|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 1 (January 1), 1998:
pp. 295-300
Long-Term Trial of Deferiprone in 51 Transfusion-Dependent Iron
Overloaded Patients
By
A. Victor Hoffbrand,
Faris AL-Refaie,
Bernard Davis,
Noppadol Siritanakatkul,
Beverly F.A. Jackson,
John Cochrane,
Emma Prescott, and
Beatrix Wonke
From the Department of Hematology, The Royal Free Hospital School of
Medicine, London, UK; and the Departments of Hematology and Surgery,
Whittington Hospital, London, UK.
 |
ABSTRACT |
Fifty-one transfusion-dependent iron-loaded adult patients (38 with
thalassemia major) were treated with the orally active iron chelator
deferiprone (1,2 dimethyl-3-hydroxypyrid-4-one, L1) at a dose of 75
mg/kg/d (range, 50 to 79). Twenty patients discontinued the drug and
five died after a mean of 18.7 months (range, 4 to 35). Of the 20, 5
had arthropathy, 5 had gastrointestinal symptoms, 4 had a rising serum
ferritin, 3 had agranulocytosis or neutropenia, 1 had tachycardia, 1
had renal failure, and 1 went abroad. Twenty-six patients continued
deferiprone for a mean of 39.4 months (range, 12 to 49). Among these
patients, there was no overall significant change in serum ferritin
(initial mean, 2,937 µg/L; range, 980 to 5,970; final mean, 2,323
µg/L; range, 825 to 5,970) or in urine iron excretion (initial mean,
31.2 mg/24 h; range, 16.3 to 58.2; final mean, 32.1 mg/24 h; range, 9.4
to 75.8), implying no overall change in iron stores. When the patients
who had received deferiprone for longer than 3 years were considered
separately, there was also no significant change in serum ferritin or
urinary iron excretion. The initial serum ferritin levels in the 26
patients who continued deferiprone treatment were significantly lower
than in those who discontinued the drug (P < .01). The
liver iron content in 17 patients who had received deferiprone for 24
to 48 months ranged from 5.9 to 41.2 mg/g dry weight, 50% having
levels above 15.0 mg, a level associated with a high risk of cardiac
disease due to iron overload. In this study the drug caused fewer side
effects and was more effective at maintaining iron status among
patients previously well chelated and with lower initial serum ferritin
levels.
| |
INTRODUCTION |
ONLY ONE DRUG, deferoxamine mesylate
(DFX), is widely available for chelating iron from
patients with refractory anemias, such as thalassemia major, who
require regular blood transfusions. Iron accumulates in
such patients at a rate of about 0.5 mg/kg/d and subcutaneous DFX 20 to
50 mg/kg/d administered over 8 to 12 hours is sufficient to produce
iron balance in most of these patients with a body iron burden about 5
to 10 times the normal level.1 DFX is unavailable to many
patients worldwide because it is too expensive; also, patients may
develop local or generalized sensitivity to the drug or may develop
toxic side effects such as growth failure, deformities of the long
bones and spine, and hearing and visual problems. These side effects
occur, however, largely in patients administered excessive doses of DFX
in the face of low iron burden. Many patients find difficulty in
complying with daily subcutaneous DFX therapy, which is burdensome,
painful, and time-consuming. Noncompliance becomes a major problem,
particularly in adolescents, leading to iron induced cardiac damage and
death.2,3 Calcium diethylenetriamine penta-acetic
acid has been used as an alternative to DFX but it also
has to be administered parenterally and it causes excessive zinc
excretion. A potential orally active alternative to DFX
is 1,2-dimethyl-3-hydroxypyrid-4-one (L1, deferiprone).
Short-term clinical studies have shown the drug to be effective but to
have toxic side effects including agranulocytosis, arthropathy, zinc
deficiency, and gastrointestinal side effects.4-7 We now
report the efficacy and side effects of deferiprone in a long-term
trial of therapy in 51 transfusion-dependent patients.
| |
MATERIALS AND METHODS |
Fifty-one iron-overloaded regularly transfused patients who were unable
to take DFX or not compliant with DFX were included in the trial.
Thirty-eight patients (36 splenectomized) had  -thalassemia major
(TM), 1 had hemoglobin E/beta thalassemia, and 1 had sickle
cell/-thalassemia. This group included 13 women and 27 men, mean age
of 30.5 years (range, 22 to 38). Additional patients included 4 with
sickle cell anemia (2 women, 32 and 63 years and 2 men, 18 and 32
years), 3 with sideroblastic anemia (1 woman, 46 years and 2 men, 16
and 45 years), and 4 men with myelodysplastic syndrome, mean age of
71.5 years (range, 58 to 83).
