小鼠血浆和脑组织中肼屈嗪的含量分析方法和肼屈嗪在小鼠体内的药代动力学研究
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摘要
肼屈嗪(Hydralazine)是一种经典的外周降血压药,常用于治疗原发性高血压。但是肼屈嗪的诸多不良反应限制了它的使用,因此,近些年来人们对它的关注也比较少。关于肼屈嗪含量测定方法的报道大多发表于90年代以前,灵敏度也相对比较差。本文应用液相色谱串联质谱技术(LC-MS-MS),建立了简单快速的BABL/C小鼠血浆和脑组织中肼屈嗪含量的测定方法,并将这个方法成功的应用于肼屈嗪的药代动力学研究,而且脑组织中肼屈嗪的含量测定方法是首次建立。
主要研究内容和方法
一、小鼠血浆和脑组织中肼屈嗪的含量测定
待测样本用乙酰丙酮进行衍生化(50℃水浴1 h)后,再用C18固相萃取小柱进行萃取、浓缩。样本采用ZORBAX SB-C18柱(150 mm×2.1 mm)进行分离,以甲醇‐0.01mol·L~(-1)醋酸铵水溶液(60:40,v/v)为流动相,流速为0.2mL·min~(-1),用ESI源进行离子化,以多反应监测(MRM)方式进行检测,用于定量的离子对为m/z 225.2→129.5。
二、肼屈嗪在BALB/C小鼠体内的药代动力学研究
BALB/C小鼠清醒状态下分别经腹腔给予20 mg·kg~(-1)肼屈嗪后,于0(对照)、5、10、15、30、45、60、90、120min从心脏取血,再快速取出脑组织。采样后,血浆样本立即进行离心,血浆用乙酰丙酮衍生化,衍生化后的样本冻存于‐60℃冰箱,待用;脑组织样本立即匀浆、离心取上清,所得上清液用乙酰丙酮衍生化,衍生化后的样本冻存于‐60℃冰箱,待用。采用上述的LC-MS-MS法测定不同时刻血浆和脑组织样品中的肼屈嗪浓度,用WinNonlin5.2软件对上述数据进行药时曲线的拟合,并计算药代动力学参数。
研究结果:
一、建立了快速、简便、灵敏、准确的LC-MS-MS法,既可用于小鼠血浆中肼屈嗪的含量测定,也可用于脑组织中肼屈嗪的含量测定。血浆和脑组织中肼屈嗪的线性范围均为10-200 ng·mL~(-1),血浆样本的检测下限为0.49 ng·mL~(-1),而脑组织样本的检测下限为1.05 ng·mL~(-1)。待测物的保留时间为4.2 min,样品的检测时间约为6 min。样本的日内精密度小于10.9%,日间精密度小于18.9%;该方法的相对回收率在96.2-113%范围内。
二、肼屈嗪可以透过血脑屏障进入脑组织,并且在血浆和脑组织中的动力学特征极为相似。腹腔给药后BALB/C小鼠血浆和脑组织中肼屈嗪的均以一级消除动力学模式消除。血浆主要动力学参数为:曲线下面积(AUC)为259 min·mg·mL~(-1),半衰期(t_(1/2))为14.4 min,清除率(CL)为0.0014 mL·min~(-1)。脑组织主要动力学参数为:曲线下面积(AUC)为296 min·mg·g~(-1),半衰期(t_(1/2))为9.3 min,清除率(CL)为0.0012 mg·min~(-1)。
Hydralazine(1-hydrazinophalazine, HYD),a potent, peripherally acting vasodilator with a general blood pressure-lowering effect, has been used as a typical hypotensor in the treatment of essential hypertension since the early 50s. Since its adverse effects and extreme variability in oral dose requirements have limited its usefulness, few attentions have been paid to HYD in the last few decades. Researches, focused on the quantitative determination of HYD, were almost published before 90s, and they are relatively poor in sensitivity. In this study, a simple and sensitive LC-MS-MS method for the quantitative determination of HYD in BALB/C mouse plasma and brain tissue has been developed and validated. This method was successfully applied to pharmacokinetic study of HYD in BALB/C mouse following a single intraperitoneal injection. In addition, the quantitative method for the determination of HYD in brain has been published for the first time.
