臺灣博碩士論文加值系統

摘要
本論文是研究單獨使用體制素(somatosatatin)衍生物-octreotide或合併粉防己鹼(tetrandrine)，治療麻醉狀態門脈高壓鼠的效果。
以膽管結紮(造成肝硬化)，或部份門靜脈結紮(不造成肝硬化)誘導Sprague- Dawley 大白鼠產生門脈高壓。
本實驗分成三部份，第一部份:每隻膽管結紮鼠接受 octreotide 8 microg/kghr 30分鐘，接著 tetrandrine 3.33 mg/kg/min共 3分鐘 或不注射粉防己鹼只注射它的的溶媒 (0.1N HCl) 做為對照組. 第二部份: octreotide改成16 microg/kg/hr，其餘方法與第一部份相同。第三部份與第二部分相同改以部份門靜脈結紮鼠為實驗動物。
結果顯示，注射 octreotide microg/kg/hr 30分鐘，造成門脈壓顯著下降 (-6.9 +/- 5.2%) , 接著注射的粉防己鹼更導致門脈壓進一步的降低 (-19.0 +/- 6.3%) 和平均動脈壓的下降 (-22.1+/- 8.9%)。與只注射溶媒的對照組比較, 粉防己鹼增強了octreotide 降門脈壓的作用，也導致顯著的平均動脈壓下降。
注射 octreotide 16 microg/kg/hr 30分鐘，導致門脈壓顯著下降(-9.9+/-5.5%)。接著注射tetrandrine導致門脈壓進一步降低 (-19.9+/- 6.6%) ，及平均動脈壓下降(-28.6+/- 6.3%)。在部分門脈結紮鼠也有類似的效果。
研究結果顯示，膽管結紮或部份門靜脈結紮大白鼠，單獨使用octreotide或合併粉防己鹼，導致門脈壓的降低，粉防己鹼 顯著地增強 octreotide 降門脈壓的作用也造成平均動脈壓的降低。

Abstract
The purpose of this study was to investigate the therapeutic effects of octreotide alone or in combination with tetrandrine on anesthetized portal hypertensive rats. Portal hypertension was induced by bile duct ligation (BDL, with cirrhosis) or portal vein ligation (PVL, without cirrhosis) in Sprague- Dawley rats.
In Study 1: Each BDL rat received only one of the two regimens: octreotide 8 microg/kg/hr for 30 min followed by tetrandrine 3.33 mg/kg/min for 3 min or octreotide 8 microg/kghr for 30 min followed by vehicle 0.1N HCl. In Study 2: The same protocols as Study 1，except the regimen of octreotide being 16 microg/kg/hr, while in study 3, octreotide 16 microg/kg/hr followed by tetrandrine 3.33 mg/kg/min was performed in PVL rats.
Infusion of octreotide (8 microg/kg/hr for 30 min) induced significant reduction of PVP (portal veinous pressure) (-6.9+/- 5.2%) from baseline, and octreotide followed by tetrandrine induced significant reduction of PVP (-19.0  6.3%) as well as MAP (mean arterial pressure) (-22.1+/- 8.9%). Compared with octreotide followed by vehicle, tetrandrine enhanced portal hypotensive effects of octreotide and induced significant reduction of MAP.
Infusion of octreotide (16 microg/kg/hr for 30 min) induced significant reduction of PVP (-9.9+/-5.5%) from baseline. Infusion of octreotide followed by tetrandrine induced significant reduction of PVP (-19.9+/-6.6%) as well as MAP (-28.6+/-6.3%). Similar effects were also found in PVL rats.
Our results suggested that octreotide, alone or in combination with tetrandrine, induced portal hypotensive effects in BDL or PVL rats. Tetrandrine significantly enhanced portal hypotensive effects of octreotide and induced significant reduction of MAP in BDL and PVL rats.

目錄
誌謝 頁數
目錄 Ⅰ
中文摘要 Ⅲ
英文摘要 Ⅴ
第一章 緒論 1
第一節 門脈高壓研究之回顧 2
壹、門脈高壓形成原因及併發症 2
貳、門脈高壓之血流動力學 3
一、 血流動力學原理 3
二、 血管阻力增加 3
三、 血流量增加 4
四、 周邊血管擴張和血漿容積增加 4
五、 側支循環和食道靜脈曲張的形成 5
六、 門脈高壓之高血流動力學特徵 5
參、門脈高壓血管的反應性 7
肆、門脈高壓之臨床治療 7
一、 降低內臟血流藥物 8
Octreotide 藥物介紹 9
二、 血管擴張性藥物 14
粉防己鹼藥物介紹 16
三、 混合療法 23
第二節 實驗動物模式 25
壹、部份門靜脈結紮法 25
貳、慢性膽道結紮法 25
參、四氯化碳誘導肝臟損壞模式 26
第三節實驗動機及目的 27
第二章 材料與方法 29
第一節 實驗材料 30
壹、儀器設備 30
貳、化學試劑及藥品 31
參、藥品配製 31
肆、實驗動物 32
第二節 實驗方法 32
壹、門脈高壓動物模式 32
一、慢性膽道結紮法 32
二、部份門靜脈結紮法 33
貳、麻醉動物活體(in vivo)反應 34
一、門脈壓及平均動脈壓之測量 34
二、藥物試驗 35
Octreotide給藥方法及劑量之選擇 35
粉防己鹼合併Octreotide之三項研究 36
第三節 計算及統計分析 38
壹、數據計算方式 38
貳、統計方法 38
第三章 實驗結果 39
Octreotide 8 microg/kg·hr 合併粉防己鹼於膽管結紮鼠之研究 40
Octreotide 16 microg/kg·hr 合併粉防己鹼於膽管結紮鼠之研究 41
Octreotide 16 microg/kg·hr 合併粉防己鹼於部份門脈結紮鼠之研究 42
第四章 討論 45
第五章 結論 53
參考資料 55
表格 72
圖 81

參考資料
Albillos A, Colombato LA, Groszmann RJ. Vasodilatation and sodium retention in prehepatic portal hypertension. Gastroenterology 1992;102: 931-5.
