Gout Clinical Update, August 3, 2011

The latest clinical research into the causes and treatments for gout.

Increasing the dose of allopurinol, the drug most commonly used to lower serum urate (SU) levels, resulted in increased plasma oxypurinol and reduced SU concentrations, according to a new study.

The treatment of gout requires a lowering of SU levels. The objectives of the new study, which was published in Clinical Pharmacology & Therapeutics, were to define the relationships between allopurinol dose on the one hand and plasma oxypurinol, renal function, and SU levels on the other.

Another goal was to determine the minimum plasma oxypurinol concentration that would result in a target level of <6 mg/dl (0.36 mmol/l) of SU, according to researchers in the department of medicine at the University of Otago in Christchurch, New Zealand, headed by Lisa K. Stamp, PhD.

“For this purpose, 82 patients who had been receiving allopurinol for at least one month were recruited. Patients with SU <6 mg/dl were followed up quarterly for 12 months. In patients with SU ≥6 mg/dl, the dose of allopurinol was increased to bring the level of SU to <6 mg/dl,” the authors wrote in the study's abstract.

These patients were followed up once a month until the SU level remained at <6 mg/dl for three consecutive months; thereafter they were seen quarterly. SU, creatinine, and plasma oxypurinol were measured six to nine hours after administration of the allopurinol dose.

“There were significant inverse correlations between creatinine clearance (CrCl) and plasma oxypurinol (P=0.002), between allopurinol dose and SU (P<0.0001), and between plasma oxypurinol and SU (P < 0.0001). Using receiver operating characteristic analysis, the target SU of <6 mg/dl was achieved in 75% of serum samples with plasma oxypurinol levels of >100 µmol/l (15.2 mg/l),” the researchers concluded. Plasma oxypurinol concentrations >100 µmol/l were required to achieve SU <6 mg/dl.

The NLRP3 Inflammasome in Health and Disease: the Good, the Bad and the Ugly

While interleukin (IL)-1β plays an important role in combating the invading pathogen as part of the innate immune response, its dysregulation is responsible for a number of autoinflammatory disorders.

Recently, inflammasome function has been implicated in more common human conditions, such as gout, type 2 diabetes, and cancer, according to researchers in the department of biochemistry at the University of Lausanne in Switzerland.

“This raises the possibility that anti-IL-1 therapeutics may have broader applications than anticipated previously, and may be utilized across diverse disease states that are linked insidiously through unwanted or heightened inflammasome activity,” the researchers wrote in a recent issue of Clinical & Experimental Immunology.

Large IL-1β activating platforms, known as inflammasomes, can assemble in response to the detection of endogenous host and pathogen-associated danger molecules.

“Formation of these protein complexes results in the autocatalysis and activation of caspase-1, which processes precursor IL-1β into its secreted biologically active form. Inflammasome and IL-1β activity is required to efficiently control viral, bacterial, and fungal pathogen infections. Conversely, excess IL-1β activity contributes to human disease, and its inhibition has proved therapeutically beneficial in the treatment of a spectrum of serious, yet relatively rare, heritable inflammasomopathies,” the authors wrote.

Sources

Relationship Between Serum Urate and Plasma Oxypurinol in the Management of Gout: Determination of Minimum Plasma Oxypurinol Concentration to Achieve a Target Serum Urate Level [Clinical Pharmacology & Therapeutics]

The NLRP3 inflammasome in health and disease: the good, the bad and the ugly [Clinical & Experimental Immunology]