598 results on '"Uricosuric"'
Search Results
2. Comparative efficacy and safety of uricosuric agents in the treatment of gout or hyperuricemia: a systematic review and network meta-analysis.
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Li, Ya-Jia, Chen, Li-Rong, Yang, Zhong-Lei, Wang, Ping, Jiang, Fang-Fang, Guo, Yu, Qian, Kai, Yang, Mei, Yin, Sun-Jun, and He, Gong-Hao
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GOUT , *HYPERURICEMIA , *URIC acid - Abstract
Objectives: The current world witnesses a greatly increased prevalence and incidence of hyperuricemia and gout with unfortunately the comparative efficacy and safety of present available uricosuric agents remaining uncertain. We herein aimed to investigate the most appropriate uricosuric agent for gout or hyperuricemia patients. Method: PubMed, Embase, Cochrane Library databases, and ClinicalTrials.gov from inception to 2 July 2022 were searched to retrieve eligible studies assessing efficacy and safety of uricosuric drugs in hyperuricemia or gout patients. Network meta-analysis was carried out using the Stata 16.0 software. Results: Twelve randomized controlled trials comprising 1851 patients were eventually included. Network meta-analysis showed that dotinurad 4 mg once daily, verinurad, dotinurad 2 mg once daily, dotinurad 1 mg once daily, and benzbromarone were the top 5 effective treatments to achieve target serum uric acid. Furthermore, dotinurad 4 mg once daily was more effective at achieving urate-lowering targets (RR of dotinurad 4 mg once daily vs. probenecid: 1.68, 95% CI [1.13; 2.50]) and safer (RR of probenecid vs. dotinurad 4 mg once daily: 1.77, 95% CI [0.69; 4.56]) than probenecid. Conclusions: This network meta-analysis demonstrated an important absolute benefit of dotinurad 4 mg once daily to achieve target serum uric acid and low risk of adverse events for drug treatment of gout or hyperuricemia patients. Additionally, verinurad might be used as an alternative uricosuric therapeutic option to dotinurad. These findings provided further comprehensive insight into the treatment value of current uricosuric agents for gout or hyperuricemia. Key Points 1. This is the first systematic review and network meta-analysis examining the efficacy and safety of currently available uricosuric agents in gout or hyperuricemia patients. 2. Recommended doses of dotinurad 4mg once daily used for the treatment of gout or hyperuricemia patients can significantly decrease serum uric acid levels. 3. The present findings will provide further comprehensive insight into the treatment value of certain uricosuric agents for gout or hyperuricemia. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Extracts of Andrographis paniculata (Burm.f.) Nees Leaves Exert Anti-Gout Effects by Lowering Uric Acid Levels and Reducing Monosodium Urate Crystal-Induced Inflammation.
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Rahmi, Eldiza Puji, Kumolosasi, Endang, Jalil, Juriyati, Buang, Fhataheya, and Jamal, Jamia Azdina
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ANDROGRAPHIS paniculata ,URIC acid ,HIGH performance liquid chromatography ,TUMOR necrosis factors ,WESTERN immunoblotting - Abstract
Andrographis paniculata (Burm.f.) Nees has been found to have anti-inflammatory and immunostimulatory effects. This study was to investigate antihyperuricemic and anti-inflammatory effects of A. paniculata leaf extracts. Andrographolide, 14-deoxy-11,12-didehydroandrographolide, and neoandrographolide were quantified in 80% ethanol (EtOH80) and water extracts using High Performance Liquid Chromatography (HPLC) analysis. Antihyperuricemic activity was evaluated using a spectrophotometric in vitro inhibitory xanthine oxidase (XO) assay. The most active extract and andrographolide were further investigated in a hyperuricemic rat model induced by potassium oxonate to determine serum uric acid levels, liver XO activity, followed by Western blot analysis for renal urate transporter URAT1, GLUT9, and OAT1 to investigate the excretion of uric acid via kidney. Anti-inflammatory activity was assessed by in vitro interleukin assay for interleukin (IL-1α, IL-1β, IL-6, IL-8), and tumor necrosis factor (TNF-α) in monosodium urate (MSU) crystal-induced human fibroblast-like synoviocyte (HFLS) cells using ELISA-kits, followed by Western blot analysis for the expression of MyD88, NLRP3, NF-κB p65, and caspase-1 proteins to investigate the inflammation pathway. In vivo assay of the most active extract and andrographolide were performed based on the swelling rate and inhibition of pro-inflammatory mediator release from synovial fluid of a rat knee joint induced by MSU crystals. The results showed that the EtOH80 extract had a greater amount of andrographolide (11.34% w/w) than the water extract (1.38% w/w). In the XO inhibitory activity, none of the samples exhibited greater than 50% inhibition. However, in a rat model, EtOH80 extract (200 mg/kg/day) and andrographolide (30 mg/kg/day) decreased serum uric acid levels and reduced liver XO activity, reduced the protein expression levels of URAT1 and GLUT9, and restored the decrease in OAT1 levels. In the in vitro anti-inflammatory study, EtOH80 extract and andrographolide significantly decreased production of IL-1α, IL-1β, IL-6, and TNF-α, as well as inhibited the synthesis of MyD88, NLRP3, NF-κB p65, and caspase-1 in a concentration-dependent manner, almost comparable to dexamethasone. The EtOH80 extract (200 mg/kg/day) and andrographolide (30 mg/kg) significantly decreased swelling rate and IL-1α, IL-1β, IL-6, and TNF-α in the synovial fluid of rat models in a time-dependent manner, comparable to indomethacin (3 mg/kg/day). In conclusion, the findings show that EtOH80 extract has a substantial anti-gout effect by lowering uric acid levels and suppressing pro-inflammatory mediator production due to the andrographolide content, that might be beneficial in the treatment of gouty-inflammation. [ABSTRACT FROM AUTHOR]
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- 2022
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4. A historical journey of searching for uricosuric drugs.
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Jansen, Tim LThA, Tanja, Giesen, and Matthijs, Janssen
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WEIGHT loss , *GOUT , *MEDICAL personnel , *DRUGS , *NLRP3 protein , *EXPERIMENTAL arthritis - Abstract
Gout is an auto-inflammatory disease driven by urate deposits with a second co-stimulatory factor evoking an (peri)arthritic fulminant inflammation often with a debute at night; inflammatory signals are enhanced via a NLRP3 pathway. In gout patients, urate metabolism has had a positive balance for a time period of weeks to years before the arthritic syndrome or tophaecous disease becomes manifest. This may be due to katabolism or weight loss, enhanced dietary affluence, and overweight resulting in increased serum urate levels. Also, a decreased urate excretion results in proneness to hyperuricaemia and clinical gout. Pharmacotherapeutically, a negative urate balance should be the aim of clinicians and then the rational choice of treatment with uricosurics seems quite logical and promising, but has not had a thorough attention of pharma, researchers nor of clinicians, though most gout patients were and still are low excretors. Here, an overview on the 70-year-old journey mankind has made in a search for uricosurics resulting so far in only 1 registered uricosuric per continent. [ABSTRACT FROM AUTHOR]
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- 2022
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5. Extracts of Andrographis paniculata (Burm.f.) Nees Leaves Exert Anti-Gout Effects by Lowering Uric Acid Levels and Reducing Monosodium Urate Crystal-Induced Inflammation
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Eldiza Puji Rahmi, Endang Kumolosasi, Juriyati Jalil, Fhataheya Buang, and Jamia Azdina Jamal
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andrographolide ,xanthine oxidase ,uricosuric ,pro-inflammatory cytokines ,MyD88 ,NLRP3 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Andrographis paniculata (Burm.f.) Nees has been found to have anti-inflammatory and immunostimulatory effects. This study was to investigate antihyperuricemic and anti-inflammatory effects of A. paniculata leaf extracts. Andrographolide, 14-deoxy-11,12-didehydroandrographolide, and neoandrographolide were quantified in 80% ethanol (EtOH80) and water extracts using High Performance Liquid Chromatography (HPLC) analysis. Antihyperuricemic activity was evaluated using a spectrophotometric in vitro inhibitory xanthine oxidase (XO) assay. The most active extract and andrographolide were further investigated in a hyperuricemic rat model induced by potassium oxonate to determine serum uric acid levels, liver XO activity, followed by Western blot analysis for renal urate transporter URAT1, GLUT9, and OAT1 to investigate the excretion of uric acid via kidney. Anti-inflammatory activity was assessed by in vitro interleukin assay for interleukin (IL-1α, IL-1β, IL-6, IL-8), and tumor necrosis factor (TNF-α) in monosodium urate (MSU) crystal-induced human fibroblast-like synoviocyte (HFLS) cells using ELISA-kits, followed by Western blot analysis for the expression of MyD88, NLRP3, NF-κB p65, and caspase-1 proteins to investigate the inflammation pathway. In vivo assay of the most active extract and andrographolide were performed based on the swelling rate and inhibition of pro-inflammatory mediator release from synovial fluid of a rat knee joint induced by MSU crystals. The results showed that the EtOH80 extract had a greater amount of andrographolide (11.34% w/w) than the water extract (1.38% w/w). In the XO inhibitory activity, none of the samples exhibited greater than 50% inhibition. However, in a rat model, EtOH80 extract (200 mg/kg/day) and andrographolide (30 mg/kg/day) decreased serum uric acid levels and reduced liver XO activity, reduced the protein expression levels of URAT1 and GLUT9, and restored the decrease in OAT1 levels. In the in vitro anti-inflammatory study, EtOH80 extract and andrographolide significantly decreased production of IL-1α, IL-1β, IL-6, and TNF-α, as well as inhibited the synthesis of MyD88, NLRP3, NF-κB p65, and caspase-1 in a concentration-dependent manner, almost comparable to dexamethasone. The EtOH80 extract (200 mg/kg/day) and andrographolide (30 mg/kg) significantly decreased swelling rate and IL-1α, IL-1β, IL-6, and TNF-α in the synovial fluid of rat models in a time-dependent manner, comparable to indomethacin (3 mg/kg/day). In conclusion, the findings show that EtOH80 extract has a substantial anti-gout effect by lowering uric acid levels and suppressing pro-inflammatory mediator production due to the andrographolide content, that might be beneficial in the treatment of gouty-inflammation.
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- 2022
- Full Text
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6. Anti-Hyperuricemic and Uricosuric Potential of Berberis vulgaris in Oxonate-Induced Hyperuricemic Rats.
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Bilal, Muhammad, Ahmad, Saeed, Rehman, Tayyeba, Ghauri, Aymen Owais, Khalid, Sana, Abbasi, Waheed Mumtaz, and Zakki, Shahbaz Ahmad
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BARBERRIES , *XANTHINE oxidase , *URIC acid , *RATS , *METABOLIC disorders - Abstract
Hyperuricemia is a metabolic disorder with characteristic elevated serum uric acid. Recently, several plant-based medicines are being used for the treatment of hyperuricemia. The study aimed to find the hypouricemic potential of Berberis vulgaris in in-vitro and in-vivo study models. In in-vitro studies, xanthine oxidase inhibition assay was performed to evaluate IC50 value and capsule absorbance of the drug, respectively. For in-vivo experiment, the study comprised 15 groups of rats. In-vitro results revealed that significant xanthine oxidase inhibition was shown by Berberis vulgaris with an IC50 value of 272.73±.3 μg/mL. Similarly, oral administration of Berberis vulgaris with dosages of 250 and 500 mg/kg decreased serum and liver uric acid levels significantly in a dose- and time-dependent manner in oxonate-induced hyperuricemic rats. Furthermore, 3-day and 7-day administration of Berberis vulgaris showed more potential compared to 1-day administrations. The present study indicated marked hypouricemic effects of Berberis vulgaris in rats. Due to caveat of the small sample size, a firm assumption of the hypouricemic effect of Berberis vulgaris cannot be made. However, extensive study is needed to find out the exact molecular mechanism involved and to translate its effects into clinical trials for the further validation of the results. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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7. Dotinurad versus benzbromarone in Japanese hyperuricemic patient with or without gout: a randomized, double-blind, parallel-group, phase 3 study.
