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1) ´Ù¸¥ PDE3 ¾ïÁ¦Á¦: ÀÌ ¾àÀº cyclic AMP PDE ¥² ¾ïÁ¦Á¦·Î¼, ½É±Ù¼öÃà·Â °ÈÁ¦(¹Ð¸®³í, ¿¡³ì½Ã¸ó, ¾Ï¸®³í, ¿ÃÇÁ¸®³í) ¹× ½Ç·Î½ºÅ¸Á¹°ú °°Àº À¯»çÇÑ ¼ºÁúÀÌ ÀÖ´Â ¾à¹°ÀÇ ÀÛ¿ëÀ» Áõ°¡½ÃŲ´Ù.
2) ¾Æ¼¼Æ¿»ì¸®½Ç»ê (¾Æ½ºÇǸ°) ¹× ÃâÇ÷ À§ÇèÀ» Áõ°¡½Ãų ¼ö ÀÖ´Â ¾à¹°: Ä¡·á ¿ë·®¿¡¼, ÀÌ ¾àÀº ´Ù¸¥ Ç÷¼ÒÆÇ ÀÀÁý ¾ïÁ¦Á¦ÀÇ È¿°ú¸¦ Áõ°¡½Ãų¼ö ÀÖ´Ù.
¨ç ¾Æ¼¼Æ¿»ì¸®½Ç»ê : º»Å¼ºÇ÷¼ÒÆÇ Áõ°¡Áõ ȯÀÚ¿¡ ´ëÇÑ ÁøÇàÁßÀÎ °üÂû¿¬±¸ ºÐ¼® °á°ú¿¡¼, ÁÖ¿äÇÑ ÃâÇ÷¼º Áõ»óÀÇ ¹ß»ý·üÀÌ ´Ù¸¥ Á¾¾çÄ¡·á¸¦ ¹ÞÀº ȯÀÚ¿¡¼ º¸´Ù ÀÌ ¾àÀ¸·Î Ä¡·á¹ÞÀº ȯÀÚ¿¡¼ ´õ ³ô¾Ò´Ù. ÁÖ¿äÇÑ ÃâÇ÷¼º »ç·ÊÀÇ ´ëºÎºÐÀº Ç×-ÀÀÁýÄ¡·áÁ¦(ÁÖ·Î ¾Æ½ºÇǸ°)µµ ¶ÇÇÑ ÇÔ²² Åõ¿©¹Þ´Â ȯÀÚ¿¡¼ ¹ß»ýÇÏ¿´´Ù. ±×·¯¹Ç·Î ƯÈ÷ ÃâÇ÷ °¡´É¼ºÀÌ ³ôÀº ȯÀÚ¿¡¼´Â Ä¡·á ½ÃÀÛ Àü¿¡ ÀÌ ¾à°ú ¾Æ½ºÇǸ°ÀÇ º´¿ë »ç¿ë½ÃÀÇ À§Ç輺ÀÌ Æò°¡µÇ¾î¾ß ÇÑ´Ù. °Ç°ÇÑ »ç¶÷¿¡ ´ëÇÑ 2°³ÀÇ ÀÓ»ó »óÈ£ÀÛ¿ë ¿¬±¸¿¡¼ ´ÜȸÅõ¿©ÀÇ ÀÌ ¾à 1mg°ú ¾Æ½ºÇǸ° 900mgÀÇ º´¿ë ¶Ç´Â ÀÌ ¾à 1ÀÏ 1ȸ 1mg°ú ¾Æ½ºÇǸ° 75mg ¹Ýº¹ Åõ¿©½Ã ¾Æ½ºÇǸ° ´Üµ¶ Åõ¿©º¸´Ù ´õ Å« ex vivo Ç×Ç÷¼ÒÆÇ ÀÀÁýÈ¿°ú¸¦ º¸¿´´Ù. º´¿ë Åõ¿©µÈ ÀÌ ¾à 1mg°ú ¾Æ½ºÇǸ° 900mg ´ÜȸÅõ¿©´Â ÃâÇ÷½Ã°£(BT), ÇÁ·ÎÆ®·Òºó½Ã°£(PT) ¶Ç´Â Ȱ¼ºÈºÎºÐÆ®·Òº¸ÇÃ¶ó½ºÆ¾½Ã°£(aPTT)¿¡ ¿µÇâÀÌ ¾ø¾ú´Ù.
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3) CYP1A2¿¡ ÀÇÇØ ´ë»çµÇ´Â ¾à¹°: ÀÌ ¾àÀº CYP1A2¿¡ ´ëÇØ ÀϺΠÁ¦ÇÑµÈ ¾ïÁ¦ÀÛ¿ëÀ» ³ªÅ¸³»¸ç, ÀÌ´Â ÀÌ·¯ÇÑ Å¬¸®¾î·±½º ±âÀüÀ» °øÀ¯ÇÏ´Â ´Ù¸¥ º´¿ë ¾à¹°(¿¹ : Å׿ÀÇʸ°)°ú º´¿ëÅõ¿©½Ã »óÈ£ÀÛ¿ë¿¡ ´ëÇÑ ÀÌ·ÐÀûÀÎ °¡´É¼ºÀ» º¸¿©ÁØ´Ù.
