REVIEW

CURRENT
OPINION New classes of glaucoma medications
Emily M. Schehlein a, Gary D. Novack b,c, and Alan L. Robin a,d,e

Purpose of review
To discuss recent advances in the medical management of glaucoma and to highlight future medical
therapies currently in development.
Recent findings
In 1996, latanoprost (Xalatan) was approved in the United States as a new chemical entity and new class
(prostaglandin analogs) for the topical treatment of ocular hypertension and glaucoma. In the period from
the late 1990s–2010s, while there were additional new chemical entities, fixed dose combinations, and
formulation improvements, there were no new classes of ocular hypotensive medications approved
worldwide. We summarize new pharmacological treatments that are currently in clinical trials – new
classes, new molecules and new delivery systems.
Summary
Although challenges in medical treatment of glaucoma exist, particularly in patient adherence, medical
therapy remains the first line treatment for almost all glaucoma patients. Few new medications for
glaucoma therapy are currently available for our patients, but multiple drugs with novel mechanisms of
action, new formulations, and new delivery mechanisms are currently in development.
Keywords
drug delivery, glaucoma, medications

INTRODUCTION TOPICAL MEDICATIONS

Glaucoma is comprised of a group of progressive
degenerative diseases characterized by a specific
pattern of axonal death. It is the second leading
cause of blindness worldwide [1] and, as both the
incidence of glaucoma increases with age and the
population is aging [2], its prevalence is projected to
increase exponentially in the coming decades [3,4].
Our current first line therapies are often
inadequate. Both the Collaborative Initial Glau-
coma Treatment Study [5] and the Ocular Hyperten-
sion Treatment Study [6], found that more than one
single class of medications is needed for the majority
of patients. Adherence is a major limiting factor in
taking medications, and an increase in ophthalmic
medications decreases adherence [7,8] and appears
to have minimal therapeutic effect in most [9]. What
is needed are therapies that last longer, thus mini-
mizing a patient’s need for constant medication
instillation, increasing both adherence and success-
ful intraocular pressure (IOP)-lowering, and mini-
mizing the risk of visual impairment and blindness.
Although there are many ways to treat glau-
coma, the primary method is with medical therapy.
In this article, we review the current literature
regarding medical therapies for glaucoma and those
in development.
IOP is currently the only target of glaucoma therapy.
All current approved medication classes act on this
glaucoma risk factor, as reducing IOP has been
shown to reduce disease progression [10,11] and
minimize the development of glaucoma in patients
with ocular hypertension [6]. Although both laser
and surgical therapy are available, topical therapy is
generally considered the first line of glaucoma
therapy for both ocular hypertension and open
angle glaucomain the developed world. This
requires both adherence and correct self-adminis-
tration. There are several classes of medical therapy
for reducing IOP, the most commonly used being
a
University of Maryland School of Medicine, Department of Ophthal-
mology and Visual Sciences, Baltimore, Maryland, bPharmaLogic Devel-
opment Inc., San Rafael, California, USA, cDepartments of Pharmacology
and Ophthalmology, University of California, Davis, School of Medicine,
California, dUniversity of Michigan, Department of Ophthalmology and
Visual Sciences, Ann Arbor, Michigan and eJohns Hopkins University
Department of Ophthalmology and School of Public Health, Baltimore,
Maryland, USA
Correspondence to Alan L. Robin, MD, 6115 Falls Road, Suite 333,
Baltimore, MD 21209-2226, USA. Tel: +1 410 377 2422;
fax: +1 410 377 7960; e-mail: arobin@glaucomaexpert.com
Curr Opin Ophthalmol 2017, 28:161–168
DOI:10.1097/ICU.0000000000000346

