Selective Inhibitor Of Xanthine Oxidase Research Articles

A rare case of thrombocytopenia secondary to taking febuxostat

A new and powerful selective xanthine oxidase inhibitor called febuxostat seems to be well tolerated by all patient populations, even those who are allopurinol-sensitive. Thrombocytopenia is an extremely uncommon side effect. The case of a 63- year-old man who presented with sudden thrombocytopenia and was ultimately linked to febuxostat consumption is described below. The case happened in our department.

Multicenter randomized controlled trial of intensive uric acid lowering therapy for CKD patients with hyperuricemia: TARGET-UA.

We investigate whether Intensive uric acid (UA)-lowering therapy (ULT) provides increased renal protection compared with standard therapy in chronic kidney disease (CKD) patients. This was a multicenter randomized controlled trial. Only CKD patients with hyperuricemia were included in this study. The participants were randomly assigned to either the Intensive therapy group (target serum UA level ≥ 4.0mg/dL and < 5.0mg/dL) or the standard therapy group (serum UA level ≥ 6.0mg/dL and < 7.0mg/dL). ULT was performed using topiroxostat, a non-purine-type selective xanthine oxidase inhibitor. The primary endpoint was change in the logarithmic value of urine albumin to the creatinine ratio (ACR) between baseline and week 52 of the treatment. Three hundred fifty-two patients were included in the full analysis set. In the Standard therapy group, mean serum UA was 8.23mg/dL at baseline and 6.13mg/dL at 52weeks. In the Intensive therapy group, mean serum UA was 8.15mg/dL at baseline and 5.25mg/dL at 52weeks. There was no significant difference in changes in log ACR at 52weeks between the Intensive therapy and the Standard therapy groups. This study did not reveal the benefit of Intensive ULT to improve albuminuria levels. (UMIN000026741 and jRCTs051180146).

Evaluation of Pharmacokinetic Feasibility of Febuxostat/L-pyroglutamic Acid Cocrystals in Rats and Mice.

Febuxostat (FBX), a selective xanthine oxidase inhibitor, belongs to BCS class II, showing low solubility and high permeability with a moderate F value (<49%). Recently, FBX/L-pyroglutamic acid cocrystal (FBX-PG) was developed with an improving 4-fold increase of FBX solubility. Nevertheless, the in vivo pharmacokinetic properties of FBX-PG have not been evaluated yet. Therefore, the pharmacokinetic feasibility of FBX in FBX- and FBX-PG-treated rats and mice was compared in this study. The results showed that the bioavailability (F) values of FBX were 210% and 159% in FBX-PG-treated rats and mice, respectively. The 2.10-fold greater total area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) of FBX was due to the increased absorption [i.e., 2.60-fold higher the first peak plasma concentration (Cmax,1) at 15 min] and entero-hepatic circulation of FBX [i.e., 1.68-fold higher the second peak plasma concentration (Cmax,2) at 600 min] in FBX-PG-treated rats compared to the FBX-treated rats. The 1.59-fold greater AUC0-inf of FBX was due to a 1.65-fold higher Cmax,1 at 5 min, and a 1.15-fold higher Cmax,2 at 720 min of FBX in FBX-PG-treated mice compared to those in FBX-treated mice. FBX was highly distributed in the liver, stomach, small intestine, and lungs in both groups of mice, and the FBX distributions to the liver and lungs were increased in FBX-PG-treated mice compared to FBX-treated mice. The results suggest the FBX-PG has a suitable pharmacokinetic profile of FBX for improving its oral F value.

Synthesis, characterization, luminescence, and catalytic properties of a zinc(II) complex with a N,O-donor ligand generated in situ from topiroxostat

Abstract By utilizing the well-known selective xanthine oxidase inhibitor topiroxostat, a new zinc(II) complex Zn(L)2(H2O)2 (1) [HL = 4-(3-(pyridine-4-yl)-1H-1,2,4-triazol-5-yl)picolinic acid] has been hydrothermally synthesized, involving in-situ ligand formation upon hydrolysis of topiroxostat. The complex has been structurally characterized by elemental analysis, IR spectroscopy, thermogravimetric analysis, powder X-ray diffraction, and single-crystal X-ray diffraction. X-ray structural analysis revealed that complex 1 is a N,O-chelating mononuclear Zn(II) complex. Complex 1 shows good thermal stability and exhibits photoluminescence in the solid state at room temperature. Moreover, complex 1 has been shown to be effective in the solvent-free ring-opening polymerization of ε-caprolactone without any co-catalyst or initiator.

