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  查詢北醫館藏
系統識別號 U0007-2107201116492400
論文名稱(中文) 海洋性貧血患者之地拉羅司療劑監測方法與應用
論文名稱(英文) Development of Analytical Methods for the Therapeutic Drug Monitoring of Deferasirox in Thalassemia Patients
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 99
學期 2
出版年 100
研究生(中文) 吳文馨
研究生(英文) Wen-Hsin Wu
學號 M301098028
學位類別 碩士
語文別 中文
口試日期 2011-06-27
論文頁數 87頁
口試委員 委員-林凱信
委員-許秀蘊
委員-何秀娥
委員-鮑力恆
指導教授-吳姿樺
中文關鍵字 地拉羅司  療劑監測  海洋性貧血  個體差異 
英文關鍵字 deferasirox  therapeutic drug monitoring  β-thalassemia  intra-individual variations 
學科別分類
中文摘要 重度β-海洋性貧血病患因需要長期輸血而使其患者需要服用鐵螯合劑以避免產生因輸血所導致之鐵質過度負荷併發症。現今鐵螯合劑的研發已進展到只需每日口服一次的地拉羅司 (deferasirox,DEFR)。本研究欲建立有效之藥物分析系統,來分析接受DEFR治療之重度β-海洋性貧血病患之藥物 (含DEFR、Fe–[DEFR]2) 之血中濃度,以期釐清病患鐵質負荷之藥物治療相關問題。研究方法: (一) 以高效液相層析儀搭配紫外光/可見光檢測器,並使用長度15 cm 的C18層析管柱同時分析DEFR與及其三價鐵複合物Fe–[DEFR]2;(二) 本研究收錄已穩定接受DEFR治療的重度海洋性貧血患者 (n=23) 之每月常規的血清鐵蛋白 (serum ferritin,SF) 檢查值,並在本療劑監測試驗時進行服藥前藥物血中濃度(Ctrough)、服藥後2小時之藥物血中濃度 (C2h) 取樣分析;同時利用經詢問病患在接受取樣前五天所得知服藥情形來進行藥物血中濃度與各因子間之相關性探討。研究結果: (一) 本研究所建立之DEFR、Fe–[DEFR]2含內部標準品檢量線以及經固相萃取血漿檢品分析檢量線皆具顯著線性關係,各精密度與準確度亦達規定標準。(二) 將本研究所建立之分析系統應用於病患血漿檢品分析,結果: 依照所給予病患之每公斤劑量之組別來比較各組的C2h-DEFR,結果顯示40 mg/kg組分別高於10 mg/kg、25 mg/kg、30 mg/kg且具顯著差異 (p<0.05)。將藥物血中濃度以測得濃度除以服用每日總劑量(C/D)來表示,所有病患(n=23)之 C2h/D(DEFR+Fe–[DEFR]2) 平均值為22.37±14.28 μmole/L/g (4.91~56.92),呈現個體間差異;但C2h-DEFR、C2h-Fe–[DEFR]2、服藥2小時後總藥物濃度(C2h-DEFR+C2h-Fe–[DEFR]2) 分別與病患所服用的DEFR總毫克劑量具顯著關聯性 (p<0.05)。已完成用藥紀錄之病患(n=10)平均Ctrough/D(DEFR+Fe–[DEFR]2)為12.30 ±10.04 μmole/L/g (3.59~31.68);而 SF檢查值小於1000 μg/L的病患(n=4),其服藥前Ctrough/D(DEFR+Fe–[DEFR]2)與服藥後C2h/D(DEFR+Fe–[DEFR]2)之比值與其停藥時間相除皆有達到0.02 μmole/L/g/h。結論: 本研究所建立之DEFR與Fe–[DEFR]2分析方法應用於病患血漿檢品分析可釐清重度β-海洋性貧血病患之DEFR療效問題;未來仍需更一步的研究以釐清病患個體間影響血中濃度之相關因子。
英文摘要 Iron chelation therapy is essential for transfusion-dependent of β-thalassemia major patients, who inevitably develop iron overload complications. In order to improve the patients’ quality of life, once daily oral chelator, deferasirox (DEFR) has been available clinically. We aimed to developed an high-performance liquid chromatography (HPLC) analytical methods for DEFR and Fe–[DEFR]2 in order to apply for therapeutic drug monitoring (TDM) of β-thalassemia major patients and to clarify the DEFR–related problems. Methods : (I) a HPLC coupled with an UV/VIS detector was set up to determine the DEFR and Fe–[DEFR]2 on C18 column;(II) 23 patients with β-thalassemia major receiving DEFR treatment have been recruited and their regular monthly serum ferritin (SF) data was collected. During the trials, blood samples taken right before (trough) and also