Table 4.

Characteristics of the anti-apoptotic drugs that were included in the systematic review and their main outcomes.

References	Design	Population	Age	Gender	Treatment	Noise Exposure	Type, Dose, and Duration of Intervention	Parameters Analyzed	Main Outcomes	Conclusions
1. Malfeld (2023). Hannover (Germany) [71]	Prospective cohort	Guinea pigs	-	male	Insulin-like Growth Factor 1 (IGF-1)	Beethoven’s 5th Symphony, 4th movement (120 dB) for 4 h, 1 week after implantation	Continuous administration of IGF-1 (0.3 ng/h) via implanted osmotic pump unilaterally	a. ABR: −7 d, 0 d, +1 d, and +7 d b. Histology	No significant difference in threshold shifts between IGF-1 and AP implanted groups. No significant improvement in NIHL with preventive IGF-1 administration.
2. Lin (2021). Taipei (Taiwan) [72]	Prospective cohort	Guinea pigs	-	-	IGF-1 MB exposed to ultrasound (US)	Narrowband noise (118 dB SPL, 8 kHz) for 5 h	200 µL MB exposed to US for 1 min (×3), followed by gelatin sponge soaked with 10 µL rhIGF-1 on the round window membrane (RWM) 24 h after noise exposure	a. ABR: 0 d, +14 d, and +28 d b. Histology c. RNA sequencing (Akt1, MAPK1, 3)	The USM group had the lowest threshold shift in ABR, the lowest loss of cochlear outer hair cells, and the lowest reduction in the number of synaptic ribbons on post-exposure day 28 among the three groups. The combination of USMBs and IGF-1 demonstrated a better treatment effect than IGF-1 alone.
3. Cho (2021). Seoul (South Korea) [73]	Prospective cohort	Sprague Dawley	6 weeks	Male	HA-TCO (1 mL) + IGF-1 (2.5 mg) + mD (5 mg)	White noise (116 dB SPL) for 3.7 h.	Intratympanic (IT) injection of 30–60 μL of the dual vehicle (HA-Tet + mDEX) + HTCA + IGF-1 + mDEX	a. ABR: 0 d, +8 d, +12 d, 30 d, and 45 d b. Light ear endoscopy c. Fluorescence ear endoscopy d. Histology e. CT scan	a. The residence time of the drug/vehicle in the middle ear was extended 10.9 times using the dual vehicle, namely, cross-linked HA and PLGA microcapsules. b. The treatment outcome in terms of hearing threshold and hair cell count was comparably good in both groups.
4. Xiaogang (2022). Shaanxi (China) [74]	Prospective cohort	C57 BL/6J mice	6–8 weeks	Male	LS19-Forskolin nanoparticles (LS19-FSK-NP)	Broadband white noise (115 dB SPL, 2–20 kHz) for 2 h	Round window membrane (RWM) injection of 10 μL LS19-FSK-NP	a. ABR: 0 d, +1, +7, and +14 b. Histology c. Immunofluorescence	The sustained release and cumulative concentration of FSK in the cell inhibited the apoptosis of cochlear OHCs. LS19 peptide modification significantly improved the protective effect of LS19-FSK-NPs against NIHL based on ABR testing at 4, 8, 16, and 32 kHz.
5. Shukla (2019). Delhi (China) [75]	Prospective cohort	Sprague Dawley	-	Male	Selective adenosine (A2A) receptor agonist (CGS21680)	White noise (100 dB SPL) 2 h daily over 15 days	Intraperitoneal (IP) injection of 100 μg/kg/day for 15 successive days	a. ABR: 0 d and +15 d b. Cognitive assessment c. Histology d. Immunofluorescence	ATS post-exposure was 50.83 ± 4.26 dB in the noise group, 32.33 ± 4.5 dB in the drug group, and a threshold shift of 24.33 dB compared with the control group. The A2A receptor agonist CGS21680 provides protection from NIHL by maintaining hearing threshold levels and promoting neurogenesis in the hippocampus.
6. Liu (2018). Mongolia (China) [76]	Prospective cohort	C57 BL/6J mice	8 weeks	-	AK-7	96 dB SPL (8–16 kHz) for 12 h or 24 h	IP injection of 30 mg/kg AK-7 1 day before noise exposure, then continuously with 15 mg/kg until the end of the experiment	a. ABR: 0 d, +1 d, +7 d, and +14 d b. Histology c. Immunostaining d. Western blot	ABR in the AK-7 group decreased significantly (p < 0.01) at days 1, 7, and 14 after NE. The SIRT2 inhibitor AK-7 reduces oxidative DNA damage and apoptosis in HEI-OC1 cells by suppressing the expression of caspase 3 and Bax, and by recovering the expression of Bcl-2.