A feasible HPTLC method for concurrent quantitation of allopurinol-montelukast co-therapy in plasma and evaluation of their hepatic and renal effects in rats: Analytical, biochemical, and histopathological study

Recent studies presented the crucial role of montelukast (MON, a leukotriene receptor antagonist) against gouty arthritis and its protective effect on drug-induced liver and kidney injury. Allopurinol (ALO, a selective xanthine oxidase inhibitor) is also used for treatment of hyperuricemia, however, it induces hepatotoxicity and acute kidney injury. Therefore, this study introduces the first analytical/biochemical/histopathological assay for MON-ALO co-therapy and aims to: inspect the hepatic and renal impacts of ALO, MON and their combination in rats via biochemical and histopathological examinations, propose and validate a facile HPTLC method for concurrent estimation of ALO-MON binary mixture in human plasma, and employ this method to attain the targeted drugs in real rat plasma. First, the cited drugs in human plasma were simultaneously separated utilizing silica gel G 60 F254-TLC plates. The separated bands were scanned at 268 nm demonstrating appropriate linearities (50.0–2000.0 ng band−1 for each drug) and correlations (0.9986 and 0.9992 for ALO and MON, correspondingly). The calculated detection and quantitation limits, as well as recoveries confirmed the method’s reliability. This procedure was validated, and the stability studies were achieved according to Bioanalytical Method Validation Guideline. This work was extended to investigate the possible hepatic and renal effects of ALO, MON and their co-therapy in rats. Using rat’s gastric tube, the following was administered to four groups of male Wistar rats: Group Ia and Ib as control (received either saline or DMSO), Groups II, III, and IV were given MON, ALO, and MON+ALO, respectively. Good correlation between the measured biochemical parameters and the observed histopathological changes was encountered. Considerable drop in aspartate transaminase and alanine transaminase levels, in addition to lower liver damage changes were observed in the combination group compared to MON or ALO-treated groups. Regarding renal changes, ALO-MON co-therapy caused elevation in the serum creatinine and blood urea nitrogen levels when compared to controls and MON- or ALO-treated groups. Severe proteinaceous casts accumulation in kidney tubular lumen, severe congestion, and severe tubular necrosis were also noticed in the combination group. Lastly, this study suggests ALO-MON co-treatment not only as a preventive therapy against gouty arthritis but also as a new line to minimize ALO-induced hepatic injury. However, co-administration of ALO and MON should be further studied to assess the benefits and risks in various tissues, adjust the MON dosing, and monitor its nephrotoxic effect.

Effect of febuxostat on the level of malondialdehyde-modified low-density lipoprotein, an oxidative stress marker: A subanalysis of the PRIZE study.

Febuxostat is a selective xanthine oxidase inhibitor that reportedly exhibits antioxidant properties. We previously performed a multicentre, randomized controlled (PRIZE) study for vascular evaluation under uric acid (UA) control by febuxostat to investigate the progression of carotid lesions in asymptomatic hyperuricemic patients with carotid atherosclerosis for 2 years. The current subanalysis of the PRIZE study aimed to assess the effect of febuxostat on the level of malondialdehyde-modified low-density lipoprotein (MDA-LDL), an oxidative stress marker. We recruited 383 patients (febuxostat group, n = 200; control group, n = 183) from the PRIZE trial for whom MDA-LDL measurements were available. The UA, MDA-LDL, low-density lipoprotein cholesterol (LDL-C) levels, and MDA-LDL/LDL-C ratio were identified, represented as the estimated difference from baseline to 24months. We also evaluated the relationship between febuxostat dose (10, ≤20 to <40, and ≤40 to ≤60 mg) and changes in the MDA-LDL level, LDL-C level, or MDA-LDL/LDL-C ratios. The estimated change in MDA-LDL/LDL-C ratio from baseline to 24monthswas significantly lower in the febuxostat group than in the control group (p = .025), whereas the estimated changes in MDA-LDL (p = .235) and LDL-C (p = .323) levels did not differ between the two groups. No significant correlation existed between the febuxostat doses and the estimated change in the MDA-LDL level (p = .626), LDL-C level (p = .896), or MDA-LDL/LDL-C ratio (p = .747). Our findings may indicate a possibility that febuxostat can lower the MDA-LDL/LDL-C ratio, a potential marker of atherosclerosis and oxidative stress, in asymptomatic hyperuricemic patients with carotid atherosclerosis. Further studies are required to validate our findings and elucidate the clinical antioxidant effect of febuxostat.

