Open-Label Study of Absorption and Clearance of 1% Voriconazole Eye Drops.

Twenty participants undergoing elective cataract surgery received 1% voriconazole eye drops (1 drop per eye) either 20, 40, 60, or 80 min before surgery. Median voriconazole concentrations of 1.9 to 3.2 mg/liter in aqueous humor samples were attained over the first 80 min, which were higher than in vitro MIC90 values for typical fungi that cause keratitis.

Adult Verbal Abstract Reasoning Assessment Instruments and their Clinimetric Properties.

OBJECTIVE: This systematic review aims to identify, examine, and compare tests used to measure and assess verbal abstract reasoning (VAR). METHOD: Seven tests were identified through a systematic search of electronic databases, neuropsychological textbooks, and online catalogs. Clinical utility, normative data, and psychometric properties (internal consistency, test-retest reliability, and construct validity) of current test versions were evaluated using recent studies. A modified version of the CanChild Outcome Measures Rating Form, and structured quality assessment criteria were used in the evaluation process. RESULTS: The WAIS-IV Similarities subtest was ranked the highest, followed by the Shipley-2 Abstraction test and Gorham's Proverbs test. These three tests had sufficient validity to recommend their use, however some caution is advised for the latter two in terms of construct purity, and age of normative data, respectively. Other tests reviewed were the Delis-Kaplan Executive Functioning System Proverbs subtest, the Stanford-Binet Intelligence Scale fifth edition Verbal Analogies subtests, the Conceptual Level Analogy Test, and the Verbal Concept Attainment Test. For the majority of tests, construct validity was lacking while reliabilities were sufficient. CONCLUSIONS: Lack of sound psychometric evidence limits the range of options for the practitioner to choose a test with confidence to assess VAR. While there is merit in the clinical utility of the majority of assessment instruments evaluated in this review, caution is recommended before deciding to use a test that does not carry sufficient psychometric evidence to support its use. Further research is recommended to improve the library of tests available to clinicians and researchers.

Penetration of topically administered 0.5-percent caspofungin eye drops into human aqueous humor.

Ten participants attending elective anterior segment eye surgery received 0.5% caspofungin eye drops either 1 drop hourly for 4 h or 1 drop an hour before surgery. The eye drops were generally well tolerated. In the absence of inflammation or corneal abrasion, topical caspofungin does not achieve clinically relevant concentrations.

Rapid and sensitive liquid chromatography/mass spectrometry assay for caspofungin in human aqueous humor.

A rapid, precise, and sensitive liquid chromatography/mass spectrometry (LC/MS) method to quantify the caspofungin concentration in human aqueous humor was developed and validated. Sample preparation involved simple dilution of aqueous humor samples with acetonitrile. Azithromycin was the internal standard. Good linearity over 10 to 5,000 ng/ml was observed. The lower limit of quantification was 10 ng/ml. The intra- and interday accuracies (percent bias) were within 11%, while the intra- and interday precisions were within 6%.

Successful use of topical voriconazole 1% alone as first-line antifungal therapy against Candida albicans keratitis.

OBJECTIVE: To report the successful use of topical voriconazole 1% given alone as primary therapy against a case of Candida albicans keratitis. CASE SUMMARY: A 48-year-old previously well man presented to the emergency department with pain and foreign body sensation in the left eye following exposure to dust while driving a forklift. He wore weekly disposable soft contact lenses. Anterior stromal scar and dense infiltrate were detected in the left eye. The anterior chamber remained deep, with flare and copious white cells. Intraocular pressure was 12 mm Hg and visual acuity was 20/200. The epithelial defect persisted, with progressive thinning despite topical fluorometholone and ofloxacin 0.3% therapy for 2 days. Microbiology testing revealed C. albicans as the affecting pathogen. Hourly administration of voriconazole 1% eye drops was initiated as antifungal therapy. The corneal infiltrate began to resolve and the epithelial defect decreased in size within 2 days. Visual acuity improved to 20/120. After 4 days of voriconazole use, the epithelial defect was completely healed and visual acuity was 20/30 in the affected eye. No fungi were isolated from a second eye scrape. DISCUSSION: Topical voriconazole as salvage monotherapy to manage fungal keratitis has been previously reported. It can be argued, however, that the primary therapy has facilitated the positive response to subsequent topical voriconazole. To date, there has been no solid evidence to suggest that topical voriconazole is effective when used as primary therapy. The current report provides evidence of topical voriconazole demonstrating clinical success when used as first-line therapy to treat C. albicans keratitis. The use of topical voriconazole can reduce the costs, toxicity, and drug interactions associated with common antifungal therapies. CONCLUSIONS: Topical voriconazole 1% eye drops administered alone demonstrated success as first-line therapy against the most common fungal keratitis, C. albicans keratitis.

