Dexrazoxane

Structural formula
General
Non-proprietary name	Dexrazoxane
other names	4 - [(2 S ) -1- (3,5-Dioxopiperazin-1-yl) propan-2-yl] piperazin-2,6-dione ( IUPAC ) Eucardion
Molecular formula	C 11 H 16 N 4 O 4
Brief description	white to off-white powder
External identifiers / databases
CAS number 24584-09-6 149003-01-0 (dexrazoxane hydrochloride ) EC number 635-584-1 ECHA InfoCard 100.163.459 PubChem 71384 DrugBank DB00380 Wikidata Q524995
Drug information
ATC code	V07 AF02
Drug class	Cytoprotectants , complexing agents , cytostatics
Mechanism of action	Chelation complex formation , topoisomerase II inhibition
properties
Molar mass	268.27 g mol −1
Physical state	firmly
density	1.3 g cm −3
Melting point	191-197 ° C
solubility	Slightly soluble in water and 0.1 N hydrochloric acid , sparingly soluble in ethanol
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 315-319-335 P: 261-305 + 351 + 338
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Dexrazoxane is a drug that is used in chemotherapy with anthracyclines to reduce their cytotoxic effects. The compound was discovered in 1964 and has been used as a cytoprotective agent since the 1990s . The name is derived from the racemate razoxane , since dexrazoxane is its right-handed enantiomer ( Latin dexter , right). While the cytoprotective effect is attributed to the ability to form complexes , dexrazoxane also has a long-known cytostatic activity due to the inhibition of topoisomerase II .

history

Dexrazoxane, together with comparable substances from the group of bis - dioxopiperazines , was first described in 1964 by chemists at JR Geigy AG and a patent applied for. Separately, scientists at Eastman Kodak did the same thing a year later. At that time, it was not only being considered for pharmaceutical use, but also as a colorant in the textile industry and as an additive in jet fuel . In 1969, a research team was able to demonstrate the cytostatic activity of dexrazoxane and similar compounds for the first time. The cardioprotective effect of dexrazoxane was discovered three years later , and this tissue-specific protection was expanded to include substance -specific protection in a study from 1983: It was shown that dexrazoxane can reduce the cytotoxic effect of anthracyclines in particular . In the late 1980s and early 1990s this protective spectrum was expanded to include cytostatics such as cisplatin , mitoxantrone and bleomycin , but these effects have no clinical significance.

chemistry

Dexrazoxane is the isolated (+) - ( S ) - enantiomer of the racemate razoxane , i.e. the mixture that contains dexrazoxane and its levorotatory equivalent in equal parts. It belongs to the group of bisdioxopiperazines and is derived from piperazine . It is more soluble in water than razoxan. By hydrolyzing both ring structures, dexrazoxane is converted into its biologically active form, in which it is both a structural and functional analogue of EDTA . This biological active form was given the designation "ADR-925" (ADR: adverse drug reaction , dt approximately. Adverse drug reaction ). Like EDTA, ADR-925 is then able to form chelate complexes , for example with iron ions (both with Fe ²⁺ and Fe ³⁺ ), whereby ADR-925 is considered a strong chelating agent, but iron complexes many times less than EDTA.

pharmacology

Dexrazoxane is a prodrug that is converted into the biologically active ADR-925 through two reactions. In the first step, the first ring is hydrolyzed by a dihydropyrimidinase , then the second ring is cleaved by a dihydroorotase . This process takes place quickly, so that within the first 15 minutes after intravenous administration a strong increase in the concentration of ADR-925 in the blood can be measured. The degradation, in turn, proceeds more slowly, so an almost unchanged concentration can be recorded four hours after intravenous administration. The toxicologically maximum tolerable single dose is 1000 mg per kg body weight, with studies showing that children have a higher tolerance for dexrazoxane.

effect

The cytostatic effect of dexrazoxane, which was first discovered, is based on an inhibition of topoisomerase II α. This enzyme loosens or unwinds the double helix of the DNA and thus enables the replication of the genetic information and ultimately cell division . Dexrazoxane binds to the N -terminal - domain and thereby prevents the binding of ATP to the enzyme. As a result, the topoisomerase loses its functionality and the cell cannot divide.

