羥基脲

羥基脲
臨床資料
商品名（英語：Drug nomenclature）	Apo-Hydroxyurea, Droxia, Hydrea
AHFS/Drugs.com	國際藥品名稱
MedlinePlus	a682004
懷孕分級	D (USA);
給藥途徑	口服
ATC碼	L01XX05 (WHO) ;
法律規範狀態
法律規範	處方藥（℞-only）;
藥物動力學數據
藥物代謝	肝臟
生物半衰期	3-4小時
排泄途徑	腎臟與肺
識別資訊
	IUPAC命名法 hydroxyurea; ;
CAS號	127-07-1
PubChem CID	3657;
DrugBank	DB01005 ;
ChemSpider	3530 ;
UNII	X6Q56QN5QC;
KEGG	D00341 ;
ChEBI	CHEBI:44423 ;
ChEMBL	ChEMBL467 ;
NIAID ChemDB	006310;
CompTox Dashboard（英語：CompTox Chemicals Dashboard） (EPA)	DTXSID6025438 ;
ECHA InfoCard	100.004.384
化學資訊
化學式	CH4N2O2
摩爾質量	76.06 g·mol−1
3D模型（JSmol（英語：JSmol））	交互式圖像;
	SMILES O=C(N)NO;
	InChI InChI=1S/CH4N2O2/c2-1(4)3-5/h5H,(H3,2,3,4) ; Key:VSNHCAURESNICA-UHFFFAOYSA-N ;

羥基脲（INN：Hydroxycarbamide，又名Hydroxyurea，商品名包括Hydrea和Droxia）是一種化療及抗逆轉錄病毒藥物，被用於治療慢性粒細胞白血病、骨髓增生性疾病和鐮刀型細胞貧血症等疾病。

作用機理

羥基脲的其中一種普遍接受的機理是它能夠通過清除酪氨醯自由基來抑制核糖核苷酸二磷酸還原酶，從而阻礙脫氧核糖核苷酸的合成。^[2]^[3]

在鐮刀型細胞貧血症的治療中，羥基脲能夠增加胎兒血紅蛋白的濃度。這點的具體作用機理仍不清楚，但有研究認為羥基脲能夠增加一氧化氮的濃度，從而激活鳥苷酸環化酶，進而增加環磷酸鳥苷的濃度，激活胎兒血紅蛋白所需的丙種球蛋白的合成，同時清除快速分裂的產生鐮刀型血紅蛋白的細胞。^[3]^[4]

用途

羥基脲被用於治療以下疾病：

骨髓增生性疾病（主要是真性紅血球增多症和原發性血小板增多症）^[5]
鐮刀型細胞貧血症（能夠減少發作時患者的疼痛）^[6]
愛滋病（用於在抗逆轉錄病毒療法輔助去羥肌苷）^[7]
銀屑病的二線治療（能夠減緩皮膚細胞的快速分裂）^[8]
肥大細胞增多症^[9]
慢性粒細胞白血病（基本上被伊馬替尼所代替，但仍因其高性價比而被使用）^[10]
頭頸癌（單獨給藥或與放療合用）
卵巢癌（同上）

除此之外，羥基脲還在生物化學研究上被用作DNA複製抑制劑，因為它能夠消耗脫氧核糖核苷酸而引起DNA雙鏈在複製叉附近斷裂（見DNA修復）。^[11]

劑量

劑量因情況而異。在骨髓增生性疾病中，一般來說是每日30mg~40mg/kg；劑量的增加與減少由血細胞計數變化及是否發生骨髓抑制而定。^[12] 對於鐮刀型細胞貧血症，起始劑量為15mg/kg（腎功能減弱者則酌情減少）；兩周之後預期血紅蛋白和血小板計數將會減少，而平均紅血球體積會增加。之後的劑量在密切觀察全血細胞計數的同時每兩周增加一次，直至劑量達到35mg/kg或血球減少發生。^[3]

副作用

有報導的副作用包括：嗜睡、噁心、嘔吐、腹瀉、便秘、食欲不振、黏膜炎、胃炎、骨髓抑制（劑量限制性毒性；停藥後1~3周可恢復）、脫髮、皮膚變化、肝功能異常、腎功能異常（肌酐和尿氮升高）。^[1]

由於羥基脲的骨髓毒性，治療時必須密切觀察全血細胞計數，且應及時應對由於白血球水平下降而引起的感染。除此之外，肝腎功能、尿酸和電解質也需經常檢查。^[12]

羥基脲主要用於治療的骨髓增生性疾病大部分都有轉化為急性粒細胞白血病的可能性。長期以來人們一直擔心羥基脲本身也會引起白血病，但研究顯示這種可能性很小或者基本上不存在。然而，這仍然阻礙了它在鐮刀型貧血症上的進一步應用。^[3]

合成

羥基脲由Dresler和Stein在1869年通過羥胺、鹽酸和氰化鉀反應合成；目前工業上生產則使用羥胺和氰酸。^[13]羥基脲也能由氨基甲酸乙酯與羥胺通過取代反應合成。^[14]

由氰酸鈉和羥胺作用合成羥基脲須利用離子交換樹脂。化學式如下：

NaOCN + NH₂OH → 羥基脲

參考資料

^ ^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.
^ 道蘭氏醫學詞典中的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. （原始內容存檔於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. （原始內容存檔於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. （原始內容存檔於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] 道蘭氏醫學詞典中的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. （原始內容存檔於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. （原始內容存檔於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. （原始內容存檔於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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