Hearing Loss and Otopathology Following Systemic and Intracerebroventricular Delivery of 2-Hydroxypropyl-Beta-Cyclodextrin

Abstract

Cyclodextrins are simple yet powerful molecules widely used in medicinal formulations and industry for their ability to stabilize and solubilize guest compounds. However, recent evidence shows that 2-hydroxypropyl-β-cyclodextrin (HPβCD) causes severe hearing loss in mice, selectively killing outer hair cells (OHC) within 1 week of subcutaneous drug treatment. In the current study, the impact of HPβCD on auditory physiology and pathology was explored further as a function of time and route of administration. When administered subcutaneously or directly into cerebrospinal fluid, single injections of HPβCD caused up to 60 dB threshold shifts and widespread OHC loss in a dose-dependent manner. Combined dosing caused no greater deficit, suggesting a common mode of action. After drug treatment, OHC loss progressed over time, beginning in the base and extending toward the apex, creating a sharp transition between normal and damaged regions of the cochlea. Administration into cerebrospinal fluid caused rapid ototoxicity when compared to subcutaneous delivery. Despite the devastating effect on the cochlea, HPβCD was relatively safe to other peripheral and central organ systems; specifically, it had no notable nephrotoxicity in contrast to other ototoxic compounds like aminoglycosides and platinum-based drugs. As cyclodextrins find expanding medicinal applications, caution should be exercised as these drugs possess a unique, poorly understood, ototoxic mechanism.

Direct administration of 2-Hydroxypropyl-Beta-Cyclodextrin into guinea pig cochleae: Effects on physiological and histological measurements

“…Ears with severe IHC and OHC damage had greater effects at the base than apex (Fig 7). While some of this variability in OHC loss may be attributable to the relatively short time-frame of our acute study, interanimal variability is nevertheless consistent with that reported from Crumling et al [5] and Cronin et al [6] who studied the chronic effects of HPβCD treatment. Treatment with MβCD consistently caused severe damage directly to the OHCs and IHCs or the regions around these sensory cells.…”

“…But, a negative side effect of HPβCD-based treatments is hearing loss. Recent studies on the chronic effects of HPβCD administered systemically or directly into cerebrospinal fluid found graduated losses of outer hair cells (OHC) along the cochlear spiral, with more severe losses at the cochlear base than the apex [5–6]. While the origins of HPβCD toxicity within the ear remain uncertain, its effects can modulate cochlear or OHC electromechanics in excised cochleae [7–8].…”

Use of 2-Hydroxypropyl-Beta-Cyclodextrin for Niemann-Pick Type C Disease

“…In other two patients, despite delaying the next dose, hearing loss was not reversed. This AE was also observed in animal studies with IT [18], ICV [53], and intracisternal [25] routes of administration. At the dosage employed, hearing loss is an expected AE, as well as a well-known NPD-C symptom.…”

Supramolecular Pharmaceutical Sciences: A Novel Concept Combining Pharmaceutical Sciences and Supramolecular Chemistry with a Focus on Cyclodextrin-Based Supermolecules

“…13,14) However, as described above CyDs occasionally show toxicity in the lung, 114) bone, 115) ears, 116) and kidney. 117) In contrast to the abundant safety data of CyDs, very few data are available on the safety of CyD-based supermolecules.…”

“…CyDs are also useful in inhibiting neuromuscular blockade by rocuronium (trade name: Bridion ® ) 111) and in increasing the immune responses of vaccines (adjuvant). 112,113) However, CyDs occasionally show toxicity in the lung, 114) bone, 115) ears, 116) and kidney. 117) Moreover, blood retention of CyDs is generally short, 13,117) resulting in low bioactivities.…”