Anagrelide

Synonyms :
Anagrelida, Anagrelidum

Status : approved

Category

Antithrombins

Therapeutic Classification

OTHER ANTINEOPLASTIC AGENTS

ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
ANTINEOPLASTIC AGENTS
OTHER ANTINEOPLASTIC AGENTS

Description

Anagrelide is a drug used for the treatment of essential thrombocytosis (ET; essential thrombocythemia). It also has been used in the treatment of chronic myeloid leukemia. [Wikipedia]

Used

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.

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 In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte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.

Dosage

Form Route Strength
Capsule oral 0.5 mg
Capsule oral .5 mg
Capsule oral 1 mg

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.

Toxic Effect

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.

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.

Half Life

At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3 hours.

Chemical Classification

This compound belongs to the class of organic compounds known as quinazolines. These are compounds containing a quinazoline moiety, which is made up of two fused six-member aromatic rings, a benzene ring and a pyrimidine ring.

Quinazolines

Organic compounds

Organoheterocyclic compounds

Naphthyridines

Quinazolines

Salt : Anagrelide Hydrochloride

Chemical Name

Anagrelida

Brands

name Dosage form Country
Agrylin capsule Canada
Agrylin capsule US
Anagrelide Hydrochloride capsule US
Anagrelide Hydrochloride capsule US
Anagrelide Hydrochloride capsule US
Anagrelide Hydrochloride capsule US
Dom-anagrelide capsule Canada
Mylan-anagrelide capsule Canada
PHL-anagrelide capsule Canada
PMS-anagrelide capsule Canada
Sandoz Anagrelide capsule Canada

Drug Drug Interactions

  •  Abciximab  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Acenocoumarol  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Acetylsalicylic acid  : Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result.
  •  Alteplase  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents.
  •  Anistreplase  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents.
  •  Apixaban  : Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased.
  •  Cilostazol  : Anagrelide may enhance the adverse/toxic effect of Cilostazol.
  •  Citric Acid  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Dabigatran etexilate  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran etexilate. This mechanism applies specifically to clopidogrel.
  •  Dalteparin  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Deoxycholic Acid  : Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased.
  •  Dicoumarol  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Edetic Acid  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Enoxaparin  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Ethyl biscoumacetate  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Fondaparinux sodium  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Glucosamine  : May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
  •  Heparin  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Ibritumomab  : Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding.
  •  Ibrutinib  : May enhance the adverse/toxic effect of Agents with Antiplatelet Properties.
  •  Ivabradine  : May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents.
  •  Mifepristone  : May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents.
  •  Obinutuzumab  : Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased.
  •  Pentosan Polysulfate  : May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents.
  •  Pentoxifylline  : May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
  •  Phenindione  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Phenprocoumon  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Reteplase  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents.
  •  Ridogrel  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents.
  •  Riociguat  : Anagrelide may enhance the hypotensive effect of Riociguat.
  •  Rivaroxaban  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban.
  •  Salicylate-sodium  : Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result.
  •  Streptokinase  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents.
  •  Sulodexide  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Tenecteplase  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents.
  •  Tipranavir  : May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
  •  Treprostinil  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Urokinase  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase.
  •  Vitamin E  : May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
  •  Warfarin  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.

Food Interactions

  • Food appears to reduce the area under the curve by 13.8%, without clinical consequence., Take without regard to meals.

Calculated Property

kind Value Source
logP 1.95 ALOGPS
logS -3 ALOGPS
Water Solubility 2.79e-01 g/l ALOGPS
logP 1.94 ChemAxon
IUPAC Name 6,7-dichloro-1H,2H,3H,5H-imidazolidino[2,1-b]quinazolin-2-one ChemAxon
Traditional IUPAC Name anagrelide ChemAxon
Molecular Weight 256.088 ChemAxon
Monoisotopic Weight 254.996617275 ChemAxon
SMILES ClC1=CC=C2N=C3NC(=O)CN3CC2=C1Cl ChemAxon
Molecular Formula C10H7Cl2N3O ChemAxon
InChI InChI=1S/C10H7Cl2N3O/c11-6-1-2-7-5(9(6)12)3-15-4-8(16)14-10(15)13-7/h1-2H,3-4H2,(H,13,14,16) ChemAxon
InChIKey InChIKey=OTBXOEAOVRKTNQ-UHFFFAOYSA-N ChemAxon
Polar Surface Area (PSA) 44.7 ChemAxon
Refractivity 63.25 ChemAxon
Polarizability 23.61 ChemAxon
Rotatable Bond Count 0 ChemAxon
H Bond Acceptor Count 3 ChemAxon
H Bond Donor Count 1 ChemAxon
pKa (strongest acidic) 12.55 ChemAxon
pKa (strongest basic) 3.62 ChemAxon
Physiological Charge 0 ChemAxon
Number of Rings 3 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 1 ChemAxon
Ghose Filter 1 ChemAxon
MDDR-Like Rule 0 ChemAxon

Affected organism

Humans and other mammals

Target within organism

  • cGMP-inhibited 3′,5′-cyclic phosphodiesterase A : in Human