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Lemon fruits lower the blood uric acid levels in humans and mice

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Abstract

Hyperuricemia is a chronic metabolic disorder leading to gouty arthritis, kidney stones, hypertension, renal failure and even cardiovascular diseases in humans. In the present study, the role of the lemon fruit juice and/or the water soluble extracts in lowering the blood uric acid level was evaluated in both human subjects and mice. Fresh lemon fruits, excluding the peel and seeds, were used to prepare the juice and/or water soluble extracts. Human subjects with hyperuricemia were given the freshly squeezed pure lemon fruit juice daily at 30 mL/day (equivalent to a lemon a day) for 6 weeks. Human serum samples were collected for biochemical assessments at weeks 0 (basal line), 3, and 6, respectively. At the end of clinical study, fasting blood samples were collected for blood tests. Mice were given oxonic acid potassium (OA) to induce hyperuricemia. Hyperuricemic Mice were orally given the lemon fruit water soluble extracts at 10 mg/kg body weight and/or allopurinol at 5 mg/body weight for 11 consecutive days. At the end of study, the mice were euthanized and the blood and liver tissues were collected for biochemical tests. The results showed that the lemon fruit juice and/or the water soluble extracts significantly lowered serum uric acid levels in both human subjects and mice. Neither renal nor liver dysfunction was observed. The mechanistic results indicated that lemon might exert the role in lowering serum uric acid independent of inhibition of xanthine oxidase. The results lay a foundation for the future development of dietary treatments of hyperuricemia in humans.

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... Another study also showed a decrease in SUA after taking freshly squeezed pure lemon fruit juice daily at 30 mL/day (equivalent to a lemon a day) for 6 weeks in males with hyperuricemia [42]. The same authors demonstrated that lemon juice also reduced SUA in a mice model with hyperuricemia [42]. ...
... Another study also showed a decrease in SUA after taking freshly squeezed pure lemon fruit juice daily at 30 mL/day (equivalent to a lemon a day) for 6 weeks in males with hyperuricemia [42]. The same authors demonstrated that lemon juice also reduced SUA in a mice model with hyperuricemia [42]. ...
... Other mechanisms independent of the inhibition of XO could also be involved in the hypouricemic action of citrus fruits [42]. In fact, it has been shown that citrus flavonoids such as nobiletin, hesperetin and naringenin inhibit the activity of the URAT1 transporter [greater than 30%] more strongly than other polyphenols [24]. ...
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Background and Objectives: Hyperuricemia and liver steatosis are risk factors for cardiovascular diseases and mortality. The use of natural compounds could be a safe and effective alternative to drugs for the treatment of fatty liver and hyperuricemia. Polyphenolic fraction of Citrus Bergamia in association with the extract of Cynara Cardunculus, as nutraceutical, is able to reduce body weight, hepatic steatosis and markers of oxidative stress. Then, we performed a secondary analysis of a double-blind placebo-controlled trial to examine the effects of this nutraceutical on serum uric acid levels in adults with fatty liver. Materials and Methods: The study included 94 individuals with hepatic steatosis. For six weeks, the intervention group was given a nutraceutical (300 mg/day) comprising a Bergamot polyphenol fraction and Cynara Cardunculus extract. The control group received a daily pill of placebo. Serum uric acid, lipids, glucose and anthropometric parameters were assessed at baseline and after 6 weeks. Results: We found a greater reduction in serum uric acid in the participants taking the nutraceutical rather than placebo (−0.1 ± 0.7 mg/dL vs. 0.3 ± 0.7 mg/dL, p = 0.004), and especially in those with moderate/severe hepatic steatosis also after adjustment for confounding variables. In addition, we analysed the two groups according to tertiles of uric acid concentration. Among participants taking the nutraceutical, we found in those with the highest baseline serum uric acid (>5.4 mg/dL) the greater reduction compared to the lowest baseline uric acid (−7.8% vs. +4.9%; adjusted p = 0.04). The stepwise multivariable analysis confirmed the association between the absolute serum uric acid change and nutraceutical treatment (B = −0.43; p = 0.004). Conclusions: A nutraceutical containing bioactive components from bergamot and wild cardoon reduced serum uric acid during 6 weeks in adults with fatty liver. Future investigations are needed to evaluate the efficacy of this nutraceutical in the treatment of hyperuricaemia.
... Decrease SUA level. ND [47] Grapefruit Block UA production, promote UA elimination, and facilitate UA secretion [32] Blueberry Clinical trial: older adults (65-80 years) experiencing mild cognitive impairment. ...
... These nutrients are important for human health. Numerous fruits i.e., orange, [45] lingonberry, [50] lemon, [46,47] grapefruit, [32] blueberry, [48,49] tart cherry, [51] Prunus mume, [52] lychee, [53] longan, [54] Chaenomeles sinensis, [55] and red guava, [56] have been reported for their anti-hyperuricemia effect. The anti-hyperuricemia activity of fruits and their bioactive compounds are presented in Figure. ...
... [32] In vivo and clinical trials have revealed that lemon fruit juice could decrease SUA level, and potassium citrate has been identified as the component with the ability to treat HUA. [46,47] Blueberries and cherry fruits have been reported for their anti-hyperuricemia effects. The pterostilbene (50 mg/kg bw) from blueberry was confirmed to reduce SUA level from 201.95 μM to 176.67 μM in adenine-and PO-induced HUA nephropathy mice model. ...
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Hyperuricemia is a global epidemic that is closely related to the development of chronic diseases. Therefore, researchers are focusing on improving the symptoms of hyperuricemia through dietary sources. Here, the anti-hyperuricemia mechanism of dietary sources and their bioactive components are summarized and discussed. Furthermore, the structure – activity relationship of these compounds is also analyzed, as well as the processing methods of anti-hyperuricemia foods. In general, the dietary sources that serve as a natural remedy for anti-hyperuricemia are mainly attributed to their bioactive ingredients, especially flavonoids. Meanwhile, the main action mechanism of bioactive ingredients is to inhibit xanthine oxidase activity, which could block the production of uric acid.
