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词条 Omacetaxine mepesuccinate
释义

  1. Medical uses

  2. Adverse effects

  3. Mechanism of action

  4. References

{{Drugbox
| IUPAC_name = 1-((1S,3aR,14bS)-2-Methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta(a)(1,3)dioxolo(4,5-h)pyrrolo(2,1-b)(3)benzazepin-1-yl) 4-methyl (2R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl)butanedioate
| image = Omacetaxine mepesuccinate.svg
| image2 = Omacetaxine_mepesuccinate3DS.svg
| tradename = Synribo
| Drugs.com = {{Drugs.com|monograph|omacetaxine-mepesuccinate}}
| licence_US = Omacetaxine_mepesuccinate
| pregnancy_AU =
| pregnancy_US = D
| pregnancy_category =
| legal_AU =
| legal_CA =
| legal_UK =
| legal_US = Rx-only
| legal_status =
| routes_of_administration = Subcutaneous, intravenous infusion
| bioavailability =
| protein_bound = 50%
| metabolism = Mostly via plasma esterases
| elimination_half-life = 6 hours
| excretion = Urine (≤15% unchanged)
| IUPHAR_ligand = 7454
| CAS_number = 26833-87-4
| ATC_prefix = L01
| ATC_suffix = XX40
| ATC_supplemental =
| PubChem = 285033
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 71019
| DrugBank =
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 6FG8041S5B
| KEGG = D08956
| ChemSpiderID = 251215
| chemical_formula =
| C=29 | H=39 | N=1 | O=9
| molecular_weight = 545.62 g/mol
| smiles = CC(C)(CCC[C@@](CC(=O)OC)(C(=O)O[C@H]1[C@H]2c3cc4c(cc3CCN5[C@@]2(CCC5)C=C1OC)OCO4)O)O
| StdInChI = 1S/C29H39NO9/c1-27(2,33)8-5-10-29(34,16-23(31)36-4)26(32)39-25-22(35-3)15-28-9-6-11-30(28)12-7-18-13-20-21(38-17-37-20)14-19(18)24(25)28/h13-15,24-25,33-34H,5-12,16-17H2,1-4H3/t24-,25-,28+,29-/m1/s1
| StdInChIKey = HYFHYPWGAURHIV-JFIAXGOJSA-N
}}Omacetaxine mepesuccinate (INN, trade names Synribo or Myelostat ), formerly named as homoharringtonine or HHT, is a pharmaceutical drug substance that is indicated for treatment of chronic myeloid leukemia (CML). It is a natural product first discovered in Cephalotaxus harringtonii, now manufactured by hemi-synthesis. It was approved by the US FDA in October 2012 for the treatment of adult patients with CML with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs).[1]

Medical uses

Omacetaxine/homoharringtonine is indicated for use as a treatment for patients with chronic myeloid leukaemia who are resistant or intolerant of tyrosine kinase inhibitors.[2][3][4]

In June 2009, results of a long-term open label Phase II study were published, which investigated the use of omacetaxine infusions in CML patients. After twelve months of treatment, about one third of patients showed a cytogenetic response.[5] A study in patients who had failed imatinib and who had the drug resistant T315I mutation achieved cytogenetic response in 28% of patients and hematologic response in 80% of patients, according to preliminary data.[6]

Phase I studies including a small number of patients have shown benefit in treating myelodysplastic syndrome (MDS, 25 patients)[7] and acute myelogenous leukaemia (AML, 76 patients).[8] Patients with solid tumors did not benefit from omacetaxine.[9]

Adverse effects

By frequency:[1][2]

Very common (>10% frequency):

{{div col|colwidth=18em}}
  • Diarrhoea
  • Myelosuppression†
  • Injection site reactions
  • Nausea
  • Fatigue
  • Fever
  • Muscle weakness
  • Joint pain
  • Headache
  • Cough
  • Hair loss
  • Constipation
  • Nosebleeds
  • Upper abdominal pain
  • Pain in the extremities
  • Oedema
  • Vomiting
  • Back pain
  • Hyperglycemia, sometimes extreme
  • Gout
  • Rash
  • Insomnia
{{div col end}}

Common (1–10% frequency):

  • Seizures
  • Haemorrhage

† Myelosuppression, including: thrombocytopenia, anaemia, neutropenia and lymphopenia, in descending order of frequency.

