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The
deferiprone-iron complex; 3 (L1) : iron
stoichiometry
Deferiprone is a bidentate molecule and forms a 3:1 octahedral complex with iron, which is excreted almost exclusively via the
kidneys.
Deferiprone is used in the removal of excess iron
from the body, but may also be used in the detoxification of
other metals such as aluminium in haemodialysis patients,
plutonium used in the nuclear industry, and uranium used by the
military. |
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Deferiprone |
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Deferiprone
(1,2-dimethyl-3-hydroxypyrid-4-one or L1) is the first oral iron chelator used clinically,
mainly in thalassaemia patients, where the annual birth
rate worldwide is estimated to be 100000. Deferiprone
belongs to the family of the alpha-ketohydroxpyridines,
a relatively new class of chelating agents, some of which are naturally
occurring. These have high affinity for binding iron and
are able to remove it from proteins that are
transporting and storing it in the body, largely sparing
other biologically important metals. These chelators are
stable in conditions that exist in the human digestive
system and are readily absorbed. Deferiprone has
undergone extensive trials in hundreds of patients all
over the world and has proved to be orally effective in
removing excess iron from various parts of the body of
iron-loaded patients, including the liver and
particularly the heart.
Studies show that Deferiprone is rapidly absorbed from the
stomach and appears in the blood minutes after ingestion. Removal and excretion of
iron depends on the dose and frequency of administration
of the drug and the amount of iron overload in the
patient.
The major adverse effects, which have been observed in
about 10% of the patients during worldwide clinical
trials over a period of ten years, have been transient
musculoskeletal and joint pains, neutropenia and
agranulocytosis, gastric intolerance and zinc
deficiency. Of these, perhaps the most disturbing is
agranulocytosis, affecting less than 0.6% of the
patients. In patients with agranulocytosis a substantial
reduction or total absence of a group of white cells
called granulocytes is observed, which amounts to
rendering the body's immune system fatally weak. This is
the reason the focus of the mandatory monitoring
procedure is primarily on levels of white blood cells
and platelets. The monitoring not only helps to
safeguard the well being of the patient but also yields
valuable data that can contribute to the development of
a diagnostic method for agranulocytosis and improvement
of the therapy with Deferiprone.
The journey across the years
1981
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Discovery,
design, synthesis and physicochemical
characterisation of L1. |
1981-1982
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Iron
binding, protein and cell studies in-vitro.
Animal studies. |
1982
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Naming
of L1 and other alpha-ketohydroxpyridines. |
1983
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Patented
in the UK. Later patented in the USA, EEC and
various other countries. |
1982-1986
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Intensive
chemical, biochemical, cell and animal
studies. |
1986
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The
UK Department of Health grants permission for
clinical trials in the UK. |
1987
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Simple,
cheap synthesis of L1. First-ever clinical
trials in London, UK. |
1988
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Multicentre
clinical trials begin worldwide. |
1989
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First
publications on joint/musculoskeletal toxicity
and agranulocytosis (London). |
1990
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Pharmacokinetic
and metabolic properties characterisation of L1
in patients. |
1992
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Approved
BAN and INN name for L1: Deferiprone.
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1994
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Registration
of L1 in India, where now more patients are
using L1 than Desferal. |
1995
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Clinical
use and multicentre clinical studies continue. |
1998
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Over
5000 patients in 35 countries have been using
L1, some daily for over 12 years. |
1999
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Registration
of L1 in European, South American and Asian
countries. |
2000
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The
new, simple, one-step synthesis of L1 is
patented in Greece. |
2002
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Worldwide
use of L1 following recent findings regarding
depletion of iron from the heart (which is the
main cause of death in thalassaemic patients). |
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Last update:
24 January 2006
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