Gout is caused by hyperuricemia and is the most common cause of acute painful arthritis. Hyperuricemia is defined as serum uric acid (sUA) concentration >7.0 mg/dL for man and > 6.0 mg/dL for woman. Uric acid is the end product of purine metabolism in humans and has a poor pH-dependent solubility. Its production is catalyzed by xanthine oxidase in the liver, and over 70% of the daily output of uric acid is excreted through the kidneys. A urate-anion transporter 1 (URAT1) plays a significant role in regulating serum urate through reabsorption of urate from the lumen to the cytosol in kidney tubules. The primary cause of gout and hyperuricemia is inefficient excretion of uric acid by the kidneys.
Uric acid has a poor pH-dependent solubility in aqueous solutions, which leads to the deposition of needle-like crystals in joints and soft tissues throughout the body. When this becomes symptomatic in a patient, gout is diagnosed. The symptoms of gout include an acute, extremely painful attack of arthritis accompanied by erythema, elevated temperature, swelling, and edema of the skin. Additionally, gout commonly presents other serious health problems (comorbidities) including cardiovascular disease, obesity, diabetes and kidney impaired renal function. It was reported that hyperuricemia is associated with the progression of chronic kidney disease (CKD). Therefore, management of sUA is clinically important to avoid complications related to hyperuricemia.
Gout management involves both short-term and long-term medications. Short-term treatment only relieves pain and reduces inflammation during an acute attack.
The goal for Long-term treatment of gout is to lower serum uric acid levels. These medications include uricosuric agents (URAT1 inhibitors) and xanthine oxidase inhibitors.
1. Uricosuric agents: to decrease uric acid in the kidneys - Benzbromarone (ex-US) and Zurampic.
Benzbromarone is not approved in the US and was withdrawn from European markets in 2003 due to serious hepatotoxicity including fulminant or fatal liver injury. It is also a strong inhibitor of CYP2C9, which would cause undesired drug-drug interactions. However, it has been marketed in more than 20 countries including Japan, Germany, Brazil, China and New Zealand for past 40 years due to the lack of good uricosuric agents in the world.
Zurampic has fateful side effects with a boxed warning for risks of acute renal failure. The major adverse cardiovascular events of Zurampic have been observed in clinical trials; Zurampic has other undesired side effects.
2. Xanthine oxidase inhibitors: to decrease the production of uric acid in the body - Allopurinol, Febuxostat.
Allopurinol may lead to Stevens Johnson syndrome (serious red skin rash), a potentially fatal disease. It also results stomach upset, nausea, diarrhea, headache, fever, loss of appetite, unexpected weight loss, painful urination, blood in the urine, itching or drowsiness.
Febuxostat has been associated with cardiovascular complications, causing the FDA to require a cautionary statement on the drug insert. In addition, this drug can result in severe GI discomfort and abnormal liver function. The other common side effects of Febuxostat include nausea, gout flares, joint pain and rash.
Either uricosuric agents or xanthine oxidase inhibitors do not currently meet the requirement of gout medications. The world needs a good gout drug with an excellent efficacy lowering uric acid and a great safety.
URAT1 Inhibitors for Gout treatment (Uricosuric Drug)
· Clinically Significant Reduction of Serum Urate from Phase 1
· Great Potency both in Vitro and in Vivo
· Very Good Safety Profiles in Monkeys and Rats
· Good PK
· Potential Safe and Potent Gout Drug for Worldwide Market