Penetration of 1% voriconazole eye drops into human vitreous humour: a prospective, open-label study.

PURPOSE: Although there have been reports describing the use of 1% voriconazole eye drops in the treatment of fungal infections, little is known about the penetration of voriconazole eye drops into the vitreous humour. The aim of this study was to elucidate if topical application of 1% voriconazole eye drops could reach therapeutic levels in the vitreous humour. METHODS: A prospective, open-label trial involving 10 participants selected from patients scheduled to undergo elective, posterior segment surgery. Participants received 1% voriconazole solution, preserved with 0.01% benzalkonium chloride, hourly for four doses or four times a day for 3 days. Vitreous humour was obtained at the start of surgery and analysed using a validated high-performance liquid chromatography assay. RESULTS: The minimum and maximum voriconazole concentration after hourly dosing (n = 5) was 0.1 and 1.1 microg/mL, respectively, whereas the median was 0.3 microg/mL. Samples were taken between 0.8 and 5.4 h after the last dose, with the median at 1.2 h. Almost all voriconazole concentrations from the four times a day group (n = 5) were below the limit of quantification. CONCLUSIONS: One per cent voriconazole eye drops are able to penetrate into human vitreous humour. Adequate concentration for treatment of sensitive Candida species can be achieved upon hourly administration.

Stability of extemporaneously prepared voriconazole ophthalmic solution.

PURPOSE: The stability of extemporaneously prepared voriconazole ophthalmic solution was studied. METHODS: Voriconazole solutions (2% and 1%) were reconstituted from the i.v. formulation. After thorough mixing, 3-mL samples of each of the resulting 2% and 1% solutions were filtered into eyedroppers. Three samples for both solutions were analyzed in triplicate at each time point. The 2% voriconazole ophthalmic solutions were stored at 2-8 degrees C, 25 degrees C, and 40 degrees C. The 1% voriconazole eye drops were stored at 2-8 degrees C. The 2% voriconazole solution samples were analyzed at time 0 and at weeks 1, 2, 4, 8, 16, and 32. The 1% solution samples were analyzed at time 0 and at weeks 6 and 14. Stability was measured using high-performance liquid chromatographic analysis. RESULTS: The 2% voriconazole ophthalmic solution demonstrated excellent stability at 2-8 degrees C and 25 degrees C for up to 16 weeks. The voriconazole solution displayed no significant change in pH at all time intervals. No change in visual appearance or clarity was observed in the 2% voriconazole eye drops at any point of the study for all study temperatures. Voriconazole 1% solution was stable at 2-8 degrees C for up to 14 weeks. CONCLUSION: Voriconazole 2% (20 mg/mL) solution preserved with 0.01% benzalkonium chloride prepared as alternative antifungal eye drops was stable for 16 weeks when stored at 2-8 degrees C and 25 degrees C and for 8 weeks when stored at 40 degrees C, while voriconazole 1% solution was stable at 2-8 degrees C for up to 14 weeks.

Prospective open-label study of the administration of two-percent voriconazole eye drops.

Thirteen human subjects scheduled for elective anterior segment eye surgery received hourly 2% voriconazole eye drops 4 hours presurgery. No side effects were reported. Significantly, the voriconazole concentration in the aqueous humor of the eye was similar to that reported for the 1% voriconazole solution, suggestive of concentration-independent absorption.

Successful salvage treatment of Scedosporium apiospermum keratitis with topical voriconazole after failure of natamycin.

OBJECTIVE: To report successful management of Scedosporium apiospermum (previously known as Monosporium apiospermum) keratitis with topical voriconazole as monotherapy. CASE SUMMARY: A 54-year-old previously well woman presented to the emergency department with a painful, injected right eye. There was no history of trauma or use of contact lenses. On examination, the right eye was estimated to have visual acuity of hand movement. Slit lamp examination detected a 2.5 x 3.5 mm dense, central corneal infiltrate with overlying epithelial defect. The eye had mild corneal edema with anterior chamber inflammation. Microbiology testing revealed S. apiospermum as the primary pathogen. Hourly administration of topical natamycin 5% resulted in initial improvement in visual acuity to 20/50, with reduction in the size of the central infiltrate. However, 1 month later, the eye infection relapsed, with recurrence of epithelial defect (3.1 x 3.1 mm) and decline in visual acuity to 20/100. Antifungal therapy was switched to topical voriconazole 1%, administered every 2 hours. Vision improved to 20/30 within 5 days, and the central defect had completely re-epithelialized within 1 week. DISCUSSION: Treatment of S. apiospermum keratitis remains inadequate. A high natamycin minimum inhibitory concentration is necessary to treat S. apiospermum infection, which may explain the persistence of central infiltration despite ongoing therapy. The combined use of topical and oral voriconazole for the treatment of S. apiospermum keratitis has been reported. However, this is the first report of a successful clinical experience using topical voriconazole without oral therapy to manage S. apiospermum keratitis. This eliminates some disadvantages associated with oral voriconazole such as high cost, potential significant toxicity, and drug interactions. CONCLUSIONS: The voriconazole 1% eye drop used alone is a promising, cost-effective, safe option for managing fungal keratitis, even that caused by S. apiospermum. It may have a larger role to play than simply that of adjunctive therapy.

