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研究生:郭士禎
研究生(外文):Shih-Chen Kuo
論文名稱:毛果芸香鹼對血液透析患者口乾,口渴和透析間體重增加的治療效果
論文名稱(外文):Effect of Pilocarpine on Dry Mouth, Thirst and Interdialytic Weight Gain in Hemodialysis Patients
指導教授:黃建鐘黃建鐘引用關係宋俊明宋俊明引用關係郭浩然郭浩然引用關係蔡瑞真蔡瑞真引用關係
指導教授(外文):Jeng-Jong HuangJunne-Ming SungHow-Ran GuoJui-Chen Tsai
學位類別:碩士
校院名稱:國立成功大學
系所名稱:臨床藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:155
中文關鍵詞:毛果芸香鹼血液透析口乾口渴
外文關鍵詞:PilocarpineHemodialysisDry MouthThirst
相關次數:
  • 被引用被引用:4
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  • 下載下載:175
  • 收藏至我的研究室書目清單書目收藏:1
接受血液透析(hemodialysis, HD)治療的慢性尿毒症(chronic uremia)患者,其唾液流量較正常人為低,但口乾(dry mouth)的相關症狀,如:口乾、口部的不舒適感、口渴(thirst)、說話、睡眠困難、咀嚼、吞嚥食物和裝戴假牙困難等,是否和唾液流量的減少有關,仍尚未釐清。口乾是否為一致渴因子(dipsogenic factor)?口乾與口渴以及患者透析間體重增加(interdialytic weight gain)是否有關?這些問題也尚未完全瞭解。因口服毛果芸香鹼(pilocarpine)能明顯提高唾液流量,有效緩解謝格連氏徵候群(Sjögren's syndrome)或接受放射線治療(irradiation therapy)的頭頸部癌症患者之口乾相關症狀,本研究利用口服毛果芸香鹼增加唾液流量的性質,以研究血液透析患者之口乾和口渴與其對透析間體重增加之關係。
本研究分成三個部分,第一部份為pilocarpine對血液透析患者唾液流量影響之有效性研究:九位血液透析患者,在透析前、後,投與十滴1% 毛果芸香鹼點眼液(1% pilocarpine HCL ophthalmic solution, O.P.D.),相當於pilocarpine 5 mg,在投藥前及其後30、60與90分鐘收集十分鐘未刺激全唾液(unstimulated whole saliva)的流量。第二部分為口乾與透析間體重增加之相關性研究:選入43位血液透析患者,以100 mm visual analog scale(VAS)與透析間體重增加作為評估。第三部分進行一為期七週(2 + 3 + 2)的隨機、單盲和安慰劑對照之交叉型研究,以評估pilocarpine對84位血液透析患者的療效與安全性;使用1% O.P.D.或生理食鹽水安慰劑一次十滴,一天滴四次,各治療二週,以VAS與3-point verbal rating scale(VRS)來評估pilocarpine投藥前與一小時後、第三和第六次血液透析後,患者口乾相關症狀之療效和對透析間體重增加之影響。
未投與pilocarpine前,血液透析患者於透析後的唾液流量比透析前為低(p < 0.05);經投與pilocarpine,患者無論於透析前或後的唾液流量皆有明顯增加(p < 0.05)。而「口乾」與其他相關症狀間,均呈明顯正相關,包括:口部越不舒適(r = 0.715,p < 0.001)、越口渴(r = 0.719,p < 0.001)、說話越困難(r = 0.628,p < 0.001)、睡眠越困難(r = 0.517,p < 0.001)以及咀嚼、吞嚥食物越困難(r = 0.552,p < 0.001);但口乾的相關症狀與平均透析間體重增加,均無相關(p > 0.05)。交叉型研究發現:(1)以VRS作評估,pilocarpine能明顯讓較多患者於投藥後一小時及第三與第六次血液透析時,口乾及相關症狀得到改善,包括:口乾、口部的不舒適感、口渴、說話困難、睡眠困難和咀嚼、吞嚥食物困難;(2)以VAS作評估,發現pilocarpine能明顯讓較多患者於投藥後第三與第六次血液透析時,口乾及相關症狀得到改善,包括:口乾、口部的不舒適感、口渴、說話困難、睡眠困難和咀嚼、吞嚥食物困難;(3)以VAS分數的改變作評估,pilocarpine能明顯讓患者於投藥後第三與第六次血液透析時,口乾的相關症狀之VAS平均值呈明顯的下降(改善),如:口乾、口部的不舒適感、口渴、說話困難;(4)依透析間體重增加之記錄加以分析,pilocarpine能讓患者間隔一天透析,其平均體重之增加(placebo: 3.62 kg vs. pilocarpine: 3.38 kg, p < 0.05),呈有意義下降。流汗與嘔吐是使用pilocarpine主要的藥物不良事件,但沒有嚴重併發症。
總之,口服毛果芸香鹼能明顯增加血液透析患者的唾液流量,並有效緩解口乾的相關症狀,而無嚴重的藥物不良事件。透析間體重增加亦呈有意義的下降。因此,我們認為口乾(唾液流量減少)是致渴因子之一,但對血液透析患者透析間的體重增加,或許並不是主要的決定因素,其臨床的顯著意義需待進一步探討。

Uremic patients undergoing hemodialysis (HD) exhibited lower salivary flow rates than those of healthy subjects. About 86% and 67% of HD patients experienced exaggerated thirst and dry mouth, respectively. However, it is unclear to date whether xerostomia and associated symptoms in HD patients, including: dry mouth, oral discomfort, thirst, difficulty in speaking, sleeping, chewing, swallowing and wearing dentures, correlate with decreased salivary flow rates, and whether decreased salivary flow rates is a dipsogenic factor. Oral pilocarpine can significantly increase salivary flow rates and relieve symptoms of xerostomia in patients with Sjögren’s syndrome or patients receiving irradiation therapy for head and neck cancer. Therefore, we conducted a clinical trial to evaluate the effects of oral pilocarpine on salivary flow rates, dry mouth, thirst and interdialytic weight gain (IDWG) in HD patients, and tested the hypothesis: “decreased salivary flow rates is a dipsogenic factor in HD patients”.
