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SURVEY OF OPHTHALMOLOGY             VOLUME 53  SUPPLEMENT 1  NOVEMBER 2008




Update on the Mechanism of Action of Topical
Prostaglandins for Intraocular Pressure Reduction
Carol B. Toris, PhD,1 B’Ann T. Gabelt, MS,2 and Paul L. Kaufman, MD2

1
 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 outflow



All 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 have
effects 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 for
the 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 Japan
ular meshwork, by increasing drainage through the               and a new analog (tafluprost) is in clinical trials in
uveoscleral 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 prodrug
outflow drugs approved for clinical use are prosta-              of 17-phenyl-PGF2a86 and has been classified
glandin (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

                                                           S107
Ó 2008 by Elsevier Inc.                                                                      0039-6257/08/$--see front matter
All rights reserved.                                                                    doi:10.1016/j.survophthal.2008.08.010
S108    Surv Ophthalmol 53 (Suppl 1) November 2008                                               TORIS ET AL

Unoprostone 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 in
been or are being investigated in animal models for     normotensive monkey eyes to account for most, if
their IOP efficacy and potential as new glaucoma         not all of the IOP reduction (Kharlamb, ARVO 2004
therapeutic drugs. None of these agonists has yet to    abstract 1035, Table 1). An older study found an
be approved for clinical use.                           increase in outflow facility at 4 hours after one
   This review summarizes recent (since 2000)           topical drop of PGF2a.35
animal and clinical English-language studies of the        One potential reason for the apparent differences
effects of topical PG agonists on aqueous humor         in trabecular outflow facility effect among the
dynamics 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 ocular
duce similar increases in uveoscleral outflow of
                                                        rigidity (a measure of eye stiffness), pseudofacility
several-fold. Increases in trabecular outflow facility
                                                        (the facility of flow of aqueous humor from the
also have been reported but this finding has not
                                                        posterior to anterior chamber resulting from the
been found consistently (Table 1). Unoprostone,
                                                        probe-induced increase in IOP), and uveoscleral
the least efficacious of the four compounds, appears
                                                        outflow facility. The name of the measured variable
to have little effect on uveoscleral outflow in
                                                        trabecular outflow facility is not entirely accurate
humans. Rather it works mainly by increasing
                                                        because of the inclusion of these other factors in
trabecular outflow facility.69 The new fluoroprosta-
                                                        the various measurements. All of the measurement
glandin F2a, tafluprost, increases uveoscleral outflow
                                                        techniques assume that uveoscleral outflow facility is
and aqueous flow in monkeys62 but has yet to be
                                                        very small and affected little by the measurement
studied 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 relatively
nous prostaglandins that may contribute to the
                                                        pressure-independent. However, if an experimental
observed ocular hypotensive effects. Tafluprost in
                                                        manipulation were to increase uveoscleral outflow
mice reportedly works in part through FP receptor-
                                                        facility, this could be interpreted erroneously, as an
mediated prostaglandin production acting through
                                                        increase in trabecular outflow facility. It is thought
the prostanoid EP3 receptor.49 Studies published
                                                        by some that PGs increase uveoscleral outflow
between 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 overshadowed
summarized in Table 1. Studies predating 2000 are
                                                        by strong effects on uveoscleral outflow and/or
found in an earlier review.67
                                                        uveoscleral outflow facility.
                                                           The length of time of treatment could be another
TRABECULAR OUTFLOW FACILITY                             factor contributing to the differing effects of PGs on
   Trabecular outflow facility is not always increased   trabecular outflow facility. The immediate IOP
following topical treatment with PG analogs but         effects that occur from a single dose of a PG analog
evidence is building that the effect is real and not    may be mediated by cellular mechanisms different
unique to any one drug of this class. Latanoprost,      from those that occur after repeated applications or
travoprost, bimatoprost, and unoprostone all have       continuous exposure.9,83,90 Therefore, findings
been 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 to
of monkeys seems to be less affected by PG analogs.     evaluate aqueous humor dynamics because of their
Trabecular outflow facility was unchanged following      potential for genetic manipulation in addition to
multiple topical treatments of monkeys with PGF2a-      their ocular similarities to humans. These animals
isopropyl ester,22 tafluprost,62 and travoprost,71 the   exhibit increases in outflow facility 2 hours after one
DP 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 of
Analog                   of Subjects           Treatment             IOP             Fa              C          Pev         Fu               Reference
FP receptor analogs, prostamides
Bimatoprost         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 days
Tafluprost          cynomolgus monkeys       QD Â 4 to 5 days Y                 [                     4                                Takagi et al, 200462
                     (n 5 8--12)
DP receptor agonist
AL-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 agonists
Butaprost           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 any
Table 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                                                            S111

EPISCLERAL VENOUS PRESSURE                                 pig organ--cultured anterior segments perfused at
   Three studies have reported no change in                a constant pressure of 15 mm Hg, showed increased
episcleral venous pressure in patients with ocular         outflow by up to 62% at 8 hours after topical
hypertension treated for one week with latanoprost,        administration of bimatoprost and by 30% at 5
travoprost, or unoprostone (Table 1). The measure-         hours after intracameral administration of PGF2a.74
ments (made with a commercially available epis-            Human trabecular meshwork monolayer cultures6
cleral venomanometer, EyeTech, Morton Grove, IL),          treated with bimatoprost had a 78% increase in
are difficult to make with accuracy and consistency.        hydraulic conductivity which also was blocked by
Nevertheless, because no study found any trend to          AGN211334.76
suggest a change, it seems reasonable to conclude             PGE1 increases outflow facility by 26% in human
that the PG effect on episcleral venous pressure is        organ-cultured anterior segments.19 This effect
minimal.                                                   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-activated
TRABECULAR 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 was
PG analogs can alter the resistance in trabecular          not stimulated and cAMP production was not
outflow (Table 2). PGs have direct effects on matrix        altered after short exposure periods with PGF2a or
metalloproteinases (MMPs), neutral proteases that          placebo in human organ-cultured anterior
initiate degradation of the extracellular matrix and       segments.19
play a major role in regulating resistance to flow             Prostaglandin receptors have been identified in
through tissues. MMPs are expressed by human               human trabecular meshwork tissue but a prostamide
trabecular meshwork2 and directly control outflow           receptor has not yet been cloned. The genes for all
resistance in human organ-cultured anterior seg-           prostanoid receptors are expressed in human
ments.9 The activity of MMPs is regulated by tissue        trabecular meshwork. Gene expression for the EP2
inhibitors 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.32
identified 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 trabecular
trabecular meshwork cells treated with latanoprost         meshwork tissue showed positive staining for EP1 on
acid 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. EP2
of human organ-cultured anterior segments infused          was localized to the outer wall and periphery of
with latanoprost acid found increased outflow               Schlemm’s canal. EP3 and EP4 labeling was present
facility 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 was
6%) but no changes in the amount of MMPs or                present in the outer portion of the trabecular
scleral 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.55
of Schlemm’s canal endothelial cells and extracel-            Human trabecular meshwork cells in culture
lular matrix in some areas of the trabecular               express many of the same PG receptors as are found
meshwork.6 The focal cell loss was reasoned to be          in intact tissue. Cultured trabecular meshwork cells
due to cytoskeletal and focal adhesion changes6            can produce PGE2 and low levels of PGF2a.83,84
because PGs in aortic smooth muscle cells cause            Additionally, FP receptors have been identified in
disassembly of actin stress fibers and inhibition of        human trabecular meshwork cells as determined by
phosphorylation of paxillin and other focal adhe-          the presence of mRNA, protein, and a functional
sion proteins.12                                           response (increased inositol phosphate accumula-
   Bimatoprost increases outflow facility by 40% in         tion and intracellular calcium release) to PGF2a5
human organ-cultured anterior segments within 48           and numerous synthetic FP-selective PG agonists.58
hours 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 stimulate
a 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 2008
Analog                          Animal/ Tissue         Duration of Treatment           Pathway/Effect                  Events                       Reference
Trabecular meshwork
PGF2a, 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
                                                                                                                contraction
PGF2a                      human trabecular           1 hour                                                  FP mediated inositol           Anthony 19985
                            meshwork cells                                                                      phosphate
                                                                                                                accumulation;
                                                                                                                intracellular calcium
                                                                                                                release
PGF2a                      human anterior segments    60 minutes per dose         outflow facility             no change in cAMP              Dijkstra 199919
                                                                                    unchanged                   production
PGF2a, butaprost           human trabecular           6 hours                                                 upregulate mRNA for            Liang 2003,200436,37
                            meshwork cells                                                                      Nur77 and connective
                                                                                                                tissue growth factor
Bimatoprost                human anterior segments    48--72 hour continuous      outflow facility increase                                   Wan 200776
                                                        infusion
Bimatoprost                human trabecular           48--72 hour continuous      hydraulic conductivity                                     Wan 200776
                            meshwork monolayer          infusion                    increase
Bimatoprost                human trabecular           6 hours                                                 no change in Nur77             Liang 2003, 200436,37
                            meshwork cells                                                                      mRNA and connective
                                                                                                                tissue growth factor
                                                                                                                expression
bimatoprost 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,-4
latanoprost 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 MMPs
latanoprost 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 DYNAMICS
Unoprostone                human trabecular          Up to 2 hours                                           decrease activity of L-type   Thieme 200565
                            meshwork cells                                                                     Ca 2þ channels via
                                                                                                               tyrosine kinase
                                                                                                               pathways
PGE1                       human anterior segments   60 minutes                   increase outflow facility   increase cAMP                 Dijkstra 199919
                                                                                                               production
AH13205                    human trabecular          Less than 10 minutes                                    EP2 agonist activation of     Stumpff 200561
                            meshwork cells                                                                     BK calcium channels
Uveoscleral tissues
PGF2a                      monkeys                   multiple topical                                        decrease collagen types I,    Sagara 199953
                                                      treatments                                               III, IV in ciliary muscle
PGF2a                      monkeys                   multiple topical                                        increase MMP-1,-2,-3 in       Gaton 200125
                                                      treatments                                               ciliary muscle
PGF2a                      monkeys                   multiple topical             scleral permeability       increase MMP-1,-2,-3 in       Weinreb 200179
                                                      treatments                                               sclera
PGF2a                      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
                                                                                    permeability
PGF2a, PhXA85              scleral organ cultures    24 hr                                                   increase mRNA for MMPs        Weinreb 200482
                                                                                                               and TIMPx
PGF2a, 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
                                                                                                               pathways
PGF2a, 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-8810
PGF2a, 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 PGF2a
PGF2a, 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 2008
latanoprost 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-4
latanoprost acid            human ciliary muscle     24 hours                                                increase MMP-1,-3,-9         Weinreb 200281
                              cells
latanoprost acid            human ciliary muscle     Up to 24 hours                                          increase TIMP-1              Anthony 20024
                              cells
latanoprost acid            nonpigmented ciliary     Up to 48 hr                                             Cyclooxygenase-2             Hinz 200527
                              epithelial cells                                                                 induction leading to
                                                                                                               increase MMP-1
latanoprost acid            rats                     Single topical dose           Initial IOP elevation                                  Husain 200629
                                                                                     followed by prolonged
                                                                                     IOP reduction
latanoprost acid            human ciliary muscle     9 days in vivo                                          decrease aquaporin-1 and     Zhao 200390
                             cells                                                                              versican gene
                                                                                                                expression; decrease in
                                                                                                                mRNA for FP receptor
latanoprost, bimatoprost,   monkeys                  topical treatments for one                              tissue spaces of ciliary     Richter 200352
  sulprostone, AH13205                                 year                                                     muscle enlarged and
                                                                                                                organized; myelinated
                                                                                                                nerve fiber bundles
                                                                                                                present
Bimatoprost                 human ciliary muscle     6 hours                                                 no change in Nur77 and       Liang 2003, 200436,37
                             cells                                                                              connective tissue
                                                                                                                growth factor
                                                                                                                expression;
                                                                                                                upregulation of Cyr61
3,7-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 studies
latanoprost, travoprost,    FP knockout mice         single topical treatment      IOP decrease              FP receptor needed for       Ota 200548
  bimatoprost,                                                                                                 IOP decrease
  unoprostone
Latanoprost                 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,-9
latanoprost, 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 of
metalloproteinase.
TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS                                                             S115

of adenylyl cyclase and elevation of intracellular         2006 ARVO annual meeting), PGF2a and latano-
cAMP (EP2 and EP4) or inhibition of adenylyl               prost did not.88
cyclase (EP3).17,43 Prolonged treatment of human              Remodeling of the extracellular matrix within the
trabecular meshwork cells with latanoprost or PGF2a        ciliary muscle and sclera is the most thoroughly
ethanolamide causes an increase in expression of           understood effect of PG treatment. Dissolution of
genes 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 longitudinally
facility. 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 in
meshwork 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 eyes
lular matrix.90                                            with topical bimatoprost, latanoprost, sulprostone
   Unoprostone free acid (UF-021) shows low                (EP3/EP1 agonist) or AH13205 and butaprost (EP2
affinity for all prostanoid receptors and weak              agonists) found that in all cases the tissue spaces of
functional responses via FP receptor activation.57         the ciliary muscle were enlarged and organized into
Several 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 basement
L-type Ca2þ channels via a signal transduction             membrane, and contained myelinated nerve fiber
pathway was mediated by tyrosine kinases.65 Activa-        bundles.44,52 These fluid pathways resembled a kind
tion of BK channels by unoprostone free acid               of lymphatic system described in the choroid.34
inhibited trabecular meshwork contraction leading          Changes in the trabecular meshwork also were
to 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 after
tractility of the trabecular meshwork. FP receptor         latanoprost acid treatment for 24 hours. The mRNA
agonists can block endothelin-1 induced contractil-        of MMP-1, -2, -3, -11, -12, -14, -15, -16, -17, -19, and
ity of the trabecular meshwork. Evidence indicates         -24 as well as TIMP-1 to -4 were found in ciliary body
this 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-4.46
UVEOSCLERAL 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-dependent
normal human donor eyes indicate the presence of           increase in TIMP-1 but not TIMP-2 mRNA and
EP-1, -2, -3, -4 and FP receptors in the ciliary body      protein.4
and sclera. FP receptors are most abundant in the             Loss of cyclooxygenase (COX)-2 expression in the
circular 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 studies
explain the PG-induced increase in uveoscleral             investigating the connection between PGs, COX-2
outflow: remodeling of the extracellular matrix of          expression and MMPs. Indeed, the IOP-lowering
the ciliary muscle45,53,80 and sclera33,82 (Molik et al,   action of latanoprost appears to be associated with
unpublished 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.27
permeability of these tissues; widening of the             MMP-1 released into the aqueous humor would be
connective tissue-filled spaces among the ciliary           expected to flow into the ciliary muscle and through
muscle bundles,39,63 which may be caused in part           the trabecular meshwork and Schlemm’s canal to
by 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 are
the cells.60                                               ongoing. PGF2a- and latanoprost-induced secretion
   Ciliary muscle relaxation has been suggested as         and activation of MMP-2 in ciliary muscle cells were
responsible for the initial reduction in IOP from          shown to occur via protein kinase C and extracellular
topical PGs. This does not appear to be the case for       signal regulated protein kinase 1/2-dependent
all PGs and their agonists. PGE1 and PGE2 relaxed          pathways.28 Mitogen-activated protein kinase activity
isolated monkey ciliary muscle strips precontracted        was stimulated in human ciliary muscle cells with
with carbachol88 but 3,7-dithia PGE1 (Kharlamb et          travoprost acid O PGF2a O latanoprost acid O
al, unpublished data, abstract 413 presented at the        bimatoprost O latanoprost 5 bimatoprost acid. The
S116     Surv Ophthalmol 53 (Suppl 1) November 2008                                                TORIS ET AL

FP antagonist AL-8810 completely inhibited the             subtypes in mediating the IOP-lowering response to
mitogen-activated protein kinase activity induced by       clinical PG analogs. Studies in FP receptor--deficient
bimatoprost and bimatoprost acid, indicating that          mice have shown that the FP receptor is essential for
both 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.48
of IOP in rats by thalidomide suggested that the           The involvement of the FP receptor in the IOP
IOP-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 in
ways. Treatment of human ciliary muscle cells with         the sclera following 7 days of topical treatment with
tumor necrosis factor-a increased the secretion of         latanoprost also was dependent on an intact FP
MMP-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 annual
meeting).                                                  meeting). EP receptor-deficient mice have been
   PGF2a can stimulate the formation of endogenous         studied in similar ways. When EP1, EP2, and EP3
PGs 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, it
or latanoprost for 9 days show a downregulation of         was found that EP3 receptors were involved in the
the 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.50
decrease IOP.90
   PG-induced changes in the sclera also are
important in the regulation of uveoscleral outflow
and may be used to enhance transscleral delivery of        PHARMACOLOGIC DIFFERENCES AMONG THE
peptides and other high-molecular-weight sub-              PROSTAGLANDINS
stances 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 respective
increased 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) and
mRNA analysis of human sclera and cultured                 their subtypes (DP1, DP2, EP1--4) in receptor-binding
human scleral fibroblasts showed the presence of            studies.57 Prostamides are also naturally occurring
EP1, EP2 and FP receptor subtypes but not EP3 and          neutral lipids which have very little activity at
EP4 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.87
following exposure to PGF2a and latanoprost acid           The therapeutic derivatives of PGF2a, either amide
for 1--3 days. Scleral permeability increased in a dose-   or ester prodrugs, are powerful ocular hypotensive
and time-dependent manner. This was accompanied            drugs and either mediate their effects primarily via
by an increase in MMP concentration in the media           FP receptor activation or potentially via some yet
with the greatest increases in MMP-2 and -3                unidentified receptor activation.57
compared 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 its
TIMPs in human scleral organ cultures.82 X-ray             effects on aqueous humor outflow, although similar
diffraction analysis of human scleral explants             to latanoprost and travoprost, are accomplished via
showed that incubation in PGF2a-containing media           a receptor distinct from these pure FP receptor
caused the collagen helix to undergo gelatinization        agonists. However, bimatoprost acid (17-phenyl
similar to what was found after incubation with            PGF2a), which is found in the aqueous humor of
MMP-enriched media (Molik et al, unpublished               humans after topical application of bimatoprost
data, abstract 406 presented at the 2006 ARVO              (Dahlin et al, ARVO 2004 abstract 2096),14,15
annual 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 and
receptor (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 progress
expression in human ciliary muscle cells and             continues to be made. Prostamide antagonists have
trabecular 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 cloned
receptors.36,37 Bimatoprost induced the upregula-        and its biosynthesis enzyme identified to conclude
tion 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-dosing
matrix-associated signaling proteins and may be          studies of each PG should be compared before
a unique mechanism by which bimatoprost exerts its       concluding that one PG analog acts through
pharmacological action to lower IOP independent          mechanisms different from all others. Live animal
of Nur77 or CTNF.37 The importance of the                and clinical studies are needed to support claims
induction or lack of induction of these various          made by in vitro experiments. Receptor subtype
genes for IOP reduction remains to be determined.        selectivity of topical PGs should be identified. The
The production of transgenic mice lacking these          importance of induction or lack of induction of
genes and their IOP responses to PGF2a, bimato-          various genes for IOP reduction needs to be
prost, 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 the
patients who are unresponsive to latanoprost,24          PGF2a analogs.