PS-C34-7: EFFECT OF FEBUXOSTAT ON THE LEVEL OF MALONDIALDEHYDE-MODIFIED LOW-DENSITY LIPOPROTEIN, AS AN OXIDANT MARKER, FROM THE SUB-ANALYSES OF PRIZE STUDY

Background: Febuxostat is a selective xanthine oxidase inhibitor that has been reported to possess antioxidant properties in experimental and animal studies. We previously conducted the program of vascular evaluation under uric acid control by xanthine oxidase inhibitor, febuxostat: multicenter, randomized controlled (PRIZE) study to evaluate the progression of carotid lesions in asymptomatic hyperuricemic patients with carotid atherosclerosis treated with febuxostat for 2 years compared with a control group. In the present sub-analysis study of the PRIZE study, the effect of febuxostat on the level of malondialdehyde modified low density lipoprotein (MDA-LDL), one of the oxidative stress markers, was examined. Methods: The subjects were 381 patients enrolled in the PRIZE trial for whom MDA-LDL measurements were available at baseline and at 24 months (182 in the febuxostat group and 199 in the control group). Uric acid (UA) levels, MDA-LDL levels, and MDA-LDL/LDL-C were determined, expressed as the estimated difference from baseline to 24 months, and compared between the two groups. We also examined the relationship between febuxostat dose (10 mg, 20–40 mg, 40–60 mg) and changes in MDA-LDL or MDA-LDL/LDL-C. Results: Febuxostat significantly reduced the level of UA, compared with that in the control group, in a dose-dependent manner (p &lt; 0.001). The estimated difference in MDA-LDL/LDL-C from baseline to 24 months was significantly lower in the Febuxostat group than that in the control group (p = 0.025), while the estimated difference in MDA-LDL from baseline to 24 months was not different in the two groups (p = 0.235). There was no significant correlation between the dose of febuxostat and the estimated difference in MDA-L/LDL-C (p = 0.626). Conclusions: In asymptomatic hypereuricemia patients with carotid atherosclerosis, febuxostat may have some antioxidant effect, but the effect may not be dose-dependent.

Long-Term Effect of Febuxostat on Endothelial Function in Patients With Asymptomatic Hyperuricemia: A Sub-Analysis of the PRIZE Study.

BackgroundXanthine oxidase is involved in the production of uric acid and the generation of superoxide anion. We evaluated the long-term effect of febuxostat, a non-purine selective xanthine oxidase inhibitor, on endothelial function in patients with asymptomatic hyperuricemia.MethodsIn the PRIZE study, patients with hyperuricemia were randomly assigned to either add-on febuxostat treatment (febuxostat group) or non-pharmacologic hyperuricemia treatment (control group). Among the 514 participants, endothelial function was assessed in 41 patients in the febuxostat group and 38 patients in the control group by flow-mediated vasodilation (FMD) of the brachial artery at the beginning of the study and after 12 and/or 24 months of treatment (63 men; median age, 68.0 years).ResultsThe least squares mean concentration of serum uric acid was significantly lower in the febuxostat group than in the control group at 6 months (mean between-group difference [febuxostat group - control group], −2.09 mg/dL [95% confidence interval (CI), −2.520 to −1.659]; P < 0.001), 12 months (mean between-group difference, −2.28 mg/dL [95% CI, −2.709 to −1.842]; P < 0.001), and 24 months (mean between-group difference, −2.61 mg/dL [95% CI, −3.059 to −2.169]; P < 0.001). No significant differences were found between groups in the least squares mean estimated percentage change in FMD at 12 months (mean between-group difference, −0.56% [95% CI, −1.670 to 0.548]; P = 0.319) and at 24 months (mean between-group difference, −0.60% [95% CI, −1.886 to 0.685]; P = 0.357).ConclusionFebuxostat treatment did not alter endothelial function assessed by FMD during a 2-year study period in patients with asymptomatic hyperuricemia.

