxidase inhibition.

PubMed

Kim, Dae Wook; Curtis-Long, Marcus J; Yuk, Heung Joo; Wang, Yan; Song, Yeong Hun; Jeong, Seong Hun; Park, Ki Hun

2014-06-15

Angelica keiskei is used as popular functional food stuff. However, quantitative analysis of this plant's metabolites has not yet been disclosed. The principal phenolic compounds (1-16) within A. keiskei were isolated, enabling us to quantify the metabolites within different parts of the plant. The specific quantification of metabolites (1-16) was accomplished by multiple reaction monitoring (MRM) using a quadruple tandem mass spectrometer. The limit of detection and limit of quantitation were calculated as 0.4-44 μg/kg and 1.5-148 μg/kg, respectively. Abundance and composition of these metabolites varied significantly across different parts of plant. For example, the abundance of chalcones (12-16) decreased as follows: root bark (10.51 mg/g)>stems (8.52 mg/g)>leaves (2.63 mg/g)>root cores (1.44 mg/g). The chalcones were found to be responsible for the xanthine oxidase (XO) inhibition shown by this plant. The most potent inhibitor, xanthoangelol inhibited XO with an IC50 of 8.5 μM. Chalcones (12-16) exhibited mixed-type inhibition characteristics. Copyright © 2013 Elsevier Ltd. All rights reserved.

Rho kinase inhibitors: a patent review (2012 - 2013).

PubMed

Feng, Yangbo; LoGrasso, Philip V

2014-03-01

The Rho kinase/ROCK is critical in vital signal transduction pathways central to many essential cellular activities. Since ROCK possess multiple substrates, modulation of ROCK activity is useful for treatment of many diseases. Significant progress has been made in the development of ROCK inhibitors over the past two years (Jan 2012 to Aug 2013). Patent search in this review was based on FPO IP Research and Communities and Espacenet Patent Search. In this review, patent applications will be classified into four groups for discussions. The grouping is mainly based on structures or scaffolds (groups 1 and 2) and biological functions of ROCK inhibitors (groups 3 and 4). These four groups are i) ROCK inhibitors based on classical structural elements for ROCK inhibition; ii) ROCK inhibitors based on new scaffolds; iii) bis-functional ROCK inhibitors; and iv) novel applications of ROCK inhibitors. Although currently only one ROCK inhibitor (fasudil) is used as a drug, more drugs based on ROCK inhibition are expected to be advanced into market in the near future. Several directions should be considered for future development of ROCK inhibitors, such as soft ROCK inhibitors, bis-functional ROCK inhibitors, ROCK2 isoform-selective inhibitors, and ROCK inhibitors as antiproliferation agents.

Inga laurina trypsin inhibitor (ILTI) obstructs Spodoptera frugiperda trypsins expressed during adaptive mechanisms against plant protease inhibitors.

PubMed

Machado, Suzy Wider; de Oliveira, Caio Fernando Ramalho; Zério, Neide Graciano; Parra, José Roberto Postali; Macedo, Maria Lígia Rodrigues

2017-08-01

Plant protease inhibitors (PIs) are elements of a common plant defense mechanism induced in response to herbivores. The fall armyworm, Spodoptera frugiperda, a highly polyphagous lepidopteran pest, responds to various PIs in its diet by expressing genes encoding trypsins. This raises the question of whether the PI-induced trypsins are also inhibited by other PIs, which we posed as the hypothesis that Inga laurina trypsin inhibitor (ILTI) inhibits PI-induced trypsins in S. frugiperda. In the process of testing our hypothesis, we compared its properties with those of selected PIs, soybean Kunitz trypsin inhibitor (SKTI), Inga vera trypsin inhibitor (IVTI), Adenanthera pavonina trypsin inhibitor (ApTI), and Entada acaciifolia trypsin inhibitor (EATI). We report that ILTI is more effective in inhibiting the induced S. frugiperda trypsins than SKTI and the other PIs, which supports our hypothesis. ILTI may be more appropriate than SKTI for studies regarding adaptive mechanisms to dietary PIs. © 2017 Wiley Periodicals, Inc.

[Fish ovarian fluid contains protease inhibitors].

PubMed

Minin, A A; Ozerova, S G

2015-01-01

Studies of the conditions under which fish egg is activated spontaneously without the sperm showed that the egg retains the ability for fertilization in the ovarian (coelomic) fluid, which surrounds it in the gonad cavity after ovulation. Earlier, we showed that, in artificial media, the spontaneous activation is suppressed by protease inhibitors. In this study, we investigated the presence of natural protease inhibitors in the ovarian fluid and showed that the ovarian fluid of zebrafish and loach contains protease inhibitors, in particular, type I serpin a, a protein inhibitor of trypsin proteases.

Template-based de novo design for type II kinase inhibitors and its extented application to acetylcholinesterase inhibitors.

PubMed

Su, Bo-Han; Huang, Yi-Syuan; Chang, Chia-Yun; Tu, Yi-Shu; Tseng, Yufeng J

2013-10-31

There is a compelling need to discover type II inhibitors targeting the unique DFG-out inactive kinase conformation since they are likely to possess greater potency and selectivity relative to traditional type I inhibitors. Using a known inhibitor, such as a currently available and approved drug or inhibitor, as a template to design new drugs via computational de novo design is helpful when working with known ligand-receptor interactions. This study proposes a new template-based de novo design protocol to discover new inhibitors that preserve and also optimize the binding interactions of the type II kinase template. First, sorafenib (Nexavar) and nilotinib (Tasigna), two type II inhibitors with different ligand-receptor interactions, were selected as the template compounds. The five-step protocol can reassemble each drug from a large fragment library. Our procedure demonstrates that the selected template compounds can be successfully reassembled while the key ligand-receptor interactions are preserved. Furthermore, to demonstrate that the algorithm is able to construct more potent compounds, we considered kinase inhibitors and other protein dataset, acetylcholinesterase (AChE) inhibitors. The de novo optimization was initiated using a template compound possessing a less than optimal activity from a series of aminoisoquinoline and TAK-285 inhibiting type II kinases, and E2020 derivatives inhibiting AChE respectively. Three compounds with greater potency than the template compound were discovered that were also included in the original congeneric series. This template-based lead optimization protocol with the fragment library can help to design compounds with preferred binding interactions of known inhibitors automatically and further optimize the compounds in the binding pockets.

Histone Deacetylase Inhibitors as Anticancer Drugs.

PubMed

Eckschlager, Tomas; Plch, Johana; Stiborova, Marie; Hrabeta, Jan

2017-07-01

Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

Histone Deacetylase Inhibitors as Anticancer Drugs

PubMed Central

Eckschlager, Tomas; Plch, Johana; Stiborova, Marie; Hrabeta, Jan

2017-01-01

Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities. PMID:28671573

Targeting cancer with kinase inhibitors

PubMed Central

Gross, Stefan; Rahal, Rami; Stransky, Nicolas; Lengauer, Christoph; Hoeflich, Klaus P.

2015-01-01

Kinase inhibitors have played an increasingly prominent role in the treatment of cancer and other diseases. Currently, more than 25 oncology drugs that target kinases have been approved, and numerous additional therapeutics are in various stages of clinical evaluation. In this Review, we provide an in-depth analysis of activation mechanisms for kinases in cancer, highlight recent successes in drug discovery, and demonstrate the clinical impact of selective kinase inhibitors. We also describe the substantial progress that has been made in designing next-generation inhibitors to circumvent on-target resistance mechanisms, as well as ongoing strategies for combining kinase inhibitors in the clinic. Last, there are numerous prospects for the discovery of novel kinase targets, and we explore cancer immunotherapy as a new and promising research area for studying kinase biology. PMID:25932675

[ACE inhibitors and the kidney].

PubMed

Hörl, W H

1996-01-01

Treatment with ACE inhibitors results in kidney protection due to reduction of systemic blood pressure, intraglomerular pressure, an antiproliferative effect, reduction of proteinuria and a lipid-lowering effect in proteinuric patients (secondary due to reduction of protein excretion). Elderly patients with diabetes melitus, coronary heart disease or peripheral vascular occlusion are at risk for deterioration of kidney function due to a high frequency of renal artery stenosis in these patients. In patients with renal insufficiency dose reduction of ACE inhibitors is necessary (exception: fosinopril) but more important is the risk for development of hyperkalemia. Patients at risk for renal artery stenosis and patients pretreated with diuretics should receive a low ACE inhibitor dosage initially ("start low - go slow"). For compliance reasons once daily ACE inhibitor dosage is recommended.

Inhibitors of Ethylene Biosynthesis and Signaling.

PubMed

Schaller, G Eric; Binder, Brad M

2017-01-01

Ethylene is a gas biosynthesized by plants which has many physiological and developmental effects on their growth. Ethylene affects agriculturally and horticulturally important traits such as fruit ripening, post-harvest physiology, senescence, and abscission, and so ethylene action is often inhibited to improve the shelf life of fruits, vegetables, and cut flowers. Chemical inhibitors of ethylene action are also useful for research to characterize the mechanisms of ethylene biosynthesis and signal transduction, and the role that ethylene plays in various physiological processes. Here, we describe the use of three inhibitors commonly used for the study of ethylene action in plants: 2-aminoethoxyvinyl glycine (AVG), silver ions (Ag), and the gaseous compound 1-methylcyclopropene (1-MCP). AVG is an inhibitor of 1-aminocyclopropane-1-carboxylic acid (ACC) synthase, a key enzyme involved in ethylene biosynthesis. Silver and 1-MCP are both inhibitors of the ethylene receptors. Inhibitor use as well as off-target effects are described with a focus on ethylene responses in dark-grown Arabidopsis seedlings. Methods for the use of these inhibitors can be applied to other plant growth assays.

A crystalline protein-proteinase inhibitor from pinto bean seeds.

PubMed

Wang, D

1975-06-26

A crystalline protein-proteinase inhibitor has been isolated from seeds of Pinto bean (Phaseolus vulgaris cultvar. Pinto). It has an average molecular weight of 19 000 as estimated by gel filtration. This crystalline inhibitor is highly active against both bovine pancreatic trypsin and alpha-chymotrypsin. Complexes of both trypsin-inhibitor and alpha-chymotrypsin-inhibitor have been isolated. The inhibitor which was derived from the dissociated trypsin-inhibitor complex was only 62% as effective as the original compound against either enzyme. In contrast, the inhibitor obtained from alpha-chymotrypsin-inhibitor complex retained its full original inhibitory activity for trypsin, but only 25% of its original activity against alpha-chymotrypsin. The dissociated inhibitor from alpha-chymotrypsin-inhibitor compex, despite its full inhibitory activity, had been modified to such an extent that it could no longer form any precipitable complex with trypsin. The crystalline protein-proteinase inhibitor is not homogeneous and has been resolved into two distinct inhibitors in terms of their physical and chemical properties. These two inhibitors are designated as Pinto bean proteinase inhibitor I and II and their respective minimum molecular weights are 9100 and 10 000. They differ most strikingly in their amino acid composition in that inhibitor II is void of both valine and methionine.

Unstable spin-ice order in the stuffed metallic pyrochlore Pr 2+xIr 2-xO 7-δ

DOE PAGES

MacLaughlin, D. E.; Bernal, O. O.; Shu, Lei; ...

2015-08-24

Specific heat, elastic neutron scattering, and muon spin rotation experiments have been carried out on a well-characterized sample of “stuffed” (Pr-rich) Pr 2+xIr 2-xO 7-δ. Elastic neutron scattering shows the onset of long-range spin-ice “2-in/2-out” magnetic order at 0.93 kelvin, with an ordered moment of 1.7(1) Bohr magnetons per Pr ion at low temperatures. Approximate lower bounds on the correlation length and correlation time in the ordered state are 170 angstroms and 0.7 nanosecond, respectively. Muon spin rotation experiments yield an upper bound 2.6(7) milliteslas on the local field B 4f loc at the muon site, which is nearly twomore » orders of magnitude smaller than the expected dipolar field for long-range spin-ice ordering of 1.7-Bohr magneton moments (120–270 milliteslas, depending on the muon site). This shortfall is due in part to splitting of the non-Kramers crystal-field ground-state doublets of near-neighbor Pr 3+ ions by the positive-muon-induced lattice distortion. For this to be the only effect, however, ~160 Pr moments out to a distance of ~14 angstroms must be suppressed. An alternative scenario—one consistent with the observed reduced nuclear hyperfine Schottky anomaly in the specific heat—invokes slow correlated Pr-moment fluctuations in the ordered state that average B 4f loc on the μSR time scale (~10 -7 second), but are static on the time scale of the elastic neutron scattering experiments (~10 -9 second). In this picture, the dynamic muon relaxation suggests a Pr 3+ 4f correlation time of a few nanoseconds, which should be observable in a neutron spin echo experiment.« less

Activity of xanthine oxidase in plasma correlates with indices of insulin resistance and liver dysfunction in Japanese patients with type 2 diabetes mellitus and metabolic syndrome: A pilot exploratory study.