This study consists of three parts. We first evaluated the effect of pilocarpine on salivary flow rates in HD patients. Nine patients received ten drops of 1% pilocarpine solution (i.e. pilocarpine 5 mg). Ten-minute unstimulated whole salivary flow rate (ml/min) was collected at 0, 30th, 60th and 90th minutes after oral pilocarpine. Then, we evaluated the correlation between xerostomia-associated symptoms and IDWG in 43 HD patients. In addition, we assessed the efficacy and safety of oral pilocarpine treatment by a seven (2 + 3 + 2)-week randomized, single-blind, placebo-controlled, and crossover study in 84 HD patients. Symptoms of xerostomia were measured by a 100 mm visual analog scale (VAS), a 3-point verbal rating scale (VRS) at baseline, 1st hour, 3rd and 6th sessions of HD after oral pilocarpine. IDWGs were also measured.
After oral administration of pilocarpine, salivary flow rates significantly increased (p < 0.05) at 30th, 60th and 90th minutes. There were significant correlations between dry mouth and other xerostomia-associated symptoms (p < 0.05). But there was no correlation between symptoms of xerostomia and mean IDWG (p > 0.05). In crossover study, by VRS, more HD patients had improvement of xerostomia at 1st hour, 3rd and 6th sessions of HD after oral pilocarpine in comparison with placebo; by VAS, more HD patients had improvement of xerostomia at 3rd and 6th sessions of HD after oral pilocarpine in comparison with placebo; by changes of VAS, HD patients had significantly decreased mean scores of xerostomia at 3rd and 6th sessions of HD after oral pilocarpine in comparison with placebo. IDWG on alternative HD day (placebo: 3.62 kg vs. pilocarpine: 3.38 kg, p < 0.05) significantly decreased after oral pilocarpine. The primary adverse drug events of oral pilocarpine were sweating and vomiting, but there was no serious adverse drug event.
In brief, oral pilocarpine can significantly increase salivary flow rates and relieve symptoms of xerostomia in HD patients, without any serious adverse drug event. Although IDWG on alternative HD day statistically significantly decreased after oral pilocarpine, its clinical significance needs further evaluation. Therefore, we concluded that dry mouth (decreased salivary flow rates) is one of dipsogenic factors and might contribute to IDWG in HD patients.

