Otology seminar
R3 戴安修
Gentamicin ototoxicity
Gentamicin  Low cost, effectiveness; Gram-negative bacterial infection,
synergize with aminopenicillins for efficacy.
Act on bacterial ribosomes  Stop synthesis of bacterial cell protein
 Accumulation of intermediate metabolic products  Toxic to the
bacterial cell.
Ototoxicity: Vestibulotoxicity, cochleotoxicity.
Vestibulotoxicity: 3%; Oscillopsia, disequilibrium; Spinning vertigo
unusual.
Cochleotoxicity: 5-10%; high frequencies (8 and 12KHz), high pitch
tinnitus.
Pathophysiology involved in the ototoxicity: Iron chelation, active
membrane lipid peroxidation and free radical formation.
Death of hair cells, auditory ganglion spared.
Iron chelation:
Promotes the release of Iron  Iron form a complex with GM
 Generate reactive oxygen species
Free radical formation:
Reactive oxygen species (ROS): Superoxide free radical ( O2), Hydrogen
peroxide (H2O2); Hydroxyl free radical ( OH); Peroxynitrite (ONOO ).
ROS caused cell death (necrosis or apoptosis), dose-dependent.
High doses  Necrosis: Progressive cell and organelle membrane
dysfunction
Mitochondria play a vital role in both apoptosis and necrosis
Mitochondria permeability transition (MPT): Cyclosporine A sensitive
pore is opened
 Influx of water into mitochondria (differences in ionic concentrations
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between the cytosol and mitochondria matrix).
 Outer mitochondria membrane rupture
 Compounds located in the intermembrane space into the cytosol.
 Loss of ion homeostasis, inability to maintain mitochondrial
respiration and ATP level.
 Energy depletion and necrotic cell death.
Moderate dose  Apoptosis:
Apoptosis
 Gene-directed self-destruction program
 Post-translational activation of intracellular signaling cascades
proteins.
GM  Plasma membrane  Activates Jun-kinase pathway  Linked to
receptor-mediated apoptosis
Apoptosis inducing factor located at the intermembrane space of
mitochondria (GM  ROS  Opening of mitochondria permeability
pore)
 Released into the cytosol
 Active the caspase cascade (endonuclease and protease)
 DNA fragmentation, chromatin condensation, and rearrangement of
the cytoskeleton
Producing blebs.
Possible treatments
Antioxidant treatments and irons chelators  Attenuated the formation of
free radicals and blocked GM-induced damage in animal models,
however no human data.
Antioxidants  Suppressing membrane lipid peroxidation (-tocopherol)
prevent neuronal cell death in cell cultures (Mattson, 1998)
Salicylate Radical scavenger and metal chelator  attenuate
GM-induced hearing loss in guinea pigs (Sha and Schacht, 1999).
D-methionine and Brain-derived neurotrophic factors restricted the
production of ROS  Limited the vestibular hair cell damage caused by
GM (Takumida, 2003)
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Why high frequencies damage
Glutathione concentrations lower in outer hair cells than supporting cells
 Lower in the cells of the basal turn as compared to the apical turn of
the cochlea.
 Early damage to the first row of outer hair cells beginning at the basal
turn of the cochlea.
 Explained the higher susceptibility of these cells mitochondria
permeability transition by GM.
Diagnosis
Exposure to GM > 2 weeks, bilateral vestibular paresis.
GM versus ototoxicity
1. Dose and kidney function: GM excreted almost purely by glomerular
filtration  Appropriate dosing interval chosen according to the renal
function. <3 days less likely cause ototoxicity.
2. Potentiating medications: Increase risk of ototoxicity if other ototoxic
drugs given, eg. cisplatin, metronidazole. . The drugs may not
necessary be present in the same time.
3. Genetic susceptibility: Mutation of mitochondria RNA, hearing loss
after one dose of GM.
4. Age: Older people approximately 50% vestibular ganglion cells have
died.
Prognosis
People do recover from ototoxicity; slow and usually incomplete.
GM ototoxicity never causes so severe imbalance as to require a
wheelchair.
Some “sick” inner ear hair cells get better.
Nobody knows how many inner ear hair cells are sick rather than dead.
Not all dead. Some remain but are not functioning at top-efficiency.
The brain adapts to the missing inner ear information.
Prevention
No monitoring protocols can reliably prevent GM toxicity.
The toxicity is delayed.
May not cause clinical symptoms for a week after intake, damage can
progress for months after the drug has stopped.
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Persons on large and prolonged doses of GM, administration with a
potentiating agent, significant renal disease, preexisting ear disease.
References
Takumida M. Anniko M. Shimizu A. Watanabe H. 2003 Neuroprotection of vestibular
sensory cells from gentamicin ototoxicity obtained using nitric oxide synthase
inhibitors, reactive oxygen species scavengers, brain-derived neurotrophic factors
and calpain inhibitors. Acta Oto-Laryngologica 123, 8-31.
Sha S.H. Schacht J. 1999 Stimulation of free radical formation by aminoglycoside
antibiotics. Hear Res. 128, 112-118.
Mattson M.P. 1998 Modification of ion hemostasis by lipid peroxidation: roles in
neuronal degeneration and adaptive plasticity. Trends neurosci 21, 53-57.
Dehne N. Rauen U. de Groot H. Lautermann J. 2002 Involvement of the
mitochondrial permeability transition in gentamicin ototoxicity. Hear Res. 169,
47-55.
Jukka Y. Liang X-Q. Jussi V. Ulla P. 2002 Blockade of c-Jun N-terminal kinase
pathway attenuates gentamicin-induced cochlear and vestibular hair cell death.
Hear Res. 166, 33-43.
Fetoni AR. Sergi B. Ferraresi A. Paludette G. Troiani D. 2004 Alpha-tocopherol
protective effects on gentamicin ototoxicity: an experimental study. Int J Audiolo.
43, 166-71.
Discussion
Ap Lin: Oscillopsia 應翻為視覺晃動， 這是雙側前庭功能低下的病患因大腦調適
所引起的 ，特別是當病患在活動時特別明顯。
另外，洗腎病患有些會有聽力的問題，有報告提出給予 EPO 對病患的聽力是有
幫助的。實驗也證實 EPO 可減緩 Gentamicin 對大鼠的 Ototoxicity。可以再看
看這方面的文章。
Gentamicin Ototoxicity 所造成的雙側前庭功能低下，大腦調適其實是很有限的。
所以上面提的 The brain adapts to the missing inner ear information 這句話還是要
存疑。
R4 謝: 臨床上有無確實可診斷的工具
Ans: 因為 Cochleotoxicity 是在 high frequencies (8 and 12KHz)，早期是可用 high
frequency audimetry。但是學者報告認為不是很實用。
R3 林: 病患使用 Gentamicin 後發生 Ototoxicity 最久到甚麼時候
Ans: 學者報告認為使用後數個月還是有可能會發生。
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