DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

daily for the 10 days preceding surgery, on the day of surgery, and
for 4 days after surgery. As an alternative, 600 units/kg can be given
on days 21, 14, and 7 before surgery, with an additional dose on the
day of surgery. This can correct a moderately severe preoperative
anemia (i.e., hematocrit 30-36%) and reduce the need for transfusion.
Epoetin alfa also has been used to improve autologous blood
donation (Goodnough et al., 1989). However, the potential benefit
generally is small, and the expense is considerable. Patients treated
for 3-4 weeks with epoetin alfa (300-600 units/kg twice a week) are
able to donate only 1 or 2 more units than untreated patients, and
most of the time this goes unused. Still, the ability to stimulate erythropoiesis
for blood storage can be invaluable in the patient with
multiple alloantibodies to red blood cells.
Other Uses. Epoetin alfa has received orphan drug status from the
FDA for the treatment of the anemia of prematurity, HIV infection,
and myelodysplasia. In the latter case, even very high doses
>1000 units/kg two to three times a week have had limited success.
The utility of very high-dose therapy in other hematologic disorders,
such as sickle cell anemia, is still under study. Highly competitive
athletes have used epoetin alfa to increase their hemoglobin levels
(“blood doping”) and improve performance. Unfortunately, this misuse
of the drug has been implicated in the deaths of several athletes
and is strongly discouraged.
T cell
IL-1
IL-3
GM-CSF
IL-4
IFN-γ
IL-2
Macrophage
Bone Marrow
B cell
IL-1
Antibody
G-CSF
Figure 37–2. Cytokine–cell interactions. Macrophages, T cells,
B cells, and marrow stem cells interact via several cytokines (IL-1,
IL-2, IL-3, IL-4, IFN [interferon]-γ, GM-CSF, and G-CSF)
in response to a bacterial or a foreign antigen challenge. See
Table 37–1 for the functional activities of these various cytokines.
1073
CHAPTER 37
HEMATOPOIETIC AGENTS
MYELOID GROWTH FACTORS
The myeloid growth factors are glycoproteins that stimulate
the proliferation and differentiation of one or more
myeloid cell lines. They also enhance the function of
mature granulocytes and monocytes. Recombinant
forms of several growth factors have been produced,
including granulocyte-macrophage colony-stimulating
factor (GM-CSF) (Wong et al., 1985), granulocyte
colony-stimulating factor (G-CSF) (Welte et al., 1985),
IL-3 (Yang et al., 1986), macrophage colony-stimulating
g factor (M-CSF) or CSF-1 (Kawasaki et al., 1985), and
stem cell factor (SCF) (Huang et al., 1990) (Table 37–1).
The myeloid growth factors are produced naturally
by a number of different cells, including fibroblasts,
endothelial cells, macrophages, and T cells (Figure 37–2).
They are active at extremely low concentrations and act
via membrane receptors of the cytokine receptor superfamily
to activate the JAK/STAT signal transduction pathway.
GM-CSF is capable of stimulating the proliferation,
differentiation, and function of a number of the myeloid
cell lineages (Figure 37–1). It acts synergistically with
other growth factors, including erythropoietin, at the level
of the BFU. GM-CSF stimulates the CFU-GEMM,
CFU-GM, CFU-M, CFU-E, and CFU-Meg to increase
cell production. It also enhances the migration, phagocytosis,
superoxide production, and antibody-dependent
cell-mediated toxicity of neutrophils, monocytes, and
eosinophils (Weisbart et al., 1987).
The activity of G-CSF is restricted to neutrophils
and their progenitors, stimulating their proliferation,
differentiation, and function. It acts primarily on the
CFU-G, although it also can play a synergistic role
with IL-3 and GM-CSF in stimulating other cell lines.
G-CSF enhances phagocytic and cytotoxic activities of
neutrophils. Unlike GM-CSF, G-CSF has little effect
on monocytes, macrophages, and eosinophils and
reduces inflammation by inhibiting IL-1, tumor necrosis
factor, and interferon gamma. G-CSF also mobilizes
primitive hematopoietic cells, including hematopoietic
stem cells, from the marrow into the peripheral blood
(Sheridan et al., 1992). This observation has virtually
transformed the practice of stem cell transplantation,
such that >90% of all such procedures today use G-
CSF–mobilized peripheral blood stem cells as the
donor product.
Granulocyte-Macrophage Colony-Stimulating Factor.
Recombinant human GM-CSF (sargramostim) is a
127–amino acid glycoprotein produced in yeast. Except
for the substitution of a leucine in position 23 and variable
levels of glycosylation, it is identical to endogenous
human GM-CSF. Although sargramostim, like
natural GM-CSF, has a wide range of effects on cells in
culture, its primary therapeutic effect is to stimulate
myelopoiesis. The initial clinical application of sargramostim
was in patients undergoing autologous bone
marrow transplantation. By shortening the duration of
neutropenia, transplant morbidity was significantly