oral iron chelation with deferiprone

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ORAL IRON CHELATION WITH DEFERIPRONE

Orna Diav-Citrin, MD, and Gideon Koren, MD, ABMT, FRCPC

Patients with refractory anemias, such as thalassemia major, who require regular red blood cell transfusions progressively accumulate iron. Each unit of red blood cells contains 200 to 250 mg of elemental iron and thus, patients on chronic transfusion programs accumulate approximately 0.5 mg/kg/day of iron. Tissue iron accumulation results in progressive organ dysfunction, leading to death if no iron-chelating therapy is initiated. Although transfusions sustain normal growth and development and improve the life expectancy of patients, they are complicated by the harmful consequences of iron overload because humans lack a physiologic mechanism for excreting excess iron.

Iron-chelating therapy for the management of transfusional iron overload was first introduced in the early 1960~.3~, 51, 63, 74 It is only since 1974, after the demonstration that it was possible to reduce the concentration of hepatic iron and arrest the progression of hepatic fibrosis in thalassemic patients with its long-term use,I6 that desferrioxamine gained acceptance as the standard form of therapy. Unfortunately, desferrioxamine is only effective when administered parenterally. Subcutaneous doses of 20 to 40 mg/kg/day for 8 to 12 hours resulted in iron excretion sufficient to produce a negative iron 68

Over the past two decades, several studies have demonstrated that regular desferrioxamine therapy ameliorates hepatic, cardiac, and endocrine dysfunction, improves growth and sexual maturation, and prolongs survival in iron- loaded patients.2z, 61

Because of its high cost (approximately $40 US/2 g vial), desferrioxamine is not available in many countries where it is most needed. Even where it is available, many patients fail to comply with a regimen of prolonged subcutaneous infusions, especially during adolescence. Other problems with desferrioxamine therapy include its serious adverse effects. Intensive therapy in young

This work was supported by an MRC-Industry grant and by Apotex, Inc, Toronto.

From the Division of Clinical Pharmacology and Toxicology, Department of Pediatrics (ODC, GK), and Research Institute (GK), The Hospital for Sick Children; and the Departments of Pediatrics, Pharmacology, and Medicine, University of Toronto, To- ronto, Ontario, Canada

PEDIATRIC CLINICS OF NORTH AMERICA

VOLUME 44 - NUMBER 1 * FEBRUARY 1997 235

236 DIAV-CITRIN & KOREN

Figure 1. Chemical structure of desferrioxarnine.

patients with low body-iron stores may result in serious neurotoxicity (auditory and visual), abnormalities of cartilage formation, and stunted linear growth.5556, 66

In the last decade we have witnessed the emergence of interest in oral iron chelation for transfusional iron-loaded patients in thalassemia and other refractory anemias. Currently, the orally active iron chelator with the broadest clinical experience is deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one, or L,). The agent is a member of the hydroxypyridones of bidentate (two binding sites) iron chelators patented by Hider et ar3 in 1982 as an alternative to desferrioxamine in the treatment of chronic iron overload.

This article summarizes the experience with this new, orally active iron chelator, deferiprone. In addition, it reviews novel uses of iron chelation and potential new applications in acute iron poisoning.

STRUCTURAL COMPARISON BETWEEN DESFERRIOXAMINE AND DEFERIPRONE

Desferrioxamine (Fig. l), a trihydroxamate siderophore derived from Strep- tomyces pilosus, is a hexadentate chelat0r.3~ It is capable of combining with ferric iron at a 1:l molar ratio because of its six binding sites with a high stability constant ( lO3I). The desferrioxamine molecule is wrapped around the iron nu- cleus, encasing it in an envelope of organic material. Because of its high molecular weight, desferrioxamine is poorly absorbed from the gastrointestinal tract, and is therefore administered parenterally.

Deferiprone (Fig. 2) is a bidentate ligand. Therefore, three chelator molecules are required to form a neutral complex with a single iron atom.

The hexadentate chelators are inherently more stable kinetically than bidentate chelators. The greater stability of the hexadentate molecules minimizes the risk of iron redistribution or the participation of unstable iron-chelate complexes

Figure 2. Chemical structure of deferiprone.

ORAL IRON CHELATION WITH DEFERIPRONE 237

in the generation of harmful free radicals; they also have the ability to scavenge iron at low concentrations. On the other hand, bidentate compounds have a lower molecular weight and are usually easily absorbed from the gut. Because of this, however, they are able to penetrate other cells more quickly with the potential risk of cellular toxicity resulting from their interaction with iron- requiring enzymes.&

ORAL IRON CHELATION WITH DEFERIPRONE

Chemistry and Pharmacology of Deferiprone

Deferiprone is a white solid compound with a molecular weight of 139 kD.44 It is water-soluble with a partition coefficient (K part, the ratio of the concentrations of the compound between an organic phase and water at a pH of 7.4) close to Deferiprone is highly stable at pH values ranging from 1 to 12" and it is resistant to cleavage by digestive enzymes?' It generally forms a 1:3 complex with iron with a stability constant of 36.40 At low concentrations of chelator, however, partially dissociated deferiprone-iron complexes (2:1, 1:l) can form and may, in turn, generate hydroxyl radicals.67 Deferiprone binds ferric iron with a high affinity (binding constant log p = 37).

Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract. It is excreted in the urine mostly as a glucuronide or unchanged, bound to iron or bound to trace metals such as zinc and aluminum.44 Glucuronidation abolishes the ability of deferiprone to chelate iron, because the hydroxyl group of deferiprone needed for iron binding is involved in the conjugation. The excretion of deferiprone-glucuronide is slower than that of free deferiprone. In patients with impaired renal function, the glucuronide derivative may accumulate in the plasma? The pharmacokinetic characteristics of deferiprone are sum- marized in Table 1.

The efficacy of the drug in heavily iron-loaded patients, assessed by the amount of the drug excreted in urine bound to iron in 24 hours compared with the size of a single oral dose, has been estimated to be approximately 4%? The urinary iron excretion in heavily iron-loaded patients following a single dose is related to the area under the concentration-time curve for plasma deferiprone.

Whether deferiprone is excreted in the stools and whether or not it increases fecal iron excretion in humans remain controversial. There are reports of iron excretion in the stool of iron-loaded patients following oral administration of deferiprone amounting to up to 30% of the total iron e x ~ r e t e d . ~ ~ , ~ ~ Another study9 indirectly suggested that approximately 20% of an oral dose of deferiprone may be excreted in the stools. Kontoghiorghes et a1,44 however, reported no increase

Table 1. A SUMMARY OF DEFERIPRONE PHARMACOKINETICS

NO. of t%, Cmax t'/2B AUC Study Dose Patients (minutes) (pg/mL) (minutes) (pg.minutelmL)

Kontoghiorghes 3000 rng 7 7.1 t 11.3 NA 74.3 ? 28.7 NA

Matsui et aP9 25 mg/kg 14 NA 17.49 ? 2.08 159.6 ? 20.5 1635 2 174.97 Al-Refaie et a19 50 mg/kg 24 22.2 2 17.7 20.1 ? 11.5 91.1 ? 33.1 3020 t 1199

et al"

1% = half-life; a = absorption; p = elimination: Cmax = maximum concentration; AUC = area under the plasma serum concentration-time cuwe from time zero to infinity; NA = not available


in iron excretion and no evidence of deferiprone in the stools of two patients with iron overload given deferiprone.

Several factors may influence deferiprone pharmacokinetics and efficacy. Food prolongs the rate of absorption of deferiprone but it does not signifi-

cantly affect the extent of absorption measured by the area under the plasma concentration-time curve. Thus, food does not change the chelation capacity of the

Vitamin C was found to have no effect on urinary iron excretion in two small trials.72 The exact effect of vitamin C therapy, however, both in vitamin C replete and deficient patients is yet to be determined.

No increase in the urinary iron excretion was found in two normal volun- teers when deferiprone complexed to iron was administered orally.57

There has been some evidence that long-term treatment with deferiprone may be associated with a fall in the deferiprone trough concentration^.^^ The findings suggest self-induction of deferiprone metabolism or decreased absorption during long-term therapy. The former is supported by the results of an in vitro study that has shown that deferiprone induces its own metabolism by human hepatocytes in

The sites from which deferiprone chelates iron are not fully established. Animal studies have shown that deferiprone concentrates mainly in the liver.” Because free deferiprone readily enters cells, it is likely that both parenchymal and reticuloendothelial cells are sources of chelated iron. Unlike desferrioxamine, deferiprone can also chelate iron from transferring, 27 and, based on studies of iron-loaded patients, it is estimated that up to 20% of iron excreted in the urine following a single oral dose may be derived from iron bound to trans- ferrimY Deferiprone also chelates iron from intact red cells that may be important in the therapeutic response to deferiprone in thalassemia intermedia.71

Clinical Trials of Deferiprone

The results of the first clinical studies on the efficacy of deferiprone in patients with myelodysplasia and thalassemia major were reported in 1987.41, 42

They showed that deferiprone could induce urinary iron excretion comparable to that achieved with desferrioxamine. Iron excretion correlated to the iron burden. Subsequent short-term clinical trials have confirmed those preliminary findings?, 72 Dose-response studies have shown that 75 mg/kg body weight was the minimal daily dose required to achieve a negative iron balance (>0.5 mg/ kg/day) in most patients with thalassemia major.57 These findings, confirmed in a later comparison study between deferiprone and desferrioxarninez3 in sickle- cell disease, provide evidence that short-term efficacy of deferiprone is inferior to that of desferrioxamine. Long-term trials of deferiprone have shown long- term effectiveness of deferiprone in the majority of patients with transfusional iron o~erload.~, 17, 43, 54, * These studies have also provided information on a number of adverse effects that were not apparent in the initial short-term trials.

