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Novel hybrid composites with polyamide 6 (PA6) matrices and binary metal/carbon allotrope reinforcements are synthesized using a two‐stage method. First, activated anionic ring‐opening polymerization (AAROP) of ε‐caprolactam is performed in suspension, in the presence of the desired amounts of different metal particles (Al, Cu, Fe, or Mg) and carbon allotropes (multi‐walled carbon nanotubes or carbon black). The AAROP produces dual core PA6 microcapsules (PAMCs) with controlled shape and size and a total metal/carbon load of up to 17 wt% in respect to the PA6 matrix. Second, these PAMC are compression molded to composite plates. The morphology and the crystalline structure of the different PAMC and their respective composites are studied by electron microscopy and thermal methods. The well‐dispersed binary metal–carbon allotrope fillers in the PA6 matrix increase its electrical conductivity by seven to nine orders of magnitude. Simultaneously, up to ca. 60% increase of the Young's modulus of the hybrids is registered. An almost total disappearance of the PA6 resonance lines in some of the binary hybrids is registered by solid state NMR spectroscopy. The tunable combination of enhanced electrical conductivity and screening of radiofrequencies can be potentially useful in electromagnetic interference shielding or radar absorbing materials., The authors gratefully acknowledge the financial support of the project TSSiPRO NORTE-01-0145-FEDER-000015, supported by the regional operation program NORTE2020, under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund, as well as funding from FCT – Portuguese Foundation for Science and Technology within the strategic projects UID/CTM/50025/2013, LA25/2013-2014 and UID/FIS/04650/2013. FMO acknowledges also the PhD grant PD/BD/114372/2016 of FCT-Portugal (AdvaMTech – PhD Program in Advanced Materials and Processing). Finally, ZZD is thankful to FCT for the SFRH/BSAB/130271/2017 personal research grant. Finally, SLM acknowledge funding from the Basque Government Industry Department under the ELKARTEK program., info:eu-repo/semantics/publishedVersion

Neat and hybrid poly(2-pyrrolidone), i.e. polyamide 4 (PA4) microparticles containing magnetic or conductive metal, metal oxide, or carbon nanotube fillers were prepared via environmentally-friendly solventless activated ring-opening polymerization of 2-pyrrolidone at 40 C. The method produces high porosity microparticles with diameters of 5e12mm and conversion to PA4 of 56e65%. Their structure and properties were characterized by light- and electron microscopy, thermal, spectral and X-ray diffraction techniques. Two crystalline polymorphs, namelya andb PА4, were found to coexist at room temperature by X-ray diffraction. The assessment of the adsorption capacity of the PA4 hybrid microparticles toward model protein showed up to 60% efficiency only after 1 h of incubation without any preliminary activation or functionalization., The authors gratefully acknowledge the financial support of the project TSSiPRO NORTE-01-0145-FEDER-000015, supported by the regional operation program NORTE2020, under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund, as well as funding from FCT – Portuguese Foundation for Science and Technology within the strategic projects UID/CTM/50025/2013 and LA25/2013–2014. ZZD is thankful to FCT for the SFRH/BSAB/130271/2017 personal research grant.

Although the possibility of using drug-loaded ophthalmic lens to promote sustained drug release has been thoroughly pursued, there are still problems to be solved associated to the different alternatives. In this work, we went back to the traditional method of drug loading by soaking in the drug solution and tried to optimize the release profiles by changing the temperature and the time of loading. Two materials commercially available under the names of CI26Y and Definitive 50 were chosen. CI26Y is used for intraocular lenses (IOLs) and Definitive 50 for soft contact lenses (SCLs). Three drugs were tested: an antibiotic, moxifloxacin, and two anti-inflammatories, diclofenac and ketorolac. Sustained drug release from CI26Y disks for, at least 15 days, was obtained for moxifloxacin and diclofenac increasing the loading temperature up to 60 °C or extending the loading time till two months. The sustained release of ketorolac was limited to about 8 days. In contrast, drug release from Definitive 50 disks could not be improved by changing the loading conditions. An attempt to interpret the impact of the loading conditions on the drug release behavior was done using solid-state NMR and differential scanning calorimetry. These studies suggested the establishment of reversible, endothermic interactions between CI26Y and the drugs, moxifloxacin and diclofenac. The loading temperature had a slight effect on the mechanical and optical properties of drug loaded CI26Y samples, which still kept adequate properties to be used as IOL materials. The in vivo efficacy of CI26Y samples, drug loaded at 60 °C for two weeks, was predicted using a simplified mathematical model to estimate the drug concentration in the aqueous humor. The estimated concentrations were found to comply with the therapeutic needs, at least, for moxifloxacin and diclofenac.

Aims To compare the levodopa/carbidopa (LC) and levodopa/benserazide (LB) pharmacokinetic profiles following repeated doses of opicapone (OPC) administered apart from levodopa. Methods Two randomized, double blind, sex-balanced, placebo-controlled studies in four groups of 12 or 18 healthy subjects each. In each group, enrolled subjects received a once-daily morning (5, 15 and 30 mg) or evening (5, 15 and 50 mg) administration of OPC or placebo for up to 28 days. On the morning of Day 11, 12 h after the OPC or placebo evening dose, or the morning of Day 21, 1 h after the OPC or placebo dose, a single dose of immediate-release 100/25 mg LC was administered. Similarly, on Day 18 morning, 12 h after the OPC or placebo evening dose, or Day 28 morning, 1 h after the OPC or placebo dose, a single dose of immediate-release 100/25 mg LB was administered. Results All OPC treatments, in relation to the placebo group, presented a higher extent of exposure (AUC) to levodopa following either LC or LB doses. A relevant but not dose-dependent increase in the levodopa AUC occurred with all OPC dose groups in relation to placebo. All active treatments significantly inhibited both peak (Emax) and extent (AUEC) of the catechol-O-methyltransferase activity in relation to placebo. The tolerability profile was favourable. Conclusion Opicapone, as once-daily oral evening regimen and/or 1 h apart from levodopa therapy, increases the bioavailability of levodopa associated with its pronounced, long-lasting and sustained catechol-O-methyltransferase inhibition. The tolerability profile was favourable and similar between OPC and placebo.

The saturation solubility of PVP:PZQ physical mixtures (PMs) and solid dispersions (SDs) prepared from ethanol (E/E) or ethanol/water (E/W) by the solvent evaporation method at 1:1, 2:1 and 3:1 ratio (w/w) was determined. The presence of PVP improves the solubility of PZQ (0.31 ± 0.01 mg/mL). A maximum of 1.29 ± 0.03 mg/mL of PZQ in solution was achieved for the 3:1 SD (E/E). The amount of PZQ in solution depends on the amount of polymer and on the preparation method. Solid-state NMR (ssNMR) and DSC were used to understand this behavior. Results show that PMs are a mixture of crystalline PZQ with the polymer, while SDs show different degrees of drug amorphization depending on the solvent used. For E/W SDs, PZQ exists in amorphous and crystalline states, with no clear correlation between the amount of crystalline PZQ and the amount of PVP. For E/E SDs, formulations with a higher percentage of PZQ are amorphous with the components miscible in domains larger than 3 nm (1H ssNMR relaxation measurements). Albeit its higher saturation solubility, the 3:1 E/E PVP:PZQ sample has a significant crystalline content, probably due to the water introduced by the polymer. High PVP content and small crystal size account for this result. Fil: Costa, Emanuel D.. Universidade de Lisboa; Portugal Fil: Priotti, Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Farmacia; Argentina Fil: Orlandi, Silvina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Farmacia; Argentina Fil: Leonardi, Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Farmacia; Argentina Fil: Lamas, Maria Celina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Farmacia; Argentina Fil: Nunes, Teresa G.. Universidade de Lisboa; Portugal Fil: Diogo, Hermínio P.. Universidade de Lisboa; Portugal Fil: Salomon, Claudio Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Farmacia; Argentina Fil: Ferreira, M. João. Universidade de Lisboa; Portugal