The 36 splenectomized TM patients were administered transfusions of red
blood cells (RBCs) 3 to 4 U monthly to raise their hemoglobin (Hb)
levels from 9.0 to 15.0 g/dL; overall yearly mean of Hb was 12.0 g/dL.
Their blood consumption ranged from 150 to 200 mL/kg/body weight of
RBCs per year. Two nonsplenectomized TM patients required 250 to 300
mL/kg/body weight of RBCs per year. Patients with sickle
cell/-thalassemia required 260 mL/kg/body weight of RBCs per year to
achieve an Hb S concentration of less than 30%. In one patient with Hb
E/-thalassemia the Hb level ranged from 7 to 12.0 g/dL, the patient
requiring only 120 mL/kg/body weight of RBCs per year. In the 11
nonthalassemic patients, RBC requirements were similar to those of
nonsplenectomized thalassemic patients. Deferiprone was administered
orally in a total daily dose of 75 mg/kg/body weight (range, 50 to 79
mg/kg) at least an hour before food every 8 to 12 hours. Deferiprone
was manufactured according to published methods and marketed by Lipomed
(Basel, Switzerland) and Vitra (Clavering, Essex, UK)
Pharmaceutical Companies. The study was approved by the Ethical
Committees of the Royal Free and Whittington Hospitals and exemption
from license certificate was obtained from the Medical Control
Agency, London, UK. Written informed consent was
obtained from each patient.
At each monthly visit detailed clinical examination was performed and
laboratory tests included full blood count, liver and renal function,
serum zinc and calcium levels, serum immunoglobulins, CD4/CD8
lymphocyte numbers and ratio, and antinuclear and rheumatoid factor.
Leukocyte ascorbic acid was measured every six months in all patients
and those with low levels were given oral vitamin C (200 mg/d) with
their daily dose of deferiprone. Urine zinc excretion was measured
every three months. The patients were monitored for side effects; in
particular, musculoskeletal complaints were noted and joints were
carefully examined for warmth, crepitus, synovial swelling, effusion,
and by the patellar compression test for retropatellar tenderness and
stability. Special investigations of the painful joints included plain
x-ray, magnetic resonance imaging, and isotope bone scans. Cardiac
function was monitored by annual multiple uptake gated acquisition
(MUGA) scans of the heart, and measuring the left ventricular ejection
fraction at rest and under stress. Compliance to
deferiprone was not assessed by computerized containers but we checked
that patients had used up supplies and new prescriptions were
administered with only a sufficient amount of drug until the next
appointment.
We assessed the efficacy of deferiprone treatment by monthly
measurements of serum ferritin concentration and of 24-hour urinary
iron excretion. In 17 patients on long-term deferiprone (mean, 39.4
months; range, 24 to 48) hepatic iron concentrations were measured,
using chemical analysis of tissue iron obtained by liver
biopsy.8
| |
RESULTS |
Patients withdrawn from long-term therapy.
Of the 51 patients, 25 (49%) discontinued deferiprone or died after a
mean of 18.7 months (range, 4 to 35). The reasons for stopping
treatment in 20 of the patients are shown in Table
1. All five patients with arthropathy had
TM. Their mean serum ferritin levels at the start of deferiprone
treatment was 4,192 µg/L (range, 1182 to 9060). Arthropathy caused
discontinuation of deferiprone during the second or third year of
therapy. Joint symptoms had usually been present for several weeks and
in these cases did not improve with lowering the dose of deferiprone to
50 mg/kg/d. The knee joints were mainly affected and the clinical
symptoms were of stiffness, crepitus, and effusion. Special tests
including plain radiography, magnetic resonance imaging, and isotope
scans were unhelpful in elucidating the pathophysiology of the
arthropathy. There was no correlation between the presence of
antinuclear factor (ANF) and rheumatoid factor
antibodies in the plasma of these patients suffering from arthropathy
compared with those without. There was also no statistical significant
difference between serum ferritin levels between the two groups.
Four TM patients stopped deferiprone treatment because of rising serum
ferritin levels. Their mean initial serum ferritin level of 4,925
µg/L had increased to 7,569 µg/L. The mean urinary iron excretion
in these four patients was 9.1 mg/24 h (range, 5.6 to 18.5). Their
blood consumption was not significantly different from that of the
other TM patients. One 63-year-old myelodysplastic patient developed
agranulocytosis after 6 weeks of deferiprone therapy (79 mg/kg/d).
