Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new fluconazole research articles will be listed here shortly after becoming available to us.
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Medical research on fluconazole
Biophys Chem. 2008 Jun 5;
Kumar RS, Arunachalam S
A new class of surfactant-cobalt(III) complex ions of the type, cis-[Co(X)(2)(C(14)H(29)NH(2))Cl](2+) (where X=ethylenediamine (en), or 2,2'-bipyridyl (bpy), or 1,10-phenanthroline (phen)) and cis-[Co(trien)(C(14)H(29)NH(2))Cl](2+) (trien=triethylenetetramine) were synthesized and characterized by IR, NMR, UV-visible electronic absorption spectra, elemental analysis and metal analysis. The critical micelle concentration (CMC) values of these surfactant-cobalt(III) complexes in aqueous solution were obtained from conductance measurements. Specific conductivity data (at 298, 308, 318 and 328 K) served for the evaluation of the temperature-dependent CMC and the thermodynamics of micellization (DeltaG(0)(m), DeltaH(0)(m) and DeltaS(0)(m)). Interactions between calf thymus DNA and the surfactant-cobalt(III) complexes in aqueous solution have been investigated by electronic absorption spectroscopy, emission spectroscopy and viscosity measurements. The electrostatic interactions, van der Waals interactions and/or partial intercalative binding have been observed in these systems. The surfactant-cobalt(III) complexes were screened for their antibacterial and antifungal activities against various microorganisms. The results were compared with the standard drugs, Ciprofloxacin and Fluconazole respectively.
J Enzyme Inhib Med Chem. 2008 Jun; 23(3): 347-51
Gopalakrishnan M, Sureshkumar P, Thanusu J, Kanagarajan V
Compound 26 is more potent against Escherichia coli. and 24 is more active against Staphylococcus aureus, beta-Heamolytic streptococcus, Vibreo cholerae, Salmonella typhii, and Shigella flexneri than the standard drug ciprofloxacin. Moreover, of all the compounds tested, 26 is more effective against Aspergillus flavus and Mucor, than the standard drug fluconazole.
Southeast Asian J Trop Med Public Health. 2008 May; 39(3): 492-5
Nadagir SD, Chunchanur SK, Halesh LH, Yasmeen K, Chandrasekhar MR, Patil BS
Oropharyngeal candidiasis (OPC) continues to be a common opportunistic infection in patients infected with Human Immunodeficiency Virus (HIV) and is predictive of increasing immunosuppression. Though Candida albicans remains the predominant isolate, a rise in the frequency of isolation of non-albicans Candida (NAC) species is being observed. The levels of virulence and the sensitivities to available antifungal drugs vary among these species. Of 340 HIV seropositive patients in this study, 132 (38.8%) had oral lesions suggestive of candidiasis. Samples were collected from the lesion using sterile cotton swabs. Isolation and speciation were done by standard techniques. Antifungal drug susceptibility testing was done by macro broth dilution. The total number of Candida isolates was 135, of which, 45 (33.3%) were NAC species and 90 were C.albicans (66.6%). Of the NAC species, C. dubliniensis was the predominant pathogen (22,48.9%). Antifungal susceptibility testing showed that 14 (31.1%) of the NAC species and 11 (12.2%) of C. albicans were resistant to fluconazole (MIC > 8 microg/ml). A very high MIC of > 32 microg/ml was noted among the NAC species resistant to fluconazole.
How Do Azoles Inhibit Cytochrome P450 Enzymes? A Density Functional Study.
J Phys Chem A. 2008 Jun 18;
Balding PR, Porro CS, McLean KJ, Sutcliffe MJ, Maréchal JD, Munro AW, Visser SP
To examine how azole inhibitors interact with the heme active site of the cytochrome P450 enzymes, we have performed a series of density functional theory studies on azole binding. These are the first density functional studies on azole interactions with a heme center and give fundamental insight into how azoles inhibit the catalytic function of P450 enzymes. Since azoles come in many varieties, we tested three typical azole motifs representing a broad range of azole and azole-type inhibitors: methylimidazolate, methyltriazolate, and pyridine. These structural motifs represent typical azoles, such as econazole, fluconazole, and metyrapone. The calculations show that azole binding is a stepwise mechanism whereby first the water molecule from the resting state of P450 is released from the sixth binding site of the heme to create a pentacoordinated active site followed by coordination of the azole nitrogen to the heme iron. This process leads to the breaking of a hydrogen bond between the resting state water molecule and the approaching inhibitor molecule. Although, formally, the water molecule is released in the first step of the reaction mechanism and a pentacoordinated heme is created, this does not lead to an observed spin state crossing. Thus, we show that release of a water molecule from the resting state of P450 enzymes to create a pentacoordinated heme will lead to a doublet to quartet spin state crossing at an Fe-OH 2 distance of approximately 3.0 A, while the azole substitution process takes place at shorter distances. Azoles bind heme with significantly stronger binding energies than a water molecule, so that these inhibitors block the catalytic cycle of the enzyme and prevent oxygen binding and the catalysis of substrate oxidation. Perturbations within the active site (e.g., a polarized environment) have little effect on the relative energies of azole binding. Studies with an extra hydrogen-bonded ethanol molecule in the model, mimicking the active site of the CYP121 P450, show that the resting state and azole binding structures are close in energy, which may lead to chemical equilibrium between the two structures, as indeed observed with recent protein structural studies that have demonstrated two distinct azole binding mechanisms to P450 heme.