Changes in Serum Ferritin Concentrations

Significant decreases in serum ferritin were reported in most of the long- term clinical studies3, 58, M, but not in all of them.29, 43, 72 Those trials were different in their design in many aspects: the duration of deferiprone treatment before repeated serum ferritin assays were conducted; different administered doses of


deferiprone; the number of patients entering the studies after being poorly compliant with desferrioxamine and, thus, starting with high serum ferritin levels; and the degree of compliance with deferiprone therapy. One prospective trial” showed a reduction in the mean serum ferritin level from approximately 4000 pg/L to approximately 2500 pg/L, whereas in all patients with initial ferritin levels below 2500 Fg/L there was no change. This may suggest that deferiprone can reduce serum ferritin to the range associated with cardiac disease-free survival in desferrioxamine-treated patients or maintain it in that range.z2

Reduction in serum ferritin concentration suggests a decline in body iron burden during long-term oral chelation with deferiprone. Serum ferritin levels may be misleading in the assessment of iron burden in individual patients;’ however, because serum ferritin is also influenced by other factors such as hemolysis, ineffective erythropoiesis, vitamin C deficiency, inflammation, and liver disease, all of which are common in iron-loaded patients.

Changes in Hepatic Iron Concentration

Initial evidence that therapy with deferiprone may reduce tissue iron stores was provided by a study of an iron-loaded patient with thalassemia intermedia in whom stores were reduced to normal over a period of 9 months.59

This was subsequently followed by a report of a significant decrease in hepatic iron concentrations in heavily iron-loaded, previously poorly chelated patients.54 The patients in that cohort were given deferiprone therapy at a dose of 75 mg/kg/day for a mean of 3.1 t 0.3 years. In 10 patients in whom previous chelation therapy with desferrioxamine had been ineffective, initial hepatic iron concentrations decreased from a mean of 125.3 f 11.5 to 60.3 t 9.6 pmol/g wet weight (P < 0.005). In the remaining 11 patients, previously effectively chelated and with initial liver iron less than 80 pmol/g wet weight, the liver iron remained below this level. Hepatic iron concentrations below 80 pmol/g wet weight are associated with prolonged survival free of clinical complications from iron overload in thalassemia patients treated with desferrioxamine.22

Improvement in Organ Function

Lightening of skin color occurring within a few months of initiating chelation with deferiprone was observed in heavily pigmented, previously inade- quately chelated patients3, l4

Improvement in cardiac function assessed by radionuclide angiography was observed in one patient with an established iron-related cardiomyopathy. This was associated over a 1-year period of study with a decrease in cardiac iron measured by MR imaging.59 In the prospective study of deferiprone in 21 patients with thalassemia,54 a reduction in cardiac stores has been by cardiac MR imaging evaluation. In other no overall change in cardiac function assessed by multiple gated acquisition (MUGA) scanning occurred among 31 patients treated for a year (Al-Refaie et al, unpublished data). Because the leading cause of death in iron-loaded patientsz6 is cardiac iron loading, the ability to prevent and reverse cardiac iron loading is crucial for any iron chelator.

In two patients with thalassemia treated with deferiprone, changes consis- tent with the reduction of anterior pituitary iron were demonstrated by MR imagi11g.5~


Progressive decline in serum aspartate aminotransferase level has been reported in some patients during long-term deferiprone treatrnent.l4, 72

Changes in Non-Transferrin Bound Iron

Non-transferrin bound iron (NTBI) is a form of iron present in the serum of heavily iron-loaded patients.30 It is believed to be involved in free-radical formation and hence tissue toxicity.3i The concentration of NTBI has been found to correlate with the degree of organ damage in thalassemia major. Serum NTBI dropped significantly after 6 months of deferiprone therapy. NTBI was suggested as an independent parameter to measure the effectiveness of chelation.'O

Adverse Effects

Deferiprone is generally well tolerated with no significant acute toxic effects at doses up to 150 mg/kg daily. Excellent compliance with the treatment has been reported in most 62 There have been several reports of side effects, however, the most important of which are agranulocytosis and arthropathy.

Neutropenia and Agranulocytosis

The first reported toxic effect of deferiprone was agranulocytosis in a woman with Blackfan-Diamond anemia.% To date, there have been 13 patients in whom neutropenia or agranulocytosis has been reported (11 of whom had neutrophil counts of 0.5 x 109/L or less at the time of diagnosis).2,",'3,29,35 The overall incidence of agranulocytosis has been estimated at approximately 2% of long-term treated patientsi3 Agranulocytosis has been observed as early as 6 weeks, and up to 21 months, after initiating therapy with deferiprone. The periods of neutropenia and of total agranulocytosis have ranged from 7 to 124 days and up to 7 weeks, respectively. Three patients have received at least one course of granulocyte colony-stimulating factor during their course of neutro- ~ e n i a ~ ~ in an attempt to accelerate recovery. The dose of deferiprone in these patients has ranged from 50 to 105 mg/kg. The patients suffered from thalassemia major, Blackfan-Diamond anemia, and myelodysplasia. Females tended to predominate (9/13) and, in general, the patients have been heavily iron- loaded. Rechallenge has invariably led to a second episode of neutropenia and should be avoided.

