dinoprost and Glaucoma

A distinguishing feature of the most common types of glaucoma is an increased intra-ocular pressure (IOP), which has a damaging effect on optic nerve axons, leading to the progressive loss of retinal ganglion cells. Therefore, IOP-lowering medications are the mainstay of glaucoma therapy. Topical prostaglandin F2 α analogs (PGAs) are a relatively new class of ocular hypotensive drugs, which have made a huge impact on the treatment of glaucoma in dogs. This study summarizes the current state of knowledge on the mechanism of action of these agents and their effect on IOP in dogs and cats. It also discusses potential harmful side effects of PGAs and presents contemporary opinions about their role and place in the medical management of glaucoma in small animals.

Topics: Administration, Topical; Animals; Cat Diseases; Cats; Dinoprost; Dog Diseases; Dogs; Glaucoma; Intraocular Pressure

Prostaglandin F2α analogs, commonly prescribed for glaucoma treatment, have been shown to induce side effects such as cutaneous hypertrichosis and hyperpigmentation. Therefore, these medications have theoretic applications in the treatment of alopecia and disorders of hypopigmentation. We reviewed the literature to find original studies assessing the use of prostaglandin F2α analogs in these settings. Studies and reports were analyzed in regards to androgenic alopecia, alopecia areata, chemotherapy-induced alopecia, vitiligo, and hypopigmented scarring. Based on the results of these studies, and consideration of pathophysiologic mechanism, the most promising applications for prostaglandin F2α analogs include androgenic alopecia, chemotherapy-induced alopecia, and alopecia areata concurrently treated with corticosteroids.

Topics: Adrenal Cortex Hormones; Alopecia; Amides; Animals; Bimatoprost; Cloprostenol; Dinoprost; Disease Models, Animal; Double-Blind Method; Drug Evaluation, Preclinical; Eyelashes; Glaucoma; Hair Follicle; Humans; Hyperpigmentation; Hypertrichosis; Hypopigmentation; Melanins; Mice; Prostaglandins F, Synthetic; Randomized Controlled Trials as Topic; Retrospective Studies; Single-Blind Method

In glaucoma treatment, beside the traditional reduction of intraocular pressure, additional therapeutic strategies have come into consideration. Therefore pleiotropic effects of medications, defined as positively acting effects independent of the main mechanism of action, represent a new research sub-field in medical therapy and play an increasingly important role in internal medicine. Using the example of local beta-blockers, alpha-2-agonists, carbonic anhydrase inhibitors and prostaglandin analogues, their pleiotropic spectra will be shown and discussed.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic beta-Antagonists; Antihypertensive Agents; Carbonic Anhydrase Inhibitors; Dinoprost; Drug Combinations; Glaucoma; Guideline Adherence; Humans; Intraocular Pressure; Ophthalmic Solutions; Optic Nerve Diseases

In the first part of the article the main information and recent research on the uveoscleral outflow pathway, including its morphology and physiology were presented. The structure of extracellular matrix of ciliary muscle and the changes of it, that are induced by prostaglandins, resulting in decreasing intraocular pressure were emphasized. In the second part biochemical characteristics of prostaglandin analogues, using nowadays were presented. Their efficacy in reducing intraocular pressure and safety profile were described.

Topics: Amides; Bimatoprost; Cloprostenol; Dinoprost; Glaucoma; Humans; Intraocular Pressure; Latanoprost; Lipids; Prostaglandins F; Prostaglandins F, Synthetic; Receptors, Prostaglandin; Travoprost; Treatment Outcome

Latanoprost, a prostaglandin F(2alpha) analog prodrug, and unoprostone, an analog of a prostaglandin metabolite, have been shown to be effective in decreasing intraocular pressure when used alone or in combination with other ocular hypotensive agents. The increase in the uveoscleral outflow and some of the side effects are probably FP-receptor mediated, which may account for some differences between the cited drugs. This article reviews the recent literature available on the clinical efficacy of these prostanoids, as well as the studies directly comparing these drugs.

Topics: Antihypertensive Agents; Dinoprost; Drug Therapy, Combination; Glaucoma; Humans; Intraocular Pressure; Latanoprost; Ocular Hypertension; Ophthalmic Solutions; Prostaglandins F, Synthetic

The characteristic loss of visual field due to glaucoma is directly associated with retinal ganglion cell (RGC) death. The process of RGC death is thought to be biphasic, starting with a primary injury, followed by a slow secondary degeneration. Retinal ischemia may establish the cellular conditions that create a fatal biochemical cascade; hypoxia, followed by high excitotoxic levels of glutamate cause pathologically elevated levels of intracellular calcium resulting in neuronal cell death via apoptosis or necrosis. Impaired ocular perfusion, primarily due to abnormal autoregulation and/or vasoconstriction caused by endothelin-1, probably contributes to the ischemic milieu. Neuroprotection, the preservation of neurons that were either not damaged or only slightly damaged during the primary insult, has become important for the clinician when considering treatment options. Unoprostone, the first synthetic docosanoid, has been demonstrated to exhibit neuroprotective properties. In an ischemic animal model, unoprostone protected RGCs in a dose-dependent manner. Unoprostone inhibits glutamate stimulation and opens maxi-K channels, which are potassium channels that reach an activation threshold only during depolarization and/or at high intracellular Ca2+ concentrations. The resultant large efflux of K+ hyperpolarizes the cell, thereby closing voltage-gated Ca2+ channels and limiting neuronal damage by decreasing influx of intracellular Ca2+. Unoprostone has also been shown to protect rat photoreceptors from constant light-induced damage. Lastly, unoprostone has vasorelaxant properties, evidenced by increased choroidal blood flow and inhibition of vasoconstrictors such as endothelin-1. These findings indicate that a substantial clinical benefit of unoprostone is neuroprotection of RGCs.

Topics: Animals; Dinoprost; Glaucoma; Humans; Neuroprotective Agents; Rats; Retina

Despite treatment, glaucoma patients may still suffer vision loss because of inadequate control of intraocular pressure or late presentation. This article reviews the latest evidence supporting a reappraisal of first-line treatment in the management of glaucoma, including a review of latanoprost, recently approved for first-line treatment of glaucoma and ocular hypertension.

Topics: Amides; Antihypertensive Agents; Bimatoprost; Brimonidine Tartrate; Cloprostenol; Dinoprost; Drug Therapy, Combination; Glaucoma; Humans; Latanoprost; Lipids; Prostaglandins; Prostaglandins F, Synthetic; Quinoxalines; Sulfonamides; Thiophenes; Travoprost

The prostaglandin analogs are new exciting drugs added to the therapeutic armamentarium for patients with glaucoma. Several studies have evaluated the ocular hypotensive properties and side effects of latanoprost in different forms of glaucoma. This drug, seems to be the most effective intraocular pressure (IOP)-reducing agent currently available, and has a low incidence of ocular and systemic side effects. Fewer data are available regarding unoprostone, but the IOP-reducing effect of this drug seems to be comparable or slightly inferior to that of timolol and it produces fewer side effects. When compared with unoprostone, latanoprost has been shown to effect a greater reduction in IOP. A major drawback to the use of prostaglandin analogues is the lack of long-term experience such as that currently available for other classes of agents.

Topics: Antihypertensive Agents; Dinoprost; Glaucoma; Humans; Intraocular Pressure; Latanoprost; Ophthalmic Solutions; Prognosis; Prostaglandins; Prostaglandins F, Synthetic; Randomized Controlled Trials as Topic

Topics: Animals; Antihypertensive Agents; Awards and Prizes; Dinoprost; Glaucoma; Humans; Intraocular Pressure; Latanoprost; Melanosis; Molecular Structure; Ophthalmology; Prostaglandins F, Synthetic; Respiratory System; Societies, Scientific

This paper presents the classification of prostaglandins and their receptors. The ocular distribution of the receptors and the effects of their agonists are presented. The efficacy in lowering intraocular pressure of different prostaglandins and their derivatives, especially the PGF2a group, is discussed. The history of latanoprost development is also presented. Good therapeutic index characterises two antiglaucomatous PG-derivatives: latanoprost and unoprostone.

Topics: Animals; Blood-Aqueous Barrier; Dinoprost; Glaucoma; Humans; Intraocular Pressure; Latanoprost; Prostaglandins; Prostaglandins F, Synthetic

Prostaglandin (PG) analogues are a new class of ocular hypotensive drugs that have been developed for the treatment of open angle glaucoma. Two of these drugs, latanoprost and unoprostone, are presently commercially available. Latanoprost was introduced in 1996 in the US and Europe. Presently it enjoys the most widespread use and is the most well documented drug of this group. It reduces the intraocular pressure (IOP) by a mechanism of action different from other drugs; namely by increasing the uveoscleral outflow. The aqueous inflow is not affected. The optimal dose regimen is one drop of 50 microg/ml once daily, which reduces the IOP by approximately 30% in patients with glaucoma. A more pronounced ocular hypotensive effect is demonstrated when latanoprost is combined with other glaucoma therapies, including beta-blockers, adrenergic and cholinergic agonists or carbonic anhydrase inhibitors. Latanoprost is well tolerated. The drug reaches a plasma concentration below that needed for stimulation of the FP-receptor, which may explain its favourable systemic tolerability profile. The major ocular adverse effect is increased iris pigmentation, which is due to increased synthesis of melanin in the melanocytes of the iris stroma. It is most frequently seen in green-brown eyes and it is probably permanent. A low frequency of cystoid macular oedema has also been reported, predominantly in predisposed eyes. Unoprostone was launched in Japan in 1994, but there is little experience with this drug outside the Japanese market and the documentation is more limited. Its main mechanism of action is on outflow, but this is not yet fully elucidated. The recommended dosage regimen is 1 drop of 1.2 mg/ml twice daily. No comparative studies in humans between the 2 drugs have yet been published.

Topics: Animals; Dinoprost; Forecasting; Glaucoma; Humans; Latanoprost; Polypharmacy; Prostaglandins F, Synthetic; Prostaglandins, Synthetic

Prostaglandin (PG) analogs are some of the most recent additions to the list of ocular hypotensive medications. Two analogs of naturally occurring PGs are available commercially, isopropyl unoprostone (Rescula [Ciba Vision, Atlanta, GA]) and latanoprost (Xalatan [Pharmacia & Upjohn, Bridgewater, NJ]). Presently, latanoprost 0. 005% is the only PG analog commercially available in the United States. These agents have been shown to be the most effective topical medications for reducing intraocular pressure. They have a different mechanism of action than other ocular hypotensives, and act primarily by increasing uveoscleral outflow. Because of this, PGs have a substantial additive effect when used with agents that reduce aqueous production (eg, beta blockers or carbonic anhydrase inhibitors) or that increase trabecular outflow facility (eg, pilocarpine). Local side effects include mild conjunctival hyperemia and local irritation, darkening of iris color, increased growth of eyelashes, and a possible association with cystoid macular edema or iritis in some patients with other risk factors. No systemic side effects have been proven to be caused by latanoprost. Recommended dosing is once daily at bedtime.

