This document provides an overview of ototoxicity and discusses various ototoxic agents. It summarizes the following key points:
1) Ototoxicity refers to damage to the inner ear from drugs, toxins, or other agents that can cause hearing loss or balance problems. Common ototoxic agents include aminoglycoside antibiotics, loop diuretics, and platinum-based chemotherapy drugs.
2) Ototoxic agents can enter the inner ear through the round window membrane from the middle ear or through the blood-perilymph barrier. Aminoglycosides preferentially damage outer hair cells in the cochlea and type 1 hair cells in the vestibule.
3) Loop diure
otosclerosis is also known as otospongiosis. otosclerosis is a condition causing bilateral progressive conductive hearing loss. it is characterized by cahart's notch in bone conduction PTA. treated by stapes surgery also known as stapedotomy/stapedectomy or fenestration surgery.
otosclerosis is also known as otospongiosis. otosclerosis is a condition causing bilateral progressive conductive hearing loss. it is characterized by cahart's notch in bone conduction PTA. treated by stapes surgery also known as stapedotomy/stapedectomy or fenestration surgery.
Inner ear malformations and ImplantationUtkal Mishra
This slide vividly describes relevant anatomy & embryology of cochlea. It gives the reader insights into various cochlear malformations & implantation.
Cochlear Fluid is the one of the most important fluid not only for hearing sensation but also for the balance of human body. It is very important to know the embryology, anatomy, and physiology of cochlear fluid mechanism to know the various pathological conditions of inner ear.
Perilymph Fistula can be difficult to diagnose as a standalone condition. Post-trauma symptoms such as dizziness, headache, etc. can be linked to other conditions like a traumatic brain injury with a concussion.
Inner ear malformations and ImplantationUtkal Mishra
This slide vividly describes relevant anatomy & embryology of cochlea. It gives the reader insights into various cochlear malformations & implantation.
Cochlear Fluid is the one of the most important fluid not only for hearing sensation but also for the balance of human body. It is very important to know the embryology, anatomy, and physiology of cochlear fluid mechanism to know the various pathological conditions of inner ear.
Perilymph Fistula can be difficult to diagnose as a standalone condition. Post-trauma symptoms such as dizziness, headache, etc. can be linked to other conditions like a traumatic brain injury with a concussion.
Eustachian tube is commonly overlooked even by many physicians as effect of chronic otitis media rather than a cause. this is a humble attempt to explain the role eustachian tube dysfunction and interventions to reduce the same
Speaker
Dr Udaya Chanukya
MS ENT
Fellow in Skull Base Surgery
Consultant ENT Surgeon
S.A.I HOSPITALS, AP
Agenda
1. Temporal Bone Fractures
2. Otalgia
3. Ear Trauma
4. Ototoxicity
M.pharm (Pharmaceutics) Molecular Pharmaceutics (NTDS) unit 1 part 1 Targeted Drug Delivery Systems: Concepts, Events and biological process involved in drug targeting.
Asbestos-related diseases include non-malignant disorders such as asbestosis, diffuse pleural thickening, pleural plaques, pleural effusion, rounded atelectasis and malignancies such as lung cancer and malignant mesothelioma.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
Adv. biopharm. APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMSAkankshaAshtankar
MIP 201T & MPH 202T
ADVANCED BIOPHARMACEUTICS & PHARMACOKINETICS : UNIT 5
APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMS By - AKANKSHA ASHTANKAR
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Best Ayurvedic medicine for Gas and IndigestionSwastikAyurveda
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
The Gram stain is a fundamental technique in microbiology used to classify bacteria based on their cell wall structure. It provides a quick and simple method to distinguish between Gram-positive and Gram-negative bacteria, which have different susceptibilities to antibiotics
2. INTRODUCTION
• The term ototoxicity is used to refer to the
process by which a number of therapeutically
useful drugs, certain environmental agents
such as industrial solvents, and bacterial
toxins cause damage to the peripheral end-
organs of hearing and balance.
• hearing impairment or balance dysfunction
through primary action on the respective
neural pathways and centres.
3. MODES OF ENTRY OF OTOTOXIC
AGENTS TO THE INNER EAR
BACTERIAL TOXINS
• Potentially, bacterial toxins associated with middle ear infections as
well as ototoxic drugs may enter the inner ear across the round
window.
