Plasma Concentration as a Proxy for Perilymph Drug Levels: Preclinical and Clinical Dexamethasone Measures with a Long-Acting Formulation for Precise Delivery to the Round Window Membrane.

Objective: To use animal pharmacokinetic data and FluidSIM modeling to estimate human dexamethasone perilymph concentrations from plasma concentration measurements over time following a single intratympanic administration of SPT-2101.

Study Design: Perilymph and plasma dexamethasone concentrations were measured in guinea pigs and African green monkeys over 3 to 6 weeks post-intratympanic administration of SPT-2101. Plasma concentrations of dexamethasone were measured in Ménière's disease patients post-intratympanic administration of SPT-2101.

Drug selection for inner ear therapy.

Introduction: One of the primary tenets in pharmacotherapy is that the applied drug must reach the target tissue at therapeutic concentration. For many therapies intended to treat hearing disorders it has become apparent that we have failed to achieve this goal, contributing to poor outcomes in several important clinical trials. The crux of the delivery problem is that small lipophilic molecules pass with relative ease through membranous boundaries of the body.

Surgical procedure of intratympanic injection and inner ear pharmacokinetics simulation in domestic pigs.

One major obstacle in validating drugs for the treatment or prevention of hearing loss is the limited data available on the distribution and concentration of drugs in the human inner ear. Although small animal models offer some insights into inner ear pharmacokinetics, their smaller organ size and different barrier (round window membrane) permeabilities compared to humans can complicate study interpretation. Therefore, developing a reliable large animal model for inner ear drug delivery is crucial.

A Guinea Pig Model Suggests That Objective Assessment of Acoustic Hearing Preservation in Human Ears With Cochlear Implants Is Confounded by Shifts in the Spatial Origin of Acoustically Evoked Potential Measurements Along the Cochlear Length.

Objectives: Our recent empirical findings have shown that the auditory nerve compound action potential (CAP) evoked by a low-level tone burst originates from a narrow cochlear region tuned to the tone burst frequency. At moderate to high sound levels, the origins shift to the most sensitive audiometric regions rather than the extended high-frequency regions of the cochlear base. This means that measurements evoked from extended high-frequency sound stimuli can shift toward the apex with increasing level.

CACHD1-deficient mice exhibit hearing and balance deficits associated with a disruption of calcium homeostasis in the inner ear.

CACHD1 recently was shown to be an α2δ-like subunit that can modulate the activity of some types of voltage-gated calcium channels, including the low-voltage activated, T-type Ca3 channels. CACHD1 is widely expressed in the central nervous system but its biological functions and relationship to disease states are unknown. Here, we report that mice with deleterious Cachd1 mutations are hearing impaired and have balance defects, demonstrating that CACHD1 is functionally important in the peripheral auditory and vestibular organs of the inner ear.

Reducing Auditory Nerve Excitability by Acute Antagonism of Ca-Permeable AMPA Receptors.

Hearing depends on glutamatergic synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where inclusion of the GluA2 subunit reduces overall channel conductance and Ca permeability. Cochlear afferent synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs) contain the AMPAR subunits GluA2, 3, and 4.

Improved Speech Intelligibility in Subjects With Stable Sensorineural Hearing Loss Following Intratympanic Dosing of FX-322 in a Phase 1b Study.

Objectives: There are no approved pharmacologic therapies for chronic sensorineural hearing loss (SNHL). The combination of CHIR99021+valproic acid (CV, FX-322) has been shown to regenerate mammalian cochlear hair cells ex vivo. The objectives were to characterize the cochlear pharmacokinetic profile of CV in guinea pigs, then measure FX-322 in human perilymph samples, and finally assess safety and audiometric effects of FX-322 in humans with chronic SNHL.

Steroid Nomenclature in Inner Ear Therapy.

: Local glucocorticosteroid ("steroid") therapy is widely used to treat the inner ears of patients with Menière's disease, idiopathic sudden sensorineural hearing loss and in combination with cochlear implants. Applied steroids have included dexamethasone, methylprednisolone, and triamcinolone. In reality, however, this is often not true and the steroid forms commonly applied are dexamethasone-phosphate, methylprednisolone-hemisuccinate, or triamcinolone-acetonide.

