Mechanochemical Synthesis of New Praziquantel Cocrystals: Solid-State Characterization and Solubility.

New cocrystals of praziquantel with suberic, 3-hydroxybenzoic, benzene-1,2,4,5-tetracarboxylic, trimesic, and 5-hydroxyisophthalic acids were obtained through ball milling experiments. The optimal conditions for the milling process were chosen by changing the solvent volume and the mechanical action time. Supramolecular interactions in the new cocrystals are detailed based on single-crystal X-ray diffraction analysis, confirming the expected formation of hydrogen bonds between the praziquantel carbonyl group and the carboxyl (or hydroxyl) moieties of the coformers. Different structural characterization techniques were performed for all samples, but the praziquantel:suberic acid cocrystal includes a wider range of investigations such as thermal analysis, infrared and X-ray photoelectron spectroscopies, and SEM microscopy. The stability for up to five months was established by keeping it under extreme conditions of temperature and humidity. Solubility studies were carried out for all the new forms disclosed herein and compared with the promising cocrystals previously reported with salicylic, 4-aminosalicylic, vanillic, and oxalic acids. HPLC analyses revealed a higher solubility for most of the new cocrystal forms, as compared to pure praziquantel.

Co-Crystals of Etravirine by Mechanochemical Activation.

The co-crystals formation of etravirine with three carboxylic acids was investigated. New co-crystals of etravirine with adipic acid, benzoic acid, and 4-hydroxybenzoic acid have been synthesized by wet milling of ingredients for 120 min. The novelty of these solid forms was first evidenced by powder X-ray diffraction. Their different morphology was evidenced by SEM microscopy. Spectroscopic analyses (FT-IR, MAS-NMR, and XPS) highlighted the hydrogen bonds between etravirine and co-formers, as a result of the solid-state reaction of the ingredients by wet milling. Thermal analyses pointed out that the milling process caused in co-crystals a reduction in the fusion enthalpy and the melting temperature, compared to the values obtained for etravirine. These co-crystals are stable up to four months on storage under extreme conditions, excepting the co-crystal with benzoic acid which begins to transform into a polymorph of etravirine after 30 days. The UV absorption spectra of the samples tested in three simulated physiological media with pH values of 6, 6.3, and 7 have evidenced the conformation change of etravirine due to hydrogen bonds between etravirine and carboxylic acids.

Thermoluminescence properties of 30Y2O3·30P2O5·40SiO2 vitroceramics in mixed neutron-gamma fields.

Powders of the 30Y2O3·30P2O5·40SiO2 vitroceramic were irradiated with broad spectrum d+Be (Eneutron = 0-14.5 MeV) and quasi-monoenergetic d+D neutrons (Eneutron = 12.4 ± 0.22 MeV). The absorbed dose of d+Be neutrons was Dn = 2.52 ± 8% Gy with Dγ = 0.22 ± 14% Gy accompanied gamma absorbed dose. The absorbed dose of d+D neutrons was Dn = 1.43 ± 8% Gy with Dγ = 0.21 ± 14% Gy gamma absorbed dose. The thermoluminescence (TL) induced in the vitroceramics was studied. Both the gamma and neutron component contributed to the TL signals. The relative neutron sensitivities were [(TLn/TLγ)/(Dn/Dγ)]d+Be = 0.04 ± 60% and [(TLn/TLγ)/(Dn/Dγ)]d+D = 0.11 ± 43%.

Treating patients with Dynamic Wave Arc: First clinical experience.