... 17 Our previous studies have found that lemon juice can reduce serum uric acid, independent of the inhibition of xanthine oxidase. 18 Thus, it is possible to find an effective agent from lemon fruits for treating hyperuricemia. However, the specific ingredients in lemon fruits reducing the serum uric acid level for treating hyperuricemia are still unknown. ...
... Our previous studies have shown that lemon juice significantly lowered serum uric acid levels in both human subjects and mice, and that the lemon juice reduced blood uric acid without inhibiting the activity of xanthine oxidase. 18 Therefore, the investigation of the effect of LET on xanthine oxidase activity was omitted in our present study. This study demonstrated that ...
... At present, one of the three types of hypouric acid drugs is xanthine oxidase inhibitors, 4 but our previous studies have shown that LET might not inhibit xanthine oxidase. 18 The second type of drug functions by inhibiting the uric acid transporter URAT1, 8 but this study showed that since potassium citrate in LET did not affect the expression of URAT1 mRNA, it could be inferred that other components in LET might affect the expression of URAT1. The third type is uric acid oxidase drugs. ...
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Lemon is a healthy fruit with high medicinal value. This study found that lemon water soluble extract (LET) can reduce uric acid levels in mice with potassium oxonate induced hyperuricemia. Histopathological analysis suggested that LET caused little damage to the kidneys of mice. It affected mABCG2 and mGLUT9 mRNA expression only in hyperuricemic mice, but not in healthy mice. Our further results show that potassium citrate, rather than citric acid, is the main ingredient in LET with a hypouricemic effect. This study also indicates that lemon does have unique medicinal value for the treatment of hyperuricemia, and that potassium citrate has the potential to be developed as a drug for hyperuricemia. Lowering uric acid through LET and potassium citrate may directly promote the degradation of excessive uric acid in patients with hyperuricemia.
... From the last few years, citrus fruits gained much attraction due to promising health benefits and minimum toxicity to animal (Haidari et al., 2009a;Muthiah, 2012;Wang et al., 2017a). The citrus fruits contain hesperidin, naringin, nobiletin, neo-460 hesperidin and many other compounds together inhibit the XO and lower the UA level (Umamaheswari, 2013), calcium oxalate calculus (Kulaksizoglu et al., 2008), hyperuricemia urinary calculus (Aras et al., 2008) and kidney calculus (Touhami et al., 2007). ...
... Albeit, the effect was weak but if 480 the concentration of orange juice increase it will more effect on UA level and XO. More recently study conducted by Wang et al. (2017a) reported that lemon fruit juice orally given to volunteer (30 ml/day, 6 weeks) and mice (10 mg/kg, 11 days) lowered serum UA level in volunteer (588.88 to 552.22 mmol/l) 485 and mice (150 to 90 mmol/l) without damaging kidney and liver function. Previously reported, that lemon fruit juice enhanced glomerular filtration and increased UA elimination in kidney (Touhami et al., 2007;Aras et al., 2008). ...
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Hyperuricemia, a condition due to high serum uric acid level and is notorious to health. It is considered to be a potent risk factor for gout and dramatically associated in the development of many chronic diseases such as malignant tumor, cardiovascular disorders and renal failure. Modern innovative medicinal and therapeutic interventions are underlying these days to combat hyperuricemia. Previously reported studies revealed the significant impact of dietary polyphenols (e.g. anthocyanins, phenolic acids, flavonoids etc.) against hyperurecemia disorder. Dietary plant polyphenols, unlike anti- hyperuricemic agents, are not reported to have any side effects in curing hyperuricemia. The current comprehensive review figure outs the use of dietary polyphenols as a natural remedy for the management of hyperuricemia. The sources, affiliated pathways, mode of actions and factors affecting their efficiency to prevent hyperuricemia are deeply discussed in this article. Additionally, limitations and suggestions regarding previously reported studies are also highlighted.
... The lemon fruit juice and/or the water -soluble extracts considerably decreased serum uric acid concentrations in both human beings and mice [16]. Study done by Shija KM et al revealed that; Lemon decoction confirmed antimalarial action in mice infected with P. berghei ANKA through parasites inhibition by 39% as contrasted to those received placebo. ...
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Medicinal plants, recognized and employed in conventional medicine practices since prehistoric era. Plants produce thousands of chemical substances for functions counting defence against insects, fungi, bacterial and parasitic diseases. Malaria is most widespread parasitic infection , it caused by coccidian protozoa of the genus plasmodium , four species are mostly infect human, P. falciparum, P. vivax, P. malriae and P. ovale, Majority of malaria cases resulted from P. falciparum and P. vivax. Uric acid regarded as one of the damaging molecular patterns of malaria parasite infection, and in this review we discussed the potential role of medicinal plants used as antimalarial to diminish the level of uric acid in gout patients. These may suggest that most of the complication associated with malaria, may attributed to amplified level of uric acid. Experimental studies recommended.
... Dietary supplementation with 1.5% lemon pulp had desirable effects on reducing abdominal fat and blood low density lipoproteins of Ross 308 chicks across the entire production period (Nobakht 2013). Being given the freshly squeezed pure lemon fruit juice at 30 mL/day could significantly lower the serum uric acid levels in humans with hyperuricaemia (Wang et al. 2017). Supplementation with 300 g dried lemon per animal per day could increase the digestible organic matter concentration of the urea-treated straw-based diets of goats (Madrid et al. 1996). ...
