Table 3.
Antioxidant drug candidates for protection against CIHL
| Drug | Main mechanism of oto-protection | Experiment model | Drug dose | Route | Outcome |
|---|---|---|---|---|---|
| STS (sodium thiosulfate) | By forming complexes with platinum & antioxidant activity (PMID: 25994788) | Phase III clinical trial on hepatoblastoma in children (n = 109) (PMID: 29924955) | Cisplatin (80 mg/m2) per dose over 6 doses | IV | Reduction in hearing loss grade 1-4 by 48%. |
| Branded as Nithiodote & PedMark | STS (20 g/m2) 6 hours after each cisplatin treatment | IV | |||
| Phase III Clinical trial on children (n = 104) with cancers (PMID: 27914822) | Cisplatin (totaling 200 mg/m2) | IV | Reduction in hearing loss grade 1-4 (OR = 0.31; 95% CI 0.13-0.73; P = 0.0036). | ||
| STS (16 g/m2) 6 hours after each cisplatin treatment | IV | ||||
| NAC (N-acetyl-L-cysteine) | Antioxidant with a thiol donating hydrogen (PMID: 29429900) | Rat cochlea cell culture treated with NAC (PMID: 35346799) | Cisplatin (50 uM) treatment to cell cultures in the background of NAC at 37°C for 48 hours | Cell culture | Hair cell loss prevented, seen through Ab staining. |
| Branded as Acetadote, Fluimucil & Mucomyst | NAC (20 mM) | ||||
| Rat treated with NAC (PMID: 15219317) | Cisplatin (6 mg/kg) | IA | Hearing protected at 4 kHz (~10 dB), 8 kHz (~20 dB), 12 kHz (~22 dB), 16 kHz (~18 dB) by change in threshold. | ||
| NAC (400 mg/kg) 15 minutes before cisplatin | IV | ||||
| Phase I clinical trial on children (n = 52) with cancers (PMID: 37134194) | Cisplatin (totaling 200 mg/m2) | IV | Reduction in the risk of SIOP ≥ 2 hearing loss post-chemotherapy (OR = 0.13, CI 0.021-0.847, P = 0.033). | ||
| NAC (6 g) 4 hours after each cisplatin treatment | IV | ||||
| Double blind clinical trial on cancer patients (n = 114) (PMID:29993216) | Cisplatin (not stated) | Not stated | No significant changes in auditory thresholds. | ||
| 0.4-0.8 ml NAC (10%) | Intratympanic | ||||
| D-methionine (D-met) | D-methionine can donate a cysteine which can act as an antioxidant (PMID: 16366723) | Mice treated with D-methionine (PMID: 8951454) | Cisplatin (16 mg/kg) | IP | Hearing protected at 1, 4, 8, 14 kHz. |
| D-met (300 mg/kg) | IP | ||||
| Chinchilla treated with D-met (PMID: 12087338) | Cisplatin (125 µg) | Intracochlear | Hearing protected at 8, 16 kHz. | ||
| D-met (4 µg) 30 minutes before cisplatin treatment | Intracochlear | ||||
| Rats with MTLn3 breast cancer cells (PMID: 11405249) | Cisplatin (5 mg/kg) per dose for 3 doses with 72 hours interval | IP | Hearing protected at 1, 2, 4, 8, 16, 18 kHz. OHC protected. | ||
| L-met (300 mg/kg) 30 minutes before each cisplatin injection | IP | ||||
| Phase II clinical trial in cancer patients (n = 27) (PMID: 34622731) | Cisplatin totaling (264 mg/m2) | IV | Hearing protected in the left ear only at 11.2 kHz by a mean difference of 22.97 dB. | ||
| D-met (100 mg/kg) oral dose 1 hour before cisplatin injection | Oral | ||||
| Amifostine (WR-2771) | Antioxidant activity through WR-1065 (PMID: 11201306) | Scid mice model of human ovarian cancer with implanted tumor cells (PMID: 9389935) | Paclitaxel (27 mg/kg) over 5 doses | IP | Amifostine improved animal survival. In cell cultures, amifostine protected normal cells from paclitaxel, while cytotoxicity was increased in malignant cells. |
| Branded as Ethyol | Amifostine (200 mg/kg) over 5 doses | IP | |||
| Hamsters treated with amifostine (PMID: 15185124) | Cisplatin (15 mg/kg) over 5 doses | IP | Protected hearing at 8 kHz (~15 db), 16 kHz (~20 db), 20 kHz (~18 db) by ABR threshold shift. | ||
| Amifostine (40 mg/kg) over 5 doses 30 minutes before cisplatin injection | IP | ||||
| Non-randomized clinical study with cancer patients (n = 62) (PMID: 18669462) | Cisplatin (300 mg/m2) over 4 doses | IV | Amifostine caused ~22% reduction in the probability of requiring hearing aid. Amifostine related adverse reaction in 19% patients. | ||
| Amifostine (600 mg/m2) 3 hours before and immediately before cisplatin injection | IV | ||||
| A randomized clinical study (n = 25) investigating medulloblastoma in children (PMID: 15999362) | Cisplatin (40 mg/m2) per day for 5 days | IV | Amifostine did not offer otoprotection against cisplatin combined with etoposide and bleomycin. | ||
| Amifostine (825 mg/m2) per day for 5 days 30 minutes before cisplatin | IV | ||||
| Etoposide (100 mg/m2) per day for 5 days | IV | ||||
| Bleomycin (15 IU/m2) per day for 5 days | IV | ||||
| Taurourso-deoxycholic acid (TUDCA) | HO1 and SOD2 mediated antioxidant activity (PMID: 32061715) | Rats treated with TUDCA (PMID: 32061715) | Cisplatin (5 mg/kg) per day for 3 days | IP | Protected hearing at 4, 8, 16, 32, 40 kHz. |
| TUDCA (100 mg/mL) 1 hour before cisplatin treatment | IP | ||||
| TUDCA | HO1 and SOD2 mediated antioxidant activity of TUDCA (PMID: 32061715) | Rats treated with TUDCA (PMID: 33631298) | Cisplatin (4.6 mg/kg) per day for 3 days | IP | Protected hearing at 8, 16, 24, 32, 40 kHz. |
| TUDCA (500 mg/kg) 1 day before cisplatin treatment | Subcutaneous | ||||
| Ebselen | Antioxidant activity acting as a GPx mimic | Mice treated with ebselen (PMID: 19286452) | Cisplatin (16 mg/kg) | IP | Protected hearing at 4, 8, 16, 32 kHz. |
| Ebselen (16 mg/kg) | IP | ||||
| Rat treated with ebselen (PMID: 21804453) | Cisplatin (14 mg/kg) | IV | Did not protect hearing. | ||
| Ebselen (12 mg/kg) 1 hour before cisplatin treatment | IP | ||||
| Rat treated with ebselen and allopurinol (PMID: 15721563) | Cisplatin (16 mg/kg) | IP | IP ebselen + allopurinol protected hearing at 8, 16, 24 kHz. | ||
| Ebselen (8 mg/kg) 1 hour before cisplatin treatment | IP/oral gavage | ||||
| Allopurinol (8 mg/kg) 1 hour before cisplatin treatment | IP/oral gavage |