Deferoxamine

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Deferoxamine
Deferoxamine-2D-skeletal.png
Deferoxamine-3D-vdW.png
Skeletal formula and spacefill model of deferoxamine
Clinical data
Trade names Desferal
Other namesdesferrioxamine B, desferoxamine B, DFO-B, DFB ,N'-[5-(Acetyl-hydroxy-amino)pentyl]-N-[5-[3-(5-aminopentyl-hydroxy-carbamoyl) propanoylamino]pentyl]-N-hydroxy-butane diamide
AHFS/Drugs.com Monograph
Routes of
administration
  • intramuscular
  • intravenous
  • subcutaneous
ATC code
Pharmacokinetic data
Elimination half-life 6 hours
Identifiers
  • N'-{5-[Acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.671 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C25H48N6O8
Molar mass 560.693 g·mol−1
3D model (JSmol)
  • CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN
  • InChI=1S/C25H48N6O8/c1-21(32)29(37)18-9-3-6-16-27-22(33)12-14-25(36)31(39)20-10-4-7-17-28-23(34)11-13-24(35)30(38)19-8-2-5-15-26/h37-39H,2-20,26H2,1H3,(H,27,33)(H,28,34)
     Yes check.svgY
  • Key:UBQYURCVBFRUQT-UHFFFAOYSA-N

Deferoxamine (DFOA), also known as desferrioxamine and sold under the brand name Desferal, is a medication that binds iron and aluminium. [1] It is specifically used in iron overdose, hemochromatosis either due to multiple blood transfusions or an underlying genetic condition, and aluminium toxicity in people on dialysis. [1] [2] It is used by injection into a muscle, vein, or under the skin. [1]

Contents

Common side effects include pain at the site of injection, diarrhea, vomiting, fever, hearing loss, and eye problems. [1] Severe allergic reactions including anaphylaxis and low blood pressure may occur. [1] It is unclear if use during pregnancy or breastfeeding is safe for the baby. [3] Deferoxamine is a siderophore from the bacteria Streptomyces pilosus . [4] [5]

Deferoxamine was approved for medical use in the United States in 1968. [1] It is on the World Health Organization's List of Essential Medicines. [6]

Medical uses

Deferoxamine is used to treat acute iron poisoning, especially in small children. [7] This agent is also frequently used to treat hemochromatosis, a disease of iron accumulation that can be either genetic or acquired. Acquired hemochromatosis is common in patients with certain types of chronic anemia (e.g. thalassemia and myelodysplastic syndrome) who require many blood transfusions, which can greatly increase the amount of iron in the body. Treatment with iron-chelating drugs such as deferoxamine reduces mortality in persons with sickle cell disease or β‐thalassemia who are transfusion dependent. [8]

Administration for chronic conditions is generally accomplished by subcutaneous injection over a period of 8–12 hours each day. Administration of deferoxamine after acute intoxication may color the urine a pinkish red, a phenomenon termed "vin rosé urine". Apart from iron toxicity, deferoxamine can be used to treat aluminium toxicity (an excess of aluminium in the body) in selected patients. In US, the drug is not FDA-approved for this use. Deferoxamine is also used to minimize doxorubicin's cardiotoxic side effects and in the treatment of patients with aceruloplasminemia. [9] Deferoxamine may be effective for improving neurologic outcomes in persons with intracranial hemorrhage, although the evidence supporting the efficacy and safety for this indication was weak. [10]

Some published manuscripts suggesting the use of deferoxamine for patients diagnosed with COVID-19 because of the high level of ferritin among them. [11] [12]

Adverse effects

It is unclear if use during pregnancy is safe for the baby. [3]

Chronic use of deferoxamine may increase the risk of hearing loss in patients with thalassemia major. [13]

Chronic use of deferoxamine may cause ocular symptoms, growth retardation, local reactions and allergy. [14]

