Influence of the progression of cryptococcal meningitis on brain penetration and efficacy of AmBisome in a murine model.
BACKGROUND
AmBisome is a small unilamellar vesicle containing amphotericin B. AmBisome is generally unable to pass through the blood-brain barrier, but the distribution of AmBisome in the brain is increased by inflammation, and in consequence, AmBisome exhibits activity against fungal meningitis. We investigated the influence of the progression of cryptococcal meningitis on the brain penetration and efficacy of AmBisome.


METHODS
Mice were infected intracerebroventricularly with Cryptococcus neoformans 4 h or 5 days prior to a single dose treatment.


RESULTS
The brain tissue level and efficacy of AmBisome when administered 5 days after infection were greater than 4 h after infection. An immunohistochemical study showed that AmBisome-derived amphotericin B was localized at the infected site in the subarachnoid space. When AmBisome was compared with Fungizone at the maximum tolerated dose, 10 mg/kg AmBisome exhibited greater efficacy than 1 mg/kg Fungizone in both regimens.


CONCLUSIONS
The brain penetration of AmBisome was enhanced by the progression of cryptococcal meningitis and correlated with the in vivo activity.
Takemoto
K
K
Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan.
Yamamoto
Y
Y
Ueda
Y
Y
D000666:Amphotericin B / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000302:isolation & purification; D004195:Disease Models, Animal; D018450:Disease Progression; D007150:Immunohistochemistry; D008297:Male; D020714:Maximum Tolerated Dose; D016919:Meningitis, Cryptococcal / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D051379:Mice; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
D000935:Antifungal Agents; D015415:Biomarkers; C068538:liposomal amphotericin B; D000666:Amphotericin B