Evaluation of a novel PET tracer [18F]-Florbetazine for Alzheimer's disease diagnosis and ß-amyloid deposition quantification.

[18F]-Florbetazine ([18F]-92) is a selective PET tracer for ß-amyloid (Aß) depositions with a novel diaryl-azine scaffold to reduce lipophilicity and to achieve higher gray-to-white matter contrast. We aimed to assess its diagnostic value in Alzheimer's disease (AD) and pharmacokinetics characteristics in human subjects. METHODS: Six healthy controls (HCs) and nine AD patients underwent dynamic PET examination with [18F]-Florbetazine and a structural MRI scan. The time-activity-curves (TACs) for volumes of interest (VOIs) in cerebral cortex, cerebellar cortex and cerebral white matter was depicted and their standardized uptake value ratios (SUVRs) with cerebellar cortex as reference were compared between HCs and AD patients. The cerebral gray-to-white matter SUV ratio (GWR) was also calculated. RESULTS: In HCs, radioactivities in the cerebral cortex VOIs were homogeneously low and at the same level as in cerebellar cortex, while in AD patients, cortical VOIs expected to contain Aß exhibited high radioactivity. Cerebral cortex SUVRs remain relatively low in HCs while keep increasing along with time in AD patients. After 15 min, the cerebral cortex SUVRs became significant higher in AD patients compared to HCs with 100 % discrimination accuracy. In AD patients, GWR remained over 1.3 for all time intervals and visual inspection showed lower uptake in cerebral white matter compared to cerebral cortex. CONCLUSION: [18F]-Florbetazine PET showed high uptake on Aß plaques and high gray-to-white contrast in AD patients that are favorable in visual read. [18F]-Florbetazine can be potentially used for detection and quantification of Aß depositions in the living human brain.

Rates of cortical thinning in Alzheimer's disease signature regions associate with vascular burden but not with ß-amyloid status in cognitively normal adults at age 70.

BACKGROUND: Consistent patterns of reduced cortical thickness have been identified in early Alzheimer's disease (AD). However, the pathological factors that influence rates of cortical thinning within these AD signature regions remain unclear. METHODS: Participants were from the Insight 46 substudy of the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort), a prospective longitudinal cohort study. Linear regression was used to examine associations of baseline cerebral ß-amyloid (Aß) deposition, measured using florbetapir positron emission tomography, and baseline white matter hyperintensity volume (WMHV) on MRI, a marker of cerebral small vessel disease, with subsequent longitudinal changes in AD signature cortical thickness quantified from baseline and repeat MRI (mean [SD] interval 2.4 [0.2] years). RESULTS: In a population-based sample of 337 cognitively normal older white adults (mean [SD] age at baseline 70.5 [0.6] years; 48.1% female), higher global WMHV at baseline related to faster subsequent rates of cortical thinning in both AD signature regions (~0.15%/year faster per 10 mL additional WMHV), whereas baseline Aß status did not. Among Aß positive participants (n=56), there was some evidence that greater global Aß standardised uptake value ratio at baseline related to faster cortical thinning in the AD signature Mayo region, but this did not reach statistical significance (p=0.08). CONCLUSIONS: Cortical thinning within AD signature regions may develop via cerebrovascular pathways. Perhaps reflecting the age of the cohort and relatively low prevalence of Aß-positivity, robust Aß-related differences were not detected. Longitudinal follow-up incorporating additional biomarkers will allow assessment of how these relationships evolve closer to expected dementia onset.

A deep learning model for generating [18F]FDG PET Images from early-phase [18F]Florbetapir and [18F]Flutemetamol PET images.