Mechanism

Deferoxamine is produced by removal of the trivalent iron moiety from ferrioxamine B, an iron-bearing sideramine produced by the actinomycetes, Streptomyces pilosus . Its discovery was a serendipitous result of research conducted by scientists at Ciba in collaboration with scientists at the Swiss Federal Institute of Technology in Zurich and the University Hospital in Freiburg, Germany [15] [4] Deferoxamine acts by binding free iron in the bloodstream and enhancing its elimination in the urine. By removing excess iron from persons with hemochromatosis, the agent reduces the damage done to various organs and tissues, such as the liver. Also, it speeds healing of nerve damage (and minimizes the extent of recent nerve trauma).[ citation needed ] Deferoxamine may modulate expression [16] and release of inflammatory mediators by specific cell types. [17]

Research

Deferoxamine is being studied as a treatment for spinal cord injury [18] and intracerebral hemorrhage. [19] [20] It is also used to induce hypoxia-like environment in mesenchymal stem cells. [21] [22] .

Since the terminal amine group of Deferoxamine does not participate in metal chelation, it has been used to immobilize Deferoxamine to surfaces and substrates for various industrial and biomedical applications. [23]

See also

Related Research Articles

<span class="mw-page-title-main">Hereditary haemochromatosis</span> Medical condition

Hereditary haemochromatosis type 1 is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. Humans, like most animals, have no mechanism to regulate excess iron, simply losing a limited amount through various means like sweating or menstruating

<span class="mw-page-title-main">Myelodysplastic syndrome</span> Diverse collection of blood-related cancers

A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.

<span class="mw-page-title-main">Thalassemia</span> Family of inherited blood disorders

Thalassemias are inherited blood disorders that result in abnormal hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe. Often there is mild to severe anemia as thalassemia can affect the production of red blood cells and also affect how long the red blood cells live. Symptoms of anemia include feeling tired and having pale skin. Other symptoms of thalassemia include bone problems, an enlarged spleen, yellowish skin, pulmonary hypertension, and dark urine. Slow growth may occur in children. Symptoms and presentations of thalassemia can change over time.

<span class="mw-page-title-main">Iron overload</span> Human disease

Iron overload or haemochromatosis indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatosis, a genetic disorder, and transfusional iron overload, which can result from repeated blood transfusions.

<span class="mw-page-title-main">Chelation therapy</span> Medical procedure to remove heavy metals from the body

Chelation therapy is a medical procedure that involves the administration of chelating agents to remove heavy metals from the body. Chelation therapy has a long history of use in clinical toxicology and remains in use for some very specific medical treatments, although it is administered under very careful medical supervision due to various inherent risks, including the mobilization of mercury and other metals through the brain and other parts of the body by the use of weak chelating agents that unbind with metals before elimination, exacerbating existing damage. To avoid mobilization, some practitioners of chelation use strong chelators, such as selenium, taken at low doses over a long period of time.

<span class="mw-page-title-main">Intracerebral hemorrhage</span> Type of intracranial bleeding that occurs within the brain tissue itself

Intracerebral hemorrhage (ICH), also known as hemorrhagic stroke, is a sudden bleeding into the tissues of the brain, into its ventricles, or into both. An ICH is a type of bleeding within the skull and one kind of stroke. Symptoms can vary dramatically depending on the severity, acuity, and location (anatomically) but can include headache, one-sided weakness, numbness, tingling, or paralysis, speech problems, vision or hearing problems, memory loss, attention problems, coordination problems, balance problems, dizziness or lightheadedness or vertigo, nausea/vomiting, seizures, decreased level of consciousness or total loss of consciousness, neck stiffness, and fever.

<span class="mw-page-title-main">Hepcidin</span> Protein-coding gene in the species Homo sapiens

Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals.

<span class="mw-page-title-main">African iron overload</span> Iron overload disorder caused by consumption of home-brewed beer

African iron overload is an iron overload disorder first observed among people of African descent in Southern Africa and Central Africa. It is now recognized to actually be two disorders with different causes, possibly compounding each other:

<span class="mw-page-title-main">Alpha-thalassemia</span> Thalassemia involving the genes HBA1and HBA2 hemoglobin genes

Alpha-thalassemia is a form of thalassemia involving the genes HBA1 and HBA2. Thalassemias are a group of inherited blood conditions which result in the impaired production of hemoglobin, the molecule that carries oxygen in the blood. Normal hemoglobin consists of two alpha chains and two beta chains; in alpha-thalassemia, there is a quantitative decrease in the amount of alpha chains, resulting in fewer normal hemoglobin molecules. Furthermore, alpha-thalassemia leads to the production of unstable beta globin molecules which cause increased red blood cell destruction. The degree of impairment is based on which clinical phenotype is present.

