dinoprost and Ocular-Hypotension

Low doses of naturally occurring prostaglandins reduce the intraocular pressure (IOP) in many species. Species differences do occur both in terms of efficiency and mechanism of action, and also among the different prostaglandins. Among the prostaglandins mainly PGF2 alpha has been tested in human eyes. Although it is an effective ocular hypotensive drug it is not clinically useful due to pronounced ocular side-effects, mainly conjunctival hyperemia and irritation, at doses that produce a maximal effect on IOP. Modification of the drug has resulted in two analogues that are now in clinical use, latanoprost and unoprostone. In long-term studies latanoprost, when applied as a once-daily dose of a 0.005% concentration, reduces IOP at least as effectively as adrenergic beta-receptor blockers. The reduction of IOP is due to increased outflow. This takes place mainly, or exclusively, through the uveoscleral routes, thus introducing a new pharmacological principle for the treatment of glaucoma. The drug reaches systemic concentrations that are below the level expected to stimulate FP-receptors outside the eye and it is rapidly eliminated with a half-life in plasma of 17 minutes, which explains why the clinical trials have not revealed any systemic side-effects with latanoprost. The most frequent side-effect observed with latanoprost is an increased pigmentation of the iris mainly in eyes with irides that are already partly brown. This effect is seen with several naturally occurring prostaglandins and is due to stimulation of melanin production in the melanocytes of the iridial stroma. No structural changes of the melanocytes have been observed in studies performed both in vivo and in vitro. The mechanism of action for unoprostone is the same as for latanoprost. No effect on iris colour has been reported for unoprostone but so far there is limited experience with the drug in eyes with a mixed iris colour.

Topics: Adrenergic Agonists; Adrenergic beta-Antagonists; Animals; Carbonic Anhydrase Inhibitors; Cholinergic Agonists; Dinoprost; Drug Therapy, Combination; Glaucoma; Humans; Intraocular Pressure; Latanoprost; Ocular Hypotension; Prostaglandins; Prostaglandins F, Synthetic

Ocular hypotensive effects and side effects of two different topically applied prostaglandin (PG) esters were evaluated in a double masked study in 12 healthy males. Three doses of 15-propionat-PGF2 alpha-isopropylester (15-prop-PGF2 alpha-IE), two doses of PGF2 alpha-isopropylester (PGF2 alpha-IE), and placebo were compared. At equipotent doses 15-prop-PGF2 alpha-IE caused similar ocular side effects as PGF2 alpha-IE. It is concluded that both PGF2 alpha-IE and 15-prop-PGF2 alpha-IE reduce the IOP in normal eyes, but the use of a diester such as 15-prop-PGF2 alpha-IE does not provide a better separation between effect on IOP and side effects than PGF2 alpha-IE.

Topics: Administration, Topical; Adult; Dinoprost; Double-Blind Method; Drug Evaluation; Humans; Hyperemia; Intraocular Pressure; Male; Ocular Hypotension

The purpose of this study was to determine whether a better IOP reduction can be observed in conscious, normotensive monkeys treated with ONO-9054, a novel dual EP3 and FP receptor agonist, compared with prostaglandin F2α analogs.. The binding affinities and agonistic activities of ONO-AG-367, a carboxylic acid of ONO-9054, to prostanoid receptors were assessed. The IOP-lowering effect of ONO-9054 in monkeys was analyzed after a single (0.3, 3, or 30 μg/mL) or 7-day repeated (30 μg/mL, every day) topical ocular administration. Ophthalmologic and histopathologic evaluations of the eye were performed after 4-week ocular administration of ONO-9054 (30 μg/mL, twice a day) in monkeys.. The ONO-AG-367 exhibited high affinity for both EP3 and FP receptors and potent agonist activity, with EC50 values of 28.6 nM for the EP3 receptor and 22.3 nM for the FP receptor. Single and repeated topical ocular administration of ONO-9054 caused IOP reductions in normotensive monkeys. The maximum IOP reductions on day 7 observed with ONO-9054 (7.3 ± 0.8 mm Hg) were significantly greater than those observed with latanoprost (50 μg/mL, 4.9 ± 0.4 mm Hg) or travoprost (40 μg/mL, 5.1 ± 0.6 mm Hg). In ophthalmologic and histopathologic evaluations, slight and transient mydriasis was occasionally observed and no histopathologic lesions attributable to ONO-9054 were noted.. A more profound and longer-lasting reduction in IOP in normotensive monkeys can be observed with ONO-9054, which simultaneously stimulates both EP3 and FP receptors, compared with prostaglandin analogs.

