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    • SURVEY OF OPHTHALMOLOGY VOLUME 53  SUPPLEMENT 1  NOVEMBER 2008Update on the Mechanism of Action of TopicalProstaglandins for Intraocular Pressure ReductionCarol B. Toris, PhD,1 B’Ann T. Gabelt, MS,2 and Paul L. Kaufman, MD21 Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA;and 2Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, USA Abstract. A decade has passed since the first topical prostaglandin analog was prescribed to reduce intraocular pressure (IOP) for the treatment of glaucoma. Now four prostaglandin analogs are available for clinical use around the world and more are in development. The three most efficacious of these drugs are latanoprost, travoprost, and bimatoprost, and their effects on IOP and aqueous humor dynamics are similar. A consistent finding is a substantial increase in uveoscleral outflow and a less consistent finding is an increase in trabecular outflow facility. Aqueous flow appears to be slightly stimulated as well. Prostaglandin receptors and their associated mRNAs have been located in the trabecular meshwork, ciliary muscle, and sclera, providing evidence that endogenous prostaglandins have a functional role in aqueous humor drainage. Earlier evidence found that topical PG analogs release endogenous prostaglandins. One well-studied mechanism for the enhancement of outflow by prostaglandins is the regulation of matrix metalloproteinases and remodeling of extracellular matrix. Other proposed mechanisms include widening of the connective tissue-filled spaces and changes in the shape of cells. All of these mechanisms alter the permeability of tissues of the outflow pathways leading to changes in outflow resistance and/or outflow rates. This review summarizes recent (since 2000) animal and clinical studies of the effects of topical prostaglandin analogs on aqueous humor dynamics and recent cellular and molecular studies designed to clarify the outflow effects. (Surv Ophthalmol 53:S107--S120, 2008. Ó 2008 Elsevier Inc. All rights reserved.) Key words. aqueous humor  intraocular pressure  matrix metalloproteinases  prostaglandin  trabecular outflow  uveoscleral outflowAll of the clinically available drugs for the treatment through the uveoscleral outflow pathway but signif-of elevated intraocular pressure (IOP) have direct icant effects on trabecular outflow facility also haveeffects on one or more parameters of aqueous been reported.67,85 Three PGF2a analogs (bimato-humor dynamics. IOP usually is reduced by slowing prost, latanoprost, and travoprost) are approved forthe production rate of aqueous humor, by de- glaucoma therapy in the United States, one addi-creasing the resistance to flow through the trabec- tional analog (unoprostone) is prescribed in Japanular meshwork, by increasing drainage through the and a new analog (tafluprost) is in clinical trials inuveoscleral outflow pathway, or by a combination of Japan. Travoprost and latanoprost are ester pro-these mechanisms. Currently, the most effective drugs of PGF2a. Bimatoprost is the amide prodrugoutflow drugs approved for clinical use are prosta- of 17-phenyl-PGF2a86 and has been classifiedglandin (PG) F2a analogs. These drugs reduce IOP by some as a prostamide,86 although this classifica-by stimulation of aqueous humor drainage primarily tion has been somewhat controversial.7,37,56--58,86,87 S107Ó 2008 by Elsevier Inc. 0039-6257/08/$--see front matterAll rights reserved. doi:10.1016/j.survophthal.2008.08.010
    • S108 Surv Ophthalmol 53 (Suppl 1) November 2008 TORIS ET ALUnoprostone is an analog of a pulmonary metabo- agonists butaprost44 and 8-iso PGE223 (Table 1).lite of PGF2a and sometimes labeled a docosanoid.26 Exceptions do exist. One drop of 17-phenyl trinor 8-Tafluprost is a difluoroprostaglandin derivative of iso PGE2 and the selective EP4 receptor agonist 3,7-PGF2a.62 Agonists of DP, EP, and TP receptors have dithia PGE1 increased outflow facility sufficiently inbeen or are being investigated in animal models for normotensive monkey eyes to account for most, iftheir IOP efficacy and potential as new glaucoma not all of the IOP reduction (Kharlamb, ARVO 2004therapeutic drugs. None of these agonists has yet to abstract 1035, Table 1). An older study found anbe approved for clinical use. increase in outflow facility at 4 hours after one This review summarizes recent (since 2000) topical drop of PGF2a.35animal and clinical English-language studies of the One potential reason for the apparent differenceseffects of topical PG agonists on aqueous humor in trabecular outflow facility effect among thedynamics and recent cellular and molecular studies various PG agonists is the method of measurement.designed to clarify the outflow effects. Two noninvasive methods, tonography and fluoro- photometry, and two invasive methods, two-level constant pressure perfusion and isotope accumula- Aqueous Humor Dynamics tion, are used to make the assessment. All methods measure trabecular