A neurotrophic approach to treating hearing loss: Translation from animal models to clinical proof-of-concept.

Currently, there are no approved medicines available for the treatment of hearing loss. However, research over the past two decades has contributed to a growing understanding of the pathological mechanisms in the cochlea that result in hearing difficulties. The concept that a loss of the synapses connecting inner hair cells with the auditory nerve (cochlear synaptopathy) contributes to hearing loss has gained considerable attention.

Hearing loss: The final frontier of pharmacology.

Despite a prevalence greater than cancer or diabetes, there are no currently approved drugs for the treatment of hearing loss. Research over the past two decades has led to a vastly improved understanding of the cellular and molecular mechanisms in the cochlea that lead to hearing deficits and the advent of novel strategies to combat them. Combined with innovative methods that enable local drug delivery to the inner ear, these insights have paved the way for promising therapies that are now under clinical investigation.

Intratympanic Administration of OTO-313 Reduces Tinnitus in Patients With Moderate to Severe, Persistent Tinnitus: A Phase 1/2 Study.

Objective: To evaluate the safety and exploratory efficacy of intratympanic administration of OTO-313 in patients with tinnitus.

Study Design: Single intratympanic injection of OTO-313 evaluated in a randomized, double-blind, placebo-controlled Phase 1/2 clinical study.

Setting: Tertiary referral centers.

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.

Local Drug Delivery for the Treatment of Neurotology Disorders.

Neurotology disorders such as vertigo, tinnitus, and hearing loss affect a significant proportion of the population (estimated 39 million in the United States with moderate to severe symptoms). Yet no pharmacological treatments have been developed, in part due to limitations in effective drug delivery to the anatomically protected inner ear compartment. Intratympanic delivery, a minimally invasive injection performed in the office setting, offers a potential direct route of administration.

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.

The Sustained-Exposure Dexamethasone Formulation OTO-104 Offers Effective Protection against Cisplatin-Induced Hearing Loss.

The otoprotective effects of OTO-104 were investigated following both acute and chronic administration of cisplatin. The acute administration of cisplatin to guinea pigs resulted in profound hearing loss (70-80 dB SPL) across all frequencies tested. A single intratympanic injection of 6% OTO-104, but not of lower doses, almost completely protected against cisplatin ototoxicity.

The Sustained-Exposure Dexamethasone Formulation OTO-104 Offers Effective Protection against Noise-Induced Hearing Loss.

The otoprotective effects of OTO-104 were investigated both prior to and following acute acoustic trauma. Guinea pigs received a single intratympanic injection of OTO-104 and were assessed in a model of acute acoustic trauma. Doses of at least 2.

OTO-201: nonclinical assessment of a sustained-release ciprofloxacin hydrogel for the treatment of otitis media.

Hypothesis: OTO-201 can provide sustained release to the middle ear and effectively treat otitis media, when compared with FDA-approved ciprofloxacin otic drop formulations.

Background: There is an unmet medical need for antibiotic therapy that can provide a full course of treatment from a single administration by an otolaryngologist at the time of tympanostomy tube placement, obviating the need for twice daily multiday treatment with short-acting otic drops.

Methods: Studies in guinea pigs and chinchillas were conducted.

Identification of the antiarrhythmic drugs amiodarone and lorcainide as potent H3 histamine receptor inverse agonists.

Use of molecular pharmacology to reprofile older drugs discovered before the advent of recombinant technologies is a fruitful method to elucidate mechanisms of drug action, expand understanding of structure-activity relationships between drugs and receptors, and in some cases, repurpose approved drugs. The H3 histamine receptor is a G-protein-coupled receptor (GPCR) primarily expressed in the central nervous system where among many things it modulates cognitive processes, nociception, feeding and drinking behavior, and sleep/wakefulness. In binding assays and functional screens of the H3 histamine receptor, the antiarrhythmic drugs lorcainide and amiodarone were identified as potent, selective antagonists/inverse agonists of human and rat H3 histamine receptors, with relatively little or no activity at over 20 other monoamine GPCRs, including H1, H2, and H4 receptors.

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.

Discovery of potential antipsychotic agents possessing pro-cognitive properties.

Current antipsychotic drug therapies for schizophrenia have limited efficacy and are notably ineffective at addressing the cognitive deficits associated with this disorder. The present study was designed to develop effective antipsychotic agents that would also ameliorate the cognitive deficits associated with this disease. In vitro studies comprised of binding and functional assays were utilized to identify compounds with the receptor profile that could provide both antipsychotic and pro-cognitive features.

Principles of inner ear sustained release following intratympanic administration.

Objective/hypothesis: Previous studies revealed that intratympanic administration of the steroid dexamethasone in poloxamer 407 hydrogel, a class of thermoreversible polymers, resulted in significant and durable exposure in the inner ear. Interestingly, varying the concentrations of the poloxamer vehicle and of the steroid impacted the pharmacokinetic profile of dexamethasone in the perilymphatic compartment. Here, the respective contributions of different vehicles (aqueous solution, poloxamer hydrogel) and steroid drugs (dexamethasone, methylprednisolone) were investigated.

Distribution of dexamethasone and preservation of inner ear function following intratympanic delivery of a gel-based formulation.