Helical mesoporous materials of the MCM-41 type with two different pore sizes were prepared by one-pot synthesis procedure using myristyl (C14) or cetyl (C16) trimethyl ammonium salts as templates. They were functionalized with the MoI2(CO)3 fragment, using a 2-aminopyridine glycidyloxypropyl derivative as anchoring ligand. TEM images showed the helical nature of the material channels. The new materials were tested as catalytic precursors in the epoxidation of cis-cyclooctene, styrene, cis-3-hexen-1-ol, trans-2-hexen-1-ol, geraniol, and R-(+)limonene, using tert-butylhydroperoxide as oxidant, and were in general moderately to highly selective towards the epoxide products. The catalytic activity of materials is higher than that of the corresponding homogeneous catalyst for epoxidation of cis-cyclooctene and styrene. The major achievement of these two catalysts, however, is the excellent product selectivity control, which in both cases reaches 100 % of the 2S,3R diastereomer in the epoxidation of trans-hex-2-en-1-ol. The catalysts were also found to be truly heterogeneous with no leaching, and stable through recycling experiments, despite losing some activity.

A Zn complex was stepwise intercalated in a Mg/Al layered double hydroxide material (HT) holding phenylalanine in its interlayer spacing. The material was characterized by powder X-ray diffraction, FTIR and solid state 13C NMR spectroscopy. By analogy, the [Zn(phe)(H2O)](NO3) complex bearing deprotonated phenylalanine (phe) amino acid as ligand and a labile water molecule, mimicking biological moieties, was also prepared as model and characterized by HR-MS, FTIR and 1H solution NMR spectroscopy. Both the Zn-containing HT material and model complex were tested in the catalytic epoxidation of cyclooctene, styrene and 1-octene. All tests were carried out with hydrogen peroxide (H2O2) or tert-butylhydroperoxide (TBHP), leading selectively to epoxides in most cases. Both temperature and oxygen source were found to be key factors in controlling epoxide selectivity, especially when using H2O2, where results were outstanding. Furthermore, the reported results show that the catalytic performance of this Zn system is at the same level of similar systems, holding heavier metals and less sustainable, found in the literature, while the Zn-containing HT catalyst had also the advantage of recyclability.

Succinyl-β-CD derivatives were obtained by green synthesis with degrees of substitution (DS) 1.3 and 2.9. The spray-drying technique was used to obtain albendazole (ABZ):succinyl-β-CD inclusion complexes. Phase solubility diagrams indicated that both succinyl-β-CD derivatives formed 1:1 molar ratio ABZ complexes, but the complex with DS 2.9 has a lower formation constant. The presence of stable inclusion complexes in aqueous solution was confirmed by NMR. For both complexes the aromatic moiety is encapsulated into the host cavity. In the solid-state, 13C and 15N NMR spectral differences between ABZ and ABZ included in spray-dried systems showed that strong structural changes occurred in the systems. At least two different ABZ amorphous species were identified based on DS. ABZ species were stable over more than six months based on spectral data. Finally, the influence of DS in the number and type of the inclusion complexes was elucidated. Fil: Priotti, Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina Fil: García, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina Fil: Leonardi, Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina Fil: Ferreira, M. J.. Instituto Superior Tecnico; Portugal Fil: Lamas, Maria Celina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina Fil: Nunes, T. G.. Instituto Superior Tecnico; Portugal

This study determined the effects of single doses of opicapone (OPC), a novel third-generation catechol-O-methyltransferase (COMT) inhibitor, on levodopa and 3-O-methyl-levodopa (3-OMD) pharmacokinetics (PK), COMT activity and motor fluctuations in patients with Parkinson disease (PD). Subjects received, in a double-blind manner, 25, 50, and 100 mg OPC or placebo (PLC) in 4 separate treatment periods. The washout period between doses was at least 10 days. During each period, the OPC/PLC capsules were to be coadministered with the morning dose of 100/25 mg levodopa/carbidopa (LC) or levodopa/benserazide (LB) on day 3. In relation to PLC, levodopa exposure increased 3.7%, 16.4%, and 34.8% following 25, 50, or 100 mg OPC, respectively. Maximum S-COMT inhibition (Emax ) ranged from 67.8% (25 mg OPC) to 100% (100 mg OPC). Peak and extent of S-COMT inhibition were dose-dependent. Maximum decrease in the plasma 3-OMD was observed following administration of 100 mg OPC. Opicapone administered concomitantly with standard-release 100/25 mg LC or LB improved motor performance. Treatments were generally well tolerated and safe. It was concluded that OPC is a new COMT inhibitor that significantly decreased COMT activity and increased systemic exposure to levodopa in PD patients with motor fluctuations.

Complexation of benznidazole (BZL), a drug of choice for the treatment of Chagas'neglected disease, with cyclodextrin (CD) derivatives was analyzed by solid-state NMR. (13)C cross polarization/magic angle spinning spectra were recorded from BZL and from BZL:β-CD, BZL:methyl β-CD and BZL:hydroxypropyl β-CD complexes, which were obtained by the solvent evaporation technique. No significant evidence was obtained on BZL inclusion complexes involving either β-CD or hydroxypropyl β-CD. Conversely, BZL:methyl β-CD displayed BZL resonances characteristic of an amorphous drug and data analysis confirmed the presence of stable BZL:methyl β-CD inclusion complexes, with benzene encapsulated into the host cavity. Further evidences on complex structure and dynamics were obtained from proton and carbon spin-lattice relaxation times in the rotating frame. These data are consistent with a common guest-host spin reservoir. The BZL interaction with methyl β-CD provided a route to stabilize amorphous BZL. Physical mixtures with identical BZL and CD compositions were also studied for comparison.

In this paper we describe the production of CaO/SiO2-based hydraulic binders formed of dendritic belite embedded in an amorphous phase. These hydraulic binders are produced by a process involving heating the raw materials with a specified CaO/SiO2 ratio to a temperature bellow the liquidus surface, followed by a two-step cooling ramp, in order to obtain during solidification a dendritic morphology of the crystalline phase. After milling the clinker obtained by this process, and by adding up to 25% of water, the paste sets showing mechanical resistances that went up to 4 times higher the values obtained for a reference round shape belite clinker. This result opens the possibility of developing a novel belite-based clinker, that may lead to a relevant reduction of the CO2 emissions, as compared to common alitic clinkers.

Helical mesoporous materials of the MCM-41 type with different pore sizes were prepared, choosing as templates myristyl (C14) or cetyl (C16) trimethyl ammonium salts, and functionalized with Mo(II) active sites based on MoI2(CO)3 (1) and MoBr(η3-C3H5)(CO)2 (2) fragments, respectively, using a pyridine-2-carbaldehyde ligand as anchor. The new materials were tested as the catalytic precursors in the epoxidation of cis-cyclooctene, styrene, R-(+)-limonene, trans-hex-2-en-1-ol, cis-3-hex-1-ol, and geraniol using tert-butylhydroperoxide (tbhp) as oxidant. All catalysts were moderately to highly selective toward the epoxide products. The materials with larger pores (C16 template) displayed a better catalytic activity, leading in general to higher conversions and selectivities, as well as faster kinetics. For instance, geraniol is epoxidized (more than 90%) with conversions above 90%. The major achievement of these catalysts, however, is the excellent product selectivity control, which is boosted when the allyl complex 1 is used, reaching 100% of the 2S, 3R species in the epoxidation of trans-hex-2-en-1-ol. The catalysts were also found to be stable through recycling experiments and truly heterogeneous with little or no leaching.