A motif-based approach to network epidemics.

Networks have become an indispensable tool in modelling infectious diseases, with the structure of epidemiologically relevant contacts known to affect both the dynamics of the infection process and the efficacy of intervention strategies. One of the key reasons for this is the presence of clustering in contact networks, which is typically analysed in terms of prevalence of triangles in the network. We present a more general approach, based on the prevalence of different four-motifs, in the context of ODE approximations to network dynamics. This is shown to outperform existing models for a range of small world networks.

Professionalism: the James Pryor memorial lecture.

James Pryor was born in country Victoria in 1928 and died there in 2002. He received his medical degree from Melbourne University in 1950 with honours in surgery. He went on to become a Fellow of the Royal College of Surgeons and of the Royal Australasian College of Surgeons.

Judging doctors.

In three distinct situations, judges may be obliged to pronounce on doctors' opinions or conduct. The first of these is where they are deciding actions involving claims for personal injuries in respect of which doctors have given opinions to the court. The second situation in which the judge may be obliged to pronounce on a doctor's opinion or conduct is when, in a civil action, that doctor is sued for negligence. The third, even less common kind of case in which a judge or a retired judge may be obliged to pronounce on a doctor's opinion or conduct is when the judge has been appointed to conduct a Commission of Inquiry, which includes an inquiry into the quality of medical services. There is a fourth kind of case in which a doctor's opinion or conduct is in question. This is when the doctor is charged with a criminal offence, usually criminal negligence but sometimes grievous bodily harm and even manslaughter, as has occurred in one case recently in Queensland. Each of these situations involves different considerations and the application of different principles, although there are some factors common to more than one. And there are defects and illogicalities in some, which are not there in others. I propose to discuss each of these situations and, in some of them, expose what I see as some defects or illogicalities and suggest how I think they should be improved.

Kinetics of formation and dissociation of aquocobalt(III) complexes with some carboxylic acids in acid perchlorate solution.

The rates of formation and dissociation of monocarboxylic complexes of aquocobalt(III) cations with propionic, malonic, and 2-ethylmalonic acids have been measured with the stopped-flow method over a range of concentrations and temperatures in acid perchlorate media at an ionic strength 3.0 M. Although the rate constants for reactions of CoOHaq2+ with neutral ligands cover only a small range, indicating a dissociative mechanism, the associated activation parameters change cooperatively. These variations are discussed in terms of differences in the structure, proton distribution, and rates of water loss in the ion-pair precursors for the different ligands. Similar activation enthalpies of dissociation indicate a common mode of coordination, and the positive activation entropies for dissociation are consistent with a neutral leaving group.

XAFS studies of cobalt(II) binding by solid peat and soil-derived humic acids and plant-derived humic acid-like substances.

This work has examined cobalt(II) binding by a variety of solid humic acids (HAs) isolated from peat, plant and soil sources at temperatures down to 60K. The results confirm that X-ray absorption near-edge spectroscopy (XANES) measurements cannot distinguish between aquo and carboxylato ligands in the inner coordination sphere of Co(II). However, between 1 and 2 inner-sphere carboxylato ligands can be detected in all the peat, plant and soil-derived HA samples by extended X-ray absorption fine structure (EXAFS) measurements, indicating inner-sphere coordination of HA-bound Co(II). The precision of C(carboxylate) detection is limited by the extent and quality of the data and the contribution from inner-sphere O to the Fourier transformed peaks used to detect carbon. Putative chelate ring formation is consistent with a relatively negative entropy change in step A, the stronger Co(II) binding step by HA functional groups, and could relate to 'non-exchangeable' metal binding by HSs.

Thermodynamics of metal cation binding by a solid soil derived humic acid. 2. Binding of Mn(II), Co(NH3)6aq3+ and Hg(II).