Comparison between febuxostat and allopurinol uric acid-lowering therapy in patients with chronic heart failure and hyperuricemia: a multicenter randomized controlled trial.

ObjectiveHeart failure (HF) is a common and highly morbid cardiovascular disorder. Oxidative stress worsens HF, and uric acid (UA) is a useful oxidative stress marker. The novel anti-hyperuricemic drug febuxostat is a potent non-purine selective xanthine oxidase inhibitor. The present study examined the UA-lowering and prognostic effects of febuxostat in patients with HF compared with conventional allopurinol.MethodsThis multicenter, randomized trial included 263 patients with chronic HF who were randomly assigned to two groups and received allopurinol or febuxostat (UA >7.0 mg/dL). All patients were followed up for 3 years after enrollment.ResultsThere were no significant differences in baseline clinical characteristics between the two groups. The UA level was significantly decreased after 3 years of drug administration compared with the baseline in both groups. Urine levels of the oxidative stress marker 8-hydroxy-2′-deoxyguanosine were lower in the febuxostat group than in the allopurinol group (11.0 ± 9.6 vs. 22.9 ± 15.9 ng/mL), and the rate of patients free from hospitalization due to worsening HF tended to be higher in the febuxostat group than in the allopurinol group (89.0% vs. 83.0%).ConclusionsFebuxostat is potentially more effective than allopurinol for treating patients with chronic HF and hyperuricemia.This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/; ID: 000009817).

Febuxostat treatment attenuates oxidative stress and inflammation due to ischemia-reperfusion injury through the necrotic pathway in skin flap of animal model

BackgroundIschemia-reperfusion (I/R) injury is a major contributor to skin flap necrosis, which is a serious complication of reconstructive surgery. The purpose of this study was to evaluate the protective effect of treatment with febuxostat, a selective xanthine oxidase inhibitor, on I/R injury in the skin flap of an animal (rat) model. MethodsSuperficial epigastric flaps were raised in Sprague-Dawley rats and subjected to ischemia for 3 h. Febuxostat at a dose of 10 mg/kg/day was administered to rats in drinking water from 1 week before the surgery (Feb group). Control animals received no drugs (Con group). The mean ratio of flap survival and contraction was evaluated and compared between animals with and without administration of febuxostat on day 5 after the surgery. In addition, infiltration by polymorphonuclear leukocytes and muscles of the panniculus carnosus in the flap were histologically evaluated using hematoxylin-eosin staining. Furthermore, xanthine oxidase activity, ATP levels, superoxide dismutase activity, and expression of 8-hydroxy-2′-deoxyguanosine (8-OHdG), tumor necrosis factor-α, and interleukin-1β were quantitatively assessed in the skin flap 24 h after the surgery. ResultsIn the Feb group, the survival and contraction rates at the 5 d timepoint post-surgery were significantly higher and lower than those in the Con group, respectively. Histological analysis showed significant reduction in polymorphonuclear leukocyte infiltration and muscle injury scores due to I/R injury in the Feb group. The expression of 8-OHdG was also significantly inhibited in animals administered febuxostat. Biochemical analysis showed a significant reduction in xanthine oxidase activity and significant increases in ATP levels and superoxide dismutase activity in the Feb group. Furthermore, the expression of interleukin-1β was significantly lower in the Feb group than in the Con group. ConclusionFebuxostat, which is clinically used for the treatment of hyperuricemia, was effective against necrosis of the skin flap via inhibition of oxidative stress and inflammation caused by I/R injury.