Albillos A, Colombato LA, Lee FY, et al. Octreotide ameliorates vasodilation and Na+ retention in portal hypertensive rats. Gastroenterology 1993;104:575-9
Albillos A, Lledo JL, Banares R, et al. Hemodynamic effects of alpha-adrenergic blockade with prazosin in cirrhotic patients with portal hypertension. Hepatology 1994; 20:611-7.
Albillos A, Rossi I, Cacho G, et al.Enhanced endothelium-dependent vasodilation in patients with cirrhosis. Am J Physiol 1995; 268: 459-64.
Anselmi E, Gomez-Lobo DM, Blazquez MA, et al. Influence of the absolute configuration on the vascular effects of tetrandrine and isotetrandrine in rat aorta. Pharmazie 1994;49:440-3.
Asbert M, Gines A, Ginés P, et al. Circulating levels of endothelin in cirrhosis. Gastroenterology 1992;104:1458-91
ATCD Panel. Benefits versus risks of medical therapy for acromegaly. Am J Med 1994;97:468-73
Battershill PE and Clissold SP. Octreotide: A review of its pharmacodynamic and pharmcokinetic properties, and therapeutic potential in conditions associated with excessive peptide secretion. Drugs 1989;38:658-702
Bauer W, Briner W, Doepfner W, et al. SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci 1982;31:1133-40
Benoit JN, Womack WA, Hernandez L, et al. "Forward" and "backward" flow mechanisms of portal hypertension. Relative contributions in the rat model of portal vein stenosis. Gastroenterology 1985; 89: 1092-6.
Benoit JN and Granger DN. Splanchanic hemodynamics in chronic portal hypertension. Semin Liver Dis 1986; 6: 287-98.
Besson I, Ingrand P, Person B, et al. Sclerotherapy with or without octreotide for acute variceal bleeding. N Engl J Med 1995;333:555-60
Bosch J, Navasa M, Garcia-Pagan JC. Portal hypertension. Med Clin N Am 1989; 73: 931-53.
Bosch J, Pizcueta P, Feu F, et al. Pathophysiology of portal hypertension. Gastroenterol Clin N Am 1992; 21: 1-14.
Bosch J, D''Amico G, Luca A, et al. Drug therapy for variceal hemorrhage. In, Portal hypertension. Pathophysiology and Treatment (Bosch J and Groszmann RJ, eds.) Oxford, Blackwell Scientific Publications, 1994:108-23.
Brazeau P, Vale W, Burgus R, et al. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 1973; 179:77-9
Buga GM, Gold ME, Fukoto JM, et al. Shear stress-induced release of nitric oxide from endothelial cells grown on beads. Hypertension 1991;17:187-93.
Burroughs AK. Octreotide in variceal bleeding. Gut 1994;38:523-7
Burroughs AK. Double blind RCT of 5 days octreotide versus placebo, associated with sclerotherapy for trial/failures. Hepatology 1996;24:352A
Cao ZF, Scavenging effect of tetrandrine on active oxygen radicals. Planta Med 1996;62:413-4.
Cerini R, Lee SS, Hadengue A, et al. Circulatory effects of somatostatin analogue in two conscious rat models of portal hypertension. Gastroenterology 1988;94:703-8
Chang FC, Huang YT, Lin HC, et al. Beneficial effects of combined terlipressin and tetramethylpyrazine administration on portal hypertensive rats. Can J Physiol Pharmacol 1999;77:1-7
Chang HM and But PPH. Pharmacology and applications of Chinese materia medica. World Scientific Publishing Co., Singapore 1986.
Chang TM, Chao KC, Lue FH, The cardiovascular effects of tetrandrine and dimethyl-tetrandrine Acta Pharm Sin 1958;6:147-54.
Chang TM, Chao KC, Lue FH, The mechanisms of the hypotensive effects of tetrandrine and dimethyl-tetrandrine. Acta Pharm Sin 1958;6:155-63.
Chatila R, Ferayorni L, Gupta T, et al. Local arterial vasoconstriction induced by octreotide in patients with cirrhosis. Hepatology 2000;31:572-6
Chen KK, Chen AL, Anderson RC, et al. The pharmaclogical action of tetrandrine, an alkaloid of han-fang-chi. Chin J Physiol 1937;11:13-24.
Chen LY, Chen X, Tian XL, et al. Effect of tetrandrine on calcium transport, protein fluorescences and membrane fluidity of sarcoplasmic reticulum. Br J Pharmacol 2000;131:530-6
Chen NH, Wang YL, Ding JH, et al. The effect of tetrandrine on rat myocardial ATPases. Acta Pharm Sin 1991;26:646-9.
