Response to febuxostat according to clinical subtypes of hyperuricemia: a prospective cohort study in primary gout.

BACKGROUND: While xanthine oxidase inhibitors target uric acid production, renal urate underexcretion is the predominant subtypes in gout. This study was to compare treatment response to the XOI febuxostat in a gout cohort according to clinical subtypes of hyperuricemia. METHODS: A prospective cohort study was conducted to compare the efficacy and safety of febuxostat (initially 20 mg daily, escalating to 40 mg daily if not at target) in 644 gout patients with the three major clinical subtypes for 12 weeks. Hyperuricemia was defined as the renal overload subtype, the renal underexcretion subtype, or the combined subtype based on UUE > or ≤ 600 mg/d/1.73 m2 and FEUA < or ≥ 5.5%. The primary endpoint was the rate of achieving serum urate (SU) < 6 mg/dL at week 12. RESULTS: Fewer participants with combined subtype achieved the SU target, 45.5% compared with 64.8% with overload subtype (P = 0.007), and 56.6% with underexcretion subtype (P = 0.022). More participants with combined subtype (82%) had febuxostat escalated to 40 mg than those with overload (62%, P = 0.001) or underexcretion subtype (68%, P = 0.001). In all participants, combined subtype hyperuricemia (OR = 0.64, 95%CI 0.41-0.99, P = 0.048) and baseline SU (OR = 0.74, 95%CI 0.62-0.89, P = 0.001) were independently associated with lower rates of achieving SU target. CONCLUSIONS: People with combined subtype have a lower response to febuxostat, compared to those with either overload or underexcretion subtype. Assessment of hyperuricemia subtype may provide useful clinical data in predicting febuxostat response.

Analysis of appropriate duration of colchicine prophylaxis to maximize the persistence of xanthine oxidase inhibitors as the first-line urate-lowering therapy in patients with gout using the Korean Health Insurance Review and Assessment Service database.

INTRODUCTION: We investigated the appropriate duration of colchicine prophylaxis to maximize the persistence of xanthine oxidase inhibitors (XOIs) as first-line urate-lowering therapy (ULT) in patients with gout. This was a nationwide population-based retrospective cohort study using the Korean Health Insurance Review and Assessment database. METHODS: Patients with gout aged ≥20 years who were newly initiated on XOIs, such as allopurinol or febuxostat, from July 2015 to June 2017 and received these medications for ≥6 months were analyzed and followed up until June 2019. Persistence of XOIs was compared according to the 6-month duration of colchicine prophylaxis. For additional subgroup analysis, we also compared the persistence of XOIs according to the 3-month duration of colchicine prophylaxis. RESULTS: This study included 43 926 patients. The frequencies of patients with gout receiving colchicine prophylaxis for ≥6 months and ≥3 months were 6.3% and 7.6%, respectively. Allopurinol (65.2%) was prescribed more frequently than febuxostat (34.8%). During the study period, 23 475 patients (53.4%) stopped using XOIs. Colchicine prophylaxis for ≥6 months did not significantly reduce the risk of XOI discontinuation in multivariable Cox regression models. Colchicine prophylaxis for ≥3 months was significantly associated with a lower risk of non-persistence to XOIs after adjusting for confounding factors (hazard ratio = 0.95, p = .041). CONCLUSION: Our data suggest that at least 3 months of colchicine prophylaxis may be more appropriate than at least 6 months in terms of maximizing the persistence of XOIs in patients with gout.

Xanthine oxidase inhibitory kinetics and mechanism of ellagic acid: In vitro, in silico and in vivo studies.

Ellagic acid (EA), which is widely distributed in many foods, has been found to possess inhibitory activity against xanthine oxidase (XO). However, there is ongoing debate about the difference in XO inhibitory activity between EA and allopurinol. Additionally, the inhibitory kinetics and mechanism of EA on XO are still unclear. Herein, the authors systematically studied the inhibitory effects of EA on XO. The authors' findings showed that EA is a reversible inhibitor with mixed-type inhibition, and its inhibitory activity is weaker than allopurinol. Fluorescence quenching experiments suggested that the generation of EA-XO complex was exothermic and spontaneous. In silico analysis further confirmed that EA entered the XO catalytic centre. Furthermore, the authors verified the anti-hyperuricemia effect of EA in vivo. This study elucidates the inhibition kinetics and mechanism of EA on XO, and lays a theoretical foundation for the further development of drugs and functional foods containing EA for the treatment of hyperuricemia.