suggesting that the prostamide bimatoprost and
the FP receptor agonist latanoprost stimulate
different receptor populations. This is consistent                 Method of Literature Search
with studies on isolated iridial cells where bimato-       These studies, dating between 2000 and 2008
prost stimulated an entirely different cell popula-      were found from a series of literature searches of
tion to those sensitive to PGF2a and bimatoprost         PubMed and from the reference lists of these
acid (17-phenyl PGF2a).59 An equally plausible           articles. The searches included the following terms
explanation is that some eyes may be deficient in         in various combinations: anterior segment organ
corneal 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 research
correlated with the variability in the IOP-lowering      articles, review articles, and meeting abstracts are
response 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           2003
reduce IOP by enhancing aqueous humor outflow.             2. Alexander JP, Samples JR, Van Buskirk EM, et al: Expression
The relative effects of PG analogs on each of the two        of matrix metalloproteinases and inhibitor by human
                                                             trabecular meshwork. Invest Ophthalmol Vis Sci 32:172--
outflow pathways may vary, but it appears that they           80, 1991
reduce IOP predominantly by increasing uveoscleral        3. Anthony TL, Lindsey JD, Aihara M, et al: Detection of
outflow and to a lesser extent trabecular outflow              prostaglandin EP(1), EP(2), and FP receptor subtypes in
                                                             human sclera. Invest Ophthalmol Vis Sci 42:3182--6, 2001
facility. Morphological studies have identified PG         4. Anthony TL, Lindsey JD, Weinreb RN: Latanoprost’s effects
receptors and described significant cellular changes          on TIMP-1 and TIMP-2 expression in human ciliary muscle
in PG-treated tissues of both outflow pathways.               cells. Invest Ophthalmol Vis Sci 43:3705--11, 2002
                                                          5. Anthony TL, Pierce KL, Stamer WD, et al: Prostaglandin F2
Biochemical studies have reported many complex               alpha receptors in the human trabecular meshwork. Invest
cellular events in PG-treated outflow tissues,                Ophthalmol Vis Sci 39:315--21, 1998
S118      Surv Ophthalmol 53 (Suppl 1) November 2008                                                                  TORIS ET AL

 6. Bahler CK, Howell KG, Hann CR, et al: Prostaglandins            27. Hinz B, Rosch S, Ramer R, et al: Latanoprost induces matrix
                                                                                   ¨
    increase trabecular meshwork outflow facility in cultured            metalloproteinase-1 expression in human nonpigmented
    human anterior segments. Am J Ophthalmol 145:114--9,                ciliary epithelial cells through a cyclooxygenase-2-dependent
    2008                                                                mechanism. FASEB J 19:1929--31, 2005
 7. Bean GW, Camras CB, et al: Commercially Available               28. Husain S, Jafri F, Crosson CE: Acute effects of PGF2alpha on
    Prostaglandin Analogs for the Reduction of Intraocular              MMP-2 secretion from human ciliary muscle cells: a PKC-
    Pressure -- Similarities and Differences. Surv Ophthalmol           and ERK-dependent process. Invest Ophthalmol Vis Sci 46:
    53(Suppl 1):S69--S84, 2008                                          1706--13, 2005
 8. Bill A: Further studies on the influence of the intraocular      29. Husain S, Whitlock NA, Rice DS, et al: Effects of latanoprost
    pressure on aqueous humor dynamics in cynomolgus                    on rodent intraocular pressure. Exp Eye Res 83:1453--8,
    monkeys. Invest Ophthalmol 6:364--72, 1967                          2006
 9. Bradley JM, Vranka J, Colvis CM, et al: Effect of matrix        30. John SW, Hagaman JR, MacTaggart TE, et al: Intraocular
    metalloproteinases activity on outflow in perfused human             pressure in inbred mouse strains. Invest Ophthalmol Vis Sci
    organ culture. Invest Ophthalmol Vis Sci 39:2649--58, 1998          38:249--53, 1997
10. Brew K, Dinakarpandian D, Nagase H: Tissue inhibitors of        31. Johnson TV, Fan S, Toris CB: Rebound tonometry in
    metalloproteinases: evolution, structure and function. Bio-         conscious, conditioned mice avoids the acute and profound
    chim Biophys Acta 1477:267--83, 2000                                effects of anesthesia on intraocular pressure. J Ocul
11. Brubaker RF, Schoff EO, Nau CB, et al: Effects of AGN               Pharmacol Ther 24:175--85, 2008
    192024, a new ocular hypotensive agent, on aqueous              32. Kamphuis W, Schneemann A, van Beek LM, et al: Prosta-
    dynamics. Am J Ophthalmol 131:19--24, 2001                          noid receptor gene expression profile in human trabecular
12. Bulin C, Albrecht U, Bode JG, et al: Differential effects of        meshwork: a quantitative real-time PCR approach. Invest
    vasodilatory prostaglandins on focal adhesions, cytoskeletal        Ophthalmol Vis Sci 42:3209--15, 2001
    architecture, and migration in human aortic smooth muscle       33. Kim JW, Lindsey JD, Wang N, et al: Increased human scleral
    cells. Arterioscler Thromb Vasc Biol 25:84--9, 2005                 permeability with prostaglandin exposure. Invest Ophthal-
13. Camras CB, Podos SM: The role of endogenous prostaglan-             mol Vis Sci 42:1514--21, 2001
    din in clinically-used and investigational glaucoma therapy,    34. Krebs W, Krebs IP: Ultrastructural evidence for lymphatic
    in Bito LZ, Stjernschantz J: The Ocular Effects of Prosta-          capillaries in the primate choroid. Arch Ophthalmol 106:
    glandins and Other Eicosanoids. New York, NY, Alan R. Liss,         1615--6, 1988
    Inc, 1989. pp 459--75                                           35. Lee PY, Podos SM, Severin C: Effect of prostaglandin F2
14. Camras CB, Toris CB, Sjoquist B, et al: Detection of the free       alpha on aqueous humor dynamics of rabbit, cat, and
    acid of bimatoprost in aqueous humor samples from human             monkey. Invest Ophthalmol Vis Sci 25:1087--93, 1984
    eyes treated with bimatoprost before cataract surgery.          36. Liang Y, Li C, Guzman VM, et al: Upregulation of orphan
    Ophthalmology 111:2193--8, 2004                                     nuclear receptor Nur77 following PGF(2alpha), Bimato-
15. Cantor LB, Hoop J, Wudunn D, et al: Levels of bimatoprost           prost, and Butaprost treatments. Essential role of a protein
    acid in the aqueous humour after bimatoprost treatment of           kinase C pathway involved in EP(2) receptor activated
    patients with cataract. Br J Ophthalmol 91:629--32, 2007            Nur77 gene transcription. Br J Pharmacol 142:737--48, 2004
16. Christiansen GA, Nau CB, McLaren JW, et al: Mechanism of        37. Liang Y, Li C, Guzman VM, et al: Comparison of
    ocular hypotensive action of bimatoprost (Lumigan) in               prostaglandin F2alpha, bimatoprost (prostamide), and
    patients with ocular hypertension or glaucoma. Ophthal-             butaprost (EP2 agonist) on Cyr61 and connective tissue
    mology 111:1658--62, 2004                                           growth factor gene expression. J Biol Chem 278:27267--77,
17. Coleman RA, Grix SP, Head SA, et al: A novel inhibitory             2003
    prostanoid receptor in piglet saphenous vein. Prostaglan-       38. Lim KS, Nau CB, O’Byrne MM, et al: Mechanism of action of
    dins 47:151--68, 1994                                               bimatoprost, latanoprost, and travoprost in healthy subjects.