Details of this patient have been reported elsewhere.9 His
neutrophil count recovered after 7 days. Two TM patients developed
neutropenia (<1.5 × 109/L) after 13 and 22 months of
therapy. Both were administered a much lower dose of deferiprone but
developed a second decrease in neutrophils which recovered on stopping
deferiprone therapy.9 Severe gastrointestinal symptoms such
as nausea, anorexia, or vomiting necessitated the discontinuation of
deferiprone therapy in five patients. Two of these patients had poor
renal function; one with sickle cell anemia and chronic
glomerulonephritis; the other with myelodysplasia was 82 years
old.
Fatalities during the study.
Five patients died, four of congestive heart failure due to iron
overload. Their mean serum ferritin at the time of death was 5,112
µg/L (range, 2,100 to 9,060) (Table 2). The fifth
patient died of adult respiratory distress syndrome. She had received
deferiprone for 35 months and her serum ferritin level at the time of
death was 720 µg/L. None of these patients had neutropenia. The
23-year-old male patient with TM and diabetes mellitus died of
bronchopneumonia and cardiac failure. Four months before his death
deferiprone treatment was stopped and an attempt was made to
reintroduce subcutaneous DFX with poor compliance. The initial MUGA
scan showed moderately severe cardiomyopathy with a left ventricular
ejection fraction (LVEF) of 55% at rest and 40% on cold stress, and 2
years later (2 months before he died), LVEF was 54% decreasing to 42%
on cold stress.
The 24-year-old female patient with TM and diabetes mellitus was
admitted to the hospital with high fever, and septicemia was diagnosed.
Her cardiac condition rapidly deteriorated and she died of heart
failure secondary to iron overload. The MUGA scan remained unchanged,
showing moderately severe cardiomyopathy initially with an LVEF of 48%
at rest and 40% on cold stress, a year later with an LVEF of 46% at
rest and 40% on cold stress.
The 30-year-old male thalassemia patient, noncompliant to DFX, with
diabetes mellitus, gonadal failure, and hypothyroidism, was taken off
deferiprone treatment 4 months before his death. He was admitted with a
short history of breathlessness and irregular heart beat. His cardiac
condition rapidly deteriorated despite continuous intravenous DFX
treatment and he died of congestive heart failure. His MUGA scan did
not show deterioration from a moderately severe cardiomyopathy on
routine yearly testing, initially LVEF 51% at rest falling to 43% on
stress and at 2 years, 49% at rest falling to 41%.
The 48-year-old patient with congenital sideroblastic anemia had taken
deferiprone irregularly for 2 months before he died because of
anorexia, nausea, and joint pains. He contracted an infection and 2
days before he died, developed cardiac failure. His MUGA scan, which
initially showed moderately severe cardiomyopathy (LVEF 60% at rest
decreasing to 52% on stress), had remained consistent throughout the
study. He had shown pulmonary hypertension with pulmonary artery
systolic pressure of 99 mm Hg and concentric left and right ventricular
hypertrophy.
Patients continuing to take deferiprone.
Twenty-six patients (20 TM, 1 sickle cell anemia, 1
sickle/-thalassemia, 1 Hb E/-thalassemia, 2 sideroblastic anemia,
and 1 myelodysplastic syndrome) have taken deferiprone for a mean of
39.4 months (range, 12 to 49). We have analyzed RBC consumption in
milliliters per kilogram per year for the 26 patients whose serum
ferritin levels are given in Fig
1. There was no significant
correlation between RBC consumption and initial or final serum ferritin
or with the liver iron levels in 17 patients (see Fig 3). The initial
mean serum ferritin level was 2,937 µg/L (range, 980 to 9,090) and at
the end of the study 2,323 µg/L (range, 825 to 5,970), with no
significant change (Fig 1). Fifteen patients have taken deferiprone for
more than 36 months without significant change in serum ferritin and
urine iron excretion. Among the 17 patients with initial serum ferritin
levels less than 2,500 µg/L, three rose to above this level. In the
remaining nine patients serum ferritin levels initially ranged from
2,920 to 9,090 µg/L. In all but one patient final values were still
above 2,500 µg/L (range, 1,250 to 5,972). The initial serum ferritin
levels in these 26 patients were significantly lower than in the 25
patients who died or discontinued deferiprone, mean, 5,095 µg/L
(range, 2,170 to 13,900) (P < .01) (Fig
2), or than in the 20 patients who
discontinued deferiprone considered alone (P < .01).
View larger version (42K):
[in this window]
[in a new window]
| Fig 1.
The initial and final serum ferritin concentrations in 26
patients who continue deferiprone therapy for a mean of 39.4 (range, 12
to 49) months. ( ), Chronic liver disease caused by hepatitis C;
threshold of effective treatment: ( ), USA; ( ), WHO.
|
|
View larger version (11K):
[in this window]
[in a new window]
| Fig 3.
