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研究生:劉正吉
研究生(外文):Cheng-Chi Liu
論文名稱:犬乾眼症的研究與治療
論文名稱(外文):Keratoconjunctivitis Sicca in dogs : Analysis and Treatment
指導教授:林中天
口試委員:張仕杰林荀龍廖泰慶林辰栖
口試日期:2015-06-25
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:獸醫學研究所
學門:獸醫學門
學類:獸醫學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:68
中文關鍵詞:環孢靈A乾眼乾燥性角結膜炎絕育淚液分泌測試傳統中藥材
外文關鍵詞:cyclosporine Adry eyeKeratoconjunctivitis siccaneuteredSchirmer tear testtraditional Chinese medicines
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摘要
本論文有三個討論主題:
1. 研究台灣201例犬乾眼症個案。
2. 研究探討犬隻絕育與淚液分泌的關係。
3. 臨床評估傳統中藥對於犬乾眼症之治療,並與環孢靈A相比較。

研究台灣201例犬乾眼症個案
本研究是用回溯性研究法,於國立台灣大學動物醫院取201例犬乾眼症(keratoconjunctivitis sicca, KCS)個案資料加以分析。其中包含23種品種,影響最大的三種:西施、馬爾濟斯和美國可卡犬占了59.2%。在所有個案中,出現臨床徵兆的平均年齡是八年又一個月,公母在統計上無顯著差異。臨床徵兆包含角膜色素沉澱、黏液樣膿性分泌物與角膜潰瘍。相較之下,西施犬與馬爾濟斯有較高的角膜潰瘍發生率;西施犬在角膜色素沉澱的狀況也較為嚴重。但在黏液樣膿性分泌物方面,品種影響在統計上無顯著差異。本研究取台灣地區多種犬種做為參考族群,針對在不同性別、年齡與發生角膜色素沉澱及角膜潰瘍的風險探討,這部分尚未有其他文獻發表。

研究探討犬隻絕育與淚液分泌的關係
本研究目的是要探討絕育犬隻與未絕育犬隻對於淚液製造的影響。研究個案包含200頭狗,性成熟的公母犬各100頭。在系統性與檢眼鏡檢查下皆是健康犬隻,並在每月定期對雙眼實施淚液分泌測試(STT)。一般公犬與絕育公犬的檢測數值中發現,前者在STT的測值是18.6 ± 3.1毫米,而後者是15.5 ± 2.9毫米;一般母犬的STT測值是19.2 ± 3.3毫米而絕育母犬則是 16.5 ± 4.5毫米。比較一般公犬與絕育公犬,會發現絕育公犬在STT測值會比一般公犬低,在一般母犬與絕育母犬的比較亦同,經統計分析皆具顯著差異。總體可得,絕育的犬隻有較少的淚液分泌。在這些樣本中,年齡差異全距約19個月,絕育公犬平均年齡為18.4 ± 7.8個月、絕育母犬平均年齡為20.3 ± 5.6 個月;STT測量值則在7.19毫米,其中絕育公犬為7.68 ± 1.1毫米、絕育母犬為6.7 ± 1.2毫米。這些數值在乾眼症的臨床診斷具有重要性。至今的獸醫文獻中,尚未有任何關乎犬隻絕育手術帶來的乾眼症表徵與臨床徵狀變化探討,而此次研究得到絕育犬隻的乾眼症發生率為9.5%,對照文獻顯示一般犬隻的乾眼症發生率為1-4%。

臨床評估傳統中藥對於犬乾眼症之治療,並與環孢靈A相比較
乾燥性角結膜炎一詞,常用以形容淚液分泌減少的狀況,另一種說法則是「乾眼」。環孢靈A對於治療此症狀有良好的效果,然而,在統計上也有顯著數量的犬隻對於環孢靈A療法無效,是以本研究目標為評估傳統中藥材對於緩解犬隻乾燥性角膜炎臨床症狀的療效,並將其與環孢靈A藥膏相較。研究個案為19隻尚未以環孢靈A治療的乾燥性角膜炎犬隻,隨機分成中藥材與環孢靈A兩組,進行八週的投藥試驗。結果顯示,以中藥治療的組別得STT數據為19.3±1.7毫米/分鐘,而用環孢靈A治療的犬隻得STT測值21.2±1.2毫米/分鐘。在統計之下,中藥材與環孢靈A療法在臨床徵狀改善程度無顯著差異(P=0.58)。研究結果顯示,於犬隻的乾眼症治療,中藥材不僅在使用上安全無虞,效用上亦等同環孢靈A,此外,以口服的方式投藥較眼藥膏單純,價位上也相對較低具有較高的接受度。


Abstract
In this thesis have three topics to discuss:
1. Investigation of 201 cases of Canine Keratoconjunctivitis Sicca in Taiwan.
2. Investigation of the association between tear production and neutering in the dog.
3. Clinical evaluation of traditional Chinese medicines for the treatment of canine
keratoconjunctivitis sicca: A comparison with cyclosporine A.