• There is evidence that some children who have had otitis media
with effusion (OME) may develop extended high-frequency hearing
loss, i.e. with a normal audiogram down to about 8 kHz but with
significant threshold shifts at higher frequencies
• loss of both inner and outer hair cells in the most basal regions of
the cochlea and this is caused by bacterial endotoxins released in
the middle ear effusion crossing the round window membrane to
access the basal coils of the cochlea
4. Access to perilymph
• The permeability properties that determine what will and
will not cross these membranes into the inner ear are not
known.
• Access to perilymph is also possible from the middle ear
cavity via the membrane covering the round window at the
base of the cochlea and that filling the oval window over
the vestibule.
• Access to the perilymphatic compartment of the inner ear
via the cochlear aqueduct from (CSF) is possible and this
may be a route of entry for bacterial toxins, such as those
associated with meningitis.
5. • The entry of aminoglycoside antibiotics
applied to the middle ear cavity across the
round and oval window membranes into the
perilymphatic spaces of the inner ear is used
as a clinical procedure to ablate hair cells in
the vestibular system in cases of severe
balance dysfunction in unilateral Meniere’s
disease
6. Blood–perilymph barrier
• Perilymph is not simply an ultrafiltrate of blood
plasma, nor does it derive from CSF. The composition
of perilymph is different both from CSF and from blood
plasma and the composition of perilymph in scala
vestibuli differs from that in scala tympani.
• This indicates that perilymph is produced and
circulated locally.
• Glucose entry, for example, requires facilitated
diffusion through glucose transporters
• Entry to endolymph in the internal compartment of
the inner ear is even more restricted and endolymph
composition is tightly controlled
7. TIGHT JUNCTIONS -COCHLEA
• The principal boundaries between endolymph
and perilymph, formed by selectively permeable
membranes and tight junctions between adjacent
cells,
• in the cochlea appear to be Reissner’s
membrane, at the level of the basal cells in the
stria vascularis, and the network formed by the
apical surfaces of the hair cells and adjacent
supporting cells in the organ of Corti at the
reticular lamina.
8. TIGHT JUNCTIONS-In the vestibular
system
• Level of the tight junctions between hair and
supporting cells in the sensory patches and
between the epithelial cells that surround the
endolymphatic, luminal spaces including
• Dark cells of the utricle and semicircular
canals, the roofs of the utricle and saccule and
the semicircular canals.
9. EFFECTS AND ACTIONS OF
OTOTOXIC DRUGS
• The occurrence and extent of ototoxicity is to some
extent dependent upon the dosing regime (or exposure
conditions) .
• the status of the patient receiving the drug and
multiple drug regimes.
• Stress produced by infection may increase sensitivity as
may malnourishment; the effects of aminoglycosides
are more pronounced in nutritionally deprived animals.
• Individuals under similar conditions and with similar
drug-dosing regimes differ in their sensitivity to
ototoxic side effects.
10. • Drug interactions can also result in much greater
damage than would be expected from single drug
regimes.
• A number of ototoxic agents, including
aminoglycosides, polypeptide antibiotics and
anti-neoplastics, are also nephrotoxic.
• So that possible damage to the kidney may result
in reduced drug clearance and higher serum
levels potentially increasing the risk to the inner
ear.
11.
12.
13. • On this basis,ototoxins can be divided into three broad groups.
• FIRST-The‘loop’ diuretics and erythromycin,have acute effects in
the stria vascularis resulting in temporaryhearing loss (temporary
‘threshold shift’ (TTS)
• SECOND-group, which includes salicylate and quinine,
predominantly produce temporary impairment of hair cell function
(TTS), often accompanied by tinnitus.
• These symptoms are completely relieved upon withdrawal of the
drug.
• THIRD-most significant, group of ototoxic agents cause death of the
hair cells and permanent hearing loss (permanent threshold shifts
(PTS)) and vestibular dysfunction.
• Aminoglycoside antibiotics and cisplatin (cis-platinum), as well as
organic solvents, fall into this category
• The sensory epithelia in the inner ear in birds and other non-
mammalian vertebrates,the organ of Corti does not spontaneously
regenerate hair cells to replace those lost.
14. Agents affecting the ion-transporting
epithelia
• LOOP DIURETICS-
Agents whose primary site of action is on the iontransporting
epithelia, the stria vascularis (SV) in the cochlea and the
vestibular dark cells, adversely affect endolymph composition
and, in the case of the SV, the endocochlear potential (EP).