BACKGROUND AND PURPOSE: Dynamic Wave Arc (DWA) is a system-specific noncoplanar arc technique that combines synchronized gantry-ring rotation with D-MLC optimization. This paper presents the clinical workflow, quality assurance program, and reports the geometric and dosimetric results of the first patient cohort treated with DWA. METHODS AND MATERIALS: The RayStation TPS was clinically integrated on the Vero SBRT platform for DWA treatments. The first 15 patients treated with DWA represent a broad range of treatment sites: breast boost, prostate, lung SBRT and bone metastases, which allowed us to explore the potentials and assess the limitations of the current DWA site-specific template solution. For the DWA verification a variety of QA equipment was used, from 3D diode array to an anthropomorphic end-to-end phantom. The geometric accuracy of each arc was verified with an independent orthogonal fluoroscopy method. RESULTS: The average beam-on delivery time was 3min, ranging from 1.22min to 8.82min. All patient QAs passed our institutional clinical criteria of gamma index. For both EBT3 film and Delta4 measurements, DWA planned versus delivered dose distributions presented an average agreement above 97%. An overall mean gantry-ring geometric deviation of -0.03°±0.46° and 0.18°±0.26° was obtained, respectively. CONCLUSION: For the first time, DWA has been translated into the clinic and used to treat various treatment sides. DWA has been successfully added to the noncoplanar rotational IMRT techniques arsenal, allowing additional flexibility in dose shaping while preserving dosimetrically robust delivery.

Initial characterization, dosimetric benchmark and performance validation of Dynamic Wave Arc.

BACKGROUND: Dynamic Wave Arc (DWA) is a clinical approach designed to maximize the versatility of Vero SBRT system by synchronizing the gantry-ring noncoplanar movement with D-MLC optimization. The purpose of this study was to verify the delivery accuracy of DWA approach and to evaluate the potential dosimetric benefits. METHODS: DWA is an extended form of VMAT with a continuous varying ring position. The main difference in the optimization modules of VMAT and DWA is during the angular spacing, where the DWA algorithm does not consider the gantry spacing, but only the Euclidian norm of the ring and gantry angle. A preclinical version of RayStation v4.6 (RaySearch Laboratories, Sweden) was used to create patient specific wave arc trajectories for 31 patients with various anatomical tumor regions (prostate, oligometatstatic cases, centrally-located non-small cell lung cancer (NSCLC) and locally advanced pancreatic cancer-LAPC). DWA was benchmarked against the current clinical approaches and coplanar VMAT. Each plan was evaluated with regards to dose distribution, modulation complexity (MCS), monitor units and treatment time efficiency. The delivery accuracy was evaluated using a 2D diode array that takes in consideration the multi-dimensionality of DWA during dose reconstruction. RESULTS: In centrally-located NSCLC cases, DWA improved the low dose spillage with 20 %, while the target coverage was increased with 17 % compared to 3D CRT. The structures that significantly benefited from using DWA were proximal bronchus and esophagus, with the maximal dose being reduced by 17 % and 24 %, respectively. For prostate and LAPC, neither technique seemed clearly superior to the other; however, DWA reduced with more than 65 % of the delivery time over IMRT. A steeper dose gradient outside the target was observed for all treatment sites (p < 0.01) with DWA. Except the oligometastatic cases, where the DWA-MCSs indicate a higher modulation, both DWA and VMAT modalities provide plans of similar complexity. The average É£ (3 % /3 mm) passing rate for DWA plans was 99.2 ± 1 % (range from 96.8 to 100 %). CONCLUSIONS: DWA proven to be a fully functional treatment technique, allowing additional flexibility in dose shaping, while preserving dosimetrically robust delivery and treatment times comparable with coplanar VMAT.

Geometric Verification of Dynamic Wave Arc Delivery With the Vero System Using Orthogonal X-ray Fluoroscopic Imaging.