Chen YY and Lu FH. The interaction of cardiac glycosides, tetrandrine and Ca2+ on the guinea pig heart Acta Pharm Sin 1982;17:8-11
Chojkier M and Groszman RJ. Measurement of portal-systemic shunting in the rat by using -labeled microspheres. Am J Physiol 1981; 240: 0371-5.
Citera I, Feu F, Luca A, et al. Effects of bolus injections and continuous infusions of somatostatin and placebo in patients with cirrhosis: a double-blind hemodynamic investigation. Hepatology 1995;22;106-11
Colombato LA, Robin M, Pomier-Layrargues G, et al. Animal models of portal hypertension. In, Portal hypertension (Holstege A, Hahn EG, Scholmerich J. eds.) Kluwer Academic Publishers. London 1995;3-14
Cort JH, Albrecht I, Novakova J, et al. Regional and systemic hemodynamic effects of some vasopressins: structure features of the hormone which prolongs activity. Eur J Clin Invest 1975; 5: 165-75.
Dai GZ, Zeng B, Zang YL, et al. Intravenous tetrandrine in terminating acute episodes of paroxysmal supraventricular tachycardia. Chin Med J 1990;103:460-3.
D''Amico G, Traina M, Vizzini G, et al. Terlipressin or vasopressin plus transdermal nitroglycerin in a treatment strategy for digestive bleeding in cirrhosis. J Hepatol 1994; 20: 206-12.
D''Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a meta-analytic review. Hepatology 1995; 22: 332-54.
DeConti RC, Muggia F, Cummings FJ, et al. Clinical and pharmacological studies with d-tetrandrine. Proc Am Assoc Cancer Res Am Soc Clin Oncol 1975;16:96.
Dong HY and Yao C. Clinical study of isotetrandrine on hypertensive patients. Chin J Integr Trad West Med 1991;11:87-90
Dong Z, Xue CS, Zhou QX, Protective effect of tetrandrine and fructose-1,6- diphsophate on the model of focal cerebral ischemia in rats. J Chin Pharm Sci 1997;6:45-50
Elkayam U. Tolerance to organic nitrates: evidence, mechanisms, clinical relevance, and strategies for prevention. Ann Intern Med 1991; 114: 667-77.
Escorsell A, Feu F, García-Pagán JC, et al. Hemodynamic effects of octreotide in cirrhotic patients with portal hypertension . A double-blind study. J Hepatol 1995; Suppl 1:WP4/26.
Escorsell A, Bandi JC, Moitinho E, et al. Time profile of the hemodynamic effects of terlipressin in portal hypertension. J Hepatol 1997; 26:621-7.
Fang DC, Yao WX, Xia GJ, et al. Effects of tetrandrine on isoprenaline and calcium-mediated positive chronotropic action in isolated rabbit atria. Acta Pharmacol Sin 1982;3:233-6
Fang DC and Jiang MX. A new calcium antagonist of Chinese medicinal origin: etrandrine. J Hypertens (Suppl 6) 1986;4:S150-2
Felix JP, King VF, Shevell JL, et al. Bis(benzylisoquinoline) analog of tetrandrine block L-type calcium channels: Evidence for interaction at the diltiazem-binding site. Biochemistry 1992;31:11793-800
Feu F, Ruiz del, Arbol LR, et al. Variceal Bleeding Group. Double-blind randomized controlled trial comparing terlipressin and somatostatin for acute variceal hemorrhage. Gastroenterology 1996;111:1291-9
Freeman JG, Cobden I, Lishman AH, et al. Controlled trial of terlipressin (''Glypressin'') versus vasopressin in the early treatment of esophageal varices. Lancet 1982; 26: 66-8.
Gandhi CR, Stephenson K, Olson MS. Endothelin- a potent peptide agonist in the liver. J Biol Chem 1990;265:17432-5
Gao Y, Chang MY, Mao HY, et al. Treatment of hypertension (270 cases) and hypertensive crisis with tetrandrine. Chin J Intern Med 1965;13:504-7
Garcia-Pagan JC, Navasa M, Bosch J, et al. Enhancement of portal pressure reduction by association of isosorbide-5-mononitrate to propranolol administration in patient with cirrhosis . Hepatology 1990;11:230-8.
Garcia-Tsao G, Grace ND, Groszmann RJ. Short term effects of propranolol on portal venous pressure. Hepatology 1986; 6:101-6.
Gencin P and Groszmann RJ. The biology of portal hypertension. In, The liver: biology and pathobiology 3rd ed. (Arias IM et al, ed.) Raven Press, New York, 1994:1327-41.
Gralla EJ, Coleman GL, Jonas AM, Toxicological studies with d- tetrandrine
(NSC-77037), a plant alkaloid with vascular and lymphotoxic effects in
dogs and monkeys. Cancer Chemother Rep 1974;5:79-85
Groszmann RJ, Kravetz D, Bosch J, et al. Nitroglycerin improves the hemodynamic reponses to vasopressin in portal hypertension. Hepatology 1982;2:757-62.
Groszmann RJ, Bosch J, Grace ND, et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 1990; 99: 1401-7.
