| 摘要: | 膀胱過動症 (overactive bladder, OAB)的發⽣率隨著年齡增加⽽提⾼，⽽台灣社會即將在 2020 年邁⼊⾼齡化社會，患病⼈數也將隨之增加。膀胱過動症主要由 4 個症狀構成，⽇間頻尿、夜尿、排尿急迫感兼有或無尿失禁。這些症狀會造成患者不敢出遠⾨、無法外出⼯作、隨時需要使⽤尿布、需要旁⼈協助清理等，進⽽嚴重影響⽣活品質、增加家⼈負擔、造成患者⾃我形象低落，引發⼼理不健康、憂鬱、焦慮等症狀。⽬前臨床上主要使⽤的西藥⼝服抗膽鹼藥物療法為第⼆線，具有⽼⼈家難以忍受的⼝乾、便秘、頭暈、視覺模糊等副作⽤。在中醫理論中，⾁桂可以改善腎陽虛、膀胱氣化不利造成的夜尿、排尿功能異常，從近代臨床研究中發現，以⾁桂為主的⽳位外⽤或內服療法有明顯改善排尿功能障礙的臨床效果。因此，希望從(I)⾁桂的臨床療效評估及(II)動物實驗探討對於膀胱過動症的作⽤機轉，利⽤科學驗證的⽅式，更深⼊了解⾁桂的療效與作⽤模式。研究結果顯⽰：(I)在膀胱過動症患者中，使⽤⾁桂貼⽚於中極⽳(CV3)、關元(CV4)、⽯⾨(CV5)、氣海(CV6)治療的受試者，療程 2 週，每 2 ⽇治療 1 次，其夜尿、排尿急迫感與尿失禁症狀獲得改善，在膀胱過動症積分量表(overactive bladder symptom score, OABSS)總積分呈現 34.74 %幅度的改善程度。同時，患者對於本⾝膀胱狀況的⾃我感覺量表(patient perception of bladder condition, PPBC)評量分數也有 36.01%程度的改善。在排尿急迫感的嚴重度量表(urgency severity scale, USS)中，呈現 38.58 %程度的緩解。同時，在研究中發現，膀胱過動症患者的中醫體質組成多為陽虛合併陰虛合併痰瘀濕滯的證型表現。未來可以使⽤⾁桂貼⽚⽳位治療作為膀胱過動症的新輔助療法，並且可利⽤中醫體質量表篩檢出陽虛合併陰虛合併痰瘀濕滯的體質證型，進⾏膀胱過動的預防與治療。(II) CYP (300 mg / kg)誘導出典型的膀胱過動症病理⽣理變化，包括排尿次數增加和尿量減少。CYP 誘導的⼩⿏還表現出與發炎反應(p65NFkB)相關的⽔腫、泌尿上⽪失去波紋形狀和規則褶皺、固有層和黏膜肌層組織結構紊亂與破裂，以及在受損組織中出現⽩⾎球浸潤增加(CD11b)/p65NFkB 與毒蕈鹼(M2 和 M3)、瞬態受體電位陽離⼦通道(transient receptor potential cation channel subfamily A member 1, TRPA1)和(transient receptor potential cation channel subfamily A member 1, TRPV1)等受體共存的出⾎性膀胱炎。CYP 誘導後 30 分鐘給予⼝服⾁桂粉(CNP, 600 mg/kg)和桂⽪醛(CNA, 10-50 mg/kg)，可顯著改善前述之 CYP 誘導出的病理變化，⽽ TRPA1 和 TRPV1 拮抗劑可明顯逆轉該變化。免疫螢光染⾊(immunohistochemistry, IHC)顯⽰，CNP 和 CNA 抑制了 MIF/TLR4相關的發炎反應和 SCF/TGFβ 媒介的纖維化途徑。本論⽂的發現指出，CYP 和 CNA 藉由抑制 MIF/TLR4 相關的發炎反應和 SCF/TGFβ 相關的纖維化作⽤對於改善 CYP 誘導的⼩⿏ OAB 症候中扮演重要的⾓⾊。
Financial Development Seminar estimates that the senior society will increase to 14% from 7% within 25 years, and Taiwan is going to be a senior society in 2020. As people getting older, they are at risk of increase in developing overactive bladder. Overactive bladder (OAB) is a clinical syndrome characterized by urine frequency, with or without urge incontinence, urgency, and nocturia. The symptoms associated with OAB can significantly affect the social, psychological, occupational, and physical aspects of those who suffer from it and increase burden of whose caregiver. Many sufferers are always wearing pads and diapers which would decreases quality of life and develops low self-esteem, depression and anxiety. Current medications for OAB treatment are second-line choice and not satisfied due to low efficacy and serious side effects, such as dry mouth, constipation, dizziness, and blurred vision which elderly patients do not tolerate. In traditional Chinese medicine theory, cinnamon have been prescribed to treat symptoms of nocturia and dysuria in patient diagnosed as a yang deficiency and inhibition of bladder qi transformation pattern. As previous study revealed the external or oral therapeutic effect of cinnamon on urinary dysfunction. In this study, (I) to evaluate the efficacy and safety of the cinnamon patch treatment for alleviating symptoms of OAB, a double-blind randomized, placebo-controlled trial (RCT) was conducted and (II) investigated CNP- and CNA-mediated protection against cyclophosphamide (CYP)-induced ongoing bladder overactivity. (I) Results showed that a total of 66 participants (40 women and 26 men), 60.35 ± 12.77 years of age, were included in the pro-protocol analyses. Baseline characteristics were comparable between 2 groups. Treatment of cinnamon patch showed significant difference in reduction in OABSS (9.70 ± 2.20 to 6.33 ± 2.42), PPBC (3.36 ± 0.60 to 2.15 ± 0.83), and USS (2.67 ± 0.54 to 1.64 ± 0.60). Based on BCQ, the three-patterns-combined subtypes (25 of 62, 40.3%) composed as the largest proportion of the unbalanced body constitution patterns of all OAB patients, among these unbalanced patients some of them could be ameliorated and returned to gentle subtype by CP in this study. Compared to placebo, treatment of cinnamon patch might be considered as an effective and safe complementary therapy for OAB. (II) Administration of CYP (300 mg/kg) induced typical OAB pathophysiological changes, including increased frequency of urination and reduced volume of urine. CYP-induced mice also displayed inflammation (p65NF-kB)-related edema, loss of the corrugated shape and regular folds of the urothelium, disordered tissue structures and fractured lamina propria and muscularis mucosae, and hemorrhagic cystitis of the bladder with increased leukocyte infiltration (CD11b)/p65NFkB colocalized with muscarinic (M2 & M3), and transient receptor potential cation channel subfamily A member 1 (TRPA1) and V member 1 (TRPV1) receptors within damaged tissue. Oral treatment of CNP (600 mg/kg) and CNA (10-50 mg/kg) 30 min after CYP induction significantly ameliorated CYP-induced pathophysiological changes that could be significantly reversed by TRPA1 and TRPV1 antagonists. IHC staining indicates that CNP and CNA treatments suppressed MIF/TLR4-associated inflammatory and SCF/TGFb-medicated fibrosis pathways. Our findings suggest that inhibition of MIF/TLR4-associated inflammation and SCF/TGFb-related fibrosis plays a key role in improving CYP-induced OAB by CNP and CNA. |