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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Glaucoma

humor. Prostaglandins increase uveoscleral outflow

KEY POINTS
 Medical therapy remains the first-line treatment
in glaucoma.
 One new class of topical IOP-lowering therapy is
available to patients in Japan, the first in almost two
decades, and there are multiple options currently
in development.
 Drug delivery systems may offer a new administration
method for glaucoma medical therapy and solve many
of the problems associated with glaucoma adherence,
but their actual efficacy remains to be determined.
 No new clinical progress has been made in glaucoma
with respect to marijuana.
topical prostaglandin analogues and b-adrenocep-
tor antagonists.
Goals for development of these new drug for-
while cholinergic agonists, such as pilocarpine, act
primarily through trabecular outflow. Use of the
latter class is greatly limited by its marked ocular
side-effect profile and need for multiple-daily dos-
ing. No new classes of IOP-lowering drugs have been
approved in the United States (US) since latanoprost
(Xalatan) in 1996. However, a Rho kinase inhibitor
has been approved in Japan and there are potentially
several new classes visible on the horizon that may
be available by or before the end of the decade in the
US (Table 1).
Ripasudil (Glanatec): a Rho kinase inhibitor
Ripasudil (Glanatec) (Kowa Company, Ltd., Nagoya,
Aichi, Japan) is the first Rho kinase inhibitor
approved for the treatment of glaucoma. Rho
kinases are serine/threonine protein kinases
expressed in the trabecular meshwork. Rho kinase
inhibitors have been shown in human [12 ,13 ] and
& &

mulations or new classes include their ability to & & &&

improve the efficacy and duration of action of cur-
rent therapies and to have a favorable adverse event
profile that minimizes obvious ocular or systemic
toxicities.
Medications with novel mechanisms of
action
Existing drug classes modulate IOP primarily by
decreasing production of aqueous humor and/or
by increasing its outflow from the conventional
or uveoscleral outflow tract. b-Adrenoceptor
animal [14 –16 ,17,18 ] models to decrease IOP.
Ripasudil decreases IOP via the conventional path-
way in rabbit and nonhuman primate models
&&
[17,18 ]. The drug has a favorable safety profile,
with over half of patients having mild conjunctival
hyperemia in both Phase I & II studies [19,20] and
&
reports of transient guttae-like findings [21 ]. IOP
decreased by 3.2, 2.7, and 3.1 mmHg with concen-
trations of 0.1%, 0.2%, and 0.4%, respectively, in
results from a Phase II clinical trial with a baseline
IOP of 23.0–23.4 mmHg [20]. The drug has also
shown additive effects with both timolol maleate
0.5%, and latanoprost 0.005% [22 ] in addition to
&

antagonists, a-agonists, and carbonic anhydrase neuroprotection benefits in mouse models when
inhibitors function to reduce formation of aqueous administered orally [23]. It is approved in Japan

Table 1. US market status of topical medications for glaucoma

Medication Sponsor Mechanism of action Current US market status

Netarsudil (AR-13324)
Netarsudil/latanoprost fixed-dose Aerie Pharmaceuticals
combination
Latanoprostene bunod
Trabodenoson (INO-8875)
DE-117
ONO-9054
Bamosiran (SYL040012)
Aerie Pharmaceuticals
Bausch þ Lomb
Inotek Pharmaceuticals
Corporation
Santen Pharmaceuticals
Ono Pharmaceuticals
Sylentis
Rho kinase
inhibitor þ norepinephrine
transporter inhibitor
Rho kinase inhibitor/
norepinephrine transporter
inhibitor þ prostaglandin analog
Nitric oxide
donor þ prostaglandin analog
Adenosine receptor agonist
Prostanoid receptor agonist
Prostanoid receptor agonist
Small interfering RNA
Phase III trials completed
Phase III trials ongoing
New Drug Application pending
with FDAa
Phase III trials ongoing
Phase II & III trials ongoing
Phase II trials completed
Phase II trials completed

a
Food and Drug Administration.

