Biodegradable multi-walled carbon nanotubes trigger anti-tumoral effects.

Carbon nanotubes are of huge biotechnological interest because they can penetrate most biological barriers and, inside cells, can biomimetically interact with the cytoskeletal filaments, triggering anti-proliferative and cytotoxic effects in highly dividing cells. Unfortunately, their intrinsic properties and bio-persistence represent a putative hazard that relapses their application as therapies against cancer. Here we investigate mild oxidation treatments to improve the intracellular enzymatic digestion of MWCNTs, but preserving their morphology, responsible for their intrinsic cytotoxic properties. Cell imaging techniques and confocal Raman spectroscopic signature analysis revealed that cultured macrophages can degrade bundles of oxidized MWCNTs (o-MWCNTs) in a few days. The isolation of nanotubes from these phagocytes 96 hours after exposure confirmed a significant reduction of approximately 30% in the total length of these filaments compared to the control o-MWCNTs extracted from the cell culture medium, or the intracellular pristine MWCNTs. More interestingly, in vivo single intratumoral injections of o-MWCNTs triggered ca. 30% solid melanoma tumour growth-inhibitory effects while displaying significant signs of biodegradation at the tumoral/peri-tumoral tissues a week after the therapy has had the effect. These results support the potential use of o-MWCNTs as antitumoral agents and reveal interesting clues of how to enhance the efficient clearance of in vivo carbon nanotubes.

The Aotus nancymaae erythrocyte proteome and its importance for biomedical research.

The Aotus nancymaae species has been of great importance in researching the biology and pathogenesis of malaria, particularly for studying Plasmodium molecules for including them in effective vaccines against such microorganism. In spite of the forgoing, there has been no report to date describing the biology of parasite target cells in primates or their biomedical importance. This study was thus designed to analyse A. nancymaae erythrocyte protein composition using MS data collected during a previous study aimed at characterising the Plasmodium vivax proteome and published in the pertinent literature. Most peptides identified were similar to those belonging to 1189 Homo sapiens molecules; >95% of them had orthologues in New World primates. GO terms revealed a correlation between categories having the greatest amount of proteins and vital cell function. Integral membrane molecules were also identified which could be possible receptors facilitating interaction with Plasmodium species. The A. nancymaae erythrocyte proteome is described here for the first time, as a starting point for more in-depth/extensive studies. The data reported represents a source of invaluable information for laboratories interested in carrying out basic and applied biomedical investigation studies which involve using this primate. SIGNIFICANCE: An understanding of the proteomics characteristics of A. nancymaae erythrocytes represents a fascinating area for research regarding the study of the pathogenesis of malaria since these are the main target for Plasmodium invasion. However, and even though Aotus is one of the non-human primate models considered most appropriate for biomedical research, knowledge of its proteome, particularly its erythrocytes, remains unknown. According to the above and bearing in mind the lack of information about the A. nancymaae species genome and transcriptome, this study involved a search for primate proteins for comparing their MS/MS spectra with the available information for Homo sapiens. The great similarity found between the primate's molecules and those for humans supported the use of the monkeys or their cells for continuing assays involved in studying malaria. Integral membrane receptors used by Plasmodium for invading cells were also found; this required timely characterisation for evaluating their therapeutic role. The list of erythrocyte protein composition reported here represents a useful source of basic knowledge for advancing biomedical investigation in this field.

Structural Metastability and Quantum Confinement in Zn1-xCoxO Nanoparticles.

This paper investigates the electronic structure of wurtzite (W) and rock-salt (RS) Zn1-xCoxO nanoparticles (NPs) by means of optical measurements under pressure (up to 25 GPa), X-ray absorption, and transmission electron microscopy. W-NPs were chemically synthesized at ambient conditions and RS-NPs were obtained by pressure-induced transformation of W-NPs. In contrast to the abrupt phase transition in W-Zn1-xCoxO as thin film or single crystal, occurring sharply at about 9 GPa, spectroscopic signatures of tetrahedral Co(2+) are observed in NPs from ambient pressure to about 17 GPa. Above this pressure, several changes in the absorption spectrum reveal a gradual and irreversible W-to-RS phase transition: (i) the fundamental band-to-band edge shifts to higher photon energies; (ii) the charge-transfer absorption band virtually disappears (or overlaps the fundamental edge); and (iii) the intensity of the crystal-field absorption peaks of Co(2+) around 2 eV decreases by an order of magnitude and shifts to 2.5 eV. After incomplete phase transition pressure cycles, the absorption edge of nontransformed W-NPs at ambient pressure exhibits a blue shift of 0.22 eV. This extra shift is interpreted in terms of quantum confinement effects. The observed gradual phase transition and metastability are related to the NP size distribution: the larger the NP, the lower the W-to-RS transition pressure.