The serum ferritin and liver iron concentrations
(measured during the same admission) in 17 TM patients who underwent
liver biopsy after 2 to 4 years of deferiprone therapy. (), Chronic
liver disease caused by hepatitis C. Liver iron: 1 mg/g = normal;
>22 mg/ g = cirrhosis develops with time.
|
|
View larger version (28K):
[in this window]
[in a new window]
| Fig 2.
The initial and final serum ferritin concentrations in 25
patients who discontinued deferiprone therapy. ( ), Agranulocytosis;
(---), renal failure; (  ), increasing ferritin; (  ), death;
( ), nausea; (), neutropenia; ( ), tachycardia; (--),
anthropathy; ( ), went abroad; threshold of effective treatment:
(), USA; (), WHO.
|
|
Figure 3 shows the chemical liver iron
content and serum ferritin levels taken at the time of biopsy in 17
iron-overloaded TM patients. The mean liver iron content was 17.4 mg/g
dry weight (range, 5.9 to 41.2). Two patients had a liver iron content
below 7.0 mg/g dry weight, which has been considered the threshold
where life expectancy is not affected. Five patients had liver iron
content between 7.9 and 14.1 mg/g dry weight and the remaining 10
patients had a liver iron content above 15.0 mg/g dry weight, ie,
falling within the range that has been associated with cardiac
disease. Overall, the serum ferritin and chemical
liver iron values did not correlate. Five of 17 patients had chronic
liver disease caused by hepatitis C virus (HCV). There
was no correlation between serum ferritin and liver iron in the 12
patients without cirrhosis or hepatitis C infection. Five of the
patients were hepatitis C-RNA positive and these all showed cirrhosis
of the liver. Among the 12 patients who were anti-HCV and hepatitis
C-RNA negative, the liver biopsy samples showed that none had cirrhosis
and they showed either no fibrosis (11 patients) or mild fibrosis (1
patient). This patient began with the highest initial serum ferritin
level, 9,087 µg/L.
Urine iron excretion in response to deferiprone among the 26 patients
initially ranged from 16.3 to 58.2 mg/24 h (mean, 31.2). There was no
significant overall change in urine iron excretion among the 26
patients who had received treatment for a mean of 39.4 months. The mean
urine iron excretion at the end of the study was 32.1 mg/24 h (range,
9.4 to 75.8). There was also no overall change in urine iron excretion
in the 15 patients who had received deferiprone for more than 36 months
(Table 3).
View this table:
[in this window]
[in a new window]
|
Table 3.
Initial and Final Serum Ferritin and Urine Iron
Excretion in 15 Patients Who Have Received Deferiprone for More
Than 36 Months
|
|
Regular blood counts were performed in all patients during the study
period. No changes in renal function, white blood cell, or platelet
counts were observed in the 26 patients. No changes were seen in
aspartate aminotransferase and alanine aminotransferase levels except
for the six patients with chronic hepatitis C, where fluctuating liver
enzyme levels were observed. During treatment with deferiprone,
marginally low serum zinc levels developed in eight patients. All eight
had biochemical evidence of diabetes or insulin dependent diabetes.
These patients were given oral zinc supplements (220 mg/d). MUGA scan
results showed no significant change at rest and on stress between
initial and final values in the 26 patients.
| |
DISCUSSION |
The results of this study show that long-term (more than 4 years) iron
chelation therapy is feasible using the orally active drug deferiprone.
They also confirm the findings of previous studies in which different
side effects of deferiprone therapy have been reported.9-11
Our earliest short-term clinical trials showed that 24-hour urine iron
excretion equivalent to that induced by subcutaneous DFX (40 to 50
mg/kg administered over 8 to 10 hours) could be achieved with 100 mg/kg
deferiprone given in two to four doses each day.12,13 No
change in overall mean serum ferritin levels was achieved in up to 1
year of treatment.14 A number of subsequent abstracts
showed decreases in serum ferritin levels, particularly in patients
starting with high serum ferritin levels.10,11,15,16 One
study, published only in abstract form, reported that deferiprone (75
mg/kg/d) was more effective in treating TM over 1- to 2-year periods
than was subcutaneous DFX.17 A subsequent abstract by the
same investigators showed that hepatic iron concentration was in an
optimal range after 2 years of therapy in 64% of patients receiving
DFX, but in only 7% of patients receiving deferiprone.18
This same group reported decreases in liver iron in 10 previously
poorly chelated patients with initial liver iron levels above 80
µmol/g wet weight treated with deferiprone for 1 to 3 years. There
was a decrease from a mean of 125.3 ± 11.5 to 60.3 ± 9.6 µmol, 8
of the 10 patients achieving a level less than 80
µmol/g.19 In a further 11 patients, previously better
chelated, liver iron content remained below 80 µmol/g. These workers
also reported among the 21 patients a significant decrease in mean
serum ferritin concentration from 3,975 to 2,546 µg/L. Because of
these encouraging results and because of our previous experience of
important side effects with deferiprone at a dose of 100 mg/kg/d, we
chose for the present long-term study deferiprone doses of 75 mg/kg/d,
in the hope of experiencing fewer side effects without significant loss
of efficacy.