Naringenin Prevents Renal Injury in Experimental Hyperuricemia Through Suppressing Xanthine Oxidase, Inflammation, Apoptotic Pathway, DNA Damage, and Activating Antioxidant System.

Background/Purpose: This research was performed to determine the effect of naringenin (NAR) in experimental hyperuricemia (HU) induced by potassium oxonate (PO) on uric acid levels and xanthine oxidase (XO), inflammation, apoptotic pathway, DNA damage, and antioxidant system in kidney tissue. Study Design: Wistar Albino rats were categorized into four groups: (1) Control group, (2) PO group, (3) [PO+NAR] (2 weeks) group, and (4) PO (2 weeks)+NAR (2 weeks) group. Methods: The first group was not administered any drug. In group 2, PO was administered intraperitoneally 250 mg/kg/day for 2 weeks. In the third group, 100 mg/kg/day NAR was given intraperitoneally 1 hr after PO injection for 2 weeks. In the fourth group, PO was injected for the first 2 weeks, followed by NAR injection for the second 2 weeks. Serum uric acid levels, XO, nuclear factor-kappa B, tumor necrosis factor-alpha, interleukin-17, cytochrome c, 8-Hydroxydeoxyguanosine (8-OHdG), glutathione peroxidase (GPx), and caspase-3 levels in kidney were determined. Results: HU increased the levels of inflammatory and apoptotic parameters, XO, and 8-OHdG levels in kidney. Administration of NAR caused a decrease in these values and an increase in GPx levels. Conclusions: The results of the study show that NAR treatment reduces serum uric acid levels, and apoptosis, inflammation, and DNA damage; increases antioxidant activity in kidney in experimental HU.

A Drug-Drug Interaction Study of a Novel Selective Urate Reabsorption Inhibitor, SHR4640, and Xanthine Oxidase Inhibitor, Febuxostat, in Patients With Primary Hyperuricemia.

SHR4640 is a novel, selective urate reabsorption inhibitor. As the mode of action of SHR4640 differs from that of a xanthine oxidase inhibitor, such as febuxostat, coadministration of these drugs may be a treatment option for patients with primary hyperuricemia. We assessed the potential drug-drug interaction between SHR4640 and febuxostat. In this single-center, open-label, randomized, drug-drug interaction study, subjects received 80 mg febuxostat or 10 mg SHR4640 alone daily in the first week, whereas during the second week a combination of SHR4640 and febuxostat was administered daily to all subjects. Plasma concentrations of SHR4640 and febuxostat were analyzed. We compared their pharmacokinetic and pharmacodynamic parameters and assessed both safety and tolerability. Compared with febuxostat alone, the geometric mean ratios (90%CIs) of the maximum concentration (Cmax ) and the area under the plasma concentration-time curve over the dosing interval τ (AUC0-τ ) for febuxostat after coadministration were 1.284 (1.016 to 1.621) and 0.984 (0.876 to 1.106), respectively. The geometric mean ratios (90%CIs) of Cmax and AUC0-τ for SHR4640 after coadministration compared with SHR4640 alone were 0.910 (0.839 to 0.988) and 0.929 (0.893 to 0.966), respectively. Febuxostat had no effect on SHR4640 pharmacokinetic parameters, as the 90%CIs of the geometric mean ratios were all within the range of 0.80 to 1.25. The coadministration of febuxostat and SHR4640 was well tolerated. The coadministration of SHR4640 with febuxostat was not associated with any clinically relevant pharmacokinetic drug interactions. SHR4640 combined with febuxostat had a synergistic effect on reducing uric acid in the pharmacodynamics, with the AUC decreasing from 7440 to 3170 h µmol/L compared with febuxostat alone and from 5730 to 2960 h µmol/L compared with SHR4640 alone.