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Hosoya, Tatsuo, Sano, Takafumi, Sasaki, Tomomitsu, Fushimi, Masahiko, and Ohashi, Tetsuo
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URATES , *GOUT , *DRUG side effects , *URIC acid - Abstract
Background: Dotinurad is a novel selective urate reabsorption inhibitor that reduces serum urate levels in hyperuricemic patients with or without gout by selectively inhibiting urate transporter 1. This study was conducted to compare the efficacy and safety of dotinurad with those of benzbromarone. Methods: In this 14-week, randomized, multicenter, double-blind, parallel-group, dose escalation, benzbromarone-controlled, phase 3 study, hyperuricemic patients with or without gout were randomized to two groups that received either dotinurad 2 mg or benzbromarone 50 mg. Dotinurad or benzbromarone was administered once a day for 14 weeks. The primary endpoint was the percent change in serum uric acid level from the baseline to the final visit. Results: A total of 201 Japanese hyperuricemic patients with or without gout (dotinurad: 102, benzbromarone: 99) received at least one dose of the study drug. The mean percent change in serum uric acid level from the baseline to the final visit in the dotinurad and benzbromarone groups was 45.9% and 43.8%, respectively. Non-inferiority of dotinurad 2 mg to benzbromarone 50 mg in lowering serum uric acid was verified by the predefined non-inferiority margin (95% CI − 1.27 to 5.37%). The incidence of adverse events and adverse drug reactions was comparable between the two groups. Conclusion: Dotinurad 2 mg was verified to have a non-inferior serum uric acid lowering effect compared with benzbromarone 50 mg, in Japanese hyperuricemic patients with or without gout. ClinicalTrials.gov Identifier: NCT03100318. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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8. Molecular Biological and Clinical Understanding of the Pathophysiology and Treatments of Hyperuricemia and Its Association with Metabolic Syndrome, Cardiovascular Diseases and Chronic Kidney Disease
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Hidekatsu Yanai, Hiroki Adachi, Mariko Hakoshima, and Hisayuki Katsuyama
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cardiovascular diseases ,chronic kidney disease ,hyperuricemia ,uricosuric ,xanthin oxidase ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Uric acid (UA) is synthesized mainly in the liver, intestines, and vascular endothelium as the end product of an exogenous purine from food and endogenously from damaged, dying, and dead cells. The kidney plays a dominant role in UA excretion, and the kidney excretes approximately 70% of daily produced UA; the remaining 30% of UA is excreted from the intestine. When UA production exceeds UA excretion, hyperuricemia occurs. Hyperuricemia is significantly associated with the development and severity of the metabolic syndrome. The increased urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) expression, and glycolytic disturbances due to insulin resistance may be associated with the development of hyperuricemia in metabolic syndrome. Hyperuricemia was previously thought to be simply the cause of gout and gouty arthritis. Further, the hyperuricemia observed in patients with renal diseases was considered to be caused by UA underexcretion due to renal failure, and was not considered as an aggressive treatment target. The evidences obtained by basic science suggests a pathogenic role of hyperuricemia in the development of chronic kidney disease (CKD) and cardiovascular diseases (CVD), by inducing inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells, and activation of the renin-angiotensin system. Further, clinical evidences suggest that hyperuricemia is associated with the development of CVD and CKD. Further, accumulated data suggested that the UA-lowering treatments slower the progression of such diseases.
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- 2021
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9. Effects of Trachyspermum ammi L. (Apiaceae) on serum, urine and hepatic uric acid levels in oxonate-induced rats and in vitro xanthine oxidase inhibition assay.
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Bilal, Muhammad, Ahmad, Saeed, Rehman, Tayyeba, Abbasi, Waheed Mumtaz, Ghauri, Aymen Owais, and Arshad, Muhammad Adeel
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UMBELLIFERAE ,XANTHINE oxidase ,LABORATORY rats ,ALLOPURINOL ,FLAVONOIDS ,URIC acid ,TRADITIONAL medicine - Abstract
Invention of many of the new synthetic drugs is based on the knowledge of traditional system of medicine. Trachyspermum ammi L. (Apiaceae) is traditionally used to treat gout and rheumatism. The study was comprised of in vitro determination of total polyphenolic and flavonoid content, xanthine oxidase inhibition assay and in vivo hypouricemic activity of T. ammi in oxonate induced hyperuricemic rat model. In vivo activity consisted of 11 groups of rats each having 6 animals. All the groups except normal control were treated with potassium oxonate. Allopurinol, T. ammi 250 and 500 mg/kg were administered for one, three and seven days (single dose/day) in different study groups (3x3=9 groups). T. ammi has total phenolic content of 145.17 ± 1.70 gallic acid equivalents/g, and the total flavonoid content of 35 ± 2.20 rutin equivalents/g. T. ammi significantly inhibited xanthine oxidase in vitro (IC
50 = 68.6±0.2 µg/mL). Oral administration of T. ammi significantly reduced serum and hepatic urate levels in hyperuricemic rats in a time-dependent manner. Furthermore, fractional excretion of uric acid was increased. The results suggested that hypouricemic effects of T. ammi could be explained, at least partly, by inhibiting xanthine oxidase in vitro and due to presence of phenolic and flavonoid contents. [ABSTRACT FROM AUTHOR]- Published
- 2019
10. Xanthine Oxidoreductase Inhibitors Suppress the Onset of Exercise-Induced AKI in High HPRT Activity Urat1-Uox Double Knockout Mice
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Shigeru Shibata, Koji Matsumoto, Naoko H. Tomioka, Takuji Hosoya, Shunya Uchida, and Makoto Hosoyamada
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Kidney ,Uricosuric ,business.industry ,Urinary system ,Acute kidney injury ,Allopurinol ,Inflammasome ,General Medicine ,Pharmacology ,medicine.disease ,Topiroxostat ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Nephrology ,Medicine ,business ,Blood urea nitrogen ,medicine.drug - Abstract
Background Hereditary renal hypouricemia type-1 (RHUC1) is caused by URAT1/SLC22A12 dysfunction, resulting in urolithiasis and exercise-induced acute kidney injury (EIAKI). Because, however, there is no useful experimental RHUC1 animal model, the precise pathophysiological mechanisms underlying EIAKI have yet to be elucidated. We established a high HPRT activity Urat1-Uox double knockout (DKO) mouse as a novel RHUC1 animal model for investigating the cause of EIAKI as well as the potential therapeutic effect of xanthine oxidoreductase inhibitors (XOIs). Methods The novel Urat1-Uox DKO mice were used in a forced swimming test as loading exercise to explore the onset mechanism of EIAKI and evaluate related purine metabolism and renal injury parameters. Results Urat1-Uox DKO mice had uricosuric effects and elevated levels of plasma creatinine (Cr) and blood urea nitrogen (BUN) as renal injury markers, and decreased Cr clearance (CLCr) observed in a forced swimming test. In addition, Urat1-Uox DKO mice had increased NLRP3 inflammasome activity and downregulated levels of Na+-K+-ATPase (NKA) protein in the kidney, as Western blot analysis showed. Finally, we demonstrated that topiroxostat and allopurinol, XOIs, improved renal injury and functional parameters of EIAKI. Conclusions Urat1-Uox DKO mice are a useful experimental animal model for human RHUC1. The pathogenic mechanism of EIAKI was found to be due to increased levels of IL-1β via NLRP3 inflammasome signaling and NKA dysfunction associated with excessive urinary UA excretion. In addition, XOIs appear to be a promising therapeutic agent for the treatment of EIAKI.
- Published
- 2022
11. International position paper on the appropriate use of uricosurics with the introduction of lesinurad.
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Jansen, Tim L., Perez-Ruiz, Fernando, Tausche, Anne-Kathrin, and Richette, Pascal
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URICOSURIC agents , *GOUT treatment , *URATES , *DRUG therapy , *GOUT - Abstract
Over the last 70 years, pharmacotherapy in gout with urate-lowering drugs has consisted of four drugs only: In 1952, a mild uricosuric probenecid became available, the xanthine oxidase inhibitor Allopurinol in 1964, and the latter became the most frequently used urate-lowering drug worldwide; in the Eurozone, the uricosuric benzbromarone was welcomed in 1977. Only in 2002, the potent non-purine xanthine oxidase inhibitor febuxostat was introduced. In many countries, uricosurics such as probenecid and benzbromarone have not been available up to now, and these days, the new uricosuric lesinurad is the first uricosuric that may be introduced in these countries, which is the reason for describing the position this novel uricosuric deserves in treating gout. Recent literature will be shortly reviewed, and the current proposed position for lesinurad will be given as an aid for clinicians. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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12. Nonsteroidal Anti-inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, and Agents Used in Gout
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Abukhalaf, Imad K., von Deutsch, Daniel A., Ansari, Naser A., Alsharif, Asma, Mozayani, Ashraf, editor, and Raymon, Lionel, editor
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- 2012
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13. Метаболічні фактори, що визначають ефективність гіпоурикемічного лікування подагричного артриту
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O.V. Syniachenko, M.V. Yermolaieva, V.V. Pylypenko, and D.M. Fedorov
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Purine ,medicine.medical_specialty ,Uricosuric ,biology ,business.industry ,medicine.disease ,Gastroenterology ,Gout ,chemistry.chemical_compound ,Adenosine deaminase ,chemistry ,Internal medicine ,biology.protein ,Medicine ,Uric acid ,Febuxostat ,Hyperuricemia ,business ,Xanthine oxidase ,medicine.drug - Abstract
Background. The treatment of some forms of articular pathology with gout remains insufficiently effective, and often it’s impossible to achieve normal indicators of uricemia on the background of uric acid-normalizing medicines. The purpose of the study is to evaluate the effect of the initial parameters of purine metabolism and molecules of medium mass (MMM) of different fractions on the effectiveness of uricodepressive and uricosuric therapy of gouty arthritis. Materials and methods. One hundred five patients with primary gout were examined: 92 % of men and 8 % of women aged 26 to 76 years. Before the beginning of the treatment, the content of purine metabolism factors (uric acid, oxypurinol, adenine, guanine, xanthine, hypoxanthine, xanthine oxidase, xanthine deaminase, adenosine deaminase, 5-nucleotidase, molybdenum, lead), as well as MMM of different fractions (aminopeptide (AF), peptide (PF), nucleotide (NF), chromatographic (ChF)) and integral medium molecular index (MMI) were studied in the blood serum. A spectrophotometer SF46, Olympus-AU640 bioanalyzer and an atomic absorption spectrometer with SolAAr-Mk2-MOZe electrographitic atomizer were used. The efficacy of treatment was assessed after 3–5 weeks. Results. In 27 % of cases, a slight improvement was observed, in 68 % — an improvement, in 8 % — a significant improvement. Primary gout occurs with disturbances in the metabolism of uric acid, oxypurinol, purine bases, purine metabolism enzymes and purine-associated microelements. The integral changes of them depend on the type of the joint syndrome, the presence of peripheral and bone tophi, determine bone-destructive articular injuries, while the predictive factor for the severity of arthropathy is considered to be the high level of purine bases in the blood. In cases of gout, the concentration of AF, PF, NF, ChF increases, as well as MMI. Meanwhile, the AF content is closely related to the severity of the joint syndrome, it determines the degree of joint space narrowing and subchondral sclerosis, the development of bone erosions and meniscus changes, and the MMM of different fractions correlate with the parameters of purine metabolism. A significant improvement and improvement during the pathogenetic therapy is observed in 3/4 of patients that is closely related to the form of arthritis, the presence of tophi and intraarticular Hoffa’s bodies, as well as the type of hyperuricemia, depends on the use of febuxostat, statins and fibrates, the state of purine metabolism, levels of MMM, NF and ChF fractions. Conclusions. The studied metabolic factors are not only involved in the pathogenesis of gouty arthritis, but also have an impact on the efficacy of uric acid-normalizing drugs.