Febuxostat, an inhibitor of xanthine oxidase, ameliorates ionizing radiation-induced lung injury by suppressing caspase-3, oxidative stress and NF-κB

Febuxostat (FBX), a selective inhibitor of xanthine oxidase, has several biological properties such as antioxidant, anti-inflammatory and anti-apoptosis activities. The purpose of this study was to evaluate the protective effect of FBX against ionizing radiation (IR)-induced lung injury through mitigation of oxidative stress, inflammation and apoptosis. Sixty-four mice were randomized into eight groups as control, FBX (5, 10, and 15 mg/kg), IR (6 Gy), and IR + FBX (IR + FBX in three doses). Mice were received FBX for 8 consecutive days and then were exposed to IR at a single dose (6 Gy) of X-ray. At 1 and 7 days after irradiation, the biochemical parameters were analyzed in lung tissue, while histological and immunohistochemical examinations were evaluated 1 week after irradiation. Irradiation led to elevate of oxidative stress parameters (an increase of MDA, PC, NO, and decrease of GSH), inflammation and apoptosis in lung of mice. Furthermore, IR resulted in histopathological changes in the lung tissues. These changes were significantly mitigated by FBX treatment. FBX also inhibited immunoreactivity of caspase-3, NF-κB, and reduced oxidative stress. This study showed that FBX is able to protect lung injury induced by IR through inhibiting apoptosis (caspase-3), oxidative stress and inflammation (NF-κB).

Optimization of amorphous solid dispersion techniques to enhance solubility of febuxostat.

Febuxostat is a selective inhibitor of xanthine oxidase and belongs to BCS class II drugs having low solubility and high permeability. Solubility is the most important parameter which directly affects dissolution, absorption and bioavailability of the drugs. There are different techniques by which we can improve solubility and dissolution rate of poorly soluble drug. Amorphous solid dispersion is one of the methods which can improve solubility as well as powder characteristics. The aim of the present study was to formulate and optimize various methods of formulating solid dispersion by using various drug-to-polymer ratios and identifying the batch which gives higher solubility as well as amorphous powder of the drug febuxostat. Different techniques like hot melt method, solvent evaporation method and spray drying techniques were selected for optimization. Attempts were made to improve solubility of febuxostat by employing Kolliphor P 188, Kolliphor P 237, Eudragit RLPO in different drug-to-polymer ratios (1:1, 1:1.5, 1:2) as carrier. The prepared solid dispersion was characterized for the saturation solubility, percentage yield, using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), powdered X-ray diffraction studies (PXRD), and residual solvent determination. Solid state characterization indicated that febuxostat was present in the amorphous form after mixing with polymeric carrier. In contrast to the pure form of drug, solid dispersion of the drug showed better solubility and amorphous characteristics which can be attributed to decreased crystallinity due to hydrotrophy. Thus, amorphous solid dispersion approach can be used successfully to enhance solubility, dissolution rate and bioavailability of febuxostat.

Association Between Kidney Function Decline and Baseline TNFR Levels or Change Ratio in TNFR by Febuxostat Chiefly in Non-diabetic CKD Patients With Asymptomatic Hyperuricemia

Background: The levels of circulating tumor necrosis factor receptor (TNFR) 1 and 2 help predict the future decline of estimated glomerular filtration rate (eGFR) chiefly in patients with diabetes. It has been recently reported that the change ratio in TNFR1 by SGLT2 inhibitor treatment is also related with future GFR decline in patients with diabetes. The aims of this study are to investigate the association between baseline TNFR levels and early change in TNFR levels by the non-purine selective xanthine oxidase inhibitor, febuxostat, and future eGFR decline chiefly in chronic kidney disease (CKD) patients without diabetes.Methods: We conducted a post-hoc analysis of the FEATHER study on patients with asymptomatic hyperuricemia and CKD stage 3, who were randomly assigned febuxostat 40 mg/day or matched placebo. This analysis included 426 patients in whom baseline stored samples were available. Serum TNFR levels at baseline were measured using enzyme-linked immunosorbent assay. Those levels were also measured using 12-week stored samples from 197 randomly selected patients.Results: Compared with placebo, short-term febuxostat treatment significantly decreased the median percent change from baseline in serum uric acid (−45.05, 95% CI −48.90 to −41.24 mg/dL), TNFR1 (1.10, 95% CI−2.25 to 4.40), and TNFR2 (1.66, 95% CI −1.72 to 4.93), but not TNFR levels. Over a median follow-up of 105 weeks, 30 patients (7.0%) experienced 30% eGFR decline from baseline. In the Cox multivariate model, high levels of baseline TNFR predicted a 30% eGFR decline, even after adjusting for age, sex, systolic blood pressure, high sensitivity C-reactive protein, uric acid, and presence or absence of febuxostat treatment and diabetes, in addition to baseline albumin to creatinine ratio and eGFR.Conclusion: Early change in circulating TNFR levels failed to predict future eGFR decline; however, regardless of febuxostat treatment, the elevated baseline level of TNFR was a strong predictor of 30% eGFR decline even in chiefly non-diabetic CKD patients with asymptomatic hyperuricemia.

