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Intratympanic Therapy inMeniere's Disease Mr Simon Lloyd,
Consultant
Neuro-otologist,
University Department
of Otolaryngology,
Central Manchester NHS
Foundation Trust,
Oxford Road,
The principle of delivering a drug to the middle ear through the tympanic membrane is not new with reports in the literature from the nineteenth century regarding its efficacy as a treatment for ‘catarrhal affections of the middle ear'.1,2 However, the use of this techniquein the treatment for inner ear disorders Manchester, M13 9WL, UK.
has only been popularised over the past 20 years particularly in treating Meniere's Disease and more latterly sudden sensorineural hearing loss. This article focuses on Email: sklloyd@me.com intratympanic therapies used in the treatment of Meniere's Disease.
Declaration of
Competing Interests
None declared.
Current delivery methods
sponge running through the central passage Intratympanic therapies aim to deliver a and this can be slid down to come in to given pharmacological agent to the inner ear contact with the round window niche.
via the tympanic cavity and in so doing opti- Drugs can then be delivered into the mise inner ear dosage and reduce the risk of external ear canal and they soak the sponge developing systemic side effects. However, and diffuse down to the middle ear (Figure delivery of drugs to the inner ear is chal- lenging. Systemic delivery has significant limi- Some authors have also described the use tations with variable penetration due to the of fine catheters placed adjacent to the presence of a blood-inner ear barrier as well round window membrane via the tympanic the risk of significant side effects. Similarly, membrane in order to allow prolonged or more direct access to the inner ear is limited repeated drug delivery. Pump systems that because the structures within the labyrinth may be either partly or fully implantable may are contained within hard bone and are only be used to deliver the drug. However, this accessible through the middle ear via the technique is associated with a high propor- round and oval windows. Access is made all tion of complications, particularly accidental the more difficult by the fact that minor dislocation of the catheter, and has not trauma to the membranous structures of entered widespread use in clinical practice.
the inner ear can result in acute labyrinthinefailure. In addition, there are a number of Current intratympanic drug
potential drawbacks to current intratym- treatments in Meniere's Disease
panic drug delivery strategies including loss There are currently two main groups of drug of drug down the Eustacian tube as well as used to treat Meniere's Disease via the poorly understood intracochlear pharmaco- intratympanic route. They are aminoglyco- kinetics. Some have also expressed concern side antibiotics and steroids.
regarding poor absorption of drug throughthe round window. However, a recent study by Bird et al. has suggested that the dose Aminoglycoside antibiotics, particularly delivered to the cochlea following intratym- gentamicin, are commonly used to treat panic therapy is 260 times greater than the gram negative bacterial and some types of dose delivered by intravenous therapy.3 mycobacterial infection. One of their side There are a number of different methods effects is ototoxicity and this is the basis for of delivering drugs intratympanically.4 The their use in Meniere's Disease.
most common method of intratympanic Most are predominantly cochleotoxic, drug delivery is injection through the resulting in sensorineural hearing loss in a tympanic membrane (Figure 1). A typical significant proportion of patients. However, regimen for this type of administration is gentamicin is predominantly vestibulotoxic shown in Figure 2.
and is less likely to result in hearing loss.
An alternative method of drug delivery is The mechanism of toxicity is unclear.
the Silverstein wick.5 This consists of a From pathology studies it would appear that grommet that is inserted into the eardrum in they induce hair cell death within the the posteroinferior quadrant over the round cochlea at high doses.6 There is probably a window niche. The grommet has a porous preference for outer hair cells. At lower does,



they appear to damage the stereocilia ofboth cochlea and crista sensory cells.7 Theyprobably also have a damaging effect on theotolithic hair cells although this may be lesssignificant. The mechanism by which thesechanges are produced is not completelyclear. Aminoglycosides are actively trans-ported into cells where they bind to iron.
This may then form a toxic metabolite thatgenerates free radicals resulting in cellularinjury and cell death.8 There may also be aneffect mediated through a reduction inmitochondrial protein production and an associated reduction in ATP production.
