emesis. Contraindicated if the patient has ingested strong acid
or alkali, CNS stimulants (further stimulation associated with vomiting
may precipitate convulsions), if he is comatose or in a state of stupor
or delirium or has inspirated a petroleum distillate (risk of aspiration
of gastric contents => ab ingestis chemical pneumonia).
stroking the posterior pharynx
PO syrup of ipecac (Psychotria ipecacuanha)
followed by a drink of water (15-30') : it acts on both the CTZ and as
a local irritant on the GI tract (hence effective even when antiemetic
drugs have been assumed. Risk : cardiotoxicity due to emetine.
SC apomorphine (3-5')
(oro)gastric lavage / stomach wash within 60' by inserting a 24-Fr
(in children) or a 36-Fr (in adults) tube into the stomach of a left-side-placed
patient and washing it with 120-300 mL normal saline at one time (so that
the poison is not pushed into the intestine) for 10-12 washings and a total
of 1.5 to 4 liters of lavage fluid. Contraindications as for emesis (aspiration
preventable by endotracheal tube with inflatable cuff and elevated table
foot) + mechanical damage
chemical adsorption to prevent absorption and enterohepatic recirculation
PO or via a gastric tube (Ultracarbon®; it doesn't adsorb
alcohols, hydrocarbons, metals, and corrosives) in a charcoal:drug ratio
universal antidote (in practice uneffective !) = 2 parts burned
toast + 1 one part tannic acid (strong tea) + 1 part MgO2
polythiol resin against methylmercury intoxication
NH4+ + formaldehyde => hexamethylenetetramine
sodium formaldehyde sulfoxylate + mercuric ion => metallic mercury
pH neutralization for intoxication with ...
... acids : bicarbonates (=> CO2 may cause gastric distention
and even perforation), antacids
antidote L4A1 (Combopen®; L5A1 is a training device).
Each 2 mL dose contains :
methane sulphonate (P2S : 31.5 mg) reactivates AChE
by exerting a nucleophilic attack on the dialkylphosphate or dialkylphosphonate
groups attached to a serine moiety of the esteratic site of the enzyme.
Following poisoning with nerve agents the stability of the inhibiting group
is enhanced by partial dealkylation (ageing), leaving a monoalkyl phosphate
or phosphonate group. The rate at which this occurs is variable and depends
on the nature of the alkyl groups. Pralidoxime will not reactivate aged
enzymes. It might have caused the Gulf
War syndrome (GWS).
sulphate (USP : 2 mg) antagonises the effects of ACh
at muscarinic sites but has little effect at nicotinic sites.
avizafone (10 mg) is rapidly hydrolysed in the blood and tissues
Shelf-life : 7 ½ years. To be stored at 0-5°C and protected
from light. The contents are not to be used if the pack is removed from
cold for > 6 months. Personnel will normally have received NAPS
: if symptoms persist, dose should be repeated at 15 minute intervals,
with a maximum total dose of 3 injections
succimer / 2,3-dimercaptosuccinic acid (DMSA) (Chemet®)
is an oral drug that binds to lead and mercury and is given every 8 hours
for 5 days and then every 12 hours for 2 more weeks. It is usually used
for blood lead levels between 45 and 69 mg/dl. The lead level should be
rechecked 7 - 21 days after treatment is begun to determine if treatment
has been adequate.
edetate calcium disodium (CaNa2EDTA) (Calcium Disodium
Edetate®, Versene®) (please note dicalcium
sodium EDTA is used as anticoagulant !) is used for blood lead levels >
69 mg/dl and is given as a continuous infusion or as intramuscular injections
for 3-5 days. Nephrotoxic.
1-2 g/day i.v.
0.3 g/day i.m.
dimercaprol / 2,3-dimercaptopropan-1-ol / British anti-lewisite
dimercaprol / 2,3-dimercaptopropan-1-ol / British anti-lewisite
(BAL) : 3-5 mg/kg deep IM q4h for 2 d, then q12h until recovery or
until PO therapy can be started. May cause nausea, vomiting, chest pain,
seizure, tachycardia, or abscess formation at the injection site; alkalinize
urine to facilitate excretion; may be nephrotoxic and may cause hypertension;
caution when administering to patients with oliguria or G-6-PD deficiency;
may induce hemolysis in patients with G-6-PD deficiency
: 15-40 mg/kg/d PO divided qid for 5 d; not to exceed 2 g/d (1 g/d in children).
Has a high incidence of adverse effects that include hypersensitivity reactions,
optic neuritis, nephrotoxicity, and thrombocytopenia; agranulocytosis and
aplastic anemia may occur. Increases effects of immunosuppressants, phenylbutazone,
and antimalarials; decreases digoxin effects; effects may decrease with
coadministration of zinc salts, antacids, and iron; may cross react with
penicillin in allergic patients
succimer / 2,3-dimercaptosuccinic acid (DMSA) (Chemet®)
: 10 mg/kg PO q8h for 5 d, followed by 10 mg/kg PO q12h for 14 d; repeat
dosing may be necessary. Do not administer concomitantly edetate calcium
disodium or penicillamine
Dimerval (DMPS) : international standard drug for heavy metal poisoning
but not approved in USA. Adult Dose 200 mg IV q4h until PO therapy can
be started, then 100 mg PO tid
dimercaprol / 2,3-dimercaptopropan-1-ol / British anti-lewisite
has 6 electrochemical coordination sites that should be tightly bound to
block the ability of the iron ions to catalyze redox reactions and to allow
efficient transport and excretion without iron redistribution.
: approximately 72,000 patients receive regular blood transfusions worldwide.
Because DFO is expensive and cumbersome to administer, about 42,000 receive
no chelation therapy; about 25,000 are prescribed DFO and 5000 (mainly
in India) receive deferiprone (C.B. Modell). Some 2000–4000 thalassemia
patients die each year from iron overload. The lack of an inexpensive orally
active iron chelator has been a major reason why iron chelation therapy
is not considered for these patients in poor countries. In many of these
countries, regular blood transfusions, which in the absence of iron chelation
will inevitably lead to death from iron overload, are not even contemplated.
