Status of the research and development of gout therapy drugs

original title: The status quo of the development of gout therapy drugs
Gout diseasegout is a crystal-dependent joint disease caused by single sodium uric acid (MSU) deposition, which is directly related to hyperuric acidemia caused by the metabolic disorder and/or decrease in uric acid excretion, and belongs to the category of metabolic rheumatismUric acid is the final product of the metabolism of radon compounds, and the metabolites can cause high uric acidemia by increasing the level of uric acidAt present, the incidence of gout in the world is increasing year by year, but there are few effective and few adverse reactionsThe prevalence of gout in the U.Srose from 2.64 percent in 1988-1994 to 3.76 percent in 2007-2010, according to the National Health and Nutrition Survey (NHANES)The prevalence of gout in the UK in 2012 was about 2.49 per cent, according to a large data on the health files of 1.2 million BritonsAt present, the prevalence of gout in China is 1%-3%, and is on the rise year by yearthe basic goal of gout treatmentis to reduce and maintain serum uric acid levels (6.8 mg/dl, so that existing uric acid crystals dissolve without further crystallization, reducing or even eliminating gout episodes)clinically divided gout into four periods:(1) asymptomatic hyperuric acidemia,(2) acute gout arthritis: patients will develop severe pain at the affected joint area,(3) the inter-onset period of the disappearance of symptoms,(4) chronic gout arthritis: ureaic acid deposits in cartilage, sliding membrane slick and soft tissue, the formation of gout stoneAcute stage gout commonly used anti-inflammatory drugs, other periods generally use drugs to promote uric acid excretion or inhibit uric acid synthesis to reduce hyperuric acidemia to prevent acute episodes of gout 1 Gout clinical diagnostic criteria 2016 China Gout Guidelines using the 2015 American Society of Rheumatosis (American Institute of Rheumatology, ACR) anti-rheumatic disease (European Union) The standard is integrated into the comprehensive analysis of clinical, laboratory and imaging parameters, and can be used for the acute and intermittent periods of gout, which can effectively distinguish gout from other diseases The classification criterion consists of 3 aspects, 8 entries, a total of 23 points, when the score of 8 points, can diagnose gout Figure 1 The gout diagnostic criteria of the 2016 China Gout Guide 2 The existing clinical drugs and problems of gout gout therapy drugs are divided into gout acute treatment drugs and high uric acidemia treatment drugs 2.1 Acute treatment drugs for gout
Table 1 The acute stage of gout clinical treatment drugs 2.2 high uric acidemia treatment drugs 3.2.1 to promote the discharge of uric acid drugs
these drugs by inhibiting the reabsorption of uric acid in the near-end renal tube Most gout patients have less uric acid excretion, so patients with normal or mild kidney function, urinary stones and ureane nephropathy may choose to use uric acid urea reabsorption transporter 1 (uratereuptaketransporter, URAT1) is the main protein found in the kidneys for the transport of uuric acid, which can be transferred from the tube cavity to the near-curved small tube epithelial cells and converted into monochotate Figure 2 URAT1 mechanism Table 2 UART1 inhibitor drugs 3.2.2 drugs to inhibit the synthesis of uric acid
jaundice oxidase (XOD) catalytic jaundice and subjatrino seine to produce uric acid process is a key target of gout and high uric acid drug research Bethanol is an inhibitor acting on the binding site of jaundice in the jaundice oxidase, and is an enzyme's substrate analogue However, there are many adverse reactions, there are liver, bone marrow toxicity in addition to XO inhibitors, inhibited uric acid formation, there are argon nucleoside phosphatase (PNP) inhibitors Their inhibition of uric acid formation pathways is shown in Figure 3 Figure 3 The formation pathway of uric acid and the role of enzyme inhibitors in table 2 Table 3 Inhibitulate acid synthesis drug 3.2.3 to promote the conversion of uric acid into uerocystic drugs
in animals, uric acid can be oxidized by uric acid oxidase into water-soluble uerocec, uric acid is an easy to excrete metabolites However, the human body is missing this uric acid oxidase, so artificially replenishing this enzyme, but also to promote uric acid excretion, reduce blood uric acid levels of a strategy rasburicase was approved by the U.S FDA in July 2002 to treat and prevent acute hyperuric acidemia in patients with high-risk tumor-dissolved syndrome, especially for patients with hyperuric acidemia caused by chemotherapy Labrease can quickly reduce uric acid levels in the serum, and can dissolve gout, the effect is better than other puritanol, more suitable for patients who do not tolerate conventional therapy, but the drug is expensive, short half-life (only 18h), need frequent injections, and easy to cause hypersensitivity and induce high-speed hemoglobin disease, so clinical use is limited 3.2.3 Problems with existing drugs
Figure 4 Existing problems of high uric acid treatment drugs
3.The current status of gout drug development
4.1 target to uric acid reabsorption transshipment 1 (URAT1) in the field of research drugs the current research hot spot in the field of gout is urea reabsorption transshipment 1 (URAT1), in the database Medtrack found in URAT1 inhibitors, research and development into the clinical stage of the drug table 4 It can be seen that the current domestic Jiangsu Hengrui SHR4640 has entered the clinical Phase I, is currently the fastest progress of domestic research and development of drugs table 4 Targeting URAT1 in the research drug (clinical stage) 4.2 other targeted in the study drug table 5 for medtrack database found in the treatment of gout other targets into the clinical stage of the drug, of which jaundice oxidase (XO) inhibitors accounted for the majority, followed by leukocyte interleukin-1 beta (IL-1 beta) inhibitors, some of the drug action mechanism has not been clear The sel037 of Shenyang Sansheng, a domestic enterprise, has entered clinical phase II worldwide and is the fastest development in the treatment of gout drugs by other mechanisms 4 Summary
At present, the clinical use of anti-inflammatory drugs are symptom-relieving drugs, can not treat gout, based on the kidney tube of urea has a heavy absorption of metabolic steps, treatment of gout needs to start from promoting uric acid discharge and inhibit uric acid production two aspects, combined drug is the mainstream therapy the star target of uric acid excretion, URAT1, has been listed on the market for two drugs, Benbron and Lesinurad and Zurampic However, both drugs have side effects such as liver and nephrotoxicity and cannot be used clinically for long periods of time, which is the biggest reason for the low sales of Lesinurad and Zurampic (Table 6) Table 6 Redtrack Sales Forecast (Medtrack) so now experts in the gout field are developing mainly to find drugs with low hepatic and renal toxicity, and to have better drug properties, including longer half-life, moderate Cmax, low efficacy doses, and high bioavailability New drugs for Me-better have been developed to meet existing clinical needs and reduce clinical drug limitations new drugs for the quality of life of the vast number of gout patients is significant, the potential market is large, research and development ideas are clear, UART1 inhibitors have been clinically proven, only need to be further improved, the risk of research and development failure is small, so UART1 is a research and development track worthy of attention references: Thelancet.August17, 2010.
Advances in the development of anti-gout drugs, Shanghai Pharma, 2015, Vol 36, Issue 17, P19-21.
[3] Medtrack Database.
Pharmaceutical ring copyright notice: This article transferred from the focus of medical health author: Dr Li Mengyuan, if you do not wish to be reproduced by the media or individuals can contact us, we will immediately delete