Combination antifungal therapy is increasingly used in the treatment of invasive aspergillosis. Whether the interaction between amphotericin B and triazoles is antagonistic against invasive aspergillosis is a controversial issue that is not likely to be resolved through a randomized clinical trial. Here, we found both in vitro and in vivo antagonism between liposomal amphotericin B and ravuconazole in simultaneous treatment of experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits. Bliss independence-based drug-interaction modeling showed significant antagonism in vitro and in vivo, with the observed drug effects being 20%-69% lower than would be expected if the drugs were acting independently. These in vitro and in vivo findings of antagonism were consistent with the findings from Loewe additivity-based drug-interaction modeling. No pharmacokinetic interaction was found. The combination of a triazole and polyene may be antagonistic in the treatment of invasive pulmonary aspergillosis.
A total of 240 outbred Sprague-Dawley rats were treated with 3 different doses of the cyclophosphamide-methotrexate-5-fluorouracil (CMF) regimen adopted from clinical chemotherapy studies in breast cancer patients. Eighty untreated rats served as controls. Individual and total doses of the drugs applied were lower than corresponding doses used in human adjuvant therapy protocols compared on a mg/m2 basis. Lifelong observation of the animals demonstrated a strong dose-related carcinogenic response to the tested scheme. Main target organs of treatment-related neoplasms were the nervous system, the hematopoietic and lymphatic tissue, the urinary bladder, and the suprarenal gland. It is concluded that the CMF drug combination evokes carcinogenic responses in several organ systems in the rat and should be regarded as representing a carcinogenic risk to humans. Uncritical clinical use of the three-drug protocol should be avoided.
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