INTRODUCTION: Amyloid-ß (Aß) plaques is a significant hallmark of Alzheimer's disease (AD), detectable via amyloid-PET imaging. The Fluorine-18-Fluorodeoxyglucose ([18F]FDG) PET scan tracks cerebral glucose metabolism, correlated with synaptic dysfunction and disease progression and is complementary for AD diagnosis. Dual-scan acquisitions of amyloid PET allows the possibility to use early-phase amyloid-PET as a biomarker for neurodegeneration, proven to have a good correlation to [18F]FDG PET. The aim of this study was to evaluate the added value of synthesizing the later from the former through deep learning (DL), aiming at reducing the number of PET scans, radiation dose, and discomfort to patients. METHODS: A total of 166 subjects including cognitively unimpaired individuals (N = 72), subjects with mild cognitive impairment (N = 73) and dementia (N = 21) were included in this study. All underwent T1-weighted MRI, dual-phase amyloid PET scans using either Fluorine-18 Florbetapir ([18F]FBP) or Fluorine-18 Flutemetamol ([18F]FMM), and an [18F]FDG PET scan. Two transformer-based DL models called SwinUNETR were trained separately to synthesize the [18F]FDG from early phase [18F]FBP and [18F]FMM (eFBP/eFMM). A clinical similarity score (1: no similarity to 3: similar) was assessed to compare the imaging information obtained by synthesized [18F]FDG as well as eFBP/eFMM to actual [18F]FDG. Quantitative evaluations include region wise correlation and single-subject voxel-wise analyses in comparison with a reference [18F]FDG PET healthy control database. Dice coefficients were calculated to quantify the whole-brain spatial overlap between hypometabolic ([18F]FDG PET) and hypoperfused (eFBP/eFMM) binary maps at the single-subject level as well as between [18F]FDG PET and synthetic [18F]FDG PET hypometabolic binary maps. RESULTS: The clinical evaluation showed that, in comparison to eFBP/eFMM (average of clinical similarity score (CSS) = 1.53), the synthetic [18F]FDG images are quite similar to the actual [18F]FDG images (average of CSS = 2.7) in terms of preserving clinically relevant uptake patterns. The single-subject voxel-wise analyses showed that at the group level, the Dice scores improved by around 13% and 5% when using the DL approach for eFBP and eFMM, respectively. The correlation analysis results indicated a relatively strong correlation between eFBP/eFMM and [18F]FDG (eFBP: slope = 0.77, R2 = 0.61, P-value < 0.0001); eFMM: slope = 0.77, R2 = 0.61, P-value < 0.0001). This correlation improved for synthetic [18F]FDG (synthetic [18F]FDG generated from eFBP (slope = 1.00, R2 = 0.68, P-value < 0.0001), eFMM (slope = 0.93, R2 = 0.72, P-value < 0.0001)). CONCLUSION: We proposed a DL model for generating the [18F]FDG from eFBP/eFMM PET images. This method may be used as an alternative for multiple radiotracer scanning in research and clinical settings allowing to adopt the currently validated [18F]FDG PET normal reference databases for data analysis.

Florbetapir PET-assessed demyelination is associated with faster tau accumulation in an APOE ε4-dependent manner.

PURPOSE: The main objectives were to test whether (1) a decrease in myelin is associated with enhanced rate of fibrillar tau accumulation and cognitive decline in Alzheimer's disease, and (2) whether apolipoprotein E (APOE) ε4 genotype is associated with worse myelin decrease and thus tau accumulation. METHODS: To address our objectives, we repurposed florbetapir-PET as a marker of myelin in the white matter (WM) based on previous validation studies showing that beta-amyloid (Aß) PET tracers bind to WM myelin. We assessed 43 Aß-biomarker negative (Aß-) cognitively normal participants and 108 Aß+ participants within the AD spectrum with florbetapir-PET at baseline and longitudinal flortaucipir-PET as a measure of fibrillar tau (tau-PET) over ~ 2 years. In linear regression analyses, we tested florbetapir-PET in the whole WM and major fiber tracts as predictors of tau-PET accumulation in a priori defined regions of interest (ROIs) and fiber-tract projection areas. In mediation analyses we tested whether tau-PET accumulation mediates the effect of florbetapir-PET in the whole WM on cognition. Finally, we assessed the role of myelin alteration on the association between APOE and tau-PET accumulation. RESULTS: Lower florbetapir-PET in the whole WM or at a given fiber tract was predictive of faster tau-PET accumulation in Braak stages or the connected grey matter areas in Aß+ participants. Faster tau-PET accumulation in higher cortical brain areas mediated the association between a decrease in florbetapir-PET in the WM and a faster rate of decline in global cognition and episodic memory. APOE ε4 genotype was associated with a worse decrease in the whole WM florbetapir-PET and thus enhanced tau-PET accumulation. CONCLUSION: Myelin alterations are associated in an APOE ε4 dependent manner with faster tau progression and cognitive decline, and may therefore play a role in the etiology of AD.

Specific Association of Worry With Amyloid-ß But Not Tau in Cognitively Unimpaired Older Adults.

