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

1074 reduced without a change in long-term survival or risk
of inducing an early relapse of the malignant process
(Brandt et al., 1988). GM-CSF has also been tested as
an adjuvant for immunotherapy, based on its stimulation
of dendritic cell growth and development.
However, its use in that setting is not discussed in this
chapter.
SECTION IV
INFLAMMATION. IMMUNOMODULATION, AND HEMATOPOIESIS
The role of GM-CSF therapy in allogeneic transplantation is
less clear. Its effect on neutrophil recovery is less pronounced in
patients receiving prophylactic treatment for graft-versus-host disease
(GVHD), and studies have failed to show a significant effect
on transplant mortality, long-term survival, the appearance of
GVHD, or disease relapse. However, it may improve survival in
transplant patients who exhibit early graft failure (Nemunaitis et al.,
1990). It also has been used to mobilize CD34-positive progenitor
cells for peripheral blood stem cell collection for transplantation
after myeloablative chemotherapy (Haas et al., 1990). Sargramostim
has been used to shorten the period of neutropenia and reduce morbidity
in patients receiving intensive cancer chemotherapy (Gerhartz
et al., 1993). It also stimulates myelopoiesis in some patients with
cyclic neutropenia, myelodysplasia, aplastic anemia, or AIDSassociated
neutropenia.
Sargramostim (LEUKINE) is administered by subcutaneous
injection or slow intravenous infusion at doses of 125-500 μg/m 2
per day. Plasma levels of GM-CSF rise rapidly after subcutaneous
injection and then decline with a t 1/2
of 2-3 hours. When given intravenously,
infusions should be maintained over 3-6 hours. With the
initiation of therapy, there is a transient decrease in the absolute
leukocyte count secondary to margination and sequestration in the
lungs. This is followed by a dose-dependent, biphasic increase in
leukocyte counts over the next 7-10 days. Once the drug is discontinued,
the leukocyte count returns to baseline within 2-10 days.
When GM-CSF is given in lower doses, the response is primarily
neutrophilic, whereas monocytosis and eosinophilia are observed at
larger doses. After hematopoietic stem cell transplantation or intensive
chemotherapy, sargramostim is given daily during the period of
maximum neutropenia until a sustained rise in the granulocyte count
is observed. Frequent blood counts are essential to avoid an excessive
rise in the granulocyte count. The dose may be increased if the
patient fails to respond after 7-14 days of therapy. However, higher
doses are associated with more pronounced side effects, including
bone pain, malaise, flu-like symptoms, fever, diarrhea, dyspnea, and
rash. An acute reaction to the first dose, characterized by flushing,
hypotension, nausea, vomiting, and dyspnea, with a fall in arterial
oxygen saturation due to granulocyte sequestration in the pulmonary
circulation occurs in sensitive patients. With prolonged administration,
a few patients may develop a capillary leak syndrome, with
peripheral edema and pleural and pericardial effusions. Other
serious side effects include transient supraventricular arrhythmia,
dyspnea, and elevation of serum creatinine, bilirubin, and hepatic
enzymes.
Granulocyte Colony-Stimulating Factor. Recombinant
human G-CSF filgrastim (NEUPOGEN) is a 175–amino
acid glycoprotein produced in Escherichia coli. Unlike
natural G-CSF, it is not glycosylated and carries an
extra N-terminal methionine. The principal action of
filgrastim is the stimulation of CFU-G to increase neutrophil
production (Figure 37–1). It also enhances the
phagocytic and cytotoxic functions of neutrophils.
Filgrastim is effective in the treatment of severe
neutropenia after autologous hematopoietic stem cell
transplantation and high-dose cancer chemotherapy
(Lieschke and Burgess, 1992). Like GM-CSF, filgrastim
shortens the period of severe neutropenia and
reduces morbidity secondary to bacterial and fungal
infections. When used as a part of an intensive
chemotherapy regimen, it can decrease the frequency
of hospitalization for febrile neutropenia and interruptions
in the chemotherapy protocol; a positive impact
on patient survival has not been demonstrated. G-CSF
also is effective in the treatment of severe congenital
neutropenias. In patients with cyclic neutropenia, G-CSF
therapy will increase the level of neutrophils and
shorten the length of the cycle sufficiently to prevent
recurrent bacterial infections (Hammond et al., 1989).
Filgrastim therapy can improve neutrophil counts in
some patients with myelodysplasia or marrow damage
(moderately severe aplastic anemia or tumor infiltration
of the marrow). The neutropenia of AIDS patients
receiving zidovudine also can be partially or completely
reversed. Filgrastim is routinely used in patients undergoing
peripheral blood stem cell (PBSC) collection for
stem cell transplantation. It promotes the release of
CD34 + progenitor cells from the marrow, reducing the
number of collections necessary for transplant.
Moreover, filgrastim-mobilized PBSCs appear more
capable of rapid engraftment. PBSC-transplanted
patients require fewer days of platelet and red blood cell
transfusions and a shorter duration of hospitalization
than do patients receiving autologous bone marrow
transplants. Finally, G-CSF–induced mobilization of
stem cells into the circulation has been promoted as a
way to enhance repair of other damaged organs in
which PBSC might play a role. For example, many
anecdotal reports have claimed improved cardiac function
following the treatment of myocardial infarction
patients with G-CSF. However, a meta-analysis of these
studies have failed to demonstrate an overall benefit
(Abdel-Latif et al., 2008).
Filgrastim is administered by subcutaneous injection or intravenous
infusion over at least 30 minutes at doses of 1-20 μg/kg per
day. The usual starting dose in a patient receiving myelosuppressive
chemotherapy is 5 μg/kg per day. The distribution and clearance rate
from plasma (t 1/2
of 3.5 hours) are similar for both routes of
administration. As with GM-CSF therapy, filgrastim given daily
after hematopoietic stem cell transplantation or intensive cancer