PubMed

Sunagawa, Sumito; Shirakura, Takashi; Hokama, Noboru; Kozuka, Chisayo; Yonamine, Masato; Namba, Toyotaka; Morishima, Satoko; Nakachi, Sawako; Nishi, Yukiko; Ikema, Tomomi; Okamoto, Shiki; Matsui, Chieko; Hase, Naoki; Tamura, Mizuho; Shimabukuro, Michio; Masuzaki, Hiroaki

2018-06-03

There is a controversy whether hyperuricemia is an independent risk for cardiometabolic diseases. Serum level of uric acid is affected by a wide variety of factors involved in its production and excretion. On the other hand, evidence has accumulated that locally and systemically activated xanthine oxidase (XO), a rate limiting enzyme for production of uric acid, is linked to metabolic derangement in humans and rodents. We therefore explored the clinical implication of plasma XO activity in patients with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). We enrolled 60 patients with T2DM and MetS. MetS was defined according to the 2005 International Diabetes Federation guidelines. Plasma XO activity was measured by highly sensitive fluorometric assay measuring the conversion of pterin to isoxanthopterin, and explored associations between the value of plasma XO activity and metabolic parameters. Value of plasma XO activity was correlated with indices of insulin resistance and level of circulating liver transaminases. On the other hand, level of serum uric acid was not correlated with indices of insulin resistance. The value of plasma XO activity was not correlated with serum uric acid level. Plasma XO activity correlates with indices of insulin resistance and liver dysfunction in Japanese patients with T2DM and MetS. Through assessing the plasma XO activity, patients demonstrating normal level of serum uric acid with higher activity of XO can be screened, thereby possibly providing a clue to uncover metabolic risks in T2DM and MetS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

[The primary structure of the alpha-amylase inhibitor Hoe 467A from Streptomyces tendae 4158. A new class of inhibitors].

PubMed

Aschauer, H; Vértesy, L; Nesemann, G; Braunitzer, G

1983-10-01

The native or modified alpha-amylase inhibitor Hoe 467A - isolated from the culture medium of Streptomyces tendae 4158 - and overlapping peptides were degraded by the automatic Edman technique. The oxidized or aminoethylated or oxidized and maleoylated inhibitor was digested with trypsin and the native inhibitor with pepsin. Further digestion with Staphylococcus aureus proteinase was also carried out. After peptic digestion two cystin peptides were isolated, which allowed the establishment of the disulfide bonds. The alpha-amylase inhibitor is a polypeptid consisting of 74 amino-acid residues with a molecular mass of 7958 Da. The inhibitor is composed of all naturally occurring amino acids except methionine and phenylalanine and shows no sequence homology to known inhibitors. The clinical and pharmacological importance in respect to the inhibitors ability for inactivation of human salivary and pancreatic alpha-amylase is discussed. Especially the proteinase resistance of the inhibitor enables a clinical application in human (e.g. Diabetes mellitus) per os.

Effect of phosphodiesterase inhibitors in the bladder.

PubMed

Chughtai, Bilal; Ali, Aizaz; Dunphy, Claire; Kaplan, Steven A

2015-01-01

Many aging men will experience lower urinary tract symptoms (LUTS). Phosphodiesterase type 5 (PDE5) inhibitors have shown promise in treating LUTS in these patients. PDE5 inhibitors mediate their effects through several pathways including cAMP, NO/cGMP, K-channel modulated pathways, and the l -cysteine/H 2 S pathway. PDE5 inhibitors exert their effect in muscle cells, nerve fibers, and interstitial cells (ICs). The use of PDE5 inhibitors led to improvement in LUTS. This included urodynamic parameters. PDE5 inhibitors may play a significant role in LUTS due to their effect on the bladder rather than the prostate.

Metabolic muscle damage and oxidative stress markers in an America's Cup yachting crew.

PubMed

Barrios, Carlos; Hadala, Michal; Almansa, Inmaculada; Bosch-Morell, Francisco; Palanca, José M; Romero, Francisco J

2011-07-01

Activities of enzymes involved in muscle damage [creatine kinase (CK) and aspartate aminotransferase (AST)] and levels of malondialdehyde (MDA) as a marker of oxidative stress were monitored in the plasma of 27 members of an America's Cup yachting crew. The preventive benefits of allopurinol on muscle damage were also tested. In racing period A, the crew was divided into two groups according to their tasks on board. Blood samples from all 27 sailors were obtained before the start of a 5-day fleet race, after the last race, and after the ten match races. In period B, crew members were divided at random into two groups. One group (13 participants) received 300 mg/day of allopurinol 3 h before racing. The other ten members received placebo. Blood samples were collected just before and after the second round of the Louis Vuitton Cup. All participants showed increased CK and AST activities after the racing period A. The increase in CK activity was highest in sailors involved in strenuous physical work. At the end of period A, plasma MDA levels were higher in all participants as compared with non-participant athletes. In period B, a significant decrease in CK activity, but not in AST, appeared among participants receiving allopurinol. Plasma MDA decreased in sailors treated with allopurinol, but this reduction did not reach statistical significance. America's Cup is a sailing sport with high physical demands, as shown by the increase in muscle-damage markers. Treatment with allopurinol appeared to decrease the levels of muscle damage markers.

Thiopurine Drugs Repositioned as Tyrosinase Inhibitors

PubMed Central

Choi, Joonhyeok; Lee, You-Mie; Jee, Jun-Goo

2017-01-01

Drug repositioning is the application of the existing drugs to new uses and has the potential to reduce the time and cost required for the typical drug discovery process. In this study, we repositioned thiopurine drugs used for the treatment of acute leukaemia as new tyrosinase inhibitors. Tyrosinase catalyses two successive oxidations in melanin biosynthesis: the conversions of tyrosine to dihydroxyphenylalanine (DOPA) and DOPA to dopaquinone. Continuous efforts are underway to discover small molecule inhibitors of tyrosinase for therapeutic and cosmetic purposes. Structure-based virtual screening predicted inhibitor candidates from the US Food and Drug Administration (FDA)-approved drugs. Enzyme assays confirmed the thiopurine leukaemia drug, thioguanine, as a tyrosinase inhibitor with the inhibitory constant of 52 μM. Two other thiopurine drugs, mercaptopurine and azathioprine, were also evaluated for their tyrosinase inhibition; mercaptopurine caused stronger inhibition than thioguanine did, whereas azathioprine was a poor inhibitor. The inhibitory constant of mercaptopurine (16 μM) was comparable to that of the well-known inhibitor kojic acid (13 μM). The cell-based assay using B16F10 melanoma cells confirmed that the compounds inhibit mammalian tyrosinase. Particularly, 50 μM thioguanine reduced the melanin content by 57%, without apparent cytotoxicity. Cheminformatics showed that the thiopurine drugs shared little chemical similarity with the known tyrosinase inhibitors. PMID:29283382

Invertase proteinaceous inhibitor of Cyphomandra betacea Sendt fruits.

PubMed

Ordóñez, R M; Isla, M I; Vattuone, M A; Sampietro, A R

2000-01-01

This work describes a new invertase proteinaceous inhibitor from Cyphomandra betacea Sendt. (tomate de arbol) fruits. The proteinaceous inhibitor was isolated and purified from a cell wall preparation. The pH stability, kinetics of the inhibition of the C. betacea invertase, inhibition of several higher plant invertases and lectin nature of the inhibitor were studied. The inhibitor structure involves a single polypeptide (Mr = 19000), as shown by gel filtration and SDS-PAGE determinations. N-terminal aminoacid sequence was determined. The properties and some structural features of the inhibitor are compared with the proteinaceous inhibitors from several plant species (Beta vulgaris L., Ipomoea batatas L. and Lycopersicon esculentum Mill.). All these inhibitors share lectinic properties, some common epitopes, some aminoacid sequences and a certain lack of specificity towards invertases of different species, genera and even plant family. In consequence, the inhibitors appear to belong to the same lectin family. It is now known that some lectins are part of the defence mechanism of higher plants against fungi and bacteria and this is a probable role of the proteinaceous inhibitors.

The efficacy and safety of febuxostat for urate lowering in gout patients ≥65 years of age

PubMed Central

2012-01-01

Background The incidence of gout rises with increasing age. Management of elderly (≥65 years) gout patients can be challenging due to high rates of comorbidities, such as renal impairment and cardiovascular disease, and concomitant medication use. However, there is little data specifically addressing the efficacy and safety of available urate-lowering therapies (ULT) in the elderly. The objective of this post hoc analysis was to examine the efficacy and safety of ULT with febuxostat or allopurinol in a subset of elderly subjects enrolled in the CONFIRMS trial. Methods Hyperuricemic (serum urate [sUA] levels ≥ 8.0 mg/dL) gout subjects were enrolled in the 6-month, double-blind, randomized, comparative CONFIRMS trial and randomized, 1:1:1, to receive febuxostat, 40 mg or 80 mg, or allopurinol (200 mg or 300 mg based on renal function) once daily. Flare prophylaxis was provided throughout the study duration. Study endpoints were the percent of elderly subjects with sUA <6.0 mg/dL at the final visit, overall and by renal function status, percent change in sUA from baseline to final visit, flare rates, and rates of adverse events (AEs). Results Of 2,269 subjects enrolled, 374 were elderly. Febuxostat 80 mg was significantly more efficacious (82.0%) than febuxostat 40 mg (61.7%; p < 0.001) or allopurinol (47.3%; p < 0.001) for achieving the primary efficacy endpoint. Febuxostat 40 mg was also superior to allopurinol in this population (p = 0.029). In subjects with mild-to-moderate renal impairment, significantly greater ULT efficacy was observed with febuxostat 40 mg (61.6%; p = 0.028) and febuxostat 80 mg (82.5%; p < 0.001) compared to allopurinol 200/300 mg (46.9%). Compared to allopurinol 200/300 mg, the mean percent change in sUA from baseline was significantly greater for both febuxostat 80 mg (p < 0.001) and febuxostat 40 mg (p = 0.011) groups. Flare rates declined steadily in all treatment groups. Rates of AEs were low and comparable across treatments

High-Throughput Detection of Bacillus Anthracis Spores using Peptide-Conjugated Nano/Micro-Beads

DTIC Science & Technology

2006-07-26

natto was a lab-stock isolated from natto . Expertise with B. anthracis ∆Sterne (pXO1-, pXO2-) and B. anthracis Sterne 34F2 (pXO1+, pXO2-) were...spore-peptide-Qdot complexes were analyzed by FACS. We found that BA1 peptide did not bind to B. subtilis DB104, B. subtilis natto and B. cereus...subtilis DB104, B. subtilis natto and B. cereus used as other more negative controls did not show fluorescence (data not shown). We then examined the

The existence of imidazoline corrosion inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martin, J.A.; Valone, F.W.

1985-05-01

Spectroscopic methods, i.e., Fourier transform infrared (FT-IR), carbon-13 nuclear magnetic reasonance (/sup 13/C NMR), and ultraviolet (UV) spectroscopy, were used to investigate the actual chemical composition of oilfield corrosion inhibitors. Inhibitor formulations consisting of an amide or imidazoline reacted with a dimer-trimer acid, along with an ethoxylated surfactant and an aromatic solvent, were used for these studies. /sup 13/C NMR and FT-IR spectra of these inhibitors, as well as spectra of pure imidazolines, showed that the imidazoline functional group was fairly rapidly hydrolyzed to the amide form. For instance, in FT-IR studies, the imine functional group decreased in intensity asmore » a function of time. Coincident with this was an increase in the intensities of the vibrational resonances attributed to the amide functionality. The relative molar ratio of imidazoline to amide in a corrosion inhibitor could be calculated via UV spectroscopy. Within a 20 day interval after inhibitor synthesis, this ratio decreased by a factor greater than 20. These results, as well as a discussion of their economic impact on oilfield corrosion inhibitor formulation, are presented in this paper.« less

Cholinesterase inhibitors: a patent review (2007 - 2011).

PubMed

de los Ríos, Cristóbal

2012-08-01

Cholinesterase inhibitors participate in the maintenance of the levels of the neurotransmitter acetylcholine by inhibiting the enzymes implicated in its degradation, namely, butyrylcholinesterase and acetylcholinesterase. This pharmacological action has an important role in several diseases, including neurodegenerative diseases such as Alzheimer's. This article reviews recent advances in the development of cholinesterase enzyme inhibitors, covering the development of new chemical entities, new pharmaceutical formulations with known inhibitors or treatments in combination with other drug families. The development of cholinesterase inhibitors has to face several issues, including the fact that the principal indication for these drugs, Alzheimer's disease, is not currently believed to derivate from a cholinergic deficiency, although most of the drugs clinically used for these disease are cholinesterase inhibitors. Moreover, the adverse effects found when administering cholinesterase inhibitors limit their use in other diseases, such as gastrointestinal diseases, glaucoma, or analgesia.

[Syk inhibitors].

PubMed

Kimura, Yukihiro; Chihara, Kazuyasu; Takeuchi, Kenji; Sada, Kiyonao

2013-07-01

Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in the University of Fukui in 1991. Syk is known to be essential for the various physiological functions, especially in hematopoietic lineage cells. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Recently, novel Syk inhibitors were developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure, and function of Syk, and then describe the novel Syk inhibitors and their current status. Furthermore, we will introduce our findings of the adaptor protein 3BP2 (c-Abl SH3 domain-binding protein-2), as a novel target of Syk.

Inhibitor development in non-severe haemophilia across Europe.