Oral availability of bilastine.

BACKGROUND AND OBJECTIVE: Bilastine (Bilaxten™) is a novel non-sedating H1 receptor antagonist (antihistamine) developed in the dosage form of oral tablets and indicated for the treatment of allergic rhinitis (seasonal and perennial) and urticaria. Several clinical trials have been performed in order to determine the efficacy and safety of bilastine. The aim of this trial was to study the absolute oral bioavailability of bilastine in humans. METHODS: Twelve male and female adults were recruited into a single centre for a randomized, single-dose, open-label, controlled two-arm crossover study with a minimum 14-day washout period between the two single doses. Two single doses of bilastine were administered: a 20-mg oral tablet and a 10-mg intravenous formulation. Blood and urine samples were collected between 0 and 72 h post each administration. The clinical trial was carried out under quality assurance and quality control systems with standard operating procedures to ensure that the study was conducted and data generated in compliance with the protocol, Good Clinical Practice standards, International Conference on Harmonisation and other applicable regulations. RESULTS: Oral bioavailability of bilastine was 60.67 % with a 90 % parametric confidence interval of 53.79-67.56. The maximum bilastine concentration was measured 1.31 h after oral administration. Pharmacokinetic parameters were similar to those observed in previous studies. Tolerance to treatment was good, with no adverse events related to study medication. CONCLUSION: The absorption of bilastine after oral administration to healthy subjects was rapid. The absolute oral bioavailability was moderate.

Temperature and pressure dependence of the optical properties of Cr3+-doped Gd3Ga5O12 nanoparticles.

Since the crystal-field strength at the Cr(3+) site is very close to the excited-state crossover (ESCO), this work investigates the optical properties of Cr(3+)-doped Gd(3)Ga(5)O(12) (GGG) nanoparticles as a function of temperature and pressure in order to establish the effect of the ESCO on the optical behaviour of nanocrystalline GGG. Luminescence, time-resolved emission and lifetime measurements have been performed on GGG:0.5% Cr(3+) nanoparticles in the 25-300 K temperature range, as well as under hydrostatic pressure up to 20 GPa. We show how low temperature and high pressure progressively transforms Cr(3+)(4)T(2) --> (4)A(2) broadband emission into a ruby-like (2)E --> (4)A(2) luminescence. This behaviour together with the lifetime dependence on pressure and temperature are explained on the basis of the spin-orbit interaction between the (4)T(2) and (2)E states of Cr(3+).

Application and comparison of four selected procedures for the isolation of cell-wall material from the skin of grapes cv. Monastrell.

In order to choose an appropriate cell-wall material (CWM) isolation procedure in grapes cv. Monastrell, four different standard procedures have been tested, and a comparison made of the amount of cell-wall material obtained, its composition and morphology. The CWM was isolated as the 70% ethanol insoluble residue (de Vries method), as the absolute ethanol insoluble residue filtered sequentially through nylon mesh (Nunan method), as the insoluble residue in sodium deoxycholate-phenol-acetic acid-water (Selvendran method) and as the N-[2-hydroxyethyl]-piperazine-N'-2-ethanesulfonic acid (HEPES) insoluble residue (Vidal method). All extractions were done in triplicate and the efficiency of the extractive procedure established. Carbohydrates, proteins, and phenolic compounds were analysed, as the main constituents of CWM. The morphology of the isolated CWM was visualized by scanning electron microscopy (SEM). The Selvendran method had the highest efficiency, while the Nunan method had the lower one. Regarding the carbohydrates composition, the four different CWM were rich in uronic acids and glucose, together with varying amounts of arabinose, xylose, mannose and galactose. The Selvendran method had the lower value of total carbohydrates and the CWM shows more plasmatic membrane impurities in SEM images. The chemical results of the Vidal and de Vries methods were quite similar, but the Vidal method was more time consuming than the de Vries method. According to the results, the de Vries method was chosen to produce a representative cell-wall material fraction from Monastrell grapes skin.

Time-resolved spectroscopy in LiCaAlF(6) doped with Cr(3+): dynamical Jahn-Teller effect and thermal shifts associated with the (4)T(2) excited state.