中文摘要 I
英文摘要 IV
縮寫表 VII
誌謝 VIII
目錄 IX
表目錄 XV
圖目錄 XVII
第壹章 研究背景 1
第一節 前言 1
第二節 口渴與口乾的定義 4
2.1 口渴的定義 4
2.2 口乾的定義 4
第三節 唾液與唾液腺 6
3.1 唾液的成分 6
3.2 唾液的主要功能 6
3.3 唾液腺的生理學 9
3.4 唾液分泌的控制 11
第四節 口乾症的症狀、臨床徵象、病因學與治療 12
4.1 口乾症的症狀(Symptoms) 12
4.2 口乾症的臨床徵象(Clinical Signs) 12
4.3 口乾症的病因學 13
4.3 口乾症的病因學 14
4.4 口乾症的治療 16
第五節 血液透析患者的口腔表現、唾液流量與口乾 18
5.1 口腔表現 18
5.2 唾液流量 18
5.3 口乾 19
第六節 血液透析患者的致渴因子 20
6.1 血液中鈉離子的濃度 21
6.2 血液中鉀離子濃度的下降 22
6.3 第二血管張力素 22
6.4 血液中尿素濃度升高 23
6.5 高血糖 24
6.6 心理因素 24
第七節 血液透析患者口乾與口渴的關係 25
第八節 口服Pilocarpine於治療口乾症的臨床應用 26
8.1 Pilocarpine的由來與治療口乾症之臨床研究 27
8.2 Pilocarpine的藥理機轉 31
8.3 口服Pilocarpine的藥物動力學 32
8.4 口服Pilocarpine的使用禁忌與交互作用 33
8.5 口服Pilocarpine安全性的評估 34
8.6 總結 35
第貳章 研究目的 36
第參章 研究材料、儀器及方法 37
第一節 研究材料 37
1.1 研究藥品 37
1.2 對照藥品(安慰劑,Placebo) 37
第二節 研究儀器 37
2.1 量筒 37
2.2 針筒 38
2.3 痰杯 38
2.4 酸鹼值測定儀(pH meter) 38
2.5 分析天平 38
2.6 軟塑膠瓶 38
第三節 測量1% O.P.D.滴數與毫克數的換算 38
第四節 配製安慰劑 40
第五節 試驗性研究(The Pilot Study) 41
5.1 反應性的研究 41
5.2 基本值的研究 44
5.3 治療性的研究 47
第六節 隨機,單盲,安慰劑對照的交叉型研究 48
6.1 研究對象 48
6.2 效果評估 48
6.3 安全性評估 48
6.4 研究流程 49
第七節 統計分析 52
7.1 統計模式設定 52
7.2 資料分析方法 52
7.3 統計軟體 53
第肆章 研究結果 54
第一節 試驗性的研究 54
1.1 反應性的研究 54
1.2 基本值的研究 57
1.3 治療性的研究 62
第二節 口乾的相關症狀與透析間體重增加之相關性 65
2.1 研究對象 65
2.2 分析結果 65
第三節 隨機,單盲,安慰劑對照的交叉型研究 67
3.1 第一治療期 68
3.2 第二治療期 76
3.3 交叉型研究 84
第伍章 討論 93
第一節 試驗性的研究 93
1.1 Pilocarpine對健康志願者唾液分泌之影響 93
1.2 Pilocarpine對血液透析患者唾液分泌之影響 95
1.3 Pilocarpine及Placebo對血液透析患者唾液分泌之影響 96
第二節 口乾的相關症狀與透析間體重增加之相關性 97
第三節 隨機,單盲,安慰劑對照的交叉型研究 98
3.1 抗組織胺藥物的使用 98
3.2 退出試驗的原因 99
3.3 效果評估 99
3.4 傳遞效應(Carry-Over Effects) 101
第四節 藥物不良事件的評估 104
第五節 研究限制 105
第六節 未來的研究 106
第陸章 結論 107
參考文獻 108
附錄 119
表一 唾液的成分 8
表二 口乾症相關的症狀/徵象 13
表三 交叉型研究的流程表 50
表四 研究對象的基本資料 57
表五 口乾的相關症狀與透析間體重增加之相關表 66
表六 完成第一治療期患者的基本資料 69
表七 第一治療期完成與退出試驗流程的患者比例及退出原因 69
表八 第一治療期患者對VRS的反應 73
表九 第一治療期患者對VAS的反應 73
表十 第一治療期患者於治療前後各項症狀獲得改善的平均值與百分比 74
表十一 第一治療期患者於治療前後透析間體重增加的平均值與百分比 74
表十二 完成第二治療期患者的基本資料 77
表十三 第二治療期完成與退出試驗流程的患者比例及退出原因 77
表十四 第二治療期患者對VRS的反應 81
表十五 第二治療期患者對VAS的反應 81
表十六 第二治療期患者於治療前後各項症狀獲得改善的平均值與百分比 82
表十七 第二治療期患者於治療前後透析間體重增加的平均值與百分比 82
表十八 交叉型研究患者對VRS的反應 88
表十九 交叉型研究患者對VAS的反應 88
表二十 口乾相關症狀的整體性治療效果(第三次血液透析) 89
表二十一 口乾相關症狀的整體性治療效果(第六次血液透析) 89
表二十二 透析間體重增加的整體性治療效果 90
表二十三 兩個治療期藥物不良事件的發生率 92
圖一 血液透析患者,口渴的感覺與平均每日體重增加成正相關 2
圖二 血液透析患者,口渴的感覺與口乾的感覺成正相關 2
圖三 主唾液腺的位置 9
圖四 鹽酸毛果芸香鹼的結構 31
圖五 試驗性研究的流程 43
圖六 1% O.P.D.試驗的藥效評估流程 51
圖七 Pilocarpine對健康志願者唾液流量之影響 56
圖八 Pilocarpine對健康志願者唾液pH值之影響 56
圖九 Pilocarpine對血液透析患者唾液流量之影響 61
圖十 Pilocarpine對血液透析患者唾液pH值之影響 61
圖十一 Pilocarpine及Placebo對血液透析患者唾液流量之影響 64
圖十二 Pilocarpine及Placebo對血液透析患者唾液pH值之影響 64
圖十三 隨機,單盲,安慰劑對照的交叉型研究之流程圖 67

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