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With the appeals for antibiotic-free production and the attention to natural feed additives in poultry. The effects of fresh lemon (FM) supplementation on older laying hens (79–96 weeks) and its comparison with citric acid (CA) and flavomycin (FLA) were evaluated in the present study. Female Jingfen chickens (n = 540) were randomly distributed into 5 dietary treatments: 0 (control), 20 g/kg (2%) and 40 g/kg (4%) FM, 0.7 g/kg CA and 0.005 g/kg FLA. Production performances were recorded daily and egg quality traits were measured biweekly. Serum biochemical indices and antibody titres were detected every 4 weeks from 84 to 96 weeks of age. Compared with the control diet, FM, CA and FLA increased the laying rate (p < .05) and average daily feed intake (ADFI), and reduced the feed to egg ratio (FER), indicating positive effects on production performance. Albumen height and HU were increased by 2% and 4% FM groups compared to the control, while albumen height was decreased in CA and FLA groups. FM improved serum antioxidant enzyme activities (p < .05) and reduced serum HDL, LDL, TG and T-CH compared to other groups, indicating favourable effects on antioxidative status and lipid metabolism. Antibody titres against H5N1, H9N2 and NDV were higher in FM groups than that in other groups during most experimental periods (p < .05). In conclusion, FM supplementation enhanced the production performance and antioxidant capacity of laying hens during the late laying period and was superior to the CA and FLA in improving albumen quality, immune status and lipid metabolism. • HIGHLIGHTS • FM supplementation in layers’ diets had positive effects on production performance, egg albumen quality and lipid metabolism, and could enhance antioxidant capacity and immune levels. • Adding FM had better effects on the albumen quality, immune status and lipid metabolism of laying hens than adding CA and FLA during the late laying period.
... Moreover, it is showing various health benefits, such as anticancer effect, antimicrobial effect, lipid-lowering effect, protective effect against cardiovascular diseases and antifungal activity (5,15,16). Furthermore, it is utilised for the treatment of stomach problem, constipation, teeth problems, memory loss, fever, bleeding, rheumatism, burns, breathing disorders, cholera, atherosclerosis, high blood pressure, treating liver ailments, promotes digestion and prevent urinary tract infections (17)(18)(19)(20)(21). In addition, there are much more applications such as cleaning agents and for hair and skin care (11,16). ...
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Article
This study is conducted to evaluate the therapeutic and antioxidant effect of lemon juice on some hematological and biochemical parameters. Thirty female mice used in this study were exposed to oxidative stress through giving them hydrogen peroxide in drinking water for 30 days. Animals randomly distributed over 3 groups, each group contained 10 animals and treated as follows: T1 control group (drinking distilled water only), T2 (0.75% hydrogen peroxide in drinking water) and T3 (0.75% hydrogen peroxide in drinking water with daily drenching with 1 mL lemon juice). At the end of the experiment, blood samples were collected from animals for evaluating the following hematological and biochemical parameters: Haemoglobin concentration (Hb), red blood cells count (RBC), white blood cells count (WBC), packed cell volume (PCV), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count (PLT), level of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total protein. The results showed that T3 exhibited an enhancement in RBC count, Hb concentration, WBC, lymphocyte and total protein and reduction in the level of AST and ALT compared to T2. These findings clearly revealed the advance protective and antioxidant features of lemon juice on hematological and biochemical parameters of the oxidatively stressed female mice.
... Moreover, it is showing various health benefits, such as anticancer effect, antimicrobial effect, lipid-lowering effect, protective effect against cardiovascular diseases and antifungal activity (5,15,16). Furthermore, it is utilised for the treatment of stomach problem, constipation, teeth problems, memory loss, fever, bleeding, rheumatism, burns, breathing disorders, cholera, atherosclerosis, high blood pressure, treating liver ailments, promotes digestion and prevent urinary tract infections (17)(18)(19)(20)(21). In addition, there are much more applications such as cleaning agents and for hair and skin care (11,16). ...
Full-text available
Article
This study is conducted to evaluate the therapeutic and antioxidant effect of lemon juice on some hematological and biochemical parameters. Thirty female mice used in this study were exposed to oxidative stress through giving them hydrogen peroxide in drinking water for 30 days. Animals randomly distributed over 3 groups, each group contained 10 animals and treated as follows: T1 control group (drinking distilled water only), T2 (0.75% hydrogen peroxide in drinking water) and T3 (0.75% hydrogen peroxide in drinking water with daily drenching with 1 mL lemon juice). At the end of the experiment, blood samples were collected from animals for evaluating the following hematological and biochemical parameters: Haemoglobin concentration (Hb), red blood cells count (RBC), white blood cells count (WBC), packed cell volume (PCV), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count (PLT), level of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total protein. The results showed that T3 exhibited an enhancement in RBC count, Hb concentration, WBC, lymphocyte and total protein and reduction in the level of AST and ALT compared to T2. These findings clearly revealed the advance protective and antioxidant features of lemon juice on hematological and biochemical parameters of the oxidatively stressed female mice.
... In another study, the intake of 600 mg/day hesperidin increased adiponectin level and decreased the endothelial inflammation in patients with myocardial infarction (Haidari et al., 2015). A recent study showed fresh lemon juice attenuated liver function biomarkers including bilirubin and liver enzymes (Wang et al., 2017). ...
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The high exposure to acrylamide (AA) due to smoking and increased consumption of processed and fast foods in recent years, has become one of the health threatening problems. This study examined the effect of lemon juice on inflammation and adipokines in acrylamide-induced oxidative stress in rats. Forty animals were divided into five groups. Toxicity was induced by AA (35mg/kg) for two weeks in all groups except normal control group. After that, lemon juice in three doses was administrated to treatment groups for 4 weeks. Serum levels of adipokines and inflammatory parameters and both serum and liver levels of oxidative stress parameters were measured. The results showed groups were received AA had significant higher levels of malondialdehyde, tumor necrosis factor alpha, leptin and C-reactive protein and lower levels of total antioxidant capacity compared to the negative control group. Lemon juice in all three doses significantly improved serum levels of TAC, MDA, TNFα and hs-CRP in treated groups. Also, 7.5 ml/kg lemon juice significantly decreased leptin levels. However, lemon juice had no significant effect on adiponectin levels. This study suggests lemon juice as a potential dietary alternative could attenuate leptin levels and manage oxidative and inflammatory damages in acrylamide- induced toxicity in rats.