13C and 15N solid-state nuclear magnetic resonance (NMR) spectra were recorded from albendazole (ABZ) and from ABZ:β-cyclodextrin, ABZ:methyl-β-cyclodextrin, ABZ:hydroxypropyl-β-cyclodextrin and ABZ:citrate-β-cyclodextrin, which were prepared by the spray-drying technique. ABZ signals were typical of a crystalline solid for the pure drug and of an amorphous compound obtained from ABZ:cyclodextrin samples. Relevant spectral differences were correlated with chemical interaction between ABZ and cyclodextrins. The number and type of complexes revealed a strong dependence on the cyclodextrin group substituent. Solid-state NMR data were consistent with the presence of stable inclusion complexes. Fil: Ferreira, M. João G.. Universidade de Lisboa. Instituto Superior Técnico; Portugal Fil: García, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina Fil: Leonardi, Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina Fil: Salomon, Claudio Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina Fil: Lamas, Maria Celina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina Fil: Nunes, T. G.. Universidade de Lisboa. Instituto Superior Técnico; Portugal

Opicapone, a novel third-generation catechol-O-methyltransferase inhibitor for use as adjunctive therapy in levodopa-treated Parkinson's disease patients, was investigated on cardiac repolarization in healthy adult volunteers. This was a single-center, randomized, double-blind, placebo-controlled, open-label active-controlled, 4-period crossover study conducted in 64 subjects. In each period, subjects received a single oral dose of 50 mg opicapone, 800 mg opicapone, placebo, or 400 mg moxifloxacin and 24-hour 12-lead Holter monitoring was performed on day -1 (baseline) and after each single dose. After a single oral administrations of 50 and 800 mg opicapone, opicapone was the major entity in the circulation, with a median tmax of 1.5-2.0 hours. Opicapone was rapidly eliminated, with an elimination half-life of 1-2 hours. There was no clinically relevant effect of 50 and 800 mg opicapone versus placebo on cardiac depolarization or repolarization. All upper bounds of the 1-sided 95% confidence interval (CI) were below 10 milliseconds, confirming that opicapone has no QT-prolonging effect. Moxifloxacin caused an increase in the QTcI, with a lower bound of the 2-sided 95% CI always higher than 5 milliseconds, around the tmax of peak concentration, demonstrating assay sensitivity. In conclusion, administration of opicapone at therapeutic (50 mg) and supratherapeutic (800 mg) doses did not induce a clinically significant prolongation of the QTc interval.

Background Eslicarbazepine acetate (ESL) is an anticonvulsant approved as an adjunctive therapy in adults with partial-onset seizures. Objective To evaluate the efficacy, safety and tolerability of ESL in the treatment of acute mania and prevention of recurrence in bipolar disorder I. Methods Two 3-week multicentre, double-blind, randomised, placebo-controlled studies in acute mania (study BIA-2093-203: dose titrated by response, ESL 600–1800 mg or 800–2400 mg, once-daily; study BIA-2093-204: fixed doses of 600, 1200 and 1800 mg, once-daily) were followed by a recurrence prevention study consisting of a 2-week open-label period (900 mg, once-daily) continued by a double-blind, parallel-group, fixed dose (300, 900 and 1800 mg, once-daily) period for a minimum of 6 months. The primary endpoint was changed from baseline until the end of the 3-week treatment period in Young Mania Rating Scale (YMRS) in studies BIA-2093-203 and BIA-2093-204, and the proportion of patients showing no worsening according to the Clinical Global Impressions – Bipolar Version (CGI-BP) over Part II in study BIA-2093-205. Results In study BIA-2093-203 ( n =160, ITT), neither dose group was statistically different from placebo in the primary endpoint, though the ESL 800–2400 mg showed a greater reduction in YMRS score ( p =0.0523). CGI-BP score changes for mania and overall bipolar illness indicate a significant improvement in patient symptomatology for the ESL 800–2400 mg group (from preceding and worst phase) and for ESL 600–1800 mg group (from worst phase only) when compared to placebo. Study BIA-2093-204 ( n =38) results were inconclusive due to premature termination caused by recruitment difficulties. In study BIA-2093-205 ( n =85, ITT), at least 50% of patients showed no worsening in all treatment groups ( p =0.250). ESL adverse events were mostly of mild and moderate intensities and consistent with previously reported observations for ESL. Conclusion ESL treatment was not significantly different from placebo in manic patients in the primary outcome, but secondary outcomes may be suggestive of efficacy. The recurrence prevention study provides preliminary support for efficacy of ESL in patients recovered from an acute manic episode.

Objective To evaluate the efficacy and safety of adjunctive eslicarbazepine acetate (ESL) in patients with refractory partial-onset seizures. Methods This randomized, placebo-controlled, double-blind, parallel-group, phase III study was conducted at 173 centers in 19 countries, including the United States and Canada. Eligible patients were aged ≥16 years and had uncontrolled partial-onset seizures despite treatment with 1–2 antiepileptic drugs (AEDs). After an 8-week baseline period, patients were randomized to once-daily placebo (n = 226), ESL 800 mg (n = 216), or ESL 1,200 mg (n = 211). Following a 2-week titration period, patients received ESL 800 or 1,200 mg once-daily for 12 weeks. Seizure data were captured and documented using event-entry or daily entry diaries. Results Standardized seizure frequency (SSF) during the maintenance period (primary end point) was reduced with ESL 1,200 mg (p = 0.004), and there was a trend toward improvement with ESL 800 mg (p = 0.06), compared with placebo. When data for titration and maintenance periods were combined, ESL 800 mg (p = 0.001) and 1,200 mg (p

Aims Etamicastat is a reversible dopamine-β-hydroxylase inhibitor that decreases noradrenaline levels in sympathetically innervated tissues and slows down sympathetic nervous system drive. In this study, the disposition, metabolism and excretion of etamicastat were evaluated following [14C]-etamicastat dosing. Methods Healthy Caucasian males (n = 4) were enrolled in this single-dose, open-label study. Subjects were administered 600 mg of unlabelled etamicastat and 98 µCi weighing 0.623 mg [14C]-etamicastat. Blood samples, urine and faeces were collected to characterize the disposition, excretion and metabolites of etamicastat. Results Eleven days after administration, 94.0% of the administered radioactivity had been excreted; 33.3 and 58.5% of the administered dose was found in the faeces and urine, respectively. Renal excretion of unchanged etamicastat and its N-acetylated metabolite (BIA 5-961) accounted for 20.0 and 10.7% of the dose, respectively. Etamicastat and BIA 5-961 accounted for most of the circulating radioactivity, with a BIA 5-961/etamicastat ratio that was highly variable both for the maximal plasma concentration (19.68–226.28%) and for the area under the plasma concentration–time curve from time zero to the last sampling time at which the concentration was above the limit of quantification (15.82– 281.71%). Alongside N-acetylation, metabolism of etamicastat also occurs through oxidative deamination of the aminoethyl moiety, alkyl oxidation, desulfation and glucuronidation. Conclusions Etamicastat is rapidly absorbed, primarily excreted via urine, and its biotransformation occurs mainly via N-acetylation (N-acetyltransferase type 2), although glucuronidation, oxidation, oxidative deamination and desulfation also take place.