The mechanism for the neutropenia or agranulocytosis associated with deferiprone administration remains obsc~re . '~ -~~ It seems most likely that the patients affected have an idiosyncratic sensitivity to a toxic effect of deferiprone or one of its metabolites. Deferiprone-associated neutropenia or agranulocytosis appears to be fully reversible to date.

Arthropathy

The second most important adverse effect and the most common clinical problem associated with deferiprone treatment is joint toxicity, first described by Bartlett et al.I7 Studies have reported an incidence in up to 38% of patients.'. 3, 14, l9 The reported incidence of arthropathy from the International Collaborative


Study Group, however, was 21Y0.~ The arthropathy or lesser degree of joint pain may occur within a few weeks after initiation of therapy with deferiprone. The syndrome consists of musculoskeletal stiffness, joint pain, and, in severe cases, joint effusions. The large joints are primarily affected. In the Indian trial, the incidence was greatest in the most iron-loaded patients receiving the largest dose of the drug (100 mg/kg/day).I4 In most patients, the symptoms and signs resolved spontaneously on discontinuation of the drug or following dose reduction. In a minority of patients who developed severe arthropathy the drug had to be permanently discontinued. Arthroscopy in seven affected patients in Bombay revealed excess iron in the synovium, cartilage, and joint fluid but no deferiprone, implying that iron may be involved in the cause of the problem.’ In the Canadian study, aspiration of synovial fluid in three patients revealed a sterile transudate without inflammatory cells; arthroscopy showed mild synovial hypertrophy and hyperplasia with iron staining; and synovial biopsy revealed lining-cell proliferation and extensive iron deposition without evidence of an inflammatory or allergic rea~ti0n.I~ In two patients, symptoms resolved during continued drug administration whereas the third has continued therapy without worsening of the symptoms.Iy

The cause of the deferiprone-associated arthropathy is still not fully known. The arthritis seems to be due to a toxic effect of deferiprone, possibly mediated by free radicals, caused by formation of 1:l or 1:2 deferiprone-iron complexes rather than the usual inert 1:3 complexes. It has been hypothesized that as iron is shifted into the synovium and incompletely complexed with deferiprone, increased production of free radicals may result in the peroxidation of synovial membranes. No relation to the presence of antinuclear factor antibody, rheumatoid factor, antihistone antibody, or antiDNA antibody in the patient’s plasma before or during deferiprone treatment has been consistently detected. The overall incidence of a positive rheumatoid factor test in patients with deferiprone long-term treatment has been estimated to increase from 13.9% to 16.2% and the incidence of antinuclear factor from 9.8% to 11.9%; minor fluctuations in the titer of these antibodies were

Other Adverse Effects Reported with Deferiprone

A decrease in the concentration of zinc in plasma and increased urinary zinc excretion in patients receiving long-term deferiprone therapy were first reported by Al-Refaie et al.14 In 8 of 10 patients on deferiprone treatment, increased urinary zinc excretion was found associated with a decrease in the serum zinc concentration to subnormal levels in four patients. One patient developed dry, scaling skin lesions that were ascribed to zinc deficiency and responded to zinc therapy. A few cases with zinc depletion have been reported by others?, 29, 38 Al-Refaie et all5 have shown that deferiprone causes increased urinary zinc excretion, particularly in patients with diabetes mellitus and to a lesser extent in patients with glucose intolerance. Decreased serum zinc levels were found in 7 of 39 patients treated with deferiprone for at least 6 months. In other studies no changes in serum zinc status have been reported. The observed difference may be partly due to the absence of diabetic patients from some trial groups. Serum zinc estimation has limited value in assessing zinc deficiency. Patients with normal zinc concentrations may be zinc deficient and subnormal serum zinc is only suggestive of zinc defi~iency.’~” The reported incidence of zinc deficiency from the International Collaborative Study Group was 14%.6


Zinc deficiency is not a major adverse effect of deferiprone therapy. It can be readily detected and easily treated.

