Indication |
For the treatment of patients with thrombocythemia, secondary to
myeloproliferative disorders, to reduce the elevated platelet count and
the risk of thrombosis and to ameliorate associated symptoms including
thrombo-hemorrhagic events. |
Pharmacodynamics |
Anagrelide is a drug used for the treatment of essential
thrombocytosis (ET; essential thrombocythemia). It works by inhibiting
the maturation of megakaryocytes into platelets. The exact mechanism of
action is unclear, although it is known to be a potent (IC50 = 36nM)
inhibitor of phosphodiesterase-III. |
Mechanism of action |
The mechanism by which anagrelide reduces blood platelet count is
still under investigation. Studies in patients support a hypothesis of
dose-related reduction in platelet production resulting from a decrease
in megakaryocyte hypermaturation. In blood withdrawn from normal
volunteers treated with anagrelide, a disruption was found in the
postmitotic phase of megakaryocyte development and a reduction in
megakaryocyte size and ploidy. At therapeutic doses, anagrelide does not
produce significant changes in white cell counts or coagulation
parameters, and may have a small, but clinically insignificant effect on
red cell parameters. Anagrelide inhibits cyclic AMP phosphodiesterase
III (PDEIII). PDEIII inhibitors can also inhibit platelet aggregation.
However, significant inhibition of platelet aggregation is observed only
at doses of anagrelide higher than those required to reduce platelet
count. |
Absorption |
Not Available |
Volume of distribution |
Not Available |
Protein binding |
Not Available |
Metabolism |
Extensive, with < 1% recovered unchanged in the urine.
Metabolized primarily in the liver by cytochrome P450 1A2 (CYP1A2).
Recently, it was found that anagrelide is bio-transformed in humans into
two major metabolites (6,7-dichloro-3-hydroxy-1,5
dihydro-imidazo[2,1-b]quinazolin-2-one (BCH24426) and
2-amino-5,6-dichloro-3,4,-dihydroquinazoline (RL603). Whether these
metabolites have biological activities that may underlie the mode of
action of the parent drug is presently unclear. |
Route of elimination |
Not Available |
Half life |
At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3 hours. |
Clearance |
Not Available |
Toxicity |
There are no reports of overdosage with anagrelide, however
thrombocytopenia, which can potentially cause bleeding, is expected from
overdosage. Single oral doses of anagrelide at 2,500, 1,500 and 200
mg/kg in mice, rats and monkeys, respectively, were not lethal. Symptoms
of acute toxicity were: decreased motor activity in mice and rats and
softened stools and decreased appetite in monkeys. |