Recent approaches to gout drug discovery: an update

Otani, Naoyuki; Ouchi, Motoshi; Kudo, Hideo; Tsuruoka, Shuichi; Hisatome, Ichiro; Anzai, Naohiko

doi:10.1080/17460441.2020.1755251

Cited by 31 publications

(39 citation statements)

References 80 publications

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“…HUA has been observed worldwide, placing a considerable public health burden on the society [ 2 ]. There are two categories of medications commonly used for the treatment of HUA: uricosuric agents such as probenecid and benzbromarone, and xanthine oxidase (XOD) inhibitors such as allopurinol [ 3 ]. However, allopurinol may produce severe cutaneous reactions and there are some unanswered questions about the pharmacological interactions of probenecid and the hepatotoxicity of benzbromarone [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Lipidomics study of the therapeutic mechanism of Plantaginis Semen in potassium oxonate-induced hyperuricemia rat

Yang

Shi

Wang

et al. 2021

BMC Complement Med Ther

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Background Plantaginis Semen has been widely used as folk medicine and health care food against hyperuricemia (HUA) and gout, but its pharmacological mechanism remains unclear. This study investigated the therapeutic mechanism of Plantaginis Semen extract on potassium oxonate -induced HUA rats based on a lipidomics approach. Methods A model of HUA was established by potassium oxonate intragastric administration. 42 Sprague-Dawley (SD) male rats were randomly divided into the control group, model group, benzbromarone group (10 mg/kg) and three Plantaginis Semen groups (n = 7). The Plantaginis Semen groups were treated orally with Plantaginis Semen, 0.9375, 1.875 or 3.75 g/kg for 28 days. The levels of serum uric acid (UA), creatinine (Cr), triacylglycerol (TG) and tumor necrosis factor-α (TNF-α) were measured using enzyme-linked immunosorbent assay kits. Ultra performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-Q-TOF/MS) was used for the serum lipidomics analysis, multivariate statistical analysis and independent samples t-test were carried out for the pattern recognition and characteristic metabolites identification. The relative levels of critical regulatory factors were determined by quantitative real-time polymerase chain reaction (RT-qPCR). Results Compared with the model group, the levels of serum UA, Cr, TG and TNF-α were significantly (p < 0.05) decreased in benzbromarone and three Plantaginis Semen groups. With lipidomics analysis, significant lipid metabolic perturbations were observed in HUA rats, 13 metabolites were identified as potential biomarkers and glycerophospholipid metabolism pathway was most affected. These perturbations were partially restored via treatment of benzbromarone and Plantaginis Semen. Additionally, the mRNA expression levels of urate anion transporter 1 (URAT1) and phosphatidylinositol 3-kinase/protein kinases B (PI3K/Akt) were significantly decreased (p < 0.01) after treatment with benzbromarone and high dose of Plantaginis Semen. Conclusions Plantaginis Semen had significant effects on anti-HUA, anti-inflammatory and renal protection. It attenuated potassium oxonate-induced HUA through regulation of lipid metabolism disorder.

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Section: Introductionmentioning

confidence: 99%

Lipidomics study of the therapeutic mechanism of Plantaginis Semen in potassium oxonate-induced hyperuricemia rat

Yang

Shi

Wang

et al. 2021

BMC Complement Med Ther

View full text Add to dashboard Cite

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“…Elevated prevalent of HUA has been observed throughout the world, placing a considerable public health burden on the society [2]. Currently, two categories medicine commonly used for the treatment of HUA are uricosuric agents such as probenecid and benzbromarone and/or xanthine oxidase (XOD) inhibitors such as allopurinol [3].…”

Section: Resultsmentioning

confidence: 99%

Lipidomics Study of the Therapeutic Mechanism of Plantaginis Semen in Potassium Oxonate-Induced Hyperuricemia Rat