Indeed, only about 3500 of the 27,000 transfusion-dependent children born
each year are transfused at all
patients with non-transfusion-dependent but nevertheless severe genetic
diseases of hemoglobin synthesis (thalassemia
who become iron overloaded because of increased iron absorption but are
too anemic to undergo phlebotomy to reduce iron overload
Iron chelators should reduce tissue iron levels, prevent excessive organ
iron accumulation and neutralize toxic labile iron pools. Based on the
number of the coordination sites, iron ligands are termed hexadentate,
tridentate and bidentate. Denticity is directly related to the molecular
weight: hexadentate chelators have a higher molecular weight as compared
to tri- and bidentate molecules. However, the diffusion through biological
membranes and hence the absorption from the gastrointestinal tract and
the cellular penetration are governed not only by molecular size, but also
by lipophilicity and net molecular chargeref.
For example, DFO, like many hexadentate chelators, is not absorbed in the
gastrointestinal tract, but derivatives of hydroxybenzyl-ethylenediamine-diacetic
acid (HBED), another hexadentate iron chelator, possess good oral availability.
In recent years extensive research has been directed toward bidentate and
tridentate ligands that are more likely than hexadentate chelators to be
orally active and to penetrate cells. Selectivity and affinity for the
ferric (Fe3+) oxidation state are important characteristics
of an iron chelator. Important properties for an ideal iron chelator.
high and specific affinity for Fe3+
high chelating efficiency
slow rate of metabolism
tissue and cell penetration
no iron redistribution
achievement of negative iron balanceIn TM, about 100–200 mL of pure red
cells/kg/y are transfused, equivalent to 0.32–0.64 mg/kg/d of ironref.1
In thalassemia intermedia, iron absorption is about 5–10 times the normal
amount, around 0.1 mg/kg/d. Excretion levels of these rates must be achieved
to maintain a "safe" level of body iron.
These properties reduce the chelation of other biologically important bivalent
metals, such as copper and zinc, while the effect on non-essential trivalent
cations, such as aluminum and gallium, remains negligible. Under biological
conditions the affinity of chelators for iron and the stability of ligand-metal
complexes is expressed as pF3+ value, that is, the negative
logarithm of the concentration of the free Fe3+, measured in
a solution of 10 µM ligand and 1 µM Fe3+ at pH 7.4ref.
The larger the pF3+, the higher is the stability of the ligand-metal
complex. Rapid conversion to glucuronidate metabolites limits the efficacy
of many iron chelators. Most of the administered DFO and DFP is rapidly
metabolized to the inactive glucuronide, resulting in a net chelating efficiency
< 10%. Therefore, one strategy to increase chelating efficiency is to
design compounds with a reduced rate of glucuronidation.
toxic effects of iron chelators : designing an ideal iron chelator is a
difficult challenge because of the iron paradox: iron is an essential element
for many important metabolic functions (oxygen transportation and utilization,
DNA synthesis, electron transport and many other biological processes),
but it becomes toxic when accumulated. A chelator should remove only excess
iron. Thus, in addition to possible direct toxic effects, iron chelators
may alter iron homeostasis (absorption, distribution and utilization),
interfere with iron-dependent enzymes (ribonucleotide reductase, lipooxygenase)
or remove other metals such as zinc or calcium from essential metabolic
pools. Characteristics of the compound such as molecular weight, lipophilicity/hydrophilicity
balance, affinity and selectivity for Fe3+, pharmacokinetics,
distribution and metabolism play a role in determining the boundary between
safety and toxicity
development of iron chelators : development of an iron chelator requires
several distinct and rigorous procedures, the first being the definition
of the chemical properties of the ligand and of the ligand-iron complex.
The second step consists of cellular studies using red blood cells, reticulocytes,
cell lines and primary cell cultures (hepatocytes, myocardial and reticuloendothelial
cells). Subsequently, animal models, both non-iron overloaded and iron-overloaded,
are critical to evaluate the safety and efficacy of iron chelators. Unfortunately,
the predictive power of the animal models is low because of the frequent
differences between iron-overloaded animals and humans, and because of
differences between species in iron metabolism. Efficacy in animals may
not translate into comparable efficacy at tolerable doses in man. Both
acute and long-term toxicity studies in different species of animals are
essential for planning clinical trials. To obtain the registration of a
new compound, Phase I, II and III clinical trials, performed according
to stringent requirements established by regulatory agencies, are necessary
to define the safety and pharmacokinetic and pharmacodynamic characteristics
of the chelator in humans, to find the therapeutic dose range and to evaluate
the tolerability and the efficacy in comparison with the reference drug.
Although the process of product development is very rigorous, the intrinsic
limitations of clinical trials (e.g., efficacy-oriented, highly selected
population, short duration, limited sample size, risk factors and exclusion
criteria) make it difficult to detect all safety concerns during this phase.
Post-marketing pharmacovigilance is defined as the ongoing process of evaluating
and improving the safety of drugs. Once a product is marketed, there is
generally a large increase in the number of patients exposed, including
those with comorbid conditions and those being treated with concomitant
medical products. Therefore, pharmacovigilance is critical to establish
and regularly review the risk/benefit ratio of iron chelators.
mesylate (Desferal Mesylate®) : the management of iron
overload using subcutaneous DFO has been extensively reviewedref.
DFO is hexadentate, 1 molecule binding 1 atom of iron. Standard therapy
is with 40 mg/kg infused subcutaneously over a period of 8–12 hours
on 5–7 nights each week using a battery-operated infusion pump. Therapy
is usually begun in children after 10–20 transfusions have been given
or when serum ferritin levels reach 1000 µg/L. Vitamin
200 mg, given orally when the infusion is started, enhances urine iron
excretion. Alternative routes of administration that have been tried
include twice-daily bolus subcutaneous injectionsref,
continuous infusions over 24 or 48 hours using disposable prefilled balloonsref,
and continuous intravenous infusion using an indwelling central line or
First introduced in 1976 as subcutaneous treatment for TM, DFO has
substantially improved the life expectancy in the diseaseref1,
Deaths continue to occur from cardiac failure due to iron overload, but
these are mainly caused by lack of complianceref1,
Defining compliance as > 250 infusions a year, Gabutti and Pigaref
found that 95% of compliant patients are alive at 30 years of age, compared
with only 12% of noncompliant patients. Modell et alref
reported that only 50% of TM patients in the UK reach 35 years, the poor
result again being attributable to cardiac failure due to poor compliance.