• The SV has one the highest rates of oxidative metabolism in
the body, with oxygen delivered from the intraepithelial
blood supply so agents that induce anoxia or ischaemia will
affect strial activity.
• Aminoglycoside antibiotics and cisplatin,may induce
permanent strial pathologies although this does not
necessarily correlate with effects on EP.
15. Loop diuretics
• Those diuretics whose principal site of action is in the
ascending limb of the loop of Henle, including ethacrynic
(etacrynic) acid, furosemide(frusemide), bumetanide and
piretanide, produce a transient hearing loss across most of
the frequency range.
• The effects are rapid in onset, within minutes or hours, and
persist for some hours but are usually completely resolved
within a day if the drug is discontinued.
• However, a single dose of diuretic when administered
closely with a single dose of an ototoxin such as
aminoglycoside or cisplatin which has the potential to
cause hair cell loss only after chronic repeated treatment,
results in rapid devastatingly extensive hearing loss and
hair cell death.
18. • Histological studies of the temporal bones from
patients who have died while on diuretic
treatment-have shown extensive oedema and
swelling of the SV.
• This oedema is also reversible, resolving within
about 2–4 hours, prior to complete recovery of
EP.
• Reversible decline in EP, falling from the usual +80
mV to negative values as low as around -40 mV,
the K+diffusion potential.
• The rapid onset of their effects suggests that
diuretics gain direct access to their site of action
through entry from the strial vasculature into the
extracellular spaces of the SV .
19. The development of oedema suggests that diuretics inhibit the ion-transporting
processes.
Ions accumulating in the extracellular spaces would be confined by the tight junction
sealing between basal cells, those between marginal cells and those between capillary
endothelial cells,resulting in osmotic uptake of fluid
20. • In the kidney, diuretics act on a Na/K/Cl cotransporter.
• The same cotransporter, NKCC1, localizes to the
basolateral membrane both of vestibular dark cells and
of marginal cell of the SV and has been shown to be a
target of the diuretics in the SV and vestibular dark
cells.
• In the cochlea, the generation of EP is thereby inhibited
and along its entire length such that the consequent
hearing impairment resulting from reduction of
cochlear amplification is across almost the entire
frequency range.
• (There is no equivalent of EP in the vestibular system
so the effects are less pronounced.)
21. • Na+/K+-ATPase is also present at high
concentration on the basolateral membrane of
marginal cells.
• Inhibition of this might have a similar effect as
inhibition of the cotransporter.
• Potassium cyanide, along with its other actions in
the body, causes TTS with a symptomatology
similar to that of loop diuretics, thought to result
from inhibition of marginal cell Na+/K+-ATPase.
• Macrolide antibiotics such as erythromycin also
produce effects similar to those of diuretics.
22. Agents causing reversible effects on hair cells
SALICYLATES
• COMPLETELY REVERSIBLE
• Decrease outer hair cellwall
stiffness and motility
• Can increase distortion
product OAE.
• Diminish spontaneous OAE
and elctromotility of OHC’s
• TTSs across most of the
detectable frequency range,
and tinnitus & dizziness.
• Affects the motor protein of
OHC’s –PRESTIN by inhibiting
the CL-ANIONS at anion
binding site.
23. Quinine
• The ototoxic effects of salicylate
and quinine thus derive from an
ability to cross the blood–
perilymph barrier freely.
• An effect of quinine at the hair
cell synapse could also explain
vertigo, with its
• Action at these efferent synapses.
• It has been found that quinine
and its derivatives such as
chloroquinine
• block nicotinic acetylcholine
receptors (nAChR)
• Acetylcholine is the predominant
efferent neurotransmitter in the
cochlea.
• Primarily they are cochleotoxic
• Reversible vasculitis and
ischemia
• Causing degenerative changes in
stria vascularis and organ of corti
• Babies born to mother taking
quinine and chloroquinine habe
B/L SNHL
• While mothers hearing
unaffected.
24. AMINOGLYCOSIDE ANTIBIOTICS-
Agents that cause permanent hearing
loss and balance disorders
• They are toxic to hair cells in all inner ear sensory patches in all
vertebrate classes.
• Although all aminoglycosides are potentially both cochleotoxic and
vestibulotoxic, the different aminoglycosides exhibit differences in
their toxic potential and organ preference.
• These have indicated that neomycin is the most toxic, gentamicin,
kanamycin and tobramycin less so, and amikacin and netilmicin
least toxic, but such differential toxicity.
