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Prevention of cisplatin-induced hearing loss by extended release fluticasone propionate intracochlear implants - PubMed Skip to main page content
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. 2019 Jun:121:157-163.
doi: 10.1016/j.ijporl.2019.03.021. Epub 2019 Mar 20.

Prevention of cisplatin-induced hearing loss by extended release fluticasone propionate intracochlear implants

Erik Pierstorff  1 , Wan-Wan Yang  2 , Yen-Jung Angel Chen  3 , Shirley Cheung  2 , Federico Kalinec  3 , William H Slattery  2
Affiliations

Prevention of cisplatin-induced hearing loss by extended release fluticasone propionate intracochlear implants

Erik Pierstorff et al. Int J Pediatr Otorhinolaryngol. 2019 Jun.

Abstract

Objective: Cisplatin is a chemotherapeutic drug known to induce hearing loss. Although corticosteroids may help to mitigate the ototoxic side effects of cisplatin, there are complications associated with their systemic and prolonged use. The goal of this study is to test the efficacy of extended-release fluticasone propionate intracochlear implant particles to protect against cisplatin-induced hearing loss.

Methods: We used guinea pigs (n = 9) injected with cisplatin (IP, 12 mg/kg weight). Fluticasone particles were delivered to the cochlear scala tympani through the round window membrane into the right ears of the guinea pigs (left ears being used as a control) two weeks prior to cisplatin administration, and hearing function was evaluated by ABR and DPOAE before implantation, immediately before cisplatin administration, and 2 weeks after the challenge with cisplatin. Data was statistically evaluated using paired t-test analysis.

Results: No significant differences were observed in ABR threshold between control and implanted ears on day 14 (23.9 ± 2.3 dB vs. 25.6 ± 1.3 dB, P = 0.524), whereas the significant cisplatin-induced hearing loss in control animals (23.9 ± 2.3 dB at day 14 vs. 40.7 ± 2.5 dB at day 28, P ≤ 0.0001) was prevented in implanted animals (25.6 ± 1.3 dB at day 14 vs. 25.0 ± 3.1 at day 28, P ≥ 0.85). A similar, though not statistically significant, trend was observed in DPOAE responses in untreated ears (7.9 ± 5.8 dB at day14 vs. -0.5 ± 5.3 dB at day 28, P = 0.654) as compared to treatment (11.1 ± 3.4 dB at day 14 vs. 13.6 ± 4.8 dB at day 28, P = 0.733).

Conclusion: These results suggest that fluticasone intracochlear implants are safe and able to provide effective otoprotection against cisplatin-induced hearing loss in the guinea pig model.

Keywords: Cisplatin; Cochlea; Corticosteroids; Implantation; Ototoxicity.

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Conflict of interest statement

Declaration of Interests

E.P. and W.S. own stock in O-Ray Pharma.

Figures

Figure 1:
Figure 1:. Scanning electron microscopy (SEM) of uncoated and coated (OR-102) fluticasone propionate crystals.
a: SEM image of uncoated crystal. Particle was examined by SEM using an XL 30 S FEG operating at 5kVa (FEI Inc, Hillsboro, OR). b: SEM image of OR-102. Coated particle was examined by SEM using an XL 30 S FEG operating at 5kVa (FEI Inc, Hillsboro, OR). Moderate agglomeration of the PVA polymer is evident on the surface of the crystal.
Figure 1:
Figure 1:. Scanning electron microscopy (SEM) of uncoated and coated (OR-102) fluticasone propionate crystals.
a: SEM image of uncoated crystal. Particle was examined by SEM using an XL 30 S FEG operating at 5kVa (FEI Inc, Hillsboro, OR). b: SEM image of OR-102. Coated particle was examined by SEM using an XL 30 S FEG operating at 5kVa (FEI Inc, Hillsboro, OR). Moderate agglomeration of the PVA polymer is evident on the surface of the crystal.
Figure 2.
Figure 2.
Study design: Animals were allowed to acclimate for a week prior to OR-102 implantation. At 14 days after implantation cisplatin was administered via intraperitoneal (IP) injection. Hearing was assessed a final time 14 days following cisplatin administration and immediately before euthanasia. One animal died shortly after cisplatin administration. Another animal experienced extreme weight loss after cisplatin administration and was euthanized.
Figure 3:
Figure 3:. Surgical procedure
a: Round window in the horizontal plane in the experimental ear. This was achieved by drilling a small hole through the bulla using a posterior approach. b: OR-102 implant sitting on round window. A 32-gauge needle was used to puncture the round window and the OR-102 implant was placed in the scala tympani. c: Round window after insertion of OR-102. After placement of OR-102 into the round window of the experimental ear, a drop of sodium hyaluronate was placed over the round window injection site to avoid leakage of perilymphatic fluids.
Figure 3:
Figure 3:. Surgical procedure
a: Round window in the horizontal plane in the experimental ear. This was achieved by drilling a small hole through the bulla using a posterior approach. b: OR-102 implant sitting on round window. A 32-gauge needle was used to puncture the round window and the OR-102 implant was placed in the scala tympani. c: Round window after insertion of OR-102. After placement of OR-102 into the round window of the experimental ear, a drop of sodium hyaluronate was placed over the round window injection site to avoid leakage of perilymphatic fluids.
Figure 3:
Figure 3:. Surgical procedure
a: Round window in the horizontal plane in the experimental ear. This was achieved by drilling a small hole through the bulla using a posterior approach. b: OR-102 implant sitting on round window. A 32-gauge needle was used to puncture the round window and the OR-102 implant was placed in the scala tympani. c: Round window after insertion of OR-102. After placement of OR-102 into the round window of the experimental ear, a drop of sodium hyaluronate was placed over the round window injection site to avoid leakage of perilymphatic fluids.
Figure 4.
Figure 4.
Auditory brainstem response (ABR) thresholds. Data shows no statistically significant hearing loss between control ears and implanted ears at day 14 based on corresponding ABR thresholds. No surgery (C) and Implant (I) ABR values (Mean±SEM) are as follows: Pre-Op: 22.8±1.9 (C), 19.4±1.3(I); 14 day: 23.9±2.3 (C), 25.6±1.3 (I); 28 day: 40.7±2.5 (C), 25.0±3.1 (I). Statistically significant hearing loss was seen in Control ears (No Surgery) following cisplatin treatment between day 14 and day 28: 23.9±2.3 dB vs. 40.7±2.5 dB; P≤0.0001, demonstrating cisplatin dependent hearing loss. There was no statistically significant difference in ABR threshold between surgery ears (Implant) between day 14 and day 28: 25.6±1.3 dB vs. 25.0±3.1 dB, P≥0.85, demonstrating otoprotection from OR-102. Stars indicate statistical significance.
Figure 5:
Figure 5:
Distortion product otoacoustic emissions (DPOAEs). No Surgery (C) and Implant (I) DPOAE values (Mean±SEM) are as follows: Pre-Op: 15.0±4.6 (C), 14.5±4.5 (I); 14 day: 7.9±5.8 (C), 11.1±3.4 (I); 28 day: −0.5±5.3 (C), 13.6±4.8 (I). Data demonstrates prevention of cisplatin dependent hearing loss from OR-102 Implant ears 14 days after cisplatin administration (Day 28). DPOAE responses were absent in Control ears 14 days after cisplatin administration but near normal in Implant ears.
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