Gastrointestinal symptoms have been reported with deferiprone therapy. Symptoms include anorexia, nausea, and vomiting3, 9, 14, 32 In some patients the gastrointestinal symptoms were a cause of discontinuing therapy. The reported incidence of nausea from the International Collaborative Study Group on oral iron chelation was 8% of patients.6

Fluctuations in liver function during deferiprone treatment were first reported by Bartlett.I7 Elevated liver function tests appeared to be more frequent in patients infected with hepatitis C. In all cases the raised serum transaminase levels gradually settled to pretreatment levels or lower after 3 months of therapy. More recently, the incidence of abnormal liver enzymes, defined as an increase of more than twice the upper limit of normal serum alanine aminotransferase (ALT) at any time during the observation period, was 50 of 84 patients (60%) in combined data from four centers? Nine of the 50 had hepatitis C and three had raised serum ALT before initiating deferiprone therapy. In 37 of the remaining 38, liver abnormalities were mild and transient, resolving spontaneously without reducing or discontinuing deferiprone therapy. In one patient abnormal liver enzymes were considered to be related to deferiprone and they fell to pre- deferiprone levels on cessation of deferiprone therapy.

ACUTE IRON POISONING

Iron intoxication remains a common and serious form of accidental poisoning, especially in children. Recently, there has been an increased number of reported iron intoxications,45 as well as increased mortality related to acute iron poisoning.20

Desferrioxamine has been used as a potent chelator in the context of acute iron poisoning.50, 73 It is currently the most effective agent in eliminating excess iron after its ab~orpt ion .~~ Desferrioxamine, however, is limited to use in countries that can afford it. For use in the treatment of acute iron poisoning, it is further limited to use in a hospital setting. Deferiprone may have a potential use in the treatment of acute iron intoxication in remote areas, far away from a medical center, as well as in countries where desferrioxamine is unavailable. Deferiprone was shown to be efficacious in the treatment of acute iron intoxication in an animal

Desferrioxamine has been reported to have adverse effects, such as hypoten- sion in the context of acute iron intoxication. Desferrioxamine covalently attached to high-molecular weight carbohydrates such as dextran and hydroxy- ethyl starch prevented the decrease in blood pressure that may occur with large desferrioxamine doses in experimental animals.47 It was generally less toxic than the free desferrioxamine when given intravenously.

NOVEL USES OF IRON CHELATION

Protection from acute and chronic iron toxicity is only one aspect of the clinical potential of iron chelation therapy. There are three categories of diseases unrelated to iron toxicity in which chelation therapy may be considered poten- tially useful by interfering with iron dependent reactions.


Diseases in Which Iron May Be Essential for the Production of Free Radicals Involved in Tissue Damage

The number of diseases known to be associated with oxygen radical damage in which treatment with iron chelators may be beneficial is increasing each year. The diseases include rheumatoid arthritis,@ adult respiratory distress syndrome,48 anthracycline cardiotoxicity,32 postischemic reperfusion injury,I8 and others. Iron-chelation therapy might be of benefit if given in these conditions; clinical trials are underway.

Diseases in Which Iron Depletion May Interfere with Cell Division

Several studies have suggested that available iron may have a role in promoting cell growth. Another study demonstrated the antitumor activity of desferrioxamine, especially in patients with neuroblastoma in whom ferritin is in part tumor-derived and high concentrations correlate with poor outcome.25

Malaria continues to represent a serious global health hazard. New strains of Plasmodium falciparum have emerged, resistant to conventional antimalarial drugs. It is estimated that 300 million patients worldwide suffer from malaria yearly.75

The pathogenicity of P. falciparum is related to its ability to reproduce rapidly. In the asexual erythrocytic stage of its life cycle, which is responsible for the clinical manifestations, a single merozoite invades the red blood cell, matures into a trophozoite, and undergoes DNA replication to give rise to up to 32 daughter cells in just 48 hours. Iron is required for a number of the parasite enzyme systems necessary for this explosive growth and proliferation. In addition, the iron-dependent enzyme ribonucleotide reductase, a rate-limiting enzyme in DNA synthesis, has been considered a potential site of action for an iron-chelating agent. Withholding iron from the parasite by iron chelators could be expected to inhibit parasitic growth, and studies in vitro and in animal models have shown that this is the case. Evidence now exists that iron chelation therapy has clinical activity in both uncomplicated and severe malaria.46

Porphyria: Iron Depletion May Promote Porphyrin Breakdown

Porphyria cutanea tarda is an inherited disease characterized by a deficiency of uroporphyrinogen decarboxylase. Desferrioxamine may be a reasonable alternative to phlebotomy in the treatment of the disease.70

SUMMARY

Deferiprone is the most widely studied oral iron chelator and, at present, the only one shown to be effective in achieving negative iron balance in long- term clinical trials for chronic iron overload. Because of its adverse effects (e.g., agranulocytosis and arthropathy) its use is presently restricted to clinical trials and to countries where desferrioxamine is unavailable. Deferiprone was licensed for clinical use in India in 1995. Clinical trials are in progress in many centers worldwide that will provide further information on the long-term effectiveness


of deferiprone as well as on the incidence of serious adverse effects in patients with iron overload. Trials of combined use of deferiprone and desferrioxamine are also in progress. In the meantime, deferiprone is an acceptable alternative for patients who cannot use desferrioxamine because of serious adverse effects, lack of compliance, or unavailability. Elucidation of the mechanisms involved in the agranulocytosis and arthropathy associated with deferiprone is still needed, as are methods to predict individual susceptibility to these adverse effects and ways of preventing them. In addition, new indications for iron- chelating therapy are continuously being explored.