Statins have been widely used as cholesterol-lowering agents. However, low aqueous solubility of crystalline statins and, consequently, reduced biovailability require seeking for alternative forms and formulations to ensure an accurate therapeutic window. The objective of the present study was to evaluate the stability of amorphous simvastatin by probing molecular dynamics using two nondestructive techniques: solid-state NMR and dielectric relaxation spectroscopy. Glassy simvastatin was obtained by the melt quench technique. (13)C cross-polarization/magic-angle-spinning (CP/MAS) NMR spectra and (1)H MAS NMR spectra were obtained from 293 K up to 333 K (Tg ≈ 302 K). The (13)C spin-lattice relaxation times in the rotating frame, T1ρ, were measured as a function of temperature, and the correlation time and activation energy data obtained for local motions in different frequency scales revealed strong dynamic heterogeneity, which appears to be essential for the stability of the amorphous form of simvastatin. In addition, the (1)H MAS measurements presented evidence for mobility of the hydrogen atoms in hydroxyl groups which was assigned to noncooperative secondary relaxations. The complex dielectric permittivity of simvastatin was monitored in isochronal mode at five frequencies (from 0.1 to 1000 kHz), by carrying out a heating/cooling cycle allowing to obtain simvastatin in the supercooled and glassy states. The results showed that no dipolar moment was lost due to immobilization, thus confirming that no crystallization had taken place. Complementarily, the present study focused on the thermal stability of simvastatin using thermogravimetric analysis while the thermal events were followed up by differential scanning calorimetry and dielectric relaxation spectroscopy. Overall, the results confirm that the simvastatin in the glass form reveals a potential use in the solid phase formulation on the pharmaceutical industry.

The new complexes [MoI 2 (CO) 3 ( L 1 )] ( 1 ) and [MoI 2 (CO) 3 ( L 2 )] ( 2 ) were prepared from reaction of [MoI 2 (CO) 3 (NCMe) 2 ] with the ligands 2-(2′-hydroxyphenyl)imidazoline ( L 1 ), and 2-(2′-hydroxyphenyl)benzimidazole ( L 2 ). These complexes were immobilized in MCM-41 and in silica gel, by grafting (3-chloropropyl)trimethylsilane on the surface of the materials and allowing it to react with [MoI 2 (CO) 3 ( L 1 )] ( 1 ) or [MoI 2 (CO) 3 ( L 2 )] ( 2 ). All the molybdenum derivatives were characterized by NMR and FTIR spectroscopies, which showed coordination of L 1 and L 2 in neutral form. The structure of the MCM materials was analyzed by powder X-ray diffraction and nitrogen adsorption isotherms. The catalytic activity of the complexes and materials was tested in several substrates ( cis -cyclooctene, styrene, 1-octene, R -(+)limonene, geraniol, cis -hex-3-en-1-ol and trans -hex-2-en-1-ol), using tert -butylhydroperoxide (TBHP) as oxidant. Complexes 1 and 2 were in general the more active catalysts and 100% selective towards the epoxide of cis -cyclooctene. Complex 1 immobilized in silica ( Si-Pr-1 ) was the best material, showing higher conversion than 1 in the oxidation of R -(+)limonene, with comparable selectivity towards the ring epoxide.

Helical mesoporous materials of the MCM-41 type are important materials that can be prepared by onepot synthesis procedures with a co-surfactant. A control of the characteristics at a local level is of the most important in the view of the applications of such materials. However, there are not many studies relating such features with synthetic approaches. In this work, we prepared both helical and regular channel materials from Si-based MCM-41 type. Afterward, a bpy derivative was used as ligand to coordinate MoII/VI. The complexes and the new materials were tested as the catalytic precursors in the epoxidation of cis-cyclooctene, styrene, 1-octene, R-(+)-limonene and trans-hex-2-en-1-ol, using tert-butylhydroperoxide (TBHP) as oxidant. Although almost all the catalysts were 100% selective toward the epoxide, the conversions were in general good. The major achievement of these catalysts is an outstanding stereocontrol of the reaction products. In addition, these catalysts were found to be very effective under several circumstances. This is certainly an important contribution for such concept and may render such materials further applications where chiral recognition is important.

Aims The aim of this study was to assess the tolerability, pharmacokinetics and inhibitory effect on erythrocyte soluble catechol-O-methyltransferase (S-COMT) activity following repeated doses of opicapone. Methods This randomized, placebo-controlled, double-blind study enrolled healthy male subjects who received either once daily placebo or opicapone 5, 10, 20 or 30 mg for 8 days. Results Opicapone was well tolerated. Its systemic exposure increased in an approximately dose-proportional manner with an apparent terminal half-life of 1.0 to 1.4 h. Sulphation was the main metabolic pathway. Opicapone metabolites recovered in urine accounted for less than 3% of the amount of opicapone administered suggesting that bile is likely the main route of excretion. Maximum S-COMT inhibition (Emax) ranged from 69.9% to 98.0% following the last dose of opicapone. The opicapone-induced S-COMT inhibition showed a half-life in excess of 100 h, which was dose-independent and much longer than plasma drug exposure. Such a half-life translates into a putative underlying rate constant that is comparable with the estimated dissociation rate constant of the COMT–opicapone complex. Conclusion Despite its short elimination half-life, opicapone markedly and sustainably inhibited erythrocyte S-COMT activity making it suitable for a once daily regimen.

Summary Objective To investigate the effect of eslicarbazepine acetate (ESL) on the pharmacokinetics of simvastatin (SMV), a known CYP3A4 substrate, in healthy subjects. Methods Single centre, two-way cross-over, randomized, open-label study in 24 healthy volunteers. The volunteers received an oral single-dose of SMV 80mg on two occasions (once administered alone and once after treatment with an oral once-daily dose of 800mg of ESL for 14 days), separated by a wash-out period of 3 weeks or more. The analysis of variance (ANOVA) was used to test for differences between Test (SMV under co-administration with ESL) and Reference (SMV administered alone) treatments for AUC 0−∞ , AUC 0−t and C max of SMV and SMV-acid. Results Mean systemic exposure (AUC) measurements for both SMV and SMV-β-hydroxyacid (SMV-acid) were up to 54% lower during ESL use. The Test / Reference geometric mean ratios (GMR) (90% CI) for the AUC 0−t of SMV and SMV-acid were 46% (38%; 55%) and 49% (44%; 55%), respectively. Mean peak concentrations ( C max ) of both SMV and SMV-acid were reduced by 60% and 41%, respectively, when SMV was administered with ESL. Conclusions A significant effect of repeated ESL administration on the pharmacokinetics of SMV and its metabolite SMV-acid was observed. Therefore, dose adjustment of SMV may be required when used concomitantly with ESL, if a clinically significant change in lipids is noted.

