(3.230.173.249) 您好!臺灣時間:2021/04/21 03:54
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果

詳目顯示:::

我願授權國圖
: 
twitterline
研究生:韓政穎
研究生(外文):Cheng-Ying, Han
論文名稱:7,3''-O-二甲基橙皮素抗氣喘的作用
論文名稱(外文):Anti-asthmatic action of hesperetin-7,3''-O -dimethylether
指導教授:柯文昌柯文昌引用關係
指導教授(外文):Wun-Chang Ko
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:69
中文關鍵詞:氣喘磷酸二酯酶亞型四
外文關鍵詞:athmaphosphodieaterase 4ovalbuminairway hyperresponsiveness
相關次數:
  • 被引用被引用:0
  • 點閱點閱:84
  • 評分評分:系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
橙皮素 (hesperetin) 是一種選擇性phosphodiesterase-4 (PDE4) 的抑制劑,為了提高其抗氣喘效果,降低副作用,我們合成hesperetin的甲基化衍生物hesperetin-7-O-methylether (7-HME) 及 hesperetin-7,3''-O-dimethylether (HDME),7-HME對PDE4幾乎沒有抑制作用,但HDME有很強的抑制作用,其IC50為3.0 µM,HDME抑制PDE4的IC50比hesperetin-5,7,3''-O-trimethylether (HTME) 還要小,所以抗氣喘的效果有希望比HTME更好。
將雌性小白鼠 (BALB/c) 腹腔內注射卵蛋白 (ovalbumin, OVA),使其敏感化,再以氣化的卵蛋白二次激釁 (secondary challenge) 後,利用整體體積描述器來分析因methacholine (MCh) 所引起的氣道過度反應 (airway hyperresponsiveness; AHR)。本文實驗結果顯示, HDME (3~30 µmol/kg, p.o.) 可以劑量依存性地、有意義地減低由MCh (6.25~50 mg/ml) 所增加的enhanced pause (Penh) 值,也可以有意義地減少肺泡灌洗液 (BALF) 之總發炎細胞、巨噬細胞、淋巴球、嗜中性白血球、及嗜伊紅性白血球的數量及第二型輔助T細胞 (Th2 cells) 釋放的細胞介素 (cytokines),如interleukin (IL)-4、IL-5、tumor necrosis factor (TNF)-α的含量,雖也會減少第一型輔助T細胞 (Th1 cells)釋放IL-2。但是interferon (INF)-γ的含量不會減少,甚至於高劑量 (30 µmol/kg, p.o.) 時,反而會有意義地增加。HDME (3~30 µmol/kg, p.o.) 可以有意義地減少血清及肺泡灌洗液中total及OVA-specific IgE的含量,相反的會使血清中IgG2a劑量依存性地增加。此外,HDME 30 μM會有意義地鬆弛敏感化離體天竺鼠氣管的基本張力,HDME (3~30 μM) 也會有意義地抑制累加OVA (10~100 μg/ml) 引起的敏感化離體天竺鼠氣管的收縮。
根據Lineweaver-Burk的分析,HDME對PDE1、PDE3、及PDE4呈現競爭性的抑制,其Ki值分別為46.1、24.1及7.7 μM,雖然HDME對PDE3及PDE4的Ki值之間沒有意義差,但PDE4與PDE1的Ki值之間有意義差,暗示HDME對PDE4的親和力較好,HDME抑制 PDE1、PDE3、及PDE4活性的IC50分別為22.1、24.6及3.0 μM,也顯示對PDE4的抑制作用較強,亦即與PDE4的low affinity rolipram binding sites (LARBS)的結合能力較強,而且HDME取代[3H]-rolipram結合在敏感化天竺鼠全腦顆粒之high affinity rolipram binding sites (HARBS)的EC50為106.6 μM,所以HDME的PDE4H/PDE4L的比值為106.6/3 (約35.5),比HTME的PDE4H/PDE4L的比值 (18.2) 還高。由於HDME同時抑制PDE3,所以會加強其抗氣喘的作用。PDE4H/PDE4L的比值雖為目前公認用於評估PDE4選擇性抑制劑抗氣喘療效的方法,但畢竟是離體試驗的結果,本文獨創活體試驗的評估法,以減少25% xylazine/ketamine麻醉時間所需的劑量 (ADD25) ,除以抑制75% Penh値所需的劑量 (ID75),所得rolipram,Ro 20-1724及luteolin的比値非常接近它們PDE4H/PDE4L的比值,如表二所列,値得信賴,而HDME (10~100 μmol/kg, s.c.) 並不會有意義地縮短xylazine/ketamine引起的麻醉時間,所以推測其噁心及嘔吐之副作用頗低,顯示HDME極具抗氣喘的潛力。