OBJECTIVE: Anxiety disorders and subsyndromal anxiety symptoms are highly prevalent in late life. Recent studies support that anxiety may be a neuropsychiatric symptom during preclinical Alzheimer's disease (AD) and that higher anxiety is associated with more rapid cognitive decline and progression to cognitive impairment. However, the associations of specific anxiety symptoms with AD pathologies and with co-occurring subjective and objective cognitive changes have not yet been established. METHODS: Baseline data from the A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration studies were analyzed. Older adult participants (n = 4,486) underwent assessments of anxiety (State-Trait Anxiety Inventory-6 item version [STAI]), and cerebral amyloid-beta (Aß; 18F-florbetapir) PET and a subset underwent tau (18F-flortaucipir) PET. Linear regressions estimated associations of Aß in a cortical composite and tau in the amygdala, entorhinal, and inferior temporal regions with STAI-Total and individual STAI item scores. Models adjusted for age, sex, education, marital status, depression, Apolipoprotein ε4 genotype, and subjective and objective cognition (Cognitive Function Index-participant; Preclinical Alzheimer Cognitive Composite). RESULTS: Greater Aß deposition was significantly associated with higher STAI-Worry, adjusting for all covariates, but not with other STAI items or STAI-Total scores. In mediation analyses, the association of Aß with STAI-Worry was partially mediated by subjective cognition with a stronger direct effect. No associations were found for regional tau deposition with STAI-Total or STAI-Worry score. CONCLUSION: Greater worry was associated with Aß but not tau deposition, independent of subjective and objective cognition in cognitively unimpaired (CU) older adults. These findings implicate worry as an early, specific behavioral marker and a possible therapeutic target in preclinical AD.

Emerging progressive atypical acute kidney injury in young children linked to ethylene glycol and diethylene glycol intoxication.

BACKGROUND: There had been a sudden surge of unusually severe and rapidly progressing acute kidney injury (AKI) incidence in Indonesia since August 2022 which did not correspond to the rise of COVID-19 incidence. We suspected this was related to ethylene glycol (EG) and diethylene glycol (DEG) intoxication. This study is aimed at describing the clinical and laboratory characteristics of AKI related to D(EG) intoxication in order to spread awareness of the possibility of intoxication in cases of rapidly progressing AKI with unknown etiology. METHODS: We conducted a cross-sectional study by collecting secondary data from the pediatric AKI registry at a national referral hospital in Jakarta, Indonesia. Data on children admitted from January to November 2022 with diagnosis of stage 3 AKI based on KDIGO criteria were included. Data regarding demographics, symptoms prior to anuria, laboratory results, infection panel including COVID-19 status, treatment administered, and mortality were analyzed. RESULTS: Sixteen patients tested positive for EG and DEG, all with history of consuming syrup-based medications. High anion gap metabolic acidosis was observed in majority of patients with mean pH 7.33 ± 0.07 and mean anion gap 15.6 ± 7.8 mEq/L. No patient had high osmolal gap (mean osmolal gap 3.46 ± 4.68). One deceased patient, who had kidney biopsy performed, showed severe damage and calcium oxalate crystals in the kidney tissue. Mortality was recorded in six patients (37.5%). CONCLUSION: Careful history taking of patient's clinical course, including consumption of syrup-based medications and laboratory findings, might aid clinicians to establish a working diagnosis of D(EG) intoxication without needing to wait for blood toxicology test. Early diagnosis and therapy are crucial to prevent substantial mortality.

Biotransformation and toxicokinetics of 2-phenoxyethanol after oral exposure in humans: a volunteer study.

2-Phenoxyethanol (PhE) is an aromatic glycol ether and is used in a variety of functions and applications, e.g., as preservative in pharmaceuticals, cosmetic and personal care products, as biocide in disinfectants (e.g. human hygiene), or as a solvent in formulations (e.g. coatings, functional fluids). Despite its widespread use, little is yet known on its biotransformation and toxicokinetics in humans. Therefore, a pilot study was conducted with oral administration of PhE (5 mg/kg body weight) to five volunteers. Blood and urine samples were collected and analyzed for PhE and three of its presumed metabolites up to 48 h post-exposure. Additionally, one volunteer was dermally exposed to PhE and monitored until 72 h post-exposure. PhE was rapidly resorbed following both oral and dermal application with tmax-levels in blood of about 1 h and 3 h, respectively. Metabolism of PhE was observed to be rather extensive with phenoxyacetic acid (PhAA) and 4-hydroxyphenoxyacetic acid (4-OH-PhAA) as the main metabolites found in blood and urine following oral and dermal exposure. PhE was excreted rapidly and efficiently via urine mostly in metabolized form: following oral exposure, on average 77% and 12% of the applied dose was excreted within 48 h as PhAA and 4-OH-PhAA, respectively. A similar metabolism pattern was observed following the single dermal exposure experiment. The obtained data on biotransformation and toxicokinetics of PhE in humans provide valuable information on this important chemical and will be highly useful for pharmacokinetic modelling and evaluation of human PhE exposure.

