A Textbook of Clinical Pharmacology and Therapeutics

Adverse effects

These include the following:

• hypertension which can be severe;


• thrombosis, for example of shunts, or causing a
  cardiovascular/cerebrovascular accident;


• influenza-like symptoms;


• iron deficiency may be unmasked;


• pure red cell aplasia associated with antibodies to
  erythropoietin has been reported during treatment with
  epoetin alfa.

HUMAN GRANULOCYTE COLONY-STIMULATING
FACTOR (FILGRASTIM, LENOGRASTIM,
PEG-FILGRASTIM).

Granulocyte colony-stimulating factor (G-CSF) is a 174 amino
acid glycoprotein. Filgrastimis unglycosylated rhG-CSF and
lenograstimis glycosylated rhG-CSF. Pegylated G-CSF (PEG-
filgrastim) has a protracted half-life and can be given much
less frequently.

Uses

Indications for G-CSF include:

• to prevent and treat the neutropenia induced by cytotoxic
  cancer chemotherapy (main use);


• congenital neutropenia;


• human immunodeficiency virus (HIV)-related
  AZT-induced neutropenia (chronic therapy);


• aplastic anaemia;


• mobilization of peripheral blood-cell progenitors and
  subsequent harvesting for transplant;


• following bone marrow transplantation.

G-CSF is usually administered by subcutaneous injection.
Therapy is monitored by regular neutrophil counts. After
stopping treatment, neutrophil counts return to baseline after
four to seven days.

Mechanism of action

G-CSF stimulates the proliferation and differentiation of progeni-
tor cells of the myelogranulocyte lineage. It binds to the G-CSF
receptor on myelogranulocyte precursors, enhancing cell repli-
cation and differentation. Once bound to its receptor, G-CSF is
internalized and signal transduction involves a number of tyro-
sine kinase proteins which induce the synthesis of proteins that
upregulate cell-cycle and differentiation processes.

Adverse effects

These include the following:

• bone pain;


• injection site reactions;


• myalgia and fevers;


• splenomegaly;


• thrombocytopenia;


• abnormal liver enzymes.

Contraindications

G-CSF should not be given to patients with myeloid or

myelomonocytic leukaemia, because it increases proliferation

of the malignant clone.

Pharmacokinetics

The bioavailability of subcutaneously administered G-CSF is

54%. The G-CSF plasma t1/2ranges from two to six hours.

Clearance of G-CSF is complex and it increases as the granulo-

cyte count rises. In addition, G-CSF is metabolized in the kid-

ney and liver to its component amino acids, with little or no

G-CSF found in the urine.

INTERLEUKIN-11 AND THROMBOPOIETIN

Interleukin-11 is a recombinant protein which enhances

megakaryocyte maturation and is used to prevent thrombocy-

topenia in patients who developed platelet counts 20 000/μL

with prior cycles of cytotoxic chemotherapy. Interleukin-11

(oprelvekin, not yet available in the UK) is given daily via sub-

cutaneous injection until the platelet count 10 000/μL. Major

side effects include fluid retention and associated cardiac symp-

toms, injection site reactions, paraesthesias and blurred vision.

Thrombopoietinis a recombinant protein which binds to

the mpl-proto-oncogene, stimulates megakaryocyte prolifera-

tion and differentiation in humans. It synergizes with stem cell

factor and G-CSF in promoting bone marrow production of

granulocytes.Thrombopoietinmay be useful in drug-induced

thrombocytopenia and in bone marrow transplantation.

394 ANAEMIA AND OTHER HAEMATOLOGICAL DISORDERS

Key points

Haematopoietic growth factors

• The clinically used haematopoietic growth factors are
  recombinant DNA products of the endogenous
  glycoprotein.


• Erythropoietin (Epo)/darbepoetin:
  
  
  • stimulate proliferation of erythroid (red cell)
    precursors;
  
  
  • are used in the treatment of the anaemia of renal
    failure (myelodysplasia);
  
  
  • are given parenterally; its toxicities include
    hypertension and thrombotic episodes.
  
  
  
  


• Granulocyte colony-stimulating factor (G-CSF):
  
  
  • stimulates proliferation of myeloid precursors;
  
  
  • is used to treat neutropenia of chemotherapy,
    aplastic anaemia and bone marrow transplant;
  
  
  • is given parenterally and its toxicities include myalgias,
    bone pain, fever, thrombocytopenia and hepatitis.
  
  
  
  

COAGULATION FACTORS AND

HAEMOPHILIAS A AND B

Pathophysiology

In haemophilia A there is a deficiency of factor VIII. In

haemophilia B there is a deficiency of factor IX. Both types

present with excessive bleeding in response to trauma, e.g.

muscle haematoma, haemarthrosis, haemorrhage after minor

(e.g. dental) or major surgery, and intracranial bleeding follow-

ing minor head injury.