betadex and Mycoses

We have previously shown that a trough concentration of at least 500 ng ml-1 itraconazole is necessary for an effective antifungal prophylaxis in neutropenic patients. Since the bioavailability of itraconazole is reduced in these patients, a satisfactory dosing regimen remains to be defined. In this study, six dosing regimens with itraconazole capsules 400, 600 or 800 mg day-1, itraconazole solution 400 mg day-1 (additional loading dose: 400 mg day-1 solution for 2 days), 800 mg day-1 or 400 mg day-1 (additional loading dose: 800 mg day-1 capsules for 7 days, s/c1200) were compared during 160 courses of myelosuppressive chemotherapy in 123 patients with acute leukaemia. After the first week, patients taking 800 mg day-1 or 400 mg day-1 (s/c1200) itraconazole solution achieved significantly higher trough concentrations (high-performance liquid chromatography) than patients in other groups (P < 0.05) and 87 and 100%, respectively, of these had concentrations > 500 ng ml-1. Contrary to a dose of 400 mg day-1, a dose of 800 mg day-1 itraconazole solution induced severe nausea and vomiting in 46% of the patients. We conclude that 400 mg day-1 itraconazole solution with a loading dose of 800 mg day-1 capsules for 7 days resulted in sufficient trough concentrations from the first week onwards and appears to be suitable for antifungal prophylaxis in neutropenic patients.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Administration, Oral; Antifungal Agents; beta-Cyclodextrins; Capsules; Cyclodextrins; Humans; Itraconazole; Mycoses; Neutropenia; Solutions

Pharmacokinetics and safety of a hydroxy-beta-propyl solution of itraconazole were assessed in 16 patients in an intensive care unit. On the first 2 days, four 1-h infusions of 200 mg were given at 0, 8, 24, and 32 h. From day 3 to 7, inclusive, a single 1-h infusion of 200 mg of itraconazole was given daily. The intravenous (i.v.) treatment was directly followed by repeated administrations of an oral solution of itraconazole at a dosage of either 200 mg once daily or 200 mg twice daily (b.i.d.). During i.v. treatment, steady-state concentrations of itraconazole and hydroxy-itraconazole in plasma were reached within 48 and 96 h, respectively. At the end of i.v. treatment, mean (+/- standard deviation) itraconazole and hydroxy-itraconazole trough concentrations in plasma were 0.344 +/- 0.140 and 0.605 +/- 0.205 microg/ml, respectively. After the 2-week oral follow-up of 200 mg once daily the mean trough concentration had decreased to 0.245 microg/ml, whereas after 200 mg b.i.d. it increased to 0.369 microg/ml. Diarrhea during oral treatment appeared to be dose related and may be due to the solvent hydroxypropyl-beta-cyclodextrin. More severe laboratory abnormalities were noted during the i.v. than the oral treatment phase, probably related to more severe illness in that period of intensive care, but none proved clinically important. These results suggest that plasma itraconazole levels above 0.250 microg/ml may be achieved and maintained with the 1-week i.v. schedule followed by b.i.d. oral administration, whereas the once-daily oral follow-up seems to be a suboptimal treatment.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adolescent; Adult; Antifungal Agents; beta-Cyclodextrins; Cyclodextrins; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Intensive Care Units; Itraconazole; Male; Middle Aged; Mycoses; Solutions

In our study, Voriconazole (VOR) was selected as an active agent to be used for the treatment of ocular fungal infections. To overcome low aqueous solubility of VOR, inclusion complexes with

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Mice; Mycoses; Solubility; Voriconazole