Targeting Oxidative Stress Markers, Xanthine Oxidase, TNFRSF11A and Cathepsin L in Curcumin-Treated Collagen-Induced Arthritis: A Physiological and COSMO-RS Study.

The effectiveness of curcumin in preventing and treating collagen-induced inflammatory arthritis (CIA) in rats and oxidative stress in rats was investigated. We investigated curcumin's curative and preventive effects on paw edema, arthritic size, body weight, and radiologic and histological joint abnormalities. It has been shown that curcumin may dramatically lower the risk of developing arthritis. In addition, the number of white blood cells (WBCs) in the body has dropped, which is a strong indication that curcumin has anti-inflammatory characteristics. A follow-up theoretical investigation of curcumin molecular docking on xanthine oxidase (XO) was carried out after the properties of curcumin were determined using the conductor-like screening model for real solvents (COSMO-RS) theory. Because of the interaction between curcumin and the residues on XO named Ile264, Val259, Asn351, and Leu404, XO may be suppressed by this molecule. Curcumin's anti-inflammatory and antioxidant properties may be responsible for the anti-arthritic effects that have been seen on oxidative stress markers and XO. On the other hand, more research is being conducted to understand its function better in the early stages of rheumatoid arthritis (RA). To determine whether or not curcumin interacts with AR targets, a molecular docking study was conducted using MVD software against TNFRSF11A and cathepsin L.

Impact of febuxostat on visit-to-visit blood pressure variability: insights from the randomised PRIZE Study.

OBJECTIVES: Although uric acid lowering therapies, including xanthine oxidase (XO) inhibition, may reduce the absolute level of blood pressure (BP), the effect of XO inhibition on BP variability is largely unknown. The aim of the present analysis was to evaluate the impact of febuxostat, an XO inhibitor, on BP variability in a randomised trial setting. METHODS: This was a subanalysis of the PRIZE Study, a randomised trial to evaluate the potential effect of febuxostat on carotid intima-media thickness progression. Patients with hyperuricemia and carotid plaques were randomly assigned to the febuxostat or control group. During a 24-month period, office BP and pulse rate (PR) were measured ≥3 times. BP and PR variabilities were assessed with SD and coefficient of variation (CV). The effect of febuxostat on BP and PR variabilities was adjusted with age, sex and baseline BP or PR, expressed with 95% CIs. RESULTS: A total of 472 patients were included into the present subanalysis. During the 24-month follow-up period, the febuxostat group had a significantly lower adjusted mean systolic BP (128.4 (126.8-130.0) vs 130.7 (129.1-132.2) mm Hg, p=0.04) and CV of systolic BP (7.4 (6.7-8.0) vs 8.2 (7.6-8.8), p=0.04) than the control group. Adjusted SD of PR was also lower in the febuxostat group than their counterpart (5.95 (4.93-6.97) vs 7.33 (6.32-8.33), p=0.04). CONCLUSION: XO inhibition with febuxostat was associated with reduced visit-to-visit BP variability as well as reduced PR variability in patients with hyperuricemia and carotid plaques. TRIAL REGISTRATION NUMBERS: University Hospital Medical Information Network Clinical Trial Registry (UMIN000012911 and UMIN000041322).

Neuroprotective Effects of Dexpanthenol on Rabbit Spinal Cord Ischemia/Reperfusion Injury Model.

OBJECTIVE: Dexpanthenol (DXP) reportedly protects tissues against oxidative damage in various inflammation models. This study aimed to evaluate its effects on oxidative stress, inflammation, apoptosis, and neurological recovery in an experimental rabbit spinal cord ischemia/reperfusion injury (SCIRI) model. METHODS: Rabbits were randomized into 5 groups of 8 animals each: group 1 (control), group 2 (ischemia), group 3 (vehicle), group 4 (methylprednisolone, 30 mg/kg), and group 5 (DXP, 500 mg/kg). The control group underwent laparotomy only, whereas other groups were subjected to spinal cord ischemia by aortic occlusion (just caudal to the 2 renal arteries) for 20 min. After 24 h, a modified Tarlov scale was employed to record neurological examination results. Malondialdehyde and caspase-3 levels and catalase and myeloperoxidase activities were analyzed in tissue and serum samples. Xanthine oxidase activity was measured in the serum. Histopathological and ultrastructural evaluations were also performed in the spinal cord. RESULTS: After SCIRI, serum and tissue malondialdehyde and caspase-3 levels and myeloperoxidase and serum xanthine oxidase activities were increased (P < 0.05-0.001). However, serum and tissue catalase activity decreased significantly (P < 0.001). DXP treatment was associated with lower malondialdehyde and caspase-3 levels and reduced myeloperoxidase and xanthine oxidase activities but increased catalase activity (P < 0.05-0.001). Furthermore, DXP was associated with better histopathological, ultrastructural, and neurological outcome scores. CONCLUSIONS: This study was the first to evaluate antioxidant, anti-inflammatory, antiapoptotic, and neuroprotective effects of DXP on SCIRI. Further experimental and clinical investigations are warranted to confirm that DXP can be administered to treat SCIRI.

