Biomedical Engineering Reference
In-Depth Information
and is excreted via the kidneys. Owing to its relatively low solubility, an increase in serum uric
acid levels often triggers the formation and precipitation of uric acid crystals, typically resulting
in conditions such as gout or urate stones in the urinary tract. Signifi cantly elevated serum uric
acid concentrations can also be associated with rapidly proliferating cancers or, in particular, with
onset of chemotherapy. In the former instance, rapid cellular turnover results in increased rates
of nucleic acid catabolism and, hence, uric acid production. In the latter case, chemotheraphy-in-
duced cellular lysis results in the release of intracellular contents, including free purines and pu-
rine-containing nucleic acids, into the bloodstream. The increased associated purine metabolism
then triggers hyperuricaemia. The elevated uric acid concentrations often trigger crystal formation
in the renal tubules, and hence renal failure.
Purine metabolism in some mammals is characterized by a further oxidation of uric acid to al-
lantoin by the enzyme urate oxidase. Allantoin is signifi cantly more water soluble than uric acid
and is also freely excreted via the renal route.
Administration of urate oxidase to humans suffering from hyperuricaemia results in the reduc-
tion of serum uric acid levels through its conversion to allantoin. Urate oxidase purifi ed directly
Box 12.2
Product case study: Aldurazyme
Aldurazyme (tradename, also known as laronidase) is a recombinant version of one polymorphic
variant of the human enzyme
- L -iduronidase. It was approved for general medical use in the
USA in 2003 and is indicated for the treatment of patients with certain forms of the rare inherited
disease MPS I. MPS I is caused by a defi ciency of a lysosomal
α
- L -iduronidase, which normally
catalyses the hydrolysis of terminal α- L -iduronic acid residues from the glycosaminoglycans der-
matan sulfate and heparin sulfate. The defi ciency results in accumulation of the glycosaminogly-
cans throughout the body, causing widespread cell and tissue dysfunction.
The 628 amino acid, 83 kDa monomeric glycosylated enzyme containing six N-linked oli-
gosaccharide side-chains is produced in an engineered CHO cell line. After cell culture it is
purifi ed by a combination of dye affi nity, metal chelate and hydrophobic interaction chroma-
tography. The fi nal product is formulated as a liquid concentrate containing laronidase, as well
as sodium phosphate buffer, sodium chloride and polysorbate 80. It is fi lled in 5 ml single-
use vials and is usually administered intravenously by infusion (0.58 mg per kilogram body
weight) over 3-4 h, once weekly. Fortuitously, two of the enzyme's oligosaccharide side-chains
terminate in mannose-6-phosphate, facilitating product cellular uptake via the mannose-6-
phosphate cell surface receptor.
Clinical evaluation entailed administration to 45 MPS I patients in a randomized, placebo-
controlled clinical trial. The primary effi cacy outcomes assessed were forced vital capacity and
distance walked in 6 min, both of which were statistically higher relative to placebo after 26
weeks of treatment. The most serious adverse reaction noted was that of a severe anaphylactic
reaction in one patient. The most common adverse effects reported were respiratory tract in-
fection, rash and injection-site reactions. The product is manufactured by BioMarin Inc. and is
distributed by Genzyme Corporation.
α
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