Efficacy and safety of itraconazole pulse therapy: Brazilian multicentric study on toenail onychomycosis caused by dermatophytes

Background Itraconazole is a large spectrum triazole with known efficacy in both continuous and pulse therapy for various mycoses.Objectives Evaluate the efficacy and tolerability of itraconazole pulse therapy for onychomycosis of the toenails due to dermatophytes, in a prospective, open, non-comparative and multicentric investigation.Patients and methods the trial was completed by 72 patients of an initial total of 89. Treatment consisted of four cycles of itraconazole, 200 mg twice a day, for seven consecutive days each month. Patients were evaluated clinically, mycologically and biochemically before, during and at the end of the investigation, and were divided into two groups according to the measure of normal portion of the most affected nail (target nail), as follows: Group 1. 0-5.9 mm; and Group 2: more than 6 mm.Results Improvement was satisfactory and progressive. Results were statistically significant, when comparing the three moments of the study: pre-treatment, end of therapy (fourth month) and follow-up (ninth month) in both groups.Conclusions Itraconazole pulse therapy was efficient and safe for the treatment of onychomycosis caused by dermatophytes, although a much higher daily dosage than the known continuous administration was used. Group 1, with nails initially more extensively affected, had a more evident improvement, by the mean variation in millimeters of normal portion of the target nail. This group showed a very satisfactory response, although not reaching total cure, thus demonstrating the great importance of early treatment of this disease. A residual therapeutic effect is maintained even after suspension of the drug. Group 2 obtained better total cure rates, and four pulses were, in general, sufficient, whereas more cycles would have been beneficial for the Group 1 patients with more extensive involvement. (C) 1998 Elsevier B.V. B.V. All rights reserved.

A SAXS study of kinetics of aggregation of TEOS-derived sonogels at different temperatures

The kinetics of aggregation of tetraethoxysilane (TEOS)-derived silica sols, produced by acid-catalyzed and ultrasound-stimulated hydrolysis, were studied by 'in situ' measurements of small-angle X-ray scattering (SAXS) at the temperatures 40 degreesC, 60 degreesC and 70 degreesC. The results were analyzed in terms of the evolution with time (t) of the SAXS intensity probing the mass fractal characteristics of the system, the average radius of gyration (Rc,) of the clusters and the number of primary particles per cluster. The aggregation process yields mass fractal structures which exhibit a scattering exponent (alpha) practically equal to 2, in the probed length scale range (5.3 nm < 1/q < 0.22 nm), beneath and even far beyond the gel point. This suggests that a is a direct measure of the real mass fractal dimension (D) of the structure. The precursor sol (pH = 2) exhibits I nm mean sized clusters with mass fractal dimension D similar to 1.9. Increasing the pH to 4.5, the cluster mean size and the number of primary particles per cluster increase but the system keeps a more opened structure (D similar to 1.4). In the first aggregation stages, D increases up to similar to2 by incorporating primary particles to the clusters without changing their mean size. From this stage, the aggregation progresses following a thermally activated scaling law well described by R-G similar tot(1/D) in all cases. This is indicative of a diffusion-controlled cluster-cluster aggregation process. The activation energy of the process was found to be 91.7 kJ/mol. (C) 2001 Elsevier B.V. B.V. All rights reserved.

Temperature dependence of fractal dimension of grain boundary region in SnO2 based ceramics

Fractal dimensions of grain boundary region in doped SnO2 ceramics were determined based on previously derived fractal model. This model considers fractal dimension as a measure of homogeneity of distribution of charge carriers. Application of the derived fractal model enables calculation of fractal dimension using results of impedance spectroscopy. The model was verified by experimentally determined temperature dependence of the fractal dimension of SnO2 ceramics. Obtained results confirm that the non-Debye response of the grain boundary region is connected with distribution of defects and consequently with a homogeneity of a distribution of the charge carriers. Also, it was found that C-T-1 function has maximum at temperature at which the change in dominant type of defects takes place. This effect could be considered as a third-order transition.

