羟基脲

羟基脲
临床资料
商品名（英语：Drug nomenclature）	Apo-Hydroxyurea, Droxia, Hydrea
AHFS/Drugs.com	国际药品名称
MedlinePlus	a682004
怀孕分级	D (USA);
给药途径	口服
ATC码	L01XX05 (WHO) ;
法律规范状态
法律规范	处方药（℞-only）;
药物动力学数据
药物代谢	肝脏
生物半衰期	3-4小时
排泄途径	肾脏与肺
识别信息
	IUPAC命名法 hydroxyurea; ;
CAS号	127-07-1
PubChem CID	3657;
DrugBank	DB01005 ;
ChemSpider	3530 ;
UNII	X6Q56QN5QC;
KEGG	D00341 ;
ChEBI	CHEBI:44423 ;
ChEMBL	ChEMBL467 ;
NIAID ChemDB	006310;
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)	DTXSID6025438 ;
ECHA InfoCard	100.004.384
化学信息
化学式	CH4N2O2
摩尔质量	76.06 g·mol−1
3D模型（JSmol（英语：JSmol））	交互式图像;
	SMILES O=C(N)NO;
	InChI InChI=1S/CH4N2O2/c2-1(4)3-5/h5H,(H3,2,3,4) ; Key:VSNHCAURESNICA-UHFFFAOYSA-N ;

羟基脲（INN：Hydroxycarbamide，又名Hydroxyurea，商品名包括Hydrea和Droxia）是一种化疗及抗逆转录病毒药物，被用于治疗慢性粒细胞白血病、骨髓增生性疾病和镰刀型细胞贫血症等疾病。

作用机理

羟基脲的其中一种普遍接受的机理是它能够通过清除酪氨酰自由基来抑制核糖核苷酸二磷酸还原酶，从而阻碍脱氧核糖核苷酸的合成。^[2]^[3]

在镰刀型细胞贫血症的治疗中，羟基脲能够增加胎儿血红蛋白的浓度。这点的具体作用机理仍不清楚，但有研究认为羟基脲能够增加一氧化氮的浓度，从而激活鸟苷酸环化酶，进而增加环磷酸鸟苷的浓度，激活胎儿血红蛋白所需的丙种球蛋白的合成，同时清除快速分裂的产生镰刀型血红蛋白的细胞。^[3]^[4]

用途

羟基脲被用于治疗以下疾病：

骨髓增生性疾病（主要是真性红细胞增多症和原发性血小板增多症）^[5]
镰刀型细胞贫血症（能够减少发作时患者的疼痛）^[6]
艾滋病（用于在抗逆转录病毒疗法辅助去羟肌苷）^[7]
银屑病的二线治疗（能够减缓皮肤细胞的快速分裂）^[8]
肥大细胞增多症^[9]
慢性粒细胞白血病（基本上被伊马替尼所代替，但仍因其高性价比而被使用）^[10]
头颈癌（单独给药或与放疗合用）
卵巢癌（同上）

除此之外，羟基脲还在生物化学研究上被用作DNA复制抑制剂，因为它能够消耗脱氧核糖核苷酸而引起DNA双链在复制叉附近断裂（见DNA修复）。^[11]

剂量

剂量因情况而异。在骨髓增生性疾病中，一般来说是每日30mg~40mg/kg；剂量的增加与减少由血细胞计数变化及是否发生骨髓抑制而定。^[12] 对于镰刀型细胞贫血症，起始剂量为15mg/kg（肾功能减弱者则酌情减少）；两周之后预期血红蛋白和血小板计数将会减少，而平均红细胞体积会增加。之后的剂量在密切观察全血细胞计数的同时每两周增加一次，直至剂量达到35mg/kg或血球减少发生。^[3]

副作用

有报导的副作用包括：嗜睡、恶心、呕吐、腹泻、便秘、食欲不振、粘膜炎、胃炎、骨髓抑制（剂量限制性毒性；停药后1~3周可恢复）、脱发、皮肤变化、肝功能异常、肾功能异常（肌酐和尿氮升高）。^[1]

由于羟基脲的骨髓毒性，治疗时必须密切观察全血细胞计数，且应及时应对由于白细胞水平下降而引起的感染。除此之外，肝肾功能、尿酸和电解质也需经常检查。^[12]