This is an attractive hypothesis given thatmitochondria have many similarities to A protocol for the administration of intratympanic gentamicin
The first description of the use of amino- The following procedure can be performed in an out patient setting glycosides via the intratympanic approach Mix the following in a 2ml syringe: was by Schuknecht in 1956. He used strep- • 1.5mls of 80mg/ml gentamicin tomycin.9 However, this drug was associatedwith a very high incidence of sensorineural • 0.3mls of water for injection hearing loss because of its ototoxicity. As a • 0.2mls of 84mg/ml sodium bicarbonate result the popularity of intratympanic injec-tion of aminoglycosides waned until it Place the patient supine with the head flat and turned away from the ear to be became clear that gentamicin was equally injected. Use topical anaesthetic agents such as EMLA or Ametop to anaesthetize effective at resolving symptoms but was less the tympanic membrane Under the operating microscope, inject the buffered gentamicin through the tym- There are several papers evaluating the panic membrane in the posteroinferior quadrant just over the round window niche efficacy of intratympanic gentamicin in using a spinal needle. The middle ear can be seen to fill up with the fluid Meniere's Disease. Unfortunately, the study Leave the patient supine with their head turned away for 40 minutes. The patient design and protocols for administration vary may feel some of the drug pass down the Eustacian tube into the nasopharynx widely and this makes comparison of Repeat injections weekly until they start to experience imbalance as a result of the outcomes difficult. Some investigate high treatment, their symptoms resolve or if there is a deterioration in their hearing. This dose single injection therapy. Others investi- is usually 2-3 injections gate staged, lower dose administration. This Some clinicians prefer to insert a ventilation tube at the time of the first injection may be given daily, weekly or monthly.
in order to avoid the need to facilitate subsequent injections Similarly, the end point of treatment varies.
This may be the rendering of the labyrinthavestibular or the onset of vestibular symp-toms. Onset of hearing should also triggercessation of therapy.
All studies suggest that intratympanic gentamicin is an effective treatment forvertigo in Meniere's Disease but treatmentmust balance the need to control symptomswith the potential for cochleotoxicity. Thedosage of gentamicin used varies in the liter-ature from 2.4 to 720mg. The effectiveness ofintratympanic gentamicin in completelyresolving vertigo symptoms in Meniere'sDisease varies from 27% to 100% dependingon the series.10-15 A meta-analysis of 27studies by Chia et al. found that the meancomplete vertigo control rate for all types ofregimen was 73.6%.16 Low dose staged treat-ments controlled vertigo completely (AAOvertigo score of 0) in 66.7% of cases. Theeffective vertigo control rates (AAO vertigoscore of 1-40) were 90.2% and 86.8% respec-tively for all regimens and low dose regimens.
The risk of hearing loss (partial and profound) ranged from 0% to 90% but subject to the same limitations of adhesions or round window thickening in the mean hearing loss for all regimens was heterogenous study design.
those who fail this form of therapy. In this 25.1% with low dose regimens producing Intratympanic steroids appear to be situation exploration of the middle ear to hearing loss in 13.1%. A recent Cochrane effective in controlling vertigo in improve access to the round window reviewhas further assessed the literature17 Meniere's Disease but they are probably followed by direct placement of gentam- and found only two well designed less efficacious than gentamicin. The liter- icin on a pledget onto the round window randomised placebo controlled trials.10,11 ature would suggest that 41-82% of resolves symptoms in the majority of The first study by Stokroos et al.
patients have complete relief of vertigo initial treatment failures.30 suggested that there was a complete and 72-91% of patients have adequate resolution of vertiginous symptoms in all control of their vestibular symptoms When to use intratympanic therapy
patients and that this was significantly following treatment. More than four Intratympanic treatment with gentamicin or greater than placebo. They had no signifi- injections may be required in some cases steroid has become the first line of treat- cant hearing deterioration in any patient.
and a proportion require further injec- ment following failure of conservative The second study by Postema et al.
tions a few months after the original management in Meniere's Disease. This is showed that vertigo scores reduced from treatment.23-27 Most studies suggest that because of the documented effectiveness of 2.1 to 0.5 in the gentamicin group hearing is not affected in either a positive these drugs and because of the simplicity compared to 2.0 to 1.8 in the placebo or negative way following steroid injec- and safety of the procedure. However, there group. Average hearing loss in the are very few studies comparing outcomes of gentamicin group was 8.1dB compared to There have been no meta-analyses these two types drug. Sennaroglu et al. have 0dB in the placebo group.
performed investigating the efficacy of shown effective vertigo control in 72% of From the literature, it would appear intratympanic steroid in Meniere's patients with intratympanic dexametha- that a dose of 30mg/ml administered Disease to date. However, a Cochrane sone, 75% of patients with intratympanic weekly with end points of resolution of review has been performed by Phillips gentamicin and 52% for endolymphatic sac symptoms, onset of vestibular symptoms and Westerberg.28 They felt that only one surgery.24 Other studies are on going because of treatment or onset of hearing randomised placebo controlled trial met (Bronstein et al. unpublished).
