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Abstract #10148 Published in IGR 6-1
Pharmacological characteristics of AFP-168 (tafluprost), a new prostanoid FP receptor agonist, as an ocular hypotensive drug
Takagi Y; Nakajima T; Shimazaki A; Kageyama M; Matsugi T; Matsumura Y; Gabelt BT; Kaufman PL; Hara HExperimental Eye Research 2004; 78: 767-776
To evaluate the pharmacological characteristics of AFP-168 (tafluprost), a new prostaglandin (PG) F2ALP 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-labeled 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 (Ki : 0.4 nm) was 12 times that of PhXA85 (Ki : 4.7 nm), 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 five days in normotensive monkeys significantly reduced IOP not only for a few hours, but also at the drug-trough time 24 hours 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.
Dr. Y. Takagi, Glaucoma Group, Research and Development Center, Santen Pharmaceutical Co., Ltd, 8916-16, Takayama-cho, Ikoma 630-0101, Nara, Japan
Classification:
11.4 Prostaglandins (Part of: 11 Medical treatment)