• Streptomycin and gentamicin are considered more vestibulotoxic
than cochleotoxic to humans, whereas amikacin and neomycin are
primarily cochleotoxic in the human inner ear.
25. • Topical application of a single dose of the drug to
the middle ear cavity can almost immediately
initiate the progressive damage observed after
chronic systemic treatment.
• The severity of the effects increases progressively
with time, continuing after drug,administration
has been stopped.
• The initial effect in the cochlea is a hearing loss
confined to the high frequencies,indicating hair
cell damage in the most basal region of the
cochlea.
26.
27. Location and nature of lesions
• In the organ of Corti, in line with the pattern of hearing
loss, hair cells in the basal (high-frequency)coil are affected
first, damage spreading progressively apical wards with
time and with increasing dosage.
• Outer hair cells are more sensitive than inner hair cells.
• IHCs do not usually appear to die until all the OHCs in their
immediate vicinity and may persist for months after there
has been complete loss of all OHCs.
• There is also significant progressive loss of spiral ganglion
neurons, the afferent nerves that innervate hair cells.
• This appears to progress following death of IHCs
28. Preferential uptake of gentamicin!
• The loss of the terminals is thought to occur by excess release of
the neurotransmitter glutamate from the IHCs at synapses with
afferent terminals causing excitotoxic damage to the nerve.
• In the vestibular system aminoglycoside-induced hair cell loss is
seen initially in the central regions of the epithelia, i.e. at the crests
of the saddle-shaped cristae and across the ‘striola’ along the
middle of utricular and saccular maculae.
• Cristae show greater HC loss than the utricle which in turn shows
more extensive damage than the saccule.
• Immunohistochemistry has shown preferential uptake of
gentamicin into the type 1 hair cells.
• The type 1 hair cells predominate on those regions where damage
is initiated and are thought to be more susceptible to
aminoglycoside induced damage than the type 2 vestibular hair
cells.
29.
30. Supporting cells-Saved!!
• The death of each hair cell is accompanied by
expansion of the supporting cells around them to
close the lesion and effect tissue repair/are not
usually affected by aminoglycosides (or other
ototoxins.
• The replacement hair cells derive from the
supporting cell population through initiation of cell
division among the supporting cells .
• And /or through direct non-mitotic
transdifferentiation, or ‘phenotypic conversion’ of
supporting cells into hair cells.
31. Reorganization of the sensory
epithelium !!
• After hair cell loss and ultimately the crest of cells that
normally constitutes the organ of Corti can become
replaced by an apparently simple cuboidal-like
epithelium across the basilar membrane.
• In the organ of Corti lost hair cells are not replaced, but
there is some evidence for regeneration of hair cells in
the mammalian utricle.
• The extent to which this occurs is limited and only a
proportion of the lost hair cells may be replaced by
new one.
32. Pharmacokinetics
• The half-life of aminoglycoside in the inner ear has been
estimated as more than 30 days.
• The peak level reached in perilymph after multiple dosing
has been reported to be approximately 50–250 μM.
Following systemic administration appears in greater
• amounts in the scala tympani of the apical turn than in the
basal coil.
Aminoglycosides also enter endolymph,
• but only after a prolonged period following entry into
perilymph
33. Pharmacokinetics and mechanisms of
toxicity
• The cell death occurs only after some critical
concentration of the drug has been reached inside the
cell.
• Aminoglycosides cause death of hair cells by inducing
apoptosis
• There is a linear relationship between serum
concentration of aminoglycoside and the perilymph
concentration.
• but aminoglycosides enter perilymph relatively slowly,
the peak concentration after extravascular injection-
much later in perilymph (about 4 hours) than in serum
(about 15–30 minutes
34. APOPTOSIS
• A programmed cell death pathway in which particular
enzymes called caspases play the crucial roles.
• Gentamicin-induced hair cell death can be prevented
by pan-caspase inhibitors,
• One significant initiator of programmed cell death
leading to apoptosis is generation of reactive free
radicals.
• The common feature of all hair cells is the
transduction apparatus at their apical poles.
• Aminoglycosides are one of the few known blockers of
the hair cell transduction channel.
• One of the major routes of entry for aminoglycosides
into hair cells is through the mechanotransduction
channels at the tips of the stereocilia
35. Why Base is affected more than the
Apex?
