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Editors Selection IGR 9-1

Medical Treatment: In-vivo histological effects of preservative-free prostaglandins

Comment by Christophe Baudouin on:

69141 Long-term topical application of preservative-free prostaglandin analogues evokes macrophage infiltration in the ocular adnexa, Trzeciecka A; Paterno JJ; Toropainen E et al., European Journal of Pharmacology, 2016; 788: 12-20

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Preservatives found in most anti-glaucoma preparations have been largely shown clinically or experimentally to induce toxic effects over the long term, with clinical manifestations that include dry eye, allergy, blepharitis, hyperhemia, chronic inflammation of the ocular surface, etc. They may impact quality of life, compliance and adherence, and negatively influence surgical outcome. Preservative-free medications are interesting options for avoiding such effects and have particular interest in patients with ocular surface diseases or receiving multiple therapies. However, some prostaglandins due to their own composition require solubilizers to remove the preservative, which can also raise possible tolerance concerns.

Following a first in-vitro study, the authors investigated in rabbits three formulations of preservative- free prostaglandins commercially available, namely Macrogol-containing latanoprost, Polysorbat 80-containing tafluprost and bimatoprost free of both preservative and solubilizer. Clinical assessments were performed, completed by complex proteomic and immunohistological techniques in tears, aqueous humor and eyelids. Overall results favored preservative-free formulations of bimatoprost and tafluprost and demonstrated a reliable irritative effect of Macrogol-containing latanoprost, consisting of increased conjunctival redness and blinking frequency, more LDH in aqueous humor, significant infiltration of macrophages in the eyelids and possible impact to goblet cells. None of the formulations did induce inflammatory cytokines in the tears. This is an interesting study pointing out the importance of active compounds and their formulations in tolerance issues, beside the major well-known impact of quaternary ammoniums and alternative preservatives. Further studies will be needed to measure clinical relevance of these results, by head-to-head comparisons or meta-analyses of clinical data in large patients populations.

Prostaglandins require solubilizers to remove the preservative, which can also raise possible tolerance concerns

Even if a preservative-free formulation is more irritative, it may remain much less toxic than a preserved one and this question has not been addressed. Indeed we can regret in this study the absence of a control group with a preserved latanoprost formulation, to measure if the solubilizer has similar, higher or lower negative impact to the ocular surface compared to benzalkonium chloride. Clinical benefit of all preservative-free formulations has been shown in clinical studies and clinical practice. It should be determined if such differences between formulations may negatively impact patient outcome and glaucoma care over the long term, especially in fragile and sensitive patients. Nevertheless, though animal models have often been criticized for the lack of relevance toward clinical practice, they have the major advantage of providing arguments to warn clinicians about possible side effects induced in the long run by apparently well tolerated eye drops and to foster innovative formulations and drug developments to limit such effects and improve local tolerance, a more and more recognized component in glaucoma care.

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