at 2 hours (2h) after the DEFR administration were subjected for concentration determinations. The correlations between (Ctrough) or C2h and other parameters were analyzed. Results: The concentrations of DEFR, Fe-[DEFR]2 standards, internal standard and peak areas were significantly linear correlated, respectively. The analysis of precision and accuracy following solid-phase extraction met the requirements. (II) The C2h-DEFR of patients given 40 mg/kg were significantly higher than the ones from the other dosing groups (10 mg/kg, 25 mg/kg and 30 mg/kg) (p< 0.05). Drug concentrations normalized by body weight (C/D) were expressed as detected concentrations divided by daily DEFR (mg). Mean C2h/D(DEFR+Fe–[DEFR]2) of all patients (n=23) was 22.37 ± 14.28 μmole/L/g (4.91~56.92) suggesting intra-individual variations. However, C2h-DEFR, C2h-Fe–[DEFR]2 and C2h-DEFR+C2h-Fe–[DEFR]2 were significantly correlated with their daily dose (p< 0.05), respectively. Mean Ctrough/D(DEFR+Fe–[DEFR]2) of patients with completed drug utilization records (n=10) was 12.30 ± 10.04 μmole/L/g (3.59~31.68). The least ratio of Ctrough/D(DEFR+Fe–[DEFR]2) and C2h/D(DEFR+Fe–[DEFR]2) of the patients whose SF value below 1000 μg/L (n=4) divided by the withdrawal time was 0.02 μmole/L/g/h among the patients. Conclusion: Currently established analysis system of DEFR and Fe-[DEFR]2 applied for TDM in patients with β-thalassemia major can be utilized to clarify DEFR-related problems. Further studies are warranted to determine the minimum required drug concentrations to obtain effective therapeutic outcomes of DEFR in iron overlaod management.
論文目次 目錄 I
中文摘要 III
Abstract IV
表目錄 V
圖目錄 VI
附錄目錄 VII
第一節 鐵質 2
第一項、鐵質恆定 2
第二項、鐵質代謝異常 4
第二節 海洋性貧血 6
第一項、血紅素之遺傳性缺陷 6
第二項、海洋性貧血之流行病學 7
第三項、β-海洋性貧血 8
第四項、鐵質過度負荷之併發症 11
第五項、鐵螯合治療 14
第六項、鐵螯合劑分析方法學 18
第三節 研究動機與目的 20
第二章 研究材料與方法 21
第一節 藥品材料與儀器設備 22
第一項、藥品試劑 22
第二項、儀器設備 23
第三項、分析材料 24
第四項、分析溶劑 24
第二節 鐵螯合劑地拉羅司血漿檢品分析方法之建立 25
第一項、高效液相層析儀與紫外光/可見光檢測器之分析條件 25
第二項、地拉羅司及其複合物之標準品與內部標準品溶液配製步驟 25
第三項、血漿檢品萃取 26
第四項、分析方法之確效 27
第三節 地拉羅司及其複合物之病患療劑監測研究 29
第一項、研究藥品來源與研究對象條件 29
第二項、試驗設計及進行方式 29
第三項、血漿檢品分析條件與資料分析 31
第三章 研究結果 32
第一節 鐵螯合劑地拉羅司血漿檢品分析方法之確效與應用 33
第一項、分析方法之確效 33
第二節 地拉羅司及其複合物之病患療劑監測研究 35
第一項、病患服藥後待測藥物血中濃度與劑量之相關性 35
第二項、病患服藥前待測藥物血中濃度與血清鐵蛋白值之相關性 36
第四章 討論 37
第一節 鐵螯合劑地拉羅司血漿檢品分析方法之確效與應用 38
第一項、分析條件之探討 38
第二項、分析方法之確效探討 40
第三項、血漿檢品萃取步驟的探討 40
第二節 地拉羅司及其複合物之病患療劑監測研究 43
第一項、病患服藥後待測藥物血中濃度與劑量之相關性 43
第二項、病患服藥前待測藥物血中濃度與血清鐵蛋白值之相關性 43
第五章 結論與展望 45
第六章 圖表與附錄說明 49
參考文獻 81

參考文獻 1. Andrews NC. Disorders of iron metabolism. N Engl J Med. Dec 23 1999;341(26):1986-1995.