Topics: Animals; Antihypertensive Agents; Aqueous Humor; Dinoprost; Glaucoma; Humans; Intraocular Pressure; Latanoprost; Molecular Structure; Ophthalmic Solutions; Prostaglandins F, Synthetic

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

A novel series of prostaglandin F (PGF) analogues have been prepared and evaluated in vivo and in vitro. Their intraocular pressure (IOP) lowering effects and potential side-effects, as prodrug eye drops, have been tested in cats, monkeys and rabbits. Furthermore, the PGF-analogues were tested as free acids for FP-receptor agonistic activity on cat iris sphincter. The results were compared to that of PGF2 alpha (C#1). Based on the structure-activity relationship investigations, inversion of the configuration, at carbon-9 (C#3) or carbon-11 (C#4), changes the potency and the receptor profile of PGF2 alpha. Replacement part of the omega-chain of PGF2 alpha with a benzene ring changes the potency and receptor profile of PGF2 alpha. The optimal position of the benzene ring is on carbon-17, 17-phenyl-18,19,20-trinor PGF2 alpha-isopropyl ester (C#8), and exhibited a much higher therapeutic index in the eye than PGF2 alpha or its ester. The biological activity of different substituents on the C#8 benzene ring have also been studied. Interestingly, introduction of a methyl group at positions 2 or 3 of the benzene ring (C#16 or C#17) affords compounds which are biologically more active than the methyl group at the 4-position (C#18). Furthermore, one of the analogues 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2 alpha-isopropyl ester (latanoprost), has been found in clinical studies to be a highly potent and efficacious IOP-reducing agent for the treatment of glaucoma.

Topics: Animals; Cats; Dinoprost; Glaucoma; Haplorhini; Humans; Intraocular Pressure; Prodrugs; Rabbits; Receptors, Prostaglandin; Structure-Activity Relationship

Several prostaglandins (PGs), their prodrugs, and their analogues have been shown to reduce intraocular pressure (IOP) in normotensive volunteers and in patients with elevated IOP. Initial clinical trials demonstrated efficacy with most of these agents, but a PGE2 analogue, PGD2, and BW245C (an analogue selective for the DP-receptor) cause an initial rise in IOP with a minimal subsequent reduction. Although PGF2 alpha tromethamine salt, PGF2 alpha-isopropyl ester (PGF2 alpha-IE), and 15-propionate-PGF2 alpha-IE are all very effective in reducing IOP, they produce unacceptable side effects, including conjunctival hyperemia and ocular irritation. Isopropyl unoprostone, a 22-carbon chain PGF2 alpha metabolite, produces a 10-25% reduction in IOP lasting approximately 2-5 hours, is well tolerated, and is commercially available for use in Japan. 17-phenyl substituted PGF2 alpha-IE analogues, such as PhXA34 or latanoprost, effectively reduce IOP by 30-40% for at least 24 hours, and are very well tolerated with minimal conjunctival hyperemia and without irritation. Latanoprost is the more potent 15R-epimer of PhXA34, and has become a useful agent in glaucoma therapy.

Topics: Animals; Clinical Trials as Topic; Dinoprost; Glaucoma; Humans; Intraocular Pressure; Prodrugs

Topics: Animals; Clinical Trials as Topic; Dinoprost; Dose-Response Relationship, Drug; Drug Administration Schedule; Glaucoma; Humans; Intraocular Pressure; Latanoprost; Prostaglandins F, Synthetic; Structure-Activity Relationship

Recently, an epidemiological study was conducted in Japan by Shiose, et al, and the prevalence of open-angle glaucoma in Japanese aged 40 years or older was found to be 2.62% [primary open-angle glaucoma 0.58%, low-tension glaucoma (LTG) 2.04%]. Historically, treatment for glaucoma has been based on lowering intraocular pressure. It is also necessary to improve intraocular blood flow. In the beginning of the study, the effect of anti-glaucoma agents on choroidal blood flow was examined in rabbit eyes. An increase of choroidal blood flow was found following topical application of the prostaglandin-related compound isopropyl unoprostone (UF-021) and the adrenergic alpha-1 antagonist bunazosin hydrochloride (DE-070). Then, a new vasoconstrictor, endothelin, showed strong effects on intraocular pressure, intraocular circulation, and visual function in rabbit eyes. Endothelin-1 (ET-1) was found to be a marked vasoconstrictor with prolonged reduction of intraocular pressure and the blood flow in the choroid and optic nerve head. The effects were suppressed by Ca2+ channel blocker and adrenergic alpha-1 blocker. Plasma concentration of ET-1 was determined by radioimmunoassay in patients with glaucoma. A significantly high level of ET-1 concentration was seen in patients with LTG. Endothelin appears to be an important tool for studying the pathogenesis of LTG. Finally, a prospective clinical trial of the therapeutic effects of bunazosin hydrochloride was performed in patients with LTG for one year. Clinical usefulness was evaluated by changes in the mean deviation value of Humphrey perimetry. Satisfactory results were obtained in maintaining the visual field and in reducing intraocular pressure. In the light of our investigations, it is advisable to introduce an adrenergic alpha-1 blocker or prostaglandin-related compound for reduction of glaucomatous damages. We look forward to the development of the neuro-protective future glaucoma therapy.

Topics: Adrenergic alpha-Antagonists; Choroid; Dinoprost; Endothelins; Glaucoma; Humans; Intraocular Pressure; Ophthalmic Solutions; Quinazolines; Regional Blood Flow

Topics: Animals; Cats; Cricetinae; Cyclooxygenase Inhibitors; Dinoprost; Dogs; Eicosanoic Acids; Glaucoma; Humans; Intraocular Pressure; Macaca fascicularis; Prostaglandins; Prostaglandins A; Rabbits; Rats; Time Factors

A need exists for new ocular hypotensive agents that are more efficacious and that have fewer side effects than those now clinically used. Laser-induced glaucoma in monkeys is an excellent model to test potential new drugs that lower intraocular pressure (IOP). A variety of agents that act through secondary messenger systems or via enzymes to lower IOP are being investigated in primates. Several alpha-adrenergic agonists and antagonists are effective ocular hypotensive agents in monkeys and humans. Para-aminoclonidine, an alpha2 agonist, inhibits the transient post-laser rise of IOP in humans. Prostaglandin F2 alpha-1-isopropyl ester significantly reduces IOP when tested in multiple dose fashion in glaucomatous monkey eyes and glaucoma patients. Modified carbonic anhydrase inhibitors, designed to enhance intraocular penetration, reduce IOP in the monkey model and in ocular hypertensive patients in single-dose studies when given topically. Studies show that forskolin and vanadate are less promising agents for glaucoma therapy.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Carbonic Anhydrase Inhibitors; Clinical Trials as Topic; Colforsin; Dinoprost; Drug Evaluation; Glaucoma; Haplorhini; Intraocular Pressure; Vanadates

Topics: Animals; Aqueous Humor; Dinoprost; Glaucoma; Humans; Intraocular Pressure; Macaca fascicularis; Rabbits; Time Factors; Tonometry, Ocular; Trabecular Meshwork; Venous Pressure

A lipid-soluble PG ester such as PGF2 alpha-IE reduces IOP in the human eye when given in considerably lower doses than are needed for the tromethamine salt of this PG to do so. However, with the pharmaceutical composition now used, the concomitant and dose-related side effects, both objective and subjective, are clearly clinically unacceptable at doses corresponding to the upper part of the dose-response curve for IOP reductions. Moderate side effects were observed after twice-daily treatment with the 0.5 microgram dose for up to two weeks. The pressure reduction obtained in healthy eyes with this dose of PGF2 alpha-IE was less than one would expect with conventional glaucoma drugs. However, the pressure reduction in response to this dose of PGF2 alpha-IE among glaucoma patients who had moderately increased IOP was adequate for clinical use. A useful approach to the development of PGs as potential drugs for the treatment of glaucoma would clearly be the identification of an alternative PG or PG formulation that will permit the use of doses at the upper portion of the IOP dose-response curve without unacceptable side effects. Long-term studies on glaucoma patients, using an appropriate PG formulation, remain to be done before we can evaluate the true clinical usefulness of this new class of ocular hypotensive drugs.

Topics: Administration, Topical; Dinoprost; Dose-Response Relationship, Drug; Evaluation Studies as Topic; Glaucoma; Humans; Intraocular Pressure; Male; Time Factors

To evaluate the effect of substituting latanoprost(LAT) 0.005% for unoprostone(UNO) 0.12% after a trial of unilateral treatment.. We treated 30 patients with primary open-angle glaucoma(n = 8), ocular hypertension (n = 1), or normal-tension glaucoma(n = 21) with UNO for 4 weeks in one eye and then substituted LAT for UNO. Four weeks later we measured the intraocular pressure(IOP) in the ipsilateral eye.. The mean baseline IOP level was 18.6 +/- 3.8(mean +/- standard deviation) mmHg. The mean IOP levels(reduction rates) after UNO and LAT therapy were 16.7 +/- 3.1 mmHg (16.6%) and 14.1 +/- 3.2 mmHg (28.9%), respectively(p < 0.001). All patients who responded to UNO also responded to LAT; however, 55% of those who did not respond to UNO responded to LAT.. If LAT is substituted for UNO, it can be predicted that 63.3% of the patients will respond.