Metabolism of alcohol ethoxylates (AEs) in rat, hamster, and human hepatocytes and liver S9: a pilot study for metabolic stability, metabolic pathway, and metabolites identification in vitro and in silico.

Alcohol ethoxylates (AEs) are a well-known class of non-ionic surfactants widely used by the personal care market. The aim of this study was to evaluate and characterize the in vitro metabolism of AEs and identify metabolites. Five selected individual homologue AEs (C8EO4, C10EO5, C12EO4, C16EO8, and C18EO3) were incubated using human, rat, and hamster liver S9 fraction and cryopreserved hepatocytes. LC-MS was used to identify metabolites following the incubation of AEs by liver S9 and hepatocytes of all three species. All AEs were metabolized in these systems with a half-life ranging from 2 to 139 min. In general, incubation of AE with human liver S9 showed a shorter half-life compared to rat liver S9. While rat hepatocytes metabolized AEs faster than human hepatocytes. Both hydrophobic alkyl chain and hydrophilic EO head group groups of AEs were found to be target sites of metabolism. Metabolites were identified that show primary hydroxylation and dehydrogenation, followed by O-dealkylation (shortening of EO head groups) and glucuronidation. Additionally, the detection of whole EO groups indicates the cleavage of the ether bond between the alkyl chain and the EO groups as a minor metabolic pathway in the current testing system. Furthermore, no difference in metabolic patterns of each individual homologue AE investigated was observed, regardless of alkyl chain length or the number of EO groups. Moreover, there is an excellent agreement between the in vitro experimental data and the metabolite profile simulations using in silico approaches (OECD QSAR Toolbox). Altogether, these data indicate fast metabolism of all AEs with a qualitatively similar metabolic pathway with some quantitative differences observed in the metabolite profiles. These metabolic studies using different species can provide important reference values for further safety evaluation.

Design and Development of a Self-nanoemulsifying Drug Delivery System for Co-delivery of Curcumin and Naringin for Improved Wound Healing Activity in an Animal Model.

The present study endeavored to design and develop a self-nanoemulsifying drug delivery system to improve the solubility and dermatological absorption of curcumin and naringin. Curcumin and naringin-loaded self-nanoemulsifying drug delivery system formulations were developed using aqueous phase titration. Phase diagrams were used to pinpoint the self-nanoemulsifying drug delivery system zones. Tween 80 and Labrasol (surfactants), Transcutol (cosurfactant), and cinnamon oil were chosen from a large pool of surfactants, cosurfactants, and oils based on their solubility and greatest nano-emulsion region. Fourier transform infrared spectroscopy, zeta sizer, and atomic force microscopy were used to characterize the optimized formulations and test for dilution and thermodynamic stability. The optimized curcumin-naringin-self-nanoemulsifying drug delivery system demonstrated the following characteristics: polydispersity index (0.412 ± 0.03), % transmittance (97%), particle size (212.5 ± 05 nm), zeta potential (- 25.7 ± 1.80 mV) and having a smooth and spherical droplet shape, as shown by atomic force microscopy. The ability of their combined formulation to cure wounds was tested in comparison to pure curcumin suspension, empty self-nanoemulsifying drug delivery system, and standard fusidic acid. Upon topical administration, the optimized curcumin-naringin-self-nanoemulsifying drug delivery system demonstrated significant wound healing activity in comparison with a pure curcumin suspension, empty self-nanoemulsifying drug delivery system, and standard fusidic acid. Based upon this result, we assume that skin penetration was increased by using the optimized curcumin-naringin-self-nanoemulsifying drug delivery system with enhanced solubility.

Immediate dry decontamination using efficient absorbent materials is beneficial following skin exposure to low-volatile toxic chemicals.

