(Investigative Ophthalmology and Visual Science. 2001;42:1134-1145.)
© 2001
by The Association for Research in Vision and Ophthalmology, Inc.
From PGF2
-Isopropyl Ester to Latanoprost: A Review of the Development of Xalatan The Proctor Lecture
Johan Wilhelm Stjernschantz
From the Department of Neuroscience, Unit of Pharmacology, Uppsala University, Uppsala, Sweden.
 |
Introduction
|
|---|
The research that led to the concept of using prostaglandins for
reduction of intraocular pressure (IOP) has been discussed by Bito and
goes back to the early 1980s, when it was shown that
PGF2
effectively reduces IOP in
monkeys.1
Because the IOP-reducing effect in primates was
found to be profound and of long duration, it was of obvious interest
to investigate whether prostaglandins could be developed into drugs for
glaucoma treatment. A fruitful collaboration between Columbia
University (New York, NY) and Pharmacia (Uppsala, Sweden), a
pharmaceutical company, was initiated. As a result of the
collaboration, a new glaucoma drug Xalatan was developed. The purpose
of this article is to present a review of the research that lead to the
identification of latanoprost, and the development of Xalatan. Some
relevant recent and previously unpublished data have been included as
well. The experimental protocols of all animal studies performed
complied with the tenets of the ARVO Statement on the Use of Animals in
Ophthalmic and Vision Research, and all protocols were submitted for
review and approval to the local Ethics Committee for Animal
Experimentation. Protocols for clinical studies were submitted to the
appropriate Ethics Committee/Internal Review Board and the Declaration
of Helsinki (1964) with subsequent revisions was adopted. Details
concerning the experimental procedures of the previously unpublished
results are given in the figure and table texts.
|
PGF2-Isopropyl Ester as a Prototype Prostaglandin
Drug for Glaucoma Treatment
|
|---|
The first approach to render prostaglandins suitable for glaucoma
treatment was esterification of the carboxylic acid to improve the
bioavailability2
and reduce the side effects. Several
esters of PGF2 were synthesized and tested for
IOP-reducing effect and side effects.3
One of the best of
these prodrugs of PGF2 was the isopropyl ester
(IE), but many other carboxylic acid esters, and di-, tri-, and
tetra-esters and lactones of PGF2 were
prepared and tested in addition (Bito LZ, Resul B, unpublished results,
1985). Similar experiments were also performed by researchers
at Allergan Pharmaceuticals (Irvine, CA).4
Other companies
(e.g., Ueno Fine Chemicals Industry, Osaka, Japan, and Alcon
Laboratories, Fort Worth, TX) subsequently adopted the isopropyl ester
prodrug concept for their respective prostaglandin analogues (isopropyl
unoprostone and travoprost, respectively).
PGF2-IE is a very efficacious and potent
IOP-reducing agent in cats, dogs, and monkeys.2
5
6
7
Comparable reductions of IOP with PGF2
tromethamine salt requires a 10 to 100 times higher dose in
monkeys.2
8
9
10
Thus, esterification of
PGF2 with isopropanol increased the
bioavailability substantially. Overall,
PGF2-IE was found to be a very good
IOP-reducing agent in many species except rabbits, in which a pressure
increase frequently is induced by a breakdown of the blood–aqueous
barrier. It is interesting that whereas cats exhibited distinct signs
of ocular pain and discomfort (e.g., closure of the lids and
lacrimation) unanesthetized monkeys usually did not (Stjernschantz J,
unpublished results, 1988). In addition, in cats and dogs
PGF2 and its esters are potent
miotics.11
In the first clinical trial with PGF2-IE,
which had the character of a pilot test, no or a minimal IOP-reducing
effect was observed in patients with glaucoma, probably because
difficult cases were selected, refractory to all medical treatment
(unpublished results, Pharmacia). Despite these discouraging results
Villumsen and Alm,12
in cooperation with Pharmacia,
started a systematic investigation to determine the IOP-reducing effect
and side effects of PGF2-IE and found that the
drug indeed effectively reduced IOP in a dose-dependent manner in
healthy volunteers. However, the IOP-reducing effect was accompanied by
conjunctival hyperemia and ocular irritation similar to the side
effects seen in studies with the tromethamine salt of
PGF2.13
14
The highest dose (10
µg) of PGF2-IE caused pain and photophobia
in all individuals.12
A dose of 0.5 µg twice daily was
chosen for further studies in patients, and this dose, as well as a
dose of 1 µg twice daily, was found to reduce IOP significantly,
alone and in combination with timolol.15
16
17
18
However, many patients reported side effects such as foreign-body
sensation and conjunctival hyperemia, and it became questionable
whether PGF2-IE would offer any advantage over
the already-established glaucoma medications. A particular problem was
the irritative response to the drug. In animal experiments, it has been
shown that PGF2-IE induces albumin leakage in
the iris and the ciliary body of monkeys at a dose of 1
µg,19
and it is possible that the 10 times higher dose
previously used in healthy individuals12
induces edema in
the anterior uvea that causes pain and photophobia.
|
Effect of PGF2-IE on the Uveoscleral Outflow Mode of
Action
|
|---|
The first evidence that PGF2 and its
isopropyl ester reduces IOP through a mechanism based on increased
uveoscleral outflow came from the studies by Crawford and
Kaufman20
and Nilsson et al.6
Both research
groups independently of each other found evidence for increased
uveoscleral outflow of aqueous humor in monkeys treated with
PGF2 tromethamine salt or
PGF2-IE and no or minimal effect on the
conventional outflow.6
20
21
Indirect evidence for a
similar mechanism in humans was also obtained in two separate studies:
PGF2-IE was not found to have any effect on
aqueous humor production or outflow facility.12
22
Thus,
the most reasonable explanation for the IOP reduction was increased
uveoscleral outflow, although it could not be excluded that the drug
may have reduced the episcleral venous pressure, too. It is important
to note that in neither of the two clinical studies was any evidence
found of a significant effect of PGF2-IE on
the blood–aqueous barrier.12
22
|
Rationale of Receptor Selectivity for Elimination of Side Effects
|
|---|
The preclinical and clinical studies with
PGF2-IE demonstrated that prostaglandins of
the F type could be useful in the treatment of glaucoma, but it was not
realistic to develop PGF2-IE into a glaucoma
drug for broader use, because of the side effects. Patients with severe
disease could have endured treatment with the drug for some time. The
question thus arose of whether it would be possible to separate the
IOP-reducing effect from the side effects—primarily the irritative and
hyperemic effects—by changing the receptor profile of
PGF2 through chemical modification. It should
be recalled in this context that the classification of the prostanoid
receptors in the mid 1980s was somewhat ambiguous, based on
conventional pharmacologic experiments only.23
24
25
However, early experiments that we had performed with two epimers of
PGF2-IE, namely
PGF2ß-IE and
11-epi-PGF2-IE indicated that the
miotic and IOP responses to PGF2-IE could be
distinctly separated by these two epimers in cats (Table 1)
. PGF2ß-IE reduced IOP with no miotic
effect, whereas 11-epi-PGF2-IE was
a potent miotic with little effect on IOP. Furthermore, the epimers
also differed from PGF2-IE with respect to the
nociceptive response (Table 1)
and the hyperemic response,
PGF2ß-IE, being a much stronger vasodilator
than both PGF2-IE and
11-epi-PGF2-IE (unpublished
results; Pharmacia). Thus, it appeared possible to separate the
different ocular responses from each other, at least partly, and there
was also an indication that the FP prostanoid receptor, which mediates
miosis in cats, may be involved at least partly in IOP reduction in
monkeys.26
(Table 1)
.
View this table:
[in this window]
[in a new window]
|
Table 1. Effects of PGF2-IE, PGF2ß-IE, and
11-epi-PGF2-IE on IOP, Pupil Diameter, and Nociception
in Cats and on IOP in Monkeys
|
|
A critical aspect in the success of the screening work was the
selection of appropriate animal models that would allow extrapolation
of the results to the human eye. The cat eye seemed very unspecific, in
that IOP reduction was brought about by widely different prostaglandin
analogues (e.g., PGF2,
PGF2ß, PGE2,
PGA2, PGB2, and
PGD2). Therefore, we regarded the cat eye as
somewhat unpredictable with respect to the IOP effect in humans and
used the cat eye primarily for studying the nociceptive and miotic
effects, whereas conscious cynomolgus monkeys were used to study the
IOP-reducing effect. However, because young healthy monkeys usually
have low IOP, often around 11 to 15 mm Hg, the test model was not ideal
but was good enough to confirm whether an analogue had an IOP-reducing
effect. The hyperemic effect was studied in albino rabbits, but there
were no attempts to study anything else in the rabbit, because the
rabbit eye is known to react very atypically to
prostaglandins.27
28
29
Thus, the selection of adequate
animal models was of paramount importance for the success of the
project.