162 www.co-ophthalmology.com Volume 28  Number 2  March 2017

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for treatment of glaucoma and ocular hypertension
when applied twice daily.
Netarsudil (AR-13324): a Rho kinase inhibitor
Netarsudil (AR-13324) (Aerie Pharmaceuticals, Dur-
ham, North Carolina, USA) is both a novel Rho
kinase inhibitor and norepinephrine transporter
&&
(NET) inhibitor [24 ]. Several mechanisms of action
for IOP-lowering with this agent have been shown in
animal models, including improving outflow
through the trabecular meshwork and the uveoscl-
eral pathway, decreasing episcleral venous pressure,
and decreasing aqueous production; the latter is
possibly related to the agent’s function as a NET
&
inhibitor [14 ]. When its IOP-lowering effects were
compared with latanoprost, this agent was less effec-
&
tive by approximately 1 mmHg [12 ]. The most
commonly associated adverse event was hyperemia
which occurred at a higher rate than with latano-
prost; however, the degree of hyperemia, as with
latanoprost, was mild in most [25]. This agent com-
pleted Phase III clinical trials in 2016 [26].
Netarsudil/latanoprost fixed-dose
combination: a Rho kinase inhibitor
combined with latanoprost
This fixed-dose combination of netarsudil 0.02%
and the first and most commonly prescribed pros-
taglandin analog, latanoprost 0.005% is also
designed to be administered once daily, at night.
There are no fixed dose combinations of prostaglan-
din analogues and other agents available in the USA
or Japan, while in much of the world there are fixed
combinations of prostaglandins combined with
timolol maleate. This combined formulation has
demonstrated statistical superiority over its individ-
&
ual components [13 ]. Phase III clinical trials are
currently ongoing for this drug and expected to
be completed in 2017.
Latanoprostene bunod: a nitric oxide donor
and prostaglandin analog
Latanoprostene bunod (Bausch þ Lomb, Bridge-
water, New Jersey, USA) is a nitric oxide-donating
prostaglandin F2-alpha analog dosed once daily that
has completed Phase III trials and is currently under
review by the FDA. This agent’s possible dual mech-
anism of action has been postulated to act strongly
on both aqueous outflow pathways, in contrast to
&
conventional prostaglandin analogs [27 ]. If
approved, this drug will likely be released within
late 2016 or early 2017. Two Phase III randomized
control trials each compared once daily
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New classes of glaucoma medications Schehlein et al.
latanoprostene bunod with twice daily timolol for
& &
3 months [28 ,29 ]. A greater percentage of patients
maintained their IOP at lower levels (25% below
baseline or 18 mmHg) with latanoprostene bunod
than timolol at almost all time points. Another
Phase III trial demonstrated statistical superiority
of 0.024% latanoprostene bunod over 0.005% lata-
noprost in IOP-lowering at 28 days (9.00 vs.
7.77 mmHg, respectively) with comparable side-
&
effect profiles [30 ].
Trabodenoson (INO-8875): an adenosine
receptor agonist
Trabodenoson (INO-8875) is an adenosine mimetic
medication currently in development by Inotek
Pharmaceuticals Corporation (Lexington, MA,
USA). This agent acts as an agonist for the adenosine
A1 receptor subtype and has been shown to success-
fully lower IOP in both humans and animals [31] by
increasing outflow at the trabecular meshwork [32].
This mechanism of action is present in few current
therapies, including both pilocarpine, carbachol,
and phospholine iodide, which both have marked
ocular side-effects limiting their use. To date, initial
trials for trabodenoson have demonstrated a favor-
&
able safety profile [33 ], but the number of subjects
and exclusion criteria prevent a complete safety
evaluation. Phase II trials showed a relatively well-
tolerated agent with adverse events including mild
to moderate hyperemia, that occurred in less than
&
20% of subjects [34 ]. These trials demonstrated a
mean IOP reduction of 4.1 mmHg at 500 mcg of
trabodenoson, the highest dose tested. A possible
neuroprotective effect, prevention of retinal
ganglion cell death, has been suggested in preclin-
ical rat models [35] but not in humans. Trabodeno-
son is currently in Phase III clinical trials and if
successful, will likely be commercially available
before the end of the decade or early next decade.
DE-117 and ONO-9054: prostanoid receptor
agonists
The prostanoid FP receptor, a receptor for prosta-
glandin F2a (PGF2a), is thought to be the target
through which IOP is lowered by prostaglandin
analogs [36]. Recently, there has been increased
interest in other prostanoid receptors, such as Ep2
and Ep3, as targets for topical IOP-lowering.
DE-117 (Santen Pharmaceutical, Ofuka-cho,
Osaka, Japan) is an Ep2 agonist. In animal models,
Ep2 agonists lower IOP by facilitating Schlemm’s
canal endothelial cell relaxation [37], increasing
uveoscleral outflow [38], and have recently been
shown to act on the trabecular meshwork by
www.co-ophthalmology.com 163
Glaucoma
decreasing both cell contractility and collagen depo-