The general cytoprotective effect of dexrazoxane is attributed to its ability to form complexes with iron. Anthracyclines have the ability not only to bind iron, but also to oxidize it from the double positive Fe ²⁺ to the triple positive Fe ³⁺ ion . The electron is transferred to various forms of oxygen ; these are reduced and reactive oxygen species are created in the form of radicals . As oxidative stress, these radicals are responsible for numerous cytotoxic processes, for example for the depolarization of the mitochondrial membranes on the heart muscle . Dexrazoxane prevents these processes by complexing the iron. The iron bound to dexrazoxane can also lead to the formation of radicals, but only to a much lesser extent than with anthracyclines.

use

Anthracyclines such as doxorubicin or epirubicin are cytotoxic drugs , because of their broad spectrum of activity in a variety of cancers as part of the chemotherapy are used. However, not only degenerate cells are attacked, but also healthy cells, whereby this undesirable effect is primarily concentrated on the heart . The consequence of this can be cardiomyopathy with subsequent irreversible heart failure . In this context, dexrazoxane has been used as an FDA and EMA approved cardioprotective drug, mostly in direct combination therapy with the anthracyclines, since the 1990s. For the primary prevention of anthracycline-related cardiotoxicity with dexrazoxane in children and adolescents, a temporary contraindication of dexrazoxane as a cardioprotective agent for the pediatric indication, which had been issued by the EMA since 2011, was lifted on July 19, 2017, as the clinical studies showed that neither the The anti-tumor effect of anthracyclines is reduced, nor the secondary malignancy is increased.

Since 2006 the active ingredient has also been approved as a treatment for anthracycline extravasation . In the case of extravasation, the infusion (usually intravenously ) punctures the blood vessel , so that the anthracyclines accumulate in the surrounding tissue and cause severe damage such as necrosis or ulcers . Studies showed that dexrazoxane was able to prevent necrosis in 98% of all patients with extravasation.

The effects of dexrazoxane and related substances in the treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's are currently being investigated . It is assumed that free iron may play an essential role in the pathogenesis and drugs that bind iron are therefore suitable for therapy.

The water-soluble dexrazoxane hydrochloride is used pharmaceutically . It is administered as an intravenous infusion.

Side effects and contraindications

Dexrazoxane is suspected to be teratogenic , so women and men are recommended to use effective contraception for up to three months after treatment . In addition, it is suspected that the drug itself has a carcinogenic effect, but a detailed investigation of this is not yet necessary, as it is always used with anthracyclines and these substances have already been confirmed in this suspicion. Other possible side effects are neutro- and thrombocytopenia , as dexrazoxane induces bone marrow suppression , as well as nausea, vomiting, asthenia and alopecia .

Trade names

Dexrazoxane is available in Europe and other countries as Cardioxane or Cyrdanax and in North America as a Zinecard to reduce cardiotoxic effects. It is sold under the name Savene as a medicine for the treatment of extravasation .

literature

• Kurt Hellmann , Walter Rhomberg : Razoxane and Dexrazoxane - Two Multifunctional Agents. Springer , New York a. a. 2010, ISBN 978-90-481-9167-3 .

Individual evidence

1. ↑ ^{a b c} Dexrazoxane data sheet from Sigma-Aldrich , accessed on March 28, 2014 ( PDF ).
2. ↑ Entry on Dexrazoxane in the ChemSpider database of the Royal Society of Chemistry , accessed on March 28, 2014.
3. ↑ ^{a b} Description of Zinecard at rxlist.com (accessed on March 31, 2014).
4. ↑ List of pharmaceutical substances in the ABDA database (April 2014)
5. ↑ ^{a b} Hellmann, Rhomberg: p. 1.
6. ^ AM Creighton, K. Hellmann, S. Whitecross: Antitumor activity in a series of bisdiketopiperazines. In: Nature , Volume 222, Number 5191, pp. 384-385, doi : 10.1038 / 222384a0 . PMID 5782118 .
7. ^ Hellmann, Rhomberg: p. 4.
8. ↑ ^{a b} Hellmann, Rhomberg: p. 160.
9. ^ Hellmann, Rhomberg: S. V (Preface).
10. ^ Hellmann, Rhomberg: p. 159.
11. ↑ ^{a b c} Hellmann, Rhomberg: p. 161.
12. ^ Hellmann, Rhomberg: p. 169.
13. ^ Hellmann, Rhomberg: p. 176.
14. ↑ ^{a b} Hellmann, Rhomberg: p. 162.
15. ↑ ^{a b c} data sheet on dexrazoxane from the Pharmazeutische Zeitung (accessed April 8, 2014).
16. ↑ https://www.ema.europa.eu/en/medicines/human/referrals/cardioxane#overview-section ; accessed on June 7, 2019
17. ↑ HT Mouridsen, SW Langer u. a .: Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies. In: Annals of Oncology , Volume 18, Number 3, pp. 546-550, doi : 10.1093 / annonc / mdl413 , PMID 17185744 .
18. ^ Hellmann, Rhomberg: p. 231.
19. ^ Hellmann, Rhomberg: p. 172.
20. ^ Hellmann, Rhomberg: p. 175.
21. ↑ Rote-Hand-Brief on Cardioxane, July 18, 2011, accessed on April 8, 2014, PDF file (244 kB).

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