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Latanoprost in the treatment of glaucoma

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Prostaglandins are approved by the European Glaucoma Society guidelines as first-line treatment for glaucoma. This review focuses on latanoprost, an ester prodrug of prostaglandin (PG) F2α, which was the first of the currently available topical PGF2α analogs to be launched for glaucoma or ocular hypertension and which still accounts for the majority of prescriptions. It is better absorbed than the parent compound through the cornea, and peak concentration of the active drug is in the aqueous humor 1-2 hours after topical dosing (15-30 ng/mL). Metabolism occurs mainly in the liver. Latanoprost (0.005%) has been very well studied in clinical trials and meta-analyses that show it to be generally as effective as the other PG analogs (bimatoprost, travoprost, and tafluprost) and more effective than timolol, dorzolamide, and brimonidine. Latanoprost has good short- and long-term safety and tolerability profiles. In common with other prostaglandins, it lacks systemic effects, but can cause ocular adverse events such as conjunctival hyperemia, pigmentation of the iris, periocular skin or eyelashes, hypertrichosis, and ocular surface effects or irritation. Latanoprost is significantly better tolerated than either bimatoprost or travoprost. Patients treated with latanoprost have better compliance and persist with therapy longer than those that are given other drugs. An improved formulation of latanoprost without the preservative benzalkonium chloride has recently been developed. It is as effective as conventional latanoprost, has a lower incidence of hyperemia, and can be stored at room temperature. In conclusion, latanoprost has the best efficacy-tolerability ratio of the PG analogs available for glaucoma treatment, and has good compliance and persistence. These factors should be improved further by the recent development of preservative-free latanoprost.
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Clinical Ophthalmology 2014:8 1967–1985
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REVIEW
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http://dx.doi.org/10.2147/OPTH.S59162
Latanoprost in the treatment of glaucoma
Albert Alm
Department of Neuroscience,
Ophthalmology, University Hospital,
Uppsala, Sweden
Correspondence: Albert Alm
Department of Neuroscience
(Ophthalmology), Uppsala University
Biomedical Centre, Husargarten 3,
SE-751 24, Uppsala, Sweden
Tel +46 186 115 135
Email albert.alm@akademiska.se
Abstract: Prostaglandins are approved by the European Glaucoma Society guidelines as first-
line treatment for glaucoma. This review focuses on latanoprost, an ester prodrug of prostaglandin
(PG) F
2α
, which was the first of the currently available topical PGF
2α
analogs to be launched for
glaucoma or ocular hypertension and which still accounts for the majority of prescriptions. It
is better absorbed than the parent compound through the cornea, and peak concentration of the
active drug is in the aqueous humor 1–2 hours after topical dosing (15–30 ng/mL). Metabolism
occurs mainly in the liver. Latanoprost (0.005%) has been very well studied in clinical trials and
meta-analyses that show it to be generally as effective as the other PG analogs (bimatoprost,
travoprost, and tafluprost) and more effective than timolol, dorzolamide, and brimonidine.
Latanoprost has good short- and long-term safety and tolerability profiles. In common with
other prostaglandins, it lacks systemic effects, but can cause ocular adverse events such as
conjunctival hyperemia, pigmentation of the iris, periocular skin or eyelashes, hypertrichosis,
and ocular surface effects or irritation. Latanoprost is significantly better tolerated than either
bimatoprost or travoprost. Patients treated with latanoprost have better compliance and persist
with therapy longer than those that are given other drugs. An improved formulation of latanoprost
without the preservative benzalkonium chloride has recently been developed. It is as effective
as conventional latanoprost, has a lower incidence of hyperemia, and can be stored at room
temperature. In conclusion, latanoprost has the best efficacy–tolerability ratio of the PG analogs
available for glaucoma treatment, and has good compliance and persistence. These factors should
be improved further by the recent development of preservative-free latanoprost.
Keywords: prostaglandin, intraocular pressure, ocular hypertension, hyperemia, glaucoma,
latanoprost
Introduction
One of the major risk factors for the development and progression of glaucoma is
elevated intraocular pressure (IOP).
1,2
Topical prostaglandins (PGs), with their pow-
erful ocular hypotensive effect (which is mainly the result of increasing uveoscleral
outflow), are therefore an important treatment option for glaucoma.
3
PGs/prostamides are approved as the first-line treatment for glaucoma in the
European Glaucoma Society guidelines.
4
The main reasons for this choice include their
IOP-lowering efficacy, their lack of relevant systemic side effects, their requirement
for only once-daily dosing, and their good overall tolerability profile.
This review focuses on the use of latanoprost, an ester prodrug of prostaglandin
F
2α
(PGF
2α
), in the management of glaucoma. Latanoprost was the first of the cur-
rently available topical PGF
2α
analogs to be launched for glaucoma treatment, and it
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still accounts for the majority of PG-analog prescriptions
due to its good efficacy–tolerability profile. It was also the
first PG analog to have generics developed, and an improved
formulation has recently been produced without benzalko-
nium chloride (BAK).
Publications to be considered for inclusion in this
review were selected in PubMed using the search terms
“latanoprost”, “glaucoma/drug therapy*[MeSH]”, “meta-
analysis[publication type]”, “comparative study[publication
type]”, and “patient compliance[MeSH]”. More recent stud-
ies that were yet to be indexed were identified from ad hoc
searches and the author’s own database.
Prostaglandins
PGs were initially isolated from prostate tissue in 1935.
5
They are now known to be produced by almost all nucle-
ated cells. They are a family of lipid compounds that are
derived enzymatically from essential fatty acids,
6
with each
one containing 20 carbon atoms, including a 5-carbon ring.
They act locally as autocrine or paracrine mediators with a
wide range of effects throughout the body.
Effects of prostaglandins
in ophthalmology and development
for glaucoma treatment
Several PGs are naturally synthesized in the iris and ciliary
body and are released following trauma to the eye.
7
One of the
PGs that is released is PGF
2α
, which is now known to cause a
powerful reduction in IOP. Animal studies have shown that this
hypotensive activity is mainly due to an enhanced uveoscleral
outflow, with minor effects on trabecular outflow and aqueous
ow.
3
One potential mechanism behind this enhanced outflow
is the regulation of matrix metalloproteinases and remodeling
of the extracellular matrix, which changes the permeability
of tissues associated with the outflow pathways resulting in
alterations in outflow resistance and/or outflow rates.
3
Discovery of the effect of PGs on IOP led to the devel-
opment of PG analogs as a potential glaucoma treatment.
Initial research focused on PGF
2α
. The initial steps included
esterification of the carboxylic acid of PGF
2α
to improve
corneal penetration and reduce side effects.
8
One of the most
promising of these prodrugs of PGF
2α
was the isopropyl ester
form. However, despite having excellent pharmacokinetic
properties, it still caused unacceptable foreign-body sen-
sation and conjunctival hyperemia.
9,10
Modification of the
omega chain of this molecule led to improved selectivity for
PGF receptors and a greatly improved tolerability profile.
11
This molecule was subsequently known as latanoprost and
underwent clinical development as a treatment for glaucoma.
Later studies in knock-out mice showed that intact PGF and
PGE
3
receptors were necessary for IOP reduction.
12,13
Latanoprost
Latanoprost (0.005%) was launched in 1996 and was the
first of the currently available topical PGF
2α
analogs on the
market for glaucoma treatment. Later introductions included
travoprost (0.004%), bimatoprost (0.03%), and, most recently,
tafluprost (0.0015%). Latanoprost still accounts for approxi-
mately 65% of PG-analog prescriptions.
Pharmacokinetics
Latanoprost is an esterified prodrug of PGF
2α
and, as such,
is more lipophilic than the parent compound.
11
This means
that it is better absorbed through the cornea, where it is
undergoes hydrolysis to latanoprost acid. In adult humans,
peak concentration of the active drug was detected in the
aqueous humor 1–2 hours after topical dosing and amounted
to 15–30 ng/mL.
14
In the systemic circulation, the peak con-
centration occurred after 5 minutes and reached a level of
53 pg/mL. The elimination half-life was 2–3 hours from the
eye and 17 minutes from the circulation. The median peak
plasma concentration and area under the concentration-time
curve after adult dosing were found to be higher in infants
less than 3 years old than in older subjects, primarily due to
lower body weight and smaller blood volume; but latanoprost
acid was rapidly eliminated in all age groups.
15
Metabolism mainly occurs in the liver where latanoprost
acid undergoes beta-oxidation to 1,2-dinor and 1,2,3,4-tetra-
nor latanoprost acid, the main metabolites of latanoprost.
14
The majority of the dose is excreted via the urine (88%) with
the remainder being recovered in the feces.
The reduction in IOP seen with latanoprost begins after
3–4 hours, reaches a maximum after 8–12 hours, and is
maintained for at least 24 hours.
16
Efcacy
Latanoprost has been very well studied, with numerous
publications of clinical trials, meta-analyses, and reviews.
17
Initial studies showed once-daily topical latanoprost (0.005%)
to be safe and effective in the short- and long-term treat-
ment of glaucoma or ocular hypertension. A review of three
masked multicenter Phase III studies in 829 patients with
elevated IOP in Scandinavia, the USA, and the UK showed
that 6 months treatment with latanoprost reduced IOP by
35%, if given in the evening, and by 31%, if given in the
morning.
18
Conjunctival hyperemia and darkening of the
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Latanoprost in glaucoma
iris color were the only notable side effects. Subsequently,
darker and longer eye lashes were also reported.
19
Later open
studies conducted over 2 years reported that the reduction in
IOP was maintained during long-term treatment and no other
clinically significant side effects developed.
20,21
Similarly
good results were reported in 5-year studies, although the
main focus was on safety and tolerability.
22–24
Latanoprost versus other prostaglandins
Bimatoprost
Latanoprost has been extensively compared with bimato-
prost in randomized controlled trials. One of the largest of
these involved 411 patients with open-angle glaucoma or
ocular hypertension treated for 12 weeks with latanoprost,
bimatoprost, or travoprost.
25
At the end of the study, there
was a significant (P,0.001) reduction in 8 am IOP in all
groups. The estimated mean reduction was 8.6±0.3 mmHg
with latanoprost and 8.7±0.3 mmHg with bimatoprost. The
adjusted differences in mean IOP reductions at 8 am also
showed equivalence between latanoprost and bimatoprost
(0.13 mmHg; 95% confidence interval [CI] 0.84–0.58).
No significant differences were observed between the two
treatments in IOP reduction at noon, 4 pm, and 8 pm, or in
changes in mean diurnal IOP levels. A subsequent study
in 48 patients with open-angle glaucoma also failed to find
statistically significant differences between latanoprost and
bimatoprost in IOP reductions at 8 am, 10 am, 1 pm, 4 pm,
8 pm, 11 pm, and 3 am after 8 weeks of treatment.