Xanthine oxidase inhibitor urate-lowering therapy titration to target decreases serum free fatty acids in gout and suppresses lipolysis by adipocytes.

OBJECTIVE: Linked metabolic and cardiovascular comorbidities are prevalent in hyperuricemia and gout. For mechanistic insight into impact on inflammatory processes and cardiometabolic risk factors of xanthine oxidase inhibitor urate-lowering therapy (ULT) titration to target, we performed a prospective study of gout serum metabolomes from a ULT trial. METHODS: Sera of gout patients meeting the 2015 ACR/EULAR gout classification criteria (n = 20) and with hyperuricemia were studied at time zero and weeks 12 and 24 of febuxostat or allopurinol dose titration ULT. Ultrahigh performance liquid chromatography-tandem mass spectroscopy acquired the serum spectra. Data were assessed using the Metabolon and Metaboloanalyst software. Lipolysis validation assays were done in febuxostat and/or colchicine-treated 3T3-L1 differentiated adipocytes. RESULTS: Serum urate decreased from time zero (8.21 ±1.139 SD) at weeks 12 (5.965 ± 1.734 SD) and 24 (5.655 ±1.763 SD). Top metabolites generated by changes in nucleotide and certain amino acid metabolism and polyamine pathways were enriched at 12 and 24 weeks ULT, respectively. Decreases in multiple fatty acid metabolites were observed at 24 weeks, linked with obesity. In cultured adipocytes, febuxostat significantly decreased while colchicine increased the lipolytic response to ß-adrenergic-agonism or TNF. CONCLUSION: Metabolomic profiles linked xanthine oxidase inhibitor-based ULT titration to target with reduced serum free fatty acids. In vitro validation studies revealed that febuxostat, but not colchicine, reduced lipolysis in cultured adipocytes. Since soluble urate, xanthine oxidase inhibitor treatment, and free fatty acids modulate inflammation, our findings suggest that by suppressing lipolysis, ULT could regulate inflammation in gout and comorbid metabolic and cardiovascular disease.

Does seasonality of the microbiota contribute to the seasonality of acute gout flare?

Gout, the most common inflammatory arthritis worldwide, is an auto-inflammatory metabolic disease that leads to monosodium urate crystal deposition. Hyperuricaemia is a significant risk factor for the development of gout; however, hyperuricaemia alone is not sufficient to induce gout.Gout flares have circadian rhythms. Gout flares vary during the day and have strong seasonality, with flares being more common in the spring. The reasons for the predominance of flares in the spring are unclear since serum urate (SU) levels show seasonal variation; however, SU levels are highest in the summer.Immune function varies significantly throughout the year, with enhanced immune responses increasing during the winter. In addition, chronic disruption of circadian rhythms is associated with metabolic syndrome and diseases driven by metabolism. The most telling example relates to Xanthine oxidase (XOD/XDH). The analysis of XOD/XDH established its circadian regulation and demonstrated that inhibition of the activity of XOD is characterised by distinct, crossregulating diurnal/seasonal patterns of activity.The gastrointestinal microbiota of gout patients is highly distinct from healthy individuals. In a small series of gout patients, Bacteroides caccae and Bacteroides xylanisolvens were found to be enriched. Bacteroidales levels were highest during the spring and summer, and loading values were highest in the spring.Our review discusses gout's circadian rhythm and seasonality, possible influences of the microbiome on gout due to our new knowledge that Bacteroidales levels were highest during spring when gout is most common, and potential opportunities for treatment based on our current understanding of this interaction.