Procedures and methods:
1. The content determination of HYD in BALB/C mouse plasma and brain
In this method, 2, 4-pentanedione was used as derivatization reagent. After derivatization at 50℃water bath for 1 h, solid phase extraction was done to purify and concentrate the samples. Chromatographic separation of analyte was performed with an Agilent ZORBAX SB-C18 column (150mm×2.1mm), with methanol–0.01 mol·L~(-1) ammonium acetate (60:40, v/v) as mobile phase, and operated at a flow rate of 0.2 mL·min~(-1). The mass spectrometer was operated in electrospray positive ionization mode. Sample analysis was performed in the multiple reaction monitoring mode (MRM). Quantification was performed using selected reaction monitoring of the transition of m/z 225.2→129.5.
2. Pharmacokinetic study of HYD in BALB/C mouse
After a single intraperitoneal injection of HYD at the dose of 20 mg·kg~(-1) to BALB/C mouse, blood and brain samples were collected at control (0 min) and 5, 10, 15, 30, 45, 60, 90 and 120 min. After collection, whole blood was submitted to centrifugation and the resulting plasma was collected. The whole brain was homogenized, then the homogenate was centrifuged to obtain the supernatant. Then the derivatization reaction with 2, 4-pentanedione were done immediately, for both plasma and brain samples. The HYD concentration at each sample was determined by the above LC-MS-MS method. The concentration-time curves and pharmacokinetic parameters were all achieved by the use of WinNonlin 5.2.
Results:
1. A rapid, simple, sensitive and accurate LC-MS-MS method was developed in this paper for the determination of HYD in both mouse plasma and brain samples. The standard curves showed good linearity over the concentration range of 10-200 ng·mL~(-1). The limit of detection were calculated to be 0.49 and 1.05 ng·mL~(-1) for mouse plasma and mouse brain homogenate, respectively. The retention time of the HYD derivative was 4.2 min, with a total run time of about 6 min. Intra-day precision was 10.9% or less and inter-day precision was 18.9% or less at all levels. The accuracy of the method ranged from 96.2% to 113% at all levels.
2. The results showed that HYD is able to pass through blood-brain barrier and it was rapidly absorbed by brain tissue, which is similar to the mouse plasma. In the use of pharmacokinetic software (WinNonlin5.2), the elimination phase of HYD was found to fit well to first order one compartment pharmacokinetic model. For plasma samples, the main pharmacokinetic parameters were as follows: AUC was 259 min·mg·mL~(-1), t_(1/2) was 14.4 min, CL was 0.0014 mL·min~(-1). For brain samples, the main pharmacokinetic parameters were as follows: AUC was 296 min·mg·g~(-1), t_(1/2) was 9.3 min, CL was 0.0014 mg·min~(-1).
主要研究内容和方法
一、小鼠血浆和脑组织中肼屈嗪的含量测定
待测样本用乙酰丙酮进行衍生化(50℃水浴1 h)后,再用C18固相萃取小柱进行萃取、浓缩。样本采用ZORBAX SB-C18柱(150 mm×2.1 mm)进行分离,以甲醇‐0.01mol·L~(-1)醋酸铵水溶液(60:40,v/v)为流动相,流速为0.2mL·min~(-1),用ESI源进行离子化,以多反应监测(MRM)方式进行检测,用于定量的离子对为m/z 225.2→129.5。
二、肼屈嗪在BALB/C小鼠体内的药代动力学研究
BALB/C小鼠清醒状态下分别经腹腔给予20 mg·kg~(-1)肼屈嗪后,于0(对照)、5、10、15、30、45、60、90、120min从心脏取血,再快速取出脑组织。采样后,血浆样本立即进行离心,血浆用乙酰丙酮衍生化,衍生化后的样本冻存于‐60℃冰箱,待用;脑组织样本立即匀浆、离心取上清,所得上清液用乙酰丙酮衍生化,衍生化后的样本冻存于‐60℃冰箱,待用。采用上述的LC-MS-MS法测定不同时刻血浆和脑组织样品中的肼屈嗪浓度,用WinNonlin5.2软件对上述数据进行药时曲线的拟合,并计算药代动力学参数。
研究结果:
一、建立了快速、简便、灵敏、准确的LC-MS-MS法,既可用于小鼠血浆中肼屈嗪的含量测定,也可用于脑组织中肼屈嗪的含量测定。血浆和脑组织中肼屈嗪的线性范围均为10-200 ng·mL~(-1),血浆样本的检测下限为0.49 ng·mL~(-1),而脑组织样本的检测下限为1.05 ng·mL~(-1)。待测物的保留时间为4.2 min,样品的检测时间约为6 min。样本的日内精密度小于10.9%,日间精密度小于18.9%;该方法的相对回收率在96.2-113%范围内。