• Entry via the transduction channels could provide one
explanation for the base-to-apex gradient in hair cell
death along the cochlea:
• the probability of the open state of the transduction
channels in OHCs in the basal coil is 50%,
• but the open state probabilities decrease towards the
cochlear apex.
• Effects of aminoglycosides that lead to the release of
free radicals to levels in excess of cellular mechanisms
to detoxify them has been considered one potential
route through which aminoglycoside-induced hair cell
death is triggered.
36.
37.
38. MITOCHONDRIA->rRna->ROS
• Mitochondria are derived during evolution from bacteria and they
contain their own distinct set of genes, separate from the genes
encoded by the cell’s nuclear DNA.
• These genes encode some of the mitochondrial proteins and the
ribosomal- (r-)RNAs necessary for their translation.
• Bacterial r-RNAs are the target for aminoglycosides as antibiotics.
Damage to mitochondria releases not only ROS but also a number
of factors normally resident within mitochondria that regulate the
cascade of reactions leading to apoptosis.
• So,that mutations in mitochondrial genes that encode for
mitochondrial rRNAs are associated with enhanced susceptibility
to Aminoglycoside induced hearing loss.
39. Effects of aminoglycosides on the
stria vascularis
• The drugs are taken up
quite rapidly into
marginal cells in the SV.
• A decrease in the volume
of the SV (strial atrophy)
has been observed in
human temporal bones
obtained within 2 weeks
of aminoglycoside
treatment.
• The decrease in the
thickness of the stria is
due to effects almost
exclusively on marginal
cells-reduced volume
40. Stria &EP
• Such alteration expected
to affect EP and the ionic
profile of endolymph.
• But EP appears to be
maintained at close to
normal levels for up to 4
weeks
• But is reduced by more
than half 12 weeks after
treatment when there is
significant decrease in
strial thicknes
• The stria is less than
onethird its normal vol,
there is a catastrophic
loss of EP.
• the stria can sustain
injury for some time
without a noticeable
effect on auditory
function.
• If ‘compromised’ state, it
might be less able to
• resist further insults
41. Confounding factors and genetics
• Mutations in the gene that
encodes 12s ribosomal RNA
of mitochondria.
• The ‘A1555G’ missense
mutation (an adenosine to
guanosine substitution at
• base position 1555),
• Thymidine to cytosine
mutation at 1095,
• Cytosine to thymidine
missense at 1494 &
• Cytosine insertion at
position 961
• Mutations appear to affect
only the cochlea’s sensitivity
t aminoglycoside; there is
no enhanced effect on the
vestibular system.
• ‘Critical -period’ : the time
of the onset of auditory
function during
development in about
weeks 18–20 of gestation.
• Sensitivity to the ototoxic
agent is greatest.
42. CONFOUNDING FACTOR
NOISE:
• High sound pressure levels
also lead to the generation
of a variety of free radical
species,which would
exacerbate the effects of
aminoglycoside-induced
cellular stress.
LOOP DIURETICS:
• The SV is also affected,
becoming progressively
thinner through loss of
marginal cells
• The loop diuretics markedly
increase the penetration of
aminoglycosides into
endolymph and enhance
uptake of gentamicin into
cochlear hair cells.
• The reduction in EP to
negative values from the
normally high positive
potential may encourage
entry of the cationic
aminoglycoside into
endolymph.
• The potentiation of
cochleotoxicity
43. CISPLATIN
Sites of action and nature of effects
• Like aminoglycosides, it is
nephrotoxic as well as
ototoxic.
• Used to treat various
tumours of soft tissue.
• Cisplatin induces a
progressive loss of hair
cells,
• the extent of which
correlates with the dose
of drug administered
44. Sites of action and nature of effects
• HairCells in the basal coil of the
cochlea are affected with
damage spreading progressively
apicalwards.
• Initial high-frequency hearing
loss measured by auditory
brainstem response (ABR), and
suppression of otoacoustic
emissions indicating an effect
on OHCs.
• Cisplatin may have direct
effects upon the spiral ganglion
cells themselves.
45. Effects on SV, Spiral Ganglion ,Basal coil, Spiral ligament
• Detachment of the myelin
sheaths from type 1 spiral
ganglion cells (those that
innervate IHCs)
• Progressively increase in
extent in parallel with loss
of OHCs.
• Affects-fibrocytes of the
spiral ligament
• Effects in the stria and in
the organ of Corti are
independent of each
other
• Strial atrophy develops
several days or weeks
after the end of the
chronic treatment.
