1 Ototoxicity is a common and troublesome side-effect of high-dose aspirin treatment but there has been little previous study of the relationships between the degree of ototoxicity and the plasma concentrations of salicylate. 2 In order to investigate the relationships between aspirin dose, total and unbound plasma salicylate concentrations and ototoxicity, eight normal volunteers were dosed with aspirin 1.95, 3.25, 4.55 and 5.85 g day-1 for 1 week at each dose level, the doses being administered in random order and double-blind, 2 weeks apart. 3 Ototoxic effects measured were hearing loss in decibels (dB) over six frequencies and tinnitus intensity, estimated both by electronic matching and a fixed interval scale (FIS). Measurements were taken after steady-state concentrations of salicylate had been achieved. 4 Total and unbound plasma salicylate concentrations increased disproportionately with increasing daily doses of aspirin. The increase in the unbound salicylate was relatively greater since the percentage of salicylate unbound in plasma increased over the dose range investigated from a mean of 3.9% to 10.4%. 5 Hearing loss and tinnitus intensity increased progressively with the aspirin dosage and increasing concentrations of total and unbound plasma salicylate concentrations. These ototoxic symptoms were observed at lower concentrations of total salicylate than previously reported. 6 There was a linear relationship between hearing loss and unbound salicylate concentations. 7 Further work is required to test the hypothesis that unbound plasma salicylate concentration is a better predictor of salicylate-induced ototoxicity than total plasma salicylate concentration.

The pharmacokinetics of the enantiomers of ibuprofen were investigated after oral administration of a single 7.6 +/‐ 0.3 mg kg‐1 dose of the racemate in 11 infants. Mean (+/‐ s.d.) half‐lives were 1.6 +/‐ 0.5 h for S(+) and 1.5 +/‐ 0.5 h for R(‐) and mean (+/‐ s.d.) AUC values were 31.5 +/‐ 14.3 mg l‐1 h for S(+) and 36.6 +/‐ 13.8 mg l‐1 h for R(‐). Since plasma concentrations of the active S(+)‐isomer were lower than those reported in adults, a higher dosage might be required in infants.

1 1-methyl xanthine (1-MX) is metabolized exclusively to 1-methyl uric acid (1-MU) by the enzyme xanthine oxidase. 2 The ratio of 1-MU to 1-MX in the urine, following a dose of 50 mg of 1-MX infused intravenously over 20 min, was used to measure the inhibition of xanthine oxidase induced by different doses of allopurinol. 3 Normal volunteers (n=8) were given allopurinol 50, 100, 300 and 600 mg daily for 1 week each, in random order and 1 week separated each treatment. Inhibition of xanthine oxidase was assessed twice, on the last 2 days of each treatment week. 4 Steady-state oxipurinol concentrations increased linearly with increasing dose of allopurinol. 5 There was a hyperbolic relationship between the 1-MU/1-MX ratio and plasma oxipurinol concentrations, with an initial steep decline in the ratio which plateaued when plasma oxipurinol was around 4-6 mg 1-1. This reduction in the ratio was quickly reversible upon cessation of allopurinol. 6 The 50% and 90% effective inhibitory oxipurinol concentrations, in relation to the 1-MU-/1-MX ratio were 1.4 ± 0.46 and 4.08 ± 2.03 mg 1-1 respectively. 7 The concentration of oxipurinol required for almost complete inhibition of the enzyme was substantially less than those often observed in clinical practice.

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