Since the earliest occurrence of colchicine, significant progress has been made in the treatment of gout. However, despite this, there are still many patients who have failed to achieve the expected therapeutic effects. At the same time, due to a high protein diet, excessive alcohol consumption, and lifestyle changes, people are exercising less and becoming obese, leading to a gradual increase in the prevalence of gout worldwide. In this context, people have gained a deeper understanding of the pathogenesis of hyperuricemia and gout, and new drugs have been introduced. This article will summarize the research progress of new drugs in the treatment of hyperuricemia and gout.
1、 New anti-inflammatory drugs
The pathogenesis of gout involves macrophage phagocytosis of monosodium urate (MSU), leading to the formation of NLRP3 inflammatory bodies, thereby activating caspase. The resulting inflammatory cascade leads to the release of cytokines, especially interleukin (IL) - 1 β And IL-18. IL-1 binding to endothelial IL-1 receptors leads to signal transduction, release of inflammatory mediators, and neutrophil recruitment, which is the cause of symptoms and progression of gout. Therefore, drugs that inhibit any of these inflammatory pathways have the potential to treat gout.
1. IL-1 inhibitor
Canakinumab is a humanized anti IL-1 β Monoclonal antibody, with a standard dose of 155 mg, has been approved in Europe for the treatment of refractory gout; Gevokizumab is a humanized anti IL-1 α Monoclonal antibodies, with a standard dose of 60 mg i.v. per month, are currently undergoing clinical trials for the treatment of refractory gout. In addition, anabolin is an IL-1 receptor antagonist that can inhibit IL-1 α And IL ‐ 1 β The standard dose for binding to receptors is 100 mg per day subcutaneous injection for 3 consecutive days; Rilonacept is a fusion protein that binds IL-1 as a soluble receptor α And IL ‐ 1 β， The standard dose is 80-120 mg per week.
2. Bucillamine
Buxilamine is a derivative of D-penicillamine with anti-inflammatory and antioxidant effects, which has been approved for the treatment of rheumatoid arthritis in Japan. Studies from the United States have found that 900 mg or 1800 mg of busilamine per day is similar or more effective than 1.8 mg of colchicine.
3. Caspase inhibitor
Pralnacasan is a reversible caspase-1 inhibitor, while Emricasan is an irreversible caspase inhibitor, both of which block IL-1 by blocking IL-1 β Secrete and act.
2、 New uric acid lowering drugs
Xanthine oxidase inhibitor
Topithostat is a highly selective inhibitor of xanthine oxidase, which is mainly inactivated by liver metabolism and excreted through urine and feces. Because topirastin and its metabolites are not affected by the kidneys, it is a better choice for patients with chronic kidney disease, and it can also reduce proteinuria in these patients with kidney disease. Studies have shown that topirastin 120 mg per day can achieve the same uric acid lowering effect as allopurinol 200 mg per day. In 2013, Topistat was approved for gout indications in Japan at a dose of 20-80mg twice daily. Side effects include nasopharyngitis, elevated transaminases, leukopenia, and eczema.
2. Uricase
Although recombinant uricase is effective against gout, it has high immunogenicity. Polyethylene glycolation can help reduce immunogenicity, but even polyethylene glycolated uricase can lead to the formation of anti drug antibodies. SEL212 is a polyethylene glycolated uricase that is administered in combination with ImmTOR7 to reduce the formation of anti drug antibodies. Currently, a phase 3 clinical trial of its treatment for gout is underway.
3. Drugs that promote uric acid excretion
These drugs are the preferred drugs for "insufficient excretion" type hyperuricemia. The novel uric acid lowering drug RDEA 594 (lesinurad) is a selective urate reabsorption inhibitor (SURI). "Lesinurad 200 mg daily and used in combination with xanthine oxidase inhibitors can continuously reduce blood uric acid levels, and has been shown to be superior to non budestar monotherapy in combination with non budestar.". The common side effects are renal dysfunction and kidney stones.
Verinsud is another SURI currently in the phase 2 clinical trial phase. It is reported that its efficacy is three times that of benzbromarone. Dotinurad is a new type of SURI, whose structural design is aimed at avoiding the hepatotoxicity of benzbromarone.
3、 Drugs with dual mechanisms
"Arhalofenate is a new drug with dual anti-inflammatory and uric acid lowering effects, which can inhibit renal tubular uric acid reabsorption and increase excretion, thereby slowly reducing blood uric acid levels.". It can also partially activate oxide body proliferators and activate receptors γ （PPAR- γ）， Thereby exerting anti-inflammatory effects and reducing gout attacks. This drug is considered an effective alternative to colchicine. Arhalofenate also has the effect of reducing blood fat and blood sugar, which has additional benefits for gout patients with diabetes and dyslipidemia.
"Merbarone (RLBN1001) is a type II DNA topoisomerase inhibitor that can double inhibit xanthine oxidase and URAT1 in the treatment of severe hyperuricemia.".
4、 Drugs with novel mechanisms of action
⏵ NLRP3 inflammatory corpuscle inhibitor: Dapansultrie can selectively inhibit NLRP3 inflammatory corpuscles, thereby inhibiting IL-1 β And IL-18 production, thereby reversing inflammation. Therefore, it has therapeutic potential in gout and other NLRP3 mediated diseases.
⏵ Purine nucleoside phosphorylase (PNP) inhibitor: Ulodesine (BCX4208) has synergistic effects when combined with allopurinol.
⏵ Other: tuna extract; Targeted participation in IL-1 β Extracellular processing of proteases may be a potential strategy for the treatment of acute gout.
5、 "Cross border" drugs in other fields
"Corticotropin (ACTH): It is believed to have anti IL-1 effects.". Studies have shown that ACTH is an effective option for treating gout patients with multiple comorbidities, especially those who take steroids after surgery and in other situations, such as after kidney transplantation.
⏵ Fenofibrate: As a PPAR agonist, it can downregulate the expression of COX-2, resulting in anti-inflammatory effects that may help prevent gout attacks.
⏵ Amlodipine: It can significantly improve glomerular filtration rate and uric acid clearance, and has been found to be an effective choice for renal transplant patients with hypertension and cyclosporin A induced hyperuricemia.
⏵ Atorvastatin: Some studies have found that Atorvastatin can significantly reduce blood uric acid levels. Although the exact mechanism is unclear, it is currently believed that it mainly plays a role in reducing uric acid excretion by reducing renal tubular reabsorption and increasing uric acid excretion.
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