- Published
- 2021
14. The Stiff Joint: Comparative Evaluation of Monotherapy and Combination Therapy With Urate Lowering Agents in Managing Acute Gout.
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Okobi OE, Oletu H, Chukwuedozie-Echeazu AB, Keke VC, Nwachukwu OB, Akunne HS, Ekpemiro CU, Oranika US, Akueme NT, Akanle OE, Ogbuagu BC, and Mbah LA
- Abstract
Gout, an extremely painful form of arthritis, is triggered by the innate immune system's response to the accumulation of monosodium urate crystals in specific joints and surrounding tissues. This condition is characterized by recurring episodes of excruciating arthritis flares, interspersed with periods of disease quiescence. Over time, gout can result in disability, tophi formation, and severe pain. The treatment of gout is centered around two main objectives: alleviating inflammation and pain during acute gout attacks and long-term management to reduce serum urate levels and mitigate the risk of future attacks. Addressing inflammation and pain during acute attacks is often complicated by various factors, including underlying health conditions commonly associated with gout, such as hypertension, chronic kidney disease, cardiovascular disease, and diabetes mellitus. Moreover, gout patients are frequently older and have multiple coexisting health issues, necessitating complex medication regimens. Given the rising prevalence of gout and its associated comorbidities, there's a growing demand for improved treatment options. While existing treatments effectively manage gout in some patients, a significant portion, particularly those with comorbidities, face contraindications to these treatments and require alternative approaches. Innovative medications are required to enhance gout treatment, especially for individuals with concurrent health conditions. These considerations underscore the importance of reviewing both monotherapy and combination therapy approaches for acute gout treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Okobi et al.)
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- 2023
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15. Individualized treatment strategies for hyperuricemia informed by a semi-mechanistic exposure-response model of uric acid dynamics.
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Aksenov, Sergey, Peck, Carl C., Eriksson, Ulf G., and Stanski, Donald R.
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HYPERURICEMIA , *INDIVIDUALIZED medicine , *URIC acid , *DRUG therapy , *KIDNEY physiology , *GLOMERULAR filtration rate , *XANTHINE oxidase , *THERAPEUTICS - Abstract
To provide insight into pharmacological treatment of hyperuricemia we developed a semi-mechanistic, dynamical model of uric acid (UA) disposition in human. Our model represents the hyperuricemic state in terms of production of UA (rate, PUA), its renal filtration (glomerular filtration rate, GFR) and proximal tubular reabsorption (fractional excretion coefficient, FE). Model parameters were estimated using data from 9 Phase I studies of xanthine oxidase inhibitors (XOI) allopurinol and febuxostat and a novel uricosuric, the selective UA reabsorption inhibitor lesinurad, approved for use in combination with a XOI. The model was qualified for prediction of the effect of patients' GFR and FE on concentration of UA in serum (sUA) and UA excretion in urine and their response to drug treatment, using data from 2 Phase I and 4 Phase III studies of lesinurad. Percent reduction in sUA from baseline by a XOI is predicted to be independent of GFR, FE or PUA. Uricosurics are more effective in underexcreters of UA or patients with normal GFR. Coadministration of a XOI and an uricosuric agent should be considered for patients with high sUA first in the treatment algorithm of gout before uptitration of XOI. The XOI dose in combination with a uricosuric can be reduced compared to XOI alone for the same target sUA to the degree dependent on patient's GFR and FE. This exposure-response model of UA can be used to rationally select the best drug treatment option to lower elevated sUA in gout patients under differing pathophysiological situations. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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16. Novel uricosurics.
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Bardin, Thomas and Richette, Pascal
- Subjects
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URICOSURIC agents , *THIAZOLES , *ALLOPURINOL , *COMBINATION drug therapy , *GOUT , *URIC acid , *SYSTEMATIC reviews , *DISEASE management , *MEMBRANE transport proteins , *THERAPEUTICS - Abstract
Objective. According to recent guidelines, the mainstay of urate-lowering therapies remains xanthine oxidase inhibition. However, some patients with gout show failure to achieve the predefined target of 5-6 mg/dl with xanthine oxidase inhibitors alone, so alternative drugs are needed. The aim of this study was to review studies of novel drugs targeting uric acid transporter 1 (URAT1) and/or other urate transporters for the management of gout. Methods. MeSH terms were used to identify phase 2/3 trials assessing the efficacy of novel uricosurics. A narrative review of novel drugs targeting URAT1 and/or other urate transporters for the management of gout is provided. Results. Lesinurad is a recently approved uricosuric that inhibits URAT1 and the organic ion transporter organic anion transporter 4 (OAT4). Phase 3 trials showed that lesinurad, combined with allopurinol or febuxostat, is a potent urate-lowering therapeutic with an acceptable safety profile. Arhalofenate, another emerging uricosuric, also interacts with URAT1 and organic anion transporter 4. Phase 2 trials suggested that it can both lower serum UA levels and reduce the risk of flares. Conclusions. New drugs inhibiting URAT1 should cover the unmet need for patients with failure to respond or with contraindications to xanthine oxidase inhibitors. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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17. Development and Validation of a Novel Stability Indicating UV-Spectrophotometric Method for Estimation of Febuxostat in Bulk and Pharmaceutical Formulation (Tablets).
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Kaur, Manpreet, Bhardwaj, Pooja, Kaur, Baldeep, Sharma, Amit, Kaur, Charanjit, and Kumar, Rajesh
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ULTRAVIOLET spectrophotometry , *DOSAGE forms of drugs - Abstract
Introduction: The present research work involves the development of a simple, economic, accurate, quick and reproducible UV spectrophotometric method for the estimation of Febuxostat in bulk as well as its pharmaceutical formulation i.e. tablets. Materials and Methods: Phosphate buffer pH 6.8 was used for the preparation of stock solution. Different solutions of drug were prepared by diluting the stock solution with the same buffer. Results: Febuxostat was estimated at UV maxima of 312 nm in pH 6.8 phosphate buffer using UV-Visible double beam spectrophotometer. The drug concentration was found to obey Beer's law over a concentration range of 1-10 μg/ml with line equation y = 0.078x+0.062 and correlation coefficient of 0.999. Results obtained were validated statistically and by recovery study method. Conclusion: The result of analysis was validated according to ICH guidelines and found that the proposed method can be used for quality control of pharmaceutical formulations and routine laboratory analysis. [ABSTRACT FROM AUTHOR]
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- 2018
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18. CDER167, a dual inhibitor of URAT1 and GLUT9, is a novel and potent uricosuric candidate for the treatment of hyperuricemia
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Yanyu Chen, Ying Cao, Yu Jiang, Yang Yang, Cuiting Lin, Lu Li, Jianxin Pang, Pingzheng Zhou, Jia-Yin Guo, Yongmei Li, Yuanxin Tian, Ting Wu, Zean Zhao, and Qunsheng Lan
- Subjects
0301 basic medicine ,Pharmacology ,Uricosuric ,biology ,Chemistry ,hERG ,Glucose transporter ,General Medicine ,medicine.disease ,Article ,Bioavailability ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Pharmacokinetics ,In vivo ,030220 oncology & carcinogenesis ,medicine ,biology.protein ,Uric acid ,Pharmacology (medical) ,Hyperuricemia - Abstract
Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of [(14)C]-uric acid in URAT1-expressing HEK293 cells with an IC(50) value of 2.08 ± 0.31 μM, which was similar to that of RDEA3170 (its IC(50) value was 1.47 ± 0.23 μM). Using site-directed mutagenesis, we demonstrated that CDER167 might interact with URAT1 at S35 and F365. In GLUT9-expressing HEK293T cells, CDER167 concentration-dependently inhibited GLUT9 with an IC(50) value of 91.55 ± 15.28 μM, whereas RDEA3170 at 100 μM had no effect on GLUT9. In potassium oxonate-induced hyperuricemic mice, oral administration of CDER167 (10 mg·kg(−1) · d(−1)) for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170 (20 mg·kg(−1) · d(−1)) administered. The animal experiment proved the safety of CDER167. In addition, CDER167 displayed better bioavailability than RDEA3170, better metabolic stability and no hERG toxicity at 100 μM. These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.
- Published
- 2021
19. On the Possible Chemical Justification of the Ethnobotanical Use of Hyptis obtusiflora in Amazonian Ecuador
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Carmen X. Luzuriaga-Quichimbo, José Blanco-Salas, Carlos E. Cerón-Martínez, Milan S. Stanković, and Trinidad Ruiz-Téllez
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Hyptis ,Lamiaceae ,Kichwa ,terpene ,caryophyllene ,xanthine oxidase ,gut ,anti-inflammatory ,uricosuric ,Botany ,QK1-989 - Abstract
In rural areas of Latin America, Hyptis infusions are very popular. Hyptis obtusiflora extends from Mexico throughout Central America to Bolivia and Peru. It has added value in Ecuador where it has been used by different ethnic groups. We aimed to learn about the traditional knowledge of ancient Kichwa cultures about this plant, and to contrast this knowledge with the published information organized in occidental databases. We proposed to use traditional knowledge as a source of innovation for social development. Our specific objectives were to catalogue the uses of H. obtusiflora in the community, to prospect on the bibliography on a possible chemical justification for its medicinal use, to propose new products for development, and to give arguments for biodiversity conservation. An ethnobotanical survey was made and a Prisma 2009 Flow Diagram was then followed for scientific validation. We rescued data that are novel contributions for the ethnobotany at the national level. The catalogued main activity of anti-inflammation can be related to the terpene composition and the inhibition of xanthine oxidase. This opens the possibility of researching the extract of this plant as an alternative to allopurinol or uricosuric drugs. This is a concrete example of an argument for biodiversity conservation.
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- 2018
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20. Natural Products and Extracts as Xantine Oxidase Inhibitors - A Hope for Gout Disease?
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Fatma Sezer Senol Deniz and Ilkay Erdogan Orhan
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Pharmacology ,Purine ,Biological Products ,Xanthine Oxidase ,Uricosuric ,Gout ,Plant Extracts ,Chemistry ,Allopurinol ,Hyperuricemia ,Xanthine ,medicine.disease ,chemistry.chemical_compound ,Biochemistry ,Drug Discovery ,medicine ,Humans ,Uric acid ,Febuxostat ,Enzyme Inhibitors ,Oxidoreductases ,Xanthine oxidase ,medicine.drug - Abstract
Xanthine oxidase (EC 1.17.3.2) (XO) is one of the main enzymatic sources that create reactive oxygen species (ROS) in the living system. It is a dehydrogenase enzyme that performs electron transfer to nicotinamide adenine dinucleotide (NAD+), while oxidizing hypoxanthin, which is an intermediate compound in purine catabolism, first to xanthine and then to uric acid. XO turns into an oxidant enzyme that oxidizes thiol groups under certain stress conditions in the tissue. The last metabolic step, in which hypoxanthin turns into uric acid, is catalyzed by XO. Uric acid, considered a waste product, can cause kidney stones and gouty-type arthritis as it is crystallized, when present in high concentrations. Thus, XO inhibitors are one of the drug classes used against gout, a purine metabolism disease that causes urate crystal storage in the joint and its surroundings caused by hyperuricemia. Urate-lowering therapy includes XO inhibitors that reduce uric acid production as well as uricosuric drugs that increase urea excretion. Current drugs that obstruct uric acid synthesis through XO inhibition are allopurinol, febuxostat, and uricase. However, since the side effects, safety and tolerability problems of some current gout medications still exist, intensive research is ongoing to look for new, effective, and safer XO inhibitors of natural or synthetic origins for the treatment of the disease. In the present review, we aimed to assess in detail XO inhibitory capacities of pure natural compounds along with the extracts from plants and other natural sources via screening Pubmed, Web of Science (WoS), Scopus, and Google Academic. The data pointed out to the fact that natural products, particularly phenolics such as flavonoids (quercetin, apigenin, and scutellarein), tannins (agrimoniin and ellagitannin), chalcones (melanoxethin), triterpenes (ginsenoside Rd and ursolic acid), stilbenes (resveratrol and piceatannol), alkaloids (berberin and palmatin) have a great potential for new XO inhibitors capable of use against gout disease. In addition, not only plants but other biological sources such as microfungi, macrofungi, lichens, insects (silk worms, ants, etc) seem to be the promising sources of novel XO inhibitors.