Comparison of the Pharmacokinetic Properties of Triamcinolone and Dexamethasone for Local Therapy of the Inner Ear.

Some forms of triamcinolone may provide alternate options for local therapy of the inner ear in addition to the steroids currently in use. We compared the perilymph pharmacokinetics of triamcinolone-acetonide, triamcinolone, and dexamethasone, each delivered as crystalline suspensions to guinea pigs. Triamcinolone-acetonide is a widely used form of the drug with molecular properties that allow it to readily permeate biological barriers.

Dexamethasone and Dexamethasone Phosphate Entry into Perilymph Compared for Middle Ear Applications in Guinea Pigs.

Dexamethasone phosphate is widely used for intratympanic therapy in humans. We assessed the pharmacokinetics of dexamethasone entry into perilymph when administered as a dexamethasone phosphate solution or as a micronized dexamethasone suspension, with and without inclusion of poloxamer gel in the medium. After a 1-h application to guinea pigs, 10 independent samples of perilymph were collected from the lateral semicircular canal of each animal, allowing entry at the round window and stapes to be independently assessed.

Hearing Changes After Intratympanic Steroids for Secondary (Salvage) Therapy of Sudden Hearing Loss: A Meta-Analysis Using Mathematical Simulations of Drug Delivery Protocols.

Objective: The use of glucocorticoids for secondary (salvage/rescue) therapy of idiopathic sudden hearing loss (ISSHL), including controlled and uncontrolled studies with intratympanic injections or continuous, catheter mediated applications, were evaluated by means of a meta-analysis in an attempt to define optimal local drug delivery protocols for ISSHL.

Study Design: A total of 30 studies with 33 treatment groups between January 2000 and June 2014 were selected based on sufficiently detailed description of application protocols. Cochlear drug levels were calculated by a validated computer model of drug dispersion in the inner ear fluids based on the concentration and volume of glucocorticoids applied, the time drug remained in the middle ear, and on the specific timing of injections.

Permeation Enhancers for Intratympanically-applied Drugs Studied Using Fluorescent Dexamethasone as a Marker.

Hypothesis: Entry of locally applied drugs into the inner ear can be enhanced by chemical manipulations.

Background: Perilymph drug concentrations achieved by intratympanic applications are well below the applied concentration due to limited entry through the round window (RW) membrane and stapes. Chemical manipulations to increase entry permeability could increase the effectiveness of drug therapy with local applications.

Pharmacokinetic principles in the inner ear: Influence of drug properties on intratympanic applications.

Local drug delivery to the ear has gained wide clinical acceptance, with the choice of drug and application protocol in humans largely empirically-derived. Here, we review the pharmacokinetics underlying local therapy of the ear using the drugs commonly used in clinical practice as examples. Based on molecular properties and perilymph measurements interpreted through computer simulations we now better understand the principles underlying entry and distribution of these and other drugs in the ear.

Communication pathways to and from the inner ear and their contributions to drug delivery.

The environment of the inner ear is highly regulated in a manner that some solutes are permitted to enter while others are excluded or transported out. Drug therapies targeting the sensory and supporting cells of the auditory and vestibular systems require the agent to gain entry to the fluid spaces of the inner ear, perilymph or endolymph, which surround the sensory organs. Access to the inner ear fluids from the vasculature is limited by the blood-labyrinth barriers, which include the blood-perilymph and blood-strial barriers.

Perilymph pharmacokinetics of marker applied through a cochlear implant in guinea pigs.

Patients undergoing cochlear implantation could benefit from a simultaneous application of drugs into the ear, helping preserve residual low-frequency hearing and afferent nerve fiber populations. One way to apply drugs is to incorporate a cannula into the implant, through which drug solution is driven. For such an approach, perilymph concentrations achieved and the distribution in the ear over time have not previously been documented.

Hearing Changes After Intratympanically Applied Steroids for Primary Therapy of Sudden Hearing Loss: A Meta-analysis Using Mathematical Simulations of Drug Delivery Protocols.