PubMed

Fischer, Kathelijn; Iorio, Alfonso; Lassila, Riitta; Peyvandi, Flora; Calizzani, Gabriele; Gatt, Alex; Lambert, Thierry; Windyga, Jerzy; Gilman, Estelle A; Hollingsworth, R; Makris, Michael

2015-10-01

Evidence about inhibitor formation in non-severe haemophilia and the potential role for clotting factor concentrate type is scant. It was the aim of this study to report inhibitor development in non-severe haemophilia patients enrolled in the European Haemophilia Safety Surveillance (EUHASS) study. Inhibitors are reported quarterly and total treated patients annually. Incidence rates and 95% confidence intervals (95% CI) were calculated according to diagnosis and concentrate used. Between 1-10-2008 and 31-12-2012, 68 centres reported on 7,969 patients with non-severe haemophilia A and 1,863 patients with non-severe haemophilia B. For haemophilia A, 37 inhibitors occurred in 8,622 treatment years, resulting in an inhibitor rate of 0.43/100 treatment years (95% CI 0.30-0.59). Inhibitors occurred at a median age of 35 years, after a median of 38 exposure days (EDs; P25-P75: 20-80); with 72% occurring within the first 50 EDs. In haemophilia B, one inhibitor was detected in 2,149 treatment years, resulting in an inhibitor rate of 0.05/100 years (95% CI 0.001-0.26). This inhibitor developed at the age of six years, after six EDs. The rate of inhibitors appeared similar across recombinant and plasma derived factor VIII (FVIII) concentrates. Rates for individual concentrates could not be calculated at this stage due to low number of events. In conclusion, inhibitors in non-severe haemophilia occur three times more frequently than in previously treated patients with severe haemophilia at a rate of 0.43/100 patient years (haemophilia A) and 0.05/100 years (haemophilia B). Although the majority of inhibitors developed in the first 50 EDs, inhibitor development continued with increasing exposure to FVIII.

Notch Inhibitors for Cancer Treatment

PubMed Central

Espinoza, Ingrid; Miele, Lucio

2013-01-01

Notch signaling is an evolutionarily conserved cell signaling pathway involved in cell fate during development, stem cell renewal and differentiation in postnatal tissues. Roles for Notch in carcinogenesis, in the biology of cancer stem cells and tumor angiogenesis have been reported. These features identify Notch as a potential therapeutic target in oncology. Based on the molecular structure of Notch receptor, Notch ligands and Notch activators, a set of Notch pathway inhibitors have been developed. Most of these inhibitors had shown anti-tumor effects in preclinical studies. At the same time, the combinatorial effect of these inhibitors with current chemotherapeutical drugs still under study in different clinical trials. In this review, we describe the basics of Notch signaling and the role of Notch in normal and cancer stem cells as a logic way to develop different Notch inhibitors and their current stage of progress for cancer patient’s treatment. PMID:23458608

A comparison of effects of DPP-4 inhibitor and SGLT2 inhibitor on lipid profile in patients with type 2 diabetes.

PubMed

Cha, Seon-Ah; Park, Yong-Moon; Yun, Jae-Seung; Lim, Tae-Seok; Song, Ki-Ho; Yoo, Ki-Dong; Ahn, Yu-Bae; Ko, Seung-Hyun

2017-04-13

Previous studies suggest that dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors have different effects on the lipid profile in patients with type 2 diabetes. We investigated the effects of DPP-4 inhibitors and SGLT2 inhibitors on the lipid profile in patients with type 2 diabetes. From January 2013 to December 2015, a total of 228 patients with type 2 diabetes who were receiving a DPP-4 inhibitor or SGLT2 inhibitor as add-on therapy to metformin and/or a sulfonylurea were consecutively enrolled. We compared the effects of DPP-4 inhibitors and SGLT2 inhibitors on the lipid profile at baseline and after 24 weeks of treatment. To compare lipid parameters between the two groups, we used the analysis of covariance (ANCOVA). A total of 184 patients completed follow-up (mean age: 53.1 ± 6.9 years, mean duration of diabetes: 7.1 ± 5.7 years). From baseline to 24 weeks, HDL-cholesterol (HDL-C) levels were increased by 0.5 (95% CI, -0.9 to 2.0) mg/dl with a DPP-4 inhibitor and by 5.1 (95% CI, 3.0 to 7.1) mg/dl with an SGLT2 inhibitor (p = 0.001). LDL-cholesterol (LDL-C) levels were reduced by 8.4 (95% CI, -14.0 to -2.8) mg/dl with a DPP-4 inhibitor, but increased by 1.3 (95% CI, -5.1 to 7.6) mg/dl with an SGLT2 inhibitor (p = 0.046). There was no significant difference in the mean hemoglobin A1c (8.3 ± 1.1 vs. 8.0 ± 0.9%, p = 0.110) and in the change of total cholesterol (TC) (p = 0.836), triglyceride (TG) (p = 0.867), apolipoprotein A (p = 0.726), apolipoprotein B (p = 0.660), and lipoprotein (a) (p = 0.991) between the DPP-4 inhibitor and the SGLT2 inhibitor. The SGLT2 inhibitor was associated with a significant increase in HDL-C and LDL-C after 24 weeks of SGLT2 inhibitor treatment in patients with type 2 diabetes compared with those with DPP-4 inhibitor treatment in this study. This study was conducted by retrospective medical record review.

Evaluation of Encapsulated Inhibitor for Autonomous Corrosion Protection

NASA Technical Reports Server (NTRS)

Johnsey, M. N.; Li, W.; Buhrow, J. W.; Calle, L. M.; Pearman, B. P.; Zhang, X.

2015-01-01

This work concerns the development of smart coating technologies based on microencapsulation for the autonomous control of corrosion. Microencapsulation allows the incorporation of corrosion inhibitors into coating which provides protection through corrosion-controlled release of these inhibitors.One critical aspect of a corrosion protective smart coating is the selection of corrosion inhibitor for encapsulation and comparison of the inhibitor function before and after encapsulation. For this purpose, a systematic approach is being used to evaluate free and encapsulated corrosion inhibitors by salt immersion. Visual, optical microscope, and Scanning Electron Microscope (with low-angle backscatter electron detector) are used to evaluate these inhibitors. It has been found that the combination of different characterization tools provide an effective method for evaluation of early stage localized corrosion and the effectiveness of corrosion inhibitors.

Cholinesterase inhibitors from botanicals

PubMed Central

Ahmed, Faiyaz; Ghalib, Raza Murad; Sasikala, P.; Ahmed, K. K. Mueen

2013-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh), appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com) are also presented and the scope for future research is discussed. PMID:24347920

Measurement of xanthine oxidase inhibition activity of phenolics and flavonoids with a modified cupric reducing antioxidant capacity (CUPRAC) method.

PubMed

Ozyürek, Mustafa; Bektaşoğlu, Burcu; Güçlü, Kubilay; Apak, Reşat

2009-03-16

Various dietary polyphenolics have been found to show an inhibitory effect on xanthine oxidase (XO) which mediates oxidative stress-originated diseases because of its ability to generate reactive oxygen species (ROS), including superoxide anion radical (O(2)(-)) and hydrogen peroxide. XO activity has usually been determined by following the rate of uric acid formation from xanthine-xanthine oxidase (X-XO) system using the classical XO activity assay (UV-method) at 295nm. Since some polyphenolics have strong absorption from the UV to visible region, XO-inhibitory activity of polyphenolics was alternatively determined without interference by directly measuring the formation of uric acid and hydrogen peroxide using the modified CUPRAC (cupric reducing antioxidant capacity) spectrophotometric method at 450nm. The CUPRAC absorbance of the incubation solution due to the reduction of Cu(II)-neocuproine reagent by the products of the X-XO system decreased in the presence of polyphenolics, the difference being proportional to the XO inhibition ability of the tested compound. The structure-activity relationship revealed that the flavones and flavonols with a 7-hydroxyl group such as apigenin, luteolin, kaempferol, quercetin, and myricetin inhibited XO-inhibitory activity at low concentrations (IC(50) values from 1.46 to 1.90microM), while the flavan-3-ols and naringin were less inhibitory. The findings of the developed method for quercetin and catechin in the presence of catalase were statistically alike with those of HPLC. In addition to polyphenolics, five kinds of herbs were evaluated for their XO-inhibitory activity using the developed method. The proposed spectrophotometric method was practical, low-cost, rapid, and could reliably assay uric acid and hydrogen peroxide in the presence of polyphenols (flavonoids, simple phenolic acids and hydroxycinnamic acids), and less open to interferences by UV-absorbing substances.

Biological abatement of cellulase inhibitors

USDA-ARS?s Scientific Manuscript database

Bio-abatement uses a fungus to metabolize and remove fermentation inhibitors. To determine whether bio-abatement could alleviate enzyme inhibitor effects observed in biomass liquors after pretreatment, corn stover at 10% (w/v) solids was pretreated with either dilute acid or liquid hot water. The ...

Lesinurad for the treatment of hyperuricaemia in people with gout.

PubMed

Robinson, Philip C; Dalbeth, Nicola

2017-12-01

Gout is a common form of inflammatory arthritis caused by deposition of monosodium urate crystals. The central strategy for effective long-term management of gout is serum urate lowering. Current urate-lowering drugs include both xanthine oxidase inhibitors and uricosuric agents. Lesinurad is a URAT1 inhibitor that selectively inhibits urate rebsorption at the proximal renal tubule. Lesinurad 200mg daily in combination with a xanthine oxidase is approved for urate-lowering therapy in patients with gout. Areas covered: The published literature was searched using Pubmed and additional information was obtained from publically available regulatory documents. Pre-clinical data and clinical trials of lesinurad are described. Serum urate-lowering efficacy and effects on other clinical endpoints are discussed. Adverse event data, focusing on renal safety are also presented. Expert opinion: Lesinurad is an effective urate-lowering drug that has a generally acceptable safety profile when used at 200mg daily dosing in combination with a xanthine oxidase inhibitor. The recent approval of fixed dose combination pills of lesinurad with allopurinol is an important step in improving adherence and reducing risk of renal adverse events. It remains to be seen if this therapy will provide additional benefit for gout management above improved use of widely available generic therapies.

Drug repurposing in kidney disease.

PubMed

Panchapakesan, Usha; Pollock, Carol

2018-07-01

Drug repurposing, is the re-tasking of known medications for new clinical indications. Advantages, compared to de novo drug development, include reduced cost and time to market plus the added benefit of a known pharmacokinetic and safety profiles. Suitable drug candidates are identified through serendipitous observations, data mining, or increased understanding of disease mechanisms. This review highlights drugs suited for repurposing in kidney disease. The main cause of mortality in patients with chronic kidney disease is cardiovascular disease. Hence, we have included CV endpoints for the drugs. This review begins with candidates in acute kidney injury: vasodilators levosimendan and vitamin D, followed by candidates in CKD, with particular focus on diabetic kidney disease, autosomal dominant polycystic kidney disease, and focal segmental glomerulosclerosis. Examples include glucose-lowering drugs (sodium glucose co-transporter 2 inhibitors, glucagon-like peptide 1 agonists, and metformin), which have mechanistic potential for cardiac and/or renal protection beyond glucose lowering, with broader applicability to the nondiabetic population; xanthine oxidase inhibitors (allopurinol, febuxostat), selective endothelin receptor A antagonist (atrasentan), Janus kinase inhibitor (baricitinib), selective costimulation modulator (abatacept), pentoxyfylline, and the DNA demethylating agent/vasodilator (hydralazine). Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Tyrosine Kinase Inhibitor-Induced Hypertension.

PubMed

Agarwal, Megha; Thareja, Nidhi; Benjamin, Melody; Akhondi, Andre; Mitchell, George D

2018-06-21

The purpose of this paper is to identify commonly used tyrosine kinase inhibitors (TKIs) that are associated with hypertension, primarily, vascular endothelial growth factor (VEGF) signaling pathway (VSP) inhibitors. We review the incidence, mechanism, and strategies for management of TKI-induced HTN. We hope to provide clinicians with guidance on how to manage similar clinical scenarios. Many of the newer VSP inhibitors are reviewed here, including cediranib, axitinib, pazopanib, and ponatinib. Trials utilizing prophylactic treatment with angiotensin system inhibitors (ASIs) are discussed as well as recent data showing an improvement in overall survival and progression-free survival in patients on ASIs and TKI-induced hypertension. The incidence of TKI-induced HTN among the VEGF inhibitors ranges from 5 to 80% and is dose dependent. Newer generation small-molecule TKIs has a lower incidence. The mechanism of action involves VSP inhibition, leading to decreased nitric oxide and increased endothelin production, which causes vasoconstriction, capillary rarefaction, and hypertension. ASIs and calcium channel blockers are first-line therapy for treatment and are associated with improved overall survival. Nitrates and beta-blockers are associated with in vitro cancer regression; however, there is a paucity of trials regarding their use as an anti-hypertensive agent in the TKI-induced HTN patient population.

X-Chromosome Dosage and the Response to Cerebral Ischemia

PubMed Central

Turtzo, L. Christine; Siegel, Chad; McCullough, Louise D.

2011-01-01

Gonadal hormones contribute to ischemic neuroprotection, but cannot fully explain the observed sexual dimorphism in stroke outcomes seen during life stages with low sex steroid hormones. Sex chromosomal complement (XX in females; XY in males) may also contribute to ischemic sexual dimorphism. A transient middle cerebral artery occlusion model was used to investigate the role of X chromosome dosage in female XX and XO littermates of two mouse strains (Paf and EdaTa). Cohorts of XX and XO gonadally intact, ovariectomized, and ovariectomized females supplemented with estrogen were examined. Infarct sizes were equivalent between ovariectomized XX and XO mice, between intact XX and XO mice, and between estrogen-supplemented ovariectomized XX and XO mice. This is the first study to investigate the role of sex chromosome dosage in the response to cerebral ischemia. Neither the number of X chromosomes, nor the parent of origin of the remaining X chromosome, had a significant effect on the degree of cerebral infarction after experimental stroke in adult female mice. Estrogen was protective against cerebral ischemia in both XX and XO mice. PMID:21917808

X chromosome dosage and the response to cerebral ischemia.