|
Structure–Activity Approach and Identification of
Phenyl-Substituted Prostaglandin Analogues
|
|---|
The first approach to modifying PGF2
included various alterations of the carboxylic acid end of the
molecule. The alterations comprised, for example, the alcohol and
simple esters but generally did not result in any clear-cut improvement
of the pharmacologic profile of PGF2. The
second approach was to change the stereochemistry, and the functional
groups in the cyclopentane ring. Although this yielded some interesting
analogues that offered certain advantages over
PGF2, such as
11-epi-PGF2,26
modifications of the cyclopentane ring resulted in no real
breakthrough. The third approach was to alter parts of the 
chain
(e.g., the double bond between carbons 13 and 14 and the 15-hydroxyl
group) and to substitute part of the chain. However, it was well known
that the 15-hydroxyl group is essential for biologic activity of
prostaglandins, and dehydrogenation of the hydroxyl group results in
marked loss of biologic activity.30
31
Thus, the approach
taken by the researchers of Ueno Fine Chemicals Industry (Osaka, Japan)
to reduce the side effects of PGF2 by
preparing the 13,14-dihydro-15-keto metabolite, or modifications of
this metabolite (e.g., isopropyl unoprostone) renders molecules with
significantly reduced potency.32
Among a group of different -chain–modified prostaglandin
analogues, we quite unexpectedly noted that
17-phenyl-18,19,20-trinor-PGF2-IE induced
marked miosis in the cat without concomitant irritation, which almost
all other prostaglandin analogues had induced. Although there was no
significant effect of the analogue on IOP in cats, conceptually, the
combination of marked miosis with absence of nociception demonstrated
that it was possible to eliminate the nociceptive effect without losing
pharmacologic activity. In contrast to cats,33
monkeys
responded to the compound with satisfactory IOP
reduction.34
35
The compound, which can be regarded as
the breakthrough, was assigned the code name PhDH100A and became the
lead compound of the group of -chain ring-substituted prostaglandin
analogues in the screening for an optimal prostaglandin analogue for
glaucoma treatment.
|
Importance of -Chain Length, Ring Structures, and Substituents
|
|---|
The identification of
17-phenyl-18,19,20-trinor-PGF2-IE lead to
medicinal chemistry experiments that were of obvious interest to
perform to understand the critical elements in the molecules for
attaining efficacy and selectivity in the eye. Three aspects seemed
particularly relevant to study: (1) the influence of the -chain
length, (2) the influence of different ring structures, and (3) the
influence of substituents in the ring structure on the pharmacologic
profile of the new analogues.
|
Influence of -Chain Length on Pharmacologic Profile
|
|---|
This aspect was studied in detail by attaching a terminal phenyl
ring to carbons 15-24 (Fig. 1)
. The analogues were studied in cats with emphasis on the miotic and
nociceptive responses. Of note, attaching the aromatic ring structure
to carbon 17 of the prostaglandin skeleton yielded an optimal compound,
in that the FP receptor function, as evident from the miotic response,
was not compromised, whereas the nociceptive response was completely
abolished34
(Table 2)
. In bizarre contrast,
16-phenyl-17,18,19,20-tetranor-PGF2-IE with
one additional carbon atom removed from the chain caused
significant irritation, albeit less than
PGF2-IE. Elongation of the chain beyond
carbon 17 with a terminal phenyl ring attached, reduced the biologic
activity34
(Table 2)
. However, it is noteworthy that most
analogues with a terminal ring structure exhibited considerably less
nociceptive effect than PGF2-IE. Substitution
of carbon 17 with oxygen afforded a compound
(16-phenoxy-17,18,19,20-tetranor-PGF2-IE) with
similar pharmacologic profile to that of
17-phenyl-18,19,20-trinor-PGF2-IE (unpublished
results; Pharmacia).
View this table:
[in this window]
[in a new window]
|
Table 2. Effect of Phenyl-Substituted PGF2-IE Analogues with
Different -Chain Lengths on IOP, Pupil Diameter, Nociception,
and Conjunctival Hyperemia
|
|
|
Influence of Different Ring Structures on the Pharmacologic Profile
|
|---|
A large number of compounds with different ring structures from
cyclopropyl to cycloheptyl and aromatic ring structures, such as
phenyl, thiophen, and furyl, attached to carbon 17 (Fig. 1)
were
prepared and tested. Overall, these analogues exhibited an improved
side-effect profile compared with PGF2-IE,
albeit with somewhat different pharmacologic activity. Thus it appears
that many different terminal ring structures attached to carbon 17 in
the chain reduce the side effects of
PGF2-IE.
|
Influence of Substituents in the Ring Structure on the
Pharmacologic Profile
|
|---|
Compounds with various substitutions in the phenyl ring (Fig. 1) were also prepared and tested for pharmacologic
activity.26
34
Introduction of a methyl group into
the ortho (2) or meta (3) position in the phenyl
ring did not appreciably change the miotic activity of
17-phenyl-18,19,20-trinor-PGF2-IE, whereas
introduction of the methyl group into the para (4) position
dramatically reduced the activity.26
34
Obviously, the
methyl group in the para position induces a steric hindrance
in the receptor ligand interaction. Introduction of an
electron-attracting trifluormethyl group into the ortho or
para position in the phenyl ring reduced the activity of the
compound, whereas introduction of the group into the meta
position only slightly reduced the activity.26
34
Substituting fluorine for the trifluormethyl in the ortho,
meta, or para position afforded compounds with
marked miotic effect and no or very little irritant effect in the cat
eye, thus indicating that the trifluormethyl group may also partly
change the pharmacologic activity through a steric
effect.26
34
Introduction of an electron-donating methoxy
group into the ortho or para position markedly
reduced miotic activity, whereas introduction of the group into the
meta position only slightly reduced miotic
activity.26
34
The
16-(4-methoxy)-phenyl-17,18,19,20-tetranor
PGF2-IE analogue had virtually no irritant
effect in the cat eye in contrast to
16-phenyl-17,18,19,20-tetranor-PGF2-IE
(unpublished results, Pharmacia). Thus, it appears that the
para position, and to some extent the ortho
position, in the phenyl ring are sensitive to steric hindrance, whereas
the meta position is much less vulnerable. However, in the
ortho position electrochemical forces may be important, at
least in part, because an electron-attracting trifluormethyl group
reduces the activity in contrast to a neutral methyl group.
Overall, the structure–activity studies indicated that the ring
structure on the chain is of paramount importance for reducing the
side effects of PGF2-IE, and furthermore that
a large number of modifications of the ring structure are possible,
still affording useful compounds in the eye.26
34
35
36
Saturation of the 13,14-trans double bond of
17-phenyl-18,19,20-trinor-PGF2-IE was found to
further improve the receptor profile somewhat, and 13,14-dihydro
prostaglandin analogues in addition exhibited improved chemical
stability. The
13,14-dihydro-15R,S-17-phenyl-18,19,20-trinor-PGF2-IE
analogue was selected as the new candidate drug, and the compound was
given the code name PhXA34. Because the 15R epimer is more potent than
the 15S epimer, with time the 15R epimer (PhXA41)
became the final candidate drug. It was given the generic name
latanoprost and is the active principle in Xalatan. The chemical
structures of PGF2-IE,
17-phenyl-18,19,20-trinor-PGF2-IE, PhXA34, and
latanoprost (PhXA41) are presented in Figure 2
.
View larger version (14K):
[in this window]
[in a new window]
|
Figure 2. Chemical structures of PGF2-IE,
17-phenyl-18,19,20-trinor-PGF2-IE,
13,14-dihydro-15R,
S-17-phenyl-18,19,20-trinor-PGF2-IE
(PhXA34), and
13,14-dihydro-15R-17-phenyl-18,19,20-trinor-PGF2-IE
(latanoprost).
|
|
|
Latanoprost
|
|---|
As is obvious from the structure–activity studies, the reason for
the good therapeutic index of latanoprost in the eye is its
pharmacologic receptor profile. It can be seen in Table 3
that latanoprost acid is a much more selective FP prostanoid receptor
agonist than PGF2. In practical terms it is
even more selective than
17-phenyl-18,19,20-trinor-PGF2 because it
spills less over on the EP1 and TP receptors
(Table 3)
. It is also apparent that latanoprost acid is a full agonist
on the FP receptor, and full or near full agonist on the
EP1 and EP3 receptors, but
has no, or only weak effect on prostanoid receptors
EP2, DP, IP, and TP (Table 3)
. In comparison
17-phenyl-18,19,20-trinor-PGF2, with the 13,14
double bond intact, is a full agonist on the FP and
EP1 receptors, and a partial agonist on the TP
receptor, but has no, or only weak effect on the other receptors (Table 3) . Thus, increasing the flexibility of the chain by saturating the
13,14 double bond has relatively little effect on the interaction with
the FP receptor, but reduces the potency on the
EP1 and TP receptors, and increases the capacity
to stimulate the EP3 receptor, albeit only at
very high concentrations.