<span class="mw-page-title-main">Deferasirox</span> Oral iron chelator

Deferasirox, sold under the brand name Exjade & Asunra & Oleptiss both by Novartis among others, is an oral iron chelator. Its main use is to reduce chronic iron overload in patients who are receiving long-term blood transfusions for conditions such as beta-thalassemia and other chronic anemias. It is the first oral medication approved in the United States for this purpose.

<span class="mw-page-title-main">Beta thalassemia</span> Thalassemia characterized by the reduced or absent synthesis of the beta globin chains of hemoglobin

Beta thalassemias are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals. Global annual incidence is estimated at one in 100,000. Beta thalassemias occur due to malfunctions in the hemoglobin subunit beta or HBB. The severity of the disease depends on the nature of the mutation.

<span class="mw-page-title-main">Deferiprone</span> Iron chelator

Deferiprone, sold under the brand name Ferriprox among others, is a medication that chelates iron and is used to treat iron overload in thalassaemia major. It was first approved and indicated for use in treating thalassaemia major in 1994 and had been licensed for use in the European Union for many years while awaiting approval in Canada and in the United States. On October 14, 2011, it was approved for use in the US under the FDA's accelerated approval program.

Transfusional hemosiderosis is the accumulation of iron in the body due to frequent blood transfusions. Iron accumulates in the liver and heart, but also endocrine organs. Frequent blood transfusions may be given to many patients, such as those with thalassemia, sickle cell disease, leukemia, aplastic anemia, or myelodysplastic syndrome, among others. It is diagnosed with a blood transferrin test and a liver biopsy. It is treated with venipuncture, erythrocytapheresis, and iron chelation therapy.

<span class="mw-page-title-main">Hemosiderosis</span> Iron metabolism disease

Hemosiderosis is a form of iron overload disorder resulting in the accumulation of hemosiderin.

Congenital hemolytic anemia (CHA) is a diverse group of rare hereditary conditions marked by decreased life expectancy and premature removal of erythrocytes from blood flow. Defects in erythrocyte membrane proteins and red cell enzyme metabolism, as well as changes at the level of erythrocyte precursors, lead to impaired bone marrow erythropoiesis. CAH is distinguished by variable anemia, chronic extravascular hemolysis, decreased erythrocyte life span, splenomegaly, jaundice, biliary lithiasis, and iron overload. Immune-mediated mechanisms may play a role in the pathogenesis of these uncommon diseases, despite the paucity of data regarding the immune system's involvement in CHAs.

<span class="mw-page-title-main">Congenital dyserythropoietic anemia</span> Red blood cell disorder

Congenital dyserythropoietic anemia (CDA) is a rare blood disorder, similar to the thalassemias. CDA is one of many types of anemia, characterized by ineffective erythropoiesis, and resulting from a decrease in the number of red blood cells (RBCs) in the body and a less than normal quantity of hemoglobin in the blood. CDA may be transmitted by both parents autosomal recessively or dominantly.

Treatment of the inherited blood disorder thalassemia depends upon the level of severity. For mild forms of the condition, advice and counseling are often all that are necessary. For more severe forms, treatment may consist in blood transfusion; chelation therapy to reverse iron overload, using drugs such as deferoxamine, deferiprone, or deferasirox; medication with the antioxidant indicaxanthin to prevent the breakdown of hemoglobin; or a bone marrow transplant using material from a compatible donor, or from the patient's mother. Removal of the spleen (splenectomy) could theoretically help to reduce the need for blood transfusions in people with thalassaemia major or intermedia but there is currently no reliable evidence from clinical trials about its effects. Population screening has had some success as a preventive measure.