Metal binding is an important function of humic acids (HAs) in soils, sediments and waters. At pH 2.0, Mn(II) and Co(NH3)6aq3+ bind tightly in one step labeled A to a solid humic acid NHA isolated from a New Hampshire soil. Two consecutive steps are observed for Hg(II) binding. All the binding isotherms fit the Langmuir model in the temperature range 10.0-50.0 degrees C. Stoichiometric site capacities indicate predominant binding by charge-neutralizing HA carboxylate groups for Mn(II) and the second step A of Hg(II) binding. The binding affinity order in step A is Co(NH3)(6)3+>Hg(II)>Mn(II). Metal binding enthalpy and entropy changes fit the linear correlation found previously for binding of other metal cations by solid HAs. Free energy buffering from cooperative enthalpy and entropy changes and lower enthalpies for metal-HA interactions in solution suggest that desolvation of the cations and HA binding sites as well as HA conformational changes to allow for inner-sphere complexation predominate metal binding by hydrated solid HAs.

Thermodynamics of metal cation binding by a solid soil-derived humic acid: binding of Fe(III), Pb(II), and Cu(II).

Metal binding and release by solid humic acids (HAs) in soils and sediments can affect metal mobility and bioavailability. Isotherms for tight binding of Fe(III), Pb(II) and Cu(II) by a solid humic acid at pH2.0 fit the Langmuir binding model. Low pH was chosen to protonate the HA carboxylate groups and avoid metal cation hydrolysis. Binding of Fe(III), Pb(II) and Cu(II) occurs in one detectable step labeled A. Site capacities nu(A) are temperature-independent from 10.0 to 40.0 degrees C and point to binding by charge-neutralization to form solid complexes M(OOC-R)(n)(s), where n appears to be 2 for Pb(II) and 3 for Fe(III). Thermodynamic data pairs (DeltaH(A), DeltaS(A)) for metal binding are linearly correlated with previous data for Ca(II), Co(II) and Mg(II) binding by solid HAs.

Elastic modulus and stress-transfer properties of tunicate cellulose whiskers.

Experimental deformation micromechanics of natural cellulose fibers using Raman spectroscopy and X-ray diffraction have been widely reported. However, little has been published on the direct measurements of the mechanical properties, and in particular the elastic modulus, of the highly crystalline material in the native state. Here we report on measurements of the elastic modulus of tunicate cellulose using a Raman spectroscopic technique. A dispersed sample of the material is deformed using a four-point bending test, and a shift in a characteristic Raman band (located at 1095 cm(-1)) is used as an indication of the stress in the material. Relatively little intensity change of the Raman band located at 1095 cm(-1) is shown to occur for samples oriented parallel and perpendicular to the polarization direction of the laser, as compared to a highly oriented flax sample. This indicates that the tunicate sample is a two-dimensional in-plane random network of fibers. By use of this result, the Raman shift, and calibrations with strain from other materials, it is shown that the modulus of the material is very high, at about 143 GPa, and a lack of Raman band broadening is thought to be due to the fact that there is pure crystalline deformation occurring without the effect of crystalline/amorphous fractions. A strain sensitivity of the shift in the 1095-cm(-1) Raman peak for this specimen is shown to be -2.4 +/- 0.2 cm(-1)/%. A molecular mechanics approach, using computer simulation and an empirical force field, was used to predict the modulus of a highly oriented chain of the material, and this is found to be 145 GPa, which is in agreement with the experimental data. However, by use of a normal-mode analysis, it is found that a number of modes have positions close to the central positions of the experimental Raman band. One in particular is found to shift at a rate of 2.5 cm(-1)/%, but due to the complex nature of the structure, it is not entirely conclusive that this band is representative of the experimental findings.

Modeling crystal and molecular deformation in regenerated cellulose fibers.

Experimental deformation micromechanics of regenerated cellulose fibers using Raman spectroscopy have been widely reported. Here we report on computer modeling simulations of Raman band shifts in modes close to the experimentally observed 1095 cm(-1) band, which has previously been shown to shift toward a lower wavenumber upon application of external fiber deformation. A molecular mechanics approach is employed using a previously published model structure of cellulose II. Changing the equilibrium c-spacing of this structure and then performing a minimization routine mimics tensile deformation. Normal-mode analysis is then performed on the minimized structure to predict the Raman-intensive vibrations. By using a dot-product analysis on the predicted eigenvectors it is shown that some Raman active modes close to the 1095 cm(-1) band interchange at certain strain levels. Nevertheless, when this is taken into account it is shown that it is possible to find reasonable agreement between theory and experiment. The effect of the experimentally observed broadening of the Raman bands is discussed in terms of crystalline and amorphous regions of cellulose, and this is compared to the lack of X-ray broadening to explain why discrepancies between theory and experiment are present. A hybrid model structure with a series-parallel arrangement of amorphous and misaligned amorphous-crystalline domains is proposed which is shown to agree with what is observed experimentally. Finally, the theoretical crystal modulus for cellulose II is reported as 98 GPa, which is shown to be in agreement with other studies and with an experimental measurement using synchrotron X-ray diffraction.