loss provides the most effective method rigorous criteria regarding quality. This The decision to use gentamicin or of symptom control with the lowest risk paper, published by Garduno-Anaya et al., steroid is dependent on the amount of of hearing impairment.16,18,19 This may be showed that intratympanic 4mg/ml hearing remaining in the ear to be treated buffered with 84% sodium bicarbonate in Dexamethasone was an effective treat- and on the status of the opposite ear. If order to reduce discomfort during injec- ment in improving vestibular symptoms there is serviceable hearing in the ear to tion. Between one and four injections in Meniere's Disease.27 Eighty-two per be treated and the opposite ear has may be required to achieve symptom cent of the steroid group achieved poorer hearing or evidence of significant control and further injections may be complete control of symptoms (AAO vestibular impairment then steroid is the required in the future. A typical regimen class A) compared to 57% in the placebo drug of choice as it is unlikely to render is shown in Figure 1. For low dose treat- group. There was no significant change in the patient deaf or avestibular. If the ear ments, the time taken until further injec- hearing. There was no significant change to be treated has poor hearing and the tions are required to control recurrent in tinnitus.
opposite ear is healthy then gentamicin is vestibular symptoms may be in the region A number of different steroids have the drug of choice. However, it is impor- of four months.20 been used in Meniere's Disease. The most tant to bear in mind that around 20% of With regards to modification of other commonly used are dexamethasone and patients will develop Meniere's Disease in Meniere's symptoms, most studies have methylprednisalone. Doses are very vari- the opposite ear at some point.
found that intratympanic gentamicin able between studies. For example does not modify tinnitus but may reduce dexamethasone doses vary between symptoms of aural fullness.10,11 1mg/ml and 19mg/ml. Pain may be trou- There are a number of papers that have blesome following injection although this investigated the response of fluctuating seems to be less of an issue for dexam- sensorineural hearing loss seen in Intratympanic steroid injections have ethasone. A dose of 4mg/ml of dexam- cochlear hydrops to intratympanic become increasingly popular as a means ethasone would seem reasonable based steroid injection. The proportion of of controlling vestibular symptoms in on the literature.
patients who have an improvement in Meniere's Disease. They have the poten- As with gentamicin, it would appear their hearing is lower than the proportion tial advantage over gentamicin of not that intratympanic steroids do not signif- of patients that get an improvement in being inherently ototoxic. They are icantly modify tinnitus associated with their balance symptoms and ranges from thought to act through an anti-inflamma- Meniere's Disease.29 40 to 74% depending on the series.31,32 tory effect but may also have an influence Care must be taken when interpreting on sodium and fluid transport within the Failure of intratympanic
this data however, as by its very nature the hearing loss is fluctuating and Steroids delivered intratympanically- It remains unclear why some patients do certainly a significant proportion may have been used to treat Meniere's not respond to intratympanic therapy have improved spontaneously without Diseasesince the early 1990s.22 However, but there is some evidence that it may intervention. Nevertheless, intratympanic the literature regarding intratympanic reflect ineffective delivery of drug in a steroid injection should be considered for steroids in Meniere's Disease is less exten- significant proportion of cases. Some the management of acute hearing loss sive than that for gentamicin and is authors have noted a high incidence of resulting from cochlear hydrops.
The future of intratympanic therapy
Drug delivery systems
1. Bronner A. On intratympanic injections in the treat- 21. Trune DR, Kempton JB, Kessi M. Aldosterone (miner- Given the challenges of access to the inner ment of chronic dry catarrh of the middle ear. Br alocorticoid) equivalent to prednisolone (glucocorti- Med J 1894;2(1763):805.
coid) in reversing hearing loss in MRL/MpJ-Fas1pr ear, a number of techniques are currently autoimmune mice. Laryngoscope 2000;110:1902-6.
being developed for the delivery of drugs 2. Weber-Liel. On intratympanic injections in catarrhal affections of the middle ear. Br Med J 22. Itoh A, Sakata E. Treatment of vestibular disorders.
not just via the middle ear but directly to Acta Otolaryngol Suppl 1991;481:617-23.
the inner ear.
3. Bird PA, Murray DP, Zhang M, Begg EJ. Intratympanic 23. Boleas-Aguirre MS, Lin FR, Della Santina CC, Minor Microcatheters that deliver drugs versus intravenous delivery of dexamethasone and LB, Carey JP. Longitudinal results with intratympanic directly into the inner ear are currently dexamethasone sodium phosphate to cochlear peri- dexamethasone in the treatment of Ménière's dis- lymph. Otol Neurotol 2011;32(6):933-6.
ease. Otol Neurotol 2008;29(1):33-8.
under development. These have been used 4. McCall AA, Swan EE, Borenstein JT, Sewell WF, 24. Sennaroglu L, Sennaroglu G, Gursel B, Dini FM.
in conjunction with pump systems such Kujawa SG, McKenna MJ. Drug delivery for treat- Intratympanic dexamethasone, intratympanic gen- as osmotic pumps or reciprocating perfu- ment of inner ear disease: current state of knowl- tamicin, and endolymphatic sac surgery for edge. Ear Hear 2010;31(2):156-65.
