The Development of New Functions of Esculin and Digitalis Glycosides Eye Drops: A Study on the Treatment of Presbyopia
Phase: PHASE4
Conditions: Presbyopia
Sponsor: Shanxi Eye Hospital

Made in 2023
Shanxi Eye Hospital
Mission statement of in-house
research fund program
Project category: Innovation Fund, Doctoral Fund □
Youth Fund
Microbial research team □
Ophthalmology specialty alliance □
Project number: C202302
Funding amount: 50,000 yuan
Project name:  The Development of New Functions of Esculin and Digitalis
 Glycosides Eye Drops: A Study on the Treatment of Presbyopia
Project Lead: Zhang Yu

Made in 2023
Implementation period: From January and February 2023
to January and February 2 0 2 5
Date of filing: 2024. 1.7
Shanxi Eye Hospital

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Iv. The project implementation period is 2 years.
V. This project plan and task book is in duplicate. It
shall become a formal contract upon being formally approved
and signed by Shanxi Provincial Eye Hospital.

Project undertakers commitment:
I guarantee the authenticity of the content of the
task book. I will perform my duties as the project leader,
strictly abide by the provisions of the Management Measures
for Scientific Research Projects of Shanxi Provincial Eye
Hospital,
effectively
guarantee
the
research
time,
conscientiously
carry
out
the
work,
and
submit
relevant
materials on time. If the information is false or violates
the regulations, I will take full responsibility.
There is no such thing as not doing scientific research,
but being listed as the first person in charge and the
first author of a paper. The problem of nominal
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host of the award;
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elses name or occupation of his/her scientific research
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various review activities such as scientific research
projects, achievement awards, talent plans and
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"talking" or "going through connections" in the above
review activities; there is no other serious violation of
scientific research integrity, scientific research ethics,
academic norms and academic style.
Signature of the applicant:

Project leader
surna
me
and
perso
nal
name
Zhang
Yu
sex
date of
birth
recor
d of
forma
l
schoo
ling
acade
mic
degre
e
profe
ssion
al
ranks
and
title
s
post
work unit
Shanxi Eye Hospital
Departme
nt of
residenc
e
pharmaceut
ical
preparatio
n section
ambit
pharmacy
Partner
information
name of organization
1.
2.
3.

Background and basis of the project
(400 words limit)
Presbyopia (Pb), characterized by difficulty focusing clear images
on
the
retina
when
viewing
nearby
objects,
predominantly
affects
individuals over 40 years old and significantly impacts daily life.
However, China has yet to report the approval of presbyopia treatment
drugs. The theory of presbyopia accommodation mechanism suggests that
human eye regulation is closely related to ciliary muscle contraction.
Studies have shown that the active ingredients in the marketed drug,
Sarcosin
and
Digitalis
Glycosides
Eye
Drops,
can
synergistically
enhance ciliary muscle function. These findings suggest that Sarcosin
and Digitalis Glycosides Eye Drops may improve presbyopia through
enhanced
ciliary
muscle
regulation.
Nevertheless,
its
therapeutic
effects
remain
unreported.
This
study
will
pioneer
the
first
validation of Sarcosin and Digitalis Glycosides Eye Drops presbyopia
treatment
efficacy
by
comparing
visual
quality
changes
between
treatment and control groups. Furthermore, we will employ optometric
techniques
and
optical
scanning
methods
to
analyze
indicators
including accommodation function, anterior segment OCT, and ocular
perfusion data, aiming to elucidate the therapeutic mechanism. We hope
this research will bridge the gap in presbyopia drug development in
China.

1. Research significance and relevance to national needs:
We are currently undergoing the Fourth Industrial Revolution, which requires
our visual systems to be capable of viewing and interpreting screen information
from smartphones and laptops in both work and daily life, placing higher demands on
near vision. With the accelerating pace of aging, presbyopia not only causes
significant inconvenience in peoples daily work and life but also hinders Chinas
economic development, becoming a pressing social challenge. However, there has been
no reported approval for presbyopia treatment drugs in China to date. Research
shows that the marketed drug, Silymarin and Digitalis Glycosides Eye Drops,
contains
two
active
components—silymarin
and
digitalis
glycosides—which
can
jointly act on the ciliary muscle to effectively enhance its regulatory function.
These findings suggest that Silymarin and Digitalis Glycosides Eye Drops may also
improve ciliary muscle regulation to treat presbyopia. This project will, for the
first time, verify the therapeutic effects of Silymarin and Digitalis Glycosides
Eye Drops on presbyopia by comparing quality changes before and after treatment
between the experimental group and control group. It will elucidate the therapeutic
mechanism, fill a gap in current presbyopia drug research, improve patients quality
of life and work productivity, and reduce economic losses caused by presbyopia.