DFO can reverse iron-induced cardiomyopathy in some but not all patientsref1,
Continuous intravenous DFO results in comparatively rapid improvement in
ventricular function compared with the slow clearance of cardiac iron,
which can remain high even after 1 year. Recent studies show that liver
iron clears more rapidly and, despite severe iron overload initially, may
be normal at 6 months (Anderson L, Bunce N, Davis B, et al. Reversal of
siderotic cardiomyopathy: a prospective study with cardiac magnetic resonance
(CMR) [abstract]. Heart. 2001;85(suppl 1):33).Although cost and lack of
compliance are the main obstacles to DFO therapy, complications may also
exclude some patients. High-frequency hearing loss, deafness, and retinal
damage with impaired vision (e.g., night blindness) can occur when large
doses of the drug are given to less severely iron-loaded patients, especially
children, in whom growth retardation and skeletal damage have also been
reported. Generalized hypersensitivity is rare, but painful local reactions
at the injection site are common and often lead to lack of compliance.
Infection with Yersinia is increased, and on rare occasions other
infections (e.g. Klebsiella) are precipitated.
(L1) / deferiprone (DFP) / CP20 (Ferriprox®, Kelfer®)
is an orally active iron chelator available for clinical use, designed
in R.C. Hider’s laboratoriesref.
First tested clinically in 1987, this drug is now licensed in 25 countries
for patients with TM unable to be effectively treated with DFO. Reviews
of its chemistry, pharmacology, and clinical results have recently been
or are being publishedref1,
It was licensed first in India in 1995 and subsequently in Europe in 1999.
At present, DFP is licensed in Europe for patients for whom treatment with
DFO is inadequate. Overall DFP is currently available in approximately
50 countries. Studies have demonstrated a stable or declining mean serum
ferritin and liver iron concentration during long-term therapy in most
transfusiondependent patients, although iron accumulation continues in
Agranulocytosis is the most serious side effect, with a reported incidence
of 0.6 per 100 patient-yearsref.
More common but less serious side effects are gastrointestinal symptoms
(e.g., nausea, vomiting, gastric discomfort), arthralgia, zinc deficiency,
and fluctuating ALT levels, particularly in anti-HCV+ patients.
Retrospective studies in patients treated with DFP have shown significant
improvement in cardiac MRI, consistent with a reduction in cardiac iron
overload and improved cardiac function, in comparison with patients treated
These observations support a potential cardioprotective role of DFP that
needs to be confirmed in prospective randomized trials.
Pharmacokinetics : deferiprone is rapidly
absorbed, appearing in plasma within 15 minutes of ingestion, with a peak
plasma level within 45–60 minutes. It forms a 3:1 chelator:iron complex
that is excreted with the free drug in urine. Only 4% of a single oral
dose of the drug is excreted bound to iron, even in heavily iron-loaded
patients. Its iron chelation site is inactivated by glucuronidation, the
speed of which varies from patient to patient. This explains much of the
individual variation in response, the area under the curve of the concentration
of free drug in plasma being related to the amount of iron excretedref.
Deferiprone mobilizes iron from parenchymal and reticuloendothelial pools
and from transferrin, ferritin, and hemosiderin. Unlike DFO, it is also
capable of chelating iron from intact red cells in vitro and in
vivo, shown in patients with sickle cell anemiaref
and thalassemia intermediaref.
The enhanced ability of DFP to cross cell membranes may underlie what is
emerging as its superior ability, compared with DFO, to protect the heart
from iron and also the "shuttle effect" for iron when the 2 drugs are given
simultaneously. The concept of combination therapy.
Abbreviations: DFO, deferoxamine; DFP, deferiprone; NTBI, non-transferrin-bound
Clinical studies : short-term studies
showed that iron excretion occurs in the urine with negligible amounts
in feces, although some subsequent studies have suggested excretion up
to 33%. Iron excretion increases with the dose of the drug and the transfusional
iron load of the patients. Although initial studies showed that 100 mg/kg/d
was more effectiveref1,
the dose used in most trials has been 75 mg/kg/day fractionated into
3 doses. This dose was reported in early studies to be as effective
as standard-dose DFO at increasing urine iron excretionref1,
In most patients urine iron excretion around 0.5 mg/kg/day was achieved
with no indication of a diminishing response with time. There were early
concerns that doses > 75 mg/kg might produce more side effects, e.g., arthropathyref.
Balance studies suggest that total iron excretion with 75 mg/kg deferiprone
is somewhat < that with 40 mg/kg DFO given over 8 hours subcutaneously,
but only small numbers of patients have been studied and there is wide
patient-to-patient variability (Grady RW, Berdoukas V, Rachmilewitz EA,
et al. Combinations of desferrioxamine and deferiprone markedly enhance
iron excretion [abstract]. Blood. 2002;100:241a). Final mean serum ferritin
concentrations in 9 published trials in patients (mainly DFO ‘failures’
with TM) treated from 1 to 56 months with deferiprone have ranged from
1779 to 3273 µg/Lref.
In 7 of the trials, there was a significant fall in serum ferritin, and
in 2 there was no significant change. Serum ferritin levels fell mainly
in the patients starting with the highest levels. In 6 studies in which
serial liver iron determinations were made, hepatic iron fell significantly
in 1, rose significantly in 1, and did not change significantly in the
other 4.22 When SQUID technique was used in 54 thalassemia patients (aged
7–22 years), median liver iron concentration rose from 1456 mg/g liver
to 2029 mg at 2 years and 2449 mg at 3.2 yearsref.