References

1. Agarwal MB Oral iron chelation: A review with special emphasis on Indian work on deferiprone (L,). Indian J Pediatr 60:509-516, 1993

2. Agarwal MB, Gupte SS, Viswanathan C, et al: Clinically significant neutropenia secondary to L, therapy in iron-loaded thalassemics is a rare and reversible event. Abstract of the Fourth International Conference on Oral Chelation, Bombay, India, 1993, p 62

3. Agarwal MB, Gupte SS, Viswanathan C, et al: Long-term assessment of efficacy and safety of L,, an oral iron chelator in transfusion-dependent thalassemia: Indian trial. Br J Haematol 82460466, 1992

4. Agarwal MB, Gupte SS, Viswanathan C, et al: Long-term efficacy and toxicity of L,- oral iron chelator in transfusion-dependent thalassemics over the last three years. Abstract of the Fifth International Conference on Thalassemias and Haemoglobinopa- thies, Nicosia, Crete, 1993, p 192

5. Agarwal MB, Viswanathan C, Ramanathan J, et al: Oral iron chelation with L,. Lancet 335:601, 1990

6. Al-Refaie FN, Hershko C, Hoffbrand AV, et al: Results of long-term deferiprone (L,) therapy: A report by the International Study Group on Oral Iron Chelators. Br J Haematol 91224229, 1995

7. Al-Refaie FN, Hoffbrand AV: Oral iron-chelating therapy: The L, experience. Bailliere’s Clin Haematol 7941-961, 1994

8. Al-Refaie FN, Hoffbrand AV Oral iron chelation therapy. Recent Advances in Haem- atology 7185-216, 1993

9. Al-Refaie FN, Sheppard LN, Nortey P, et a1 Pharmacokinetics of the oral iron chelator deferiprone (L,) in patients with iron overload. Br J Haematol 89:403-408, 1995

10. Al-Refaie FN, Wickens DG, Wonke B, et a1 Serum non-transferrin-bound iron in beta-thalassemia major patients treated with desferrioxamine and L,. Br J Haematol 82:431436, 1992

11. Al-Refaie FN, Wilkes S, Veys PA, et al: Agranulocytosis in a patient with thalassemia major during treatment with oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one. Acta Haematol 89:86-90, 1993

12. Al-Refaie FN, Wilkes S, Wonke 8, et al: The effect of deferiprone (L,) and desferrioxamine on myelopoiesis using a liquid culture system. Br J Haematol 87196-198, 1994

13. Al-Refaie FN, Wonke B, Hoffbrand AV Deferiprone-associated myelotoxicity. Eur J Haematol 53298-301, 1994

14. Al-Refaie FN, Wonke B, Hoffbrand AV, et a1 Efficacy and possible adverse effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L,) in thalassemia major. Blood 80:593-599, 1992

15. Al-Refaie FN, Wonke 8, Wickens DG, et a1 Zinc concentration in patients with iron overload receiving oral iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one or desferrioxamine. J Clin Pathol47657-660, 1994

15a. American Academy of Pediatrics, Committee on Nutrition: Zinc. Pediatrics 62408- 412, 1978

16. Barry M, Flynn DM, Letsky EA, et a1 Long-term chelation therapy in thalassemia


major: Effect on liver iron concentration, liver histology, and clinical progress. BMJ 2:16-20, 1974

17. Bartlett AN, Hoffbrand AV, Kontoghiorghes GJ: Long-term trial with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (Ll). 11. Clinical observations. Br J Haema-

18. Be1 A, Martinod E, Menasche P: Cardioprotective effect of desferrioxamine. Acta Haematol 95:63-65, 1996

19. Berkovitch M, Laxer RM, Inman R, et al: Arthropathy in thalassemia patients receiving deferiprone. Lancet 343:1471-1472,1994

20. Berkovitch M, Matsui D, Lamm SH, et al: Recent increases in numbers and risk of fatalities in young children ingesting iron preparations. Vet Hum Toxicol 36:53-55, 1994

21. Brittenham GM, Cohen AR, McLaren CE, et a1 Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major. Am J Haematol 42:81-85, 1993

22. Brittenham GM, Griffith PM, Nienhuis AW, et al: Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 331:567-573, 1994

23. Collins AF, Fassos F, Stobie S, et al: Iron balance and dose response studies of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L,) in iron-loaded patients with sickle cell disease. Blood 83:2329-2333, 1994