PURPOSE: The purpose of this study was to define an independent verification method based on on-board orthogonal fluoroscopy to determine the geometric accuracy of synchronized gantry-ring (G/R) rotations during dynamic wave arc (DWA) delivery available on the Vero system. METHODS AND MATERIALS: A verification method for DWA was developed to calculate O-ring-gantry (G/R) positional information from ball-bearing positions retrieved from fluoroscopic images of a cubic phantom acquired during DWA delivery. Different noncoplanar trajectories were generated in order to investigate the influence of path complexity on delivery accuracy. The G/R positions detected from the fluoroscopy images (DetPositions) were benchmarked against the G/R angulations retrieved from the control points (CP) of the DWA RT plan and the DWA log files recorded by the treatment console during DWA delivery (LogActed). The G/R rotational accuracy was quantified as the mean absolute deviation ± standard deviation. The maximum G/R absolute deviation was calculated as the maximum 3-dimensional distance between the CP and the closest DetPositions. RESULTS: In the CP versus DetPositions comparison, an overall mean G/R deviation of 0.13°/0.16° ± 0.16°/0.16° was obtained, with a maximum G/R deviation of 0.6°/0.2°. For the LogActed versus DetPositions evaluation, the overall mean deviation was 0.08°/0.15° ± 0.10°/0.10° with a maximum G/R of 0.3°/0.4°. The largest decoupled deviations registered for gantry and ring were 0.6° and 0.4° respectively. No directional dependence was observed between clockwise and counterclockwise rotations. Doubling the dose resulted in a double number of detected points around each CP, and an angular deviation reduction in all cases. CONCLUSIONS: An independent geometric quality assurance approach was developed for DWA delivery verification and was successfully applied on diverse trajectories. Results showed that the Vero system is capable of following complex G/R trajectories with maximum deviations during DWA below 0.6°.

Thermoluminescence investigations on xY2O3 (60-x)P2O5·40SiO2 vitroceramics.

Thermoluminescence properties of xY2O3·(60-x)P2O5·40SiO2 vitroceramic compounds doped with xY2O3 at various concentrations (0≤x≤30mol%) were studied. Compounds with reduced Y2O3 concentration showed unsatisfactory dosimetric properties, while the vitroceramics composed of 20Y2O3·40P2O5·40SiO2 and 30Y2O3·30P2O5·40SiO2 exhibited bright signals, linear dose response and minimum detectable doses of 16mGy and 4mGy, respectively. Moreover, 30mol% Y2O3 doped vitroceramic exhibited good repeatability, acceptable batch homogeneity and poor fading signal, features that are recommending this material for dosimetry purposes.

Bioactivity evolution of the surface functionalized bioactive glasses.

The formation of a calcium phosphate layer on the surface of the SiO2 -CaO-P2 O5 glasses after immersion in simulated body fluid (SBF) generally demonstrates the bioactivity of these materials. Grafting of the surface by chemical bonding can minimize the structural changes in protein adsorbed on the surface. Therefore, in this study our interest was to evaluate the bioactivity and blood biocompatibility of the SiO2 -CaO-P2 O5 glasses after their surface modification by functionalization with aminopropyl-triethoxysilane and/or by fibrinogen. It is shown that the fibrinogen adsorbed on the glass surfaces induces a growing of the apatite-like layer. It is also evidenced that the protein content from SBF influences the growth of the apatite-like layer. Furthermore, the good blood compatibility of the materials after fibrinogen and bovine serum albumin adsorption is proved from the assessment of the ß-sheet-ß-turn ratio.

Spark plasma sintered Al2O3-YSZ-TiO2 composites: processing, characterization and in vivo evaluation.

Al2O3 and Al2O3-YSZ composites containing 3 and 5 wt.% TiO2 were prepared by spark plasma sintering at temperatures of 1350-1400°C for 300s under a pressure of 40 MPa. The grain growth of alumina was suppressed by the addition of YSZ. Al2O3-YSZ composites showed higher hardness than monolithic Al2O3. There was not a considerable difference in hardness values for Al2O3-YSZ composites containing 10 and 20 vol.% YSZ and the addition of TiO2 decreased the hardness of the composites. The fracture toughness of Al2O3 increased from 2.8 MPa·m(1/2) to 4.3 MPa·m(1/2) with the addition of 10vol.% YSZ, further addition resulted in higher fracture toughness values. The fracture toughness values were increased with TiO2 addition and the highest value of fracture toughness, 5.3 MPa·m(1/2), was achieved with the addition of 20 vol.% YSZ and 5 wt.% TiO2. Preliminary in vivo tests demonstrated the biocompatibility and osseointegration of the composites after 6 week post-implantation in femur of Wistar rats.

Feasibility of using the Vero SBRT system for intracranial SRS.

