Concentration‐response relationships for salicylate‐induced ototoxicity in normal volunteers.

Abstract

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.

Aspirin Targets SIRT1 and AMPK to Induce Senescence of Colorectal Carcinoma Cells

“…However, other studies have suggested that the treatment benefits of aspirin are increased at higher doses. Typically, the plasma salicylate concentrations in humans treated with high doses of aspirin (30-90 mg/kg) are 1-3 mM, which is moderately relevant to the pharmacological levels obtained in clinical practice (Day et al, 1989;Hundal et al, 2002;Hawley et al, 2012). However, it is difficult to equate the cells were treated with resveratrol or AICAR for 6 hours, and SIRT1 enzyme activity was measured.…”

Changes in the Numbers of Ribbon Synapses and Expression of RIBEYE in Salicylate-Induced Tinnitus

“…Salicylate, a widely used anti-inflammatory drug, has been shown to induce tinnitus [5,6,7,8,36,37,38]. In this work, we performed experiments with salicylate at a concentration of 350 mg/kg based on the literature [4,39,40,41,42,43].…”

“…Natriumsalicylicum (salicylate), the active component of aspirin, is widely used for its antipyretic, analgesic and anti-inflammatory effects. It has been revealed that salicylate can induce reversible tinnitus in both humans and animals [4,5,6,7,8,9,10,11]. Therefore, salicylate is commonly utilized to induce tinnitus in animal models for studies of tinnitus, and salicylate-induced tinnitus could be detected by the conditioned suppression/avoidance procedure [11].…”

The Safety Pharmacology of Auditory Function

“…Salicylates reduce pain and fever by inhibiting cyclooxygenase, an enzyme responsible for producing prostaglandins which mediate inflammation and thermoregulation (Vane and Botting 1998). Over this century, there have been numerous reports showing salicylate-induced tinnitus and reversible sensorineural hearing loss (Day et al 1989;Guitton et al 2003;Halla and Hardin 1988;Halla et al 1991).…”