26
One double-blind, crossover study focused on circadian
IOP in 44 patients with open-angle glaucoma or ocular
hypertension.
27
After 1 month, latanoprost and bimatoprost
were equally effective in reducing IOP, with no significant
differences between them, and the authors concluded that
they were both powerful agents in controlling around-the-
clock IOP. A more recent crossover study assessed IOP
reduction in 54 patients with angle-closure glaucoma treated
with latanoprost or bimatoprost for 6 weeks.
28
At the end of
treatment, mean IOP was reduced by 8.4±3.8 mmHg with
latanoprost and 8.9±3.9 mmHg with bimatoprost, with no
significant differences between the groups.
Some discrepancies have been reported in other stud-
ies, however, with bimatoprost being significantly more
effective than latanoprost at certain time points. An older
study in 232 patients with glaucoma or ocular hyperten-
sion found that bimatoprost reduced IOP significantly
more than latanoprost at noon (P=0.021), but not at 8 am
(primary efficacy parameter), 4 pm, or 8 pm after 3 months
of treatment.
29
In another double-blind study, no statistically
significant differences in IOP reduction were seen between
latanoprost (20%–31%) and bimatoprost (26%–34%) at
any time point measured on day 14 or 29 in 64 patients with
open-angle glaucoma or ocular hypertension.
30
However,
on day 29, bimatoprost had a significantly (P=0.0378)
larger area under the curve for IOP reduction. Similarly, in
a 7-week double-blind crossover study in 44 patients with
open-angle glaucoma, bimatoprost was significantly more
effective than latanoprost regarding diurnal curve IOP only
at 6 pm (P=0.008 after Bonferroni correction), but not at
2 am, 6 am, 10 am, 2 pm, or 10 pm.
31
The mean 24 hour
IOP was also significantly (P=0.01) lower with bimatoprost
(16.7±2.4 mmHg) than latanoprost (17.3±2.8 mmHg).
Significant between-group differences in mean IOP reduc-
tion in favor of bimatoprost were seen at 8 am (P#0.033),
but not at noon or 4 pm, in a 3-month double-blind trial in
60 patients with normal tension glaucoma.
32
In contrast to
these findings, a 6-month study involving 269 patients with
glaucoma or ocular hypertension showed bimatoprost to be
significantly (P,0.004) more effective than latanoprost in
reducing IOP at all time points measured (8 am, noon, and
4 pm).
33
Recent studies have evaluated the effects of latanoprost
on central corneal thickness, which allows for a more accurate
estimate of IOP.
34,35
Central corneal thickness was signifi-
cantly (P,0.001) reduced by latanoprost (14.95±5.04 µm)
and bimatoprost (17.00±6.23 µm) after a mean follow-up
of 17 months in 69 patients with glaucoma or ocular
hypertension.
36
The duration of treatment had no effect, with
a lack of significant difference being seen in patients treated
for #6 months as well as those treated for .6 months.
In summary, the considerable amount of data avail-
able indicates that latanoprost is equally as effective as
bimatoprost. Some studies have shown small advantages for
bimatoprost at certain time points, although there appears to
be no consistency in these findings. There is some evidence
to suggest that bimatoprost is hydrolyzed to its free acid,
a potent PG F receptor agonist, in sufficient levels in the
aqueous humor to account for at least some of its ability to
reduce IOP.
37
Travoprost
As with bimatoprost, a considerable number of randomized
controlled trials have compared travoprost and latanoprost.
In a 12-week trial in 411 patients with open-angle glau-
coma or ocular hypertension, the estimated mean reduction
in 8 am IOP at the end of treatment was 8.6±0.3 mmHg
with latanoprost and 8.0±0.3 mmHg with travoprost.
25
The
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adjusted differences in mean 8 am IOP reductions also
showed no significant difference between latanoprost and
travoprost (0.56 mmHg; 95% CI 0.15–1.26) as did all second-
ary efficacy parameters. Similarly, a 1-month double-blind
crossover study in 44 patients with open-angle glaucoma
or ocular hypertension showed no statistically significant
difference between latanoprost and travoprost in circadian
IOP reduction.
27
A study in 48 patients with open-angle
glaucoma reported no significant differences in efficacy
on overall diurnal IOP between latanoprost and travoprost
(and bimatoprost that was also included in the study), but
significantly greater IOP reductions at 8 am and 10 am, but
not at 1 pm, 4 pm, 8 pm, 11 pm, and 3 am, after 8 weeks of
treatment with travoprost versus latanoprost or bimatoprost.
26
A more recent double-blind study in 302 patients with open-
angle glaucoma or ocular hypertension found no statistically
significant differences in IOP values after 6 weeks’ treatment
with travoprost (16.1 mmHg) or latanoprost (16.4 mmHg).
38
The pooled changes in IOP from baseline after 1, 2, 4, and
6 weeks of treatment did, however, show a significant differ-
ence in favor of travoprost (8.3 mmHg versus 7.5 mmHg;
P=0.009). IOP was measured at 5 pm, 20 hours after drug
administration. In 69 patients with glaucoma or ocular
hypertension, central corneal thickness was significantly
(P,0.001) reduced by both latanoprost (14.95±5.04 µm)
and travoprost (15.73±3.25 µm) after a mean follow-up of
17 months.
36
The overall results from randomized controlled studies
therefore show that latanoprost is as effective as travoprost.
Further evidence is available from meta-analyses that will
be discussed later in the review.
Tauprost
Only two studies have so far been published comparing
latanoprost with tafluprost. The first of these was a random-
ized double-blind Phase II trial comparing latanoprost with
tafluprost treatment for 42 days in 38 patients with open-angle
glaucoma, exfoliation glaucoma, or ocular hypertension.
39
There was no significant difference between the treatments,
with maximum IOP reduction occurring after 7 days and
being maintained on day 42 and day 43. A subsequent
randomized double-blind Phase III study was considerably
larger, enrolling 533 patients with open-angle glaucoma or
ocular hypertension.
40
Treatment was given with latanoprost
or tafluprost for 24 months. Both treatments substantially
reduced IOP, with a 7.7 mmHg decrease with latanoprost
and 7.1 mmHg decrease with tafluprost after 24 months. The
effect of latanoprost was somewhat larger, but non-inferiority
of tafluprost over all diurnal IOP measurements was shown
with analysis of variance and almost reached with analysis
of covariance (upper limits of the 95% CIs 1.38 and 1.52,
respectively). The non-inferiority limit was 1.5 mmHg. In this
study, there were 18 discontinuations for lack of efficacy on
tafluprost compared with only three on latanoprost.
Overall, the relatively restricted amount of data currently
available suggests no clinically significant difference in
efficacy between latanoprost and tafluprost, although more
studies are required.
Results of meta-analyses
A number of recent meta-analyses of randomized controlled
trials have compared latanoprost with bimatoprost and tra-
voprost in patients with glaucoma or ocular hypertension
(Table 1);
41–49
to date, only one meta-analysis has included
a comparison with tafluprost (Table 1).
50
One of the largest of these analyses was performed by
Eyawo et al, in 2009,
41
who assessed randomized single- or
double-blind head-to-head comparisons of latanoprost,
bimatoprost, and travoprost of at least 3 months’ duration.
Data were included from a total of 15 studies (up to
12 months’ duration), five of which had more than two treat-
ment arms. Thus, nine trials compared latanoprost and travo-
prost (n=1,098), eight compared travoprost and bimatoprost
(n=714), and eight compared latanoprost and bimatoprost
(n=943). The IOP-lowering effect at study conclusion was
expressed by the weighted mean difference across groups.
This was 0.24 mmHg (95% CI 0.87–0.38) for travoprost
versus latanoprost and 0.73 mmHg (95% CI 0.10–1.37) for
latanoprost versus bimatoprost. Response rates were also
compared between studies that had similar definitions of
response; three trials comparing latanoprost to bimatoprost
found a pooled relative risk of 0.98 (95% CI 0.76–1.26,
P=0.87) and two comparing travoprost to latanoprost found
a pooled relative risk of 1.15 (95% CI 0.99–1.33, P=0.07).
A study specifically designed to identify the nonresponder
rate during latanoprost treatment found that only 14 of 340
newly diagnosed patients failed to respond to latanoprost.
51
Another large analysis was conducted in 2010 and
involved 2,943 patients treated with latanoprost, bimatoprost,
travoprost, or timolol in 18 studies.
42
A mixed treatment
comparison was used to assess the relative efficacy of the
treatments in terms of absolute on-treatment IOP at 3 months.
Latanoprost and bimatoprost produced significantly
(P,0.05) lower on-treatment IOP compared with timolol.
There was no significant difference between latanoprost and
bimatoprost.
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Latanoprost in glaucoma
A somewhat smaller analysis in 1,090 patients showed no
significant difference in the IOP-lowering effects from baseline
of latanoprost, bimatoprost, travoprost, or timolol in studies
ranging from 2 weeks to 3 months.
43
The difference in absolute
IOP reduction between PG analogs and timolol ranged from
0.4–1.6 mmHg for the diurnal curve, 0.9–2.3 mmHg for the
peak, and 1.3–2.4 mmHg for the trough. For latanoprost, the
relative IOP reduction was 31% (95% CI 27%–34%) for the
diurnal curve, 34% (95% CI 31%–37%) for the peak, and 31%
(95% CI 28%–35%) for the trough. The corresponding values
were 26% (95% CI 21%–30%), 28% (95% CI 24%–32%),
and 27% (95% CI 23%–30%) for bimatoprost and 28% (95%
CI 20%–36%), 32% (95% CI 31%–34%), and 31% (95% CI
29%–33%) for travoprost, respectively.
Another analysis by Cheng et al in 450 patients with
normal tension glaucoma reported no statistically significant
differences between latanoprost and bimatoprost with regard
to reductions in IOP at peak, trough, and diurnal assessments
(20% at all assessments with latanoprost versus 21%, 18%,
and 17%, respectively, with bimatoprost).
44
The 24-hour IOP lowering efficacy, determined in one
analysis of 386 patients, showed a statistically significant
difference between monotherapy treatments with PG ana-
logs, timolol, brimonidine, and dorzolamide (P=0.026).
48
Table 1 Summary of meta-analyses of randomized controlled trials for the effect of latanoprost and other PG analogs on IOP in
patients with glaucoma or ocular hypertension
Study PG analogs Other drugs
assessed
Studies
(n)
Patients
(n)
Duration Primary efcacy variables
Cucherat
et al
50
LAT (BAK-preserved
and preservative-free),
BIM
ƒ
(BAK-preserved),
TRA (preserved with BAK,
polyquaternium-1 or sofzia),
TAF (BAK-preserved)
None 21 Not
reported
$2 months
Preservative-free LAT signicantly
more effective than TAF regarding IOP
at 3 months. No signicant difference
between other PG analogs.