24. Cunningham JM, Al-Refaie FN, Hunter A, et al: Differential toxicity of a-ketohydroxypyridine iron chelators and desferrioxamine to human hemopoietic precursors in vitro. Eur J Haematol5217G179, 1994

25. Donfrancesco A, Deb G, DeSio L Role of deferoxamine in tumor therapy. Acta Haematol 95:66-69, 1996

26. Engle MA, Erlandson M, Smith C H Late cardiac complications of chronic, severe, refractory anemia with hemochromatosis. Circulation 30698-705, 1964

27. Evans RW, Sharma M, Ogwang W, et al: The effect of a-ketohydroxypyridine chelators on transferrin saturation in vitro and in vivo. Drugs of Today 28(suppl):19-23, 1992

28. Fassos FF, Berkovitch M, Daneman N, et al: Efficacy of deferiprone in the treatment of acute iron intoxication in rats. Clin Toxicol 34:279-287, 1996

29. Goudsmit R, Kersten MJ: Long-term treatment of transfusion hemosiderosis with the oral iron chelator L,. Drugs of Today 28(suppl):133-135, 1992

30. Gutteridge JMC, Rowley DA, Griffiths E, et a1 Low-molecular weight iron complexes and oxygen radical reactions in idiopathic haemochromatosis. Clin Sci 68:463-467, 1985

31. Halliwell B, Gutteridge JMC: Oxygen, free radicals, and iron in relation to biology and medicine: Some problems and concepts. Arch Biochem Biophys 246:501-514,1986

32. Hershko C, Pinson A, Link G: Prevention of anthracycline cardiotoxicity by iron chelation. Acta Haematol 95237-92, 1996

33. Hider RC, Kontoghiorghes GJ, Silver J: UK Patent: GB-2118176, 1982 34. Hileti D, Panayiotidis P, Hoffbrand AV Iron chelators induce apoptosis in proliferat-

35. Hoffbrand AV Oral iron chelation. Semin Hematol 33:l-8, 1996 36. Hoffbrand AV, Bartlett AN, Veys PA, et al: Agranulocytosis and thrombocytopenia in

patient with Blackfan-Diamond anaemia during oral chelator trial. Lancet 2:457, 1989 37. Hussain MAM, Flynn DM, Green N, et al: Subcutaneous infusion and intramuscular

injection of desferrioxamine in patients with transfusional iron overload. Lancet

38. Jaeger M, Aul C, Sohngen D, et al: Iron overload in polytransfused patients with MDS Use of L, for oral iron chelation. Drugs of Today 28(suppl):143-147, 1992

39. Keberle H The biochemistry of desferrioxamine and its relation to iron metabolism. Ann N Y Acad Sci 119:758-768, 1964

40. Kline MA, W i g C: Complexation of iron with the orally active decorporation drug L, (3-hydroxy-1,2-dimethyl-4-pyridinone). Clin Chem 38562-565, 1992

41. Kontoghiorghes GJ, Aldouri MA, Hoffbrand AV, et a1 Effective chelation of iron in

to1 76:301-304, 1990

ing cells. Br J Haematol 89:181-187, 1995

1:977-979, 1976


P-thalassemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one. BMJ

42. Kontoghiorghes GJ, Aldouri MA, Sheppard LN, et al: 1,2-dimethyl-3-hydroxypyrid- 4-one, an orally active chelator for the treatment of transfusional iron overload. Lancet 1:1294-1295, 1987

43. Kontoghiorghes GJ, Bartlett AN, Hoffbrand AV, et al: Long-term trial with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L,). I. Iron chelation and metabolic studies. Br J Haematol 76295-300, 1990

44. Kontoghiorghes GJ, Goddard G, Bartlett AN, et al: Pharmacokinetic studies in humans with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one. Clin Pharmacol Ther 48:255-261, 1990

45. Litovitz TL, Holm KC, Clancy C, et a]: 1992 Annual Report of the American Associa- tion of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med

46. Mabeza GF, Biemba G, Gordeuk VR Clinical studies of iron chelators in malaria. Acta Haematol95:78-86, 1996

47. Mahoney JR, Hallaway PE, Hedland BE, et al: Acute iron poisoning: Rescue with macromolecular chelators. J Clin Invest 841362-1366, 1989

48. Marx JJM, Van-Asbeck BS Use of iron chelators in preventing hydroxyl radical damage: Adult respiratory distress syndrome as a model for the pathophysiology and treatment of free radical-mediated tissue damage. Acta Haematol 95:49-62, 1996

49. Matsui D, Klein J, Hermann C, et al: Relationship between the pharmacokinetics and iron excretion pharmacodynamics of the new oral iron chelator 1,2-dimethyl-3- hydroxypyrid-4-one in patients with thalassemia. Clin Pharmacol Ther 50294-298, 1991