Topics: Adult; Aged; Antihypertensive Agents; Dinoprost; Drug Therapy, Combination; Female; Glaucoma; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Latanoprost; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Prospective Studies; Prostaglandins F, Synthetic; Treatment Outcome

Histological changes of, in particular, collagen and extracellular matrix after administration of topical prostaglandin F(2alpha)(PGF (2alpha)) analogues have been reported. In view of this observation, we investigated the influence of PGF(2alpha) analogues on the central corneal thickness.. In a non-randomized, controlled, cross-sectional study, 403 eyes from 208 consecutive patients were examined: 149 eyes (normals/controls) and 79 with ocular hypertension (OHT), 119 eyes with primary open angle glaucoma (POAG) and 56 eyes with normal tension glaucoma (NTG). One experienced ophthalmologist measured the central corneal thickness (CCT) using ultrasound pachymetry (Tomey AL-2000, sequence of 5 measurements with an SD < 3 microm). The central corneal power was measured with the Zeiss keratometer. Depending on the topical treatment, the patients were classified into 4 groups: A) PGF(2alpha) analogues (n = 78), B) carbonic anhydrase inhibitors (n = 26), C) combination of PGF (2)(alpha) analogues and carbonic anhydrase inhibitors (n = 41), D) none of these drugs (n = 258). T tests and multiple linear regression analyses were used for statistical analysis.. CCT was decreased significantly (p < 0.01 each) in eyes treated with PGF(2alpha) analogues (group A: 529 +/- 34 microM), in comparison with the untreated and non-glaucomatous eyes (part of group D: 542 +/- 35 microM, n = 148), untreated glaucomatous/OHT eyes (part of group D: 563 +/- 37 microM, n = 110), eyes treated with carbonic anhydrase inhibitors (group B: 561 +/- 32 microm) and eyes with a topical application of both PGF (2)(alpha) analogues and carbonic anhydrase inhibitors (group C: 555 +/- 48 microM. No correlation was found between CCT and diagnosis (OHT, POAG, NTG, control), gender, central corneal power, and intraocular pressure in a multivariate analysis.. The present findings suggest that the topical application of prostaglandin F(2alpha) analogues onto the cornea reduces the central corneal thickness significantly. These changes might be attributed to effects of PGF(2alpha) analogues on the extracellular matrix of the corneal stroma via upregulation of matrix metalloproteinases. In clinical practice, corneal thinning under local PGF (2)(alpha) analogue treatment could result in underestimation of intraocular pressure levels as measured by applanation tonometry.

Topics: Acetazolamide; Administration, Topical; Adult; Aged; Carbonic Anhydrase Inhibitors; Cloprostenol; Collagen; Cornea; Corneal Topography; Cross-Sectional Studies; Dinoprost; Drug Therapy, Combination; Extracellular Matrix; Female; Glaucoma; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Latanoprost; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Prostaglandins F, Synthetic; Sulfonamides; Thiophenes; Travoprost; Ultrasonography

To compare incidence of iridial pigmentation prospectively induced by long term treatment with latanoprost and isopropyl unoprostone (hereafter, unoprostone) in Japanese patients with glaucoma.. Patients with glaucoma treated with prostaglandin (PG) related ophthalmic solutions were sequentially enrolled. Patients treated for more than 30 months with PG related ophthalmic solutions were subjected to analysis. The entry criteria were no history of intraocular surgery, laser iridotomy, and/or laser trabeculoplasty within 12 months before and after the enrolment; and no history of uveitis; no changes in antiglaucoma drugs within 6 months before and after the enrolment. Photographs of the irides were taken under the same conditions and three glaucoma specialists evaluated the iridial pigmentation with masking of patient information. The correlation of iridial pigmentation with the background factors and the reduction of intraocular pressure (IOP) before and after the treatment were investigated.. 48 eyes in 48 patients satisfied the enrolment criteria (25 eyes in the latanoprost group, 23 eyes in the unoprostone group). At the end of the follow up period, iridial pigmentation was present in 15 patients (60.0%) in the latanoprost group and seven patients (30.4%) in the unoprostone group. The correlation between development of iridial pigmentation and age, sex, concurrent use of other ophthalmic solutions, and IOP reduction was not significant.. The incidence of iridial pigmentation induced by latanoprost or unoprostone is high in the case of long term treatment. Iridial pigmentation did not affect PG related ophthalmic solution induced IOP reduction.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Dinoprost; Eye Color; Female; Follow-Up Studies; Glaucoma; Humans; Iris Diseases; Latanoprost; Male; Middle Aged; Ophthalmic Solutions; Pigmentation Disorders; Prospective Studies; Prostaglandins F, Synthetic; Risk Factors

Prostaglandin F2 alpha (PGF2 alpha) as its tromethamine salt was topically applied, and hypotensive and other ocular effects were studied, in glaucomatous human eyes. After baseline intraocular pressure (IOP) measurements, 100 micrograms PGF2 alpha tromethamine salt dissolved in 50 milligrams saline was applied to 23 glaucomatous eyes of 20 patients. The pretreatment diurnal IOP values of the same eye served as control group. It was found that in comparison with baseline values, PGF2 alpha caused significant but transient elevation in IOP in the first half-hour (mean 1.95 mm Hg, p < 0.01), but it decreased below baseline values at the first hour. A significant decrease in IOP from baseline was observed at the 2nd hour (p < 0.05), which became more prominent between the 4th and 24th hours (p < 0.001). PGF2 alpha produced a maximal IOP reduction of 10.21 mm Hg at the 12th hour (p < 0.001). The IOP differences between PGF2 alpha-treated and control groups were significant between the 4th and 24th hours (p < 0.001), with the maximal IOP difference of 9.21 mm Hg at the 12th hour (p < 0.001). PGF2 alpha caused marked conjunctival hyperaemia in all eyes. Aqueous flare and cellular response were not seen in any of the eyes. Half of the patients experienced ocular smarting or a foreign-body sensation, periocular pain and headache. PGF2 alpha reduced IOP effectively in glaucomatous human eyes.

Topics: Administration, Topical; Adult; Aged; Dinoprost; Eye; Female; Glaucoma; Humans; Intraocular Pressure; Male; Middle Aged; Ocular Physiological Phenomena; Time Factors

We administered UF-021 isopropyl unoprostone (Rescula) ophthalmic solution, a new prostaglandin-related compound developed as an anti-glaucoma agent, to 13 low tension glaucoma patients for 24 weeks, and clinically evaluated the effect of the intraocular pressure (IOP) reduction, visual field change, and side effects of the agent. Intraocular pressure was reduced in 11 out of 12 patients who were studied for statistical analysis. In these 12 patients, significant IOP reduction was recognized in the mean IOP for 24 weeks after the administration of UF-021. No side effects were detected in any of the 13 patients. From these results, UF-021 could be used as a new anti-glaucoma agent for low tension glaucoma, and also safer than many other anti-glaucoma agents.

Topics: Adult; Aged; Dinoprost; Female; Glaucoma; Humans; Intraocular Pressure; Male; Middle Aged; Ophthalmic Solutions

Four clinical studies were performed in 54 healthy Japanese volunteers to assess the efficacy and the safety of two phenyl-substituted PGF2 alpha-isopropyl ester analogues, PhXA34 and PhXA41 after both single and repeated administrations. PhXA34 and PhXA41 reduced intraocular pressure (IOP) significantly in a dose-dependent way. The maximum IOP reductions were 14.5% to 17.5% with baseline adjustment at 10 to 12 hours after a single administration. No transient early elevation in IOP after treatment was observed. Based on the maximum IOP reducing effect of 1 microgram of PhXA34 and PhXA41, PhXA41 appeared to be at least 1.5 times more active than PhXA34. Tachyphylaxis of the ocular hypotensive effect did not develop during repeated administration for 5 days. A mild conjunctival hyperemia occurred in some subjects at high doses; it tended to diminish with time during the repeated administration of both drugs. Neither PhXA34 nor PhXA41 caused any change at any time in the aqueous flare intensity measured with a laser flare-cell meter. There were no changes in pupillary diameter after treatment. Each drug was well tolerated and caused no other ocular or systemic side effects.

Topics: Adolescent; Adult; Aqueous Humor; Dinoprost; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Tolerance; Evaluation Studies as Topic; Glaucoma; Humans; Hyperemia; Intraocular Pressure; Latanoprost; Male; Ophthalmic Solutions; Prostaglandins F, Synthetic

UF-021 ophthalmic solution, a novel prostaglandin-related therapeutic agent for glaucoma, was additionally applied to the eyes in intractable cases of primary open angle glaucoma (14 cases, 21 eyes) and ocular hypertension (1 case, 2 eyes) in which intraocular pressure (IOP) had not been kept under satisfactory control even with combined drug therapy by conventional, existing anti-glaucoma agents including sympathetic beta-blockers. Decrease of IOP by UF-021 ophthalmic solution (0.12%) in the treated eyes was observed from not less than one month after the initial application by 3 mmHg and more in about 85%, and by 5 mmHg and more in about 76% of the enrolled patients, respectively. The IOP reduction induced by the additional application of UF-021 was sustained for more than 6 months, resulting in successful avoidance of surgical operations in many patients. When UF-021 ophthalmic solution was applied concurrently with various anti-glaucoma agents including carbonic anhydrase inhibitors, it caused no controversial side-effects and yielded therapeutic efficacy for a prolonged period. These findings suggest that UF-021 can yield IOP-reducing activity through a novel pharmacological mechanism different from other existing drugs. In conclusion, UF-021 ophthalmic solution is extremely useful for the treatment of glaucoma.

Topics: Dinoprost; Female; Glaucoma; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Ophthalmic Solutions

A need exists for new ocular hypotensive agents that are more efficacious and that have fewer side effects than those now clinically used. Laser-induced glaucoma in monkeys is an excellent model to test potential new drugs that lower intraocular pressure (IOP). A variety of agents that act through secondary messenger systems or via enzymes to lower IOP are being investigated in primates. Several alpha-adrenergic agonists and antagonists are effective ocular hypotensive agents in monkeys and humans. Para-aminoclonidine, an alpha2 agonist, inhibits the transient post-laser rise of IOP in humans. Prostaglandin F2 alpha-1-isopropyl ester significantly reduces IOP when tested in multiple dose fashion in glaucomatous monkey eyes and glaucoma patients. Modified carbonic anhydrase inhibitors, designed to enhance intraocular penetration, reduce IOP in the monkey model and in ocular hypertensive patients in single-dose studies when given topically. Studies show that forskolin and vanadate are less promising agents for glaucoma therapy.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Carbonic Anhydrase Inhibitors; Clinical Trials as Topic; Colforsin; Dinoprost; Drug Evaluation; Glaucoma; Haplorhini; Intraocular Pressure; Vanadates

Low corneal hysteresis (CH) is associated with an increased risk of glaucoma. Prostaglandin analogue (PGA) eye drops may exert their intraocular pressure (IOP)-lowering effect partially by increasing CH.. Twelve pairs of organ-cultured human donor corneas were used in an ex vivo model. In each case, one cornea was treated with PGA (Travoprost) for 30 days, whereas the other served as an untreated control. IOP levels were simulated in an artificial anterior chamber model. CH was measured using the Ocular Response Analyzer (ORA). Corneal expression of matrix-metalloproteinases (MMPs) was assessed by immunhistochemistry and real-time polymerase chain reaction (RT-PCR).. Increased CH was observed in the PGA-treated corneas. However, at IOP between 10 and 20 mm Hg, CH was increased in PGA-treated corneas (13.12 ± 0.63 mm Hg; control: 12.34 ± 0.49 mm Hg), although not significantly (P = 0.14). CH was significantly increased at higher IOP levels (21-40 mm Hg; PGA-treated: 17.62 ± 0.40 mm Hg; control: 11.60 ± 0.39, P < 0.0001). Treatment with PGA resulted in increased expression of MMP-3 and MMP-9.. CH was increased after exposure to PGA. However, this increase was significant only in eyes with higher IOP (>21 mm Hg). A significant increase in MMP-3 and -9 was observed in PGA-treated corneas, indicating structural changes in corneal biomechanics caused by PGA.. PGAs alter biomechanical structures by directly upregulating MMP-3 and -9, and the increase in CH is dependent on the level of IOP. Therefore, PGAs may have a greater effect when baseline IOP is higher.

