Thromboreductin Mechanism of Action

Pharmacology: Pharmacodynamics: Anagrelide causes a dose dependent decrease in platelet count; the mechanism of action is unknown. The mechanism of action is species specific for humans, there are no data on a platelet count reducing effect in any experimental animal model. It is therefore hypothesized that Anagrelide acts via a metabolite that is generated in man.
Anagrelide exerts its action via reducing the size and ploidy of megakaryocytes in the post mitotic phase of maturation.
Anagrelide does not cause significant changes in white blood cells and coagulation parameters, minor changes in red blood cells were observed.
When administered in high, non-therapeutic doses Anagrelide inhibits the c-AmP Phosphodiesterase and ADP and collagen induced thrombocyte aggregation.
Pharmacokinetics: The bioavailability of Anagrelide after oral administration is 70% according to data from a mass balance study. In healthy volunteers, the time to maximal plasma (Tmax) level was about 1 to 2 hours, the elimination half-life is short (1 to 2 hours). Anagrelide has a high volume of distribution (120 L/Kg), the distribution in different compartments is unknown, as is plasma protein binding. Anagrelide is intensively metabolised, at least 4 metabolites emerge. After administration of C labeled Anagrelide 75% of radioactivity are excreted within 6 days via urine, 10% via faeces.
The clinical experience in fasted or non-fasted patients shows that there is no effect of food on the efficacy of Anagrelide.
Accumulation of Anagrelide should not occur upon long-term administration because of the short half-life. This assumption is supported by clinical experience: upon stopping treatment platelet counts recover to pre-therapy levels within 4 to 8 days.
No data are available for elderly patients and patients with renal or liver insufficiency. When using Anagrelide in these patients careful monitoring especially when beginning therapy should be performed.
Toxicology: Preclinical Safety data: Experimental studies in different species including mice, rats, dogs and monkeys were performed for evaluation of anti-aggregatory properties and acute and chronic toxicity. However, since the platelet reducing effect of Anagrelide cannot be reproduced in experimental animals because of the lack or insufficient metabolism into the active substance the results of these studies are of limited value for interpretation of the safety of Anagrelide. Anagrelide is used in man for over 15 years, there is no single report described on a potential cancerogenicity, in particular no case of leukaemigenicity. A teratogenic effect has not been executed so far.
Acute Toxicity: The LD50 in mice and rats with a pharmacologically active metabolite is 40.5 mg/Kg and 71.4 mg/Kg, respectively.
Chronic Toxicity: Published data on long term exposure data with different species (rat, dog and monkey) for up to 1 year were generated, their relevance is unclear. There is no carcinogenicity study available.
Mutagenic and cancerogenic potential: Anagrelide did not show a mutagenic potential in three in vitro and in vivo experiments (Ames test, mouse lymphoma cell test, micronucleus test). The meaning of these results is unclear, because in humans other metabolites might emerge compared to these standard tests with metabolic activation.
Anagrelide does not show any mutagenic activity at the TK locus in L5178Y mouse lymphoma cells. However, in a direct comparison hydroxyurea exhibits potent mutagenic activity both after short- and long-term exposure without metabolic activation. In contrast Anagrelide does not show any mutagenic potential after metabolic activation with human S9 microsomes.
There is no long-term cancerogenicity study.
Published data show that Anagrelide has potent inotropic and vasodilatatory effects in anaesthetised dogs and dogs with heart failure. A dose of 100 mg/kg reduced the peripheral resistance in healthy dogs and dogs with heart failure by 21% and 51%, respectively the end diastolic pressure in the left ventricle by 4 mm Hg and 6 mm Hg, respectively, the frequency by 19% and 30%, respectively, and contractibility by 51% and 450%, respectively. The mean arterial pressure in healthy dogs was reduced by 23%, however, unchanged in dogs with heart failure, blood flow in the aorta was increased by 200%.
Reproductive Toxicity: Teratogenicity has not been excluded.
Since Anagrelide exerts a species-specific effect in man, data on the reproductive toxicity in rats are of limited value. Therefore, Anagrelide is contraindicated in pregnancy.