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Dexrazoxane hydrochloride (Zinecard by Pfizer in USA and Canada; Cardioxane by Novartis for EU and other countries) is a cardioprotective agent. It was discovered by Kurt Hellmann in 1972. Dexrazoxane is a sterile, pyrogen-free lyophilizate intended for intravenous administration. The IV administration of dexrazoxane is in acidic condition with HCl adjusting the pH.^[1]

Uses

Dexrazoxane has been used to protect the heart against the cardiotoxic side effects of chemotherapeutic drugs such as anthracyclines,^[2] such as daunorubicin or doxorubicin or other chemotherapeutic agents.^[3] However, in July 2011 the US Food and Drug Administration released a statement restricting use only in adult patients with cancer who have received > 300 mg/m2 doxorubicin (an anthracycline) or > 540 mg/m2 epirubicin (another chemotherapeutic agent) and general approval for use for cardioprotection.^[4]^[5] That showed a possibly higher rate of secondary malignancies and acute myelogenous leukemia in pediatric patients treated for different cancers with both dexrazoxane and other chemotherapeutic agents that are associated with secondary malignancies.^[6]

The United States Food and Drug Administration has also approved a dexrazoxane hydrochloride drug, brand name Totect or Savene (developed by TopoTarget), for use as a treatment of extravasation resulting from IV anthracycline chemotherapy.^[7]^[8] Extravasation is an adverse event in which chemotherapies containing anthracylines leak out of the blood vessel and necrotize the surrounding tissue.

Mechanism

As a derivative of EDTA, dexrazoxane chelates iron and thus reduces the number of metal ions complexed with anthracycline and, consequently, decrease the formation of superoxide radicals.^[9] The exact chelation mechanism is unknown, but it has been postulated that dexrazoxane can be converted into ring-opened form intracellularly and interfere with iron-mediated free radical generation that is in part thought to be responsible for anthryacycline induced cadiomyopathy.^[10] It was speculated that dexrazoxane could be used for further investigation to synthesize new antimalarial drugs.^[11]

References

^ http://www.rxlist.com/zinecard-drug.htm
^ Lipshultz, Steven E.; Rifai, Nader; Dalton, Virginia M.; Levy, Donna E.; Silverman, Lewis B.; Lipsitz, Stuart R.; Colan, Steven D.; Asselin, Barbara L.; et al. (2004). "The Effect of Dexrazoxane on Myocardial Injury in Doxorubicin-Treated Children with Acute Lymphoblastic Leukemia". New England Journal of Medicine 351 (2): 145–53. doi:10.1056/NEJMoa035153. PMID 15247354.
^ Bjelogrlic, Snezana K.; Radic, Jelena; Radulovic, Sinisa; Jokanovic, Milan; Jovic, Viktor (2007). "Effects of Dexrazoxane and Amifostine on Evolution of Doxorubicin Cardiomyopathy in Vivo". Experimental Biology and Medicine 232 (11): 1414–24. doi:10.3181/0705-RM-138. PMID 18040065.
^ Tebbi CK, et al. J Clin Oncol 2007; 25: 493–500
^ Salzer WL, et al. Leukemia 2010; 24: 355–70
^ "FDA Statement on Dexrazoxane".
^ Totect label on FDA's website
^ Kane, Robert C.; McGuinn, W. David; Dagher, Ramzi; Justice, Robert; Pazdur, Richard (2008). "Dexrazoxane (Totect™): FDA Review and Approval for the Treatment of Accidental Extravasation Following Intravenous Anthracycline Chemotherapy". The Oncologist 13 (4): 445–50. doi:10.1634/theoncologist.2007-0247. PMID 18448560.
^ Jones, Robin L. (2008). "Utility of dexrazoxane for the reduction of anthracycline-induced cardiotoxicity". Expert Review of Cardiovascular Therapy 6 (10): 1311–7. doi:10.1586/14779072.6.10.1311. PMID 19018683.
^ http://labeling.pfizer.com/ShowLabeling.aspx?id=514
^ Loyevsky, Mark; Sacci, John B.; Boehme, Patricia; Weglicki, William; John, Christy; Gordeuk, Victor R. (1999). "Plasmodium falciparum and Plasmodium yoelii: Effect of the Iron Chelation Prodrug Dexrazoxane on in Vitro Cultures". Experimental Parasitology 91 (2): 105–14. doi:10.1006/expr.1998.4371. PMID 9990337.