J Clin Microbiol. 2008 Jun 18;
Lockhart SR, Messer SA, Pfaller MA, Diekema DJ
Candida orthopsilosis and Candida metapsilosis are recently described species, having previously been grouped with the more prevalent species Candida parapsilosis. Current literature contains very little data pertaining to the distribution and antifungal susceptibility of these Candida species. We determined the species and antifungal susceptibility of 1929 invasive clinical isolates from the ARTEMIS antifungal surveillance program collected between 2001 and 2006 and identified as C. parapsilosis using VITEK and conventional methods. Of the 1929 isolates of presumed C. parapsilosis tested, 117 (6.1%) were identified as C. orthopsilosis and 34 (1.8%) as Candida metapsilosis. The percent of presumed C. parapsilosis found to be C. orthopsilosis varied greatly by region, with the highest percentage (10.9%) from South America and the lowest (0.7%) from Africa. The minimum inhibitory concentration (MIC) distributions of the C. orthopsilosis and C. metapsilosis isolates were statistically significantly lower than those of C. parapsilosis for all drugs except for fluconazole, for which they were significantly higher (p
In vitro susceptibility of Cryptococcus gattii clinical isolates.
Clin Microbiol Infect. 2008 Jul; 14(7): 727-30
Gomez-Lopez A, Zaragoza O, Dos Anjos Martins M, Melhem MC, Rodriguez-Tudela JL, Cuenca-Estrella M
The data available in the literature concerning Cryptococcus gattii in vitro antifungal susceptibility are contradictory. We have analyzed the activity of eight antifungal agents against 23 C. gattii clinical isolates and compared the susceptibility profiles with those of C. neoformans. MIC analysis (mg/L) revealed that C. gattii isolates were more susceptible to amphotericin B and flucytosine than were C. neoformans isolates. Fluconazole and other azole compounds showed high MIC values for C. gattii. Posaconazole displayed good activity. Further studies are required to ascertain the predictive value of the in vitro data presented here.
Risk Management of Simvastatin or Atorvastatin Interactions with CYP3A4 Inhibitors.
Drug Saf. 2008; 31(7): 587-96
Molden E, Skovlund E, Braathen P
BACKGROUND: Co-administration of cytochrome P450 (CYP) 3A4 inhibitors with simvastatin or atorvastatin is associated with increased risk of developing myopathy or rhabdomyolysis. OBJECTIVE: To detect co-prescriptions of CYP3A4 inhibitors with simvastatin or atorvastatin in community pharmacies and assess the risk-preventive actions taken by the prescribing physicians who were alerted about the co-prescription by the pharmacist. METHODS: This naturalistic study was performed during four separate 6-week periods in 2004 and 2005, and involved 110 Norwegian community pharmacists (25-30 in each period). Co-prescription of the selected CYP3A4 inhibitors diltiazem, verapamil, clarithromycin, erythromycin, fluconazole, itraconazole and ketoconazole with either simvastatin or atorvastatin was detected with the aid of a simple computer programme. In instances where the pharmacist alerted the prescribing physician about the co-prescription, information on possible strategies to minimize the risk associated with the interaction was also provided. Odds ratios (ORs) were estimated to describe the associations between prescription variables and frequencies of physician information and prescription change, respectively. RESULTS: In total, 245 co-prescriptions of CYP3A4 inhibitors with simvastatin (134 events) or atorvastatin (111) were detected. Diltiazem (86 events), verapamil (72), erythromycin (48) and clarithromycin (29) were the most commonly co-prescribed CYP3A4 inhibitors. Physicians were informed in 168 out of 245 cases (68.6%). The prescription was subsequently changed in 100 out of 168 cases (59.5%). Another 50 physicians (29.8%) responded that they would consult the patient and monitor potential adverse effects, while only 18 physicians (10.7%) replied that they had already managed the interactions or considered the issue as irrelevant. The adjusted OR for the informing of the physician was 1.89 (95% CI 0.98, 3.63) in patients receiving a daily HMG-CoA reductase inhibitor ('statin') dose of >/=40 mg compared with patients receiving a statin dose of
Clin Ther. 2008 May; 30(5): 964-73
Schonfeld W, Wang Cheng J, Tong KB, Seifeldin R