outflow facility, but confound- Latanoprost, travoprost, and bimatoprost pro- ing factors are known to exist, including ocularduce similar increases in uveoscleral outflow of rigidity (a measure of eye stiffness), pseudofacilityseveral-fold. Increases in trabecular outflow facility (the facility of flow of aqueous humor from thealso have been reported but this finding has not posterior to anterior chamber resulting from thebeen found consistently (Table 1). Unoprostone, probe-induced increase in IOP), and uveoscleralthe least efficacious of the four compounds, appears outflow facility. The name of the measured variableto have little effect on uveoscleral outflow in trabecular outflow facility is not entirely accuratehumans. Rather it works mainly by increasing because of the inclusion of these other factors intrabecular outflow facility.69 The new fluoroprosta- the various measurements. All of the measurementglandin F2a, tafluprost, increases uveoscleral outflow techniques assume that uveoscleral outflow facility isand aqueous flow in monkeys62 but has yet to be very small and affected little by the measurementstudied in humans. Earlier studies13,89 have re- itself. This assumption is based on monkey stud-ported that the topical PG analogs release endoge- ies8,68 reporting that uveoscleral outflow is relativelynous prostaglandins that may contribute to the pressure-independent. However, if an experimentalobserved ocular hypotensive effects. Tafluprost in manipulation were to increase uveoscleral outflowmice reportedly works in part through FP receptor- facility, this could be interpreted erroneously, as anmediated prostaglandin production acting through increase in trabecular outflow facility. It is thoughtthe prostanoid EP3 receptor.49 Studies published by some that PGs increase uveoscleral outflowbetween 2000 and 2008 of FP, DP, and EP receptor facility but this has yet to be proven experimentally.agonists and their effects on aqueous humor These methods may not detect changes in trabecu-dynamics in humans and nonhuman primates are lar outflow facility if the changes are overshadowedsummarized in Table 1. Studies predating 2000 are by strong effects on uveoscleral outflow and/orfound in an earlier review.67 uveoscleral outflow facility. The length of time of treatment could be anotherTRABECULAR OUTFLOW FACILITY factor contributing to the differing effects of PGs on Trabecular outflow facility is not always increased trabecular outflow facility. The immediate IOPfollowing topical treatment with PG analogs but effects that occur from a single dose of a PG analogevidence is building that the effect is real and not may be mediated by cellular mechanisms differentunique to any one drug of this class. Latanoprost, from those that occur after repeated applications ortravoprost, bimatoprost, and unoprostone all have continuous exposure.9,83,90 Therefore, findingsbeen found to significantly increase trabecular from multiple doses of each PG should be com-outflow facility in at least one clinical study pared before concluding that one PG analog acts(Table 1). through mechanisms different from all others. Compared to humans, the trabecular meshwork Mice are being used with increasing frequency toof monkeys seems to be less affected by PG analogs. evaluate aqueous humor dynamics because of theirTrabecular outflow facility was unchanged following potential for genetic manipulation in addition tomultiple topical treatments of monkeys with PGF2a- their ocular similarities to humans. These animalsisopropyl ester,22 tafluprost,62 and travoprost,71 the exhibit increases in outflow facility 2 hours after oneDP receptor agonist AL-6598,72 and EP receptor 4-ml drop of latanoprost.18 Several limitations to
    • TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS TABLE 1 Studies of Aqueous Humor Dynamics in Humans and Nonhuman Primates Treated with Prostaglandin Analogs Published from 2000 to 2008 Type and Number Duration ofAnalog of Subjects Treatment IOP Fa C Pev Fu ReferenceFP receptor analogs, prostamidesBimatoprost ONT volunteers QD Â 2 days Y(day) [(day) [day [day Brubaker et al, 200111 (n 5 25) QD Â 3 days Y(night) [(night) OHT or POAG patients QD Â 7 days Y 4 [ [ Christiansen et al, (n 5 29) 200416 ONT volunteers QD Â 7 days Y 4 [ [ Lim et al, 200838 (n 5 30)Latanoprost OHT patients (n 5 30) QD Â 7 days Y 4 4 4 [ Toris et al, 200173 OHT or POAG patients QD Â 14 days Y 4 [ Dinslage et al, 200420 (n 5 30) ONT volunteers QD Â 7 days Y 4 [ [ Lim et al , 200838 (n 5 30)15-keto latanoprost Cynomolgus, ONT One drop Y 4 4 Wang et al, 200777 monkeys (n 5 30)Travoprost OHT & POAG patients QD Â 17 days Y(day and night) 4 [(day) 4 [(marginally Toris et al, 200770 (n 5 26) insignificant) ONT volunteers QD Â 7 days Y 4 [ [ Lim et al, 200838 (n 5 30) cynomolgus BID Â 3 days Y 4 4 [a Toris et al, 200571 monkeys unilateral OHT (n 5 12)Unoprostone OHT patients (n 5 30) BID 5 days Y 4 [ 4 4 Toris et al, 200469 and 28 daysTafluprost cynomolgus monkeys QD Â 4 to 5 days Y [ 4 Takagi et al, 200462 (n 5 8--12)DP receptor agonistAL-6598 cynomolgus monkeys, BID Â 3 days YONT eye only [ONT eye only 4 [ONT eye only Toris et al, 200672 unilateral OHT (n 5 11)EP2 receptor agonistsButaprost Cynomolgus monkeys, One drop YOHT and ONT 4One drop, 4One drop, ONT [QD Â 5 Nilsson et al, 200644 ONT and OHT or QD Â 5 days ONT days, ONT (n 5 6--8)8-iso PGE2 Cynomolgus monkeys, BID, 9--29 doses Y 4 4Two methods [ Gabelt et al, 200423 ONT (n 5 7--10) S109 (continued on next page)