... In addition to their unique Phytochemical properties, these fruits are excellent source of vitamin-C one of the most important antioxidants in nature. Citrus fruits such as lemon contain antioxidant that neutralize free radicals and help to reduce chronic metabolic diseases like gouty arthritis, kidney stones, hypertension, even cardiovascular diseases in humans (Wang, Cheng, Lin, Ma, & Deng, 2017). During processing and storage of citrus fruit juices considerable amount of vitamin-C is lost which mostly follows first order kinetic model . ...
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The aim of this study was to assess the quality of the developed mixed marmalade using lemon and orange juice with peels in different ratios. The developed mixed fruit marmalades were analyzed for proximate compositions, microbiological status and sensory attributes. The kinetic degradation of vitamin-C and effect of storage temperature on marmalade samples were also investigated. Storage study was conducted on the mixed fruit marmalades for six months at room temperature (23-30ºC) and refrigeration temperature (4ºC) at relative humidity 80 to 85%. The Sample S3 (lemon: orange: orange peel=6:2:1) was found as the best of all samples with respect to chemical composition and sensory attributes. The sample S3 has a composition of 27.15% moisture, 0.75% ash, 66.3% total sugar, 67.85% TSS and 15mg/100gm vitamin-C. Small amount of mold and bacterial attack was also observed in all samples after 48hours of incubation period at room temperature (27 ºC). The result showed that vitamin-C degradation was followed first order kinetic model in all developed marmalade samples. The activation energy for the vitamin-C degradation of the sample S1, S2, S3 and S4 was estimated to be 3.009 kcal/ mol, 2.082 kcal/mol, 2.022 kcal/mol and 2.090 kcal/ mol respectively.
Chapter
Considering the importance of reducing the production of uric acid in the treatment of hyperuricemia and its complications, many antihyperuricemic drugs have been developed recently. However, some uric acid-lowering drugs have clinically toxic side effects. In order to treat the allergic reactions of the antihyperuricemic drugs, alternatives from natural products have been selected to investigate the beneficial promotion. Bioactive peptides are potential candidates with safe, effective, and a potential inhibitory effect on the key enzyme—Xanthine oxidase (XOD) that promotes uric acid production. Generally, there is a lack of systematic review about peptides with antihyperuricemic and antigout properties. Here, we reviewed and summarized (1) the preparations and structural properties of purified antihyperuricemic peptides; (2) the antihyperuricemic and antigout effects of purified peptides or peptides-rich components in vivo and in vitro; and (3) the molecular mechanism of the active peptides focusing on XOD inhibitory activities. This review sheds light on understanding the bioactivity mechanism of antihyperuricemic peptides and large-scale commercial production that should be further exploited.
Chapter
Uric acid has attracted much interest of the scientific community due to its versatile role in health. This organic compound is renowned as being a powerful ROS and peroxynitrite scavenger but also as a major contributor to several pathologies. Furthermore, this weak acid can act both as an antioxidant and pro-oxidant molecule. Its antioxidant properties is restricted to hydrophilic environment only and occurs in the plasma. As a pro-oxidant uric acid can mediate the formation of reactive radicals through a chain reaction leading to a state of high oxidative stress. This environment makes lipid molecules such as low-density lipids susceptible to oxidation targeting membranes rather than cell components. The switch between the antioxidant and pro-oxidant activity of uric acid thus depend on its microenvironment and generation rate of radicals. However, high level of uric acid in the body can generate several health complications like decreasing the life expectancy of sick patients, gout and eclampsia among others. Uric acid has also some beneficial effects, for instance, antioxidant properties where it helps to scavenge ROS and peroxynitrite, helps in maintaining good endothelial functions, boost type 2 immune response and provides defence against neurological and autoimmune diseases. The availability of uric acid can be influenced by taking food such as olives, lemons and Barringtonia racemose L.
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Hyperuricemia ensues due to the reabsorption and diminished evacuation of uric acid which is accountable for the advancement of gout and radically concomitant with the progress of numerous long-lasting ailments for instance malignant tumor, cardiovascular ailments, and kidney failure. Underlying factors such as excessive intake of purine containing supplements, obesity, age, sex, sugar, and alcohol intake may condense the formation of uric acid and exaggerate the injurious effects of uric acid. Novel inventive pharmaceutical and curative mediations are being used for the tackling of hyperuricemia but the problem arises when patients complain about adverse reactions with serious complications that may increase the rate of developing new diseases. Medicinal and dietary plants with bioactive phytochemicals like polyphenols, flavonoids are more feasible due to less toxicity, more economical for developing countries, formulation advantages for primary healthcare, better appropriateness with human physiological conditions. To facilitate the design of plant-based alternative therapy it is a prerequisite to connecting herbal medicine with novel prescription and additional precise explorations have to be ensured for the authentication of the effectiveness and safety of herbal formulations. The existing assessment outlines production, metabolism, and excretion of uric acid, hazard influences (overabundance and low excretion of uric acid), conventional pharmacotherapy for hyperuricemia and its related complications, the use of plants, its origin; parts to be used, mechanism of actions to preclude hyperuricemia are highlighted based on of previously issued literature.