Summary Objective To investigate the effect of once-daily (QD) eslicarbazepine acetate (ESL) 800mg and 1200mg administration on pharmacokinetics of a combined ethinylestradiol/levonorgestrel oral contraceptive (OC) in women of childbearing potential. Methods Two two-way, crossover, two-period, randomized, open-label studies were performed in 20 healthy female subjects, each. In one period (ESL+OC period), subjects received ESL 800mg QD in one study and ESL 1200mg QD in the other study, for 15 days; concomitantly with the Day 14 ESL dose, an oral single dose of 30μg ethinylestradiol and 150μg levonorgestrel was administered. In the other period (OC alone), a single dose of 30μg ethinylestradiol and 150μg levonorgestrel was administered. Three weeks or more separated the periods. An analysis of variance (ANOVA) was used to test for differences between pharmacokinetic parameters of 30μg ethinylestradiol and 150μg levonorgestrel following ESL+OC and OC alone, and 90% confidence intervals (90%CI) for the ESL+OC/OC alone geometric mean ratio (GMR) were calculated. Results ESL significantly decreased the systemic exposure to both ethinylestradiol and levonorgestrel. GMR (90%CI) for AUC 0–24 of ethinylestradiol were 68% (64%; 71%) following 1200mg ESL and 75% (71%; 79%) following 800mg ESL. GMR (90%CI) for AUC 0–24 of levonorgestrel were 76% (68%; 86%) following 1200mg ESL and 89% (82%; 97%) following 800mg ESL. Conclusions A clinically relevant dose-dependent effect of ESL administration on the pharmacokinetics of ethinylestradiol and levonorgestrel was observed. Therefore, to avoid inadvertent pregnancy, women of childbearing potential should use other adequate methods of contraception during treatment with ESL, and, in case ESL treatment is discontinued, until CYP3A4 activity returns to normal.

Summary Purpose Investigate the pharmacokinetics of once-daily (QD; 900 mg) and twice-daily (BID; 450 mg) regimens of eslicarbazepine acetate (ESL) and BID (450 mg) regimen of oxcarbazepine (OXC) at steady state in healthy volunteers. Methods Single-center, open-label, randomized, three-way (n = 12) crossover studies in healthy volunteers. Key Findings Mean eslicarbazepine Cmax,ss (in μm) following ESL QD (87.3) was 33.3% higher (p

Purpose To compare the bioavailability (BA) and pharmacokinetic (PK) properties and to demonstrate the bioequivalence (BE) between two active product ingredient (API) sources of eslicarbazepine acetate (ESL) in healthy volunteers. Design, subjects and methods Forty healthy male and female subjects aged 18–40 years were randomized to treatment with 400 or 800 mg ESL marketed (MF) formulation [current active pharmaceutical ingredient (API) source] and 400 or 800 mg ESL to-be-marketed (TBM) formulation (new API source) under a gender-balanced, two-period, two-sequence crossover open-label study design. Subjects were assigned to receive either 400 or 800 mg ESL dose strengths, and each was randomly administered on two occasions—either a single oral tablet of MF or a single oral tablet of TBM—separated by a washout period of at least 7 days. Formulations were to be considered bioequivalent if, for both 400 or 800 mg ESL dosage strengths, the test (TBM)/reference (MF) geometric mean ratios (GMR) and 90 % confidence intervals (90 % CI) of the area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) were within the predetermined range of 80–125 %. Results Test/reference GMR (90 % CI) for the Cmax and AUC was respectively 100 % (94–109 %) and 96 % (94–98 %) following 400 mg ESL and 100 % (95–105 %) and 100 % (97–103 %) following 800 mg ESL. Conclusion Oral tablet formulations of either 400 or 800 mg ESL from the new API source were found to be bioequivalent to the corresponding marketed Zebinix® formulation according to the regulatory definition of bioequivalence.

Two new Mo(II) complexes [MoBr(η3-C3H5)(CO)2(8-aq)] (1) and [MoI2(CO)3(8-aq)] (2) containing the bidentate 8-aminoquinoline ligand (8-aq) were synthesized and characterized. They were immobilized in MCM-41. A 3-iodopropyltrimethoxysilane spacer reacted both with the surface, through the silane, and through the other end, with the coordinated 8-aq of complexes 1 and 2, leading to an immobilized form of the complex (MCM-Pr-1,2). In an alternative route, 8-aq reacted with 3-iodopropyltrimethoxysilane to form a new ligand L1, which could be supported in the MCM-41 and then react with the metal precursors to afford (MCM-L1-1,2). The complexes and the materials were characterized using FTIR and NMR spectroscopies, and the structure of the materials was checked with powder X-ray diffraction and nitrogen adsorption isotherms. The first synthetic procedure was less efficient in terms of metal load inside the channels of the materials. The complexes and the new materials were tested as catalytic precursors in the epoxidation of cis-cycloctene, styrene, 1-octene, R-(+)limonene, geraniol, cis-3-hexene-1-ol and trans-2-hexene-1-ol, using tert-butylhydroperoxide (TBHP) as oxidant. Although almost all the catalysts were 100% selective toward the epoxide, the conversions were in general poor. The best catalyst was complex 1, but the conversions dropped after immobilization. Conversions could be a bit improved by a careful choice of reaction conditions, the most effective being the absence of added solvent (the substrate acted as solvent).

Summary Purpose: To evaluate the efficacy and safety profile of eslicarbazepine acetate (ESL) added to stable antiepileptic therapy in adults with partial-onset seizures. Methods: Data from 1,049 patients enrolled from 125 centers, in 23 countries, in three phase III double-blind, randomized, placebo-controlled studies were pooled and analyzed. Following a 2-week titration period, ESL was administered at 400 mg, 800 mg, and 1,200 mg once-daily doses for 12 weeks. Key Findings: Seizure frequency was significantly reduced with ESL 800 mg (p 10% patients) were dizziness, somnolence, and headache. The incidence of AEs in ESL groups compared to placebo was generally consistent among different subpopulations. Significance: Once-daily ESL 800 mg and 1,200 mg showed consistent results across all efficacy and safety end points. Results were independent of study population characteristics and type and number of concomitant AEDs.

SUMMARY Purpose: To evaluate the pharmacokinetics and tolerability of once-daily eslicarbazepine acetate (ESL) and twicedaily oxcarbazepine (OXC) and their metabolites in cerebrospinal fluid (CSF) and plasma following repeated oral administration. Methods: Single-center, open-label, randomized, parallelgroup study in healthy volunteers. Volunteers in ESL group (n = 7) received 600 mg on days 1‐3 and 1,200 mg on days 4‐9, once daily. Volunteers in the OXC group (n = 7) received 300 mg on days 1‐3 and 600 mg on days 4‐9, twice daily. Plasma and CSF sampling was performed following the last dose. Key Findings: Eslicarbazepine was the major drug entity in plasma and CSF, accounting for, respectively, 93.84% and 91.96% of total exposure in the ESL group and 78.06% and 76.42% in the OXC group. The extent of exposure to drug entities R-licarbazepine and oxcarbazepine was approximately four-fold higher with OXC as compared with ESL. There was relatively little fluctuation from peak-to-trough (ratio) in the CSF for both eslicarbazepine (ESL = 1.5; OXC = 1.2) and R-licarbazepine (ESL = 1.2; OXC = 1.2). In contrast, oxcarbazepine showed larger differences between peak and trough (ESL = 3.1; OXC = 6.4). A total of 84 and 24 treatment-emergent adverse events (TEAEs) were reported with OXC and ESL, respectively. Significance: In comparison to OXC, administration of ESLresultedinmoreeslicarbazepine,lessR-licarbazepine, and less oxcarbazepine in plasma and CSF, which may correlate with the tolerability profile reported with ESL. The smaller peak-to-trough fluctuation of eslicarbazepine in CSF (a measure of sustained delivery to the brain) than in plasma supportsonce-daily dosing of ESL.