The serum ferritin concentration is a relatively inaccurate measure of
body iron burden compared with liver iron estimation. Nevertheless, the
results here show that for the 15 patients who have taken the drug
constantly for over 3 years, there has been no significant change in
serum ferritin concentration or in urine iron excretion in response to
deferiprone, implying no significant overall change in iron stores.
Deferiprone, therefore, has been effective in these patients at
balancing iron input from blood transfusions by iron excretion in the
urine. This is consistent with a mean urinary excretion of about 25
mg/24 h in these patients, representing 0.5 mg/kg/24 h for a 50-kg
individual. Whether additional iron excretion occurs through the stools
in response to deferiprone is uncertain.
The results of our liver iron estimations were disappointing. Among the
17 patients tested, after a mean of 40 months therapy (range, 27 to 49
months) only 2 showed liver iron levels below 7 mg/g, a level
considered safe,20 while 8 had levels above 15 mg/g, levels
at which liver and cardiac damage are likely to occur.21 In
a group of 12 patients who had received subcutaneous DFX for 4 to 8
years, we found 50% had liver iron levels less than 7
mg/g.1 Moreover, in contrast to Olivieri et
al,19 we found no significant correlation between serum
ferritin and liver iron. Nine of the 15 patients who have received
deferiprone for more than 3 years show serum ferritin levels over 2,500
µg/L, a level taken by some to indicate inadequate chelation
therapy.22 The discrepancies between our results and that
reported by Olivieri et al19 may be more apparent than
real. In both studies, the majority of patients starting therapy with
serum ferritin levels greater than 2,500 µg/L still showed levels in
this range after several years of therapy. Also, the majority of
previously poorly chelated patients in both studies showed hepatic iron
levels greater than 15 mg/g dry weight after more than 2 years of
deferiprone therapy.
Our study included a substantial number of nonthalassemic patients, but
overall there were no significant differences either in efficacy or
incidence of side effects among the 40 patients with thalassemia
syndromes or the 11 patients with other diseases. Our liver biopsy
samples showed no evidence of direct toxicity of the drug to hepatic
cells. Fibrosis was mild in only 1 of 12 patients without hepatitis C
infection. Among the hepatitis C positive patients, the appearances
were consistent with changes known to be associated with the virus
infection.
The wide variation in iron excretion among the patients may relate
partly to a wide range in body iron stores, with iron excretion being
greater in those with greater body iron burden.12,13 Iron
excretion also relates to the area under the curve of free deferiprone
in plasma after a single oral dose.23 The drug is
glucuronidated at a different rate in different patients. Efficacy will
be affected since glucuronidation inactivates the drug's iron binding
site. The lack of efficacy in some patients despite high iron body
loads, as in four patients with rising serum ferritin levels during
treatment, may be the result of particularly fast glucuronidation of
deferiprone.
Nearly 50% of the patients commencing deferiprone discontinued the
drug. Overall, these patients initially showed significantly higher
iron stores, assessed by serum ferritin, than the patients who were
able to continue the drug. Five patients died, but in none could this
be attributed a toxic effect of the drug. In four previously, poorly
chelated patients, death was due to cardiac disease induced by iron
overload. However, these findings imply that deferiprone is
inappropriate therapy for patients with iron-induced cardiomyopathy in
whom continuous intravenous DFX is needed to cause continuous removal
of toxic, nontransferrin-bound iron from plasma. Moreover,
substantially more iron excretion can be achieved with continuous DFX
administered intravenously than with either intermittent subcutaneous
infusion of DFX or with oral doses of deferiprone.
Joint symptoms in association with deferiprone therapy were first
reported by Bartlett et al.24 They occurred in up to 33%
of patients in the Indian trial,11 a study showing that
high doses of deferiprone and greater degrees of iron overload of the
patient were both predisposing factors. No relation with changes in ANF
or rheumatoid factor titres have been shown in this or any other study,
and the mechanism of the damage, whether free radical generation or
immunological, remains to be determined.