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Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout. We randomly assigned 762 patients with gout and with serum urate concentrations of at least 8.0 mg per deciliter (480 micromol per liter) to receive either febuxostat (80 mg or 120 mg) or allopurinol (300 mg) once daily for 52 weeks; 760 received the study drug. Prophylaxis against gout flares with naproxen or colchicine was provided during weeks 1 through 8. The primary end point was a serum urate concentration of less than 6.0 mg per deciliter (360 micromol per liter) at the last three monthly measurements. The secondary end points included reduction in the incidence of gout flares and in tophus area. The primary end point was reached in 53 percent of patients receiving 80 mg of febuxostat, 62 percent of those receiving 120 mg of febuxostat, and 21 percent of those receiving allopurinol (P<0.001 for the comparison of each febuxostat group with the allopurinol group). Although the incidence of gout flares diminished with continued treatment, the overall incidence during weeks 9 through 52 was similar in all groups: 64 percent of patients receiving 80 mg of febuxostat, 70 percent of those receiving 120 mg of febuxostat, and 64 percent of those receiving allopurinol (P=0.99 for 80 mg of febuxostat vs. allopurinol; P=0.23 for 120 mg of febuxostat vs. allopurinol). The median reduction in tophus area was 83 percent in patients receiving 80 mg of febuxostat and 66 percent in those receiving 120 mg of febuxostat, as compared with 50 percent in those receiving allopurinol (P=0.08 for 80 mg of febuxostat vs. allopurinol; P=0.16 for 120 mg of febuxostat vs. allopurinol). More patients in the high-dose febuxostat group than in the allopurinol group (P=0.003) or the low-dose febuxostat group discontinued the study. Four of the 507 patients in the two febuxostat groups (0.8 percent) and none of the 253 patients in the allopurinol group died; all deaths were from causes that the investigators (while still blinded to treatment) judged to be unrelated to the study drugs (P=0.31 for the comparison between the combined febuxostat groups and the allopurinol group). Febuxostat, at a daily dose of 80 mg or 120 mg, was more effective than allopurinol at the commonly used fixed daily dose of 300 mg in lowering serum urate. Similar reductions in gout flares and tophus area occurred in all treatment groups.
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To investigate the association between serum uric acid level and risk of type 2 diabetes. The population for analysis consisted of 4,536 subjects free from diabetes at baseline. During a mean of 10.1 years of follow-up, 462 subjects developed diabetes. The age- and sex-adjusted hazard ratios (HRs) (95% CIs) for diabetes were 1.30 (0.96-1.76) for the second, 1.63 (1.21-2.19) for the third, and 2.83 (2.13-3.76) for the fourth quartile of serum uric acid, in comparison with the first quartile. After adjustment for BMI, waist circumference, systolic and diastolic blood pressure, and HDL cholesterol, the HRs decreased to 1.08 (0.78-1.49), 1.12 (0.81-1.53), and 1.68 (1.22-2.30), respectively. The results of this population-based study suggest that serum uric acid is a strong and independent risk factor for diabetes.
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Hyperuricemia depends on the balance of endogenous production and renal excretion of uric acid. Transporters for urate are located in the proximal tubule where uric acid is secreted and extensively reabsorbed: secretion is principally ensured by the highly variable ABCG2 gene. Enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) plays a central role in purine metabolism and its deficiency is an X-linked inherited metabolic disorder associated with clinical manifestations of purine overproduction. Here we report the case of a middle-aged man with severe chronic tophaceous gout with a poor response to allopurinol and requiring repeated surgical intervention. We identified the causal mutations in the HPRT1 gene, variant c.481G>T (p.A161S), and in the crucial urate transporter ABCG2, a heterozygous variant c.421C>A (p.Q141K). This case shows the value of an analysis of the genetic background of serum uric acid.
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Elevated serum levels of uric acid are associated with an increased risk for hyperuricemia, gout, hypertension, cardiovascular disease, and renal failure. Recent attention has focused on the bioactive properties of edible plants in preventing disease. Hibiscus sabdariffa L., a local soft drink material and medicinal herb in Taiwan, is used effectively in native medicines against hypertension, pyrexia, and liver disorders. We investigated the effects of the Hibiscus sabdariffa extract (HSE) on oxonic acid (OA)-induced hyperuricemia in rats. The HSE affected serum uric acid levels and urate enzymes such as uricase and xanthine oxidase (XO). We treated rats intraperitoneally with normal saline and oxonate solution for 1 week and with or without feeding allopurinol (an XO inhibitor) or HSE (1%, 2%, and 5%) for 5 weeks. We observed that treatment with HSE inhibited OA-induced hyperuricemia, with a greater uric acid lowering effect than allopurinol treatment. Our results showed that HSE effectively inhibited OA-induced hyperuricemia by decreasing uric acid and increasing uricase activity, but not by affecting XO activity.
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Uric acid, the end product of purine metabolism, is excreted predominantly by the proximal tubules. Abnormal serum levels of uric acid are due to alterations in production or excretion. Fractional excretion of uric acid is helpful in determining the underlying etiology of hypouricemia or hyperuricemia in children. Abnormalities in the molecular mechanisms that control renal uric acid tubular transport are implicated in various disorders associated with abnormal uric acid levels. Gout is rare in children; yet its presence necessitates evaluation for enzymatic defects in purine metabolism. Well-known effects of uric acid on the kidney include nephrolithiasis and acute kidney injury (AKI) in the setting of tumor lysis. However, recent data suggest that uric acid may be an important factor in the pathogenesis of AKI in general, as well as of chronic kidney disease (CKD) and hypertension. Hence, uric acid may not only be a marker but also a potential therapeutic target in kidney disease. Nonetheless, because of confounders, more studies are needed to clarify the association between uric acid and multifactorial disorders of the kidney.