Topics: Cornea; Dinoprost; Glaucoma; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Matrix Metalloproteinase 3

Glaucoma is a neurodegenerative disease that leads to blindness, and lowering intraocular pressure (IOP) is very important in glaucoma treatment. The trabecular meshwork is responsible for aqueous humor outflow, and the accumulation of fibronectin in trabecular meshwork is known to cause ocular hypertension. We have already shown that Piezo1 activation has an IOP lowering effect in mice and suppresses fibronectin expression level in human trabecular meshwork cells (HTMC). In this study, we report the mechanism of the reduction of fibronectin caused by Piezo1 activation. Activation of Piezo1 in HTMC showed increased expression of matrix metalloproteinase-2 (MMP-2) and cyclooxygenase (COX)-2, and decreased fibronectin expression. In addition, Piezo1 activation enhanced phosphorylation of cytosolic phospholipase A2 (cPLA2), and inhibitors targeting cPLA2 and COX-2 suppressed Yoda 1, a Piezo1 agonist, induced fibronectin reduction. These results indicate that the arachidonic acid cascade underlies this reaction, and, in support of this hypothesis, activation of Piezo1 promoted secretion of prostaglandin F2α (PGF2α) in HTMC. These results indicate that the activation of Piezo1 in HTMC promotes the degrading of fibronectin by promoting the arachidonic acid cascade and increasing the expression of PGF2α and MMP-2.

Topics: Animals; Aqueous Humor; Arachidonic Acid; Dinoprost; Fibronectins; Glaucoma; Intraocular Pressure; Ion Channels; Matrix Metalloproteinase 2; Mice; Neurodegenerative Diseases; Ocular Hypertension; Phospholipases A2, Cytosolic; Trabecular Meshwork

Topics: Administration, Topical; Benzalkonium Compounds; Cross-Sectional Studies; Dinoprost; Glaucoma; Humans; Latanoprost; Oxidative Stress; Poland; Prostaglandins F; Tears

　Prostaglandin F2α (PGF2α) analog formulations are the most commonly used drugs for glaucoma treatment. They are known to be superior to β-blockers for reducing intraocular pressure and can be effective all through the day. Because of the action, topical β-blockers are contraindicated for patients with bronchial asthma. PGF2α is also known to act as a constrictor of the respiratory tract. The present study aims to analyze the relationship between PGF2α analogs and asthma. In addition, we utilized β-blockers and combined formulations of both contents to evaluate for comparison with PGF2α analogs. Data from Japanese adverse drug event reports (JADERs) from April 2004 to January 2016 were used for analysis. The drugs of interest were 4 PGF2α analogs, 4 β-blockers, and 2 combined formulations of both. For quantitative signal detection, the reporting odds ratios (RORs) with Haldane-Anscombe 1/2 correction were calculated. The corrected RORs (95%CI) were detected to be 4.73 (2.30-9.75) for PGF2α analogs, 4.61 (1.82-11.7) for β-blockers, and 28.7 (12.1-68.1) for combined formulations. Our results suggest that not only topical β-blockers but also PGF2α analogs are associated with asthma, and the combined formulations have stronger associations with asthma than when administered alone. Therefore, further clinical research will be necessary, and careful attention should be paid to any glaucoma patient using PGF2α analogs for asthma symptoms.

Topics: Adrenergic beta-Antagonists; Adverse Drug Reaction Reporting Systems; Asthma; Contraindications, Drug; Databases, Pharmaceutical; Dinoprost; Drug Combinations; Glaucoma; Humans

Tafluprost (AFP-168, 5) is a unique 15-deoxy-15,15-difluoro-16-phenoxy prostaglandin F2α (PGF2α) analog used as an efficacious ocular hypotensive agent in the treatment of glaucoma and ocular hypertension, as monotherapy, or as adjunctive therapy to β-blockers. A novel convergent synthesis of 5 was developed employing Julia-Lythgoe olefination of the structurally advanced prostaglandin phenylsulfone 16, also successfully applied for manufacturing of pharmaceutical grade latanoprost (2), travoprost (3) and bimatoprost (4), with an aldehyde ω-chain synthon 17. The use of the same prostaglandin phenylsulfone 16, as a starting material in parallel syntheses of all commercially available antiglaucoma PGF2α analogs 2-5, significantly reduces manufacturing costs resulting from its synthesis on an industrial scale and development of technological documentation. Another key aspect of the route developed is deoxydifluorination of a trans-13,14-en-15-one 30 with Deoxo-Fluor. Subsequent hydrolysis of protecting groups and final esterification of acid 6 yielded tafluprost (5). The main advantages are the preparation of high purity tafluprost (5) and the application of comparatively cheap reagents. The preparation and identification of two other tafluprost acid derivatives, tafluprost methyl ester (32) and tafluprost ethyl amide (33), are also described.

Topics: Antihypertensive Agents; Chemistry Techniques, Synthetic; Dinoprost; Glaucoma; Molecular Structure; Ocular Hypertension; Prostaglandins F

Prostaglandin F2α analogues are the first-line medication for the treatment of ocular hypertension (OHT), and prostanoid EP2 receptor agonists are under clinical development for this indication. The goal of this study was to investigate the effects of F prostanoid (FP) and EP2 receptor activation on the myofibroblast transition of primary trabecular meshwork (TM) cells, which could be a causal mechanism of TM dysfunction in glaucoma.. Human primary TM cells were treated with either latanoprost or butaprost and TGF-β2. Trabecular meshwork contraction was measured in a three-dimensional (3D) TM cell-populated collagen gel (CPCG) model. Expression of α-smooth muscle actin (α-SMA) and phosphorylation of myosin light chain (MLC) were determined by Western blot. Assembly of actin stress fibers and collagen deposition were evaluated by immunocytochemistry. Involvement of p38, extracellular signal-regulated kinase (ERK), and Rho-associated kinase (ROCK) pathways as well as matrix metalloproteinase activation was tested with specific inhibitors.. In one source of validated adult TM cells, latanoprost induced cell contraction as observed by CPCG surface reduction and increased actin polymerization, α-SMA expression, and MLC phosphorylation, whereas butaprost inhibited TGF-β2-induced CPCG contraction, actin polymerization, and MLC phosphorylation. Both agonists inhibited TGF-β2-dependent collagen deposition. The latanoprost effects were mediated by p38 pathway.. Latanoprost decreased TM collagen accumulation but promoted a contractile phenotype in a source of adult TM cells that could modulate the conventional outflow pathway. In contrast, butaprost attenuated both TM contraction and collagen deposition induced by TGF-β2, thereby inhibiting myofibroblast transition of TM cells. These results open new perspectives for the management of OHT.

Topics: Actins; Adult; Alprostadil; Animals; Antihypertensive Agents; Blotting, Western; Cell Survival; Cells, Cultured; Dinoprost; Glaucoma; Humans; Immunohistochemistry; Latanoprost; Male; Myofibroblasts; Myosin Light Chains; Neuroprotective Agents; Prostaglandins E, Synthetic; Prostaglandins F, Synthetic; Rats; Real-Time Polymerase Chain Reaction; Receptors, Prostaglandin; Receptors, Prostaglandin E, EP2 Subtype; RNA; Signal Transduction; Trabecular Meshwork

Lowering of intra-ocular pressure is the primary pharmacologic approach for the treatment of glaucoma and a number of distinct mechanisms of action have been clinically validated. Targeting of multiple mechanisms in combination therapies has proven effective both clinically and commercially although potential improvements with regards to efficacy, tolerability and dosing frequency remain. Application of Theravance's multivalent approach to drug discovery towards linked dual-pharmacology prostaglandin F receptor (FP) agonist/carbonic anhydrase (CA)-II inhibitor compounds is described. Compound 29 exhibits weak potency (pEC(50)=5.7, IA>1.0) as an FP agonist with high binding affinity (pK(i)=8.1) to the CA-II enzyme, and has comparable corneal permeability to the CA-II inhibitor dorzolamide.

Topics: Carbonic Anhydrase Inhibitors; Drug Discovery; Glaucoma; Humans; Models, Molecular; Prostaglandins F, Synthetic; Receptors, Prostaglandin

The 17-phenyl PGF(2α) analogue bimatoprost (10a) is the most efficacious ocular hypotensive agent currently available for the treatment of glaucoma or ocular hypertension. A novel convergent synthesis of 13,14-en-15-ol prostamideF(2α) analogues was developed employing Julia-Lythgoe olefination of the structurally advanced phenylsulfone (+)-(5Z)-15 with an enantiomerically pure aldehyde ω-chain synthon (-)-(S)-16a. Subsequent hydrolysis of protecting groups and final amidation of the diol 26a yielded bimatoprost (10a). The main advantage of the current strategy is the preparation of high-purity bimatoprost (10a). The novel convergent strategy allows the synthesis of a whole series of 13,14-en-15-ol prostamideF(2α) analogues with the desired C-15 asymmetric center configuration from a common and structurally advanced prostaglandin intermediate (+)-(5Z)-15. The preparation and identification of two synthetic impurities, 15-epi isomer (10b) of bimatoprost and a new prostaglandin related amide (+)-(5Z)-18, are also described.

