Clinical Evaluation of Traditional Clinical Evaluation of Traditional Chinese Prescription “Chi-Ju-Di-Chinese Prescription “Chi-Ju-Di-

Huang-Wan” on the Dry EyeHuang-Wan” on the Dry EyeRandomized CRandomized Controlled Trial ontrolled Trial

Yung-Hsien Chang ,Hui-Ju LinYung-Hsien Chang ,Hui-Ju Lin

China Medical University and Hospital China Medical University and Hospital

FDA( Food Drug Administration )FDA( Food Drug Administration )

●●1994 Dietary Supplement1994 Dietary Supplement

●●20042004

Guidance for Industry Guidance for Industry

Botanical Drug Products Botanical Drug Products

Dry eye syndromeDry eye syndrome

•one of the most frequent eye diseases one of the most frequent eye diseases

in the industrial world.in the industrial world.

•Population : 14.47%Population : 14.47%

Male : 11.47%Male : 11.47%

Female: 16.7 %Female: 16.7 %

•In USAIn USA ， ， one fifth of the populationone fifth of the population

(60 million patients )(60 million patients )

Symptoms of dry eyeSymptoms of dry eyeDrynessDrynessForeign bodyForeign body sensationsensationBurning sensationBurning sensationPhotophobiaPhotophobiaTearing or drynessTearing or dryness when eye facing when eye facing windedwinded

Fluctuation of Fluctuation of visual acuityvisual acuityCongestion of Congestion of conjunctivaconjunctivaLoss of cornealLoss of corneal lusterlusterFrequent blinkingFrequent blinkingDecrease in visualDecrease in visual activity activity

TearsTears

Tears are secreted from the lacriTears are secreted from the lacrimal gland and are spread by blinmal gland and are spread by blinking to protect the ocular surface. king to protect the ocular surface. Tears defend the eye from foreigTears defend the eye from foreign bodies and clean the corneal sun bodies and clean the corneal surface. rface.

Tears film ( 3 layers )Tears film ( 3 layers )Lipid layer (outer layer): containing wax anLipid layer (outer layer): containing wax an

d cholesterold cholesterolAqueous layer (middle layer): containing inAqueous layer (middle layer): containing in

organic iron, glucose, lactoferritin, β lysozyorganic iron, glucose, lactoferritin, β lysozyme immunoglobulin A, complement, protein me immunoglobulin A, complement, protein

Mucin layer (inner layer): containing lysozMucin layer (inner layer): containing lysozyme, maintains the stability of tear filmyme, maintains the stability of tear film

Dry eye (diseases)Dry eye (diseases)

Deficiency of lipid layer, aDeficiency of lipid layer, aqueous layer and mucin layqueous layer and mucin layersers

Sjorgens’ syndromeSjorgens’ syndromeRheumatoid arthritis Rheumatoid arthritis

Dry eye (most patients) etiologyDry eye (most patients) etiology

Prolonged use of computerProlonged use of computer

Air conditioningAir conditioning

Low humidityLow humidity

Evaporation of tear filmEvaporation of tear film

Air pollutionAir pollution

BlepharitisBlepharitis

ConjunctivitisConjunctivitis

AgingAging

Drug abuseDrug abuse

Contact lensContact lens

Treatment of dry eyeTreatment of dry eyeArtificial eye dropsArtificial eye dropsArtificial tear ointmentArtificial tear ointmentVitamin A ointmentVitamin A ointmentSpecial eyewearSpecial eyewearAnti-autoimmunity drugs (cyclosAnti-autoimmunity drugs (cyclos

porine)porine)lacrimal putum occlusionlacrimal putum occlusion

枸杞子 枸杞子 Fructus lyciiFructus lycii菊 花 菊 花 Hos chrysanthemiHos chrysanthemifor treating blurred vision, eye pain, dfor treating blurred vision, eye pain, dry eyes, epiphora, dull headache, severy eyes, epiphora, dull headache, severe dizziness, tinnitus, deafness, night re dizziness, tinnitus, deafness, night sweat. Red tongue with little coating sweat. Red tongue with little coating (liver and kidney yin insufficiency) (liver and kidney yin insufficiency)

杞菊地黃丸杞菊地黃丸 Chi-Ju-Di-Huang WanChi-Ju-Di-Huang Wan六味地黃丸六味地黃丸 Liu-Wei-Di-Huang WaLiu-Wei-Di-Huang Wann

