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In search of improved prostaglandin treatment for glaucoma

2008; Wiley; Volume: 86; Linguagem: Inglês

10.1111/j.1755-3768.2008.01379.x

1755-3768

John Thygesen,

Ocular Surface and Contact Lens

This Acta Ophthalmologica supplement includes two papers describing the clinical effects of tafluprost (Taflotan®; Santen Oy, Helsinki, Finland), a new bi-fluorinated prostaglandin F2α analogue developed for the treatment of glaucoma. The first article reports an investigation into the systemic pharmacokinetics and intraocular pressure (IOP)-lowering effects of tafluprost in healthy volunteers (Uusitalo et al. 2008). The second paper compares the IOP-lowering efficacy of tafluprost in a conventional preserved formulation with that of preservative-free tafluprost in patients suffering from glaucoma or ocular hypertension (Hamacher et al. 2008). Tafluprost is the first prostaglandin analogue to be available in a preservative-free formulation. The efficacy and safety of tafluprost has been investigated in several clinical trials. A 6-month study showed that tafluprost 0.0015% once/day was at least as effective as timolol 0.5% twice/day (achieving IOP reductions of 5–7 mmHg and 4–6 mmHg, respectively). This effect was maintained for ≤ 12 months (Taflotan Summary of Product Characteristics; [2008]). Another 6-month study showed IOP reductions of 6–8 mmHg with tafluprost 0.0015% once/day and 7–9 mmHg with latanoprost 0.005% once/day (Taflotan Summary of Product Characteristics; [2008]). These data demonstrate that tafluprost is effective at lowering IOP. Preservatives are added routinely to multi-dose antiglaucoma medications. The most commonly used preservative is benzalkonium chloride (BAC). Historically, BAC has been used as a preservative and ocular penetration enhancer for topically applied medications because it destroys tight junctions and thus may facilitate paracellular diffusion across the ocular surface (Okabe et al. 2005; McCarey & Edelhauser 2007; Majumdar et al. 2008). There is a perception that BAC is required for ocular penetration and good drug activity. However, Pellinen & Lokkila (2008) found equivalent concentrations of tafluprost acid in the aqueous humour of rabbits following topical applications of preserved and preservative-free tafluprost solutions. Uusitalo et al. (2008) report comparable reductions in IOP by preservative-free and preserved formulations of tafluprost. Hamacher et al. (2008) compared the IOP-lowering efficacy of preserved versus preservative-free tafluprost eyedrops in patients diagnosed with either primary open-angle glaucoma or ocular hypertension. No differences were found between the two groups of patients in terms of the IOP-lowering efficacy of the medications throughout the 4-week treatment period of this study (Hamacher et al. 2008). Likewise, no differences in IOP reductions were found between BAC-preserved and BAC-free formulations of β-blockers (Baudouin & de Lunardo 1998; Bron et al. 2003; Easty et al. 2006) and travoprost (Lewis et al. 2007). These data provide clear evidence that BAC is not required for IOP reduction, at least not with lipophilic drugs such as prostaglandins. Virtually, all preservatives have inherent toxic properties associated with their mechanism as preservatives, and there is an increasing body of evidence to support the hypothesis that BAC has a concentration-dependent toxic action on the ocular surface (De Saint Jean et al. 1999; Debbasch et al. 2001). In vitro studies have demonstrated that high concentrations of BAC induce oxidative stress (Debbasch et al. 2001), promote the expression of inflammatory and apoptotic markers (De Saint Jean et al. 1999), and result in epithelial cell death (Rolando et al. 1991). In vivo models have also confirmed the adverse effects of BAC (Labbé et al. 2006). In rabbit models, preserved formulations of antiglaucoma medications display significantly more adverse effects than preservative-free formulations (Pisella et al. 2000). The relative toxicity of preserved antiglaucoma formulations appears to be directly proportional to their respective concentrations of BAC (Guenoun et al. 2005; Brasnu et al. 2008). In the two short-term studies reported in this supplement, both the preserved and preservative-free tafluprost formulations were generally well tolerated (Hamacher et al. 2008; Uusitalo et al. 2008). In clinical practice, many patients with glaucoma use several medications simultaneously, leading to substantial exposure to preservatives such as BAC. Ocular signs and symptoms have been reduced when patients switch from preserved to preservative-free formulations, or reduce the number of preserved eyedrops administered (Pisella et al. 2002; Jaenen et al. 2007). Thus, the data from the studies published in this supplement (Hamacher et al. 2008; Uusitalo et al. 2008) demonstrate that the preservative-free tafluprost formulation achieves a reduction in IOP equivalent to that obtained by the preserved formulation. Further larger-scale and longer-term studies are required to assess the effects of preservative-free tafluprost ophthalmic solution in the treatment of glaucoma. For patients suffering from dry or sensitive eyes, tafluprost seems to be a beneficial addition to the prostaglandin glaucoma medications group. The author has acted as a paid consultant to Santen Inc.