Latanoprost has virtually no IOP-reducing effect in cats or rabbits,
but induces a moderate IOP reduction in conscious normotensive monkeys
as measured 3 to 6 hours after topical application. During continuous
treatment with 3 µg once daily for 5 days the IOP reduction lasted
around the clock (unpublished results; Pharmacia). In ocular
hypertensive monkeys a good IOP-reducing effect of latanoprost has also
been seen.37
The absence of effects in cats and rabbits
may be due to several factors—for example, different anatomy of the
ciliary muscle and aqueous humor outflow pathways compared with
primates, and the absence of expression or different coupling of FP
receptors in the ciliary muscle. Of note, recently it was demonstrated
that the prostanoid receptor EP1 seems to mediate
the IOP reduction of PGF2 in the
cat.38
|
Mode of Action
|
|---|
Thorough pharmacodynamic studies in cannulated monkey eyes were
performed to investigate the mode of action of latanoprost, because the
mechanism could differ from that of PGF2-IE
due to the different receptor profiles of the compounds. Cynomolgus
monkeys were treated for 5 days topically on one eye with 3 µg
latanoprost daily; the other eye received vehicle only and served as
the control. A detailed description of the pharmacodynamic method has
been presented.39
The results showed that latanoprost had
a statistically significant effect on the uveoscleral outflow, which
increased by approximately 60% compared with the contralateral control
eye.39
40
Neither the trabecular outflow of aqueous humor,
nor the total outflow facility changed during latanoprost
treatment.39
40
The reason for the increase in flux of aqueous humor through the
ciliary muscle during prostaglandin treatment has been studied in
detail at the cellular level by Lindsey et al.41
42
43
44
45
46
47
PGF2 seems to increase the expression of c-Fos
in human ciliary muscle cells, which in turn may increase the
expression of matrix metalloproteinases (MMPs)—for example, MMP-1,
MMP-2, MMP-9 and MMP-10—as well as their precursors,42
43
thereby perturbing the balance in the turnover of extracellular matrix
components toward catabolism.44
45
46
PGF2-IE was found to reduce collagens I, III,
and IV in the ciliary muscle and adjacent sclera of the monkey after
topical treatment with 2 µg twice daily for 5 days.47
Similar results were obtained by Ocklind48
who
demonstrated a decrease in collagens I, III, and IV; laminin;
fibronectin; and hyaluronan in human ciliary muscle cell cultures
exposed to latanoprost acid in parallel with an increase in MMP-2 and
MMP-3. She also found evidence for reduced collagens IV and VI levels
in the ciliary muscle after 10 days of topical treatment with 3 µg
latanoprost daily in monkeys.48
Furthermore, evidence for
a change in the shape of ciliary muscle cells was also found after
exposure to latanoprost acid in vitro, with alterations in the actin
and vinculin localization in the cells.39
Thus, the
results indicate that latanoprost may have complex effects on ciliary
muscle, the net effect being increased percolation of aqueous humor
through the tissue.
|
Vascular Effects of Latanoprost
|
|---|
Both the local and systemic vascular effects of latanoprost have
been studied in detail. In the rabbit eye latanoprost induced no or
minimal change in blood flow,19
in sharp contrast to
PGF2-IE, which induced marked increase in
blood flow to the surface structures and the anterior uvea after
topical application.49
The hyperemic effect of
PGF2-IE seems to be based on a release of
nitric oxide (NO), and apparently the mechanism leading to NO release
does not involve FP receptors.49
Of interest, sensory
denervation by electrocoagulation of the ophthalmic nerve, almost
completely abolished the hyperemic effect of
PGF2-IE in rabbits, implying that the effect
is nerve-mediated.50
This fits well with the absence
of nociceptive effect of FP prostanoid receptor agonists such as
latanoprost. By using selective agonists we studied which of the
prostanoid receptors mediate the nociceptive response to prostaglandins
in the cat eye and found that the FP and EP2
receptors are of little or no importance (Fig. 3)
. Stimulation of the DP, IP, EP1, and
EP3 receptors, on the contrary, induced a
nociceptive response in the cat eye (Fig. 3)
. Whether
PGF2-IE–induced conjunctival hyperemia in
humans also involves sensory nerves is unknown, but it is quite
possible.
View larger version (28K):
[in this window]
[in a new window]
|
Figure 3. Maximum nociceptive effect of selective prostanoid receptor agonists in
the cat eye. The agonists were applied unilaterally at three different
doses. The irritation was estimated by observing the animals for 6
hours after administration of the test substances. An arbitrary scale
of 0 to 3 was used: 0, no signs of ocular irritation; 1, slight; 2,
moderate; and 3, marked signs of irritation as evident from complete
lid closure and lacrimation. The complete name of the EP3
agonist is
13,14-dihydro- 14-trans-15-deoxy-17-phenyl-18,19,20-trinor-PGF2-IE,
and the compound is not a full agonist on the EP3 receptor.
Thus, the effect on the EP3 receptor may be underestimated.
Mean ± SEM; n = 4–6 for each compound and
dose; *P < 0.01, paired t-test. IE,
isopropyl ester; ME, methyl ester.
|
|
Latanoprost and PhXA34 tested at a dose of approximately four times the
clinical dose of latanoprost in Xalatan had a negligible effect on the
regional blood flow in the monkey eye after topical
application.51
Neither was any effect seen on capillary
permeability to albumin in the monkey eye.51
Intravenous
injection of latanoprost in escalating doses of up to 6 µg/kg body
weight had no statistically significant effect on the uveal or retinal
blood flow in monkeys, although a tendency toward increased blood flow
was observed (Table 4)
.19
In aphakic monkey eyes with intact posterior lens
capsule, latanoprost induced no capillary leakage in the retina as
studied with fluorescein angiography during 6 months of treatment, and
similar results were also obtained during shorter treatment periods in
pseudophakic patients.52
Thus, it appears that the FP
receptor, if expressed in the vasculature, plays no or only a limited
role in the regulation of vessel tone and capillary permeability in the
eye.
View this table:
[in this window]
[in a new window]
|
Table 4. Effect of Intravenous Injection of Escalating Doses of Latanoprost on
the Blood Flow in the Monkey Eye and Vital Organs as Studied with
Radioactively Labeled Microspheres19
|
|
The effects of latanoprost on the systemic circulation have been
studied in monkeys after intravenous administration. With escalating
doses of up to 6 µg/kg body weight an increase of the blood flow in
parts of the brain as well as the heart was found, whereas very little
effect was seen in other vital organs, such as the liver,
gastrointestinal tract, and kidneys (Table 4)
. A tendency toward a
slight increase in blood pressure was found. This effect seems to be
based on increased cardiac output induced by high doses of the drug in
anesthetized animals.19
It should be emphasized that the
highest dose of 6 µg/kg body weight is approximately 100 times the
clinical dose of latanoprost in Xalatan (per body weight) applied
topically on the eye.
|
Effects of Latanoprost on the Respiratory System
|
|---|
As PGF2 is a well-known constrictor of
human bronchi,53
54
55
56
the effect of latanoprost on
pulmonary function in healthy volunteers and patients who have
bronchial asthma was important to investigate. No negative effects on
pulmonary function were observed in two specially designed clinical
studies.57
58
In monkeys, however, intravenous infusion of
high doses of latanoprost was found to increase the intrathoracic
inspiration–expiration pressure difference consistent with
bronchoconstriction (unpublished results; Pharmacia). A study was
therefore undertaken to determine the effects of latanoprost acid on
human bronchioles in vitro. Both PGF2 and
latanoprost acid contracted the smooth muscle of the bronchioles, as
measured in small-vessel myographs with an EC50
value of approximately 10-6 M. Latanoprost acid
exerted about half the maximum effect of
PGF2.59
Both the contraction to
PGF2 and latanoprost acid was completely
abolished by a TP receptor antagonist (GR32191B). Thus, it appears that
the effect is mediated primarily by TP receptors and not FP receptors.
A concentration of 10-7 M was necessary to
elicit any response at all to latanoprost acid.59
This
concentration exceeds the maximum concentration in plasma of
latanoprost acid during long-term treatment with Xalatan by
approximately 1000 times. It is therefore unlikely, although not to be
excluded completely, that the respiratory function of patients with
glaucoma who have severe asthma would be negatively affected by
latanoprost.
|
Clinical Studies with Latanoprost
|
|---|
In the phase I clinical trials, four phenyl-substituted
PGF2-IE analogues were compared:
17-phenyl-18,19,20-trinor-PGF2-IE,
15-keto-17-phenyl-18,19,20-trinor-PGF2-IE,
PhXA34, and latanoprost. Of these analogues PHXA34 and latanoprost
appeared to be optimal, when considering the relationship between the
IOP-reducing effect and the conjunctival hyperemic effect. None of the
compounds had any appreciable irritant effect.
The first phase II clinical trials were performed with PhXA34, and
these studies demonstrated a good IOP-reducing effect and advantageous
therapeutic index of the drug in the eye.60
61
62
63
Studies
with oral fluorescein demonstrated that latanoprost, used at a dosage
about twice that of Xalatan, had no effect on the blood-aqueous
barrier,64
whereas PhXA34 at a dose approximately four
times the clinical dose of latanoprost in Xalatan induced a small but
statistically significant increase in the fluorescein content of the
aqueous humor.60
The mode of action of latanoprost was
confirmed to be increased uveoscleral outflow also in
humans.65
A somewhat surprising finding was that part of
the initial IOP reduction during the first few days of treatment was
lost as the treatment went on,62
66
and a once-daily dose
regimen resulted in better IOP reduction than twice
daily.67
68
The reason for this may be desensitization
caused by too frequent administration of the drug, but the level of the
signaling pathway at which the desensitization possibly occurs has not
been determined. Several dose–response, and dose-regimen studies
indicated that a once-daily dosage of approximately 50 µg/ml
(0.005%) is optimal or close to optimal,61
66
67
68
69
70
71
and
hence this dose was chosen for the phase III clinical trials, although
lower doses of latanoprost have been found relatively effective,
too.72
73
74
Four randomized, double-masked phase III clinical trials in which the
efficacy and safety of 0.005% latanoprost once daily was compared with
0.5% timolol twice daily were performed: one each in
Scandinavia,75
the United States,76
the
United Kingdom,77
and Japan.78
A total of 540
of the 992 patients with primary-open angle glaucoma, ocular
hypertension, capsular glaucoma, or pigmentary glaucoma, who enrolled
in the studies, were treated with latanoprost, and 496 of the
latanoprost-treated patients completed the studies. The treatment time
was 6 months, except for the study in Japan in which the treatment time
was 3 months. The diurnal IOP was based on a morning, noon and
afternoon measurement. In three of these studies latanoprost reduced
IOP significantly better than timolol, whereas the two drugs were about
equally effective in the study performed in the United
Kingdom77
(Table 5)
. The average diurnal IOP reduction achieved with latanoprost was 27%
to 34% from a baseline diurnal pressure level before treatment of 24
to 25 mm Hg, which can be considered satisfactory and clinically
useful. No significant upward drift in IOP was found during 12 to 24
months of treatment.79
80
81
82
View this table:
[in this window]
[in a new window]
|
Table 5. IOP-Reducing Effect of 0.005% Latanoprost Once Daily and 0.5% Timolol
Twice Daily in Phase III Clinical Trials
|
|
The main side effects of latanoprost in the phase III clinical trials
comprised slight conjunctival hyperemia and increased pigmentation of
the iris, a new side effect. The latter side effect documented by
sequential color photographs occurred at different frequencies in the
different studies, with highest incidence in the United Kingdom
study.77
The incidence, appearance, and dependence on eye
color of the side effect have previously been described in
detail.83
Patients with hazel or heterochromic eye color
(e.g., blue-brown or green-brown) seem to be predisposed to the side
effect, whereas the incidence in patients with homogenous eye color
(e.g., blue, gray, or brown) was less than 5% during 2 years of
treatment.83
Increased iridial pigmentation has also been
reported during isopropyl unoprostone treatment, another prostaglandin
analogue used to treat glaucoma.84
In addition to the
iridial pigmentation side effect, latanoprost has been shown to cause
darker and longer eye lashes in many patients.75
85
86
The
underlying mechanisms of these side effects are discussed in more
detail in the following section.
