Additivity of Bimatoprost or Travoprost to Latanoprost in GlaucomatousMonkey Eyes

Abstract

To compare the ocular hypotensive effect of the commercially available preparations of bimatoprost or travoprost added to latanoprost in monkey eyes with laser-induced unilateral glaucoma. Methods: Four monkeys with unilateral laser-induced glaucoma were used in each treatment group and received drops in the glaucomatous eye only. Intraocular pressure (IOP) was measured hourly for 6 hours, beginning at 9:30 AM on day 1 (untreated baseline), days 6 and 7 (single-agent therapy), and days 13 and 14 (2-drug combination therapy). On days 2 through 7, 1 drop of the scheduled single agent was given immediately after the 9:30 AM IOP measurement, and on days 8 through 14, the second scheduled drug was given 5 minutes after the first. The following 5 different dosing protocols were studied: latanoprost with bimatoprost added, bimatoprost with latanoprost added, latanoprost with travoprost added, travoprost with latanoprost added, and latanoprost with a second dose of latanoprost added. Results: There were no statistically significant (P=.95) differences among the mean baseline IOPs in any of the 5 treatment groups. When applied as single agents, latanoprost, bimatoprost, and travoprost all produced significant (PϽ.05) and equivalent (P=.98) reductions in IOP. The mean ±SEM maximum reduction (PϽ.05) from baseline IOP was 7.0±0.4 mm Hg (20% reduction) with tra-voprost alone, 6.5±1.6 mm Hg (18%) with bimatoprost alone, and 7.5±1.0 mm Hg (22%) with latanoprost alone. The mean ±SEM maximum additive reductions in IOP were 3.0±0.6 mm Hg (PϽ.05) for travoprost added to latanoprost; 2.0±0.4 mm Hg (PϽ.05) for latanoprost added to travoprost; 4.8±1.3 mm Hg (PϽ.05) for bimatoprost added to latanoprost; 4.3±0.6 mm Hg (PϽ.05) for latanoprost added to bimatoprost; and 0.3±0.5 mm Hg (PϾ.60) for latanoprost added to itself. The combination of bimatoprost and latanoprost produced a greater (PϽ.05) lowering of IOP at trough and peak than the combination of travoprost and latanoprost. Conclusions: Latanoprost, bimatoprost, and travoprost used as monotherapy produced significant and equivalent reductions in IOP in glaucomatous monkey eyes. The IOP effects of the commercial concentrations of bimatoprost or travoprost were additive to that of latanoprost, with bimatoprost showing a greater additive response than travoprost. Clinical Relevance: Because treatment with multiple medications is common among patients with glaucoma, determining which glaucoma medications produce an additive ocular hypotensive response when used in combination has practical implications for clinicians.

Identification and pharmacological characterization of the prostaglandin FP receptor and FP receptor variant complexes

“…It is not easy to rule out the possibility that the FP‐altFP heterodimers are putative prostamide receptors. It appears that prostamide activity observed in freshly isolated cells ( Gagliuso et al ., 2004 ; Spada et al ., 2005 ) and tissues ( Woodward et al ., 2003 , 2007 ; Matias et al ., 2004 ), such as the feline iris described here, may be modelled by a recombinant system involving co‐expression of FP and altFP receptors, as suggested by the effects of bimatoprost.…”

“…The action of prostamides has been found to involve mechanisms different from prostanoid FP receptor‐mediated responses in the primate eye. First, the effect of bimatoprost in the ocular hypertensive monkey model of glaucoma ( Gagliuso et al ., 2004 ) has been shown to be additive to that of latanoprost, the FP receptor agonist prodrug ( Resul et al ., 1997 ). This fits with the FP‐altFP heterodimeric receptor concept, as divergent secondary Ca 2+ signalling pathways may translate into an additive effect for prostamides and prostanoid FP receptor agonists on IOP.…”

Prostamides (prostaglandin‐ethanolamides) and their pharmacology

“…Glaucoma patients refractory to latanoprost treatment were found to be susceptible to bimatoprost, which produced a pronounced lowering of intraocular pressure ( Williams, 2002 ; Gandolfi and Cimino, 2003 ). In ‘glaucomatous’ monkeys that responded to latanoprost, travoprost and bimatoprost, a combination of bimatoprost and latanoprost produced a greater lowering of trough and peak intraocular pressure than a latanoprost/travoprost combination ( Gagliuso et al , 2004 ). Given these results, combined latanoprost/bimatoprost therapy could even be considered as a glaucoma treatment regimen.…”

Recent Progress in Prostaglandin F2αEthanolamide (Prostamide F2α) Research and Therapeutics

“…Bimatoprost is efficacious in patients unresponsive to latanoprost (Williams, 2002;Gandolfi and Cimino, 2003;Sonty et al, 2008); this would almost certainly not be the case if these drugs were pharmacologically identical. Bimatoprost is also additive to FP agonist prodrugs (Gagliuso et al, 2004).…”