These patients were well chelated before starting deferiprone, but their
iron intake from transfusions rose substantially during the study. Recent
MRI data retrospectively comparing 15 patients treated long term with deferiprone
with 30 matched patients treated with DFO, in which liver MRI T2* was converted
to estimated dry-weight liver iron, showed significantly higher liver iron:
5.1 versus 3.5 mg/g in the deferiprone compared with the DFO groupref.
In a short-term study, raising the dose of deferiprone to around 100 mg/kg
led to reduction of serum ferritin levels in patients inadequately chelated
at 75 mg/kgref.
Prospective trials are needed to assess whether doses of deferiprone (around
100 mg/kg daily) can safely be given long term and will result in more
effective iron chelation in patients inadequately chelated on 75 mg/kg
daily. There is also a need for further (> 3 years) long-term studies to
determine liver iron levels in large numbers of patients receiving deferiprone
to determine more accurately the proportion of patients in whom liver iron
is adequately controlled. The most important aspect of iron chelation therapy
is protection of the heart. Two recent studies, albeit retrospective, show
significant benefit for the patients receiving deferiprone compared with
DFO. In a London study, 15 TM patients who had received deferiprone 75
mg/kg/d for 3 years showed a lower incidence of cardiac disease (assessed
by echocardiography and need for cardiac drug therapy) and lower cardiac
iron estimated indirectly by MRI T2* than 30 age- and sex-matched patients
who had received DFO 40 mg/kg/d subcutaneously on 5–7 days each week (median
myocardial T2* 34.0 vs 11.4 ms, P = .02)ref.
Excess myocardial iron (T2* < 20 ms) was significantly less common in
the deferiprone group (27%) than in the DFO group (67%), P = .025. In a
Turin study, 54 patients who had received deferiprone were compared retrospectively
with 75 patients who had received DFO; the drugs were given at standard
doses over an average of 6 yearsref.
No patient in the deferiprone group compared with 3 in the DFO group died
of cardiac failure. Deterioration of preexisting cardiac dysfunction or
new cardiac disease occurred in 2 (4%) of the deferiprone-treated patients
compared with 15 (20%) of the DFO group (P = .007)ref.
Formal prospective studies are needed to confirm the apparent greater cardioprotective
effect against iron toxicity of deferiprone compared with subcutaneous
DFO suggested by these two retrospective studies. In a short-term (12 months)
prospective randomized study, Maggio et alref
found no difference in any of the parameters used to detect cardiac abnormalities
between patients receiving DFO and patients receiving deferiprone.
Complications : the incidence of the now
well-established complications of deferiprone therapy—agranulocytosis,
neutropenia, arthralgia, gastrointestinal symptoms, transient changes in
liver enzymes, and zinc deficiency—has been established in recent prospective
Hepatic fibrosis has also been suggested in one small retrospective study
to be a consequence of deferiprone therapyref.
However, recent evidence based on 56 repeat biopsies in patients treated
for a mean of 3.1 years shows no evidence for thisref.
No other study has reported significant increase in hepatic fibrosis ascribed
to deferiprone. Transient changes in ALT levels, especially in the first
few months of therapy and in hepatitis C antibody–positive patients, have
been observed. The mean ALT levels did not increase among 151 patients
treated for 3 yearsref.
Occasional patients have, however, been withdrawn from therapy in some
trials because of concerns about raised ALT levelsref.
Agranulocytosis, the most serious complication of deferiprone, occurs in
about 1% of patients and appears to be idiosyncratic; it is probably more
frequent in females. Patients with agranulocytosis should be permanently
withdrawn from therapy, although a proportion of patients with less severe
degrees of neutropenia have successfully been re-exposed to the drug. Most
patients with the other side effects can usually continue with the drug,
often after a period of withdrawal and retreatment initially at a lower
Combination therapy with DFO and deferiprone commenced in 1998, when
it was reported that DFO and deferiprone could be safely given simultaneously
and that the urine iron excretion achieved is at least equivalent to the
iron excretion resulting when the 2 drugs are given on separate daysref.
6 clinical studies of combination therapy have now been reported. All show
decreasing serum ferritin levels and, where measured, decreasing liver
iron. Mourad et alref,
for instance, report that deferiprone 75 mg/kg 7 days a week and DFO 40
mg/kg subcutaneously over 8–12 hours 2 days a week gives approximately
equivalent iron chelation, based on serum ferritin levels, to 5 days a
week of DFO. Compliance is likely to be improved longer term for a patient
needing 2 rather than 5 days of subcutaneous infusions. Combined therapy
with deferiprone and deferoxamine (from Liuref)
Farmaki K, Anagnostopoulos G, Platis O, Gotsis E, Toulas P. Combined
chelation therapy in patients with thalassemia major: a fast and effective
method of reducing ferritin levels and cardiological complications [abstract].
Hematol J. 2002;3(suppl 1):79
40 (significant improvement in ventricular dimensions
and function and increase in myocardial T2 relaxation time)
Alymara V, Bourantas DK, Chaidos A, et al. Combined iron chelation
therapy with desferrioxamine and deferiprone in ß-thalassemic patients
[abstract]. Hematol J. 2002;3(suppl 1):81
Galanello R, Doneddu I, Dessi E, et al. Iron chelation in thalassemia
major: combined treatment with deferiprone and deferoxamine [abstract].
In: 11th International Conference on Oral Chelation in the Treatment of
Thalassemia and Other Diseases. Catania; 2001:73
34 (agranulocytosis in 2 patients reversed after 4–5 days;
1 withdrawal with nausea. Transient moderate ALT rise in 6 HCV-negative
and 12 HCV-positive patients. One stopped therapy)
18 (agranulocytosis in 2 patients—reversed with drug discontinuation)
P < .007
The basis for this additive or synergistic effect is given by the studies
of Grady et al (Grady RW, Berdoukas V, Rachmilewitz EA, et al. Combinations
of desferrioxamine and deferiprone markedly enhance iron excretion [abstract].
