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

mixed GH- and prolactin-secreting adenomas and for nonfunctioning
pituitary adenomas (Pawlikowski and Melen-Mucha, 2004).
Based on the apparent formation of heterodimers between the SST 2
and D 2
receptors, such chimeric compounds may have efficacy for
certain tumors that do not respond to either classic SST analogs or
DA agonists (Florio et al., 2008).
Therapeutic Uses
Currently, the two somatostatin analogs used widely are octreotide
and lanreotide, synthetic derivatives that have longer half-lives
and bind preferentially to SST 2
and SST 5
receptors. Octreotide (100
μg) administered subcutaneously three times daily is virtually 100%
bioactive, peak effects are seen within 30 min, serum t 1/2
is ~90 min,
and duration of action is ~12 hour. This formulation successfully
controls the biochemical parameters of acromegaly in 50-60% of
patients.
The need to inject octreotide three times daily poses a significant
obstacle to patient compliance. A long-acting, slow-release
form (SANDOSTATIN-LAR DEPOT) in which the active species is incorporated
into microspheres of a biodegradable polymer greatly
reduces the injection frequency. Administered intramuscularly in a
dose of 20 or 30 mg once every 4 week, typically to patients who
have tolerated and responded to the shorter-acting formulation,
octreotide LAR is at least as effective as the regular formulation
(Murray and Melmed, 2008). Like the shorter-acting formulation, the
longer-acting formulation of octreotide generally is well tolerated
with a similar incidence of side effects (see following discussion). A
lower dose of 10 mg per injection should be used in patients requiring
hemodialysis or with hepatic cirrhosis.
In addition to its effect on GH secretion, octreotide can
decrease tumor size, although tumor growth generally resumes after
octreotide treatment is stopped.
Lanreotide is another long-acting octapeptide SST analog
that causes prolonged suppression of GH secretion when administered
in a 30-mg dose intramuscularly. Although its efficacy appears
comparable to that of the long-acting formulation of octreotide, its
duration of action is shorter; thus, it is administered at 10- or 14-day
intervals.
A supersaturated aqueous formulation of lanreotide, lanreotide
autogel (SOMATULINE DEPOT), has recently been approved for use in
the U.S. It is supplied in prefilled syringes containing 60, 90, or
120 mg lanreotide and administered by deep subcutaneous injection.
Administered once every 4 weeks, lanreotide autogel provides
more uniform drug levels than the depot formulation of octreotide.
Results of current clinical trials are at least comparable to those with
the slow-release octreotide formulation (Murray and Melmed, 2008).
Adverse Effects. GI side effects—including diarrhea, nausea, and
abdominal pain—occur in up to 50% of patients receiving octreotide.
In most patients, these symptoms diminish over time and do not
require cessation of therapy. Approximately 25% of patients receiving
octreotide develop gallbladder sludge or even gallstones, presumably
due to decreased gallbladder contraction and bile secretion.
In the absence of symptoms, gallstones are not a contraindication to
continued use of octreotide. Compared with SST, octreotide reduces
insulin secretion to a lesser extent and only infrequently affects
glycemic control. Inhibitory effects on TSH secretion may lead to
hypothyroidism, and thyroid function tests should be evaluated
periodically. The incidence and severity of side effects associated
with lanreotide are similar to those of octreotide. Perhaps related to
its more global inhibition of SST receptors, pasireotide has exhibited
a relatively greater impairment in glycemic control than octreotide
or lanreotide. The degree to which this may limit its clinical utility
is not yet established.
Other Therapeutic Uses. Somatostatin blocks not only GH secretion
but also the secretion of other hormones, growth factors, and
cytokines. Thus octreotide and the slow-release formulations of SST
analogs have been used to treat symptoms associated with metastatic
carcinoid tumors (e.g., flushing and diarrhea) and adenomas
secreting vasoactive intestinal peptide (e.g., watery diarrhea).
Octreotide also is used for treatment of acute variceal bleeding and
for perioperative prophylaxis in pancreatic surgery (see Chapter 46
for discussion of the uses of SST analogs in GI disease). Octreotide
also has significant inhibitory effects on TSH secretion, and it is the
treatment of choice for patients who have thyrotrope adenomas that
oversecrete TSH who are not good candidates for surgery. Finally,
modified forms of octreotide labeled with indium or technetium have
been used for diagnostic imaging of neuroendocrine tumors such as
pituitary adenomas and carcinoids (OCTREOSCAN); modified forms
labeled with ß emitters such as 90 Y have been used in selective
destruction of SST 2
receptor-positive tumors.
Novel uses under evaluation include the treatment of eye diseases
associated with excessive proliferation and inflammation (e.g.,
Graves’ orbitopathy and diabetic retinopathy), diabetic nephropathy, and
various diseases associated with inflammation (e.g., rheumatoid arthritis,
inflammatory bowel disease, pulmonary fibrosis, and psoriasis).
Growth Hormone Antagonists. Pegvisomant (SOMAVERT)
is a GH receptor antagonist that is FDA-approved for the
treatment of acromegaly. Pegvisomant binds to the GH
receptor but does not activate JAK-STAT signaling or stimulate
IGF-1 secretion (Figure 38–5).
Pegvisomant is administered subcutaneously as a 40-mg
loading dose under physician supervision, followed by self-administration
of 10 mg per day. Based on serum IGF-1 levels, the dose is
titrated at 4- to 6-week intervals to a maximum of 40 mg per day.
Pegvisomant should not be used in patients with an unexplained elevation
of hepatic transaminases, and liver function tests should be
monitored in all patients. In addition, lipohypertrophy has occurred
at injection sites, sometimes requiring cessation of therapy; this is
believed to reflect the inhibition of direct actions of GH on
adipocytes. Because of concerns that loss of negative feedback by
GH and IGF-1 may increase the growth of GH-secreting adenomas,
careful follow-up by pituitary MRI is strongly recommended,
although this may change as more data become available (Jimenez
et al., 2008). Pegvisomant differs structurally from native GH and
induces the formation of specific antibodies in ~15% of patients
despite the covalent coupling of Lys residues to 4-5 molecules of a
polyethylene glycol polymer per modified GH molecule.
Nevertheless, the development of tachyphylaxis due to these antibodies
has not been reported.
In clinical trials, pegvisomant at higher doses decreased serum
IGF-1 to normal age- and sex-adjusted levels in >90% of patients and
significantly improved clinical parameters such as ring size, softtissue
swelling, excessive perspiration, and fatigue. Thus pegvisomant
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CHAPTER 38
INTRODUCTION TO ENDOCRINOLOGY: THE HYPOTHALAMIC-PITUITARY AXIS