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Milan Meloun, Aneta Čápová, Lucie Pilařová, Tomáš Pekárek
Potentiometric and spectrophotometric pH-titrations of the lesinurad for three consecutive dissociation constants determination were compared. Lesinurad is a selective inhibitor of uric acid reabsorption as part of a combination of medicines to treat high levels of uric acid in blood, also called hyperuricemia. Nonlinear regression of the pH-spectra with REACTLAB and SQUAD84 and of the pH-titration curve with ESAB determined three multiple close dissociation constants. The protonation scheme of lesinurad was suggested...
June 4, 2018: Journal of Pharmaceutical and Biomedical Analysis
Robert W Klein, Shaum Kabadi, Frank N Cinfio, Christopher A Bly, Douglas Ca Taylor, Keith A Szymanski
AIM: Estimate budget impact of adopting lesinurad as add-on to allopurinol for urate-lowering therapy in gout. METHODS: A budget impact model was developed for a US payer perspective, using a Markov model to estimate costs, survival and discontinuation in a one-million-member health plan. The population included patients failing first-line gout therapy, followed for 5 years. RESULTS: Incremental costs of adding lesinurad versus no lesinurad were US$241,907 and US$1,098,220 in first and fifth years, respectively...
May 24, 2018: Journal of Comparative Effectiveness Research
Scott Baumgartner, Li-Tain Yeh, Zancong Shen, Bradley Kerr, Kimberly Manhard, Barry Quart
The objective of the study was to evaluate the effect of lesinurad, a selective uric acid uptake inhibitor, alone and in combination with the xanthine oxidase inhibitor allopurinol, on serum uric acid and urinary urate excretion in patients with gout and hyperuricemia. A phase 1b, multicenter, open-label, multiple-dose study was carried out in patients with gout with serum uric acid ≥8 mg/dL following washout of urate-lowering therapy. Patients were treated with allopurinol 300 mg/day alone in week 1; lesinurad 400 or 600 mg/day was added in week 2, followed by lesinurad 400 or 600 mg/day alone in week 3...
May 7, 2018: Journal of Clinical Pharmacology
Phung C On
No abstract text is available yet for this article.
March 15, 2018: American Family Physician
M Ruggeri, M Basile, C Drago, F R Rolli, A Cicchetti
BACKGROUND: Until very recently the only therapeutic alternative for the management of patients affected by gout/hyperuricemia that did not respond to a first-line treatment based on allopurinol alone or who cannot tolerate allopurinol was febuxostat, a xanthine oxidase non-purine-selective inhibitor. Lately, however, a new therapeutic alternative has become available for the management of this pathology: lesinurad, a urate transporter inhibitor. OBJECTIVE: To objective of this study was to evaluate the cost effectiveness of lesinurad/allopurinol in comparison with febuxostat as a second-line therapeutic strategy for the management of patients affected by gout and hyperuricemia that did not respond to a first-line therapy based on allopurinol alone...
May 2018: PharmacoEconomics
Carlo Alberto Scirè, Cristina Rossi, Leonardo Punzi, Augusto Genderini, Claudio Borghi, Walter Grassi
BACKGROUND: Despite being regarded as an easily-treatable disease, gout diagnosis and management can be challenging. REVIEW: This review discusses current issues in gout management and proposes some potential solutions. Gout diagnosis should be reached as early as possible and often requires specific tests, such as synovial fluid analysis or imaging techniques that are not available in most centers, leaving healthcare professionals to rely only on clinical presentations and their experience...
April 12, 2018: Current Medical Research and Opinion
Sergey Aksenov, Carl C Peck, Ulf G Eriksson, Donald R Stanski
To provide insight into pharmacological treatment of hyperuricemia we developed a semi-mechanistic, dynamical model of uric acid (UA) disposition in human. Our model represents the hyperuricemic state in terms of production of UA (rate, PUA), its renal filtration (glomerular filtration rate, GFR) and proximal tubular reabsorption (fractional excretion coefficient, FE). Model parameters were estimated using data from 9 Phase I studies of xanthine oxidase inhibitors (XOI) allopurinol and febuxostat and a novel uricosuric, the selective UA reabsorption inhibitor lesinurad, approved for use in combination with a XOI...
March 2018: Physiological Reports
Stacy L Haber, Gelila Fente, Skylar N Fenton, Elise P Walker, Brianne M Weaver, Alexander J Cano, Katherine Vu
OBJECTIVE: To review the pharmacology, efficacy, and safety of lesinurad and determine its role relative to other agents in the management of chronic gout. DATA SOURCES: A PubMed search (1946 to February 2018) using the terms lesinurad and RDEA594 was conducted to identify relevant articles. STUDY SELECTION AND DATA EXTRACTION: In vitro or in vivo evaluations of lesinurad published in the English language were eligible for inclusion. Phase II and III trials were selected for review of efficacy and safety...
February 1, 2018: Annals of Pharmacotherapy
Khalid A M Attia, Nasr M El-Abasawi, Ahmed El-Olemy, Ahmed H Abdelazim
Lesinurad is a novel selective uric acid reabsorption inhibitor which has been newly approved for the treatment of the chronic gout. The behavior of lesinurad under various stress conditions (hydrolysis, oxidation, thermal and photolysis) has been investigated as per ICH guidelines. The drug has been found to be labile to acidic hydrolysis, basic hydrolysis and oxidation but stable in neutral, thermal and photolytic conditions. A high performance liquid chromatographic method has been developed for selective determination of the studied drug in the presence of its related degradation products...