2. Munoz M, Garcia-Erce JA, Remacha AF. Disorders of iron metabolism. Part 1: molecular basis of iron homoeostasis. J Clin Pathol. Dec 20 2010.
3. Rich GB. Article reviewed: Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Sleep Med. Oct 1 2000;1(4):325-326.
4. Knovich MA, Storey JA, Coffman LG, Torti SV, Torti FM. Ferritin for the clinician. Blood Rev. May 2009;23(3):95-104.
5. Jacobs A, Beamish MR, Allison M. The measurement of circulating ferritin. J Clin Pathol. Nov 1972;25(11):1003.
6. Kohgo Y, Ikuta K, Ohtake T, Torimoto Y, Kato J. Body iron metabolism and pathophysiology of iron overload. Int J Hematol. Jul 2008;88(1):7-15.
7. Huebers HA, Finch CA. The physiology of transferrin and transferrin receptors. Physiol Rev. Apr 1987;67(2):520-582.
8. Miret S, Simpson RJ, McKie AT. Physiology and molecular biology of dietary iron absorption. Annu Rev Nutr. 2003;23:283-301.
9. Pietrangelo A. Hereditary hemochromatosis--a new look at an old disease. N Engl J Med. Jun 3 2004;350(23):2383-2397.
10. Nojilana B, Norman R, Dhansay MA, Labadarios D, van Stuijvenberg ME, Bradshaw D. Estimating the burden of disease attributable to iron deficiency anaemia in South Africa in 2000. S Afr Med J. Aug 2007;97(8 Pt 2):741-746.
11. Munoz M, Garcia-Erce JA, Remacha AF. Disorders of iron metabolism. Part II: iron deficiency and iron overload. J Clin Pathol. Dec 20 2010.
12. Beutler E, Hoffbrand AV, Cook JD. Iron deficiency and overload. Hematology Am Soc Hematol Educ Program. 2003:40-61.
13. Beutler E. Iron storage disease: facts, fiction and progress. Blood Cells Mol Dis. Sep-Oct 2007;39(2):140-147.
14. Yen AW, Fancher TL, Bowlus CL. Revisiting hereditary hemochromatosis: current concepts and progress. Am J Med. May 2006;119(5):391-399.
15. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. Aug 1996;13(4):399-408.
16. Franchini M. Hereditary iron overload: update on pathophysiology, diagnosis, and treatment. Am J Hematol. Mar 2006;81(3):202-209.
17. Gordeuk V, Mukiibi J, Hasstedt SJ, et al. Iron overload in Africa. Interaction between a gene and dietary iron content. N Engl J Med. Jan 9 1992;326(2):95-100.
18. Belcher JD, Beckman JD, Balla G, Balla J, Vercellotti G. Heme degradation and vascular injury. Antioxid Redox Signal. Feb 2010;12(2):233-248.
19. Manca L, Masala B. Disorders of the synthesis of human fetal hemoglobin. IUBMB Life. Feb 2008;60(2):94-111.
20. Stamatoyannopoulos G. Control of globin gene expression during development and erythroid differentiation. Exp Hematol. Mar 2005;33(3):259-271.
21. Old JM. Screening and genetic diagnosis of haemoglobinopathies. Scand J Clin Lab Invest. 2007;67(1):71-86.
22. Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ. Jun 2008;86(6):480-487.
