Dear Editor,

We read with great interest the article by Chiba and co-workers about the possible effect on intraocular pressure (IOP) induced by non-steroidal anti-inflammatory (NSAID) ophthalmic solution in patients affected by primary open angle glaucoma (POAG) or ocular hypertension (OH) and treated with latanoprost [1].

In 2003, Kashiwagi and Tsukahara (two co-authors of the above-mentioned Chiba et al. paper) have already published a similar study conducted on a very small number of healthy volunteers (thirteen Japanese young adults), concluding that the co-administration of bromfenac significantly inhibited latanoprost induced IOP reduction [2]. In June 2005, we have published an article on the same topic, but carried out on thirty-two POAG patients [3]. This paper described discrepant results as compared to those obtained by both Chiba and co-workers [1], and Kashiwagi and Tsukahara [2]. In fact, within our Caucasian glaucomatous study group, diclofenac eyedrops significantly enhances the ocular hypotensive effect of latanoprost.

We have tried to explain the contradictory data obtained in 2003 by Kashiwagi and Tsukahara [2], in comparison with our results [3] and those achieved by Sponsel et al. in 2002 [4], also indicating several possible bias of the first mentioned trial. Finally, we have speculatively discussed the reliable pathophysiological causes of this more marked, latanoprost-induced IOP reduction in NSAID-treated POAG patients [3] mainly considering that: i. therapeutic and side-effect profiles of latanoprost is explainable by its prevalent action on FP, EP and TP prostaglandin (PG) receptors [5-7]; ii. in human cultured ciliary muscle (CM) cells the same NSAID level, obtained after drug topical administration, inhibits the PGs synthesis [8]; iii. in experimental models, an up-regulation of PG receptors occurs via cyclooxygenases inhibition [9-11].

Rationally, we have concluded that a NSAID-related fall in endogenous PGs synthesis could be responsible for a PG receptors over- expression, increasing the IOP-lowering effect of topical PG analogues. The effect of this pharmacological interaction, essentially based on the well-known plasticity of PG receptors system [9-13], should be realistically investigated only in patients with a definite and definitive diagnosis of glaucoma, such as POAG patients studied by ours in 2005 [3]. In fact, only in glaucomatous CM cells an over-expression of PG receptors occurs [12], whereas these receptors are scarcely present in the same cells of healthy subjects [13] and, reliably, also in CM of OH patients. This hypothesis has been developed starting from different points of view respect to Chiba et al. [1], whose paper has also briefly commented by Alm in an Editorial published in the same BJO issue [14]. In our opinion, none of the investigations existing in the current literature are able to conclusively verify the possibility of an interaction between NSAIDs and PG analogues. Particularly, the recent study of Chiba et al. is characterized by an insufficient and heterogeneous patient's recruitment (just nine POAG and four OH subjects), resembling the crucial weak-point of Kashiwagi and Tsukahara trial, which was previously conducted on healthy volunteers [1,2].

Curiously, Chiba and co-workers have not considered these biases. On the contrary, they have emphasized, at the top of the Discussion section, that their "study clearly demonstrated that ophthalmic NSAID inhibits the IOP reduction by latanoprost ophthalmic solution in glaucomatous eyes", partially or totally ignoring: i. the results of other Authors who had utilized a more numerous and / or homogeneous study populations [3, 4, 15]; ii. the possible variability of PG receptors expression in different ethnic groups [16, 17].

References

1. Chiba T, Kashiwagi K, Chiba N, Tsukahara S. Effect of non- steroidal anti-inflammatory ophthalmic solution on intraocular pressure reduction by latanoprost in patients with primary open angle glaucoma or ocular hypertension. Br J Ophthalmol 2006; 90: 314-17.

2. Kashiwagi K, Tsukahara S. Effect of non-steroidal anti- inflammatory ophthalmic solution on intraocular pressure reduction by latanoprost. Br J Ophthalmol 2003; 87: 297-301.