- Published
- 2021
21. Hypouricemia in type 2 diabetes mellitus without nephropathy: A case control study
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Shruti Mohanty, Bindu Pavani.CH, and Archana A Dharwadkar
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030213 general clinical medicine ,medicine.medical_specialty ,Kidney ,Uricosuric ,Urinary system ,Case-control study ,Type 2 Diabetes Mellitus ,030209 endocrinology & metabolism ,medicine.disease ,Gastroenterology ,Pathophysiology ,Nephropathy ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Internal medicine ,medicine ,Hypouricemia - Abstract
Introduction: Some previous studies and our recent study had shown low serum uric acid (UA) in Diabetic patients compared to Non diabetics and it was suggested that low serum UA levels in Diabetics are probably due to uricosuric effect of urinary Glucose. This study was conducted to have an insight regarding the pathophysiology of low serum UA levels in Diabetics. Materials And Methods:Fasting blood glucose(FBG) , Post lunch blood glucose(PLBG), serum UA and 24 hr urinary excretion were estimated in Type 2 Diabetics without nephropathy (Cases) and in Nondiabetic inpatients(Controls) who got admitted into various Departments of KIMS hospital. The comparison of serum UA and 24hr urinary excretion between cases and controls and correlation between 24 hr urinary excretion, FBG and serum UA in cases was tested using SPSS 19 version. Result: Serum UA Mean is low in Diabetics compared to Non diabetics and this difference is significant whereas 24 hr urinary excretion is significantly higher in Diabetics compared to Nondiabetics. Significant negative association between FBG and serum UA and positive association between 24hr urinary UA and FBG and negative association of 24 hr urinary excretion with serum UA in Diabetics which is nonsignificant. Summary and Conclusions:At high concentrations of FBG there is increase in 24 hr urinary excretion providing an objective evidence to hypothesis that low UA levels in diabetics are probably due to inhibition of UA reabsorption in the proximal convoluted tubule of kidney by glucose. Keywords: Type 2 Diabetics, Fasting blood glucose, serum UA, 24 hr urinary excretion.
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- 2020
22. Lesinurad: what the nephrologist should know.
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Sanchez-Niño, Maria Dolores, Binbin Zheng-Lin, Valiño-Rivas, Lara, Sanz, Ana Belen, Ramos, Adrian Mario, Luño, Jose, Goicoechea, Marian, and Ortiz, Alberto
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- *
NEPHROTOXICOLOGY , *URICOSURIC agents , *XANTHINE oxidase - Abstract
Lesinurad is an oral inhibitor of the monocarboxylic/urate transporter URAT1 encoded by the SLC22A12 gene. Market authorization was granted in February 2016 in Europe and December 2015 in the USA. As a potentially nephrotoxic uricosuric drug acting on the kidney, nephrologists should become familiar with its indications and safety profile. The approved indication is treatment of gout in combination with a xanthine oxidase (XO) inhibitor in adult patients who have not achieved target serum uric acid levels with an XO inhibitor alone. It is not indicated for asymptomatic hyperuricaemia or for patients with estimated creatinine clearance <45 mL/min. The only authorized daily dose is 200mg and cannot be exceeded because of the nephrotoxicity risk. Nephrotoxicity is thought to be related to uricosuria. At the 200 mg/day dose, serum creatinine more than doubled in 1.8% of lesinurad patients (versus 0% in placebo) and in 11% of these it was not reversible. In addition, it is subject to a risk management plan given the potential association with cardiovascular events. In randomized clinical trials, the association of lesinurad with either allopurinol or febuxostat achieved a greater reduction in serum uric acid (~1 mg/dL lower) than the XO inhibitors alone, and this allowed the serum uric acid target to be met in a higher proportion of patients, which was the primary endpoint. However, no clinical differences were observed in gout flares or tophi, although these were not the primary endpoints. [ABSTRACT FROM AUTHOR]
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- 2017
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23. Discovery of novel curcumin derivatives targeting xanthine oxidase and urate transporter 1 as anti-hyperuricemic agents.
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Ao, Gui-Zhen, Zhou, Meng-Ze, Li, Yu-Yao, Li, Si-Ning, Wang, Hua-Nian, Wan, Qian-Wen, Li, Huan-Qiu, and Hu, Qing-Hua
- Subjects
- *
XANTHINE oxidase , *CARRIER proteins , *CHEMICAL inhibitors , *CURCUMIN , *URICOSURIC agents - Abstract
A series of curcumin derivatives as potent dual inhibitors of xanthine oxidase (XOD) and urate transporter 1 (URAT1) was discovered as anti-hyperuricemic agents. These compounds proved efficient effects on anti-hyperuricemic activity and uricosuric activity in vivo. More importantly, some of them exhibited proved efficient effects on inhibiting XOD activity and suppressing uptake of uric acid via URAT1 in vitro. Especially, the treatment of 4d was demonstrated to improve uric acid over-production and under-excretion in oxonate-induced hyperuricemic mice through regulating XOD activity and URAT1 expression. Docking study was performed to elucidate the potent XOD inhibition of 4d . Compound 4d may serve as a tool compound for further design of anti-hyperuricemic drugs targeting both XOD and URAT1. [ABSTRACT FROM AUTHOR]
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- 2017
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24. Therapie der Gicht und des akuten Gichtanfalls
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Max Mischkewitz and Rieke Alten
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musculoskeletal diseases ,030203 arthritis & rheumatology ,Gynecology ,medicine.medical_specialty ,Uricosuric ,Nonsteroidal ,Combination therapy ,business.industry ,Allopurinol ,General Medicine ,medicine.disease ,Gout ,03 medical and health sciences ,chemistry.chemical_compound ,Canakinumab ,0302 clinical medicine ,Pegloticase ,chemistry ,medicine ,030212 general & internal medicine ,Febuxostat ,business ,medicine.drug - Abstract
Fur die bestmogliche Behandlung der Gicht ist eine umfangreiche Aufklarung des Patienten uber die Erkrankung und Therapieoptionen sowie systematisches Screening auf Komorbiditaten und eine Lebensstilmodifikation elementar. Beim Management des akuten Gichtanfalls sollte moglichst fruhzeitig mit der medikamentosen Therapie begonnen werden. Hier stehen Colchicin, nichtsteroidale Antirheumatika (NSAR) und Glukokortikoide oral oder intraartikular oder eine Kombinationstherapie zur Verfugung. Canakinumab ist Mittel der Wahl bei unzureichendem Ansprechen auf die Behandlung. Fur bis zu 6 Monate nach einem Anfall ist eine medikamentose Prophylaxe indiziert. Die harnsauresenkende Therapie (ULT) sollte zeitnah nach Indikationsstellung begonnen werden. Allopurinol ist Mittel der 1. Wahl. Liegen schwere Nierenfunktionseinschrankungen, Unvertraglichkeit oder unzureichendes Therapieansprechen vor, kommen alternativ Urikosurika, Febuxostat oder die Kombination aus einem Urikosurikum mit Febuxostat in Frage. Bei unzureichendem Therapieansprechen ist auch die Kombination von Allopurinol und einem Urikosurikum moglich. Zuletzt kann auch Pegloticase off-label eingesetzt werden. Die Therapieadharenz der ULT ist unzureichend. Comprehensive education about the disease and therapeutic options as well as lifestyle modification and screening for comorbidities are essential to treating gout optimally. Early onset of therapy is important in managing acute gout flares. Colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids applied either orally or intraarticularly and combination therapy are regarded first choice in gout flare therapy. In case of insufficient treatment response, Canakinumab is indicated. Gout flare prophylaxis should be implemented for up to six months after the flare. Urate-lowering therapy is recommended to be commenced as early as possible. Whilst allopurinol is the substance of first choice, patients with severe renal impairment, allopurinol intolerance or an insufficient treatment response should be treated with febuxostat, a uricosuric or a combination of both. An additional option for patients responding inadequately to allopurinol is combining allopurinol with a uricosuric. In the last resort Pegloticase can be used off-label. Treatment adherence in ULT is poor.
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- 2020
25. 'Kidney Tea' and Its Bioactive Secondary Metabolites for Treatment of Gout
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Qiong Jin, Ying-Jie He, Yun-Li Zhao, Xiao-Dong Luo, Wen-Jie Sun, Wei-Di Chen, Ya-Ping Liu, and Xing-Wei Yang
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Male ,0106 biological sciences ,China ,Uricosuric ,Gout ,Secondary Metabolism ,Arthritis ,01 natural sciences ,Gout Suppressants ,Mice ,chemistry.chemical_compound ,Benzbromarone ,medicine ,Animals ,Humans ,Hyperuricemia ,Orthosiphon ,Mice, Inbred ICR ,Molecular Structure ,Traditional medicine ,010401 analytical chemistry ,General Chemistry ,Phenolic acid ,medicine.disease ,Uric Acid ,0104 chemical sciences ,chemistry ,Phytochemical ,Uric acid ,Female ,General Agricultural and Biological Sciences ,Drugs, Chinese Herbal ,010606 plant biology & botany - Abstract
Clerodendranthus spicatus, popularly known as "kidney tea" in China, is consumed traditionally as a functional food for treatment of renal inflammation, dysuria, and gout. We evaluated the effects of C. spicatus on gout by assessing activities of antihyperuricemia, anti-gouty arthritis, and analgesia in vivo, and the results indicated that the ethyl acetate fraction shows potential activities. Subsequent phytochemical investigation of this fraction led to the isolation of 32 compounds, consisting of 20 diterpenoids (including the new orthosiphonones E and F), 2 triterpenoids, 6 flavonoids, 2 lignanoids, and 2 phenolic acid derivatives. Pharmacological investigation of the pure compounds in the cellular model of hyperuricemia indicated that 12 compounds could promote the excretion of uric acid at 10 μg/mL, and compounds 3, 4, 5, and 21 had better effects than that of benzbromarone, a famous uricosuric drug. Furthermore, compounds 4, 6, 7, 9, 14, 15, 23, 26, and 31 showed significant anti-gouty arthritis activity in monosodium urate (MSU)-induced joint swelling at the dose of 50 mg/kg, while compounds 4, 5, 7, 9, and 26 exhibited significant inhibition of pain induced by acetic acid. Our findings provided scientific justification to support the traditional application of "kidney tea" for treating gout and suggested its good application prospects in the future.