Orme
et al
42
LAT, BIM, TRA TIM 18 2,943 3 months No signicant difference between LAT
and BIM in on-treatment IOP. LAT and
BIM signicantly more effective than
TIM. No signicant difference between
TRA and TIM.
Cheng
et al
43
LAT, BIM, TRA TIM 9 1,090 2 weeks to
3 months
No signicant difference in IOP-
lowering effect from baseline between
LAT, BIM, TRA, and TIM.
Cheng
et al
44
LAT, BIM TIM, DOR,
BRIM
15 450 3 weeks to
2 months
No signicant difference between LAT
and BIM in IOP reduction from baseline
at peak, trough, and diurnal assessments.
Eyawo
et al
41
LAT, BIM, TRA None 15 2,755 3–12 months No signicant differences in IOP-
lowering effects at study conclusion
between LAT, BIM, and TRA.
Aptel
et al
45
LAT, BIM, TRA None 8 1,610 1–6 months Signicantly greater change in IOP with
BIM than LAT at 8 am, noon, 4 pm, and
8 pm after 3 months. No signicant
difference between LAT and TRA.
Cheng
and Wei
46
LAT, BIM None 13 1,302 1–6 months Percentage reduction in morning IOP
signicantly greater with BIM than LAT
at 1, 3, and 6 months.
Stewart
et al
48
LAT, BIM, TRA TIM, DOR,
BRIM
11 386 1–2 months No signicant differences reported in
the publication between LAT, BIM, and
TRA in 24-hour IOP efcacy.
Denis
et al
49
LAT, BIM, TRA None 9 1,318 2 weeks to
12 months
No signicant difference between LAT
and BIM or TRA in IOP levels at the
end of follow-up.
Van der
Valk et al
47
LAT, BIM, TRA TIM, DOR,
BRIM, BET,
BRIN
28 6,953 (trough)
6,841 (peak)
1–6 months No signicant difference between LAT,
BIM, and TRA in IOP change from
baseline at 1 month.
Note:
ƒ
0.01% and 0.03%.
Abbreviations: BAK, benzalkonium chloride; BET, betaxolol; BIM, bimatoprost (0.03%); BRIN, brinzolamide; BRIM, brimonidine; DOR, dorzolamide; IOP, intraocular
pressure; LAT, latanoprost (0.005%); PG, prostaglandin; TAF, tauprost (0.0015%); TIM, timolol; TRA, travoprost (0.004%).
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As a class, the PG analogs were reported to be the most
effective, with reductions of 24% with latanoprost, 27% with
travoprost, and 29% with bimatoprost. The mean reduction
seen at night-time assessments was significantly lower than
that at day-time assessments for latanoprost (P=0.031) but
not for the other PG analogs.
Two slightly older meta-analyses, each of which
included more than 1,000 patients, also failed to report
statistically significant differences in IOP-lowering efficacy
between latanoprost and bimatoprost or travoprost.
47,49
The
only exception to this was a significantly higher adjusted
favorable response rate (IOP ,18 mmHg) with bimato-
prost and travoprost than with latanoprost (incidence rate
ratio 1.17; 95% CI 1.00–1.35l, P,0.040) in one of the
analyses.
49
In contrast to these previous meta-analyses, Aptel et al
45
found that latanoprost was significantly less effective than
bimatoprost, and equally as effective as travoprost, in reduc-
ing IOP after 3 months in an analysis of 1,610 patients.
The IOP change from baseline was statistically signifi-
cantly greater with bimatoprost than latanoprost at all time
points assessed: 8 am (weighted mean 0.50 mmHg; 95%
CI 0.01–0.99, P=0.05), noon (weighted mean 1.17 mmHg;
95% CI 0.68–1.66, P,0.001), 4 pm (weighted mean 0.78
mmHg; 95% CI 0.26–1.29, P=0.003), and 8 pm (weighted
mean 0.67 mmHg; 95% CI 0.02–1.32, P=0.04). Data for 8
pm were available from only three studies compared with
data for the other time-points which were available from
five studies. No significant heterogeneity was seen between
studies.
Another meta-analysis published in the same year
and in a similar number of patients reported significant
advantages of bimatoprost over latanoprost on some, but
not all, parameters.
46
Bimatoprost resulted in statistically
significantly greater reductions from baseline in morning
(8 am to 10 am) IOP compared with latanoprost after 1, 3,
and 6 months (weighted mean differences 2.59%, 2.41%, and
5.60%, respectively). In contrast, there were no statistically
significant differences between the treatments in diurnal
reduction in IOP after 1 and 3 months (no data available at
6 months) or in the proportion of patients achieving the target
IOP (#17 mmHg) after 1 or 6 months. At 3 months, more
patients treated with bimatoprost reached target IOP (pooled
rate difference 12%; 95% CI 4–21, P=0.004). However, the
number of studies measuring diurnal IOP reduction and
achievement of target IOP is small. Interestingly, in a post-hoc
analysis excluding studies that were not industry- sponsored,
the difference between bimatoprost and latanoprost in the
reduction in morning IOP remained statistically significant
only at 6 months.
46
Finally, the most recent meta-analysis has included
tafluprost in a comparison with latanoprost, including
preservative-free latanoprost, and the other PG analogs.
50
In contrast to the previous meta-analyses, which involved
direct pairwise comparisons between treatments, this analy-
sis used adjusted indirect comparisons in the absence of
head-to-head trial data. Although the evidence from large
double-blind randomized trials directly comparing the
available treatments would clearly be stronger, it has been
suggested that indirect comparisons are more appropriate
than pairwise direct comparisons of a limited number of
treatments as they allow comparison of all the options.
50
A total of 21 trials of $2 months’ duration were included in
the analysis; five trials comparing more than two treatments
in a three-arm design were included as a total of ten entries,
thus yielding 26 pairwise comparisons overall. Where no
3-month data were available, the data at 2–6 months were
used, taking the longest period in case of multiple time points.
The treatments compared were BAK-preserved latanoprost
(12 trials), preservative-free latanoprost (one trial), BAK-
preserved bimatoprost 0.03% (15 trials), BAK-preserved
bimatoprost 0.01% (two trials), BAK-preserved travoprost
(15 trials), travoprost preserved with polyquaternium-1
or sofZia (two trials), and BAK-preserved tafluprost (one
trial). There were no statistically significant differences in
mean IOP at 3 months between preservative-free latanoprost
and polyquaternium-1-travoprost (weighted mean differ-
ence 0.47; 95% CI 0.58–1.51), BAK bimatoprost 0.03%
(weighted mean difference 0.49; 95% CI 0.13–1.10), BAK
bimatoprost 0.01% (weighted mean difference 0.19; 95%
CI 0.60–1.06), BAK travoprost (weighted mean difference
0.27; 95% CI 0.50–1.03), or BAK latanoprost (weighted
mean difference 0.40; 95% CI 0.02 to 0.82). However,
preservative-free latanoprost was statistically significantly
superior to BAK tafluprost (weighted mean difference 0.90;
95% CI 1.52 to 0.28). No data were available for sofZia
travoprost.
Overall, the majority of meta-analyses have found no
statistically significant differences between the efficacy of
latanoprost and that of bimatoprost or travoprost. In a few
cases, bimatoprost has shown significantly better efficacy
than latanoprost in some parameters, but the numerical dif-
ferences tend to be small and the clinical relevance unknown.
The only meta-analysis that has so far included tafluprost
reported it to be significantly less effective than preservative-
free latanoprost.
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Latanoprost in glaucoma
Latanoprost versus other agents
Timolol
Latanoprost is more effective than conventional treatment
with the beta-blocker timolol (0.5%) and has the added advan-
tage of being required only once-daily, while beta-blockers
are often applied twice daily. The benefits of latanoprost
have been demonstrated in numerous clinical trials and
meta-analyses.
One meta-analysis involving 829 patients with open-
angle glaucoma or ocular hypertension enrolled in three
double-blind randomized studies reported that latanoprost
reduced mean diurnal IOP by 7.7 mmHg after 6 months,
compared with 6.5 mmHg with timolol.
52
This difference of
1.2 mmHg was statistically significant (P,0.001). Morning
IOP was reduced significantly (P,0.001) more at 6 months
than at 2 weeks in patients treated with latanoprost; no such
increased efficacy was seen with timolol. In a subanalysis
of 441 patients with ocular hypertension, mean diurnal IOP
was reduced to a significantly greater extent with latanoprost
than timolol (1.1±0.2 mmHg; 95% CI 1.6–0.7, P,0.001).
53
A reduction in diurnal IOP from baseline of $20% was
achieved in 83% of patients treated with latanoprost and
62% treated with timolol.
Analogous findings were seen in another meta-analysis of
eleven randomized controlled trials, ten of which were double-
blind, conducted in 1,256 patients with open-angle glaucoma or
ocular hypertension.
54
Both drugs significantly decreased IOP.
However, the reductions were greater with latanoprost than with
timolol for assessments performed at 1 week (6.9 mmHg; 95%
CI 0.4–13.4), 1 month (3.8 mmHg; 95% CI 1.2–6.3), 3 months
(5.0 mmHg; 95% CI 2.8–7.3), 6 months (5.0 mmHg; 95% CI
2.8–7.3), and 12 months (4.9 mmHg; 95% CI 5.9–15.8). The
differences were all statistically significant apart from that from
the single 12-month study.
A recent randomized double-blind trial showed that
latanoprost was at least as effective as timolol in 137 pediatric
patients (#18 years old; mean age 8.8 years) with glaucoma.
55
After 12 weeks, the mean reduction in IOP was 7.2 mmHg
with latanoprost and 5.7 mmHg with timolol (difference
1.5 mmHg; 95% CI 0.8–3.7). The responder rates were
60% with latanoprost and 52% with timolol.
Dorzolamide
Another conventional treatment option the carbonic
anhydrase inhibitor dorzolamide is also significantly less
effective than latanoprost. For example, a systematic review
conducted in 2008 evaluated 1,722 glaucoma patients treated
with latanoprost, dorzolamide, or brimonidine in eight
randomized controlled trials.
56
The mean reduction in IOP
was statistically significantly larger with latanoprost than dor-
zolamide (weighted mean difference 2.64; P,0.00001).
Brimonidine
Superior efficacy of latanoprost has also been confirmed in
comparisons with the α
2
-adrenergic agonist brimonidine.
A meta-analysis of nine randomized controlled clinical trials
in 2,152 patients with an IOP of $20 mmHg observed a
significantly greater reduction in IOP with latanoprost than
brimonidine after 3 months (8.4 versus 6.5 mmHg; P=0.004)
and 6 months (8.0 versus 6.2 mmHg; P=0.045).