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One of the primary limitations of 5. Silverstein H, Jackson LE, Rosenberg SI. Silverstein Microwick for treatment of inner ear disease. Oper 25. Hirvonen TP, Peltomaa M, Ylikoski J. Intratympanic current intratympanic therapy tech- Tech Otolaryngol Head Neck Surg 2001;12:144–147.
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niques is the limited exposure that the ORL J Otorhinolaryngol Relat Spec 2000;62:117-20.
6. Polgar R, Collison T, Slepecky NB, Wanamaker HH.
round window has to the drug being Anatomic and morphometric changes to gerbil pos- 26. Barrs DM, Keyser JS, Stallworth C, McElveen JT.
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terior cristas following transtympanic administration Intratympanic steroid injections for intractable of gentamicin and streptomycin. JARO 2001;2:147-58.
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Hydrogels that can be loaded with a drugand placed over the round window have 7. Oei ML, Segenhout HM, Dijk F Stokroos I, van der 27. Garduno-Anaya MA, Couthino De Toledo H, Want JJ, Albers FW. Functional and anatomic alter- Hinojosa GR, Pane PC, Rios Castaneda LC.
been demonstrated to improve exposure ations in the gentamicin-damaged vestibular system Dexamethasone inner ear perfusion by intratympan- to the round window by maintaining in the guinea pig. Otol Neurotol 2004;25(1):57-64.
ic injection in unilateral Meniere's disease: a two-yearprospective, placebo-controlled, double- blind, ran- contact with the drug for a prolonged 8. Song BB, Anderson DJ, Schacht J. Protection from domized trial. Otolaryngol Head Neck Surg gentamicin toxicity by iron chelators in guinea pig in vivo. J Pharmacol Exp Th 1997;282(1):369-77.
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Syst Rev 2011;6(7).
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11. Stokroos R, Kingma H. Selective vestibular ablation can be facilitated by the addition of Middle ear exploration in patients with Ménière's by intratympanic gentamicin in patients with unilat- disease who have failed outpatient intratympanic ligands to their surface that aid in trans- eral active Meniere's disease: a prospective, double- gentamicin therapy.Otol Neurotol 2009;30(5):619-24.
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Mann W. Intratympanic dexamethasone and 12. De Stefano A, Dispenza F, De Donato G, Caruso A, hyaluronic acid in patients with low-frequency and Taibah A, Sanna M. Intratympanic gentamicin: a 1- Ménière's-associated sudden sensorineural hearing day protocol treatment for unilateral Meniere's dis- loss. Otol Neurotol 2005;26(5):890-5.
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than steroids but has a small risk of 37. Tessarollo L, Coppola V, Fritzsch B. NT-3 replacement inducing sensorineural hearing loss. There 19. Beck C, Schmidt CL. 10 years of experience with with brain-derived neurotrophic factor redirects are many new drug delivery systems and intratympanally applied streptomycin (gentamycin) vestibular nerve fibers to the cochlea. J Neurosci in the therapy of Morbus Meniere. Arch pharmacological agents under develop- 38. Izumikawa M, Minoda R, Kawamoto K, Abrashkin ment and these may result in the ability 20. Nguyen KD, Minor LB, Della Santina CC, Carey JP.
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ment by Atoh1 gene therapy in deaf mammals. Nat

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Heft 26 6. Jahrgang u Gefahr auf der Weide Eine vorbeugende Parasitenbehandlung sichert zwangsläufig nicht nur die Gesund-heit und Leistungsfähigkeit der Rinder sondern auch den wirtschaftlichen Ertrag. Außerdem verursacht ein Parasitenbefall weitere unnötige Kosten. Demgegenüber stehen im ökologischen Landbau die Ansprüche an eine Minimie-rung des Tierarzneimitteleinsatzes und die damit verbundenen Risiken. Aber auch in ökologisch bewirtschafteten Betrieben ist eine Kontrolle des Parasitenbefalls der Weidetiere zur Erhaltung der Tiergesund-heit unabdingbar, da eine ökologische Fütterung und Haltung allein zur Vorbeu-gung und Bekämpfung eines Parasiten-befalls nicht ausreichen.

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The Analysis of Estrogens Using Liquid Chromatography and Negative Electrospray Ionization Mass SpectrometryKatie estridge1,2, carol Babyak2, wendy lewis2 1environmental science Program, appalachian state University, Boone, nc 2a.R. smith department of chemistry, appalachian state University, Boone, nc estridgeke@appstate.edu