Biomedical Engineering Reference
In-Depth Information
Study Design and Methodologies for Evaluation
of Anti-glaucoma Drugs
Paul E. Miller
Abstract
A large number of factors are important in conducting anti-glaucoma drug efficacy studies. It is essential to
have an understanding of aqueous humor dynamics and how the tonometer, tonometrist, and animal may
affect IOP estimates. Additional critical considerations in the design of an anti-glaucoma drug efficacy
studies include the following: (1) selecting the most appropriate species, (2) identifying the rate of
nonresponders within the study population, (3) determining whether normotensive or glaucomatous
animals should be used, and deciding (4) what secondary endpoints (if any) to include, and (5) whether
one eye or both should be dosed. Anti-glaucoma drug efficacy studies have an acclimation phase in which
the animal becomes conditioned to the procedures, a predose phase in which baseline data is collected, a
dosing phase in which the drug is administered and IOP and possibly other endpoints are monitored, and
a recovery phase in which IOP returns to predose values as the drug is washed out before another predose
phase is started.
Key words
Glaucoma, Anti-glaucoma drugs, Intraocular pressure, Tonometry, Aqueous humor
dynamics, Animal models
1
Introduction
Glaucoma
is a group of diseases which result in a characteristic
pattern of damage to the optic nerve and subsequently vision loss
[
1
,
2
]. In animals with spontaneous glaucoma this injury is believed
to be almost always initiated by an abnormal increase in intraocular
pressure (IOP) [
2
]. In humans, however, the relationship between
glaucomatous optic neuropathy and IOP appears to be more com-
plex and other risk factors are thought to play significant roles such
as the ease with which the lamina cribrosa (the sieve-like portion of
the sclera through which the axons of the retinal ganglion cells
[RGCs] exit the eye) becomes distorted and vascular alterations in
the perfusion of the optic nerve (Fig.
1
)[
2
,
3
]. Hence, some
humans may exhibit mild increases in IOP with no signs of glauco-
matous damage or vision loss (so-called
ocular hypertension
), pre-
sumably due to a lamina cribrosa that offers greater resistance to
distortion and compression of the optic nerve fibers (RGC axons)
passing through it, or due to an increased ability to maintain
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