AMINO-ACID-SEQUENCE OF TSTX-V, AN ALPHA-TOXIN FROM TITYUS-SERRULATUS SCORPION-VENOM, AND ITS EFFECT ON K+ PERMEABILITY OF BETA-CELLS FROM ISOLATED RAT ISLETS OF LANGERHANS

Highly purified Tityustoxin V (TsTX-V), an alpha-toxin isolated from the venom of the Brazilian scorpion Tityus serrulatus, was obtained by ion exchange chromatography on carboxymethylcellulose-52. It was shown to be homogeneous by reverse phase high performance liquid chromatography, N-terminal sequencing (first 39 residues) of the reduced and alkylated protein and by polyacrylamide gel electrophoresis in the presence of sodium dodecylsulfate and tricine. Following enzymatic digestion, the complete amino acid sequence (64 residues) was determined. The sequence showed higher homology with the toxins from the venoms of the North African than with those of the North and South American scorpions. Using the rate of Rb-86(+) release from depolarized rat pancreatic beta-cells as a measure of K+ permeability changes, TsTX-V (5.6 mu g/ml) was found to increase by 2.0-2.4-fold the rate of marker outflow in the presence of 8.3 mM glucose. This effect was persistent and slowly reversible, showing similarity to that induced by 100 mu-M veratridine, an agent that increases the open period of Na+ channels, delaying their inactivation. It is suggested that, by extending the depolarized period, TsTX-V indirectly affects beta-cell voltage-dependent K+ channels, thus increasing K+ permeability.

Water regulation of actinomycin-D binding to DNA: the interplay among drug affinity, DNA long-range conformation, and hydration

Actiaomycin-D (actD) binds to natural DNA at two different classes of binding sites, weak and strong. The affinity for these sites is highly dependent on DNA se(sequence and solution conditions, and the interaction appears to be purely entropic driven Although the entropic character of this reaction has been attributed to the release of water molecules upon drug to DNA complex formation, the mechanism by which hydration regulates actD binding and discrimination between different classes of binding sites on natural DNA is still unknown. In this work, we investigate the role of hydration on this reaction using the osmotic stress method. We skew that the decrease of solution water activity, due to the addition of sucrose, glycerol ethylene glycol, and betaine, favors drug binding to the strong binding sites on DNA by increasing both the apparent binding affinity Delta G, and the number of DNA base pairs apparently occupied by the bound drug n(bp/actD). These binding parameters vary linearly with the logarithm of the molar fraction of water in solution log(X-w), which indicates the contribution of water binding to the energetic of the reaction. It is demonstrated that the hydration change measured upon binding increases proportionally to the apparent size of the binding site n(bp/uctD). This indicates that n(bp/actD) measured from the Scatchard plod is a measure of the size of the DNA molecule changing conformation due to ligand binding. We also find that the contribution of DNA deformation, gauged by n(bp/act) to the total free energy of binding Delta G, is given by Delta G = Delta G(local) + n(bp/actD) x delta G(DNA), where Delta G(local), = -8020 +/- 51 cal/mol of actD bound and delta G(DNa) = -24.1 +/- 1.7cal/mol of base pair at 25 degrees C. We interpret Delta G(local), as the energetic contribution due to the direct interactions of actD with the actual tetranucleotide binding site, and it n(bp/actB) X delta G(DNA) as that due to change inconformation, induced by binding, of it n(bp/actD) DNA base pairs flanking the local site. This interpretation is supported by the agreement found between the value of delta G(DNA) and the torsional free energy change measured independently. We conclude suggesting an allosteric model for ligand binding to DNA, such that the increase in binding affinity is achieved by increasing the relaxation of the unfavorable free energy of binding storage at the local site through a larger number of DNA base pairs. The new aspect on this model is that the size of the complex is not fixed but determined by solutions conditions, such as water activity, which modulate the energetic barrier to change helix conformation. These results may suggest that long-range allosteric transitions of duplex DNA are involved in the inhibition of RNA synthesis by actD, and more generally, in the regulation of transcription. (C) 2000 John Wiley & Sons, Inc.