This work investigates the centre distribution of the Cr(3+) impurity, the dynamical Jahn-Teller effect in the first (4)T(2) excited state and the thermal shifts of the absorption and emission peaks in LiCaAlF(6):Cr(3+) by means of time-resolved emission spectroscopy. The electronic and vibrational fine structure observed in both the absorption and emission spectra at low temperature are assigned according to the vibrational modes of the internal (CrF(6))(3-) complex and the lattice modes. Zero-phonon lines associated with (4)T(2) --> (4)A(2) and (2)E --> (4)A(2) transitions were detected and assigned on the basis of available high pressure data in LiCaAlF(6):Cr(3+). We have identified the vibrational coupled modes responsible for the vibrational structure of the low temperature emission spectrum and the reduction of the zero-phonon line (ZPL) splitting caused by the dynamical Jahn-Teller effect in the (4)T(2) excited state (Huang-Rhys factor, S(e) = 0.92). In addition, from the temperature variation of the emission intensity I(T), transition energy E(T) and bandwidth H(T), we obtained the vibrational modes that are coupled to the emitting state. We have evaluated the two main contributions to the photoluminescence thermal shift through thermal expansion and high pressure measurements: the implicit contribution induced by changes of thermal population and the explicit contribution induced by thermal expansion effects--40% and 60% of the total shift, respectively.

Comparison of the efficacy and safety of bilastine 20 mg vs levocetirizine 5 mg for the treatment of chronic idiopathic urticaria: a multi-centre, double-blind, randomized, placebo-controlled study.

BACKGROUND: Bilastine is a novel nonsedative H(1)-receptor antagonist, which may be used for the symptomatic treatment of chronic idiopathic urticaria (CU). The aim of this study was to compare the clinical efficacy and safety of bilastine 20 mg vs levocetirizine 5 mg and placebo in CU patients with moderate-to-severe symptoms. METHODS: Overall 525 male and female subjects aged 18-70 years were randomized to receive bilastine 20 mg, levocetirizine 5 mg or placebo, once daily for 28 days, in double-blind manner, in 46 centres across Europe and Argentina. Patients rated symptoms of pruritus, number of wheals, and maximum size of wheals (on predefined scales) as reflective (over past 12 h) symptoms twice daily, for assessment of change from baseline in the total symptoms scores (TSS) over 28 days as the primary efficacy measure. Changes in reflective and instantaneous symptoms scores, Dermatology Life Quality Index (DLQI), and CU-associated discomfort and sleep disturbance were assessed as secondary outcomes. Safety was assessed according to adverse events, laboratory tests and electrocardiograms. RESULTS: Bilastine reduced patients' mean reflective and instantaneous TSS from baseline to a significantly greater degree than placebo (P < 0.001); from day 2 onwards of treatment. The DLQI, general discomfort, and sleep disruption were also improved significantly in bilastine-treated patients as compared with placebo-treated patients (P < 0.001 for all parameters). Comparison with levocetirizine indicated both treatments to be equally efficacious as well as equally safe and well tolerated as compared with placebo. CONCLUSIONS: Bilastine 20 mg is a novel effective and safe treatment option for the management of CU.

Efficacy and safety of bilastine 20 mg compared with cetirizine 10 mg and placebo for the symptomatic treatment of seasonal allergic rhinitis: a randomized, double-blind, parallel-group study.

BACKGROUND: Bilastine is a new non-sedative H(1) receptor antagonist, indicated for the treatment of allergic rhinitis (AR) (seasonal and perennial). OBJECTIVE: To assess and compare the efficacy and safety of bilastine 20 mg vs. cetirizine 10 mg and placebo in relieving the symptoms of seasonal allergic rhinitis (SAR). METHODS: Overall, 683 SAR patients, aged 12-70 years, were randomized to a double-blind treatment with bilastine 20 mg, cetirizine 10 mg or placebo, once daily for 14 days, in 61 centres across Europe. Patients recorded reflective (over the past 12 h) and instantaneous nasal (obstruction, rhinorrhoea, itching and sneezing) and non-nasal (ocular tearing, redness and itching) symptom scores (NSS and NNSS, respectively) twice daily, according to a pre-determined severity scale to provide reflective and instantaneous total symptom scores (TSS). The primary efficacy measure was the area under curve (AUC) of reflective TSS over 14 days of treatment (TSS-AUC(0-14 days)). Secondary efficacy measures included mean change from baseline in TSS, NSS and NNSS; discomfort caused by AR; and investigator's clinical global impression of the treatment. Safety was assessed according to adverse events (AEs), laboratory tests and electrocardiograms. RESULTS: The mean TSS-AUC(0-14 days) (score x day) was reduced in bilastine- and cetirizine-treated groups to a similar and significantly greater extent, compared with placebo (76.5, 72.3 and 100.6, respectively; P<0.001). Similarly, bilastine and cetirizine were comparable and significantly superior to placebo for all secondary outcomes. While all treatments were well tolerated and the AE profiles of bilastine and placebo were similar, significantly fewer patients in the bilastine-treated group experienced somnolence (1.8%; P<0.001) and fatigue (0.4%; P=0.02) than patients in the cetirizine-treated group (7.5% and 4.8%, respectively). CONCLUSIONS: Bilastine 20 mg once daily was significantly superior to placebo and comparable to cetirizine 10 mg in relieving symptoms of SAR, although it demonstrated a significantly better AE profile than cetirizine.

