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Introduction: 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...
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Introduction: 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.
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Three chemometric assisted spectrophotometric approaches were designed for precise quantitative analysis of lesinurad and allopurinol, in their recently FDA approved combination pharmaceutical dosage form. By utilizing the recorde...
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Three chemometric assisted spectrophotometric approaches were designed for precise quantitative analysis of lesinurad and allopurinol, in their recently FDA approved combination pharmaceutical dosage form. By utilizing the recorded absorption spectral data of lesinurad and allopurinol mixtures, principle component regression, partial least squares and genetic algorithm partial least squares were developed and compared for the spectrophotometric quantitative analysis of the cited drugs in their binary mixture. Experimental design for different concentrations of the studied drugs was done based on the spectral sensitivity and the commercial ratio of the two drugs in the combined pharmaceutical dosage form. Optimization of the described models was done using five-levels, two factors experimental design principle. Quantitative assay of the two drugs in Duzallo (R) tablet was successfully done and the data obtained was statistically compared with the results of another published HPLC quantitative analytical method. (c) 2020 Published by Elsevier B.V.
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(+)- and (?)-Lesinurad were isolated as atropisomers from racemic lesinurad for the first time. No interconversion was observed between the two atropisomers under various conditions tested. The two atropisomers showed significant ...
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(+)- and (?)-Lesinurad were isolated as atropisomers from racemic lesinurad for the first time. No interconversion was observed between the two atropisomers under various conditions tested. The two atropisomers showed significant differences in hURAT1 highly expressed HEK293 cell-based inhibition assays, monkey pharmacokinetic studies, and in vitro human recombinant CYP2C9 stability studies. It was speculated that (+)-lesinurad might offer a better hyperuricemia/gout therapy than (?)-lesinurad or the racemate.
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Abstract Lesinurad is a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors (XOIs). Open‐label pharmacokinetic studies were...
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Abstract Lesinurad is a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors (XOIs). Open‐label pharmacokinetic studies were performed in volunteers or subjects with hyperuricemia (serum uric acid ≥ 8 mg/dL) to investigate interactions of lesinurad (with and without concurrent XOIs) with colchicine and 2 nonsteroidal anti‐inflammatory drugs: naproxen and indomethacin. Colchicine studies included consecutive 7‐day treatment periods of (1) allopurinol 300 mg, allopurinol 300 mg plus lesinurad 400 or 600 mg, and continued lesinurad 400 or 600 mg; or (2) febuxostat 40 or 80 mg, febuxostat 40 or 80 mg plus lesinurad 400 mg, and continued febuxostat 40 or 80 mg plus lesinurad 600 mg. Naproxen and indomethacin studies included lesinurad 400 mg on day 1, naproxen 250 mg twice daily or indomethacin 25 mg twice daily on days 2–6, and lesinurad 400 mg plus continued naproxen or indomethacin on days 7–13 and the morning of day 14. Lesinurad did not alter the pharmacokinetics of naproxen and modestly altered exposure to colchicine (AUC decrease of ≤ 25%) and indomethacin (AUC increase of ~35%). Indomethacin did not alter the pharmacokinetics of lesinurad, whereas naproxen modestly decreased the C max of lesinurad by ~27%.
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Abstract Lesinurad is a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors (XOIs). Open‐label pharmacokinetic studies were...
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Abstract Lesinurad is a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors (XOIs). Open‐label pharmacokinetic studies were performed in volunteers or subjects with hyperuricemia (serum uric acid ≥ 8 mg/dL) to investigate interactions of lesinurad (with and without concurrent XOIs) with colchicine and 2 nonsteroidal anti‐inflammatory drugs: naproxen and indomethacin. Colchicine studies included consecutive 7‐day treatment periods of (1) allopurinol 300 mg, allopurinol 300 mg plus lesinurad 400 or 600 mg, and continued lesinurad 400 or 600 mg; or (2) febuxostat 40 or 80 mg, febuxostat 40 or 80 mg plus lesinurad 400 mg, and continued febuxostat 40 or 80 mg plus lesinurad 600 mg. Naproxen and indomethacin studies included lesinurad 400 mg on day 1, naproxen 250 mg twice daily or indomethacin 25 mg twice daily on days 2–6, and lesinurad 400 mg plus continued naproxen or indomethacin on days 7–13 and the morning of day 14. Lesinurad did not alter the pharmacokinetics of naproxen and modestly altered exposure to colchicine (AUC decrease of ≤ 25%) and indomethacin (AUC increase of ~35%). Indomethacin did not alter the pharmacokinetics of lesinurad, whereas naproxen modestly decreased the C max of lesinurad by ~27%.