二、肼屈嗪可以透过血脑屏障进入脑组织,并且在血浆和脑组织中的动力学特征极为相似。腹腔给药后BALB/C小鼠血浆和脑组织中肼屈嗪的均以一级消除动力学模式消除。血浆主要动力学参数为:曲线下面积(AUC)为259 min·mg·mL~(-1),半衰期(t_(1/2))为14.4 min,清除率(CL)为0.0014 mL·min~(-1)。脑组织主要动力学参数为:曲线下面积(AUC)为296 min·mg·g~(-1),半衰期(t_(1/2))为9.3 min,清除率(CL)为0.0012 mg·min~(-1)。
Hydralazine(1-hydrazinophalazine, HYD),a potent, peripherally acting vasodilator with a general blood pressure-lowering effect, has been used as a typical hypotensor in the treatment of essential hypertension since the early 50s. Since its adverse effects and extreme variability in oral dose requirements have limited its usefulness, few attentions have been paid to HYD in the last few decades. Researches, focused on the quantitative determination of HYD, were almost published before 90s, and they are relatively poor in sensitivity. In this study, a simple and sensitive LC-MS-MS method for the quantitative determination of HYD in BALB/C mouse plasma and brain tissue has been developed and validated. This method was successfully applied to pharmacokinetic study of HYD in BALB/C mouse following a single intraperitoneal injection. In addition, the quantitative method for the determination of HYD in brain has been published for the first time.
Procedures and methods:
1. The content determination of HYD in BALB/C mouse plasma and brain
In this method, 2, 4-pentanedione was used as derivatization reagent. After derivatization at 50℃water bath for 1 h, solid phase extraction was done to purify and concentrate the samples. Chromatographic separation of analyte was performed with an Agilent ZORBAX SB-C18 column (150mm×2.1mm), with methanol–0.01 mol·L~(-1) ammonium acetate (60:40, v/v) as mobile phase, and operated at a flow rate of 0.2 mL·min~(-1). The mass spectrometer was operated in electrospray positive ionization mode. Sample analysis was performed in the multiple reaction monitoring mode (MRM). Quantification was performed using selected reaction monitoring of the transition of m/z 225.2→129.5.
2. Pharmacokinetic study of HYD in BALB/C mouse
After a single intraperitoneal injection of HYD at the dose of 20 mg·kg~(-1) to BALB/C mouse, blood and brain samples were collected at control (0 min) and 5, 10, 15, 30, 45, 60, 90 and 120 min. After collection, whole blood was submitted to centrifugation and the resulting plasma was collected. The whole brain was homogenized, then the homogenate was centrifuged to obtain the supernatant. Then the derivatization reaction with 2, 4-pentanedione were done immediately, for both plasma and brain samples. The HYD concentration at each sample was determined by the above LC-MS-MS method. The concentration-time curves and pharmacokinetic parameters were all achieved by the use of WinNonlin 5.2.
Results:
1. A rapid, simple, sensitive and accurate LC-MS-MS method was developed in this paper for the determination of HYD in both mouse plasma and brain samples. The standard curves showed good linearity over the concentration range of 10-200 ng·mL~(-1). The limit of detection were calculated to be 0.49 and 1.05 ng·mL~(-1) for mouse plasma and mouse brain homogenate, respectively. The retention time of the HYD derivative was 4.2 min, with a total run time of about 6 min. Intra-day precision was 10.9% or less and inter-day precision was 18.9% or less at all levels. The accuracy of the method ranged from 96.2% to 113% at all levels.
