Febuxostat Research Articles

Clinical curative effect of Febuxostat in the treatment of hyperuricemia in senile patients without gout

Objective To observe the efficacy and safety of Febuxostat on elderly patients with hyperuricemia. Methods 112 elderly male patients with hyperuricemia, aged over 65 years with mean age of(72.6±5.8)years.All patients were randomly divided into Febuxostat 40 mg(37 cases), Febuxostat 80mg(38 cases)and Allopurinol(37 cases)groups.Blood samples were taken before and 2, 4, 8, 12, 16, 20, and 24 weeks after treatment.And fasting venous blood samples were taken for detections.The changes of blood uric acid level, blood biochemical indexes(triglyceride, low density lipoprotein cholesterol, urea, creatinine, Cystatin C, etc.)and side effects during treatment, and the blood uric acid targeting rate after 24 weeks of treatment were observed. Results After 2 weeks of treatment, the blood uric acid level was(500.23±54.72)μmol/L in Allopurinol group and(380.07±48.18)and(373.53±43.42)μmol/L in two Febuxostat groups, with the statistically significant difference(F=77.740, P=0.000). After 4 weeks, the level of serum uric acid was basically targeted in Febuxostat group, although Allopurinol group showed uric acid level was reduced, but was not less than the 356.88 μmol/L.After 4 weeks of treatment, serum uric acid level was(294.43±40.45)μmol/L in 80mg febuxostat group, (312.86±38.66)μmol/L in Febuxostat 40 mg group, (464.54±51.75)μmol/L in allopurinol group(F=165.330, P=0.000). After 8 weeks of treatment, the blood uric acid level was basically targeted in all three groups.Compared with pre-treatment, after the treatment, the serum levels of low density lipoprotein cholesterol, Cystatin C and creatinine in the groups of 40 mg and 80 mg Febuxostat showed a certain degree of reduction(P=0.027, 0.039; both P=0.004, P=0.037, 0.000 respectively). And no serious adverse reactions were found. Conclusions Compared with Allopurinol treatment, Febuxostat tretment shows that the blood uric acid level drops faster, the target-reaching rate is higher at the end of treatment, no serious side effects are observed, and it may improve blood lipid regulation and renal protection. Key words: Hyperuricemia; Xanthine oxidase

Renal and Vascular Effects of Uric Acid Lowering in Normouricemic Patients With Uncomplicated Type 1 Diabetes.

Higher plasma uric acid (PUA) levels are associated with lower glomerular filtration rate (GFR) and higher blood pressure (BP) in patients with type 1 diabetes (T1D). Our aim was to determine the impact of PUA lowering on renal and vascular function in patients with uncomplicated T1D. T1D patients (n = 49) were studied under euglycemic and hyperglycemic conditions at baseline and after PUA lowering with febuxostat (FBX) for 8 weeks. Healthy control subjects were studied under normoglycemic conditions (n = 24). PUA, GFR (inulin), effective renal plasma flow (para-aminohippurate), BP, and hemodynamic responses to an infusion of angiotensin II (assessment of intrarenal renin-angiotensin-aldosterone system [RAAS]) were measured before and after FBX treatment. Arterial stiffness, flow-mediated dilation (FMD), nitroglycerin-mediated dilation (GMD), urinary nitric oxide (NO), and inflammatory markers were measured before and after FBX treatment. Gomez equations were used to estimate arteriolar afferent resistance, efferent resistance (RE), and glomerular hydrostatic pressure (PGLO). FBX had a modest systolic BP-lowering effect in T1D patients (112 ± 10 to 109 ± 9 mmHg, P = 0.049) without impacting arterial stiffness, FMD, GMD, or NO. FBX enhanced the filtration fraction response to hyperglycemia in T1D patients through larger increases in RE, PGLO, and interleukin-18 but without impacting the RAAS. FBX lowered systolic BP and modulated the renal RE responses to hyperglycemia but without impacting the RAAS or NO levels, suggesting that PUA may augment other hemodynamic or inflammatory mechanisms that control the renal response to hyperglycemia at the efferent arteriole. Ongoing outcome trials will determine cardiorenal outcomes of PUA lowering in patients with T1D.

