Deferoxamine administration

Koren G, Kochavi-Atiya Y, Bentur Y, Olivieri NF. The effects of subcutaneous deferoxamine administration on renal function in thalassemia major. Int J Hematol 1991 54(5) 371-5. 

Rapid infusion of deferoxamine over 15 min results in hypotension and tachycardia. An infusion rates of 15mgkg h or longer is recommended. Intravenous deferoxamine administration has been reported to cause renal insufficiency indicated by a progressive increase in serum creatinine and decrease in creatinine clearance. 

Tenenbein M, Kowalski S, and Sienko A (1992) Pulmonary toxic effects of continuous deferoxamine administration in acute iron poisoning. Lancet 339 699-701. 

Deferoxamine interferes with photometric measurements of iron and UIBC, an important consideration if serum iron and UIBC measurements are used to monitor therapy with deferoxamine. Deferoxamine has a short tm ( lh) therefore, a delay of at least 4h after deferoxamine administration would be appropriate before measurements of serum iron and UIBC are repeated. 

In the support of hematology patients, the therapy candidates for home care may be chemotherapy, IV antibiotics in febrile neutropenia, blood products, IV immunoglobulins, fluid/electrolyte replacement, central line maintenance, and specific treatments such as deferoxamine administration. 

Combinations of these drugs are increasingly utilised so far, no synergies in side effects are evident. A major meta-analysis of 22 trials involving 2187 participants included eight deferoxamine to deferiprone comparisons, five deferoxamine to deferoxamine/deferiprone comparisons, two deferoxamine to deferasirox comparisons, and two comparisons of different routes of deferoxamine administration (bolus versus continuous infusion). The authors concluded that adverse events were less likely with deferoxamine than with deferiprone in one trial and less likely with deferoxamine than deferoxamine and deferiprone combination therapy in two trials [47 ]. 

Zarogiannis, S.G., Jurkuvenaite, A., Fernandez, S., et al., 2011. Ascorbate and deferoxamine administration after chlorine exposure decrease mortality and lung injury in mice. Am. J. Respir. Cell. Mol. Biol. 45, 386-392. 

Ereret T, Valable S, Chazalviel L, Saulnier R, Mackenzie ET, Petit E, Bemaudin M, Boulouard M, Schumann-Bard P. Delayed administration of deferoxamine reduces brain damage and promotes functional recovery after transient focal cerebral iscbemia in tbe rat. Eur J Neurosci 2006 23 1757-1765. 

Deferoxamine (see also Chapters 58 and 59) Chelates excess iron Reduces the toxicity associated with acute or chronic iron overload Treatment of acute iron poisoning and for inherited or acquired hemochromatosis that is not adequately treated by phlebotomy Preferred route of administration is IM or SC Toxicity Rapid IV administration may cause hypotension acute respiratory distress has been observed with long infusions neurotoxicity and increased susceptibility to certain infections has occurred with longterm use... 

Rapid intravenous administration may result in hypotension. Adverse idiosyncratic responses such as flushing, abdominal discomfort, and rash have also been observed. Pulmonary complications (eg, acute respiratory distress syndrome) have been reported in some patients undergoing deferoxamine infusions lasting longer than 24 hours, and neurotoxicity and increased susceptibility to certain infections (eg, with Yersinia enterocolitica) have been described after long-term therapy of iron overload conditions (eg, thalassemia major). 

Connor DJ, Harrell LE, Jope RS. 1989. Reversal of an aluminum-induced behavioral deficit by administration of deferoxamine. Behav Neurosci 103 779-783. 

Deferoxamine derives from Streptomyces pilosus. The substance possesses a very high iron-binding capacity but does not withdraw iron from hemoglobin or cytochromes. It is poorly absorbed enterally and must be given parenterally to cause increased excretion of iron. Oral administration is indicated only if enteral absorption of iron is to be curtailed. Unwanted effects include allergic reactions. 