Green and red light emission by upconversion from the near-IR in Yb(3+) doped CsMnBr3.

Direct near-IR excitation of Yb(3+) 2F(7/2)-->(2)F(5/2) levels at 10126, 10138, and 10596 cm(-1) in CsMnBr3:0.5%Yb(3+) leads to three types of luminescence at cryogenic temperatures: near-IR Yb(3+) emission and green and red upconverted luminescence. The green luminescence around 20 000 cm(-1) is identified as cooperative Yb(3+) pair upconversion. The broad red upconversion luminescence band centered at 14 700 cm(-1) is ascribed to the 4T(1g)-->6A(1g) transition of Mn(2+). Pulsed measurements indicate a sequence of ground-state absorption and excited-state absorption steps for the red upconversion process. One- and two-color excitation experiments support this, and we conclude that the red upconversion occurs by an exchange mechanism involving Yb(3+) and Mn(2+). The Yb(3+) 2F(5/2)-->(2)F(7/2) near-IR emission around 10 000 cm(-1) is also observed after Mn(2+) excitation at 21 838 cm(-1). This is indicative of a Mn(2+) 4T(1g)--> Yb(3+) 2F(5/2) relaxation process, which is a potential loss process for upconversion efficiency.

Negative life events and adolescent suicidal behavior: a critical analysis from the stress process perspective.

In the present review we examine empirical evidence concerning relationships between negative life events and adolescent suicidal behavior. Separate critical analyses were made for suicidal ideation, suicide attempts and completed suicide, suggesting common and differential aspects. Although there is evidence supporting the hypothesis that life events may comprise a risk factor for adolescent suicidal behavior, their contribution tends to be moderate or weak. A problem with past research is that it has not adequately incorporated mediating and moderating variables into pathways that link psychosocial stressors and suicidal outcomes. A stress process model is presented as a possible alternative to better understanding the relationships between stress and suicide, and to provide a conceptual and heuristic framework for future research.

Comparative bioavailability of a dispersible formulation of diclofenac and finding of double plasma peaks.

We carried out a comparative study of the bioavailability of a typical, enteric-coated diclofenac with regard to a new dispersible formulation whose faster dissolution results in an earlier onset of its analgesic effect. This randomized, crossover study was conducted in 12 healthy male volunteers, who received in fasting 100 mg of enteric-coated diclofenac (Dolotrén, FAES) and 100 mg of dispersible diclofenac (Dolotrén Dispersable, FAES), with one-week interval between both. Blood samples were taken at pre-established times during the 24 hours after dosing, and plasma concentrations of diclofenac were determined by HPLC. Possible adverse experiences were monitored with a check-list, and blood and urinalysis were performed for safety assessment. The dispersible formulation showed a relative extent of bioavailability between 78% and 99% (90% CI) for the AUC0-infinity, being the 90% CI for the Cmax 63%-129%. The time to Cmax (Tmax) was significantly shorter with the dispersible than with the enteric-coated formulation (95% CI for the difference = 1.5-4.25 hours) as the T0(lag) or time to measurable plasma concentrations (1.9-4.2 hours, 95% CI). A relevant feature in the study was the finding of a second peak at 2-2.5 hours post-dosing in 7 out of 11 profiles of subjects receiving the dispersible formulation. Both formulations were well tolerated in clinical and laboratory terms. In conclusion, the new dispersible formulation of diclofenac allows absorption to begin more rapidly and plasma peak is reached earlier, a fact that may be relevant to the analgesic treatment of acute pain.

[Comparative bioavailability and pharmacokinetics of Dolotren retard and Dolotren]. / Biodisponibilidad y farmacocinética comparadas de Dolotrén Retard frente a Dolotrén.

