Clinical Evaluation of Traditional Chinese Prescription “Chi-Ju-Di- Huang-Wan” on the Dry Eye Randomized C ontrolled Trial Yung-Hsien Chang,Hui-Ju Lin China Medical University and Hospital

FDA( Food Drug Administration ) ● 1994 Dietary Supplement ● 2004 Guidance for Industry Botanical Drug Products

Dry eye syndrome one of the most frequent eye diseasesone 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 USA ， one fifth of the populationIn USA ， one fifth of the population (60 million patients ) (60 million patients )

Symptoms of dry eye Dryness Dryness Foreign body Foreign body sensation sensation Burning sensation Burning sensation Photophobia Photophobia Tearing or dryness Tearing or dryness when eye facing when eye facing winded winded Fluctuation of Fluctuation of visual acuity visual acuity Congestion of Congestion of conjunctiva conjunctiva Loss of corneal Loss of corneal luster luster Frequent blinking Frequent blinking Decrease in visual Decrease in visual activity activity

Tears Tears are secreted from the lacrimal gland and are spread by blinking to protect the ocular surface. Tears defend the eye from foreign bodies and clean the corneal surface.

Tears film ( 3 layers ) Lipid layer (outer layer): containing wax and cholesterol Lipid layer (outer layer): containing wax and cholesterol Aqueous layer (middle layer): containing inorganic iron, glucose, lactoferritin, β lysozyme immunoglobulin A, complement, protein Aqueous layer (middle layer): containing inorganic iron, glucose, lactoferritin, β lysozyme immunoglobulin A, complement, protein Mucin layer (inner layer): containing lysozyme, maintains the stability of tear film Mucin layer (inner layer): containing lysozyme, maintains the stability of tear film

Dry eye (diseases) Deficiency of lipid layer, aqueous layer and mucin layers Deficiency of lipid layer, aqueous layer and mucin layers Sjorgens’ syndrome Sjorgens’ syndrome Rheumatoid arthritis Rheumatoid arthritis

Dry eye (most patients) etiology Prolonged use of computer Prolonged use of computer Air conditioning Air conditioning Low humidity Low humidity Evaporation of tear film Evaporation of tear film Air pollution Air pollution Blepharitis Blepharitis Conjunctivitis Conjunctivitis Aging Aging Drug abuse Drug abuse Contact lens Contact lens

Treatment of dry eye Artificial eye drops Artificial eye drops Artificial tear ointment Artificial tear ointment Vitamin A ointment Vitamin A ointment Special eyewear Special eyewear Anti-autoimmunity drugs (cyclosporine) Anti-autoimmunity drugs (cyclosporine) lacrimal putum occlusion lacrimal putum occlusion

枸杞子 Fructus lycii 菊 花 Hos chrysanthemi for treating blurred vision, eye pain, dry eyes, epiphora, dull headache, severe dizziness, tinnitus, deafness, night sweat. Red tongue with little coating (liver and kidney yin insufficiency) 杞菊地黃丸 Chi-Ju-Di-Huang Wan 六味地黃丸 Liu-Wei-Di-Huang Wan

六味地黃丸 Liu-Wei-Di-Huang Wan Insufficient liver and kidney “yin” 熟地黃 rehmanniae radix 山茱萸 corni fructus 山藥 batatatis rhizoma 丹皮 moutan radicis cortex 澤瀉 alismatis rhizoma 茯苓 poria cocoa

澤瀉 茯苓 地黃 山茱萸 山藥 菊花菊花 枸杞 牡丹皮 杞 菊 地 黃 丸杞 菊 地 黃 丸

化學製造與管制 (CMC) 技術性資料查檢 表 ( 一 ) 藥材 (Raw material) 藥材 (Raw material)

化學製造與管制 (CMC) 技術性資料查檢 表 ( 二 )

化學製造與管制 (CMC) 技術性資料查檢表 ( 三 )

Dry eye patient (inclusion criteria) Age: years old Dryness and burning sensation of eye (primary dry eye) 1 year No taking herbal drugs, 6 months Schirmer’s test ( ＋ ) ＜ 5mm /5 min

Exclusion criteria Sjogren’s syndrome Sjogren’s syndrome Systemic disease / medications Systemic disease / medications Ocular disorders, ocular operation, trauma, diseases Ocular disorders, ocular operation, trauma, diseases Pregnancy, lactating Pregnancy, lactating Other ocular eye drops Other ocular eye drops Rose Bengal test ＞ 7 Rose Bengal test ＞ 7 BUT test ＞ 7 BUT test ＞ 7 Fluorescein test ＋ Rose Bengal test ＋ BUT test ＞ 21 Fluorescein test ＋ Rose Bengal test ＋ BUT test ＞ 21

Basic schirmeris test (1993) ( ＜ 5mm/5min) Standardized filter paper was placed at the junction of the lateral and middle thirds of the lower lid fornix of each eye for 5 minutes: schirmer’s test: less then 5mm/5min

Schirmer’s test

Fluorescein test (0-9) (1969) Moistened fluorescein strip was lightly applied to the inferior tarsal conjunctiva to evaluate corneal epithelium defects. Corneal fluorescein staining defect from 0 (none) to 3 (severe) (upper, middle, lower 3 section)

Fluorescein Stain

Rose Bengal test (0-9) (1993) 1% Rose Bengal was instilled into the low eyelid fornix. Rose Bengal test was used to locate degenerated corneal epithelial cells. The intensity of vital staining dyes on the ocular surface was graded 0-9 according to the criteria proposed. A high intensity of staining indicated increased cell degeneration.

