Biomedical Engineering Reference
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4 leukopenia and fever requiring intravenous antibiotics, and, in two
of them, severe stomatitis (grades 3 and 4) was observed. Significant
hair loss was apparent in all patients receiving doses higher than 50
mg/m
2
. This also should have been a warning signal (which we did
not understood then) of the possibility of fast drug release from the
OLV upon infusion. The maximal tolerated dose (MTD) of OLV-DOX
appears to be 120 mg/m
2
, with leukopenia and stomatitis being
the dose-limiting factors. While the sub-acute toxicity of OLV-DOX
appeared to be qualitatively similar to that of F-DOX, its tolerance
was better, as it exceeded the recommended dose of free drug (75
mg/mL) in the standard 3-weekly schedule.
This clinical study with OLV-DOX shows that administration of this
formulation to humans is feasible even at higher than conventional
dose levels of free drug (60-75 mg/m
2
), and it appears to be well
tolerated. Based on this phase I study, the recommended starting
dose for phase II studies would be 100 mg/m
2
. It should be noted
that most of the patients in this study suff ered from heavy neoplastic
involvement of the liver, and most of them had been previously
treated with various cytotoxic agents including doxorubicin. There
is suggestive evidence that doxorubicin-induced myelosuppression
is more severe when the tumor shows a major liver involvement
(McKelvey et al., 1976; Gundersen et al., 1986) , This may lead to
increase in liposome localization in the bone marrow (Perez-Soler
et al., 1985). Therefore it seems that patient populations that have
heavy neoplastic involvement of the liver are not suitable for being
treated with a high dose of OLV-DOX. However, higher doses could
be administered to other patient populations with acceptable
toxicity. Regarding acute toxicity, nausea and vomiting appear to be
substantially attenuated when compared with the common clinical
experience with free DOX at standard 3-weekly doses (Blum and
Carter, 1974). Fever, a rather uncommon side eff ect of free DOX
therapy, was observed in a relatively high percentage of cases.
Although the immediate reaction may still be attributable to a low
amount of endotoxin, undetectable in the rabbit test, the delayed
reaction appears to be a specific feature of DOX-OLV. One possible
explanation is that this treatment induces interleukin-l secretion by
doxorubicin-activated macrophages (Mace et al., 1988) following
DOX-OLV localization in tissue macrophages and breakdown of
endocytosed liposomes. The sub-acute toxicity of OLV-DOX appears
to be qualitatively similar to that of free DOX, with leucopenia and
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