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Author: admin, 14.01.2015
A new drug may treat epilepsy and prevent tinnitus by selectively affecting potassium channels in the brain, UConn neurophysiologist Anastasios Tzingounis and colleagues report in the 10 June Journal of Neuroscience. The existing drugs to treat epilepsy don’t always work and can have serious side effects. Several years ago, doctors around the world began reporting infants with severe, brain-damaging seizures. Tzingounis began working in 2013 with Thanos Tzounopoulos, a tinnitus expert at the University of Pittsburgh, on a new drug candidate.
The most important question to answer was whether SF0034 works on KCNQ potassium channels the same way retigabine does, and if so, was it better or worse that its parent compound?
There are five different kinds of KCNQ potassium channels in the body, but only two are important in epilepsy and tinnitus: KCNQ2 and KCNQ3. Tzingounis and Tzounopoulos first tested SF0034 in neurons, and found that it was more selective than retigabine. Our aim was to elucidate the importance of anatomical aspects in planning local therapies for inner-ear diseases. Intratympanic administration of drugs for inner-ear disease therapy started when Schuknecht [1,2] presented the results of this novel treatment for vertigo in Meniere's disease in eight patients, using the ototoxic drug streptomycin.
Today, we know that the round-window membrane is involved with several physiological aspects of the ear's function.
During the almost 50 years since the publication of the Schuknecht study, intermittent enthusiasm has occurred for methods using intratympanic administration of an agent to treat an inner-ear disease, particularly because of the variable results obtained with the use of any drug, either in abating the symptoms or in deleterious effects on hearing. Several studies emphasized the importance of anatomical conditions of the round-window niche in the variability of responses to local therapies for the treatment of inner-ear diseases [4,5].
The purpose of our study was to investigate the importance of anatomical aspects in planning local therapies for inner-ear diseases.
We dissected 20 fresh temporal bones obtained in the pathological unit of the Department of Otolaryngology, Hospital de Egas Moniz, Lisbon, Portugal.
We found mucoperiosteal folds partially or completely obstructing the round-window niche in five temporal bones (25%; Fig.
A remarkable result of our study is the demonstration of the proximity of the true membrane to the false membrane in the anterior edge of the window. When promised clinical results do not materialize suitably, sometimes investigation must come back to basics. The first and only study directly addressing the implications of the round-window patency for perfusion of the inner ear via intratympanic instillation of medications was published by Silverstein et al.
Our study undertook the anatomical evaluation, from a surgical-approach perspective, of the relationship between false and true round-window membranes.
We have invented, optimized, and tested in animal experiments a magnetic injection system that can safely deliver therapeutics to the inner and middle ear. The inner ear is behind the blood-labyrinth barrier, thus drugs taken orally or injected systemically do not elute out of inner-ear blood vessels to reach inner ear tissue. In this talk I will summarize how our magnetic system works, compare it to prior results (e.g. A new drug that selectively affects potassium channels promises relief with fewer side effects. Genetic testing showed that the children with this problem had genetic differences in their KCNQ potassium channels. The drug, SF0034, was chemically identical to retigabine, except that it had an extra fluorine atom. KCNQ potassium channels are found in the initial segment of axons, long nerve fibers that reach out and almost, but don’t quite, touch other cells.