The Vero SBRT system was benchmarked in a planning study against the Novalis SRS system for quality of delivered dose distributions to intracranial lesions and assessing the Vero system's capacity for SRS. A total of 27 patients with one brain lesion treated on the Novalis system, with 3 mm leaf width MLC and C-arm gantry, were replanned for Vero, with a 5 mm leaf width MLC mounted on an O-ring gantry allowing rotations around both the horizontal and vertical axis. The Novalis dynamic conformal arc (DCA) planning included vertex arcs, using 90° couch rotation. These vertex arcs cannot be reproduced with Vero due to the mechanical limitations of the O-ring gantry. Alternative class solutions were investigated for the Vero. Additionally, to distinguish between the effect of MLC leaf width and different beam arrangements on dose distributions, the Vero class solutions were also applied for Novalis. In addition, the added value of noncoplanar IMRT was investigated in this study. Quality of the achieved dose distributions was expressed in the conformity index (CI) and gradient index (GI), and compared using a paired Student's t-test with statistical significance for p-values ≤ 0.05. For lesions larger than 5 cm3, no statistical significant difference in conformity was observed between Vero and Novalis, but for smaller lesions, the dose distributions showed a significantly better conformity for the Novalis (ΔCI = 13.74%, p = 0.0002) mainly due to the smaller MLC leaf width. Using IMRT on Vero reduces this conformity difference to nonsignificant levels. The cutoff for achieving a GI around 3, characterizing a sharp dose falloff outside the target volume was 4 cm3 for Novalis and 7 cm3 for Vero using DCA technique. Using noncoplanar IMRT, this threshold was reduced to 3 cm3 for the Vero system. The smaller MLC and the presence of the vertex fields allow the Novalis system to better conform the dose around the lesion and to obtain steeper dose falloff outside the lesion. Comparable dosimetric characteristics can be achieved with Vero for lesions larger than 3 cm3 and using IMRT.

Freeze-dried and spray-dried zinc-containing silica microparticles entrapping insulin.

New approaches for oral administration of insulin are strongly related to novel insulin carriers. The aim of this study was the insulin microencapsulation in a new zinc-silica matrix for drug protection and controlled release. Zinc-silica microparticles loaded with insulin were obtained by sol-gel process via spray drying and freeze drying methods. Inorganic silica matrix isolates and constrains the movement of the biomolecules preventing their aggregation and denaturation, while the zinc oxide improves the system stability. Moreover, formation of insulin hexamers in the presence of zinc ions leads to an increased stability of the insulin three-dimensional structure during preparation, storage and release. The particles were characterized with respect to average size, specific surface area, porosity and morphology. In vitro behavior of insulin-loaded particles together with protein structural conformation was also evaluated. The release profile can be adapted by synthesis route of microparticles.

Addressing the optimal silver content in bioactive glass systems in terms of BSA adsorption.

Bioactive glasses doped with silver are aimed to minimize the risk of microbial contamination; therefore, the influence of silver on the bioactive properties is intensely investigated. However, information related to the role played by silver, when added to the bioactive glass composition, on biocompatibility properties is scarce. This aspect is essential as long as the silver content can influence blood protein adsorption onto the surface of the glass, thus affecting the material's biocompatibility. Therefore, from the perspective of the biocompatibility standpoint, the finding of an optimal silver content in a bioactive glass is an extremely important issue. In this study, silver-doped bioactive glasses were prepared by a melt-derived technique, which eliminates the pores' influence in the protein adsorption process. The obtained glasses were characterized by X-ray diffraction, UV-vis, X-ray photoelectron (XPS) and Fourier transform infrared (FT-IR) spectroscopy; afterwards, they were investigated in terms of protein adsorption. Both UV-vis and XPS spectroscopy revealed the presence of Ag+ ions in all silver containing samples. By increasing the silver content, metallic Ag0 appears, the highest amount being observed for the sample with 1 mol% AgO2. Electron paramagnetic resonance measurements evidenced that the amount of spin-labeled serum albumin attached to the surface increases with the silver content. The results obtained by analyzing the information derived from atomic force microscopy and FT-IR measurements indicate that the occurrence of metallic Ag0 in the samples' structure influences the secondary structure of the adsorbed protein. Based on the results derived from the protein response upon interaction with the investigated glass calcium-phosphate based system, the optimal silver oxide concentration was determined for which the secondary structure of the adsorbed protein is similar with that of the free one. This concentration was found to be 0.5 mol%.