4) µð°î½Å : »ç¶÷¿¡ ´ëÇÑ in vivo »óÈ£ÀÛ¿ë ¿¬±¸¿¡¼ µð°î½ÅÀº ÀÌ ¾àÀÇ ¾à¹°µ¿ÅÂÇÐ(PK)Àû Ư¼º¿¡ ¿µÇâÀ» ¹ÌÄ¡Áö ¾ÊÀ¸¸ç, ÀÌ ¾à ¶ÇÇÑ µð°î½ÅÀÇ ¾à¹°µ¿ÅÂÇÐ(PK)Àû Ư¼º¿¡ ¿µÇâÀ» ¹ÌÄ¡Áö ¾Ê´Â´Ù´Â °ÍÀÌ Áõ¸íµÇ¾ú´Ù.
5) CYP1A2 ¾ïÁ¦Á¦: ÀÌ ¾à°ú ÀÌ ¾àÀÇ È°¼º ´ë»çü´Â ÁÖ·Î CYP1A2¿¡ ÀÇÇØ ´ë»çµÈ´Ù. CYP1A2´Â Ç÷纹»ç¹Î ¹× ½ÃÇÁ·ÎÇ÷ϻç½Å µî°ú °°Àº ¸î¸î ¾à¹°¿¡ ÀÇÇØ ¾ïÁ¦µÈ´Ù°í ¾Ë·ÁÁ® ÀÖÀ¸¸ç, ÀÌ·¯ÇÑ ¾à¹°µéÀº ÀÌ·ÐÀûÀ¸·Î ÀÌ ¾àÀÇ Å¬¸®¾î·±½º¸¦ °¨¼Ò½Ãų ¼ö ÀÖÀ¸¸ç, °á°úÀûÀ¸·Î Ç÷Áß ³óµµ¸¦ Áõ°¡½Ãų ¼ö ÀÖ´Ù.
6) CYP1A2 À¯µµÁ¦: CYP1A2 À¯µµÁ¦´Â ÀÌ ¾à¿¡ÀÇ ³ëÃâÀ» °¨¼Ò½Ãų¼ö ÀÖ´Ù. CYP1A2 À¯µµÁ¦(¿¹: ¿À¸ÞÇÁ¶óÁ¹)¸¦ ÇÔ²² º¹¿ëÇϴ ȯÀÚ´Â ÀÌ ¾à¿¡ÀÇ ³ëÃâ °¨¼Ò¸¦ º¸»óÇϱâ À§ÇØ Åõ¿©·®À» ÀûÁ¤(titration)ÇÏ¿©¾ß ÇÒ Çʿ䰡 ÀÖÀ» ¼ö ÀÖ´Ù.
CYP1A2 À¯µµÁ¦ÀÎ ¿À¸ÞÇÁ¶óÁ¹ÀÌ ÀÌ ¾àÀÇ ¾à¹°µ¿ÅÂÇÐ(PK)¿¡ ¹ÌÄ¡´Â ¿µÇâÀ» È®ÀÎÇϱâ À§ÇÑ ¿¬±¸°¡ ¼öÇàµÇ¾ú´Ù. 20¸íÀÇ °Ç°ÇÑ ¼ºÀÎÀ» ´ë»óÀ¸·Î ¿À¸ÞÇÁ¶óÁ¹ 1ÀÏ 1ȸ 40mgÀ» ¹Ýº¹ Åõ¾àÇÑ °á°ú, ¿À¸ÞÇÁ¶óÁ¹ÀÇ Ç÷Áß³óµµ ÇÏ¿¡¼ ÀÌ ¾àÀÇ AUC0- ¡Ä , AUC0-t ¹× Cmax °¡ °¢°¢ 27%, 26% ¹× 36% °¨¼ÒÇÏ¿´À¸¸ç, ÀÌ ¾àÀÇ È°¼º´ë»ç»ê¹°ÀÎ 3-hydroxy-anagrelide´Â °¢°¢ 13%, 14% ¹× 18% °¨¼ÒÇÏ¿´´Ù.
7) ÀÓ»ó½ÃÇè¿¡¼ Åë»óÀûÀ¸·Î ÀÌ ¾à°ú º´¿ë Åõ¿©µÈ ¾à¹°ÀÎ ¾Æ¼¼Æ®¾Æ¹Ì³ëÆæ, Ǫ·Î¼¼¹Ìµå, ö, ¶ó´ÏƼµò, ÇÏÀ̵å·Ï½Ã¿ì·¹¾Æ, ¾Ë·ÎǪ¸®³î°úÀÇ ¾à¹°»óÈ£ÀÛ¿ë ¿¬±¸´Â ¼öÇàµÇÁö ¾Ê¾Ò´Ù.