Gupta TK, Toruner M, Chung MK, et al. Endothelial dyfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology 1998;28:926-31
Hadengue A, Lee SS, Moreau R, et al. Beneficial hemodynamic effects of ketanserin in patients with cirrhosis: possible role of serotonergic mechanisms in portal hypertension. Hepatology 1987; 7: 644-7.
Harris AG. Octreotide treatment of disorders of the gastrointestinal tract. Drug Invest 1992;4:1-54.
Harris AG. Somatostatin and somatostatin analogues : Pharmacokinetics and pharmacodynamic effects. Gut 1994;35:S1- 4.
Harris AG. Acromegaly. Sandostatin (Octreotide). Literature review 8 (January-December 1994), Sandoz Pharma Ltd. 1995.
Hayes PC, Davis JM, Lewis JA, et al. Meta-analysis of value of propranolol in prevention of variceal hemorrhage. Lancet 1990;335:153-6.
He SX and Huang ZJ. Biotransformation of tetrandrine. Tianjin Med J 1983; 11:231-3.
He Y, Dai GZ, Fung YB, Hemodynamic effects of tetrandrine in healthy adults and hypertensive patients. Acta Univ Med Tongji 1996;25:443-5
Herman EH and Chadwick DP, Cardiovascular effects of d-tetrandrine. Pharmacology 1974;12:97-109
Hori N, Okanoue T, Sawa Y, et al. Effect of a somatostatin analogue (SMS 201-995) on hemodynamics and glucagon secretion in cirrhotic rats. Gastoenterol Jpn 1993;28:276-83
Hori N, Okanoue T, Sawa Y et al., Hemodynamic effects of combined treatment with somatostatin analogue (SMS 201-995) and low-dose isosorbide dinitrate on portal hypertension in conscious cirrhotic rats. J Gastroenterol 1994; 29: 460-8
Hu GX, Hu Y, Fang DC, et al. Hemodynamic effects of tetrandrine on conscious rats. Acta Pharmacol Sin 1987;8:325-8.
Hu WS, Zhou ZH, Hu CJ, et al. Effects of tetrandrine on seven vascular smooth muscles. Acta Pharmacol Sin 1984;5:257-60.
Huang YT, Lo JW, Lin HC, et al. Change in vascular cAMP and cGMP contents in portal hypertensive rats. Pharmacology 1995a; 50: 86-91.
Huang YT, Yu PC, Lee MF, et al. Decreased vascular contractile and inositol phosphate responses in portal hypertensive rats. Can J Physiol Pharm 1995b; 73: 378-82.
Huang YT, Lin HC, Yu PC, et al. Decreased vascular reactivity of portal vein in rats with portal hypertension. J Hepatol 1996a; 24:194-9.
Huang YT, Tsai JF, Liu TB, et al. Chronic administration of octreotide increases vascular responsiveness in rats with portal hypertension. Clin Sci 1996b;91:601-6.
Huang YT, Wang CF, Yang MCM, et al. Vascular hyporesponsiveness in aorta from portal hypertensive rats:possible sites of involvement. J Pharm Exp Ther 1996c; 278: 535-41.
Huang YT, Chang SP, Lin HC, et al. Decrease inositol phosphate responses in portal veins from portal hypertensive rats: role of receptor-G-protein coupling. J Hepatol 1997a; 26: 376-81.
Huang YT, Cheng YR, Lin HC, et al. Hemodynamic effects of chronic tetrandrine treatment in portal hypertensive rats. J Gastroenterol Hepatol 1997b;12:585-9.
Huang YT, Cheng YR, Lin HC, et al. Hemodynamic effects of chronic tetrandrine treatment in Sprague-Dawley rats. Chin J Physiol 1997c;40:175-8.
Huang YT, Lin HC, Tsai JF, et al. Chronic administration of propranolol improves vascular contractile responsiveness in portal hypertensive rats . Eur J Clin Invest 1997d; 27:550-5.
Huang YT, Liu TB, Lin HC, et al. Chronic portal hypotensive effects of tetrandrine and verapamil on portal hypertensive rats Asia Pac J Pharmacol 1997e;12:31-5
Huang YT, Tsai JF, Lin HC, et al. Hemodynamic effects of acute tetrandrine and terlipressin administration on portal hypertensive rats. Can J Physiol Pharm 1997f; 75:1220-5.
Huang YT, Cheng YR, Lin HC, et al. Hemodynamic effects of chronic octreotide and tetrandrine administration in portal hypertensive rats. J Gastroenterol Hepatol 1998a;13:266-72
Huang YT and Hong CY, Tetrandrine. Cardiovascular Drug Reviews 1998b;16:1-15.
Huang YT, Chang FC, Chen KJ, et al. Acute hemodynamic effects of tetramethylpyrazine and tetrandrine on cirrhosis rats. Planta Med 1999; 65: 131-4.
Hui SC, Chan TY, Chen YY, Tetrandrine inhibits lipid peroxidation but lacks reactivity towards superoxide anion and hydrogen peroxide. Pharmacol Toxicol 1996;78:200-1.
Iwata T, Joh T, Kawai T, et al. Role of EDRF in splanchnic blood flow of normal and chronic portal hypertensive rats. Am J Physiol 1992; 263: 149-54.