Hyperuricemia and Acute Renal Failure in Renal Transplant Recipients Treated With High-Dose Mizoribine

BackgroundHyperuricemia is a common adverse event frequently found in renal transplant recipients with mizoribine (MZ). Hyperuricemia itself will be a cause of renal dysfunction, and renal dysfunction also will be a cause of hyperuricemia simultaneously. This study investigates frequency of hyperuricemia and renal failure in renal transplant recipients treated with high-dose MZ. Patients and MethodsFrom December 2007 to October 2015, there was a total of 32 living related renal transplant recipients treated with high-dose MZ. Of the 32 patients, 28 were treated with urate-lowering medications. ResultsOne patient received allopurinol (AP) and 13 patients received benzbromarone (BB). For 6 of them, their urate-lowering medications were converted to febuxostat (FX) form AP or BB. In the remaining 14 patients, FX was administered from the beginning. In 2 cases of ABO-incompatible living related renal transplant recipients who were maintained with high-dose MZ and BB, severe hyperuricemia and acute renal failure occurred. One patient was a 48-year-old man, and his creatinine (Cr) level increased to 8.14 mg/dL and his serum uric acid (UA) was 24.6 mg/dL. Another patient was a 57-year-old man, and his Cr level increased to 3.59 mg/dL and his UA was 13.2 mg/dL. In both cases Cr and UA were improved, and no finding of acute rejection and drug toxicity was observed in graft biopsy specimens. BB was switched to FX and discontinuance or reduction of MZ was done. ConclusionCombination of MZ and BB has the risk of acute renal dysfunction after renal transplantation. Latent renal dysfunction should be watched for in renal transplant recipients receiving high-dose MZ.

Febuxostat attenuates paroxysmal atrial fibrillation-induced regional endothelial dysfunction

BackgroundParoxysmal atrial fibrillation (PAF) can increase thrombogenesis risk, especially in the left atrium (LA). The exact mechanism is still unclear. ObjectiveWe assessed the effects of PAF on endothelial function, and investigated if febuxostat (FX) can attenuate endothelial dysfunction by inhibition of xanthine oxidase (XO). Materials and methodsEighteen male New Zealand white rabbits were divided randomly into sham-operated (S), PAF (P) or FX+pacing (FP) groups. Group P and group FP received rapid atrial pacing (RAP). Group FP was administered febuxostat (FX) for 7days before RAP. Post-procedure, blood samples were collected from the LA, right atrium (RA) and peripheral circulation. Tissues from the LA and RA were obtained. Endothelial dysfunction (thrombomodulin [TM], von Willebrand factor [VWF], asymmetric dimethylarginine [ADMA]), and indirect thrombin generation (thrombin-antithrombin complex [TAT], prothrombin fragment 1+2 [F1.2]) and oxidative stress in atrial tissue (xanthine oxidase [XO], superoxide dismutase [SOD], malondialdehyde [MDA]) were measured using an Enzyme-linked immunosorbent assay. Atrial endothelial expression of TM and VWF was measured by histology/western blotting. Results and conclusionsEndothelial dysfunction (TM, VWF, ADMA), TAT generation and oxidative stress (XO, SOD, MDA) in group P were more significant compared with that in group S (p<0.05, respectively). In group P, all of these changes occurred to a greater extent in the LA compared with those in the RA or peripheral circulation. In group FP, FX attenuated endothelial dysfunction and reduced TAT levels by inhibition of XO-mediated oxidative stress.PAF can lead to endothelial dysfunction and TAT generation by XO-mediated oxidative stress. The LA is more susceptible to these effects. FX can attenuate these changes by inhibition XO and XO-mediated oxidative stress.

Salting-Out Assisted Liquid-Liquid Extraction for Quantification of Febuxostat in Plasma Using RP-HPLC and Its Pharmacokinetic Application.