Agranulocytosis is the most serious complication so far reported with
deferiprone therapy. The incidence of this and of lesser degrees of
neutropenia as occurred in two patients here (and previously
reported9) is not yet determined. It may depend partly on
the dose of deferiprone, the iron load of the patient, the patient's
ethnic group, and the nature of the underlying disease. Among 13
patients reviewed by Hoffbrand,6 nine were female,
suggesting a possible increased susceptibility in females as occurs
with other idiosyncratic drug agranulocytosis. Patients with TM,
myelodysplasia, and Blackfan-Diamond anemia have all suffered
agranulocytosis but all have recovered. Despite experiments designed to
elucidate a toxic or immune mediated mechanism, no evidence for either
has been established.25,26 The licensing of deferiprone in
India and its subsequent widespread use in therapy of thalassemia is
likely to result in new cases of agranulocytosis or neutropenia and it
is hoped that any such cases will be fully documented and reported. A
recently completed multicenter Italian trial will give additional
information on the incidence of neutropenia.
Five patients withdrew from the present study because of
gastrointestinal symptoms on taking the drug. Two of the patients
showed renal impairment at the start of therapy and in one of these,
which involved a man of 82 years, pharmacokinetic studies have shown
prolonged accumulation of deferiprone-glucuronide in plasma after a
single oral dose. A significant correlation between creatinine
clearance and area under the curve for the glucuronide derivative in
plasma after a single oral dose has been shown.23 It may be
that nausea in these two patients was caused by accumulation of the
glucuronide in plasma. At all events this side effect, not previously
highlighted, resulted in 10% of our patients reverting back to
subcutaneous DFX for chelation therapy.
How can we improve on these results? The efficacy of deferiprone is
dose related and it might be that increasing the dose from 75 to 100
mg/kg/d in those that can tolerate it may be more effective in some
patients. In preliminary studies we have increased the dose of
deferiprone to 85 mg/kg in 10 of the 26 patients still taking the drug,
with no new side effects and with increased iron excretion. Another
possibility is to administer intravenous DFX therapy at the time of
blood transfusion and deferiprone between transfusions or to use the
newly introduced DFX continuous infusers27 for a day or two
each week with chelation with deferiprone on the same and other days,
possibly increasing overall iron excretion but reducing side effects of
both drugs in this way.
| |
FOOTNOTES |
Submitted February 19, 1997;
accepted August 25, 1997.
Address reprint requests to A. Victor Hoffbrand, FRCP,
Department of Haematology, Royal Free Hospital, Pond St, London, NW3
2QG UK.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
REFERENCES |
1.
Aldouri MA,
Wonke B,
Hoffbrand AV,
Flynn DM,
Laulicht M,
Fenton LA,
Scheuer PJ,
Kibbler CC,
Allwood CA,
Brown D,
Thomas HC:
Iron state and hepatic disease in patients with thalassemia major, treated with long term subcutaneous desferrioxamine.
J Clin Pathol
40:1353,
1987[Abstract/Free Full Text]
2.
Wolfe L,
Olivieri N,
Sallan D,
Steven Colan RN,
Rose V,
Propper R,
Freedman MH,
Nathan DG:
Prevention of cardiac disease by subcutaneous deferoxamine in patients with thalassemia major.
N Engl J Med
312:1602,
1985
3.
Aldouri MA,
Wonke B,
Hoffbrand AV,
Flynn DM,
Ward SE,
Agnew JE,
Hilson AJW:
High incidence of cardiomyopathy in beta thalassemia patients receiving regular transfusion and iron chelation: Reversal by intensified chelation.
Acta Haematol
84:113,
1990[Medline]
[Order article via Infotrieve]
4.
Al-Refaie FN,
Hoffbrand AV:
Oral iron chelation therapy.
Recent Adv Haematol
7:185,
1993
5.
Al-Refaie FN,
Hoffbrand AV:
Oral iron chelation therapy: The L1 experience.
Baillieres Clin Haematol
7:941,
1994[Medline]
[Order article via Infotrieve]
6.
Hoffbrand AV:
Oral iron chelation.
Semin Hematol
33:1,
1996[Medline]
[Order article via Infotrieve]
7.
Olivieri NF,
Brittenham GM:
Iron chelation therapy and treatment of thalassemia.
Blood
3:739,
1997
8.
Barry M,
Sherlock S:
Measurement of liver iron concentration in needle biopsy specimen.
Lancet
1:100,
1971[Medline]
[Order article via Infotrieve]
9.
Al-Refaie FN,
Wonke B,
Hoffbrand AV:
Deferiprone-associated myelotoxicity.
Eur J Haematol
53:298,
1994[Medline]
[Order article via Infotrieve]
10.
Al-Refaie FN,
Wonke B,
Hoffbrand AV,
Wickens DG,
Nortey P,
Kontoghiorghes GJ:
Efficacy and possible adverse effects of the oral iron chelator 1,2dimethyl-3-hydroxypyrid-4-one (L1) in thalassemia major.
