Anagrelide (Agrylin/Xagrid,

Shire Shire is a traditional term for an administrative division of land in Great Britain and some other English-speaking countries such as Australia and New Zealand. It is generally synonymous with county. It was first used in Wessex from the beginn ...

and Thromboreductin, AOP Orphan Pharmaceuticals AG) is a drug used for the treatment of

essential thrombocytosis Essential thrombocythemia (ET) is a rare chronic blood cancer (myeloproliferative neoplasm) characterised by the overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow. It may, albeit rarely, develop into acute myeloid le ...

(also known as essential thrombocythemia), or overproduction of blood platelets. It also has been used in the treatment of

chronic myeloid leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulat ...

. Anagrelide controlled release (GALE-401) is in phase III clinical trials by

Galena Biopharma Galena Biopharma (originally RXi Pharmaceuticals) was a publicly traded pharmaceutical company based in San Ramon, California. The company was founded in Worcester, Massachusetts. In 2011, it moved to Oregon, and in 2015 moved to San Ramon, Calif ...

for the treatment of essential thrombocytosis.

Medical uses

Anagrelide is used to treat

, 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: * age over 60 years * platelet count over 1000×10⁹/ L * a history of

thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...

According to a 2005 Medical Research Council randomized trial, the combination of

hydroxyurea Hydroxycarbamide, also known as hydroxyurea, is a medication used in sickle-cell disease, essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, and cervical cancer. In sickle-cell disease it increases fetal hemoglobin and ...

with

aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...

is superior to the combination of anagrelide and

for the initial management of essential thrombocytosis. The

arm had a lower likelihood of

myelofibrosis Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is growth of abnormal cells in the bone marrow. ...

arterial An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pul ...

, and

bleeding Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...

, but it had a slightly higher rate of

venous thrombosis Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...

. Anagrelide can be useful in times when hydroxyurea proves ineffective.

Side-effects

Common

side effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

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 Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...

from

megakaryocytes A megakaryocyte (''mega-'' + '' karyo-'' + '' -cyte'', "large-nucleus cell") is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. In hum ...

. The exact mechanism of action is unclear, although it is known to be a

phosphodiesterase inhibitor A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cycli ...

. It is a potent ( IC₅₀ = 36nM) inhibitor of

phosphodiesterase A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many oth ...

-II. It inhibits PDE-3 and phospholipase A2.

Synthesis

Phosphodiesterase inhibitor with antiplatelet activity. 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 Cyanogen bromide is the inorganic compound with the formula (CN)Br or BrCN. It is a colorless solid that is widely used to modify biopolymers, fragment proteins and peptides (cuts the C-terminus of methionine), and synthesize other compounds. ...

possibly gives cyanamide 3 as the initial intermediate. Addition of the aliphatic would then lead to formation of the

quinazoline Quinazoline is an organic compound with the formula C8H6N2. It is an aromatic heterocycle with a bicyclic structure consisting of two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. It is a light yellow crystalline solid ...

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).

References

External links

Shire Pharmaceuticals Agrylin/Xagrid website for international visitorsShire Pharmaceuticals Xagrid website for UK visitors
{{Phosphodiesterase inhibitors Drugs with unknown mechanisms of action Orphan drugs Antineoplastic drugs Phosphodiesterase inhibitors Imidazoquinazolines Lactams Chloroarenes Takeda Pharmaceutical Company brands