After the introduction of the drug on the market other less frequent
side effects have appeared. The most relevant are anterior
uveitis87
88
and cystoid macular edema
(CME).88
89
The exact mechanisms of these side effects
remain unknown, but it appears that in the majority of cases the side
effects have been confined to predisposed compromised eyes (e.g.,
aphakic or pseudophakic vitrectomized eyes) that not infrequently
previously have exhibited similar symptoms. Even in such eyes, the
incidence seems to be relatively low, and the side effects have usually
disappeared on termination of the treatment with the drug (unpublished
results, Pharmacia). However, CME is a serious side effect, and all
ophthalmologists prescribing the drug should be aware of the risk of
the side effect, particularly in aphakic and pseudophakic compromised
eyes.
Several clinical trials have also demonstrated that latanoprost can
successfully be combined with other glaucoma medications90
such as timolol,68
91
acetazolamide,92
epinephrine,93
and pilocarpine,94
the reason
for this probably being the unique IOP-reducing mechanism of
latanoprost.
|
Increased Iridial Pigmentation and Melanogenic Side Effect of
Prostaglandins
|
|---|
The property of latanoprost to induce increased iridial
pigmentation was first observed in the chronic toxicity tests. The
effect was obvious because cynomolgus monkeys with yellowish irides
were used, and one eye only was treated.95
96
Histologic
examination of the iris did not reveal any pathologic changes, and a
large well-controlled morphometric study was performed to assess
whether the color change was based on a proliferative effect of
latanoprost on the iridial melanocytes (unpublished results;
Pharmacia). The study showed that a 1-year treatment with doses ranging
from 2 to100 µg of latanoprost per day had no or, at most, a minimal
effect on the number of melanocytes in the iris (Fig. 4) . For instance, in the group of animals receiving a dose of 20 µg per
day, no difference was found in the melanocyte number between the
treated and control irides, although the most marked and frequent
effects of increased pigmentation were found in this dose group. At the
electron microscopic level no or only minute differences between
melanocytes in the control iris and the treated iris were seen in
another study in rhesus monkeys treated for 2 years with latanoprost
(unpublished results; Pharmacia), although at least in some animals
there seemed to be a tendency toward larger and more mature melanosomes
in the melanocytes of the treated eye (Fig. 5)
. Many in vitro studies have confirmed that latanoprost (or latanoprost
acid) has no significant proliferative effect on human iridial
melanocytes or uveal melanoma cell lines.97
98
99
View larger version (40K):
[in this window]
[in a new window]
|
Figure 4. Number of iridial melanocytes in histologic sections of latanoprost-
and vehicle-treated eyes of cynomolgus monkeys. The animals were
topically treated daily with the doses indicated for 1 year. In the
animals of the control group, one eye was treated with vehicle, and the
other eye served as an untreated control. The melanocytes in three
microscopic fields of five potassium permanganate semibleached,
hematoxylin-stained sections of the iris of each eye of all animals
were counted under masked conditions, and the means were calculated.
Open columns: contralateral control eyes; hatched
columns: treated eyes; n = 9 to 10 for each
dose group and 16 for the control group; mean ± SEM;
*P < 0.05, paired t-test.
(Collaboration with Pharmacon, Europe, L’Arbreslie, France.)
|
|
View larger version (156K):
[in this window]
[in a new window]
|
Figure 5. Electron micrograph of iridial melanocyte in vehicle-treated
contralateral control eye (A) and latanoprost-treated eye
(B) of a rhesus monkey. The animal was treated topically
with 20 µg latanoprost daily for 2 years. The melanosomes in the
treated eye appear larger and more mature than the melanosomes in the
contralateral control eye. Magnification, x6000. (Collaboration with
Pharmacon, Europe, L’Arbreslie, France.)
|
|
Several studies have also been performed in patients to investigate
whether the darkening of the iris color is due to a proliferative or
some sinister effect of latanoprost on the iridial melanocytes, but
there have been no abnormal findings. For instance, an
immunohistochemical study with monoclonal antibodies to proliferating
cell nuclear antigen (PCNA) and Ki-67 revealed no signs of cell
proliferation in iridectomy specimens of patients treated for 3 months
with latanoprost,100
101
and neither were any pathologic
changes detected in iridectomy specimens from patients treated for 6
months with latanoprost when studied with electron
microscopy.101
102
Similarly, in a large histopathologic
study in progress no clear-cut pathologic changes in iridectomy
specimens from patients treated with latanoprost have been found,
except for an apparent increase in pigmentation of the melanocytes in
some specimens.103
However, the end point of the increase
in iridial pigmentation in affected patients is not known, nor is it
known whether the newly formed pigment will disperse with time.
Evidence for the latter in controlled clinical trials so far has not
been found.83
The amount of eumelanin in the iridial melanocytes was found to be
significantly increased in cynomolgus monkeys that exhibited increased
pigmentation after 25 to 38 weeks of latanoprost treatment, whereas no
increase of the content of pheomelanin was found.104
This
demonstrates that latanoprost has an eumelanogenic effect on the
iridial melanocytes, and the results also argue against a local
migration of melanocytes as the main cause of the darkening of the
iris, because then the total amount of eumelanin would not have changed
significantly. We have also shown an increase of tyrosinase
transcription in the iridial melanocytes, both in vivo and in vitro,
during latanoprost treatment.105
In addition, a
melanogenic effect of latanoprost in the monkey iris was recently shown
by autoradiographic technique with tritiated methimazole which is
incorporated into newly formed melanin.106
No labeling of
the iridial pigment epithelium was found, indicating the absence of a
melanogenic effect of latanoprost in the pigment epithelium. Thus,
there is ample evidence that latanoprost induces melanogenesis in
iridial melanocytes of primates including humans.
Because latanoprost is a relatively selective FP receptor agonist, it
is reasonable to assume that the melanogenic effect is mediated by FP
receptors in the melanocytes. We have found the FP receptor transcript
and protein in monkey iridial melanocytes by in situ hybridization and
immunohistochemical techniques.107
At the genomic level,
we found no significant variation in the FP receptor protein among 10
randomly selected blood donors and 15 patients who acquired increased
iridial pigmentation during latanoprost treatment108
(Fig. 6)
. Only one variation was found at the amino acid level: Isoleucine was
exchanged for valine in the carboxyl-terminal part of the receptor.
Thus, genetic variation in the FP receptor cannot explain why some
individuals display increased pigmentation of the iris, whereas others
do not during latanoprost treatment.
View larger version (24K):
[in this window]
[in a new window]
|
Figure 6. Genetic variation of the FP prostanoid receptor in 10 healthy
individuals and 15 patients in whom increased pigmentation of the iris
developed during latanoprost treatment. Genomic DNA was isolated from
leukocytes, the gene was amplified by polymerase chain reaction, and
the fragments were sequenced using the A. L. F. Express
System (Amersham-Pharmacia Biotech, Uppsala, Sweden). The sequences
were compared with the cDNA sequence in the EMBL database (European
Molecular Biology Laboratory, Heidelberg, Germany; available in the
public domain at www.ebi.ac.uk/embl/), and deviations
from the latter were defined as genetic variation. Of four variations
found in the 25 individuals, only one resulted in a change of amino
acid, isoleucine being exchanged for valine in amino acid position 338.