57
A more
recent analysis included 1,784 patients with open-angle
glaucoma, ocular hypertension, or normal-tension glaucoma
enrolled in 14 randomized controlled trials of up to 12 months’
duration.
58
The overall reduction in IOP was significantly
greater with latanoprost than brimonidine (weighted mean
difference =1.10 mmHg; 95% CI 0.57–1.63).
Combination therapies
A wide range of treatment combinations with two or even
three agents is used clinically in patients who do not respond
to a single agent. One of the drugs more commonly given in
combination is timolol; latanoprost has been used effectively
with this agent
59,60
as well as with others such as cholinergic
agonists,
61
dorzolamide,
62
and brimonidine.
62
A combina-
tion of latanoprost with 0.5% timolol was suggested to have
better IOP-lowering efficacy than timolol combined with
bimatoprost, dorzolamide, brinzolamide, or brimonidine,
and comparable efficacy to a timolol–travoprost combina-
tion, in a recent meta-analysis of 41 randomized controlled
trials in 5,261 patients with open- angle glaucoma or ocular
hypertension.
60
Combination of latanoprost and cholinergic
agonists is usually not recommended. However, latanoprost
given in combination with physostigmine has a mainly
additive ocular hypotensive effect, and high doses of physo-
stigmine, therefore, do not abolish the IOP-lowering effect
of latanoprost.
63
Latanoprost alone has also been compared with a variety
of drug combinations. In a meta-analysis of 14 random-
ized controlled studies in 2,149 patients with elevated IOP,
latanoprost was significantly more effective in reducing mean
diurnal IOP at 3 months than combined timolol and dorzol-
amide in patients whose IOP was insufficiently controlled by
timolol alone at baseline (weighted mean difference 3.12%;
95% CI 0.47–5.78).
64
Latanoprost proved at least as effec-
tive as the combination treatment in patients not receiving
timolol at baseline.
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Alm
Although combination treatments may have the benefit of
improved efficacy in some cases, they also increase the risk of
ocular adverse events. This risk appears to correlate with the
number of treatments used. In an investigation of 630 patients
receiving IOP-lowering medications, 305 were found to have
an ocular surface disease index indicating mild (n=134), mod-
erate (n=84), or severe (n=87) symptoms.
65
Those taking a
single medication had a significantly lower mean index score
(12.9±13.1) than those taking two (16.7±17.0; P=0.007) or
three medications (19.4±18.1; P=0.0001).
Safety and tolerability
A good safety and tolerability profile is essential in light of
the long-term treatment required for patients with glaucoma
or ocular hypertension. Latanoprost does not have any proven
systemic effect but can cause ocular adverse events such as
conjunctival hyperemia; pigmentation of the iris, periocular
skin or eyelashes; hypertrichosis; and ocular surface effects
or irritation.
Numerous individual clinical studies and meta-analyses
have shown that latanoprost is better tolerated than bimato-
prost or travoprost.
25,29,31,33,41,42,45,46.50,66–69
Data currently avail-
able from two studies show that the safety and tolerability
profile (including adverse events and drop discomfort) of
latanoprost is comparable to that of tafluprost, although more
information is required from further studies.
39,40
However, the
only available meta-analysis including tafluprost showed that
the preservative-free formulation of latanoprost was better
tolerated with regard to hyperemia.
50
Conjunctival hyperemia
Conjunctival hyperemia has been associated with virtually
all topical IOP-lowering medications including PG analogs,
alpha-adrenergic agonists, beta-adrenergic antagonists, and
carbonic anhydrase inhibitors.
70
As well as representing
a cosmetic problem for the patient, hyperemia may also
compromise the outcome of filtration surgery.
71
There are
a number of different scales used in grading hyperemia as
well as difficulties associated with comparing the results of
studies that use different grading scales. Although it is pos-
sible to cross-calibrate such scales, the differences between
them should always be borne in mind when comparing
treatments.
72
It is the most frequently reported side effect of
the PG analogs and is commonly a cause of treatment dis-
continuation,
66
although it is less common with latanoprost
than with bimatoprost or travoprost.
A considerable amount of data has been collected in
clinical studies. For example, a randomized double-blind
crossover study in 28 healthy volunteers showed that latano-
prost had significantly less hyperemia and/or change in
hyperemia than bimatoprost or travoprost at hour 0 and/or 1.
68
A large randomized controlled trial compared latanoprost,
bimatoprost, and travoprost over 12 weeks in 411 patients
with open-angle glaucoma or ocular hypertension.
25
The
incidence of hyperemia was 47.1% with latanoprost, 68.6%
with bimatoprost, and 58.0% with travoprost (P=0.001 for
difference between latanoprost and bimatoprost). A greater
proportion of hyperemia was observed at the end of the study
in the bimatoprost (60.9%) and travoprost (58.9%) groups
than in patients treated with latanoprost (46.5%). Latanoprost
was also associated with less hyperemia than bimatoprost in
three other randomized, single- or double-blind studies in
232, 44 and 269 patients.
29,31,33
A summary of meta-analyses of randomized controlled
trials assessing the incidence of conjunctival hyperemia with
latanoprost and other PG analogs in patients with glaucoma
or ocular hypertension is shown in Table 2.
41,42,45,46,50,66
One
of these, published in 2009, was solely designed to assess the
risk of conjunctival hyperemia with latanoprost versus other
PG analogs.
66
A total of 13 trials conducted between 1995 and
2007 including 2,222 patients (931 treated with latanoprost,
624 with bimatoprost, and 667 with travoprost) were included
in the final analysis. The average period of follow-up was 4.1
months. Compared with latanoprost, there was a significantly
higher risk of developing hyperemia with travoprost (odds
ratio 0.51; P,0.0001; 95% CI 0.39–0.67) and bimatoprost
(odds ratio 0.32; P,0.0001; 95% CI 0.24–0.42). No signifi-
cant heterogeneity was found between the trials and there was
no evidence of a publication bias. Sensitivity analyses showed
that none of the included trials had an important impact on
the global estimation of the odds ratio.
Other meta-analyses have investigated hyperemia in addi-
tion to analysis of effects on IOP. The results are consistent,
with a significantly lower risk for developing hyperemia in
patients treated with latanoprost. For example, six studies
comparing latanoprost with travoprost, and five comparing
latanoprost with bimatoprost, showed a significantly lower
risk with latanoprost than travoprost (relative risk 5.71;
P#0.001) or bimatoprost (relative risk 1.59; P=0.04).
41
Two
other recent meta-analyses, both conducted in more than
1,000 patients, reported a significantly lower incidence with
latanoprost than bimatoprost, with a relative risk of 0.59
(P,0.001) in one case
45
and a rate difference of 20% in
the other.
46
A particularly large analysis of 14,849 patients
enrolled in 72 studies assessing 19 treatment regimens
found that latanoprost monotherapy was associated with
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Latanoprost in glaucoma
Table 2 Summary of meta-analyses of randomized controlled trials of latanoprost and other PG analogs in patients with glaucoma or
ocular hypertension: occurrence of conjunctival hyperemia
Study Studies analyzed Conjunctival hyperemia
Cucherat et al
50
21 studies with LAT (BAK-preserved and preservative-
free), BIM
ƒ
(BAK-preserved), TRA (preserved with BAK,
polyquaternium-1, or sofZia), or TAF (BAK-preserved)
over $2 months.
Signicantly higher risk with polyquaternium-1 TRA (odds ratio
[95% CI]: 0.24 [0.11;0.55]), sofZia TRA (odds ratio [95% CI]:
0.37 [0.16;0.84]), BAK BIM 0.03% (odds ratio [95% CI]: 0.18
[0.10;0.33]), BAK BIM 0.01% (odds ratio [95% CI]: 0.27
[0.13;0.56]), BAK TAF (odds ratio [95% CI]: 0.18 [0.05;0.65]),
BAK TRA (odds ratio [95% CI]: 0.25 [0.14;0.46]), and BAK LAT
(odds ratio [95% CI]: 0.52 [0.31;0.86]) than with BAK-free LAT.
Orme et al
42
72 studies of 19 different single or combination
treatment regimens in 14,849 patients.
LAT monotherapy had a signicantly (P,0.05) lower odds of
hyperemia-type events than TRA, BIM, TRA plus TIM, and BIM
plus TIM.
Honrubia et al
66
Meta-analysis specically designed to assess conjunctival
hyperemia. 13 studies in 2,222 patients treated for 2 weeks to
9 months compared LAT versus TRA (5 studies), LAT versus
BIM (7 studies), and LAT versus TRA versus BIM (1 study).
Signicantly higher risk with TRA than LAT (odds ratio 0.51;
P,0.0001; 95% CI 0.39–0.67) and with BIM than LAT (odds
ratio 0.32; P,0.0001; 95% CI 0.24–0.42).
Eyawo et al
41
Out of 15 studies in 2,755 patients treated for 3–12 months,
6 compared LAT and TRA, 5 compared LAT and BIM,
and 1 compared BIM and TRA.
Signicantly higher risk with TRA than LAT (relative risk 5.71;
P#0.001; 95% CI 1.81–18.02), with BIM than LAT (relative
risk 1.59; P=0.04; 95% CI 1.02–2.48), and with TRA than BIM
(relative risk 0.82; P=0.02; 95% CI 0.69–0.97).
Aptel et al
45
8 studies in 1,610 patients treated with LAT, BIM,
or TRA for 1–6 months.
Signicantly higher incidence with BIM than LAT (relative risk
0.59; P,0.001; 95% CI 0.50–0.69) or TRA (relative risk 0.84;
P=0.05; 95% CI 0.70–1.00).
Cheng and
Wei
46
13 studies in 1,302 patients treated with LAT or BIM
for 1–6 months.
Signicantly higher frequency with BIM than LAT
(rate difference 20%; 95% CI 15–24).
Stewart et al
48
11 studies in 386 patients treated with LAT, BIM, TRA,
or non-PG analogs for 1–2 months.
Signicantly higher incidence with TRA (23%; P,0.001) than any
other treatment. Incidence 8% with LAT and 17% with BIM.
Note:
ƒ
0.01% and 0.03%.
Abbreviations: BAK, benzalkonium chloride; BIM, bimatoprost (0.03%); CI, condence interval; LAT, latanoprost (0.005%); PG, prostaglandin; TAF, tauprost (0.0015%);
TIM, timolol; TRA, travoprost (0.004%).
significantly (P,0.05) lower odds of hyperemia-type events
than travoprost, bimatoprost, travoprost plus timolol, and
bimatoprost plus timolol.