Co-administration of artemisinin derivatives, such as artesunate, with deferoxamine may be useful in patients with cerebral malaria, because of the combination of rapid parasite clearance by the former and central nervous system protection by the latter. Artesunate has been studied alone and in combination with deferoxamine in a singleblind comparison (40). Adverse effects were generally mild and there were no differences between the two regimens. 

Deferiprone has a concentration-dependent affinity for iron, with a higher binding constant than deferoxamine or diethylenetriaminepentaacetic acid (DTPA). However, it takes three molecules of deferiprone to bind one molecule of iron, whereas deferoxamine binds iron in a 1 1 ratio. For this reason, deferiprone must be present in very high concentrations, close to toxic concentrations, to be effective (2). Deferiprone dissociates from iron when its concentration in body fluids falls to the concentration achieved just a few hours after oral administration (3). Deferiprone is effective in excreting iron in iron storage diseases and aluminium in patients on hemodialysis (1). 

Sensorimotor neurotoxicity, with paresthesia, areflexia, reduced vibration and position sense, muscle weakness of the arms, and concomitant disturbances of vision and hearing, has been described in two thalassemia patients during the intravenous administration of high dosages of deferoxamine (120 mg/kg/day) (28). 

The administration of deferoxamine to dialysis patients in order to chelate aluminium is often associated with asymptomatic hypocalcemia, which can in turn aggravate hyperparathyroidism (12). Deferoxamine-induced hypocalcemia can be corrected with supplements of vitamin D and calcium carbonate. 

In an 8-month-old child the administration of deferoxamine for chelation of aluminium, which had accumulated as a result of total parenteral nutrition, caused sustained hypocalcemia without concomitant hjrpercalciuria (71). 

When used in patients without iron overload, deferoxamine can cause iron deficiency (12). In 20 patients, there were falls in ferritin concentrations in six, requiring withdrawal of deferoxamine and parenteral administration of iron dextran (12). Monitoring ferritin concentrations is therefore recommended in patients receiving deferoxamine for aluminium overload. On the other hand, the administration of deferoxamine (500mg/day by subcutaneous infusion) improves chronic anemia in patients with rheumatoid arthritis (77). This effect is thought to be achieved through increased erythropoietin responsiveness, secondary to iron chelation. Iron chelation with deferoxamine also improves hemopoiesis in patients with myelodysplastic syndromes and can reduce transfusion dependency (78). Exactly how deferoxamine works in these patients remains to be explained. 

Gastrointestinal upsets are frequent after parenteral administration of deferoxamine (12). In addition to nausea, vomiting, and abdominal cramps, passage of black stools can occur, perhaps because of increased stool iron content. Nausea, anorexia, and vomiting often occur when deferoxamine is used in rheumatoid arthritis or Alzheimer s disease (32,83). 

Deferoxamine has occasionally been reported to cause renal insufficiency (85,86) and adequate hydration and repeated measurements of renal function are recommended in patients receiving intravenous deferoxamine. Perhaps the inability to reabsorb sodium and to concentrate urine during administration of deferoxamine is due to a diuretic effect of ferrioxamine (87). 

Generalized hypersensitivity reactions and anaphylactic shock can occur but are infrequent. H5rpersensitivity reactions to deferoxamine may require permanent withdrawal, worsening the prognosis in thalassemia. However, successful desensitization has been achieved in three patients with previous deferoxamine hypersensitivity, enabling continued administration of deferoxamine (8,114,115). 

The administration of high subcutaneous doses of deferoxamine to young children with thalassemia before iron... 

Children are also susceptible to opportunistic infection, notably Y. enterocolitica sepsis (142). In 10 children receiving intravenous deferoxamine (25 mg/kg) there were unexpected infections in four three had episodes of fever and S. aureus in blood cultures, and one had Y. enterocolitica sepsis (128). Because of the possibility of septicemic dissemination secondary to digestive Y. enterocolitica infection, the occurrence of febrile diarrhea in a child with thalassemia is a reason for immediate withdrawal of deferoxamine and the administration of antimicrobial therapy (co-trimoxazole) (142). 