18. Crowston JG, Aihara M, Lindsey JD, et al: Effect of                 A crossover study. Ophthalmology 115:790--5. e4, 2008
    latanoprost on outflow facility in the mouse. Invest             39. Lutjen-Drecoll E, Tamm E: Morphological study of the
                                                                          ¨
    Ophthalmol Vis Sci 45:2240--5, 2004                                 anterior segment of cynomolgus monkey eyes following
19. Dijkstra BG, Schneemann A, Hoyng PF: Flow after prosta-             treatment with prostaglandin F2 alpha. Exp Eye Res 47:761--
    glandin E1 is mediated by receptor-coupled adenylyl cyclase         9, 1988
    in human anterior segments. Invest Ophthalmol Vis Sci 40:       40. Maihofner C, Schlotzer-Schrehardt U, Guhring H, et al:
                                                                              ¨                ¨                     ¨
    2622--6, 1999                                                       Expression of cyclooxygenase-1 and -2 in normal and
20. Dinslage S, Hueber A, Diestelhorst M, et al: The influence of        glaucomatous human eyes. Invest Ophthalmol Vis Sci 42:
    Latanoprost 0.005% on aqueous humor flow and outflow                  2616--24, 2001
    facility in glaucoma patients: a double-masked placebo-         41. Mishima HK, Kiuchi Y, Takamatsu M, et al: Circadian
    controlled clinical study. Graefes Arch Clin Exp Ophthalmol         intraocular pressure management with latanoprost: diurnal
    242:654--60, 2004                                                   and nocturnal intraocular pressure reduction and increased
21. Eisenberg D: Latanoprost versus bimatoprost. Ophthalmol-            uveoscleral outflow. Surv Ophthalmol 41(Suppl 2):S139--44,
    ogy 110:2003, 1861--2; author reply, 1862                           1997
22. Gabelt BT, Kaufman PL: The effect of prostaglandin F2           42. Murphy G, Docherty AJ: The matrix metalloproteinases and
    alpha on trabecular outflow facility in cynomolgus monkeys.          their inhibitors. Am J Respir Cell Mol Biol 7:120--5, 1992
    Exp Eye Res 51:87--91, 1990                                     43. Negishi M, Sugimoto Y, Irie A, et al: Two isoforms of
23. Gabelt BT, Seeman JL, Podos SM, et al: Aqueous humor                prostaglandin E receptor EP3 subtype. Different COOH-
    dynamics in monkeys after topical 8-iso PGE(2). Invest              terminal domains determine sensitivity to agonist-induced
    Ophthalmol Vis Sci 45:892--9, 2004                                  desensitization. J Biol Chem 268:9517--21, 1993
24. Gandolfi SA, Cimino L: Effect of bimatoprost on patients         44. Nilsson SF, Drecoll E, Lutjen-Drecoll E, et al: The prostanoid
                                                                                                   ¨
    with primary open-angle glaucoma or ocular hypertension             EP2 receptor agonist butaprost increases uveoscleral outflow
    who are nonresponders to latanoprost. Ophthalmology 110:            in the cynomolgus monkey. Invest Ophthalmol Vis Sci 47:
    609--14, 2003                                                       4042--9, 2006
25. Gaton DD, Sagara T, Lindsey JD, et al: Increased matrix         45. Ocklind A: Effect of latanoprost on the extracellular matrix
    metalloproteinases 1, 2, and 3 in the monkey uveoscleral            of the ciliary muscle. A study on cultured cells and tissue
    outflow pathway after topical prostaglandin F(2 alpha)-              sections. Exp Eye Res 67:179--91, 1998
    isopropyl ester treatment. Arch Ophthalmol 119:1165--70,        46. Oh DJ, Martin JL, Williams AJ, et al: Analysis of expression of
    2001                                                                matrix metalloproteinases and tissue inhibitors of metal-
26. Haria M, Spencer CM: Unoprostone (isopropyl unopro-                 loproteinases in human ciliary body after latanoprost. Invest
    stone). Drugs Aging 9:213--8, discussion 219--20, 1996              Ophthalmol Vis Sci 47:953--63, 2006
TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS                                                                             S119

47. Oh DJ, Martin JL, Williams AJ, et al: Effect of latanoprost on   65. Thieme H, Steinhausen K, Ottlecz A, et al: Effects of
    the expression of matrix metalloproteinases and their tissue         unoprostone and endothelin 1 on L-type channel currents
    inhibitors in human trabecular meshwork cells. Invest                in human trabecular meshwork cells. Ophthalmic Res 37:
    Ophthalmol Vis Sci 47:3887--95, 2006                                 293--300, 2005
48. Ota T, Aihara M, Narumiya S, et al: The effects of               66. Thieme H, Stumpff F, Ottlecz A, et al: Mechanisms of action
    prostaglandin analogues on IOP in prostanoid FP-recep-               of unoprostone on trabecular meshwork contractility. Invest
    tor-deficient mice. Invest Ophthalmol Vis Sci 46:4159--63,            Ophthalmol Vis Sci 42:3193--201, 2001
    2005                                                             67. Toris CB, Camras CB, Yablonski ME, et al: Effects of
49. Ota T, Aihara M, Saeki T, et al: The IOP-lowering effects and        exogenous prostaglandins on aqueous humor dynamics
    mechanism of action of tafluprost in prostanoid receptor-             and blood-aqueous barrier function. Surv Ophthalmol
    deficient mice. Br J Ophthalmol 91:673--6, 2007                       41(Suppl 2):S69--75, 1997
50. Ota T, Aihara M, Saeki T, et al: The effects of                  68. Toris CB, Pederson JE: Effect of intraocular pressure on
    prostaglandin analogues on prostanoid EP1, EP2, and                  uveoscleral outflow following cyclodialysis in the monkey
    EP3 receptor-deficient mice. Invest Ophthalmol Vis Sci 47:            eye. Invest Ophthalmol Vis Sci 26:1745--9, 1985
    3395--9, 2006                                                    69. Toris CB, Zhan G, Camras CB: Increase in outflow facility
51. Poyer JF, Millar C, Kaufman PL: Prostaglandin F2 alpha               with unoprostone treatment in ocular hypertensive patients.
    effects on isolated rhesus monkey ciliary muscle. Invest             Arch Ophthalmol 122:1782--7, 2004
    Ophthalmol Vis Sci 36:2461--5, 1995                              70. Toris CB, Zhan G, Fan S, et al: Effects of travoprost on
52. Richter M, Krauss AH, Woodward DF, et al: Morphological              aqueous humor dynamics in patients with elevated in-
    changes in the anterior eye segment after long-term                  traocular pressure. J Glaucoma 16:189--95, 2007
    treatment with different receptor selective prostaglandin        71. Toris CB, Zhan GL, Camras CB, et al: Effects of travoprost
    agonists and a prostamide. Invest Ophthalmol Vis Sci 44:             on aqueous humor dynamics in monkeys. J Glaucoma 14:
    4419--26, 2003                                                       70--3, 2005
53. Sagara T, Gaton DD, Lindsey JD, et al: Topical prostaglandin     72. Toris CB, Zhan GL, Feilmeier MR, et al: Effects of
    F2alpha treatment reduces collagen types I, III, and IV in           a prostaglandin DP receptor agonist, AL-6598, on aqueous
    the monkey uveoscleral outflow pathway. Arch Ophthalmol               humor dynamics in a nonhuman primate model of
    117:794--801, 1999                                                   glaucoma. J Ocul Pharmacol Ther 22:86--92, 2006
54. Sakurai M, Higashide T, Takahashi M, et al: Association          73. Toris CB, Zhan GL, Zhao J, et al: Potential mechanism for
    between genetic polymorphisms of the prostaglandin                   the additivity of pilocarpine and latanoprost. Am J Oph-
    F2alpha receptor gene and response to latanoprost.                   thalmol 131:722--8, 2001
    Ophthalmology 114:1039--45, 2007                                 74. Vaajanen A, Vapaatalo H, Oksala O: A modified in vitro
55. Schlotzer-Schrehardt U, Zenkel M: Nusing RM: Expression
                                            ¨                            method for aqueous humor outflow studies in enucleated
    and localization of FP and EP prostanoid receptor subtypes           porcine eyes. J Ocul Pharmacol Ther 23:124--31, 2007
    in human ocular tissues. Invest Ophthalmol Vis Sci 43:1475--     75. Van Alphen GWHM, Wilhelm PB, Elsenfeld PW: The effect
    87, 2002                                                             of prostaglandins on the isolated internal muscles of the
56. Sharif NA, Crider JY, Husain S, et al: Human ciliary muscle          mammalian eye, including man. Doc Ophthalmol 42:397--
    cell responses to FP-class prostaglandin analogs: phosphoi-          415, 1977
    nositide hydrolysis, intracellular Ca2þ mobilization and         76. Wan Z, Woodward DF, Cornell CL, et al: Bimatoprost,
    MAP kinase activation. J Ocul Pharmacol Ther 19:437--55,             prostamide activity, and conventional drainage. Invest
    2003                                                                 Ophthalmol Vis Sci 48:4107--15, 2007
57. Sharif NA, Kelly CR, Crider JY, et al: Ocular hypotensive FP     77. Wang RF, Gagliuso DJ, Mittag TW, et al: Effect of 15-keto
    prostaglandin (PG) analogs: PG receptor subtype binding              latanoprost on intraocular pressure and aqueous humor
    affinities and selectivities, and agonist potencies at FP and         dynamics in monkey eyes. Invest Ophthalmol Vis Sci 48:
    other PG receptors in cultured cells. J Ocul Pharmacol Ther          4143--7, 2007
    19:501--15, 2003                                                 78. Wang RF, Lee PY, Mittag TW, et al: Effect of 8-iso
58. Sharif NA, Kelly CR, Crider JY: Human trabecular meshwork            prostaglandin E2 on aqueous humor dynamics in monkeys.
    cell responses induced by bimatoprost, travoprost, unopro-           Arch Ophthalmol 116:1213--6, 1998
    stone, and other FP prostaglandin receptor agonist ana-          79. Weinreb RN: Enhancement of scleral macromolecular
    logues. Invest Ophthalmol Vis Sci 44:715--21, 2003                   permeability with prostaglandins. Trans Am Ophthalmol
59. Spada CS, Krauss AH, Woodward DF, et al: Bimatoprost and             Soc 99:319--43, 2001
    prostaglandin F(2 alpha) selectively stimulate intracellular     80. Weinreb RN, Kashiwagi K, Kashiwagi F, et al: Prostaglandins
    calcium signaling in different cat iris sphincter cells. Exp         increase matrix metalloproteinase release from human
    Eye Res 80:135--45, 2005                                             ciliary smooth muscle cells. Invest Ophthalmol Vis Sci 38:
60. Stjernschantz J, Selen G, Ocklind A, Resul B: Weinreb RN:
                         ´                                               2772--80, 1997
    Uveoscleral Outflow. Biology and Clinical Aspects: Effects of     81. Weinreb RN, Lindsey JD: Metalloproteinase gene transcrip-
    latanoprost and related prostaglandin analogues, in Alm A.           tion in human ciliary muscle cells with latanoprost. Invest
    London, UK, Mosby International Limited, 1998. pp                    Ophthalmol Vis Sci 43:716--22, 2002
    57--72                                                           82. Weinreb RN, Lindsey JD, Marchenko G, et al: Prostaglandin
61. Stumpff F, Boxberger M, Krauss A, et al: Stimulation of              FP agonists alter metalloproteinase gene expression in
    cannabinoid (CB1) and prostanoid (EP2) receptors opens               sclera. Invest Ophthalmol Vis Sci 45:4368--77, 2004
    BKCa channels and relaxes ocular trabecular meshwork.            83. Weinreb RN, Mitchell MD, Polansky JR: Prostaglandin
    Exp Eye Res 80:697--708, 2005                                        production by human trabecular cells: in vitro inhibition
62. Takagi Y, Nakajima T, Shimazaki A, et al: Pharmacological            by dexamethasone. Invest Ophthalmol Vis Sci 24:1541--5,
    characteristics of AFP-168 (tafluprost), a new prostanoid FP          1983
    receptor agonist, as an ocular hypotensive drug. Exp Eye Res     84. Weinreb RN, Polansky JR, Alvarado JA, et al: Arachidonic
    78:767--76, 2004                                                     acid metabolism in human trabecular meshwork cells. Invest
63. Tamm E, Rittig M: Lutjen-Drecoll E: [Electron microscopy
                           ¨                                             Ophthalmol Vis Sci 29:1708--12, 1988
    and immunohistochemical studies of the intraocular pres-         85. Weinreb RN, Toris CB, Gabelt BT, et al: Effects of
    sure lowering effect of prostaglandin F2 alpha]. Fortschr            prostaglandins on the aqueous humor outflow pathways.