April 1, 2018: Journal of Chromatographic Science
Robert Case, Brian Wentworth, Grant Jester
A 33-year-old male with poorly controlled chronic tophaceous gout and chronic kidney disease (CKD) with estimated glomerular filtration rate (GFR) of 37 cc/min. His uric acid was 11 mg/dL despite maximal dosing of febuxostat. He had previously failed pegloticase infusions as well. This patient had a reduction in his uric acid level to less than 6 mg/dL following addition of probenecid to his febuxostat regimen. Most guidelines recommend against utilisation of probenecid therapy in patients with GFR <50, but there is no obvious contraindication to its use, provided renal calculi do not develop...
January 31, 2018: BMJ Case Reports
Wenqing Cai, Jingwei Wu, Wei Liu, Yafei Xie, Yuqiang Liu, Shuo Zhang, Weiren Xu, Lida Tang, Jianwu Wang, Guilong Zhao
In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds ( 1a - 1x and 1ha - 1hi ) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50 ) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h , which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0...
January 27, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
(no author information available yet)
No abstract text is available yet for this article.
January 9, 2018: JAMA: the Journal of the American Medical Association
Abhishek Abhishek
PURPOSE OF REVIEW: To discuss recent studies of lesinurad and arhalofenate. RECENT FINDINGS: Lesinurad acts by blocking urate reabsorption channels URAT-1 and OAT-4. It has urate-lowering effect when used alone and in combination with xanthine oxidase inhibitors (XOIs). Its uricosuric activity depends on glomerular filtration, and its' efficacy is impaired at eGFR less than 30 ml/min. Lesinurad monotherapy (400 mg/day) associates with serum creatinine elevations...
March 2018: Current Opinion in Rheumatology
Xiao-Yang Zhou, Ling-Jing Yuan, Zhe Chen, Peng-Fei Tang, Xiang-Yu Li, Guo-Xin Hu, Jian-Ping Cai
Lesinurad is an oral inhibitor of urate-anion exchanger transporter 1 and has been approved by the US Food and Drug Administration for combination therapy with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with refractory gout. In the present study, a sensitive and specific ultra high-performance liquid chromatography with tandem mass spectrometry assay was established and verified for the determination of lesinurad in rat plasma and was described in details for the first time. Chromatographic separation of lesinurad and diazepam (internal standard, IS) was performed on a Rapid Resolution HT C18 column (3...
November 28, 2017: Chemistry Central Journal
(no author information available yet)
No abstract text is available yet for this article.
November 6, 2017: Medical Letter on Drugs and Therapeutics
Graeme Jones, Elena Panova, Richard Day
The aim of this review was to summarize the evidence for combination therapy to achieve serum urate (SUA) target levels in gout. Within this overarching aim, a second aim was to evaluate the evidence for a new uricosuric agent lesinurad, which inhibits urate transport in the kidney. In summary, this review indicates that there are a number of ways to approach patients who do not achieve a target serum urate with allopurinol (APL) monotherapy. These include higher doses of APL up to 600-800 mg/d, switching to febuxostat, or adding in a uricosuric...
2017: Drug Design, Development and Therapy
Philip C Robinson, Nicola Dalbeth
Gout is a common form of inflammatory arthritis caused by deposition of monosodium urate crystals. The central strategy for effective long-term management of gout is serum urate lowering. Current urate-lowering drugs include both xanthine oxidase inhibitors and uricosuric agents. Lesinurad is a URAT1 inhibitor that selectively inhibits urate rebsorption at the proximal renal tubule. Lesinurad 200mg daily in combination with a xanthine oxidase is approved for urate-lowering therapy in patients with gout. Areas covered: The published literature was searched using Pubmed and additional information was obtained from publically available regulatory documents...
December 2017: Expert Opinion on Pharmacotherapy
Anne-Kathrin Tausche, Rieke Alten, Nicola Dalbeth, Jeff Kopicko, Maple Fung, Scott Adler, Nihar Bhakta, Chris Storgard, Scott Baumgartner, Kenneth Saag
Objective: To investigate the efficacy and safety of lesinurad, a selective uric acid reabsorption inhibitor, in a 6 month, phase 3 clinical trial and extension study. Methods: Patients with gout who cannot take a xanthine oxidase inhibitor (XOI) and have serum uric acid (sUA) ⩾6.5 mg/dl were randomized to receive oral lesinurad (400 mg daily) or placebo. The primary endpoint was the proportion of patients with sUA <6.0 mg/dl at month 6. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory data...
December 1, 2017: Rheumatology
Ting Wu, Jiasheng Chen, Shuai Dong, Haixin Li, Ying Cao, Yuanxin Tian, Weimin Fu, Pingzheng Zhou, Baomin Xi, Jianxin Pang
BACKGROUND: Selective inhibitors of human urate transporter 1 (hURAT1) are considered to be effective treatment for hyperuricemia and gout, which can reduce the reabsorption of more than 90% of uric acid in the proximal tubule of the kidney. We aimed to design and synthesize a more potent hURAT1 based on the structure of Lesinurad (LU), which was reported to lower uric acid levels with IC50 value of hURAT1 (about 60μM). METHODS: A cell model was conducted and characterized via Real-time qRCR and Western blot...
May 6, 2017: Pharmacological Reports: PR
Emily Huneycutt, Chase Board, Jennifer N Clements
OBJECTIVE: To review the pharmacokinetics, clinical efficacy, safety, and role of lesinurad for the management of hyperuricemia associated with gout. DATA SELECTION: A MEDLINE search (2000 to April 2017) was conducted using the terms hyperuricemia, gout, URAT-1, URAT-1 transporter, and lesinurad. Published articles and scientific posters relevant to the efficacy and safety of lesinurad were reviewed and summarized. DATA SYNTHESIS: Lesinurad was evaluated in 3 randomized, phase 3 clinical trials (CRYSTAL, CLEAR 1 and 2)...
January 1, 2017: Journal of Pharmacy Practice
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