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Gout is common in the elderly and its management is frequently complicated by the presence of co-morbid conditions and medications prescribed for other conditions. The management of gout is 2-fold: (i) treatment of the acute attack to rapidly resolve the pain and inflammation; and (ii) long-term urate-lowering therapy (ULT) to prevent further gouty episodes. NSAIDs, colchicine, corticosteroids and more recently interleukin (IL)-1 inhibitors are effective treatments for acute gout. The choice of agent is determined by the patient’s age, co-morbidities and concomitant medications. Renal impairment is of particular concern in the elderly and may preclude the use of NSAIDs and colchicine. The IL-1 inhibitors are rapidly effective but data in the elderly are limited. ULT aiming for a serum urate Probenecid is ineffective in patients with renal impairment (creatinine clearance
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Acacia confusa Merr. (Leguminosae) is traditionally used as a medicinal plant in Taiwan. In the present study, the XOD-inhibitory activity of ethanolic extracts from A. confusa was investigated for the first time. Results demonstrated that the ethanolic extract of A. confusa heartwood had a strong XOD-inhibitory activity. Among all fractions derived from heartwood extracts, the EtOAc fraction exhibited the best inhibitory activity. Following column chromatography and reverse-phase high-performance liquid chromatography, eight specific phytochemicals including melanoxetin, 7,8,3',4'-tetrahydroxyflavone, transilitin, okanin, 3,7,8,3'-tetrahydroxy-4'-methoxyflavone, 7,8,3'-trihydroxy-3,4'-dimethoxyflavone, 7,3',4'-trihydroxyflavone, and 7,3',4'-trihydroxy-3-methoxyflavone were isolated and identified from the EtOAc fraction. In addition, the IC(50) values indicated that okanin showed the strongest XOD-inhibitory effect (IC(50) value of 0.076 microM), followed by melanoxetin (0.274 microM) and allopurinol (4.784 microM). The present study revealed that okanin and melanoxetin showed excellent inhibition on XOD in noncompetitive and competitive mode, respectively, and their inhibitory activity is better than that of allopurinol. This is the first study that demonstrates the XOD-inhibitory performance of okanin and melanoxetin.
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To investigate that lemon juice could be an alternative to potassium citrate in the treatment of urinary calcium stones in patients with hypocitraturia, 30 patients with hypocitraturic urinary calcium stones were enrolled into study. The patients were divided into three groups equally. Exactly 60 mEq/day fresh lemon juice ( approximately 85 cc/day) and potassium citrate (60 mEq/day) were given to the patients of first and second group, respectively. Dietary recommendations were made for the third group. Blood and 24-h urine tests were performed before treatment and repeated 3 months later. The differences between demographic datas of groups were not significant. There was no significant difference between values of blood tests performed before and after treatment in all groups. Statistically significant differences were found between pre- and post-treatment urine values in each group. Although there was no significant difference between pre-treatment citrate levels of the groups. A significant difference was found between post-treatment citrate levels of the groups. There was 2.5-, 3.5- and 0.8-fold increase in urinary citrate level of lemon juice, potassium citrate and dietary recommendation groups, respectively. Urinary calcium level was decreased only in lemon juice and potassium citrate groups after treatment. While there was no significant difference between pre- and post-treatment urinary oxalate levels in all groups, a significant decrease in urinary uric acid levels was determined in all groups. We suggest that lemon juice can be an alternative in the treatment of urinary calcium stones in patients with hypocitraturia. Additionally, dietary recommendations can increase effectiveness of the treatment.
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We now have sufficient knowledge to be able to identify the factors contributing to hyperuricemia in most patients with gout. Some of these factors, such as obesity, a high-purine diet, regular alcohol consumption, and diuretic therapy, may be correctable. In patients with persistent hyperuricemia, regular medication should lower the serum urate concentration to an optimal level. The continuing challenge is to educate patients about correctable factors and the importance of regular medication and ensure their compliance so that attacks of gout do not recur.
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Objective: Aspirin is known to have a bimodal effect on the renal handling of uric acid (UA). High dosages (>3 gm/day) are uricosuric, while low dosages (1-2 gm/day) cause UA retention. Although very-low-dose (mini-dose) aspirin is used increasingly as a platelet aggregation inhibitor, no studies have been published on whether aspirin's renal effects occur at dosages of <0.5 gm/day. The aim of the present study was to evaluate the effects of commonly used mini-dosages of aspirin on renal function and UA handling in elderly patients. Methods: The study included 49 elderly inpatients (age 61-94). Patients were excluded if they had renal failure, hyperuricemia, gout, or a history of bleeding, or if they were receiving anticoagulants, aspirin, or nonsteroidal antiinflammatory drugs. Previous medications and diet were kept unchanged. Aspirin was administered as follows: 75 mg/day (week 1), 150 mg/day (week 2), 325 mg/day (week 3), and 0 mg/day (week 4). Baseline and weekly samples of blood and urine were evaluated for UA, creatinine, blood urea nitrogen, creatinine clearance, UA excretion, UA clearance, and plasma levels of aspirin. Results: At the lowest dosage, aspirin caused a 15% decrease in the rate of UA excretion (P = 0.045 by t-test), which was associated with a slight but significant increase in serum levels of UA (P = 0.009). These effects on UA levels were gradually reduced with increasing dosages of aspirin (multivariate analysis of variance with repeated measures showed no statistically significant difference in the rate of UA excretion between weeks 1-3 and week 0 [baseline], but the difference in serum UA levels for the same comparison was statistically significant [P = 0.038]). Generally, creatinine and UA clearance rates paralleled each other during aspirin treatment. However, 1 week after aspirin was discontinued, creatinine clearance remained decreased while UA clearance returned to baseline. Plasma aspirin concentrations were low and variable. However, patients with above-median aspirin levels had significantly greater changes in serum creatinine levels, urinary UA excretion rates, and UA clearance rates following the first week of aspirin treatment. Hypoalbuminemia and concomitant treatment with diuretics enhanced the effects of aspirin on renal function and UA retention. Conclusion: Mini-dose aspirin, even at a dosage of 75 mg/day, caused significant changes in renal function and UA handling within 1 week in a group of elderly inpatients, mainly in those with preexisting hypoalbuminemia. Given the widespread (and often unmonitored) use of mini-dose aspirin, especially among the elderly, these findings call for clinician alertness as well as for further studies to clarify the mechanisms underlying these phenomena.
