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Instructions,
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CRITICAL
REVIEW AND COMMENTARY Reference:
Efficacy of aerosolized amphotericin B desoxycholate and liposomal amphotericin
B in the treatment of invasive pulmonary aspergillosis in severely
immunocompromised rats. by Elisabeth
J Ruijgrok, Arnold G Vulto and Els W.M. Van Etten.Journal of Antimicrobial
Chemotherapy. 2001. 48. 89-95.
Invasive pulmonary aspergillosis is a life threatening disease. Current clinical treatment, intravenously administered antifungals, is poor especially in immunocompromised patients. This paper explores the inhalation delivery route as a relevant and effective treatment of this disease. Female
rats, immunocompromised with cyclophosphamide were infected with Aspergillus fumigatus by
intratracheal instillation into the left lung. They were then treated with
different inhalation exposure regimens of two antifungal formulations,
amphotericin B desoxycholate (Fungizone) or Liposomal amphotericin B. The
study was designed with group sizes of 15 animals.
Controls were exposed to 5% aerosolised glucose or placebo liposomes.
A separate group was exposed to an aerosol of pure amphotericin B in 5%
glucose. Nominal nebuliser
concentrations were quoted. The dose of Aspergillus
fumigatus to the animals could not be quoted because aerosol concentrations and particle size analyses
were not undertaken. This may have influenced interpretation of the results. A nebuliser concentration of 2mg/mL amphotericin B desoxycholate 30 hours after infection did significantly prolong the survival of rats by up to 5 days. Neither 1mg/mL nor 4mg/mL showed any significant effect on survival. The authors give reasons for these differences. Without estimates of the actual dose or support of the statement concerning pulmonary toxicity of the 4mg/mL solution, these statements are speculative. A single exposure to a 4mg/mL liposomal formulation of amphotericin B was as effective in prolonging survival for up to 4 days as were 2 exposures in 24 hours or 2 or 4 exposures in 24hours. This indicates the limited advantage of additional exposures. The rats exposed to 4mg/mL suspension of amphotericin B in 5% glucose alone showed no improvement in survival. These data are only mentioned in the discussion. They should have been emphasised in the results as they could suggest that the modified formulations were critical in enhancing survival. It is difficult to draw any clear conclusions because it could not be determined whether any drug was delivered to the lungs of the rats without aerosol concentration and particle size measurements or information on whether the suspension was micronised. All
rats infected showed positive organ cultures in both lungs and the liver, the
only organs examined. No systemic drug estimations were undertaken in this study
but the authors report previous work indicating low systemic exposure following
inhalation delivery. This suggests that aerosol delivery alone would be
insufficient to treat the disseminated disease as indicated by the authors.
Their suggestions of observing low systemic doses of amphotericin and other
antifungals delivered by inhalation is a well-founded extension of this work. The
authors undertook additional surface tension work to demonstrate that inhalation
of amphotericin B desoxycholate but not the liposomal amphotericin B leads to
surfactant dysfunction. This could
have clinical implications. This
interesting paper emphasises the value of using the inhalation route of delivery
as an effective means of delivering drugs to the respiratory tract to treat
pulmonary disease while limiting systemic toxicity. This should encourage
further development of inhaled drug delivery for the treatment of invasive Aspergillus fumigatus infections. By: David
Alexander Guest
Writer,
Independent pharmaceutical Consultant Email:
david_a@ntlworld .com
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