A randomized crossover study was designed in order to evaluate the bioequivalence of a sustained-release preparation (DR) of diclofenac sodium (Dolotrén RETARD) with respect to an enteric coated (D) tablet (Dolotren). For this purpose the bioavailability of both formulations, orally administered in single and multiple doses, was determined. Nine healthy volunteers were included in this study, receiving 100 mg of D and 100 mg of DR, firstly in single dose and then for 15 days b.i.d. for D group and once a day for DR group. For the analytical determination of diclofenac, blood samples at established time intervals, the day of the single dose and the 3rd, 7th and 15th day of multiple dose administration, were taken. The following kinetic parameters were determined: Cmac, tmax, alpha and beta, clearance, ka, area under the curve and absolute and relative bioavailability. When administered both endovenous and orally, the great interindividual variability in the kinetic characteristics of diclofenac sodium is evidenced. The lag time (tlag) for DR is 0.4 h, shorter than for D (2.2 h), which indicates a faster absorption in the upper sections of the gastrointestinal tract. Also tmax was shorter for Dr (1.9 h) than for D (4.3 h). Cmax obtained with D was higher tan with DR. The diclofenac sodium elimination process from plasma is significantly slower with DR than with D (t1/2 beta = 18.1 h and 2.5 h, respectively). In consequence, quantifiable plasmatic levels are maintained for at least 24 hours after administration of DR, but not of D. Absolute bioavailability of both preparations is about 80%, with great interindividual variations. Significant differences between the two preparations could not be demonstrated. Relative bioavailability between DR and D was 91.5%. None of the preparations when administered in repeated doses, D every 12 hours and DR every 24 hours, produced accumulation, neither their pharmacokinetic characteristics changed. Clinical and biological tolerance of both preparations were excellent, at doses used and for the period of time studied. Dolotren Retard is absorbed orally faster than Dolotren and maintains plasmatic levels longer, which allows it to be administered once a day, with a lesser incidence of undesirable effects related to Cmax.

Therapeutic effects of hidrosmin on chronic venous insufficiency of the lower limbs.

A double-blind, placebo-controlled trial was carried out to assess the effectiveness of a new synthetic bioflavonoid, hidrosmin, in patients with chronic venous insufficiency of the lower limbs. Fifty-seven patients, showing varicose veins and ankle swelling and suffering from local pain and heaviness of the legs, were allocated at random to receive treatment for 45 days with 1 capsule 3-times daily of either 200 mg hidrosmin (30 patients) or placebo (27 patients). Pain and heavy legs were assessed using rating scales; swelling was assessed by a photographic method. The results showed that hidrosmin produced a significant clinical improvement in all of the parameters evaluated; compared with placebo, there was a marked reduction in the main subjective symptoms accompanied by a 10% reduction in swelling. Apart from 1 patient who complained of epigastric pain, there were no reports of adverse events during the study period.

Platelet GABA-aminotransferase in epileptic patients.

Platelet GABA-aminotransferase (GABA-T) activity was determined in 12 adults (six healthy volunteers and six long-term treated epileptic patients) and 17 children (six non-epileptic, and 11 long-term treated epileptic patients). Platelet GABA-T activity was about 60% higher in the epileptic patients than in the controls, both in adults (14.7 +/- 8.6 versus 8.8 +/- 3.5 pmol/min/mg of protein,) and children (13.1 +/- 4.8 versus 8.3 +/- 3.3 pmol/min/mg of protein, p less than 0.05). The relationship between this increase and either epilepsy or anti-epileptic treatment should be clarified in further studies.

Poor correlation between single-dose data and steady-state kinetics for phenobarbitone, primidone, carbamazepine and sodium valproate in children during monotherapy. Possible reasons for the lack of correlation.

An investigation was performed to determine the relationship between the serum drug concentration/dose ratio at 24 hours following a first dose and that at steady-state for phenobarbitone, primidone (as phenobarbitone and as primidone), carbamazepine and sodium valproate, in order to assess the utility of this method in clinical practice. The drugs were given as monotherapy to 63 children for the treatment of epilepsy or febrile convulsions. The correlation between concentration/dose ratios, instead of between serum concentrations, was investigated with the aim of allowing the use of variable doses. The correlation coefficients were: r = 0.30 for phenobarbitone; r = 0.05 for phenobarbitone derived from primidone; r = 0.38 for primidone; r = 0.19 for carbamazepine; and r = 0.52 for sodium valproate. None of these correlation coefficients differed statistically from 0. These low correlation coefficients contrast with the acceptable results found by other authors for other drugs, indicating that several factors may have a greater influence on this correlation than earlier investigations suggest. The poor correlation obtained emphasises the need for clinical verification of mathematical models based on theoretical considerations which do not always apply in practice.