Iwato T, Toyonaga A, Ikegami M, et al. Nicardipine infusion improved hepatic function but failed to reduce hepatic venous pressure gradient in patients with cirrhosis. Am J Gastroenterol 1992; 87: 326-31.
Jenkins SA, Yates J, Nott DM, et al. Effects of somatostatin, sandostatin and vasopressin on portal pressure and collateral blood flow in portal hypertensive rats. Gut 1989;30:1498A
Jenkins SA, Nott DM, Baxter JN. Pharmacokinetics of octreotide in patients with cirrhosis and portal hypertension; relationship between the plasma levels of the analogue and the magnitude and duration of the reduction in corrected wedged hepatic venous pressure. HPB Surgery 1998;11:13-21.
Jia JF, Xia GJ, Chao DY, et al. Effects of tetrandrine on coronary blood flow , myocardial perfusion and oxygen consumption in animals. Bull Wuhan Med Coll 1983;12:373-6.
Jia JF, Gao NN, Xia GJ, et al. Studies on the calcium antagonistic action of tetrandrine: IX. Effects of tetrandrine on contractility of isolated swine coronary arterial strips. Acta Acad Med Wuhan 1985;5:15-19.
Joh T, Granger DN, Benoit JM. Endogenous vasoconstrictor tone in intestine of normal and portal hypertensive rats. Am J Phys 1993; 264: 171-7.
Junquera F, López-Talavera JC, Mearin F, et al. Somatostatin plus 5-mononitrate versus somatostatin in the control of acute gastro-esophageal variceal bleeding: a double blind, randomized, placebo controlled clinical trial. Gut 2000;46:127-32
Kiel JW, Pitts V, Benoit JN, et al. Reduced vascular sensitivity to norepineptirine in portal-hypertensive rats. Am J Phys 1985; 248: 192-5.
King VF, Garcia ML, Himmel D, et al. Interaction of tetrandrine with slowly inactivating calcium channels: characterization of calcium channel modulation by alkaloid of Chinese medicinal herb origin. J Biol Chem 1988;263:2238-44
Koch BD, Dorflinger LJ, Schonbrunn A. Pertussis toxin blocks both cyclic AMP-mediated and cyclic AMP-independent actions of somatostatin. Evidence for coupling of Ni to decreases in intracellular free calcium. J Biol Chem 1985;260:13138-45
Kong CW, Lay CS, Tsau YT et al. The hemodynamic effect of verapamil on portal hypertension in patients with postnecrotic cirrhosis. Hepatology 1986;6:423-6
Koshy A, Hadengue A, Lee SS, et al. Possible deleterious hemodynamic effect of nifedipine on portal hypertension in patients with cirrhosis. Clin Pharmacol Ther 1987;42:295-8
Koshy A, Sekiyama T, Hadengue A, et al. Effects of alpha-1 and beta-adrenergic antagonists and 5-hydroxytryptamine receptor antagonist on portal-systemic collateral vascular resistance in conscious rats with portal hypertension. J Gastroenterol Hepatol 1992;7:449-54.
Kountouras J, Billing BH, Scheuer PJ. Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat. Br J Exp Pathol 1984; 65: 305-11
Krulich L, Dhariwal APS, McCann SM. Stimulatory and inhibitory effects of purified hypothalamic extracts on growth hormone release from rat pituitary in vitro. Endocrinology 1968;83:783-90.
Kubota A, Yamada K, Kagimoto S, et al. Identification of somatostatin receptor subtypes and an implication for the efficacy of somatostatin analogue SMS 201-995 in treatment of human endocrine tumors. J Clin Invest 1994; 93 :1321-5
Kutz K, Nüesch E, Rosenthaler J. Pharmacokinetics of SMS 201-995 in healthy subjects. Scand J Gastroenterol 1986;21 Supple 119:65-72
Kwan CY and Wang ZL. Tetrandrine: a vasodilator of medicinal herb origin with a novel contractile effect on dog saphenous vein. Eur J Pharmacol. 1993; 238:431-4
Kwan CY, Chen YY, Ma MF, et al. Tetrandrine, a calcium antagonist of Chinese herbal origin, interacts with vascular muscle 1-adrenoceptors. Life Sci 1996;59:PL359-64
Kwan CY, Ma FM, Hui SC. Inhibition of endothelium-dependent vascular relaxation by tetrandrine. Life Sci 1999;64:2391-400.
Lai JH, Ho LJ, Kwan CY, et al. Plant alkaloid tetrandrine and its analog block CD28-costimulated activities of human peripheral blood T cells Transplantation 1999;68:1383-92
Lamberts SW, Oosterom R, Neufeld M, et al.The somatostatin analog SMS 201- 995 induces long-acting inhibition of growth hormone secretion without rebound hypersecretion in acromegaly patients. J Clin Endocrinol Metab 1985;60:1161-5
Lamberts SW. The role of somatostatin in the regulation of anterior pituitary hormone secretion and the use of its analogs in the treatment of human pituitary tumors. Endocr Rev 1988;9:417-36
Lamberts SW, Hofland LJ, van Koetsveld PM, et al. Parallel in vivo and in vitro detection of functional somatostatin receptors in humans endocrine pancreatic tumors:consequences with regard to diagnosis, localization, and therapy. J Clin Endocrinol Metab 1990;71:566-74
Lebrec D. Pharmacological treatment of portal hypertension: hemodynamic effects and prevention of bleeding. Pharmacol Ther 1994;61:65-107
Lebrec D. Pharmacolotherapeutic agents in the treatment of portal hypertension. J Gastroenterol Hepatol 1997;22:332-54
Lee FY, Tsai YT, Lin HC, et al. Hemodynamic effects of a combination of vasopressin and ketanserin in patients with hepatitis B related cirrhosis.J Hepatol;1992:15:54-8
Lee FY, Colombato LA, Albillos A, et al. Nω-nitro-L--arginine administration corrects peripheral vasodilation and systemic capillary hypotension. And ameliorates plasma volume expansion and sodium retention in portal hypertensive rats. Hepatology 1993; 17: 84-90.
