ravuconazole and Disease-Models--Animal

Combination therapy has been proposed as an alternative therapeutic approach for the treatment of Chagas disease. In this study, we evaluated the effect of treatment with benznidazole combined with E1224 (ravuconazole prodrug) in an experimental murine model of acute infection. The first set of experiments assessed the range of E1224 doses required to induce parasitological cure using

Topics: Animals; Combined Modality Therapy; Disease Models, Animal; Drug Interactions; Female; Mice; Microbial Sensitivity Tests; Nitroimidazoles; Thiazoles; Triazoles; Trypanocidal Agents; Trypanosoma cruzi

Invasive pulmonary aspergillosis (IPA) is a life-threatening disease of immunocompromised patients that requires aggressive therapy. Detection of the disease and monitoring of the therapeutic response during IPA are complex, and current molecular diagnostics are not suitably robust. Here, we explored proteomic profiles of bronchoalveolar lavage fluid (BALF) specimens from a persistently neutropenic rabbit model of IPA. Three experimental arms, uninfected control animals, infected untreated animals, and animals infected and treated with ravuconazole/amphotericin B, were studied. Total proteins were evaluated by two-dimensional (2D) gel electrophoresis, followed by matrix-assisted laser desorption ionization-time of flight/time of flight (MALDI-TOF/TOF) mass spectrometry (MS) and quantified by enzyme-linked immunosorbent assay (ELISA). Host-derived proteins haptoglobin (Hp), C-reactive protein (CRP), and annexin A1 (Anx A1) were prominently found in BALF during the IPA infection and showed significant changes in response to antifungal therapy (P < 0.0001). In serum, differences in Hp (P = 0.0001) between infected and treated rabbits were observed. Preliminary in vitro studies revealed that Aspergillus fumigatus-secreted proteases may contribute to the cleavage of Anx A1 during IPA. In summary, host protein biomarkers Hp, CRP, and Anx A1 may have value in monitoring therapeutic response to antifungal agents in IPA patients with confirmed disease.

Topics: Amphotericin B; Animals; Annexin A1; Antifungal Agents; Aspergillus fumigatus; Biomarkers; Bronchoalveolar Lavage Fluid; C-Reactive Protein; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Humans; Invasive Pulmonary Aspergillosis; Neutropenia; Proteomics; Rabbits; Thiazoles; Triazoles

The in vitro and in vivo activities of a series of (2R,3R)-2-(2,4-difluorophenyl)-3-(substituted indazol-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol as potential antifungal agents are described. In particular, the analog 12j having 5-bromo substitution on the indazole ring exhibited significant antifungal activity against a variety of fungal cultures (Candida spp. and Aspergillus spp.). In addition, oral administration of 12j showed its excellent efficacy against Candida albicans in a murine infection model and the significantly improved survival rates of the infected mice.

Topics: Administration, Oral; Animals; Antifungal Agents; Aspergillus; Candida; Disease Models, Animal; Indazoles; Mice; Microbial Sensitivity Tests; Rats; Stereoisomerism; Triazoles

In vivo studies have characterized the pharmacodynamic characteristics of the triazole fluconazole. These investigations demonstrated that the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (24-h AUC/MIC ratio) is the critical pharmacokinetic/pharmacodynamic (PK/PD) parameter associated with treatment efficacy. Further analysis demonstrated that a fluconazole 24-h AUC/MIC ratio of 20 to 25 was predictive of treatment success in both experimental models and clinical trials. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the time course activity of the new triazole ravuconazole. The PK/PD parameters (percent time above the MIC, AUC/MIC ratio, and peak level in serum/MIC ratio) were correlated with in vivo efficacy, as measured by organism number in kidney cultures after 24 and 72 h of therapy. Ravuconazole kinetics and protein binding were performed in neutropenic infected mice. Peak/dose and AUC/dose values ranged from 0.03 to 0.04 and 0.30 to 0.34, respectively. Serum elimination half-life ranged from 3.9 to 4.8 h. Protein binding was 95.8%. Single-dose postantifungal effect studies demonstrated prolonged suppression of organism regrowth after serum ravuconazole levels had fallen below the MIC. Treatment efficacies with the five dosing intervals studied were similar, supporting the argument for the AUC/MIC ratio as the PK/PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (AUC/MIC ratio, R(2) = 91%; peak/MIC ratio, R(2) = 85%; percent time above the MIC, R(2) = 47 to 65%). Similar studies were conducted with seven additional C. albicans isolates with various ravuconazole susceptibilities (MIC, 0.016 to 0.12 micro g/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The ravuconazole free-drug AUC/MIC ratios were similar for all of the organisms studied (10 to 36; mean +/- SD = 20.3 +/- 8.2; P = 0.43). These free-drug AUC/MIC ratios are similar to those observed for fluconazole in this model.

