latanoprost and Melanosis

This review summarizes the Ernst H. Bárány Prize Lecture given at the meeting of the International Society of Eye Research in Geneva 2002. In the paper the path from the author's early studies on neurogenic inflammation in the eye to the search for a suitable prostaglandin analogue for glaucoma treatment, and the development of latanoprost are described. In particular the solution to the nociceptive and hyperemic side-effects of naturally occurring prostaglandins in the eye, the mechanism of action of FP prostanoid receptor agonists as well as the selection of dose for glaucoma treatment are discussed. In addition, pharmacokinetical aspects of latanoprost, and the melanogenic side-effect of prostaglandins in the iris are addressed. The paper is primarily focused on studies performed by the author and complete reference to other previous, or contemporary studies is therefore not always given as the purpose is not to present a comprehensive review article.

Topics: Dose-Response Relationship, Drug; Eye Color; Glaucoma; Humans; Intraocular Pressure; Latanoprost; Melanosis; Neurogenic Inflammation; Prostaglandins F, Synthetic; Prostaglandins, Synthetic

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 introductory overview considers the advantages of a class of local hormones-the prostaglandins (PGs)-for the management of intraocular pressure (IOP) in glaucoma, over agonists and antagonists of neurotransmitters that dominated this field in the 20th century. PGs and PG analogues, in particular esterified prodrug forms of PGF2 alpha, are effective ocular hypotensive agents, but cause some conjunctival hyperemia and corneal sensory irritation at higher concentrations. Based on structure-activity studies, a 17-phenyl PGF2 alpha prodrug, latanoprost (PhXA41), was found to have a greatly improved therapeutic index, without compromising the ocular hypotensive potency of PGF2 alpha prodrugs. The IOP lowering mechanism of such PGF2 alpha s, increased uveoscleral outflow, can be expected to have great physiologic advantages, especially with respect to normal tension glaucoma, over most currently used ocular hypotensive drugs. The introduction of this new approach has already led to a new insight into the control and clinical significance of this outflow route. Similarly, the newly discovered ocular side effect, PG-induced increase in iridial pigmentation, can be expected to provide insight into the oculo-protective role of iridial melanocytes and into the punative association between a decline in the ocular melanin system and the vulnerability of the eye to some age-related diseases.

Topics: Animals; Eye Color; Glaucoma; Humans; Intraocular Pressure; Iris Diseases; Latanoprost; Melanosis; Prostaglandins F, Synthetic

To investigate the incidence of iridial pigmentation induced by latanoprost ophthalmic solution in Japanese glaucoma patients by a prospective and observer-masked study.. Sixty-nine eyes of 69 glaucoma patients were included. Patients who had undergone intraocular surgery, laser trabeculoplasty, and laser iridotomy within 12 months before enrollment, and patients with history of uveitis and any changes in antiglaucoma drugs within 6 months before enrollment were excluded. Iridial photographs were taken by one examiner under the same conditions at 1, 3, and 6 months after the initiation of latanoprost treatment. Three glaucoma specialists, masked of patient information, independently assessed the iridial pigmentation. Cases with iridial pigmentation diagnosed by three specialists were categorized as showing a definite increase in iridial pigmentation.. A definite increase in iridial pigmentation occurred in 3.5%, 9.7%, and 35.0% of eyes within 1, 3, and 6 months of treatment, respectively. Age, gender, or concomitantly used eyedrops did not significantly influence the incidence of iridial pigmentation within 6 months of instillation. A reduction of intraocular pressure by latanoprost did not differ significantly between patients with and without iridial pigmentation.. The incidence of iridial pigmentation by latanoprost ophthalmic solution in Japanese patients was higher than previously reported values in pigmented races.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Eye Color; Female; Glaucoma; Humans; Incidence; Intraocular Pressure; Iris; Iris Diseases; Japan; Latanoprost; Male; Melanosis; Middle Aged; Ophthalmic Solutions; Prospective Studies; Prostaglandins F, Synthetic

Latanoprost, a phenyl-substituted analogue of prostaglandin F2 alpha administered as eye drops, induces increased melanogenesis in the iridial melanocytes of monkeys. Similar effects were seen in 12, 23 and 11% of patients in the USA, United Kingdom (UK) and Scandinavia, respectively, during one year of treatment. The highest incidence of induced pigmentation was seen in green-brown, yellow-brown and blue/grey-brown eyes, in that order. The relatively high proportion of patients with green-brown eyes in the UK explains the larger number of affected patients in this country. Typically, a concentric increase of the iris pigmentation appeared after six months (range: 3-17) and was judged to be noticeable by the patient in about 2/3 of the cases. After cessation of latanoprost, no change of the induced pigmentation has been seen in patients followed for two years, and there have been no signs of dispersion of pigment into the anterior chamber. Irides, homogeneously blue, grey, green or brown, were seldom affected. Naevi or freckles on iris, conjunctiva, or eye lids were not affected. It is intriguing that many patients with mixed eye color, particularly the blue-brown eyes, have not developed increased pigmentation even during two years of treatment. This could be due to a relatively slow melanogenesis or to refractory melanocytes in these individuals.