Objective: Controlled and uncontrolled studies with primary intratympanic or combined intratympanic and systemic application of glucocorticosteroids for idiopathic sudden hearing loss were analyzed by means of a meta-analysis in an attempt to establish optimal local drug delivery protocols.

Study Design: A total of 25 studies with 28 treatment groups between January 2000 and June 2014 were selected that adequately described drug delivery protocols. Cochlear drug levels were calculated by a validated computer model of drug dispersion in the inner ear fluids based on the concentration and volume of glucocorticoids applied, the time the drug remained in the middle ear, and the specific timing of injections.

Intracochlear Drug Injections through the Round Window Membrane: Measures to Improve Drug Retention.

The goal of this study was to develop an appropriate methodology to apply drugs quantitatively to the perilymph of the ear. Intratympanic applications of drugs to the inner ear often result in variable drug levels in the perilymph and can only be used for molecules that readily permeate the round window (RW) membrane. Direct intracochlear and intralabyrinthine application procedures for drugs, genes or cell-based therapies bypass the tight boundaries at the RW, oval window, otic capsule and the blood-labyrinth barrier.

Systemic lipopolysaccharide compromises the blood-labyrinth barrier and increases entry of serum fluorescein into the perilymph.

The blood vessels that supply the inner ear form a barrier between the blood and the inner ear fluids to control the exchange of solutes, protein, and water. This barrier, called the blood-labyrinth barrier (BLB) is analogous to the blood-brain barrier (BBB), which plays a critical role in limiting the entry of inflammatory and infectious agents into the central nervous system. We have developed an in vivo method to assess the functional integrity of the BLB by injecting sodium fluorescein into the systemic circulation of mice and measuring the amount of fluorescein that enters perilymph in live animals.

Controlled release dexamethasone implants in the round window niche for salvage treatment of idiopathic sudden sensorineural hearing loss.

Objective: To evaluate the feasibility and hearing outcome of a biocompatible degradable dexamethasone releasing implant for continuous drug delivery to the round window membrane in patients with idiopathic sudden sensorineural hearing loss (ISSHL) and insufficient recovery after systemic high dose glucocorticoid therapy.

Patients: Five patients with profound or moderate-to-severe hearing loss after systemic high-dose prednisolone for ISSHL received local salvage therapy with a controlled release dexamethasone implant in the middle ear.

Intervention: Pieces of a sterile rod shaped poly(D,L-lactide-co-glycolide) PLGA polymer matrix containing a total of 0.

Gentamicin concentration gradients in scala tympani perilymph following systemic applications.

It has been shown in prior studies that round window membrane (RWM) application of gentamicin produced a robust basal-apical concentration gradient in the perilymph of scala tympani (ST) with peak concentrations in the basal turn of ST. These gradients potentially contribute to the clinical efficacy and safety of intratympanic gentamicin applications for the treatment of Ménière's disease. The present study aimed to establish the distribution of gentamicin along ST perilymph after systemic applications.

Large endolymphatic potentials from low-frequency and infrasonic tones in the guinea pig.

Responses of the ear to low-frequency and infrasonic sounds have not been extensively studied. Understanding how the ear responds to low frequencies is increasingly important as environmental infrasounds are becoming more pervasive from sources such as wind turbines. This study shows endolymphatic potentials in the third cochlear turn from acoustic infrasound (5 Hz) are larger than from tones in the audible range (e.

Perilymph pharmacokinetics of markers and dexamethasone applied and sampled at the lateral semi-circular canal.

Perilymph pharmacokinetics was investigated by a novel approach, in which solutions containing drug or marker were injected from a pipette sealed into the perilymphatic space of the lateral semi-circular canal (LSCC). The cochlear aqueduct provides the outlet for fluid flow so this procedure allows almost the entire perilymph to be exchanged. After wait times of up to 4 h the injection pipette was removed and multiple, sequential samples of perilymph were collected from the LSCC.

Progress in cochlear physiology after Békésy.

In the fifty years since Békésy was awarded the Nobel Prize, cochlear physiology has blossomed. Many topics that are now current are things Békésy could not have imagined. In this review we start by describing progress in understanding the origin of cochlear gross potentials, particularly the cochlear microphonic, an area in which Békésy had extensive experience.