Hemochromatosis type 4 is a hereditary iron overload disorder that affects ferroportin, an iron transport protein needed to export iron from cells into circulation. Although the disease is rare, it is found throughout the world and affects people from various ethnic groups. While the majority of individuals with type 4 hemochromatosis have a relatively mild form of the disease, some affected individuals have a more severe form. As the disease progresses, iron may accumulate in the tissues of affected individuals over time, potentially resulting in organ damage.

<span class="mw-page-title-main">Transfusion-dependent anemia</span>

Transfusion-dependent anemia is a form of anemia characterized by the need for continuous blood transfusion. It is a condition that results from various diseases, and is associated with decreased survival rates. Regular transfusion is required to reduce the symptoms of anemia by increasing functional red blood cells and hemoglobin count. Symptoms may vary based on the severity of the condition and the most common symptom is fatigue. Various diseases can lead to transfusion-dependent anemia, most notably myelodysplastic syndromes (MDS) and thalassemia. Due to the number of diseases that can cause transfusion-dependent anemia, diagnosing it is more complicated. Transfusion dependence occurs when an average of more than 2 units of blood transfused every 28 days is required over a period of at least 3 months. Myelodysplastic syndromes is often only diagnosed when patients become anemic, and transfusion-dependent thalassemia is diagnosed based on gene mutations. Screening for heterozygosity in the thalassemia gene is an option for early detection.

Iron preparation is the formulation for iron supplements indicated in prophylaxis and treatment of iron-deficiency anemia. Examples of iron preparation include ferrous sulfate, ferrous gluconate, and ferrous fumarate. It can be administered orally, and by intravenous injection, or intramuscular injection.