羟基脲主要用于治疗的骨髓增生性疾病大部分都有转化为急性粒细胞白血病的可能性。长期以来人们一直担心羟基脲本身也会引起白血病，但研究显示这种可能性很小或者基本上不存在。然而，这仍然阻碍了它在镰刀型贫血症上的进一步应用。^[3]

合成

羟基脲由Dresler和Stein在1869年通过羟胺、盐酸和氰化钾反应合成；目前工业上生产则使用羟胺和氰酸。^[13]羟基脲也能由氨基甲酸乙酯与羟胺通过取代反应合成。^[14]

由氰酸钠和羟胺作用合成羟基脲须利用离子交换树脂。化学式如下：

NaOCN + NH₂OH → 羟基脲

参考资料

^ ^1.0 ^1.1 Liebelt, E.; Balk, S.; Faber, W.; Fisher, J.; Hughes, C.; Lanzkron, S.; Lewis, K.; Marchetti, F.; Mehendale, H. NTP-CERHR expert panel report on the reproductive and developmental toxicity of hydroxyurea. Birth defects research. Part B, Developmental and reproductive toxicology. 2007, 80 (4): 259–366. PMID 17712860. doi:10.1002/bdrb.20123.
^ 道兰氏医学词典中的hydroxyurea
^ ^3.0 ^3.1 ^3.2 ^3.3 Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N. Engl. J. Med. 2008, 358 (13): 1362–9. PMID 18367739. doi:10.1056/NEJMct0708272.
^ Cokic VP, Smith RD, Beleslin-Cokic BB; et al. Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase. J Clin Invest. 2003, 111 (2): 231–9 [2012-05-20]. PMC 151872  . PMID 12531879. doi:10.1172/JCI16672. （原始内容存档于2009-01-15）. PMC 151872
^ Harrison CN, Campbell PJ, Buck G; et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N. Engl. J. Med. July 2005, 353 (1): 33–45. PMID 16000354. doi:10.1056/NEJMoa043800.
^ Lanzkron S, Strouse JJ, Wilson R; et al. Systematic review: Hydroxyurea for the treatment of adults with sickle cell disease. Ann. Intern. Med. June 2008, 148 (12): 939–55. PMID 18458272.
^ Frank I, Bosch RJ, Fiscus S; et al. Activity, safety, and immunological effects of hydroxyurea added to didanosine in antiretroviral-naive and experienced HIV type 1-infected subjects: a randomized, placebo-controlled trial, ACTG 307. AIDS Res. Hum. Retroviruses. September 2004, 20 (9): 916–26. PMID 15597521. doi:10.1089/aid.2004.20.916.
^ Sharma VK, Dutta B, Ramam M. Hydroxyurea as an alternative therapy for psoriasis. Indian J Dermatol Venereol Leprol. 2004, 70 (1): 13–7 [2012-05-20]. PMID 17642550. （原始内容存档于2009-07-03）.
^ Escribano, L.; Álvarez-Twose, I. N.; Sánchez-Muñoz, L.; Garcia-Montero, A.; Núñez, R.; Almeida, J.; Jara-Acevedo, M.; Teodósio, C.; García-Cosío, M. N. Prognosis in adult indolent systemic mastocytosis: A long-term study of the Spanish Network on Mastocytosis in a series of 145 patients. Journal of Allergy and Clinical Immunology. 2009, 124 (3): 514–521. PMID 19541349. doi:10.1016/j.jaci.2009.05.003.
^ Dalziel, K.; Round, A.; Stein, K.; Garside, R.; Price, A. Effectiveness and cost-effectiveness of imatinib for first-line treatment of chronic myeloid leukaemia in chronic phase: A systematic review and economic analysis. Health technology assessment (Winchester, England). 2004, 8 (28): iii, ii1–120. PMID 15245690.
^ Koç A, Wheeler LJ, Mathews CK, Merrill GF. Hydroxyurea arrests DNA replication by a mechanism that preserves basal dNTP pools. J. Biol. Chem. January 2004, 279 (1): 223–30 [2012-05-20]. PMID 14573610. doi:10.1074/jbc.M303952200. （原始内容存档于2023-10-11）.
^ ^12.0 ^12.1 Thackery, Ellen. The Gale Encyclopedia of Cancer: A-K. Detroit: Thomson Gale. 2002: 514-516. ISBN 0-7876-5610-0.
^ Lunghi, A; Aloni, C; Gigante, L; Mazzei, N; Cardillo, P. Hydroxyurea explosion: a thermoanalytical and calorimetric study. Journal of Loss Prevention in the Process Industries. 2002, 15 (6): 489–495. doi:10.1016/S0950-4230(02)00044-X.
^ R. Deghenghi (1973). "Hydroxyurea". Org. Synth.; Coll. Vol. 5: 645.