Open symbols: absence of genetic variation;
shaded symbols: variation at the nucleotide level;
filled symbol: variation at the nucleotide and amino
acid levels. (Collaboration with Eurona Medical, Uppsala, Sweden.)
|
|
Recently, we also found that latanoprost acid consistently induces the
production of PGE2 in iridial melanocytes in
vitro, an effect possibly mediated by the cyclooxygenase (COX)-2
enzyme. Because EP receptors (e.g., EP1
receptors) have been demonstrated in the nuclear envelope in certain
cell systems,109
it is possible that
PGE2 functions as an intracellular signaling
substance to promote gene transcription.109
This
hypothetical mechanism could be important for the melanogenic response
to exogenous prostaglandins, such as latanoprost and isopropyl
unoprostone. In epidermal melanocytes, protein kinase C (PKC)ß has
been shown to activate the tyrosinase enzyme by phosphorylating two
serine residues,110
and it is possible that latanoprost,
which probably releases diacylglycerol in the iridial melanocytes
through FP receptor activation, has a similar effect.
|
Hypertrichotic Effect of Prostaglandins
|
|---|
Contradictory reports have previously been published concerning
the hypertrichotic effect of prostaglandins.111
112
113
However, as mentioned earlier latanoprost exerts a hypertrichotic
effect at least on the eye lashes, and this phenomenon is relatively
consistent.85
We have studied the receptor pharmacology of
the hypertrichotic effect of prostaglandins using a mouse model in
which the fur is shaved and the regrowth of the fur during local
treatment with selective prostanoid receptor agonists is studied. The
hypertrichotic effect seems to be mediated primarily by the FP receptor
(Fig. 7) . However, at the cellular level the mechanism in the hair follicle
remains unknown, and we have not found, for example, a proliferative
effect of latanoprost on fibroblasts or keratinocytes (Stjernschantz J,
unpublished results, 2000). A possibility is that latanoprost activates
follicular melanocytes, which in turn regulate the proliferation of
keratinocytes in the hair follicle.
View larger version (23K):
[in this window]
[in a new window]
|
Figure 7. Effect of selective prostanoid receptor agonists on hair growth
determined by measuring the rate of the regrowth of the fur in adult
male CBA-J mice. Approximately 4 cm2 of the fur was shaved,
and for the following 10 days the animals were treated with selective
prostanoid receptor agonists topically on the shaved area once daily.
The regrowth of the fur was assessed from photographs taken at regular
intervals during 28 days from the beginning of the treatment, and the
end point at day 28 is depicted. The control animals received vehicle
(0.5% Tween-80). The analogues were used as isopropyl or methyl esters
except for sulprostone. Mean ± SEM; n = 4 to
8 in each group; *P < 0.01 compared with the
control group, t-test.
|
|
|
Prostaglandins as Antiglaucoma Drugs
|
|---|
The concept of using autacoids such as prostaglandins as
IOP-reducing agents for glaucoma treatment is very attractive. It seems
logical that such local hormones would have a positive synchronized
effect in the tissue without untoward effects. However, a disadvantage
may be that the receptors to the autacoid are widely distributed in the
eye. The FP receptor, for example, has been demonstrated by in situ
hybridization and immunohistochemical techniques in the corneal
epithelium and endothelium, the lens epithelium, the ciliary muscle and
epithelium, and the iridial melanocytes; in different layers of the
retina, including the ganglion cell layer; and in the optic nerve and
the extraocular muscles.107
Thus, the tissue selectivity
is low. Another problem is the widely different functions of
prostaglandins reflected by the many subtypes of receptors. In spite of
this, it seems that the local hormone concept can be used successfully
with prostaglandins for the treatment of glaucoma, by using selective
analogues such as latanoprost, as was predicted by Bito114
in the early 1980s.
|
Acknowledgements
|
|---|
The author thanks Bernard Regnier and Roger Burnett (Pharmacon
Europe, L’Arbreslie, France); Lena Jonsson (Eurona Medical, Uppsala,
Sweden); Bahram Resul, Kiyo No, Henrik Jernstedt, Kerstin Bergh, Parri
Wentzel, Sofia Mikko, Eva Kumlin, and Therese Lifvendahl for advice and
technical assistance; and Iréne Aspman for help with editing of
the manuscript.
|
Footnotes
|
|---|
Submitted for publication July 17, 2000; accepted September 8, 2000.
Commercial relationships policy: F, I, P. (The author is a former
employee of Pharmacia and is a recipient of a research grant from
Pharmacia, but has no commercial interest in Xalatan.)
Corresponding author: Johan Stjernschantz, Department of Neuroscience,
Unit of Pharmacology, Box 593, Uppsala University Biomedical Center,
S-751 24 Uppsala, Sweden.
johan.stjernschantz{at}neuro.uu.se
|
References
|
|---|
-
Camras, CB, Bito, LZ (1981) Reduction of intraocular pressure in normal and glaucomatous primate (Aotus trivirgatus) eyes by topically applied PGF2 Curr Eye Res 1,205-209[Medline][Order article via Infotrieve]
-
Bito, LZ, Baroody, RA (1987) The ocular pharmacokinetics of eicosanoids and their derivatives, 1: comparison of ocular eicosanoid penetration and distribution following the topical application of PGF2, PGF2-1-methyl ester, and PGF2-1-isopropyl ester Exp Eye Res 44,217-226[Medline][Order article via Infotrieve]
-
Bito, LZ, Camras, CB, Gum, GG, Resul, B. (1989) The ocular hypotensive effects and side effects of prostaglandins on the eyes of experimental animals Bito, LZ Stjernschantz, J eds. The Ocular Effects of Prostaglandins and Other Eicosanoids ,349-368 Alan R Liss New York.
-
Woodward, DF, Chan, MF, Burke, JA, Cheng-Bennett, A, et al (1994) Studies on the ocular hypotensive effects of prostaglandin F2 ester prodrugs and receptor selective prostaglandin analogs J Ocul Pharmacol 10,177-193[Medline][Order article via Infotrieve]
-
Groeneboer, MC, Hoyng, PFJ, Kuizenga, A. (1989) Prostaglandin F2 isopropyl ester versus iloprost phenacyl ester in rabbit and beagle eyes Curr Eye Res 8,131-138[Medline][Order article via Infotrieve]
-
Nilsson, SFE, Samuelsson, M, Bill, A, Stjernschantz, J. (1989) Increased uveoscleral outflow as a possible mechanism of ocular hypotension caused by prostaglandin F2-1-isopropylester in the cynomolgus monkey Exp Eye Res 48,707-716[Medline][Order article via Infotrieve]
-
Wang, R-F, Camras, CB, Lee, P-Y, et al (1990) Effects of prostaglandins F2, A2, and their esters in glaucomatous monkey eyes Invest Ophthalmol Vis Sci 31,2466-2470[Abstract]
-
Stern, FA, Bito, LZ (1982) Comparison of the hypotensive and other ocular effects of prostaglandins E2 and F2 on cat and rhesus monkey eyes Invest Ophthalmol Vis Sci 22,588-598[Abstract/Free Full Text]
-
Bito, LZ, Draga, A, Blanco, DJ, Camras, CB (1983) Long-term maintenance of reduced intraocular pressure by daily or twice daily topical application of prostaglandins to cat or rhesus monkey eyes Invest Ophthalmol Vis Sci 24,312-319[Abstract/Free Full Text]
-
Lee, P-Y, Podos, SM, Severin, CH (1984) Effect of prostaglandin F2 on aqueous humor dynamics of rabbit, cat, and monkey Invest Ophthalmol Vis Sci 25,1087-1093[Abstract/Free Full Text]
-
Cariño, Miranda O, Bito, LZ (1989) The putative and demonstrated miotic
effects of prostaglandins in mammals Bito, LZ Stjernschantz, J eds. The Ocular Effects of Prostaglandins and Other
Eicosanoids ,171-195 Alan R Liss New York.
-
Villumsen, J, Alm, A. (1989) Prostaglandin F2-isopropylester eye drops: effects in normal human eyes Br J Ophthalmol 73,419-426[Abstract/Free Full Text]
-
Giuffrè, G. (1985) The effects of prostaglandin F2 in the human eye Graefe’s Arch Clin Exp Ophthalmol 222,139-141[Medline][Order article via Infotrieve]
-
Lee, P-Y, Shao, H, Liang, X, Qu, C-K. (1988) The effect of prostaglandin F2 on intraocular pressure in normotensive human subjects Invest Ophthalmol Vis Sci 29,1474-1477[Abstract/Free Full Text]
-
Camras, CB, Siebold, EC, Lustgarten, JS, Serle, JB, et al (1989) Maintained reduction of intraocular pressure by prostaglandin F2-1-isopropyl ester applied in multiple doses in ocular hypertensive and glaucoma patients Ophthalmology 96,1329-1336[Medline][Order article via Infotrieve]
-
Villumsen, J, Alm, A, Söderström, M. (1989) Prostaglandin F2-isopropylester eye drops: effect on intraocular pressure in open angle glaucoma Br J Ophthalmol 73,975-979[Abstract/Free Full Text]
-
Villumsen, J, Alm, A. (1990) The effect on intraocular pressure of adding prostaglandin F2-isopropylester to timolol in patients with open angle glaucoma: a randomized, masked, placebo-controlled study Arch Ophthalmol 108,1102-1105[Abstract/Free Full Text]
-
Lee, P-Y, Shao, H, Camras, CB, Podos, SM (1991) Additivity of prostaglandin F2-1-isopropyl ester to timolol in glaucoma patients Ophthalmology 98,1079-1082[Medline][Order article via Infotrieve]
-
Stjernschantz, J, Selén, G, Astin, M, Resul, B. (2000) Microvascular effects of selective prostaglandin analogues in the eye with special reference to latanoprost and glaucoma treatment Prog Retinal Eye Res 19,459-496[Medline][Order article via Infotrieve]
-
Crawford, K, Kaufman, PL (1987) Pilocarpine antagonizes prostaglandin F2-induced ocular hypotension in monkeys Arch Ophthalmol 105,1112-1116[Abstract/Free Full Text]
-
Gabelt, BT, Kaufman, PL (1989) Prostaglandin F2 increases uveoscleral outflow in the cynomolgus monkey Exp Eye Res 49,389-402[Medline][Order article via Infotrieve]
-
Kerstetter, JR, Brubaker, RF, Wilson, SE, Kullerstrand, LJ (1988) Prostaglandin F2-1-isopropylester lowers intraocular pressure without decreasing aqueous humor flow Am J Ophthalmol 105,30-34[Medline][Order article via Infotrieve]
-
Kennedy, I, Coleman, RA, Humphrey, PPA, Levy, GP, Lumley, P. (1982) Studies on characterisation of prostanoid receptors: a proposed classification Prostaglandins 24,667-689[Medline][Order article via Infotrieve]
-
Coleman, RA, Kennedy, I, Humphrey, PPA, Bunce, K, Lumley, P. (1990) Prostanoids and their receptors Emmett, JC eds. Comprehensive Medicinal Chemistry. Membranes and Receptors 3,643-714 Pergamon Press Oxford.