Triterpenoid acids from medicinal mushroom Inonotus obliquus (Chaga) alleviate hyperuricemia and inflammation in hyperuricemic mice: Possible inhibitory effects on xanthine oxidase activity.

The purpose of this study was to explore the hypouricemic effect in hyperuricemia mice of triterpenoid acids from Inonotus obliquus (TAIO), and decipher of the underlying xanthine oxidase inhibitory mechanism. Measurement of xanthine oxidase (XO) inhibitory activity was assayed. Organ indexes and serum biochemical indicators were measured in potassium oxonate-induced hyperuricemia mice. Studies showed that TAIO had the strong inhibitory effect on XO activity, and its inhibition type was mixed and reversible. In vivo, TAIO decreased efficiently uric acid level, hepatic XO, serum blood urea nitrogen activities in hyperuricemia mice. Indicating that TAIO may ameliorate kidney damage and relieve inflammation in hyperuricemic mice, and had the inhibitory effect on XO activity. Furthermore, eight triterpenoids were identified by Ultra performance liquid chromatography electrospray quadrupole time of flight mass spectrometry. These findings proved that triterpenoids from Inonotus obliquus would have potential biological characteristics and effect on controlling hyperuricemia and gout as an active supplement. PRACTICAL APPLICATIONS: There are a large amount of evidence indicating that hyperuricemia and gout are related to the hypertension and obesity. And gout and hyperuricemia are also possible connection with cardiovascular disease and metabolic syndrome. Currently, xanthine oxidase is the target of many kinds of chemical drugs at present, but the therapeutic drugs used in clinical medicine will produce more or less side effects. Therefore, the aim of this study was to explore the material basis of effective substances for reducing uric acid in Inonotus obliquus and to evaluate its effect. This study can provide a promising application of Inonotus obliquus in the fields of functional foods or medicines for gout and hyperuricemia.

In vitro enzyme inhibition and in vivo anti-hyperuricemic potential of eugenol: an experimental approach.

Xanthine oxidase (XO) is accountable for the uric acid synthesis in the body and is considered as a prominent therapeutic target in urate lowering treatment. Eugenol is a natural compound commonly found in clove, cinnamon, etc. and has various biological activities. This study was designed to examine the anti-hyperuricemic effect of eugenol by in vitro and in vivo studies. Potassium oxonate (PO) was used to induce hyperuricemia in Wistar rats. Different doses of eugenol (1.25, 2.5, and 5 mg/kg bwt orally) were used for the treatment and various biological function markers (renal, hepatic, and hematological) were analyzed. The IC50 value obtained for eugenol was 3.51 ± 0.002 µM. The kinetic studies revealed that the eugenol exhibited a mixed type of inhibition. Abnormality in the levels of various biological function markers was observed in the PO treated rats. Upon the eugenol treatment, those biological function markers were retained near to its normal values. The study proved the anti-hyperuricemic potential of eugenol against the PO induced hyperuricemia model.

Class effect of xanthine oxidase inhibitors on flow-mediated dilatation in hypertensive patients: A randomized controlled trial.

A direct comparison of the effects of febuxostat and allopurinol on flow-mediated dilatation (FMD) will help to clarify which agent provides a better reduction of cardiovascular risk in hypertensive patients. Hypertensive patients with hyperuricemia were randomized into a febuxostat (10-40 mg, n = 33) or allopurinol (100-200 mg, n = 31) group and followed up for 6 months. Both the febuxostat (7.9 ± 1.3 mg/dL vs 5.6 ± 1.0 mg/dL, P < .001) and allopurinol (8.2 ± 1.3 mg/dL vs 6.1 ± 1.0 mg/dL, P < .001) groups exhibited significant reductions in uric acid after treatment. There was no significant difference in the change in FMD between the two treatment groups (0.6 ± 2.6% vs 0.2 ± 2.3%, P = .504). However, stratified analysis showed that febuxostat achieved a significantly greater change in FMD compared to allopurinol in the elderly group (1.3 ± 2.9% vs -0.7%±1.8%, P = .047). There was no difference in the improvement of FMD between febuxostat and allopurinol, but febuxostat may provide an improvement of FMD in elderly people.

