A reversible monoamine oxidase inhibitor, toloxatone: Structural and electronic properties

Toloxatone is a reversible MAO_A-inhibitor, marketed as antidepressant (Humoryl^®), with an original chemical structure. It differs from first generation irreversible MAOIs, known to induce covalent bonds with the enzyme active site. In order to understand the mechanism of the reversible inactivation of the MAO, as a first step, a detailed structural and electronic analysis was undertaken. An X-ray diffraction-crystallographic study showed that toloxatone is a planar molecule and brought to light hydrogen bonds and π-π interactions. MO calculations confirmed the planar structure as energetically favoured. Electronic analysis demonstrated a delocalization of both ring systems. The combined results give evidence for the potential of toloxatone to participate in reversible, long distance interactions with an appropriate partner.     

The use of 18F-fluorodeoxyglucose positron emission tomography for the diagnosis and management of invasive mould infections.

There is limited information on the utility of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for the diagnosis and management of invasive mould infections (IMIs). We retrospectively evaluated patients with IMIs who underwent FDG-PET in our institution (n = 13; December 1999 to April 2004), and reviewed the available literature (n = 9). In 16 non-neutropenic patients with available FDG-PET imaging studies (11 from our institution), FDG-PET revealed an occult IMI site (n = 3; 2 unidentified CNS involvement) and was helpful in guiding the duration of treatment (n = 8). Prospective evaluation of the role of FDG-PET in the work-up and management of IMIs is needed.     

An analysis of eccentric photo refraction

The optics of eccentric photo refraction are analysed. The variation of photo refractive lunula area with refractive error, pupil size, flash eccentricity and camera aperture were calculated using a model eye. Measurements from photographs of paraxial (eccentric) photo refraction of model eyes show that a good agreement exists between theory and experiment over a range of refractive errors from — 10 D to +10 D. Calculations were also made for a standard reduced eye. The optimal set-up for measuring refractive error accurately over a wide range of refractive states is discussed, as are the problems which arise from non-central fixation.     

Inflammatory bowel disease and the X chromosome

A review of documented cases demonstrates a significant association of Turner's syndrome with Crohn's disease and ulcerative colitis; this association relates particularly to genetic constitutions comprising an abnormal rather than an absent X chromosome. The karyotype 46XiXq, in pure or mosaic form, appears to be a significant susceptibility factor for inflammatory bowel disease. This karyotype often gives rise to relatively weak phenotypic characteristics of Turner's syndrome, which may be overlooked in short females with inflammatory bowel disease. The association of inflammatory bowel disease with Turner's syndrome may reflect the presence on the X chromosome of genes involved in disease pathogenesis. Linkage analysis studies, involving microsatellite markers on the X chromosome, are being performed.      

Albumin Enhances Caspofungin Activity against Aspergillus Species by Facilitating Drug Delivery to Germinating Hyphae

The modest in vitro activity of echinocandins against Aspergillus implies that host-related factors augment the action of these antifungal agents in vivo. We found that, in contrast to the other antifungal agents (voriconazole, amphotericin B) tested, caspofungin exhibited a profound increase in activity against various Aspergillus species under conditions of cell culture growth, as evidenced by a ≥4-fold decrease in minimum effective concentrations (MECs) (P = 0. 0005). Importantly, the enhanced activity of caspofungin against Aspergillus spp. under cell culture conditions was strictly dependent on serum albumin and was not observed with the other two echinocandins, micafungin and anidulafungin. Of interest, fluorescently labeled albumin bound preferentially on the surface of germinating Aspergillus hyphae, and this interaction was further enhanced upon treatment with caspofungin. In addition, supplementation of cell culture medium with albumin resulted in a significant, 5-fold increase in association of fluorescently labeled caspofungin with Aspergillus hyphae (P < 0.0001). Collectively, we found a novel synergistic interaction between albumin and caspofungin, with albumin acting as a potential carrier molecule to facilitate antifungal drug delivery to Aspergillus hyphae.     

Role of mini-host models in the study of medically important fungi

Mini-host models have emerged as simple experimental systems to study the pathogenesis and host innate immune responses in fungal invaders and also to test drug efficacy against these organisms. A growing number of medically important fungi, including Aspergillus spp, Candida spp, Cryptococcus spp, and species in the class Zygomycetes, have been shown to infect and kill invertebrates such as roundworms, fruit flies, and wax moths. These studies have shown that several genes implicated in the virulence of fungi in mammalian models also have a similarly important pathogenic role in mini-host organisms. These mini-host models provide a unique opportunity of simultaneously exploring the molecular mechanisms of fungal pathogenicity and candidate agents with antifungal activity. Furthermore, the fact that some of these mini-hosts have well-defined genetics and conserved innate immunity offers the advantage of a comprehensive analysis of the molecular aspects of host immune response. We examine the relevance, advantages, and pitfalls of experimental systems of fungal infections in various mini-hosts and compare them with what is known in experimental systems in mammalian animal models.     

Random plasma concentrations of voriconazole decline over time

We retrospectively collected information about 29 cancer patients who underwent measurement of their plasma concentration (PC) of voriconazole (VRC) (2002-2006). Nine patients (31%) had VRC PC <1 microg/ml. VRC PC <1 microg/ml occurred in 7 of 10 patients who were on VRC >2 months versus only 2 of 19 patients who were on VRC <2 months (P=0.001). VRC PCs were infrequently ordered, did not follow clear indications, and the use of the results was variable.