A rapid and sensitive reversed-phase high-performance liquid chromatography (HPLC) method using novel salting-out assisted liquid-liquid extraction technique has been developed for the quantitative determination of febuxostat (FEB), used for the treatment of gout, in rat plasma. The method was validated according to US FDA guideline. Separation was achieved using a Phenomenex Luna-C18 (250×4.60 mm, 5 µm) column and mobile phase composed of potassium dihydrogen orthophosphate buffer 25 mM, adjusted to pH 6.8 with triethylamine:methanol in a ratio of 35:65 (v/v) showing retention time 5.56 and 8.86 min for FEB and internal standard, respectively. The optimal salting-out parameters; 1 mL of acetonitrile and 200 µL of 2 M ammonium acetate salt showed extraction recovery >90% for FEB from plasma. This extraction procedure afforded clear samples resulting in convenient and cost-saving procedure and showed good linear relationship (r>0.9997) between peak area ratio and concentration from 0.3 to 20 µg/mL. The results of pharmacokinetic study showed that absorption profile of spherical agglomerate of FEB compared to marketed formulation was higher indicating greater systemic absorption. In conclusion, the developed SALLE-HPLC method with simple ultraviolet detection offered a number of advantages including good quantitative ability, wide linear range, high recovery, short analysis time as well as low cost.

Design of experiment approach in development of febuxostat nanocrystal: Application of Soluplus® as stabilizer

The objective of present study was to explore the application of Soluplus® as a stabilizer for the preparation of febuxostat (FEB) nanocrystals using ball milling technique. Preliminary trials were performed for the selection of stabilizer from HPMC VLV, PVA, PVP K30, Poloxamer 188 and Soluplus®. Soluplus® stabilized FEB nanocrystals were found stable and had least particle size as compared to the batches prepared using other stabilizers. A systematic optimization of critical process parameters, stirring time and amount of bead, of ball milling process was performed with aid of central composite design. Particle size (D50 and D90) and the size distribution (SPAN) were taken as responses for the evaluation of design batches and were used as the criteria for selection of optimized batch. Optimized formulation was characterized using SEM, XRD and DSC, depicted conversion of crystalline FEB into amorphous form having 26.08 times (in pH1.2) and 1.67 times (in pH6.0) more saturation solubility. In vitro drug dissolution study showed 9 times faster drug release while in vivo pharmacokinetic study showed an increase in oral bioavailability, Cmax and AUC, of FEB nanocrystals as compared to FEB API. Thus, current study supports the suitability of Soluplus® as stabilizer for the preparation of FEB nanocrystals.

Abstract 111: Xanthine Oxidoreductase Plays a Key Role in Nitrate, Nitrite and Nitric Oxide Homeostasis When the Endothelial Nitric Oxide Synthase is Compromised

Xanthine oxidoreductase (XOR) is generally known as a source of superoxide production, but this enzyme has also been suggested to mediate NO production via reduction of inorganic nitrate (NO 3 - ) and nitrite(NO 2 - ). This pathway for NO generation is of particular importance during certain pathologies, whereas endothelial NO synthase (eNOS) is the primary source of vascular NO generation under normal physiological conditions. The exact interplay between the NOS and XOR-derived NO is not yet fully elucidated. The aim of the present study was to investigate if eNOS deficiency is partly compensated by XOR upregulation and sensitization of the NO 3 - - NO 2 - - NO pathway. NO 3 - and NO 2 - were similar between naïve eNOS KO and wildtype (wt) mice, but reduced upon chronic treatment with the non-selective NOS inhibitor L-NAME (wt: 25.0±5.2, eNOS KO: 39.2±6.4, L-NAME: 8.2±1.6 μ NO 3 - -, wt: 0.38±0.07, eNOS KO: 0.42±0.04, L-NAME: 0.12±0.02 μ NO 2 - ). XOR function was upregulated in eNOS KO compared with wt mice [(mRNA: wt 1±0.07, eNOS KO 1.38±0.17), (activity: wt 825±54, eNOS KO 1327±280 CLU/mg/min), (uric acid: wt 32.87±1.53, eNOS KO 43.23±3.54 μ)]. None of these markers of XOR activity was increased in nNOS KO and iNOS KO mice. Following acute dose of NO 3 - (10 mg/kg bw, i.p.), the increase of plasma NO 2 - was more pronounced in eNOS KO (+0.51±0.13 μ) compared with wt (+0.22±0.09 μ), and this augmented response in the eNOS KO was abolished by treatment with the highly selective XOR inhibitor febuxostat (FEB). Liver from eNOS KO had higher reducing capacity of NO 2 - to NO compared with wt, and this effect was attenuated by FEB (Δppb of NO: wt +8.7±4.2, eNOS KO +44.2±15.0, wt+FEB +22.2±9.6, eNOS KO+FEB +26.8±10.2). Treatment with FEB increased blood pressure in eNOS KO (ΔMAP:+10.2±5.6 mmHg), but had no effect in wt (ΔMAP:-0.6±3.3 mmHg). Supplementation with NO 3 - (10 mM, drinking water) reduced blood pressure in eNOS KO (ΔMAP: -6.3±2.2 mmHg), and this effect was abolished by FEB (ΔMAP: +1.1±1.9 mmHg). In conclusion, upregulated and altered XOR function in conditions with eNOS deficiency can facilitate the NO 3 - - NO 2 - - NO pathway and hence play a significant role in vascular NO homeostasis.