-
Coleman, RA, Smith, WL, Narumiya, S., VIII (1994) International union of pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes Pharmacol Rev. 46,205-229[Medline][Order article via Infotrieve]
-
Resul, B, Stjernschantz, J, Selén, G, Bito, LZ (1997) Structure-activity relationships and receptor profiles of some ocular hypotensive prostanoids Surv Ophthalmol 41(suppl 2),S47-S52
-
Bito, LZ (1984) Species differences in the responses of the eye to irritation and trauma: a hypothesis of divergence in ocular defense mechanisms, and the choice of experimental animals for eye research Exp Eye Res 39,807-829[Medline][Order article via Infotrieve]
-
Stjernschantz, J. (1984) Autacoids and neuropeptides Sears, ML eds. Handbook of Experimental Pharmacology 69,311-365 Springer Verlag Berlin.
-
Unger, WG (1989) Mediation of the ocular response to injury and irritation: peptides versus prostaglandins Bito, LZ Stjernschantz, J eds. The Ocular Effects of Prostaglandins and Other Eicosanoids ,293-328 Alan R Liss New York.
-
Änggård, E. (1966) The biological activities of three metabolites of prostaglandin E1 Acta Physiol Scand 66,509[Medline][Order article via Infotrieve]
-
Andersen, NH (1988) Structure-activity correlations for prostanoid action Curtis-Prior, PB eds. Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids ,152-170 Churchill Livingstone Edinburgh.
-
Sakurai, M, Araie, M, Oshika, T, Mori, M, et al (1991) Effects of topical application of UF-021, a novel prostaglandin derivative, on aqueous humor dynamics in normal human eyes Jpn J Ophthalmol 35,156-165[Medline][Order article via Infotrieve]
-
Woodward, DF, Burke, LS, Williams, BP, Palmer, LA, et al (1989) Prostaglandin F2 effects on intraocular pressure negatively correlate with FP-receptor stimulation Invest Ophthalmol Vis Sci 30,1838-1842[Abstract/Free Full Text]
-
Stjernschantz, J, Resul, B. (1992) Phenyl substituted prostaglandin analogs for glaucoma treatment Drugs Future 17,691-704
-
Resul, B, Stjernschantz, J, No, K, et al (1993) Phenyl-substituted prostaglandins: potent and selective antiglaucoma agents J Med Chem 36,243-248[Medline][Order article via Infotrieve]
-
Liljebris, C, Selén, G, Resul, B, Stjernschantz, J, Hacksell, U. (1995) Derivatives of 17-phenyl-18,19,20-trinor prostaglandin F2 isopropyl ester: potential antiglaucoma agents J Med Chem 38,289-304[Medline][Order article via Infotrieve]
-
Serle, JB, Podos, SM, Kitazawa, Y, Wang, R-F. (1998) A comparative study of latanoprost (Xalatan) and isopropyl unoprostone (Rescula) in normal and glaucomatous monkey eyes Jpn J Ophthalmol 42,95-100[Medline][Order article via Infotrieve]
-
Bhattacherjee, P, Williams, BS, Paterson, CA (1999) Responses of intraocular pressure and the pupil of feline eyes to prostaglandin EP1 and FP receptor agonists Invest Ophthalmol Vis Sci 40,3047-3053[Abstract/Free Full Text]
-
Stjernschantz, J, Selén, G, Ocklind, A, Resul, B. (1998) Effects of latanoprost and related prostaglandin analogues Alm, A Weinreb, RN eds. Uveoscleral Outflow. Biology and Clinical Aspects ,57-72 Mosby-Wolfe Medical Communications London.
-
Stjernschantz, J, Selén, G, Sjöquist, B, Resul, B (1995) Preclinical pharmacology of latanoprost, a phenyl-substituted
PGF2 analogue Adv Prostaglandin, Thromboxane Leukot Res. 23,513-5180[Medline][Order article via Infotrieve]
-
Lindsey, JD, To, HD, Weinreb, RN (1994) Induction of c-Fos by prostaglandin F2 in human ciliary smooth muscle cells Invest Ophthalmol Vis Sci 35,242-250[Abstract/Free Full Text]
-
Lindsey, JD, Kashiwagi, K, Boyle, D, et al (1996) Prostaglandins increase proMMP-1 and proMMP-3 secretion by human ciliary smooth muscle cells Curr Eye Res 15,869-875[Medline][Order article via Infotrieve]
-
Weinreb, RN, Kashiwagi, K, Kashiwagi, F, Tsukahara, S, Lindsey, JD (1997) Prostaglandins increase matrix metalloproteinase release from human ciliary smooth muscle cells Invest Ophthalmol Vis Sci 38,2772-2780[Abstract/Free Full Text]
-
Lindsey, JD, Kashiwagi, K, Kashiwagi, F, Weinreb, RN (1997) Prostaglandin action on ciliary smooth muscle extracellular matrix metabolism: implications for uveoscleral outflow Surv Ophthalmol 41(suppl 2),S53-S59
-
Lindsey, JD, Kashiwagi, K, Kashiwagi, F, Weinreb, RN (1997) Prostaglandins alter extracellular matrix adjacent to human ciliary muscle cells in vitro Invest Ophthalmol Vis Sci 38,2214-2223[Abstract/Free Full Text]
-
Lindsey, JD, Weinreb, RN (1998) Effects of prostaglandins on uveoscleral outflow Alm, A Weinreb, RN eds. Uveoscleral Outflow. Biology and Clinical Aspects ,41-55 Mosby-Wolfe Medical Communications London.
-
Sagara, T, Gaton, DD, Lindsey, JD, et al (1999) Topical prostaglandin F2 treatment reduces collagen types I, III and IV in the monkey uveoscleral outflow pathway Arch Ophthalmol 117,794-801[Abstract/Free Full Text]
-
Ocklind, A. (1998) Effect of latanoprost on the extracellular matrix of the ciliary muscle: a study on cultured cells and tissue sections Exp Eye Res 67,179-191[Medline][Order article via Infotrieve]
-
Astin, M, Stjernschantz, J, Selén, G. (1994) Role of nitric oxide in PGF2-induced ocular hyperemia Exp Eye Res 59,401-408[Medline][Order article via Infotrieve]
-
Astin, M, Stjernschantz, J. (1998) Mediation of prostaglandin F2-induced ocular surface hyperemia by sensory nerves in rabbits Curr Eye Res 16,886-890
-
Stjernschantz, J, Selén, G, Astin, M, Karlsson, M, Resul, B. (1999) Effect of latanoprost on regional blood flow and capillary permeability in the monkey eye Arch Ophthalmol 117,1363-1367[Abstract/Free Full Text]
-
Hoyng, PFJ, Rulo, AH, Greve, EL, Astin, M, Gjötterberg, M. (1997) Fluorescein angiographic evaluation of the effect of latanoprost treatment on blood-retinal barrier integrity: a review of studies conducted on pseudophakic glaucoma patients and on phakic and aphakic monkeys Surv Ophthalmol 41(suppl 2),S83-S88
-
Smith, AP, Cutbert, MF, Dunlop, LS (1975) Effects of inhaled prostaglandins E1, E2, and F2 on the airway resistance of healthy and asthmatic men Clin Sci Mol Med 48,421-430[Medline][Order article via Infotrieve]
-
Mathé, AA, Hedqvist, P. (1975) Effect of prostaglandins F2 and E2 on airway conductance in healthy subjects and asthmatic patients Am Rev Resp Dis 111,313-320[Medline][Order article via Infotrieve]
-
Featherstone, RL, Robinson, C, Holgate, ST, Church, MK (1990) Evidence for thromboxane receptor mediated contraction of guinea-pig and human airways in vitro by prostaglandin (PG) D2, 9, 11ß-PGF2 and PGF2 Arch Pharmacol 341,439-443
-
Hanley, SP (1986) Prostaglandins and the lung Lung 164,65-77[Medline][Order article via Infotrieve]
-
Hedner, J, Svedmyr, N, Lunde, H, Mandahl, A. (1997) The lack of respiratory effects of the ocular hypotensive drug latanoprost in patients with moderate-steroid treated asthma Surv Ophthalmol 41(suppl 2),S111-S115
-
Hedner, J, Everts, B, Ström, Möller C (1999) Latanoprost and respiratory function in asthmatic patients: randomized, double-masked, placebo-controlled crossover evaluation Arch Ophthalmol. 117,1305-1309[Abstract/Free Full Text]
-
Kumlin, E, Gustafsson, G, Stjernschantz, J. (2000) Effect of latanoprost acid and PGF2 on bronchial smooth muscle in vitro [ARVO Abstract] Invest Ophthalmol Vis Sci 41,S573Abstract nr 3041
-
Alm, A, Villumsen, J. (1991) PhXA34, a new potent ocular hypotensive drug: a study on dose-response relationship and on aqueous humor dynamics in healthy volunteers Arch Ophthalmol 109,1564-1568[Abstract/Free Full Text]
-
Villumsen, J, Alm, A. (1992) PhXA34–a prostaglandin F2 analogue: effect on intraocular pressure in patients with ocular hypertension Br J Ophthalmol 76,214-217[Abstract/Free Full Text]
-
Camras, CB, Schumer, RA, Marsk, A, et al (1992) Intraocular pressure reduction with PhXA34, a new prostaglandin analogue, in patients with ocular hypertension Arch Ophthalmol 110,1733-1738[Abstract/Free Full Text]
-
Hotehama, Y, Mishima, HK (1993) Clinical efficacy of PhXA34 and PhXA41, two novel prostaglandin F2-isopropyl ester analogues for glaucoma treatment Jpn J Ophthalmol 37,259-269[Medline][Order article via Infotrieve]
-
Ziai, N, Dolan, JW, Kacere, RD, Brubaker, RF (1993) The effects on aqueous dynamics of PhXA41, a new prostaglandin F2 analogue, after topical application in normal and ocular hypertensive human eyes Arch Ophthalmol 111,1351-1358[Abstract/Free Full Text]
-
Toris, CB, Camras, CB, Yablonski, ME (1993) Effects of PhX41, a new prostaglandin F2 analog, on aqueous humor dynamics in human eyes Ophthalmology 100,1297-1304[Medline][Order article via Infotrieve]
-
Alm, A, Villumsen, J, Törnquist, P, Mandahl, A, et al (1993) Intraocular pressure-reducing effect of PhXA41 in patients with increased eye pressure: a one-month study Ophthalmology 100,1312-1317[Medline][Order article via Infotrieve]
-
Nagasubramanian, S, Sheth, GP, Hitchings, RA, Stjernschantz, J. (1993) Intraocular pressure-reducing effect of PhXA41 in ocular hypertension: comparison of dose regimens Ophthalmology 100,1305-1311[Medline][Order article via Infotrieve]
-
Alm, A, Widengård, I, Kjellgren, D, Söderström, M, et al (1995) Latanoprost administered once daily caused a maintained reduction of intraocular pressure in glaucoma patients treated concomitantly with timolol Br J Ophthalmol 79,12-16[Abstract/Free Full Text]
-
Hotehama, Y, Mishima, HK, Kitazawa, Y, Masuda, K. (1993) Ocular hypotensive effect of PhXA41 in patients with ocular hypertension or primary open-angle glaucoma Jpn J Ophthalmol 37,270-274[Medline][Order article via Infotrieve]
-
Coakes, RL, O’Neill, E, Potts, MJ, Longstaff, S. (1993) Dose-finding study with PhXA41 (latanoprost) in patients with elevated intraocular pressure College of Ophthalmologists, Annual Congress Birmingham, UK.