42
The only meta-analysis to include
tafluprost showed that the risk of hyperemia was significantly
(P,0.05) lower with preservative-free latanoprost than with
BAK-preserved bimatoprost 0.03%, BAK-preserved bimato-
prost 0.01%, BAK-preserved travoprost, BAK-preserved
latanoprost, travoprost preserved with polyquaternium-1 or
sofZia, and BAK-preserved tafluprost.
50
Hyperemia is a significant contributor to treatment
discontinuation with the PG analogs, especially as many
patients fail to appreciate any benefits relating to symptoms
during short-term treatment. A review of 300 patient charts
found that hyperemia was the most common side effect with
PG-analog treatment, and that it accounted for stopping or
changing medication in 63% of patients in whom changes
were made due to side effects.
71
In order to determine the
costs associated with stopping or switching treatment, data
from 13,977 newly treated glaucoma patients were extracted
from the HealthCore Integrated Research Database of the
Glaucoma Adherence and Persistency Study.
73
Of these, 8,743
were treated with PG-analog monotherapy (5,726 with latano-
prost, 1,633 with bimatoprost, and 1,384 with travoprost).
Overall, the per-patient cost of treating hyperemia-free
patients was US$73.67, compared with US$140.02, in those
who discontinued treatment due to hyperemia. The lowest
per-patient costs were seen in the group given latanoprost;
increased costs due to a hyperemia-induced change in treat-
ment were US$5.92 with bimatoprost and US$5.43 with
travoprost.
Iris pigmentation
This well recognized side effect of PG analogs is irreversible
and is seen markedly more often in green-brown and yellow-
brown eyes than in blue-grey or brown eyes.
22
The incidence
is difficult to compare considering the wide range of eye
colors, but there do not appear to be any marked differences
between latanoprost and other PG analogs.
There is no evidence that an increase in pigmenta-
tion increases the risk of ocular or cutaneous melanoma
with latanoprost. In order to assess this, a recent study
reviewed two safety databases: one included all latano-
prost (n=24) and fixed-combination latanoprost/timolol
(n=16) clinical trials conducted between 1992 and 2007;
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and the other included all spontaneous global safety
reports (not occurring in clinical trials) over 13 years for
latanoprost and 9 years for latanoprost/timolol.
74
There
were three cases of cutaneous melanoma and none of
ocular melanoma in the 12,880 patients in clinical trials.
In the global safety database, which comprised 19,940
cases, there were eleven reports of ocular melanoma and
six of cutaneous melanomas. A possible association with
latanoprost was excluded for all but three ocular and
one periorbital case. The potential mechanism of action
by which prostaglandins increase iris pigmentation is
thought to be due to stimulation of melanin synthesis via
induction of tyrosinase transcription without an increase
in mitotic activity.
75
Hypertrichosis
Hypertrichosis refers to an increase in the length, thickness,
and/or number of eyelashes. Although this can be desirable
from a cosmetic point of view in some patients, unilateral
occurrence can be unwanted. It can also influence drop
instillation.
The incidence is reported to be higher with bimatoprost
and travoprost than with latanoprost in some studies. In the
large study by Parrish et al,
25
no patients in the latanoprost
group had hypertrichosis whilst it occurred in 2.9% in
the bimatoprost group and 0.7% in the travoprost group.
A lower incidence was also reported with latanoprost than
bimatoprost (4.4% versus 12.6%; P=0.026) in the study by
Gandolfi et al.
29
Periocular skin pigmentation
This is a relatively rare side effect of the PG analogs and is
reversible upon treatment discontinuation. The incidence
has been reported to be higher with bimatoprost (2.9%) and
travoprost (2.9%) than with latanoprost (1.5%) in one study
by Parrish et al.
25
Ocular surface problems and irritation
These include eye irritation, dry eye, itching, blurred vision,
burning, discharge, allergy, and blepharitis, and these side
effects occur at a similar incidence with all PG analogs.
Many of these problems may be preservative related and,
thus, may be reduced by the development of preservative-
free product.
Other local events
Less common events seen with PG analogs include iris cysts,
cystoid macular edema, anterior uveitis, reactivation of
herpes simplex keratitis, and deepening of the upper eyelid
sulcus.
76,77
Systemic adverse events
Systemic adverse events occurring via nasopharyngeal
mucosal absorption of PG analogs are extremely infrequent
due to their rapid elimination half-life.
78
PGs do contract
human airway muscles, but this seems to be mainly mediated
by thromboxane receptors.
79
Also, a randomized double-
blind cross-over study in 24 glaucoma patients with stable
asthma exposed to 6 days of latanoprost treatment followed
by a 2-week washout showed no significant effects on peak
expiratory flow, asthma symptoms, or requirement for asthma
medications.
78
Similarly, there was no evidence of any adverse
cardiovascular or respiratory effects with latanoprost in a
randomized controlled study specifically designed to assess
these parameters.
80
Forty newly-diagnosed glaucoma patients
were treated with latanoprost 0.005% or betaxolol 0.25% for
3 months. At the end of the study, there were no significant
changes in cardiovascular or spirometric measurements in
the latanoprost group.
A recent study of pediatric patients (,3 years, 3–,12
years, or 12–,18 years) receiving adult latanoprost solu-
tion 0.005% once daily for $2 weeks resulted in no dis-
continuations or dose reductions due to adverse events.
15
The findings suggest that the adult dose of latanoprost has
an adequate safety margin for systemic adverse effects in
pediatric patients.
Long-term studies
Good long-term safety and tolerability is vitally important
for drugs given for prolonged conditions such as glaucoma.
For this reason, three long-term studies have assessed the
safety and tolerability of latanoprost treatment over periods
of 5 years.
22–24
The first of these was conducted by Alm et al in 1984
and focused on the development and progression of iris
pigmentation.
22
Five hundred and nineteen patients with
primary open-angle or exfoliation glaucoma enrolled in a
3-year open-label multinational uncontrolled prospective trial.
Of these, 380 (approximately 89% of whom had an eye color
known to be susceptible to color change) entered a subsequent
2-year extension phase. High-resolution color photographs
of irises were taken at baseline and at 14 subsequent visits,
and were assessed for change in iris pigmentation compared
with baseline. Intraocular pressures and adverse events were
also recorded. Overall, 127 patients (33.4%) developed
increased iris pigmentation in one or both eyes after 5 years.
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Latanoprost in glaucoma
At baseline, abnormalities of the optic nerve head and dis-
orders of the iris were slightly, but not significantly, more
common in those who developed increased iris pigmentation,
but retinal damage was slightly, but not significantly, less com-
mon in patients who developed increased iris pigmentation.
All patients with increased iris pigmentation developed the
condition by month 36. Regression analysis of photographic
ranking versus chronological order showed that there was
increased progression over the first 3 post-baseline years and
stability over the final 2 years. Almost all patients (92.6%)
reported a vision-related adverse event during the study most
commonly visual field defect, eye irritation, cataract, and eye
abnormality. The incidences were between 30% and 40%, and
the majority were mild in intensity.
The second open-label study was larger and more wide-
ranging, involving a total of 5,854 patients on IOP-reducing
therapy other than latanoprost who required a change in
therapy.
23
Patients were randomly assigned (2:1, respectively)
to latanoprost (n=3,936) or to any other commercially avail-
able medication (n=1,918). Of those initially randomized to
latanoprost, 2,707 (68.8%) completed the study and 4,638
(79.2%) received at least one dose of latanoprost. The patients
were examined at baseline and every 6 months for 5 years.
The 5-year incidence of macular edema, iritis/uveitis, and
corneal erosions was low (#2.72%) and was similar for
patients treated with latanoprost and those treated with other
medication. Kaplan–Meier estimates indicated a low risk
(#3.17%) for each event at 5 years. Treatment discontinua-
tion over 5 years due to macular edema, iritis/uveitis, corneal
erosions, iris pigmentation, and asthma/chronic obstructive
pulmonary disease occurred in 197/5,854 (0.3%) patients.
The rates were similar with latanoprost and with other medi-
cation. Discontinuation due to asthma/chronic obstructive
pulmonary disease was more common with other medication
than with latanoprost. Amongst patients who had ever been
treated with latanoprost, investigators judged that 12.4%
had increased iris pigmentation, 40.3% had eyelash changes,
and 7.8% had increased pigmentation of the periorbital skin,
although fewer patients considered that they had increased
iris pigmentation (8.2%) or eyelash changes (28.7%).
The final one of these studies, also conducted by Alm
et al, assessed a fixed combination of latanoprost and
timolol.
24
Nine hundred and eighty-two patients with open-
angle glaucoma or ocular hypertension were included in this
open multination study and were assessed at baseline and 12,
36, and 60 months. Increased iris pigmentation incidence was
compared with a historical control in a similarly designed
latanoprost study. Amongst 828/974 treated patients with
assessable iris photographs, 233 (28.1%) developed increased
iris pigmentation compared with 127/380 (33.4%) in the
historic controls. Patents with mixed eye colors had a greater
susceptibility to increased iris pigmentation (85.8% in both
studies). Most cases of iris pigmentation in this study were
only mild. Eyelash changes were seen in 58.1% of patients
and darkening of the eyelids in 5%–6%.
In conclusion, these large long-term studies indicate
that latanoprost is safe and well tolerated during treatment
over 5 years.
Compliance and persistence
In common with other insidious but symptomless conditions
such as hypertension and dyslipidemia, compliance in glau-
coma patients represents a real clinical challenge. Quigley pro-
posed that improving compliance would be the equivalent of a
second drop of medication.
81
A systematic review of treatment
with glaucoma medication in the US recently demonstrated
how poor compliance is; prescription records suggested suf-
ficient medication was only dispensed for around 56% of the
treatment days during the first year of treatment.
82
A recent
comprehensive systematic review identified 58 studies of
glaucoma eye-drop compliance and persistence, but con-
cluded that compliance remains a problem for existing ocular
hypotensive users, and that both compliance and persistence
are problems for newly treated patients.
82
The extent of the
persistence issue was identified in a study of 167,907 patients
receiving long-term treatment with statins, bisphosphonates,
oral diabetics, angiotensin receptor antagonists, and overac-
tive bladder medications. Persistence rates were lower for
prostaglandin eye drops than for any other medication with
the exception of those for overactive bladder.
83
Among a
population of 2,440 newly diagnosed glaucoma patients,
23% did not fill a prescription for their medication during
the 12 months after their first prescription.
84
As is the case
in other therapeutic domains, multiple drug administration
diminishes compliance and persistence.
85
Clearly, even with
modern drugs such as the prostaglandin analogs, compliance
and persistence remains a significant problem in the effective
treatment of glaucoma.