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- 2020
26. Changing Paradigms in the Management of Gout
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Philip Riches and George Nuki
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medicine.medical_specialty ,Uricosuric ,Gout ,Allopurinol ,Disease ,Urate transport ,Gout Suppressants ,Education ,03 medical and health sciences ,chemistry.chemical_compound ,Febuxostat ,0302 clinical medicine ,Humans ,Medicine ,030212 general & internal medicine ,Intensive care medicine ,business.industry ,Lesinurad ,General Medicine ,medicine.disease ,Uric Acid ,chemistry ,Pegloticase ,business ,medicine.drug - Abstract
The incidence and prevalence of gout have increased, as have comorbid obesity, diabetes mellitus, hypertension, chronic kidney and cardiovascular disease. Gout is now the commonest type of inflammatory arthritis despite availability of safe, effective and potentially ‘curative’ urate-lowering drugs. Modern imaging studies show that gout is a chronic inflammatory crystal deposition disorder even at the first acute attack and they illuminate the need to eliminate urate crystals by continuing reduction of the serum urate below its solubility threshold. Clinical outcomes, adherence to therapy and quality of gout care in primary care and hospital practice can be greatly improved by better use of allopurinol and flare prophylaxis, greater patient engagement, education and follow-up, and by nurse-led models of care that employ a ‘treat-to-target’ principle (SUA< 360 or 300μmol/l). Advances in understanding the physiology and genetic control of urate transport in the kidney and gut have led to novel, more selective uricosuric drugs, and basic research on mediators of urate crystal-induced inflammation has pointed to alternative therapeutic targets for treating and preventing gout flares. Current guidelines for the management of gout and indications for the use of some more recently introduced drugs; febuxostat, lesinurad, pegloticase and interleukin-1 antagonists are also briefly reviewed.
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- 2020
27. Dotinurad versus benzbromarone in Japanese hyperuricemic patient with or without gout: a randomized, double-blind, parallel-group, phase 3 study
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Takafumi Sano, Tatsuo Hosoya, Tomomitsu Sasaki, Masahiko Fushimi, and Tetsuo Ohashi
- Subjects
Adult ,Male ,Nephrology ,medicine.medical_specialty ,Uricosuric ,Gout ,Physiology ,Urology ,Phases of clinical research ,Hyperuricemia ,030204 cardiovascular system & hematology ,03 medical and health sciences ,Benzbromarone ,chemistry.chemical_compound ,0302 clinical medicine ,Double-Blind Method ,Japan ,Physiology (medical) ,Internal medicine ,Clinical endpoint ,Humans ,Medicine ,Benzothiazoles ,Adverse effect ,Aged ,business.industry ,Middle Aged ,Uricosuric Agents ,medicine.disease ,Dotinurad ,Uric Acid ,Treatment Outcome ,chemistry ,FYU-981 ,Female ,Original Article ,business ,030217 neurology & neurosurgery ,Selective urate reabsorption inhibitor - Abstract
Background Dotinurad is a novel selective urate reabsorption inhibitor that reduces serum urate levels in hyperuricemic patients with or without gout by selectively inhibiting urate transporter 1. This study was conducted to compare the efficacy and safety of dotinurad with those of benzbromarone. Methods In this 14-week, randomized, multicenter, double-blind, parallel-group, dose escalation, benzbromarone-controlled, phase 3 study, hyperuricemic patients with or without gout were randomized to two groups that received either dotinurad 2 mg or benzbromarone 50 mg. Dotinurad or benzbromarone was administered once a day for 14 weeks. The primary endpoint was the percent change in serum uric acid level from the baseline to the final visit. Results A total of 201 Japanese hyperuricemic patients with or without gout (dotinurad: 102, benzbromarone: 99) received at least one dose of the study drug. The mean percent change in serum uric acid level from the baseline to the final visit in the dotinurad and benzbromarone groups was 45.9% and 43.8%, respectively. Non-inferiority of dotinurad 2 mg to benzbromarone 50 mg in lowering serum uric acid was verified by the predefined non-inferiority margin (95% CI − 1.27 to 5.37%). The incidence of adverse events and adverse drug reactions was comparable between the two groups. Conclusion Dotinurad 2 mg was verified to have a non-inferior serum uric acid lowering effect compared with benzbromarone 50 mg, in Japanese hyperuricemic patients with or without gout. ClinicalTrials.gov Identifier NCT03100318.
- Published
- 2020
28. Lipophilic Extract and Tanshinone IIA Derived from Salvia miltiorrhiza Attenuate Uric Acid Nephropathy through Suppressing Oxidative Stress-Activated MAPK Pathways
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Ping Li, Lin An, Xiao-Wei Zhang, Ping Zhang, Mei Zhou, and Jun Chen
- Subjects
chemistry.chemical_classification ,0303 health sciences ,Reactive oxygen species ,Uricosuric ,biology ,NOX4 ,General Medicine ,Pharmacology ,medicine.disease_cause ,Salvia miltiorrhiza ,Nitric oxide synthase ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Complementary and alternative medicine ,chemistry ,030220 oncology & carcinogenesis ,medicine ,biology.protein ,Uric acid ,Oxidative stress ,Nicotinamide adenine dinucleotide phosphate ,030304 developmental biology - Abstract
Uric acid nephropathy (UAN) is caused by excessive uric acid, which results in the damage of renal tissue via urate crystals deposition in the kidneys. The roots and rhizomes of Salvia miltiorrhiza Bunge (S. miltiorrhiza) have been clinically used in many prescriptions to treat uric acid-induced renal damage. This study investigates the uricosuric and nephroprotective effects of the ethyl acetate extract of S. miltiorrhiza (EASM) and tanshinone IIA (a major component of S. miltiorrhiza, Tan-IIA) on UAN and explores the underlying molecular mechanism. Both EASM and Tan-IIA significantly decreased serum uric acid (SUA), serum creatinine (SCR), urine uric acid (UUA), and increased urine creatinine (UCR), and blood urea nitrogen (BUN) levels in experimental UAN mice. In adenine and potassium oxonate-induced mice, EASM and Tan-IIA treatment alleviated renal dysfunction and downregulated the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Moreover, EASM treatment significantly prevented excessive reactive oxygen species (ROS) production in uric acid-induced HK-2 cells and suppressed the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). EASM also suppressed ROS-activated mitogen-activated protein kinases (MAPKs) in vivo and in vitro. These results suggest that both EASM and Tan-IIA demonstrated inhibitory effects on UAN through relieving NOX4-mediated oxidative stress and suppressing MAPK pathways activation.
- Published
- 2020
29. Hyperuricemia of The Pregnancy and Gestasional Diabetes
- Author
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Irene Maria Elena, El Nissi, Marshell Tendean, and Guntur Darmawan
- Subjects
medicine.medical_specialty ,Uricosuric ,business.industry ,nutritional and metabolic diseases ,Type 2 Diabetes Mellitus ,urologic and male genital diseases ,medicine.disease ,Gestational diabetes ,chemistry.chemical_compound ,Insulin resistance ,Endocrinology ,chemistry ,Internal medicine ,Diabetes mellitus ,Uric acid ,Medicine ,Hyperuricemia ,Metabolic syndrome ,business - Abstract
This review aims to determine the metabolic effect of hyperuricemia in pregnant woman, especially those with gestational diabetes mellitus (GDM). In women, the serum uric acid level is lower compared to men of similar age. The value is related to higher estrogen concentration to increase uric acid clearance. Hyperuricemia already established as independent risk factors for metabolic syndrome and cardiovascular disease (CVD) as well as type 2 Diabetes Mellitus (DM). Asymptomatic hyperuricemia in non-pregnant adult women will increase insulin resistance due to oxidative stress, and production of inflammatory cytokine (tumor necrosis factor-a), which inevitably increases blood sugar level. Uric acid level and serum creatinine is lower in normal pregnancy due to increased renal clearance and the uricosuric effect of estrogen. Hyperuricemia is one of the contributing factors associated with insulin resistance among pregnancy instead direct effect of placental hormones. Earlier in the first trimester of pregnancy, the risk for GDM is increased. However, the causal effect of uric acid levels on DM still requires further study .
- Published
- 2019
30. Effects of mild and moderate renal dysfunction on pharmacokinetics, pharmacodynamics, and safety of dotinurad: a novel selective urate reabsorption inhibitor
- Author
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Tatsuo Hosoya, Tomomitsu Sasaki, Hiroyuki Fukase, Masahiko Fushimi, Daisuke Okui, and Tetsuo Ohashi
- Subjects
Adult ,Male ,Nephrology ,medicine.medical_specialty ,Uricosuric ,Physiology ,Renal function ,urologic and male genital diseases ,Pharmacokinetics ,URAT1 inhibitor ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Benzothiazoles ,Renal Insufficiency ,Hyperuricemia ,Adverse effect ,Aged ,Reabsorption ,business.industry ,Middle Aged ,Uricosuric Agents ,medicine.disease ,Dotinurad ,Uric Acid ,Endocrinology ,Pharmacodynamics ,Renal dysfunction ,Original Article ,business ,Selective urate reabsorption inhibitor ,Glomerular Filtration Rate - Abstract
Background Dotinurad, a novel selective urate reabsorption inhibitor, exerts a serum uric acid-lowering effect by selectively inhibiting urate transporter 1 (URAT1) in patients with hyperuricemia. It is generally known that the progression of renal dysfunction is associated with a reduction in the serum uric acid-lowering effects of uricosuric drugs. We, therefore, investigated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of dotinurad in subjects with renal dysfunction. Methods This was a parallel-group, open-label, single-dose clinical pharmacology study. Dotinurad (1 mg) was administered once, orally to subjects with mild (estimated glomerular filtration rate [eGFR], ≥ 60 to 2) or moderate (eGFR, ≥ 30 to 2) renal dysfunction or normal (eGFR, ≥ 90 mL/min/1.73 m2) renal function. Results The time-course of mean plasma concentration of dotinurad had similar profiles across the groups. Regarding PK, there was no significant difference between the renal dysfunction groups and normal renal function group. Regarding PD, the maximum reduction rate in serum uric acid levels and the fractional uric acid excretion (FE) ratio (FE0–24/FE−24–0) were significantly lower in the moderate renal dysfunction group than in the normal renal function group. However, other PD parameters were not significantly different among the groups. No notable adverse events or adverse drug reactions were observed in this study. Conclusion These results suggested that no dose adjustment might be necessary when administering dotinurad to patients with mild-to-moderate renal dysfunction. ClinicalTrials.gov Identifier: NCT02347046.
- Published
- 2019
31. Gout Management in Chronic Kidney Disease: Pearls and Pitfalls
- Author
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Pascale Schwab and Julianna Desmarais
- Subjects
musculoskeletal diseases ,Anakinra ,medicine.medical_specialty ,Uricosuric ,business.industry ,Allopurinol ,Renal function ,General Medicine ,medicine.disease ,Gout ,Pegloticase ,medicine ,Febuxostat ,business ,Intensive care medicine ,medicine.drug ,Kidney disease - Abstract
Gout is more prevalent than ever and is associated with multiple chronic comorbidities, including Chronic Kidney Disease (CKD). While goals of treatment are the same as in those without renal impairment, co-morbid CKD poses a challenge in treatment selection and requires a solid understanding of potential drug-drug interaction and drug-related toxicity. In acute gout complicated by CKD, NSAIDs should be avoided, and colchicine used with caution. Systemic corticosteroids are effective but may be replaced by anakinra, in particular in inpatients with additional comorbidities that may make corticosteroids less desirable. Allopurinol remains the first line urate lowering therapy (ULT), starting at a low dose followed by careful goal driven up-titration. Febuxostat is a reasonable alternative, though second line in light of recent cardiovascular data. Uricosuric drugs are generally less effective, while pegloticase is reserved for refractory cases of polyarticular tophaceous disease. Gout treatment must be guided by renal function but in spite of renal disease can be successfully managed.