-
Rácz, P, Ruzsonyi, MR, Zoltán, TN, Bito, LZ (1993) Maintained intraocular pressure reduction with once-a-day application of a new prostaglandin F2 analogue (PhXA41): an in-hospital, placebo-controlled study Arch Ophthalmol 111,657-661[Abstract/Free Full Text]
-
Diestelhorst, M, Roters, S, Krieglstein, GK (1997) The effect of latanoprost 0.005% once daily versus 0.0015% twice daily on intraocular pressure and aqueous humour protein concentration in glaucoma patients: a randomized, double-masked comparison with timolol 0.5% Graefes Arch Clin Exp Ophthalmol. 235,20-26[Medline][Order article via Infotrieve]
-
Lusky, M, Ticho, U, Glovinsky, J, et al (1997) A comparative study of two dose regimens of latanoprost in patients with elevated intraocular pressure Ophthalmology 104,1720-1724[Medline][Order article via Infotrieve]
-
Friström, B, Nilsson, SE (1997) A double masked comparison of the intraocular pressure reducing effect of latanoprost 0.005% and 0.001% administered once daily in open angle glaucoma and ocular hypertension. Br J Ophthalmol. 81,867-870[Abstract/Free Full Text]
-
Alm, A, Stjernschantz, J, . the Scandinavian Latanoprost Study Group (1995) Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning: a comparison with timolol Ophthalmology 102,1743-1752[Medline][Order article via Infotrieve]
-
Camras, CB, . the United States Latanoprost Study Group (1996) Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: a six-month, masked, multicenter trial in the United States Ophthalmology 103,138-147[Medline][Order article via Infotrieve]
-
Watson, P, Stjernschantz, J, . the Latanoprost Study Group (1996) A six-month, randomized, double-masked study comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension Ophthalmology. 103,126-137[Medline][Order article via Infotrieve]
-
Mishima, HK, Masuda, K, Kitazawa, Y, Azuma, I, Araie, M (19968) A comparison of latanoprost and timolol in primary open-angle glaucoma and ocular hypertension. A 12-week study Arch Ophthalmol. 114,929-932[Abstract/Free Full Text]
-
Camras, CB, Alm, A, Watson, P, Stjernschantz, J, . the Latanoprost Study Groups (1996) Latanoprost, a prostaglandin analog, for glaucoma therapy:
efficacy and safety after 1 year of treatment in 198 patients Ophthalmology 103,1916-1924[Medline][Order article via Infotrieve]
-
Camras, CB, Wax, MB, Ritch, R, et al (1998) Latanoprost treatment for glaucoma: effects of treating for 1 year and of switching from timolol Am J Ophthalmol 126,390-399[Medline][Order article via Infotrieve]
-
Watson, P, . the Latanoprost Study Group (1998) Latanoprost: two years’ experience of its use in the United Kingdom Ophthalmology 105,82-87[Medline][Order article via Infotrieve]
-
Alm, A, Widengård, I. (2000) Latanoprost: experience of 2-year treatment in Scandinavia Acta Ophthalmol Scand 78,71-76[Medline][Order article via Infotrieve]
-
Wistrand, PJ, Stjernschantz, J, Olsson, K. (1997) The incidence and time-course of latanoprost-induced iridial pigmentation as a function of eye color Surv Ophthalmol 41(suppl 2),S129-S138
-
Yamamoto, T, Kitazawa, Y. (1997) Iris-color change developed after topical isopropyl unoprostone treatment J Glaucoma 6,430-432[Medline][Order article via Infotrieve]
-
Johnstone, MA (1997) Hypertrichosis and increased pigmentation of eyelashes and adjacent hair in region of the ipsilateral eyelids of patients treated with unilateral topical latanoprost Am J Ophthalmol 124,544-547[Medline][Order article via Infotrieve]
-
Wand, M. (1997) Latanoprost and hyperpigmentation of eyelashes Arch Ophthalmol 115,1206-1208[Abstract/Free Full Text]
-
Fechtner, RD, Khouri, AS, Zimmerman, TJ, et al (1998) Anterior uveitis associated with latanoprost Am J Ophthalmol 126,37-41[Medline][Order article via Infotrieve]
-
Warwar, RE, Bullock, JD, Ballal, D. (1998) Cystoid macular edema and anterior uveitis associated with latanoprost use: experience and incidence in a retrospective review of 94 patients Ophthalmology 105,263-268[Medline][Order article via Infotrieve]
-
Schumer, RA, Camras, CB, Mandahl, AK (2000) Latanoprost and cystoid macular edema: is there a causal relation? Curr Opin Ophthalmol 11,94-100[Medline][Order article via Infotrieve]
-
Hoyng, PFJ, Rulo, A, Greve, E, Watson, P, Alm, A. (1997) The additive intraocular pressure-lowering effect of latanoprost in combined therapy with other ocular hypotensive agents Surv Ophthalmol 41(suppl 2),S93-S98
-
Rulo, AH, Greve, EL, Hoyng, PF (1994) Additive effect of latanoprost, a prostaglandin F2 analogue, and timolol in patients with elevated intraocular pressure Br J Ophthalmol 78,899-902[Abstract/Free Full Text]
-
Rulo, AH, Greve, EL, Hoyng, PF (1997) Additive ocular hypotensive effect of latanoprost and acetazolamide: a short-term study in patients with elevated intraocular pressure Ophthalmology 104,1503-1507[Medline][Order article via Infotrieve]
-
Widengård, I, Maepea, O, Alm, A. (1998) Effects of latanoprost and dipivefrin, alone or combined, on intraocular pressure and on blood-aqueous barrier permeability Br J Ophthalmol 82,404-406[Abstract/Free Full Text]
-
Friström, B, Nilsson, SEG (1993) Interaction of PhXA41, a new prostaglandin analogue, with pilocarpine: a study on patients with elevated intraocular pressure Arch Ophthalmol 111,662-665[Abstract/Free Full Text]
-
Stjernschantz, J. (1998) Significance and time-course of prostaglandin-induced increase in iridial pigmentation in primates and man Diestelhorst, M eds. Prostaglandins in Ophthalmology ,111-116 Kaden Verlag Heidelberg.
