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Early investigational drugs for hearing loss.

ABSTRACT: Sensorineural hearing loss (HL) is becoming a global phenomenon at an alarming rate. Nearly 600 million people have been estimated to have significant HL in at least one ear. There are several different causes of sensorineural HL included in this review of new investigational drugs for HL. They are noise-induced, drug-induced, sudden sensorineural HL, presbycusis and HL due to cytomegalovirus infections.This review presents trends in research for new investigational drugs encompassing a variety of causes of HL. The studies presented here are the latest developments either in the research laboratories or in preclinical, Phase 0, Phase I or Phase II clinical trials for drugs targeting HL.While it is important that prophylactic measures are developed, it is extremely crucial that rescue strategies for unexpected or unavoidable cochlear insult be established. To achieve this goal for the development of drugs for HL, innovative strategies and extensive testing are required for progress from the bench to bedside. However, although a great deal of research needs to be done to achieve the ultimate goal of protecting the ear against acquired sensorineural HL, we are likely to see exciting breakthroughs in the near future.

SUBMITTER: Mukherjea D

PROVIDER: S-EPMC5488860 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Early investigational drugs for hearing loss.

Mukherjea Debashree D Ghosh Sumana S Bhatta Puspanjali P Sheth Sandeep S Tupal Srinivasan S Borse Vikrant V Brozoski Thomas T Sheehan Kelly E KE Rybak Leonard P LP Ramkumar Vickram V

Expert opinion on investigational drugs 20140922 2

<h4>Introduction</h4>Sensorineural hearing loss (HL) is becoming a global phenomenon at an alarming rate. Nearly 600 million people have been estimated to have significant HL in at least one ear. There are several different causes of sensorineural HL included in this review of new investigational drugs for HL. They are noise-induced, drug-induced, sudden sensorineural HL, presbycusis and HL due to cytomegalovirus infections.<h4>Areas covered</h4>This review presents trends in research for new in ...[more]

PMID: 25243609

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Project description:Cyclodextrins are a family of cyclic oligosaccharides with widespread usage in medicine, industry and basic sciences owing to their ability to solubilize and stabilize guest compounds. In medicine, cyclodextrins primarily act as a complexing vehicle and consequently serve as powerful drug delivery agents. Recently, uncomplexed cyclodextrins have emerged as potent therapeutic compounds in their own right, based on their ability to sequester and mobilize cellular lipids. In particular, 2-hydroxypropyl-?-cyclodextrin (HP?CD) has garnered attention because of its cholesterol chelating properties, which appear to treat a rare neurodegenerative disorder and to promote atherosclerosis regression related to stroke and heart disease. Despite the potential health benefits, use of HP?CD has been linked to significant hearing loss in several species, including humans. Evidence in mice supports a rapid onset of hearing loss that is dose-dependent. Ototoxicity can occur following central or peripheral drug delivery, with either route resulting in the preferential loss of cochlear outer hair cells (OHCs) within hours of dosing. Inner hair cells and spiral ganglion cells are spared at doses that cause ~85% OHC loss; additionally, no other major organ systems appear adversely affected. Evidence from a first-to-human phase 1 clinical trial mirrors animal studies to a large extent, indicating rapid onset and involvement of OHCs. All patients in the trial experienced some permanent hearing loss, although a temporary loss of function can be observed acutely following drug delivery. The long-term impact of HP?CD use as a maintenance drug, and the mechanism(s) of ototoxicity, are unknown. ?-cyclodextrins preferentially target membrane cholesterol, but other lipid species and proteins may be directly or indirectly involved. Moreover, as cholesterol is ubiquitous in cell membranes, it remains unclear why OHCs are preferentially susceptible to HP?CD. It is possible that HP?CD acts upon several targets-for example, ion channels, tight junctions (TJ), membrane integrity, and bioenergetics-that collectively increase the sensitivity of OHCs over other cell types.

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Early investigational drugs for hearing loss.

Publications

Early investigational drugs for hearing loss.

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