NEW METHOD DEVELOPMENT AND VALIDATION FOR THE DETERMINATION OF FEBUXOSTAT IN HUMAN PLASMA BY LIQUID CHROMATOGRAPHY–MASS SPECTROMETRY

&lt;p&gt;&lt;strong&gt;Objective&lt;/strong&gt;:&lt;strong&gt; &lt;/strong&gt;To develop a new method and validate the same for the determination of Febuxostat (FBS) in human plasma by liquid chromatography–mass spectrometry (LCMS).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods&lt;/strong&gt;:&lt;strong&gt; &lt;/strong&gt;The present method utilized reversed-phase high-performance liquid chromatography with tandem mass spectroscopy. Febuxostat D9 (FBS D9) was used as internal standard (IS). The analyte and internal standard were separated from human plasma by using solid phase extraction method. Zorbax Eclipse XDB, C&lt;sub&gt;8&lt;/sub&gt;, 100 mm x 4.6 mm, 3.5 µm column was used and HPLC grade acetonitrile, 5 millimolar (mM) ammonium format (80: 20, v/v) as mobile phase, detected by mass spectrometry operating in positive ion and multiple reaction monitoring modes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results&lt;/strong&gt;:&lt;strong&gt; &lt;/strong&gt;The parent and production transitions for FBS and internal standard were at m/z 317.1→261.0 and 326.1→262.0 respectively. The method was validated for system suitability, specificity, carryover effect, linearity, precision, accuracy, matrix effect, sensitivity and stability. The linearity range was from 20.131 ng/ml to10015. 534 ng/ml with a correlation coefficient of 0.999. Precision results (%CV) across six quality control samples were within the limit. The percentage recovery of FBS and internal standard from matrix samples was found to be 76.57% and 75.03% respectively.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion&lt;/strong&gt;:&lt;strong&gt; &lt;/strong&gt;Present study describes new LC-MS method for the quantification of FBS in a pharmaceutical formulation. According to validation results, it was found to be a simple, sensitive, accurate and precise method and also free from any kind of interference. Therefore the proposed analytical method can be used for routine analysis for the estimation of FBS in its formulation.&lt;/p&gt;

Preparation, optimization and in vitro–in vivo investigation for capsules of the choline salt of febuxostat

The objective of the present study was to exhibit the enhanced water-solubility and in vivo oral absorption when febuxostat (FXT) became the salt formation of choline. The formation of the choline salt of febuxostat was confirmed by X-ray powder diffraction, infrared spectroscopy analysis and differential scanning calorimetry. The direct filling method was used to develop a capsule formulation. Cellactose 80 was used as the filler due to its good fluidity, while cross-linked polyvinylpyrrolidone (PVPP) and magnesium stearate (MS) were used as the disintegrant and lubricant, respectively. Then the in vitro release of the formulation was carried out in five different dissolution media including HCl solution (pH 1.2), acetate buffer (pH 4.5), phosphate buffer (pH 6.8 and pH 7.2) and water. Evident improvement of release for choline febuxostat (CXT) was presented in water while the dissolution degree was decreased for CXT in the medium of phosphate buffer (pH 6.8) in comparison with FXT. Furthermore, the pharmacokinetics of CXT was studied in rats using UPLC-MS/MS compared with FXT. The data acquired illustrated that AUC0-24h of CXT and FXT were 22,245.96 ± 7342.92 µg⋅h/l and 12,249.70 ± 2024.04 µg⋅h/l, respectively. The relative bioavailability of CXT to FXT was about 181.6% and the P value of AUC0-24h was less than 0.05. It showed significant difference between the two drugs after oral administration. In conclusion, the water-solubility and oral bioavailability were both improved remarkably for the choline salt of febuxostat and choline salinization was proved an effective way to increase the in vivo absorption for FXT.

