Biomedical Engineering Reference
In-Depth Information
HSA is used therapeutically as an aqueous solution; it is available in concentrated form
(15-25 per cent protein) or as an isotonic solution (4-5 per cent protein). In both cases, in excess
of 95 per cent of the protein present is albumin. It can be prepared by fractionation from normal
plasma or serum, or purifi ed from placentas. The source material must fi rst be screened for the
presence of indicator pathogens. After purifi cation, a suitable stabilizer (often sodium caprylate)
is added, but no preservative. The solution is then sterilized by fi ltration and aseptically fi lled into
fi nal sterile containers. The relative heat stability of HSA allows a measure of subsequent heat
treatment, which further reduces the risk of accidental transmission of viable pathogens (par-
ticularly viruses). This treatment normally entails heating the product to 60
C for 10 h. It is then
normally incubated at 30-32
C for a further 14 days and subsequently examined for any signs of
microbial growth.
HSA is used as a plasma expander in the treatment of haemorrhage, shock, burns and oedema,
as well as being administered to some patients after surgery. For adults, an initial infusion contain-
ing at least 25 g of albumin is used. The annual world demand for HSA exceeds 300 t, representing
a market value of the order of US$1 billion.
Despite screening of raw material and heat treatment of fi nal product, HSA derived from na-
tive blood sometimes (though rarely) will harbour pathogens. rDNA technology provides a way
of overcoming such concerns, and the HSA gene and cDNA have been expressed in a wide va-
riety of microbial systems, including
E. coli
,
Bacillus subtilis
,
S. cerevisiae
,
Pichia pastoris
and
Aspergillus niger
. (Its lack of glycosylation renders possible production of native HSA in
prokaryotic and eukaryotic systems.) However, HSA's relatively large size, as well as the presence
of so many disulfi de bonds, can complicate recombinant production of high levels of correctly
folded products in some production systems. The main stumbling block in replacing native HSA
with a recombinant version, however, is an economic one. Unlike most biopharmaceuticals, HSA
can be produced in large quantities and inexpensively by direct extraction from its native source.
Native HSA currently sells at US$2-3 per gram. Although it can be guaranteed blood pathogen
free, recombinant HSA products will fi nd it diffi cult to compete with this price.
12.5 Enzymes of therapeutic value
Enzymes are used for a variety of therapeutic purposes, the most signifi cant of which are listed in
Table 12.8. A number of specifi c examples have already been discussed in detail within this chap-
ter, including tPA, urokinase, and factor IXa. The additional therapeutic enzymes now become the
focus of the remainder of the chapter. Although a limited number of polymer-degrading enzymes
(used as digestive aids) are given orally, most enzymes are administered intravenously.
12.5.1 Asparaginase
Asparaginase is an enzyme capable of catalysing the hydrolysis of
L
-asparagine, yielding aspartic
acid and ammonia (Figure 12.14). In the late 1970s, researchers illustrated that serum transferred
from healthy guinea pigs into mice suffering from leukaemia contained some agent capable of in-
hibiting the proliferation of the leukaemic cells. A search revealed the agent to be asparaginase.
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