Blood. 2002;100:241a) and Breuer et alref.
These suggest that deferiprone enters cells and chelates iron, which it
brings into plasma. The iron is then transferred to DFO for excretion in
urine and feces. If combination therapy in longer-term studies does not
show any unexpected toxicity, it is an exciting therapeutic advance for
improving compliance and avoiding large, potentially toxic doses of either
drug. Alternating (sequential) therapy with DFO and deferiprone has also
been studied in 7 children noncompliant to DFOref.
Compliance was improved when deferiprone was given for 4 days and then
DFO for 2 days each week. Over 6 months, liver iron fell significantly
and there was a nonsignificant fall in mean serum ferritin from 5536 to
3778 µg/L. More prolonged studies are needed to determine the place
of this approach.
Thalassemia intermedia : oral iron chelation
therapy is a potentially attractive option for patients with iron overload
who are too anemic for phlebotomy. Olivieri et alref
first reported a patient with thalassemia intermedia in whom deferiprone
was effective in reducing both liver iron and serum ferritin to normal
within 12 months of therapy. In 8 thalassemia intermedia patients in Thailand
(mainly suffering from thalassemia/HbE) deferiprone at the low dose of
50 mg/kg/d not only significantly reduced serum ferritin and red cell membrane
liver iron over 12 months but also resulted in an increase in hemoglobin
and serum erythropoietin levels and improvement in weight and appetite.
No side effects requiring drug withdrawal were encounteredref.
Other transfusion-dependent anemias :
similar results to those in TM have been obtained with deferiprone in patients
with myelodysplasia, myelofibrosis, and other acquired marrow diseases.
Although there has been theoretical concern that agranulocytosis may be
more frequent in these acquired bone marrow disorders than in TM, there
are no data to suggest this.
desferrithiocin (DFT) is a siderophore
originally isolated from
Streptomyces antibioticus in 1980 and then
produced by chemical synthesis. DFT is an orally available, tridentate,
potent iron chelator with a high affinity for Fe3+. Soon after
its discovery, DFT was actively tested in iron overloaded rats, where effective
reduction of liver ferritin iron was demonstrated. Initial single dose
safety data showed no relevant acute toxic effects, but longer exposure
in rats showed moderate to severe degenerative changes in the proximal
tubules of the kidney. The damage was believed to be due to toxic effects
of the Fe3+
Several DFT analogs have subsequently been synthesized and tested in animals.
One of these analogs, 4-OH-desaza-desmethyldesferrithiocin, appears to
be less toxic while remaining biologically active as an orally administered
iron chelator in Cebus apella primatesref.
This analog may enter Phase I human trials shortly.
acid (HBED) is a synthetic hexadentate phenolic aminocarboxylate chelator,
first synthesized more than 30 years ago, which forms a 1:1 complex with
Fe3+ with high affinity and selectivity. Initial studies in
rodents showed that it was able to clear radiolabeled iron when administered
parenterally and that it remained active after oral administration. However,
further evaluation in both iron-loaded primates and humans revealed that
the oral activity was too small to be of value in the treatment of iron
Recently Bergeron et al13 continued the preclinical evaluation of the efficacy
and safety of HBED monosodium salt for the treatment of both transfusional
iron overload and of acute iron poisoning in animals. Na-HBED was compared
with DFO at equimolar doses in iron-loaded Cebus apella monkeys,
either as a subcutaneous (SC) bolus or a 20-minute intravenous infusion
(IV). In both conditions Na-HBED was consistently about twice as efficient
as DFO in promoting iron excretion. Safety evaluation showed no systemic
toxicity after either IV administration once daily or SC administration
every other day for 14 days in dogs without iron overload. No local irritation
at injection sites was found when the Na-HBED concentration was reduced
to < 15% in a volume that would be clinically tolerable. Interestingly,
the rapid IV infusion of Na-HBED, as may be required for treatment of acute
iron poisoning, had little detrimental effect on blood pressure and heart
rate. If these results are confirmed in human studies, Na-HBED may prove
to be an alternative to DFO for the treatment of acute iron poisoning or
chronic iron overload, although it would still require parenteral administrationref.
This alternative may be particularly important for patients allergic to
DFO since HBED is a member of a different family of chelators
hydrazone (PIH) is one of a family of aromatic hydrazones produced
by chemical synthesis and identified as an effective iron chelator in 1979.
PIH is a tridentate chelator with a selectivity for iron comparable to
that of DFO. Initially it was found to be effective when given parenterally
to mice and orally to rats. Interestingly, PIH and some of its analogs
were shown to be potent inhibitors of the production of toxic oxygen-free
Over the years, various PIH analogs have been synthesized and some of them,
such as pyridoxal-benzoyl hydrazones, were as much as 280% more effective
than PIH. Studies in iron-overloaded patients treated with 30 mg/kg/day
of PIH have shown a modest net iron excretion of 0.12 ± 0.07 mg/kg/day,
which is much less than the 0.5 mg/kg/day that is required, on average,
to achieve negative iron balance in regularly transfused patientsref.
Despite these unsatisfactory results several arguments have been raised
in favor of PIHref.
First, the dose used was lower than the effective dose of 125–500 mg/kg
used in experimental animals. Second, the preparation was given to patients
after calcium carbonate to prevent acid hydrolysis of PIH, but this approach
might have limited the chelator’s absorption because of the low solubility
of PIH at a neutral pH. Progress in the development of PIH and its derivatives
has been very slow, not only because of the discouraging results in humans,
but also because its patent rights are limited. However, recently investigators
have examined the chelating potential of 2 additional PIH analogs, alone
or in combination with DFO, in cultured iron-loaded heart cells and in
The latter studies have shown that the orally administered analogs are
about 2–6 times more effective than intraperitoneally administered DFO
in mobilizing liver iron in rats
GT56-252 is a novel orally available iron
chelator derived from DFT that forms a 2:1 complex with Fe3+ref
(Marquis JK, Aoude-Dagher R, Guillumat PO. Pharmacology and toxicology
of GT56-252, a novel orally available iron chelator [abstract]. 12th International
Conference on Oral Chelation in the Treatment of Thalassaemia & Other
Disease (ICOC Santorini). 2002:112). Pharmacokinetics studies conducted
in rats, dogs and Cebus apella monkeys showed that the compound
was orally bioavailable in all 3 species, and the elimination half-life
ranged from 3 hours in the rats to 7–8 hours in the dogs. Pharmacokinetic
(PK) profiles were similar in iron-loaded and non-iron-loaded animals,
plasma levels increased in a dose-related manner and maximum plasma levels
were reached about 1 hour after dosing. In Cebus apella monkeys, the iron-clearing
efficiency was 13–18%, about three times that of DFO in the same model.