[Liebelt2007-1] 1.0 ^1.1 Liebelt, E.; Balk, S.; Faber, W.; Fisher, J.; Hughes, C.; Lanzkron, S.; Lewis, K.; Marchetti, F.; Mehendale, H. NTP-CERHR expert panel report on the reproductive and developmental toxicity of hydroxyurea. Birth defects research. Part B, Developmental and reproductive toxicology. 2007, 80 (4): 259–366. PMID 17712860. doi:10.1002/bdrb.20123.

[2] 道兰氏医学词典中的hydroxyurea

[Platt2008-3] 3.0 ^3.1 ^3.2 ^3.3 Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N. Engl. J. Med. 2008, 358 (13): 1362–9. PMID 18367739. doi:10.1056/NEJMct0708272.

[pmid12531879-4] Cokic VP, Smith RD, Beleslin-Cokic BB; et al. Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase. J Clin Invest. 2003, 111 (2): 231–9 [2012-05-20]. PMC 151872  . PMID 12531879. doi:10.1172/JCI16672. （原始内容存档于2009-01-15）. PMC 151872

[pmid16000354-5] Harrison CN, Campbell PJ, Buck G; et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N. Engl. J. Med. July 2005, 353 (1): 33–45. PMID 16000354. doi:10.1056/NEJMoa043800.

[pmid18458272-6] Lanzkron S, Strouse JJ, Wilson R; et al. Systematic review: Hydroxyurea for the treatment of adults with sickle cell disease. Ann. Intern. Med. June 2008, 148 (12): 939–55. PMID 18458272.

[pmid15597521-7] Frank I, Bosch RJ, Fiscus S; et al. Activity, safety, and immunological effects of hydroxyurea added to didanosine in antiretroviral-naive and experienced HIV type 1-infected subjects: a randomized, placebo-controlled trial, ACTG 307. AIDS Res. Hum. Retroviruses. September 2004, 20 (9): 916–26. PMID 15597521. doi:10.1089/aid.2004.20.916.

[pmid17642550-8] Sharma VK, Dutta B, Ramam M. Hydroxyurea as an alternative therapy for psoriasis. Indian J Dermatol Venereol Leprol. 2004, 70 (1): 13–7 [2012-05-20]. PMID 17642550. （原始内容存档于2009-07-03）.

[9] Escribano, L.; Álvarez-Twose, I. N.; Sánchez-Muñoz, L.; Garcia-Montero, A.; Núñez, R.; Almeida, J.; Jara-Acevedo, M.; Teodósio, C.; García-Cosío, M. N. Prognosis in adult indolent systemic mastocytosis: A long-term study of the Spanish Network on Mastocytosis in a series of 145 patients. Journal of Allergy and Clinical Immunology. 2009, 124 (3): 514–521. PMID 19541349. doi:10.1016/j.jaci.2009.05.003.

[10] Dalziel, K.; Round, A.; Stein, K.; Garside, R.; Price, A. Effectiveness and cost-effectiveness of imatinib for first-line treatment of chronic myeloid leukaemia in chronic phase: A systematic review and economic analysis. Health technology assessment (Winchester, England). 2004, 8 (28): iii, ii1–120. PMID 15245690.

[pmid14573610-11] Koç A, Wheeler LJ, Mathews CK, Merrill GF. Hydroxyurea arrests DNA replication by a mechanism that preserves basal dNTP pools. J. Biol. Chem. January 2004, 279 (1): 223–30 [2012-05-20]. PMID 14573610. doi:10.1074/jbc.M303952200. （原始内容存档于2023-10-11）.

[gale-12] 12.0 ^12.1 Thackery, Ellen. The Gale Encyclopedia of Cancer: A-K. Detroit: Thomson Gale. 2002: 514-516. ISBN 0-7876-5610-0.

[13] Lunghi, A; Aloni, C; Gigante, L; Mazzei, N; Cardillo, P. Hydroxyurea explosion: a thermoanalytical and calorimetric study. Journal of Loss Prevention in the Process Industries. 2002, 15 (6): 489–495. doi:10.1016/S0950-4230(02)00044-X.

[14] R. Deghenghi (1973). "Hydroxyurea". Org. Synth.; Coll. Vol. 5: 645.

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