Article
To investigate the incidence of gout and the interaction between uric acid level and other risk factors in the development of gout. Two hundred twenty-three asymptomatic hyperuricemic men initially studied in 1991-92 were reassessed in 1996-97. Gout was clinically diagnosed by a senior rheumatologist based on history and physical according to the clinical criteria of Wallace. Basic demographic and lifestyle variables as well as biochemical data were collected in both baseline and followup periods. Both the stability analysis and the analysis of repeated relationships were applied. The 5-year cumulative incidence of gout was 18.83% (42/223). The risk factors for gout based on the analysis of repeated relationships were uric acid level, alcohol consumption, use of diuretics, and obesity. The only predictor of gout at baseline was uric acid level. After adjusting for baseline uric acid level, followup uric acid increase, persistent alcohol consumption, use of diuretics in the followup period, and body mass index increase were independent predictors for gout among asymptomatic hyperuricemic men. Excessive alcohol consumption, particularly if occasional, was the most important factor in the development of gout, even when the concentration of uric acid level was below 8 mg/dl. Uric acid level is the key factor for prevention of gout and needs constant monitoring. Other contributing or possible etiologic factors such as alcohol consumption, diuretics use, and excess weight gain carry an increased risk of gout attack among patients with hyperuricemia.
Hyperuricemia is one of the common complications in hypertension. The presence of hyperuricemia is closely correlated with the initiation of hypertension. In addition, the hypertension is known to increase the rate of hyperuricemia. Recently, it has been recognized that the hyperuricemia is one of the risk factors for cardiovascular events in hypertension. Therefore, the control of hyperuricemia might be critical for treatment of hypertension. Although the diuretics are important for the treatment of chronic heart failure and hypertension, it is reported to induce the hyperuricemia. Therefore, the careful and combination therapy for diuretics might be necessary to prevent the treatment-induced hyperuricemia. In the treatment of hypertension, especially with hyperuricemia, it might be important to select the drug, which does not influence or reduce the concentration of uric acid.
Article
An elevation in circulating serum uric acid is strongly associated with the development of hypertension and renal disease, but whether uric acid has a causal role or whether it simply indicates patients at risk for these complications remains controversial. We tested the hypothesis that uric acid may have a causal role in the development of hypertension and renal disease by examining the effects of mild hyperuricemia in rats. Mild hyperuricemia was induced in rats by providing a uricase inhibitor (oxonic acid) in the diet. Hyperuricemic rats developed elevated blood pressure after 3 weeks, whereas control rats remained normotensive. The development of hypertension was prevented by concurrent treatment with either a xanthine oxidase inhibitor (allopurinol) or a uricosuric agent (benziodarone), both of which lowered uric acid levels. Blood pressure could also be lowered by reducing uric acid levels with either allopurinol or oxonic acid withdrawal. A direct relationship was found between blood pressure and uric acid (r=0.75, n=69), with a 10-mm Hg blood pressure increase for each 0.03-mmol/L (0.5-mg/dL) incremental rise in serum uric acid. The kidneys were devoid of urate crystals and were normal by light microscopy. However, immunohistochemical stains documented an ischemic type of injury with collagen deposition, macrophage infiltration, and an increase in tubular expression of osteopontin. Hyperuricemic rats also exhibited an increase in juxtaglomerular renin and a decrease in macula densa neuronal NO synthase. Both the renal injury and hypertension were reduced by treatment with enalapril or L-arginine. In conclusion, mild hyperuricemia causes hypertension and renal injury in the rat via a crystal-independent mechanism, with stimulation of the renin-angiotensin system and inhibition of neuronal NO synthase.
Article
Although hyperuricemia has long been associated with renal disease, uric acid has not been considered as a true mediator of progression of renal disease. The observation that hyperuricemia commonly is associated with other risk factors of cardiovascular and renal disease, especially hypertension, has made it difficult to dissect the effect of uric acid itself. However, recent epidemiologic evidence suggests a significant and independent association between the level of serum uric acid and renal disease progression with beneficial effect of decreasing uric acid levels. Furthermore, our experimental data using hyperuricemic animals and cultured cells have provided robust evidence regarding the role of uric acid on progression of renal disease. Hyperuricemia increased systemic blood pressure, proteinuria, renal dysfunction, vascular disease, and progressive renal scarring in rats. Recent data also suggest hyperuricemia may be one of the key and previously unknown mechanisms for the activation of the renin-angiotensin and cyclooxygenase-2 (COX-2) systems in progressive renal disease. Although we must be cautious in the interpretation of animal models to human disease, these studies provide a mechanism to explain epidemiologic data that show uric acid is an independent risk factor for renal progression. Although there is no concrete evidence yet that uric acid bears a causal or reversible relationship to progressive renal disease in humans, it is time to reevaluate the implication of hyperuricemia as an important player for progression of renal disease and to try to find safe and reasonable therapeutic modalities in individual patients based on their clinical data, medication history, and the presence of cardiovascular complications.