Alopurinol y su papel en el tratamiento de la sarcopenia / Allopurinol and its role in the treatment of sarcopenia

La xantina oxidasa (XO) es la enzima que cataliza la oxidación de hipoxantina a xantina y de esta a ácido úrico, por lo que desempeña un importante papel en el catabolismo de las purinas. El alopurinol, un análogo de las purinas, es un conocido inhibidor de la XO ampliamente utilizado en la práctica clínica para el tratamiento de la gota. Estudios recientes indican que el alopurinol reduce el estrés oxidativo y mejora la función vascular en diversas enfemedades cardiometabólicas, aumenta el tiempo de ejercicio en pacientes con angina de pecho y mejora la eficiencia de la contractilidad miocárdica en la insuficiencia cardiaca. La XO también ejerce un papel importante en la generación de radicales libres durante la contracción muscular, y por tanto se ha relacionado con el daño muscular asociado al ejercicio físico agotador. Diversos grupos de investigación han demostrado el efecto protector del alopurinol en la prevención de este tipo de daño. Teniendo en cuenta estos antecedentes, en este trabajo nos hemos planteado revisar el posible papel del alopurinol en el tratamiento de la sarcopenia, un síndrome geriátrico caracterizado por la progresiva y generalizada pérdida de masa y fuerza muscular, que supone un aumento del riesgo de discapacidad, baja calidad de vida y muerte (AU)

Xanthine oxidase (XO) is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and uric acid and plays an important role in purine catabolism. The purine analogue, allopurinol, is a well-known inhibitor of XO widely used in the clinical management of gout and conditions associated with hyperuricemia. More recent data indicate that allopurinol reduces oxidative stress and improves vascular function in several cardiometabolic diseases, prolongs exercise time in angina, and improves the efficiency of cardiac contractility in heart failure. XO also plays an important role in free radical generation during skeletal muscle contraction and thus, it has been related to the muscle damage associated to exhaustive exercise. Several research groups have shown the protective effect of allopurinol in the prevention of this type of damage. Based on this background, a critical overview is presented on the possible role of allopurinol in the treatment of sarcopenia, a geriatric syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes, such as physical disability, poor quality of life and death (AU)

Management of hyperuricemia in gout: focus on febuxostat.

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.

Gene therapy approaches to enhance bioreductive drug treatment.

Hypoxia, or a lack of oxygen, occurs in 50-60% of solid human tumours. Clinical studies have shown that the presence and extent of hypoxia in a tumour cannot be predicted by size or histopathological stage but it is predictive of a poor outcome following radiotherapy, chemotherapy and surgery. However, as a physiological feature of tumours, it can be exploited and researchers have developed many hypoxia-selective chemotherapies or bioreductive drugs that are in varying stages of clinical development. These agents are prodrugs that have two key requirements for their biological activation: they require the reductive environment of a hypoxic tumour cell and the appropriate complement of cellular reductase enzymes. To overcome tumour heterogeneity in reductase enzyme levels and enhance bioreductive drug metabolism a gene therapy strategy can be employed. We have reviewed this field and also present our own pre-clinical research using gene therapy to enhance bioreductive drug treatment for the treatment of cancer. We have specifically focused on studies enhancing lead clinical bioreductive drugs. We consider the metabolic requirements for their activation and we highlight the key in vivo studies supporting the future clinical development of hypoxia-targeted gene-directed enzyme prodrug therapy.

Hypouricemic effects of acacetin and 4,5-o-dicaffeoylquinic acid methyl ester on serum uric acid levels in potassium oxonate-pretreated rats.