Although the early symptoms of glaucoma do not appear
to be particularly troublesome to patients,
86
vision-related
quality of life is diminished by the side effects of glaucoma
therapy,
87
although treatments such as latanoprost, timolol,
and their combination treatments may be better in this
respect.
45,88
Local adverse reactions are the most common
cause of poor compliance
86,87
and the second most common
reason for switching medication after lack of efficacy.
116
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The comparative persistence and compliance to pre-
scribed treatments has been well studied for latanoprost
predominantly in retrospective observational studies but also
in prospective studies. The results of the great majority of
these studies (summarized in Table 3) show that treatment
compliance and persistence are better with latanoprost eye
drops than with other medications.
105,108–110,112,113,115–118
However,
this finding is not unequivocal, with two studies finding either
an equivocal advantage or no advantage for latanoprost in
comparison with other glaucoma treatments.
114,120
Compliance remains a problem in the treatment of glau-
coma and this problem is far from solved; however, the great
weight of evidence suggests that latanoprost has an advantage
in this area compared with other glaucoma treatments.
Use of preservatives
Preservatives are commonly used in ophthalmic preparations
but can have adverse effects on the ocular surface, resulting
in symptoms such as hyperemia, tearing, burning, irritation,
itching, dryness, blurred vision, fluctuating visual acuity,
pain, and decrease in vision.
4,89,90
Even at very low concentra-
tions, preservatives are cytotoxic for conjunctival cells and
cause inflammation, apoptosis, and free radical production.
91
Impairment of the ocular surface also increases with age; tear
film thickness decreases, whilst there is an increase in tear
evaporation rate, prevalence of meibomian dysfunction, and
dry eye.
92–95
This is particularly important as the incidence of
glaucoma also increases with age, and so the patients’ eyes
are particularly sensitive to further damage.
As glaucoma requires lifetime treatment, a large propor-
tion of patients receive multiple therapies over time.
2
The
Ocular Hypertension Treatment Study, carried out in 1,636
patients with no evidence of glaucomatous damage, showed
that approximately 40% of patients initially diagnosed with
ocular hypertension were using two drugs after 5 years,
while 9% used three or more drugs. Such a combination of
several eye drops is likely to increase the cumulative dose
of preservatives.
96
A number of studies have demonstrated that products
without preservatives are more likely to be better tolerated and,
therefore, improve compliance and quality of life, and possibly
even efficacy.
97–99
For example, 4,107 patients with glaucoma
were treated with preserved eye drops (84%), preservative-
free eye drops (13%), or a combination of the two (3%).
97
All symptoms were significantly (P,0.001) more prevalent
with preservative eye drops than preservative-free eye drops.
This included discomfort upon instillation (43% versus 17%),
burning/stinging (40% versus 22%), foreign body sensation
(31% versus 14%), dry eye sensation (23% versus 14%), tear-
ing (21% versus 14%), and eyelid itching (18% versus 10%).
The prevalence of signs and symptoms was dose dependent,
increasing with the number of preservative eye drops. In a
multinational study in 9,658 patients using preservative or
preservative-free beta-blocking eye drops, a total of 74%
used preservative eye drops, 12% used preservative-free eye
drops, 10% used a combination, and 4% used an unknown
type.
97
Each symptom and all palpebral, conjunctival, and
corneal signs were significantly more frequent (P,0.0001)
in the preservative group than in the preservative-free group.
Upon a second evaluation, there was a significant decrease
(P,0.0001) in all ocular symptoms and signs in patients in
whom the dose of preserved eye drops was diminished or was
swapped to preservative-free drops (Figure 1).
Development of preservative-free latanoprost eye drops
The original latanoprost formulation contains the preserva-
tive BAK, and was required to be stored in the refrigerator
to prevent degeneration (although recent advice permits
storage at room temperature). In order to improve the
ocular side-effect profile, a preservative-free unidose for-
mulation of latanoprost (Monoprost
®
; Laboratioires Thea,
Clermont Ferrand, Germany) has recently been developed
and approved in Europe. The pharmaceutical formulation
includes Protriaxin
®
(Laboratioires Thea) a complex of
polymers including carbomer (widely used in artificial tears
and other ophthalmic and medical preparations) with benign
safety profiles.
100
As well as ensuring the stability of the
active ingredient at room temperature, the stability polymer
complex also prevents adsorption of latanoprost onto the
plastic surfaces of the delivery system, and provides pH
stability and an appropriate viscosity to the drops.
Initial studies in an animal model showed that a pre-
servative-free latanoprost formulation was as effective and
was better tolerated than a formulation containing BAK.
101
Both formulations were well tolerated, but the incidence of
conjunctival hyperemia was reduced by 42% with the BAK-
free latanoprost formulation. Subsequent studies in humans
confirmed these findings.
A Phase III noninferiority randomized investigator-
masked two-parallel-group study of Monoprost
®
versus
reference preservative-containing drug formulations in
402 patients with open-angle glaucoma or ocular hyperten-
sion treated over a period of 3 months has been reported.
102
The results showed that Monoprost
®
was noninferior for IOP-
lowering efficacy, with an IOP decrease of 8.6 and 9 mmHg
in the Monoprost
®
and control groups, respectively, without
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Table 3 Summary of discontinuation/persistence studies with a latanoprost cohort and at least one comparator cohort
Reference Study type Patients Duration Results
Dasgupta
et al
103
Retrospective
cohort study
1,330 Relative risk for therapy
discontinuation or change
Relative risk for therapy
discontinuation (excluding change)
Latanoprost 1 1
Beta-blockers 1.24 1.63
Carbonic anhydrase inhibitors 2.22 2.37
Shaya et al
104
Retrospective
cohort study
72,744 325 days
Relative risk for discontinuation (adjusted for sex and age) (CI)
Latanoprost 1
Timolol 1.34 [1.27–1.41]
Brimonidine 1,54 [1.45–1.62]
Spooner
et al
105
Retrospective
observational
cohort study
1,006 18 months
Hazard ratio (95% CI)
Latanoprost 1
Timolol 1.73 (1.40–2.15)
Betaxolol 1.63 (1.20–2.21)
Brimonidine 1.70 (1.22–2.34)
Reardon
et al
106
Retrospective
cohort study
7,527 180 days
Relative risk of discontinuation Relative risk of discontinuation
or change in therapy
Latanoprost
1 (P,0.001) 1 (P,0.001)
Bimatoprost 1.38 (1.24–1.36) 1.31 (1.19–1.44)
Travoprost 1.36 (1.21–1.51) 1.39 (1.17–1.42)
Brimonidine 2.41 2.26
Diestelhorst
et al
107
Observational
multicenter
retrospective medical
chart review
260 2 years
Percentage of patients not switched Percentage of patients switched
more than twice
Latanoprost 73.4% 4.3%
Beta-blocker 20.5% 14.5%
Day et al
108
Retrospective
multicenter parallel
active controlled
comparison
1,182 1 year
Risk ratio to discontinue treatment
Latanoprost 1
Bimatoprost
1.15 (95% CI .1.01 to .1.16)
Beta blocker
1.08 (95% CI .1.03 to .1.27)
Haverkamp
et al
109
Switch to
latanoprost
1,068 36 months
Switch to latanoprost associated with:
Reduced intraocular pressure (P,0.0012)
Ocular allergy as the most common side effect
Patient preference for latanoprost
Reardon
et al
110
Retrospective
cohort study
28,741 1 year
Rate ratio for discontinuation
of initial therapy
Patients having only one
ll of index drug
Latanoprost 1
Timolol 1.37 (95% CI 1.31–1.42)
34 (P,0.001)
Brimonidine 1.45 (95% CI 1.38–1.52)
48 (P,0.001)
Betaxolol 1.42 (95% CI 1.34–1.51)
46 (P,0.001)
Dorzolamide 1.41 (95% CI 1.30–1.53)
52 (P,0.001)
Bimatoprost 1.58 (95% CI 1.36–1.83)
48 (P,0.001)
Travoprost 1.72 (95% CI 1.50–1.97)
50 (P,0.001)
(Continued)
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Table 3 (Continued)
Reference Study type Patients Duration Results
Schwartz
et al
111
Retrospective
cohort study
1,474 12 months No discontinuation of therapy No discontinuation or change
in therapy
Latanoprost 39% 30%
Timolol 25% 18%
Wilensky
et al
112
Retrospective
population-based
study
2,424 12 months Percentage of patients
persistent for 12 months
Mean adherence Number of days adherent
Latanoprost 69.4% 75.4% 287
Travoprost 70.6% 77.1% 281
Bimatoprost 68.1% 78.2% 291.2
Bhosle et al
113
Retrospective
observational
cohort study
268 1 year Treatment adherence rate Medication persistence
Latanoprost
Other treatment
0.51±0.26
0.40±0.25
Hazard ratio 0.9
(95% CI 0.68–0.98)
Zimmerman
et al
114
Prospective
multicenter active
historical-controlled
trial
Pharmacy
claims data
for 6,271
patients
2001–2004 Continuous rell
of prescription
during 1 year
Patients persisting for
1 year or restarting
medication
Patients
switched to other
medications
Overall
discontinuation
of treatment
Latanoprost
11% (P,0.0001) 68% (P,0.0001) 17% (P,0.0001) 18% (P,0.0047)
Bimatoprost 9% 61 21% 21%
Travoprost 5% 58% 21% 21%
Arias et al
115
Retrospective
observational
cohort study
191 24 months No discontinuation of treatment
Latanoprost
81.6% (P,0.0001)
Bimatoprost 22.9%
Travoprost 65.4%
Timolol 60.5%
Friström
et al
116
Open-label
multicenter
time-on-therapy
study
326 36 months Mean time to treatment failure Patients remaining on therapy at 36
months
Latanoprost
36 months (P,0.001)
51%
Non-PG therapy 12 months 24%
Reardon
et al
117
Retrospective
cohort study
7,873 358 days Medication possession Days covered
Latanoprost
31% (P,0.001) 141±89 (P,0.001)
Bimatoprost 23%
119±80
Travoprost 43%
108±76
Rahman
et al
118
Retrospective
analysis of medical
records
1,006 1997–2001
and 2002–
2009
Hazard ratio for time to initial treatment
change; 1997–2001 (95% CI)
Hazard ratio for time to treatment
change; 2002–2009 (95% CI)
Betaxolol versus latanoprost 2.59 (2.02–3.32)
Brimonidine versus latanoprost 2.55 (1.76–3.69)
Timolol versus latanoprost 1.49 (1.05–2.11)
Bimatoprost versus latanoprost 1.18 (0.71–1.97)
Travoprost versus latanoprost 0.75 (0.51–1.12)
Abbreviations: CI, condence interval; PG, prostaglandin.
