Page 686 - Basic _ Clinical Pharmacology ( PDFDrive )

672 SECTION VII Endocrine Drugs

could increase antibiotic use and result in greater antibiotic The most important adverse effect observed with mecaser-
residues in milk and meat. min is hypoglycemia. To avoid hypoglycemia, the prescribing
instructions require consumption of a carbohydrate-containing
Toxicity & Contraindications meal or snack 20 minutes before or after mecasermin administra-
tion. Several patients have experienced intracranial hypertension,
Children generally tolerate growth hormone treatment well. adenotonsillar hypertrophy, and asymptomatic elevation of liver
Adverse events are relatively rare and include pseudotumor cere- enzymes.
bri, slipped capital femoral epiphysis, progression of scoliosis,
edema, hyperglycemia, and increased risk of asphyxiation in
severely obese patients with Prader-Willi syndrome and upper GROWTH HORMONE ANTAGONISTS
airway obstruction or sleep apnea. Patients with Turner syndrome
have an increased risk of otitis media while taking GH. In chil- Antagonists of GH are used to reverse the effects of GH-
dren with GH deficiency, periodic evaluation of the other anterior producing cells (somatotrophs) in the anterior pituitary that tend
pituitary hormones may reveal concurrent deficiencies, which to form GH-secreting tumors. Hormone-secreting pituitary ade-
also require treatment (ie, with hydrocortisone, levothyroxine, or nomas occur most commonly in adults. In adults, GH-secreting
gonadal hormones). Pancreatitis, gynecomastia, and nevus growth adenomas cause acromegaly, which is characterized by abnormal
have occurred in patients receiving GH. Adults tend to have more growth of cartilage and bone tissue, and many organs including
adverse effects from GH therapy. Peripheral edema, myalgias, skin, muscle, heart, liver, and the gastrointestinal tract. When a
and arthralgias (especially in the hands and wrists) occur com- GH-secreting adenoma occurs before the long bone epiphyses
monly but remit with dosage reduction. Carpal tunnel syndrome close, it leads to a rare condition, gigantism. Larger pituitary ade-
can occur. Growth hormone treatment increases the activity of nomas produce greater amounts of GH and also can impair visual
cytochrome P450 isoforms, which may reduce the serum levels of and central nervous system function by encroaching on nearby
drugs metabolized by that enzyme system (see Chapter 4). There brain structures. The initial therapy of choice for GH-secreting
has been no increased incidence of malignancy among patients adenomas is endoscopic transsphenoidal surgery. Medical therapy
receiving GH therapy, but such treatment is contraindicated in with GH antagonists is introduced if GH hypersecretion persists
a patient with a known active malignancy. Proliferative retinopa- after surgery. These agents include somatostatin analogs and dopa-
thy may rarely occur. Growth hormone treatment of critically ill mine receptor agonists, which reduce the production of GH, and
patients appears to increase mortality. The long-term health effects the novel GH receptor antagonist pegvisomant, which prevents
of GH treatment in childhood are unknown. The results from the GH from activating GH signaling pathways. Radiation therapy
Safety and Appropriateness of GH in Europe (SAGHE) study are is reserved for patients with inadequate response to surgical and
variable. A higher all-cause mortality (mostly due to cardiovascu- medical therapies.
lar disease) was found in the GH treatment group in the French
arm of the study, but no long-term risks of GH treatment were Somatostatin Analogs
observed in the study arm from another region of Europe.
Somatostatin, a 14-amino-acid peptide (Figure 37–2), is found in
the hypothalamus, other parts of the central nervous system, the
MECASERMIN pancreas, and other sites in the gastrointestinal tract. It functions
primarily as an inhibitory paracrine factor and inhibits the release
A small number of children with growth failure have severe of GH, TSH, glucagon, insulin, and gastrin. Somatostatin is rap-
IGF-I deficiency that is not responsive to exogenous GH. idly cleared from the circulation, with a half-life of 1–3 minutes.
Causes include mutations in the GH receptor and in the GH
receptor signaling pathway, neutralizing antibodies to GH, and
IGF-I gene defects. In 2005, the FDA approved two forms of
recombinant human IGF-I (rhIGF-I) for treatment of severe S S
IGF-I deficiency that is not responsive to GH: mecasermin
and mecasermin rinfabate. Mecasermin is rhIGF-I alone, while Somatostatin
mecasermin rinfabate is a complex of rhIGF-I and recom- Ala Cys
binant human insulin-like growth factor–binding protein-3 1 Gly Cys Lys Asn Thr Phe Thr Ser 14
(rhIGFBP-3). This binding protein significantly increases the 2 3 4 Phe Phe Trp Lys 10 11 12 13
circulating half-life of rhIGF-I. Normally, the great majority 5 6 7 8 9
of the circulating IGF-I is bound to IGFBP-3, which is pro-
duced principally by the liver under the control of GH. Due to Octreotide S S
a patent settlement, mecasermin rinfabate is not available for
short stature-related indications. Mecasermin is administered D-Phe Cys Phe D-Trp Lys Thr Cys Thr-ol Acetate
subcutaneously twice daily at a recommended starting dosage
of 0.04–0.08 mg/kg per dose and increased weekly up to a FIGURE 37–2 Above: Amino acid sequence of somatostatin.
maximum twice-daily dosage of 0.12 mg/kg per dose. Below: Sequence of the synthetic analog, octreotide.