Blood
3:593,
1992
11.
Agarwal MB,
Gupta SS,
Vismanathan C,
Vasandani D,
Ramanathan J,
Desai N,
Puniyani RR,
Chhablani T:
Long-term assessment of efficacy and safety of L1, an oral iron chelator, in transfusion dependent thalassaemia: Indian trial.
Br J Haematol
82:460,
1992[Medline]
[Order article via Infotrieve]
12.
Kontoghiorghes GJ,
Aldouri MA,
Hoffbrand AV,
Barr J,
Wonke B,
Kourouclaris T,
Sheppard L:
Effective chelation of iron in thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxyprid-4-one.
BMJ
295:1509,
1987
13.
Kontoghiorghes GJ,
Aldouri MA,
Sheppard LN,
Hoffbrand AV:
1,2-dimethyl-3-hydroxypyrid-4-one, an orally active chelator for the treatment of transfusional iron overload.
Lancet
1:1294,
1987[Medline]
[Order article via Infotrieve]
14.
Kontoghiorghes GJ,
Bartlett AN,
Hoffbrand AV,
Goddard JG,
Sheppard L,
Barr J,
Nortey P:
Long-term trial with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1).
Br J Haematol
76:295,
1990[Medline]
[Order article via Infotrieve]
15.
Olivieri NF,
Koren G,
Hermann G,
Bentur Y,
Chung D,
Klein J,
St Louis P,
Freedman MH,
McClelland RA,
Templeton DM:
Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients.
Lancet
336:1275,
1990[Medline]
[Order article via Infotrieve]
16. (suppl A)
Töndury P,
Wagner HP,
Kontoghiorghes GJ:
Update of long term clinical trials with L1 in beta thalassaemia major patients in Bern, Switzerland.
Drugs Today
28:115,
1992
17. (abstr, suppl 1)
Olivieri NF,
Brittenham GM,
Armstrong SAM,
Basran RK,
Daneman R,
Daneman N,
Ivanchko RM,
Talbot AL,
Koren G:
First prospective randomized trial of the chelators deferiprone (L1) and deferoxamine.
Blood
86:249a,
1995
18. Olivieri NF, for The Iron Chelation Research Group (Toronto,
Canada): Randomised trial of deferiprone (L1) and deferoxamine (DFO) in
thalassemia major. Blood 88:651a, 1996 (abstr, suppl 1)
19.
Olivieri NF,
Brittenham GM,
Matsui D,
Berkovitch M,
Blendis LM,
Cameron RG,
McClelland RA,
Lin PP,
Templeton DM,
Koren G:
Iron-chelation therapy with oral deferiprone in patients with thalassemia major.
N Engl J Med
332:918,
1995[Abstract/Free Full Text]
20.
Bassett ML,
Halliday JW,
Powell LW:
Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis.
Hepatology
6:24,
1986[Medline]
[Order article via Infotrieve]
21.
Brittenham GM,
Griffith PM,
Nienhuis AW,
McLaren CE,
Young NS,
Tucker EE,
Allen CJ,
Farrell DE,
Harris JW:
Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major.
N Engl J Med
331:567,
1994[Abstract/Free Full Text]
22. Cao A, Gabutti V, Masera G, Modell B, Sirchia G, Vullo C, Wonke
B: Management Protocol for the treatment of thalassemia patients.
Cooleys Anemia Foundation, New York, 1992
23.
Al-Refaie FN,
Shepphard LN,
Nortey P,
Wonke B,
Hoffbrand AV:
Pharmacokinetics of the oral iron chelator deferiprone (L1) in patients with iron overload.
Br J Haematol
89:403,
1995[Medline]
[Order article via Infotrieve]
24.
Bartlett AN,
Hoffbrand AV,
Kontoghiorghes GJ:
Long term trial with the oral iron chelator 1-2-dimethyl-3-hydroxypyrid-4-one (L1): Clinical observations.
Br J Haematol
76:301,
1990[Medline]
[Order article via Infotrieve]
25.
Cunningham JM,
Hunter AB,
Hoffbrand AV,
Al-Refaie FN,
Veys P,
Wilkes S,
Francis GE:
Differential toxicity of  -ketohydroxypyridine iron chelators and desferrioxamine to human hemopoietic precursors in vitro.
Eur J Haematol
52:176,
1994[Medline]
[Order article via Infotrieve]
26.
Al-Refaie FN,
Wonke B,
Hoffbrand AV:
The effect of deferiprone (L1) and desferrioxamine on myelopoiesis using a liquid culture system.