Contrasting effects of acute and chronic treatment with imipramine and fluoxetine on inhibitory avoidance and escape responses in mice exposed to the elevated T-maze

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Porosity measurement of solid pharmaceutical dosage forms by gamma-ray transmission

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Anxiogenic-like effects induced by NMDA receptor activation are prevented by inhibition of neuronal nitric oxide synthase in the periaqueductal gray in mice

Glutamate-NMDA (N-methyl-D-aspartate) receptor activation within the periaqueductal gray (PAG) leads to antinociceptive, autonomic and behavioral responses characterized as the fear reaction. We have recently demonstrated that the vigorous defensive-like behaviors (e.g. jumping and running) and antinociception induced by intra-PAG injection of N-methyl-D-aspartate (NMDA) were completely blocked by prior infusion of N(omega)-propyl-L-arginine (NPLA), a specific neuronal nitric oxide synthesis (nNOS) enzyme inhibitor, into the same midbrain structure. It remains unclear however, whether the inhibition of nNOS within the mouse PAG changes the anxiety-like behavior per se or the effects of the inhibition of nNOS depend on the suppression of downstream of glutamate-NMDA receptor activation. This study investigated whether intra-PAG infusion of NPLA (i) attenuates anxiety in the elevated plus-maze (EPM) and (ii) antagonizes the anxiogenic-like effects induced by intra-PAG injection of NMDA. Test sessions were videotaped and subsequently scored for conventional indices of anxiety (percentage of open arm entries and percentage of open arm time) and locomotor activity (closed arm entries). Results showed that intra-PAG infusions of NPLA (0.2, 0.4 or 0.8 nmol/0.1 mu l) did not alter significantly any behavioral response in the EPM when compared to control group (Experiment 1). Intra-PAG infusion of NMDA (0 and 0.02 nmol/0.1 mu l; a dose that does not provoke vigorous defensive behaviors per se in mice) significantly reduced open arm exploration, confirming an anxiogenic-like effect (Experiment 2). When injected into the PAG 10 min prior local NMDA injection (0.02 nmol/0.1 mu l), NPLA (0.4 nmol/0.1 mu l) was able to revert the anxiogenic-like effect of glutamate-NMDA receptor activation. Neither intra-PAG infusion of NMDA nor NPLA altered closed arm entries, a widely used measure of locomotor activity in the EPM. These results suggest that intra-PAG nitric oxide synthesis does not play a role on anxiety-like behavior elicited during EPM exposure; however its synthesis is important for the proaversive effects produced by activation of glutamate-NMDA receptors located within this limbic midbrain structure. (C) 2008 Elsevier B.V. All rights reserved.

Microinjection of histamine into the cerebellar vermis impairs emotional memory consolidation in mice

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Interaction of the nonionic surfactant C12E8 with high molar mass poly(ethylene oxide) studied by dynamic light scattering and fluorescence quenching methods

Dynamic light scattering has been used to investigate ternary aqueous solutions of n-dodecyl octaoxyethylene glycol monoetber (C12E8) with high molar mass poly(ethylene oxide) (PEO). The measurements were made at 20 °C, always below the cloud point temperature (Tc) of the mixed solutions. The relaxation time distributions are bimodal at higher PEO and surfactant concentrations, owing to the preacute of free surfactant micelles, which coexist with the slower component, representing the polymer coil/micellar cluster comptex. As the surfactant concentration is increased, the apparent hydrodynamic radius (RH) of the coil becomes progressively larger. It is suggested that the complex structure consists of clusters of micelles sited within the polymer coil, as previously concluded for the PEO-C12E8-water system. However. C12E8 interacts less strongly than C12E8 with PEO; at low concentrations of surfactant the complex does not contribute significantly to the total scattered intensity. The perturbation of the PEO coil radius with C12E8 is also smaller than that in the C12E8 system. The addition of PEO strongly decreases the clouding temperature of the system, as previously observed for C12E8/PEO mixtures in solution Addition of PEO up to 0.2% to C12E8 (10 wt %) solutions doss not alter the aggregation number (Nagg) of the micelles probably because the surfactant monomers are equally partitioned as bound and unbound micelles. The critical micelle concentration (cmc), obtained from the I1/I3 ratio (a measure of the dependence of the vibronic band intensities on the pyrene probe environment), does not change when PEO is added, suggesting that for neutral polymer/surfactant systems the trends in Nagg and the cmc do not unambiguously reflect the strength of interaction.