23. Angastiniotis M, Modell B. Global epidemiology of hemoglobin disorders. Ann N Y Acad Sci. Jun 30 1998;850:251-269.
24. Rund D, Rachmilewitz E. Beta-thalassemia. N Engl J Med. Sep 15 2005;353(11):1135-1146.
25. Vichinsky EP. Changing patterns of thalassemia worldwide. Ann N Y Acad Sci. 2005;1054:18-24.
26. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010;5:11.
27. Weatherall DJ. Genetic variation and susceptibility to infection: the red cell and malaria. Br J Haematol. May 2008;141(3):276-286.
28. Cao A, Galanello R. Beta-thalassemia. Genet Med. Feb 2010;12(2):61-76.
29. Flint J, Harding RM, Boyce AJ, Clegg JB. The population genetics of the haemoglobinopathies. Baillieres Clin Haematol. Mar 1998;11(1):1-51.
30. Muncie HL, Jr., Campbell J. Alpha and beta thalassemia. Am Fam Physician. Aug 15 2009;80(4):339-344.
31. Thein SL. Pathophysiology of beta thalassemia--a guide to molecular therapies. Hematology Am Soc Hematol Educ Program. 2005:31-37.
32. Pootrakul P, Sirankapracha P, Hemsorach S, et al. A correlation of erythrokinetics, ineffective erythropoiesis, and erythroid precursor apoptosis in thai patients with thalassemia. Blood. Oct 1 2000;96(7):2606-2612.
33. Dhaliwal G, Cornett PA, Tierney LM, Jr. Hemolytic anemia. Am Fam Physician. Jun 1 2004;69(11):2599-2606.
34. Thein SL. Dominant beta thalassaemia: molecular basis and pathophysiology. Br J Haematol. Mar 1992;80(3):273-277.
35. Voskaridou E, Terpos E. New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia. Br J Haematol. Oct 2004;127(2):127-139.
36. Dubey AP, Parakh A, Dublish S. Current trends in the management of beta thalassemia. Indian J Pediatr. Jul 2008;75(7):739-743.
37. Santiago M. Thalassemia trait: what every NP should know. Nurse Pract. Dec 2009;34(12):14-21; quiz 21-12.
38. Kwiatkowski JL. Oral iron chelators. Hematol Oncol Clin North Am. Feb 2010;24(1):229-248.
39. Cabantchik ZI, Breuer W, Zanninelli G, Cianciulli P. LPI-labile plasma iron in iron overload. Best Pract Res Clin Haematol. Jun 2005;18(2):277-287.
40. Trinder D, Fox C, Vautier G, Olynyk JK. Molecular pathogenesis of iron overload. Gut. Aug 2002;51(2):290-295.
41. Breuer W, Hershko C, Cabantchik ZI. The importance of non-transferrin bound iron in disorders of iron metabolism. Transfus Sci. Dec 2000;23(3):185-192.
42. Crichton RR, Wilmet S, Legssyer R, Ward RJ. Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells. J Inorg Biochem. Jul 25 2002;91(1):9-18.
43. Fibach E, Rachmilewitz EA. The role of antioxidants and iron chelators in the treatment of oxidative stress in thalassemia. Ann N Y Acad Sci. Aug 2010;1202:10-16.
44. Agarwal MB. Deferasirox: oral, once daily iron chelator--an expert opinion. Indian J Pediatr. Feb 2010;77(2):185-191.
45. Olivieri NF. Progression of iron overload in sickle cell disease. Semin Hematol. Jan 2001;38(1 Suppl 1):57-62.
46. Borgna-Pignatti C, De Stefano P, Zonta L, et al. Growth and sexual maturation in thalassemia major. J Pediatr. Jan 1985;106(1):150-155.
47. Cunningham MJ, Macklin EA, Neufeld EJ, Cohen AR. Complications of beta-thalassemia major in North America. Blood. Jul 1 2004;104(1):34-39.