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Latanoprost in glaucoma
Foreign body sensation
Pain or discomfort during instillation
Ocular symptoms (during and after instillation)
Palpebral signs
Conjunctival signs
Corneal signs (superficial punctate keratitis)
Stinging or burning
Dry eye sensation
Tearing
Eyelid itching
Anterior blepharitis
Posterior blepharitis
Eczema
Hyperemia
Conjunctival follicles
Fluorescein staining in the nasal bulbar
Absent
Mild
Moderate/severe
Preserved eye drops
Preservative-free eydrops
P<0.0001
% patients
010 20 30 40 50 60 70 80 90 100
Figure 1 Ocular symptoms and signs with preserved and preservative-free glaucoma medications.
Notes: Frequency of signs and functional symptoms at visit 1 and visit 2 after switch from preserved to preservative-free eye drops or decrease of the number of preserved
eye drops. Republished with permission of Wichtig Editore Srl, from Eur J Ophthalmol, Ocular symptoms and signs with preserved and preservative-free glaucoma medications,
Jaenen N, Baudouin C, Pouliquen P, Manni G, Figueiredo A, Zeyen T, volume 17, 2007;
97
permission conveyed through Copyright Clearance Center, Inc.
statistically significant difference.
103
Conjunctival hyperemia
was less frequent and less severe in the Monoprost
®
group,
with a statistically significant lower incidence apparent in the
worse eye at day 42 (20.2% versus 30.6%, P=0.003) and day
84 (21.4% versus 29.1%, P=0.019).
This study was also included into a meta-analysis,
50
together with all previous randomized clinical trials of
at least 2 months duration, investigating any PG analog
(with or without a preservative) compared to one another as
monotherapy. Twenty-one relevant randomized controlled
trials of head-to-head comparison between PG analogs,
corresponding in 26 pairwise comparisons published before
December 2011, were extracted by systematic review of
Medline, Cochrane, and Embase databases to be included in
a meta-analysis. The results showed no statistically significant
differences in mean IOP at 3 months between Monoprost
®
and most other PG analogs, with the exception of BAK-
tafluprost, which was found to be statistically significantly
inferior to Monoprost
®
with respect to this parameter. The
risk of hyperemia was statistically significantly lower with
Monoprost
®
than all other PG analogs.
Conclusion
Latanoprost has been extensively studied in the treatment of
raised IOP, and the data presented in Tables 1 and 2 clearly
attest to its efficacy. Latanoprost is at least as effective
as other therapies in terms of the key efficacy parameter:
IOP reduction. Moreover, since this agent has formed part
of the glaucoma armamentarium for more than 15 years,
practitioners can call upon considerable clinical experience
with this agent.
Nevertheless, proven efficacy is of little value if side
effects cause poor compliance and persistence with therapy.
Compliance and persistence have been, and remain, signifi-
cant problems for the treatment of glaucoma. The latest itera-
tion of the European Glaucoma Society guidelines state:
While meta-analyses focus on IOP reduction, other aspects
like patient characteristics, quality of life, side effects,
convenience/compliance and cost-effectiveness should be
taken into consideration in making a drug therapy choice
particularly when IOP differences between the compounds
are small.
4
Latanoprost eye drops are not associated with systemic
side effects. Local adverse effects may be troublesome in a
proportion of patients, but its efficacy–tolerability relation-
ship can be considered the best in its class. Specific studies
strongly suggest that compliance and persistence with latano-
prost is superior to that with other glaucoma treatments.
The disadvantages of preservatives in topical ocular thera-
pies have been underestimated until recently. Fortunately,
the problems such preservatives cause have now been recog-
nized, and manufacturers of these therapies have responded
with the development of ingenious formulations that avoid
preservatives but maintain the sterility and other necessary
properties of the preparation. Latanoprost is intended to be a
chronic or lifetime treatment, so its availability in convenient
preservative-free formulations is to be much welcomed.
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Overall, latanoprost is an effective and well-tolerated
treatment for raised IOP. The superior compliance and per-
sistence of patients using latanoprost, as well as the avail-
ability of a preservative-free formulation, mean it should be
considered as an option for all glaucoma patients.
Acknowledgments
Dr JF Stolz provided assistance with the preparation of the
manuscript; this assistance was reimbursed by Laboratoires
Thea.
Disclosure
Prof A Alm has received remuneration from Laboratoires
Thea. Dr JF Stolz assisted in the preparation of the manu-
script. This work was reimbursed by Laboratoires Thea. The
author reports no other conflicts of interest in this work.
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... In addition, there are also effects directly related to certain classes of medication. Prostaglandins and/or prostamides are responsible for conjunctival hyperemia, hypertrichosis, change of iris color (pigmentation), hyperpigmentation of the periocular area, burning, and sensation of foreign body [30]. When chronically applied, it may be useful to evaluate a therapeutic change towards solutions with a lower concentration of the active drug, which, however, exhibits a non-inferiority in the IOP control. ...
Article
Full-text available
This study aimed to evaluate whether the therapeutic switch from a formulation of Bimatoprost 0.1 mg/mL with benzalkonium chloride (BAK) or Bimatoprost 0.3 mg/mL preservative-free to a formulation of Bimatoprost 0.1 mg/mL preservative-free could improve eye surface conditions in patients with glaucoma; intraocular pressure (IOP) was also evaluated. All patients meeting the inclusion criteria were eligible for the therapeutic switch to Bimatoprost 0.1 mg/mL preservative-free. At each check visit, enrolled patients underwent a break-up time (BUT) test, an ocular surface disease index (OSDI) test, and a three-point tonometric curve. A total of 40 patients were enrolled (23 were in therapy with Bimatoprost 0.1 mg/mL with BAK and 17 with Bimatoprost 0.3 mg/mL preservative-free). Significant differences of OSDI and BUT between Bimatoprost 0.1 mg/mL with BAK at baseline vs. Bimatoprost 0.1 mg/mL preservative-free at 14 and 28 days (p < 0.0001 and p = 0.0003, respectively) were recorded. Similarly, significant differences of OSDI and BUT between Bimatoprost 0.3 mg/mL preservative-free at baseline vs. Bimatoprost 0.1 mg/mL preservative-free at 14 and 28 days (p < 0.0001 for both) were found. Bimatoprost 0.1 mg/mL preservative-free has a better tolerability profile associated with non-therapeutical inferiority in the control of IOP compared to the other Bimatoprost formulations.
... Indeed, BAK is known to induce adverse effects on the ocular surface and is, at the same time, considered useful in promoting the permeation of active molecules. But, it is interesting to note, that, the formulation of prostaglandin analogs as an ester prodrug, with a high lipophilicity, further hydrolyzed by cellular esterases into the acid form of prostaglandin, allows a better absorption by the cornea [30]. Additionally, several studies comparing prostaglandin analogs, with or without BAK showed similar efficacy especially on lowering IOP [31][32][33] suggesting that a penetration enhancer might not be helpful. ...
Article
Background: Benzalkonium chloride (BAK)-containing antiglaucoma therapies alter the ocular surface over the long term. We used an in vitro scraping model to compare the effects of preserved and unpreserved topical commercial prostaglandins (PGs) in a wound-healing model. Methods: Standardized mechanical scraping was performed in confluent immortalized human corneal/conjunctival epithelial cell layers. Cytotoxicity, cell migration and proliferation, as well as the percentage of closure, were analyzed 2 h and 1/2/3/6 days after a 30-min exposure to 1/10 dilutions in phosphate buffered saline (PBS) used also as control, BAK solutions at concentrations ranging from 0.0001% to 0.1%, latanoprost-0.02%BAK, travoprost-0.015%BAK, bimatoprost-0.005%BAK, BAK-free Tafluprost, latanoprost in cationic emulsion, and travoprost (Polyquad® and SofZia®). Results: PG eyedrop preparations with BAK preservative delayed corneal healing, which is primarily related to the presence of BAK, in a dose-dependent manner, especially at day 1, as evidenced through actin disorganization and decreased Ki-67-positive cell numbers. The PGs (BAK-free tafluprost, latanoprost in cationic emulsion,travoprost (Polyquad® and SofZia®)) maintained a normal healing process with results similar to those of control. Conjunctiva-derived cell layers healed more slowly than corneal cell layers and were more sensitive in in vitro cytotoxicity tests. Conclusions: This novel in vitro scraping model mimics the damaged ocular surface epithelia observed in glaucoma patients affected by ocular surface disease, such as toxic-induced dry eye (TIDE) and offers a tool to assess the potential cytotoxic effects of PG formulations with or without BAK.
... However, latanoprost was considered as the most relevant comparator given its wide use in clinical practice, and its well-established safety and efficacy profile. 19 In conclusion, NCX 470 was noninferior to latanoprost and generally well tolerated at all doses studied. The dosedependent response suggests that concentrations higher than 0.065% may provide even greater IOP-lowering efficacy in future clinical trials. ...
Article
Full-text available
Prcis: NCX 470 0.042% and 0.065% were statistically superior in IOP-lowering to latanoprost 0.005%, and NCX 470 0.021% was non-inferior. All NCX 470 concentrations were safe and well tolerated. Purpose: To compare varying concentrations of NCX 470 (a nitric oxide-donating bimatoprost) to latanoprost in a dose-response safety and efficacy trial. Patients and methods: Adult patients with bilateral open-angle glaucoma or ocular hypertension were randomized to NCX 470 0.021% (n=111), 0.042% (n=108), 0.065% (n=107) or latanoprost 0.005% (n=107) QD PM. IOP was measured at 8:00 AM, 10:00 AM, and 4:00 PM at weeks 1, 2 and 4. The primary efficacy endpoint was the reduction from baseline in mean diurnal IOP at week 4. Secondary efficacy endpoints included reductions from baseline in mean diurnal IOP at weeks 1 and 2, and reductions from baseline in time-matched IOP at 8:00 AM, 10:00 AM and 4:00 PM at weeks 1, 2 and 4. Adverse events were evaluated. Results: All concentrations of NCX 470 resulted in significant reductions of mean diurnal IOP. The 0.042% and 0.065% concentrations were statistically superior to latanoprost 0.005%, and 0.021% was non-inferior to latanoprost for change from baseline in mean diurnal IOP at week 4. The 0.065% concentration was also superior to latanoprost by up to 1.4▒mm Hg for reduction from baseline at 8:00 AM, 10:00 AM and 4:00 PM at week 4. NCX 470 was safe and well tolerated; conjunctival hyperemia was the most frequently reported adverse event. Conclusions: NCX 470 demonstrated dose-dependent reductions in IOP. The 0.042% and 0.065% concentrations demonstrated significantly greater reductions from baseline in mean diurnal IOP than latanoprost 0.005% at week 4, suggesting that higher concentrations may show even greater efficacy.