六味地黃丸六味地黃丸Liu-Wei-Di-Huang WanLiu-Wei-Di-Huang Wan

Insufficient liver and kidney “yin”Insufficient liver and kidney “yin”

熟地黃 熟地黃 rehmanniae radixrehmanniae radix

山茱萸 山茱萸 corni fructuscorni fructus

山藥 山藥 batatatis rhizomabatatatis rhizoma

丹皮 丹皮 moutan radicis cortexmoutan radicis cortex

澤瀉 澤瀉 alismatis rhizomaalismatis rhizoma

茯苓 茯苓 poria cocoa poria cocoa

澤瀉

茯苓

地黃

山茱萸

山藥

菊花

枸杞

牡丹皮

杞 菊 地 黃 丸

化學製造與管制化學製造與管制 (CMC)(CMC) 技術性資料查檢技術性資料查檢表表 (( 一一 )) 藥材藥材 (Raw material)(Raw material)

化學製造與管制化學製造與管制 (CMC)(CMC) 技術性資料查檢技術性資料查檢表表 (( 二二 ))

化學製造與管制化學製造與管制 (CMC)(CMC) 技術性資料查檢技術性資料查檢表表 (( 三三 ))

Dry eye patient (inclusion criteria)Dry eye patient (inclusion criteria)

Age: 20-70 years oldAge: 20-70 years old

Dryness and burning sensation of eye (prDryness and burning sensation of eye (primary dry eye) 1 yearimary dry eye) 1 year

No taking herbal drugs, 6 monthsNo taking herbal drugs, 6 months

Schirmer’s test (Schirmer’s test ( ＋＋ )) ＜＜ 5mm /5 min 5mm /5 min

Exclusion criteriaExclusion criteriaSjogren’s syndromeSjogren’s syndromeSystemic disease / medicationsSystemic disease / medicationsOcular disorders, ocular operation, trauma, diseaOcular disorders, ocular operation, trauma, disea

ses ses Pregnancy, lactatingPregnancy, lactatingOther ocular eye dropsOther ocular eye dropsRose Bengal testRose Bengal test ＞＞ 77BUT testBUT test ＞＞ 77Fluorescein testFluorescein test ＋＋ Rose Bengal testRose Bengal test ＋＋ BUT testBUT test＞＞ 21 21

Basic schirmeris test (1993) Basic schirmeris test (1993) (( ＜＜ 5mm/5min)5mm/5min)

Standardized filter paper was placed at Standardized filter paper was placed at the junction of the lateral and middle tthe junction of the lateral and middle thirds of the lower lid fornix of each eyhirds of the lower lid fornix of each eye for 5 minutes: schirmer’s test: less the for 5 minutes: schirmer’s test: less then 5mm/5min en 5mm/5min

Schirmer’s testSchirmer’s test

Fluorescein test (0-9) (1969)Fluorescein test (0-9) (1969)

Moistened fluorescein strip was lightMoistened fluorescein strip was lightly applied to the inferior tarsal conjuly applied to the inferior tarsal conjunctiva to evaluate corneal epithelium nctiva to evaluate corneal epithelium defects. Corneal fluorescein staining defects. Corneal fluorescein staining defect from 0 (none) to 3 (severe) (udefect from 0 (none) to 3 (severe) (upper, middle, lower 3 section) pper, middle, lower 3 section)

Fluorescein StainFluorescein Stain

Rose Bengal test (0-9) (1993)Rose Bengal test (0-9) (1993)

1% Rose Bengal was instilled into the low 1% Rose Bengal was instilled into the low eyelid fornix. Rose Bengal test was used to eyelid fornix. Rose Bengal test was used to locate degenerated corneal epithelial cells. locate degenerated corneal epithelial cells.

The intensity of vital staining dyes on the The intensity of vital staining dyes on the ocular surface was graded 0-9 according to ocular surface was graded 0-9 according to the criteria proposed. A high intensity of the criteria proposed. A high intensity of staining indicated increased cell degeneration. staining indicated increased cell degeneration.

Rose bengal testRose bengal test

Tear break up time (BUT) Tear break up time (BUT) (1993)(1993)

Moistened fluorescein strip was applied lMoistened fluorescein strip was applied lightly to the inferior tarsal conjunctiva.ightly to the inferior tarsal conjunctiva.

BUTBUT is the time between a complete blin is the time between a complete blink and the appearance of the first randomlk and the appearance of the first randomly distributed corneal dry spot. Decrease iy distributed corneal dry spot. Decrease in BUT can be caused by deficiency of mn BUT can be caused by deficiency of mucin or aqueous tears. ucin or aqueous tears.