- Published
- 2019
32. Teriflunomide‐associated urolithiasis: a new adverse reaction explained by its uricosuric effect
- Author
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Bérenger Largeau, Jacques Vannier, Frédéric J. Bera, and Annie-Pierre Jonville-Béra
- Subjects
Male ,medicine.medical_specialty ,Multiple Sclerosis ,Uricosuric ,Toluidines ,Urology ,Hydroxybutyrates ,Uric Acid Urolithiasis ,Urine ,030226 pharmacology & pharmacy ,Diagnosis, Differential ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Urolithiasis ,Uricosuric Agent ,Nitriles ,Teriflunomide ,Humans ,Medicine ,Pharmacology (medical) ,Pharmacology ,business.industry ,Middle Aged ,medicine.disease ,chemistry ,Crotonates ,Uric acid ,Kidney stones ,Bladder stones ,business ,Immunosuppressive Agents ,030217 neurology & neurosurgery - Abstract
In clinical trials, few investigations have been conducted to determine the mechanism involved in teriflunomide-associated kidney stone formation. We report the first case of recurrent teriflunomide-induced uric acid urolithiasis. A 55-year-old man with relapsing-remitting multiple sclerosis experienced three occurrences of urolithiasis several months after the initiation of teriflunomide. While serum uric acid remained stable at 280 mmol/L, 24-hour urine uric acid was increased to 2195 mmol/24h. For the third episode, computed tomography showed three bladder stones and one stone in the right calyceal group. Endovesical lithotripsy was used to extract four orange-colored stones of more than 20 mm. Stone analysis exhibited morphology subtype IIIb with 100% of anhydrous uric acid. Given the disease control, teriflunomide was continued. After urinary alkalinisation by potassium citrate, the patient remained asymptomatic at 18 months follow-up. An inhibitory effect of dihydroorotate and/or teriflunomide on urate tubular reabsorption could explain teriflunomide-associated uric acid urolithiasis. This case in a patient without risk factors suggests that multiple sclerosis patients may be at greater risk of forming uric acid urinary stones when taking teriflunomide. Alkalinization of the urine may reduce the risk of recurrence, allowing further treatment with teriflunomide.
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- 2021
33. The impact of an URAT1 polymorphism on the losartan treatment of hypertension and hyperuricemia
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Liting Wu, Yingchao Fan, Zhumeng Li, Wenfang Zhuang, Delong Mao, and Yuan Wang
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CYP2C9 ,Adult ,Male ,Microbiology (medical) ,medicine.medical_specialty ,Uricosuric ,Organic Cation Transport Proteins ,Pharmacogenomic Variants ,losartan ,Clinical Biochemistry ,Organic Anion Transporters ,Single-nucleotide polymorphism ,Hyperuricemia ,Creatine ,Polymorphism, Single Nucleotide ,chemistry.chemical_compound ,Polymorphism (computer science) ,Internal medicine ,Humans ,Immunology and Allergy ,Medicine ,hypertension with hyperuricemia ,Research Articles ,Antihypertensive Agents ,Aged ,Cytochrome P-450 CYP2C9 ,business.industry ,Biochemistry (medical) ,Public Health, Environmental and Occupational Health ,Hematology ,Middle Aged ,medicine.disease ,Pharmacogenomic Testing ,Medical Laboratory Technology ,Endocrinology ,Losartan ,chemistry ,Hypertension ,Female ,URAT1 ,business ,Research Article ,Lipoprotein ,medicine.drug - Abstract
Background This study was designed to evaluate the impact of polymorphisms in the urate transporter 1 (URAT1) gene on the uricosuric action of losartan therapy in hypertensive patients suffering from hyperuricemia. Methods A MassARRAY approach was used to detect single nucleotide polymorphism (SNP) loci in the URAT1 and CYP2C9 genes (16 and 2 loci, respectively) in 111 patients with hypertension and hyperuricemia taking losartan and in 121 healthy controls. In addition, we compared serum urate (SUA) levels and other key clinical biochemistry indices between these two patient groups. Results We detected significant differences between the two patient groups with respect to age, SUA, urea, creatine, triglycerides, high‐density lipoprotein, low‐density lipoprotein, and fasting plasma glucose (all p, 121 healthy people and 111 patients with hypertension and hyperuric acid were screened out, 16 SNP loci of URAT.1 and 2 SNP loci of CYP2C9 were detected by MASS‐ARRAY technology. Through analysis, it was found that only rs3825016 was meaningful, We observed that patients with the heterozygous genotype (CT) exhibited a more pronounced decrease in uric acid levels.
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- 2021
34. Probenecid in the treatment of neurosyphilis in men who have sex with men: a commentary
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David Goldmeier and Daniel Richardson
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Male ,Uricosuric ,Organic anion transporter 1 ,Physiology ,HIV Infections ,Dermatology ,urologic and male genital diseases ,Men who have sex with men ,Neurosyphilis ,Procaine ,Sexual and Gender Minorities ,polycyclic compounds ,medicine ,Humans ,Syphilis ,Homosexuality, Male ,biology ,business.industry ,Probenecid ,medicine.disease ,Penicillin ,Infectious Diseases ,biology.protein ,business ,medicine.drug - Abstract
Probenecid is a uricosuric drug, which inhibits the renal excretion of procaine penicillin via inhibition of the organic anion transporter (OAT-1) system in the proximal renal tubule producing higher plasma and cerebrospinal fluid (CSF) penicillin levels.1 2 Oral probenecid is recommended to be used with intramuscular procaine penicillin for the treatment of neurosyphilis. Rates of syphilis and neurosyphilis have increased significantly over the past 20 years particularly in men who have sex with men (MSM). There …
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- 2021
35. Effects of Pimenta pseudocaryophyllus extracts on gout: Anti-inflammatory activity and anti-hyperuricemic effect through xantine oxidase and uricosuric action.
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Ferrari, Fernanda Cristina, Lemos Lima, Rita de Cássia, Schimith Ferraz Filha, Zilma, Barros, Camila Helena, de Paula Michel Araújo, Marcela Carolina, and Antunes Saúde-Guimarães, Dênia
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ANTI-inflammatory agents , *BIOLOGICAL models , *EDEMA , *OXIDOREDUCTASES , *RATS , *SERUM , *URIC acid , *PLANT extracts , *URICOSURIC agents , *LATIN American traditional medicine - Abstract
Ethnopharmacological relevance Leaves infusion of Pimenta pseudocaryophyllus (Gomes) Landrum is used in Brazilian folk medicine to treat the predisposition to arthritical and gouty affections of the joints, fever and other diseases. A refreshing drink prepared with the specie is also used due to its diuretic, sedative and aphrodisiac actions. Aim of the study The study was undertaken to investigate the mechanisms of anti-hyperuricemic effect and anti-inflammatory activity of P. pseudocaryophyllus extracts. Materials and methods Anti-hyperuricemic effect was investigated using xanthine oxidase assay and uricosuric studies with rats in which hyperuricemia was induced by potassium oxonate and uric acid. Anti-inflammatory activity was investigated on MSU crystal-induced paw edema model. Ethyl acetate extracts of the leaves (EAL) and branches (EAB), ethanolic extracts of leaves (EEL) and branches (EEB) and aqueous extracts of leaves (AL) and branches (AB) were evaluated. Results The extracts of P. pseudocaryophyllus evaluated showed expressive results regarding the inhibition of xanthine oxidase enzyme in vitro and they were also able to reduce serum uric acid levels in hyperuricemic rats. The investigation of the mechanism of action, it was found that EAL, EAB, EEB, AB (125 and 250 mg/kg) and AL (250 mg/kg) promoted an increase on the urinary excretion of uric acid and EEL, EEB, AB (125 and 250 mg/kg) and EAB (250 mg/kg) were capable to inhibit liver xanthine oxidase. Treatments with EEL (125 and 250 mg/kg) and EEB (250 mg/kg) were able to reduce edema at 48th h. EAL and EAB (125 and 250 mg/kg) showed significant anti-inflammatory activity on monosodium urate crystal-induced paw edema model at all evaluated times. Conclusions The specie P. pseudocaryophyllus showed remarkable anti-hyperuricemic effects through uricosuric effects and inhibition of xanthine oxidase and therefore can be considered as a promise in the treatment of diseases related to hyperuricemia. Moreover, ethyl acetate extracts had significant anti-inflammatory activity. [ABSTRACT FROM AUTHOR]
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- 2016
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36. A historical journey of searching for uricosuric drugs
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T.L.Th.A. Jansen, Janssen Matthijs, and Giesen Tanja
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medicine.medical_specialty ,Uricosuric ,Gout ,Fulminant ,Disease ,Hyperuricemia ,Benzbromarone ,chemistry.chemical_compound ,Rheumatology ,Weight loss ,Internal medicine ,medicine ,Humans ,Aged ,business.industry ,General Medicine ,Uricosuric Agents ,medicine.disease ,Uric Acid ,Probenecid ,chemistry ,Pharmaceutical Preparations ,medicine.symptom ,business ,medicine.drug - Abstract
Gout is an auto-inflammatory disease driven by urate deposits with a second co-stimulatory factor evoking an (peri)arthritic fulminant inflammation often with a debute at night; inflammatory signals are enhanced via a NLRP3 pathway. In gout patients, urate metabolism has had a positive balance for a time period of weeks to years before the arthritic syndrome or tophaecous disease becomes manifest. This may be due to katabolism or weight loss, enhanced dietary affluence, and overweight resulting in increased serum urate levels. Also, a decreased urate excretion results in proneness to hyperuricaemia and clinical gout. Pharmacotherapeutically, a negative urate balance should be the aim of clinicians and then the rational choice of treatment with uricosurics seems quite logical and promising, but has not had a thorough attention of pharma, researchers nor of clinicians, though most gout patients were and still are low excretors. Here, an overview on the 70-year-old journey mankind has made in a search for uricosurics resulting so far in only 1 registered uricosuric per continent.
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- 2021
37. Antihyperuricemic Effect of Dendropanax morbifera Leaf Extract in Rodent Models
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Kwang Il Park, Yongjae Han, Dongho Lee, and Jin-Kyoung Kim
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Uricosuric ,Article Subject ,business.industry ,Allopurinol ,Pharmacology ,medicine.disease ,Probenecid ,Other systems of medicine ,03 medical and health sciences ,chemistry.chemical_compound ,Benzbromarone ,0302 clinical medicine ,Complementary and alternative medicine ,chemistry ,030220 oncology & carcinogenesis ,medicine ,Uric acid ,Hyperuricemia ,Febuxostat ,Xanthine oxidase ,business ,RZ201-999 ,030217 neurology & neurosurgery ,medicine.drug ,Research Article - Abstract
Dendropanax morbifera is a well-known traditional medicine used in China and Korea to treat intestinal disorders, urosis, diuresis, and chronic glomerulonephritis. Hyperuricemia is a metabolic disorder characterized by a high uric acid level in serum due to an imbalance between uric acid production and excretion and causes gout. Recently, the prevalence of hyperuricemia worldwide has been continuously increasing. Xanthine oxidase (XOD) inhibitors (allopurinol (ALP) and febuxostat) and uricosuric agents (benzbromarone and probenecid) are used to treat hyperuricemia clinically. However, because these drugs are poorly tolerated and cause side effects, such as kidney diseases, hepatotoxicity, gastrointestinal symptoms, and hypersensitivity syndrome, only a limited number of drugs are available. We investigated the antihyperuricemic effects of Dendropanax morbifera leaf ethanol extract (DMLE) and its underlying mechanisms of action through in vitro and in vivo studies. We evaluated uric acid levels in serum and urine, and xanthine oxidase (XOD) inhibition activity in the serum and liver tissue of a hyperuricemic rat model of potassium oxonate (PO)-induced hyperuricemic rats. In vitro study, XOD-inhibitory activity was the lowest among the test substances at the IC50 of ALP. However, the IC50 of DMLE-70 was significantly low compared with that of other DMLEs ( p < 0.05 ). In PO-induced hyperuricemic rats, uric acid (UA) levels in serum and urine were significantly reduced in all DMLE-70 and allopurinol-treated (ALT) groups than in the PC group ( p < 0.05 ). UA levels in urine were lower than those in serum in all DME groups. In PO-induced hyperuricemic rats, DMEE-200 reduced UA concentration in serum and increased UA excretion in the urine. These findings suggest that DMLE exerts antihyperuricemic and uricosuric effects on promoting UA excretion by enhanced secretion and inhibition of UA reabsorption in the kidneys. Thus, DMLE may be a potential treatment for hyperuricemia and gout.