Article
To assess the safety, pharmacokinetics, and pharmacodynamics of febuxostat in subjects with normal renal function or renal impairment, febuxostat (80 mg/d) was orally administered for 7 days to subjects with normal renal function (n = 11, CLcr >80 mL/min/1.73 m) or to subjects with mild (n = 6, CLcr 50-80 mL/min/1.73 m), moderate (n = 7, CLcr 30-49 mL/min/1.73 m), or severe renal impairment (n = 7, CLcr 10-29 mL/min/1.73 m). The pharmacokinetics of febuxostat and its active quantifiable metabolites 67M-1, 67M-2, and 67M-4 as well as the pharmacodynamics of uric acid, xanthine, and hypoxanthine were determined in plasma (or serum) and urine. Febuxostat was safe and well tolerated. Regression analyses indicated that febuxostat tmax and Cmax,u values were not affected by CLcr. However, for AUC24,u, CLu/F, and t1/2z, regression analyses indicated a statistically significant relationship with CLcr. With the exception of 67M-1 Cmax, regression analyses for 67M-2 and 67M-4 Cmax, and for AUC24 for all 3 metabolites indicated a statistically significant linear relationship with CLcr. Irrespective of renal function group, the mean serum uric acid concentrations decreased by 55% to 64% by day 7. Although plasma exposure to febuxostat and its metabolites was generally higher in subjects with increasing degrees of renal impairment, the percentages of decrease in serum uric acid were comparable regardless of the renal function group. A once-daily 80-mg dose of febuxostat appears to be safe and well tolerated in different renal function groups and does not appear to require any dose adjustment based on differences in renal function.
Article
The purine analogue, allopurinol, has been in clinical use for more than 30 years as an inhibitor of xanthine oxidase (XO) in the treatment of hyperuricemia and gout. As consequences of structural similarities to purine compounds, however, allopurinol, its major active product, oxypurinol, and their respective metabolites inhibit other enzymes involved in purine and pyrimidine metabolism. Febuxostat (TEI-6720, TMX-67) is a potent, non-purine inhibitor of XO, currently under clinical evaluation for the treatment of hyperuricemia and gout. In this study, we investigated the effects of febuxostat on several enzymes in purine and pyrimidine metabolism and characterized the mechanism of febuxostat inhibition of XO activity. Febuxostat displayed potent mixed-type inhibition of the activity of purified bovine milk XO, with Ki and Ki' values of 0.6 and 3.1 nM respectively, indicating inhibition of both the oxidized and reduced forms of XO. In contrast, at concentrations up to 100 muM, febuxostat had no significant effects on the activities of the following enzymes of purine and pyrimidine metabolism: guanine deaminase, hypoxanthine-guanine phosphoribosyltransferase, purine nucleoside phosphorylase, orotate phosphoribosyltransferase and orotidine-5'-monophosphate decarboxylase. These results demonstrate that febuxostat is a potent non-purine, selective inhibitor of XO, and could be useful for the treatment of hyperuricemia and gout.
Article
Gout is one of the most common rheumatic diseases worldwide. Colchicine is regarded as beneficial in the treatment of acute gout, but has a high frequency of gastrointestinal adverse events. To evaluate the efficacy and safety of colchicine for relief of the signs and symptoms of acute gouty arthritis, compared to placebo and other treatment interventions. We searched the following electronic databases to March 2006: Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2006), MEDLINE (from 1966), EMBASE (from 1980), CINAHL (from 1982), AMED (from 1985), Web of Science (from 1945) and Current Controlled Trials. Published randomised controlled trials (RCTs) and controlled clinical trials evaluating symptom relief and adverse outcomes of colchicine therapy in acute gout were considered for this review. Two reviewers independently screened search results for inclusion, collected the data in a standardized form and assessed the methodological quality of the trial using validated criteria. Results for continuous outcome measures were expressed as weighted mean differences. Dichotomous outcome measures were pooled using relative risk. The number needed to treat was calculated for significant outcomes. One RCT (N=43) comparing colchicine to placebo for the treatment of acute gout was included in this review. The results favour the use of colchicine over placebo with an absolute reduction of 34% for pain and a 30% reduction in clinical symptoms such as tenderness on palpation, swelling, redness, and pain. The number needed to treat (NNT) with colchicine versus placebo to reduce pain was 3 and the NNT to reduce clinical symptoms was 2. All participants treated with colchicine experienced gastrointestinal side effects (diarrhea and/or vomiting) and the number needed to harm (NNH) with colchicine versus placebo was 1. No studies comparing colchicine to NSAIDs or other treatments such as corticosteroids or ACTH were identified. Colchicine is an effective treatment for the reduction of pain and clinical symptoms in patients experiencing acute attacks of gout, although in the regimen studied its low benefit to toxicity ratio limits its usefulness. It should be used as a second line therapy when NSAIDs or corticosteroids are contraindicated or ineffective. More evidence is needed to compare the efficacy of colchicine to that of NSAIDs or corticosteroids, the current first line therapy for acute gout.
Article
In recent years significant progress has been made in identifying and quantitating physico-chemical processes involved in urinary stone formation. The ability of urine to inhibit calcium oxalate crystallization is an important mechanism against stone formation. Dietary factors appear to affect the ability of urine to inhibit calcium oxalate crystallization. These factors encouraged us to study the effects of lemon and orange juices on calcium oxalate crystallization in vitro. The nucleation and aggregation of calcium oxalate monohydrate crystals were studied using turbidimetric 30-min time course measurements of optic density at 620 nm after mixing solutions containing calcium chloride and sodium oxalate at 37 degrees C, pH 5.7. The formation of crystals is induced by the addition of the oxalate and calcium solution. The effects on calcium oxalate crystal growth of trisodium citrate, lemon and orange juices were examined. The effects of lemon and orange juices were evaluated by the addition of 50 ml of juices. The optical density is measured at physiological conditions. The maximum increase of optic density with time, termed SN, reflects maximum rate of formation of new particles. After an equilibrium has been reached, a progressive decrease of optic density with time is observed. Rate of aggregation, SA, is derived from the maximum decrease in optic density. Among the modifiers studied, citrate decreased both SN and SA (P<0.001). Lemon juice was also found to inhibit the rate of crystal nucleation and aggregation. But orange juice did not have any effect on the calcium oxalate crystallization (P>0.05). These results show that effective prevention of urinary stone formation should aim at restoring the urine's ability to inhibit calcium oxalate crystallization and more emphasis should be given to dietary measures.