2. The results showed that HYD is able to pass through blood-brain barrier and it was rapidly absorbed by brain tissue, which is similar to the mouse plasma. In the use of pharmacokinetic software (WinNonlin5.2), the elimination phase of HYD was found to fit well to first order one compartment pharmacokinetic model. For plasma samples, the main pharmacokinetic parameters were as follows: AUC was 259 min·mg·mL~(-1), t_(1/2) was 14.4 min, CL was 0.0014 mL·min~(-1). For brain samples, the main pharmacokinetic parameters were as follows: AUC was 296 min·mg·g~(-1), t_(1/2) was 9.3 min, CL was 0.0014 mg·min~(-1).
引文
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44. Boomsma F, Derks FH, van den Meiracker AH, Man in’t Veld AJ, Schalekamp MA. Plasma semicarbazide-sensitive amine oxidase activity is elevated in diabetes mellitus and correlates with glycosylated haemoglobin. Clin Sci, 1995, 88: 675–79.
45. Ishizaki F. Plasma benzylamine oxidase activity in cerebrovascular disease. Eur Neurol, 1990, 30: 104–07.
46. Boomsma F, van Veldhuisen DJ, de Kam PJ, et al. Plasma semicarbazide-sensitive amine oxidase is elevated in patients with congestive heart failure. Cardiovasc Res, 1997, 33: 387–91.
47. Boomsma F, van den Meiracker AH, Winkel S, et al. Circulating semicarbazide-sensitive amine oxidase is raised both in type I (insulin-dependent), in type II (non-insulin-dependent) diabetes mellitus and even in childhood type I diabetes at first clinical diagnosis. Diabetologia, 1999, 42: 233–37.
48. Mészáros Z, Szombathy T, Raimondi L, Karadi I, Romics L, Magyar K. Elevated serum semicarbazide-sensitive amine oxidase activity in non-insulin-dependent diabetes mellitus: correlation with BMI and serum triglyceride. Metabolism Clin Exp, 1999, 48: 113–17.
49. Garpenstrand H, Ekblom J, Backlund LB, Oreland L, Rosenqvist U. Elevated plasma semicarbazide-sensitive amine oxidase (SSAO) activity in Type 2 diabetes mellitus complicated by retinopathy. Diabet Med, 1999, 16: 514–21.
50. Boomsma F, de Kam PJ, Tjeerdsma G, van den Meiracker AH, van Veldhuisen DJ. Plasma semicarbazide-sensitive amine oxidase (SSAO) is an independent prognostic marker formortality in chronic heart failure. Eur Heart J, 2000, 21:1859-63.
51. Hayes BE, Clarke DE. Semicarbazide-sensitive amine oxidase activity in streptozotocin diabetic rats. Res Comm Chem Pathol Pharmacol, 1990, 69: 71–83.
52. Elliott J, Fowden AL, Callingham BA, Sharman DF, Silver M. Physiological and pathological influences on sheep blood plasma amine oxidase: effect of pregnancy and experimental alloxan-induced diabetes mellitus. Res Vet Science, 1991, 50:334–39.
53. Kahn SE, Andrikopoulos S, Verchere CB. Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes. Diabetes, 1999; 48: 241–523.
54. Yu PH, Zuo DM. Formaldehyde produced endogenously via deamination of methylamine; a potential risk factor for initiation of endothelial injury. Atherosclerosis, 1996, 120: 189–97.
55.李芳序,卢静,许亚杰,童志前,聂春来,赫荣乔.老年性痴呆发病过程中内源性甲醛慢性损伤机制.生物化学与生物物理进展,2008, 35(4): 393-400.
56. Salmi M, Kalimo K, Jalkanen S. Induction and function of adhesion protein-1 at sites of information. J Exp Med, 1993,178:2255-60.
1. Ludden TM, Goggin LK, Mcnay JL, Haegele KD and Shepherd AMM. High-pressure liquid chromatographic assay for hydralazien in human plasma. J Pharm Sci, 1979, 68(11): 1423-25.
2. Waltrip J, Mylott W, Jenkins R. Quantitative determination of unchanged hydralazine in human whole blood using LC/MS/MS.2007, PPD presentation
3. Proveaux WJ, O’Donnell JP, Ma JK. Liquid chromatographic analysis of hydralazine and metabolites in plasma. J Chromatogr. 1979, 176: 480-84.
