|Trade names||Agrylin, Xagrid, others|
|Main uses||High platelets in essential thrombocytosis|
|Side effects||Headache, palpitations, diarrhea, weakness, swelling, nausea, shortness of breath, itchiness, heart burn|
|Metabolism||Liver, partially through CYP1A2|
|Elimination half-life||1.3 hours|
|Chemical and physical data|
|Molar mass||256.09 g·mol−1|
|3D model (JSmol)|
Anagrelide, sold under the brand name Agrylin among others, is a medication used to treat high platelets in essential thrombocytosis or other myeloproliferative disorders. It is used when other treatments are not effective or tolerated. It is taken by mouth.
Common side effects may include headache, palpitations, diarrhea, weakness, swelling, nausea, shortness of breath, itchiness, and heart burn. Other side effects may include arrhythmias, QT prolongation, bleeding, and interstitial nephritis. Safety in pregnancy is unclear, with evidence of harm in other animals. It is an antithrombotic.
Anagrelide was approved for medical use in the United States in 1997 and Europe in 2004. It is available as a generic medication. In the United Kingdom 100 pills of 500 micrograms costs the NHS about £400 as of 2021. This amount in the United States costs about 52 USD.
Anagrelide is used to treat essential thrombocytosis, especially when the current treatment of the patient is insufficient. Essential thrombocytosis patients who are suitable for anagrelide often meet one or more of the following factors:
According to a 2005 trial, the combination of hydroxyurea with aspirin is superior to the combination of anagrelide and aspirin for the initial management of essential thrombocytosis. The hydroxyurea arm had a lower likelihood of myelofibrosis, arterial thrombosis, and bleeding, but it had a slightly higher rate of venous thrombosis. Anagrelide can be useful in times when hydroxyurea proves ineffective.
It is generally started at a dose of 500 micrograms twice per day. This is increased to a typical dose of 500 micrograms to 1,500 micrograms twice per day. Doses up to 10,000 micrograms per day may be used.
Common side effects are headache, diarrhea, unusual weakness/fatigue, hair loss, nausea.
The same MRC trial mentioned above also analyzed the effects of anagrelide on bone marrow fibrosis, a common feature in patients with myelofibrosis. The use of anagrelide was associated with a rapid increase in the degree of reticulin deposition (the mechanism by which fibrosis occurs), when compared to those in whom hydroxyurea was used. Patients with myeloproliferative conditions are known to have a very slow and somewhat variable course of marrow fibrosis increase. This trend may be accelerated by anagrelide. This increase in fibrosis appeared to be linked to a drop in hemoglobin as it progressed. Stopping anagrelide (and switching patients to hydroxyurea) appeared to reverse the degree of marrow fibrosis. Thus, patients on anagrelide may need to be monitored on a periodic basis for marrow reticulin scores, especially if anemia develops, or becomes more pronounced if present initially.
Less common side effects include: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericarditis, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, pancreatitis, gastric/duodenal ulceration, renal impairment/failure and seizure.
Due to these issues, anagrelide should not generally be considered for first line therapy for essential thrombocytosis.
Mechanism of action
Anagrelide works by inhibiting the maturation of platelets from megakaryocytes. The exact mechanism of action is unclear, although it is known to be a phosphodiesterase inhibitor. It is a potent (IC50 = 36nM) inhibitor of phosphodiesterase-II. It inhibits PDE-3 and phospholipase A2.
Phosphodiesterase inhibitor with antiplatelet activity.
|Synthesis 1||Synthesis 2|
Condensation of benzyl chloride 1 with ethyl ester of glycine gives alkylated product 2. Reduction of the nitro group leads to the aniline and reaction of this with cyanogen bromide possibly gives cyanamide 3 as the initial intermediate. Addition of the aliphatic would then lead to formation of the quinazoline ring (4). Amide formation between the newly formed imide and the ester would then serve to form the imidazolone ring, whatever the details of the sequence, there is obtained anagrelide (5).
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