Dotinurad: a novel selective urate reabsorption inhibitor as a future therapeutic option for hyperuricemia.

Gout is a chronic inflammatory disease caused by precipitation of urate crystals in the joints, kidneys, and urinary tract. Independent of urate deposition disorders, recent studies have shown a positive association between circulating uric acid (UA) levels and cardiovascular (CV) diseases. These results indicate that UA is a precipitating factor of both gout and the progression of CV diseases, including hypertension and/or chronic kidney disease (CKD). A large body of evidence has shown that UA-lowering therapies are effective in preventing the progression of hypertension/CKD and that a causal relationship exists between serum UA level and CV diseases. Despite the urgent need for effective UA-lowering drugs that can be used to obtain better therapeutic outcomes and prognosis, only few drugs have been developed in the past decades. Recently, febuxostat and topiroxostat, which are xanthine oxidoreductase inhibitors, were developed and used in clinical practice. Of note, after the approval of lesinurad, which is a urate transporter-1 (URAT-1) inhibitor, in the United States in 2015, dotinurad (Fig. 1), a novel promising drug with selective UA reabsorption inhibitory property, was recently developed in Japan in 2018. Dotinurad is indicated for patients with hyperuricemia/gout as most patients with hyperuricemia are classified into "underexcretion type", which requires the inhibition of URAT-1 to excrete excess UA via the kidney. Focusing on dotinurad, the present study highlighted the multifaceted preliminary new trials that assessed for drug efficacy and safety, pharmacokinetics (PK) according to age and gender, the presence or absence of liver and kidney disorders, drug interactions with NSAID, and non-inferiority of dotinurad to either febuxostat or benzbromarone. A series of studies included in this supplemental review indicate that dotinurad reduces serum UA levels, and its efficacy and safety are similar to those of other UA-lowering agents currently used even in hyperuricemic patients with various clinical conditions. Moreover, two exploratory studies with a small sample size were conducted to compare PK parameters between patients with overproduction- and underexcretion-type hyperuricemia, and results showed that the effects of UA-lowering agents were comparable between the two subtype groups.Fig. 1Chemical structural formula of dotinurad.

Association of gout medications and risk of cataract: a population-based case-control study.

BACKGROUND: The relationship between gout medication use and cataract development is controversial. Moreover, limited clinical studies have evaluated this relationship. AIM: To assess the effects of colchicine, allopurinol and benzbromarone on the risk of cataract in patients with gout. DESIGN: Population-based nested case-control study. METHODS: We enrolled 7900 patients who had received a new diagnosis of cataract >3 years after gout diagnosis into the study group and 33 475 patients who did not receive a diagnosis of cataract into the control group by matching for age, sex and the year of gout diagnosis at a ratio of 1:1. We used World Health Organization's defined daily dose (DDD) as a measure to assess the dosage of colchicine, allopurinol and benzbromarone exposure. Logistic regression was used to estimate crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of cataract. RESULTS: The risk of cataract significantly increased in patients who received colchicine at a cumulative DDD of ≥66.5 (OR = 1.17, 95% CI = 1.01-1.36, P = 0.041). In the age-stratified analysis, patients with gout aged >60 years had a higher risk of cataract (OR = 1.27, 95% CI = 1.06-1.53, P = 0.011) than did patients aged <60 years. Allopurinol and benzbromarone had no association with cataract. CONCLUSIONS: In this population-based nested case-control study, we observed that colchicine use increased the risk of cataract in patients with gout, especially in those aged >60 years who received colchicine at a cumulative DDD of >66.5.

Activation of peripheral KCNQ channels relieves gout pain.

Intense inflammatory pain caused by urate crystals in joints and other tissues is a major symptom of gout. Among therapy drugs that lower urate, benzbromarone (BBR), an inhibitor of urate transporters, is widely used because it is well tolerated and highly effective. We demonstrate that BBR is also an activator of voltage-gated KCNQ potassium channels. In cultured recombinant cells, BBR exhibited significant potentiation effects on KCNQ channels comparable to previously reported classical activators. In native dorsal root ganglion neurons, BBR effectively overcame the suppression of KCNQ currents, and the resultant neuronal hyperexcitability caused by inflammatory mediators, such as bradykinin (BK). Benzbromarone consistently attenuates BK-, formalin-, or monosodium urate-induced inflammatory pain in rat and mouse models. Notably, the analgesic effects of BBR are largely mediated through peripheral and not through central KCNQ channels, an observation supported both by pharmacokinetic studies and in vivo experiments. Moreover, multiple residues in the superficial part of the voltage sensing domain of KCNQ channels were identified critical for the potentiation activity of BBR by a molecular determinant investigation. Our data indicate that activation of peripheral KCNQ channels mediates the pain relief effects of BBR, potentially providing a new strategy for the development of more effective therapies for gout.

Anti-inflammatory and immunomodulatory effects of iridoid glycosides from Paederia scandens (LOUR.) MERRILL (Rubiaceae) on uric acid nephropathy rats.

AIMS: Uric acid nephropathy (UAN) is due to excessive uric acid, which leads to hyperuricemia and kidney damage via the deposition of urate microcrystals in the kidneys. Iridoid glycosides of Paederia scandens (IGPS) is a major active component isolated from the traditional Chinese herb P. scandens (LOUR.) MERRILL (Rubiaceae). This study aimed to evaluate the anti-inflammatory and immunomodulatory effects of IGPS and its mechanism on UAN rats. MAIN METHODS: The experimental model of UAN rats was induced by using uricopoiesis promoter adenine and uricase inhibitor potassium oxonate (PO). Treatment groups received three different doses of IGPS, allopurinol (AP) and benzbromarone (BEN) daily for 24days respectively. The histopathology of renal tissues in UAN rats were assessed for conventional morphological evaluation. The nuclear factor-κBp65 (NF-κBp65), monocyte chemoattractant protein-1 (MCP-1) and α-smooth muscle actin (α-SMA) protein expression of renal tissues in UAN rats were investigated by immunohistochemistry. MCP-1 and α-SMA mRNA levels were monitored by method of reverse transcription polymerase chain reaction (RT-PCR). KEY FINDINGS: Treatment with IGPS significantly ameliorated UAN induced renal tissue injury, inhibited the biological activity of NF-κBp65, MCP-1 and α-SMA, and suppressed the mRNA expressions of MCP-1 and α-SMA. SIGNIFICANCE: IGPS exerts a protective effect against renal injury in UAN rats, possesses anti-inflammatory and immunomodulatory effects by inactivating NF-κBp65 pathway transmembrane signal transduction, down regulating the expression of MCP-1 and α-SMA to modulate pro-inflammatory mediator production in nephropathy tissue to improve renal fibrosis in UAN rats.

[Stage-based treatment of integrative medicine on the quality of life in patients with gout].

OBJECTIVE: To investigate the quality of life in patients with gout and their influencing factors, and to observe the effects of the intervention program of stage-based treatment of integrative medicine (IM). METHODS: Totally 120 patients with acute attack of gout within 72 h were randomly assigned to the treatment group and the control group, 60 in each group. Patients in the treatment group were treated with Huzhang Tongfeng Granule (HTG), diclofenac sodium extended-release capsule and Jinhuang Ointment (JO) in the acute stage, and Yinlian Tongfeng Granule (YTG) and Benzbromarone Tablet (BT) in the intermission stage. Patients in the control group were treated with diclofenac sodium extended-release capsule in the acute stage, and BT in the intermission stage. All patients were treated for 12 weeks. The quality of life (QOL) before and after treatment was investigated by questionnaire. RESULTS: Before treatment there were no statistical difference in the physiological function, psychological function, social function, health self-awareness and total score between the two groups (P > 0.05). After treatment the scores of the four aspects and the total score were significantly improved in the two groups (P < 0.01). And the improvement of the treatment group was better than that of the control group (P < 0.01). There was no statistical difference in the gender, age, marital status, educational level, QOL with or without associated disease between the two groups (P > 0.05). The QOL of patients with joint stiffness or deformity was less than that of those without joint stiffness or deformity (P < 0.01). The total QOL scores of the gout patients were obviously correlated with the course of diseases (r = -0.324, P < 0.01). CONCLUSIONS: The QOL of patients with gout was correlated with the course of disease and joint stiffness or deformity. Stage-based treatment of IM could significantly improve the QOL of f out patients.

[Assessment on the clinical efficacy and safety of xiezhuo chubi recipe in treating hyperuricemia].

OBJECTIVE: To observe the clinical efficacy and safety of Xiezhuo Chubi Recipe (XCR) on hyperuricemic patients. METHODS: 99 patients with hyperuricemia were randomly assigned to the XCR group, the Benzbromarone group, and the blank control group. Patients in the XCR group took XCR, one dosage daily, twice per day. Patients in the Benzbromarone group took Benzbromarone Tablet (50 mg each tablet, once per day). Patients in the blank control group were not treated with any drug, but only with clinical observation. Twenty days consisted of one course of treatment. The laboratory data including uric acid, blood routines, urine routines, the liver function, and the renal function were statistically analyzed before and after treatment. RESULTS: The blood uric acid decreased in the three groups after treatment (P<0.05). The total effective rate was 85.71% in the XCR group, 92.86% in the Benzbromarone group, and 23.33% in the blank control group. There was no statistical difference between the XCR group and the Benzbromarone group (P>0.0167). There was no significant difference in the safety indices such as blood routines, urine routines, liver functions, and renal functions of the XCR group between before and after treatment (P>0.05). CONCLUSION: XCR could effectively reduce the uric acid level with higher safety.

A benefit-risk assessment of benzbromarone in the treatment of gout. Was its withdrawal from the market in the best interest of patients?

Benzbromarone, a potent uricosuric drug, was introduced in the 1970s and was viewed as having few associated serious adverse reactions. It was registered in about 20 countries throughout Asia, South America and Europe. In 2003, the drug was withdrawn by Sanofi-Synthélabo, after reports of serious hepatotoxicity, although it is still marketed in several countries by other drug companies. The withdrawal has greatly limited its availability around the world, and increased difficulty in accessing it in other countries where it has never been available.The overall aim of this paper is to determine if the withdrawal of benzbromarone was in the best interests of gouty patients and to present a benefit-risk assessment of benzbromarone. To determine this, we examined (i) the clinical benefits associated with benzbromarone treatment and compared them with the success of alternative therapies such as allopurinol and probenecid, particularly in patients with renal impairment; (ii) the attribution of the reported cases of hepatotoxicity to treatment with benzbromarone; (iii) the incidence of hepatotoxicity possibly due to benzbromarone; (iv) adverse reactions to allopurinol and probenecid. From these analyses, we present recommendations on the use of benzbromarone.Large reductions in plasma urate concentrations in patients with hyperuricaemia are achieved with benzbromarone and most patients normalize their plasma urate. The half-life of benzbromarone is generally short (about 3 hours); however, a uricosuric metabolite, 6-hydroxybenzbromarone, has a much longer half-life (up to 30 hours) and is the major species responsible for the uricosuric activity of benzbromarone, although its metabolism by cytochrome P450 (CYP) 2C9 in the liver may vary between patients as a result of polymorphisms in this enzyme. It is effective in patients with moderate renal impairment. Standard dosages of benzbromarone (100 mg/day) tend to produce greater hypouricaemic effects than standard doses of allopourinol (300 mg/day) or probenecid (1000 mg/day).Adverse effects associated with benzbromarone are relatively infrequent, but potentially severe. Four cases of benzbromarone-induced hepatotoxicity were identified from the literature. Eleven cases have been reported by Sanofi-Synthélabo, but details are not available in the public domain. Only one of the four published cases demonstrated a clear relationship between the drug and liver injury as demonstrated by rechallenge. The other three cases lacked incontrovertible evidence to support a diagnosis of benzbromarone-induced hepatotoxicity. If all the reported cases are assumed to be due to benzbromarone, the estimated risk of hepatotoxicity in Europe was approximately 1 in 17 000 patients but may be higher in Japan.Benzbromarone is also an inhibitor of CYP2C9 and so may be involved in drug interactions with drugs dependent on this enzyme for clearance, such as warfarin. Alternative drugs to benzbromarone have significant adverse reactions. Allopurinol is associated with rare life-threatening hypersensitivity syndromes; the risk of these reactions is approximately 1 in 56 000. Rash occurs in approximately 2% of patients taking allopurinol and usually leads to cessation of prescription of the drug. Probenecid has also been associated with life-threatening reactions in a very small number of case reports, but it frequently interacts with many renally excreted drugs. Febuxostat is a new xanthine oxidoreductase inhibitor, which is still in clinical trials, but abnormal liver function is the most commonly reported adverse reaction.Even assuming a causal relationship between benzbromarone and hepatotoxicity in the identified cases, benefit-risk assessment based on total exposure to the drug does not support the decision by the drug company to withdraw benzbromarone from the market given the paucity of alternative options. It is likely that the risks of hepatotoxicity could be ameliorated by employing a graded dosage increase, together with regular monitoring of liver function. Determination of CYP2C9 status and consideration of potential interactions through inhibition of this enzyme should be considered. The case for wider and easier availability of benzbromarone for treating selected cases of gout is compelling, particularly for patients in whom allopurinol produces insufficient response or toxicity.We conclude that the withdrawal of benzbromarone was not in the best interest of patients with gout.

[Stage-based treatment of gouty arthritis by combination therapy of traditional Chinese and Western medicines: a randomized controlled trial].

OBJECTIVE: To evaluate the clinical therapeutic effect of the combination therapy of traditional Chinese and Western medicines in treating gouty arthritis based on the stage of disease, and to explore a safe, effective and reasonable therapeutic regimen for prevention and treatment of gouty arthritis. METHODS: One hundred and sixty-six cases of gouty arthritis were divided into three groups randomly, 58 cases in traditional Chinese drug (TCD)-treated group, 56 cases in Western medicine (WM)-treated group and 52 cases in TCD plus WM-treated group. They were all treated for 12 weeks. In the acute stage, patients in TCD-treated group were treated with Huzhang Gout Granule and Jinhuang Ointment, and patients in WM-treated group were treated with diclofenac sodium dual release enteric-coated capsules. In the intermission, patients in TCD-treated group were given Yinlian Gout Granule, and patients in WM-treated group were given benzbromarone or allopurinol. Patients in TCD plus WM-treated group were given both TCD and WM. Clinical symptom score and blood uric acid (BUA) level were measured. The effect initiating time, relapse rate, efficacy rate and the incidence rate of adverse effects were also studied. RESULTS: There were no significant differences in the efficacy rate and effect initiating time among the three groups in the acute stage. The clinical symptom score and BUA level were obviously reduced in three groups. In the intermission, BUA level in the WM-treated group and TCD plus WM-treated group were obviously reduced. Although there was a drop tendency in the BUA level in TCD-treated group, there was no statistical difference. The relapse rates in TCD-, WM- and TCD plus WM-treated groups were 12.07%, 26.79% and 9.62%, respectively. There was statistical difference in relapse rates among the three groups (P<0.05). The relapse rate was decreased in TCD plus WM-treated group as compared with those in TCD-treated and WM-treated groups. The average clinical symptom scores during recurrence in the three groups were (10.00+/-3.61), (12.38+/-1.85) and (10.75+/-1.89), respectively. The incidence of adverse effects in TCD-treated group (3.45%) was lower than the other two groups (21.43% and 15.38%). CONCLUSION: The combination therapy of traditional Chinese and Western medicines based on the stage of disease can control the symptoms of gouty arthritis in the acute stage, improve joint function, and can control the BUA level during the intermission, prevent recurrence and relieve the adverse effects.

[The effect of benzbromarone on fasting-hyperuricemia as a model (author's transl)]. / Zur Wirkung von Benzbromaron am Modell der "Fastenhyperurikämie".

The effect of daily therapeutic doses of 100 mg benzbromarone (Normurat) and 2.0 g probenecid on the purine metabolism of 40 test subjects was investigated. Fasting-hyperuricemia was used as the model and particular attention paid to the mechanisms of renal elimination. Urate concentration remains under the solubility threshold when benzbromarone is administered, in contrast to medication with probenecid. The significantly greater hypouricemic effect of benzbromarone correlates with a significant rise in the excretion and clearance of uric acid in comparison to probenecid, accompanied by a stronger depression of tubular reabsorption. Serum levels, clearances and reabsorption rates demonstrate the prolonged effect of the benzofurane derivative Normurat even during strict fasting. Supplementary allantoin and urea determinations gave no indication of increased enterobacterial uricolysis. Normurat was well tolerated, side effects were not noted.