• Primarily due to apoptotic
death of the marginal
cells
• Cisplatin causes a decline
in EP within 1 day of
single intravenous high
dose and it may become
completely lost.
46.
47. Entry via The apical end of the hair cells-
mechanotransduction channels
• Like aminoglycosides, cisplatin
gains entry to endolymph from
the SV, -an affinity for the hair
cell transduction channel.
• Once inside a cell cisplatin
leads to
1. cross-linking of nuclear DNA,
which in proliferating cells,
such as those of tumours,
2. inhibits DNA synthesis,
3. induces cell cycle arrest,
4. suppresses transcription
5. ultimately leads to
apoptosis.
• Damage to DNA is likely to
occur which will activate DNA
repair mechanisms.
• Polymorphisms in genes for
two DNA repair enzymes,
ERCC2 and XPC= risk factors
for cisplatin-induced hearing
loss
48. Scavenger of free radicals
• Cisplatin binds to to sulphhydryl-
containing molecules such as
metallothineins and glutathione
and negatively affects redox
balance.
• Decrease in cochlear glutathione
and significant decrease in the
activity of glutathione
peroxidise& glutathione
reductase in cochlear tissues
• Agents such as d-methionine and
4-methylbenzoic acid, enable
maintenance of glutathione
levels may be effective in
preventing the ototoxic effects of
cisplatin .
49.
50. Interactions
Noise exposures-
• Above 70 dB concurrent with
cisplatin administration can
induce hearing impairments
and hair cell loss.
• Patients who received
cisplatin even some years prior
to noise exposure-Increased
susceptibility to hearing loss
has also been reported.
• Due to long persistence of
platinum in the body and
prolonged suppression of
antioxidant mechanisms
Diuretics-
• Leads to extensive and quite
rapid hearing loss and death of
OHCs
• Decline in EP enhancing
uptake of the cisplatin
• into endolymph.
51. ORGANIC SOLVENTS
• Exposure to high
concentrations of organic
solvents induce acute,
reversible narcosis and
neurotoxicity and
ototoxic damage.
• Workers in the chemical
Industry and solvent
abusers showed a high
incidence of hearing loss.
• The effects of solvents
may be exacerbated by
concurrent exposure to
high noise levels,
• i.e. noise-induce hearing
loss becoming more
pronounced with
concomitant exposure to
certain solvents
presenting a significant
• occupational hazard
52.
53. Aromatic solvents
• A number of different aromatic
solvents have been implicated in
ototoxicity.
• toluene, p-xylene, ethylbenzene,
n-propylbenzene,
• styrene, ά-methylstyrene, trans-
β-methylstyrene and
allylbenzene.
• Trichlroethylene has also been
reported to be ototoxic- The cell
bodies of the afferent neurones
may also be a target of
trichloroethylene.
Characteristic features of toluene
are:
• It is the mid-frequency ranges of
hearing that are affected
Rather than the high frequencies,
with HC loss in the middle and apical
turns of the organ of Corti
• There is a distinct spread of
damage from the third (outermost)
row of OHCs inwards to involve
subsequently
the second and maybe the first row
of OHCs.
Additionally, the supporting cells,
especially the third (outermost) row
of Deiters cells, are affected
54. SV in the middle and apical cochlear turns is affected, perhaps indicating some
characteristic of the vascular pathways and blood flow that may influence solvent
distribution
55. MODE OF ENTRY
• Since organic solvents are minimally water-soluble their distribution
in the inner ear is unlikely to be determined by entry into the fluid
spaces.
• It is their distribution in the tissue that is significant.
• The pattern of damage across the organ of Corti, from outside to in,
has suggested that the solvents reach the inner ear from the
vasculature of the SV or the spiral prominence region just below it
and
• then pass through the tissues to the organ of Corti.
• The cuboidal cells of the outer sulcus,epithelia of lateral wall to the
organ of Corti along the basilar membrane may be a major
transport route.
• Upon reaching the organ of Corti, the supporting cells of the organ
of Corti, the Hensen’s cells that form the outer ridge of the
sensory epithelium and the Deiters’ cells that surround the hair
cells, may then become injured
56. SUPPORTING CELLS-INJURED!!
• Deiters’ cells:
the outermost row, -most
vulnerable cells in the organ of
Corti following styrene
administration.
• Supporting cells:
involved in the reuptake of K+
from around the hair cells.