PubMed

Turtzo, L Christine; Siegel, Chad; McCullough, Louise D

2011-09-14

Gonadal hormones contribute to ischemic neuroprotection, but cannot fully explain the observed sexual dimorphism in stroke outcomes seen during life stages with low sex steroid hormones. Sex chromosomal complement (XX in females; XY in males) may also contribute to ischemic sexual dimorphism. A transient middle cerebral artery occlusion model was used to investigate the role of X chromosome dosage in female XX and XO littermates of two mouse strains (Paf and Eda(Ta)). Cohorts of XX and XO gonadally intact, ovariectomized, and ovariectomized females supplemented with estrogen were examined. Infarct sizes were equivalent between ovariectomized XX and XO mice, between intact XX and XO mice, and between estrogen-supplemented ovariectomized XX and XO mice. This is the first study to investigate the role of sex chromosome dosage in the response to cerebral ischemia. Neither the number of X chromosomes nor the parent of origin of the remaining X chromosome had a significant effect on the degree of cerebral infarction after experimental stroke in adult female mice. Estrogen was protective against cerebral ischemia in both XX and XO mice.

Oxidative Stress and Proinflammatory Cytokines Contribute to Demyelination and Axonal Damage in a Cerebellar Culture Model of Neuroinflammation

PubMed Central

di Penta, Alessandra; Moreno, Beatriz; Reix, Stephanie; Fernandez-Diez, Begoña; Villanueva, Maite; Errea, Oihana; Escala, Nagore; Vandenbroeck, Koen; Comella, Joan X.; Villoslada, Pablo

2013-01-01

Background Demyelination and axonal damage are critical processes in the pathogenesis of multiple sclerosis (MS). Oxidative stress and pro-inflammatory cytokines elicited by inflammation mediates tissue damage. Methods/Principal Findings To monitor the demyelination and axonal injury associated with microglia activation we employed a model using cerebellar organotypic cultures stimulated with lipopolysaccharide (LPS). Microglia activated by LPS released pro-inflammatory cytokines (IL-1β, IL-6 and TNFα), and increased the expression of inducible nitric oxide synthase (iNOS) and production of reactive oxygen species (ROS). This activation was associated with demyelination and axonal damage in cerebellar cultures. Axonal damage, as revealed by the presence of non-phosphorylated neurofilaments, mitochondrial accumulation in axonal spheroids, and axonal transection, was associated with stronger iNOS expression and concomitant increases in ROS. Moreover, we analyzed the contribution of pro-inflammatory cytokines and oxidative stress in demyelination and axonal degeneration using the iNOS inhibitor ethyl pyruvate, a free-scavenger and xanthine oxidase inhibitor allopurinol, as well as via blockage of pro-inflammatory cytokines using a Fc-TNFR1 construct. We found that blocking microglia activation with ethyl pyruvate or allopurinol significantly decreased axonal damage, and to a lesser extent, demyelination. Blocking TNFα significantly decreased demyelination but did not prevented axonal damage. Moreover, the most common therapy for MS, interferon-beta, was used as an example of an immunomodulator compound that can be tested in this model. In vitro, interferon-beta treatment decreased oxidative stress (iNOS and ROS levels) and the release of pro-inflammatory cytokines after LPS stimulation, reducing axonal damage. Conclusion The model of neuroinflammation using cerebellar culture stimulated with endotoxin mimicked myelin and axonal damage mediated by the combination of

Pseudo Jahn-Teller coupling in trioxides XO3(0,1,-1) with 22 and 23 valence electrons

NASA Astrophysics Data System (ADS)

Grein, Friedrich

2013-05-01

D3h and C2v geometries and energies, vertical excitation energies, as well as minimal energy paths as function of the O1(z)-X-O2 angle α were obtained for XO3(0,1,-1) (X = B, Al, Ga; C, Si, Ge; N, P, As; S, Se) molecules and ions with 22 and 23 valence electrons (VE), using density functional theory (DFT), coupled cluster with single and double substitutions with noniterative triple excitations (CCSD(T)), equation of motion (EOM)-CCSD, time-dependent DFT, and multi-reference configuration interaction methods. It is shown that pseudo Jahn-Teller (PJT) coupling increases as the central atom X becomes heavier, due to decreases in excitation energies. As is well known for CO3, the excited 1E' states of the 22 VE systems SiO3, GeO3; NO_3 ^ +, PO3+, AsO3+; BO3-, AlO3-, GaO3- have strong vibronic coupling with the 1A1' ground state via the e' vibrational modes, leading to a C2v minimum around α = 145°. For first and second row X atoms, there is an additional D3h minimum (α = 120°). Interacting excited states have minima around 135°. In the 23 VE systems CO3-, SiO3-; NO3, PO3; SO3+, coupling of the excited 2E' with the 2A2' ground state via the e' mode does not generate a C2v state. Minima of interacting excited states are close to 120°. However, due to very strong PJT coupling, a double-well potential is predicted for GeO3-, AsO3, and SeO3+, with a saddle point at D3h symmetry. Interaction of the b2 highest occupied molecular orbital with the b2 lowest unoccupied molecular orbital, both oxygen lone pair molecular orbitals, is seen as the reason for the C2v stabilization of 22 VE molecules.

Development of Heat Shock Protein (Hsp90) Inhibitors To Combat Resistance to Tyrosine Kinase Inhibitors through Hsp90-Kinase Interactions.

PubMed

Wang, Meining; Shen, Aijun; Zhang, Chi; Song, Zilan; Ai, Jing; Liu, Hongchun; Sun, Liping; Ding, Jian; Geng, Meiyu; Zhang, Ao

2016-06-23

Heat shock protein 90 (Hsp90) is a ubiquitous chaperone of all of the oncogenic tyrosine kinases. Many Hsp90 inhibitors, alone or in combination, have shown significant antitumor efficacy against the kinase-positive naïve and mutant models. However, clinical trials of these inhibitors are unsuccessful due to insufficient clinical benefits and nonoptimal safety profiles. Recently, much progress has been reported on the Hsp90-cochaperone-client complex, which will undoubtedly assist in the understanding of the interactions between Hsp90 and its clients. Meanwhile, Hsp90 inhibitors have shown promise against patients' resistance caused by early generation tyrosine kinase inhibitors (TKIs), and at least 13 Hsp90 inhibitors are being reevaluated in the clinic. In this regard, the objectives of the current perspective are to summarize the structure and function of the Hsp90-cochaperone-client complex, to analyze the structural and functional insights into the Hsp90-client interactions to address several existing unresolved problems with Hsp90 inhibitors, and to highlight the preclinical and clinical studies of Hsp90 inhibitors as an effective treatment against resistance to tyrosine kinase inhibitors.

Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Tianjun; Commodore, Lois; Huang, Wei-Sheng

2012-01-20

The BCR-ABL inhibitor imatinib has revolutionized the treatment of chronic myeloid leukemia. However, drug resistance caused by kinase domain mutations has necessitated the development of new mutation-resistant inhibitors, most recently against the T315I gatekeeper residue mutation. Ponatinib (AP24534) inhibits both native and mutant BCR-ABL, including T315I, acting as a pan-BCR-ABL inhibitor. Here, we undertook a combined crystallographic and structure-activity relationship analysis on ponatinib to understand this unique profile. While the ethynyl linker is a key inhibitor functionality that interacts with the gatekeeper, virtually all other components of ponatinib play an essential role in its T315I inhibitory activity. The extensive networkmore » of optimized molecular contacts found in the DFG-out binding mode leads to high potency and renders binding less susceptible to disruption by single point mutations. The inhibitory mechanism exemplified by ponatinib may have broad relevance to designing inhibitors against other kinases with mutated gatekeeper residues.« less

First-principles calculations of dynamical and thermodynamic properties of cuprite doped with silver (Cu2(1‑x)Ag2xO)

NASA Astrophysics Data System (ADS)

Musari, A. A.; Joubert, D. P.; Adebayo, G. A.

2018-04-01

Cuprite (Cu2O) is a solid mineral and a compound whose simplicity of preparation, non toxic nature, low band gap and its abundance has made it a prospective candidate for the realisation of low cost photovoltaic applications. The present work successfully dopes Cuprite with Ag ({{{Cu}}}2(1-{{x})}{{{Ag}}}2{{x}}{{O}}) at different concentrations x = 0, 0.25, 0.5, 0.75 and 1, their first-principle calculations of their electronic, dynamical and thermodynamic properties have been investigated extensively within the generalised gradient approximation. Direct band gap energies at {{Γ }} are predicted for all the studied systems. A small bowing parameter for lattice constants ba and bulk modulus bB of 0.4245 \\mathring{{A}} and 0.8747 GPa were obtained when compared to Vegard’s law. The results of phonon dispersion when x = 0 and 1 indicate stability, these agree with available theoretical and experimental results while negative frequencies observed along the Brillouin zone for the doped systems when x = 0.25, 0.5 and 0.75 imply that they are dynamically unstable. The thermodynamic properties between 0 to 800 K were determined using the calculated phonon density of states within the harmonic approximation and the values of the specific heat capacity at constant volume at ambient temperature and the temperature at which lattice vibrations and thermal motion of electrons contribute to the constant volume specific heat capacity are presented for all the systems.

Oxymetazoline plus dexpanthenol in nasal congestion.

PubMed

Jagade, Mohan V; Langade, Deepak G; Pophale, Rupesh R; Prabhu, Arun

2008-12-01

To compare the efficacy and tolerability of Oxymetazoline 0.05 % plus Dexpanthanol 5% versus Xylometazoline 0.1 % nasal drops in patients with nasal congestion due to allergic rhinitis and following nasal surgery. An investigator-blind, randomized, controlled, phase IV clinical trial conducted in 100 patients with acute allergic rhinitis or patients post-nasal surgery. Patients received either Oxymetazoline 0.05% with Dexpanthanol 5% (OD) or Xylometazoline 0.1% (XO) nasal drops. Relief from nasal congestion was significantly better in the OD group then in the XO group (mean nasal scores 1.24 vs 1.86). Significantly more improvement in sneezing and decrease in nasal discharge was seen in the OD group than the XO group. Nasal irritation in the OD group was significantly less as compared to XO group (0.38 v/s 1.12 on second day and 0.10 vs 0.36 on the fourth day). The recovery time for OD group was 1.08 hours, which was significantly (46 min) lesser than that of the XO group. Rebound congestion was significantly less in OD as compared to XO group (6.25% vs 82.98%). 93.75% of the physicians in the OD group and 51.28% in XO group reported response to therapy as good to excellent. 95.83% patients in the OD group and only 52.91% patients in the XO group rated tolerability to therapy as good to excellent. Oxymetazoline and dexpanthenol combination has a better efficacy, shorter recovery time, causes lesser rebound congestion and has better tolerability than xylometazoline.

Is Xanthine oxidase activity in polycystic ovary syndrome associated with inflammatory and cardiovascular risk factors?

PubMed

Isık, Hatice; Aynıoglu, Oner; Tımur, Hakan; Sahbaz, Ahmet; Harma, Muge; Can, Murat; Guven, Berrak; Alptekin, Husnu; Kokturk, Furuzan

2016-08-01

The aim of this study is to examine women with polycystic ovary syndrome (PCOS) to determine the relationship between xanthine oxidase (XO) and oxidative stress, inflammatory status, and various clinical and biochemical parameters. In this cross-sectional study a total of 83 women including 45 PCOS patients and 38 healthy women were enrolled. We collected blood samples for XO and superoxide dismutase (SOD) activity, hormone levels, cholesterol values, and inflammatory markers. Body mass index (BMI) , waist-to-hip ratio (WHR), and blood pressure were assessed. Blood samples were taken for hormonal levels, cholesterol levels, fasting plasma glucose (FPG), fasting plasma insulin (FPI), homeostatic model assessment-insulin resistance (HOMA-IR) index, quantitative insulin sensitivity check index (QUICKI), C-reactive protein (CRP), white blood cell and neutrophil counts, XO and SOD activities. The basal hormone levels, triglyceride (TG) levels, TG/HDL-C (high density lipoprotein-cholesterol) ratios FPG, FPI and HOMA-IR levels were higher in PCOS patients compared to controls (p<0.05). Platelet and plateletcrit (PCT) values, CRP, and XO activity were significantly increased, however SOD activity was decreased in PCOS patients (p<0.001). XO activity was positively correlated with LH/FSH and TG/HDL ratios, CRP, PCT, FPG, FPI, and HOMA-IR, and negatively correlated with QUICKI levels. In conclusion, XO is a useful marker to assess oxidative stress in PCOS patients. Positive correlations between XO and inflammatory markers and cardiovascular disease risk factors suggest that XO plays an important role in the pathogenesis of PCOS and its metabolic complications. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms

PubMed Central

Meyer, Sara C.; Keller, Matthew D.; Chiu, Sophia; Koppikar, Priya; Guryanova, Olga A.; Rapaport, Franck; Xu, Ke; Manova, Katia; Pankov, Dmitry; O’Reilly, Richard J.; Kleppe, Maria; McKenney, Anna Sophia; Shih, Alan H.; Shank, Kaitlyn; Ahn, Jihae; Papalexi, Eftymia; Spitzer, Barbara; Socci, Nick; Viale, Agnes; Mandon, Emeline; Ebel, Nicolas; Andraos, Rita; Rubert, Joëlle; Dammassa, Ernesta; Romanet, Vincent; Dölemeyer, Arno; Zender, Michael; Heinlein, Melanie; Rampal, Rajit; Weinberg, Rona Singer; Hoffman, Ron; Sellers, William R.; Hofmann, Francesco; Murakami, Masato; Baffert, Fabienne; Gaul, Christoph; Radimerski, Thomas; Levine, Ross L.