Approximately 80% of iron was excreted in the feces. Pharmacodynamics of
repeat doses of GT56-252, from 5 to 45 mg/kg once a day over a 3-day period,
in 8 iron-loaded Cebus monkeys showed a dose-related clearing efficiency
in a range from 0.06 mg/kg/dose to 0.53 mg/kg/doseref.
These studies provided sufficient background data to undertake Phase I
clinical trials. Eighteen adult patients with ß-thalassemia received
3–8 mg/kg in 2 doses with food or fasting. The compound was well tolerated,
with no related serious adverse clinical events, laboratory abnormalities
or changes in the electrocardigram (ECG). GT56-252 was very well absorbed
and area under the curve (AUC) values with or without food were similar
(Donovan JM, Palmer PA, Plone MA, Wonke B. The safety and pharmacokinetics
of GT56-252, a novel orally available iron chelator [abstract]. 38th Annual
Meeting of the European Society for Clinical Investigation. Eur J Clin
Invest. 2004;139:39). Further studies are in progress to define the effect
of GT56-252 on iron balance
40SD02 / CHF1540 is a new entity
synthesized by chemically attaching DFO to a modified starch polymer (Harmatz
P, Madden J, Vichinsky E, et al. A phase Ib study of safety, pharmacokinetics,
acute tolerability, and efficacy of ascending single doses of 40SD02 (CHF1540)
in iron-loaded patients [abstract]. The International BioIron Society World
Congress on Iron Metabolism. 2003;54). The resulting high molecular weight
chelator has a prolonged half-life and preserves the affinity and specificity
of DFO for Fe3+, but does not produce the acute toxic effects
of DFO such as hypotension. A Phase I study in 10 patients with thalassemia
and chronic iron overload showed that single doses of up to 600 mg/kg of
the compound were safe and well tolerated, and stimulated a clinically
significant amount of iron excretion. Average total iron excretion over
7 days was 0.46 mg/kg and 0.72 mg/kg in the 150 and 300 mg/kg dose groups,
respectively. In a more recent Phase I clinical trial 12 patients were
treated, each subject receiving a single dose, with 4 patients at 150 mg/Kg,
4 at 300mg/Kg, and 4 at 600 mg/Kg (Harmatz P, Grady WB, Vichinsky E, et
al. A phase 1b study of safety, pharmacokinetics, acute tolerability, and
efficacy of ascending single doses of 40SD02 (CHF1540, GS 460) in iron-loaded
patients [abstract]. Blood. 2004;(suppl 1):121a). No drug-related adverse
effects on vital signs, ECG, or laboratory tests have been described. A
skin reaction, judged to be related to the drug, was reported in 3 different
patients. At the highest dose level of 900 mg/kg, a single infusion induced
cumulative urinary iron excretion of 0.84–1.93 mg/kg for 7 days following
deferasirox / ICL670 / 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-y1]
benzoic acid (Exjade®, Asunra®) was developed
by Novartis Pharma AG after 700 potential orally active iron chelators
were screened. Preclinical studies show that it forms a 2:1 chelator:iron
complex and produces an increase predominantly in fecal iron excretion
after a single oral dose, only 6% of iron excretion accruing in
the urine. It is highly selective for iron, is rapidly absorbed, and circulates
for several hours. In the non-iron-loaded marmoset and rat, its main toxic
effect was on the renal tubular epithelial cells, but this effect was abrogated
in iron-loaded marmosets and substantially reduced in iron-loaded rats
(Nick HP, Acklin P, Fallen B, et al. ICL 670A: a new, potent, orally active
iron chelator. In: Bergeron R, Badman D, Brittenham G, eds. Iron Chelators:
New Development Strategies. Ponte Vedra, FL: Saratoga Publishers; 2000:311–331).
Short-term clinical trials have recently been reportedref.
Single daily doses of 10, 20, and 40 mg/kg body weight were studied. Peak
plasma concentration after a single oral dose occurred at about 2 hours,
and the drug was still detectable in plasma in almost all patients at 24
hours; the mean elimination half-life was between 11–16 hours after multiple
dose administration. Net iron excretion after 6 days of exposure was linearly
related to the dose of the drug. Iron excretion at 12 days was related
to the area under the curve of the concentration of free drug in plasma.
5 of 6 patients receiving 20 mg/kg were calculated to excrete iron equivalent
to the amount received in blood transfusions. Longer-term studies of the
drug at the dose of 20 mg/kg have been carried out (Piga A, Galanello R,
Cappellini MD, et al. Phase II study of oral chelator ICL 670 in thalassemia
patients with transfusional iron overload: safety, pharmacokinetics (PK)
and pharmacodynamics (PD) after 6 months of therapy [abstract]. Blood.
2002;100:5). These showed that total body iron excretion ranged from 7.7–28.5
mg iron/d. These did not show any additional toxic effects and showed that
liver iron decreased in 12 (57.1%), was unchanged in 8 (38.1%), and rose
in 1 (4.8%) of 21 patients studied using the SQUID technique. ICL670 represents
a new class of tridentate iron chelators with a high specificity for iron
that was developed on the basis of computer modelingref.