Intratympanic (IT) delivery of drugs to the ear is increasingly used for both clinical and research purposes. One limitation of IT delivery is that drugs are rapidly lost from the middle ear by a number of processes, so that prolonged delivery of drug is technically difficult. In the present study, the delivery characteristics of a poloxamer hydrogel formulation containing dexamethasone (dex) were evaluated.

OTO-104: a sustained-release dexamethasone hydrogel for the treatment of otic disorders.

Hypothesis: To investigate whether OTO-104, a poloxamer-based hydrogel containing micronized dexamethasone for intratympanic delivery, can provide long-lasting inner ear exposure and be well tolerated.

Methods: OTO-104 was administered intratympanically to guinea pigs and sheep, and its pharmacokinetic and toxicity profiles were examined.

Results: After a single intratympanic injection of OTO-104 (from 0.

Inverse agonist activity of steroidogenic factor SF-1.

Steroidogenic factor 1 (SF-1) is a key regulator of endocrine function, especially steroidogenesis and reproduction. Unlike most nuclear receptors, SF-1 is constitutively activated and still remains an orphan receptor. To study its function, it is imperative to have reliable assays that can assess potential pharmacological modulators.

Pharmacokinetics of dexamethasone solution following intratympanic injection in guinea pig and sheep.

Information on inner ear pharmacokinetics is limited in the literature, especially in large animals and in humans. A preliminary study was designed to explore the differences in inner ear exposure between guinea pigs and sheep following a single intratympanic injection of a 2% dexamethasone sodium phosphate solution. In both species, significant levels of dexamethasone were observed in the perilymph within 1 h, and decreasing by 50- to 100-fold within 12 h.

Dose-dependent sustained release of dexamethasone in inner ear cochlear fluids using a novel local delivery approach.

The thermo-reversible triblock copolymer poloxamer 407 was investigated as a drug delivery vehicle for micronized dexamethasone into the middle and inner ears of guinea pigs. The study characterized the gelation and in vitro release kinetics of poloxamer formulations. In vivo, the pharmacokinetic profile of formulations containing varying concentrations of poloxamer and dexamethasone was examined following intratympanic administration.

Synthesis, structure-activity relationships, and characterization of novel nonsteroidal and selective androgen receptor modulators.

Herein we describe the discovery of ACP-105 (1), a novel and potent nonsteroidal selective androgen receptor modulator (SARM) with partial agonist activity relative to the natural androgen testosterone. Compound 1 was developed from a series of compounds found in a HTS screen using the receptor selection and amplification technology (R-SAT). In vivo, 1 improved anabolic parameters in a 2-week chronic study in castrated male rats.

Synthesis and evaluation of dibenzothiazepines: a novel class of selective cannabinoid-1 receptor inverse agonists.

A novel class of CB1 inverse agonists was discovered. To efficiently establish structure-activity relationships (SARs), new synthetic methodologies amenable for parallel synthesis were developed. The compounds were evaluated in a mammalian cell-based functional assay and in radioligand binding assays expressing recombinant human cannabinoid receptors (CB1 and CB2).

Design, synthesis, and structure-activity analysis of isoform-selective retinoic acid receptor beta ligands.

We recently discovered the isoform selective RAR beta 2 ligand 4'-octyl-4-biphenylcarboxylic acid (3, AC-55649). Although 3 is highly potent at RAR beta 2 and displays excellent selectivity, solubility issues make it unsuitable for drug development. Herein we describe the exploration of the SAR in a biphenyl and a phenylthiazole series of analogues of 3.

Chemical genomics: massively parallel technologies for rapid lead identification and target validation.

Chemical genomics is a new research paradigm with importantapplications in drug discovery. It links genomic targets withsmall-molecule chemistries thereby allowing for efficient targetvalidation and lead compound identification. ACADIA'schemical-genomics platform consists of a large and diverse small-moleculelibrary (800,000), a reference drug library (2,000), druggablegenomic targets (>300) and a cell-based functional assaytechnology (R-SAT(TM); Receptor Selection and AmplificationTechnology) that allows for ultra-high throughput screening(>500,000 data points/week) as well as high throughputpharmacology and profiling over a wide range of targets.

Identification of novel selective V2 receptor non-peptide agonists.

Peptides with agonist activity at the vasopressin V(2) receptor are used clinically to treat fluid homeostasis disorders such as polyuria and central diabetes insipidus. Of these peptides, the most commonly used is desmopressin, which displays poor bioavailability as well as potent activity at the V(1b) receptor, with possible stress-related adverse effects. Thus, there is a strong need for the development of small molecule chemistries with selective V(2) receptor agonist activity.

Differential modulation of inflammatory pain by a selective estrogen receptor beta agonist.

To understand the contribution of the estrogen receptor beta, the potent and selective agonist ERb-131 was evaluated in animal models of inflammatory pain. In paradigms of acute and persistent inflammatory pain, ERb-131 did not alleviate the nociception induced by either carrageenan or formalin. However, in the chronic complete Freund's adjuvant model, ERb-131 resolved both inflammatory and hyperalgesic components.

Broad modulation of neuropathic pain states by a selective estrogen receptor beta agonist.

The effects of estrogens on pain perception remain controversial. In animal models, both beneficial and detrimental effects of non-selective estrogens have been reported. ERb-131 a non-steroidal estrogen receptor beta ligand was evaluated in several pain animal models involving nerve injury or sensitization.