Ototossicità dei farmaci aminoglicosidici

Streptomyces griseus, batterio gram-positivo

Produttore di streptomicina

STREPTO

Esame audiometrico di individuo di 55 anni (F) trattato con Garasone (gentamicina + betametasone gocce auricolari) per tre settimane in seguito ad infezione postoperatoria

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�The return of stereocilia to their initial position is activated by Ca2+ (its internal

concentration upregulates when channels are open) which triggers a motor protein (myosin VIIa) which drives down the tip links. �

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Meccanismo ototossico degli aminoglicosidi

in soggetti NON geneticamente predisposti

(cicli di terapia prolungati, alte dosi, polisomministrazione giornaliera, ecc.)

Ros attivano JNK (Jun N-terminal Kinase), che induce trascrizione Jun-mediata attraverso AP1 di geni pro-apoptotici =>release di citocromo c mitocondriale, caspasi =>=> apoptosi

Complesso Gntamicina-ferro-acido grasso di membrana

Sito di azione dei ROS prodotti dagli aminoglicosidi:

GIRO BASALE

(rileva alte frequenze!)

STREPTO

BATTERIO MITOCONDRIO

Ionic composition (mM) Perilymph Endolymph Na+ 154 1 K+ 3 161 Cl- 128 131

STRIA

VASCULARIS

Streptomicina: vestibulotossica

Neomicina: cocleotossica

P.Meniere, 1799-1862

LA MALATTIA DI MENIERE

SINTOMI:

1.  Intensa vertigine

2.  Tinnito

3.  Sordità

Normale Meniére

Schuknecht [1957] first modified the method of delivery of chemical ablation and perfused the middle ear with streptomycin for treatment of unilateral Meniere's disease.

All his patients had resolution of their vertigo, but five of eight suffered complete hearing loss.

Gentamicin is now used, due to its perceived preferential vestibular toxicity.

Intratympanic gentamicin is thought to be a relatively safe, effective treatment for unilateral

Meniere's disease.

Several studies, however, have shown this not to be the case [Hoffer et al., 2001; Keene et al., 1982; Tran Ba Huy and Deffrennes, 1988;Wanamaker 1998].

Investigators are still struggling to find the elusive balance of method, administration, dose,

schedule, and end-point of therapy in order to preserve cochlear function.

Waksman