The safety, tolerability, pharmacokinetics, and pharmacodynamics of etamicastat (BIA 5-453), a novel dopamine β-hydroxylase (DβH) inhibitor, were investigated in 10 sequential groups of 8 healthy male subjects under a double-blind, randomized, placebo-controlled design. In each group, 6 subjects received a single dose of etamicastat (2, 10, 20, 50, 100, 200, 400, 600, 900, or 1200 mg) and 2 subjects received placebo. Etamicastat was well tolerated at all dose levels tested. Maximum plasma etamicastat concentrations occurred at 1 to 3 hours postdose. Elimination was biphasic, characterized by a first short early elimination half-life followed by a longer elimination phase of 16 to 20 hours for etamicastat doses of 100 mg and above. A high interindividual variability of pharmacokinetic parameters of etamicastat and its acetylated metabolite was observed. Pharmacogenomic data showed that N-acetyltransferase type 2 (NAT2) phenotype (rapid or slow N-acetylating ability) was a major source of variability. In NAT2 poor acetylators, the area under the plasma concentration-time curve from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUC0-t ) of etamicastat was twice that observed in rapid acetylators. Consistent with that finding, AUC0-t of the acetylated metabolite was markedly higher in NAT2 rapid acetylators compared with poor acetylators. Inhibition of DβH activity was observed, reaching statistical significance for etamicastat doses of 100 mg and above.

MCM-41 based materials were prepared with immobilized Mo II and Mo VI active sites based on [MoI 2 (CO) 3 ] and [MoO 2 Cl 2 ] cores, respectively, using a 2-aminopyridine glycidyloxypropyl derivative as anchoring ligand. Suitable characterization by powder X-ray diffraction, FTIR and, 13 C and 29 Si solid state NMR spectroscopy was accomplished. All new materials were successfully used in photodegradation experiments of rhodamine B under aerobic conditions. Control experiments using neat MCM-41 and direct photolysis of rhodamine B were also carried out. All experiments were run without any external source of oxygen other than air. Photocatalytic results show that the presence of Mo and its oxidation state is not innocent in this process. In addition, Mo catalysts act most probably by quenching rhodamine B excited state leading to extended degradation of the dye, through secondary photochemistry, beyond a simple de-ethylation process. Density functional theory (DFT) results corroborate with this showing that when rhodamine B is in excited state the xanthene moiety bond orders change.

This study investigated the effect of eslicarbazepine acetate (ESL) on cardiac repolarization in healthy adult volunteers. A randomized, placebo/active-controlled, 4-period crossover study was conducted in 67 participants. In 3 periods, participants received once-daily doses of ESL 1200 mg, ESL 2400 mg, and placebo for 5 days; in 1 period, participants received placebo on days 1 to 4 and a 400-mg moxifloxacin single dose on day 5. In each period, 24-hour 12-lead Holter monitoring was performed on days -;1 (baseline) and 5. There was no clinically relevant effect of ESL 1200 mg and 2400 mg versus placebo on cardiac depolarization or repolarization as measured by the QRS or QTc intervals, respectively. Mean PR interval increased following ESL 1200 mg and 2400 mg, but there was no participant with a PR interval above the upper limit of the normal range (200 ms). The upper bound of the 95% confidence interval for the placebo-corrected change from baseline of the individually corrected QT interval (QTcI) following administration of ESL 1200 mg and ESL 2400 mg was

The [Mo VI O 2 Cl 2 (thf) 2 ] and [Mo II I 2 (CO) 3 (MeCN) 2 ] precursor complexes, were immobilized in a hybrid periodic mesoporous organosilicas (PMO)-type material. These new hybrid matrix materials were prepared in one pot synthesis, containing the bidentate N , N ′-ligand ( glypy ) in the material. In a second approach, the ordered mesoporous silica MCM- glypy was prepared using a tethered approach by a stepwise procedure. The metal complexes were grafted in both types of materials to obtain heterogeneous pre-catalysts. The modified materials have been characterized by powder X-ray diffraction, N 2 adsorption, and solid-state CP MAS NMR ( 13 C, 29 Si). All metal containing materials were tested as catalysts in epoxidation of 1-octene, cyclooctene and styrene with tert -butylhydroperoxide (TBHP) at 328 K. Selectivity to octene and cyclooctene epoxides was complete. The new PMO materials described in this work are outstanding catalysts for any of the transformations described. In fact, cyclooctene selectivity based on TBHP consumption is found to be almost independent of the mol ratio attesting the efficiency of the catalysts. They are also effective under stoichiometric olefin/oxidant ratio. In addition, a mechanism for acid catalyzed benzaldehyde formation is proposed as well as the conversion of Mo(II) to Mo(VI) under catalysis.

Background Etamicastat is a new dopamine-β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure. Objectives To evaluate the pharmacokinetics and tolerability of etamicastat after single and repeated administration in elderly subjects (aged ≥65 years) relative to young adult healthy controls (aged 18–45 years). Methods This was a single-center, open-label, parallel-group study in young male adults (n = 13; mean [SD] age 32.6 [16.4] years; range, 18–44 years; weight 79.0 [16.4] kg; systolic blood pressure 117 [12] mm Hg and diastolic blood pressure 61 [7] mm Hg) and 12 elderly male volunteers (n = 12; age 69.3 [3.3] years; weight 69.2 [9.5] kg; systolic blood pressure 115 [13] mm Hg and diastolic blood pressure 64 [4] mm Hg), conducted in 2 consecutive periods. All subjects were white, except for 1 black elderly subject. In Phase A, subjects received a single dose of 100 mg etamicastat. In Phase B, subjects received 100 mg/d etamicastat for 7 days. The pharmacokinetic parameters of etamicastat and its acetylated metabolite BIA 5-961 were calculated after the single dose of Phase A and the last dose of Phase B. Subjects' N -acetyltransferase type 1 (NAT1) and type 2 (NAT2) genotyping was performed and acetylator status inferred. Results After a single dose of etamicastat 100 mg, mean (SD) plasma C max and plasma AUC 0–∞ were, respectively, 1.3 (0.5) ng/mL/kg and 12.4 (7.8) ng × h/mL/kg in elderly subjects, and 1.3 (0.4) ng/mL/kg and 10.0 (6.6) ng × h/mL/kg in young subjects. At steady-state, C max and AUC 0–24 were 1.8 (0.5) ng/mL/kg and 15.0 (6.4) ng × h/mL/kg in elderly subjects, and 1.5 (0.7) ng/mL/kg and 12.5 (6.5) ng × h/mL/kg in young subjects. Elderly/young geometric mean ratios and 90% CIs were, respectively, 0.944 (0.788–1.131) and 1.164 (0.730–1.855) for etamicastat C max and AUC 0–∞ after a single dose, and 1.225 (0.960–1.563) and 1.171 (0.850–1.612) for etamicastat C max and AUC 0–24 at steady state. Etamicastat steady-state plasma concentrations were reached after 3 to 4 days of dosing. The mean etamicastat accumulation ratio was 1.7 in both age groups. Following etamicastat single dose, mean (SD) BIA 5-961 C max and AUC 0–∞ were, respectively, 3.5 (2.1) ng/mL/kg and 28.4 (14.7) ng × h/mL/kg in elderly subjects, and 2.5 (1.5) ng/mL/kg and 16.5 (9.7) in young subjects. At steady state, BIA 5-961, C max , and AUC 0–24 were 4.3 (2.6) ng/mL/kg and 34.6 (17.6) ng × h/mL/kg in elderly subjects, and 3.1 (2.0) ng/mL/kg and 22.2 (11.8) ng × h/mL/kg in young subjects. Large interindividual variability dependent on the NAT2 acetylator status was found in the pharmacokinetic parameters of etamicastat and BIA 5-961. Systemic exposure to etamicastat was higher and systemic exposure to BIA 5-961 was lower in NAT2 poor metabolizers compared with rapid metabolizers. No effect on heart rate and blood pressure was found in the young group. In the elderly, a decrease of supine blood pressure was observed. Postural changes in blood pressure were unaffected. Four adverse events (AEs) were reported by each group: nasopharyngeal pain, sciatica, asthenia, and back pain the elderly group, and headache (2 cases), insomnia, and myopericarditis by the young group. Myopericarditis led to study discontinuation for this subject and was considered to be of probable viral etiology. All other AEs were mild to moderate in intensity. Conclusion The pharmacokinetic profile of etamicastat was not significantly different in these small groups of healthy young versus elderly adult male volunteers.

