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PubMed | University of Chicago, East West Medical Research Institute, Astrazeneca, Ardea Biosciences Inc. and University of Alabama at Birmingham
Type: | Journal: Arthritis & rheumatology (Hoboken, N.J.) | Year: 2016

Lesinurad is a selective uric acid reabsorption inhibitor for treatment of gout in combination with xanthine oxidase inhibitors. CLEAR 1 (Combining Lesinurad with Allopurinol Standard of Care in Inadequate Responders) was a 12-month, randomized, phase-III trial of daily lesinurad (200-mg or 400-mg orally) added to allopurinol in subjects with serum urate (sUA) above <6.0 mg/dL target. Subjects on allopurinol 300 mg (200 mg in moderate renal impairment) had sUA 6.5 mg/dL at screening and 2 gout flares in the prior year. Primary endpoint was the proportion of subjects achieving sUA <6.0 mg/dL (Month 6). Key secondary endpoints were mean gout flare rate requiring treatment (Months 7 through 12) and proportions of subjects with complete resolution of 1 target tophi (Month 12). Safety assessments included adverse events and laboratory data. Subjects (N=603) were predominantly male, meanSD age 51.911.3 years, gout duration 11.89.4 years, baseline sUA 6.941.27 mg/dL, and at allopurinol dose 306.659.58 mg/day. Lesinurad at 200-mg and 400-mg doses, added to allopurinol, significantly increased proportions of subjects achieving sUA target versus allopurinol alone by Month 6 (54.2%, 59.2%, and 27.9%, respectively, P<0.0001). Lesinurad was not significantly superior in secondary endpoints: rates of gout flares and complete tophus resolution. Lesinurad was generally well-tolerated; the safety profile of the 200-mg dose was comparable to allopurinol alone, except for higher incidences of predominantly-reversible serum creatinine elevation. Lesinurad added to allopurinol provided benefit versus allopurinol alone in reducing sUA levels and is a new treatment option for patients needing additional urate-lowering. This article is protected by copyright. All rights reserved.


Tsimafeyeu I.,Kidney Cancer Research Bureau | Demidov L.,Nn Blokhin Russian Cancer Research Center | Kharkevich G.,Nn Blokhin Russian Cancer Research Center | Petenko N.,Nn Blokhin Russian Cancer Research Center | And 3 more authors.
American Journal of Clinical Oncology: Cancer Clinical Trials | Year: 2012

Background: Although significant progress has been made for metastatic renal cell carcinoma (MRCC), very little progress has been achieved for non-clear cell MRCC. Thus, we performed a phase II, multicenter trial of capecitabine in patients with non-clear cell MRCC. PATIENTS AND Methods: Adult patients with MRCC containing <50% of clear cells were eligible. All patients received oral capecitabine (1,250 mg/m 2) twice daily for 14 days, followed by 14 days of rest. Primary end point was objective response rate. On the basis of Chen and Ng 2-stage accrual design, maximum planned enrollment was 51 patients. This study is registered with ClinicalTrials.gov, NCT01182142. Results: Fifty-one patients enrolled between February 2006 and January 2009. Most patients were men (72.5%), who had papillary RCC (76.5%), Memorial Sloan Kettering Cancer Center intermediate prognosis (86%), and had not been treated earlier (92%). The objective response rate was 26%. Two patients (4%) had a complete response. Stable disease was achieved in 24 (47%) patients. The median progression-free survival was 10.1 months [95% confidence interval (CI), 8.7-11.5], and overall survival was 18.3 months (95% CI, 15.5-21.1). The 1-year overall survival was 71% (95% CI, 63%-79%). Major grades 3 to 4, treatment-related toxicities included diarrhea (2%), esophageal mucosal inflammation (2%), hand-foot syndrome (4%), thrombocytopenia (9.8%), and neutropenia (8%). No patients were withdrawn because of laboratory abnormalities. Conclusions: Capecitabine has clinical activity in MRCC patients who have non-clear cell histology and a good or intermediate prognosis. Additional prospective randomized trial comparing capecitabine with placebo is required. Copyright © 2011 by Lippincott Williams & Wilkins.