HPTLC and Spectrophotometric Estimation of Febuxostat and Diclofenac Potassium in Their Combined Tablets.

An accurate, precise, rapid, specific and economic high-performance thin-layer chromatographic (HPTLC) method has been developed for the simultaneous quantitative determination of febuxostat (FEB) and diclofenac potassium (DIC). The chromatographic separation was performed on precoated silica gel 60 GF254 plates with chloroform-methanol 7:3 (v/v) as the mobile phase. The developed plates were scanned and quantified at 289 nm. Experimental conditions including band size, mobile phase composition and chamber-saturation time were critically studied, and the optimum conditions were selected. A satisfactory resolution (Rs = 2.67) with RF 0.48 and 0.69 and high sensitivity with limits of detection of 4 and 7 ng/band for FEB and DIC, respectively, were obtained. In addition, derivative ratio and ratio difference spectrophotometric methods were established for the analysis of such a mixture. All methods were validated as per the ICH guidelines. In the HPTLC method, the calibration plots were linear between 0.01-0.55 and 0.02-0.60 µg/band, for FEB and DIC, respectively. For the spectrophotometric methods, the calibration graphs were linear between 2-14 and 4-18 µg/mL for FEB and DIC, respectively. The simplicity and specificity of the proposed methods suggest their application in quality control analysis of FEB and DIC in their raw materials and tablets. A comparison of the proposed methods with the existing methods is presented.

Physico-chemical Characterization and In Vitro Evaluation of Biopharmaceutics Classification System Class II Drug Febuxostat

Aim: Febuxostat (FBX) is a non-purine selective inhibitor of xanthine oxidase/xanthine reductase. It belongs to Biopharmaceutics Classification System Class II with low solubility and high permeability. Because of low solubility, the bioavailability of the drug is hampered, food also interferes with the absorption of the drug and decreases the Cmax by 38-49%. The bioavailability of a drug is a function of dissolution rate of the drug which is controlled by the surface area of the drug. In the category of poorly soluble drugs, the change in surface area of the drug will show considerable changes in the solubility and dissolution of the drug. Materials and Methods: In the present study, the attempts were made to improve the bioavailability of FBX by solid dispersions technique by employing poly vinyl pyrrolidone K30 (PVP K30) and hydroxy propyl methyl cellulose E15 (HPMC E15) as carrier molecules. Different ratios on weight basis were prepared, viz., 1:1,1:2,1:3,2:1 with PVP and 1:1, 1:2, 1:3,1:4 with HPMC were prepared. Results and Discussion: These preparations were characterized in liquid state by phase solubility studies and in solid state by differential scanning calorimetry, Fourier transform infrared spectroscopy, Powdered X-ray diffraction studies, and scanning electron microscopy. The aqueous solubility of FBX is favored by the presence of both the carriers. Solid state characterization indicated that FBX was present as fine amorphous form in the carrier polymeric molecules. Conclusion: In contrast to the solution rate of pure FBX, the dissolution of drug in carriers considerably improved the dissolution rate, this can be attributed to the increased wettability and dispersibility as well as decreased crystallinity and increased amorphous fraction of the drug

Febuxostat associated with DRESS

Febuxostat associated with DRESS

Determination of Febuxostat in Human Plasma Using RP-LC-UV Method.

A simple and sensitive bioanalytical high-performance liquid chromatographic method with ultraviolet detection was developed and validated for the quantification of febuxostat (FEB) in human plasma. Ketoprofen was used as an internal standard. The analytes were extracted from human plasma samples by precipitation with acetonitrile. The reconstituted samples were chromatographed on C18 Bondapack 10 µm, 250 × 4.6 mm, Waters Column (Ireland) by using a mixture of acetonitrile and 0.5% aqueous phosphoric acid (pH 3) (52 : 48, v/v) as the mobile phase. The chromatographic separation was isocratically performed at room temperature at a flow rate of 1.0 mL/min with UV detection at 315 nm. The method exhibited a linear dynamic range over 0.05-5.00 µg/mL FEB in human plasma. The lower limit of quantification was 0.05 µg/mL. The results of the intra- and interday precision and accuracy studies were within the acceptable limits. The validated method was successfully applied for the determination of FEB in human plasma samples for application in bioequivalence studies.