Topics: Adrenergic beta-Antagonists; Double-Blind Method; Europe; Eye Color; Glaucoma; Humans; Incidence; Intraocular Pressure; Iris; Iris Diseases; Latanoprost; Melanins; Melanosis; Ophthalmic Solutions; Prostaglandins F, Synthetic; Time Factors; Timolol; United States

Topics: Antihypertensive Agents; Face; Glaucoma, Open-Angle; Humans; Latanoprost; Melanosis; Prostaglandins F, Synthetic; Skin Pigmentation; Skin Transplantation

To study the histopathological features of latanoprost-treated irides with or without darkening, compared with non-latanoprost-treated irides.. Iridectomy specimens and patient history forms were independently examined by 3 ophthalmic pathologists in a masked fashion. Specimens were evaluated for premalignant changes and for differences in level of pigmentation and degrees of cellularity, inflammation, and vascular abnormalities.. The specimens consisted of 22 latanoprost-treated darkened irides, 35 latanoprost-treated irides without darkening, and 35 non-latanoprost-treated irides. There was a statistically significant decrease in the number of nuclear invaginations and prominent nucleoli in latanoprost-treated darkened irides compared with the other 2 groups (P = .004 and P = .005, respectively). The average thickness and pigmentation of the anterior border layer was greater in the latanoprost-treated darkened irides than in the other 2 groups (P = .03 and P = .02, respectively). The latanoprost-treated darkened irides had increased pigmentation of the stroma (P < .001), stromal fibroblasts (P < .001), melanocytes (P = .005), vascular endothelium (P = .02), and adventitia (P < .001) relative to the other 2 groups.. There is no histopathological evidence of premalignant changes in latanoprost-treated darkened irides. The latanoprost-induced iris color changes are due to a thickening of the anterior border layer and an increased amount of melanin in the anterior border layer and within the stromal melanocytes.

Topics: Antihypertensive Agents; Endothelium, Vascular; Fibroblasts; Glaucoma; Humans; Iridectomy; Iris; Iris Diseases; Latanoprost; Melanins; Melanocytes; Melanosis; Prostaglandins F, Synthetic

Topics: Aged; Antihypertensive Agents; Face; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Latanoprost; Melanoma; Melanosis; Prostaglandins F, Synthetic; Skin Neoplasms; Skin Pigmentation; Skin Transplantation

To evaluate the pharmacological characteristics of AFP-168 (tafluprost), a new prostaglandin (PG) F(2alpha) derivative, we examined its receptor-binding affinities, intraocular pressure (IOP)-lowering effect, effects on aqueous humor dynamics, and stimulating effect on melanogenesis. The receptor-binding profile for AFP-172, a carboxylic acid of AFP-168, was determined by measuring muscle contractions in an organ bath, inhibition of platelet aggregation, and competitive binding of a radio-labelled ligand. For the IOP-measurement study, ocular normotensive and laser-induced ocular hypertensive cynomolgus monkeys were used, and IOP was measured using a pneumatonograph. For the studies of aqueous humor dynamics, IOP (Goldmann applanation tonometry), fluorophotometry, two-level constant pressure perfusion, and isotope dilution and accumulation techniques were used in ocular normotensive monkeys. The melanin contents in the medium and in the cell bodies of cultured B16-F0 melanoma cells were measured. The affinity for the FP receptor shown by AFP-172 (Ki : 0.4 nm) was 12 times that of PhXA85 ( Ki : 4.7 nm), a carboxylic acid of latanoprost. A single application of AFP-168 at 0.0025% significantly lowered IOP in both ocular normotensive and hypertensive monkeys (3.1 and 11.8 mmHg, respectively, p < 0.01) and latanoprost at 0.005% significantly lowered IOP (2.1 mmHg, p < 0.01 and 9.5 mmHg, p = 0.059 respectively). Once daily instillation of AFP-168 at 0.001, 0.0025, or 0.005% for 5 days in normotensive monkeys significantly reduced IOP not only for a few hours, but also at the drug-trough time 24hr after application. Latanoprost at 0.005% also reduced IOP, but not at the drug-trough time. AFP-168 decreased IOP mainly by increasing uveoscleral outflow by 65% (p < 0.05) and, as sometimes seen with other prostanoids, also increased total outflow facility (33% increase, p < 0.05). In cultured B16-F0 melanoma cells, AFP-172 (100 microM) did not stimulate melanogenesis, but PhXA85 (100 microM) did. These findings indicate that AFP-168 has a high affinity for the prostanoid FP receptor, has potent IOP-lowering effects in both ocular normotensive and hypertensive monkeys that exceed those of latanoprost, and has less stimulating effect on melanogenesis in melanoma cells.

