Biomedical Engineering Reference
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(below the level of detection at 5 h). Daily administered for 5 days on beige mouse
acute infection model (10
7
MAC i.v. incoculated) at 40 mg/kg bw, liposomal AMK
reduced the viable cell count in the liver and spleen compared with free AMK. At
110 mg/kg bw twice a week for 3 weeks, liposomal AMK and free AMK reduced
the viable cell counts in the liver, spleen and lung compared with counts in the control
group. Liposomal AMK was more active than the free drug for organisms in the liver
and spleen but not for organisms in the lung. The ability of both free and liposomal
amikacin to reduce the viable count of organisms per organ was directly related to
the interval between infection and the initiation of therapy. The earlier therapy was
started, the greater the reduction in bacterial load (Cynamon et al.
1989
).
The very high levels of AMK activity in the spleen and liver as well as sustained
levels in the serum, suggested a saturation of the RES to some extent with the lipid
doses used. On the other hand, treatment with empty liposomes resulted in
increased numbers of organisms in the spleens and livers of mice. Since distribution
to nonhepatic RES tissues (such as the spleen, bone marrow, and lung) and sus-
tained levels in serum would appear to be desirable in the treatment of MAC, it may
be necessary to carefully balance the advantages and potential disadvantages of
high lipid doses to achieve the optimum therapy of this disease.
In a second approach, AMK and the quinolone ciprofloxacin (CIP) were loaded
in oligolamelar liposomes and either a single dose of 600 mg of free or liposomal
AMK or 1,000 mg of free or liposomal CIP were administered to C57BL/6 mice
(Leitzke et al.
1998
). At 24 h postinjection, only liposomal AMK resulted in a sus-
tained accumulation of drug in liver and spleen (59.1 +/− 7.5 and 194.0 +/− 51.0 mg/
kg, respectively), while CIP concentrations had fallen below the threshold of detec-
tion. These results indicated a fast re-distribution of liposomal CIP from the target
tissues and excluded its further application. Upon administering 2,000 mg of lipo-
somal AMK, a concentration exceeding 8 mg/kg was found in liver and spleen at the
end of 28 days. In contrast, the same dose of free AMK dissapaired within 2-9 h.
Different to liver and spleen, levels of AMK in lungs were not increased neither
sustained. Liposomal encapsulation of AMK, but not of CIP, resulted in high and
sustained drug levels in infected tissues, exceeding the MIC for
M. avium
for at least
28 days. The therapeutic efficacy of 2,000 mg of liposomal AMK administered
once-weekly and once-monthly (6 consecutive weeks or months) on C57BL/6 mice
i.v. infected with 10
5
CFU of the virulent
M. avium
strain TMC 724 was determined.
This model of infection leads to the death of even immunocompetent mice 120-150
days after infection. Thus, a once-weekly treatment schedule proved to be as effec-
tive as previously reported regimens of twice weekly or even daily injections of other
liposomal AMK (Bermudez et al.
1990
; Cynamon et al.
1989
; Duzgunes et al.
1988
;
Ehlers et al.
1996
). Monthly treatment led to a significantly prolonged survival time
of the treated animals, which all survived the observation period of 7 months,
whereas all control infected animals died approximately 4 months after time of
infection. This benefit was also observed when treatment was initiated at an advanced
stage of infection. Again, overall treatment efficacy in the lungs was poor.
In a further work, the aminoglycoside gentamicin (GEN) was loaded in MLV
(eggPC) and administered to murine model of disseminated MAC infection at
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