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- 2021
38. Perfluoroalkyl substance excretion: Effects of organic anion-inhibiting and resin-binding drugs in a community setting
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Alan M. Ducatman, Tony Fletcher, and Michael I. Luster
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Adult ,Male ,medicine.medical_specialty ,Uricosuric ,Organic anion transporter 1 ,medicine.drug_class ,Health, Toxicology and Mutagenesis ,Cholestyramine Resin ,Organic Anion Transporters ,010501 environmental sciences ,Toxicology ,01 natural sciences ,Excretion ,Perfluorononanoic acid ,03 medical and health sciences ,chemistry.chemical_compound ,Bile acid sequestrant ,Internal medicine ,medicine ,Humans ,030304 developmental biology ,0105 earth and related environmental sciences ,Aged ,Pharmacology ,0303 health sciences ,Fluorocarbons ,Cholestyramine ,biology ,Chemistry ,Probenecid ,Anticholesteremic Agents ,General Medicine ,Middle Aged ,Uricosuric Agents ,Endocrinology ,biology.protein ,Perfluorooctanoic acid ,Environmental Pollutants ,Female ,Sulfonic Acids ,medicine.drug - Abstract
Background Longer serum half-lives of perfluoroalkyl substances (PFAS) in humans compared to other species has been attributed to differences in the activity of organic anion transporters (OAT). Methods Among 56,175 adult participants in the community-based C8 Health Project, 23 subjects were taking the uricosuric OAT-inhibitor probenecid, and 36 subjects were taking the bile acid sequestrant cholestyramine. In regression models of log transformed serum PFAS, medication effects were estimated in terms of mean ratios, adjusting for age, gender, BMI, estimated glomerular filtration rate (eGFR) and water-district of residence. Results Probenecid was associated with modest, but not statistically significant increases in serum PFAS concentrations. In contrast, cholestyramine significantly lowered serum PFAS concentrations, notably for perfluorooctane sulfonic acid (PFOS). Conclusions The effectiveness of cholestyramine in a community setting supports the importance of gastrointestinal physiology for PFAS excretion kinetics, especially for PFOS. We did not find clear evidence that probenecid, an inhibitor of OAT, affects PFAS clearance.
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- 2021
39. Antihyperuricemic, Anti-Inflammatory and Antihypertensive Effect of a Dry Extract from Solidago virgaurea L. (Asteraceae)
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Ildiko Lung, Elena Dinte, Alexandru Gavan, Loredana Soran, Ocsana Opriş, Oliviu Vostinaru, Cristina Mogosan, Anca Toiu, and Mircea Tamas
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Uricosuric ,medicine.drug_class ,Solidago virgaurea L ,medicine.medical_treatment ,Pharmaceutical Science ,antihyperuricemic ,Solidago virgaurea ,Anti-inflammatory ,03 medical and health sciences ,Rutin ,chemistry.chemical_compound ,0302 clinical medicine ,Diclofenac ,Pharmacy and materia medica ,medicine ,Caffeic acid ,Hyperuricemia ,antihypertensive ,030304 developmental biology ,anti-inflammatory ,030203 arthritis & rheumatology ,0303 health sciences ,biology ,Traditional medicine ,business.industry ,biology.organism_classification ,medicine.disease ,RS1-441 ,chemistry ,Diuretic ,business ,medicine.drug - Abstract
Solidago virgaurea L. is a perennial plant used in European traditional medicine as a diuretic or a remedy for inflammatory conditions of the urinary tract but also for gout, especially in the Balkans. The present study was focused on a preclinical, in vivo evaluation of antihyperuricemic, anti-inflammatory, and antihypertensive effects of a dry extract from S. virgaurea L. (ESV). Colorimetric and HPLC–MS techniques were used to identify the main chemical constituents of ESV. Antihyperuricemic effect of ESV was assessed in a rat model of hyperuricemia induced by the administration of potassium oxonate. Antihypertensive effect of ESV was evaluated in hyperuricemic rats by monitoring systolic blood pressure with a non-invasive blood-pressure recording system. The anti-inflammatory effect of ESV was tested using a rat model of paw edema. The main chemical constituents of ESV were rutin and phenolic acids represented by chlorogenic and caffeic acid. ESV demonstrated significant antihyperuricemic effects in rats due to an uricosuric mechanism. Additionally, ESV reduced the progression of arterial hypertension in hyperuricemic rats and also showed anti-inflammatory properties slightly inferior to diclofenac. The results suggest that ESV could be a natural remedy for the treatment of gout and protection against endothelial dysfunction caused by hyperuricemia.
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- 2021
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40. Modulation of Urate Transport by Drugs
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Péter Tátrai, Peter Krajcsi, Gabriella Dörnyei, and Franciska Erdő
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Drug ,Uricosuric ,media_common.quotation_subject ,Pharmaceutical Science ,Review ,hyperuricemia ,Pharmacology ,Urate transport ,03 medical and health sciences ,Pharmacy and materia medica ,0302 clinical medicine ,medicine ,in vitro prediction ,Hyperuricemia ,Hypouricemia ,030304 developmental biology ,media_common ,030203 arthritis & rheumatology ,0303 health sciences ,business.industry ,Transporter ,medicine.disease ,Gout ,RS1-441 ,Drug development ,hypouricemia ,drug-transporter interactions ,urate ,business - Abstract
Background: Serum urate (SU) levels in primates are extraordinarily high among mammals. Urate is a Janus-faced molecule that acts physiologically as a protective antioxidant but provokes inflammation and gout when it precipitates at high concentrations. Transporters play crucial roles in urate disposition, and drugs that interact with urate transporters either by intention or by accident may modulate SU levels. We examined whether in vitro transporter interaction studies may clarify and predict such effects. Methods: Transporter interaction profiles of clinically proven urate-lowering (uricosuric) and hyperuricemic drugs were compiled from the literature, and the predictive value of in vitro-derived cut-offs like Cmax/IC50 on the in vivo outcome (clinically relevant decrease or increase of SU) was assessed. Results: Interaction with the major reabsorptive urate transporter URAT1 appears to be dominant over interactions with secretory transporters in determining the net effect of a drug on SU levels. In vitro inhibition interpreted using the recommended cut-offs is useful at predicting the clinical outcome. Conclusions: In vitro safety assessments regarding urate transport should be done early in drug development to identify candidates at risk of causing major imbalances. Attention should be paid both to the inhibition of secretory transporters and inhibition or trans-stimulation of reabsorptive transporters, especially URAT1.
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- 2021
41. Association of urate‐lowering drugs with the risk of future urolithiasis in patients with gout: A population‐based nested case–control study
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Chih-Jung Yeh, Yu-Hsun Wang, James Cheng-Chung Wei, Sheng-Wen Wu, and Chin-Yin Liu
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Male ,medicine.medical_specialty ,Uricosuric ,Gout ,Taiwan ,MEDLINE ,Population based ,030204 cardiovascular system & hematology ,Gout Suppressants ,03 medical and health sciences ,0302 clinical medicine ,Urolithiasis ,Uricosuric Agent ,Internal medicine ,medicine ,Humans ,In patient ,Prospective Studies ,030212 general & internal medicine ,Medical prescription ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Uric Acid ,Pharmaceutical Preparations ,Case-Control Studies ,Nested case-control study ,business - Abstract
Background Patients with gout have an increased risk of urolithiasis and usually need urate-lowering therapy (ULT) for the prevention of disease progression. However, there is a paucity of clinical data regarding the risk of future urolithiasis in ULT users. Methods This nested case-control study was performed using the Taiwan National Health Insurance Research Database. The aim of this study was to examine whether ULT (xanthine oxidase inhibitors [XOIs] or uricosuric agents) is associated with risk of future urolithiasis in patients with gout. Data were collected from January 2000 to December 2012. Results This study included 2307 case patients and 2307 matched controls. Case patients had gout that developed into urolithiasis, and control patients had gout but were not diagnosed with urolithiasis during the study period. Patients had a mean age of 56.3 years at diagnosis of gout, and 83.2% were male patients. No association was detected between use of XOIs or uricosuric agents and risk of future urolithiasis. Furthermore, there was no significant difference in the risk of future urolithiasis in patients exposed to various cumulative days of XOI or uricosuric prescriptions. Conclusion The present study provides evidence that neither XOIs nor uricosuric agents are associated with risk of future urolithiasis in patients with gout. Before the availability of more clinical evidence, ensuring high fluid intake and prospective monitoring of urolithiasis development are still important for uricosuric agent users.
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- 2021
42. Dual actions of norathyriol as a new candidate hypouricaemic agent: uricosuric effects and xanthine oxidase inhibition
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Yanfen Niu, Ling Li, Lihui Gao, Aiping Xu, Na Li, Tu Caixia, Hua Lin, Fashuang Li, and Lixian Yuan
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0301 basic medicine ,Xanthine Oxidase ,Uricosuric ,Organic anion transporter 1 ,Organic Anion Transporters ,Hyperuricemia ,Pharmacology ,Kidney ,Excretion ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Organic Anion Transport Protein 1 ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,Xanthine oxidase ,biology ,Transporter ,Uric Acid ,HEK293 Cells ,030104 developmental biology ,medicine.anatomical_structure ,Xanthenes ,chemistry ,biology.protein ,Uric acid ,030217 neurology & neurosurgery - Abstract
Hyperuricaemia, which results from the overproduction and underexcretion of uric acid, has been linked with chronic renal dysfunction, cardiovascular diseases, diabetes and metabolic syndrome. However, available clinical drugs cannot simultaneously target the production and excretion of uric acid. Norathyriol, a natural xanthone, was expected to have the dual actions. We previously reported that norathyriol possessed potent anti-hyperuricaemic activity related to the inhibition of uric acid production. Here, we investigated the uricosuric actions in hyperuricaemic animals and explored the possible molecular mechanisms associated with renal urate transporters and xanthine oxidase (XO). The results showed that norathyriol (0.5–4.0 mg/kg) dose- and time-dependently decreased serum urate levels in uric acid-induced hyperuricaemic mice and markedly increased the fractional excretion of urate in oxonate-induced hyperuricaemic rats, demonstrating a promotion of urate excretion in the kidney. Further evidence showed that norathyriol markedly increased renal mRNA and protein expression of the secretory organic anion transporter 1 (OAT1) in hyperuricaemic mice and strengthened its transport function in vitro. Moreover, norathyriol also upregulated the mRNA expression of the secretory transporters OAT3, ATP-binding cassette transporter G2 and multidrug resistance protein 4, but not their protein expression. Changes in the expression of the reabsorptive transporters were not observed. This is the first report that norathyriol has uricosuric effects by targeting OAT1. Moreover, norathyriol significantly inhibited XO activity in an uncompetitive manner. Taken together, these findings suggest that norathyriol has the potential to be developed as a new anti-hyperuricaemic agent with dual actions that activate OAT1 and inhibit XO activity.