&
sition [39 ]. This is in contrast to latanoprost, which
decreases collagen deposition but may increase
trabecular meshwork contractility. Phase II trials
for DE-117 showed similar safety and efficacy to
latanoprost [40]. Phase II and III trials are currently
ongoing.
ONO-9054 (Ono Pharmaceuticals, Chuo-ku,
Osaka, Japan) is both an Ep3 agonist and a FP
receptor agonist. Subhuman primate studies have
suggested that this drug may decrease IOP more
than both latanoprost and travoprost, in addition
to maintaining the lower IOPs for a longer period of
&
time [41 ]. Initial Phase I trials showed tolerability
and a peak IOP-lowering at 9 h, with a mean 28–29%
& &
reduction [42 ,43 ], which is consistent with morn-
&
ing or evening once-daily dosing [44 ]. A Phase II
study of this drug has recently been completed in
the USA and results showed that ONO-9054 was
more likely to have IOP reductions of 25–35% than
Xalatan [45].
Bamosiran (SYL040012): a small interfering
RNA (siRNA)
Bamosiran (SYL040012) (Sylentis S.A., Tres Cantos,
Madrid, Spain) is a naked siRNA which blocks the
b2-adrenergic receptor (ADRB2) via specific gene
silencing. This compound specifically targets
ADRB2 and thus the ciliary body’s production of
&
aqueous humor [46 ]. It has been shown to reduce
IOP in preclinical studies [47]. Phase I studies dem-
onstrated that both a tolerable safety profile and the
drug was only present in ocular tissues, thereby
potentially eliminating safety issues in patients with
asthma and congestive heart failure which have
often limited the use of nonselective topical b-adre-
noceptor antagonists [48]. Interim results from a
Phase IIb trial showed that 1.125% bamosiran
achieved noninferiority to twice-daily timolol only
in the patients with baseline IOPs greater than
25 mmHg. The trial also had excellent tolerability
with less related adverse events in the bamosiran
group than in the timolol group [49]. Actual values
of IOP-lowering have not been reported.
Preservative-free
The prevalence of both ocular surface diseases and
glaucoma increases with increasing age. The inci-
dence of ocular symptoms, such as dry eye, foreign
body sensation, stinging, and burning, is increased
in glaucoma patients using drops with preservatives
and it may be difficult to tell if these symptoms are
actually age related, exacerbated by glaucoma medi-
cations, or due to the preservatives [50]. These
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symptoms have been postulated to possibly lead
to decreased quality of life and thus decreased adher-
ence [51], especially because many patients must use
more than one IOP-lowering medication concur-
rently. A preservative-free prostaglandin, tafluprost,
was introduced in the United States in 2012 and was
not a large commercial success. Likewise, there are
commercially available preservative-free formu-
lations of both timolol maleate and the fixed com-
bination of dorzolamide and timolol maleate;
however, neither of these have been commercial
successes. A preservative-free formulation of bima-
toprost/timolol 0.3/5.0 mg/ml is currently under
investigation. Additionally, preservative-free lata-
noprost is commonly available in India manufac-
tured by both Aurolab (Madurai, Tamil Nadu, India)
and Sun Pharmaceutical Industries Ltd. (Mumbai,
Maharashtra, India). The Sun Pharmaceutical prod-
uct is currently under FDA evaluation.
It is difficult to separate the need for such for-
mulations from their lack of acceptance by phar-
macy benefit managers, making these preservative-
free medications much costlier. In the subset of
patients who do need preservative-free formu-
lations, the inability to acquire the drug may itself
be a barrier to adherence. Documentation of failure
of regular topical medications is often required by
many insurance companies before preservative-free
options will be covered. This can be time consuming
and costly both for the patient and the eye
care provider.
DRUG DELIVERY SYSTEMS
Several injectable products and implants are cur-
rently under investigation as alternatives to topical
IOP-lowering therapies. These longer lasting thera-
pies could eliminate the problems associated with
the ability to actually administer an eye drop
[52,53,54] and patients’ adherence to therapy
(Table 2). This sustained IOP-lowering might also
decrease the rate of glaucomatous progression.
Allergan (Irvine, CA, USA) has developed a bio-
degradable sustained-release bimatoprost implant.
The implant is administered as an intracameral
injection and remains in the anterior chamber to
deliver the drug for 4 to 6 months. This implant is
currently in Phase III clinical trials. Interim results of
a 24-month Phase I/II trial found all concentrations
of the implant to be comparable with topical bima-
toprost 0.03% [55]. This is true through 4 months of
the trial, with topical bimatoprost reducing IOP by
8.4 mmHg and the implant reducing IOP by
7.2 mmHg to 9.5 mmHg. At 6 months, no trial
subjects had received an additional injection of
the implant or a topical IOP-lowering rescue
Volume 28  Number 2  March 2017

