A kinetics-based approach to amyloid PET semi-quantification.

PURPOSE: To develop and validate a semi-quantification method (time-delayed ratio, TDr) applied to amyloid PET scans, based on tracer kinetics information. METHODS: The TDr method requires two static scans per subject: one early (~ 0-10 min after the injection) and one late (typically 50-70 min or 90-100 min after the injection, depending on the tracer). High perfusion regions are delineated on the early scan and applied onto the late scan. A SUVr-like ratio is calculated between the average intensities in the high perfusion regions and the late scan hotspot. TDr was applied to a naturalistic multicenter dataset of 143 subjects acquired with [18F]florbetapir. TDr values are compared to visual evaluation, cortical-cerebellar SUVr, and to the geometrical semi-quantification method ELBA. All three methods are gauged versus the heterogeneity of the dataset. RESULTS: TDr shows excellent agreement with respect to the binary visual assessment (AUC = 0.99) and significantly correlates with both validated semi-quantification methods, reaching a Pearson correlation coefficient of 0.86 with respect to ELBA. CONCLUSIONS: TDr is an alternative approach to previously validated ones (SUVr and ELBA). It requires minimal image processing; it is independent on predefined regions of interest and does not require MR registration. Besides, it takes advantage on the availability of early scans which are becoming common practice while imposing a negligible added patient discomfort.

Semi-quantification and grading of amyloid PET: A project of the European Alzheimer's Disease Consortium (EADC).

BACKGROUND: amyloid-PET reading has been classically implemented as a binary assessment, although the clinical experience has shown that the number of borderline cases is non negligible not only in epidemiological studies of asymptomatic subjects but also in naturalistic groups of symptomatic patients attending memory clinics. In this work we develop a model to compare and integrate visual reading with two independent semi-quantification methods in order to obtain a tracer-independent multi-parametric evaluation. METHODS: We retrospectively enrolled three cohorts of cognitively impaired patients submitted to 18F-florbetaben (53 subjects), 18F-flutemetamol (62 subjects), 18F-florbetapir (60 subjects) PET/CT respectively, in 6 European centres belonging to the EADC. The 175 scans were visually classified as positive/negative following approved criteria and further classified with a 5-step grading as negative, mild negative, borderline, mild positive, positive by 5 independent readers, blind to clinical data. Scan quality was also visually assessed and recorded. Semi-quantification was based on two quantifiers: the standardized uptake value (SUVr) and the ELBA method. We used a sigmoid model to relate the grading with the quantifiers. We measured the readers accord and inconsistencies in the visual assessment as well as the relationship between discrepancies on the grading and semi-quantifications. CONCLUSION: It is possible to construct a map between different tracers and different quantification methods without resorting to ad-hoc acquired cases. We used a 5-level visual scale which, together with a mathematical model, delivered cut-offs and transition regions on tracers that are (largely) independent from the population. All fluorinated tracers appeared to have the same contrast and discrimination ability with respect to the negative-to-positive grading. We validated the integration of both visual reading and different quantifiers in a more robust framework thus bridging the gap between a binary and a user-independent continuous scale.

Hemp-seed and olive oils: their stability against oxidation and use in O/W emulsions.

Hemp-seed oil has several positive effects on the skin: thanks to its unsaturated fatty acid (PUFA) content it alleviates skin problems such as dryness and those related to the aging process. We present a comparative study of hemp-seed and olive oils, determining some physicochemical indices and evaluating their stability against oxidation. The peroxide value of hemp-seed oil was below 20, the threshold limit for edible oils. Hemp-seed oil was less stable against peroxidation than olive oil, but MDA and MONO assays showed its stability to be above expectations. The chlorophyll contained in extra virgin olive oil had a higher photostability than that contained in hemp-seed oil, possibly due to the larger amount of antioxidant in the olive oil. A certain amount of Vitamin E was found in hemp-seed oil. Since quality analyses indicated that hemp-seed oil is relatively stable, emulsions were prepared with the two oils, and their stability and rheological characteristics were tested. Some of the resulting gel-emulsions were suitable for spraying on the skin.

The effect of formulation and concentration of cholesteryl butyrate solid lipid nanospheres (SLN) on NIH-H460 cell proliferation.