Lemaire M, Azria M, Dannecker R, et al. Disposition of sandostatin, a new synthetic somatostatin analogue, in rats. Drug Metab Dispos 1989;17:699-703
Li KJ, Liu KL, Shih SY, et al. Effect of tetrandrine on rat electrocardiogram and action potential of left ventricular myocardium. J Beijing Coll Trad Chin Med 1989;12:35-7.
Liao JF, Yu PC, Lin HC, et al. Study on the vascular reactivity and alpha1- adrenoceptors of portal hypertensive rats. Br J Pharmacol 1994; 111: 439- 44.
Lin CI, Wei J, Cheng KK, et al. Electropharmacological effects of sandostatin in human atrial fibres. Int J Cardiol 1991;31:313-8
Lin HC, Tsai YT, Yang MCM, et al. Haemodynamic effects of a combination of propranolol and clonidine in patients with post-hepatic cirhosis. J Gastroen Hepatol 1995; 10: 54-58.
Lin HC, Yang MCM, Hou MC. Effects of long-term administration of octreotide in portal vein stenosed rats. Hepatology 1996; 23: 537-43.
Liu QY, Karpinski E, Pang PKT. Tetrandrine inhibits both T and L calcium channel currents in ventricular cells. J Cardiovasc Pharmacol 1992;20:513- 9
Liu QY, Li B, Gang JM, et al. Tetrandrine a Ca2+ antagonist: effects and mechanisms of action in vascular smooth muscle cells. J Pharmacol Exp Ther 1995;273:32-9
Liu TB, Lin HC, Huang YT, et al. Portal hypotensive effects of tetrandrine and verapamil in portal hypertensive rats. J Pharm Pharmacol 1997; 49 : 85-8.
Londong W, Angerer M, Kutz K, et al. Diminishing efficacy of octreotide (SMS 201-995) on gastric functions of healthy subjects during one-week administration. Gastroenterology 1989;96:713-22
Low AM. Berdik M, Sormaz L, et al. Plant alkaloids. Tetrandrine and hernandezin inhibit calcium depletion stimulated calcium entry in human and bovine endothelial cells. Life Sci 1996;58:2327-35
Marteau P, Ballet F, Chazouilleres O. Effect of vasodilators on hepatic microcirculation in cirrhosis: A study in the isolated perfused rat liver. Hepatology 1989; 9: 820-3.
Martínez-Prieto C, Ortíz MC, Fortepiani LA, et al. Haemodynamic and renal evolution of the bile duct-ligated rat. Clin Sci 2000;98:611-7.
Mastai R, Brault A, Huet PM. Effects of serotonin on the microcirculation of the normal perfused rat liver (abstract). Hepatology 1987: 7:1032.
McCormick PA, Dick R, Siringo S, et al. Octreotide reduces azygous blood flow in cirrhotic patients with portal hypertension. Eur J Gastroenterol Hepatol 1990;2:489-92
McCormick PA, Chin J, Greenslade L, et al. Cardiovascular effects of octreotide in patients with hepatic cirrhosis. Hepatology 1995;21:1255-60
Mengs U, Lang W, Poch JA. The carcinogenic action of aristolochic acid in rats. Arch Toxicol 1982;51:107-19
Merkel C, Bolognesi M, Sacerdoti D, et al. A. The hemodynamic response to medical treatment of portal hypertension as a predictor of clinical effectiveness in the primary prophylaxis of variceal bleeding in cirrhosis. Hepatology 2000;32:930-4
Mesh CL, Joh T, Korthuis RJ, et al. Intestinal vascular sensitivity to norepinephrine in portal hypertensive rats. Gastroenterology 1991; 100: 916-921.
Moreau R, Cailmail S, Lebrec D. Effect of vasopressin on haemodynamic in portal hypertensive rats receiving clonidine. Liver 1994;14:45-9
Mountokalakis T, Kallivretakis N, Mayopoulou-Symvoulidou D, et al. Enhancement of renal function by a long acting somatostatin analogue in patients with decompensated cirrhosis . Nephrol Dial Transplant
1988;3:604-7
Mψller S, Brinch K, Henriksen JH, et al. Effect of octreotide on systemic, central
and splanchnic haemodynamics in cirrhosis. J Hepatol 1997;26:1026-33
Murray BM and Paller MS. Decreased pressor reactivity to angiotensin II in
cirrhotic rats: evidence for a post-receptor defect in angiotensin action.
Circ Res 1985; 57: 424-31.