Histological findings in the Wistar rat cornea following UVB irradiation.

The acute clinical effect of UVR on the eye is photokeratitis, which is an inflammatory state that might be regarded as the sunburn of the eye. In this study, we used a rat model to assess the histological injuries induced in the intact rat cornea following its exposure to UVB radiation. A total of 15 two-months-old female Wistar rats were purchased from the Animal Facility of "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania. The rats were fed ad libitum and kept under standard conditions with a 12 hours light/dark cycle. The rats were randomly divided into five groups, including control group (no UVB exposure), group II (a single exposure to a dose of 45 mJ UVB/cm(2) for 47 seconds), group III (a single exposure to 90 mJ UVB/cm(2) for one minute and 57 seconds), group IV (a single exposure to 180 mJ UVB/cm(2) for three minutes and 57 seconds), and group V (a single exposure to 360 mJ UVB/cm(2)² for five minutes and 26 seconds). After 24 hours of recovery, the rats were sacrificed by cervical dislocation. The rat eyes were extracted, harvested and fixed in 10% buffered formalin. The eye samples were then processed through paraffin technique for further histological examination. We found that, following the UVB exposure, the cornea showed significant inflammatory responses (infiltration of polymorphonuclear leukocytes), hemorrhage and gross damages such as superficial and deep ulcerous keratitis and epithelial exfoliation. The severity of these findings was associated with the increase of UVB radiation intensity and exposure period.

The photochemical reaction cycle of retinal reconstituted bacteriorhodopsin.

The function of three types of bacteriorhodopsins was compared: the wild-type, the bleached and retinal reconstituted and retinal deficient bacteriorhodopsin after retinal addition. The apparent pK(a) of the proton acceptor group for the bleached BR and retinal deficient BR shifted toward higher pH values compared to the wild-type BR. Fitting the photocycle model to the absorption kinetic signals for all three proteins showed the existence of the same intermediates, but the time-dependent concentration of the intermediates was different. Although measurements were made at pH 7, the absorption kinetics and photoelectric signals in both retinal reconstituted samples acted as wild-type bacteriorhodopsin at significantly higher pH. Below pH 3 the retinal deficient and reconstituted sample bleached. These results suggested that the added retinal was not able to rebind in the same position in the protein as in native bacteriorhodopsin. This points out that care should be taken, when bleached bacteriorhodopsin is reconstituted with different retinal analogs.

The influence of the halide ions on the photochemical reaction cycle of pharaonis halorhodopsin.

Sodium salt of chloride, bromide and iodide were used to elucidate the effect of the size of the anion on the binding to pharaonis halorhodopsin and its transport during the photocycle of this retinal protein. Spectroscopic titration revealed an apparent strong binding constant of 2 mM for chloride, 0.23 mM for bromide and 5 mM for iodide. In the case of iodide a second, week binding constant of about 10 M could be estimated. This second binding constant was similar to that observed earlier for nitrate. By changing the halide ions, only the transitions in the second half of the photocycle were affected, which contained intermediates N, O, and HR'. The O to HR' transition becomes faster with increasing ion volume, meaning that the ion uptake is accelerated. This effect shows a direct correlation with the ion radius. With increasing ion concentration the N-O-HR' equilibrium changed in such a way that the accumulated O tended to decrease. This tendency was overruled in iodide, by the appearance of the second binding constant. The increasing iodide concentration, up to 100mM decreases the accumulation of the intermediate O, due to kinetic reasons, but at higher ion concentration the amount of O increases, although its decay becomes faster. This effect correlates with the appearance of the second iodide bound to the protein.