Experimental factorial design was used to evaluate the influence of two factors involved in producing cholesteryl butyrate (chol-but) solid lipid nanospheres (SLN), microemulsion formulation and microemulsion/water ratio, on the effect of the SLN on the proliferation of NIH-H460, a non-small-cell lung carcinoma; six experimental settings were tested. The cells were treated with scalar concentrations of cholesteryl butyrate (from 0.008 to 1.000 mM) for each experimental condition; NIH-H460 cell growth was inhibited in all cases. The best experimental setting provided complete inhibition at 0.125 mM chol-but, while at the same concentration sodium butyrate provided only 38% inhibition.

Transdermal permeation of apomorphine through hairless mouse skin from microemulsions.

The in vitro transdermal absorption of apomorphine from microemulsions was studied using the skin of the hairless mouse as a membrane. Two microemulsions (no. 1 and 2) were prepared and thickened both containing 3.9% of apomorphine hydrochloride. The lipophilicity of the drug was increased by forming apomorphine-octanoic acid ion-pairs. The fluxes of the drug from the microemulsions through hairless mouse skin were 100 microg h(-1) cm(-2) from no. 1 and 88 microg h(-1) cm(-2) from no. 2. Apomorphine in microemulsions, protected from light with antioxidants, showed no degradation for up to 6 months.

Elastic liposomes for skin delivery of dipotassium glycyrrhizinate.

The aim of this study was to evaluate the possibility of using liposomes for skin delivery of dipotassium glycyrrhizinate (KG), an anti-inflammatory agent employed in treating acute and chronic dermatitis, and of formulating such liposomes in an oil-in-water emulsion (O/W). KG had emulsifying properties and the possibility of producing elastic liposomes was verified. Liposomes containing soya lecithin (PC) or hydrogenated soya lecithin (HPC) mixed with KG in w/w ratios of 2:1, 4:1 or 8:1 were prepared by the solvent evaporation method and then passed through a high pressure homogeniser. Liposome size and entrapment efficiency were determined and the interaction between KG and HPC was investigated using differential scanning calorimetry (DSC). Transepidermal permeation through intact pig skin and skin deposition of KG from liposomes and O/W emulsion containing liposomes were assessed and compared with values for aqueous control solutions. No marked differences were observed between PC and HPC liposomes. Liposome sizes ranged from 90 to 120 nm. Entrapment efficiency depended on the lipid:KG ratio; the maximum efficiency was obtained at 4:1 w/w. KG interacted with liposomes disrupting and fluidising the lipid bilayer, forming elastic liposomes able to penetrate through membrane pores of diameter much smaller than their own diameter. The liposome structure was maintained when dispersed in an O/W emulsion. The skin fluxes were less than the HPLC detection limit for all systems, while skin deposition increased 4.5-fold compared with aqueous solutions when KG was formulated in liposomes.

Solid lipid nanoparticles as carriers of hydrocortisone and progesterone complexes with beta-cyclodextrins.

Inclusion complexes of hydrocortisone and progesterone were formed with beta-cyclodextrin or 2-hydroxypropyl-beta-cyclodextrin. The formation of the complexes was confirmed by differential scanning calorimetry (DSC). The inclusion complexes were incorporated in two types of solid lipid nanoparticles (SLN). In the presence of the complexes the sizes of SLN remained below 100 nm. DSC analysis showed that hydrocortisone and progesterone are dispersed in SLN in an amorphous state. Using the beta-cyclodextrin complexes the incorporation of the more hydrophilic drug, hydrocortisone, was higher than that of progesterone. Release of hydrocortisone and progesterone from SLN was lower when they were incorporated as inclusion complexes than as free molecules.

Development of O/W nanoemulsions for ophthalmic administration of timolol.

After an initial screening of ingredients and production methods, nanoemulsions for ocular administration of timolol containing the drug as maleate (TM) or as ion-pair with AOT (TM/AOT) were prepared. The physico-chemical characterization of nanoemulsions, regarding mean diameter, pH, zeta potential, osmolarity, viscosity and surface tension, underlined their feasibility to be instilled into the eyes. Single components and emulsions were tested ex vivo on rabbit corneas to evaluate corneal irritation, that was measured according to opacity test. A marked decrease in corneal opacity was observed using the drug formulated in nanoemulsions rather than in aqueous solutions. Drug permeation and accumulation studies were performed on excised rabbit corneas. An increase in drug permeation through and accumulation into the corneas were observed using TM-AOT compared to TM due to an increase of lipophilicity of the drug as ion-pair. The introduction of chitosan (a positive charged mucoadhesive polymer) into emulsions allowed to increase TM permeation probably due to the interaction of chitosan with corneal epithelial cells.