Abstract
To evaluate the pharmacological characteristics of AFP-168 (tafluprost), a new prostaglandin (PG) F 2α derivative, we examined its receptor-binding affinities, intraocular pressure (IOP)-lowering effect, effects on aqueous humor dynamics, and stimulating effect on melanogenesis. The receptor-binding profile for AFP-172, a carboxylic acid of AFP-168, was determined by measuring muscle contractions in an organ bath, inhibition of platelet aggregation, and competitive binding of a radio-labelled ligand. For the IOP-measurement study, ocular normotensive and laser-induced ocular hypertensive cynomolgus monkeys were used, and IOP was measured using a pneumatonograph. For the studies of aqueous humor dynamics, IOP (Goldmann applanation tonometry), fluorophotometry, two-level constant pressure perfusion, and isotope dilution and accumulation techniques were used in ocular normotensive monkeys. The melanin contents in the medium and in the cell bodies of cultured B16-F0 melanoma cells were measured. The affinity for the FP receptor shown by AFP-172 ( K i: 0·4 n m) was 12 times that of PhXA85 ( K i: 4·7 n m), a carboxylic acid of latanoprost. A single application of AFP-168 at 0·0025% significantly lowered IOP in both ocular normotensive and hypertensive monkeys (3·1 and 11·8 mmHg, respectively, p<0·01) and latanoprost at 0·005% significantly lowered IOP (2·1 mmHg, p<0·01 and 9·5 mmHg, p=0·059, respectively). Once daily instillation of AFP-168 at 0·001, 0·0025, or 0·005% for 5 days in normotensive monkeys significantly reduced IOP not only for a few hours, but also at the drug-trough time 24 hr after application. Latanoprost at 0·005% also reduced IOP, but not at the drug-trough time. AFP-168 decreased IOP mainly by increasing uveoscleral outflow by 65% ( p<0·05) and, as sometimes seen with other prostanoids, also increased total outflow facility (33% increase, p<0·05). In cultured B16-F0 melanoma cells, AFP-172 (100 μM) did not stimulate melanogenesis, but PhXA85 (100 μM) did. These findings indicate that AFP-168 has a high affinity for the prostanoid FP receptor, has potent IOP-lowering effects in both ocular normotensive and hypertensive monkeys that exceed those of latanoprost, and has less stimulating effect on melanogenesis in melanoma cells.
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