結論,HDME競爭性且選擇性抑制PDE4及PDE3,而有支氣管擴張及抗發炎作用,但很少有不良反應,它的PDE4H/PDE4L 比值是35.5,是當今全世界最大者,顯示它具有治療氣喘的潛力。
To improve antiasthmatic and reduce adverse effects of hesperetin, a phosphodieasterase(PDE)-4 inhibitor, we synthesized hesperetin-7-O-methylether (7-HME) and hesperetin-7,3''-O-dimethylether (HDME). In the present results, HDME was highly effective in the inhibition of PDE4 activity with a IC50 value of 3.23 µM, but 7-HME almost had no effect on the PDE4 inhibition. The IC50 value of HDME is obviously smaller than that of hesperetin-5,7,3''-O-trimethylether (HTME) in the previouse report. Therefore, the anti-asthmatic effects of HDME may be better than those of HTME.
In the sensitized and OVA-secondarily challenged BALB/c mice, an asthmatic animal model, the airway hyperresponsiveness (AHR) was measured in unrestrained animals by barometric plethysmography using a whole-body plethysmograph after exposure of methacholine (MCh, 6.25~50 mg/ml) and enhanced pause (Penh) values were determined. In the present results, HDME (3~30 µmol/kg, p.o.) dose-dependently and significantly suppressed the enhancement of MCh (25~50 mg/ml)-induced Penh values. In the bronchoaveolar lavage fluid (BALF) of mice, it also significantly reduced the increase of total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils and significantly reduced the release of helper T cell subtype 2 (Th2) cytokines, such as interleukin(IL)-4, IL-5, and tumor necrosis fator(TNF)-α. In contrast, HDME at 30 µmol/kg (p.o.) significantly increased the release of interferon(INF)-γ, a Th1 cytokine, although it at dose ranged from 3 to 30 µmol/kg (p.o.) suppressed the release of IL-2, another Th1 cytokine. HDME (3~30 µmol/kg, p.o.) also significantly (P<0.05) reduced total and OVA-specific IgE in serum and BALF, but dose-dependently and significantly increased IgG2a in serum. In addition, HDME (30 µM) significantly relaxed the baseline tension, and in concentration ranged from 3 to 30 µM it also suppressed OVA (10~100 µg/ml)-induced contractions in isolated sensitized guinea pig trachealis.