Topics: Amides; Bimatoprost; Cloprostenol; Dinoprost; Glaucoma; Molecular Structure

The IOP lowering effects of NCX 139, a new chemical entity comprising latanoprost amide and a NO-donating moiety, were compared to those of the respective des-nitro analog in in vitro assays and in rabbit and dog models of ocular hypertension. The NO donor, molsidomine as well as the prostamide bimatoprost (Lumigan(®)) and the prostaglandin agonist, latanoprost (Xalatan(®)) were also investigated for comparison. NCX 139 but not its des-nitro analog resulted in NO-mediated vascular relaxant effect in pre-contracted rabbit aortic rings (EC(50)=0.70±0.06 μM; E(max)=80.6±2.9%). Like bimatoprost (IC(50)=3.07±1.3 μM) or latanoprost (IC(50)=0.48±0.15 μM), NCX 139 displaced (3)H-PGF2α binding on recombinant human prostaglandin-F (FP) receptors with an estimated potency of 0.77±0.13 μM. In transient ocular hypertensive rabbits, bimatoprost and latanoprost were not effective while molsidomine elicited a dose-dependent reduction of IOP confirming the responsiveness of rabbits to NO but not to FP receptor agonists. NCX 139 tested at a therapeutically relevant dose, significantly lowered IOP while the des-nitro analog was not effective (0.03% NCX 139, Δ(max)=-12.8±2.0 mmHg). In glaucomatous dogs, 0.03% NCX 139 decreased IOP to a greater extent compared to an equimolar dose of the respective des-nitro derivative (Δ(max)=-4.6±1.0 and -2.7±1.3 mmHg, respectively for NCX 139 and its des-nitro analog). Albeit with low potency, NCX 139 also resulted effective in normotensive dogs while it did not reduce IOP in normotensive rabbits. NCX 139, a compound targeting two different and important mechanisms, is endowed with ocular hypotensive effects more evident in hypertensive conditions which may be of interest in the search of more effective treatments for hypertensive glaucoma.

Topics: Amides; Animals; Antihypertensive Agents; Aorta; Bimatoprost; Chromatography, High Pressure Liquid; Cloprostenol; Dinoprost; Disease Models, Animal; Dogs; Glaucoma; Intraocular Pressure; Latanoprost; Male; Molsidomine; Nitrates; Nitric Oxide; Nitric Oxide Donors; Ocular Hypertension; Prostaglandins F, Synthetic; Rabbits; Tandem Mass Spectrometry; Tonometry, Ocular; Vasodilation; Vasodilator Agents

The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as reference drug. NO, downstream effector cGMP, and latanoprost acid were determined in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 μg) and 0.12% (36 μg), respectively. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 μg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, respectively. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aqueous humor as was cGMP in aqueous humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension.

Topics: Administration, Topical; Animals; Antihypertensive Agents; Aqueous Humor; Cell Line; Ciliary Body; Cyclic GMP; Dinoprost; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Female; Glaucoma; Guanylate Cyclase; Intraocular Pressure; Iris; Latanoprost; Macaca fascicularis; Male; Nitric Oxide; Nitric Oxide Donors; Ocular Hypertension; Prostaglandins F, Synthetic; Rabbits; Rats; Tonometry, Ocular

Topics: Animals; Dinoprost; Drug Design; Glaucoma; Humans

FP-Class prostaglandin analogs have demonstrated utility for the treatment of glaucoma and ocular hypertension. A series of novel FP prostaglandin analogs was designed to optimize topical ocular activity and reduce ocular side-effects by replacing 13-carbon with oxygen. A facile synthesis was successfully developed for synthesis of the 13-oxa prostaglandins from the commercially available Corey aldehyde benzoate. Among the compounds synthesized, AL-16082 was the most potent prostaglandin FP agonist in vitro. In a prostaglandin FP receptor-linked second-messenger assay, phosphoinositide (PI) turnover, it exhibited a potency value (EC(50)) of 1.9 nM (78% max. response relative to fluprostenol). The isopropyl ester of AL-16082, compound AL-16049, significantly lowered intraocular pressure (IOP) in the ocular hypertensive monkey eyes by 30%. In the study of acute ocular irritation response in New Zealand albino rabbits, AL-16049 produced lower incidence of hyperemia, swelling, and discharge than PGF(2alpha) (1 microg), and a similar incidence of hyperemia, swelling, and discharge to latanoprost (1.8 microg). AL-16049 also produced no signs of ocular irritation or discomfort in the cat at the doses evaluated.

Topics: Administration, Topical; Animals; Cats; Dinoprost; Drug Discovery; Eye Diseases; Glaucoma; Haplorhini; Hypertension; Intraocular Pressure; Prostaglandins F, Synthetic; Prostaglandins, Synthetic; Rabbits; Structure-Activity Relationship

This study compared the toxicity profiles of three antiglaucoma prostaglandin F2alpha analogs, latanoprost, travoprost, and bimatoprost which contain benzalkonium chloride (BAK), with tafluprost, a new preservative-free prostaglandin analog.. IOBA-NHC cells were exposed to BAK-containing prostanoid solutions, their respective BAK concentrations, and preservative-free tafluprost solution for 30 min. Membrane integrity, apoptosis, oxidative stress, and cells morphology were evaluated.. Preservative-free tafluprost resulted in significantly higher membrane integrity and lower pro-apoptotic and pro-oxidative effects than preservative-containing prostaglandin analog preparations.. These results suggest that tafluprost, a new preservative-free prostaglandin analog, has very low or no pro-apoptotic, pro-necrotic, or pro-oxidative effects in vitro compared to preservative-containing formulations.

Topics: Amides; Apoptosis; Benzalkonium Compounds; Bimatoprost; Cell Line; Cell Membrane; Cell Survival; Cloprostenol; Conjunctiva; Dinoprost; DNA; Drug Combinations; Epithelial Cells; Glaucoma; Humans; Latanoprost; Ocular Hypertension; Preservatives, Pharmaceutical; Prostaglandins F; Prostaglandins F, Synthetic; Receptors, Purinergic P2; Receptors, Purinergic P2X7; Superoxides; Travoprost

To compare the ocular hypotensive effects of 15-keto latanoprost (KL) with the commercial preparation of latanoprost (Xalatan; Pfizer, New York, NY) in monkey eyes with laser-induced unilateral glaucoma and to evaluate the effects of topical 0.005% KL on aqueous humor dynamics in normal monkey eyes.. Intraocular pressure (IOP) was measured hourly for 6 hours beginning at 9:30 AM on day 1 (untreated baseline); day 2 (vehicle only); and treatment days 1, 3, and 5 (topical, 30 microL of study drug) in the glaucomatous eyes of four to eight monkeys with unilateral laser-induced glaucoma. KL concentrations of 0.0001%, 0.001%, and 0.01% and latanoprost at 0.005% were studied separately, with a minimum washout period of 2 weeks between studies. Tonographic outflow facility (C) and fluorophotometric aqueous humor flow rates (F) were measured in nine normal monkeys before and after a single topical dose of 0.005% KL in one eye, with a vehicle-only control in the fellow eye.. When applied once daily to glaucomatous monkey eyes, all three concentrations of KL and a 0.005% concentration of latanoprost produced significant (P < 0.05) reductions in IOP, with the maximum reduction on treatment day 5, regardless of the drug or concentration studied. The maximum reduction (P < 0.001) from vehicle-only baseline IOP was (mean +/- SEM) 3.0 +/- 0.3 mm Hg (9%) for 0.0001% KL, 7.6 +/- 0.6 mm Hg (23%) for 0.001% KL, 6.3 +/- 0.4 mm Hg (18%) for 0.01% KL, and 6.6 +/- 0.6 mm Hg (20%) for 0.005% latanoprost. After application of a single dose of 0.005% KL in nine normal monkey eyes, neither C nor F was altered (P > 0.80) when compared with untreated baseline values or vehicle-treated control eyes.. The reduction in IOP produced by 0.001% KL was equivalent to, and at some measured time points, greater than the effect produced by 0.005% latanoprost. The IOP reduction by KL in normal monkeys appeared to have no effect on aqueous humor production or tonographic outflow facility and may thus indicate a drug-induced increase in uveoscleral outflow.

Topics: Animals; Antihypertensive Agents; Aqueous Humor; Dinoprost; Disease Models, Animal; Female; Fluorophotometry; Glaucoma; Intraocular Pressure; Latanoprost; Macaca fascicularis; Prostaglandins F, Synthetic; Tonometry, Ocular

This study examines, in 11 cynomolgus monkeys with unilateral laser-induced glaucoma, the ocular hypotensive mechanism of action of AL-6598, partial agonist at the DP and EP prostanoid receptors. In a crossover fashion, both eyes of each monkey were dosed twice daily with 25 microL of either AL-6598 0.01% or vehicle for 2 days and on the morning of the 3rd day. Measurements were made on day 3 of each treatment. Alternative treatments were separated by at least 2 weeks. Intraocular pressures (IOPs) were measured by pneumatonometry and aqueous flow and outflow facility by fluorophotometry. Uveoscleral outflow was calculated mathematically. In the normotensive eyes, compared to vehicle treatment, AL-6598 decreased IOP from 22.5 +/- 0.7 to 18.7 +/- 0.9 mmHg (P = 0.006), increased uveoscleral outflow from 0.47 +/- 0.17 to 1.22 +/- 0.17 microL/min (P = 0.03), and increased aqueous flow from 1.49 +/- 0.10 to 1.93 +/- 0.13 microL/min (P = 0.01). No measurement in AL-6598-treated hypertensive eyes was significantly different from vehicle treatment. It is concluded that AL-6598 reduces IOP by increasing uveoscleral outflow in normotensive eyes of ketamine-sedated monkeys, despite an increase in aqueous flow. This effect is different from that of PGD(2), which decreases aqueous flow, and of the selective DP receptor agonist, BW245C, which increases both outflow facility and uveoscleral outflow in addition to decreasing aqueous flow.