The effects of acacetin (1) and 4,5-O-dicaffeoylquinic acid methyl ester (2), compounds contained in the flowers of Chrysanthemum sinense SABINE, on the serum uric acid level were investigated using the rats pretreated with the uricase inhibitor potassium oxonate as an animal model for hyperuricemia. When administered per orally at doses of 20 and 50 mg/kg, 1 reduced the serum uric acid level by 49.9 and 63.9%, respectively and 2 reduced the level by 31.2 and 44.4%, respectively. On the other hand, when the same doses were given intraperitoneally, both of compounds also exhibited a dose-dependent and more marked reduction of the serum uric acid level (% reduction at 20 and 50 mg/kg were 63.0 and 95.1% in 1, respectively and 66.9 and 86.5% in 2, respectively). Furthermore, the compounds 1 and 2 inhibited the rat liver xanthine oxidase activity with IC(50) values of 2.22 muM and 5.27 muM, respectively. These results demonstrated the hypouricemic action of 1 and 2, which may be attributable to their xanthine oxidase inhibitory activity.

Allopurinol does not affect the anticonvulsant activity of carbamazepine and valproate in maximal electroshock-induced convulsions in mice.

Allopurinol, an inhibitor of xanthine oxidase, is indicated in the management of patients with elevated serum and urinary uric acid levels. It was also reported to be beneficial in patients with epilepsy when added to traditional antiepileptic drug. Here, we investigated the effect of allopurinol upon the electrical seizure threshold and its effect on the protective efficacy of common antiepileptic drugs, carbamazepine (CBZ) and valproate (VPA) against maximal electroshock (MES)-induced convulsions in mice. We found that allopurinol administered at doses of 5, 15 or 45 mg/kg, did not affect electrical seizure threshold. When administered acutely or for a prolonged period of time (5 times every 24 h), it did not affect anticonvulsant activity of CBZ and VPAin MES. Free plasma concentration of both anticonvulsants was not affected by allopurinol given at a dose of 45 mg/kg for 5 days. Thus, our results did not support suggestions that allopurinol can be beneficial as add-on drug in the management of epilepsy at least in patients treated with CBZ or VPA.

2-Methoxyestradiol enhances reactive oxygen species formation and increases the efficacy of oxygen radical generating tumor treatment.

In an investigation of the antitumor effects of 2-methoxyestradiol (2-ME) in combination with other reactive oxygen generating treatments, 2-ME (0.5 microM) was found to completely inhibit cell proliferation of rat DS-sarcoma cells in vitro, with 71% of cells dying after exposure to 5 microM 2-ME. Concentration-dependent increases in ROS-formation, lipid peroxidation and mitochondrial changes were also observed, and an elevation in caspase-3 activity resulted in DNA fragmentation and apoptosis. Combination of 2-ME with hypoxanthine and xanthine oxidase enhanced in vitro cytotoxicity. In vivo, 2-ME caused a slight inhibition of tumor growth, with no tumors cured. Combination of 2-ME treatment with localized 44 degrees C hyperthermia, respiratory hyperoxia and xanthine oxidase caused a tumor growth delay with 51% of tumors cured. These results suggest that amplifying the levels of reactive oxygen species within tumor tissue with substances such as 2-ME may prove to be a promising strategy for adjuvant treatment of solid tumors.

Tratamiento del síndrome de Lesch-Nyhan / Treatment of Lesch-Nyhan syndrome

Objetivo. En este trabajo se revisan los tratamientos empleados hasta la fecha, dirigidos a paliar las diversas manifestaciones características del síndrome de Lesch-Nyhan (SLN), los efectos adversos registrados y las líneas actuales de investigación que abren futuras esperanzas terapéuticas. Desarrollo. El SLN es un defecto congénito del metabolismo de las purinas ocasionado por el déficit de la enzima hipoxantina-guanina fosforribosiltransferasa (HPRT). Desde el punto de vista clínico se caracteriza por hiperuricemia y trastornos neurológicos graves, que parecen relacionarse con la magnitud del defecto enzimático. Conclusiones. La escasa frecuencia del SLN, junto con el desconocimiento de la fisiopatología de los trastornos neurológicos, explica que la terapéutica se fundamente en recomendaciones sintomáticas. Los fármacos inhibidores de la enzima xantina oxidasa ayudan a controlar la excreción elevada de ácido úrico, pero hasta la fecha no se ha encontrado ningún tratamiento eficaz para los síntomas neurológicos (AU)