50. McEnery JT, Greengard J: Treatment of acute iron ingestion with deferoxamine in 20 children. J Pediatr 68:773-779, 1966

51. Meyer-Brunot HG, Keberle H: The metabolism of desferrioxamine B. Biochem Phar- macol 16:527-537, 1967

52. Neuman MG, Klein J, Koren G, et al: Oral iron chelator L1 induces its metabolism in vitro in human hepatocyte lines. In Proceedings of the Sixteenth World Congress of Anatomic and Clinical Pathology, Vancouver, 1991, p 15

53. Olivieri NF, Beluzzo N, Muraca M, et al: Evidence of reduction in hepatic, cardiac, and pituitary iron stores in patients with thalassemia major during long-term therapy with the orally active iron chelating agent L,. Blood 84(suppl):109, 1994

54. Olivieri NF, Brittenham GM, Matsui D, et al: Iron chelation therapy with oral deferiprone in patients with thalassemia major. N Engl J Med 14:918-922, 1995

55. Olivieri NF, Buncic JR, Chew E, et al: Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. N Engl J Med 314:869-873, 1986

56. Olivieri NF, Harris J, Koren G, et al: Growth failure and bony changes induced by deferoxamine. Am J Pediatr Hematol Oncol 14:48-56, 1992

57. Olivieri NF, Koren G, Hermann C, et a1 Comparison of oral iron chelator L, and desferrioxamine in iron-loaded patients. Lancet 336:1275-1279, 1990

58. Olivieri NF, Koren G, Matsui D, et al: Oral iron chelation with 1,2-dimethyl-3- hydroxypyrid-4-one (L,) in thalassemia major: One-year comparison with subcutaneous desferrioxamine. Blood 78(suppl):369, 1991

59. Olivieri NF, Koren G, Matsui D, et a1 Reduction of tissue iron stores and normaliza- tion of serum ferritin during treatment with the oral iron chelator L, in thalassemia intermedia. Blood 792741-2748, 1992

60. Olivieri NF, Matsui D, Berkovitch M, et a1 Superior effectiveness of the oral chelator versus subcutaneous desferrioxamine in patients with homozygous beta-thalassemia (HBT): The impact of patient compliance during 2 years of therapy. Blood 8O(suppl):344, 1992

61. Olivieri NF, Nathan DG, MacMillan JH, et a1 Survival in medically treated patients with homozygous P-thalassemia. N Engl J Med 331:574-578, 1994

62. Olivieri NF, Sher GD, MacKinnon JA, et al: The first prospective randomized trial of subcutaneous deferoxamine and the orally active iron chelating agent L,. Blood 84(suppl):363, 1994

295~1509-1512, 1987

11:494-555, 1993


63. Peters G, Keberle H, Schmid K, et al: Distribution and renal excretion of desferrioxamine and ferrioxamine in the dog and in the rat. Biochem Pharmacol 15:93-109,1966

64. Polson RJ, Jawad ASM, Bomford A, et al: Treatment of rheumatoid arthritis with desferrioxamine. QJM 61:1153-1158, 1986

65. Porter JB: Evaluation of new iron chelators for clinical use. Acta Haematol 95:13-25, 1996

66. Porter JB, Huehns ER: The toxic effects of desferrioxamine. Clin Haematol 2459- 474, 1989

67. Porter JB, Huens ER, Hider R The development of iron chelating drugs. Baillieres Clin Haematol 2257-292, 1989

68. Propper RD, Cooper B, Rufo R, et al: Continuous subcutaneous administration of desferrioxamine in patients with iron overload. N Engl J Med 297418423, 1977

69. Proudfoot AT, Simpson D, Dyson EH: Management of acute iron poisoning. Med Toxicol 1233-100, 1986

70. Rocchi E, Gilbertini P, Cassanelli M, et al: Iron removal therapy in porphyria cutanea tarda: Phlebotomy versus slow subcutaneous desferrioxamine infusion. Br J Dermatol

71. Shalev 0, Repka T, Goldfarb L, et a1 Deferiprone (L,) chelates pathologic iron deposits from membranes of intact thalassemic and sickle red blood cells both in vitro and in vivo. Blood 862008-2013, 1995

72. Tondury P, Kontoghiorghes GJ, Ridolfi-Luthy A, et al: L, (1,2-dimethyl-3-hydroxypyrid-4-one) for oral iron chelation in patients with beta-thalassemia major. Br J Haematol 76:550-553, 1990

73. Weslin WF: Deferoxamine in the treatment of acute iron poisoning. Clinical experience with 172 children. Clin Pediatr 5:531-535, 1966

74. Wohler F: The treatment of haemochromatosis with desferrioxamine. Acta Haematol

75. Wyler DJ: Bark, weeds, and iron chelators-drugs for malaria. N Engl J Med 3271519-

114~621-629, 1986

3065-87, 1963

1521, 1992

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oral iron chelation with deferiprone

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