    Ophthalmol 87:623--9, 1990                                           Surv Ophthalmol 47(Suppl 1):S53--64, 2002
64. Thieme H, Schimmat C, Munzer G, et al: Endothelin
                                     ¨                               86. Woodward DF, Krauss AH, Chen J, et al: Pharmacological
    antagonism: effects of FP receptor agonists prostaglandin            characterization of a novel antiglaucoma agent, Bimato-
    F2alpha and fluprostenol on trabecular meshwork contrac-              prost (AGN 192024). J Pharmacol Exp Ther 305:772--85,
    tility. Invest Ophthalmol Vis Sci 47:938--45, 2006                   2003
S120      Surv Ophthalmol 53 (Suppl 1) November 2008                                                              TORIS ET AL

87. 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 concept
88. 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 P30
89. 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 Research
90. 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.

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Pge s

  • 1. SURVEY OF OPHTHALMOLOGY VOLUME 53 SUPPLEMENT 1 NOVEMBER 2008 Update on the Mechanism of Action of Topical Prostaglandins for Intraocular Pressure Reduction Carol B. Toris, PhD,1 B’Ann T. Gabelt, MS,2 and Paul L. Kaufman, MD2 1 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 outflow All 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 have effects 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 for the 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 Japan ular meshwork, by increasing drainage through the and a new analog (tafluprost) is in clinical trials in uveoscleral 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 prodrug outflow drugs approved for clinical use are prosta- of 17-phenyl-PGF2a86 and has been classified glandin (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 S107 Ó 2008 by Elsevier Inc. 0039-6257/08/$--see front matter All rights reserved. doi:10.1016/j.survophthal.2008.08.010
  • 2. S108 Surv Ophthalmol 53 (Suppl 1) November 2008 TORIS ET AL Unoprostone 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 in been or are being investigated in animal models for normotensive monkey eyes to account for most, if their IOP efficacy and potential as new glaucoma not all of the IOP reduction (Kharlamb, ARVO 2004 therapeutic drugs. None of these agonists has yet to abstract 1035, Table 1). An older study found an be approved for clinical use. increase in outflow facility at 4 hours after one This review summarizes recent (since 2000) topical drop of PGF2a.35 animal and clinical English-language studies of the One potential reason for the apparent differences effects of topical PG agonists on aqueous humor in trabecular outflow facility effect among the dynamics 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 ocular duce similar increases in uveoscleral outflow of rigidity (a measure of eye stiffness), pseudofacility several-fold. Increases in trabecular outflow facility (the facility of flow of aqueous humor from the also have been reported but this finding has not posterior to anterior chamber resulting from the been found consistently (Table 1). Unoprostone, probe-induced increase in IOP), and uveoscleral the least efficacious of the four compounds, appears outflow facility. The name of the measured variable to have little effect on uveoscleral outflow in trabecular outflow facility is not entirely accurate humans. Rather it works mainly by increasing because of the inclusion of these other factors in trabecular outflow facility.69 The new fluoroprosta- the various measurements. All of the measurement glandin F2a, tafluprost, increases uveoscleral outflow techniques assume that uveoscleral outflow facility is and aqueous flow in monkeys62 but has yet to be very small and affected little by the measurement studied 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 relatively nous prostaglandins that may contribute to the pressure-independent. However, if an experimental observed ocular hypotensive effects. Tafluprost in manipulation were to increase uveoscleral outflow mice reportedly works in part through FP receptor- facility, this could be interpreted erroneously, as an mediated prostaglandin production acting through increase in trabecular outflow facility. It is thought the prostanoid EP3 receptor.49 Studies published by some that PGs increase uveoscleral outflow between 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 overshadowed summarized in Table 1. Studies predating 2000 are by strong effects on uveoscleral outflow and/or found in an earlier review.67 uveoscleral outflow facility. The length of time of treatment could be another TRABECULAR OUTFLOW FACILITY factor contributing to the differing effects of PGs on Trabecular outflow facility is not always increased trabecular outflow facility. The immediate IOP following topical treatment with PG analogs but effects that occur from a single dose of a PG analog evidence is building that the effect is real and not may be mediated by cellular mechanisms different unique to any one drug of this class. Latanoprost, from those that occur after repeated applications or travoprost, bimatoprost, and unoprostone all have continuous exposure.9,83,90 Therefore, findings been 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 to of monkeys seems to be less affected by PG analogs. evaluate aqueous humor dynamics because of their Trabecular outflow facility was unchanged following potential for genetic manipulation in addition to multiple topical treatments of monkeys with PGF2a- their ocular similarities to humans. These animals isopropyl ester,22 tafluprost,62 and travoprost,71 the exhibit increases in outflow facility 2 hours after one DP receptor agonist AL-6598,72 and EP receptor 4-ml drop of latanoprost.18 Several limitations to
  • 3. 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 of Analog of Subjects Treatment IOP Fa C Pev Fu Reference FP receptor analogs, prostamides Bimatoprost 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 days Tafluprost cynomolgus monkeys QD Â 4 to 5 days Y [ 4 Takagi et al, 200462 (n 5 8--12) DP receptor agonist AL-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 agonists Butaprost 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)
  • 4. 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 any Table 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.
  • 5. TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS S111 EPISCLERAL VENOUS PRESSURE pig organ--cultured anterior segments perfused at Three studies have reported no change in a constant pressure of 15 mm Hg, showed increased episcleral venous pressure in patients with ocular outflow by up to 62% at 8 hours after topical hypertension treated for one week with latanoprost, administration of bimatoprost and by 30% at 5 travoprost, or unoprostone (Table 1). The measure- hours after intracameral administration of PGF2a.74 ments (made with a commercially available epis- Human trabecular meshwork monolayer cultures6 cleral venomanometer, EyeTech, Morton Grove, IL), treated with bimatoprost had a 78% increase in are difficult to make with accuracy and consistency. hydraulic conductivity which also was blocked by Nevertheless, because no study found any trend to AGN211334.76 suggest a change, it seems reasonable to conclude PGE1 increases outflow facility by 26% in human that the PG effect on episcleral venous pressure is organ-cultured anterior segments.19 This effect minimal. 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-activated TRABECULAR 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 was PG analogs can alter the resistance in trabecular not stimulated and cAMP production was not outflow (Table 2). PGs have direct effects on matrix altered after short exposure periods with PGF2a or metalloproteinases (MMPs), neutral proteases that placebo in human organ-cultured anterior initiate degradation of the extracellular matrix and segments.19 play a major role in regulating resistance to flow Prostaglandin receptors have been identified in through tissues. MMPs are expressed by human human trabecular meshwork tissue but a prostamide trabecular meshwork2 and directly control outflow receptor has not yet been cloned. The genes for all resistance in human organ-cultured anterior seg- prostanoid receptors are expressed in human ments.9 The activity of MMPs is regulated by tissue trabecular meshwork. Gene expression for the EP2 inhibitors 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.32 identified 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 trabecular trabecular meshwork cells treated with latanoprost meshwork tissue showed positive staining for EP1 on acid 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. EP2 of human organ-cultured anterior segments infused was localized to the outer wall and periphery of with latanoprost acid found increased outflow Schlemm’s canal. EP3 and EP4 labeling was present facility 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 was 6%) but no changes in the amount of MMPs or present in the outer portion of the trabecular scleral 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.55 of Schlemm’s canal endothelial cells and extracel- Human trabecular meshwork cells in culture lular matrix in some areas of the trabecular express many of the same PG receptors as are found meshwork.6 The focal cell loss was reasoned to be in intact tissue. Cultured trabecular meshwork cells due to cytoskeletal and focal adhesion changes6 can produce PGE2 and low levels of PGF2a.83,84 because PGs in aortic smooth muscle cells cause Additionally, FP receptors have been identified in disassembly of actin stress fibers and inhibition of human trabecular meshwork cells as determined by phosphorylation of paxillin and other focal adhe- the presence of mRNA, protein, and a functional sion proteins.12 response (increased inositol phosphate accumula- Bimatoprost increases outflow facility by 40% in tion and intracellular calcium release) to PGF2a5 human organ-cultured anterior segments within 48 and numerous synthetic FP-selective PG agonists.58 hours 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 stimulate a 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
  • 6. 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 2008 Analog Animal/ Tissue Duration of Treatment Pathway/Effect Events Reference Trabecular meshwork PGF2a, 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 contraction PGF2a human trabecular 1 hour FP mediated inositol Anthony 19985 meshwork cells phosphate accumulation; intracellular calcium release PGF2a human anterior segments 60 minutes per dose outflow facility no change in cAMP Dijkstra 199919 unchanged production PGF2a, butaprost human trabecular 6 hours upregulate mRNA for Liang 2003,200436,37 meshwork cells Nur77 and connective tissue growth factor Bimatoprost human anterior segments 48--72 hour continuous outflow facility increase Wan 200776 infusion Bimatoprost human trabecular 48--72 hour continuous hydraulic conductivity Wan 200776 meshwork monolayer infusion increase Bimatoprost human trabecular 6 hours no change in Nur77 Liang 2003, 200436,37 meshwork cells mRNA and connective tissue growth factor expression bimatoprost 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,-4 latanoprost 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 MMPs latanoprost acid human trabecular 9 days in vivo increase insulin growth Zhao 200390 meshwork cells factor-1 gene and fibroleukin gene expression
  • 7. TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS Unoprostone human trabecular Up to 2 hours decrease activity of L-type Thieme 200565 meshwork cells Ca 2þ channels via tyrosine kinase pathways PGE1 human anterior segments 60 minutes increase outflow facility increase cAMP Dijkstra 199919 production AH13205 human trabecular Less than 10 minutes EP2 agonist activation of Stumpff 200561 meshwork cells BK calcium channels Uveoscleral tissues PGF2a monkeys multiple topical decrease collagen types I, Sagara 199953 treatments III, IV in ciliary muscle PGF2a monkeys multiple topical increase MMP-1,-2,-3 in Gaton 200125 treatments ciliary muscle PGF2a monkeys multiple topical scleral permeability increase MMP-1,-2,-3 in Weinreb 200179 treatments sclera PGF2a 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 permeability PGF2a, PhXA85 scleral organ cultures 24 hr increase mRNA for MMPs Weinreb 200482 and TIMPx PGF2a, 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 pathways PGF2a, 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-8810 PGF2a, 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 PGF2a PGF2a, butaprost human ciliary muscle 6 hours upregulate Nur77 and Liang 2003, 200436,37 cells connective tissue growth factor (Continued on next page) S113
  • 8. Table 2 (continued ) S114 Cellular/Molecular Analog Animal/ Tissue Duration of Treatment Pathway/Effect Events Reference Surv Ophthalmol 53 (Suppl 1) November 2008 latanoprost 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-4 latanoprost acid human ciliary muscle 24 hours increase MMP-1,-3,-9 Weinreb 200281 cells latanoprost acid human ciliary muscle Up to 24 hours increase TIMP-1 Anthony 20024 cells latanoprost acid nonpigmented ciliary Up to 48 hr Cyclooxygenase-2 Hinz 200527 epithelial cells induction leading to increase MMP-1 latanoprost acid rats Single topical dose Initial IOP elevation Husain 200629 followed by prolonged IOP reduction latanoprost acid human ciliary muscle 9 days in vivo decrease aquaporin-1 and Zhao 200390 cells versican gene expression; decrease in mRNA for FP receptor latanoprost, bimatoprost, monkeys topical treatments for one tissue spaces of ciliary Richter 200352 sulprostone, AH13205 year muscle enlarged and organized; myelinated nerve fiber bundles present Bimatoprost human ciliary muscle 6 hours no change in Nur77 and Liang 2003, 200436,37 cells connective tissue growth factor expression; upregulation of Cyr61 3,7-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 studies latanoprost, travoprost, FP knockout mice single topical treatment IOP decrease FP receptor needed for Ota 200548 bimatoprost, IOP decrease unoprostone Latanoprost 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,-9 latanoprost, 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 of metalloproteinase.