Lee E.,Kyung Hee University | Kim D.Y.,Kyung Hee University | Kim D.Y.,Cell and Bio Inc | Chung E.,Kyung Hee University | And 4 more authors.
Cell Transplantation | Year: 2014

Mechanical stimulation is a known modulator of survival and proliferation for many cells, including endothelial cells, smooth muscle cells, and bone marrow-derived mesenchymal stem cells. In this study, we found that mechanical strain prevents apoptosis and increases the adhesive ability of dermal fibroblasts in vitro and thus confers the survival advantage in vivo after transplantation of fibroblasts into the full-thickness wound of diabetic mice. Cyclic stretch at a frequency of 0.5 Hz and maximum elongation of 20% stimulates cellular survival mediated by the activation of extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and the serine/threonine kinase Akt (AKT). Stretching of the fibroblasts increases the synthesis of extracellular matrix proteins and the formation of denser focal adhesion structures, both of which are required for fibroblast adhesion. The stretched fibroblasts also upregulate the expression of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1α (SDF-1α), which enhanced wound healing in vivo. Indeed, preconditioning with mechanical stretch allows better survival of the transplanted fibroblasts, when compared to unstretched control cells, in the wound environment of mice with streptozotocin-induced diabetes and thus accelerates the wound-healing process in these mice. © 2014 Cognizant Comm. Corp.


Dubon M.J.,Kyung Hee University | Byeon Y.,Kyung Hee University | Park K.-S.,East West Medical Research Institute | Park K.-S.,Kyung Hee University
Molecular Medicine Reports | Year: 2015

The rescue of glucose tolerance and insulin-sensitivity in peripheral tissues, including adipose tissue, is essential in therapeutic strategies for diabetes. The present study demonstrated that substance P (SP) increases the accumulation of lipids in 3T3-L1 cells during their differentiation into adipocytes in response to a high concentration of glucose. SP reciprocally regulated the activities of AMP-activated protein kinase (AMPK) and Akt: SP enhanced the activation of AMPK, although the activity of Akt was downregulated. Notably, SP induced an increase in the expression level of glucose transporter 4 in the 3T3-L1 adipocytes. Therefore, it is possible that SP leads to an increase in glucose uptake and the accumulation of lipids in adipocytes, and may contribute towards the rescue of insulin-sensitivity in diabetes.


Becker M.A.,University of Chicago | Fitz-Patrick D.,East West Medical Research Institute | Choi H.K.,Harvard University | Choi H.K.,Massachusetts General Hospital | And 4 more authors.
Seminars in Arthritis and Rheumatism | Year: 2015

Objectives: Allopurinol is the most widely prescribed serum uric acid-lowering therapy (ULT) in gout. To achieve serum uric acid (sUA) concentrations associated with clinical benefit, allopurinol is serially uptitrated with sUA monitoring. Suboptimal dosing is a key contributor to poor clinical outcomes, but few data are available on the safety and efficacy of dose-titrated allopurinol, particularly at doses >300. mg/d. The objective of this open-label study was to investigate the safety and efficacy of allopurinol under conditions where investigators were encouraged to titrate to optimal, medically appropriate doses. Methods: Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO) was a large, 6-month, multicenter study of allopurinol (NCT01391325). Adults meeting American Rheumatism Association Criteria for Classification of Acute Arthritis of Primary Gout and ≥2 gout flares in the previous year were eligible. Investigators were encouraged (but not required) to titrate allopurinol doses to achieve target sUA < 6.0. mg/dL. The primary objective was evaluation of the safety of dose-titrated allopurinol by clinical and laboratory examinations at monthly visits. Secondary objectives included sUA-lowering efficacy and gout flare frequency. Results: Of 1735 patients enrolled, 1732 received ≥1 allopurinol doses. The maximal daily allopurinol dose during study was <300. mg in 14.4%, 300. mg in 65.4%, and >300. mg in 20.2% of patients; dosing duration was 115.5, 152.0, and 159.7 days, respectively. Overall, baseline demographic characteristics and comorbidity rates were similar across these three categories, but patients receiving >300-mg maximal dose had more severe gout. Treatment-emergent adverse events possibly related to allopurinol occurred in 15.2%, 9.5%, and 11.4% of patients in the <300-, 300-, and >300-mg categories, respectively. Rash incidence was low (1.5%) and allopurinol hypersensitivity syndrome was not reported. No clinically meaningful changes occurred in laboratory values. sUA < 6.0. mg/dL at month 6 was achieved by 35.9% of patients overall: 22.4%, 35.0%, and 48.3% in dosing categories <300, 300, and >300. mg, respectively. Conclusions: This large multicenter study found that the allopurinol dose-titration strategy was well tolerated, without new safety signals emerging over 6 months. However, despite encouragement to treat to target, significant proportions of patients did not achieve target sUA. © 2015 The Authors. Published by Elsevier HS Journals, Inc.

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