In a chemical mass casualty incident requiring skin decontamination, dry removal using absorbent materials may be beneficial to enable immediate decontamination. The efficacy of absorbent materials has therefore been evaluated, alone or procedures including both dry and wet decontamination, following skin exposure to two low volatile toxic chemicals using an in vitro human skin penetration model. Additionally, removal using active carbon wipes was evaluated with or without the Dahlgren Decon solution. All dry decontamination procedures resulted in a significantly decreased skin penetration rate of the industrial chemical 2-butoxyethanol compared to the control without decontamination. Wet decontamination following dry absorption significantly improved the efficacy compared to dry removal alone. Dry decontamination post-exposure to the chemical warfare nerve agent VX showed no decontamination efficacy. However, dry and wet decontamination resulted in a decreased agent skin penetration rate during the last hour of the experiment. At -15°C, significantly reduced VX skin penetration rates were demonstrated for both dry decontamination alone and the dry and wet decontamination procedure. The Dahlgren Decon solution significantly reduced the amount of VX penetrating the skin, but the active carbon wipe alone did not impact the skin penetration rate. In conclusion, absorbent materials are beneficial for the removal of low-volatile chemicals from the skin, but the degree of efficacy varies between chemicals. Despite the variability, immediate dry decontamination using available absorbent materials prior to wet decontamination is recommended as a general procedure for skin decontamination. The procedure should also be prioritized in cold-weather conditions to prevent patient hypothermia.

Harmonizing florbetapir and PiB PET measurements of cortical Aß plaque burden using multiple regions-of-interest and machine learning techniques: An alternative to the Centiloid approach.

INTRODUCTION: Machine learning (ML) can optimize amyloid (Aß) comparability among positron emission tomography (PET) radiotracers. Using multi-regional florbetapir (FBP) measures and ML, we report better Pittsburgh compound-B (PiB)/FBP harmonization of mean-cortical Aß (mcAß) than Centiloid. METHODS: PiB-FBP pairs from 92 subjects in www.oasis-brains.org and 46 in www.gaain.org/centiloid-project were used as the training/testing sets. FreeSurfer-extracted FBP multi-regional Aß and actual PiB mcAß in the training set were used to train ML models generating synthetic PiB mcAß. The correlation coefficient (R) between the synthetic/actual PiB mcAß in the testing set was assessed. RESULTS: In the testing set, the synthetic/actual PiB mcAß correlation R = 0.985 (R2  = 0.970) using artificial neural network was significantly higher (p ≤ 6.6e-4) than the FBP/PiB correlation R = 0.927 (R2  = 0.860), improving total variance percentage (R2 ) from 86% to 97%. Other ML models such as partial least square, ensemble, and relevance vector regressions also improved R (p = 9.677e-05 /0.045/0.0017). DISCUSSION: ML improved mcAß comparability. Additional studies are needed for the generalizability to other amyloid tracers, and to tau PET. Highlights Centiloid is a calibration of the amyloid scale, not harmonization. Centiloid unifies the amyloid scale without improving inter-tracer association (R2 ). Machine learning (ML) can harmonize the amyloid scale by improving R2 . ML harmonization maps multi-regional florbetapir SUVRs to PiB mean-cortical SUVR. Artificial neural network ML increases Centiloid R2 from 86% to 97%.

Neurometabolic topography and associations with cognition in Alzheimer's disease: A whole-brain high-resolution 3D MRSI study.

INTRODUCTION: Altered neurometabolism, detectable via proton magnetic resonance spectroscopic imaging (1H-MRSI), is spatially heterogeneous and underpins cognitive impairments in Alzheimer's disease (AD). However, the spatial relationships between neurometabolic topography and cognitive impairment in AD remain unexplored due to technical limitations. METHODS: We used a novel whole-brain high-resolution 1H-MRSI technique, with simultaneously acquired 18F-florbetapir positron emission tomography (PET) imaging, to investigate the relationship between neurometabolic topography and cognitive functions in 117 participants, including 22 prodromal AD, 51 AD dementia, and 44 controls. RESULTS: Prodromal AD and AD dementia patients exhibited spatially distinct reductions in N-acetylaspartate, and increases in myo-inositol. Reduced N-acetylaspartate and increased myo-inositol were associated with worse global cognitive performance, and N-acetylaspartate correlated with five specific cognitive scores. Neurometabolic topography provides biological insights into diverse cognitive dysfunctions. DISCUSSION: Whole-brain high-resolution 1H-MRSI revealed spatially distinct neurometabolic topographies associated with cognitive decline in AD, suggesting potential for noninvasive brain metabolic imaging to track AD progression. HIGHLIGHTS: Whole-brain high-resolution 1H-MRSI unveils neurometabolic topography in AD. Spatially distinct reductions in NAA, and increases in mI, are demonstrated. NAA and mI topography correlates with global cognitive performance. NAA topography correlates with specific cognitive performance.

Revolutionizing treatment for topical fungal infections: evaluating penetration-enhancer-containing vesicles as a fluconazole delivery system: Ex-vivo and in-vivo dermal testing.