    • S110 Surv Ophthalmol 53 (Suppl 1) November 2008 TORIS ET AL BID 5 twice daily; Cfl 5 outflow facility determined by fluorophotometry; Fa 5 aqueous flow; Fu 5 uveoscleral outflow IOP 5 Intraocular pressure; OHT 5 ocular hypertension 5 ONT 5 ocular normotension; Pev 5 episcleral venous pressure; POAG 5 primary open angle glaucoma; QD 5 once daily; Y 5 decreased effect; 4 5 no using this animal model should be mentioned. The Kharlamb (ARVO 2004 size of the eye makes accurate measurement Wang (ARVO 2007 difficult. Inflow and outflow are very slow (many- Reference abstract 4803) abstract 1035) fold slower than in humans),1 and changes in flow can be near the limit of detection. Additionally, the anesthesia needed for most measurements quickly and profoundly affects IOP.31 IOPs vary among strains of mice,30 and aqueous humor outflow rates may vary among strains as well. Further research is days, ONT needed to characterize differences in aqueous 4QD Â 5 humor dynamics among the murine strains. Fu UVEOSCLERAL OUTFLOW Pev Increases in uveoscleral outflow have been re- [One drop, ONT ported with topical treatment of bimatoprost and latanoprost in ocular normotensive and hyperten- sive subjects (Table 1).11,16,20,73 Travoprost increased [ C uveoscleral outflow in monkeys71 and marginally increased it in ocular hypertensive patients as well.70 Unoprostone, the weakest of the four prescribed PG analogs, is the only one that did not affect uveoscleral outflow in humans despite 5 days of drop, ONT twice-daily dosing.69 Fa Multiple topical drops of agonists for FP receptors YOHT and ONT, 4One (tafluprost62), DP receptors (AL-659872), and EP2 4 receptors (butaprost44 and 8-iso PGE278) increased uveoscleral outflow in monkeys (Table 1). In contrast, one drop of the EP4 agonist 3,7-dithia PGE1 had no effect on uveoscleral outflow in IOP monkeys (Kharlamb et al, unpublished data, ab- stract 1035 presented at the 2004 ARVO annual meeting). A multiple dose study is needed to clarify Y effect; [ 5 increased effect. Blank cell indicates no data reported. whether the effect persists with repeat dosing. or QD Â 5 days Duration of Treatment One drop One drop AQUEOUS FLOW Most studies investigating aqueous flow have found that PG analogs produce a small (10--15%) increase that may or may not be statistically and OHT (n 5 6--8) Cynomolgus monkeys, Cynomolgus monkeys, Type and Number significant and is not clinically important. A of Subjects significant increase in aqueous flow was found at ONT (n 5 6) night in young healthy Japanese volunteers treated with latanoprost,41 and during the day and at night in healthy predominantly white volunteers treated ONT with bimatoprost.11 Additionally, aqueous flow in- creased during the day in monkeys treated with a DP agonist.72 This effect does not contribute to anyTable 1 (continued ) receptor agonist 3,7-dithia PGE1 reduction in IOP but an increase in aqueous flow 17-phenyl trinor could be considered a healthy side effect of topical selective EP4 8-iso PGE2 PG analogs because aqueous humor carries essential nutrients and removes waste products, crucial for Analog keeping the avascular tissues of the anterior segment healthy.
    • TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS S111EPISCLERAL VENOUS PRESSURE pig organ--cultured anterior segments perfused at Three studies have reported no change in a constant pressure of 15 mm Hg, showed increasedepiscleral venous pressure in patients with ocular outflow by up to 62% at 8 hours after topicalhypertension treated for one week with latanoprost, administration of bimatoprost and by 30% at 5travoprost, or unoprostone (Table 1). The measure- hours after intracameral administration of PGF2a.74ments (made with a commercially available epis- Human trabecular meshwork monolayer cultures6cleral venomanometer, EyeTech, Morton Grove, IL), treated with bimatoprost had a 78% increase inare difficult to make with accuracy and consistency. hydraulic conductivity which also was blocked byNevertheless, because no study found any trend to AGN211334.76suggest a change, it seems reasonable to conclude PGE1 increases outflow facility by 26% in humanthat the PG effect on episcleral venous pressure is organ-cultured anterior segments.19 This effectminimal. probably occurs by an adenylyl cyclase-dependent pathway activated primarily by the predominant EP2 receptors in the trabecular meshwork.32 Stimulation Cellular and Molecular Studies of EP2 receptors