原文節錄如下
In substrate reduction therapy, the substrate burden is reduced by the inhibition of
substrate synthesis by chemical agents. Whereas ERT is aimed at increasing the amount of
active enzyme available to metabolise accumulated substrates, the rationale behind substrate
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reduction therapy is to prevent the build-up of substrate in the first instance. This treatment
may have the most benefit when used in combination with a second therapy such as ERT or
BMT (Jeyakumar et al, 2001).
Miglustat (Zavesca®, Actelion Pharmaceuticals; N-butyldeoxynojirimycin, NB-DNJ)
is a glucose analogue and is commercially available as a substrate reduction therapy for
Gaucher type I patients. In these patients, intravenous administration of NB-DNJ reduces liver
and spleen sizes (Cox et al, 2000; Elstein et al, 2004) as well as improving haemoglobin and
platelet counts (Giraldo et al, 2006). Miglustat has also been effective in reducing
glycosphingolipid storage in B lymphocytes isolated from a Niemann Pick disease (type C)
patient and could be detected in cerebrospinal fluid after 7-months of administration
(Lachmann et al, 2004). Miglustat acts by inhibiting the first enzyme in glucocerebroside
synthesis, glucosylceramide synthase (ceramide glucosyltransferase). Consequently,
Miglustat can potentially be used to treat lysosomal glycosphingolipid disorders where
glucoceramide-based components are not degraded (e.g. Gaucher, Fabry, Tay-Sachs,
Sandhoff, Niemann-Pick diseases and GM1 gangliosidosis). In addition, Miglustat may also be
beneficial in diseases such as MPS IIIA where there is secondary accumulation of
glycosphingolipids, to reduce the overall disease burden. After 4- or 36-wks of administering
1200 mg/kg/day NB-DNJ to juvenile (4-wk-old) MPS IIIA mice, marked reductions in
immunocytochemical-positive staining of GM2 and GM3 gangliosides, as well as reduced
autofluorescence, were observed in treated MPS IIIA brains (Walkley, 2005).
However, side-effects, including body weight loss and gastrointestinal problems, have
also been reported after NB-DNJ administration (Andersson et al, 2004; Giraldo et al, 2006).
A more selective glycosphingolipid inhibitor, the galactose analogue Nbutyldeoxygalactonojirimycin
(NB-DGJ), has shown promise in Sandhoff disease mice with
improvements in life expectancy, delay in the onset of disease symptoms (hind limb strength
and coordination) and reduction of GM2 and GA2 storage in brain homogenates, without the
side-effects observed with NB-DNJ administration (Andersson et al, 2004). NB-DGJ is also
effective in GM1 gangliosidosis mice, mediating significant reductions in the total ganglioside
and GM1 ganglioside content in brain tissues when administered in both the neonatal and
postnatal periods (Kasperzyk et al, 2004; 2005).
I''m glad to know you all came back safe. It is not easy to bring 38 people, old & young, weak & strong for an overseas trip. God is always on good people side. What a great job you''ve done! Jeff & I also came back from our cruise to West Mediterranean from 6/23 to 7/5. The weather was very hot.
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