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

chemotherapy will increase granulocyte production and shorten the
period of severe neutropenia. Frequent blood counts should be
obtained to determine the effectiveness of the treatment and guide
dosage adjustment. In patients who received intensive myelosuppressive
cancer chemotherapy, daily administration of G-CSF for
≥14-21 days may be necessary to correct the neutropenia. With less
intensive chemotherapy, <7 days of treatment may suffice. In AIDS
patients on zidovudine or patients with cyclic neutropenia, chronic
G-CSF therapy often is required.
One indication for G-CSF presently under investigation is its
use to increase the number of peripheral blood neutrophils in leukocyte
donors. For many years it had been hoped that, like platelet
transfusions for the bleeding associated with severe thrombocytopenia,
neutrophil transfusion could diminish the infectious complications
of neutropenia. However, given the short circulatory t 1/2
of
neutrophils (~6 hours) and the need for large numbers of cells, the
practical collection of sufficient cell numbers has eluded hematologists.
With few complications of therapy in >15 years of clinical
experience, G-CSF now has been used to increase peripheral neutrophil
counts in prospective donors and neutrophil transfusions
(Hubel et al., 2002). Although initial results were modest, the therapy
is likely to be optimized and greater efficacy is anticipated.
Adverse reactions to filgrastim include mild to moderate bone
pain in patients receiving high doses over a protracted period, local
skin reactions following subcutaneous injection, and rare cutaneous
necrotizing vasculitis. Patients with a history of hypersensitivity to
proteins produced by E. coli should not receive the drug. Marked granulocytosis,
with counts >100,000/μL, can occur in patients receiving
filgrastim over a prolonged period of time. However, this is not associated
with any reported clinical morbidity or mortality and rapidly
resolves once therapy is discontinued. Mild to moderate splenomegaly
has been observed in patients on long-term therapy.
Pegylated recombinant human G-CSF pegfilgrastim
(NEULASTA) is generated through conjugation of a
20,000-Da polyethylene glycol moiety to the N-terminal
methionyl residue of the 175–amino acid G-CSF glycoprotein
produced in E. coli. The clearance of pegfilgrastim
by glomerular filtration is minimized, thus making
neutrophil-mediated clearance the primary route of
elimination. Consequently the circulating t 1/2
of pegfilgrastim
is longer than that of filgrastim, allowing
for more sustained duration of action and less frequent
dosing. Clinical studies suggest that neutrophilmediated
clearance of pegfilgrastim may be selfregulating
and therefore specific to each patient’s
hematopoietic recovery (Crawford, 2002). As such, the
recommended dose for pegfilgrastim is fixed at 6 mg
administered subcutaneously.
The therapeutic roles of other growth factors still need to be
defined, although IL-3 and IL-6 have been removed from testing due
to poor efficacy and/or significant toxicity. M-CSF may play a role
in stimulating monocyte and macrophage production, although with
significant side effects, including splenomegaly and thrombocytopenia.
Stem cell factor (SCF) has been shown to augment peripheral blood
mobilization of primitive hematopoietic progenitor cells (Moskowitz
et al., 1997).
Thrombopoietic Growth Factors
Interleukin-11. Interleukin-11 was cloned based on its
activity to promote proliferation of an IL-6–dependent
myeloma cell line (Du and Williams, 1994). The 23,000-
Da cytokine contains 178 amino acids and stimulates
hematopoiesis, intestinal epithelial cell growth, and
osteoclasto-genesis and inhibits adipogenesis. Interleukin-
11 enhances megakaryocyte maturation in vitro
(Teramura et al., 1992), and its in vivo administration to
animals modestly increases peripheral blood platelet
counts (Neben et al., 1993). Clinical trials in patients who
previously demonstrated significant chemotherapyinduced
thrombocytopenia demonstrated that administration
of the recombinant cytokine was associated with
less severe thrombocytopenia and reduced use of platelet
transfusions (Tepler et al., 1996), leading to its approval
for clinical use by the FDA.
Recombinant human IL-11 oprelvekin (NEUMEGA)
is a bacterially derived 19,000-Da polypeptide of 177
amino acids that differs from the native protein only
because it lacks the amino terminal proline residue and
is not glycosylated. The recombinant protein has a
7-hour t 1/2
after subcutaneous injection. In normal subjects,
daily administration of oprelvekin leads to a
thrombopoietic response in 5-9 days.
The drug is available in single-use vials containing 5 mg and
is administered to patients at 25-50 μg/kg per day subcutaneously.
Oprelvekin is approved for use in patients undergoing chemotherapy
for nonmyeloid malignancies that displayed severe thrombocytopenia
(platelet count <20,000/μL) on a prior cycle of the same
chemotherapy, and it is administered until the platelet count returns
to >100,000/μL. The major complications of therapy are fluid
retention and associated cardiac symptoms, such as tachycardia,
palpitation, edema, and shortness of breath; this is a significant
concern in elderly patients and often requires concomitant therapy
with diuretics. Fluid retention reverses upon drug discontinuation,
but volume status should be carefully monitored in elderly patients,
those with a history of heart failure, or those with preexisting fluid
collections in the pleura, pericardium, or peritoneal cavity. Also
reported are blurred vision, injection-site rash or erythema, and
paresthesias.
Thrombopoietin. The cloning and expression of
recombinant thrombopoietin, a cytokine that predominantly
stimulates megakaryopoiesis, is potentially
another milestone in the development of hematopoietic
growth factors as therapeutic agents (Lok et al.,
1994) (Table 37–1). Thrombopoietin is a 45,000- to
75,000-Da glycoprotein containing 332 amino acids
that is produced by the liver, marrow stromal cells,
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HEMATOPOIETIC AGENTS