Cyclodextrins and Iatrogenic Hearing Loss: New Drugs with Significant Risk

Abstract

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-β-cyclodextrin (HPβCD) 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 HPβCD 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 HPβCD use as a maintenance drug, and the mechanism(s) of ototoxicity, are unknown. β-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 HPβCD. It is possible that HPβCD 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.

Alpha-cyclodextrin inhibits cholesterol crystal-induced complement-mediated inflammation: A potential new compound for treatment of atherosclerosis

“…When administered orally, ACD and 2HPBCD are well tolerated and are Generally Recognized As Safe (GRAS) by FDA. However, 2HPBCD, experimentally used to treat the rare neurodegenerative disorder Niemann-Pick Disease Type C (NPC), has recently been linked to significant hearing loss 30 . Hearing loss has been shown in several species including human, and occur as a result of both central and peripheral administration [31][32][33] .…”

Methyl-β-Cyclodextrin Impairs the Phosphorylation of the β2 Subunit of L-Type Calcium Channels and Cytosolic Calcium Homeostasis in Mature Cerebellar Granule Neurons

“…Cyclodextrins are also used as anti-browning agents in different foods and foodstuffs [ 3 ]. However, a link between cyclodextrins and iatrogenic hearing loss has been noted in several species, including humans [ 4 ]. In particular, methyl-β-cyclodextrin has been widely used for the selective removal of cholesterol and disruption of lipid rafts in different cell lines (see, e.g., [ 5 , 6 ]).…”

Delivery of therapeutics to the inner ear: The challenge of the blood-labyrinth barrier

“…Cyclodextrin entry into the inner ear environment may be possible by perforating the BLB. When used in this manner, high doses of cyclodextrin are toxic to outer hair cells, causing moderate to severe hearing loss (86).…”