Negrao AB, Deuster PA, Gold PW, et al. Individual reactivity and physiology of the stress response. Biomed Pharmacother 2000;54(3):122-8
Nortier JL, Muniz Martinez MC, Schmeiser HH et al. Urothelial carcinoma associated with the use of a chinese herb (Aristolochia fangchi). N Engl J Med 2000;342:1686-92.
Oberti F, Rifflet H, Maiga MY et al. Prevention of portal hypertension by propranolol and spironolatone in rats with bile duct ligation. J Hepatol 1997;26:167-73
Oberti F, Veal N, Kaassis M, Pilette C, et al. Hemodynamic effects of terlipressin and octreotide administration alone or in combination in portal hypertensive rats. J Hepatol 1998;29:103-11
Park PH, Nan JX, Park EJ, et al. Effect of tetrandrine on experimental hepatic fibrosis induced by bile duct ligation and scission in rats. Pharmacol Toxicol 2000;87:261-8
Patel YC, Greenwood MT, Warszyuska A, et al. All five cloned human somatostatin receptors (hsstr 1-5) are functionally coupled to adenylyl cyclase. Biochem Biophys Res Commun 1994;198:605-12
Perlow D, Paleveda J, Holly FW, et al. A potent cyclic hexapeptide analogue of somatostatin . Nature 1981;292:55-8
Peters GE. Distribution and metabolism of exogenous somatostatin in the rat. Regul Pept 1982;3:361-9
Pizcueta MP, Garcia-Pagan, Fernandez M, et al. Glucagon hinders the effects of somatostatin on portal hypertension. A study in rats with partial portal vein ligation. Gastroenterology 1991; 101: 1710-5.
Pizcueta MP, Pique JM, Bosch J, et al. Effects of inhibiting nitric oxide biosynthesis on the systemic and splanchnic circulation of rats with portal hypertension. Br J Pharm 1992; 105: 184-90.
Polio J, Sieber CC, Lerner E. Cardiovascular hyporesponsiveness to norepinephrine, propranolol and nitroglycerin in portal hypertensive and aged rats. Hepatology 1993; 18:128-56.
Primignani M, Vazzoler MC, Carpinelli L, et al. Short-term effect of octreotide on intraesophageal variceal pressure: a double-blind placebo-controlled study. Eur J Gastroenterol Hepatol 1994;6:1027-31
Qi ST, Zhu C, Lu YC. The protective effects of tetrandrine on cerebral ischemia. Chin Pharmacol Bull 1992;8:63-5
Qian JQ, Thoolen MJMC, van Meel JCA, et al. Hypotensive activity of tetrandrine in rats: investigation into its mode of action. Pharmacology 1983;26:187- 97
Rainer TH, Beattie T, Crofton P, et al. Systemic hormonal, electrolyte, and substrate changes after non-thermal limb injury in children. Emerg Med J 1999;16(2):104-7
Reichen J, Hirlinger A, Ha HR, et al. Chronic verapamil administration lowers portal pressure and improves hepatic function in rats with liver cirrhosis. J Hepatol 1986; 3: 49-58.
Reichen J, Gerbes AL, Steiner MJ, et al. The effect of endothelin and its antagonist Bosentan on hemodynamics and microvascular exchange in cirrhotic rat liver. J Hepatol 1998;28:1020-30
Reichlin S. Somatostatin (two parts). N Eng J Med 1983;309:1495- 501 and 1556-63
Ren ZJ, Zeng DY, Zhang XH, et al. Protective effects of tetrandrine on experimental myocardial ischemia and reperfusion injury in rabbits. Chin J Pharmacol Toxicol 1995;9:303-4
Rockey DC and Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology 1998; 114: 344-51.
Rodriguez-Perez F and Groszmann RJ. Phamacologic treatment of portal hypertension. Gastroenterol Clin N Am 1992; 21:15-40.
Rubanyi GM, Romero JC, Vanhoutte PM. Flow-induced release of endothelium-derived relaxing factor. Am J Physiol 1986; 250: 1145-9.
Rubio LR, Garrido G, Llanes L, et al. Effect of tetrandrine on Ca2+- and Na+-currents of single bullfrog cardiomyocytes. J Mol Cell Cardiol 1993;25:801-13
Ruiz del Arbol L, Monescillo A, et al. Variceal pressure changes in relation with glypressin injection vs. somatostatin infusion during the treatment of variceal bleeding in patients with cirrhosis. Hepatology 1993;18:286A
Ryan US and Rubanyi CM (eds). Endothelial Regulation of the Vascular Tone. Marcel Decker, New York.1992; 21-36.341-54.
Sabat M, Guarner C, Soriano G, et al. Effect of subcutaneous administration of octreotide on endogenous vasoactive systems and renal function in cirrhotic patients with ascites. Dig Dis Sci 1998;43:2184-9
Shen YC, Chen CF, Sung YI. Tetrandrine ameliorates ischemia-reperfusion injury of rat myocardium through inhibition of neutrophil priming and activation. Br J Pharmacol 1999;128(7):1593-601.