EFFECTS OF FEBUXOSTAT ON CAROTID INTIMA-MEDIA THICKNESS IN ASYMPTOMATIC HYPERURICEMIA: A RANDOMIZED CLINICAL TRIAL (PRIZE)

Objective: Elevated levels of serum uric acid (SUA) increase the risk of gout and may be associated with the risk of cardiometabolic disorders and subsequent cardiovascular disease. Clinical evidence regarding the effects of xanthine oxidase (XO) inhibitors on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat, a non-purine selective inhibitor of XO, delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia. Design and method: This was an investigator-initiated, multicenter, randomized, controlled, open-label clinical trial undertaken at 48 Japanese sites. A total of 514 adults, who had both asymptomatic hyperuricemia with SUA &gt;7.0 mg/dL and maximum IMT of the common carotid artery (CCA) 1.1 mm or greater at screening, were equally allocated to receive either dose-titrated febuxostat (10–60 mg daily) or non-pharmacological lifestyle modification for hyperuricemia as a control-arm. The primary endpoint was the percentage change from baseline in mean IMT of the CCA at 24 months. Key secondary outcomes included other carotid ultrasonographic parameters, SUA, and adverse events. Results: Compared with the control group, febuxostat had no significant effect on the primary endpoint (1.2% [95% CI, -0.6% to 3.0%] in the febuxostat group vs 1.4% [95% CI, -0.5% to 3.3%] in the control group; between-group difference [febuxostat-control], -0.2% [95% CI, -2.3% to 1.9%]; P = 0.83) and any other carotid ultrasonographic parameters. At 24 months, the between-group difference [febuxostat-control] in the SUA change from baseline was significant (-2.65 mg/dL [95% CI, -2.93 mg/dL to -2.37 mg/dL]; P &lt; 0.001), and gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. Conclusions: In Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population. However, febuxostat treatment was tolerable and did not increase the incidence of cardiovascular and all-cause mortality.

Effects of the xanthine oxidase inhibitor, febuxostat, on the expression of monocyte chemoattractant protein-1 and synchronous genes in MDCK cells treated with calcium oxalate monohydrate crystals.

To examine the effects of the selective xanthine oxidase inhibitor febuxostat on the expression of inflammation-related genes involved in stone formation. Madin-Darby canine kidney cells were exposed to febuxostat, followed by calcium oxalate monohydrate crystals. Monocyte chemoattractant protein-1 messenger ribonucleic acid expression levels were determined by real-time reverse transcription polymerase chain reaction analysis. Deoxyribonucleic acid microarray analysis was utilized to evaluate gene expression. Calcium oxalate monohydrate crystals activated monocyte chemoattractant protein-1 messenger ribonucleic acid expression in a time- and concentration-dependent manner. Febuxostat suppressed monocyte chemoattractant protein-1 expression. The expression levels of a group of inflammatory genes, including interleukin-8 and chemokine (C-X-C motif) ligand10, which are downstream of reactive oxygen species, fluctuated similarly to the observed monocyte chemoattractant protein-1 fluctuations and were reduced by febuxostat pretreatment. Febuxostat exerts preventive effects against reactive oxygen species production and oxidative stress, and might represent a potential treatment for calcium oxalate stones. In the present study, febuxostat downregulated the calcium oxalate monohydrate crystal-induced monocyte chemoattractant protein-1 messenger ribonucleic acid expression.