Rose bengal test

Tear break up time (BUT) (1993) Moistened fluorescein strip was applied lightly to the inferior tarsal conjunctiva. BUT is the time between a complete blink and the appearance of the first randomly distributed corneal dry spot. Decrease in BUT can be caused by deficiency of mucin or aqueous tears.

Tear Break Up Time

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

Questionnaire (0-100) 1.Eye dryness 2.Photophobia 3.Gritty eye 4.Eye pain 5.Eye discharge 6.Sticky eye 7.Tearing when windy 8.Blinking 9.Eye soreness 10.Red eye 11.Eyelid swelling 12.Increased use of artificial tear 13.Eye soreness

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

Examination of dry eye Basic schirmeris test ( ＜ 5mm) Basic schirmeris test ( ＜ 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 months 2 months

Treatment Randomized double trial (RCT) 2 groups 2 groups Control groupControl group placebo medicine 4gm Tid /day placebo medicine 4gm Tid /day Study groupStudy group Chi-Ju-Di-Huang Wan 4gm Tid /day Chi-Ju-Di-Huang Wan 4gm Tid /day Artificial tear (Artelac. Dr. Gerhard Co. Berlin, Germany)1 drop 4 times/day Artificial tear (Artelac. Dr. Gerhard Co. Berlin, Germany)1 drop 4 times/day

Safety monitor Urine test (PH, protein, occult blood) BUNCreatinine GOT, GPT Before, 4 week, 2 months Adverse event observation

Changes from the baseline in schirmer’s tests Group2 weeks4 weeks2 months p value Mean  SD 2 weeks4 weeks2 months Control n=    Study n=    0.02 * p < 0.05

Changes from the baseline in Rose Bengal tests Group2 weeks4 weeks2 monthsp value Mean  SD 2 weeks4 weeks2 months Control n=    * Study n=    0.02 * p < 0.05

Changes from the baseline in fluorescein stain tests Group2 weeks4 weeks2 monthsp value Mean±SD 2 weeks 4 weeks2 months Control n=    Study n=    0.01 * p < 0.05

Changes from the baseline in tear break up time tests (BUT) Group2 weeks4 weeks2 monthsp value Mean  SD 2 weeks4 weeks2 months Control n=    *0.26 Study n=    0.03 * p < 0.05

Changes from the baseline in questionnaires Group2 weeks4 weeks2 monthsp value Mean  SD 2 weeks4 weeks2 months Control n=    Study n=    0.45 * p < 0.05

Side effect Normal blood GOT, GPT,BUN, creatinine and urine examinationNormal blood GOT, GPT,BUN, creatinine and urine examination 40 control groups40 control groups 40 study groups40 study groups One case─skin rash during the study periodOne case─skin rash during the study period Control group─diarrheaControl group─diarrhea

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

Discussion Dry eye syndrome may be caused by unstable tear film in each of the 3 tear layers. According to the result of the Rose Bengal test, “Chi-Ju-Di-Huang Wan” is an effective drug for treating dry eye because it repairs epithelial anomalies. Besides, “Chi-Ju-Di-Huang Wan” also effects the stability of tear film. The stability of tear film is influenced by mucin or aqueous layers of tear and is not correlated with the amount of tear aqueous production. The tear aqueous production is mainly measured by schirmer’s test. Dry eye syndrome may be caused by unstable tear film in each of the 3 tear layers. According to the result of the Rose Bengal test, “Chi-Ju-Di-Huang Wan” is an effective drug for treating dry eye because it repairs epithelial anomalies. Besides, “Chi-Ju-Di-Huang Wan” also effects the stability of tear film. The stability of tear film is influenced by mucin or aqueous layers of tear and is not correlated with the amount of tear aqueous production. The tear aqueous production is mainly measured by schirmer’s test.

Conclusion According to Schirmer’s test, Rose Bengal test, fluorescing test, BUT and questionnaire, there were improvements in dry eye syndrome after treatment.According to Schirmer’s test, Rose Bengal test, fluorescing test, BUT and questionnaire, there were improvements in dry eye syndrome after treatment. The study group improved more than the control group in every test but only the Rose Bengal test at week 2 and the tear break up time test at week 4 showed significant statistical differences between the two groups.The study group improved more than the control group in every test but only the Rose Bengal test at week 2 and the tear break up time test at week 4 showed significant statistical differences between the two groups.

Conclusion 2 months might have been too short for a herbal drug to be effective.2 months might have been too short for a herbal drug to be effective. We could not stop using artificial tears during the period of study, because IRB was against the act.We could not stop using artificial tears during the period of study, because IRB was against the act. Pattern Identification should be considered in the future study.Pattern Identification should be considered in the future study.

Clinical Evaluation of the Traditional Chinese Prescription Chi-Ju-Di-Huang- Wan for Dry Eye Yung-Hsien Chang, Hui-Ju Lin Yung-Hsien Chang, Hui-Ju Lin and Wei-Chu Li and Wei-Chu Li PHYTOTHERAPY RESEARCH PHYTOTHERAPY RESEARCH Phytother. Res. 19, 349–354 (2005) Phytother. Res. 19, 349–354 (2005)