Efficient and selective mobilization of tissue iron has been demonstrated
in several animal models, with efficiency being greater than DFO and considerably
greater than DFP at comparable levels of iron binding potential. The Phase
I clinical evaluation of ICL670 showed this novel agent to be well tolerated,
with no major safety concerns at doses up to 80 mg/kg/dayref.
Iron excretion is dose-dependent and is almost entirely in the feces. Excretion
averaged 0.127, 0.344 and 0.564 mg/kg/day at the 10, 20 and 40 mg/kg doses,
The plasma half-life (11–19 hours) supports the once daily oral dosing
regimen used in subsequent clinical studies. A 12-month Phase II study
assessed the tolerability and efficacy of ICL670 in comparison with DFO
in 71 patients with transfusional hemosiderosis. Patients were randomized
to receive ICL670 (10 or 20 mg/kg/day) or DFO (40 mg/kg SC 5 days per week).
The overall incidence of adverse events was similar in all groups.
Side effects : the main side effect was
skin rashes that required withdrawal of 4 patients given the highest dose
of 40 mg/kg over 8–10 days. Sporadic transaminase rises occurred in 1 of
these patients and in 4 other patients. Mild nausea, diarrhea, and abdominal
pain—none requiring discontinuation of the drug—occurred in other patients.
Transient mild to moderate nausea and vomiting were more common in patients
receiving ICL670 at 20 mg/kg/day but did not require discontinuation of
the drug. One patient receiving ICL670 at a dose of 10 mg/kg/day developed
a mild skin rash with a suspected relationship to the study drug; the rash
subsided spontaneously despite continued therapy. Elevations in urinary
ß2 microglobulin, sometimes accompanied by a mild increase
in urinary 24-hour total protein excretion, have been observed in all dose
groups but predominantly in patients treated with ICL670 at 20 mg/kg/day.
The clinical significance of these renal findings remains uncertain, even
if in 2007 the FDA issued a warning after some fatal cases of acute
There were no significant changes in serum creatinine levels. Decreases
in liver iron concentration (LIC), determined by biomagnetic susceptometry,
were similar in the groups treated with ICL670 at 20 mg/kg/day and DFO.
At baseline, LIC values in the 2 groups were 8.5 and 7.9 mg/g dry weight
respectively, falling to 6.6 and 5.9 mg/g dry weight at 12 months. A Phase
III international study including about 500 patients was completed by the
end of 2004
combined chelation therapy
: simultaneously or sequentially. Chelators with distinct chemical properties
may have different ironcarrying capacities. Potential advantages :
access to different iron pools
prevention of nontransferrin bound iron (NTBI) accumulation
improved quality of life
Formal balance studies have shown that 2 chelators may have additive or
synergistic effects, resulting in an increased efficacyref1,
(Grady RW, Berdoukas V, Rachmilewitz EA, et al. Iron chelation therapy:
metabolic aspects of combining deferiprone and deferoxamine [abstract].
11th International Conference on Oral Chelation in the Treatment of Thalassaemia
Major and Other Disease (Catania). 2001;74–78; Galanello R, Doneddu I,
Dessi’ E, et al. Iron chelation in thalassemia major: combined treatment
with deferiprone and deferoxamine [abstract]. 11th International Conference
on Oral Chelation in the Treatment of Thalassaemia and Other Disease (Catania).
2001;Abs:73). To explain these effects, it has been proposed that a bidentate
or tridentate ligand, with access to a variety of tissues, acts as a "shuttle"
to mobilize iron from tissue compartments to the bloodstream, where the
chelator may exchange iron with a larger hexandentate "sink" (Grady RW,
Berdoukas V, Rachmilewitz EA, et al. Iron chelation therapy: metabolic
aspects of combining deferiprone and deferoxamine [abstract]. 11th International
Conference on Oral Chelation in the Treatment of Thalassaemia Major and
Other Disease (Catania). 2001;74–78).
DFO + DFP
: "shuttle effect"ref.
While monotherapy with DFP resulted in temporary accumulation of chelated
iron in the plasma, the addition of DFO produced a transfer of DFP-chelated
iron to DFO and an increase in total chelated iron. Giving DFP every day
and DFO 2 days a week produced iron excretion comparable to that achieved
with DFO administered 5 days a weekref.
This regimen of chelation is more tolerable and may be attractive for patients
who are unable to comply with regular daily use of DFO. Since some of the
toxic effects of the chelators are dose-dependent, combination therapy
might make it possible to lower the dose of one or both drugs, reducing
toxicity but maintaining effective chelation. Giving 2 drugs sequentially,
e.g., DFP during the day and DFO at night, might also reduce the level
of NTBI. To date, no unexpected side effects have been consistently observed
in patients receiving combination therapy with DFO and DFP. However, prospective,
randomized studies are needed to establish firmly the risks and benefits
of this approach. Using the iron-loaded gerbil model, combined DFP and
DFO treatment was particularly efficient in reducing liver iron concentration
and normalizing the mitochondrial respiratory enzyme activityref.
to patients with thalassemia greatly enhanced the effectiveness of HBED
(Grady RW, Giardina PJ. Oral iron chelation: a potential role for HBED
in combination therapy [abstract]. Blood. 1999;94(Suppl1): #3293). Total
iron excretion was 148% and 227% of that with each drug alone.
PIH analogs + DFO have shown an additive effect
on hepatocellular iron excretionref
DFO + ICL670 : studies in heart cell cultures
have shown a favorable interaction, manifested as improved chelating efficiency
Monitoring of iron chelation therapy :
estimation of tissue iron content of different organs :
serum ferritin : this is a useful technique for assessing changes in body
iron, although the absolute level is an imprecise measure of body iron.
This is partly because inflammation—for example, hepatitis C—raises the
level, while vitamin C deficiency lowers it, both frequent complications
of TM. Most studies have found a wide range in liver iron at any given
serum ferritin level. The Thalassemia International Federation guidelines
(Capellini N, Cohen A, Eleftheriou A, Piga A, Porter J, eds. Guidelines
for Clinical Management of Thalassemia. Nicosia, Cyprus: Thalassemia International
Federation; 2000) recommend maintaining serum ferritin levels around 1000
µg/L; nevertheless, levels below this may in some individuals be
associated with cardiac complications. One study in TM patients receiving
DFO found that those with at least two-thirds of serial serum ferritin
estimations < 2500 µg/L had significantly less cardiac disease
than those with higher levelsref.