Topics: Animals; Antihypertensive Agents; Dinoprost; Disease Models, Animal; Follow-Up Studies; Intraocular Pressure; Latanoprost; Macaca fascicularis; Ocular Hypotension; Ophthalmic Solutions; Prostaglandins F, Synthetic; Receptors, Prostaglandin; Receptors, Prostaglandin E, EP3 Subtype

A series of 11-oxa prostaglandin analogs was evaluated for FP receptor binding and activation. Several compounds having aryloxy-terminated lower chains were found to be potent agonists. Topical ocular dosing of AL-12182, the isopropyl ester prodrug of the potent agonist 13, lowered intraocular pressure in the monkey by 40% accompanied by minimal conjunctival hyperemia in the rabbit. AL-12182 was synthesized on multigram scale starting with D-sorbitol.

Topics: Administration, Topical; Animals; Cats; Haplorhini; Ocular Hypotension; Prostaglandins; Rabbits

The objective of this study was to identify prostaglandin F2alpha (PGF2alpha) prodrugs that have an optimal ocular absorption profile and therefore could be potentially useful for the treatment of glaucoma. Rabbit cornea, conjunctiva, and iris/ciliary body were mounted in a flow-through chamber to evaluate the permeability and bioconversion of PGF2alpha and its prodrugs. The prodrugs tested were PGF2alpha 1-isopropyl, 1,11-lactone, 15-acetyl, 15-pivaloyl, 15-valeryl, and 11,15-dipivaloyl esters. After 4 h in the donor or acceptor compartments, the products and formation of PGF2alpha were analyzed by HPLC. Effects on intraocular pressure and ocular surface hyperemia were also determined. All prodrugs penetrated the rabbit cornea faster than PGF2alpha by 4- to 83-fold. All prodrugs penetrated conjunctiva faster than PGF2alpha, except the 15-acetyl ester prodrug, which was equally permeable. No direct correlation between drug lipophilicity and permeability across the cornea or conjunctiva was apparent. The most metabolically stable prodrug was the 1,11-lactone, followed by the 11,15-dipivaloyl, 15-pivaloyl, 15-acetyl, 1-isopropyl, and the 15-valeryl esters, the latter of which was extensively converted to PGF2alpha. A separation index for various prodrugs was calculated from the ratio of the bioavailable PGF2alpha for ocular hypotension to the bioavailable PGF2alpha for hyperemia. The highest separation index was observed for the 1,11-lactone prodrug (2.33), followed by the 11,15-dipivaloyl ester prodrug (1.80). Thus the 1,11-lactone and 11,15-dipivaloyl ester prodrugs appeared to be superior to the others in providing bioavailable PGF2alpha for ocular hypotension, while minimizing hyperemia. The favorable separation index for these compounds appeared to be due to their metabolic stability at the corneal surface and conjunctiva combined with sufficient bioavailability for ocular hypotension.

Topics: Absorption; Animals; Biotransformation; Conjunctiva; Cornea; Dinoprost; Eye; Female; Hyperemia; Intraocular Pressure; Ocular Hypotension; Permeability; Prodrugs; Rabbits