in trabecular meshwork is coupled to the activation of high-conductance Caþ2-activatedTRABECULAR MESHWORK Kþ channels (BK) which may contribute to the Organ-cultured anterior segments and trabecular relaxant activity of EP2 agonists in isolated trabec-meshwork cell cultures provide strong evidence that ular meshwork strips.61 However, outflow facility wasPG analogs can alter the resistance in trabecular not stimulated and cAMP production was notoutflow (Table 2). PGs have direct effects on matrix altered after short exposure periods with PGF2a ormetalloproteinases (MMPs), neutral proteases that placebo in human organ-cultured anteriorinitiate degradation of the extracellular matrix and segments.19play a major role in regulating resistance to flow Prostaglandin receptors have been identified inthrough tissues. MMPs are expressed by human human trabecular meshwork tissue but a prostamidetrabecular meshwork2 and directly control outflow receptor has not yet been cloned. The genes for allresistance in human organ-cultured anterior seg- prostanoid receptors are expressed in humanments.9 The activity of MMPs is regulated by tissue trabecular meshwork. Gene expression for the EP2inhibitors of metalloproteinases (TIMPs).10 Cur- receptor is most abundant, followed by FP, TP, IP,rently four TIMPS (TIMP-1, -2, -3, -4) have been and EP4, with DP and EP3 at the lowest levels.32identified in mammals and each TIMP targets Immunofluorescent labeling of FP and EP prosta-specific MMPs.42 In one study,47 cultures of human noid receptor subtypes in normal human trabeculartrabecular meshwork cells treated with latanoprost meshwork tissue showed positive staining for EP1 onacid for 24 hours had increased expression of MMPs trabecular cells of the outer portion of the-1, -3, -17, and -24 and TIMPs -2, -3, and -4. A study6 meshwork and cells lining Schlemm’s canal. EP2of human organ-cultured anterior segments infused was localized to the outer wall and periphery ofwith latanoprost acid found increased outflow Schlemm’s canal. EP3 and EP4 labeling was presentfacility at 24 hours after administration when on trabecular cells along the entire meshwork.compared to control anterior segments (67% vs Moderate expression of FP receptor protein was6%) but no changes in the amount of MMPs or present in the outer portion of the trabecularscleral hydraulic conductivity.6 Histological exami- meshwork and endothelial cells of Schlemm’s canal,nation found regions of focal detachment and loss collector channels and aqueous veins.55of Schlemm’s canal endothelial cells and extracel- Human trabecular meshwork cells in culturelular matrix in some areas of the trabecular express many of the same PG receptors as are foundmeshwork.6 The focal cell loss was reasoned to be in intact tissue. Cultured trabecular meshwork cellsdue to cytoskeletal and focal adhesion changes6 can produce PGE2 and low levels of PGF2a.83,84because PGs in aortic smooth muscle cells cause Additionally, FP receptors have been identified indisassembly of actin stress fibers and inhibition of human trabecular meshwork cells as determined byphosphorylation of paxillin and other focal adhe- the presence of mRNA, protein, and a functionalsion proteins.12 response (increased inositol phosphate accumula- Bimatoprost increases outflow facility by 40% in tion and intracellular calcium release) to PGF2a5human organ-cultured anterior segments within 48 and numerous synthetic FP-selective PG agonists.58hours of treatment. This effect was blocked by PGE2 elicits its biological effects via four G-protein-preincubation with AGN211334, thought to be coupled receptor subtypes which stimulatea prostamide-selective antagonist,76 or , alternatively, phosphoinositide turnover with elevation in intra-an inhibitor of bimatoprost hydrolysis.7 Similarly, cellular-free calcium (EP1 and some EP3), activation
    • TABLE 2 S112 Molecular and Cellular Studies of the Effects of Prostaglandin-Related Compounds on the Aqueous Humor Outflow Pathways Cellular/Molecular Surv Ophthalmol 53 (Suppl 1) November 2008Analog Animal/ Tissue Duration of Treatment Pathway/Effect Events ReferenceTrabecular meshworkPGF2a, fluprostenol trabecular meshwork Up to 2 hours FP receptor mediated Thieme 200664 strips (bovine) inhibition of endothelin-1 contractility; no effect on baseline tension or carbachol-induced contractionPGF2a human trabecular 1 hour FP mediated inositol Anthony 19985 meshwork cells phosphate accumulation; intracellular calcium releasePGF2a human anterior segments 60 minutes per dose outflow facility no change in cAMP Dijkstra 199919 unchanged productionPGF2a, butaprost human trabecular 6 hours upregulate mRNA for Liang 2003,200436,37 meshwork cells Nur77 and connective tissue growth factorBimatoprost human anterior segments 48--72 hour continuous outflow facility increase Wan 200776 infusionBimatoprost human trabecular 48--72 hour continuous hydraulic conductivity Wan 200776 meshwork monolayer infusion increaseBimatoprost