Table 2. United States market status of drug delivery systems for glaucoma
Medication Sponsor
Sustained-release bimatoprost implant Allergan
ENV515 Envisia Therapeutics
Travoprost punctal plug Ocular Therapeutix, Inc
Bimatoprost corneal ring ForSight VISION5
medication. These interim results also demon-
strated an improved safety and side-effect profile
with conjunctival hyperemia decreased in the
implant group (7%) as compared with the topical
bimatoprost group (17%). Additionally, given the
breach of the anterior chamber with intracameral
administration, more research is needed to assess
infection risk, herpetic or otherwise, with this
implant. It will be interesting to see, if approved,
whether the incidence of iris pigmentation, cystoid
macular edema, and uveitis will increase and if local
changes such as hyperemia, lash growth, lid pig-
mentation, and periorbital fatty atrophy will dimin-
ish with an intracameral route of administration.
ENV515 (Envisia Therapeutics, Morrisville,
North Carolina, USA) is a biodegradable particle
formulation of travoprost also intended for intra-
cameral injection meant to last for 6 months. This
formulation is currently in Phase II clinical trials [56]
and no results have been published.
The Travoprost punctal plug (Ocular Therapeu-
tix, Inc., Bedford, Massachusetts, USA) is inserted
into the punctum and remains within the canal-
iculus. The plug contains a color additive which aids
in visualization to determine the product’s place-
ment and retention over the treatment period. A
study conducted in Singapore with 26 plugs placed
in 17 patients and an endpoint of 30 days showed a
24% and 15.6% reduction in IOP from baseline on
days 10 and 30, respectively. The plug also had a
tolerable safety profile with itching reported by two
patients and epiphora in one patient [57].
A bimatoprost corneal ring (ForSight VISION5,
Menlo Park, California, USA) is designed to rest on
the surface of the eye in the conjunctival fornices.
Results of a Phase II study were recently published,
and while underpowered, observed a decrease in IOP
of 3.2 to 6.4 mmHg for patients with the ring and
4.2 to 6.4 mmHg in patients using twice daily
&&
timolol maleate 0.5% [58 ]. The ring appeared
slightly less effective than timolol. Almost 90% of
patients retained the ring at 6 months and were fully
aware if the product dislodged. The product was well
tolerated with a safety profile similar to topical bima-
toprost 0.03% and the incidence of ocular hyperemia
was slightly less (14.1 vs. 25–45% respectively) [59].
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New classes of glaucoma medications Schehlein et al.
Mechanism of administration Current US market status
Intracameral injection Phase III trials ongoing
Intracameral injection Phase II trials ongoing
Insertion into punctum Phase III trials ongoing
Insertion into conjunctival fornices Phase II trials completed
Drug delivery systems potentially remove many
barriers to adherence that are present with topical
drop medications for glaucoma by eliminating
daily administration. Medications with alternative
methods of administration could be important not
only for the typical glaucoma patient, but for those
with physical or mental handicaps which prevent
drop instillation. However, these devices have not
yet proven to be superior to conventional topical
medications. Additionally, some of these adminis-
trations require injections or placement of foreign
materials in the eye which raises concern for vision
threatening endophthalmitis or loss of the product.
The latter may lead to increased pressure on the
physician for monitoring and maintenance.
CANNABINOIDS
Although no new clinical papers exist evaluating the
treatment of glaucoma with cannabinoids, it is
important to include in this review given quickly
moving legislation regarding the legalization of
marijuana in multiple states both for medical and
&&
recreational use. Belyea et al. [60 ] demonstrated
that in a city with legal medical and recreational
marijuana, patients’ intentions to utilize marijuana
as a treatment option was associated with the per-
ception that marijuana should have acceptable legal
and social status. Additionally, patients in the study
who held misconceptions about the effectiveness
and usability of marijuana as a glaucoma drug and
were dissatisfied with current treatments were likely