According to the Lineweaver-Burk analysis, HDME competitively inhibited PDE1, PDE3, and PDE4 activities, with a Ki value of 46.1, 24.1, and 7.7 μM, respectively. Although the latter two values did not significantly differ from each other, the last one was significantly lower than the first one. It suggests that HDME has a higher affinity for PDE4. HDME concentration-dependently inhibited activities of PDE1, PDE3, and PDE4 with an IC50 value of 22.1, 24.6, and 3.0 μM, respectively. It also revealed to have the most potency in PDE4 inhibition, suggesting that its binding ability on low affinity rolipram binding sites (LARBS) of PDE4 is the greatest. HDME displaced [3H]-rolipram from high affinity rolipram binding sites (HARBS) of particulates of whole brains isolated from sensitized guinea pigs, with an EC50 value of 106.6 μM. Therefore, the PDE4H/PDE4L ratio of HDME was 106.6/3 (aproximately 35.3), which is greater than that of HTME (18.2). It is possibly due to its concomitant inhibition on PDE3, and potentiates its antiasthmatic effects. To evaluate the antiasthmatic effects of selective PDE4 inhibitor, the PDE4H/PDE4L ratio is recognized as the best method today. However, it eventually is a result from in vitro studies. In the present results, we first time reported an in vivo evaluating method, dose (ADD25) for reducing 25% of duration of anesthesia induced by xylazine/ketamine is divided by dose (ID75) for inhibiting 75% of enhanced pause value. The ADD25/ID75 ratios of rolipram, Ro 20-1724, and luteolin are similar to PDE4H/PDE4L ratios of these three compounds, as shown in Table 2. In the present results, HDME (10~100 μmol/kg, s.c.) did not significantly shorten duration of anathesia induced by xylazine/ketamine, therefore HDME may have little adverse effects, such as nausea and vomiting, although ID75 value of HDME was not determined.
In conclusion, HDME competitively and selectively inhibits PDE4/PDE3 and have bronchodilatory and anti-inflammatory effects with little adverse effect. The PDE4H/PDE4L ratio of HDME was 35.5, in the present result, and is the greastest nowadays in the world, suggesting HDME may have the potential for treating asthma.
標題…………………………………………………………1
圖表目錄……………………………………………………4
縮寫表………………………………………………………6
中文摘要……………………………………………………8
英文摘要……………………………………………………11
壹、緒論……………………………………………………15
貳、實驗材料與方法………………………………………23
參、結果……………………………………………………40
肆、討論……………………………………………………46
伍、參考文獻………………………………………………52
圖……………………………………………………………59
圖解…………………………………………………………81
表……………………………………………………………82
1. Joetham A, Takada K, Taube C, Miyahara N, Matsubara S, Koya T, Rha YH, Dakhama A, and Gelfand EW, Naturally occurring lung CD4(+)CD25(+) T cell regulation of airway allergic responses depends on IL-10 induction of TGF-beta. J. Immunol. 178: 1433-1442, 2007.
2. Corrigan CJ and Kay AB, The roles of inflammatory cells in the pathogenesis of asthma and of chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 143: 1165-1168, 1991.
3. Barnes PJ, Endogenous inhibitory mechanisms in asthma. Am. J. Respir. Crit Care Med. 161: S176-S181, 2000.
4. Herberth G, Daegelmann C, Weber A, Roder S, Giese T, Kramer U, Schins RP, Behrendt H, Borte M, and Lehmann I, Association of neuropeptides with Th1/Th2 balance and allergic sensitization in children. Clin. Exp. Allergy 36: 1408-1416, 2006.
5. Rupa P and Mine Y, Engineered recombinant ovomucoid third domain can desensitize Balb/c mice of egg allergy. Allergy 61: 836-842, 2006.
6. Zhang K, Accessibility control and machinery of immunoglobulin class switch recombination. J. Leukoc. Biol. 73: 323-332, 2003.
7. Erwin EA, Ronmark E, Wickens K, Perzanowski MS, Barry D, Lundback B, Crane J, and Platts-Mills TA, Contribution of dust mite and cat specific IgE to total IgE: relevance to asthma prevalence. J. Allergy Clin. Immunol. 119: 359-365, 2007.
8. Randolph DA, Carruthers CJ, Szabo SJ, Murphy KM, and Chaplin DD, Modulation of airway inflammation by passive transfer of allergen-specific Th1 and Th2 cells in a mouse model of asthma. J. Immunol. 162: 2375-2383, 1999.
9. Blanco P, Palucka AK, Gill M, Pascual V, and Banchereau J, Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science 294: 1540-1543, 2001.
10. Cookson WO and Moffatt MF, Asthma: an epidemic in the absence of infection? Science 275: 41-42, 1997.
11. von ME, Environmental factors influencing the development and progression of pediatric asthma. J. Allergy Clin.Immunol. 109: S525-S532, 2002.