... In addition to the first-line drugs, prostaglandin (PG) F2α agonists (PGF2α-ags) are used in the treatment of patients with glaucoma and ocular hypertension (OH) [10][11][12], omidenepag isopropyl (OMDI), a non-prostaglandin, a prostanoid EP2 agonist, has recently become available [13,14]. Pharmacologically, (1) OMDI is metabolized into the active form (omidenepag, OMD) by hydrolysis after its administration, and (2) the hypotensive mechanisms for OMD involve an increase in the ease of uveoscleral outflow, similar to PGF2α-ags [15]. ...
Article
Full-text available
To compare the drug-induced efficacies between omidenepag (OMD), an EP2 agonist, and prostaglandin F2α (PGF2α) on glaucomatous trabecular meshwork (TM) cells, two- and three-dimensional (2D and 3D) cultures of TGF-β2-modulated human trabecular meshwork (HTM) cells were used. The following analyses were performed: (1) transendothelial electrical resistance (TEER) and FITC-dextran permeability measurements (2D), (2) the size and stiffness of the 3D spheroids, and (3) the expression (both 2D and 3D) by several extracellular matrix (ECM) molecules including collagen (COL) 1, 4 and 6, and fibronectin (FN), and α smooth muscle actin (αSMA), tight junction (TJ)-related molecules, claudin11 (Cldn11) and ZO1, the tissue inhibitor of metalloproteinase (TIMP) 1–4, matrix metalloproteinase (MMP) 2, 9 and 14, connective tissue growth factor (CTGF), and several endoplasmic reticulum (ER) stress-related factors. TGF-β2 significantly increased the TEER values and decreased FITC-dextran permeability, respectively, in the 2D HTM monolayers, and induced the formation of downsized and stiffer 3D HTM spheroids. TGF-β2-induced changes in TEER levels and FITC-dextran permeability were remarkably inhibited by PGF2α. PGF2α induced increases in the sizes and stiffness of the TGF-β2-treated 3D spheroids, but OMD enhanced only spheroid size. Upon exposure to TGF-β2, the expression of most of the molecules that were evaluated were significantly up-regulated, except some of ER stress-related factors were down-regulated. TJ-related molecules or ER stress-related factors were significantly up-regulated (2D) or down-regulated (3D), and down-regulated (2D) by PGF2α and OMD, while both drugs altered the expression of some of the other genes in the 3D spheroids in a different manner. The findings presented herein suggest that PGF2α and OMD differently modulate the permeability of the TGFβ2-modulated 2D monolayers and the physical properties of the 3D HTM spheroids.
... 6 Latanoprost is an esterified prodrug of Prostaglandin F 2α (PGF2α), which is more lipophilic than the main compound. 7 Eyelash hypertrichosis is a common complication of the chronic use of latanoprost, that manifests as increases the number, thickness, and length of eyelashes. 8 The stimulatory effect of latanoprost on mouse hair follicles has been proven previously. ...
Article
Full-text available
Background: Alopecia areata (AA) is a recurrent chronic disease that affects hair follicles and results in hair loss. Make an increase in the number, thickness, and length of eyelashes is an important side effect of latanoprost eye drop. Objective: This study aimed to evaluate the effect of hypertrichosis property of latanoprost in the treatment of scalp AA. Methods: In this randomized double-blind placebo-controlled trial, thirty participants with scalp AA assigned to receive either topical latanoprost 0.005% solution or placebo for 12 weeks. In both arms, patients also received clobetasol 0.05% cream in isopropyl alcohol (1:1). The hair loss area pictured at baseline and the end of the fourth, eighth, and twelfth weeks. According to the images, the dermatologist assessed the hair loss area, hair density, and the severity of alopecia. Results: Latanoprost significantly increased hair density (37.2± 26.1 vs. 14.6 ± 18.6) and regrowth (58.3 ± 39.3 vs. 21.6 ± 24.1) based on the Severity of Alopecia Tool (SALT) system compared to the control group (P=0.03 and 0.02, respectively). However, there were no significant differences between the two groups in reduction in the hair loss area and SALT, and the incidence of side effects (P=0.718, 0.262, and ≥0.99, respectively). Conclusion: Results showed the acceptable safety and efficacy of latanoprost 0.005% solution to increase hair density and regrowth. So, it could be safely used for the management of scalp AA. This article is protected by copyright. All rights reserved.
... 17 FP receptor agonists are currently the most commonly used first-line therapy to treat POAG, because of their effective IOP-lowering ability, convenience of once-daily (QD) dosing, limited systemic side effects, and good tolerability. 1,3,13,18,19 However, despite being the most effective monotherapy for glaucoma treatment, it is estimated that 35%-40% of patients require adjunctive treatment to effectively manage their IOP. [20][21][22] Fixed-dose combinations of different ocular hypotensives have been utilized to improve adherence and achieve improvements in IOP reduction compared with either monotherapy alone. ...
Article
Purpose: This phase 2b, randomized, observer-masked, placebo- and active-controlled, parallel-group, multinational (USA and Japan), multicenter study (NCT03216902) assessed the optimal dose of sepetaprost ophthalmic solution in patients with primary open-angle glaucoma or ocular hypertension. Methods: After washout, patients ≥18 years (USA) or ≥20 years of age (Japan) received once-daily sepetaprost for 3 months [0.0005% (n = 43); 0.001% (n = 43); 0.002% (n = 44); and 0.003% (n = 45)], latanoprost 0.005% (n = 44) or placebo until week 6, followed by sepetaprost 0.003% until month 3 (n = 22). Safety assessments included adverse event (AE) occurrence. Results: Baseline mean diurnal intraocular pressure (IOP) was 24.3 mmHg for latanoprost and ranged between 24.1 and 24.5 mmHg for the sepetaprost groups. Sepetaprost 0.002% had the lowest IOP at each month 3 time point (9:00 AM; 1:00 PM; 5:00 PM) of all sepetaprost concentrations (mean ± standard error: 17.6 ± 0.5; 17.4 ± 0.4; 16.7 ± 0.4 mmHg); similar values were observed with latanoprost (18.1 ± 0.6; 17.3 ± 0.5; 17.2 ± 0.5 mmHg). A positive dose-response relationship was observed with the 3 lower sepetaprost doses; sepetaprost 0.002% had numerically greater IOP-lowering effects than sepetaprost 0.003%. All sepetaprost doses had statistically significantly greater IOP reductions from baseline versus placebo at week 6 (P < 0.0001). This IOP-lowering effect was consistent between Japan- and USA-based patients. Most AEs were mild and occurred numerically less frequently with sepetaprost 0.002% (34.1%) versus latanoprost (50.0%). The most frequently reported AE was conjunctival hyperemia. Conclusions: In this study, sepetaprost 0.002% was the optimal concentration, showing comparable IOP-lowering efficacy and safety with latanoprost 0.005%. Most AEs were mild; occurrence was numerically lower with sepetaprost 0.002% than latanoprost 0.005%.
... Latanoprost is a prostaglandin F2 alpha analog that, like minoxidil, was initially developed to treat other conditions (glaucoma in this case) but later repositioned for the topical treatment of alopecia [13][14][15]. ...
Article
Alopecia is a condition associated with different etiologies, ranging from hormonal changes to chemotherapy, that affects over 80 million people in the USA. Nevertheless, there are currently few FDA-approved drugs for topical treatment, and existing formulations still present skin irritation issues, compromising treatment adherence. This work aimed to develop a safe formulation based on nanostructured lipid carriers (NLC) that entrap an association of minoxidil and latanoprost and target drug delivery to the hair follicles. To do so, thermal techniques combined with FTIR were used to assess the chemical compatibility of the proposed drug association. Then, NLC with 393.5 ± 36.0 nm (PdI<0.4) and +22.5 ± 0.2 mV zeta potential were produced and shown to entrap 86.9% of minoxidil and 99.9% of latanoprost efficiently. In vitro, the free drug combination was indicated to exert positive effects over human primary epidermal keratinocytes, supporting cell proliferation, migration and inducing the mRNA expression of MKI67 proliferation marker and VEGF – a possible effector for minoxidil-mediated hair growth. Interestingly, such a favorable drug combination profile was optimized when delivered using our NLC. Furthermore, according to the HET-CAM and reconstructed human epidermis assays, the nanoformulation was well tolerated. Finally, drug penetration was evaluated in vitro using porcine skin. Such experiments indicated that the NLC could be deposited preferentially into the hair follicles, causing a considerable increase in the penetration of the two drugs in such structures, compared to the control (composed of the free compounds) and generating a target-effect of approximately 50% for both drugs. In summary, present results suggest that hair follicle-targeted delivery of the minoxidil and latanoprost combination is a promising alternative to treat alopecia.
... Latanoprost is a prostaglandin F2 alpha analog that, like minoxidil, was initially developed to treat other conditions (glaucoma in this case) but later repositioned for the topical treatment of alopecia [13][14][15]. ...
... 5 Latanoprost (LT) eye drops make up the majority of prescribed PGs worldwide. 6 Although generally well tolerated, lifelong use of preserved LT eye drops can cause ocular side effects and affect patients' quality of life. This may lead to reduced compliance, can have serious consequences for the therapeutic effect and thus worsen the disease. ...
Article
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Objective To investigate the short-term impact on human conjunctival goblet cell (GC) survival and mucin release of acute exposure to benzalkonium chloride (BAK) preserved and preservative-free (PF) 0.005% (w/v) latanoprost (LT) eye drops, and to compare the eye drops’ physicochemical properties. Methods and analysis Primary GC cultures were established from human conjunctival donor tissue. The impact of eye drops on GC survival was assessed using a lactate dehydrogenase assay. Mucin release was evaluated through mucin-specific immunostaining. pH value, osmolality, drop mass and surface tension for all LT eye drops were measured. Results After application with PF-LT for 30 min (min), the GC survival was maintained compared with control (p=0.9941), while all BAK-LT eye drops reduced survival with approximately 30% (p<0.02). Following application with PF-LT for 30 min, mucin was found around the GC nucleus, as seen in the vehicle control, indicating no secretion. In contrast, BAK-LT caused diffuse staining of mucin, similar to the secretagogue histamine, indicating stimulation of secretion. The pH value of the BAK-LT and PF-LT eye drops were 6.0–6.9 and 6.8, respectively. The osmolality was 258–288 mOsm/kg for the BAK-LT eye drops and 276 for PF-LT eye drops. The mean drop mass was 26–31 mg for the BAK-LT eye drops and 30 mg for PF-LT. The surface tension was lower for all BAK-LT eye drops (31.1–32.1 mN/m) compared with PF-LT (42 mN/m). Conclusion PF-LT compared with various branded and generic LT preparations containing BAK are less cytotoxic when applied to cultured GCs.