Tear Break Up TimeTear Break Up Time

Questionnaire (0-100)Questionnaire (0-100)25 questions QOL (5 grades)25 questions QOL (5 grades) 0 never0 never 1 seldom1 seldom 2 sometimes2 sometimes 3 often3 often 4 always4 alwaysThe higher the score obtained, the poorer The higher the score obtained, the poorer the quality of life the quality of life

Questionnaire (0-100)Questionnaire (0-100)1.1. Eye dryness Eye dryness 2.2. Photophobia Photophobia 3.3. Gritty eye Gritty eye 4.4. Eye pain Eye pain 5.5. Eye discharge Eye discharge 6.6. Sticky eye Sticky eye 7.7. Tearing when windy Tearing when windy 8.8. Blinking Blinking 9.9. Eye soreness Eye soreness 10.10.Red eye Red eye 11.11.Eyelid swelling Eyelid swelling 12.12.Increased use of artificial tear Increased use of artificial tear 13.13.Eye soreness Eye soreness

Questionnaire (0-100)Questionnaire (0-100)14. Fullness sensation in eye 14. Fullness sensation in eye 15. Hotness sensation of eye 15. Hotness sensation of eye 16. Decrease visual acuity during the day 16. Decrease visual acuity during the day 17. Decrease visual acuity at night 17. Decrease visual acuity at night 18. Can not open eye 18. Can not open eye 19. Sustained conjunctivitis 19. Sustained conjunctivitis 20. Eye itch 20. Eye itch 21. Sensation of a membrane before eye surface 21. Sensation of a membrane before eye surface 22. Eye tenderness 22. Eye tenderness 23. Discharge from eye 23. Discharge from eye 24. Headache when watching 24. Headache when watching 25. Diplopia 25. Diplopia

Examination of dry eyeExamination of dry eye

Basic schirmeris test (Basic schirmeris test ( ＜＜ 5mm)5mm)Fluorescein test (0-9)Fluorescein test (0-9)Rose Bengal test (0-9)Rose Bengal test (0-9)Tear break up time (BUT) Tear break up time (BUT) questionnaire (0-100)questionnaire (0-100)Before, after 2 weeks, 4 weeks, Before, after 2 weeks, 4 weeks,

2 months2 months

Treatment Randomized double trial Treatment Randomized double trial (RCT)(RCT)

2 groups2 groups• Control groupControl group placebo medicine 4gm Tid /dayplacebo medicine 4gm Tid /day• Study groupStudy group

Chi-Ju-Di-Huang Wan 4gm Tid /dayChi-Ju-Di-Huang Wan 4gm Tid /day

Artificial tear (Artelac. Dr. Gerhard Co. Artificial tear (Artelac. Dr. Gerhard Co. Berlin, Germany)1 drop 4 times/dayBerlin, Germany)1 drop 4 times/day

Safety monitorSafety monitor

Urine test (PH, protein, occult blood)Urine test (PH, protein, occult blood)

BUNBUN

CreatinineCreatinine

GOT, GPTGOT, GPT

Before, 4 week, 2 monthsBefore, 4 week, 2 months

Adverse event observation Adverse event observation

Changes from the baseline in schirmer’s testsChanges from the baseline in schirmer’s tests

Group 2 weeks 4 weeks 2 months p value  

MeanSDMeanS

DMeanSD 2 weeks 4 weeks 2 months

Controln=40

0.740.05 10.1 0.230.01

0.79 1.0 0.43

Studyn=40

0.930.02 10.66 0.820.02

* p < 0.05

Changes from the baseline in Rose Bengal tests Changes from the baseline in Rose Bengal tests

Group 2 weeks 4 weeks 2 months p value

MeanSD MeanSD MeanSD 2 weeks 4 weeks 2 months

Controln=40

-0.030.00

-0.410.01 -0.320.00

0.04* 0.49 0.31

Studyn=40

-0.970.09

-0.760.01 -0.910.02

* p < 0.05

Changes from the baseline in fluorescein stain Changes from the baseline in fluorescein stain

teststests

Group 2 weeks 4 weeks 2 months p value

Mean±SD Mean±SD Mean±SD2

weeks4 weeks 2 months

Controln=40

0.190.05 0.191.39 0.320.02

0.12 0.27 0.20

Studyn=40

-0.380.01

-0.190.02

-0.320.01

* p < 0.05

Changes from the baseline in tear break up time Changes from the baseline in tear break up time

tests (BUT)tests (BUT)

