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Anagrelide (Agrylin/Xagrid, Shire and Thromboreductin, AOP Orphan Pharmaceuticals) is a drug used for the treatment of essential thrombocytosis (ET; essential thrombocythemia), or overproduction of blood platelets. It also has been used in the treatment of chronic myeloid leukemia.^[1]

Medical uses

Anagrelide is used to treat essential thrombocytosis, especially when the current treatment of the patient is insufficient.^[2] Essential thrombocytosis patients who are suitable for anagrelide often meet one or more of the following factors:^[3]^[4]

age over 60 years
platelet count over 1000×10⁹/L
a history of thrombosis

According to a 2005 Medical Research Council randomized trial, the combination of hydroxyurea with aspirin is superior to the combination of anagrelide and aspirin for the initial management of ET. The hydroxyurea arm had a lower likelihood of myelofibrosis, arterial thrombosis, and bleeding, but it had a slightly higher rate of venous thrombosis.^[2] Anagrelide can be useful in times when hydroxyurea proves ineffective.

Side-effects

Common side effects are headache, diarrhea, unusual weakness/fatigue, hair loss, nausea and dizziness.

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. Interestingly, this increase in fibrosis appeared to be linked to a drop in hemoglobin as it progressed. Fortunately, stopping the drug (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.^[5]

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 in ET.

Mechanism of action

Anagrelide works by inhibiting the maturation of platelets from megakaryocytes.^[6] The exact mechanism of action is unclear, although it is known to be a phosphodiesterase inhibitor.^[7] It is a potent (IC₅₀ = 36nM) inhibitor of phosphodiesterase-II.^{[citation needed]} It inhibits PDE-3 and phospholipase A2.^[8]

Synthesis of anagrelide

References

^ Voglová J, Maisnar V, Beránek M, Chrobák L (2006). "[Combination of imatinib and anagrelide in treatment of chronic myeloid leukemia in blastic phase]". Vnitr̆ní lékar̆ství (in Czech) 52 (9): 819–22. PMID 17091608.
^ ^a ^b Harrison CN, Campbell PJ, Buck G, et al. (July 2005). "Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia". N. Engl. J. Med. 353 (1): 33–45. doi:10.1056/NEJMoa043800. PMID 16000354.
^ Reilly, John T. (1 February 2009). "Anagrelide for the treatment of essential thrombocythemia: a survey among European hematologists/oncologists". Hematology 14 (1): 1–10. doi:10.1179/102453309X385115. PMID 19154658.
^ Brière, Jean B (1 January 2007). "Essential thrombocythemia". Orphanet Journal of Rare Diseases 2 (1): 3. doi:10.1186/1750-1172-2-3. PMC 1781427. PMID 17210076.
^ Campbell PJ, Bareford D, Erber WN, et al. (June 2009). "Reticulin accumulation in essential thrombocythemia: prognostic significance and relationship to therapy". J. Clin. Oncol. 27 (18): 2991–9. doi:10.1200/JCO.2008.20.3174. PMC 3398138. PMID 19364963.
^ Petrides PE (2006). "Anagrelide: what was new in 2004 and 2005?". Semin. Thromb. Hemost. 32 (4 Pt 2): 399–408. doi:10.1055/s-2006-942760. PMID 16810615.
^ Jones GH, Venuti MC, Alvarez R, Bruno JJ, Berks AH, Prince A (February 1987). "Inhibitors of cyclic AMP phosphodiesterase. 1. Analogues of cilostamide and anagrelide". J. Med. Chem. 30 (2): 295–303. doi:10.1021/jm00385a011. PMID 3027338.
^ Harrison CN, Bareford D, Butt N, et al. (May 2010). "Guideline for investigation and management of adults and children presenting with a thrombocytosis". Br. J. Haematol. 149 (3): 352–75. doi:10.1111/j.1365-2141.2010.08122.x. PMID 20331456.

External links

Shire Pharmaceuticals Agrylin/Xagrid website for international visitors
Shire Pharmaceuticals Xagrid website for UK visitors
AOP Orphan Pharmceuticals website

UpToDate Contents

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1. 本態性血小板血症の予後および治療 prognosis and treatment of essential thrombocythemia
2. 真性多血症の予後および治療 prognosis and treatment of polycythemia vera
3. 心不全患者において使用をさけるべき、または慎重に使用するべき薬 drugs that should be avoided or used with caution in patients with heart failure
4. Management of primary myelofibrosis
5. 高拍出性心不全 high output heart failure

English Journal

Anagrelide platelet-lowering effect is due to inhibition of both megakaryocyte maturation and proplatelet formation: insight into potential mechanisms.

Espasandin Y1, Glembotsky A, Grodzielski M, Lev P, Goette N, Molinas F, Marta R, Heller P.
Journal of thrombosis and haemostasis : JTH.J Thromb Haemost.2015 Jan 20. doi: 10.1111/jth.12850. [Epub ahead of print]
BACKGROUND AND OBJECTIVES: Anagrelide represents a treatment option for essential thrombocythemia patients. It lowers platelet counts through inhibition of megakaryocyte maturation and polyploidization, although the basis for this effect remains unclear. Based on its rapid onset of action, we assess
PMID 25604267

Prophylaxis and management of venous thromboembolism in patients with myeloproliferative neoplasms: consensus statement of the Haemostasis Working Party of the German Society of Hematology and Oncology (DGHO), the Austrian Society of Hematology and Oncology (ÖGHO) and Society of Thrombosis and Haemostasis Research (GTH e.V.).