  • 9. TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS S115 of adenylyl cyclase and elevation of intracellular 2006 ARVO annual meeting), PGF2a and latano- cAMP (EP2 and EP4) or inhibition of adenylyl prost did not.88 cyclase (EP3).17,43 Prolonged treatment of human Remodeling of the extracellular matrix within the trabecular meshwork cells with latanoprost or PGF2a ciliary muscle and sclera is the most thoroughly ethanolamide causes an increase in expression of understood effect of PG treatment. Dissolution of genes 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 longitudinally facility. 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 in meshwork 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 eyes lular matrix.90 with topical bimatoprost, latanoprost, sulprostone Unoprostone free acid (UF-021) shows low (EP3/EP1 agonist) or AH13205 and butaprost (EP2 affinity for all prostanoid receptors and weak agonists) found that in all cases the tissue spaces of functional responses via FP receptor activation.57 the ciliary muscle were enlarged and organized into Several 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 basement L-type Ca2þ channels via a signal transduction membrane, and contained myelinated nerve fiber pathway was mediated by tyrosine kinases.65 Activa- bundles.44,52 These fluid pathways resembled a kind tion of BK channels by unoprostone free acid of lymphatic system described in the choroid.34 inhibited trabecular meshwork contraction leading Changes in the trabecular meshwork also were to 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 after tractility of the trabecular meshwork. FP receptor latanoprost acid treatment for 24 hours. The mRNA agonists can block endothelin-1 induced contractil- of MMP-1, -2, -3, -11, -12, -14, -15, -16, -17, -19, and ity of the trabecular meshwork. Evidence indicates -24 as well as TIMP-1 to -4 were found in ciliary body this 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-4.46 UVEOSCLERAL 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-dependent normal human donor eyes indicate the presence of increase in TIMP-1 but not TIMP-2 mRNA and EP-1, -2, -3, -4 and FP receptors in the ciliary body protein.4 and sclera. FP receptors are most abundant in the Loss of cyclooxygenase (COX)-2 expression in the circular 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 studies explain the PG-induced increase in uveoscleral investigating the connection between PGs, COX-2 outflow: remodeling of the extracellular matrix of expression and MMPs. Indeed, the IOP-lowering the ciliary muscle45,53,80 and sclera33,82 (Molik et al, action of latanoprost appears to be associated with unpublished 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.27 permeability of these tissues; widening of the MMP-1 released into the aqueous humor would be connective tissue-filled spaces among the ciliary expected to flow into the ciliary muscle and through muscle bundles,39,63 which may be caused in part the trabecular meshwork and Schlemm’s canal to by 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 are the cells.60 ongoing. PGF2a- and latanoprost-induced secretion Ciliary muscle relaxation has been suggested as and activation of MMP-2 in ciliary muscle cells were responsible for the initial reduction in IOP from shown to occur via protein kinase C and extracellular topical PGs. This does not appear to be the case for signal regulated protein kinase 1/2-dependent all PGs and their agonists. PGE1 and PGE2 relaxed pathways.28 Mitogen-activated protein kinase activity isolated monkey ciliary muscle strips precontracted was stimulated in human ciliary muscle cells with with carbachol88 but 3,7-dithia PGE1 (Kharlamb et travoprost acid O PGF2a O latanoprost acid O al, unpublished data, abstract 413 presented at the bimatoprost O latanoprost 5 bimatoprost acid. The
  • 10. S116 Surv Ophthalmol 53 (Suppl 1) November 2008 TORIS ET AL FP antagonist AL-8810 completely inhibited the subtypes in mediating the IOP-lowering response to mitogen-activated protein kinase activity induced by clinical PG analogs. Studies in FP receptor--deficient bimatoprost and bimatoprost acid, indicating that mice have shown that the FP receptor is essential for both 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.48 of IOP in rats by thalidomide suggested that the The involvement of the FP receptor in the IOP IOP-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 in ways. Treatment of human ciliary muscle cells with the sclera following 7 days of topical treatment with tumor necrosis factor-a increased the secretion of latanoprost also was dependent on an intact FP MMP-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 annual meeting). meeting). EP receptor-deficient mice have been PGF2a can stimulate the formation of endogenous studied in similar ways. When EP1, EP2, and EP3 PGs 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, it or latanoprost for 9 days show a downregulation of was found that EP3 receptors were involved in the the 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.50 decrease IOP.90 PG-induced changes in the sclera also are important in the regulation of uveoscleral outflow and may be used to enhance transscleral delivery of PHARMACOLOGIC DIFFERENCES AMONG THE peptides and other high-molecular-weight sub- PROSTAGLANDINS stances 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 respective increased 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) and mRNA analysis of human sclera and cultured their subtypes (DP1, DP2, EP1--4) in receptor-binding human scleral fibroblasts showed the presence of studies.57 Prostamides are also naturally occurring EP1, EP2 and FP receptor subtypes but not EP3 and neutral lipids which have very little activity at EP4 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.87 following exposure to PGF2a and latanoprost acid The therapeutic derivatives of PGF2a, either amide for 1--3 days. Scleral permeability increased in a dose- or ester prodrugs, are powerful ocular hypotensive and time-dependent manner. This was accompanied drugs and either mediate their effects primarily via by an increase in MMP concentration in the media FP receptor activation or potentially via some yet with the greatest increases in MMP-2 and -3 unidentified receptor activation.57 compared 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 its TIMPs in human scleral organ cultures.82 X-ray effects on aqueous humor outflow, although similar diffraction analysis of human scleral explants to latanoprost and travoprost, are accomplished via showed that incubation in PGF2a-containing media a receptor distinct from these pure FP receptor caused the collagen helix to undergo gelatinization agonists. However, bimatoprost acid (17-phenyl similar to what was found after incubation with PGF2a), which is found in the aqueous humor of MMP-enriched media (Molik et al, unpublished humans after topical application of bimatoprost data, abstract 406 presented at the 2006 ARVO (Dahlin et al, ARVO 2004 abstract 2096),14,15 annual 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.