2015-01-01

Summary Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasms (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated if CHZ868, a type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells, murine MPN models, and MPN patient samples. JAK2- and MPL-mutant cell lines were sensitive to CHZ868, including type I JAK inhibitor persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable therapeutic approach for MPN patients. PMID:26175413

SGLT2 Inhibitors May Predispose to Ketoacidosis.

PubMed

Taylor, Simeon I; Blau, Jenny E; Rother, Kristina I

2015-08-01

Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that increase urinary excretion of glucose, thereby improving glycemic control and promoting weight loss. Since approval of the first-in-class drug in 2013, data have emerged suggesting that these drugs increase the risk of diabetic ketoacidosis. In May 2015, the Food and Drug Administration issued a warning that SGLT2 inhibitors may lead to ketoacidosis. Using PubMed and Google, we conducted Boolean searches including terms related to ketone bodies or ketoacidosis with terms for SGLT2 inhibitors or phlorizin. Priority was assigned to publications that shed light on molecular mechanisms whereby SGLT2 inhibitors could affect ketone body metabolism. SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis. When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia. The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis. Furthermore, SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion. Finally, phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels. Based on the physiology of SGLT2 and the pharmacology of SGLT2 inhibitors, there are several biologically plausible mechanisms whereby this class of drugs has the potential to increase the risk of developing diabetic ketoacidosis. Future research should be directed toward identifying which patients are at greatest risk for this side effect and also to optimizing pharmacotherapy to minimize the risk to patients.

Corrosion inhibitors for solar heating and cooling systems

NASA Technical Reports Server (NTRS)

Humphries, T. S.

1978-01-01

Inhibitors which appeared promising in previous tests and additional inhibitors including several proprietary products were evaluated. Evaluation of the inhibitors was based on corrosion protection afforded an aluminum-mild steel-copper-stainless steel assembly in a hot corrosive water. Of the inhibitors tested two were found to be effective and show promise for protecting multimetallic solar heating systems.

Synthesis, structural and magnetic properties of Mg0.6Zn0.4CrxFe2-xO4 (0.0 ≤ x ≤ 2.0) nano ferrite

NASA Astrophysics Data System (ADS)

Verma, R.; Kane, S. N.; Raghuvanshi, S.; Satalkar, M.; Modak, S. S.; Mazaleyrat, F.

2018-05-01

Present study reports, effect on structural, magnetic properties of Cr doped Mg-Zn nano-ferrite: Mg0.6Zn0.4CrxFe2-xO4 (0.0≤ x≤2.0), synthesized by sol-gel auto combustion method. X-ray diffraction (XRD), vibrating sample magnetometer (VSM), scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) techniques were utilized to monitor the effect of Cr substitution on structural, magnetic properties, and correlation between them. XRD confirms the formation of single phase spinel nano ferrite with particle size ranging between 3.9 - 40.5 nm, whereas EDS confirms the formation of the estimated ferrite composition. Distribution of Mg, Zn, Cr, Fe cations on tetrahedral (A), octahedral (B) site show mixed spinel structure. Increase of Cr content leads to increase of specific surface area (4.35 - 28.28 m2/g), decrease of experimental saturation magnetization at 300 K (varies between 0.57 - 40.95 Am2/kg), and theoretical magnetization at 0 K (range between 13.37 - 56.77 Am2/kg). Observed changes in coercivity values reflect soft magnetic nature of the studied ferrites.

Cocrystal Structures of Primed Side-Extending α-Ketoamide Inhibitors Reveal Novel Calpain-Inhibitor Aromatic Interactions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qian,J.; Cuerrier, D.; Davies, P.

Calpains are intracellular cysteine proteases that catalyze the cleavage of target proteins in response to Ca2+ signaling. When Ca2+ homeostasis is disrupted, calpain overactivation causes unregulated proteolysis, which can contribute to diseases such as postischemic injury and cataract formation. Potent calpain inhibitors exist, but of these many cross-react with other cysteine proteases and will need modification to specifically target calpain. Here, we present crystal structures of rat calpain 1 protease core ({mu}I-II) bound to two a-ketoamide-based calpain inhibitors containing adenyl and piperazyl primed-side extensions. An unexpected aromatic-stacking interaction is observed between the primed-side adenine moiety and the Trp298 side chain.more » This interaction increased the potency of the inhibitor toward {mu}I-II and heterodimeric m-calpain. Moreover, stacking orients the adenine such that it can be used as a scaffold for designing novel primed-side address regions, which could be incorporated into future inhibitors to enhance their calpain specificity.« less

Xanthine Oxidoreductase Function Contributes to Normal Wound Healing.

PubMed

Madigan, Michael C; McEnaney, Ryan M; Shukla, Ankur J; Hong, Guiying; Kelley, Eric E; Tarpey, Margaret M; Gladwin, Mark; Zuckerbraun, Brian S; Tzeng, Edith

2015-04-14

Chronic, nonhealing wounds result in patient morbidity and disability. Reactive oxygen species (ROS) and nitric oxide (NO) are both required for normal wound repair, and derangements of these result in impaired healing. Xanthine oxidoreductase (XOR) has the unique capacity to produce both ROS and NO. We hypothesize that XOR contributes to normal wound healing. Cutaneous wounds were created in C57Bl6 mice. XOR was inhibited with dietary tungsten or allopurinol. Topical hydrogen peroxide (H2O2, 0.15%) or allopurinol (30 μg) was applied to wounds every other day. Wounds were monitored until closure or collected at d 5 to assess XOR expression and activity, cell proliferation and histology. The effects of XOR, nitrite, H2O2 and allopurinol on keratinocyte cell (KC) and endothelial cell (EC) behavior were assessed. We identified XOR expression and activity in the skin and wound edges as well as granulation tissue. Cultured human KCs also expressed XOR. Tungsten significantly inhibited XOR activity and impaired healing with reduced ROS production with reduced angiogenesis and KC proliferation. The expression and activity of other tungsten-sensitive enzymes were minimal in the wound tissues. Oral allopurinol did not reduce XOR activity or alter wound healing but topical allopurinol significantly reduced XOR activity and delayed healing. Topical H2O2 restored wound healing in tungsten-fed mice. In vitro, nitrite and H2O2 both stimulated KC and EC proliferation and EC migration. These studies demonstrate for the first time that XOR is abundant in wounds and participates in normal wound healing through effects on ROS production.

NADPH oxidase inhibitors: a patent review.

PubMed

Kim, Jung-Ae; Neupane, Ganesh Prasad; Lee, Eung Seok; Jeong, Byeong-Seon; Park, Byung Chul; Thapa, Pritam

2011-08-01

NADPH oxidases, a family of multi-subunit enzyme complexes, catalyze the production of reactive oxygen species (ROS), which may contribute to the pathogenesis of a variety of diseases. In addition to the first NADPH oxidase found in phagocytes, four non-phagocytic NADPH oxidase isoforms have been identified, which all differ in their catalytic subunit (Nox1-5) and tissue distribution. This paper provides a comprehensive review of the patent literature on NADPH oxidase inhibitors, small molecule Nox inhibitors, peptides and siRNAs. Since each member of the NADPH oxidase family has great potential as a therapeutic target, several different compounds have been registered as NADPH oxidase inhibitors in the patent literature. As yet, none have gone through clinical trials, and some have not completed preclinical trials, including safety and specificity evaluation. Recently, small molecule pyrazolopyridine and triazolopyrimidine derivatives have been submitted as potent NADPH oxidase inhibitors and reported as first-in-class inhibitors for idiopathic pulmonary fibrosis and acute stroke, respectively. Further clinical efficacy and safety data are warranted to prove their actual clinical utility.

Molecular mechanism of respiratory syncytial virus fusion inhibitors

PubMed Central

Battles, Michael B; Langedijk, Johannes P; Furmanova-Hollenstein, Polina; Chaiwatpongsakorn, Supranee; Costello, Heather M; Kwanten, Leen; Vranckx, Luc; Vink, Paul; Jaensch, Steffen; Jonckers, Tim H M; Koul, Anil; Arnoult, Eric; Peeples, Mark E; Roymans, Dirk; McLellan, Jason S

2016-01-01

Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. Here we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors. PMID:26641933

Inhibitory Effects of Respiration Inhibitors on Aflatoxin Production

PubMed Central

Sakuda, Shohei; Prabowo, Diyan Febri; Takagi, Keiko; Shiomi, Kazuro; Mori, Mihoko; Ōmura, Satoshi; Nagasawa, Hiromichi

2014-01-01

Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A) inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III) and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control. PMID:24674936

Small-Molecule Inhibitors of Urea Transporters

PubMed Central

Verkman, Alan S.; Esteva-Font, Cristina; Cil, Onur; Anderson, Marc O.; Li, Fei; Li, Min; Lei, Tianluo; Ren, Huiwen; Yang, Baoxue

2015-01-01

Urea transporter (UT) proteins, which include isoforms of UT-A in kidney tubule epithelia and UT-B in vasa recta endothelia and erythrocytes, facilitate urinary concentrating function. Inhibitors of urea transporter function have potential clinical applications as sodium-sparing diuretics, or ‘urearetics,’ in edema from different etiologies, such as congestive heart failure and cirrhosis, as well as in syndrome of inappropriate antidiuretic hormone (SIADH). High-throughput screening of drug-like small molecules has identified UT-A and UT-B inhibitors with nanomolar potency. Inhibitors have been identified with different UT-A versus UT-B selectivity profiles and putative binding sites on UT proteins. Studies in rodent models support the utility of UT inhibitors in reducing urinary concentration, though testing in clinically relevant animal models of edema has not yet been done. PMID:25298345

Phosphodiesterase inhibitors in clinical urology.

PubMed

Ückert, Stefan; Kuczyk, Markus A; Oelke, Matthias

2013-05-01

To date, benign diseases of the male and female lower urinary and genital tract, such as erectile dysfunction, bladder overactivity, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and symptoms of female sexual dysfunction (including arousal and orgasmic disorders), can be therapeutically approached by influencing the function of the smooth musculature of the respective tissues. The use of isoenzyme-selective phosphodiesterase (PDE) inhibitors is considered a great opportunity to treat various diseases of the human urogenital tract. PDE inhibitors, in particular the PDE5 (cyclic GMP PDE) inhibitors avanafil, lodenafil, sildenafil, tadalafil, udenafil and vardenafil, are regarded as efficacious, having a fast onset of drug action and an improved effect-to-adverse event ratio, combining a high response rate with the advantage of an on-demand intake. The purpose of this review is to summarize recent as well as potential future indications, namely, erectile dysfunction, Peyronie's disease, overactive bladder, urinary stone disease, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and premature ejaculation, for the use of PDE inhibitors in clinical urology.

Biological abatement of cellulase inhibitors.

PubMed

Cao, Guangli; Ximenes, Eduardo; Nichols, Nancy N; Zhang, Leyu; Ladisch, Michael

2013-10-01

Removal of enzyme inhibitors released during lignocellulose pretreatment is essential for economically feasible biofuel production. We tested bio-abatement to mitigate enzyme inhibitor effects observed in corn stover liquors after pretreatment with either dilute acid or liquid hot water at 10% (w/v) solids. Bio-abatement of liquors was followed by enzymatic hydrolysis of cellulose. To distinguish between inhibitor effects on enzymes and recalcitrance of the substrate, pretreated corn stover solids were removed and replaced with 1% (w/v) Solka Floc. Cellulose conversion in the presence of bio-abated liquors from dilute acid pretreatment was 8.6% (0.1x enzyme) and 16% (1x enzyme) higher than control (non-abated) samples. In the presence of bio-abated liquor from liquid hot water pretreated corn stover, 10% (0.1x enzyme) and 13% (1x enzyme) higher cellulose conversion was obtained compared to control. Bio-abatement yielded improved enzyme hydrolysis in the same range as that obtained using a chemical (overliming) method for mitigating inhibitors. Copyright © 2013 Elsevier Ltd. All rights reserved.

HZE ⁵⁶Fe-ion irradiation induces endothelial dysfunction in rat aorta: role of xanthine oxidase.