4. Reece PA, Cozamanis I, Zacest R. selective high-performance liquid chromatographic assays for hydralazine and its metabolites in plasma of man. J Chromatogr.1980, 181: 427-40.
5. Rouan MC, Campestrini J. Liquid chromatographic determination of dihydralazine and hydralazine in human plasma and its application to pharmatokinetic studies of dihydralazine. J Pharm Sci, 1985, 74(12): 1270-73.
6. Zak SB, Lukas G, Gilleran TG. Plasma levels of real and“apparent”hydralazine in man and rat. Drug Metab Dispos, 1977, 5(2): 116-21
7. Haegele KD, Skrdlant HB, Robie NW, Lalka D, McNay JL. Determination of hydralazine and its metabolites by gas chromatography-mass spectrometry. J Chromatogr, 1976, 126: 517-34.
8. Wong JK, Joyce TH 3rd, Morrow DH. Determination of hydralazine in human plasma by high performance liquid chromatography with electrochemical detection. J Chromatogr, 1987, 385: 261-66.
9. Zak SB,Bartlett MF,Wagner WE, Gilleran TG, Lukas G.Disposition of hydralazine in man and a specific method for its determination in biological fluids. J Pharm Sci, 1974, 63(2):225-29.
10. Manes J, Mari J, Garcia R, Font G. Liquid chromatographic determination of hydralazine in human plasma with 2-hydroxy-1-naphthaldehyde pre-column derivatization. J Pharm Biomed Anal, 1990,8:795-98.
11. Facchini V, Streeter AJ, Timbrell JA. Determination of hydralazine and its acetylated metabolites in urine by gas chromatography and high-pressure liquid chromatography. JChromatogr. 1980, 187: 218-23.
12. Degen PH. Determination of unchanged hydralazine in plasma by gas-liquid chromatography using nitrogen-specific detection. J Chromatogr. 1979, 176:375-80.
13.互动百科:亚硝酸.http://www.hudong.com/wiki/%E4%BA%9A%E7%A1%9D%E9%85%B8
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8. Heck HD, Casanova M, Starr TB. Formaldehyde toxicity- new understanding. Crit Rev Toxicology, 1990, 20(6): 397-426.
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10. Nagaraj RH, Shipanova IN, Faust FM. Protein cross-linking by the Mailard reaction. Isolation, characterization and in vivo detection of a lysine-lysine cross-link derived from methylglyoxal. J Bio Chem, 1996, 271: 19338–45.
11. Unzeta M, Sole M, Boada M, Herna′ndez M. Semicarbazide-sensitive amine oxidase (SSAO) and its possible contribution to vascular damage in Alzheimer’s disease. J Neural Transm, 2007, 114: 857–62.
12.王鸿飞,安丽.阿尔兹海默病的发病机制及营养调节.国家老年医学杂志, 2010, 31:230-33.
13. Zhu X, Raina AK, Lee HG, Casadesus G, Smith MA, Perry G. Oxidative Stress Signaling in Alzheimer’s Disease. Brain Res, 2004, 1000: 32–39.
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17. Yu PH, Zuo DM. Oxidative deamination of methylamine by semicarbazide-sensitive amine oxidase leads to cytotoxic damage in endothelial cells; Possible consequence for diabetes. Diabetes, 1993; 42: 594–603
18. Zak SB, Lukas G, Gilleran TG. Plasma levels of real and“apparent”hydralazine in man and rat. Drug Metab Dispos, 1977, 5(2): 116-21
19. Haegele KD, Skrdlant HB, Robie NW, Lalka D, McNay JL. Determination ofhydralazine and its metabolites by gas chromatography-mass spectrometry. J Chromatogr, 1976, 126: 517-34.
20. Facchini V, Streeter AJ, Timbrell JA. Determination of hydralazine and its acetylated metabolites in urine by gas chromatography and high-pressure liquid chromatography. J Chromatogr. 1980, 187: 218-23.
21. Degen PH. Determination of unchanged hydralazine in plasma by gas-liquid chromatography using nitrogen-specific detection. J Chromatogr. 1979, 176:375-80.
