Yung-Hsien Chang ,Hui-Ju Lin China Medical University and Hospital

1. Clinical Evaluation of Traditional Chinese Prescription “Chi-Ju-Di-Huang-Wan” on the Dry EyeRandomized Controlled Trial Yung-Hsien Chang ,Hui-Ju Lin China Medical University and Hospital

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

3. Dry eye syndrome • one of the most frequent eye diseases • in the industrial world. • Population : 14.47% Male : 11.47% Female: 16.7 % • In USA， one fifth of the population • (60 million patients )

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

5. 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.

6. Tears film ( 3 layers ) • Lipid layer (outer layer): containing wax and cholesterol • 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

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

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

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

11. 杞菊地黃丸Chi-Ju-Di-Huang Wan六味地黃丸Liu-Wei-Di-Huang Wan • 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)

12. 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

13. 澤瀉 山藥 地黃 菊花 山茱萸 茯苓 枸杞 牡丹皮 杞 菊 地 黃 丸

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

15. 化學製造與管制(CMC)技術性資料查檢表(二)

16. 化學製造與管制(CMC)技術性資料查檢表(三)

17. Dry eye patient (inclusion criteria) • Age: 20-70 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

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

19. 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

20. Schirmer’s test

23. 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)

24. Fluorescein Stain

25. 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.

26. Rose bengal test

30. 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.

31. Tear Break Up Time

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

33. Questionnaire (0-100) • Eye dryness • Photophobia • Gritty eye • Eye pain • Eye discharge • Sticky eye • Tearing when windy • Blinking • Eye soreness • Red eye • Eyelid swelling • Increased use of artificial tear • Eye soreness

34. 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

35. Examination of dry eye • Basic schirmeris test (＜5mm) • Fluorescein test (0-9) • Rose Bengal test (0-9) • Tear break up time (BUT) • questionnaire (0-100) • Before, after 2 weeks, 4 weeks, 2 months

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

37. Safety monitor • Urine test (PH, protein, occult blood) • BUN • Creatinine • GOT, GPT • Before, 4 week, 2 months • Adverse event observation

38. Changes from the baseline in schirmer’s tests * p < 0.05

39. Changes from the baseline in Rose Bengal tests * p < 0.05

40. Changes from the baseline in fluorescein stain tests * p < 0.05

41. Changes from the baseline in tear break up time tests (BUT) * p < 0.05

42. Changes from the baseline in questionnaires * p < 0.05

43. Side effect • Normal blood GOT, GPT,BUN, creatinine and urine examination • 40 control groups • 40 study groups • One case─skin rash during the study period • Control group─diarrhea

44. 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.

45. 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.

46. Conclusion • 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.

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

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