Rat Model Of Pulmonary Aspergillosis Research Articles

Effect of PTX3 and Voriconazole Combination in a Rat Model of Invasive Pulmonary Aspergillosis

This study evaluated the pharmacological activity of PTX3, administered in combination with voriconazole, in a rat model of pulmonary aspergillosis. The data indicated additive therapeutic activities of these compounds, as demonstrated by the amelioration of respiratory function changes, reduction of lung fungal burden, and increased survival. Overall, we provide clear evidence that the combination of PTX3 with a suboptimal dose of voriconazole might represent a therapeutic option under those clinical conditions where the use of voriconazole alone is not warranted for efficacy and tolerability reasons.

Lanoconazole and Its Related Optically Active Compound NND-502: Novel Antifungal Imidazoles with a Ketene Dithioacetal Structure

Imidazole antifungal agents have been successfully developed in medicine mainly for the treatment of superficial skin fungal infections. Through the screening for novel imidazole compounds, it was found that remarkable augmentation of in vitro antifungal activity is brought by the introduction of imidazole moiety to a unique structure ketene dithioacetal, and among these imidazole compounds (±)-(E)-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile (generic name: lanoconazole, CAS 101530-10-3) is now available as a topical drug used for the treatment of superficial skin fungal infections in Japan. Lanoconazole exerted 30-700 times more potent activity as measured by MICs (minimun inhibitory concentrations) against dermatophytes than did other antifungal imidazole compounds, bifonazole and clotrimazole. In therapeutic experiments using guinea pig models of infections, lanoconazole also exhibited excellent curative effect on two tinea models (tinea pedis and tinea corporis) and a cutaneous candidiasis model as compared to other reference agent, bifonazole, clotrimazole and / or tolnaftate, a thiocarbamate class of compound, in term of eradicating fungi from the infected loci. Since lanoconazole is a racemic compound and only the R-enantiomer was found to be active, extensive screening for optically active-related compound was further conducted. As a result, an optically active compound NND-502 was found to have more potent antifungal activity than lanoconazole and terbinafine, an allylamine class of antifungal agent. In an in vivo study with a guinea pig model of tinea pedis, short-term treatment regimen of topical NND-502 achieved a complete mycological cure, while that of topical lanoconazole and terbinafine did not. Furthermore, the potentiality of the compound for the oral and intravenous treatment of aspergillosis, one of the major deep-seated fungal infections, has been found out as well as for the topical treatment of dermatophytosis. The oral regimen of NND-502 in a murine model of systemic aspergillosis was apparently superior to that of itraconazole, a triazole compound, in terms of prolonging survival. Intravenous NND-502 also proved highly effective in a rat model of pulmonary aspergillosis compared with intravenous amphotericin B in terms of not only prolonging survival but also eradication of fungi from the lung. These encouraging results suggest that the related compounds of lanoconazole could bring considerable progress in the antifungal chemotherapy. Keywords: antifungal agent, Imidazole, lanoconazole, nnd-502

Efficacy of NND-502, a novel imidazole antimycotic agent, in experimental models of Candida albicans and Aspergillus fumigatus infections

In vitro and in vivo anti- Candida albicans and anti- Aspergillus fumigatus activities of NND-502, a new imidazole-antimycotic, were compared with those of fluconazole (FCZ), itraconazole (ITZ) and/or amphotericin B (AmB). NND-502 exhibited strong in vitro antifungal activity against both fungal species; its MIC against C. albicans was 1–4 times lower than that of FCZ, and its MIC against A. fumigatus was at least 60–2000 times lower than that of ITZ and AmB. In vivo antifungal treatments with each drug were initiated 1 h after inoculation in the experimental models, so that antifungal potential reflected prophylactic activity rather than therapeutic activity. The oral regimen of NND-502 in a murine model of systemic C. albicans infection was much less effective than that of FCZ. In vivo anti -A. fumigatus activity of oral NND-502 in a murine model of systemic infection was apparently superior to that of FCZ and ITZ in terms of prolonging survival. In addition to the murine model of systemic aspergillosis, intravenous NND-502 was shown to be highly effective in a rat model of pulmonary aspergillosis compared with intravenous AmB; 90% of animals survived at a dose of 2.5 mg/kg per day of NND-502 while only 30% of animals escaped death when 5 mg/kg per day of AmB was used. This potent efficacy of NND-502 was also confirmed in a sublethal challenge study in which the administration of the agent at a dose as low as 1.25 mg/kg per day resulted in the significant reduction of organisms in the lung; no comparable effect of AmB was found.

Inactivity of terbinafine in a rat model of pulmonary aspergillosis

In a model of bronchopulmonary aspergillosis terbinafine did not improve survival of experimental animals in doses up to 80 mg/kg/day despite adequate lung concentrations. Pretreatment and aerosolization of the compound were also ineffective. Terbinafine was markedly less active in vitro when serum was used instead of Yeast-Nitrogen-Glucose-broth. It is concluded that a lack of bioavailability in the presence of serum may explain the lack of activity of terbinafine in experimental aspergillosis.

Aerosol amphotericin B is effective for prophylaxis and therapy in a rat model of pulmonary aspergillosis.

Invasive pulmonary aspergillosis is a major life-threatening complication among transplant recipients and patients receiving cancer chemotherapy. In a rat model of progressive pulmonary aspergillosis that is characterized by hyphal bronchopneumonia, aerosol amphotericin B (aero-AmB; 1.6 mg/kg given 2 days before infection) significantly delayed mortality in rats compared with animals in a control group. The first death in the aero-AmB-treated group occurred on day 11, by which time seven of the eight control animals had died. The same dose of aero-AmB given as treatment (1.6 mg/kg given 24 h after infection and then daily for 6 days) was also effective. In this trial, eight of the ten animals treated with aero-AmB survived for 7 days, whereas only one of ten control animals survived. Colony counts in lung homogenates obtained 24 h after infection showed an 80-fold reduction in the number of viable spores in animals that had received 6.4-mg/kg doses of aero-AmB 2 days prior to infection. At 48 h after administering a single 1.6- or 3.2-mg/kg dose of aero-AmB, mean lung concentrations were 2.79 and 5.22 micrograms/g of tissue, respectively. We conclude, therefore, that aero-AmB kills inhaled spores and delays the progression of pulmonary aspergillosis by inhibiting mycelial proliferation.