  • 11. 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 and receptor (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 progress expression in human ciliary muscle cells and continues to be made. Prostamide antagonists have trabecular 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 cloned receptors.36,37 Bimatoprost induced the upregula- and its biosynthesis enzyme identified to conclude tion 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-dosing matrix-associated signaling proteins and may be studies of each PG should be compared before a unique mechanism by which bimatoprost exerts its concluding that one PG analog acts through pharmacological action to lower IOP independent mechanisms different from all others. Live animal of Nur77 or CTNF.37 The importance of the and clinical studies are needed to support claims induction or lack of induction of these various made by in vitro experiments. Receptor subtype genes for IOP reduction remains to be determined. selectivity of topical PGs should be identified. The The production of transgenic mice lacking these importance of induction or lack of induction of genes and their IOP responses to PGF2a, bimato- various genes for IOP reduction needs to be prost, 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 the patients who are unresponsive to latanoprost,24 PGF2a analogs. suggesting that the prostamide bimatoprost and the FP receptor agonist latanoprost stimulate different receptor populations. This is consistent Method of Literature Search with studies on isolated iridial cells where bimato- These studies, dating between 2000 and 2008 prost stimulated an entirely different cell popula- were found from a series of literature searches of tion to those sensitive to PGF2a and bimatoprost PubMed and from the reference lists of these acid (17-phenyl PGF2a).59 An equally plausible articles. The searches included the following terms explanation is that some eyes may be deficient in in various combinations: anterior segment organ corneal 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 research correlated with the variability in the IOP-lowering articles, review articles, and meeting abstracts are response 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 2003 reduce IOP by enhancing aqueous humor outflow. 2. Alexander JP, Samples JR, Van Buskirk EM, et al: Expression The relative effects of PG analogs on each of the two of matrix metalloproteinases and inhibitor by human trabecular meshwork. Invest Ophthalmol Vis Sci 32:172-- outflow pathways may vary, but it appears that they 80, 1991 reduce IOP predominantly by increasing uveoscleral 3. Anthony TL, Lindsey JD, Aihara M, et al: Detection of outflow and to a lesser extent trabecular outflow prostaglandin EP(1), EP(2), and FP receptor subtypes in human sclera. Invest Ophthalmol Vis Sci 42:3182--6, 2001 facility. Morphological studies have identified PG 4. Anthony TL, Lindsey JD, Weinreb RN: Latanoprost’s effects receptors and described significant cellular changes on TIMP-1 and TIMP-2 expression in human ciliary muscle in PG-treated tissues of both outflow pathways. cells. Invest Ophthalmol Vis Sci 43:3705--11, 2002 5. Anthony TL, Pierce KL, Stamer WD, et al: Prostaglandin F2 Biochemical studies have reported many complex alpha receptors in the human trabecular meshwork. Invest cellular events in PG-treated outflow tissues, Ophthalmol Vis Sci 39:315--21, 1998
  • 12. S118 Surv Ophthalmol 53 (Suppl 1) November 2008 TORIS ET AL 6. Bahler CK, Howell KG, Hann CR, et al: Prostaglandins 27. Hinz B, Rosch S, Ramer R, et al: Latanoprost induces matrix ¨ increase trabecular meshwork outflow facility in cultured metalloproteinase-1 expression in human nonpigmented human anterior segments. Am J Ophthalmol 145:114--9, ciliary epithelial cells through a cyclooxygenase-2-dependent 2008 mechanism. FASEB J 19:1929--31, 2005 7. Bean GW, Camras CB, et al: Commercially Available 28. Husain S, Jafri F, Crosson CE: Acute effects of PGF2alpha on Prostaglandin Analogs for the Reduction of Intraocular MMP-2 secretion from human ciliary muscle cells: a PKC- Pressure -- Similarities and Differences. Surv Ophthalmol and ERK-dependent process. Invest Ophthalmol Vis Sci 46: 53(Suppl 1):S69--S84, 2008 1706--13, 2005 8. Bill A: Further studies on the influence of the intraocular 29. Husain S, Whitlock NA, Rice DS, et al: Effects of latanoprost pressure on aqueous humor dynamics in cynomolgus on rodent intraocular pressure. Exp Eye Res 83:1453--8, monkeys. Invest Ophthalmol 6:364--72, 1967 2006 9. Bradley JM, Vranka J, Colvis CM, et al: Effect of matrix 30. John SW, Hagaman JR, MacTaggart TE, et al: Intraocular metalloproteinases activity on outflow in perfused human pressure in inbred mouse strains. Invest Ophthalmol Vis Sci organ culture. Invest Ophthalmol Vis Sci 39:2649--58, 1998 38:249--53, 1997 10. Brew K, Dinakarpandian D, Nagase H: Tissue inhibitors of 31. Johnson TV, Fan S, Toris CB: Rebound tonometry in metalloproteinases: evolution, structure and function. Bio- conscious, conditioned mice avoids the acute and profound chim Biophys Acta 1477:267--83, 2000 effects of anesthesia on intraocular pressure. J Ocul 11. Brubaker RF, Schoff EO, Nau CB, et al: Effects of AGN Pharmacol Ther 24:175--85, 2008 192024, a new ocular hypotensive agent, on aqueous 32. Kamphuis W, Schneemann A, van Beek LM, et al: Prosta- dynamics. Am J Ophthalmol 131:19--24, 2001 noid receptor gene expression profile in human trabecular 12. Bulin C, Albrecht U, Bode JG, et al: Differential effects of meshwork: a quantitative real-time PCR approach. Invest vasodilatory prostaglandins on focal adhesions, cytoskeletal Ophthalmol Vis Sci 42:3209--15, 2001 architecture, and migration in human aortic smooth muscle 33. Kim JW, Lindsey JD, Wang N, et al: Increased human scleral cells. Arterioscler Thromb Vasc Biol 25:84--9, 2005 permeability with prostaglandin exposure. Invest Ophthal- 13. Camras CB, Podos SM: The role of endogenous prostaglan- mol Vis Sci 42:1514--21, 2001 din in clinically-used and investigational glaucoma therapy, 34. Krebs W, Krebs IP: Ultrastructural evidence for lymphatic in Bito LZ, Stjernschantz J: The Ocular Effects of Prosta- capillaries in the primate choroid. Arch Ophthalmol 106: glandins and Other Eicosanoids. New York, NY, Alan R. Liss, 1615--6, 1988 Inc, 1989. pp 459--75 35. Lee PY, Podos SM, Severin C: Effect of prostaglandin F2 14. Camras CB, Toris CB, Sjoquist B, et al: Detection of the free alpha on aqueous humor dynamics of rabbit, cat, and acid of bimatoprost in aqueous humor samples from human monkey. Invest Ophthalmol Vis Sci 25:1087--93, 1984 eyes treated with bimatoprost before cataract surgery. 36. Liang Y, Li C, Guzman VM, et al: Upregulation of orphan Ophthalmology 111:2193--8, 2004 nuclear receptor Nur77 following PGF(2alpha), Bimato- 15. Cantor LB, Hoop J, Wudunn D, et al: Levels of bimatoprost prost, and Butaprost treatments. Essential role of a protein acid in the aqueous humour after bimatoprost treatment of kinase C pathway involved in EP(2) receptor activated patients with cataract. Br J Ophthalmol 91:629--32, 2007 Nur77 gene transcription. Br J Pharmacol 142:737--48, 2004 16. Christiansen GA, Nau CB, McLaren JW, et al: Mechanism of 37. Liang Y, Li C, Guzman VM, et al: Comparison of ocular hypotensive action of bimatoprost (Lumigan) in prostaglandin F2alpha, bimatoprost (prostamide), and patients with ocular hypertension or glaucoma. Ophthal- butaprost (EP2 agonist) on Cyr61 and connective tissue mology 111:1658--62, 2004 growth factor gene expression. J Biol Chem 278:27267--77, 17. Coleman RA, Grix SP, Head SA, et al: A novel inhibitory 2003 prostanoid receptor in piglet saphenous vein. Prostaglan- 38. Lim KS, Nau CB, O’Byrne MM, et al: Mechanism of action of dins 47:151--68, 1994 bimatoprost, latanoprost, and travoprost in healthy subjects. 18. Crowston JG, Aihara M, Lindsey JD, et al: Effect of A crossover study. Ophthalmology 115:790--5. e4, 2008 latanoprost on outflow facility in the mouse. Invest 39. Lutjen-Drecoll E, Tamm E: Morphological study of the ¨ Ophthalmol Vis Sci 45:2240--5, 2004 anterior segment of cynomolgus monkey eyes following 19. Dijkstra BG, Schneemann A, Hoyng PF: Flow after prosta- treatment with prostaglandin F2 alpha. Exp Eye Res 47:761-- glandin E1 is mediated by receptor-coupled adenylyl cyclase 9, 1988 in human anterior segments. Invest Ophthalmol Vis Sci 40: 40. Maihofner C, Schlotzer-Schrehardt U, Guhring H, et al: ¨ ¨ ¨ 2622--6, 1999 Expression of cyclooxygenase-1 and -2 in normal and 20. Dinslage S, Hueber A, Diestelhorst M, et al: The influence of glaucomatous human eyes. Invest Ophthalmol Vis Sci 42: Latanoprost 0.005% on aqueous humor flow and outflow 2616--24, 2001 facility in glaucoma patients: a double-masked placebo- 41. Mishima HK, Kiuchi Y, Takamatsu M, et al: Circadian controlled clinical study. Graefes Arch Clin Exp Ophthalmol intraocular pressure management with latanoprost: diurnal 242:654--60, 2004 and nocturnal intraocular pressure reduction and increased 21. Eisenberg D: Latanoprost versus bimatoprost. Ophthalmol- uveoscleral outflow. Surv Ophthalmol 41(Suppl 2):S139--44, ogy 110:2003, 1861--2; author reply, 1862 1997 22. Gabelt BT, Kaufman PL: The effect of prostaglandin F2 42. Murphy G, Docherty AJ: The matrix metalloproteinases and