8) ¼öÅ©¶öÆäÀÌÆ®°¡ ÀÌ ¾àÀÇ Èí¼ö¸¦ ¹æÇØÇÒ ¼ö ÀÖÀ½À» ½Ã»çÇÏ´Â ÇÑ °ÇÀÇ º¸°í°¡ ÀÖ¾ú´Ù.
9) À½½ÄÀÌ ÀÌ ¾àÀÇ »ýüÀÌ¿ëÀ²¿¡ ÀÓ»óÀûÀ¸·Î À¯ÀÇÇÑ ¿µÇâÀ» ¹ÌÄ¡Áö´Â ¾Ê´Â´Ù.
Related FDA Approved Drug
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Mechanism of Action
Anagrelide¿¡ ´ëÇÑ Mechanism_Of_Action Á¤º¸ The mechanism by which anagrelide reduces blood platelet count is still under investigation. Studies in patients support a hypothesis of dose-related reduction in platelet production resulting from a decrease in megakaryocyte hypermaturation. In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide does not produce significant changes in white cell counts or coagulation parameters, and may have a small, but clinically insignificant effect on red cell parameters. Anagrelide inhibits cyclic AMP phosphodiesterase III (PDEIII). PDEIII inhibitors can also inhibit platelet aggregation. However, significant inhibition of platelet aggregation is observed only at doses of anagrelide higher than those required to reduce platelet count.
Pharmacology
Anagrelide¿¡ ´ëÇÑ Pharmacology Á¤º¸ Anagrelide is a drug used for the treatment of essential thrombocytosis (ET; essential thrombocythemia). It works by inhibiting the maturation of megakaryocytes into platelets. The exact mechanism of action is unclear, although it is known to be a potent (IC50 = 36nM) inhibitor of phosphodiesterase-III.
Metabolism
Anagrelide¿¡ ´ëÇÑ Metabolism Á¤º¸ # Phase_1_Metabolizing_Enzyme:Cytochrome P450 1A2 (CYP1A2)
Half-life
Anagrelide¿¡ ´ëÇÑ ¹Ý°¨±â Á¤º¸ At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3 hours.
Absorption
Anagrelide¿¡ ´ëÇÑ Absorption Á¤º¸ Not Available
Pharmacokinetics
Anagrelide HClÀÇ ¾à¹°µ¿·ÂÇÐÀÚ·á
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Biotransformation
Anagrelide¿¡ ´ëÇÑ Biotransformation Á¤º¸ Extensive, with < 1% recovered unchanged in the urine. Metabolized primarily in the liver by cytochrome P450 1A2 (CYP1A2). 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.
Toxicity
Anagrelide¿¡ ´ëÇÑ Toxicity Á¤º¸ There are no reports of overdosage with anagrelide, however thrombocytopenia, which can potentially cause bleeding, is expected from overdosage. Single oral doses of anagrelide at 2,500, 1,500 and 200 mg/kg in mice, rats and monkeys, respectively, were not lethal. Symptoms of acute toxicity were: decreased motor activity in mice and rats and softened stools and decreased appetite in monkeys.
Drug Interactions
Anagrelide¿¡ ´ëÇÑ Drug_Interactions Á¤º¸ Not Available
CYP450 Drug Interaction
[CYP450 TableÁ÷Á¢Á¶È¸]
Food Interaction
Anagrelide¿¡ ´ëÇÑ Food Interaction Á¤º¸ Take without regard to meals.Food appears to reduce the area under the curve by 13.8%, without clinical consequence.
Drug Target
[Drug Target]
Description
Anagrelide¿¡ ´ëÇÑ Description Á¤º¸ Anagrelide is a drug used for the treatment of essential thrombocytosis (ET; essential thrombocythemia). It also has been used in the treatment of chronic myeloid leukemia. [Wikipedia]
Drug Category
Anagrelide¿¡ ´ëÇÑ Drug_Category Á¤º¸ Antithrombotic AgentsFibrinolytic AgentsPlatelet Aggregation Inhibitors
Smiles String Canonical
Anagrelide¿¡ ´ëÇÑ Smiles_String_canonical Á¤º¸ ClC1=C(Cl)C2=C(NC3=NC(=O)CN3C2)C=C1
Smiles String Isomeric
Anagrelide¿¡ ´ëÇÑ Smiles_String_isomeric Á¤º¸ ClC1=C(Cl)C2=C(NC3=NC(=O)C[N@]3C2)C=C1
InChI Identifier
Anagrelide¿¡ ´ëÇÑ InChI_Identifier Á¤º¸ InChI=1/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)/f/h13H
Chemical IUPAC Name
Anagrelide¿¡ ´ëÇÑ Chemical_IUPAC_Name Á¤º¸ 6,7-dichloro-5,10-dihydro-3H-imidazo[2,1-b]quinazolin-2-one
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