Investigation of 201 cases of Canine Keratoconjunctivitis Sicca in Taiwan
This is a retrospective study of data analyses from 201 cases with keratoconjunctivitis sicca (KCS) referred to the National Taiwan University Veterinary Hospital, Taiwan. There were 23 breeds in the study, with three most affected breeds, namely Shih-Tzu, Maltese and American cocker spaniel, making up 59.2% of the cases. Among all cases, the mean age at onset of clinical signs was eight years and one month, with no statistical difference between females and males. Clinical signs consisted mainly of corneal pigmentation, mucopurulent discharge and corneal ulceration. In contrast, shih-tzu and malteses showed higher incidence of corneal ulceration. Severe corneal pigmentation occurred in shih-tzu. There was no significant difference in mucopurulent discharge in all breeds. The results of this study revealed interbreed differences with respect to sex, age and risks of corneal pigmentation, and corneal ulceration that have not been detailed previously in a referral population in Taiwan.

Investigation of the association between tear production and neutering in the dog
Abstract
To investigate the effects of gender on tear production in normal and neutered dogs. Two-hundred healthy ophthalmoscopically and systemically unremarkable dogs. Schirmer tear tests (STT) were performed every month on two eyes of each of 200 dogs: 100 sexually mature females, 100 sexually mature males. There was a significant effect of gender in neutered dogs on the STT measurement. When compared to normal male dogs, the mean STT value of neutered male ones decreased from 18.6 ± 3.1 mm to 15.5 ± 2.9 mm. Similar results were found in neutered female dogs which their mean STT value was significantly lower than normal female dogs (from 19.2 ± 3.3 mm to 16.5 ± 4.5 mm). Tear production decreased with gender in the neutered dog. In this population of dogs, the largest difference was nearly 19 months (male neutered dogs: 18.4 ± 7.8 months; female neutered dogs: 20.3 ± 5.6 months), STT measurements that amounted to 7.19 mm (male neutered dogs: 7.68 ± 1.1 mm; female neutered dogs: 6.7 ± 1.2 mm). This value is likely to be of clinical significance in the diagnosis of keratoconjunctivitis sicca (KCS). No studies in the veterinary literature have investigated variations in the presentation and clinical signs of KCS between neutering and KCS in dogs. Our results showed that incidence of KCS in the neutered dogs is 9.5%, depending on the report and how the data were obtained, while the incidence in normal dogs is approximately 1–4%.

Clinical evaluation of traditional Chinese medicines for the treatment of canine keratoconjunctivitis sicca: A comparison with cyclosporine A
Keratoconjunctivitis sicca (KCS) is a term used to describe a condition of decreased tear production. Another commonly used term to describe this disease is "dry eye". Cyclosporine A (CsA) is an efficient treatment for KCS. However, a significant number of canine KCS patients do not respond to CsA treatment. The aim of this study was to evaluate the efficacy of traditional Chinese medicines (TCM) in alleviating the clinical signs of KCS in dogs and to compare the efficacy with that of CsA ointment. This study included 19 dogs with KCS previously untreated with CsA. Dogs were randomly assigned to a treatment group and medicated daily for 8 weeks. After that time, the schirmer tear test result was 19.3±1.7 mm/min in the TCM group and 21.2±1.2 mm/min in the CsA group. The improvement in the clinical signs of inflammation in eyes treated with the TCM was equal to that in eyes treated with CsA (P=0.58). In conclusion, the results of this study showed that the TCM is safe to use and the efficacy was equal to that of CsA. In addition, the method of oral administration was simpler, and the treatment was less expensive than CsA ointment for the control of KCS in dogs.