-
Selén, G, Stjernschantz, J, Resul, B. (1997) Prostaglandin-induced iridial pigmentation in primates Surv Ophthalmol 41(suppl 2),S125-S128
-
Drago, F, Marino, A, La Manna, C. (1999) -methyl-p-tyrosine inhibits latanoprost-induced melanogenesis in vitro Exp Eye Res 68,85-90[Medline][Order article via Infotrieve]
-
Hu, D-N, Stjernschantz, J, McCormick, SA (2000) Effect of prostaglandins A2, E1, F2 and latanoprost on cultured human iridal melanocytes Exp Eye Res 70,113-120[Medline][Order article via Infotrieve]
-
Dutkiewicz, R, Albert, DM, Levin, LA (2000) Effects of latanoprost on tyrosinase activity and mitotic index of cultured melanoma lines Exp Eye Res 70,563-569[Medline][Order article via Infotrieve]
-
Grierson, I, Pfeiffer, N, Davies, H, Sell, E, Wingken-Böhres, A, Hochgesand, D. (1998) Immunohistochemical evaluation of the iris with proliferation markers after treatment with latanoprost [ARVO Abstract] Invest Ophthalmol Vis Sci 39(4),S421Abstract nr 1964
-
Grierson, I, Pfeiffer, N. (1998) The morphology if irides treated with latanoprost: a review of current studies Diestelhorst, M eds. Prostaglandins in Ophthalmology ,105-110 Kaden Verlag Heidelberg.
-
Pfeiffer, N, Grierson, I, Sell, E, Davies, H, Wingken-Böhres, A, Hochgesand, D. (1997) Morphological evaluation of the iris after treatment with latanoprost [ARVO Abstract] Invest Ophthalmol Vis Sci 38(4),S244Abstract nr 1134
-
Albert, DM, Green, WR, Grossniklaus, HE, Zimbric, ML, Gangnon, RE, Fisher, MR, . Xalatan Pigment Study Group (2000) Histopathological findings in iris specimens from patients with glaucoma treated with latanoprost [ARVO Abstract] Invest Ophthalmol Vis Sci. 41(4),S509Abstract nr 2712
-
Prota, G, Vincensi, MR, Napolitano, A, Selén, G, Stjernschantz, J. (2000) Latanoprost stimulates eumelanogenesis in iridial melanocytes of cynomolgus monkeys Pigment Cell Res 13,147-150[Medline][Order article via Infotrieve]
-
Stjernschantz, J, Ocklind, A, Wentzel, P, Lake, S, Hu, D-N. (2000) Latanoprost-induced increase of tyrosinase transcription in iridial melanocytes Acta Ophthalmol Scand 78,618-622[Medline][Order article via Infotrieve]
-
Lindquist, NG, Larsson, BS, Stjernschantz, J. (1999) Increased pigmentation of iridial melanocytes in primates induced by a prostaglandin analogue Exp Eye Res 68,431-436[Medline][Order article via Infotrieve]
-
Ocklind, A, Lake, S, Wentzel, P, Nistér, M, Stjernschantz, J. (1996) Localization of the prostaglandin F2 receptor messenger RNA and protein in the cynomolgus monkey eye Invest Ophthalmol Vis Sci 37,716-726[Abstract/Free Full Text]
-
Stjernschantz, J, Jonsson, L, Alm, A, Lindén, C, Resul, B. (1998) Genetic variation in the coding regions of the FP prostanoid receptor in patients exhibiting increased pigmentation of the iris during latanoprost treatment [ARVO Abstract] Invest Ophthalmol Vis Sci 39(4),S514Abstract nr 2354
-
Bhattacharya, M, Peri, KG, Almazan, G, et al (1998) Nuclear localization of prostaglandin E2 receptors Proc Natl Acad Sci USA 95,15792-15797[Abstract/Free Full Text]
-
Park, H-Y, Perez, JM, Laursen, R, Hara, M, Gilchrest, BA (1999) Protein kinase C-ß activates tyrosinase by phosphorylating serine residues in its cytoplasmic domain J Biol Chem 274,16470-16478[Abstract/Free Full Text]
-
Houssay, AB, Arias, NH, Davison, TA, Epper, CE (1976) Effects of prostaglandins upon hair growth in mice Acta Physiol Lat Am 26,186-191[Medline][Order article via Infotrieve]
-
Olsen, EA, DeLong, E. (1990) Transdermal viprostol in the treatment of male pattern baldness J Am Acad Dermatol 23,470-472[Medline][Order article via Infotrieve]
-
Malkinson, FD, Geng, L, Hanson, WR (1993) Prostaglandins protect against murine hair injury produced by ionizing radiation or doxorubicin J Invest Dermatol 101(suppl),135S-137S[Medline][Order article via Infotrieve]
-
Bito, LZ (1984) Prostaglandins, other eicosanoids, and their derivatives as potential antiglaucoma agents Drance, SM Neufeld, AH eds. Glaucoma: Applied Pharmacology in Medical Treatment ,477-505 Grune & Stratton Orlando.
This article has been cited by other articles:
|
|
|
|
 
D. F. Woodward, S. F. E. Nilsson, C. B. Toris, A. B. Kharlamb, A. L. Nieves, and A. H.-P. Krauss
Prostanoid EP4 Receptor Stimulation Produces Ocular Hypotension by a Mechanism That Does Not Appear to Involve Uveoscleral Outflow
Invest. Ophthalmol. Vis. Sci.,
July 1, 2009;
50(7):
3320 - 3328.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F Honrubia, J Garcia-Sanchez, V Polo, J M M. de la Casa, and J Soto
Conjunctival hyperaemia with the use of latanoprost versus other prostaglandin analogues in patients with ocular hypertension or glaucoma: a meta-analysis of randomised clinical trials
Br J Ophthalmol,
March 1, 2009;
93(3):
316 - 321.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J H Chang, P McCluskey, T Missotten, P Ferrante, B Jalaludin, and S Lightman
Use of ocular hypotensive prostaglandin analogues in patients with uveitis: does their use increase anterior uveitis and cystoid macular oedema?
Br J Ophthalmol,
July 1, 2008;
92(7):
916 - 921.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C B Camras, N A Sharif, M B Wax, and J Stjernschantz
Bimatoprost, the prodrug of a prostaglandin analogue
Br J Ophthalmol,
June 1, 2008;
92(6):
862 - 863.
[Full Text]
[PDF]
|
|
|
|
|
|
|
L B Cantor
Author's reply
Br J Ophthalmol,
June 1, 2008;
92(6):
863 - 864.
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. B Cantor, J. Hoop, D. Wudunn, C.-W. Yung, Y. Catoira, S. Valluri, A. Cortes, A. Acheampong, D. F Woodward, and L. A Wheeler
Levels of bimatoprost acid in the aqueous humour after bimatoprost treatment of patients with cataract
Br J Ophthalmol,
May 1, 2007;
91(5):
629 - 632.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. Gonzalez, L. Baiza-Duran, J. Quintana-Hau, R. Tornero-Montano, G. Castaneda-Hernandez, M. Ortiz, F. Alarcon-Oceguera, M. Beltran-Loustaunau, M. Cortez-Gastelum, J. Garciduenas-Mejia, et al.
Comparison of the Stability, Efficacy, and Adverse Effect Profile of the Innovator 0.005% Latanoprost Ophthalmic Solution and a Novel Cyclodextrin-containing Formulation
J. Clin. Pharmacol.,
January 1, 2007;
47(1):
121 - 126.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A Alm
Can NSAIDs and prostaglandin analogues be combined?
Br J Ophthalmol,
March 1, 2006;
90(3):
259 - 260.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Ota, M. Aihara, S. Narumiya, and M. Araie
The Effects of Prostaglandin Analogues on IOP in Prostanoid FP-Receptor-Deficient Mice
Invest. Ophthalmol. Vis. Sci.,
November 1, 2005;
46(11):
4159 - 4163.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. L. Hebert, M. Carmosino, O. Saito, G. Yang, C. A. Jackson, Z. Qi, R. M. Breyer, C. Natarajan, A. N. Hata, Y. Zhang, et al.
Characterization of a Rabbit Kidney Prostaglandin F2{alpha} Receptor Exhibiting Gi-restricted Signaling That Inhibits Water Absorption in the Collecting Duct
J. Biol. Chem.,
October 14, 2005;
280(41):
35028 - 35037.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-M. Guenoun, C. Baudouin, P. Rat, A. Pauly, J.-M. Warnet, and F. Brignole-Baudouin
In Vitro Study of Inflammatory Potential and Toxicity Profile of Latanoprost, Travoprost, and Bimatoprost in Conjunctiva-Derived Epithelial Cells
Invest. Ophthalmol. Vis. Sci.,
July 1, 2005;
46(7):
2444 - 2450.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Ota, H. Murata, E.-i. Sugimoto, M. Aihara, and M. Araie
Prostaglandin Analogues and Mouse Intraocular Pressure: Effects of Tafluprost, Latanoprost, Travoprost, and Unoprostone, Considering 24-Hour Variation
Invest. Ophthalmol. Vis. Sci.,
June 1, 2005;
46(6):
2006 - 2011.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H Kang, L. R Pasquale, W. C Willett, B. A Rosner, K. M Egan, N. Faberowski, and S. E Hankinson
Dietary fat consumption and primary open-angle glaucoma
Am. J. Clinical Nutrition,
May 1, 2004;
79(5):
755 - 764.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B'A. T. Gabelt, J. L. Seeman, S. M. Podos, T. W. Mittag, and P. L. Kaufman
Aqueous Humor Dynamics in Monkeys after Topical 8-Iso PGE2
Invest. Ophthalmol. Vis. Sci.,
March 1, 2004;
45(3):
892 - 899.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Richter, A. H.-P. Krauss, D. F. Woodward, and E. Lutjen-Drecoll
Morphological Changes in the Anterior Eye Segment after Long-Term Treatment with Different Receptor Selective Prostaglandin Agonists and a Prostamide
Invest. Ophthalmol. Vis. Sci.,
October 1, 2003;
44(10):
4419 - 4426.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Introduction
PGF2{alpha}-Isopropyl Ester as a...
