Anagrelide HCl

Anagrelide is a selective thrombocytopenic agent [1].

Anagrelide is a FDA-approved drug for the treatment of essential thrombocythemia. It is originally identified as a potential inhibitor of platelet aggregation. Anagrelide selectively affects thrombocytes while shows no significant effect on white blood cells, erythrocytes, or coagulation. Anagrelide is revealed to be available in 0.5mg capsules for oral administration.

Anagrelide is a potent inotropic agent for dogs with remarkable vasodilatory activity. Additionally, anagrelide can reduce renal blood flow. Furthermore, anagrelide has shown to play roles in other chronic myeloproliferative disorders, such as polycythemia vera, chronic myeloid leukemia and agnogenic myeloid metaplasia. Anagrelide has some side effects involving headache, diarrhea, edema, palpitations, and abdominal pain [1].

References:
[1] Oertel MD. Anagrelide, a selective thrombocytopenic agent. Am J Health Syst Pharm. 1998 Oct 1;55(19):1979-86.

Chemotherapy of chronic haematological malignancies.[Pubmed:2039859]

Baillieres Clin Haematol. 1991 Jan;4(1):197-221.

After years of stagnation in the treatment of chronic haematological malignancies, some interesting agents have emerged which might improve the prognosis of these diseases. For chronic leukaemias of lymphoid lineage, three new chemical agents, all purine analogues, seem to be of particular interest. Pentostatin is a specific inhibitor of ADA and has been shown to be highly efficient in producing CR in patients with HCL. Its relative merit compared with IFN-alpha for the treatment of HCL is being studied in ongoing randomized trials. Pentostatin is also active in B-CLL and promising activities have been demonstrated in T- or B-PLL and ATCL. Fludarabine is an analogue of adenine which is resistant to the deamination of ADA. It has been reported to be highly active for patients with both pretreated or non-treated B-CLL. CR rates of 13% with overall response rates of 57% can be achieved, even in heavily pretreated patients. Its activity in the other lymphoid malignancies is not yet known. CdA, a substrate analogue of ADA, has also produced encouraging results in B-CLL, HCL and T cell malignancies, and in some patients with just one single course. Thus far, experience with this drug comes from one institution and requires further confirmation. For chronic myeloproliferative diseases, little progress has yet been made. Although IFN-alpha seems to be active in CML and to result in cytogenetic remissions in bone marrow, a definite advantage of this biological agent over conventional chemotherapy as regards survival and life quality has not yet been proven. Allogeneic bone marrow transplantation is beneficial for those patients who are eligible. No remarkable advances have been made in the treatment of myeloproliferative disorders except for the development of an antiplatelet drug, anagrelide. This agent seems to be highly effective in controlling thrombocytosis. The relative merit of this agent as compared with IFN-alpha, as well as the impact of this agent on the survival and on life-quality of patients with myeloproliferative disorders, have yet to be defined.

Comparison of the biological activities of anagrelide and its major metabolites in haematopoietic cell cultures.[Pubmed:16041400]

Br J Pharmacol. 2005 Oct;146(3):324-32.

The platelet-lowering drug anagrelide inhibits bone marrow megakaryocytopoiesis by an unknown mechanism. 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. To clarify this question here we have compared the activities of anagrelide, BCH24426 and RL603 on the growth and differentiation of CD34(+) haematopoietic progenitor cells in liquid culture and on the migration of differentiated megakaryocytes. Incubation with either anagrelide, BCH24426 or RL603 did not affect the early expansion of CD34(+) cells stimulated by thrombopoietin. In contrast, both anagrelide and BCH24426 potently inhibited the development of megakaryocytes (IC(50) +/- s.e.m. = 26 +/- 4 and 44 +/- 6 nM, respectively), whereas RL603 showed no significant effect. Anagrelide and BCH24426 did not affect erythroid or myelomonocytic differentiation stimulated by erythropoietin or granulocyte-macrophage colony-stimulating factor, demonstrating the selectivity of these compounds against the megakaryocytic lineage. Neither anagrelide nor its metabolites showed a significant effect on the migratory response of megakaryocytes towards stromal cell-derived factor-1alpha. Although BCH24426 was shown to be considerably more potent than anagrelide as an inhibitor of phosphodiesterase type III (PDEIII) (IC(50) = 0.9 vs 36 nM) this activity did not correlate with the potency of inhibition of megakaryocyte development. Furthermore, other PDEIII inhibitors of widely differing potency were shown to have negligible effects on megakaryocytopoiesis. Taken together our results demonstrate that anagrelide and BCH24426 target a cellular event involved specifically in the megakaryocyte differentiation programme, which is independent of PDEIII inhibition.

Analysis of the mechanism of anagrelide-induced thrombocytopenia in humans.[Pubmed:1562721]

Blood. 1992 Apr 15;79(8):1931-7.

Anagrelide is a new therapeutic compound recently demonstrated to have a rapid and selective thrombocytopenic effect in humans. The effects of anagrelide were evaluated in plasma clot and liquid suspension cultures of optimally stimulated normal human peripheral blood megakaryocyte progenitors in order to determine the mechanism of its thrombocytopenic activity. In plasma clot cultures, at clinically relevant, therapeutic concentrations (5 to 50 ng/mL), anagrelide exerted no significant inhibitory effect on megakaryocyte colony numbers or colony size. Only at anagrelide concentrations of 10 to 500 times therapeutic doses did anagrelide inhibit megakaryocyte colony development: an anagrelide concentration of 5 micrograms/mL reduced colony numbers by 57% and colony size by 31%. In contrast, lower, therapeutic anagrelide concentrations exerted profound effects in liquid culture on megakaryocyte cytoplasmic maturation, size, and DNA content. When present for the entire 12-day culture duration, anagrelide induced left-shifted megakaryocyte maturation and reduced both megakaryocyte ploidy and megakaryocyte diameter. Anagrelide, at concentrations of 5 to 50 ng/mL, shifted the modal cultured megakaryocyte morphologic stage from III to II, reduced the model ploidy value from 16N to 8N, and decreased the mean megakaryocyte diameter by up to 22%, from 27.6 microns to 21.6 microns. Megakaryocyte diameter was significantly reduced in most instances, even when analyzed as a function of morphologic stage. When anagrelide was added to the cultures after 6- and 9-day delays (during the final 6 and 3 days, respectively, of culture), similar inhibitory effects on megakaryocyte maturation stage and ploidy distribution were observed. However, the magnitude of the left-shift in ploidy appeared to be less as the duration of anagrelide exposure was reduced. Conversely, megakaryocyte diameter was not significantly affected by the shorter 3- and 6-day anagrelide exposures. These data indicate that therapeutic concentrations of anagrelide influence primarily the postmitotic phase of megakaryocyte development, decreasing platelet production by reducing megakaryocyte size and ploidy, as well as by disrupting full megakaryocyte maturation. Inhibition of megakaryocyte diameter appears to require more prolonged anagrelide exposure than inhibition of maturation stage and ploidy. The molecular mechanisms responsible for the inhibitory effects of anagrelide on megakaryocytopoiesis remain to be defined.