Background: Micafungin sodium is indicated for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation (HSCT). One Phase III, multi-institutional, randomized, doubleblind comparative trial involving 882 adult and pediatric patients found that micafungin was more effective, in terms of significantly lower rates of systemic fungal infections and empiric antifungal therapy (AFT), than fluconazole as antifungal prophylaxis during the neutropenic phase following HSCT. Thus, despite the higher cost of micafungin versus fluconazole, micafungin prophylaxis may be associated with reduced costs. Objective: The aim of this analysis was to determine the cost-effectiveness of micafungin prophylaxis compared with fluconazole prophylaxis in patients undergoing HSCT. Methods: Efficacy data were taken from the clinical study. The economic analysis was conducted from the hospital perspective, using costs incurred from admission through discharge. Each of the patients was assigned costs and effectiveness based on outcomes data from the clinical study. Published literature was used to estimate hospital costs associated with HSCT and prophylaxis, empiric AFT, and treatment of a probable or proven Candida or Aspergillus infection. Mean costs and effectiveness were calculated in each treatment group. To test the variability of the results using repeated sampling, a bootstrapping analysis was also conducted, with 1000 simulations of random samples of 100 patients from each treatment group. If appropriate to describe the results, incremental cost effectiveness ratios were calculated, and sensitivity analyses were conducted by varying components of cost. Results: This analysis included data from 882 patients (527 males, 355 females; micafungin, 425 patients, mean age, 43.2 years [range, 0.6-73.0 years]; fluconazole, 457 patients, mean age, 41.9 years [range, 0.6-71.0 years]). Total hospital costs per patient were $121,098 and $124,957 in micafungin and fluconazole recipients, respectively-a difference of $3859. The bootstrapping analysis found that micafungin prophylaxis was cost-saving in 72.4% of the samples compared with 9.2% with fluconazole prophylaxis. Sensitivity analyses on estimated hospital costs found that micafungin was a cost-effective therapy. Conclusion: In this analysis of data from a clinical study in adults and children undergoing HSCT, micafungin prophylaxis was associated with reduced hospital costs, and resultant total patient costs, compared with fluconazole prophylaxis.
Significant differences in drug susceptibility among species in the Candida parapsilosis group.
Diagn Microbiol Infect Dis. 2008 Jun 12;
van Asbeck E, Clemons KV, Martinez M, Tong AJ, Stevens DA
Candida parapsilosis family has 3 proposed species: C. parapsilosis sensu stricto, Candida orthopsilosis, and Candida metapsilosis. C. parapsilosis sensu stricto had significantly higher caspofungin (CAS) and anidulafungin MICs than C. orthopsilosis or C. metapsilosis; C. metapsilosis was least susceptible to fluconazole. C. parapsilosis sensu stricto more frequently displayed (37%) paradoxical growth in CAS (P
Cell Microbiol. 2008 Jun 12;
Zaragoza O, Chrisman CJ, Castelli MV, Frases S, Cuenca-Estrella M, Rodríguez Tudela JL, Casadevall A
Cryptococcus neoformans is a facultative intracellular pathogen. The most distinctive feature of C. neoformans is a polysaccharide capsule that enlarges depending on environmental stimuli. The mechanism by which C. neoformans avoids killing during phagocytosis is unknown. We hypothesized that capsule growth conferred resistance to microbicidal molecules produced by the host during infection, particularly during phagocytosis. We observed that capsule enlargement conferred resistance reactive oxygen species produced by H(2)O(2 )that was not associated with a higher catalase activity, suggesting a new function for the capsule as a scavenger of reactive oxidative intermediates. Soluble capsular polysaccharide protected C. neoformans and S. cerevisiae from killing by H(2)O(2). Acapsular mutants had higher susceptibility to free radicals. Capsular polysaccharide acted as an antioxidant in the NBT reduction coupled to NADH/PMS assay. Capsule enlargement conferred resistance to antimicrobial peptides and the antifungal drug Amphotericin B. Interestingly, the capsule had no effect on susceptibility to azoles and increased the susceptibility to fluconazole. Capsule enlargement reduced phagocytosis by environmental predators, although we also noticed that in this system, starvation of C. neoformans cells produced resistance to phagocytosis. Our results suggest that capsular enlargement is a mechanism that enhances C. neoformans survival when ingested by phagocytic cells.