Ototoxicity of New and Potent Diuretics: A Preliminary Study

Mathog, Robert H.; Thomas, W. G.; Hudson, W R

doi:10.1001/archotol.1970.04310010033002

Cited by 78 publications

(18 citation statements)

References 8 publications

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“…Unlike numerous other wellknown inhibitors of NF-B activation, such as pyrollidine dithiocarbamate (49,50) and parthenolide (34), EA has been used extensively in patients. Although EA is associated with some undesirable side effects, most notably ototoxicity (51), this agent continues to have a role in the modern practice of medicine. In addition to its potential anti-inflammatory effects, EA, of course, is also a diuretic.…”

Section: Discussionmentioning

confidence: 99%

Ethacrynic Acid Inhibits Multiple Steps in the Nf-??B Signaling Pathway

Han¹,

Englert²,

Delude³

et al. 2005

Shock

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Ethacrynic acid has been used as a safe and effective diuretic for more than 30 years. In this study, we tested the hypothesis that ethacrynic acid is also an anti-inflammatory agent that inhibits signaling by the proinflammatory transcription factor NF-kappaB. We showed that ethacrynic acid inhibited luciferase expression in lipopolysaccharide-stimulated macrophage-like RAW 264.7 cells transfected with an NF-kappaB-dependent luciferase reporter vector and also inhibited NF-kappaB DNA binding in lipopolysaccharide-stimulated RAW 264.7 cells (electrophoretic mobility shift assay). Ethacrynic acid inhibited degradation of IkappaBalpha and IkappaBbeta in lipopolysaccharide-stimulated RAW 264.7 cells. Ethacrynic acid impaired DNA binding of wild-type p65 subunits of NF-kappaB in cells. However, DNA binding of a Cys--> Ser p65 mutant was not inhibited by ethacrynic acid, suggesting that ethacrynic acid inhibits DNA binding by alkylating p65 at Cys. In a cell-free system, binding of p50 homodimers to an NF-kappaB consensus sequence was inhibited by ethacrynic acid at concentrations from 10 to 100 microM, indicating that ethacrynic acid probably also covalently modifies the p50 subunit. These data indicate that ethacrynic acid inhibits activation of the NF-kappaB pathway at multiple points and suggest that this well-studied drug warrants further investigation as a potential therapeutic for various conditions that are associated with excessive inflammation.

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Section: Discussionmentioning

confidence: 99%

Ethacrynic Acid Inhibits Multiple Steps in the Nf-??B Signaling Pathway

Han¹,

Englert²,

Delude³

et al. 2005

Shock

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“…injection of 40-50 mg/kg furosemide in the guinea pig (Forge, 1976). Ethacrynic acid produces cytopathological changes in the stria vascularis and in the outer hair cells of the basal part of the cochlea in a number of species, including cat (Quick & Duvall, 1970;Mathog, Thomas & Hudson, 1970;Nakai, 1971;Bosher, Smith & Warren, 1973a, b, Silverstein & Begin, 1974Bosher, 1980b). The question therefore arises whether the effect of furosemide on the organ of Corti are secondary to primary effects on the stria, mediated via the endocochlear potential (e.p.).…”

Section: E F Evans and R Klinkementioning

confidence: 99%

The effects of intracochlear and systemic furosemide on the properties of single cochlear nerve fibres in the cat

Evans

Klinke

1982

The Journal of Physiology

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SUMMARY1. Tuning properties and spontaneous discharge rate of single cochlear fibres in the anaesthetized cat were determined during short-and long-term poisoning of the cochlea by locally and systemically applied furosemide.2. With intra-arterial administration offurosemide, short-term reversible elevation occurred of the low threshold sharply tuned 'tip' segment of the frequency threshold ('tuning') curve (f.t.c.) by up to 40 db, without substantial changes in the threshold of the low frequency 'tail' segment of the f.t.c. These changes could occur in part without changes in the spontaneous activity and entirely without changes in the maximal evoked activity. These effects were observed in all fibres examined, the characteristic frequencies of which ranged from 3-5 to 31 kHz.3. Intracochlear administration of furosemide in 0-9 mm concentrations produced similar changes, but these were not reversible.4. The changes correlated with the depression of the amplitude of the gross cochlear action potential. The cochlear microphonic potential, however, was either unchanged, or only slightly reduced.5. In long-term furosemide poisoning of the cochlea, fibres with anomalous response properties were found alongside fibres having normal tuning. The former exhibited either reduced excitability of the low threshold tip segment, or a tip segment attenuated in both excitability and threshold.6. It is concluded that the selective effects of furosemide on the tip segment of cochlear fibre f.t.c.s offer further evidence for a physiologically vulnerable 'second filter' in the cochlea. The selective influence of the furosemide on the low threshold tip segment provides support for the hypothesis that the normal f.t.c. is generated by two largely independent processes: one vulnerable, low threshold and sharply tuned, and the other less vulnerable, but high threshold and more broadly tuned.7. The findings, obtained with an agent known to produce reversible impairment of hearing in man, provide direct physiological evidence in support of the hypothesis that in sensorineural hearing loss of cochlear origin the frequency selectivity of cochlear nerve fibres is impaired.

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“…Less sensitive to ethacrynic acid are the cochlear microphonic and auditory nerve action potential which undergo a reduction in amplitude with doses of 10 mg/kg. Complete recovery within 1 hour is the rule, but a second dose of ethacrynic acid produces a greater amplitude reduction and recovery then requires days (48). Various pathological changes occur with ethacrynic acid from atrophy of cells of stria vascularis (49) to destruction of outer hair cells in the basal and middle turns of the cochlea (48).…”

Section: Drug-induced Ototoxicitymentioning

confidence: 99%