CONTENTS
1 INTRODUCTION …….. 1
1.1 General Background Information and Literature Review …….. 1
A What is Keratoconjunctivitis Sicca? …….. 1
B What are the Symptoms of KCS? …….. 4
C How is KCS Diagnosed? …….. 7
D What is the Cause of KCS? …….. 8
E How is KCS Treated? …….. 12
a Initial Medical Treatment …….. 12
b Long Term Medical Treatment …….. 12
c Surgical Treatment …….. 15
1.2 Research Purpose …….. 17
2 METHOD …….. 18
2.1 Research Strategy …….. 18
2.2 Subjects/ Materials …….. 19
A. Subjects/ Participants …….. 19
a Investigation of 201 cases of Canine Keratoconjunctivitis Sicca in Taiwan …….. 19
b Investigation of the association between tear production and neutering in the dog …….. 19
c Clinical evaluation of traditional Chinese medicines for the treatment of canine keratoconjunctivitis sicca: A comparison with cyclosporine A …….. 20
B. Materials/ Instruments …….. 21
a Investigation of 201 cases of Canine Keratoconjunctivitis Sicca in Taiwan …….. 21
I. Study population and diagnosis …….. 21
II. Data processing …….. 21
III. Statistical analyses …….. 22
b. Investigation of the association between tear production and neutering in the dog …….. 23
I. Animals …….. 23
II. Schirmer tear test (STT) …….. 23
III. Statistical analysis …….. 23
IV. The Quantitative Determination of Progesterone in canine serum (Progesterone ELISA -IBL RE52231) …….. 24
V. The Quantitative Determination of 17beta-Estradiol in canine serum (17beta-Estradiol ELISA-IBL RE52041) …….. 26
VI. The Quantitative measurement of testosterone in canine serum (Trstosterone EIA-ACTIVE DSL-10-4000) …….. 28
c. Clinical evaluation of traditional Chinese medicines for the treatment of canine keratoconjunctivitis sicca: A comparison with cyclosporine A …….. 31
I. Animals …….. 31
II. Treatments …….. 31
III. Schirmer tear test (STT) …….. 32
IV. Evaluation of clinical efficacy …….. 32
V. Statistical analysis …….. 33
3 RESULTS …….. 34
3.1 Investigation of 201 cases of Canine Keratoconjunctivitis Sicca in Taiwan …….. 34
A. Breed …….. 34
B. Age …….. 34
C. Gender …….. 35
D. Clinical signs …….. 35
3.2 Investigation of the association between tear production and neutering in the dog …….. 37
A. Distributions of age in the groups …….. 37
B. Clinical test results and hormone profiles …….. 37
C. The STT values …….. 37
3.3 Clinical evaluation of traditional Chinese medicines for the treatment of canine keratoconjunctivitis sicca: A comparison with cyclosporine A …….. 39
A. Distributions of age in the groups …….. 39
B. Study population …….. 39
C. Increase in tear production …….. 39
4 DISCUSSION/ CONCLUSIONS …….. 40
4.1 Investigation of 201 cases of Canine Keratoconjunctivitis Sicca in Taiwan …….. 40
4.2 Investigation of the association between tear production and neutering in the dog …….. 45
4.3 Clinical evaluation of traditional Chinese medicines for the treatment of canine keratoconjunctivitis sicca: A comparison with cyclosporine A …….. 49
5 TABLES …….. 51
Table 1 Ingredients of the traditional Chinese medicines (TCM) used in this study …….. 51
Table 2 Breeds represented in the study and number of animals per breed. …….. 52
Table 3 Breeds represented in the study and mean age at onset of clinic signs (months) of the animals of eachbreed. …….. 53
Table 4 The differences in the proportions of animals affected with KCS in each age group for the 3 most affected breeds (years of age). …….. 54
Table 5 The number of animals of the 3 most affected breeds presenting with KCS. …….. 54
Table 6 Distributions of age and neutering durations in the dry eye cases. …….. 55
6.1 ale dogs (n=5) …….. 55
6.2 female dogs (n=14) …….. 55
Table 7 Clinical test results and hormone profiles. …….. 56
7.1 Serum hormone levels (pre-neutering)-Female …….. 56
7.2 Serum hormone levels (post-neutering 3 months) …….. 56
7.3 Serum hormone levels (post-neutering 6 months) …….. 56
Table 8 The means and SDs of the STT1 values obtained before and after neutering in 200 dogs. …….. 58
Table 9 Distributions of age and neutering duration in the dry eye cases. …….. 59
9.1 Male …….. 59
9.2 Female …….. 59
6 FIGURES …….. 60
Figure 1 Relationship between clinical signs and degree of KCS divided into 3 levels. …….. 60
Figure 2 Distributions of age in the groups before neutering. …….. 61
Figure 3 Effect of the TCM powders on tear production in dogs with KCS. …….. 62
Figure 4 Effect of CsA ointment on tear production in dogs with KCS. …….. 63
Figure 5 Effects of the TCM powders (●) and CsA ointment (■) on tear production in dogs with KCS. …….. 64
7 REFERENCES …….. 65




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