human trabecular 6 hours no change in Nur77 Liang 2003, 200436,37 meshwork cells mRNA and connective tissue growth factor expressionbimatoprost acid (B), human trabecular 1 hr (PI turnover); 3 min FP receptor activation: Sharif 200358 latanoprost acid (L), meshwork cells (Ca 2þ mobilization) stimulate travoprost acid (T), phosphoinositide unoprostone (U), turnover PGF2a (P) (B,L,T,U,P)stimulate intracellular Ca 2þ mobilization (T,U,P)latanoprost acid, PGE1 human trabecular 24 hours increase mRNA for MMP- Oh 200646 meshwork cells 1,-3,-17,-24; TIMP-2,-3,-4latanoprost acid; PGE1 human anterior segments 24 hours outflow facility increase; focal detachment and loss Bahler 20086 TORIS ET AL scleral hydraulic of Schlemm’s canal conductivity cells; extracellular unchanged matrix loss; no change in MMPslatanoprost acid human trabecular 9 days in vivo increase insulin growth Zhao 200390 meshwork cells factor-1 gene and fibroleukin gene expression
    • TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICSUnoprostone human trabecular Up to 2 hours decrease activity of L-type Thieme 200565 meshwork cells Ca 2þ channels via tyrosine kinase pathwaysPGE1 human anterior segments 60 minutes increase outflow facility increase cAMP Dijkstra 199919 productionAH13205 human trabecular Less than 10 minutes EP2 agonist activation of Stumpff 200561 meshwork cells BK calcium channelsUveoscleral tissuesPGF2a monkeys multiple topical decrease collagen types I, Sagara 199953 treatments III, IV in ciliary musclePGF2a monkeys multiple topical increase MMP-1,-2,-3 in Gaton 200125 treatments ciliary musclePGF2a monkeys multiple topical scleral permeability increase MMP-1,-2,-3 in Weinreb 200179 treatments scleraPGF2a human sclera explants collagen gelatinization Molik 2006 (ARVO 2006 abstract)PGF2a, latanoprost human sclera 1--3 days increase scleral increase MMP-1,-2,-3 Kim 200133 permeabilityPGF2a, PhXA85 scleral organ cultures 24 hr increase mRNA for MMPs Weinreb 200482 and TIMPxPGF2a, latanoprost acid human ciliary muscle 5 min for ERK1/2, PKC; increase MMP-2 via Husain 200528 cells 4hr for MMP-2 analysis protein kinase C- and extracellular signal regulated protein kinase 1/2- dependent pathwaysPGF2a, latanoprost acid, human ciliary muscle 1hr for PI turnover; 3 min increase mitogen Sharif 200356 bimatoprost acid, cells for Ca2þ mobilization; activated protein kinase travoprost acid 5 min for p42/p44 MAP activity; kinase phosphoinositide hydrolysis; intracellular calcium mobilization; inhibited by FP antagonist AL-8810PGF2a, latanoprost, ciliary muscle tissue 5--10 min increase phospholipase Yousufzai 199689 PhXA85 (several species) A2 and release of arachidonic acid leading to formation of PGE2, PGD2 and PGF2aPGF2a, butaprost human ciliary muscle 6 hours upregulate Nur77 and Liang 2003, 200436,37 cells connective tissue growth factor (Continued on next page) S113
    • Table 2 (continued ) S114 Cellular/Molecular Analog Animal/ Tissue Duration of Treatment Pathway/Effect Events Reference Surv Ophthalmol 53 (Suppl 1) November 2008latanoprost acid human ciliary muscle 24 hours increase mRNA for MMP- Oh 200647 cells 3,-9,-17; increase mRNA for TIMP-3; decrease mRNA for MMP-1,-2,- 12,-14,-15,-16, TIMP-4latanoprost acid human ciliary muscle 24 hours increase MMP-1,-3,-9 Weinreb 200281 cellslatanoprost acid human ciliary muscle Up to 24 hours increase TIMP-1 Anthony 20024 cellslatanoprost acid nonpigmented ciliary Up to 48 hr Cyclooxygenase-2 Hinz 200527 epithelial cells induction leading to increase MMP-1latanoprost acid rats Single topical dose Initial IOP elevation Husain 200629 followed by prolonged IOP reductionlatanoprost acid human ciliary muscle 9 days in vivo decrease aquaporin-1 and Zhao 200390 cells versican gene expression; decrease in mRNA for FP receptorlatanoprost, bimatoprost, monkeys topical treatments for one tissue spaces of ciliary Richter 200352 sulprostone, AH13205 year muscle enlarged and organized; myelinated nerve fiber bundles presentBimatoprost human ciliary muscle 6 hours no change in Nur77 and Liang 2003, 200436,37 cells connective tissue growth factor expression; upregulation of Cyr613,7-dithia PGE1 ciliary muscle tissue No details -- probably less no EP4 mediated Kharlamb, 2006 (ARVO (human and monkey) than 2 hours relaxation 2006 abstract)Genetic studieslatanoprost, travoprost, FP knockout mice single topical treatment IOP decrease FP receptor needed for Ota 200548 bimatoprost, IOP decrease unoprostoneLatanoprost FP knockout mice 7 days topical sclera intact FP receptor gene Crowston 2007 (ARVO needed for 2007 abstract) TORIS ET AL upregulation of MMP- 2,-3,-9latanoprost, travoprost, EP1, EP2, EP3 knockout single topical treatment IOP decrease EP1 and EP2 not involved Ota 200548 bimatoprost, mice in IOP decrease; EP3 unoprostone may have a role IOP 5 intraocular pressure; MMP 5 matrix metalloproteinase; PG 5 prostaglandin; PI 5 phospholipase C-mediated phosphoinositide; TIMP 5 tissue inhibitor ofmetalloproteinase.
    • TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS S115of adenylyl cyclase and elevation of intracellular 2006 ARVO annual meeting), PGF2a and latano-cAMP (EP2 and EP4) or inhibition of adenylyl prost did not.88cyclase (EP3).17,43 Prolonged treatment of human Remodeling of the extracellular matrix within thetrabecular meshwork cells with latanoprost or PGF2a ciliary muscle and sclera is the most thoroughlyethanolamide causes an increase in expression of understood effect of PG treatment. Dissolution ofgenes for insulin-like growth factor-1 (IGF-1) and collagen types I and III within the connective tissue-fibroleukin that could act to increase outflow filled spaces between the outer longitudinallyfacility. IGF-1 is reported to increase the level of oriented muscle bundles39,63 results from PG-stim-MMPs, stromelysin, and gelatinase in trabecular ulated induction of enzymes MMP-1, -2, and -3 inmeshwork cells. The protease activity of fibroleukin the ciliary muscle and surrounding sclera. 25 Long-may be active against a component in the extracel- term (1 year) unilateral treatment of monkey eyeslular matrix.90 with topical bimatoprost, latanoprost, sulprostone Unoprostone free acid (UF-021) shows low (EP3/EP1 agonist) or AH13205 and butaprost (EP2affinity for all prostanoid receptors and weak agonists) found that in all cases the tissue spaces offunctional responses via FP receptor activation.57 the ciliary muscle were enlarged and organized intoSeveral molecular events have been associated with elongated tube-like spaces, covered by endothelial-unoprostone exposure. A reduction in the activity of like cells often in contact with the basementL-type Ca2þ channels via a signal transduction membrane, and contained myelinated nerve fiberpathway was mediated by tyrosine kinases.65 Activa- bundles.44,52 These fluid pathways resembled a kindtion of BK channels by unoprostone free acid of lymphatic system described in the choroid.34inhibited trabecular meshwork contraction leading Changes in the trabecular meshwork also wereto an increase in outflow.66 present. MMP expression in human ciliary body Endothelin-1 is involved in regulating the con- tissue and ciliary muscle cells was determined aftertractility of the trabecular meshwork. FP receptor latanoprost acid treatment for 24 hours. The mRNAagonists can block endothelin-1 induced contractil- of MMP-1, -2, -3, -11, -12, -14, -15, -16, -17, -19, andity of the trabecular meshwork. Evidence indicates -24 as well as TIMP-1 to -4 were found in ciliary bodythis inhibition is mediated by the FP receptor.64 tissue and ciliary muscle cells. Latanoprost increased MMP-3, -9, -17, and TIMP-3 and down-regulated MMP-1, -2, -12, -14, -15, and -16 and TIMP-4.46UVEOSCLERAL TISSUES Latanoprost acid induced a concentration-depen- Immunohistochemistry studies of EP and FP dent increase in MMP-1, -3, and -9 gene transcrip-receptor localization in the uveoscleral tissue in tion81 and a concentration- and time-dependentnormal human donor eyes indicate the presence of increase in TIMP-1 but not TIMP-2 mRNA andEP-1, -2, -3, -4 and FP receptors in the ciliary body protein.4and sclera. FP receptors are most abundant in the Loss of cyclooxygenase (COX)-2 expression in thecircular portion of the ciliary muscle.55 ciliary body of humans has been associated with Several mechanisms have been proposed to glaucoma.40 This association has led to studiesexplain the PG-induced increase in uveoscleral investigating the connection between PGs, COX-2outflow: remodeling of the extracellular matrix of expression and MMPs. Indeed, the IOP-loweringthe ciliary muscle45,53,80 and sclera33,82 (Molik et al, action of latanoprost appears to be associated withunpublished data, abstract 406 presented at the induction of COX-2 and subsequent MMP-1 expres-2006 ARVO annual meeting) causing changes in the sion in human nonpigmented epithelial cells.27permeability of these tissues; widening of the MMP-1 released into the aqueous humor would beconnective tissue-filled spaces among the ciliary expected to flow into the ciliary muscle and throughmuscle bundles,39,63 which may be caused in part the trabecular meshwork and Schlemm’s canal toby relaxation of the ciliary muscle51,75 and changes potentially increase outflow via multiple routes.in the shape of ciliary muscle cells as a result of Studies to elucidate additional cellular mecha-alterations in actin and vinculin localization within nisms associated with PG-induced MMP secretion arethe cells.60 ongoing. PGF2a- and latanoprost-induced secretion Ciliary muscle relaxation has been suggested as and activation of MMP-2 in ciliary muscle cells wereresponsible for the initial reduction in IOP from shown to occur via protein kinase C and extracellulartopical PGs. This does not appear to be the case for signal regulated protein kinase 1/2-dependentall PGs and their agonists. PGE1 and PGE2 relaxed pathways.28 Mitogen-activated protein kinase activityisolated monkey ciliary muscle strips precontracted was stimulated in human ciliary muscle cells withwith carbachol88 but 3,7-dithia PGE1 (Kharlamb et travoprost acid O PGF2a O latanoprost acid Oal, unpublished data, abstract 413 presented at the bimatoprost O latanoprost 5 bimatoprost acid. The