Invasive fungal wound infections (IFIs) were an unexpected complication associated with blast-related wounds during Operation Enduring Freedom. Between 2010 and 2012, IFI incidence rates were as high as 10-12% for patients injured during Operation Enduring Freedom and admitted to the intensive care unit at the Landstuhl Regional Medical Center. Independent risk factors for the development of IFIs include dismounted blast injuries, above knee amputations and massive (>20 units) packed red blood cell transfusions within 24 hours after injury. The Joint Trauma System developed a Clinical Practice Guideline on IFI prevention, identification and management. Aggressive and frequent surgical debridement remains the primary therapy accompanied by topical antifungal therapy (e.g., Dakins solution). Empiric systemic antifungal therapy with both liposomal amphotericin B and an intravenous broad-spectrum triazole (e.g., voriconazole or posaconazole) should be administered when there is strong suspicion of IFI based on the occurrence of recurrent wound necrosis following serial surgical debridements, since many cases involve multiple fungal species. Other recommendations include: (1) early tissue sampling for wound histopathology and fungal cultures, (2) early consultation with infectious disease specialists, and (3) coordination with surgical pathology and clinical microbiology.

Topics: Administration, Topical; Afghan Campaign 2001-; Amphotericin B; Antifungal Agents; beta-Cyclodextrins; Debridement; Excipients; Humans; Mycoses; Recurrence; Risk Factors; Tobramycin; Treatment Outcome; Triazoles; Vancomycin; Voriconazole; Wounds and Injuries

This study aimed to prepare and characterize the inclusion complex between posaconazole (POS) and hydroxypropyl-β-cyclodextrin (HP-β-CD). Phase solubility study was conducted to investigate the drug/CD interaction in solution, including the stoichiometry and apparent stability constant. The solid complex (HP-β-CD-POS) obtained was characterized through Fourier transform infrared spectroscopy, powder X-ray diffraction, (1)H and ROESY 2D nuclear magnetic resonance, differential scanning calorimetry, and scanning electron microscopy. These approaches confirmed the formation of the inclusion complex. The HP-β-CD-POS inclusion complex exhibited better water solubility and higher dissolution rate than the free POS did; the water solubility of POS was increased by 82 times and almost 90% of the loaded drug dissolved after 10 min in the dissolution media. In addition, preliminary in vitro antifungal susceptibility testing revealed that HP-β-CD-POS maintains a high level of antifungal activities. Therefore, the HP-β-CD complex may be useful in the delivery of posaconazole.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Antifungal Agents; beta-Cyclodextrins; Drug Carriers; Fungi; Humans; Models, Molecular; Mycoses; Solubility; Triazoles; Water

Many natural broad-spectrum cationic antimicrobial peptides (AMPs) possess a general mode of action that is dependent on lipophilicity and charge. Modulating the lipophilicity of AMPs by the addition of a fatty acid has been an effective strategy to increase the lytic activity and can further broaden the spectrum of AMPs. However, lipophilic modifications that narrow the spectrum of activity and exclusively direct peptides to fungi are less common. Here, we show that short peptide sequences can be targeted to fungi with structured lipophilic biomolecules, such as vitamin E and cholesterol. The conjugates were active against Aspergillus fumigatus, Cryptococcus neoformans, and Candida albicans but not against bacteria and were observed to cause membrane perturbation by transmission electron microscopy and in membrane permeability studies. However, for C. albicans, selected compounds were effective without the perturbation of the cell membrane, and synergism was seen with a vitamin E conjugate and amphotericin B. Moreover, in combination with β-cyclodextrin, antibacterial activity emerged in selected compounds. Biocompatibility for selected active compounds was tested in vitro and in vivo using toxicity assays on erythrocytes, macrophages, and mice. In vitro cytotoxicity experiments led to selective toxicity ratios (50% lethal concentration/MIC) of up to 64 for highly active antifungal compounds, and no in vivo murine toxicity was seen. Taken together, these results highlight the importance of the conjugated lipophilic structure and suggest that the modulation of other biologically relevant peptides with hydrophobic moieties, such as cholesterol and vitamin E, generate compounds with unique bioactivity.