Intravenous deferoxamine can be indicated in gross iron overload, serious cardiomyopathy, or intolerance of or non-adherence to subcutaneous administration. The results of continuous 24-hour deferoxamine infusion via indwelling intravenous catheters in 17 patients (25 intravenous lines) have been presented (154). The doses of deferoxamine were calculated with reference to the serum ferritin concentration, with a view to maintaining the therapeutic index (mean daily dose in mg/kg divided by the serum ferritin concentration in ng/ml) below... 

Sofroniadou K, Drossou M, Foundoulaki L, Konstantopoulos K, Kyriakoy D, Zervas J. Acute bone marrow aplasia associated with intravenous administration of deferoxamine (desferrioxamine). Drug Saf 1990 5(2) 152-4. 

Specific treatment for iron toxicity involves administration of deferoxamine to chelate unbound iron. " The defer-oxamine-Fe complex is then excreted in the urme, often... 

In hemochromatosis secondary to refractory anemias (e.g., Cooley s anemia, sickle cell anemia), patients require repeated blood transfusions to survive childhood and adulthood. Therapy consists of administration of ironchelating agents. Deferoxamine, an iron chelator isolated from Streptomyces pilosis, has the structure ... 

Deferoxamine given orally complexes with dietary iron, making the drug and the iron unavailable for absorption. The preferred route of administration is by intramuscular injection. Irritation and pain at the site of administration and the need for daily injections make the treatment unpopular. In addition, even with coadministration of large amounts of ascorbie acid, the iron loss produced is far below that necessary to remove all of the iron accumulated during chronic transfusion therapy. 

Deferoxamine is a highly selective chelator of iron that theoretically binds ferric (Fe +) iron in a 1 1 molar ratio (100 mg deferoxamine to 8.5 mg ferric iron) that is more stable than the binding of iron to transferrin. Deferoxamine removes excess iron from the circulation and some iron from transferrin by chelating ferric complexes in equilibrium with transferrin. The resulting iron-deferoxamine complex, ferrioxamine, is then excreted in the urine. Its action on intracellular iron is unclear, but it may have a protective intracellular effect or may chelate extramitochondrial iron. The parenteral administration of deferoxamine produces an orange-red-colored urine within 3 to 6 hours because of the presence of ferrioxamine in the urine. For mild to moderate cases of iron poisoning, where its use is unclear, the presence of discolored urine indicates the persistent presence of chelatable iron and the need to continue deferoxamine. The reliance on discolored urine as a therapeutic end point has been challenged because it is not sensitive and is difficult to detect. ... 

Deferoxamine deferoxamine mesylate, desferal mesylate) is poorly absorbed after oral administration, and parenteral administration is required in most cases. For severe iron toxicity (serum iron levels >500 /rg/dL), the intravenous route is preferred. The drug is administered at 10-15 mg/kg/h by constant infusion. Faster rates of infusion (45 mg/kg/h) have been used in a few cases rapid boluses usually are associated with hypotension. Deferoxamine may be given intramuscularly in moderately toxic cases (serum iron 350-500 )ig/dL) at a dose of 50 mg/kg with a maximum dose of 1 g. Hypotension also can occur with the intramuscular route. 

For chronic iron intoxication e.g., thalassemia), an intramuscular dose of 0.5-1.0 g/day is recommended, although continuous subcutaneous administration (1-2 g/day) is almost as effective as intravenous administration. When blood is being transfused to patients with thalassemia, 2 g deferoxamine (per unit of blood) should be given by slow intravenous infusion (rate not to exceed 15 mg/kg/h) during the transfusion but not by the same intravenous fine. Deferoxamine is not recommended in primary hemochromatosis phlebotomy is the treatment of choice. Deferoxamine also has been used for the chelation of aluminum in dialysis patients. Deferoxamine is metabohzed principally by plasma enzymes, but the pathways have not been defined. The drug also is excreted readily in the urine. 

Treatment of acute iron intoxication Immediate treatment is necessary and usually consists of removal of unab.sorbed tablets from the gut. correction of acid-ba.se and electrolyte abnormalities, and parenteral administration of deferoxamine, which chelates circulating iron. 

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