A solid-state NMR (SSNMR) study is reported on the effect of temperature on the molecular mobility of amorphous gentiobiose, which is complemented with data obtained from crystalline samples. (13)C cross-polarization/magic-angle-spinning (CPMAS) spectra and (1)H MAS spectra were obtained for gentiobiose at natural abundance, in the amorphous state, from 293 K up to the glass transformation region (T(g) = 359 K). Two well-defined molecular mobility regimes were observed, corresponding to different motional modes. NMR results on molecular dynamics are discussed and compared with those obtained by thermally stimulated depolarization currents (TSDC) and dielectric relaxation spectroscopy (DRS). SSNMR spectra presented evidence for a new polymorphic form of gentiobiose, not yet reported in the literature, which is obtained by slow heating of the amorphous solid up to 364 K inside the NMR zirconia rotor.

New hydrotalcite clay materials functionalized with molybdenum(II) complexes holding potential catalytic properties were prepared by a stepwise procedure. The material was first calcined at 823 K for 4 h, to eliminate all the carbonate ions; the layered structure was reconstructed after treatment with a solution of either tryptophane (trpH) or phenylalanine (pheH) in a KOH aqueous solution of dmf at 343 K. Subsequent impregnation with a solution of the organometallic precursor [MoI 2 (CO) 3 (NCCH 3 ) 2 ] led to substitution of the nitriles by the ligands affording the organometallic derivatized clays. The equivalent homogeneous phase complexes [MoI 2 (CO) 3 L] (L = trpH or pheH) were also prepared for comparison purposes. All the materials were characterized by powder X-ray diffraction, FTIR and 13 C CP MAS-DD solid state NMR. The complexes were also characterized by FTIR, UV/vis, elemental analysis, and 1 H and 13 C solution NMR accordingly. Both the complexes and these new materials, the latter containing 3.90 wt.% and 5.42 wt.% of Mo, respectively for HT–trp–Mo and HT–phe–Mo materials, catalyzed the epoxidation of cyclooctene and styrene at 328 K. The heterogeneous catalytic systems performed better showing that the presence of the clay is not innocent. In addition, further oxidation of styrene yielding benzaldehyde has occurred. A possible mechanism is proposed based on the detection of two reaction intermediaries by GC/MS. The heterogeneous catalysts also show superior handling capabilities due to Mo increased resistance to moisture and to separation from reaction medium.

The results of two single-blind studies conducted to evaluate the cognitive and psychomotor effects of eslicarbazepine acetate and oxcarbazepine following single and repeated administration in healthy volunteers are reported. The cognitive and psychomotor evaluation consisted of several computerized and paper-and-pencil measures. Eslicarbazepine acetate and oxcarbazepine had similar overall cognitive profiles and did not cause clinically relevant cognitive impairment. The incidence of adverse events was lower with eslicarbazepine acetate than with oxcarbazepine.

An alternative route for the preparation of polar polyolefins involving “site specific” functionalisation is presented. In this approach, the functionalisation of polyethylene is achieved by the combination of two well known processes: the copolymerization of ethylene with a non conjugated diene, followed by the reaction of the copolymer with maleic anhydride (MAH) via Alder Ene reaction. This route avoids the use of peroxides and consequently limits degradation and other undesirable reactions such as chain scission, crosslinking and coupling, usually occurring under free radical conditions. The molecular structure of the MAH modified ethylene-diene copolymer is investigated by spectroscopic techniques, such as FTIR and 1H-NMR, applied to the modified copolymer as well to model compounds and copolymers. The spectroscopic studies confirm that the functionalisation of the ethylene/5,7-dimethyl-1,6-diene (EDMO) copolymer proceeds mainly through the Alder Ene mechanism, under our experimental conditions, and provide data to elucidate the molecular structure of the modified MAH copolymer.

The two complexes [Mo(η 3 -C 3 H 5 )Br(CO) 2 (L)] (L = L 1 , C1 , and L 2 , C2 ), where L 1 and L 2 are the ligands 2-(2′-pyridyl)imidazole ( L 1 , pym) and 2-(2′-pyridyl)benzimidazole ( L 2 , pyb) were immobilized in mesoporous MCM-41 and in Mg/Al hydrotalcite (HTC), in order to obtain new heterogeneous catalysts. Both the ligands and the complexes reacted with MCM-41 functionalized with a chloropropyl pendant arm; in the first approach, the immobilized ligands were then allowed to react with [Mo(η 3 -C 3 H 5 )Br(CO) 2 (NCMe) 2 ] to afford supported C1 and C2 . While spectroscopic data, DRX, and nitrogen isotherm adsorptions revealed the similarity of the two kinds of materials, and the preservation of the MCM characteristic structure, elemental analysis showed that the stepwise approach (ligand + complex precursor) allowed the introduction of a much larger amount of molybdenum. The attempts at immobilization of the complexes in HTC were less successful. Neither the deprotonated ligands or complexes were able to intercalate between the material layers, the experimental evidence suggesting the intercalation of OH − anions and the adsorption of the deprotonated ligands or complexes on the outside of the clay. Both materials exhibited higher activities in the epoxidation of cycloctene and styrene, in the presence of TBHP, than the free complexes in homogeneous conditions, with conversions close to 100% for both substrates, in the MCM based materials prepared through a stepwise route.

Iminopyrrolyl complexes of sodium were prepared from the reaction of 2-arylformiminopyrrole ligand precursors (aryl = C(6)H(5) (I); 2,6-Me(2)C(6)H(3) (II); 2,4,6-Me(3)C(6)H(2) (III); 2,6-(i)Pr(2)C(6)H(3) (IV)) with one equivalent of sodium hydride. The resulting corresponding compounds 1-4, [{Na(mu(2):kappa(2)N,N'-iminopyrrolyl)}(2n)(OEt(2))(2x)] (nor = 1; x = 0 or 1), were obtained in moderate to high yields and were characterised by NMR spectroscopy, high resolution mass spectrometry and X-ray diffraction, when suitable crystals were obtained. The X-ray structure of compound 1 (n1; x = 0) reveals the formation of a coordination polymer with repeating units consisting of dimers that contain two iminopyrrolyl ligands chelating two sodium atoms, where both pyrrolyl rings exhibit bridging sigma + sigma coordination to the Na atoms within the dimer; the self-assembling of the polymer is established by additional pi-bonds (eta(5)-coordination) of each of the pyrrolyl rings to the sodium atoms of the adjacent dimer units. Conversely, the structure of complex D(IV) (n = x = 1) shows it as one of such dimers capped by two diethyl ether molecules, each coordinated to the sodium atoms (n = 2; x = 1). DFT calculations indicate that the differences between the structures 1-4 of arise from the increasing bulkiness imposed by the corresponding substituents of the iminic aryl groups.