12. Hammad H and Lambrecht BN, Recent progress in the biology of airway dendritic cells and implications for understanding the regulation of asthmatic inflammation. J. Allergy Clin. Immunol. 118: 331-336, 2006.
13. Coffman RL, Ohara J, Bond MW, Carty J, Zlotnik A, and Paul WE, B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide-activated B cells. J. Immunol. 136: 4538-4541, 1986.
14. Schleimer RP, Sterbinsky SA, Kaiser J, Bickel CA, Klunk DA, Tomioka K, Newman W, Luscinskas FW, Gimbrone MA, Jr., McIntyre BW, and Bochner BS, IL-4 induces adherence of human eosinophils and basophils but not neutrophils to endothelium. Association with expression of VCAM-1. J. Immunol. 148: 1086-1092, 1992.
15. Turner H and Kinet JP, Signalling through the high-affinity IgE receptor Fc epsilonRI. Nature 402: B24-B30, 1999.
16. Garlisi CG, Falcone A, Hey JA, Paster TM, Fernandez X, Rizzo CA, Minnicozzi M, Jones H, Billah MM, Egan RW, and Umland SP, Airway eosinophils, T cells, Th2-type cytokine mRNA, and hyperreactivity in response to aerosol challenge of allergic mice with previously established pulmonary inflammation. Am. J. Respir. Cell Mol. Biol. 17: 642-651, 1997.
17. Busse WW and Sedgwick JB, Eosinophils in asthma. Ann. Allergy 68: 286-290, 1992.
18. Robinson DS, Durham SR, and Kay AB, Cytokines. 3. Cytokines in asthma. Thorax 48: 845-853, 1993.
19. Sanderson CJ, Interleukin-5, eosinophils, and disease. Blood 79: 3101-3109, 1992.
20. Williams TJ, The eosinophil enigma. J. Clin. Invest 113: 507-509, 2004.
21. Alam R and Busse WW, The eosinophil--quo vadis? J. Allergy Clin. Immunol. 113: 38-42, 2004.
22. Kuna P, [Longterm effects of steroid therapy]. Wiad. Lek. 51 Suppl 1: 12-18, 1998.
23. Actis GC, Bugianesi E, Ottobrelli A, and Rizzetto M, Fatal liver failure following food supplements during chronic treatment with montelukast. Dig. Liver Dis. 2006 (in press).
24. Su CW, Wu JC, Huang YH, Huang YS, Chang FY, and Lee SD, Zafirlukast-induced acute hepatitis. Zhonghua Yi. Xue. Za Zhi. (Taipei) 65: 553-556, 2002.
25. Beavo JA, Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol. Rev. 75: 725-748, 1995.
26. Conti M and Jin SL, The molecular biology of cyclic nucleotide phosphodiesterases. Prog. Nucleic Acid Res. Mol. Biol. 63: 1-38, 1999.
27. Nicholson CD and Shahid M, Inhibitors of cyclic nucleotide phosphodiesterase isoenzymes--their potential utility in the therapy of asthma. Pulm. Pharmacol. 7: 1-17, 1994.
28. Nicholson CD, Challiss RA, and Shahid M, Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. Trends Pharmacol. Sci. 12: 19-27, 1991.
29. Essayan DM, Cyclic nucleotide phosphodiesterases. J. Allergy Clin. Immunol. 108: 671-680, 2001.
30. Christie P, Roflumilast: a selective phosphodiesterase 4 inhibitor . Drugs Today (Barc.) 41: 667-675, 2005.
31. Martin C, Goggel R, Dal P, V, Vergelli C, Giovannoni P, Ernst M, and Uhlig S, Airway relaxant and anti-inflammatory properties of a PDE4 inhibitor with low affinity for the high-affinity rolipram binding site. Naunyn Schmiedebergs Arch. Pharmacol. 365: 284-289, 2002.