Topics: Animals; Aqueous Humor; Dinoprost; Disease Models, Animal; Female; Fluorophotometry; Glaucoma; Intraocular Pressure; Macaca fascicularis; Receptors, Immunologic; Receptors, Prostaglandin; Sclera; Treatment Outcome; Uvea

The purpose of this study was to evaluate both the intraocular pressure (IOP)-decreasing and neuroprotective effects of Rescula (0.12% unoprostone isopropyl) as an alternative therapy to betablockers with a long-term drift effect in patients with glaucoma. Twenty-eight patients with unilateral or bilateral glaucoma were treated with Rescula instead of the original beta-blocker therapy. IOP was measured using a Goldmann applanation tonometer, and visual field defects were evaluated quantitatively by Humphrey automatic perimetry central 30-2 threshold test. The mean follow-up time was at least 1 year. Rescula achieved a significant (p = 0.00001) and long-lasting reduction in IOP (from 20.78 +/- 2.71 to 17.14 +/- 2.70 mmHg) in patients with open-angle glaucoma after 12 months of follow-up. It also demonstrated a significant (p = 0.02) IOP-reducing effect (from 20.67 +/- 3.60 to 16.36 +/- 3.67 mmHg) in patients with angle-closure glaucoma 12 months later. The mean deviation of visual field defects changed from -13.27 dB baseline to -10.64 dB at 12 months as evaluated by Humphrey field analyzer II central 30-2 threshold test after Rescula; however, there was no statistical difference (p = 0.098). Our results showed that Rescula has a significant IOP-reducing effect as an alternative therapy to beta-blockers with long-term drift effect in patients with open-angle and angle-closure glaucoma. However, a neuroprotective effect to prevent further progression of the visual field defect in patients with glaucoma was not demonstrated in this study.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Antihypertensive Agents; Dinoprost; Female; Glaucoma; Humans; Intraocular Pressure; Male; Middle Aged; Neuroprotective Agents; Prospective Studies; Visual Fields

We retrospectively investigated the long-term effects of isopropyl unoprostone monotherapy on intraocular pressure and visual field for normal-tension glaucoma and primary open-angle glaucoma patients. Among 80 eyes of 49 subjects receiving isopropyl unoprostone monotherapy for 2 years or more, 32 eyes of 32 subjects were analyzed because of the good reliability of their visual acuity and visual field (age, 68.1 +/- 10.1 yrs, follow-up period 47.8 +/- 14.7 months). The mean values of intraocular pressure and visual field indices were compared with baseline data before medication. The visual field changes were also analyzed using the Kaplan-Meier life-table method. The mean intraocular pressure decreased for 4 years from 14.7 +/- 4.3 mmHg (mean +/- SD) at baseline, to 12.7 +/- 4.4mmHg at 4 years. The global index of visual field (mean defect, loss variance) did not change significantly during the 4 years. The accumulative probability of survival was 80.7 +/- 8.0% after 4 years when the endpoint was defined as 3dB progression in mean defect. Isopropyl unoprostone might have the possibility of stabilizing the visual field for a long period of time.

Topics: Aged; Dinoprost; Female; Glaucoma; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Retrospective Studies; Visual Fields

To investigate the effects of antiglaucoma eyedrops and vehicles on the proliferation of human corneal epithelial cells.. Seven eyedrops[prostaglandin F2 alpha analogs(2), beta blockers(40), topical carbonic anhydrase inhibitor(1)], and six of the eyedrop vehicles, excluding that of Xalatan, were used. Anti-glaucoma eyedrops and vehicles were serially diluted 2-fold with culture medium(10-2,560 fold). The mixture was added to human corneal epithelial cells and incubated for 48 hrs. Cell proliferation was measured by commercial assay kit. Dye-reagents were added to the wells and incubated for 1 h at 37 degrees C. Optical density were measured at 490 nm. The dilution rate for 50% inhibition was calculated as the dilution rate of drugs or vehicles necessary to produce 50% inhibition of cell proliferation.. All drugs completely inhibited cell proliferation when the dilution rate was low. At 40-fold dilution, Trusopt and Timoptol showed a significant decrease in cell growth inhibition. On the other hand, Rescula showed almost 100% inhibition at 160-fold dilution. Above 640-fold dilution, the inhibition rate of all drugs became 50% or less and there was no significant difference between drugs. Vehicles also inhibited cell growth. The dilution rates for growth inhibition by vehicles were different from those of drugs. The dilution rate at 50% inhibition of anti-glaucoma eyedrops decreased in the following order: Rescula > Xalatan > Betoptic > Hypadil > Mikelan > Timoptol > Trusopt. The dilution rate for 50% inhibition of vehicles decreased in the following order: Rescula vehicle > Hypadil vehicle > Betoptic vehicle > Mikelan vehicle > Timoptol vehicle > Trusopt vehicle.. All anti-glaucoma eyedrops inhibited cell proliferation. These effects were stronger in prostaglandin F2 alpha analogs and weakest in Trusopt. Furthermore, the inhibition of cell proliferation was caused also by the vehicle of eyedrops, and the influence of the vehicle varied in each type of eyedrops.

Topics: Adrenergic beta-Antagonists; Carbonic Anhydrase Inhibitors; Cell Division; Dinoprost; Epithelium, Corneal; Glaucoma; Growth Inhibitors; Humans; Ophthalmic Solutions; Sulfonamides; Thiophenes

Topics: Amides; Antihypertensive Agents; Bimatoprost; Cloprostenol; Dinoprost; Evidence-Based Medicine; Fluorescein Angiography; Glaucoma; Humans; Latanoprost; Lipids; Prostaglandins F, Synthetic; Trabeculectomy; Travoprost

Replacement of the carboxylic acid group of prostaglandin (PG) F(2alpha) with a nonacidic moiety, such as hydroxyl, methoxy, or amido, results in compounds with unique pharmacology. Bimatoprost (AGN 192024) is also a pharmacologically novel PGF(2alpha) analog, where the carboxylic acid is replaced by a neutral ethylamide substituent. Bimatoprost potently contracted the feline lung parenchymal preparation (EC(50) value of 35-55 nM) but exhibited no meaningful activity in a variety of PG-sensitive tissue and cell preparations. Its activity seemed unrelated to FP receptor stimulation according to the following evidence. 1) Bimatoprost exhibited no meaningful activity in tissues and cells containing functional FP receptors. 2) Bimatoprost activity in the cat lung parenchyma is not species-specific because its potent activity in this preparation could not be reproduced in cells stably expressing the feline FP receptor. 3) Radioligand binding studies using feline and human recombinant FP receptors exhibited minimal competition versus [(3)H]17-phenyl PGF(2a) for Bimatoprost. 4) Bimatoprost pretreatment did not attenuate PGF(2alpha)-induced Ca(2+) signals in Swiss 3T3 cells. 5) Regional differences were apparent for Bimatoprost but not FP agonist effects in the cat lung. Bimatoprost reduced intraocular pressure in ocular normotensive and hypertensive monkeys over a 0.001 to 0.1% dose range. A single-dose and multiple-dose ocular distribution/metabolism studies using [(3)H]Bimatoprost (0.1%) were performed. Within the globe, bimatoprost concentrations were 10- to 100-fold higher in anterior segment tissues compared with the aqueous humor. Bimatoprost was overwhelmingly the predominant molecular species identified at all time points in ocular tissues, indicating that the intact molecule reduces intraocular pressure.

Topics: Amides; Animals; Bimatoprost; Calcium Signaling; Cats; Cloprostenol; Colon; Dinoprost; Eye; Female; Gastric Fundus; Genes, Reporter; Gerbillinae; Glaucoma; Humans; Ileum; In Vitro Techniques; Inositol Phosphates; Intraocular Pressure; Lipids; Luciferases; Mice; Muscle Contraction; Muscle, Smooth; Rats; Receptors, Prostaglandin

Connective tissue growth factor (CTGF) and Cyr61 (cysteine-rich angiogenic protein 61) are members of the CCN gene family that encode multifunctional, extracellular matrix-associated signaling proteins. Because the mechanism of action of certain anti-glaucoma drugs involves extracellular matrix remodeling of ocular ciliary muscle, with a resultant increase in drainage of aqueous humor from the eye, we compared the effects of three pharmacologically distinct ocular hypotensive agents on Cyr61 and CTGF gene expression. Thus, prostaglandin F2alpha (PGF2alpha) (FP receptor agonist), Butaprost (EP2 receptor agonist), and Bimatoprost (a prostamide) were compared. Using Affymetrix gene chip technology, we first identified that PGF2alpha dramatically up-regulated Cyr61 and CTGF mRNA expression in HEK 293/EBNA cells (hFP-HEK 293/EBNA). Northern blot further confirmed the Cyr61 and CTGF up-regulation is in a dose- and time-dependent manner. PGF2alpha-induced up-regulation of Cyr61 appeared to exclusively involve the Rho pathway, and up-regulation of CTGF was via multiple intracellular pathways. Because prostamide receptors are, to date, defined only at the pharmacological level, Bimatoprost effects on Cyr61 and CTGF were studied in the isolated feline iris sphincter preparation, a tissue highly responsive to prostamides. Both PGF2alpha and Bimatoprost up-regulated Cyr61 mRNA expression in the cat iris tissue. Only PGF2alpha up-regulated CTGF mRNA expression in the cat iris. Therefore, PGF2alpha and Bimatoprost appear to interact with different receptors populations in the cat iris, according to their markedly different effects on CTGF. Activation of prostaglandin EP2 receptors (Gs-coupled) also up-regulated Cyr61 but not CTGF mRNA expression in the isolated cat iris. Similar data were observed in human primary ciliary smooth muscle cells. Thus, despite quite different signal transduction pathways, FP receptor stimulation up-regulates CTGF and Cyr61. The prostamide analog Bimatoprost and an EP2-selective agonist affects only Cyr61.

Topics: Alprostadil; Amides; Animals; Bimatoprost; Cats; Cell Line; Cells, Cultured; Ciliary Body; Cloprostenol; Connective Tissue Growth Factor; Cysteine-Rich Protein 61; Dinoprost; Gene Expression; Glaucoma; Humans; Immediate-Early Proteins; In Vitro Techniques; Intercellular Signaling Peptides and Proteins; Iris; Kinetics; Lipids; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; RNA, Messenger; Signal Transduction; Trabecular Meshwork; Up-Regulation

Topics: Amides; Bimatoprost; Cloprostenol; Dinoprost; Glaucoma; Humans; Intraocular Pressure; Laser Therapy; Latanoprost; Lipids; Practice Guidelines as Topic; Prostaglandins F, Synthetic; Travoprost; United States

To report angiographically documented cystoid macula edema associated with the use of each of the three newly available ocular hypotensive lipids: unoprostone, travaprost, and bimatoprost.. Observational case series.. Retrospective review of three patients in a clinical practice who had uncontrolled glaucoma on maximal tolerable therapy except for an ocular hypotensive lipids. All three patients also had previous cataract and filtration surgery, and all had an absent or open posterior lens capsule. The patients were informed of the potential risks of cystoid macula edema associated with the use of an ocular hypotensive lipids versus the risks of repeat filtration surgery.. An ocular hypotensive lipids was started in the affected eye in each patient, and the patient was instructed to check visual acuity everyday and report back any change in vision occurred.. Decreased vision of at least two lines caused by angiographically confirmed cystoid macula edema was noted in each of three patients started, respectively, on unoprostone, travaprost, and bimatoprost. The visual acuity returned to baseline, and the cystoid macula edema was angiographically resolved after discontinuation of the ocular hypotensive lipids and the initiation of a topical steroid and non-steroidal anti-inflammatory eyedrops. Until a causal relationship between cystoid macula edema and ocular hypotensive lipids is proved or disproved, caution in their use in high-risk eyes would be prudent.