Fungal infections pose a significant challenge in numerous developing nations and worldwide, necessitating urgent solutions. Oral administration of antifungal medications often leads to severe adverse reactions. Hence, employing topical delivery systems is preferred to ensure efficient dermal delivery of antifungal agents while minimizing side effects. Furthermore, the incorporation of penetration enhancers into nanocarriers loaded with antifungal agents has demonstrated enhanced efficacy in combating mycotic infections. Consequently, ultra-deformable penetration enhancer-containing vesicles (PEVs) were developed to explore this promising approach. In this study, Labrasol® and Transcutol® were used as penetration enhancers in formulating ultra-deformable PEVs containing the antifungal agent Fluconazole (FCZ). The PEVs underwent comprehensive characterization, including measurements of particle size (PS), charge, and entrapment efficiency (EE%). The results revealed that the size of tested PEVs ranged from 100 to 762 nm. All particles exhibited a negative charge, with a minimum zeta potential (ZP) of -38.26 mV, and an intermediate entrapment efficiency (EE%) that reached approximately 40%w/w. Ex-vivo studies demonstrated the ability of PEVs to deliver FCZ to the dermis while minimizing transdermal delivery. The selected formula was tested in-vivo using candidiasis-induced rat model and showed a superiority in its antifungal effect against Candida Albicans compared to the drug control. Stability studies were executed for the selected formula, and revealed good stability shown by the insignificant change in the PS, ZP& EE% over a six-month period.

Self-Nanoemulsion Intrigues the Gold Phytopharmaceutical Chrysin: In Vitro Assessment and Intrinsic Analgesic Effect.

Chrysin is a natural flavonoid with a wide range of bioactivities. Only a few investigations have assessed the analgesic activity of chrysin. The lipophilicity of chrysin reduces its aqueous solubility and bioavailability. Hence, self-nanoemulsifying drug delivery systems (SNEDDS) were designed to overcome this problem. Kollisolv GTA, Tween 80, and Transcutol HP were selected as oil, surfactant, and cosurfactant, respectively. SNEDDS A, B, and C were prepared, loaded with chrysin (0.1%w/w), and extensively evaluated. The optimized formula (B) encompasses 25% Kollisolv GTA, 18.75% Tween 80, and 56.25% Transcutol HP was further assessed. TEM, in vitro release, and biocompatibility towards the normal oral epithelial cell line (OEC) were estimated. Brain targeting and acetic acid-induced writhing in a mouse model were studied. After testing several adsorbents, powdered SNEDDS B was formulated and evaluated. The surfactant/cosurfactant (S/CoS) ratio of 1:3 w/w was appropriate for the preparation of SNEDDS. Formula B exhibited instant self-emulsification, spherical nanoscaled droplets of 155.4 ± 32.02 nm, and a zeta potential of - 12.5 ± 3.40 mV. The in vitro release proved the superiority of formula B over chrysin suspension (56.16 ± 10.23 and 9.26 ± 1.67%, respectively). The biocompatibility of formula B towards OEC was duplicated (5.69 ± 0.03 µg/mL). The nociceptive pain was mitigated by formula B more efficiently than chrysin suspension as the writhing numbers reduced from 8.33 ± 0.96 to 0 after 60 min of oral administration. Aerosil R972 was selected as an adsorbent, and its chemical compatibility was confirmed. In conclusion, our findings prove the therapeutic efficacy of chrysin self-nanoemulsion as a potential targeting platform to combat pain.

Skin Penetration and Permeation Properties of Transcutol® in Complex Formulations.

Percutaneous delivery is explored as alternative pathway for addressing the drawbacks associated with the oral administration of otherwise efficacious drugs. Short of breaching the skin by physical means, the preference goes to formulation strategies that augment passive diffusion across the skin. One such strategy lies in the use of skin penetration and permeation enhancers notably of hydroxylated solvents like propylene glycol (PG), ethanol (EtOH), and diethylene glycol monoethyl ether (Transcutol®, TRC). In a previous publication, we focused on the role of Transcutol® as enhancer in neat or diluted systems. Herein, we explore its' role in complex formulation systems, including patches, emulsions, vesicles, solid lipid nanoparticles, and micro or nanoemulsions. This review discusses enhancement mechanisms associated with hydroalcoholic solvents in general and TRC in particular, as manifested in multi-component formulation settings alongside other solvents and enhancers. The principles that govern skin penetration and permeation, notably the importance of drug diffusion due to solubilization and thermodynamic activity in the vehicle (formulation), drug solubilization and partitioning in the stratum corneum (SC), and/or solvent drag across the skin into deeper tissue for systemic absorption are discussed. Emphasized also are the interplay between the drug properties, the skin barrier function and the formulation parameters that are key to successful (trans)dermal delivery.