22. Angelo HR, Christensen JM, Kristensen M, McNair A. Gas chromatographic method for the simultaneous determination of hydralazine and its acetylated metabolite in serum using a nitrogen-selective detector. J chromatogr, 1980, 183: 159-66.
23. Waltrip J, Mylott W, Jenkins R. Quantitative determination of unchanged hydralazine in human whole blood using LC/MS/MS.2007, PPD presentation
24. Ludden TM, Goggin LK, Mcnay JL, Haegele KD and Shepherd AMM. High-pressure liquid chromatographic assay for hydralazien in human plasma. J Pharm Sci. 1979, 68(11): 1423-25.
25. Proveaux WJ, O’Donnell JP, Ma JK. Liquid chromatographic analysis of hydralazine and metabolites in plasma. J Chromatogr. 1979, 176: 480-84.
26. Reece PA, Cozamanis I, Zacest R. selective high-performance liquid chromatographic assays for hydralazine and its metabolites in plasma of man. J Chromatogr.1980, 181: 427-40.
27. Rouan MC, Campestrini J. Liquid chromatographic determination of dihydralazine and hydralazine in human plasma and its application to pharmatokinetic studies of dihydralazine. J Pharm Sci, 1985, 74(12): 1270-73.
28. Wong JK, Joyce TH 3rd, Morrow DH. Determination of hydralazine in human plasma by high performance liquid chromatography with electrochemical detection. J Chromatogr, 1987, 385: 261-66.
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40. Unzeta M, Sole M, Boada M, Hernandez M. Semicarbazide-sensitive amine oxidase (SSAO) and its possible contribution to vascular damage in Alzheimer’s disease. J Neural Transm, 2007, 114: 857–62.
41. Yu PH, Zuo DM. Oxidative deamination of methylamine by semicarbazide-sensitive amine oxidase leads to cytotoxic damage in endothelial cells; Possible consequence for diabetes. Diabetes, 1993, 42: 594–603.
42. Nilsson SE, Tryding N, Tufvesson G. Serum monoamine oxidase in diabetes mellitus and some other internal diseases. Acta Med Scand, 1968, 184: 105–08.
43. Yuen CT, Easton D, Misch K, Rhodes EL. Increased activity of serum amine oxidase in granuloma annulare, necrobiosis lipoidics and diabetes. Brit J Dermatol, 1987, 11: 643–49.
44. Boomsma F, Derks FH, van den Meiracker AH, Man in’t Veld AJ, Schalekamp MA. Plasma semicarbazide-sensitive amine oxidase activity is elevated in diabetes mellitus and correlates with glycosylated haemoglobin. Clin Sci, 1995, 88: 675–79.
45. Ishizaki F. Plasma benzylamine oxidase activity in cerebrovascular disease. Eur Neurol, 1990, 30: 104–07.
46. Boomsma F, van Veldhuisen DJ, de Kam PJ, et al. Plasma semicarbazide-sensitive amine oxidase is elevated in patients with congestive heart failure. Cardiovasc Res, 1997, 33: 387–91.
47. Boomsma F, van den Meiracker AH, Winkel S, et al. Circulating semicarbazide-sensitive amine oxidase is raised both in type I (insulin-dependent), in type II (non-insulin-dependent) diabetes mellitus and even in childhood type I diabetes at first clinical diagnosis. Diabetologia, 1999, 42: 233–37.
48. Mészáros Z, Szombathy T, Raimondi L, Karadi I, Romics L, Magyar K. Elevated serum semicarbazide-sensitive amine oxidase activity in non-insulin-dependent diabetes mellitus: correlation with BMI and serum triglyceride. Metabolism Clin Exp, 1999, 48: 113–17.
49. Garpenstrand H, Ekblom J, Backlund LB, Oreland L, Rosenqvist U. Elevated plasma semicarbazide-sensitive amine oxidase (SSAO) activity in Type 2 diabetes mellitus complicated by retinopathy. Diabet Med, 1999, 16: 514–21.
50. Boomsma F, de Kam PJ, Tjeerdsma G, van den Meiracker AH, van Veldhuisen DJ. Plasma semicarbazide-sensitive amine oxidase (SSAO) is an independent prognostic marker formortality in chronic heart failure. Eur Heart J, 2000, 21:1859-63.
