Biomedical Engineering Reference
In-Depth Information
incidence in adults, particularly females. First-line treatment is surgical removal of all/most of
the thyroid gland (thyroidectomy). This is followed by thyroid hormone suppression therapy,
which entails administration of T
3
or T
4
at levels suffi cient to maintain low serum TSH levels
through the negative feedback mechanism mentioned earlier. TSH suppression is required in
order to prevent TSH-mediated stimulation of remnant thyroid cancer cells. The reoccurrence of
active thyroid cancer can be detected by administration of TSH along with radioactive iodine.
TSH promotes uptake of radioactivity, which can then be detected by appropriate radioimaging
techniques.
The commercial recombinant TSH product (tradename, thyrogen; international non-proprietary
name; thyrotrophin alfa) is produced in a CHO cell line co-transfected with plasmids harbouring
the DNA sequences coding for the
-TSH subunits. The cells are grown in batch harvest
animal cell culture bioreactors. Following recovery and concentration (ultrafi ltration), the TSH
is chromatographically purifi ed and formulated to a concentration of 0.9 mg ml
1
in phosphate
buffer containing mannitol and sodium chloride as excipients. After sterile fi ltration and aseptic
fi lling into glass vials, the product is freeze-dried. Finished product has been assigned a shelf life
of 3 years when stored at 2-8
C.
Human parathyroid hormone (hPTH) is an 84 amino acid polypeptide that functions as a pri-
mary regulator of calcium and phosphate metabolism in bones. It stimulates bone formation by
osteoblasts, which display high-affi nity cell surface receptors for the hormone. PTH also increases
intestinal absorption of calcium.
A truncated version of PTH (tradenames Forsteo and Forteo) has been approved for the treat-
ment of osteoporosis in postmenopausal women. This 4 kDa polypeptide is identical in sequence
to the N-terminal residues 1-34 of endogenous hPTH, it binds to the native PTH receptor and
triggers the same effects. The product is produced in
E. coli
, purifi ed and presented as a sterile
solution containing 250
α
- and
β
g active substance per millilitre.
Osteoporosis affects some 75 million people in Europe, Japan and the USA combined. The
condition is characterized by progressive thinning of the bones, leading to bone fragility and
increased risk of fracture. Treatment with Forsteo increases bone mineral density and generally
entails daily s.c. injection for several months at dosage levels of 20
µ
g active/dose.
Calcitonin is a polypeptide hormone that (along with PTH and the vitamin D derivative, 1,25-
dihydroxycholecalciferol) plays a central role in regulating serum ionized calcium (Ca
2
) and
inorganic phosphate (P
i
) levels. The adult human body contains up to 2 kg of calcium, of which
98 per cent is present in the skeleton (i.e. bone). Up to 85 per cent of the 1 kg of phosphorus present
in the body is also found in the skeleton (the so-called mineral fraction of bone is largely com-
posed of Ca
3
(PO
4
)
2
, which acts as a body reservoir for both calcium and phosphorus). Calcium
concentrations in human serum approximate to 0.1 mg ml
1
and are regulated very tightly (serum
phosphate levels are more variable).
Calcitonin lowers serum Ca
2
and P
i
levels, primarily by inhibiting the process of bone
resorption, but also by decreasing resorption of P
i
and Ca
2
in the kidney. Calcitonin recep-
tors are predictably found primarily on bone cells (osteoclasts) and renal cells, and gen-
eration of cAMP via adenylate cyclase activation plays a prominent role in hormone signal
transduction.
Calcitonin is used clinically to treat hypercalcaemia associated with some forms of malignancy
and Paget's disease. The latter condition is a chronic disorder of the skeleton in which bone grows
abnormally in some regions. It is characterized by substantially increased bone turnover rates,
µ
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