2. Research content, new methods and technical routes to be adopted, key
problems to be solved, test scale and main indicators:
【
r e s e a r c h
c o n t e n t s
】
(1) Changes in subjective visual quality and objective visual quality of
subjects and control group before and after treatment, as well as contrast
sensitivity function (CSF), diffusion function (PSF), modulation transfer function
(MTF) and so on.
(2) Effects of different pupil diameters (PD) and frequency bands on higher-
order aberrations (HOA) under different presbyopia conditions with different
severity.
(3) Research on the influence of adjustment function and higher order
aberration on visual quality and discussion on related mechanism.
(4) The dose-effect relationship between treatment course and effect under
different severity of presbyopia conditions.
[ R e s e a r c h
P r o g r a m m e ]
Research object: 30 cases of presbyopia patients who visited our hospital
and met the inclusion criteria of this study.
Exclusion
criteria:
①
Age
40-55
years;
②
After
cycloplegic
refraction,
exclude
cases
if
one
eye
has
a
refractive
power
greater
than-0.5D~2.0D
or
astigmatism exceeding 1.0D; ③For uncorrected distance vision (UDVA) below 1.25
or uncorrected near vision (UNVA) above 0.8 in both eyes, exclude cases using
standard logarithmic visual acuity charts; ④Use slit-lamp examination according
to LOCS protocol
The three-tier screening criteria for cataract development are as follows: ①
Exclusion
criteria
include:
NO3-NC3
lens
opacity
or
more
severe
opacities
detected, or presence of ocular surface diseases, visual fatigue, any corneal
conditions (dry eye syndrome, corneal injury, corneal opacity, keratoconus, or
history of refractive surgery); ②Exclusion criteria for subjects who have used
digitoxin
digoxin
diphosphate
eye
drops
within
two
weeks,
or
those
with
known/suspected allergies to digitalis drugs, or taking insulin, anti-anxiety
medications, antidepressants, antipsychotics, antihistamines, antispasmodics, or
diuretics.
This project has been approved by the ethics committee of this hospital.
Research and work in

Experimental protocol: The treatment group received Eclipta Paridis Dioscin
Eye Drops (Suiduling Pharmaceutical Co., Ltd., Germany), while the control group
received normal saline (Otsuka Pharmaceutical Co., Ltd., China). Administration
was 1 drop per eye per application, three times daily, for both eyes. Each
treatment course lasted two weeks, with a total of two courses administered. All
patients discontinued other similar medications, glucocorticoids, and analgesics
during treatment.
Subject withdrawal or termination: The subject has the right to voluntarily
withdraw from this study at any time for any reason without specifying the specific
reason. In each follow-up visit, if ocular surface disease signs or unilateral or
bilateral IOP higher than 21mmHg are found, the case will be excluded.
Statistical analysis: SPSS19.0 software was used for statistical analysis,
and Spearman correlation coefficient was used to analyze the correlation.
Observation method:
(1) The short-range activity visual questionnaire (NAVQ) was used to
investigate the quality of life of patients.
(2) Instrumental examination. Before and after treatment: ①Measure
uncorrected visual acuity under 30 lux and 180 lux conditions, including 5m
uncorrected distance vision (UDVA), 80cm intermediate vision (UIVA), 30cm near
vision (UNVA), and corrected vision using the same examination method after
subjective refraction, including multiple measurements
Far vision (CDVA), corrected intermediate vision (CIVA), corrected near
vision (CNVA), DCNVA, far corrected intermediate vision (DCIVA and CSF,
refractive power (D), astigmatism (DC) and so on.

②Total higher-order aberrations, spherical aberration,慧差and three-leaf
aberration of the whole eye and lens in the frequency regions of 3c/d, 6c/d and
12~18c/d with pupil diameters of 3mm and 6mm, recording PSF and MTF. ④OCT
sweep frequency anterior pupillary diameter (PD), lens thickness (LT) and lens
dome height
(LV), anterior chamber depth (ACD), anterior and posterior surface curvature, etc.
Therapeutic evaluation:
(1) Therapeutic effect and evaluation of therapeutic effect according to
different severity.
(2) Calculation of the rate of removing glasses: the rate of removing glasses
= the number of patients who removed glasses/total number ×100%, which is
calculated to calculate the rate of removing glasses in close reading after
treatment.
(3) Satisfaction assessment: Questionnaires were used to investigate and
evaluate whether the subjects had visual interference symptoms and their
satisfaction degree after treatment.
(4) Safety assessment: evaluate whether adverse reactions such as stinging,
conjunctival congestion, photophobia, redness and so on occurred during
medication. Grouping method:
Implementation of Centralized Randomized Blinding: Statistical professionals
independent of the research team generate randomized allocation sequences based on
study protocols. Group information is sealed in opaque envelopes. After
participants are enrolled and baseline assessments completed, researchers follow
procedures to open the envelopes and deblind the groups. This ensures that group
assignment remains concealed during enrollment and baseline data collection
phases, thereby preventing selection bias.
blind method ：
Double-blind design: subjects, investigators (including efficacy assessment and
data recording personnel), and statisticians were unaware
Group Information. Both drug groups use identical containers and packaging with
identical dosing instructions to maintain blinding. Group information is managed
by an independent third party using sealed password-protected envelopes and a
central randomization system. Blinding is only lifted by the third party following