Topics: Animals; Antihypertensive Agents; Aqueous Humor; Binding, Competitive; Cell Line, Tumor; Eye Color; Glaucoma; Guinea Pigs; Intraocular Pressure; Latanoprost; Macaca fascicularis; Male; Melanosis; Prostaglandins F; Prostaglandins F, Synthetic; Protein Binding; Receptors, Prostaglandin

To study the histologic aspects of irises subjected to extended latanoprost treatment.. Prospective, observer-masked study.. Iris biopsies of eyes treated with latanoprost were analyzed (all had a photographically documented increase in iris pigmentation) plus control eyes (untreated with prostanoids) using optical microscopy. PATIENT OR STUDY POPULATION: There were 14 study eyes treated with latanoprost and 8 untreated control eyes.. The morphologic characteristics of the irises.. The irises treated with latanoprost had an increased number of melanocytes with nuclear inclusions, granules of melanin in the vascular walls and the melanocytes and free granules in the stroma compared with control eyes (P = .001, P = .01, P = .004, P = .01, respectively, by the chi(2) test).. Chronic therapy with latanoprost appears to induce more changes in the iris than a simple increase in the melanin content of the melanocytes.

Topics: Aged; Antihypertensive Agents; Biopsy; Exfoliation Syndrome; Eye Color; Female; Glaucoma, Open-Angle; Humans; Inclusion Bodies; Iris; Iris Diseases; Latanoprost; Male; Melanins; Melanocytes; Melanosis; Middle Aged; Prospective Studies; Prostaglandins F, Synthetic

To examine the histopathologic features of iridectomy specimens from patients undergoing glaucoma surgery and to compare histologic abnormalities in a group of patients with a history of latanoprost therapy with those in a group of patients who had no history of prostaglandin therapy (controls).. Iridectomy specimens and patient history forms were submitted to the central Latanoprost Pathology Center. These were independently examined by 3 ophthalmic pathologists in a masked fashion. Specimens were evaluated for malignant, premalignant, and other changes including differences in levels of pigmentation, degrees of cellularity, inflammation, vascular abnormalities, and changes in the iris pigment epithelium.. Specimens were received from 449 patients with a history of latanoprost treatment and 142 patients who had no history of treatment with latanoprost or other prostaglandin analogues. No evidence of malignant or premalignant changes was found. In latanoprost-treated irides, the prevalence of iris freckles was higher (P = .001) than in control irides, as was the combined number of stromal fibroblasts and melanocytes (P<.001). In a subgroup of specimens received through June 2002, there was no significant difference in mean melanocyte counts (P=.35) obtained by immunohistochemical staining techniques between the latanoprost-treated and control groups.. These findings support previous studies indicating that latanoprost-induced eye color changes are due to an increased amount of melanin within the iris stromal melanocytes. The increased numbers of freckles may be a focal manifestation of this effect.

Topics: Antihypertensive Agents; Eye Color; Female; Glaucoma; Humans; Intraocular Pressure; Iridectomy; Iris; Latanoprost; Male; Melanins; Melanocytes; Melanosis; Prostaglandins F, Synthetic

To report the histopathologic and immunohistochemical findings from the iridectomy specimen of a patient with acquired unilateral iris heterochromia due to latanoprost.. A 45-year-old woman with open-angle glaucoma and unilateral iris heterochromia was evaluated for uncontrolled intraocular pressure increase. Subsequently, the patient underwent trabeculectomy with mitomycin C and an iridectomy specimen was obtained for analysis.. The histopathologic analysis of the iridectomy specimen did not reveal any nuclear atypia, nuclear crowding, or mitotic figures. Immunohistochemical studies showed that the iris melanocytes were negative for HMB45 and S-100, and weakly positive for Melan A.. Latanoprost-associated iris color change may exhibit a diffuse, uniform, dark velvet-brown appearance, thereby simulating diffuse iris melanoma. Histopathologic and immunohistochemical analysis confirmed the benign characteristics of the affected iris melanocytes.

Topics: Antihypertensive Agents; Diagnosis, Differential; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Iris; Iris Diseases; Latanoprost; Melanosis; Middle Aged; Mitomycin; Prostaglandins F, Synthetic; Trabeculectomy

Latanoprost, a new ocular hypotensive prostaglandin F2 alpha analogue prodrug, was found to induce increased pigmentation of monkey irides in chronic toxicity studies. This prompted us to investigate the effect of naturally occurring prostaglandins on the monkey iris to determine whether this pigmentary effect is unique for latanoprost or whether it is a class effect of prostaglandins. PGF2 alpha-isopropyl ester (IE), PGE2-IE and latanoprost were applied topically to cynomolgus monkey eyes for 18-44 weeks. One eye of each animal was treated, while the other served as control. In addition, latanoprost was applied to sympathectomized monkey eyes. PGF2 alpha-IE, PGE2-IE, as well as latanoprost, induced increased pigmentation in the monkey eye. The first signs of this effect were seen after about two months of treatment. Latanoprost also induced increased pigmentation in sympathectomized eyes. It is concluded that both naturally occurring prostaglandins and their synthetic analogues can induce increased iridial pigmentation in cynomolgus monkeys, and that the effect does not require the presence of sympathetic nerves.

Topics: Administration, Topical; Animals; Dinoprost; Dinoprostone; Eye Color; Iris; Iris Diseases; Latanoprost; Macaca fascicularis; Melanosis; Ophthalmic Solutions; Pigment Epithelium of Eye; Prostaglandins; Prostaglandins F, Synthetic; Sympathectomy