48. Zurlo MG, De Stefano P, Borgna-Pignatti C, et al. Survival and causes of death in thalassaemia major. Lancet. Jul 1 1989;2(8653):27-30.
49. Cappellini MD, Taher A. Deferasirox (Exjade) for the treatment of iron overload. Acta Haematol. 2009;122(2-3):165-173.
50. Telfer P. Update on survival in thalassemia major. Hemoglobin. 2009;33 Suppl 1:S76-80.
51. Kowdley KV, Kaplan MM. Iron-chelation therapy with oral deferiprone--toxicity or lack of efficacy? N Engl J Med. Aug 13 1998;339(7):468-469.
52. Hershko C. Treating iron overload: the state of the art. Semin Hematol. Apr 2005;42(2 Suppl 1):S2-4.
53. Neufeld EJ. Update on iron chelators in thalassemia. Hematology Am Soc Hematol Educ Program. 2010;2010:451-455.
54. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood. Feb 1 1997;89(3):739-761.
55. Barry M, Flynn DM, Letsky EA, Risdon RA. Long-term chelation therapy in thalassaemia major: effect on liver iron concentration, liver histology, and clinical progress. Br Med J. Apr 6 1974;2(5909):16-20.
56. Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med. Sep 1 1994;331(9):567-573.
57. Lee P, Mohammed N, Marshall L, et al. Intravenous infusion pharmacokinetics of desferrioxamine in thalassaemic patients. Drug Metab Dispos. Jul-Aug 1993;21(4):640-644.
58. Ceci A, Baiardi P, Catapano M, et al. Risk factors for death in patients with beta-thalassemia major: results of a case-control study. Haematologica. Oct 2006;91(10):1420-1421.
59. Hider RC, Singh S, Porter JB, Huehns ER. The development of hydroxypyridin-4-ones as orally active iron chelators. Ann N Y Acad Sci. 1990;612:327-338.
60. Olivieri NF, Brittenham GM, McLaren CE, et al. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N Engl J Med. Aug 13 1998;339(7):417-423.
61. Anderson LJ, Wonke B, Prescott E, Holden S, Walker JM, Pennell DJ. Comparison of effects of oral deferiprone and subcutaneous desferrioxamine on myocardial iron concentrations and ventricular function in beta-thalassaemia. Lancet. Aug 17 2002;360(9332):516-520.
62. Daar S, Pathare AV. Combined therapy with desferrioxamine and deferiprone in beta thalassemia major patients with transfusional iron overload. Ann Hematol. May 2006;85(5):315-319.
63. Wonke B, Wright C, Hoffbrand AV. Combined therapy with deferiprone and desferrioxamine. Br J Haematol. Nov 1998;103(2):361-364.
64. Ceci A, Baiardi P, Felisi M, et al. The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients. Br J Haematol. Jul 2002;118(1):330-336.
65. Stumpf JL. Deferasirox. Am J Health Syst Pharm. Mar 15 2007;64(6):606-616.
66. Barton JC. Deferasirox Novartis. Curr Opin Investig Drugs. Mar 2005;6(3):327-335.
67. Nisbet-Brown E, Olivieri NF, Giardina PJ, et al. Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. May 10 2003;361(9369):1597-1602.
68. Galanello R, Piga A, Alberti D, Rouan MC, Bigler H, Sechaud R. Safety, tolerability, and pharmacokinetics of ICL670, a new orally active iron-chelating agent in patients with transfusion-dependent iron overload due to beta-thalassemia. J Clin Pharmacol. Jun 2003;43(6):565-572.
69. Weiss HM, Fresneau M, Camenisch GP, Kretz O, Gross G. In vitro blood distribution and plasma protein binding of the iron chelator deferasirox (ICL670) and its iron complex Fe-[ICL670]2 for rat, marmoset, rabbit, mouse, dog, and human. Drug Metab Dispos. Jun 2006;34(6):971-975.
70. Waldmeier F, Bruin GJ, Glaenzel U, et al. Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalassemic patients with transfusion-dependent iron overload who are at pharmacokinetic steady state. Drug Metab Dispos. May 2010;38(5):808-816.
