Biomedical Engineering Reference
In-Depth Information
response rate (as defined by a 15 % reduction in IOP) latanoprost is
approximately 89 % whereas it is 0-20 % for timolol [
67
,
68
,
103
].
In humans the response rate is approximately 82 % for latanoprost
and 74 % for timolol after 3 months of use [
104
]. In one study
using cynomolgus monkeys, 72 % were found to respond to lata-
noprost whereas the remaining 28 % exhibited no IOP reduction at
all [
101
].
Often it is valuable to use only “responders” to conduct studies
which are designed tomake comparisons between various concentra-
tions, formulations, or congeners. If the test article is closely related
to a commercially available compound, or is a derivative of a parent
compound, it may be possible to assess the potential for responsive-
ness by using the commercial or parent compound, but this is not a
foolproof approach [
101
]. For example, PGF2
α
lowers IOP in nor-
mal cats but the commercially available PGF2
α
derivatives does not,
and the commercially available PGF2
analogue talfluprost can lower
IOP in monkeys that are unresponsive to the closely related PGF2
α
α
analogue latanoprost [
66
,
101
]. For truly novel compounds often the
nonresponse rate of a given species can only be experimentally
derived. In studies involving repeated or prolonged exposure to one
or more test articles it may also be important to periodically conduct a
single-dose efficacy trial using the parent compound (or class stan-
dard) to verify that tachyphylaxis has not occurred.
Another consideration is whether the test animals should be nor-
motensive or if one of the ocular hypertension models should be
used. Advantages of normotensive animals is their ready availability,
the ability to relatively rapidly initiate a study without the need for
additional interventions, decreased animal care requirements,
reduced costs, and the high probability that if IOP lowering is
seen in normotensive animals that an even greater reduction in
IOP is likely in glaucomatous patients. Normotensive animals,
however, have fully intact aqueous humor dynamics and compen-
satory pathways that often blunt IOP decreases. Their numerically
lower IOP values also leave less room for IOP to decrease. (To get
around this some researchers only use normal animals with IOPs at
the higher end of the normal range). These two factors increase the
risk that a modest IOP reduction in a specific animal species would
be lost in the
5.4 Normotensive
or Hypertensive?
2 mm inherent variability in the tonometer. Addi-
tionally, the need to overcome intact aqueous humor dynamics in
preclinical studies often leads to an overestimation of the therapeu-
tic dose that will be required in glaucomatous patients. Because of
this it is often advisable in definitive preclinical toxicity and safety
studies to include dose levels that are lower than those required to
achieve peak efficacy in normal animals (or even normal humans).
Ocular hypertensive models have abnormal aqueous humor
dynamics which magnify minor changes in aqueous production or
outflow, thereby increasing the reduction in IOP and the ability to
detect these changes. Additionally, the resting IOP levels are