An Advanced Twin-Screw Granulation Technology: The use of Non-Volatile Solvents with High Solubilizing Capacity.

PURPOSE: Twin-screw wet granulation (TSWG) is a manufacturing process that offers several advantages for the processing of water-insoluble active pharmaceutical ingredients (APIs) and has been used for increasing the solubility and dissolution rates. Here we introduce a novel TSWG approach with reduced downstream processing steps by using non-volatile solvents as granulating binders. METHODS: Herein, TSWG was carried out using Transcutol a non-volatile protic solvent as a granulating binder and dissolution enhancer of ibuprofen (IBU) blends with cellulose polymer grades (Pharmacoat® 603, Affinisol™, and AQOAT®). RESULTS: The physicochemical characterisation of the produced granules showed excellent powder flow and the complete transformation of IBU into the amorphous state. Dissolution studies presented immediate release rates for all IBU formulations due to the high drug-polymer miscibility and the Transcutol solubilising capacity. CONCLUSIONS: Overall, the study demonstrated an innovative approach for the development of extruded granules by processing water-insoluble APIs with non-volatile solvents for enhanced dissolution rates at high drug loadings.

Solubility and thermodynamics properties of salicylic acid in binary mixtures 1-propanol and propylene glycol/ethylene glycol monomethyl ether at different temperatures.

The research aimed to investigate the solubility and thermodynamics of salicylic acid in two binary solvent mixtures of (1-propanol+propylene glycol) and (ethylene glycol monomethyl ether+1-propanol). The study was conducted in the temperature range of 293.2 to 313.2K. To analyze the experimental solubility data, several linear and nonlinear cosolvency models, such as the van't Hoff, Jouyban-Acree, Jouyban-Acree-van't Hoff, mixture response surface, and modified Wilson models were employed. The models' effectiveness was evaluated by comparing the mean relative deviations of the back-calculated solubility data to the experimental values. In addition, the apparent thermodynamic parameters, including Gibbs energy, enthalpy, and entropy, were calculated using the van't Hoff and Gibbs equations. Furthermore, the study measured the density values for salicylic acid-saturated mixtures and represented them mathematically through the Jouyban-Acree model.

Longitudinal head-to-head comparison of 11C-PiB and 18F-florbetapir PET in a Phase 2/3 clinical trial of anti-amyloid-ß monoclonal antibodies in dominantly inherited Alzheimer's disease.

PURPOSE: Pittsburgh Compound-B (11C-PiB) and 18F-florbetapir are amyloid-ß (Aß) positron emission tomography (PET) radiotracers that have been used as endpoints in Alzheimer's disease (AD) clinical trials to evaluate the efficacy of anti-Aß monoclonal antibodies. However, comparing drug effects between and within trials may become complicated if different Aß radiotracers were used. To study the consequences of using different Aß radiotracers to measure Aß clearance, we performed a head-to-head comparison of 11C-PiB and 18F-florbetapir in a Phase 2/3 clinical trial of anti-Aß monoclonal antibodies. METHODS: Sixty-six mutation-positive participants enrolled in the gantenerumab and placebo arms of the first Dominantly Inherited Alzheimer Network Trials Unit clinical trial (DIAN-TU-001) underwent both 11C-PiB and 18F-florbetapir PET imaging at baseline and during at least one follow-up visit. For each PET scan, regional standardized uptake value ratios (SUVRs), regional Centiloids, a global cortical SUVR, and a global cortical Centiloid value were calculated. Longitudinal changes in SUVRs and Centiloids were estimated using linear mixed models. Differences in longitudinal change between PET radiotracers and between drug arms were estimated using paired and Welch two sample t-tests, respectively. Simulated clinical trials were conducted to evaluate the consequences of some research sites using 11C-PiB while other sites use 18F-florbetapir for Aß PET imaging. RESULTS: In the placebo arm, the absolute rate of longitudinal change measured by global cortical 11C-PiB SUVRs did not differ from that of global cortical 18F-florbetapir SUVRs. In the gantenerumab arm, global cortical 11C-PiB SUVRs decreased more rapidly than global cortical 18F-florbetapir SUVRs. Drug effects were statistically significant across both Aß radiotracers. In contrast, the rates of longitudinal change measured in global cortical Centiloids did not differ between Aß radiotracers in either the placebo or gantenerumab arms, and drug effects remained statistically significant. Regional analyses largely recapitulated these global cortical analyses. Across simulated clinical trials, type I error was higher in trials where both Aß radiotracers were used versus trials where only one Aß radiotracer was used. Power was lower in trials where 18F-florbetapir was primarily used versus trials where 11C-PiB was primarily used. CONCLUSION: Gantenerumab treatment induces longitudinal changes in Aß PET, and the absolute rates of these longitudinal changes differ significantly between Aß radiotracers. These differences were not seen in the placebo arm, suggesting that Aß-clearing treatments may pose unique challenges when attempting to compare longitudinal results across different Aß radiotracers. Our results suggest converting Aß PET SUVR measurements to Centiloids (both globally and regionally) can harmonize these differences without losing sensitivity to drug effects. Nonetheless, until consensus is achieved on how to harmonize drug effects across radiotracers, and since using multiple radiotracers in the same trial may increase type I error, multisite studies should consider potential variability due to different radiotracers when interpreting Aß PET biomarker data and, if feasible, use a single radiotracer for the best results. TRIAL REGISTRATION: ClinicalTrials.gov NCT01760005. Registered 31 December 2012. Retrospectively registered.

