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BACKGROUND Excess body burden of uric acid promotes gout. Diminished renal clearance of uric acid causes hyperuricemia in most patients with gout, and the renal urate transporter (URAT)1 is important for regulation of serum uric acid (sUA) levels. The URAT1 inhibitors probenecid and benzbromarone are used as gout therapies; however, their use is limited by(More)
The RAS-RAF-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway provides numerous opportunities for targeted oncology therapeutics. In particular, the MEK enzyme is attractive due to high selectivity for its target ERK and the central role that activated ERK plays in driving cell proliferation. The(More)
Ribavirin, part of the current first line combination therapy for the treatment of chronic hepatitis C, may cause haemolytic anaemia and poses a significant challenge to the clinical management of the disease. Viramidine, a prodrug of ribavirin, is currently under development. In-vitro partition demonstrated that viramidine had less association with RBCs(More)
A sensitive and specific method using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the analysis of total ribavirin in monkey liver is developed and validated. In this method, ribavirin and its phosphorylated metabolites are extracted with perchloric acid. The metabolites are converted to ribavirin using acid phosphatase and(More)
The pharmacokinetics of pradefovir and adefovir, 9-(2-phosphonylmethoxyethyl) adenine (PMEA), was evaluated in healthy male volunteers after oral dosing of pradefovir (10, 30, or 60 mg). Pradefovir was absorbed rapidly. The maximum serum concentration, the area under the concentration-time curve between 0 and 96 hours after dosing (AUC(0-96)), and the area(More)
The safety of viramidine was evaluated and compared with ribavirin in one-month and six-month studies in rats and one-month and nine-month studies in monkeys. Viramidine administration produced hemolytic anemia, characterized by decreases in hemoglobin (Hgb) concentrations, which was accompanied by erythroid hyperplasia of the bone marrow or increase in(More)
OBJECTIVE The aim of this study was to evaluate the pharmacodynamics (PDs), pharmacokinetics (PKs) and safety of lesinurad (selective uric acid reabsorption inhibitor) in combination with febuxostat (xanthine oxidase inhibitor) in patients with gout. METHODS This study was a phase IB, multicentre, open-label, multiple-dose study of gout patients with(More)
PURPOSE To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors. EXPERIMENTAL DESIGN BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish(More)
Absorption, pharmacokinetics, distribution, metabolism, and excretion of [(14)C]ribavirin were studied in rats (30 mg/kg of body weight) and cynomolgus monkeys (10 mg/kg) after intravenous (i.v.) and oral administration. The oral absorption and bioavailability were 83 and 59%, respectively, in rats and 87 and 55%, respectively, in monkeys. After i.v.(More)
Ribavirin, part of the current first-line combination therapy for the treatment of chronic hepatitis C, has side effects-in particular, hemolytic anemia-that is frequently dose limiting. Based on animal studies, viramidine, a prodrug of ribavirin, is converted to ribavirin in the liver. Viramidine dosing yielded 50% higher ribavirin levels in the monkey(More)