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Hematopoietic agents(growth factors)

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hematopoetic factors

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Hematopoietic agents(growth factors)

  1. 1. Hematopoietic Agents (growth factors)
  2. 2. Introduction: • Hematopoiesis is a natural process and can be increased many folds in response to certain stimuli and diseases. • Erythrocyte production : 20-fold in response to anemia or hypoxemia • leukocyte production increases dramatically in response to systemic infections • platelet production : 10- to 20-fold when platelet consumption results in thrombocytopenia • Sites of hematopoiesis: skull, vertebral bodies, pelvis, and proximal long bones
  3. 3. Factors affecting hematopoiesis: • Growth Factors • Minerals • Vitamins
  4. 4. HEMATOPOIETIC GROWTH FACTORS: Erythropoietin (EPO) Stem cell factor (SCF, c-kit ligand, Steel factor) Interleukins Granulocyte-macrophage colony-stimulating factor (GM-CSF) Granulocyte colony-stimulating factor (G-CSF) Monocyte/macrophage colony-stimulating factor (M-CSF) Thrombopoietin (TPO)
  5. 5. Growth Factor Physiology: • Stem cells • burstforming units (BFUs) & colony-forming units (CFUs) • proliferation(upto 30 folds) • lineage-committed growth factors(G-CSF, M-CSF, erythropoietin, and thrombopoietin) effect • proliferation and maturation of the CFU for each cell line(upto 30 folds) • 1000 mature cells from each committed stem cell
  6. 6. Erythropoiesis-Stimulating Agents: Erythropoietin: • Most important regulator of the proliferation of committed erythroid progenitors (CFU-E) • feedback system: a sensor in the kidney detects changes in oxygen delivery : modulate the erythropoietin secretion. • Hypoxia-inducible factor(HIF-1α and HIF-1β) enhances expression of genes for vascular endothelial growth factor and erythropoietin • HIF-2α contribute to iron absorption
  7. 7. continued….. • With anemia or hypoxemia, synthesis rapidly increases by 100-fold or more • Acts by : Stimulating marrow progenitor cell survival, proliferation and maturation • feedback loop can be disrupted by: • kidney disease • marrow damage • deficiency in iron or an essential vitamin • Infection or an inflammatory state(cytokines action): suppression of • erythropoietin secretion • iron delivery • progenitor proliferation • Iron metabolism(effects on the hepatic protein hepcidin) • Contributes to resultant anemia
  8. 8. Preparations: epoetin alfa(nearly identical to the endogenous hormone), epoetin beta, epoetin omega, and epoetin zeta, Differ almost exclusively in carbohydrate modifications due to manufacturing differences t1/2 : 4–8 h(epoetin alfa) once-weekly dosing
  9. 9. Therapeutic Uses: • anemias associated with surgery, • AIDS, • cancer chemotherapy, • prematurity, • and certain chronic inflammatory conditions • Darbepoetin alfa : approved for use in patients with anemia associated with chronic kidney disease
  10. 10. Adverse Effects & abuses: • absolute or functional iron deficiency • Functional iron deficiency(i.e., normal ferritin levels but low transferrin saturation) • Supplemental iron therapy is recommended: Serum ferritin is less than 100 μg/L serum transferrin saturation is below 20% • stimulation of tumor cells • Increase hemoglobin levels and improve performance in athletes: “blood doping”
  11. 11. Myeloid Growth Factors: • GM-CSF, G-CSF, IL-3, M-CSF or CSF-1, and stem cell factor (SCF) • Only G-CSF and GM-CSF have found meaningful clinical applications • Produced naturally by: fibroblasts, endothelial cells, macrophages, and T cells • cytokine receptor superfamily: Jak/STAT signal transduction pathway • GM-CSF • Stimulates: CFU-GM, CFU-M, CFU-E, and CFU-Meg • Also enhances: migration, phagocytosis, superoxide production, and antibody-dependent cell-mediated toxicity of neutrophils, monocytes, and eosinophils • G-CSF: restricted to neutrophils • Anti-inflammatory: inhibit IL-1, tumor necrosis factor, and interferon gamma • mobilizes primitive hematopoietic cells
  12. 12. Granulocyte-Macrophage Colony-Stimulating Factor(GM-CSF) • Sargramostim : Recombinant human GM-CSF(a glycoprotein) Uses: • Shortens duration of neutropenia in • transplant patients • patients receiving intensive cancer chemotherapy • stimulates myelopoiesis in some patients with • cyclic neutropenia, • myelodysplasia, • aplastic anemia, • or AIDS-associated neutropenia
  13. 13. Pharmacokinetics & dynamics: • Subcutaneous injection or slow intravenous infusion(maintained over 3–6 h) • t1/2 = 2–3 h • (transient decrease in the absolute leukocyte count secondary to cell margination and pulmonary vascular sequestration) • Followed by dose dependent biphasic rise in leukocyte count: 7-10 days & return to normal in 2-10 days after discontinuation • Low dose: primarily neutrophilic • High dose: monocytosis, eosiniphilia
  14. 14. ADR: • Bone pain, • malaise, • flu-like symptoms, • fever, • diarrhea, • dyspnea, • and rash. • Acute reaction to the first dose: flushing, hypotension, nausea, vomiting, and dyspnea, with a fall in arterial oxygen saturation due to granulocyte sequestration in the pulmonary circulation(sensitive people) • prolonged administration: capillary leak syndrome(rarely) • Rare side effects: transient supraventricular arrhythmia, dyspnea, an elevation of serum creatinine, bilirubin, and hepatic enzymes
  15. 15. Granulocyte Colony-Stimulating Factor(G- CSF): • Filgrastim: stimulates CFU-G to increase neutrophil production • longer-acting pegylated forms: pegfilgrastim and lipegfilgrastim. Uses: • treatment of severe neutropenia after • autologous hematopoietic stem cell transplantation • high-dose cancer chemotherapy • severe congenital neutropenias • Myelodysplasia or marrow damage • neutropenia of patients with AIDS receiving zidovudine • patients undergoing PBSC collection for stem cell transplantation
  16. 16. Pharmacokinetics & dynamics: • subcutaneous injection or intravenous infusion(over 30 mins) • dose: 1–20 μg/kg/d. • t1/2 = 3.5 h • Pegfilgrastim: 6 mg for patients weighing more than 20 kg once per chemotherapy cycle
  17. 17. Adverse Reactions: • mild-to-moderate bone pain • local skin reactions • rare cutaneous necrotizing vasculitis. • Mild-to-moderate splenomegaly • Contra indicated: patients with a history of hypersensitivity to proteins produced by Escherichia sickle cell anemia
  18. 18. Thrombopoietic Growth Factors: Interleukin 11: • Stimulates • hematopoiesis, • intestinal epithelial cell growth, • and osteoclastogenesis • Inhibits: adipogenesis • enhances megakaryocyte maturation & thrombopoesis Oprelvekin: Recombinant human IL-11 • t1/2 about 7 h • Uses: chemotherapy for nonmyeloid malignancies with severe thrombocytopenia • ADR: fluid retention and associated cardiac symptoms
  19. 19. Thrombopoietin Receptor Agonists: Thrombopoietin: • Produced by the liver, marrow stromal cells, and other organs • primary regulator of platelet production • Uses: • immune thrombocytopenia (ITP), • severe aplastic anemia (SAA) Romiplostim: • administered weekly by subcutaneous injection to ITP patients Eltrombopag: • administered orally