Br J Haematol
87:196,
1994[Medline]
[Order article via Infotrieve]
27.
Araujo A,
Kosaryan M,
MacDowell A,
Wickens D,
Puri S,
Wonke B,
Hoffbrand AV:
A novel delivery system for continuous desferrioxamine infusion in transfusional iron overload.
Br J Haematol
93:835,
1996[Medline]
[Order article via Infotrieve]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
M. K. Jones and J. D. Oliver
Vibrio vulnificus: Disease and Pathogenesis
Infect. Immun.,
May 1, 2009;
77(5):
1723 - 1733.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Walker Jr., C. P. Epling, C. Parris, S. Cansino, P. Ghosh, D. H. Desai, R. G. Morrison, G. L. Wright, P. Wehner, E. I. Mangiarua, et al.
Acetaminophen Protects Against Iron-Induced Cardiac Damage in Gerbils
Ann. Clin. Lab. Sci.,
January 1, 2007;
37(1):
22 - 33.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A M Emara, R S El Kelany, and K A Moustafa
Comparative study of the protective effect between deferoxamine and deferiprone on chronic iron overload induced cardiotoxicity in rats
Human and Experimental Toxicology,
July 1, 2006;
25(7):
375 - 385.
[Abstract]
[PDF]
|
|
|
|
|
|
|
C. Borgna-Pignatti, M. D. Cappellini, P. De Stefano, G. C. Del Vecchio, G. L. Forni, M. R. Gamberini, R. Ghilardi, A. Piga, M. A. Romeo, H. Zhao, et al.
Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major
Blood,
May 1, 2006;
107(9):
3733 - 3737.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. J. Kellenberger, M. Schmugge, T. Saurenmann, L. D. Gennaro, S. W. Eber, U. V. Willi, and P. S. Babyn
Radiographic and MRI Features of Deferiprone-Related Arthropathy of the Knees in Patients with {beta}-Thalassemia
Am. J. Roentgenol.,
October 1, 2004;
183(4):
989 - 994.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. V. Hoffbrand, A. Cohen, and C. Hershko
Role of deferiprone in chelation therapy for transfusional iron overload
Blood,
July 1, 2003;
102(1):
17 - 24.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. G. Nathan and D. J. Weatherall
Academic Freedom in Clinical Research
N. Engl. J. Med.,
October 24, 2002;
347(17):
1368 - 1371.
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. R. Wanless, G. Sweeney, A. P. Dhillon, M. Guido, A. Piga, R. Galanello, M. R. Gamberini, E. Schwartz, and A. R. Cohen
Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia
Blood,
August 13, 2002;
100(5):
1566 - 1569.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Hershko, A. M. Konijn, H. P. Nick, W. Breuer, Z. I. Cabantchik, and G. Link
ICL670A: a new synthetic oral chelator: evaluation in hypertransfused rats with selective radioiron probes of hepatocellular and reticuloendothelial iron stores and in iron-loaded rat heart cells in culture
Blood,
February 15, 2001;
97(4):
1115 - 1122.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Kushner, J. P. Porter, and N. F. Olivieri
Secondary Iron Overload
Hematology,
January 1, 2001;
2001(1):
47 - 61.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. F. Olivieri
The {beta}-Thalassemias
N. Engl. J. Med.,
July 8, 1999;
341(2):
99 - 109.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Tricta, M. Spino, F. Callea, D. G. Nathan, D. J. Weatherall, M. Stella, G. Pinzello, A. Maggio, B. Wonke, P. Telfer, et al.
Iron Chelation with Oral Deferiprone in Patients with Thalassemia
N. Engl. J. Med.,
December 3, 1998;
339(23):
1710 - 1714.
[Full Text]
|
|
|
|
|
|
|
N. F. Olivieri, G. M. Brittenham, C. E. McLaren, D. M. Templeton, R. G. Cameron, R. A. McClelland, A. D. Burt, and K. A. Fleming
Long-Term Safety and Effectiveness of Iron-Chelation Therapy with Deferiprone for Thalassemia Major
N. Engl. J. Med.,
August 13, 1998;
339(7):
417 - 423.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. V. Kowdley and M. M. Kaplan
Iron-Chelation Therapy with Oral Deferiprone -- Toxicity or Lack of Efficacy?
N. Engl. J. Med.,
August 13, 1998;
339(7):
468 - 469.
[Full Text]
|
|
|
|
|
|
|
K. Blaha, M. Cikrt, J. Nerudova, H. Fornuskova, and P. Ponka
Biliary Iron Excretion in Rats Following Treatment With Analogs of Pyridoxal Isonicotinoyl Hydrazone
Blood,
June 1, 1998;
91(11):
4368 - 4372.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract