Introduction: Urate-lowering therapy (ULT) is the cornerstone of gout management, which is a widespread chronic illness characterized by hyperuricemia, arthropathy, tophus development, and urolithiasis. Since asymptomatic increased serum urate levels are associated with a higher risk of cardiovascular, renal and metabolic disorders, a larger use of ULTs in the general population is expected in the near future.Areas covered: This review will focus on the safety and tolerability profile of the available urate-lowering drugs: xanthine oxidase inhibitors (XOIs), uricosuric agents and injectable uricases.Expert opinion: Older drugs for ULT like allopurinol are well studied and extensively described from typical adverse effects (mild skin rash) to unusual fatal reactions, while febuxostat seems to be overall well tolerated. More evidence is required to define the safety profile of topiroxostat, arhalofenate, tranilast, and sulfinpyrazone. Furthermore, there are some unanswered questions about the pharma...

Safety and tolerability of available urate-lowering drugs: a critical review.

This review aims to critically present the available clinical evidence supporting the treatment of chronic hyperuricemia with xanthine oxidase inhibitors. For this reason, the studies published on uric acid (UA)-lowering drugs in the English language from 2000 to August 2019 have been carefully reviewed. The terms "serum uric acid," "xanthine oxidase," "allopurinol," "febuxostat," and "topiroxostat" were incorporated into an electronic search strategy, alone and in combinations, in both MEDLINE (National Library of Medicine, Bethesda, MD) and the Cochrane Register of Controlled Trials (The Cochrane Collaboration, Oxford, UK). Even if new urate-lowering drugs seem of particular efficacy for acute treatment of refractory hyperuricemia, their use is supported by relatively small clinical evidence. On the contrary, large long-term clinical trials have demonstrated that xanthine oxidase inhibitors (XOIs, namely, allopurinol and febuxostat) are effective, safe, and relatively well-tolerated in most of the patients. They have mainly been tested in the elderly, in patients affected by chronic diseases such as heart failure and cancer, and in patients taking a large number of drugs, confirming their safety profile. Recent data also show that they could exert some positive effects on vascular health, renal function, and glucose metabolism. Their cost is also low. In conclusion, XOIs remain the first choice of UA-lowering drug for chronic treatment.

/pdf/clinical-effects-of-xanthine-oxidase-inhibitors-in-5a675ncrhi.pdf

Clinical Effects of Xanthine Oxidase Inhibitors in Hyperuricemic Patients.

This article aims to critically review the evidence on the available therapeutic strategies for the treatment of hyperuricemia. For this reason, several papers were reviewed. Xanthine oxidase inhibitors are the safest and most effective uric acid lowering drugs for the management of chronic hyperuricemia, while the efficacy of uricosuric agents is strongly modulated by pharmacogenetics. Emergent drugs (lesinurad, peglotidase) were found to be more effective for the acute management of refractory hyperuricemia, but their use is supported by a relatively small number of clinical trials so that further well-designed clinical research is needed to deepen their efficacy and safety profile.

https://www.mdpi.com/1648-9144/57/1/58/pdf

Therapeutic Strategies for the Treatment of Chronic Hyperuricemia: An Evidence-Based Update

Introduction: The significant proportion of gout patients not reaching serum urate levels below 6.0 mg/dL and the debated pathogenicity of hyperuricemia (HU) itself motivate investigators to develo...

Investigational drugs for hyperuricemia, an update on recent developments.

Introduction: Inflammation induced by urate deposition in joints causes gout. Healthy individuals maintain serum levels of urate by balancing urate production/excretion, whereas a production/excret...

Recent approaches to gout drug discovery: an update

Objective Verinurad (RDEA3170) is a high-affinity, selective URAT1 inhibitor in development for treating gout and asymptomatic hyperuricaemia. This study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad in combination with febuxostat in adults with gout. Methods The phase IIa, open-label, multicentre study randomised 64 subjects into one of five cohorts to receive febuxostat (40 or 80 mg) alone or in combination with verinurad 2.5–20 mg. Serial plasma/serum and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse events, chemistry panels, ECGs and physical examinations. Results Serum pharmacodynamic data demonstrated the maximum percent decrease in serum urate (sUA) from baseline (E max ) at 8–12 hours after dosing. Verinurad with febuxostat decreased sUA in a dose-dependent manner. E max for verinurad with febuxostat 40 mg ranged from 52% to 77% vs 42% for febuxostat 40 mg alone; E max for verinurad with febuxostat 80 mg was 62%–82% vs 55% for febuxostat 80 mg alone. Urinary uric acid excretion rate was reduced below baseline by febuxostat alone and was comparable to baseline for verinurad with febuxostat. Verinurad plasma exposure increased with dose and was comparable when combined with febuxostat. No drug-drug interactions were observed. Verinurad was well tolerated with no clinically meaningful changes in laboratory values. Conclusion Verinurad administered with febuxostat produced dose-dependent decreases in sUA while maintaining urinary uric acid levels comparable to baseline. These dose combinations of verinurad and febuxostat were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout. Trial registration number NCT02246673

https://rmdopen.bmj.com/content/rmdopen/4/1/e000584.full.pdf

Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study.

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Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study.