References

  1. 1 2 3 4 5 6 "Deferoxamine Mesylate". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  2. ↑ World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. pp. 61–62. hdl: 10665/44053 . ISBN   9789241547659.
  3. 1 2 "Deferoxamine (Desferal) Use During Pregnancy". www.drugs.com. Archived from the original on 21 December 2016. Retrieved 13 December 2016.
  4. 1 2 Giardina PJ, Rivella S (2012). "Thalassemia Syndromes". In Hoffman R, Benz Jr EJ, Silberstein LE, Heslop H, Weitz J, Anastasi J (eds.). Hematology: Diagnosis and Treatment (6th ed.). Elsevier Health Sciences. p. 515. ISBN   978-1-4557-4041-3. Archived from the original on 2016-12-20.
  5. ↑ Keberle H (October 1964). "The Biochemistry of Desferrioxamine and its Relation to Iron Metabolism". Annals of the New York Academy of Sciences. 119 (2): 758–768. doi:10.1111/j.1749-6632.1965.tb54077.x. PMID   14219455. S2CID   37277528.
  6. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ↑ Merlot AM, Kalinowski DS, Richardson DR (March 2013). "Novel chelators for cancer treatment: where are we now?". Antioxidants & Redox Signaling. 18 (8): 973–1006. doi:10.1089/ars.2012.4540. PMID   22424293.
  8. ↑ Ballas SK, Zeidan AM, Duong VH, DeVeaux M, Heeney MM (July 2018). "The effect of iron chelation therapy on overall survival in sickle cell disease and β-thalassemia: A systematic review". American Journal of Hematology. 93 (7): 943–952. doi: 10.1002/ajh.25103 . PMID   29635754.
  9. ↑ Miyajima H, Takahashi Y, Kamata T, Shimizu H, Sakai N, Gitlin JD (March 1997). "Use of desferrioxamine in the treatment of aceruloplasminemia". Annals of Neurology. 41 (3): 404–407. doi:10.1002/ana.410410318. PMID   9066364. S2CID   22425032.
  10. ↑ Zeng L, Tan L, Li H, Zhang Q, Li Y, Guo J (2018). "Deferoxamine therapy for intracerebral hemorrhage: A systematic review". PLOS ONE. 13 (3): e0193615. Bibcode:2018PLoSO..1393615Z. doi: 10.1371/journal.pone.0193615 . PMC   5863956 . PMID   29566000.
  11. ↑ Abobaker A (November 2020). "Can iron chelation as an adjunct treatment of COVID-19 improve the clinical outcome?". European Journal of Clinical Pharmacology. 76 (11): 1619–1620. doi:10.1007/s00228-020-02942-9. PMC   7325475 . PMID   32607779.
  12. ↑ Alkattan A, Alabdulkareem K, Kamel A, Abdelseed H, Almutairi Y, Alsalameen E (January 2021). "Correlation between Micronutrient plasma concentration and disease severity in COVID-19 patients". Alexandria Journal of Medicine. 57 (1): 21–27. doi:10.1080/20905068.2020.1870788. PMC   8108185 .
  13. ↑ Badfar G, Mansouri A, Shohani M, Karimi H, Khalighi Z, Rahmati S, et al. (2017). "Hearing loss in Iranian thalassemia major patients treated with deferoxamine: A systematic review and meta-analysis". Caspian Journal of Internal Medicine. 8 (4): 239–249. doi:10.22088/cjim.8.4.239. PMC   5686301 . PMID   29201313.
  14. ↑ Taher AT, Musallam KM, Cappellini MD (February 2021). "β-Thalassemias". The New England Journal of Medicine. 384 (8): 727–743. doi:10.1056/NEJMra2021838. PMID   33626255. S2CID   232049825.
  15. ↑ Yawalkar SJ (1993). "Milestones in the research and development of desferrioxamine". Nephrology, Dialysis, Transplantation. 8 (Suppl 1): 40–42. doi:10.1093/ndt/8.supp1.40. PMID   8389019.
  16. ↑ Lee HJ, Lee J, Lee SK, Lee SK, Kim EC (September 2007). "Differential regulation of iron chelator-induced IL-8 synthesis via MAP kinase and NF-kappaB in immortalized and malignant oral keratinocytes". BMC Cancer. 7: 176. doi: 10.1186/1471-2407-7-176 . PMC   2078595 . PMID   17850672.
  17. ↑ Choi EY, Kim EC, Oh HM, Kim S, Lee HJ, Cho EY, et al. (June 2004). "Iron chelator triggers inflammatory signals in human intestinal epithelial cells: involvement of p38 and extracellular signal-regulated kinase signaling pathways". Journal of Immunology. 172 (11): 7069–7077. doi: 10.4049/jimmunol.172.11.7069 . PMID   15153529.
  18. ↑ "Public summary of opinion on orphan designation: Deferoxamine mesylate for the treatment of traumatic spinal cord injury". Committee for Orphan Medicinal Products. European Medicines Agency. 3 October 2013. Archived from the original on 2013-07-17.
  19. ↑ Wu H, Wu T, Xu X, Wang J, Wang J (May 2011). "Iron toxicity in mice with collagenase-induced intracerebral hemorrhage". Journal of Cerebral Blood Flow and Metabolism. 31 (5): 1243–1250. doi:10.1038/jcbfm.2010.209. PMC   3099628 . PMID   21102602.
  20. ↑ Ren H, Han R, Chen X, Liu X, Wan J, Wang L, et al. (September 2020). "Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update". Journal of Cerebral Blood Flow and Metabolism. 40 (9): 1752–1768. doi:10.1177/0271678X20923551. PMC   7446569 . PMID   32423330.
  21. ↑ Ren H, Cao Y, Zhao Q, Li J, Zhou C, Liao L, et al. (August 2006). "Proliferation and differentiation of bone marrow stromal cells under hypoxic conditions". Biochemical and Biophysical Research Communications. 347 (1): 12–21. doi:10.1016/j.bbrc.2006.05.169. PMID   16814746.
  22. ↑ Woo KJ, Lee TJ, Park JW, Kwon TK (April 2006). "Desferrioxamine, an iron chelator, enhances HIF-1alpha accumulation via cyclooxygenase-2 signaling pathway". Biochemical and Biophysical Research Communications. 343 (1): 8–14. doi:10.1016/j.bbrc.2006.02.116. PMID   16527254.
  23. ↑ Touma, J. G.; Kelly, C.; Coblyn, M.; Jovanovic, G. N.; Schilke, K. (2023). "Reversible Covalent Binding of Desferrioxamine B (DFOB) to Polystyrene Microspheres for the Chelation of Aqueous Iron Citrate". Industrial & Engineering Chemistry Research. 62 (37): 15109–15119. doi:10.1021/acs.iecr.3c00812.
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