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- 2019
43. The new generation uricosuric drugs, xanthine oxidase inhibitors, and combination therapy as options for gout pharmacotherapy – a review paper
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Daniel Wiśniewski and Izabela Uzar
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Pharmacology ,Uricosuric ,Combination therapy ,business.industry ,Pharmaceutical Science ,medicine.disease ,Gout ,chemistry.chemical_compound ,Pharmacotherapy ,chemistry ,Medicine ,Xanthine oxidase ,business ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) - Published
- 2019
44. Efficacy and safety of lesinurad for the treatment of hyperuricemia in gout
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Ravichandra Karra Gurunath, T.L.Th.A. Jansen, Pascal Richette, Anne-Katrin Tausche, Fernando Perez-Ruiz, and Mónica Juárez-Campo
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Uricosuric ,Allopurinol ,Review ,hyperuricemia ,Pharmacology ,allopurinol ,serum uric acid levels ,030226 pharmacology & pharmacy ,03 medical and health sciences ,chemistry.chemical_compound ,lesinurad ,0302 clinical medicine ,gout ,medicine ,Hyperuricemia ,urate lowering ,030203 arthritis & rheumatology ,business.industry ,febuxostat ,lcsh:RM1-950 ,Lesinurad ,General Medicine ,medicine.disease ,Gout ,lcsh:Therapeutics. Pharmacology ,chemistry ,uric acid transporter 1 ,Adjunctive treatment ,Molecular Medicine ,Uric acid ,Febuxostat ,business ,medicine.drug - Abstract
The aim of this review is to present current evidence about the efficacy and safety of lesinurad in combination with xanthine oxidase inhibitors (XOIs) in the treatment of hyperuricemia in patients with gout. Gout is the most common inflammatory form of arthritis. It is caused by an elevated concentration of serum uric acid (UA) that leads to the formation of monosodium urate crystals in joints and different tissues. The goal of therapy is to maintain serum UA levels at
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- 2019
45. Pharmacological urate-lowering approaches in chronic kidney disease
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Jing Liu, Ping Fu, Liang Ma, and Xinrui Li
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Nephrology ,medicine.medical_specialty ,Uricosuric ,Renal function ,Pharmacology ,urologic and male genital diseases ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Internal medicine ,Drug Discovery ,medicine ,Humans ,Hyperuricemia ,Renal Insufficiency, Chronic ,Xanthine oxidase ,030304 developmental biology ,Flavonoids ,Biological Products ,0303 health sciences ,Kidney ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,General Medicine ,medicine.disease ,Uric Acid ,0104 chemical sciences ,medicine.anatomical_structure ,Uric acid ,Kidney disease - Abstract
Chronic kidney disease (CKD) has become a global public health issue and uric acid (UA) remains a major risk factor of CKD. As the main organ for the elimination of UA, kidney owned a group of urate transporters in tubular epithelium. Kidney disease hampered the UA excretion, and the accumulation of serum UA in return harmed the renal function. Commercially, there are three kinds of agents targeting at urate-lowering, xanthine oxidoreductase inhibitor which prevents the production of UA, uricosuric which increases the concentration of UA in urine thus decreasing serum UA level, and uricase which converts UA to allantoin resulting in the dramatic decrement of serum UA. Of note, in patients with CKD, administration of above-mentioned agents, alone or combined, needs special attention. New evidence is emerging for the efficacy of several urate-lowering drugs for the treatment of hyperuricemia in patients with CKD. Besides, loads of novel and promising drug candidates and phytochemicals are in the different phases of research and development. As of today, there is insufficient evidence to recommend the widespread use of UA-lowering therapy to prevent or slow down the progression of CKD. The review summarized the evidence and perspectives about the treatment of hyperuricemia with CKD for medicinal chemist and nephrologist.
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- 2019
46. In vivo anti-hyperuricemic activity of sesquiterpene lactones from Lychnophora species
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Ana Catharina Fernandes Pereira Ferreira Bernardes, Marcela Carolina de Paula Michel Araújo, Dênia Antunes Saúde-Guimarães, and Grazielle Brandão Coelho
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Uricosuric ,Gout ,010405 organic chemistry ,lcsh:RS1-441 ,Hyperuricemia ,Pharmacology ,medicine.disease ,Sesquiterpene ,01 natural sciences ,Terpenoid ,Uricosuric effect ,0104 chemical sciences ,lcsh:Pharmacy and materia medica ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,In vivo ,medicine ,Uric acid ,Xanthine oxidase ,General Pharmacology, Toxicology and Pharmaceutics ,Sesquiterpene lactones - Abstract
Hyperuricemia is the main cause of gout, an inflammation induced by uric acid deposition in joints. Drugs available present side effects, so there is a need for new treatment alternatives. Lychnophora species are used in folk medicine to treat inflammation, rheumatism and muscle pain. Goyazensolide (10 mg/kg), eremantholide C (25 mg/kg) and lychnopholide (25 mg/kg), sesquiterpene lactones isolated from Lychnophora species were previously studied and showed anti-hyperuricemic effects in mice. However, the mechanisms of this effect were not elucidated. The methodology of this study consisted in treatment of hyperuricemic-induced rats, and comparison between control groups, clinically used anti-hyperuricemic drugs and sesquiterpene lactones. Urine and blood were collected for uric acid quantification. Xanthine oxidase inhibition was measured in liver homogenates. Results showed that all evaluated sesquiterpene lactones presented anti-hyperuricemic activity at the doses of 5 and 10 mg/kg and can act through one or both mechanisms, depending on the dose administrated. Goyazensolide and lychnopholide at dose of 5 mg/kg showed important uricosuric effect. Goyazensolide and lychnopholide at dose of 10 mg/kg, and eremantholide C (5 and 10 mg/kg) presented notable inhibition of hepatic xanthine oxidase activity and uricosuric effect. Thus, these sesquiterpene lactones are promising hypouricemic agent to treat hyperuricemia and gout. Keywords: Sesquiterpene lactones, Hyperuricemia, Xanthine oxidase, Uricosuric effect, Gout
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- 2019
47. Chicory (Cichorium intybus L.) inhibits renal reabsorption by regulating expression of urate transporters in fructose-induced hyperuricemia
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Meng-Zhen Chu, Bing Zhang, Lin Zhijian, Xiao Wang, and Yu Wang
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0303 health sciences ,medicine.medical_specialty ,Creatinine ,Uricosuric ,Organic anion transporter 1 ,biology ,Reabsorption ,Renal Reabsorption ,medicine.disease ,lcsh:RZ409.7-999 ,030226 pharmacology & pharmacy ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Complementary and alternative medicine ,chemistry ,Renal physiology ,Internal medicine ,medicine ,biology.protein ,Uric acid ,Hyperuricemia ,lcsh:Miscellaneous systems and treatments ,030304 developmental biology - Abstract
Objective: Hyperuricemia is an excess of urate in blood. The kidneys play important parts in urate excretion, which involves handling reabsorption and secretion. A series of urate transporters is responsible for this process: urate transporter (URAT)1, glucose transporter (GLUT)9, organic anion transporter (OAT)1 and OAT3. Excessive fructose intake may result in increased serum urate levels. Chicory (Cichorium intybus L.) has been used as an edible vegetable and traditional Chinese medicine. Studies have shown that chicory is a promising anti-hyperuricemia agent and we explored the mechanism of its uricosuric effect via a renal pathway. Methods: Hyperuricemia was induced in rats by administration of 10% fructose. The uricosuric effect was evaluated by determining the serum urate level. Renal excretory function was detected by the clearance rate of creatinine, clearance rate of uric acid and histology. The location and expression of URAT1, GLUT9, OAT1 and OAT3 their mRNA expression in kidneys were analyzed. Results: Chicory decreased serum levels of urate and creatinine significantly, and promoted the clearance of creatinine and urate, as well as improving renal pathologic changes due to hyperuricemia. Chicory inhibited expression of URAT1 and GLUT9 markedly in a dose-dependent manner, but showed no influence on expression of OAT1 or OAT3. Conclusion: Chicory might be a promising anti-hyperuricemia agent. It can promote renal excretion of urate by inhibiting urate reabsorption, which may be related to down-regulation of mRNA and protein expression of URAT1 and GLUT9. Keywords: Chicory, Fructose, Hyperuricemia, Renal resorption, Urate transporters
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- 2019
48. Pharmacological Review on Uricosuric activity
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Veeram Anjali, Bandi Somasekhar, and Kaipa Vanaja
- Subjects
Uricosuric ,business.industry ,nutritional and metabolic diseases ,Pharmacology ,medicine.disease ,Nephropathy ,Gout ,Excretion ,chemistry.chemical_compound ,chemistry ,Uricosuric Agent ,medicine ,Uric acid ,Kidney stones ,Hyperuricemia ,business - Abstract
The naturally available uricosuric agents are Tinospora cardifolia, Allium sepa, Cajanus Cajan, Piper nigrum etc., Natural medicinal plants having no side effects are more preferred when compared to synthetic medications. Uricosuric agents increase the urinary excretion of uric acid hence the natural uricosuric agent is preferred to prevent many diseases like gout, arthritis, kidney stones etc., without side effect. Uricosuric medications are the substances that increase the excretion of uric acid in urine, thus reducing the concentration of uric acid in blood plasma. Prolonged and untreated hyperuricemia results into gout, a severe inflammatory condition. Sustain hyperuricemia leads to impaired blood pressure control, renal impairment and nephropathy. The common factors for deposition of uric acid in blood are drinking alcohol and taking high purine diet. The various screening methods for the uricosuric activity are uricosuric activity in mice, Potassium oxonate induced activity, and Phenol red excretion methods are explained in this review.
- Published
- 2018
49. Anti-hyperuricemic, Uricosuric and Xanthine-oxidase Inhibitory Activities of Watermelon Powder in a Rat Gout Model
- Author
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Basim Jasim Hameed, Falah Hassan Shari, and Usama Hamid Ramadhan
- Subjects
0301 basic medicine ,Uricosuric ,Cell Biology ,030204 cardiovascular system & hematology ,Pharmacology ,medicine.disease ,Inhibitory postsynaptic potential ,Gout ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,medicine ,Molecular Medicine ,Xanthine oxidase - Published
- 2018
50. Screening of xanthine oxidase inhibitor from selected edible plants and hypouricemic effect of Rhizoma Alpiniae Officinarum extract on hyperuricemic rats
- Author
-
Lianzhu Lin, Liu Xuemei, and Mouming Zhao
- Subjects
0301 basic medicine ,Antioxidant ,Uricosuric ,medicine.drug_class ,medicine.medical_treatment ,Medicine (miscellaneous) ,medicine.disease_cause ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Diarylheptanoids ,medicine ,TX341-641 ,Hyperuricemia ,Xanthine oxidase ,Xanthine oxidase inhibitory effect ,Xanthine oxidase inhibitor ,Edible plants with health-promoting effects ,Hypouricemic effect ,Flavonoids ,030109 nutrition & dietetics ,Nutrition and Dietetics ,Traditional medicine ,Nutrition. Foods and food supply ,010401 analytical chemistry ,medicine.disease ,Rhizoma Alpiniae Officinarum ,0104 chemical sciences ,Galangin ,chemistry ,Kaempferide ,Oxidative stress ,Food Science - Abstract
This study was aimed at screening a potential anti-hyperuricemia agent with dual xanthine oxidase (XOD) inhibitory effect (XOI) and antioxidant activity from edible plants with health-promoting effects using non-targeted chemometric analysis (hierarchical cluster analysis and principal component analysis), evaluating its in vivo hypouricemic effect and mechanism, and identifying the key XOD inhibitor using ultrafiltration UPLC-MS/MS. Rhizoma Alpiniae Officinarum extract (GE), which has high contents of total phenolics and flavonoids, as well as dual XOI and antioxidant activity, showed significant hypouricemic and renal protective effects on hyperuricemic rats through inhibiting XOD activity, alleviating oxidative stress, down-regulating URAT1 and GLUT9 protein expression, and reducing urea nitrogen and creatinine levels. GE could be a dual-acting agent with XOI and uricosuric effect for preventing and treating hyperuricemia. Four flavonoids and eight diarylheptanoids were identified as potential XOD inhibitors from GE. Galangin, kaempferide and 3-methoxyl-galangin contributing to 70.1% of XOI were the key XOD inhibitors.
- Published
- 2018
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