Improving tumor/muscle and tumor/blood ratios of 99mTc-labeled nitroimidazole propylene amine oxime (PnAO) complexes with ethylene glycol linkers.

Three nitroimidazole propylene amine oxime (PnAO) derivatives with different lengths of ethylene glycol chain were synthesized and radiolabeled with 99mTc. The radiochemical purities of three 99mTc-labeled complexes, oxo[[6,6,12,12-tetramethyl-1,17-bis(2-nitro-1H-imidazol-1-yl)-3,15-dioxa-7,11-diazaheptadecane-5, 13-dione dioximato] (3-)-N,N',N'',N''']-technetium-99m (99mTc-2P2O1), oxo[[9,9,15,15-tetramethyl-1,23-bis(2-nitro-1H-imidazol-1-yl)-3,6,18,21-tetraoxa-10, 14-diazatricosane-8,16-dione dioximato] (3-)-N,N',N'',N''']-technetium-99m (99mTc-2P2O2) and oxo[[15,15,21,21-tetramethyl-1,35-bis(2-nitro-1H-imidazol-1-yl)-3,6,9,12,24,27,30,33-octaoxa-16,20-diazapentatriacontane-14,22-dione dioximato] (3-)-N,N',N'',N''']-technetium-99m (99mTc-2P2O4), were above 90%, and they were all stable both in vitro and in vivo. The hypoxia/normoxia uptake ratios of the three complexes were 2.92 ± 0.61, 2.63 ± 0.64 and 2.29 ± 0.67 in S180 cellular uptake assay (4 h). All of these complexes presented good hypoxia selectivity. The results of biodistribution studies in S180 tumor-bearing mice revealed that the tumor/muscle (T/M) ratios (7.20 ± 2.37, 7.19 ± 1.75, 5.56 ± 1.10) and tumor/blood (T/B) ratios (1.66 ± 0.34, 1.73 ± 0.25, 2.13 ± 0.19) at 4 h of three complexes were significantly higher than those of 99mTc-2P2 (3.24 ± 0.65, 0.81 ± 0.34) without the ethylene glycol chains. Among them, 99mTc-2P2O4 had the best T/B ratio. The new complexes have higher tumor/blood and tumor/muscle ratios by adding suitable length of ethylene glycol chain. It is helpful for the design and optimization of hypoxic imaging agents.

The acute vapour inhalation toxicity of 2-butoxyethanol. Points considered when designing and conducting a study in Guinea pigs and evaluating existing inhalation toxicity data on low volatility solvents.

This publication reports the outcome of an acute inhalation toxicity study with guinea pigs by nose-only exposure to the substance 2-butoxyethanol at exposures close to the maximum attainable saturation vapour concentration. We describe the methods used to ensure exposure only to saturation vapour at a level as high as could be practically achieved whilst avoiding aerosol formation. We consider the practical difficulties and implications of testing substances at or close to their saturation vapour concentration and the criteria that should be used to critically assess such studies, especially with reference to the GHS (Globally Harmonised System) for classification and labelling, where a clear differentiation between gases, vapours and dust and mists applies. Guinea pigs showed no adverse effects when exposed for 4 h to the maximum attainable concentration of pure 2-butoxyethanol vapour. If guinea pigs are regarded as the most appropriate species to assess short term toxicity to humans from exposure to 2-butoxyethanol, because they are like humans not sensitive to haemolysis of red blood cells caused by exposure to the substance, then the data from this study shows that 2-butoxyethanol presents a low acute inhalation toxicity hazard.