More recently, a level consistently below 1500 µg/L was found to
be associated with few complications in 32 patients with TM followed for
approximately 15 yearsref.
When effective chelation therapy is initiated, the serum ferritin falls
more rapidly than body iron. This may happen partly because of improvement
in liver function and partly because serum ferritin may reflect predominantly
reticular endothelial iron rather than parenchymal iron in the liver and
liver iron has been described as the "gold standard" for determining body
iron and has been recently shown to correlate with total body iron storesref.
It can be measured chemically after liver biopsy (which can be inaccurate
because of fibrosis, cirrhosis, or uneven distribution of iron) or noninvasively
by the superconducting quantum interface device (SQUID) (available in only
a few centers) or by magnetic resonance imaging (MRI). Brittenham et alref
studied 59 TM patients who were > 7 years old. All patients who died had
liver iron concentrations > 15 mg/g dry weight, and this level has been
subsequently regarded as an index of high risk of death from cardiac disease.
More recently, Angelucci et alref
have shown that this level is also associated with liver fibrosis and cirrhosis.
The level of 7 mg/g is the upper limit found in carriers of genetic hemochromatosis.
For levels between 7 and 15 mg/g, Angelucci et al found no evidence of
liver damage except in patients who had hepatitis C and were messenger
RNA positive; the combination of iron overload and hepatitis C infection
is particularly damaging to the liver. The value of liver iron, whether
> 15 mg/g or in the range of 7 to 15 mg/g, as a predictor of cardiac iron
has recently been questioned. MRI data using the T2* technique (Figure
have shown no correlation between cardiac and liver iron, although other
MRI techniques, possibly less sensitive and accurate, have shown such a
correlation. Possible explanations for these discrepant observations have
cardiac iron : direct measurement of cardiac iron by endomyocardial biopsy
of the right atrium is inappropriate since iron locates mainly to the myocardium
of the ventricles. The recent development of a reproducible, sensitive,
and accurate indirect measure of cardiac iron using the MRI T2* techniqueref
has provided substantial important new data. A T2* value < 20 ms has
been found to correlate with the presence of cardiac dysfunction, detected
by echocardiography, 24-hour monitoring, or the need for cardiac therapy.
It is also valuable for monitoring changes in cardiac iron during intensive
chelation therapy (Anderson L, Bunce N, Davis B, et al. Reversal of siderotic
cardiomyopathy: a prospective study with cardiac magnetic resonance (CMR)
[abstract]. Heart. 2001;85(suppl 1):33)
non-transferrin-bound iron : in severely iron-loaded patients, non-transferrin-bound
iron (NTBI) is present in plasma. It occurs in 80% of patients with TM
and represents a highly toxic species causing tissue iron loading. NTBI
is also found in patients receiving chemotherapy or undergoing heart bypass
operations and those having other conditions in which large amounts of
iron from hemoglobin breakdown are released into the circulationref.
NTBI is removed by administration of DFO or DFP but reappears rapidly (i.e.,
usually within 1 hour of discontinuing intravenous DFO therapy) unless
body iron burden is substantially reduced.
urine iron excretion : iron excreted in response to a single dose of DFO
or deferiprone has been taken as an index of body iron burden. It will
vary, however, with the dose of chelator used and, for DFO, whether vitamin
C is also given and with the hemoglobin level. There is also considerable
day-to-day variation, even with apparently the same conditionsref.
Nevertheless, in one recent study it has been found to correlate closely
with cardiac iron measured by MRIref
estimation of iron-induced tissue damage : in addition to measuring iron
status, it is important to assess the function of the heart, liver, and
endocrine glands, the organs particularly damaged by iron overload. Early
detection of cardiac dysfunction is especially important so that increased
chelation therapy can be instituted before cardiac damage is irreversible.
Once the patient has started chelation therapy, it will also be necessary
to monitor for potential side effects of the iron chelator being used
assessment of the function of the heart, liver, and endocrine glands, the
organs particularly damaged by iron overload. These aspects have recently
been extensively reviewed and are only briefly discussed hereref1,
amyl nitrite and 4-dimethylaminophenol oxidize hemoglobin
to methemoglobin, which competes with cytochrome oxidase for the CN-
ion, creating cyanmethemogobin : the reactions favor methemoglobin
because of mass action.
hydroxocobalamin (Cyanokit® (containing hydroxocobalamin,
intravenous tubing and a sterile spike for reconstituting the drug product
with saline; source : EMD Pharmaceuticals, Inc = Dey,
L.P.) => cyanocobalamin. The initial dose of Cyanokit for adults
is 5 g, administered by intravenous infusion. Depending upon the severity
of the poisoning and the clinical response, a second dose of 5 g may be
administered up to a total dose of 10 g.
bacterial phosphotriesterase genetically engineered via directed
evolution destroys the nerve gas soman
1,000-folds faster : a more efficient version could form part of a mask
to protect against nerve agents. In bacteria, phosphotriesterase severs
chemical bonds between phosphorus and oxygen atoms. It has been investigated
before for cleaning up pollution from toxic organophosphorus pesticides
biliary excretion can be enhanced by CYPs inducers but the effect
is slow in onset
urinary excretion :
decrease passive reabsorption by decreasing the concentration gradient
of the drug from the lumen to the tubular cell and by increasing flow through
nonionized compounds are reabsorbed far more rapidly than ionized, polar
molecules; for acids with 3 < pKa < 7.5 and bases
with 7.5 < pKa < 10.5, a shift from the nonionized
to the ionized species of the toxicant by alteration of the pH of the
tubular fluid (IV sodium bicarbonate to alkalinize and ammonium chloride
or ascorbic acid to acidify) may hasten elimination.