PubMed

Soucy, Kevin G; Lim, Hyun Kyo; Kim, Jae Hyung; Oh, Young; Attarzadeh, David O; Sevinc, Baris; Kuo, Maggie M; Shoukas, Artin A; Vazquez, Marcelo E; Berkowitz, Dan E

2011-10-01

Ionizing radiation has been implicated in the development of significant cardiovascular complications. Since radiation exposure is associated with space exploration, astronauts are potentially at increased risk of accelerated cardiovascular disease. This study investigated the effect of high atomic number, high-energy (HZE) iron-ion radiation on vascular and endothelial function as a model of space radiation. Rats were exposed to a single whole-body dose of iron-ion radiation at doses of 0, 0.5 or 1 Gy. In vivo aortic stiffness and ex vivo aortic tension responses were measured 6 and 8 months after exposure as indicators of chronic vascular injury. Rats exposed to 1 Gy iron ions demonstrated significantly increased aortic stiffness, as measured by pulse wave velocity. Aortic rings from irradiated rats exhibited impaired endothelial-dependent relaxation consistent with endothelial dysfunction. Acute xanthine oxidase (XO) inhibition or reactive oxygen species (ROS) scavenging restored endothelial-dependent responses to normal. In addition, XO activity was significantly elevated in rat aorta 4 months after whole-body irradiation. Furthermore, XO inhibition, initiated immediately after radiation exposure and continued until euthanasia, completely inhibited radiation-dependent XO activation. ROS production was elevated after 1 Gy irradiation while production of nitric oxide (NO) was significantly impaired. XO inhibition restored NO and ROS production. Finally, dietary XO inhibition preserved normal endothelial function and vascular stiffness after radiation exposure. These results demonstrate that radiation induced XO-dependent ROS production and nitroso-redox imbalance, leading to chronic vascular dysfunction. As a result, XO is a potential target for radioprotection. Enhancing the understanding of vascular radiation injury could lead to the development of effective methods to ameliorate radiation-induced vascular damage.

NADH oxidase activity of rat and human liver xanthine oxidoreductase: potential role in superoxide production.

PubMed

Maia, Luisa; Duarte, Rui O; Ponces-Freire, Ana; Moura, José J G; Mira, Lurdes

2007-08-01

To characterise the NADH oxidase activity of both xanthine dehydrogenase (XD) and xanthine oxidase (XO) forms of rat liver xanthine oxidoreductase (XOR) and to evaluate the potential role of this mammalian enzyme as an O2*- source, kinetics and electron paramagnetic resonance (EPR) spectroscopic studies were performed. A steady-state kinetics study of XD showed that it catalyses NADH oxidation, leading to the formation of one O2*- molecule and half a H(2)O(2) molecule per NADH molecule, at rates 3 times those observed for XO (29.2 +/- 1.6 and 9.38 +/- 0.31 min(-1), respectively). EPR spectra of NADH-reduced XD and XO were qualitatively similar, but they were quantitatively quite different. While NADH efficiently reduced XD, only a great excess of NADH reduced XO. In agreement with reductive titration data, the XD specificity constant for NADH (8.73 +/- 1.36 microM(-1) min(-1)) was found to be higher than that of the XO specificity constant (1.07 +/- 0.09 microM(-1) min(-1)). It was confirmed that, for the reducing substrate xanthine, rat liver XD is also a better O2*- source than XO. These data show that the dehydrogenase form of liver XOR is, thus, intrinsically more efficient at generating O2*- than the oxidase form, independently of the reducing substrate. Most importantly, for comparative purposes, human liver XO activity towards NADH oxidation was also studied, and the kinetics parameters obtained were found to be very similar to those of the XO form of rat liver XOR, foreseeing potential applications of rat liver XOR as a model of the human liver enzyme.

F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

PubMed Central

Schwarz, John; Astermark, Jan; Menius, Erika D.; Carrington, Mary; Donfield, Sharyne M.; Gomperts, Edward D.; Nelson, George W.; Oldenburg, Johannes; Pavlova, Anna; Shapiro, Amy D.; Winkler, Cheryl A.; Berntorp, Erik

2012-01-01

Background Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in hemophilia A. It has been suggested that differences in the distribution of factor VIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Design and Methods Data from the HIGS Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1+H2) and inhibitor risk among individuals of genetically-determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and HLA were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Results H3 was associated with higher inhibitor risk among those genetically-identified (N=49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N=223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Conclusion H3 was not an independent predictor of inhibitor risk. Further, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual. PMID:22958194

Theoretical study on the interaction of pyrrolopyrimidine derivatives as LIMK2 inhibitors: insight into structure-based inhibitor design.

PubMed

Shen, Mingyun; Zhou, Shunye; Li, Youyong; Li, Dan; Hou, Tingjun

2013-10-01

LIM kinases (LIMKs), downstream of Rho-associated protein kinases (ROCKs) and p21-activated protein kinases (PAKs), are shown to be promising targets for the treatment of cancers. In this study, the inhibition mechanism of 41 pyrrolopyrimidine derivatives as LIMK2 inhibitors was explored through a series of theoretical approaches. First, a model of LIMK2 was generated through molecular homology modeling, and the studied inhibitors were docked into the binding active site of LIMK2 by the docking protocol, taking into consideration the flexibility of the protein. The binding poses predicted by molecular docking for 17 selected inhibitors with different bioactivities complexed with LIMK2 underwent molecular dynamics (MD) simulations, and the binding free energies for the complexes were predicted by using the molecular mechanics/generalized born surface area (MM/GBSA) method. The predicted binding free energies correlated well with the experimental bioactivities (r(2) = 0.63 or 0.62). Next, the free energy decomposition analysis was utilized to highlight the following key structural features related to biological activity: (1) the important H-bond between Ile408 and pyrrolopyrimidine, (2) the H-bonds between the inhibitors and Asp469 and Gly471 which maintain the stability of the DFG-out conformation, and (3) the hydrophobic interactions between the inhibitors and several key residues (Leu337, Phe342, Ala345, Val358, Lys360, Leu389, Ile408, Leu458 and Leu472). Finally, a variety of LIMK2 inhibitors with a pyrrolopyrimidine scaffold were designed, some of which showed improved potency according to the predictions. Our studies suggest that the use of molecular docking with MD simulations and free energy calculations could be a powerful tool for understanding the binding mechanism of LIMK2 inhibitors and for the design of more potent LIMK2 inhibitors.

Aromatic inhibitors derived from ammonia-pretreated lignocellulose hinder bacterial ethanologenesis by activating regulatory circuits controlling inhibitor efflux and detoxification

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keating, David H.; Zhang, Yaoping; Ong, Irene M.

2014-08-13

Efficient microbial conversion of lignocellulosic hydrolysates to biofuels is a key barrier to the economically viable deployment of lignocellulosic biofuels. A chief contributor to this barrier is the impact on microbial processes and energy metabolism of lignocellulose-derived inhibitors, including phenolic carboxylates, phenolic amides (for ammonia-pretreated biomass), phenolic aldehydes, and furfurals. To understand the bacterial pathways induced by inhibitors present in ammonia-pretreated biomass hydrolysates, which are less well studied than acid-pretreated biomass hydrolysates, we developed and exploited synthetic mimics of ammonia-pretreated corn stover hydrolysate (ACSH). To determine regulatory responses to the inhibitors normally present in ACSH, we measured transcript and proteinmore » levels in an Escherichia coli ethanologen using RNA-seq and quantitative proteomics during fermentation to ethanol of synthetic hydrolysates containing or lacking the inhibitors. Our study identified four major regulators mediating these responses, the MarA/SoxS/Rob network, AaeR, FrmR, and YqhC. Induction of these regulons was correlated with a reduced rate of ethanol production, buildup of pyruvate, depletion of ATP and NAD(P)H, and an inhibition of xylose conversion. The aromatic aldehyde inhibitor 5-hydroxymethylfurfural appeared to be reduced to its alcohol form by the ethanologen during fermentation, whereas phenolic acid and amide inhibitors were not metabolized. Together, our findings establish that the major regulatory responses to lignocellulose-derived inhibitors are mediated by transcriptional rather than translational regulators, suggest that energy consumed for inhibitor efflux and detoxification may limit biofuel production, and identify a network of regulators for future synthetic biology efforts.« less

Characterization of a Novel Class of Polyphenolic Inhibitors of Plasminogen Activator Inhibitor-1*

PubMed Central

Cale, Jacqueline M.; Li, Shih-Hon; Warnock, Mark; Su, Enming J.; North, Paul R.; Sanders, Karen L.; Puscau, Maria M.; Emal, Cory D.; Lawrence, Daniel A.

2010-01-01

Plasminogen activator inhibitor type 1, (PAI-1) the primary inhibitor of the tissue-type (tPA) and urokinase-type (uPA) plasminogen activators, has been implicated in a wide range of pathological processes, making it an attractive target for pharmacologic inhibition. Currently available small-molecule inhibitors of PAI-1 bind with relatively low affinity and do not inactivate PAI-1 in the presence of its cofactor, vitronectin. To search for novel PAI-1 inhibitors with improved potencies and new mechanisms of action, we screened a library selected to provide a range of biological activities and structural diversity. Five potential PAI-1 inhibitors were identified, and all were polyphenolic compounds including two related, naturally occurring plant polyphenols that were structurally similar to compounds previously shown to provide cardiovascular benefit in vivo. Unique second generation compounds were synthesized and characterized, and several showed IC50 values for PAI-1 between 10 and 200 nm. This represents an enhanced potency of 10–1000-fold over previously reported PAI-1 inactivators. Inhibition of PAI-1 by these compounds was reversible, and their primary mechanism of action was to block the initial association of PAI-1 with a protease. Consistent with this mechanism and in contrast to previously described PAI-1 inactivators, these compounds inactivate PAI-1 in the presence of vitronectin. Two of the compounds showed efficacy in ex vivo plasma and one blocked PAI-1 activity in vivo in mice. These data describe a novel family of high affinity PAI-1-inactivating compounds with improved characteristics and in vivo efficacy, and suggest that the known cardiovascular benefits of dietary polyphenols may derive in part from their inactivation of PAI-1. PMID:20061381

Predicting DPP-IV inhibitors with machine learning approaches

NASA Astrophysics Data System (ADS)

Cai, Jie; Li, Chanjuan; Liu, Zhihong; Du, Jiewen; Ye, Jiming; Gu, Qiong; Xu, Jun

2017-04-01

Dipeptidyl peptidase IV (DPP-IV) is a promising Type 2 diabetes mellitus (T2DM) drug target. DPP-IV inhibitors prolong the action of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), improve glucose homeostasis without weight gain, edema, and hypoglycemia. However, the marketed DPP-IV inhibitors have adverse effects such as nasopharyngitis, headache, nausea, hypersensitivity, skin reactions and pancreatitis. Therefore, it is still expected for novel DPP-IV inhibitors with minimal adverse effects. The scaffolds of existing DPP-IV inhibitors are structurally diversified. This makes it difficult to build virtual screening models based upon the known DPP-IV inhibitor libraries using conventional QSAR approaches. In this paper, we report a new strategy to predict DPP-IV inhibitors with machine learning approaches involving naïve Bayesian (NB) and recursive partitioning (RP) methods. We built 247 machine learning models based on 1307 known DPP-IV inhibitors with optimized molecular properties and topological fingerprints as descriptors. The overall predictive accuracies of the optimized models were greater than 80%. An external test set, composed of 65 recently reported compounds, was employed to validate the optimized models. The results demonstrated that both NB and RP models have a good predictive ability based on different combinations of descriptors. Twenty "good" and twenty "bad" structural fragments for DPP-IV inhibitors can also be derived from these models for inspiring the new DPP-IV inhibitor scaffold design.

Selective JAK inhibitors in development for rheumatoid arthritis.

PubMed

Norman, Peter

2014-08-01

The JAK kinases are a family of four tyrosine receptor kinases that play a pivotal role in cytokine receptor signalling pathways via their interaction with signal transducers and activators of transcription proteins. Selective inhibitors of JAK kinases are viewed as of considerable potential as disease-modifying anti-inflammatory drugs for the treatment of rheumatoid arthritis. This article provides a review of the clinical development and available clinical results for those JAK inhibitors currently under investigation. Phase II data for four JAK inhibitors (baricitinib, decernotinib, filgotinib and INCB-039110) are contrasted with that reported for the recently approved JAK inhibitor tofacitinib. The preclinical data on these, in addition to peficitinib, ABT-494, INCB-047986 and AC-410 are also discussed, as are some of the inhibitors in preclinical development. JAK inhibitors are effective in the treatment of rheumatoid arthritis as evidenced by several inhibitors enabling the majority of treated patients to achieve ACR20 responses, with baricitinib and INCB-039110 both effective when administered once daily. JAK inhibitors differ in isoform specificity profiles, with good efficacy achievable by selective inhibition of either JAK1 (filgotinib or INCB-039110) or JAK3 (decernotinib). It remains to be seen what selectivity provides the optimal side-effect profile and to what extent inhibition of JAK2 should be avoided.

HIV-1 IN Inhibitors: 2010 Update and Perspectives

PubMed Central

Marchand, Christophe; Maddali, Kasthuraiah; Metifiot, Mathieu; Pommier, Yves

2010-01-01

Integrase (IN) is the newest validated target against AIDS and retroviral infections. The remarkable activity of raltegravir (Isentress®) led to its rapid approval by the FDA in 2007 as the first IN inhibitor. Several other IN strand transfer inhibitors (STIs) are in development with the primary goal to overcome resistance due to the rapid occurrence of IN mutations in raltegravir-treated patients. Thus, many scientists and drug companies are actively pursuing clinically useful IN inhibitors. The objective of this review is to provide an update on the IN inhibitors reported in the last two years, including second generation strand transfer inhibitors (STI), recently developed hydroxylated aromatics, natural products, peptide, antibody and oligonucleotide inhibitors. Additionally, the targeting of IN cofactors such as LEDGF and Vpr will be discussed as novel strategies for the treatment of AIDS. PMID:19747122

Aromatase inhibitors and breast cancer prevention.

PubMed

Litton, Jennifer Keating; Arun, Banu K; Brown, Powel H; Hortobagyi, Gabriel N

2012-02-01

Endocrine therapy with selective estrogen receptor modulators (SERMs) has been the mainstay of breast cancer prevention trials to date. The aromatase inhibitors, which inhibit the final chemical conversion of androgens to estrogens, have shown increased disease-free survival benefit over tamoxifen in patients with primary hormone receptor-positive breast cancer, as well as reducing the risk of developing contralateral breast cancers. The aromatase inhibitors are being actively evaluated as prevention agents for women with a history of ductal carcinoma in situ as well as for women who are considered to be at high risk for developing primary invasive breast cancer. This review evaluates the available prevention data, as evidenced by the decrease in contralateral breast cancers, when aromatase inhibitors are used in the adjuvant setting, as well as the emerging data of the aromatase inhibitors specifically tested in the prevention setting for women at high risk. Exemestane is a viable option for breast cancer prevention. We continue to await further follow-up on exemestane as well as other aromatase inhibitors in the prevention setting for women at high risk of developing breast cancer or with a history of ductal carcinoma in situ.

Stability of Allopurinol, Amitriptyline Hydrochloride, Carbamazepine, Domperidone, Isoniazid, Ketoconazole, Lisinopril, Naproxen, Paracetamol (Acetaminophen), and Sertraline Hydrochloride in SyrSpend SF PH4 Oral Suspensions.

PubMed

Polonini, Hudson C; Loures, Sharlene; de Araujo, Edson Peter; Brandão, Marcos Antônio F; Ferreira, Anderson O

2016-01-01

Oral liquids are safe alternatives to solid dosage forms, notably for elderly and pediatric patients that present dysphagia. The use of ready-to-use suspending vehicles such as SyrSpend SF PH4 is a suitable resource for pharmacists as they constitute a safe and timesaving option that has been studied often. The objective of this study was to evaluate the stability of 10 commonly used active pharmaceutical ingredients (allopurinol 20 mg/mL; amitriptyline hydrochloride 10 mg/mL; carbamazepine 25 mg/mL; domperidone 5 mg/mL; isoniazid 10 mg/mL; ketoconazole 20 mg/mL; lisinopril 1 mg/mL; naproxen 25 mg/mL; paracetamol [acetaminophen] 50 mg/mL; and sertraline hydrochloride 10 mg/mL) compounded in oral suspensions using SyrSpend SF PH4 as the vehicle throughout the study period and stored both at controlled refrigerated (2°C to 8°C) and room temperature (20°C to 25°C). Stability was assessed by means of measuring the percent recovery at varying time points throughout a 90-day period. The quantification of the active pharmaceutical ingredients was performed by high-performance liquid chromatography through a stability-indicating method. Methods were adequately validated. Forced-degradation studies showed that at least one parameter influenced the stability of the active pharmaceutical ingredients. All suspensions were assayed and showed active pharmaceutical ingredient contents between 90% and 110% during the 90-day study period. Although the forced-degradation experiments led to visible fluctuations in the chromatographic responses, the final preparations were stable in the storage conditions. The beyond-use dates of the preparations were found to be at least 90 days for all suspensions, both for controlled refrigerated temperature and room temperature. This confirms that SyrSpend SF PH4 is a stable suspending vehicle for compounding with a broad range of different active pharmaceutical ingredients for different medical usages. Copyright© by International Journal of

Heterocyclic HIV-protease inhibitors.

PubMed

Calugi, C; Guarna, A; Trabocchi, A

2013-01-01

In the panorama of HIV protease inhibitors (HIV PIs), many efforts have been devoted to the development of new compounds with reduced peptidic nature in order to improve pharmacokinetics and pharmacodynamics features. The introduction of cyclic scaffolds in the design of new chemical entities reduces flexibility and affords more rigid inhibitors. Specifically, common dipeptide isosteres are replaced by a central cyclic scaffold designed to address the key interactions with catalytic aspartic acids and residues belonging to the flap region of the active site. The current interest in cyclic chemotypes addressing key interactions of HIV protease is motivated by the different nature of interactions formed with the enzyme, although maintaining key structural resemblance to a peptide substrate, hopefully giving rise to novel HIV-1 PIs displaying an improved profile towards multidrug resistant strains. This approach has been demonstrated for Tipranavir, which is a potent FDA approved HIV-1 PI representing the most famous example of heterocyclic aspartic protease inhibitors.

Characterization of Covalent-Reversible EGFR Inhibitors

PubMed Central

2017-01-01

Within the spectrum of kinase inhibitors, covalent-reversible inhibitors (CRIs) provide a valuable alternative approach to classical covalent inhibitors. This special class of inhibitors can be optimized for an extended drug-target residence time. For CRIs, it was shown that the fast addition of thiols to electron-deficient olefins leads to a covalent bond that can break reversibly under proteolytic conditions. Research groups are just beginning to include CRIs in their arsenal of compound classes, and, with that, the understanding of this interesting set of chemical warheads is growing. However, systems to assess both characteristics of the covalent-reversible bond in a simple experimental setting are sparse. Here, we have developed an efficient methodology to characterize the covalent and reversible properties of CRIs and to investigate their potential in targeting clinically relevant variants of the receptor tyrosine kinase EGFR.

Monoamine Oxidase B Inhibitors in Parkinson's Disease.

PubMed

Dezsi, Livia; Vecsei, Laszlo

2017-01-01

Parkinson's disease (PD) is a neurodegenerative disorder with a prevalence increasing with age. Oxidative stress and glutamate toxicity are involved in its pathomechanism. There are still many unmet needs of PD patients, including the alleviation of motor fluctuations and dyskinesias, and the development of therapies with neuroprotective potential. To give an overview of the pharmacological properties, the efficacy and safety of the monoamine oxidase B (MAO-B) inhibitors in the treatment of PD, with special focus on the results of randomized clinical trials. A literature search was conducted in PubMed for 'PD treatment', 'MAO-B inhibitors', 'selegiline', 'rasagiline', 'safinamide' and 'clinical trials' with 'MAO-B inhibitors' in 'Parkinson' disease'. MAO-B inhibitors have a favorable pharmacokinetic profile, improve the dopamine deficient state and may have neuroprotective properties. Safinamide exhibits an anti-glutamatergic effect as well. When applied as monotherapy, MAO-B inhibitors provide a modest, but significant improvement of motor function and delay the need for levodopa. Rasagiline and safinamide were proven safe and effective when added to a dopamine agonist in early PD. As add-on to levodopa, MAO-B inhibitors significantly reduced off-time and were comparable in efficacy to COMT inhibitors. Improvements were achieved as regards certain non-motor symptoms as well. Due to the efficacy shown in clinical trials and their favorable side-effect profile, MAO-B inhibitors are valuable drugs in the treatment of PD. They are recommended as monotherapy in the early stages of the disease and as add-on therapy to levodopa in advanced PD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

ELISA analysis of soybean trypsin inhibitors in processed foods.

PubMed

Brandon, D L; Bates, A H; Friedman, M

1991-01-01

Soybean proteins are widely used in human foods in a variety of forms, including infant formulas, flour, protein concentrates, protein isolates, soy sauces, textured soy fibers, and tofu. The presence of inhibitors of digestive enzymes in soy proteins impairs the nutritional quality and possibly the safety of soybeans and other legumes. Processing, based on the use of heat or fractionation of protein isolates, does not completely inactivate or remove these inhibitors, so that residual amounts of inhibitors are consumed by animals and humans. New monoclonal antibody-based immunoassays can measure low levels of the soybean Kunitz trypsin inhibitor (KTI) and the Bowman-Birk trypsin and chymotrypsin inhibitor (BBI) and the Bowman-Birk foods. The enzyme-linked immunosorbent assay (ELISA) was used to measure the inhibitor content of soy concentrates, isolates, and flours, both heated and unheated; a commercial soy infant formula; KTI and BBI with rearranged disulfide bonds; browning products derived from heat-treatment of KTI with glucose and starch; and KTI exposed to high pH. The results indicate that even low inhibitor isolates contain significant amounts of specific inhibitors. Thus, infants on soy formula consume about 10 mg of KTI plus BBI per day. The immunoassays complement the established enzymatic assays of trypsin and chymotrypsin inhibitors, and have advantages in (a) measuring low levels of inhibitors in processed foods; and (b) differentiating between the Kunitz and Bowman-Birk inhibitors. The significance of our findings for food safety are discussed.

Retro-binding thrombin active site inhibitors: identification of an orally active inhibitor of thrombin catalytic activity.

PubMed

Iwanowicz, Edwin J; Kimball, S David; Lin, James; Lau, Wan; Han, W-C; Wang, Tammy C; Roberts, Daniel G M; Schumacher, W A; Ogletree, Martin L; Seiler, Steven M

2002-11-04

A series of retro-binding inhibitors of human alpha-thrombin was prepared to elucidate structure-activity relationships (SAR) and optimize in vivo performance. Compounds 9 and 11, orally active inhibitors of thrombin catalytic activity, were identified to be efficacious in a thrombin-induced lethality model in mice.

Isoprenoid Biosynthesis Inhibitors Targeting Bacterial Cell Growth.

PubMed

Desai, Janish; Wang, Yang; Wang, Ke; Malwal, Satish R; Oldfield, Eric

2016-10-06

We synthesized potential inhibitors of farnesyl diphosphate synthase (FPPS), undecaprenyl diphosphate synthase (UPPS), or undecaprenyl diphosphate phosphatase (UPPP), and tested them in bacterial cell growth and enzyme inhibition assays. The most active compounds were found to be bisphosphonates with electron-withdrawing aryl-alkyl side chains which inhibited the growth of Gram-negative bacteria (Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa) at ∼1-4 μg mL -1 levels. They were found to be potent inhibitors of FPPS; cell growth was partially "rescued" by the addition of farnesol or overexpression of FPPS, and there was synergistic activity with known isoprenoid biosynthesis pathway inhibitors. Lipophilic hydroxyalkyl phosphonic acids inhibited UPPS and UPPP at micromolar levels; they were active (∼2-6 μg mL -1 ) against Gram-positive but not Gram-negative organisms, and again exhibited synergistic activity with cell wall biosynthesis inhibitors, but only indifferent effects with other inhibitors. The results are of interest because they describe novel inhibitors of FPPS, UPPS, and UPPP with cell growth inhibitory activities as low as ∼1-2 μg mL -1 . © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Recent development of small molecule glutaminase inhibitors.

PubMed

Song, Minsoo; Kim, Soong-Hyun; Im, Chun Young; Hwang, Hee-Jong

2018-05-24

Glutaminase (GLS) which is responsible for the conversion of glutamine to glutamate plays vital role in up-regulating cell metabolism for tumor cell growth, and is considered as a valuable therapeutic target for cancer treatment. Based on this important function of glutaminase in cancer, several GLS inhibitors have been developed from both academia and industries. Most importantly, Calithera Biosciences Inc. is actively developing glutaminase inhibitor CB-839 for the treatment of various cancers in phase 1 and 2 clinical trials at present. In this review, it is discussed about recent efforts to develop small molecule glutaminase inhibitors targeting glutamine metabolism both in the preclinical and clinical studies. In particular, more emphasis is placed on CB-839 since it is the only small molecule GLS inhibitor being studied in clinical setting. Inhibition mechanism is discussed based on x-ray structure study of thiadiazole derivatives as well. Finally, recent medicinal chemistry efforts to develop a new class of GLS inhibitors are given herein in the hope of providing useful information for GLS inhibitors of the next generation. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Skin problems and EGFR-tyrosine kinase inhibitor

PubMed Central

Kozuki, Toshiyuki

2016-01-01

Epidermal growth factor receptor inhibition is a good target for the treatment of lung, colon, pancreatic and head and neck cancers. Epidermal growth factor receptor-tyrosine kinase inhibitor was first approved for the treatment of advanced lung cancer in 2002. Epidermal growth factor receptor-tyrosine kinase inhibitor plays an essential role in the treatment of cancer, especially for patients harbouring epidermal growth factor receptor activating mutation. Hence, skin toxicity is the most concerning issue for the epidermal growth factor receptor-tyrosine kinase inhibitor treatment. Skin toxicity is bothersome and sometimes affects the quality of life and treatment compliance. Thus, it is important for physicians to understand the background and how to manage epidermal growth factor receptor-tyrosine kinase inhibitor-associated skin toxicity. Here, the author reviewed the mechanism and upfront preventive and reactive treatments for epidermal growth factor receptor inhibitor-associated skin toxicities. PMID:26826719

Inhibitor(s) of the classical complement pathway in mouse serum limit the utility of mice as experimental models of neuromyelitis optica.

PubMed

Ratelade, Julien; Verkman, A S

2014-11-01

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system in which anti-aquaporin-4 (AQP4) autoantibodies (AQP4-IgG) cause damage to astrocytes by complement-dependent cytotoxicity (CDC). Various approaches have been attempted to produce NMO lesions in rodents, some involving genetically modified mice with altered immune cell function. Here, we found that mouse serum strongly inhibits complement from multiple species, preventing AQP4-IgG-dependent CDC. Effects of mouse serum on complement activation were tested in CDC assays in which AQP4-expressing cells were incubated with AQP4-IgG and complement from different species. Biochemical assays and mass spectrometry were used to characterize complement inhibitor(s) in mouse serum. Sera from different strains of mice produced almost no AQP4-IgG-dependent CDC compared with human, rat and guinea pig sera. Remarkably, addition of mouse serum prevented AQP4-IgG-dependent CDC caused by human, rat or guinea pig serum, with 50% inhibition at <5% mouse serum. Hemolysis assays indicated that the inhibitor(s) in mouse serum target the classical and not the alternative complement pathway. We found that the complement inhibitor(s) in mouse serum were contained in a serum fraction purified with protein-A resin; however, the inhibitor was not IgG as determined using serum from IgG-deficient mice. Mass spectrometry on the protein A-purified fraction produced several inhibitor candidates. The low intrinsic complement activity of mouse serum and the presence of complement inhibitor(s) limit the utility of mouse models to study disorders, such as NMO, involving the classical complement pathway. Copyright © 2014 Elsevier Ltd. All rights reserved.

Chelation: A Fundamental Mechanism of Action of AGE Inhibitors, AGE Breakers, and Other Inhibitors of Diabetes Complications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nagai, Rhoji; Murray, David B.; Metz, Thomas O.

2012-03-01

Advanced glycation or glycoxidation end-products (AGE) increase in tissue proteins with age, and their rate of accumulation is increased in diabetes, nephropathy and inflammatory diseases. AGE inhibitors include a range of compounds that are proposed to act by trapping carbonyl and dicarbonyl intermediates in AGE formation. However, some among the newer generation of AGE inhibitors lack reactive functional groups that would trap reaction intermediates, indicating an alternative mechanism of action. We propose that AGE inhibitors function primarily as chelators, inhibiting metal-catalyzed oxidation reactions. The AGE-inhibitory activity of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers is also consistent with their chelatingmore » activity. Finally, compounds described as AGE breakers, or their hydrolysis products, also have strong chelating activity, suggesting that these compounds also act through their chelating activity. We conclude that chelation is the common, and perhaps the primary, mechanism of action of AGE inhibitors and breakers, and that chronic, mild chelation therapy should prove useful in treatment of diabetes and age-related diseases characterized by oxidative stress, inflammation and increased chemical modification of tissue proteins by advanced glycoxidation and lipoxidation end-products.« less

Potential non-oncological applications of histone deacetylase inhibitors.

PubMed

Ververis, Katherine; Karagiannis, Tom C

2011-01-01

Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutic drugs. Their clinical utility in oncology stems from their intrinsic cytotoxic properties and combinatorial effects with other conventional cancer therapies. To date, the histone deacetylase inhibitors suberoylanilide hydroxamic acid (Vorinostat, Zolinza®) and depsipeptide (Romidepsin, Istodax®) have been approved by the US Food and Drug Administration for the treatment of refractory cutaneous T-cell lymphoma. Further, there are currently over 100 clinical trials involving the use of histone deacetylase inhibitors in a wide range of solid and hematological malignancies. The therapeutic potential of histone deacetylase inhibitors has also been investigated for numerous other diseases. For example, the cytotoxic properties of histone deacetylase inhibitors are currently being harnessed as a potential treatment for malaria, whereas the efficacy of these compounds for HIV relies on de-silencing latent virus. The anti-inflammatory properties of histone deacetylase inhibitors are the predominant mechanisms for other diseases, such as hepatitis, systemic lupus erythematosus and a wide range of neurodegenerative conditions. Additionally, histone deacetylase inhibitors have been shown to be efficacious in animal models of cardiac hypertrophy and asthma. Broad-spectrum histone deacetylase inhibitors are clinically available and have been used almost exclusively in preclinical systems to date. However, it is emerging that class- or isoform-specific compounds, which are becoming more readily available, may be more efficacious particularly for non-oncological applications. The aim of this review is to provide an overview of the effects and clinical potential of histone deacetylase inhibitors in various diseases. Apart from applications in oncology, the discussion is focused on the potential efficacy of histone deacetylase inhibitors for the treatment of neurodegenerative diseases, cardiac

Potential non-oncological applications of histone deacetylase inhibitors

PubMed Central

Ververis, Katherine; Karagiannis, Tom C

2011-01-01

Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutic drugs. Their clinical utility in oncology stems from their intrinsic cytotoxic properties and combinatorial effects with other conventional cancer therapies. To date, the histone deacetylase inhibitors suberoylanilide hydroxamic acid (Vorinostat, Zolinza®) and depsipeptide (Romidepsin, Istodax®) have been approved by the US Food and Drug Administration for the treatment of refractory cutaneous T-cell lymphoma. Further, there are currently over 100 clinical trials involving the use of histone deacetylase inhibitors in a wide range of solid and hematological malignancies. The therapeutic potential of histone deacetylase inhibitors has also been investigated for numerous other diseases. For example, the cytotoxic properties of histone deacetylase inhibitors are currently being harnessed as a potential treatment for malaria, whereas the efficacy of these compounds for HIV relies on de-silencing latent virus. The anti-inflammatory properties of histone deacetylase inhibitors are the predominant mechanisms for other diseases, such as hepatitis, systemic lupus erythematosus and a wide range of neurodegenerative conditions. Additionally, histone deacetylase inhibitors have been shown to be efficacious in animal models of cardiac hypertrophy and asthma. Broad-spectrum histone deacetylase inhibitors are clinically available and have been used almost exclusively in preclinical systems to date. However, it is emerging that class- or isoform-specific compounds, which are becoming more readily available, may be more efficacious particularly for non-oncological applications. The aim of this review is to provide an overview of the effects and clinical potential of histone deacetylase inhibitors in various diseases. Apart from applications in oncology, the discussion is focused on the potential efficacy of histone deacetylase inhibitors for the treatment of neurodegenerative diseases, cardiac

The "SWOT" of BRAF inhibition in melanoma: RAF inhibitors, MEK inhibitors or both?

PubMed

Nissan, Moriah H; Solit, David B

2011-12-01

Activating mutations in the BRAF gene are among the most prevalent kinase mutations in human cancer. BRAF mutations are most frequent in patients with melanoma where they occur in approximately 50% of patients with advanced disease. Remarkable clinical activity has recently been reported with highly selective RAF inhibitors in melanoma patients whose tumors harbor V600E BRAF mutations. The response rates of RAF inhibitors in patients with BRAF-mutant melanomas far exceed the activity level of any prior therapy studied in this disease. The results suggest that we have entered an era of personalized therapy for patients with metastatic melanoma in which treatment selection will be guided by BRAF mutational status. This review will discuss the strengths, weaknesses, opportunities and threats ("SWOT") of developing RAF and MEK selective inhibitors as anti-cancer therapies, recent insights into the mechanisms of intrinsic and acquired resistance to these agents, and current efforts to develop mechanism-based combination therapies.

Inhibitors of cyclin-dependent kinases as cancer therapeutics.

PubMed

Whittaker, Steven R; Mallinger, Aurélie; Workman, Paul; Clarke, Paul A

2017-05-01

Over the past two decades there has been a great deal of interest in the development of inhibitors of the cyclin-dependent kinases (CDKs). This attention initially stemmed from observations that different CDK isoforms have key roles in cancer cell proliferation through loss of regulation of the cell cycle, a hallmark feature of cancer. CDKs have now been shown to regulate other processes, particularly various aspects of transcription. The early non-selective CDK inhibitors exhibited considerable toxicity and proved to be insufficiently active in most cancers. The lack of patient selection biomarkers and an absence of understanding of the inhibitory profile required for efficacy hampered the development of these inhibitors. However, the advent of potent isoform-selective inhibitors with accompanying biomarkers has re-ignited interest. Palbociclib, a selective CDK4/6 inhibitor, is now approved for the treatment of ER+/HER2- advanced breast cancer. Current developments in the field include the identification of potent and selective inhibitors of the transcriptional CDKs; these include tool compounds that have allowed exploration of individual CDKs as cancer targets and the determination of their potential therapeutic windows. Biomarkers that allow the selection of patients likely to respond are now being discovered. Drug resistance has emerged as a major hurdle in the clinic for most protein kinase inhibitors and resistance mechanism are beginning to be identified for CDK inhibitors. This suggests that the selective inhibitors may be best used combined with standard of care or other molecularly targeted agents now in development rather than in isolation as monotherapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Heme-Coordinating Inhibitors of Neuronal Nitric Oxide Synthase. Iron-Thioether Coordination is Stabilized by Hydrophobic Contacts Without Increased Inhibitor Potency

PubMed Central

Martell, Jeffrey D.; Li, Huiying; Doukov, Tzanko; Martásek, Pavel; Roman, Linda J.; Soltis, Michael; Poulos, Thomas L.; Silverman, Richard B.

2010-01-01

The heme-thioether ligand interaction often occurs between heme iron and native methionine ligands, but thioether-based heme-coordinating (type II) inhibitors are uncommon due to the difficulty in stabilizing the Fe-S bond. Here, a thioether-based inhibitor (3) of neuronal nitric oxide synthase (nNOS) was designed, and its binding was characterized by spectrophotometry and crystallography. A crystal structure of inhibitor 3 coordinated to heme iron was obtained, representing, to our knowledge, the first crystal structure of a thioether inhibitor complexed to any heme enzyme. A series of related potential inhibitors (4-8) also were evaluated. Compounds 4-8 were all found to be type I (non-heme-coordinating) inhibitors of ferric nNOS, but 4 and 6-8 were found to switch to type II upon heme reduction to the ferrous state, reflecting the higher affinity of thioethers for ferrous heme than for ferric heme. Contrary to what has been widely thought, thioether-heme ligation was found not to increase inhibitor potency, illustrating the intrinsic weakness of the thioether-ferric heme linkage. Subtle changes in the alkyl groups attached to the thioether sulfur caused drastic changes in binding conformation, indicating that hydrophobic contacts play a crucial role in stabilizing the thioether-heme coordination. PMID:20014790

p21-activated kinase inhibitors.

PubMed

Rudolph, Joachim; Crawford, James J; Hoeflich, Klaus P; Chernoff, Jonathan

2013-01-01

The p21-activated kinases (PAKs) are Ser/Thr kinases in the STE20 kinase family with important roles in regulating cytoskeletal organization, cell migration, and signaling. The PAK enzyme family comprises six members subdivided into two groups: Group I, represented by PAK1, 2, and 3, and Group II, represented by PAK 4, 5, and 6, based on sequence and structural homology. Individual PAK isoforms were found to be overexpressed and amplified in a variety of human cancers, and in vitro and in vivo studies using genetically engineered systems as well as small-molecule tool compounds have suggested therapeutic utility of PAKs as oncology targets. The identification of potent and kinome-selective ATP-competitive PAK inhibitors has proven challenging, likely caused by the openness and unique plasticity of the ATP-binding site of PAK enzymes. Progress in achieving increased kinase selectivity has been achieved with certain inhibitors but at the expense of increased molecular weight. Allosteric inhibitors, such as IPA-3, leverage the unique Group I PAK autoregulatory domain for selective inhibition, and this approach might provide an outlet to evade the kinase selectivity challenges observed with ATP-competitive PAK inhibitors. © 2013 Elsevier Inc. All rights reserved.

Molecular design of new aggrecanases-2 inhibitors.

PubMed

Shan, Zhi Jie; Zhai, Hong Lin; Huang, Xiao Yan; Li, Li Na; Zhang, Xiao Yun

2013-10-01

Aggrecanases-2 is a very important potential drug target for the treatment of osteoarthritis. In this study, a series of known aggrecanases-2 inhibitors was analyzed by the technologies of three-dimensional quantitative structure-activity relationships (3D-QSAR) and molecular docking. Two 3D-QSAR models, which based on comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) methods, were established. Molecular docking was employed to explore the details of the interaction between inhibitors and aggrecanases-2 protein. According to the analyses for these models, several new potential inhibitors with higher activity predicted were designed, and were supported by the simulation of molecular docking. This work propose the fast and effective approach to design and prediction for new potential inhibitors, and the study of the interaction mechanism provide a better understanding for the inhibitors binding into the target protein, which will be useful for the structure-based drug design and modifications. Copyright © 2013 Elsevier Ltd. All rights reserved.

Skin problems and EGFR-tyrosine kinase inhibitor.

PubMed

Kozuki, Toshiyuki

2016-04-01

Epidermal growth factor receptor inhibition is a good target for the treatment of lung, colon, pancreatic and head and neck cancers. Epidermal growth factor receptor-tyrosine kinase inhibitor was first approved for the treatment of advanced lung cancer in 2002. Epidermal growth factor receptor-tyrosine kinase inhibitor plays an essential role in the treatment of cancer, especially for patients harbouring epidermal growth factor receptor activating mutation. Hence, skin toxicity is the most concerning issue for the epidermal growth factor receptor-tyrosine kinase inhibitor treatment. Skin toxicity is bothersome and sometimes affects the quality of life and treatment compliance. Thus, it is important for physicians to understand the background and how to manage epidermal growth factor receptor-tyrosine kinase inhibitor-associated skin toxicity. Here, the author reviewed the mechanism and upfront preventive and reactive treatments for epidermal growth factor receptor inhibitor-associated skin toxicities. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

High catalytic activity and stability of Ni/CexZr1-xO2/MSU-H for CH4/CO2 reforming reaction

NASA Astrophysics Data System (ADS)

Chang, Xiaoqian; Liu, Bingsi; Xia, Hong; Amin, Roohul

2018-06-01