Amelioration of testosterone-induced benign prostatic hyperplasia using febuxostat in rats: The role of VEGF/TGFβ and iNOS/COX-2

Benign prostatic hyperplasia (BPH) is a common male disorder. Febuxostat is a non-purine, selective inhibitor of xanthine oxidase (XO), which has a strong antioxidant capacity and pleiotropic pharmacological properties. This study's objective was to explore the potential ameliorative effects of febuxostat against testosterone-induced BPH in rats. Febuxostat (10 mg/kg/day, per os [p.o.]) prevented increased prostate index levels, serum levels of prostate-specific antigen (PSA), and testosterone levels compared to animals treated with testosterone alone, when administered for 28 days. Histological examination indicated that febuxostat dramatically ameliorated pathological changes in the prostate architecture compared to the testosterone group. Similarly, febuxostat markedly improved testosterone-induced oxidative stress by inhibiting the increase in lipid peroxide and nitrite content, and by reducing the level of depletion of reduced glutathione (GSH) and superoxide dismutase (SOD) activity, which significantly reduced the prostate content of pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6). Furthermore, febuxostat significantly reduced the prostatic content, both in terms of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) messenger ribonucleic acid (mRNA) levels, and of protein levels. Moreover, compared to the testosterone group, febuxostat's beneficial effects prevented the increase in growth factors, comprising vascular endothelial cell growth factor A (VEGF-A) and transforming growth factor beta (TGF-β) protein levels. Its ameliorating effects were equal to those of finasteride, which is the most widely used remedy for BPH. In conclusion, this study provides novel evidence that febuxostat experimentally attenuates testosterone-induced BPH in rats, at least in part by inhibiting iNOS/COX-2 and VEGF/TGF-β pathways.

Current Gout Management Guidelines

Only 20 % of patients have hyperuricemia implemented in gout as a clinically defined disease. In Madrid, at the Congress of the European League Against Rheumatism (EULAR) in 2013, it was concluded that gout is two different diseases, one of which is metabolic and manifests as hyperuricemia (also called “chemical gout”), and the other the gout component is actually a typical inflammation of the joints of the favorite localization due to the deposition of sodium monourate crystals in the tissues. That is, gout is always hyperuricemia, but hyperuricemia is not always gout.The main principles of gout management are the treatment of acute gout attack with colchicine, non-steroidal anti-inflammatory drugs, glucocorticosteroids, and combinations thereof; further prevention of acute attack with minimal doses of the aforementioned drugs; long-term lifesaving therapy. A non-purine selective xanthine oxidase inhibitor with potent hypouricemic action and evidence-based febuxostat is thought to be 2–3 times more effective than allopurinol.

Febuxostat does not delay progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia: A randomized, controlled trial.