3. Costagliola C, Parmeggiani F, Antinozzi PP, Caccavale A, Cotticelli L, Sebastiani A. The influence of diclofenac ophthalmic solution on the intraocular pressure-lowering effect of topical 0.5% timolol and 0.005% latanoprost in primary open-angle glaucoma patients. Exp Eye Res 2005; 81: 610-15.

4. Sponsel WE, Paris G, Trigo Y, Pena M, Weber A, Sanford K, McKinnon S. Latanoprost and brimonidine: therapeutic and physiologic assessment before and after oral nonsteroidal anti-inflammatory therapy. Am J Ophthalmol 2002; 133: 11-8.

5. Stjernschantz J, Selen G, Astin M, Resul B. Microvascular effects of selective prostaglandin analogues in the eye with special reference to latanoprost and glaucoma treatment. Prog Retin Eye Res 2000; 19: 459-96.

6. Weinreb RN, Toris CB, Gabelt BT, Lindsey JD, Kaufman PL. Effects of prostaglandins on the aqueous humor outflow pathways. Surv Ophthalmol 2002; 47: S53–S64.

7. Stjernschantz J. Studies on ocular inflammation and development of a prostaglandin analogue for glaucoma treatment. Exp Eye Res 2004; 78: 759 -66.

8. Yousufzai SY, Abdel-latif AA. Endothelin-1 stimulates the release of arachidonic acid and prostaglandins in cultured human ciliary muscle cells: activation of phospholipase A2. Exp Eye Res 1997; 65: 73-81.

9. Li DY, Varma DR, Chemtob S. Up-regulation of brain PGE2 and PGF2 alpha receptors and receptor-coupled second messengers by cyclooxygenase inhibition in newborn pigs. J Pharmacol Exp Ther 1995; 272: 15-9.

10. Li DY, Abran D, Peri KG, Varma DR, Chemtob S. Inhibition of prostaglandin synthesis in newborn pigs increases cerebral microvessel prostaglandin F2 alpha and prostaglandin E2 receptors, their second messengers and vasoconstrictor response to adult levels. J Pharmacol Exp Ther 1996; 278: 370-7.

11. Hardy P, Bhattacharya M, Abran D, Peri KG, Asselin P, Varma DR, Chemtob S, Bhatthacharya M. Increases in retinovascular prostaglandin receptor functions by cyclooxygenase-1 and -2 inhibition. Invest Ophthalmol Vis Sci 1998; 39: 1888-98.

12. Husain S, Kaddour-Djebbar I, Abdel-Latif AA. Alterations in arachidonic acid release and phospholipase C-beta(1) expression in glaucomatous human ciliary muscle cells. Invest Ophthalmol Vis Sci 2002; 43: 1127-34.

13. Mukhopadhyay P, Geoghegan TE, Patil RV, Bhattacherjee P, Paterson CA. Detection of EP2, EP4, and FP receptors in human ciliary epithelial and ciliary muscle cells. Biochem Pharmacol 1997; 53, 1249-55.

14. Alm A. Can NSAIDs and prostaglandin analogues be combined? Br J Ophthalmol 2006; 90: 259-60.

15. Miyake K, Ota I, Maekubo K, Ichihashi S, Miyake S. Latanoprost accelerates disruption of the blood-aqueous barrier and the incidence of angiographic cystoid macular edema in early postoperative pseudophakias. Arch Ophthalmol 1999; 117: 34-40.

16. Stein M, O'Malley K, Kilfeather S. Ethnic differences in cyclic AMP accumulation: effect on alpha 2, beta 2, and prostanoid receptor responses. Clin Pharmacol Ther 1990; 47: 360-5.

17. Oguma T, Palmer LJ, Birben E, Sonna LA, Asano K, Lilly CM. Role of prostanoid DP receptor variants in susceptibility to asthma. N Engl J Med 2004; 351: 1752-63.