Topics: Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Bimatoprost; Cloprostenol; Dinoprost; Female; Fluorescein Angiography; Glaucoma; Humans; Intraocular Pressure; Lens Implantation, Intraocular; Lipids; Macular Edema; Male; Phacoemulsification; Retrospective Studies; Trabeculectomy; Travoprost; Visual Acuity

A series of prostaglandin DP agonists containing a 3-oxa-15-cyclohexyl motif was synthesized and evaluated in several in vitro and in vivo biological assays. The reference compound ZK 118.182 (9beta-chloro-15-cyclohexyl-3-oxa-omega-pentanor PGF(2alpha)) is a potent full agonist at the prostaglandin DP receptor. Saturation of the 13,14 olefin affords AL-6556, which is less potent but is still a full agonist. Replacement of the 9-chlorine with a hydrogen atom or inversion of the carbon 15 stereochemistry also reduces affinity. In in vivo studies ZK 118.182 lowers intraocular pressure (IOP) upon topical application in the ocular hypertensive monkey. Ester, 1-alcohol, and selected amide prodrugs of the carboxylic acid enhance in vivo potency, presumably by increasing bioavailability. The clinical candidate AL-6598, the isopropyl ester prodrug of AL-6556, produces a maximum 53% drop in monkey IOP with a 1 microg dose (0.003% w/w) using a twice-daily dosing regime. Synthetically, AL-6598 was accessed from known intermediate 1 using a novel key sequence to install the cis allyl ether in the alpha chain, involving a selective Swern oxidative desilylation of a primary silyl ether in the presence of a secondary silyl ether. In this manner, 136 g of AL-6598 was synthesized under GMP conditions for evaluation in phase I clinical trials.

Topics: Administration, Topical; Animals; Antihypertensive Agents; Dinoprost; Glaucoma; Haplorhini; Intraocular Pressure; Molecular Structure; Protein Binding; Rabbits; Receptors, Prostaglandin; Structure-Activity Relationship

Rescula (0.12% unoprostone isopropyl) is the first docosanoid compound approved for treatment of glaucoma in humans. It is commercially available in Japan, and is undergoing clinical testing elsewhere. The aim of this study was to evaluate the effect of Rescula on intraocular pressure (IOP) in normotensive dogs. After establishing a baseline diurnal IOP curve, six dogs were unilaterally treated with Rescula while the contralateral eye was treated with a placebo. Applanation tonometry was performed in both eyes, and pupil size was evaluated, 30 min after treatment, and at 1-hr intervals for the next 9 hr. Rescula caused a significant (p=0.014) and long-lasting decrease in IOP, from 20.49+/-2.02 mm Hg in control eyes to 15.49+/-0.69 mm Hg in treated eyes. These results suggest that Rescula is potentially efficacious in treatment of canine glaucoma.

Topics: Animals; Dinoprost; Dog Diseases; Dogs; Fatty Acids; Glaucoma; Intraocular Pressure; Ophthalmic Solutions; Random Allocation; Tonometry, Ocular

Topics: Administration, Topical; Adult; Ciliary Body; Corneal Edema; Dinoprost; Female; Glaucoma; Humans; Intraocular Pressure; Laser Therapy; Latanoprost; Ocular Hypertension; Prostaglandins F, Synthetic; Retinitis Pigmentosa

Corneal epithelial disorders due to isopropyl unoprostone (unoprostone) eye drops, a prostaglandin F2alpha-related substance and antiglaucoma agent, have been reported since the agent became commercially available. The in vitro study was performed to clarify the mechanism of cell injury due to unoprostone. After Chang's human conjunctival cells were cultured and exposed for 2, 4 and 8 min to 0.03, 0.06, and 0.12% unoprostone and its vehicle containing 1% polysorbate 80, a cell growth assay and DNA histogram analysis using a flow cytometer and scanning electron microscopy were performed. The number of living cells was reduced, and the floating cell number increased immediately after exposure to 0.12% unoprostone for 8 min. When the cells were cultured for another 48 hr after exposure to unoprostone, the cell number was reduced dose and time dependently. Exposure for 2 min to 0.12% unoprostone showed no effect on the cell cycle. However, exposure for 2 min to 0.12% unoprostone caused alteration of the cell surface, such as reduction of microvilli and filopodia. The vehicle did not affect the cell surface or cell growth. These results suggest that clinically instilled eye drops ofunoprostone can affect cell structure, inhibit cell growth, and gradually cause corneal epithelial disorders.

Topics: Cell Division; Cell Survival; Cells, Cultured; Conjunctiva; Dinoprost; DNA; Dose-Response Relationship, Drug; Flow Cytometry; Glaucoma; Humans; Microscopy, Electron, Scanning; Ophthalmic Solutions; Time Factors

Topics: Adrenergic alpha-Agonists; Brimonidine Tartrate; Carbonic Anhydrase Inhibitors; Dinoprost; Glaucoma; Humans; Quinoxalines; Sulfonamides; Thiophenes

Topics: Animals; Astrocytes; Cells, Cultured; CHO Cells; Ciliary Body; Cricetinae; Cricetulus; Dinoprost; Dinoprostone; Glaucoma; Humans; Intraocular Pressure; Lens, Crystalline; Models, Biological; Neuroblastoma; Rabbits; Rats; Receptors, Prostaglandin; Recombinant Fusion Proteins; Transfection; Tumor Cells, Cultured

To present a case in which iris pigmentation developed after treatment with isopropyl unoprostone, an analogue of a prostaglandin metabolite.. Case report.. A Japanese man with dark brown irises, treated unilaterally with isopropyl unoprostone, developed iris-color change in the treated eye after a 20-month treatment.. Isopropyl unoprostone can induce iris pigmentation as does latanoprost.

Topics: Administration, Topical; Dinoprost; Eye Color; Follow-Up Studies; Glaucoma; Humans; Iris; Iris Diseases; Male; Middle Aged; Ophthalmic Solutions

Unoprostone (isopropyl unoprostone) is a docosanoid compound which is related to a metabolite of prostaglandin (PG)F2 alpha. Unoprostone has oculo-hypotensive effects. The drug is thought to lower intraocular pressure (IOP) by increasing aqueous humour outflow. Aqueous humour production remains unaffected. Marked reductions in IOP have been demonstrated in healthy volunteers and patients with glaucoma or ocular hypertension after instillation of unoprostone 0.12%. Unoprostone 0.12% appears to have similar efficacy to timolol 0.5% in patients with primary open-angle glaucoma or ocular hypertension. In phase II and III clinical studies, adverse events observed with unoprostone were predominantly local; systemic effects occurred less frequently.

Topics: Animals; Clinical Trials as Topic; Dinoprost; Glaucoma; Humans

The 15R and 15S epimers of a series of phenyl substituted analogs of 17-phenyl-18,19,20-trinorprostaglandin F2 alpha isopropyl ester [(15S)-3] have been synthesized. The intraocular pressure (IOP) lowering effects and potential side effects of these novel derivatives have been studied in cats and rabbits. In addition, the effects of selected analogues on IOP have been studied in monkeys. Furthermore, we have hydrolyzed some of the isopropyl esters and assessed the ability of the resulting carboxylic acids to contract the cat iris sphincter muscle in vitro. In general, the 15S-derivatives were more active than the 15R-epimers. Derivatives substituted with an acetyl group in the benzene ring appeared to have a better side effect profile as compared to (15S)-3. Furthermore, substitution with an aromatic moiety had a dramatic effect on the activity in that the resulting compounds reduced IOP in cats but had little effect on the pupil diameter. Thus, the activity profile of (15S)-3 may be changed by the introduction of substituents in the benzene ring.

Topics: Animals; Capillary Permeability; Cats; Dinoprost; Glaucoma; Haplorhini; Humans; Intraocular Pressure; Iris; Muscle Contraction; Rabbits; Structure-Activity Relationship

In the preinflammatory phase of S-antigen (S-ag) induced uveitis, an ocular hypotension occurs between day 2 and day 6 after S-ag injection. To better understand this phenomenon, we studied the levels of prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) in the aqueous humor of S-ag injected rats at various time points after induction of disease.. Twenty-five female Lewis rats weighting 150 to 175 gm were injected in the hind foot-pad with 50 micrograms of S-antigen. IOP was measured each day at 9 am with a Tono-Pen tonometer. Aqueous humor was collected at days 0, 2, 4, 6, 9, 14 and 18 after S-ag injection. PGE2 and PGF2-alpha were assayed in the aqueous humor using an enzyme immunoassay method.. The concentration of PGE2 increased after day 6 and peaked at day 14 after S-ag injection (45.6 +/- 9.0 mu/ml vs 1.1 +/- 0.1 mu/ml in controls, P = 0.04). The peak of PGE2 corresponded to the maximum inflammation and ocular hypertension. PGF2-alpha was increased from day 2 to day 6, with a peak at day 6 after S-ag injection (128.0 +/- 51 pg/ml vs 56 +/- 2.0 pg/ml in controls, P = 0.047), which corresponded to the preinflammatory ocular hypotension. A second peak was observed at day 18 after S-ag injection (3643 +/- 824 pg/ml, P = 0.049), which corresponded to the cessation of intraocular inflammation and ocular hypertension.. The early increased concentration of PGF2-alpha in the aqueous humor of rats with S-ag induced uveitis may explain the ocular hypotension observed from day 2 to day 6 after S-ag injection.

Topics: Animals; Aqueous Humor; Dinoprost; Dinoprostone; Female; Glaucoma; Intraocular Pressure; Rats; Rats, Inbred Lew; Uveitis

Topics: Animals; Dinoprost; Glaucoma; Haplorhini; Humans; Intraocular Pressure; Latanoprost; Prostaglandins F, Synthetic; Prostaglandins, Synthetic; Rabbits

A novel series of prostaglandin F2 alpha (PGF2 alpha) prodrugs, with acyl ester groups at the 9, 11, and 15 positions, was prepared in order to design clinically acceptable prostaglandins for treating glaucoma. Studies involving isolated esterases and ocular tissue homogenates indicated that 9-acyl esters cannot provide a prodrug since PGF2 alpha would not be formed as a product. In contrast, 11-mono, 15-mono, and 11, 15-diesters were converted to PGF2 alpha in ocular tissues and could, therefore, be considered as prodrugs of PGF2 alpha. Carboxylesterase (CE) appeared critically important for the hydrolytic conversion of those PGF2 alpha prodrugs where the 11 or 15-OH group was esterified and such prodrugs were not substrates for acetylcholinesterase (ACHE) or butyrylcholinesterase (BuCHE). The enzymatic hydrolysis of PGF2 alpha-1-isopropyl ester was also investigated for comparative purposes. This PGF2 alpha prodrug was a good substrate for CE, but was also hydrolysed by BuCHE, albeit at a much slower rate. The most striking feature of the enzymatic hydrolysis of PGF2 alpha-1-isopropyl ester in ocular tissue homogenates was that it was much faster than for prodrugs esterified at the 11 and/or 15 positions. In terms of ocular hypotensive activity, all prodrugs which showed detectable conversion to nascent PGF2 alpha were potent ocular hypotensives. Although no separation of ocular hypotensive and ocular surface hyperaemic effects was apparent for PGF2 alpha-1-isopropyl ester, a temporal separation of these effects was apparent for the novel PGF2 alpha ester series. This difference may reflect an unfavourably rapid conversion of PGF2 alpha-1-isopropyl ester in ocular surface tissues compared with anterior segment tissues.