BackgroundAn elevated level of serum uric acid (SUA) is associated with an increased risk of cardiovascular disease. Pharmacological intervention with urate-lowering agents, such as the conventional purine analogue xanthine oxidase (XO) inhibitor, allopurinol, has been used widely for a long period of time in clinical practice to reduce SUA levels. Febuxostat, a novel non-purine selective inhibitor of XO, has higher potency for inhibition of XO activity and greater urate-lowering efficacy than conventional allopurinol. However, clinical evidence regarding the effects of febuxostat on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia.Methods and findingsThe study was a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial undertaken at 48 sites throughout Japan between May 2014 and August 2018. Adults with both asymptomatic hyperuricemia (SUA >7.0 mg/dL) and maximum IMT of the common carotid artery (CCA) ≥1.1 mm at screening were allocated equally using a central web system to receive either dose-titrated febuxostat (10–60 mg daily) or as a control-arm, non-pharmacological lifestyle modification for hyperuricemia, such as a healthy diet and exercise therapy. Of the 514 enrolled participants, 31 were excluded from the analysis, with the remaining 483 people (mean age 69.1 years [standard deviation 10.4 years], female 19.7%) included in the primary analysis (febuxostat group, 239; control group, 244), based on a modified intention-to-treat principal. The carotid IMT images were recorded by a single sonographer at each site and read in a treatment-blinded manner by a single analyzer at a central core laboratory. The primary endpoint was the percentage change from baseline to 24 months in mean IMT of the CCA, determined by analysis of covariance using the allocation adjustment factors (age, gender, history of type 2 diabetes, baseline SUA, and baseline maximum IMT of the CCA) as the covariates. Key secondary endpoints included changes in other carotid ultrasonographic parameters and SUA and the incidence of clinical events. The mean values (± standard deviation) of CCA-IMT were 0.825 mm ± 0.173 mm in the febuxostat group and 0.832 mm ± 0.175 mm in the control group (mean between-group difference [febuxostat − control], −0.007 mm [95% confidence interval (CI) −0.039 mm to 0.024 mm; P = 0.65]) at baseline; 0.832 mm ± 0.182 mm in the febuxostat group and 0.848 mm ± 0.176 mm in the control group (mean between-group difference, −0.016 mm [95% CI −0.051 mm to 0.019 mm; P = 0.37]) at 24 months. Compared with the control group, febuxostat had no significant effect on the primary endpoint (mean percentage change 1.2% [95% CI −0.6% to 3.0%] in the febuxostat group (n = 207) versus 1.4% [95% CI −0.5% to 3.3%] in the control group (n = 193); mean between-group difference, −0.2% [95% CI −2.3% to 1.9%; P = 0.83]). Febuxostat also had no effect on the other carotid ultrasonographic parameters. The mean baseline values of SUA were comparable between the two groups (febuxostat, 7.76 mg/dL ± 0.98 mg/dL versus control, 7.73 mg/dL ± 1.04 mg/dL; mean between-group difference, 0.03 mg/dL [95% CI −0.15 mg/dL to 0.21 mg/dL; P = 0.75]). The mean value of SUA at 24 months was significantly lower in the febuxostat group than in the control group (febuxostat, 4.66 mg/dL ± 1.27 mg/dL versus control, 7.28 mg/dL ± 1.27 mg/dL; mean between-group difference, −2.62 mg/dL [95% CI −2.86 mg/dL to −2.38 mg/dL; P < 0.001]). Episodes of gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. A limitation of the study was the study design, as it was not a placebo-controlled trial, had a relatively small sample size and a short intervention period, and only enrolled Japanese patients with asymptomatic hyperuricemia.ConclusionsIn Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population.Trial registrationUniversity Hospital Medical Information Network Clinical Trial Registry UMIN000012911.

EFFECTS OF FEBUXOSTAT ON CAROTID INTIMA-MEDIA THICKNESS IN ASYMPTOMATIC HYPERURICEMIA: A RANDOMIZED CLINICAL TRIAL (PRIZE)

Clinical evidence regarding the effects of xanthine oxidase (XO) inhibitors on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat, a non-purine selective inhibitor of XO, delays carotid intima-media thickness (IMT) progression in patients with

Heterometallic Cu(II)-M(II) (M = Mg, Ca and Sr) complexes with a N,O-donor ligand in situ generated from topiroxostat

By introducing alkaline-earth metal ions (Mg2+, Ca2+, and Sr2+) as structure-directing agents, three new heterometallic complexes, Mg(H2O)6·[Cu2Mg(L)4(H2O)4]·4H2O (1), [CuCa(L)2(H2O)4] n (2) and [CuSr(L)2(H2O)4] n (3) [H2L = 4-(3-(pyridine-4-yl)-1H-1,2,4-triazol-5-yl)picolinic acid], have been synthesized under hydrothermal conditions and structurally characterized. H2L was in situ generated from hydrolysis of the well-known selective xanthine oxidase inhibitor topiroxostat. Complex 1 crystallizes in the space group P21/c and exhibits a zero-dimensional (0-D) structure containing the discrete [Mg(H2O)6]2+ cationic and [Cu2Mg(L)4(H2O)4]2– dianionic moieties. Complexes 2 and 3 are isostructural and crystallize in the space group C2/c, with one-dimensional (1-D) polymeric structure with infinite Cu(II)–Ca/Sr–carboxylate chains. The results reveal the significant influence of the alkaline-earth metal ions on the molecular structure. Their spectroscopic, thermal and solid-state luminescent properties have also been investigated.