Clinical doses of latanoprost, bimatoprost, and travoprost administered q.d. pm
produced maximal IOP-lowering responses in normotensive monkeys, compared to b.i.d
treatments or threefold higher doses given q.d. Latanoprost, bimatoprost, and
travoprost were similar in their efficacies. Prescreening the monkeys for strong
responsiveness to PGF2
α-ie may have eliminated some
variability in IOP efficacies, as reported in humans, where nonresponders to
latanoprost may still respond to bimatoprost.17–19
The EP1 (EP1>EP3) agonist 17PhTPGE2 had little effect on IOP alone or in
combination with butaprost or latanoprost. The EP1 receptor was shown to mediate the
IOP-lowering response to PGF2
α in cats.
EP1 and EP3 receptors were shown to be prominently expressed in human ciliary
body and cornea
as well as in trabecular cells.
EP1 receptor mRNA transcripts were present in all muscle fibers of the human
It is also possible the b.i.d. treatment regimen utilized in the current
study may not be optimal, as was the case with latanoprost and bimatoprost.
The EP2 agonist, butaprost, lowered IOP similarly to what has been previously reported.
The addition of butaprost to latanoprost did not significantly enhance the
IOP-lowering response to latanoprost. Immunohistochemistry studies showed that EP2
receptors were the most abundantly expressed EP subtype in human ocular tissues.
The EP3 (EP3 ≥ EP111,13,14
) agonist, sulprostone, had very little effect on IOP when used
alone. This is in contrast to early studies in monkeys, where a
2.5–3-mmHg reduction was reported after a single 25-μg dose
of sulprostone or an ~4-mmHg reduction after twice-daily treatment with 25
μg of another EP3 agonist, MB 28767.
The addition of sulprostone to latanoprost did not further enhance the
IOP-lowering response. In EP and FP receptor knockout mice, part of the ocular
hypotensive response to the PGF2
α analog, tafluprost, were
found to be mediated by EP3 receptors.
Similarly, in knockout mice, it was concluded that the EP3 receptor plays a
role in the IOP-lowering response to latanoprost, travoprost, and bimatoprost.
This is in contrast to what would be expected from in vitro
and functional assays,
in which FP-receptor binding and functional responses (e.g., phosphoinositide
turnover) were at least two orders of magnitude greater than for EP3 receptors. The
EP3 receptor has also been detected in trabecular cells in human donor eyes.
It was hypothesized that the FP+EP2+EP3 combination would give the greatest effect,
based on individual agonist IOP-lowering studies conducted in monkeys by other
Combined therapy with
latanoprost+sulprostone+ butaprost decreased IOP more that latanoprost alone, but
the IOP-lowering response was not as great as with the nonselective agonist,
α-ie, in normotensive cynomolgus monkeys (). However, the addition of the EP1
agonist, 17PhTPGE2, to the combination of latanoprost+sulprostone + butaprost did
reproduce the magnitude and time course of the IOP-lowering response to
α-ie. Perhaps PG subtypes, which alone have no effect on
IOP, may act in synergistic ways to enhance IOP reduction when combined with current
IOP-lowering PG compounds. The combination of latanoprost+17PhTPGE2+butaprost was
not tested, so it is not known if sulprostone is necessary in the formulation to
reproduce the magnitude of the PGF2
response. Once-daily treatment with the other compounds should be investigated as
well in order to possibly further optimize the IOP-lowering responses and minimize
side effects. Also, there was no analysis of the combined formulation to determine
if any alteration of the individual components occurred when they were combined that
could have contributed to the response.
The EP4 agonist, ONO-123A, has been reported to increase outflow facility by 43% in
monkeys after a single dose.
Another EP4 agonist, 3,7-dithia PGE1, did not relax primate ciliary muscle
precontracted with carbachol.
α is known to effectively bind to EP4 receptors.
No further enhancement would be expected by the addition of an EP4 agonist,
since the magnitude of the PGF2
α-ie IOP lowering was achieved
with the combination of the FP+EP1+EP2+EP3 agonists.
However, this does not exclude the possibility that the addition of the EP4
agonist to PGF2
α-ie, or to the combination that equaled it,
might produce IOP lowering beyond either of those. It is also possible that an EP4
agonist might be substituted for one of the others to produce the same, or more
consistent, IOP-lowering response and to eliminate adverse side effects, such as
were encountered in some instances with butaprost.