Xanthine oxidoreductase activation is implicated in the onset of metabolic arthritis

A metabolic syndrome (MetS) is accompanied by hyperuricemia, during which xanthine oxidoreductase (XOR) catalyzes the production of uric acid. In the cohort study, a correlation between uric acid concentration in the synovial fluid and osteoarthritis (OA) incidence is observed. The purpose of our study was to elucidate XOR function in terms of correlation between MetS and OA. Seven week-old male C57BL6J mice were fed normal diet (ND) or high fat diet (HFD) with or without febuxostat (FEB), a XOR inhibitor. HFD stimulated xanthine oxidase activity in the IPFP and the visceral fat. OA changes at the site of the knee joints had progressed due to HFD, but these changes were reduced upon FEB administration. IL-1β expression in the HFD group was increased in accordance with the enhancement of NLRP3 or iNOS expression in the IPFP, whereas it was inhibited by FEB administration. In the organ culture system, when the IPFP was stimulated with insulin, IL-1β expression was increased in accordance with the increase of NLRP3 expression; however, they were reduced by FEB administration. Based on the above results, we showed that inflammasome activation accompanied by an increase in XOR activity contributed to IPFP inflammation followed by OA progression.

Phase behavior, intermolecular interaction, and solid state characterization of amorphous solid dispersion of Febuxostat

The aim of this work was to prepare and characterize the amorphous molecular dispersion of Febuxostat (FXT) using PVP K30, HPMC-AS, Soluplus®, and PVP VA64. The solid dispersions were prepared by solvent evaporation technique. Their physical properties were studied by differential scanning calorimetry, powder X-ray diffraction, Fourier transformation infrared spectroscopy, and compared to that of same physical mixtures. The success of physicochemical stability of the dispersions is often revealed as glass transition temperature (Tg) versus composition (w) dependencies. The shape of the Tg versus composition was mathematically modeled using the Gordon–Taylor equation, Couchman–Karasz equation, Brekner–Schneider–Cantow equation, and a three-parameter BCKV equation. In this work, different types of Tg patterns obtained for FXT–polymer binary mixtures are analyzed in terms of the above equations and relations between their prime fitting parameters are presented. The theoretical values and modeled parameters were compared using various results obtained by thermal analysis. The influence of important physicochemical phenomena and properties of the mixtures on the shape of the Tg versus composition patterns are also illustrated. The interaction between drug and polymers and the model parameters were analyzed, aiming to assess the state of mixing and intermolecular interactions.

Development and Validation of a High-Performance Thin-Layer Chromatographic Method for the Simultaneous Determination of Two Binary Mixtures Containing Ketorolac Tromethamine with Phenylephrine Hydrochloride and with Febuxostat.

A validated and highly selective high-performance thin-layer chromatography (HPTLC) method was developed for the determination of ketorolac tromethamine (KTC) with phenylephrine hydrochloride (PHE) (Mixture 1) and with febuxostat (FBX) (Mixture 2) in bulk drug and in combined dosage forms. The proposed method was based on HPTLC separation of the drugs followed by densitometric measurements of their spots at 273 and 320 nm for Mixtures 1 and 2, respectively. The separation was carried out on Merck HPTLC aluminum sheets of silica gel 60 F254 using chloroform-methanol-ammonia (7:3:0.1, v/v) and (7.5:2.5:0.1, v/v) as mobile phase for KTC/PHE and KTC/FBX mixtures, respectively. Linear regression lines were obtained over the concentration ranges 0.20-0.60 and 0.60-1.95 µg band(-1)for KTC and PHE (Mixture 1), respectively, and 0.10-1.00 and 0.25-2.50 µg band(-1) for KTC and FBX (Mixture 2), respectively, with correlation coefficients higher than 0.999. The method was successfully applied to the analysis of the two drugs in their synthetic mixtures and in their dosage forms. The mean percentage recoveries were in the range of 98-102%, and the RSD did not exceed 2%. The method was validated according to ICH guidelines and showed good performances in terms of linearity, sensitivity, precision, accuracy and stability.

Specific and highly sensitive spectrofluorimetric method for determination of febuxostat in its tablets and real human plasma. Application to stability studies

A simple, rapid, specific and highly sensitive spectrofluorimetric method has been developed for determination of febuxostat (FEB) in its tablets and real human plasma.

