Hematopoietic stimulants

Pegfilgrastim/Neulasta Hematopoietic stimulant Amgen SC Nonlinear PK 15-80 h... 

The three types of recombinant CSFs (GM-CSF, G-CSF, and M-CSF) are used as hematopoietic stimulators, in the treatment of infectious diseases, some types of cancer, bone marrow transplants, and neutropenia, a disease characterized by a reduced level of neutrophils, the precursors of white blood cells (Table 16.1). 

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic stimulant (i.e., encourages formation of new blood cells and is given to patients who have undergone chemotherapy, bone marrow transplants, etc.). It can be produced by expression from genetically modified . coli, as described in U.S. 4,810,643 Example 7. Estimate the cost of production of hpG-CSE using the method of this example. 

IL-3 has been used in clinical trials designed to assess the benefit from hematopoietic stimulation, shortening the... 

D. R. Mould, PKPD models for white cell responses to hematopoietic stimulation with and without chemotherapy. American Society of Clinical Pharmacology and Therapeutics Annual Meeting, Orlando, FL, March 2-5, 2005. 

When Cohn, ct al. in 1927 (15, 16) prepared an active liver extract free from vitamins, Koessler and Maurer (69) argued that although liver undoubtedly contains a hematopoietic-stimulating substance, liver alone in the absence of ample vitamins will not lead to permanent lasting results. 

In 1929, Jones, Phillips, Larsell, and Nokes (65) reported the hematopoietic effect of nuclear extractives in human anemias. They believed that nuclear extractives from various organ sources—considered to be nucleoproteins and the sodium salts of nucleic acids—contained an unknown hematopoietic stimulant. Oral administration of such extractives, prepared from chicken corpuscles, beef spleen, beef liver, beef kidney, beef heart muscle, salmon liver, beef thymus and beef pancreas, in J g. doses, yielded satisfactory results in pernicious as well as other anemias. They thus tentatively concluded that the hematopoietic stimulant is an integral part of the cell nucleus. 

Hematopoietic cytokines/colony-stimulating factors IL-3, IL-5, IL-6, IL-7, erythropoietin, GM-CSF, G-CSF, M-CSF, thrombo-poietin... 

Colony-stimulating factors Hematopoietic colony-stimulating factors... 

All mature blood cells arise from primitive hematopoietic cells in the bone marrow, the pluripotent stem cells. Approximately 0.1% of the nucleated cells of the bone marrow are pluripotent stem cells and approximately 5% of these cells may be actively cycling at any one time. The stem cell pool maintains itself through a process of asymmetrical cell division when a stem cell divides, one daughter cell remains a stem cell and the other becomes a committed colony-forming cell (CFC). The proliferation and differentiation of CFCs are controlled by hematopoietic growth factors. The hematopoietic growth factors stimulate cell division, differentiation and maturation, and convert the dividing cells into a population of terminally differentiated functional cells. 

SCF (recombinant product ancestim) is an early-acting hematopoietic growth factor that stimulates the proliferation of primitive hematopoietic and nonhema-topoietic cells [7]. In vitro, SCF has minimal effect on hematopoietic and nonhematopoietic progenitor cells, but it synergistically increases the activity of other hematopoietic growth factors, such as G-CSF, GM-CSF, and EPO. SCF stimulates the generation of dendritic cells in vitro and mast cells in vivo. 

A cytokine, secreted by TH2-cells and mast cells, stimulates B-cell growth, acts as hematopoietic factor for growth factor eosinophils, and extends the life span of eosinophils. 

Cytokine receptors that couple to the JAK-STAT Pathway decode the signaling though hematopoietic cytokines (erythropoietin, thrombopoietin, colony-stimulating factors), prolactin, growth hormone, the a-, (3- and y- interferons, and a number of immunomodulatory interleukins [3], They form homodimetic or heterodimeric receptor complexes, which after ligandbinding recruit and activate isotypes of Janus kinases (JAKs). Activated JAKs in turn... 

Fak (focal adhesion kinase) is expressed in most tissues and is evolutionary conserved across species. It is activated by integrin clustering and by stimulation of several G protein-coupled recqrtors and RTKs. Fak is associated with focal adhesions and regulates cell spreading and migration. The kinase is essential for embryonic development since the homozygote Fak knockout is embryonic lethal. Pyk2 (proline-rich tyrosine kinase 2), the second member of the Fak kinase family has a more restricted expression pattern (primarily neuronal and hematopoietic cells) and does not localize to focal adhesions. 

IL-6 T lymphocytes, monocytes, macrophages, synovial fibroblasts Activates T lymphocytes, induces acute-phase response, stimulates growth and differentiation of hematopoietic precursor cells stimulates synovial fibroblasts... 

Thomas J, Liu F, Link DC. Mechanisms of mobilization of hematopoietic progenitors with granulocyte colony-stimulating factor. Curr Opin Hematol 2002 9(3) 183-189. 

IL-6 (21-28) Monocyte/macrophage, T cell endothelium, fibroblast, keratinocyte Induction of fever and the hepatic acute phase response. Stimulates cortisol production. Decreases IL-1 and TNF production. Participates in activation of B and T cells, facilitates Ig production by B cells. Induction of granulocyte-macrophage colony-stimulating factor, stimulation of hematopoietic progenitors. 

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