Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 12 IMMUNOMODULATORY THERAPY
Muramyl tripeptide
Clinical applications
Muramyl tripeptide is a derivative of the cell wall
of Mycobacterium spp that acts on monocytemacrophages,
causing enhanced release of proinflammatory
cytokines and cytotoxic function of these cells. The
agent has been incorporated into liposomes (muramyl
tripeptide phosphatidyl-ethanolamine) and used in
several studies to treat canine patients with osteosarcoma,
hemangiosarcoma and malignant melanoma. In
these studies muramyl tripeptide was used as an adjunct
to surgery and chemotherapy and appeared to reduce
the prevalence of metastasis and enhance survival
time. By contrast, in studies of canine and feline
mammary adenocarcinoma, administration of lipo -
some-encapsulated muramyl tripeptide did not enhance
survival time of affected animals.
Recombinant cytokines
Cytokines are a key regulatory component of the
immune system that may be involved in the activation
or suppression of an immune response (see Fig. 12.1).
Those cytokines that positively influence immune effector
mechanisms are logical candidates for therapeutic
application in immunosuppressed patients. Knowledge
of the molecular sequence of cytokine molecules enables
preparation of commercial quantities of recombinant
cytokines and such products are now routinely employed
in human medicine.
Although sequence data for numerous canine and
feline cytokines are published and some recombinant
dog and cat cytokines have been produced, there is only
one licensed product for companion animal use (Virbagen
Omega®, see below). However, the close sequence
homology between some human and companion animal
cytokines has historically enabled the clinical use of
recombinant human (rHu) cytokines in veterinary
species.
Although profound effects are often reported following
the administration of rHu cytokines, these molecules
still bear a degree of antigenic dissimilarity to those of
the dog or cat, permitting recipient animals to mount
an anti-rHu cytokine antibody response. The onset of
this antibody response not only neutralizes any therapeutically
administered rHu cytokine, but the antibodies
can also bind to and neutralize the activity of the
corresponding endogenous cytokine. For this reason,
administration of rHu cytokines to animals is generally
only of short-term benefit, although regimens have been
developed that minimize the onset of the anticytokine
response. Such responses are not engendered when
endogenous canine or feline recombinant cytokines are
administered.
Granulocyte colony-stimulating factor (G-CSF)
The effect of G-CSF is to enhance bone marrow granulopoiesis,
so this molecule has clinical application to
animals with neutropenia induced by:
● infection (e.g. canine ehrlichiosis or parvovirus,
FeLV, FIV)
● myelosuppressive drugs used in chemotherapy
● bone marrow lymphoid neoplasia or
myeloproliferative disease
● bone marrow immune-mediated aplasia.
rHuG-CSF (Neupogen®, 300 µg/mL solution for injection)
can induce neutrophilia in the dog and cat, which
reaches a maximum level on days 10–14 of therapy.
Neutralizing antibodies to the human molecule develop
after 21 days (in normal dogs and cats, but probably
not in those undergoing intensive chemotherapy), so
treatment beyond this time is inadvisable as profound
neutropenia may occur.
A range of dosage regimens is reported for treatment
of neutropenia associated with chemotherapy, including
10–100 µg/kg q.24 h SC in the dog and 3–10 µg/kg
q.12 h SC in the cat. There is some evidence that
rHuG-CSF can modify neutrophil counts in puppies with
parvovirus infection, but this cytokine did not elevate
blood neutrophil levels in cats with panleukopenia.
There are a number of published studies that have
investigated use of the recombinant canine molecule
(rCaG-CSF). When administered to healthy dogs (5 µg/
kg q.24 h SC for 4 weeks) there was rapid elevation
of blood neutrophil count 24 h after the first injection
and this peaked on day 19. There was an additional
monocytosis, but leukocyte counts returned to normal
levels 5 d after cessation of therapy. No toxicity was
observed.
rCaG-CSF has been administered to dogs with cyclic
hematopoiesis (up to 2.5 µg/kg q.12 h) and was shown
to prevent neutropenia and the associated clinical signs
in these patients, without totally eliminating the cycling
of neutrophils.
rCaG-CSF (daily for 20 d) was able to prevent neutropenia
in normal dogs given the myelosuppressive
agent mitoxantrone (or mitozantrone – British Approved
Name) and therefore has application in the prevention
of neutropenia associated with chemotherapy. Canine
G-CSF has also been administered to normal cats (5 µg/
kg q.24 h SC for 42 d) with marked neutrophilia developing
24 h after the first injection and persisting for the
duration of treatment. No adverse effects were recorded
in these cats and no antibody was produced to the
canine protein. Administration of rCaG-CSF to cats
with Chédiak–Higashi syndrome enhanced neutrophil
number and function.
Fewer investigations have been performed
with recombinant granulocyte-macrophage colony-
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