TABLE 5.
Recent relevant in-vivo, ex-vivo, and in-vitro animal studies reporting ocular surface disease manifestations of PLMs.
| Cell type | Agents used | Study description | Preservatives | Findings | |
|---|---|---|---|---|---|
| References | |||||
| Krauss et al. (2011) | In vivo OHT model in monkeys, dogs, and rabbits | NO-donating PGAs | To compare the hypotensive effects between LAT and NO-donating LAT | BAK | NO-donating LAT was more effective in lowering the intraocular pressure with no ocular side effects reported |
| Taketani et al. (2014) | In vitro mouse adipocytes | PGAs | Evaluate the effects of all PGAs on adipogenesis | None | All PGAs, except unoprostone, promoted lipolysis and suppressed adipogenesis, potentially explaining DUES |
| Jiang et al. (2022) | Ex-vivo mouse MGs | PGAs | Evaluate the effects of LAT on chemokine and cytokine secretion | None | LAT induced inflammation in Meibomian gland epithelial cells and suppressed differentiation by overexpressing of IL-1β, IL-6, TNF-α, MMP-9, among other cytokines |
| Young et al. (1990) | Ex-vivo rabbit conjunctiva | Miotics and BBs | To evaluate the effects of PIL and TIM on the conjunctiva | BAK | PIL produced higher myofibroblastic cell proliferation and thickened conjunctival epithelium and stroma |
| Pisella et al. (2000) | In vivo and ex-vivo rabbit cornea and conjunctiva | BBs | Evaluate the ocular surface tolerance to preserved and PF TIM | BAK | The PF-formulation exhibited significantly decreased TFBUT compared with BAK-containing TIM. Furthermore, PF-formulations also had less histological stromal edema |
| Liang et al. (2011) | In vivo rabbit cornea and conjunctiva | BBs and PGAs | Assess the toxicological profile of TRV/TIM and LAT/TIM fixed combinations | BAK, PQ | BAK-containing LAT/TIM produced more hyperemia, chemosis, tearing, and cytotoxicity (assessed by IVCM) compared to PQ-preserved TRV/TIM |
| Ayaki et al. (2012) | In vitro rabbit and bovine cornea | CAIs, PGAs, BBs, and AAs | To evaluate in-vitro cytotoxicity on corneal epithelial cells of BAK-containing PLMs | BAK | Decreased cell viability scores across most CAIs, B-blockers, and PGAs, or their fixed combinations |
| Shin et al. (2015) | Ex-vivo rat conjunctiva, cornea, and aqueous humor | AAs | Evaluate effect of brimonidine in the level of various inflammatory markers | PUR | Corneoconjunctival levels of inflammatory markers (TNFa, IL-1a, IL-1b, IL-6) were significantly lower in the brimonidine group, but increased in the aqueous humor |
| Lee et al. (2015) | In vivo rabbit cornea and conjunctiva | PGAs | Evaluate the ocular surface effects of various preserved PGAs | BAK, PQ | Decreased conjunctival goblet cell density, increased corneal pyknotic changes, and increased tear IL-6 were found in BAK-containing formulations |
| Kim et al. (2015) | In vivo mouse cornea | PGAs | Evaluate the effects of preserved and PF PGAs | BAK, PQ | PQ and PF formulations showed less SPK, epithelial desquamation, anisocytosis, and cell shrinkage compared with BAK |
| Lin et al. (2018) | In vitro rabbit, monkey, dog, pig, and human corneas | ROCK inhibitors | Preclinical characterization of netarsudil comparing its effects with other rho-associated protein kinase inhibitors | None | Netarsudil exhibited significant intraocular pressure reductions with only mild hyperemia |
| In vivo rabbit conjunctiva | |||||
| Leary et al. (2021) | In vivo dog conjunctiva | ROCK inhibitors | Evaluate the safety and efficacy of netarsudil | BAK | Increased conjunctival hyperemia in treated eyes compared with balance salt solution |
PLMs, pressure-lowering medications; NO, nitric oxide; PGAs, prostaglandin analogs; LAT, latanoprost; BAK, benzalkonium chloride; DUES, deepening upper eyelid sulcus; MGs, Meibomian glands; IL, interleukin; TNF, tumor necrosis factor; MMP, matrix metalloproteinase; BBs, beta blockers; PIL, pilocarpine; TIM, timolol; PF, preservative-free; TFBUT, tear film breakup time; TRV, travoprost; PQ, polyquad; IVCM, in-vivo confocal microscopy; CAIs, carbonic anhydrase inhibitors; AAs, alpha agonists; ROCK, rho kinase.