Topics: Animals; Antifungal Agents; Area Under Curve; Candidiasis; Disease Models, Animal; Female; Humans; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Thiazoles; Triazoles

Invasive pulmonary aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Simultaneous inhibition of fungal cell-wall and cell-membrane biosynthesis may result in synergistic interaction against Aspergillus fumigatus. We studied the antifungal activity of micafungin, a new echinocandin, in combination with ravuconazole, a second-generation triazole, against experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits. This combination led to significant reductions in mortality (P

Topics: Animals; Aspergillosis; Aspergillus fumigatus; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Echinocandins; Female; Lipopeptides; Lipoproteins; Lung; Lung Diseases, Fungal; Micafungin; Organ Size; Peptides, Cyclic; Rabbits; Thiazoles; Triazoles

Ravuconazole (BMS-207147, ER-30346), an oral triazole, was evaluated in an immunosuppressed temporarily neutropenic guinea pig model of invasive aspergillosis. In this model, guinea pigs were immunosuppressed with triamcinolone 20 mg/kg sc od beginning 4 days before challenge and made neutropenic with cyclophosphamide 300 mg/kg ip 1 day before challenge. Treatments of ravuconazole 5, 10 and 25 mg/kg po od were compared with itraconazole 2.5 and 5.0 mg/kg po bd and amphotericin B 1.25 mg/kg ip od. Treatment began 24 h after lethal intravenous challenge with Aspergillus fumigatus and continued for 5 days. Mortality occurred in eight of eight untreated control animals versus none of eight treated with ravuconazole 5 or 10 mg/kg/day or itraconazole 10 mg/kg/day. Mortality occurred in one of eight animals treated with ravuconazole 25 mg/kg/day, one of eight with amphotericin B and two of eight treated with itraconazole 5 mg/kg/day. Compared with controls, each of the antifungals examined significantly reduced the tissue burden in liver and brain, although only the highest doses of the azole drugs and amphotericin B significantly reduced tissue burden in the kidney. All three doses of ravuconazole improved survival and also reduced the tissue burden of ASPERGILLUS: In this model of invasive aspergillosis, ravuconazole showed significant activity and may be a useful compound in human disease.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Disease Models, Animal; Drug Evaluation, Preclinical; Guinea Pigs; Humans; Male; Organ Culture Techniques; Organ Specificity; Thiazoles; Triazoles

The efficacy of ravuconazole, a new triazole antifungal agent, and the echinocandin LY-303366 were evaluated in an immunosuppressed, temporarily leukopenic rabbit model of invasive aspergillosis. Oral therapy with ravuconazole at a dosage of 30 mg/kg of body weight per day or the echinocandin LY-303366, given intravenously in a dosage of 5 or 10 mg/kg, was begun 24 h after a lethal or sublethal challenge, and results were compared with those for amphotericin B therapy and untreated controls. Prophylaxis was also studied with LY-303366 given at a dosage of 5 or 10 mg/kg/day 48 h before lethal or sublethal challenge. Ravuconazole eliminated mortality, cleared aspergillus antigen from the serum, and eliminated Aspergillus fumigatus organisms from tissues of both lethally and sublethally challenged immunosuppressed animals with invasive aspergillosis. Although LY-303366, at both doses, prolonged survival and reduced aspergillus antigenemia, it did not eliminate aspergillus organisms from organ tissues. The half-lives of ravuconazole and LY-303366 in rabbits were 13 and 12.5 h, respectively, and no accumulation of either drug was seen after 6 days of treatment. Although LY-303366 showed activity in this rabbit model of invasive aspergillosis, ravuconazole was the more active agent, comparable to amphotericin B. Additional studies are needed to determine the potential of ravuconazole for use in the treatment of this infection.

Topics: Anidulafungin; Animals; Antibiotic Prophylaxis; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Brain; Disease Models, Animal; Echinocandins; Liver; Lung; Peptides, Cyclic; Rabbits; Thiazoles; Triazoles