Group 2 weeks 4 weeks 2 months p value

MeanSD

MeanSD

MeanSD 2 weeks 4 weeks 2 months  

Controln=40

0.080.01

0.490.06

0.450.03

0.14 0.04* 0.26

 

Studyn=40

-0.920.0

7

-0.860.0

9

-0.730.03

 

* p < 0.05

Changes from the baseline in questionnairesChanges from the baseline in questionnaires

Group 2 weeks 4 weeks 2 months p value

MeanSDMeanS

DMeanSD 2 weeks 4 weeks 2 months  

Controln=40

-2.680.66

-6.190.4

5-6.50.67

0.10 0.37 0.16

 

Studyn=40

-7.950.77

-9.030.4

4

-12.860.45

 

* p < 0.05

Side effectSide effect• Normal blood GOT, GPT,BUN, creatiNormal blood GOT, GPT,BUN, creati

nine and urine examinationnine and urine examination• 40 control groups40 control groups• 40 study groups40 study groups• One case─skin rash during the study pOne case─skin rash during the study p

erioderiod• Control group─diarrheaControl group─diarrhea

DiscussionDiscussion

There are 3 layers of tear film : the outer There are 3 layers of tear film : the outer layer is composed of a lipid layer , the middle layer is composed of a lipid layer , the middle layer is an aqueous layer and the inner layer layer is an aqueous layer and the inner layer maintains the stability of tear film. Dry eye maintains the stability of tear film. Dry eye syndrome may be caused by an inadequate syndrome may be caused by an inadequate “quality” of tear components supplied to the “quality” of tear components supplied to the ocular surface rather than a lack of lachrymal ocular surface rather than a lack of lachrymal gland secretion. gland secretion.

DiscussionDiscussion Dry eye syndrome may be caused by unstable tear fiDry eye syndrome may be caused by unstable tear fi

lm in each of the 3 tear layers. According to the resulm in each of the 3 tear layers. According to the result of the Rose Bengal test , “Chi-Ju-Di-Huang Wan” lt of the Rose Bengal test , “Chi-Ju-Di-Huang Wan” is an effective drug for treating dry eye because it reis an effective drug for treating dry eye because it repairs epithelial anomalies. Besides , “Chi-Ju-Di-Huapairs epithelial anomalies. Besides , “Chi-Ju-Di-Huang Wan” also effects the stability of tear film. The stng Wan” also effects the stability of tear film. The stability of tear film is influenced by mucin or aqueouability of tear film is influenced by mucin or aqueous layers of tear and is not correlated with the amount s layers of tear and is not correlated with the amount of tear aqueous production. The tear aqueous producof tear aqueous production. The tear aqueous production is mainly measured by schirmer’s test.tion is mainly measured by schirmer’s test.

ConclusionConclusion• According to Schirmer’s test , Rose Bengal tesAccording to Schirmer’s test , Rose Bengal tes

t , fluorescing test , BUT and questionnaire , tht , fluorescing test , BUT and questionnaire , there were improvements in dry eye ere were improvements in dry eye syndromesyndrome after treatment.after treatment.

• The study group improved more than the contrThe study group improved more than the control group in every test but only the Rose Bengal ol group in every test but only the Rose Bengal test at week 2 and the tear break up time test at test at week 2 and the tear break up time test at week 4 showed significant statistical differencweek 4 showed significant statistical differences between the two groups. es between the two groups.

ConclusionConclusion• 2 months might have been too short for 2 months might have been too short for

a herbal drug to be effective.a herbal drug to be effective.• We could not stop using artificial tears We could not stop using artificial tears

during the period of study , because during the period of study , because IRB was against the act.IRB was against the act.

• Pattern Identification should be Pattern Identification should be considered in the future study.considered in the future study.

Clinical Evaluation of the TraditioClinical Evaluation of the Traditional Chinese nal Chinese

Prescription Chi-Ju-Di-Huang-WaPrescription Chi-Ju-Di-Huang-Wan for Dry Eye n for Dry Eye

Yung-Hsien Chang, Hui-Ju Lin Yung-Hsien Chang, Hui-Ju Lin

and Wei-Chu Liand Wei-Chu Li PHYTOTHERAPY RESEARCH PHYTOTHERAPY RESEARCH

Phytother. Res. 19, 349–354 (2005) Phytother. Res. 19, 349–354 (2005)