32. Duplantier AJ, Biggers MS, Chambers RJ, Cheng JB, Cooper K, Damon DB, Eggler JF, Kraus KG, Marfat A, Masamune H, Pillar JS, Shirley JT, Umland JP, and Watson JW, Biarylcarboxylic acids and -amides: inhibition of phosphodiesterase type IV versus [3H]rolipram binding activity and their relationship to emetic behavior in the ferret. J. Med. Chem. 39: 120-125, 1996.
33. Giembycz MA, Phosphodiesterase 4 and tolerance to beta 2-adrenoceptor agonists in asthma. Trends Pharmacol. Sci. 17: 331-336, 1996.
34. Manning CD, Burman M, Christensen SB, Cieslinski LB, Essayan DM, Grous M, Torphy TJ, and Barnette MS, Suppression of human inflammatory cell function by subtype-selective PDE4 inhibitors correlates with inhibition of PDE4A and PDE4B. Br. J. Pharmacol. 128: 1393-1398, 1999.
35. Nielson CP, Vestal RE, Sturm RJ, and Heaslip R, Effects of selective phosphodiesterase inhibitors on the polymorphonuclear leukocyte respiratory burst. J. Allergy Clin. Immunol. 86: 801-808, 1990.
36. Schneider HH, Schmiechen R, Brezinski M, and Seidler J, Stereospecific binding of the antidepressant rolipram to brain protein structures. Eur. J. Pharmacol. 127: 105-115, 1986.
37. Zhao Y, Zhang HT, and O''Donnell JM, Inhibitor binding to type 4 phosphodiesterase (PDE4) assessed using [3H]piclamilast and [3H]rolipram. J. Pharmacol. Exp. Ther. 305: 565-572, 2003.
38. Hatzelmann A and Schudt C, Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J. Pharmacol. Exp. Ther. 297: 267-279, 2001.
39. Draheim R, Egerland U, and Rundfeldt C, Anti-inflammatory potential of the selective phosphodiesterase 4 inhibitor N-(3,5-dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-gly oxylic acid amide (AWD 12-281), in human cell preparations. J. Pharmacol. Exp. Ther. 308: 555-563, 2004.
40. Robichaud A, Savoie C, Stamatiou PB, Tattersall FD, and Chan CC, PDE4 inhibitors induce emesis in ferrets via a noradrenergic pathway. Neuropharmacology 40: 262-269, 2001.
41. Robichaud A, Tattersall FD, Choudhury I, and Rodger IW, Emesis induced by inhibitors of type IV cyclic nucleotide phosphodiesterase (PDE IV) in the ferret. Neuropharmacology 38: 289-297, 1999.
42. Robichaud A, Savoie C, Stamatiou PB, Lachance N, Jolicoeur P, Rasori R, and Chan CC, Assessing the emetic potential of PDE4 inhibitors in rats. Br. J. Pharmacol. 135: 113-118, 2002.
43. Robichaud A, Stamatiou PB, Jin SL, Lachance N, MacDonald D, Laliberte F, Liu S, Huang Z, Conti M, and Chan CC, Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J. Clin. Invest 110: 1045-1052, 2002.
44. Ko WC, Shih CM, Lai YH, Chen JH, and Huang HL, Inhibitory effects of flavonoids on phosphodiesterase isozymes from guinea pig and their structure-activity relationships. Biochem. Pharmacol. 68: 2087-2094, 2004.
45. Furniss BS, Hannaford A. J., Smith P. W. G., and Tatchell A. K. Preparation of diazomethane, In Vogel''s Textbook of Practical Organic Chemistry. [5th], Longman Scientific and Technical with John Wiley & Sons, New York p. 432-433, 2007.
46. Ko WC, Chen MC, Wang SH, Lai YH, Chen JH, and Lin CN, 3-O-methylquercetin more selectively inhibits phosphodiesterase subtype 3. Planta Med. 69: 310-315, 2003.
47. Thompson WJ and Appleman MM, Multiple cyclic nucleotide phosphodiesterase activities from rat brain. Biochemistry 10: 311-316, 1971.