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Lesinurad is a novel selective uric acid reabsorption inhibitor which has been recently approved for the treatment of the chronic gout. Four simple mathematical spectrophotometric methods have been developed for the quantitative a...
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Lesinurad is a novel selective uric acid reabsorption inhibitor which has been recently approved for the treatment of the chronic gout. Four simple mathematical spectrophotometric methods have been developed for the quantitative and selective determination of lesinurad in the presence of its oxidative degradation product. Complete oxidative degradation of lesinurad to its degradation product has been done. The developed methods namely, ratio difference spectrophotometric, first derivative of the ratio spectra, mean centering of the ratio spectra and continuous wavelet transform spectrophotometric methods. These methods have been developed and optimized to resolve the existed overlapping between the zero order UV absorption spectra of lesinurad and its oxidative degradation product. The described spectrophotometric methods have achieved selective determination of lesinurad without any interference from the oxidative degradation product. Also, they have been validated and applied for quantitative analysis of the studied drug in its new pharmaceutical preparation.
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Computational studies introduce an integral approach for finding greener methods through testing solvents for reactions and extractions. Lesinurad is a novel selective uric acid reabsorption inhibitor prescribed for the treatment ...
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Computational studies introduce an integral approach for finding greener methods through testing solvents for reactions and extractions. Lesinurad is a novel selective uric acid reabsorption inhibitor prescribed for the treatment of chronic gout. Computational calculations were achieved to choose the best acid dye used for sensitive visible spectrophotometric determination of lesinurad. The calculations were performed using Gaussian 03 software based on density functional theory method with B3LYP/631G(d) basis set. The obtained results revealed that bromophenol blue was preferred for lesinurad than other acid dyes based on the higher calculated interaction energy. The described method was based on the reaction of lesinurad with the theoretically selected acid dye bromophenol blue to form a yellow ion-pair complex. The absorption spectra showed maximum sharp peaks at 418 nm. Different factors affecting the reaction were optimized. Beer's law was demonstrated over the concentration range of 2-12 lg/mL lesinurad. The described reaction was utilized for the spectrophotometric determination of lesinurad in pure form and in the pharmaceutical preparation. The greenness of the described method was assessed using four different tools namely, the national environmental method index, the analytical eco-scale, the green analytical procedure index and the novel analytical greenness metric. The proposed method seemed to be superior to the reported HPLC method with respect to the metrics of the greenness characters.
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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 wi...
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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. However, this risk is substantially attenuated with coprescription of a XOI and when prescribed at a dose of 200?mg/day. Given its’ modest urate-lowering effect, and the risk of serum creatinine elevation when used alone, it is licenced for use in combination with XOI for people unable to achieve target serum uric acid with XOI alone. Lesinurad does not have the drug interactions associated with probenecid, however, it is metabolized by CYP2C9, and should be used with caution if CYP2C9 inhibitors are coprescribed. Arhalofenate also acts by blocking URAT-1; however, it also blocks the NALP-3 inflammasome providing gout-specific anti-inflammatory effect. Arhalofenate has a weaker urate-lowering effect than lesinurad and further phase III evaluation is planned. Summary Lesinurad provides an additional option for people with gout unable to achieve target serum uric acid with XOI alone.
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Aim: To 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, sur...
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Aim: To 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. Cumulative 5-year incremental cost was US$3,633,440. Estimated incremental mean cost per treated patient with gout per year was US$112. The mean per-member per-month cost increased by US$0.06. Conclusion: Initiating lesinurad would result in an incremental per-member per-month cost of US$0.06 over 5?years.
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In order to systematically explore and understand the structure-activity relationship (SAR) of a lesinurad-based hit (1c) derived from the replacement of the S atom in lesinurad with CH2, 18 compounds (1a-1r) were designed, synthe...
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In order to systematically explore and understand the structure-activity relationship (SAR) of a lesinurad-based hit (1c) derived from the replacement of the S atom in lesinurad with CH2, 18 compounds (1a-1r) were designed, synthesized and subjected to in vitro URAT1 inhibitory assay. The SAR exploration led to the discovery of a highly potent flexible URAT1 inhibitor, 1q, which was 31-fold more potent than parent lesinurad (IC50 = 0.23 mu M against human URAT1 for 1q vs. 7.18 mu M for lesinurad). The present study discovered a flexible molecular scaffold, as represented by 1q, which might serve as a promising prototype scaffold for further development of potent URAT1 inhibitors, and also demonstrated that the S atom in lesinurad was not indispensable for its URAT1 inhibitory activity.
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