Objectives The objectives of this work were to study the spatially resolved extent of photopolymerization and the final volumetric contraction of the self-etching adhesive Xeno IV (Dentsply/Caulk, Milford, DE, USA) in association with the self-curing agent Aurora (Dentsply/Caulk, Milford, DE, USA), using 1H Stray-Field magnetic resonance imaging (1H STRAFI-MRI). Methods One-dimensional 1H STRAFI-MRI images (projections along an axis, profiles) were acquired from the adhesive with and without Aurora, before and after solvent removal. Specimens were observed after the irradiation period recommended by the manufacturers and new profiles were recorded. Extent of polymerization and volumetric contraction were obtained by subtracting the profile of the cured adhesive from the profile of the liquid; the profiles were previously normalized using an external reference signal and the highest magnetization intensity recorded from the cured adhesive, respectively. Data were obtained in the presence of oxygen. Solvent evaporation was measured by gravimetry. Results High volumetric contraction was observed for Xeno IV and Xeno IV and Aurora mixture mainly related to solvent evaporation. A drying period favourably influenced the extent of photopolymerization of Xeno IV, which did not increase in the presence of Aurora. Conclusions The incorporation of Aurora reduced the extent of polymerization of the one-step adhesive, probably due to the increase in the solvent content of the mixture. It may be that enhancing solvent evaporation is important in order to reach a higher extent of polymerization during the bonding procedure.

[Mo(η3-C3H5)X(CO)2(NCCH3)2] (X = Br, 1a; X = Cl, 1b) complexes reacted with the bidentate ligand RN C(Ph)–C(Ph) NR, R = (CH2)2CH3 (DAB, 2) affording [Mo(η3-C3H5)X(CO)2(DAB)] (X = Br, 4a; X = Cl, 4b), which were characterized by elemental analysis, FTIR and 1H and 13C NMR spectroscopy. The modified silylated ligand RN C(Ph) C(Ph) NR, R = (CH2)3Si(OCH2CH3)3 (DAB–Si, 3), was used to immobilize the two complexes in MCM-41 (MCM) mesoporous silica. The new materials were characterized by powder X-ray diffraction, N2 adsorption analysis, FTIR and 29Si and 13C CPMAS solid state NMR spectroscopy. Both the materials and the complexes were tested in the oxidation of cyclooctene and styrene and behaved as active catalyst precursors for cyclooctene and styrene epoxidation with TBHP (t-butylhydroperoxide), leading selectively to epoxides with high conversions and TOFs. Although the homogeneous systems reach 100% conversion of cyclooctene and slightly less for styrene, the loss of catalytic activity in the heterogeneous systems is small, with a 98% conversion of styrene achieved by the chloride containing material.

Background and Objective An assessment of clinically important change is useful in interpreting clinical trial outcomes. The 4-point Ashworth Scale (AS) is a widely accepted measure of muscle tone, and the 9-point Physician Global Assessment Score (PGAS) is a global measure of post-treatment change as evaluated by the physician. The quantitative relationship between AS and PGAS has not previously been described in spasticity. Methods Data from three clinical trials of botulinum toxin type A (BOTOX; Allergan, Irvine, CA) in poststroke spasticity were analyzed ( n = 442). Mean change from baseline in AS score was plotted as a function of PGAS and correlations were calculated. Receiver–operator curve (ROC) analyses with the wrist flexor AS change from baseline as the independent variable and PGAS as the dependent variable were performed using the following criteria: PGAS of ≥1 (mild improvement or better) and PGAS of ≥2 (moderate improvement or better). Results In pooled data, the Pearson's correlation coefficient r between the change in wrist Ashworth Score and the PGAS was −0.44 ( p = 0, t = −26.5). Pearson correlations by individual study were also statistically significant. By ROC analysis, a PGAS of ≥1 was associated with 33% reduction of wrist AS and a PGAS of ≥2 was associated with approximately 50% reduction. In a well-powered phase 3 study, the Pearson's correlation coefficient was even higher ( r = −0.76, p = 0, t = −28.5). Conclusions Changes in disease-specific scales that correlate significantly with changes in physician global assessments are considered clinically meaningful. In clinical trials of chronic spasticity, we found that 33% and 50% changes in the Ashworth Scale scores correlate with 1-point or 2-point changes in PGAS. This is similar to findings from pooled chronic pain studies, in which 30% and 50% changes on the pain numeric rating scale were considered clinically important (Farrar et al., Pain 2001;94:149–158). Study supported by Allergan, Irvine, CA.

The objective of this study is to manufacture and investigate novel nanostructured polymer composites (NPC) based on oriented blends of high-density polyethylene (HDPE) and polyamide 6 (PA6). Conventional polymer processing techniques are used for this purpose including extrusion blending, cold drawing and compression molding. Thus, various polymer blends are prepared comprising 10 and 20 wt% of PA6 and 0-10 wt% of a copolymeric compatibilizer. These blends are cold-drawn to high draw ratios and the oriented strands so produced are further compression molded at various temperatures between the melting points of HDPE and PA6. All NPC obtained are characterized by microscopy techniques, solid state NMR, mechanical tests and wide- and small-angle X-ray scattering from synchrotron. The mechanical and structural data of NPCs are discussed with relation with the polyamide fibrils’ orientation, as well as with the effect of compatibilizer at the matrix-fibrils interface.

Electron paramagnetic resonance (EPR) was used to study the kinetics of methacrylate radical formation in the monomer mixture 2,2-bis [4-(2-hydroxy-3-methacryloxyprop-1-oxy) phenyl] propane (Bis-GMA)/triethylene glycol dimethacrylate (TEGDMA), in the presence of a photo-initiator system (camphorquinone, CQ/N,N-dimethyl-p-toluidine, DET). Curing-time dependences on the filler (0-40 wt%) and TEGDMA content (15-90 wt%) were evaluated; the influence of irradiation protocol, uncured sample storage time and aging of cured systems were also studied. EPR enabled observing at least two different kinetic regimes during polymerization. The final radical concentration decreased both with Bis-GMA and filler content. However, a reverse trend was obtained when the relative photo-initiator concentrations were considered. Filler also showed a significant effect on the radical life-time reduction. Irradiation protocol and storage time of uncured matrices showed to affect the free radical concentration. The observed changes on the EPR signal lineshape with post-curing time suggests that the distribution of CH(2) conformations also changes with time.

Objective To investigate the influence of anxiety, social anxiety and depressive symptoms on the willingness of healthy subjects to volunteer for phase I studies and to report adverse events. Materials and methods A group of healthy subjects who had never participated in a clinical trial (“Naive Subjects” )w ere invited to participate in a phase I study. All subjects were assessed for trait anxiety (State-Trait Anxiety Inventory, STAIT), social anxiety (Social Avoidance and Distress, SAD, and Fear of Negative Evaluation, FNE) and depressive symptomatology (Beck Depression Inventory, BDI-II). Subjects who accepted the invitation to participate were compared with those who refused. The personality traits of a group of “Actual Participants” were examined, and the relation of these traits to adverse events reported during participation was evaluated. Results A significant inverse correlation was found between the STAI-T (R=−0.203, p