UpToDate Contents

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1. アントラサイクリン系化学療法剤の心毒性 cardiotoxicity of anthracycline like chemotherapy agents
2. 化学療法の血管外漏出による傷害およびその他の非抗腫瘍薬による水疱 extravasation injury from chemotherapy and other non antineoplastic vesicants
3. 高齢女性における転移性乳癌の治療 treatment of metastatic breast cancer in older women
4. 女性の転移性乳癌に対する全身療法：化学療法 systemic treatment of metastatic breast cancer in women chemotherapy
5. 急性骨髄性白血病における細胞遺伝学 cytogenetics in acute myeloid leukemia

English Journal

Early and delayed cardioprotective intervention with dexrazoxane each show different potential for prevention of chronic anthracycline cardiotoxicity in rabbits.

Jirkovský E, Lenčová-Popelová O, Hroch M, Adamcová M, Mazurová Y, Vávrová J, Mičuda S, Simůnek T, Geršl V, Stěrba M.SourceDepartment of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, Hradec Králové 500 38, Czech Republic.
Toxicology.Toxicology.2013 Sep 15;311(3):191-204. doi: 10.1016/j.tox.2013.06.012. Epub 2013 Jul 4.
Despite incomplete understanding to its mechanism of action, dexrazoxane (DEX) is still the only clearly effective cardioprotectant against chronic anthracycline (ANT) cardiotoxicity. However, its clinical use is currently restricted to patients exceeding significant ANT cumulative dose (300mg/m(2))
PMID 23831762

Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: A systematic review and meta-analysis.

Kalam K, Marwick TH.SourceMenzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.
European journal of cancer (Oxford, England : 1990).Eur J Cancer.2013 Sep;49(13):2900-9. doi: 10.1016/j.ejca.2013.04.030. Epub 2013 May 22.
BACKGROUND: Cardiotoxicity is a well-recognised complication of chemotherapy with anthracycline and/or trastuzumab, and its prevention remains an important challenge in cancer survivorship. Several successful preventative strategies have been identified in animal trials. We sought to assemble the cl
PMID 23706982

Educational Paper: Decreasing the burden of cardiovascular disease in childhood cancer survivors: An update for the pediatrician.

Dillenburg RF, Nathan P, Mertens L.SourceDivision of Cardiology, Department of Pediatrics, McMaster University Children's Hospital, Hamilton, Ontario, Canada.
European journal of pediatrics.Eur J Pediatr.2013 Sep;172(9):1149-60. doi: 10.1007/s00431-013-1931-9. Epub 2013 Jan 30.
The cardiovascular impact of cancer therapies on the heart is one of the major concerns in the long-term follow-up of childhood cancer survivors (CCSs). Long-term cardiovascular effects include the development of left ventricular dysfunction resulting in congestive heart failure and ischemic heart d
PMID 23361962

Japanese Journal

抗がん剤漏出時の対応法 (特集造血器腫瘍の治療における支持療法の進歩)

佐々木純
血液・腫瘍科 60(6), 732-737, 2010-06
NAID 40019064443

Intrapleural extravasation of epirubicin, 5-fluouracil, and cyclophosphamide, treated with dexrazoxane

UGES Joris W. F.,VOLLAARD Albert M.,WILMS Erik B.,BROUWER Rolf E.
International journal of clinical oncology : official journal of the Japan Society of Clinical Oncology 11(6), 467-470, 2006-12-01
NAID 10020571872

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★リンクテーブル★

リンク元	「デクスラゾキサン」「razoxane」

「デクスラゾキサン」

Dexrazoxane
Systematic (IUPAC) name
	4-[(2S)-2-(3,5-dioxopiperazin-1-yl)propyl]piperazine-2,6-dione
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a609010
Identifiers
CAS Number	24584-09-6
ATC code	V03AF02
PubChem	CID 71384
IUPHAR/BPS	7330
DrugBank	DB00380
ChemSpider	64479
UNII	048L81261F
KEGG	D03730
ChEBI	CHEBI:50223
ChEMBL	CHEMBL1738
Chemical data
Formula	C11H16N4O4
Molar mass	268.269 g/mol
	SMILES O=C2NC(=O)CN(C[C@@H](N1CC(=O)NC(=O)C1)C)C2 ;
	InChI InChI=1S/C11H16N4O4/c1-7(15-5-10(18)13-11(19)6-15)2-14-3-8(16)12-9(17)4-14/h7H,2-6H2,1H3,(H,12,16,17)(H,13,18,19)/t7-/m0/s1 ; Key:BMKDZUISNHGIBY-ZETCQYMHSA-N ;
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