    • S116 Surv Ophthalmol 53 (Suppl 1) November 2008 TORIS ET ALFP antagonist AL-8810 completely inhibited the subtypes in mediating the IOP-lowering response tomitogen-activated protein kinase activity induced by clinical PG analogs. Studies in FP receptor--deficientbimatoprost and bimatoprost acid, indicating that mice have shown that the FP receptor is essential forboth agonists were activating the FP receptor.57 the early IOP-lowering response to topical latano- Inhibition of the latanoprost-induced reduction prost, travoprost, bimatoprost, and unoprostone.48of IOP in rats by thalidomide suggested that the The involvement of the FP receptor in the IOPIOP-lowering response is mediated, in part, through reduction with long-term dosing is unknown.tumor necrosis factor-a-dependent signaling path- Upregulation of MMP-2, -3, -9 and FP mRNA inways. Treatment of human ciliary muscle cells with the sclera following 7 days of topical treatment withtumor necrosis factor-a increased the secretion of latanoprost also was dependent on an intact FPMMP-1, and -2 (Husain et al, unpublished data, receptor gene (Crowston et al, unpublished data,abstract 219 presented at the 2006 ARVO annual abstract 1551 presented at the 2007 ARVO annualmeeting). meeting). EP receptor-deficient mice have been PGF2a can stimulate the formation of endogenous studied in similar ways. When EP1, EP2, and EP3PGs by stimulation of phospholipase A2 and release receptor--deficient mice and their wild-type back-of arachidonic acid for PG synthesis.89 Human ground strain were treated topically with latano-ciliary muscle cells exposed to PGF2a ethanolamide prost, travoprost, bimatoprost, or unoprostone, itor latanoprost for 9 days show a downregulation of was found that EP3 receptors were involved in thethe FP receptor. In the same study, downregulation IOP-lowering response to latanoprost, travoprost,of the aquaporin-1 and versican genes are proposed and bimatoprost at 3 hours after drug administra-to increase flow through the ciliary muscle and tion but EP1 and EP2 receptors were not.50decrease IOP.90 PG-induced changes in the sclera also areimportant in the regulation of uveoscleral outflowand may be used to enhance transscleral delivery of PHARMACOLOGIC DIFFERENCES AMONG THEpeptides and other high-molecular-weight sub- PROSTAGLANDINSstances to the posterior segment of the eye. Five Natural prostaglandins (PGF2a, PGE2, PGD2,days of topical treatment with PGF2a-isopropyl ester PGI2) have the highest affinity for their respectiveincreased MMP-1, -2, and -3 in the sclera of receptors (FP, EP, DP, IP) but are relatively non-monkeys.79 Immunocytochemistry studies and selective for these and other PG receptors (TP) andmRNA analysis of human sclera and cultured their subtypes (DP1, DP2, EP1--4) in receptor-bindinghuman scleral fibroblasts showed the presence of studies.57 Prostamides are also naturally occurringEP1, EP2 and FP receptor subtypes but not EP3 and neutral lipids which have very little activity atEP4 subtypes.3 Human scleral permeability to prostaglandin receptors but, thus far, only pharma-dextrans was measured in an Ussing chamber cologic evidences exists for a prostamide receptor.87following exposure to PGF2a and latanoprost acid The therapeutic derivatives of PGF2a, either amidefor 1--3 days. Scleral permeability increased in a dose- or ester prodrugs, are powerful ocular hypotensiveand time-dependent manner. This was accompanied drugs and either mediate their effects primarily viaby an increase in MMP concentration in the media FP receptor activation or potentially via some yetwith the greatest increases in MMP-2 and -3 unidentified receptor activation.57compared to MMP-1.33 PGF2a and latanoprost acid It has been reported that the prostamide bimato-also induced increases in mRNA for MMPs and prost stimulates neither FP nor EP2 receptors and itsTIMPs in human scleral organ cultures.82 X-ray effects on aqueous humor outflow, although similardiffraction analysis of human scleral explants to latanoprost and travoprost, are accomplished viashowed that incubation in PGF2a-containing media a receptor distinct from these pure FP receptorcaused the collagen helix to undergo gelatinization agonists. However, bimatoprost acid (17-phenylsimilar to what was found after incubation with PGF2a), which is found in the aqueous humor ofMMP-enriched media (Molik et al, unpublished humans after topical application of bimatoprostdata, abstract 406 presented at the 2006 ARVO (Dahlin et al, ARVO 2004 abstract 2096),14,15annual meeting). exhibits a relatively high affinity for three different PG receptors (i.e., FP [Ki 5 83 nM], EP1 [Ki 5 95 nM], EP3 [Ki 5 387 nM]). Bimatoprost acid also exhibits functional activity (phosphoinositide turn-GENETIC STUDIES over) at the EP1 (EC50 5 2.7 nM) and FP (EC50 5 Mice deficient in various PG receptors have been 2.8--3.8 nM) receptors in most cell types.57 Bimato-used to determine the role of prostanoid receptor prost acid is a potent, non-selective PGF2a analog.
    • TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS S117 Unlike PGF2a or the EP2 agonist butaprost, including activation of multiple signaling pathways,bimatoprost did not upregulate orphan nuclear and increased expression of some factors andreceptor (Nur77) or connective tissue growth factor downregulation of others. Genetic studies of knock-(CTNF) expression in human ciliary muscle cells or out mice treated with PGs have found that a re-trabecular meshwork. In addition, the FP antagonist duction in IOP requires intact FP and EP3 receptors.AL-8810 blocked the PGF2a-induced Nur77 mRNA Many questions remain unanswered but progressexpression in human ciliary muscle cells and continues to be made. Prostamide antagonists havetrabecular meshwork indicating PGF2a-induced been described76,87 but this has raised new ques-Nur77 mRNA expression is via the activation of FP tions.7 A prostamide receptor needs to be clonedreceptors.36,37 Bimatoprost induced the upregula- and its biosynthesis enzyme identified to concludetion of Cyr61 (cysteine-rich angiogenic protein 61) that a unique prostamide-sensitive receptor exists.gene expression in cat iris and human ciliary muscle Further work is required to confirm that bimato-cells. Cry61 is involved in regulating extracellular prost acts through this receptor. Multiple-dosingmatrix-associated signaling proteins and may be studies of each PG should be compared beforea unique mechanism by which bimatoprost exerts its concluding that one PG analog acts throughpharmacological action to lower IOP independent mechanisms different from all others. Live animalof Nur77 or CTNF.37 The importance of the and clinical studies are needed to support claimsinduction or lack of induction of these various made by in vitro experiments. Receptor subtypegenes for IOP reduction remains to be determined. selectivity of topical PGs should be identified. TheThe production of transgenic mice lacking these importance of induction or lack of induction ofgenes and their IOP responses to PGF2a, bimato- various genes for IOP reduction needs to beprost, and butaprost is needed. clarified. One day, the current research may lead Bimatoprost appears to reduce the IOP of to future new drugs that exceed the utility of thepatients who are unresponsive to latanoprost,24 PGF2a analogs.suggesting that the prostamide bimatoprost andthe FP receptor agonist latanoprost stimulatedifferent receptor populations. This is consistent Method of Literature Searchwith studies on isolated iridial cells where bimato- These studies, dating between 2000 and 2008prost stimulated an entirely different cell popula- were found from a series of literature searches oftion to those sensitive to PGF2a and bimatoprost PubMed and from the reference lists of theseacid (17-phenyl PGF2a).59 An equally plausible articles. The searches included the following termsexplanation is that some eyes may be deficient in in various combinations: anterior segment organcorneal esterase and thus are not able to adequately culture, aqueous flow, aqueous humor dynamics, bimato-convert the prodrug latanoprost into its free acid prost, ciliary muscle, DP receptor, EP receptor, fluoropho-active form.21 Also splice variants of the FP receptor tometry, FP receptor, latanoprost, matrix metalloproteinase,may exist that have not yet been discovered. Single monkey, ocular, outflow facility, prostaglandins, prosta-nucleotide polymorphisms in the promoter and mide, prostanoid, tafluprost, tonography, travoprost,intron 1 regions of the FP receptor gene are unoprostone, uveoscleral outflow. Original researchcorrelated with the variability in the IOP-lowering articles, review articles, and meeting abstracts areresponse to latanoprost in normal human eyes.54 included in this review. Summary References Clinical and animal studies of aqueous humor 1. Aihara M, Lindsey JD, Weinreb RN: Aqueous humor dynamics in mice. Invest Ophthalmol Vis Sci 44:5168--73,dynamics have reported that PG analogs effectively 2003reduce IOP by enhancing aqueous humor outflow. 2. Alexander JP, Samples JR, Van Buskirk EM, et al: ExpressionThe relative effects of PG analogs on each of the two of matrix metalloproteinases and inhibitor by human trabecular meshwork. 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    • S120 Surv Ophthalmol 53 (Suppl 1) November 2008 TORIS ET AL87. Woodward DF, Liang Y, Krauss AH: Prostamides (prosta- The supplement in which this article is published was glandin-ethanolamides) and their pharmacology. Br J funded by Pfizer. The authors reported no proprietary or Pharmacol 153:410--9, 2008 commercial interest in any product mentioned or concept88. Yamaji K, Yoshitomi T, Ishikawa H, et al: Prostaglandins E1 discussed in this article. The article was supported in part by and E2, but not F2alpha or latanoprost, inhibit monkey unrestricted grants from Research to Prevent Blindness, Inc., ciliary muscle contraction. Curr Eye Res 30:661--5, 2005 New York, NY (C.T., P.K.), NIH/NEI EY002698 (P.K.); NEI P3089. Yousufzai SY, Ye Z: Abdel-Latif AA: Prostaglandin F2 alpha EY016665 (Core Grant for Vision Research) (P.K.); unre- and its analogs induce release of endogenous prostaglan- stricted departmental and Physician-Scientist awards (P.K.); dins in iris and ciliary muscles isolated from cat and other Ocular Physiology Research and Education Foundation (P.K.); mammalian species. Exp Eye Res 63:305--10, 1996 and the Walter Helmerich Chair from the Retina Research90. Zhao X, Pearson KE, Stephan DA, et al: Effects of Foundation (P.K.). prostaglandin analogues on human ciliary muscle and Reprint address: Carol B. Toris, PhD, Department of trabecular meshwork cells. Invest Ophthalmol Vis Sci 44: Ophthalmology, 985840 Nebraska Medical Center, Omaha, NE 1945--52, 2003 68198-5840. e-mail: ctoris@unmc.edu.