Topics: Amphotericin B; Animals; Antimicrobial Cationic Peptides; Aspergillus fumigatus; Bacteria; beta-Cyclodextrins; Candida albicans; Cell Membrane; Cell Membrane Permeability; Cholesterol; Cryptococcus neoformans; Drug Synergism; Erythrocytes; Hemolysis; Hydrophobic and Hydrophilic Interactions; Macrophages; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Microscopy, Electron, Transmission; Mycoses; Species Specificity; Static Electricity; Vitamin E

Topics: Aged; Animals; Antifungal Agents; beta-Cyclodextrins; Critical Illness; Female; Humans; Male; Middle Aged; Mycoses; Pyrimidines; Renal Dialysis; Renal Insufficiency; Triazoles; Voriconazole

This investigation was designed to evaluate the single-dose pharmacokinetics of itraconazole, hydroxyitraconazole, and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) after intravenous administration to children at risk for fungal infection. Thirty-three children aged 7 months to 17 years received a single dose of itraconazole (2.5 mg/kg in 0.1-g/kg HP-beta-CD) administered over 1 h by intravenous infusion. Plasma samples for the determination of the analytes of interest were drawn over 120 h and analyzed by high-pressure liquid chromatography, and the pharmacokinetics were determined by traditional noncompartmental analysis. Consistent with the role of CYP3A4 in the biotransformation of itraconazole, a substantial degree of variability was observed in the pharmacokinetics of this drug after IV administration. The maximum plasma concentrations (C(max)) for itraconazole, hydroxyitraconazole, and HP-beta-CD averaged 1,015 +/- 692 ng/ml, 293 +/- 133 ng/ml, and 329 +/- 200 mug/ml, respectively. The total body exposures (area under the concentration-time curve from 0 to 24 h) for itraconazole, hydroxyitraconazole, and HP-beta-CD averaged 4,922 +/- 6,784 ng.h/ml, 3,811 +/- 2,794 ng.h/ml, and 641.5 +/- 265.0 mug.h/ml, respectively, with no significant age dependence observed among the children evaluated. Similarly, there was no relationship between age and total body clearance (702.8 +/- 499.4 ml/h/kg); however, weak associations between age and the itraconazole distribution volume (r(2) = 0.18, P = 0.02), C(max) (r(2) = 0.14, P = 0.045), and terminal elimination rate (r(2) = 0.26, P < 0.01) were noted. Itraconazole infusion appeared to be well tolerated in this population with a single adverse event (stinging at the site of infusion) deemed to be related to study drug administration. Based on the findings of this investigation, it appears that intravenous itraconazole can be administered to infants beyond 6 months, children, and adolescents using a weight-normalized approach to dosing.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adolescent; Antifungal Agents; beta-Cyclodextrins; Child; Child, Preschool; Female; Humans; Infant; Injections, Intravenous; Itraconazole; Male; Mycoses

Natural occurring volatiles such as hexanal have a well know antifungal capacity but limited post harvest use due to their volatility. Taking this into consideration, hexanal was inserted into beta-cyclodextrins (beta-CD) to develop a controlled release mechanism and then evaluated in vitro against Colletotrichum acutatum, Alternaria alternata and Botrytis cinerea, the three main causes of post harvest diseases in berries. Different concentrations of both pure volatile hexanal and its inclusion complexes (IC) were analyzed for their fungistatic and fungicidal effects for 7 days at 23 degrees C. Hexanal has fungistatic effect on all fungi tested, however, fungicidal activity was only observed on C. acutatum. Results showed that hexanal's effectiveness was greater against C. acutatum than A. alternata and B. cinerea. Concentrations of 1.1, 2.3 and 1.3 microL hexanal/L air respectively were necessary to prevent C. acutatum, A. alternata and B. cinerea growth. Lower concentrations reduced fungal growth depending on the included amount and type of fungus. Same amount of hexanal released from beta-cyclodextrin had a lower antifungal effect on C. acutatum. Thus, ICs beta-cyclodextrin-hexanal can be used to reduce or avoid post harvest berry diseases because of their capacity to provide an antifungal volatile during storage, distribution, and consumer purchasing.

Topics: Aldehydes; Alternaria; Antifungal Agents; beta-Cyclodextrins; Botrytis; Colletotrichum; Dose-Response Relationship, Drug; Food Contamination; Food Handling; Food Microbiology; Food Preservation; Fruit; Humans; Kinetics; Mitosporic Fungi; Mycoses; Plant Diseases; Temperature; Time Factors; Volatilization