Shi

Yang

Wang

et al. 2020

Preprint

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BackgroundPlantaginis semen has been widely used as folk medicine and health care food against hyperuricemia (HUA) and gout, but little was known about its pharmacological mechanism. MethodsThe model was established by potassium oxonate intragastric administration. 42 Sprague-Dawley (SD) male rats were randomly divided into the control group, model group, benzbromarone group (10 mg/kg) and three Plantaginis semen groups (n = 7). The Plantaginis semen groups were treated orally with Plantaginis semen at 0.9375, 1.875 and 3.75 g/kg for 28 days. The levels of serum uric acid (UA), creatinine (Cr), triacylglycerol (TG) and tumor necrosis factor-α (TNF-α) were detected using enzyme-linked immunosorbent assay kits. Ultra performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-Q-TOF/MS) was used as the basis for serum lipidomics analysis, and orthogonal partial least squares discriminant analysis (OPLS-DA) was carried out for the pattern recognition and characteristic metabolites identification. The relative levels of critical regulatory factors of urate anion transporter 1(URAT1) and phosphatidylinositol 3-kinase/ protein kinases B (PI3K/Akt) were determined by quantitative real-time polymerase chain reaction (RT-qPCR). ResultsCompared with the model group, the levels of serum UA, Cr, and TG were significantly (p<0.01) decreased in benzbromarone and three Plantaginis semen groups and the level of serum TNF-α was significantly (p<0.05) decreased in benzbromarone and low dose of Plantaginis semen group. With lipidomics analysis, significant lipid metabolic perturbations were observed in HUA rats, 13 metabolites were identified as potential biomarkers and glycerophospholipid metabolism pathway was mostly affected. These perturbations can be partially restored via treatment of benzbromarone and Plantaginis semen. Additionally, the URAT1 and PI3K/Akt mRNA expression levels were significantly decreased (p<0.05) after treatment with benzbromarone and high dose of Plantaginis semen. ConclusionsPlantaginis semen had significant anti-HUA, anti-inflammatory and renal protection effects and could attenuate potassium oxonate-induced HUA through regulation of lipid metabolism disorder. Trial registrationNot applicable

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“…This approach is briefly discussed in 5.1, but otherwise not covered herein. Instead, the present manuscript focuses on another therapeutic strategy, the inhibition of transporters involved in urate reabsorption [ 76 ]. Both approaches are depicted in Figure 1 with select drugs and drug candidates.…”

Section: Therapeutic Approaches To Treat Hyperuricemia and Goutmentioning

confidence: 99%

“…Albeit some old uricosurics like benzbromarone or probenecid have persisted on the market for decades, the discovery of novel uricosuric drugs is still a hot field with many candidate drugs in various phases of development [ 76 , 89 , 90 ]. Nevertheless, in this review we only discuss drugs and drug candidates with a clinically confirmed uricosuric effect and a well-characterized and publicly available transporter interaction profile.…”

Section: Therapeutic Approaches To Treat Hyperuricemia and Goutmentioning

confidence: 99%

“…Development of dual inhibitors (i.e., inhibitors of XO and URAT1) is an alternative to combination treatment with XO inhibitors and URAT1 inhibitors. Several inhibitors targeting both proteins are in development [ 76 ]. Transporter interaction information, however, is only known for URC-102 (epaminurad), which was described as a selective inhibitor of URAT1 as it inhibits URAT1 more potently than OAT1 or OAT2 [ 132 ].…”

Section: Therapeutic Approaches To Treat Hyperuricemia and Goutmentioning

confidence: 99%

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Modulation of Urate Transport by Drugs

2021

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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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Recent approaches to gout drug discovery: an update

Cited by 31 publications

References 80 publications

Lipidomics study of the therapeutic mechanism of Plantaginis Semen in potassium oxonate-induced hyperuricemia rat

Lipidomics study of the therapeutic mechanism of Plantaginis Semen in potassium oxonate-induced hyperuricemia rat

Lipidomics Study of the Therapeutic Mechanism of Plantaginis Semen in Potassium Oxonate-Induced Hyperuricemia Rat

Modulation of Urate Transport by Drugs

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