Imatinib

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Definition
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Tyrosine kinase inhibitor for the treatment of oncological diseases.

Pharmacodynamics (Effect)
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The translocation between chromosomes 9 and 22 is characteristic of chronic myeloid leukemia (CML) (Philadelphia chromosome). This leads to the oncogene known as BCR-ABL. This oncogene is a non-receptor tyrosine kinase tyrosine kinase that phosphorylates various substrates. BCR-ABL inhibits the normal proliferation and differentiation of cells.

Imatinib inhibits the intracellularly localized BCR-ABL tyrosine kinase , which is responsible for uncontrolled growth in chronic myeloid leukemia (CML). Imatinib specifically blocks the binding site for ATP at the tyrosine kinase BCR-ABL. This inhibits the transfer of ATP phosphate groups to tyrosine residues of the substrates.

In addition, imatinib also inhibits the c-kit receptor tyrosine kinase (for the growth factor CSF = cytokine stem cell factor", which in mutated form is important for the growth of gastrointestinal stromal cell tumours (GIST).

In addition, the PDGFR (platelet-derived-growth-factor receptor) receptor is inhibited, which plays a role in myelodysplastic/myeloproliferative diseases. If the various tyrosine kinases are listed according to decreasing affinity of the active substances, the tyrosine kinase preference for imatinib is PDGFR > KIT > BCR-ABL, for nilotinib BCR-ABL > PDGFR > KIT.

In this way, signal transduction within cells is prevented. Thus, processes of migration, invasion angiogenesis, proliferation and anti-apoptosis are disturbed.

Indication
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Chronic myeloid leukemia, primary eosinophilia.

Gastrointestinal stromal tumors and myeloproliferative diseases.

Possible applications ( off-label use): dermatofibrosarcoma protuberans; chronic graft-versus-host disease; systemic scleroderma; hypereosinophilia syndrome (off-label use); mastocytosis (off-label use); acrolentiginous malignant melanoma; mucosal melanoma.

Pregnancy/nursing period
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Teratogenicity was described in animal experiments. Do not use during pregnancy or lactation!

Dosage and method of use
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For the treatment of CML: 400 mg/day (in the chronic phase) or 600 mg/day (in blast crises). Under certain circumstances, e.g. progression of the disease, increase to 800 mg/day is possible.

Undesirable effects
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autoimmune phenomena and diseases whose management and, if necessary, prophylactic treatment are of great importance. The most frequent side effect is immune-mediated colitis, which, depending on its severity, can also lead to severe, even long-lasting diarrhoea. In addition, other immune-mediated diseases such as hypophysitis, hepatitis, iridocyclitis and the exacerbation of lupus nephritis are also observed.

Contraindication
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Hypersensitivity to the active substance or any of the other ingredients.

Preparations
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Glivec®

Literature
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  1. Gabrielli A et al (2007) Stimulatory autoantibodies to the PDGF receptor: a link to fibrosis in scleroderma and a pathway for novel therapeutic targets. Autoimmune Rev 7: 121-126
  2. Gabrielli A et al (2007) Pathogenic autoantibodies in systemic sclerosis. Curr Opin Immunol 19: 640-645
  3. Goldman JM et al (2003) Chronic myeloid leukemia - advances in biology and new approaches to treatment. N Engl J Med 349: 1451-1464
  4. Kähler HC et al. (2009) Skin changes caused by "targeted therapies" in oncological patients. Dermatologist 60: 433-440
  5. Svegliati S et al (2007) Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease. Blood 110: 237-241

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Last updated on: 29.10.2020