Damage to these cells may
therefore result in excessive K+
levels around the OHC that
would lead to their death
57. The cell-death is principally apoptotic or necrotic
• Loss of membrane
integrity and cell
swelling- as a
consequence of
membrane damage.
• Death of Deiters’ cells,
unlike that of hair cells, is
not prevented by
antioxidants, suggesting
that different
mechanisms of cell death
operate in the two cell
types
58. OTHER OTOTOXIC AGENTS
• VIOMYCIN:
Reported to be predominantly
vestibulotoxic following chronic
treatment regimes,
Repeated systemic injections of
relatively high doses, viomycin
causes hair cell death in the
vestibular sensory organs.
• Vancomycin :
has been reported to cause transient
hearing loss and/or Tinnitus.
• Polymyxin B:
when perfused through the
perilymphatic spaces caused an
almost immediate decline in
cochlear microphonic (CM) followed
by a decline in EP, shows
Separate effects on both the organ
of Corti and the SV.
• Chloramphenicol: in animals
causes irreversible hearing loss
following infusion into the middle
ear cavity-
gaining access to the perilymph
following uptake across the round
window membrane.
59. Desferrioxamine
• DFO attenuates
aminoglycoside-induced
hair cell loss.
• repeated highdose
systemic administration
of DFO - cause high-
frequency hearing loss
in about 20–40%
receiving long-term
therapy
• Desferrioxamine
(deferoxamine mesylate
(DFO)
binds iron and is used in
patients with b-
thalassaemia to remove
excess iron from the
serum
60. MONITORING
• Audiologic monitoring for
ototoxicity is primarily
performed for two reasons:
(1) early detection of hearing
status changes presumed to
be attributed to a drug so
that changes in the drug
regimen may be considered,
and
(2) audiologic intervention when
hearing impairment has occurred
OTOTOXICITY MONITORING
TESTS
• Three main approaches to
audiologic monitoring :
1. basic audiologic
assessment,
2. high-frequency audiometry
(HFA), and
3. otoacoustic emission
(OAE) measurement
61. Ototoxicity monitoring
HIGH FREQUENCY AUDIOMETRY
• The earliest effects of ototoxic
drugs are commonly manifested
by the outer hair cells (OHCs) of
the basal cochlear turn.
• HFA comprises air-conduction
threshold testing for the
frequencies above 8 kHz,
detection of aminoglycoside-
induced or cisplatin-induced
ototoxicity long before changes
may be detected in the
conventional range.
• HFA usually detects ototoxic
change earlier than DPOAEs, and
is less affected by otitis media
than OAEs.
OTOACOUSTIC EMISSION
• The most commonly used OAEs are
transient OAEs (TEOAEs) or
distortion product OAEs (DPOAEs).
• TEOAE responses typically change
before hearing threshold in the
conventional range, but not before
changes in the HFA thresholds
• DPOAEs may detect ototoxic
change earlier than TEOAEs, likely
due to the fact that DPOAEs can be
measured at higher frequencies
62. Grades of Ototoxicity
ASHA
• The most commonly used
criteria was published in
1994 by the American
Speech-Language-Hearing
Association
• Retesting must be
completed within 24 hours
to confirm results .
One of the following must be met to
identify significant ototoxic change:
● 20 dB or greater decrease in pure-
tone threshold at one frequency
(20 dB is equivalent to a whisper or
rustling leaves)
● 10 dB or greater decrease at 2
adjacent frequencies
(10 dB is equivalent to breathing)
● Or loss of response at 3
consecutive test frequencies
63. Adverse event scales for hearing
• The two most commonly used are the National Cancer Institute (NCI) -Common
Terminology Criteria for Adverse Events (CTCAE) Ototoxicity Grades and Brock’s
Hearing Loss Grades
64. The Brock’s Hearing Loss Grade test
To determine platinum-induced ototoxicity. The grades of hearing loss are
assigned based on the standard pure-tone audiologic frequencies at which
hearing thresholds equal or exceed 40 dB hearing loss.
65. Patient Education
• The patient should avoid significant noise
exposure during and for several months after
taking an ototoxic drug.
• Patients with hearing aids should ensure that
their power output is carefully monitored to
avoid any noise damage.
• Patients should inform their physician of any
changes to hearing, balance, or tinnitus.
66.
67. Journals on prevention of cisplatin
induced ototoxicity
• Intra tympanic dexamethasone
• Sodium thiosulphate
• Vitamin E