alpha on trabecular outflow facility in cynomolgus monkeys. their inhibitors. Am J Respir Cell Mol Biol 7:120--5, 1992 Exp Eye Res 51:87--91, 1990 43. Negishi M, Sugimoto Y, Irie A, et al: Two isoforms of 23. Gabelt BT, Seeman JL, Podos SM, et al: Aqueous humor prostaglandin E receptor EP3 subtype. Different COOH- dynamics in monkeys after topical 8-iso PGE(2). Invest terminal domains determine sensitivity to agonist-induced Ophthalmol Vis Sci 45:892--9, 2004 desensitization. J Biol Chem 268:9517--21, 1993 24. Gandolfi SA, Cimino L: Effect of bimatoprost on patients 44. Nilsson SF, Drecoll E, Lutjen-Drecoll E, et al: The prostanoid ¨ with primary open-angle glaucoma or ocular hypertension EP2 receptor agonist butaprost increases uveoscleral outflow who are nonresponders to latanoprost. Ophthalmology 110: in the cynomolgus monkey. Invest Ophthalmol Vis Sci 47: 609--14, 2003 4042--9, 2006 25. Gaton DD, Sagara T, Lindsey JD, et al: Increased matrix 45. Ocklind A: Effect of latanoprost on the extracellular matrix metalloproteinases 1, 2, and 3 in the monkey uveoscleral of the ciliary muscle. A study on cultured cells and tissue outflow pathway after topical prostaglandin F(2 alpha)- sections. Exp Eye Res 67:179--91, 1998 isopropyl ester treatment. Arch Ophthalmol 119:1165--70, 46. Oh DJ, Martin JL, Williams AJ, et al: Analysis of expression of 2001 matrix metalloproteinases and tissue inhibitors of metal- 26. Haria M, Spencer CM: Unoprostone (isopropyl unopro- loproteinases in human ciliary body after latanoprost. Invest stone). Drugs Aging 9:213--8, discussion 219--20, 1996 Ophthalmol Vis Sci 47:953--63, 2006
  • 13. TOPICAL PROSTAGLANDINS AND AQUEOUS HUMOR DYNAMICS S119 47. Oh DJ, Martin JL, Williams AJ, et al: Effect of latanoprost on 65. Thieme H, Steinhausen K, Ottlecz A, et al: Effects of the expression of matrix metalloproteinases and their tissue unoprostone and endothelin 1 on L-type channel currents inhibitors in human trabecular meshwork cells. Invest in human trabecular meshwork cells. Ophthalmic Res 37: Ophthalmol Vis Sci 47:3887--95, 2006 293--300, 2005 48. Ota T, Aihara M, Narumiya S, et al: The effects of 66. Thieme H, Stumpff F, Ottlecz A, et al: Mechanisms of action prostaglandin analogues on IOP in prostanoid FP-recep- of unoprostone on trabecular meshwork contractility. Invest tor-deficient mice. Invest Ophthalmol Vis Sci 46:4159--63, Ophthalmol Vis Sci 42:3193--201, 2001 2005 67. Toris CB, Camras CB, Yablonski ME, et al: Effects of 49. Ota T, Aihara M, Saeki T, et al: The IOP-lowering effects and exogenous prostaglandins on aqueous humor dynamics mechanism of action of tafluprost in prostanoid receptor- and blood-aqueous barrier function. Surv Ophthalmol deficient mice. Br J Ophthalmol 91:673--6, 2007 41(Suppl 2):S69--75, 1997 50. Ota T, Aihara M, Saeki T, et al: The effects of 68. Toris CB, Pederson JE: Effect of intraocular pressure on prostaglandin analogues on prostanoid EP1, EP2, and uveoscleral outflow following cyclodialysis in the monkey EP3 receptor-deficient mice. Invest Ophthalmol Vis Sci 47: eye. Invest Ophthalmol Vis Sci 26:1745--9, 1985 3395--9, 2006 69. Toris CB, Zhan G, Camras CB: Increase in outflow facility 51. Poyer JF, Millar C, Kaufman PL: Prostaglandin F2 alpha with unoprostone treatment in ocular hypertensive patients. effects on isolated rhesus monkey ciliary muscle. Invest Arch Ophthalmol 122:1782--7, 2004 Ophthalmol Vis Sci 36:2461--5, 1995 70. Toris CB, Zhan G, Fan S, et al: Effects of travoprost on 52. Richter M, Krauss AH, Woodward DF, et al: Morphological aqueous humor dynamics in patients with elevated in- changes in the anterior eye segment after long-term traocular pressure. J Glaucoma 16:189--95, 2007 treatment with different receptor selective prostaglandin 71. Toris CB, Zhan GL, Camras CB, et al: Effects of travoprost agonists and a prostamide. Invest Ophthalmol Vis Sci 44: on aqueous humor dynamics in monkeys. J Glaucoma 14: 4419--26, 2003 70--3, 2005 53. Sagara T, Gaton DD, Lindsey JD, et al: Topical prostaglandin 72. Toris CB, Zhan GL, Feilmeier MR, et al: Effects of F2alpha treatment reduces collagen types I, III, and IV in a prostaglandin DP receptor agonist, AL-6598, on aqueous the monkey uveoscleral outflow pathway. Arch Ophthalmol humor dynamics in a nonhuman primate model of 117:794--801, 1999 glaucoma. J Ocul Pharmacol Ther 22:86--92, 2006 54. Sakurai M, Higashide T, Takahashi M, et al: Association 73. Toris CB, Zhan GL, Zhao J, et al: Potential mechanism for between genetic polymorphisms of the prostaglandin the additivity of pilocarpine and latanoprost. Am J Oph- F2alpha receptor gene and response to latanoprost. thalmol 131:722--8, 2001 Ophthalmology 114:1039--45, 2007 74. Vaajanen A, Vapaatalo H, Oksala O: A modified in vitro 55. Schlotzer-Schrehardt U, Zenkel M: Nusing RM: Expression ¨ method for aqueous humor outflow studies in enucleated and localization of FP and EP prostanoid receptor subtypes porcine eyes. J Ocul Pharmacol Ther 23:124--31, 2007 in human ocular tissues. Invest Ophthalmol Vis Sci 43:1475-- 75. Van Alphen GWHM, Wilhelm PB, Elsenfeld PW: The effect 87, 2002 of prostaglandins on the isolated internal muscles of the 56. Sharif NA, Crider JY, Husain S, et al: Human ciliary muscle mammalian eye, including man. Doc Ophthalmol 42:397-- cell responses to FP-class prostaglandin analogs: phosphoi- 415, 1977 nositide hydrolysis, intracellular Ca2þ mobilization and 76. Wan Z, Woodward DF, Cornell CL, et al: Bimatoprost, MAP kinase activation. J Ocul Pharmacol Ther 19:437--55, prostamide activity, and conventional drainage. Invest 2003 Ophthalmol Vis Sci 48:4107--15, 2007 57. Sharif NA, Kelly CR, Crider JY, et al: Ocular hypotensive FP 77. Wang RF, Gagliuso DJ, Mittag TW, et al: Effect of 15-keto prostaglandin (PG) analogs: PG receptor subtype binding latanoprost on intraocular pressure and aqueous humor affinities and selectivities, and agonist potencies at FP and dynamics in monkey eyes. Invest Ophthalmol Vis Sci 48: other PG receptors in cultured cells. J Ocul Pharmacol Ther 4143--7, 2007 19:501--15, 2003 78. Wang RF, Lee PY, Mittag TW, et al: Effect of 8-iso 58. Sharif NA, Kelly CR, Crider JY: Human trabecular meshwork prostaglandin E2 on aqueous humor dynamics in monkeys. cell responses induced by bimatoprost, travoprost, unopro- Arch Ophthalmol 116:1213--6, 1998 stone, and other FP prostaglandin receptor agonist ana- 79. Weinreb RN: Enhancement of scleral macromolecular logues. Invest Ophthalmol Vis Sci 44:715--21, 2003 permeability with prostaglandins. Trans Am Ophthalmol 59. Spada CS, Krauss AH, Woodward DF, et al: Bimatoprost and Soc 99:319--43, 2001 prostaglandin F(2 alpha) selectively stimulate intracellular 80. Weinreb RN, Kashiwagi K, Kashiwagi F, et al: Prostaglandins calcium signaling in different cat iris sphincter cells. Exp increase matrix metalloproteinase release from human Eye Res 80:135--45, 2005 ciliary smooth muscle cells. Invest Ophthalmol Vis Sci 38: 60. Stjernschantz J, Selen G, Ocklind A, Resul B: Weinreb RN: ´ 2772--80, 1997 Uveoscleral Outflow. Biology and Clinical Aspects: Effects of 81. Weinreb RN, Lindsey JD: Metalloproteinase gene transcrip- latanoprost and related prostaglandin analogues, in Alm A. tion in human ciliary muscle cells with latanoprost. Invest London, UK, Mosby International Limited, 1998. pp Ophthalmol Vis Sci 43:716--22, 2002 57--72 82. Weinreb RN, Lindsey JD, Marchenko G, et al: Prostaglandin 61. Stumpff F, Boxberger M, Krauss A, et al: Stimulation of FP agonists alter metalloproteinase gene expression in cannabinoid (CB1) and prostanoid (EP2) receptors opens sclera. Invest Ophthalmol Vis Sci 45:4368--77, 2004 BKCa channels and relaxes ocular trabecular meshwork. 83. Weinreb RN, Mitchell MD, Polansky JR: Prostaglandin Exp Eye Res 80:697--708, 2005 production by human trabecular cells: in vitro inhibition 62. Takagi Y, Nakajima T, Shimazaki A, et al: Pharmacological by dexamethasone. Invest Ophthalmol Vis Sci 24:1541--5, characteristics of AFP-168 (tafluprost), a new prostanoid FP 1983 receptor agonist, as an ocular hypotensive drug. Exp Eye Res 84. Weinreb RN, Polansky JR, Alvarado JA, et al: Arachidonic 78:767--76, 2004 acid metabolism in human trabecular meshwork cells. Invest 63. Tamm E, Rittig M: Lutjen-Drecoll E: [Electron microscopy ¨ Ophthalmol Vis Sci 29:1708--12, 1988 and immunohistochemical studies of the intraocular pres- 85. Weinreb RN, Toris CB, Gabelt BT, et al: Effects of sure lowering effect of prostaglandin F2 alpha]. Fortschr prostaglandins on the aqueous humor outflow pathways. Ophthalmol 87:623--9, 1990 Surv Ophthalmol 47(Suppl 1):S53--64, 2002 64. Thieme H, Schimmat C, Munzer G, et al: Endothelin ¨ 86. Woodward DF, Krauss AH, Chen J, et al: Pharmacological antagonism: effects of FP receptor agonists prostaglandin characterization of a novel antiglaucoma agent, Bimato- F2alpha and fluprostenol on trabecular meshwork contrac- prost (AGN 192024). J Pharmacol Exp Ther 305:772--85, tility. Invest Ophthalmol Vis Sci 47:938--45, 2006 2003
  • 14. S120 Surv Ophthalmol 53 (Suppl 1) November 2008 TORIS ET AL 87. 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 concept 88. 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 P30 89. 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 Research 90. 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.