48. Ahn HS, Crim W, Romano M, Sybertz E, and Pitts B, Effects of selective inhibitors on cyclic nucleotide phosphodiesterases of rabbit aorta. Biochem. Pharmacol. 38: 3331-3339, 1989.
49. Podzuweit T, Nennstiel P, and Muller A, Isozyme selective inhibition of cGMP-stimulated cyclic nucleotide phosphodiesterases by erythro-9-(2-hydroxy-3-nonyl) adenine. Cell Signal. 7: 733-738, 1995.
50. Harrison SA, Reifsnyder DH, Gallis B, Cadd GG, and Beavo JA, Isolation and characterization of bovine cardiac muscle cGMP-inhibited phosphodiesterase: a receptor for new cardiotonic drugs. Mol. Pharmacol. 29: 506-514, 1986.
51. Reeves ML, Leigh BK, and England PJ, The identification of a new cyclic nucleotide phosphodiesterase activity in human and guinea-pig cardiac ventricle. Implications for the mechanism of action of selective phosphodiesterase inhibitors. Biochem. J. 241: 535-541, 1987.
52. Gillespie PG and Beavo JA, Inhibition and stimulation of photoreceptor phosphodiesterases by dipyridamole and M&B 22,948. Mol. Pharmacol. 36: 773-781, 1989.
53. Bradford MM, A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72: 248-254, 1976.
54. Kanehiro A, Ikemura T, Makela MJ, Lahn M, Joetham A, Dakhama A, and Gelfand EW, Inhibition of phosphodiesterase 4 attenuates airway hyperresponsiveness and airway inflammation in a model of secondary allergen challenge. Am. J. Respir. Crit Care Med. 163: 173-184, 2001.
55. Hamelmann E, Schwarze J, Takeda K, Oshiba A, Larsen GL, Irvin CG, and Gelfand EW, Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am. J. Respir. Crit Care Med. 156: 766-775, 1997.
56. Cho YS, Kwon B, Lee TH, Kim TB, Moon KA, La S, Lee J, Lee SD, Oh YM, and Moon HB, 4-1 BB stimulation inhibits allergen-specific immunoglobulin E production and airway hyper-reactivity but partially suppresses bronchial eosinophilic inflammation in a mouse asthma model. Clin. Exp. Allergy 36: 377-385, 2006.
57. Underwood DC, Kotzer CJ, Bochnowicz S, Osborn RR, Luttmann MA, Hay DW, and Torphy TJ, Comparison of phosphodiesterase III, IV and dual III/IV inhibitors on bronchospasm and pulmonary eosinophil influx in guinea pigs. J. Pharmacol. Exp. Ther. 270: 250-259, 1994.
58. Miles CO and Main L. Kinetics and Mechanism of the Cyclisation of 2'',6''-Dihydroychalcone and derivatives. J. Chem. Soc. Perkin Trans. II, 1623-1632. 1989.
59. Townley RG and Horiba M, Airway hyperresponsiveness: a story of mice and men and cytokines. Clin. Rev. Allergy Immunol. 24: 85-110, 2003.
60. Moore AR and Willoughby DA, The role of cAMP regulation in controlling inflammation. Clin. Exp. Immunol. 101: 387-389, 1995.
61. Kammer GM, The adenylate cyclase-cAMP-protein kinase A pathway and regulation of the immune response. Immunol. Today 9: 222-229, 1988.
62. Kuehl FA, Jr., Zanetti ME, Soderman DD, Miller DK, and Ham EA, Cyclic AMP-dependent regulation of lipid mediators in white cells. A unifying concept for explaining the efficacy of theophylline in asthma. Am. Rev. Respir. Dis. 136: 210-213, 1987.
63. Dent G, Giembycz MA, Evans PM, Rabe KF, and Barnes PJ, Suppression of human eosinophil respiratory burst and cyclic AMP hydrolysis by inhibitors of type IV phosphodiesterase: interaction with the beta adrenoceptor agonist albuterol. J. Pharmacol. Exp. Ther. 271(3): 1167-74, 1994
64. Tenor H, Staniciu L, Schudt C, Hatzelmann A, Wendel A, Djukanovic R, Church MK, and Shute JK, Cyclic nucleotide phosphodiesterases from purified human CD4+ and CD8+ T lymphocytes. Clin. Exp. Allergy. 25 (7): 616-24, 1995.