Mechanism of action

Omacetaxine is a protein translation inhibitor. It inhibits protein translation by preventing the initial elongation step of protein synthesis. It interacts with the ribosomal A-site and prevents the correct positioning of amino acid side chains of incoming aminoacyl-tRNAs. Omacetaxine acts only on the initial step of protein translation and does not inhibit protein synthesis from mRNAs that have already commenced translation.[10]

References

1. ^1 {{cite web|title=Synribo (omacetaxine) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|accessdate=18 February 2014|url=http://reference.medscape.com/drug/synribo-omacetaxine-999786#showall}}
2. ^1 {{cite web|title=SYNRIBO (omacetaxine mepesuccinate) injection, powder, lyophilized, for solution [Cephalon, Inc.]|work=DailyMed|publisher=Cephalon, Inc.|date=October 2012|accessdate=18 February 2014|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=83a504ef-cf92-467d-9ecf-d251194a3484}}
3. ^{{cite book|title=Martindale: The Complete Drug Reference|work=Medicines Complete|publisher=Pharmaceutical Press|date=14 November 2012|accessdate=18 February 2014|chapter=Omacetaxine Mepesuccinate|editor=Sweetman, S}}
4. ^{{cite book|last1=Lacroix|first1=Marc|title=Targeted Therapies in Cancer|date=2014|publisher=Nova Sciences Publishers|location=Hauppauge , NY|isbn=978-1-63321-687-7|url=https://www.novapublishers.com/catalog/product_info.php?products_id=50994}}
5. ^{{Cite journal | last1 = Li | first1 = Y. F. | last2 = Deng | first2 = Z. K. | last3 = Xuan | first3 = H. B. | last4 = Zhu | first4 = J. B. | last5 = Ding | first5 = B. H. | last6 = Liu | first6 = X. N. | last7 = Chen | first7 = B. A. | title = Prolonged chronic phase in chronic myelogenous leukemia after homoharringtonine therapy | journal = Chinese Medical Journal | volume = 122 | issue = 12 | pages = 1413–1417 | year = 2009 | pmid = 19567163}}
6. ^{{Cite journal | last1 = Quintás-Cardama | first1 = A. | last2 = Kantarjian | first2 = H. | last3 = Cortes | first3 = J. | title = Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009 | journal = Cancer | volume = 115 | issue = 23 | pages = 5382–5393 | year = 2009 | pmid = 19739234 | doi = 10.1002/cncr.24601}}
7. ^{{Cite journal | last1 = Wu | first1 = L. | last2 = Li | first2 = X. | last3 = Su | first3 = J. | last4 = Chang | first4 = C. | last5 = He | first5 = Q. | last6 = Zhang | first6 = X. | last7 = Xu | first7 = L. | last8 = Song | first8 = L. | last9 = Pu | first9 = Q. | title = Effect of low-dose cytarabine, homoharringtonine and granulocyte colony-stimulating factor priming regimen on patients with advanced myelodysplastic syndrome or acute myeloid leukemia transformed from myelodysplastic syndrome | journal = Leukemia & Lymphoma | volume = 50 | issue = 9 | pages = 1461–7 | year = 2009 | doi = 10.1080/10428190903096719 | pmid=19672772}}
8. ^{{Cite journal | last1 = Gu | first1 = L. F. | last2 = Zhang | first2 = W. G. | last3 = Wang | first3 = F. X. | last4 = Cao | first4 = X. M. | last5 = Chen | first5 = Y. X. | last6 = He | first6 = A. L. | last7 = Liu | first7 = J. | last8 = Ma | first8 = X. R. | title = Low dose of homoharringtonine and cytarabine combined with granulocyte colony-stimulating factor priming on the outcome of relapsed or refractory acute myeloid leukemia | journal = Journal of Cancer Research and Clinical Oncology | volume = 137 | issue = 6 | pages = 997–1003 | year = 2010 | pmid = 21152934 | doi = 10.1007/s00432-010-0947-z}}
9. ^{{Cite journal | last1 = Kantarjian | first1 = H. M. | last2 = Talpaz | first2 = M. | last3 = Santini | first3 = V. | last4 = Murgo | first4 = A. | last5 = Cheson | first5 = B. | last6 = O'Brien | first6 = S. M. | title = Homoharringtonine | journal = Cancer | volume = 92 | issue = 6 | pages = 1591–1605 | year = 2001 | pmid = 11745238 | doi = 10.1002/1097-0142(20010915)92:6<1591::AID-CNCR1485>3.0.CO;2-U}}
10. ^Wetzler M, Segal D. Omacetaxine as an Anticancer Therapeutic: What is Old is New Again. Current Pharmaceutical Design 2011;17:59–64
{{Intracellular chemotherapeutic agents}}

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