Round-Window Anatomical Considerations in Intratympanic Drug Therapy for Inner-Ear Diseases. The study undertakes the anatomical evaluation, from a surgical-approach perspective, of the relationship between the false and true round-window membranes.
That study started a new era of interest about the round window and round-window membrane, particularly in aspects related to permeability of the membrane by several substances and pathogens [3]. First, in its auditory function, it serves as a compensatory area of the bony labyrinth, permitting movement of inner-ear fluids in association with movement of the stapedial footplate.
A natural consequence is to investigate the reasons why standardization of these techniques has not yet been obtained.
A great variability in the middle-ear anatomy-particularly in the roundwindow niche opening-and three-dimensional configuration is easily documented in the images of the most important anatomical textbooks [6].
The dissection started with an exploratory tympanotomy and atticotomy, exposing the tympanic cavity that included the oval and round-window regions.
1), we drilled the promontory in the vicinity of the roundwindow opening (anterosuperior edge of the roundwindow niche) until the round-window membrane was completely exposed (Fig. When the round-window region is exposed by the tympanomeatal flap approach, the round-window niche is only partially exposed, and the round-window membrane is not visible. Only after extensive drilling on the anterosuperior (promontory) edge of the oval-window niche can the ovalwindow membrane be seen clearly. This proximity renders making a clear distinction between the two very difficult from a surgical approach. As to the intratympanic administration of drugs to treat inner-ear diseases, anatomical particularities of the roundwindow niche had been mentioned as one factor accounting potentially for variability of responses [5]. We started with the temporal bone in the usual surgical position, where the round-window content is almost completely hidden, and we ended with the complete exposure of the round-window membrane. In contrast to prior magnetic systems, which can only pull-on (attract) magnetic nanoparticles and so would have to pull through the width of the human head in order to delivery nano-therapy into the middle or inner ear, our system can push (it can magnetically inject). It is thought that drugs delivered intra-tympanically into the middle ear also do not cross the oval window membranes sufficiently to effectively treat inner ear diseases. But in some people this braking system doesn’t work, and the nerves run amok, signaling so much that the brain gets overloaded and has a seizure (epilepsy) or hears phantom ringing (tinnitus). A company called SciFluor had developed SF0034, and wanted to know whether the compound had promise against epilepsy and tinnitus.
It was more effective than retigabine at preventing seizures in animals, and it was also less toxic.The results are promising, both for research and medicine. As our design, we chose a human temporal bone dissection study, for which we used 20 fresh temporal bones. Second, the roundwindow membrane has a definite role as a soft-tissue barrier between the middle and inner ear, and permeability of the membrane to substances can be altered drastically by diseases, particularly otitis media.
Surely that morphological variability will have consequences in administering drugs intratympanically to the inner ear, independent of the method or the device used for the application. When the edge of the round window was dissected, the false membrane was disrupted, and the round-window niche and membrane were then exposed. Nomura [7] described investigations of human temporal bones in which the round-window niche was found to be limited by mucoperiosteal folds in 70% of specimens (the so-called false round-window membrane).
In that study, endoscopic evaluation of the roundwindow niche obstruction through a tympanostomy hole was performed in 41 ears before inner-ear perfusion. The results of our study confirmed the results of previous studies, wherein mucoperiosteal folds partially or completely obstructing the round-window niche were found in a significant proportion of ears.
Anatomical particularities of the round-window niche account, at least partially, for the great variability of the results of these treatments.


Intratympanic gentamicin instillation as treatment of unilateral Meniere's disease: Update of an ongoing study.
This allows us to use reasonable (safe, below FDA limits) magnetic fields over a short distance to delivery therapies into the middle or inner ear.
We have shown in preliminary rat experiments that our magnetic push forces can safely drive drug coated nanoparticles through the oval window membranes from the middle into the inner ear (without effecting hearing or causing other measurable side effects). When the cell wants to signal to the axon, it floods the synapse with sodium ions to create an electrical potential. SciFluor now plans to start FDA trials with SF0034 and see if it is safe and effective in people. After an exploratory tympanotomy and atticotomy, we drilled the anterosuperior (promontory) edge of the round-window niche until the true round-window membrane was completely exposed. Third, the round-window membrane can be the place of delivery of drugs influencing inner-ear activity, either as a primary or as an iatrogenic effect. In each case, we registered the absence or presence and the extent of the mucoperiosteal folds or veils (false round-window membranes) on the round-window niche. In the same study, in 30% of the temporal bones, the roundwindow niche was completely occluded by these folds. The authors found that the round-window niche was partially obstructed in seven ears (17%) and completely obstructed in five ears (12%).
The relationship between the degree of round-window niche obstruction and the results of inner-ear perfusion should be addressed in future studies so as to standardize the techniques of local therapy for inner-ear diseases. Using steroid-coated nano-particles we have shown therapeutic effect for treatment of acute tinnitus and noise-induced hearing loss. The numbers on tinnitus are not as clearcut, but the American Tinnitus Association estimates 2 million people have tinnitus so disabling they have troubling functioning in daily life. When that electrical potential goes on too long, or gets out of hand, the KCNQ potassium channel kicks in. Treating epilepsy is the primary goal, but tinnitus can be similarly debilitating, and sufferers would be thrilled to have a decent treatment.
We registered the presence or absence and the extent of the false round-window membranes on the round-window niche.
We have also demonstrated that magnetic pushing can drive nano-particles through the tympanic membrane, providing a non-invasive alternative to syringe or laser intra-tympanic injection. It opens, potassium ions flood out, and the sodium-induced electrical potential shuts down. We found false round-window membranes obstructing the round-window niche partially or completely in five temporal bones (25%). In some types of epilepsy, the KCNQ potassium channels have trouble opening and shutting down runaway electrical potentials in the nerve synapse. We found mucoperiosteal folds obstructing the round-window niche partially or completely in a significant proportion of the ears. These anatomical particularities could account, at least partially, for the great variability of the results of intratympanic therapies for inner-ear diseases.



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