predefined protocols after data lock-up at study completion or in the event of
serious adverse events. Blinding information is not disclosed to the research
team.
The treatment group received a seven-leaf digitoxin total glycoside eye
drop (Pharma Stulln GmbH, Import Drug Registration No.: 0909803; H20130295).
Patients were instructed to use one drop in each affected eye three times
daily, strictly following aseptic techniques. Care was taken to prevent
contact between the dropper and the ocular surface.
The control group received an equal amount of sterile, preservative-free and
non-irritating saline solution. The containers were packaged in the same
appearance, specifications, and labels as the treatment group. Only the designated
personnel responsible for group management in the research team knew the grouping
information, while the subjects were unaware of their own group to maintain the
double-blind status. Both groups received treatment for one month.
[Key issues to be resolved]
(1) The correlation between higher-order aberrations (tHOA), differential spherical
aberration (TSA), cloverleaf aberration (TT), and慧差(TC) and adjustment functions such
as adjustment amplitude (AMP), adjustment response (BCC), adjustment sensitivity (CPM),
and positive/negative adjustment (PRA/NRA).
(2) The variation of wavefront higher-order aberration (WA) and its mechanism
during the treatment.

【
te c h n o l o g y
r o a d m a p
】
Treatment of presbyopia with seven-leaf
digitoxin diphenylglycoside eye drops
Participants were assigned to groups
Pre-treatment, 14 days after treatment, and 28 days after
treatment
comparative analysis
Near,
medium
and
far
vision
in
light
and
dark
conditions
higher order
aberration
class
regulating
function
AMP/BCC
CPMDPRA/
NRA class
OCI
parameter
sPD,LT
LV,ACD,
surface
curvature
The
present
section
VD、VDI
SD、AFI
class
Different
frequencie
s
A shadow
of a
section
sound
The pupils are
straight
The
infl
uenc
e of
diam
eter
Self-
recovery
The force
of
contractio
n
influence
Blood
supply is
good
modulatory
infl
uenc
e
The moderating function of
correlation studies on visual
St u d y
on
th e
co r re l a t i on
be t we e n
tr e a t me n t

3. Expected project results (including publishing relevant papers, applying
for invention patents, training talents, making contributions to the
construction of academic degrees, etc.)
[Expected Research Results]
(1) Theoretical achievements: The therapeutic effect of saponin dioscin
eye drops on presbyopia was clarified, the therapeutic mechanism was
elucidated, and the therapeutic effect of the same degree of presbyopia was
scientifically evaluated, providing a new direction for the treatment of
presbyopia.
(2) Publication of papers: Publish 2 high-quality academic papers.
(3) Academic conferences: Participate in one domestic academic
conference.
(4) Talent training: teach 1-2 interns.
4. Project schedule by stage (time is accurate to month)
temporal
interval
The schedule of the project and the main
research work to be completed
2023.12～2024.12
Continue to collect clinical subjects, complete the
selection and grouping of subjects, clinical treatment
and observation data collection, experimental data
summary, data analysis.
2025.01～2025.12
Write and publish papers, summarize projects.

6. Project budget unit: 10,000 yuan
Budget of source of funds
Budget of expenditure
subject
Budget
figures
subject
Budget
figures
Total project
investment
5
Budget
expenditure
summary
5
(1) Application for
grants
5
1. Equipment
costs
(2) Other funds
2. Material
cost
0.9
3. Test, laboratory
and processing
costs
4. Fuel and power
costs
5. Travel costs
0.2
6. Conference
costs
0.3
7. Collaborative
research and
exchange fees
8.
Publication/liter
ature/information
dissemination/int
ellectual
property affairs
fee
0.9
9. Labor costs
1.7
10. Expert
consultation fees
11. Compensation for
subjects and
other
1.0

expenses

7. Expected social and economic benefits after the completion of the
project
This
groundbreaking
project
addresses
the
critical
pathological
mechanism
where
ciliary
muscle
regulation
influences
presbyopia
development,
while
addressing
Chinas
current
shortage
of
presbyopia
treatment options. It establishes the feasibility of using the marketed
drug Erythromycin Dihydrochloride Eye Drops for presbyopia management.
This innovation not only provides a simple, safe, and effective medication
selection
for
presbyopia
treatment,
alleviating
the
work-life
inconveniences
caused
by
myopia
complications,
but
also
significantly
enhances quality of life and productivity. Furthermore, it demonstrates
substantial market potential and economic value in the field.
8. Form, content and opinions of the cooperative unit
1. Forms and contents of cooperation
2. Opinions of the cooperative unit (on the content, form of cooperation,
quality of participants and guarantee of working conditions, etc.) sign
specific opinions:

9. Sign the task book
Project Manager (signature)
January 8, 2024
Opinions of project undertaking unit:
agree
Unit responsible
person
(signature)
pter
20> 4
Date: 18th
2
ho r s e s
c