Topics: 3T3 Cells; Animals; Calcium; Dinoprost; Drug Design; Eye; Female; Glaucoma; Hydrolysis; Hyperemia; Intraocular Pressure; Male; Mice; Prodrugs; Rabbits

A series of phenyl-substituted analogues of prostaglandin F2 alpha (PGF2 alpha) were prepared and evaluated for ocular hypotensive effect and side effects in different animal models. In addition, the activity of the analogues on FP receptors was studied in vitro. The results were compared with those of PGF2 alpha and its isopropyl ester. The phenyl-substituted PGF2 alpha analogues exhibited good intraocular pressure reducing effect, were more selective, and exhibited a much higher therapeutic index in the eye than PGF2 alpha or its isopropyl ester. The analogues exhibited high activity on FP receptors in a stereoselective manner for the 15 alpha-hydroxyl group.

Topics: Animals; Cats; Dinoprost; Female; Glaucoma; Intraocular Pressure; Macaca fascicularis; Muscle Contraction; Ophthalmic Solutions; Rabbits; Species Specificity; Structure-Activity Relationship

Topics: 15-Oxoprostaglandin 13-Reductase; Animals; Cornea; Dinoprost; Glaucoma; In Vitro Techniques; Swine

The ophthalmic solution of UF-021, a novel prostaglandin (PG) related compound, was investigated for its intraocular pressure (IOP) reducing activity and local ocular side effects in different species of animals. UF-021 ophthalmic solution (0.03 to 0.24%), when topically applied to the eyes of rabbits, caused dose-dependent IOP reduction (2.8 to 5.2 mmHg), without transient IOP rise. Both in cats and monkeys, UF-021 ophthalmic solution (0.12%) elicited rapid, significant IOP reduction (ca. 9 mmHg and 2 mmHg, respectively), without any controversial, local ocular side effects being revealed. On the other hand, PGE2, PGF2 alpha-isopropyl ester all brought about marked increases in IOP prior to development of their IOP reducing activities. In addition, these primary PGs showed intense local ocular irritation, which presented a striking contrast with UF-021. Enhancement of IOP reducing activity, coupled with freedom from any significant ocular side effects, as described above, suggests that UF-021 ophthalmic solution could be promising as a new anti-glaucoma agent.

Topics: Animals; Cats; Dinoprost; Dinoprostone; Female; Glaucoma; Intraocular Pressure; Macaca; Male; Rabbits

Topical instillations of 1.0, 10, and 20 micrograms/50 microliters of prostaglandin PGA2, 0.5 and 1.0 microgram/50 microliters of PGA2 isopropyl ester, and 0.5, 1.0, 5.0 and 10.0 micrograms/50 microliters of PGF2 alpha isopropyl ester were evaluated in the normal dogs and glaucomatous beagles eyes. Each concentration of drug was evaluated for a seven day period. On Day 1 baseline values were obtained, days 2-4, the drug was instilled (once a day) and on days 5-7 post-treatment values were measured. All concentrations of PGA2 failed to lower intraocular pressure (IOP) in the normal and the glaucomatous (P greater than 0.72) dogs. PGA2 isopropyl ester decreased IOP in the normal dogs and in the glaucomatous beagles (P less than 0.01). The declines in IOP were significant at 1/2 to 1 hour and continued for up to 5 hours. No significant change in IOP occurred in the non-treated fellow eye of the normotensive dog (P less than 0.54) and the glaucomatous beagle (P less than 0.29). All concentrations of PGF2 alpha isopropyl ester significantly decreased IOP in the treated eyes of the normotensive dog (P less than 0.05) and the glaucomatous beagle (P less than 0.01). The significant change in IOP occurred within one hour after the instillation of PGF2 alpha isopropyl ester. The IOP remained lower than the baseline pressures 24 hours post-treatment for both the normotensive and glaucomatous dogs. Maximal change in IOP for normal dogs was a decrease of 9 mm Hg while the glaucomatous beagle had a decrease of 19 mm Hg. No significant change in IOP occurred in the non-treated fellow eye of the normotensive animal (P less than 0.16) and the glaucomatous beagle (P less than 0.40). The side effects of PGF2 alpha isopropyl ester were miosis and mild conjunctival irritation.

Topics: Administration, Topical; Animals; Antihypertensive Agents; Conjunctival Diseases; Dinoprost; Dogs; Female; Glaucoma; Intraocular Pressure; Male; Miosis; Prostaglandins A

The effect of prostaglandin (PG) F2 alpha-isopropyl ester (IE), PGA2, or PGA2-IE on intraocular pressure (IOP) was tested in eight cynomolgus monkey eyes with argon laser-induced glaucoma. Dose-response testing and baseline IOP measurements were done. For multiple dose testing, 5 micrograms in 25 microliters (0.02%) of each PG was topically applied twice daily for 5 days. The IOP was measured at 30- or 60-minute intervals for 6 hours after the morning dose each day. A significant (P less than 0.05) reduction of IOP peaked at 5-9 mm Hg below baseline values on the 5th day of treatment for each PG. The ocular hypotensive effect of these PGs progressively became more pronounced during the course of twice-daily dosing, with a significant reduction maintained at least 17 hours after some doses. No more than trace aqueous flare and no cells were observed in any eye during the course of treatment. These findings demonstrate that PGs other than F2 alpha are potent ocular hypotensive agents in primates.

Topics: Administration, Topical; Animals; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Glaucoma; Intraocular Pressure; Macaca fascicularis; Prostaglandins A

Topics: Administration, Topical; Animals; Aqueous Humor; Clonidine; Dinoprost; Dinoprostone; Disease Models, Animal; Female; Flurbiprofen; Glaucoma; Intraocular Pressure; Laser Therapy; Macaca fascicularis; Pupil

Glaucoma was induced in cynomolgus monkeys by photocoagulating the trabecular meshwork with the argon laser. Repeat treatments were often necessary and wide intraocular pressure fluctuations were characteristic. Baseline intraocular pressure was measured with a calibrated pneumatonometer hourly for six hours. On a succeeding day a baseline measurement was made, 50 microliter of the drug to be tested applied, and six hourly measurements of intraocular pressure repeated. The effects on intraocular pressure of timolol, epinephrine, pilocarpine, vanadate, prostaglandin F2 alpha (PGF2 alpha), forskolin, and corynanthine were tested in at least eight eyes. Significant (p less than 0.05) reductions of intraocular pressure were produced by 0.5% timolol, 2% epinephrine, 4% pilocarpine, 1% vanadate, 500 micrograms of PGF2 alpha and 1% forskolin. Five per cent corynanthine produced no significant lowering of intraocular pressure. Tonography revealed an increased outflow facility associated with the reduction of intraocular pressure 2 hours after the administration of 4% pilocarpine. This glaucoma animal model may be useful in investigating agents that lower intraocular pressure by a variety of mechanisms.

Topics: Administration, Topical; Animals; Colforsin; Dinoprost; Diterpenes; Epinephrine; Glaucoma; Intraocular Pressure; Lasers; Macaca fascicularis; Pilocarpine; Prostaglandins F; Radiation Injuries, Experimental; Sodium Chloride; Timolol; Vanadates; Vanadium; Yohimbine

Topical administration of prostaglandin F2 alpha (PGF2 alpha) produced a reduction in intraocular pressure in eyes of rabbits, cats, and cynomolgus monkeys. In rabbit eyes at 5 or 6 hr, 50 micrograms, 100 micrograms, or 250 micrograms of PGF2 alpha caused a significant intraocular pressure reduction with a small miotic effect. Treatment with 500 micrograms, 750 micrograms, or 1000 micrograms of PGF2 alpha lowered intraocular pressure significantly in cat eyes for at least 24 hr with the development of profound pupillary constriction. Administration of 500 micrograms, 750 micrograms, or 1000 micrograms of PGF2 alpha produced a significant reduction of intraocular pressure in monkey eyes lasting at least 24 hr, with an initial hypertensive phase and a small decrease in pupillary diameter in the treated eyes. Tonography revealed an increased facility of outflow simultaneous with the reduction of intraocular pressure in the eyes of cats and monkeys. These increases of outflow facility could not explain completely the reductions in intraocular pressure. The aqueous humor flow measured by fluorophotometry was unaltered in both species, and possible reasons for this finding are discussed. Anterior chamber aqueous humor protein was significantly higher in cat eyes topically treated with 750 micrograms of PGF2 alpha than in the diluent-treated fellow eyes.

Topics: Animals; Aqueous Humor; Cats; Dinoprost; Glaucoma; Macaca fascicularis; Prostaglandins F; Pupil; Rabbits

Topical application of a single dose of 1.0 mg prostaglandin F2 alpha (PGF2 alpha) onto the cornea of five trained owl monkeys (Aotus trivirgatus) caused a prolonged and highly significant ocular hypotony. The intraocular pressure (IOP) of the treated eye was 4.7 +/- 0.9 mm Hg below that of the control eye 18 to 24 hr after PGF2 alpha application and remained significantly reduced for over 72 hr. Miosis, aqueous flare, and accumulation of cells in the anterior chamber were minimal in extent. The hypotensive effect of PGF2 alpha was even more pronounced when applied to a glaucomatous owl monkey eye with angle recession, which had IOPs consistently in the 45 to 55 mm Hg range (mean: 47.2 +/- 0.7) as measured periodically over a one-year period. The application of a single dose of 1.0 mg of PGF2 alpha to this hypertensive eye reduced IOP by over 25 mm Hg within 4 hr, with a relative hypotony lasting for at least 6 days. These results show that topical application of certain PGs to normotensive or hypertensive primate eyes can cause a long lasting and highly significant decrease in IOP, and suggest that prostaglandins or their analogues may aid in the therapeutic control of ocular hypertension and glaucoma.

Topics: Administration, Topical; Animals; Aotus trivirgatus; Dinoprost; Glaucoma; Intraocular Pressure; Male; Prostaglandins F; Time Factors