to indicate an intention to use marijuana for their
glaucoma treatment. It may be important to counsel
patients on the effectiveness of cannabinoids as a
glaucoma therapy, as legalization could lead to
patient self-medication with perception of efficacy
that is not yet proven. Jampel [61] found no signifi-
cant IOP-lowering with marijuana. Novack [62] has
summarized the work to date.
ADHERENCE
Adherence is a cornerstone of nonsurgical glaucoma
care as it is with all chronic diseases, as the rate of
nonadherence in glaucoma patients is reported to be
www.co-ophthalmology.com 165
Glaucoma
as high as 59% [63]. Barriers to adherence include
complex medication schedules, difficulty with
self-administration, forgetfulness, lack of under-
standing of the disease, and cost of medications,
&
to name a few [64 ]. Drug delivery systems and
novel formulations with once-daily administration
in development may help to combat several of these
barriers. Recent studies on topical administration
found that education on eye drop technique
and the disease itself may improve patient self-
& &
administration technique [65 ,66 ], patient self-
& &
efficacy [67 ], and patient adherence [68 ]. Another
barrier, the cost of glaucoma medications, has
recently been the subject of interest in studies on
the implementation of Medicare Part D. Blumberg
&
et al. [69 ] found that Part D increased the number of
covered beneficiaries with glaucoma, but that dis-
parities in coverage persist, particularly among the
near poor. In another manuscript, Blumberg et al.
&&
[70 ] found that although several nonadherence
behaviors decreased with Part D, such as skipping
doses or taking smaller doses, some behaviors, such
as lack of prescription usage due to cost, remained
stable. Lastly, adherence itself is difficult to measure
& 6. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension
with topical medications [71 ]. Drug delivery sys-
tems with consistent presence in the eye may pro-
vide a more reliable way to measure medication
adherence. More research is needed when these
novel therapies and administrations are introduced
into clinical practice to assess their effects on
patient adherence.
CONCLUSION
There are many promising options for glaucoma
medical therapy in development. New classes of
topical medications are present globally and immi-
nent in the United States. They bring with them
varying efficacies and side-effect profiles that the
discerning clinician must consider carefully.
Although there seem to be plentiful drop therapies
with novel mechanisms of action on the horizon, it
is clear that topical therapy for glaucoma has limita-
tions, especially in adherence and self-adminis-
tration. New methods of drug administration,
such as injectables and implants continue to blur
the line between medical and surgical therapy and
may offer advances in IOP-lowering for glaucoma
care.
Acknowledgements
None.
Financial support and sponsorship
None.
166 www.co-ophthalmology.com
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Conflicts of interest
E.M.S. has no conflicts to declare. G.D.N. serves as a
consultant to numerous pharmaceutical and medical
device firms. He does not own stock in any. A.L.R. is a
stock holder, option holder, and is on the Scientific
Advisory Board of Aerie Pharmaceuticals, is a consultant
to Clearside Medical, Biolight Pharmaceuticals, DSM,
and Macuclear, and chief medical officer to Novaliq.
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20. Tanihara H, Inoue T, Yamamoto T, et al. Phase 2 randomized clinical study of a
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&& patients with glaucoma in a city with legalized medical marijuana use. JAMA
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65. Carpenter DM, Sayner R, Blalock SJ, et al. The effect of eye drop technique
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66. Lazcano-Gomez G, Castillejos A, Kahook M, et al. Videographic assessment
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67. Carpenter DM, Blalock SJ, Sayner R, et al. Communication predicts medica-
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69. Blumberg DM, Prager AJ, Liebmann JM. Variation in prescription drug cover-
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71. Novack GD. Time to take your medicines, seriously. Ocul Surf 2016;
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Volume 28  Number 2  March 2017