This study was performed to clarify the ocular hypotensive mechanism of topical isopropyl unoprostone (unoprostone), a novel prostaglandin (PG) metabolite-related drug, in the rabbit eye. The intraperitoneal administration of indomethacin (50 mg/kg) 1 hour before administration of topical 0.12% unoprostone partially diminished the intraocular pressure (IOP) reduction, and completely blocked the increase in aqueous PGE2 concentration caused by unoprostone. Aqueous humor dynamics measurements in the unoprostone- and the vehicle-treated contralateral eyes with indomethacin pretreatment revealed that aqueous flow determined by fluorophotometry was not significantly different, 2.3 +/- 0.3 and 2.4 +/- 0.2 microliters/min, respectively; the total outflow facility measurements determined by the two-level constant pressure perfusion method were 0.20 +/- 0.01 and 0.14 +/- 0.01 microliters/min/mmHg, respectively (p < 0.05); the uveoscleral outflow measurements determined by the fluorescein isothiocyanate-dextran perfusion method were 0.49 +/- 0.02 and 0.46 +/- 0.02 microliters/min, respectively (p < 0.05). The magnitude of the IOP reduction induced by unoprostone was estimated to be 5.2 mmHg, which agrees well with the actual IOP reduction. In conclusion, unoprostone lowers the IOP by affecting aqueous outflow pathways, primarily the pressure-dependent conventional pathway and the secondary uveoscleral outflow pathway in rabbits. Endogenous PGs induced by topical unoprostone are also involved in lowering the IOP in rabbits.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aqueous Humor; Dinoprost; Dinoprostone; Female; Fluorophotometry; Indomethacin; Injections, Intraperitoneal; Intraocular Pressure; Male; Ocular Hypotension; Ophthalmic Solutions; Rabbits

The ocular effects of topical prostaglandin F2 alpha (PGF2 alpha) were studied in normotensive human eyes. PGF2 alpha as tromethamine salt, 100 micrograms, was applied to one eye of 23 normotensive subjects, intraocular pressure (IOP) and pupil size were measured, objective and subjective findings recorded during the first 24 h. Tonography was performed in 10 subjects. As compared with the baseline, PGF2 alpha caused a significant IOP reduction between 1 and 24 h (p < 0.001), being maximal (4.9 +/- 0.5 mm Hg, mean +/- SEM, p < 0.001) between 4 and 8 h. As compared with the contralateral control eyes, which received 50 microliters of saline, treated eyes exhibited significant IOP reduction between 1 and 24 h (p < 0.001), being maximal (4.2 +/- 0.4 mm Hg, mean +/- SEM, p < 0.001) at 4 h. PGF2 alpha caused marked conjunctival hyperemia in all eyes. Pupillary diameter was not altered. Aqueous flare and cellular response were not seen. Half of the subjects complained of ocular smarting, mild ocular pain or headache. Total outflow facility did not change (p > 0.05).

Topics: Administration, Topical; Adolescent; Adult; Aqueous Humor; Dinoprost; Female; Humans; Intraocular Pressure; Male; Middle Aged; Ocular Hypotension; Ophthalmic Solutions; Pupil; Tonometry, Ocular

The use of natural prostaglandins (PG), such as PGD2, PGE2, PGF2 alpha, and PGI2, for treating glaucoma is limited by their ocular side effects. One approach to achieve the required separation of ocular hypotensive activity from side effects is to employ ester prodrugs. From a novel series of 11- and 15-mono and 11,15-diacyl esters of PGF2 alpha we identified prodrugs where PGF2 alpha formation rates in the iris-ciliary body exceeded those in the conjunctiva, sclera, and corneal endothelium. Compared to PGF2 alpha-1-isopropyl ester the ocular tissue hydrolysis rates of the 11-monopivaloyl, the 11,15-dipivaloyl ester and the 1,11-lactone were up to 1000 fold less. Despite this large disparity in hydrolysis rates, the pivaloyl esters and the 1,11-lactone were potent ocular hypotensives in our animal models. In studying prostaglandin analogs, we found that a diverse variety of prostanoid receptor selective agonists lowered intraocular pressure in dogs and/or monkeys. These included DP-, EP1-, EP2-, EP3-, and FP-receptor selective compounds. These findings were surprising and prompted us to re-examine the receptor selectivity of these agonists by radioligand binding studies. Using radiolabelled PGE2, 17-phenyl PGF2 alpha, and sulprostone we were able to confirm the selectivity of the agonists currently used for receptor characterization directly by radioligand binding competition studies. It appears that multiple prostanoid receptor subtypes may be involved in regulating intraocular pressure.

Topics: 3T3 Cells; Animals; Cell Membrane; Cells, Cultured; Dinoprost; Dogs; Esters; Female; Intraocular Pressure; Macaca fascicularis; Male; Mice; Myometrium; Ocular Hypotension; Prodrugs; Prostaglandins, Synthetic; Rabbits; Rats; Receptors, Prostaglandin; Uterus