71. Piga A, Galanello R, Forni GL, et al. Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haematologica. Jul 2006;91(7):873-880.
72. Sechaud R, Robeva A, Belleli R, Balez S. Absolute oral bioavailability and disposition of deferasirox in healthy human subjects. J Clin Pharmacol. Aug 2008;48(8):919-925.
73. Cappellini MD, Taher A. Long-term experience with deferasirox (ICL670), a once-daily oral iron chelator, in the treatment of transfusional iron overload. Expert Opin Pharmacother. Sep 2008;9(13):2391-2402.
74. Cappellini MD. Long-term efficacy and safety of deferasirox. Blood Rev. Dec 2008;22 Suppl 2:S35-41.
75. Taher A, El-Beshlawy A, Elalfy MS, et al. Efficacy and safety of deferasirox, an oral iron chelator, in heavily iron-overloaded patients with beta-thalassaemia: the ESCALATOR study. Eur J Haematol. Jun 2009;82(6):458-465.
76. Porter JB. Optimizing iron chelation strategies in beta-thalassaemia major. Blood Rev. Dec 2009;23 Suppl 1:S3-7.
77. Cappellini MD, Porter J, El-Beshlawy A, et al. Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias. Haematologica. Apr 2010;95(4):557-566.
78. Pennell DJ, Porter JB, Cappellini MD, et al. Efficacy of deferasirox in reducing and preventing cardiac iron overload in beta-thalassemia. Blood. Mar 25 2010;115(12):2364-2371.
79. Cappellini MD, Pattoneri P. Oral iron chelators. Annu Rev Med. 2009;60:25-38.
80. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood. May 1 2006;107(9):3455-3462.
81. Venkataram S, Rahman YE. High-performance liquid chromatographic analysis of desferrioxamine using a metal-free system. J Chromatogr. Dec 18 1987;411:494-497.
82. Lehmann WD, Heinrich HC. Ferrioxamine and its hexadentate iron-chelating metabolites in human post-desferal urine studied by high-performance liquid chromatography and fast atom bombardment mass spectrometry. Anal Biochem. Feb 1 1990;184(2):219-227.
83. Cramer SM, Nathanael B, Horvath C. High-performance liquid chromatography of deferoxamine and ferrioxamine: interference by iron present in the chromatographic system. J Chromatogr. Jul 20 1984;295(2):405-411.
84. Goddard JG, Kontoghiorghes GJ. Development of an HPLC method for measuring orally administered 1-substituted 2-alkyl-3-hydroxypyrid-4-one iron chelators in biological fluids. Clin Chem. Jan 1990;36(1):5-8.
85. Epemolu RO, Singh S, Hider RC, Damani LA. High-performance liquid chromatographic determination of 1,2-diethyl-3-hydroxypyridin-4-one and its 2-(1-hydroxyethyl) metabolite in rat blood. J Chromatogr. Jan 3 1992;573(1):178-182.
86. Rouan MC, Marfil F, Mangoni P, Sechaud R, Humbert H, Maurer G. Determination of a new oral iron chelator, ICL670, and its iron complex in plasma by high-performance liquid chromatography and ultraviolet detection. J Chromatogr B Biomed Sci Appl. May 5 2001;755(1-2):203-213.
87. Chirnomas D, Smith AL, Braunstein J, et al. Deferasirox pharmacokinetics in patients with adequate versus inadequate response. Blood. Nov 5 2009;114(19):4009-4013.
88. Vichinsky E. Standards of Care Guidelines for Thalassemia Children' s Hospital & Research Center Oakland 2009.
89. Prakash D, Bhat K, Shetty R, Chaudhary P, Pathak SR, Ghosh A. Quantification of quetiapine in human plasma by reverse phase high performance liquid chromatography. Arzneimittelforschung. 2010;60(11):654-659.
90. Bakkali A, Corta E, Ciria JI, Berrueta LA, Gallo B, Vicente F. Solid-phase extraction with liquid chromatography and ultraviolet detection for the assay of antidepressant drugs in human plasma. Talanta. Jul 12 1999;49(4):773-783.
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