Study of Febuxostat for the Management of Hyperuricemia in Gout

The past decade has seen an exponential increase of novel therapeutic modalities for a variety of rheumatic disorders, including gout. Gout is the common inflammatory arthritis in an elderly population and can be challenging because its typical appearances are more common in elderly. The management of hyperuricemia in elderly with gout requires special consideration in terms of co-medication, contraindications and risk of adverse reactions. So the Urate-lowering agents including allopurinol and uricosuric agents are also used sensibly in the elderly. The novel therapeutic agent recently approved by USFDA for the treatment of rheumatic disorders in gout is Febuxostat, a nonpurine selective xanthine oxidase inhibitor. This review presents its pharmacokinetics and pharmacodynamics, efficacy and safety profile and its usefulness in gout patients. Febuxostat can be used in patients with mild-to-moderate renal or hepatic impairment. Sachin S. Shinde*, Amol S. Deshmukh, Pallavi P. Nagadkar, Kundan J. Tiwari Department of Pharmaceutics, S.M.B.T. College of Pharmacy, Nandi Hills, Dhamangaon, Nashik, India. Submission: 7 October 2015 Accepted: 14 October 2015 Published: 25 October 2015 www.ijppr.humanjournals.com Citation: Sachin S. Shinde et al. Ijppr.Human, 2015; Vol. 4 (3): 279-288. 280 INTRODUCTION Gout is a metabolic disorder characterized by hyperuricemia (normal plasma urate 2-6 mg/dl). Uric acid, a product of purine metabolism, has low water solubility, especially at low pH. When blood levels are high, it precipitates and deposits in joints, kidney and subcutaneous tissue. Chronic goutWhen pain and stiffness persist in a joint between attacks, gout has become chronic.[1] Pain is a designation for a spectrum of sensations of highly divergent characters and intensity ranging from unpleasant to intolerable.[2,3] Other cardinal features are hyperuricemia, tophi (chalk like stones under the skin in pinna, eyelids, nose, around joints and other places) and urate stones in the kidney. In majority of patients, hyperuricemia is due to under secretion of uric acid, while in few it is due to over production. Chronic gouty arthritis may cause progressive disability and permanent deformities.[1] Gout is the collective name for several disorders that are characterized by formation and deposition of monosodium urate (MSUr) crystals. The condition is associated with recurrent episodes of acute joint pain due to deposition of MSUr crystals in the synovial fluid. In addition to the effects observed in joints, skin/subcutaneous tissue and kidneys may also be affected by tophaceous deposits, cellulitis, urate nephropathy, and/or kidney stones, respectively. In most cases, no identifiable underlying cause of gout is present, but evident factors are usually present that may contribute to increases in urate (uric acid) levels, which may include reduced renal function, obesity and the use of diuretics. Hyperuricemia may exist for several years to decades before the first symptoms of gout attacks appear; therefore it is a disease associated and correlated with aging. Gout is one of the most common inflammatory arthritis affecting the elderly; however in general it appears to be poorly managed.[4-6] The incidence and prevalence of gout in the elderly is increasing. This appears related to improved lifespan leading to similar increases in age-related diseases (e.g, cardiovascular diseases) and their associated adverse effects of treatment (e.g, diuretics and low-dose salicylates) which can increase the risk of gout. “Elderly onset gout” differs from “classical” gout found in middle-aged men in several respects: no male predominance but an equal gender distribution, polyarticular presentation with upper-extremity joint involvement, fewer acute gouty episodes, indolent clinical course, and an increased incidence of tophi.[7-9] This review will focus on Febuxostat for the management of gout in the elderly. www.ijppr.humanjournals.com Citation: Sachin S. Shinde et al. Ijppr.Human, 2015; Vol. 4 (3): 279-288. 281 Gout pathophysiology Uric acid is formed from nucleic acid either endogenously from cell breakdown or exogenously from metabolism of food. Cooling and acidification of the microenvironment, which can result in acute formation of urate crystals, reduce the solubility of MSUr. The gut excretes one-third of urate and two-third amount gets excreted through urine. Renal urate transport is typically explained by a 4-component model: glomerular filtration, a near-complete reabsorption of filtered urate, subsequent secretion, and post secretory reabsorption in the remaining proximal tubule. Recently, several new urate transporters have been identified which play key roles in urate homeostasis, including URAT-1 and Glut-9. The regulation of serum uric acid levels is under a strong genetic control. A recent meta-analysis of genome-wide association scans shows that common DNA variants at 9 different loci are associated with uric acid concentrations. Excessive consumption of alcohol (particularly beer), sweetened soft drinks, fructose, meat, and seafood can also increase levels of serum urate (sUr). Inhibition of urate transporters can be achieved by uricosurics, and production of uric acid can be inhibited using xanthine oxidase inhibitors, such as allopurinol. Febuxostat is a new selective inhibitor of xanthine oxidase. Uric acid deposits can also be lysed by the enzyme uricase, the coding gene for which became defective in humans in the Miocene because of an evolutionary mutation. The combined absence of uricase and almost total reabsorption of filtered urate explains that humans (and the greater apes) have 10-fold higher sUr levels than other mammals.[10] Drug-induced hyperuricemia Chronic diuretic therapy is associated with reduced excretion of uric acid. Mechanisms are increased uric acid reabsorption in the proximal tubule secondary to volume depletion, and competition between the diuretic and uric acid for the organic acid secretory mechanism in the proximal tubule. Low-dose diuretic therapy in hypertensive patients does not seem to alter serum urate levels significantly.[11,12] Indeed, the requirement for anti-gout therapy in hypertensive patients is doubled for thiazide doses of ≥25 mg/day (in hydrochlorothiazide equivalents); no significant increase in risk is seen for lower doses. Similarly, low-dose therapy with a loop diuretic is not associated with hyperuricemia.[13,14] www.ijppr.humanjournals.com Citation: Sachin S. Shinde et al. Ijppr.Human, 2015; Vol. 4 (3): 279-288. 282 Treatment strategies for gout Several approaches to the treatment of gout are available depending on the patient’s disease status. Optimal treatment often requires a combination of pharmacological intervention and lifestyle changes. Treatment should be tailored to the patient’s prognostic factors (high sUr, previous attacks, and radiographic signs), the clinical phase of disease (acute, recurrent, tophaceous) and general risk factors, such as obesity, alcohol consumption, renal impairment, use of diuretics or other risk factors for secondary hyperuricemia. Primary prevention of gout often involves changes in lifestyle, such as a low-purine/weight reducing diet or restricting alcohol intake.[15] Acute gout is usually treated by reducing the inflammation of the affected joint with non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, corticosteroids, and cooling.[16,17] Primary prevention of gout Primary prevention of gout involves changes in lifestyle, such as changes to diet (lowpurine/weight-reducing diet) and restricting alcohol consumption. No randomized studies have been conducted evaluating the effect of lifestyle changes on the incidence of attacks in patients with gout. Nevertheless, experts agree that lifestyle changes may have some effect. Physicians in daily practice also give lifestyle advice, when gout symptoms appear. However, fewer than 20% of patients with gout seeking medical advice are prepared to make long term changes in lifestyle.[18] Recently, the negative role of meat, seafood and beer consumption, and the protective role of dairy products in the development of gout were demonstrated in a prospective study over a 12-year period among a population of around 47,000 healthy male subjects.[19]