65. Robicsek SA, Blanchard DK, Djeu JY, Krzanowski JJ, Szentivanyi A, and Polson JB, Multiple high-affinity cAMP-phosphodiesterases in human T-lymphocytes. Biochem. Pharmacol. 42: 869-877, 1991.
66. Barnette MS, Bartus JO, Burman M, Christensen SB, Cieslinski LB, Esser KM, Prabhakar US, Rush JA, and Torphy TJ, Association of the anti-inflammatory activity of phosphodiesterase 4 (PDE4) inhibitors with either inhibition of PDE4 catalytic activity or competition for [3H]rolipram binding. Biochem. Pharmacol. 51: 949-956, 1996.
67. Giembycz MA, Corrigan CJ, Seybold J, Newton R, and Barnes PJ, Identification of cyclic AMP phosphodiesterases 3, 4 and 7 in human CD4+ and CD8+ T-lymphocytes: role in regulating proliferation and the biosynthesis of interleukin-2. Br. J. Pharmacol. 118: 1945-1958, 1996.
68. Kroegel C and Foerster M, Phosphodiesterase-4 inhibitors as a novel approach for the treatment of respiratory disease: cilomilast. Expert. Opin. Investig. Drugs 16: 109-124, 2007.
69. Boswell-Smith V, Spina D, Oxford AW, Comer MB, Seeds EA, and Page CP, The Pharmacology of Two Novel Long-Acting Phosphodiesterase 3/4 Inhibitors, RPL554 [9,10-Dimethoxy-2(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl) -3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-Dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]i soquinolin-4-one]. J. Pharmacol. Exp. Ther. 318: 840-848, 2006.
70. Manabe H, Akuta K, Sejimo H, Kawasaki H, Nukui E, Ichimura M, Kase H, Kawakita T, Suzuki F, Kitamura S, Sato S, and Ohmori K, Anti-inflammatory and bronchodilator properties of KF19514, a phosphodiesterase 4 and 1 inhibitor. Eur. J. Pharmacol. 332: 97-107, 1997.
71. Howell RE, Sickels BD, and Woeppel SL, Pulmonary antiallergic and bronchodilator effects of isozyme-selective phosphodiesterase inhibitors in guinea pigs. J. Pharmacol. Exp. Ther. 264: 609-615, 1993.
72. Underwood DC, Osborn RR, Novak LB, Matthews JK, Newsholme SJ, Undem BJ, Hand JM, and Torphy TJ, Inhibition of antigen-induced bronchoconstriction and eosinophil infiltration in the guinea pig by the cyclic AMP-specific phosphodiesterase inhibitor, rolipram. J. Pharmacol. Exp. Ther. 266: 306-313, 1993.
73. Giembycz MA, Phosphodiesterase 4 inhibitors and the treatment of asthma: where are we now and where do we go from here? Drugs 59: 193-212, 2000.
74. Kim E, Chun HO, Jung SH, Kim JH, Lee JM, Suh BC, Xiang MX, and Rhee CK, Improvement of therapeutic index of phosphodiesterase type IV inhibitors as anti-Asthmatics. Bioorg. Med. Chem. Lett. 13: 2355-2358, 2003.
75. Compton CH, Gubb J, Nieman R, Edelson J, Amit O, Bakst A, Ayres JG, Creemers JP, Schultze-Werninghaus G, Brambilla C, and Barnes NC, Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study. Lancet 358: 265-270, 2001.
76. Correa-Sales C, Nacif-Coelho C, Reid K, and Maze M, Inhibition of adenylate cyclase in the locus coeruleus mediates the hypnotic response to an alpha 2 agonist in the rat. J. Pharmacol. Exp. Ther. 263: 1046-1049, 1992.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
系統版面圖檔 系統版面圖檔