Cathodic Stripping Voltammetric Determination of Febuxostat in Pharmaceutical Dosage Form and Plasma Samples

Feb uxostat FEB was determined by differential pulse “DP” adsorptive stripping voltammetry and hanging mercury drop electrode. In 0.04 mol L - 1 Britton - Robinson buffer solution, pH 10, an irreversible electrochemical reaction took place at about - 350 mV , and th e peak current was linearly varied over the concentration range of 12.5 - 200 ng mL - 1 FEB, with correlation coefficients of 0.9995, after 60 s accumulation time, stirring at a speed of 600 rpm, rest for 10 s, then cathodic stripping sweep from - 100 to 600 m V, with a scan rate of 60 mV/s. The limits of detection and quantization were 6.93, 23.09 ng mL - 1 . The method was applicable for determining FEB in pharmaceutical tablets and in spiked plasma. The results of the proposed method were compa red with that obta ined by the UV - spectrophotometric technique .

Characterization and Thermodynamic Relationship of Three Polymorphs of a Xanthine Oxidase Inhibitor, Febuxostat

Febuxostat (FXT), a xanthine oxidase inhibitor, is an interesting and unique molecule, which exhibits extensive polymorphism, with over 15 polymorphic forms reported to date. The primary purpose of the study was to characterize the three polymorphic forms with respect to their thermodynamic quantities and establish thermodynamic relationship between them. The polymorphs were characterized by thermal and powder X-ray diffraction methods. Three different methods were used to calculate the transition temperatures (Ttr) and thereby their thermodynamic relationships. Although the first and second method used calorimetric data (melting point and heat of fusion), the third method employed the use of configurational free energy phase diagram. The onset melting points of three polymorphic forms were found to be 482.89 ± 0.37 K for form I, 476.30 ± 1.21 K for form II, and 474.19 ± 0.11 K for form III. Moreover, the powder X-ray diffraction patterns for each form were also unique. The polymorphic pair of form I and II and of form I and III was found to be enantiotropic, whereas pair of form II and III was monotropic. Besides the relative thermodynamic aspects (free energy differences, enthalpy, entropy contributions) using different methods, the pharmaceutical implications and phase transformation aspects have also been covered.

Role of xanthine oxidoreductase in the anti-thrombotic effects of nitrite in rats in vivo

The mechanisms underlying nitrite-induced effects on thrombosis and hemostasis in vivo are not clear. The goal of the work described here was to investigate the role of xanthine oxidoreductase (XOR) in the anti-platelet and anti-thrombotic activities of nitrite in rats in vivo. Arterial thrombosis was induced electrically in rats with renovascular hypertension by partial ligation of the left renal artery. Sodium nitrite (NaNO2, 0.17 mmol/kg twice daily for 3 days, p.o) was administered with or without one of the XOR-inhibitors: allopurinol (ALLO) and febuxostat (FEB) (100 and 5 mg/kg, p.o., for 3 days). Nitrite treatment (0.17 mmol/kg), which was associated with a significant increase in NOHb, nitrite/nitrate plasma concentration, resulted in a substantial decrease in thrombus weight (TW) (0.48 ± 0.03 mg vs. vehicle [VEH] 0.88 ± 0.08 mg, p < 0.001) without a significant hypotensive effect. The anti-thrombotic effect of nitrite was partially reversed by FEB (TW = 0.63 ± 0.06 mg, p < 0.05 vs. nitrites), but not by ALLO (TW = 0.43 ± 0.02 mg). In turn, profound anti-platelet effect of nitrite measured ex vivo using collagen-induced whole-blood platelet aggregation (70.5 ± 7.1% vs. VEH 100 ± 4.5%, p < 0.05) and dynamic thromboxaneB2 generation was fully reversed by both XOR-inhibitors. In addition, nitrite decreased plasminogen activator inhibitor-1 concentration (0.47 ± 0.13 ng/ml vs. VEH 0.62 ± 0.04 ng/ml, p < 0.05) and FEB/ALLO reversed this effect. In vitro the anti-platelet effect of nitrite (1 mM) was reversed by FEB (0.1 mM) under hypoxia (0.5%O2) and normoxia (20%O2). Nitrite treatment had no effect on coagulation parameters. In conclusion, the nitrite-induced anti-platelet effect in rats in vivo is mediated by XOR, but XOR does not fully account for the anti-thrombotic effects of nitrite.