Sheppard M, Shapiro B, Berelowitz M, et al. Metabolic clearance and plasma half disappearance time of exogenous somatostatin in man. J Clin Endocrinol Metab 1979;48:50-3
Shields R, Jenkins SA, Baxter JN, et al. A prospective randomised controlled trial comparing the efficacy of somatostatin win injection sclerotherapy in the control of bleeding oesophageal varices. J Hepatol 1992;16:128-137
Sieber C, Gnadinger M, del Pozo E, et al.Effect of a new somatostatin anlogue SMS 201-995 (Sandostatin) on the renin-aldosterone axis. Clin Endocrinol 1988;28:25-32
Sieber CC, Mosca PG, Groszmann RJ. Effect of somatostatin on mesenteric vascular resistance in normal and portal hypertensive rats. Am J Physiol 1992;262:G274-7
Sieber CC, Lee FY, Groszmann RJ. Long-term octreotide treatment prevents vascular hyporeactivity in portal-hypertensive rats. Hepatology 1996;23:1218-23
Sitzmann JV, Bulkley GB, Mitchell MC, et al. Role of prostacyclin in the splanchnic hyperemia contributing to portal hypertension. Ann Surg 1989; 209: 322-7.
Sitzmann JV, Li SS, Adkinson NF. Evidence for role of prostacyclin as a systemic hormone in portal hypertension. Surgery 1991; 109: 149-53
Smith RE, Robison NM, McPeake JR, et al. Induction and role of NO synthase in hypotensive hepatic failure. Arterioscler Thromb Vasc Biol.1997;17:3079- 82
Soderlund C, Magnusson I, Torngren S, et al. Terlipressin (triglycyl-lysine vasopressin) controls acute bleeding esophageal varices. A double-blind, randomized, placebo-controlled trial. Scand J Gastroenterol 1990; 25: 622-30.
Soupison T, Yang S, Bernard C, et al. Acute hemodynamic responses and inhibition of tumor necrosis factor-alpha by pentoxyfylline in rats with cirrhosis. Clin Sci 1996;91:29-33.
Stanley AJ, Redhead DN, Hayes PC. Review article: update on the role of transjugular intrahepatic portosystemic stent-shunt (TIPSS) in the management of complications of portal hypertension. Alimen Pharm Therap 1997; 11: 261-72.
Sung JJY, Chung SCS, Lai CW, et al. Octreotide infusion or emergency sclerotherapy for variceal haemorrhage. Lancet 1993;342:637-41
Suttie JW: The metabolic role of vitamin K. Fed Proc 1980;39:2730
Tsai YT, Lay CS, Lai KH, et al. Controlled trial of vasopressin plus nitroglycerin vs. vasopressin alone in the treatment of bleeding esophageal varices. Hepatology 1986;6:406-9
Vachiery F, Moreau R, Gadano A. Hemodynamic and metabolic effects of terlipressin in patients with cirrhosis receiving a nonselective beta-blocker. Digest Dis Sci 1996; 41: 1722-6.
Vanherweghem JL, Depierreux M, Tielemans C, et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 1993;341:387-91.
Veber DF, Freidinger RM, Schwenk-Perlow D, et al. A potent cyclic hexapeptide analogue of somatostatin. Nature 1981;292:55-8
Vinel JP, Caucanas JP, Combis JM, et al. Verapamil has no effect on porto-hepatic pressure gradient, hepatic blood flow and elimination function of the liver in patients with liver cirrhosis. J Hepatol 1989;8:302-7
Vorobioff J, Bredfeldt JE, Groszmann RJ. Increased blood flow through the portal system in cirrhotic rats. Gastroenterology 1984;87:1120-6
Walker S, Stiehl A, Raedsch R, et al. Terlipressin in bleeding esophageal varices: a placebo-controlled, double-blind study. Hepatology 1986; 6: 112-5.
Wang G, Lemos JR. Tetrandrine: a new ligand to block voltage- dependant Ca2+ and Ca2+- activated K+ channels. Life Sci. 1995;56:295-306
Whittle BJR, Moncada S. Nitric oxide: the elusive mediator of the hyperdynamic circulation in cirrhosis? Hepatology 1992; 16: 1089-92.
Wu SN, Li HE, Lo YC. Characterization of tetrandrine-induced inhibition of large-conductance calcium-activated potassium channels in a human endothelial cell line (HUV-EC-C). J Pharmacol Exp Ther 2000;292(1): 188-95.
Xia GJ, Yao WX, Liu Y, et al. The protective effects of tetrandrine on myocardial ischemia -reperfusion injury in isolated rat heart. Acta Univ Med Tongji 1994;23:446-9
Yang XM, Fang DC, Jiang MX. Protective effect of tetrandrine on myocardial hypoxia and necrosis induced by isoprenaline in rats. Bull Wuhan Med Coll 1984;13:201-4
Zeng FD, Shaw DH Jr, OgilvieRI. Kinetic disposition and hemodynamic effects of tetrandrine in anesthetized dogs. J Cardiovasc Pharmacol 1985;7: 1034-9
Zeng GQ, Ju DW, Sun DX, et al. Effects of dauricine and tetrandrine on [3H]WEB 2086-specific binding to bovine anterior cerebral arterial smooth muscle cells in vitro. Acta Pharm Sin 1993;28:499-503
Zeng XF, Pan HW, Bian RL. Effects of tetrandrine on release of calcium- dependent endothelium-derived relaxing factor. Acta Pharmacol Sin 1987;8:525-9
行政院衛生署，臺灣地區主要死亡原因，中華民國公共衛生年報 2000.
李時珍. 本草綱目，1596首次出版，臺北:宏業書局,1979;18:61-3