51. Hayes BE, Clarke DE. Semicarbazide-sensitive amine oxidase activity in streptozotocin diabetic rats. Res Comm Chem Pathol Pharmacol, 1990, 69: 71–83.
52. Elliott J, Fowden AL, Callingham BA, Sharman DF, Silver M. Physiological and pathological influences on sheep blood plasma amine oxidase: effect of pregnancy and experimental alloxan-induced diabetes mellitus. Res Vet Science, 1991, 50:334–39.
53. Kahn SE, Andrikopoulos S, Verchere CB. Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes. Diabetes, 1999; 48: 241–523.
54. Yu PH, Zuo DM. Formaldehyde produced endogenously via deamination of methylamine; a potential risk factor for initiation of endothelial injury. Atherosclerosis, 1996, 120: 189–97.
55.李芳序,卢静,许亚杰,童志前,聂春来,赫荣乔.老年性痴呆发病过程中内源性甲醛慢性损伤机制.生物化学与生物物理进展,2008, 35(4): 393-400.
56. Salmi M, Kalimo K, Jalkanen S. Induction and function of adhesion protein-1 at sites of information. J Exp Med, 1993,178:2255-60.
1. Ludden TM, Goggin LK, Mcnay JL, Haegele KD and Shepherd AMM. High-pressure liquid chromatographic assay for hydralazien in human plasma. J Pharm Sci, 1979, 68(11): 1423-25.
2. Waltrip J, Mylott W, Jenkins R. Quantitative determination of unchanged hydralazine in human whole blood using LC/MS/MS.2007, PPD presentation
3. Proveaux WJ, O’Donnell JP, Ma JK. Liquid chromatographic analysis of hydralazine and metabolites in plasma. J Chromatogr. 1979, 176: 480-84.
4. Reece PA, Cozamanis I, Zacest R. selective high-performance liquid chromatographic assays for hydralazine and its metabolites in plasma of man. J Chromatogr.1980, 181: 427-40.
5. Rouan MC, Campestrini J. Liquid chromatographic determination of dihydralazine and hydralazine in human plasma and its application to pharmatokinetic studies of dihydralazine. J Pharm Sci, 1985, 74(12): 1270-73.
6. Zak SB, Lukas G, Gilleran TG. Plasma levels of real and“apparent”hydralazine in man and rat. Drug Metab Dispos, 1977, 5(2): 116-21
7. Haegele KD, Skrdlant HB, Robie NW, Lalka D, McNay JL. Determination of hydralazine and its metabolites by gas chromatography-mass spectrometry. J Chromatogr, 1976, 126: 517-34.
8. Wong JK, Joyce TH 3rd, Morrow DH. Determination of hydralazine in human plasma by high performance liquid chromatography with electrochemical detection. J Chromatogr, 1987, 385: 261-66.
9. Zak SB,Bartlett MF,Wagner WE, Gilleran TG, Lukas G.Disposition of hydralazine in man and a specific method for its determination in biological fluids. J Pharm Sci, 1974, 63(2):225-29.
10. Manes J, Mari J, Garcia R, Font G. Liquid chromatographic determination of hydralazine in human plasma with 2-hydroxy-1-naphthaldehyde pre-column derivatization. J Pharm Biomed Anal, 1990,8:795-98.
11. Facchini V, Streeter AJ, Timbrell JA. Determination of hydralazine and its acetylated metabolites in urine by gas chromatography and high-pressure liquid chromatography. JChromatogr. 1980, 187: 218-23.
12. Degen PH. Determination of unchanged hydralazine in plasma by gas-liquid chromatography using nitrogen-specific detection. J Chromatogr. 1979, 176:375-80.
13.互动百科:亚硝酸.http://www.hudong.com/wiki/%E4%BA%9A%E7%A1%9D%E9%85%B8
14.邢其毅,徐瑞秋,周政等.基础有机化学(M).第二版.高等教育出版社.1993,455.
15. Angelo HR, Christensen JM, Kristensen M, McNair A. Gas chromatographic method for the simultaneous determination of hydralazine and its acetylated metabolite in serum using a nitrogen-selective detector. J chromatogr, 1980, 183: 159-66.
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