Kreher S1, Ochsenreither S, Trappe RU, Pabinger I, Bergmann F, Petrides PE, Koschmieder S, Matzdorff A, Tiede A, Griesshammer M, Riess H; Haemostasis Working Party of the German Society of Hematology and Oncology; Austrian Society of Hematology and Oncology; Society of Thrombosis and Haemostasis Research.
Annals of hematology.Ann Hematol.2014 Dec;93(12):1953-63. doi: 10.1007/s00277-014-2224-8. Epub 2014 Oct 14.
Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) like polycythemia vera and essential thrombocythemia are at increased risk of arterial and venous thrombosis. Strategies of prevention may consist of platelet aggregation inhibitors and/or cytoreductive agents dependin
PMID 25307456

Leukemic transformation in essential thrombocythemia.

Bhatt VR.
Future oncology (London, England).Future Oncol.2014 Dec;10(16):2593-602. doi: 10.2217/fon.14.239.
ABSTRACT Essential thrombocythemia patients develop acute myeloid leukemia (AML) at a rate of 1-4% during a median follow-up of 7-10 years. The risk increases with advanced age, anemia, platelet count ≥1000 × 10(9)/l, the presence of ≥2 somatic mutations and after the first decade of diagnos
PMID 25531047

Japanese Journal

アナグレライド

日本血栓止血学会誌 27(1), 49-53, 2016
NAID 130005127659

本態性血小板血症に対するアナグレリドの有効性と安全性

血液内科 = Hematology 71(4), 523-528, 2015-10
NAID 40020643123

本態性血小板血症の治療 : anagrelide vs.ハイドロキシウレア

血液内科 68(2), 244-249, 2014-02
NAID 40020006927

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★リンクテーブル★

リンク元	「アナグレリド」
拡張検索	「anagrelide hydrochloride」

「アナグレリド」

Anagrelide
Systematic (IUPAC) name
	6,7-dichloro-1,5-dihydroimidazo; (2,1-b)quinazolin-2(3H)-one
Clinical data
Trade names	Agrylin
AHFS/Drugs.com	monograph
MedlinePlus	a601020
Pregnancy cat.	AU: B3; US: C;
Legal status	AU: Prescription Only (S4); CA: ℞-only; UK: POM; US: ℞-only;
Routes	Oral
Pharmacokinetic data
Metabolism	Hepatic, partially through CYP1A2
Half-life	1.3 hours
Excretion	Urine (<1%)
Identifiers
CAS number	68475-42-3
ATC code	L01XX35
PubChem	CID 2182
DrugBank	DB00261
ChemSpider	2097
UNII	K9X45X0051
KEGG	D07455
ChEBI	CHEBI:142290
ChEMBL	CHEMBL760
Chemical data
Formula	C10H7Cl2N3O
Mol. mass	256.088 g/mol
	SMILES Clc1ccc3c(c1Cl)CN2/C(=N\C(=O)C2)N3;
	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) ; Key:OTBXOEAOVRKTNQ-UHFFFAOYSA-N ;
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英: anagrelide、anagrelide hydrochloride
関: 塩酸アナグレリド

「anagrelide hydrochloride」

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塩酸アナグレリド

関: anagrelide

[pmid17091608-1] Voglová J, Maisnar V, Beránek M, Chrobák L (2006). "[Combination of imatinib and anagrelide in treatment of chronic myeloid leukemia in blastic phase]". Vnitr̆ní lékar̆ství (in Czech) 52 (9): 819–22. PMID 17091608.

[HarrisonCN2-2] Harrison CN, Campbell PJ, Buck G, et al. (July 2005). "Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia". N. Engl. J. Med. 353 (1): 33–45. doi:10.1056/NEJMoa043800. PMID 16000354.

[ReillyJT-3] Reilly, John T. (1 February 2009). "Anagrelide for the treatment of essential thrombocythemia: a survey among European hematologists/oncologists". Hematology 14 (1): 1–10. doi:10.1179/102453309X385115. PMID 19154658.

[BriereJB-4] Brière, Jean B (1 January 2007). "Essential thrombocythemia". Orphanet Journal of Rare Diseases 2 (1): 3. doi:10.1186/1750-1172-2-3. PMC 1781427. PMID 17210076.

[5] Campbell PJ, Bareford D, Erber WN, et al. (June 2009). "Reticulin accumulation in essential thrombocythemia: prognostic significance and relationship to therapy". J. Clin. Oncol. 27 (18): 2991–9. doi:10.1200/JCO.2008.20.3174. PMC 3398138. PMID 19364963.

[pmid16810615-6] Petrides PE (2006). "Anagrelide: what was new in 2004 and 2005?". Semin. Thromb. Hemost. 32 (4 Pt 2): 399–408. doi:10.1055/s-2006-942760. PMID 16810615.

[7] Jones GH, Venuti MC, Alvarez R, Bruno JJ, Berks AH, Prince A (February 1987). "Inhibitors of cyclic AMP phosphodiesterase. 1. Analogues of cilostamide and anagrelide". J. Med. Chem. 30 (2): 295–303. doi:10.1021/jm00385a011. PMID 3027338.

[8] Harrison CN, Bareford D, Butt N, et al. (May 2010). "Guideline for investigation and management of adults and children presenting with a thrombocytosis". Br. J. Haematol. 149 (3): 352–75. doi:10.1111/j.1365-2141.2010.08122.x. PMID 20331456.

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anagrelide