Salvatore Guccione

PREPARATION, CHARACTERISATION AND PHOTOSENSITIVITY STUDIES OF SOLID DISPERSIONS OF DIFLUNISAL AND EUDRAGIT RS100 AND RL100

Solid dispersions of diflunisal (DIF) with Eudragit RS100 (RS) and RL100 (RL) with different drug-to-polymer ratios were prepared by a solvent method (coevaporates) and were characterised in the solid state in comparison with the corresponding physical mixtures. The work was aimed at characterising the interactions occurring between DIF and RS or RL polymers, along with their influence on the in-vitro drug-dissolution pattern. The findings suggest that the drug did not change its crystalline form within the polymer network. Drug dispersion in the polymer matrix strongly influences its dissolution rate, which appears slower and more gradual while increasing the polymer ratios. Moreover, DIF is known to be a photosensitive compound, and its photoproduct has been found to be a toxic agent. This can be evidenced by testing red blood cell membranes for their resistance to the osmotic shock induced by UVA irradiation in the presence of DIF. The presence of some DIF/RS coevaporates was shown to reduce significantly the drug photosensitization process towards cell membranes. This suggests the possibility of combining the design of a drug delivery system with a photoprotective strategy.

Molecular Properties of Ibuprofen and Its Solid Dispersions with Eudragit RL100 Studied by Solid-State Nuclear Magnetic Resonance

PurposeThe aim of this study was to investigate, at a molecular level, the structural and dynamic properties of the acidic and sodium salt forms of ibuprofen and their solid dispersions with Eudragit RL-100, obtained by two different preparation methods (physical mixtures and coevaporates), which may affect the release properties of these drugs in their dispersed forms.Methods1H and 13C high-resolution solid-state nuclear magnetic resonance techniques, including single-pulse excitation magic-angle spinning, cross-polarization magic-angle spinning, and other selective 1D spectra, as well as more advanced 2D techniques Frequency Switched Lee-Goldburg HETeronuclear CORrelation (FSLG-HETCOR) and Magic Angle Spinning -J- Heteronuclear Multiple-Quantum Coherence (MAS-J-HMQC) and relaxation time measurements were used.ResultsA full assignment of 13C resonances and precise 1H chemical shift values were achieved for the first time for the two forms of ibuprofen that showed very different interconformational dynamic behavior; drug–polymer interactions were observed and characterized in the coevaporates of the two forms but were much stronger for the acidic form.ConclusionsA combined analysis of several high-resolution solid-state nuclear magnetic resonance experiments allowed the investigation of the structural and dynamic properties of the pure drugs and of the solid dispersions with the polymer, as well as of the degree of mixing between drug and polymer and of the chemical nature of their interaction. Such information could be related to the in vitro drug release profiles observed for the tested coevaporates.

Novel Benzo[b]thiophene Derivatives as New Potential Antidepressants with Rapid Onset of Action

We report benzo[b]thiophene derivatives synthesized according to a dual strategy. 8j, 9c, and 9e with affinity values toward 5-HT(7)R and 5-HTT were selected to probe their antidepressant activity in vivo using the forced swimming text (FST). The results showed significant antidepressant activity after chronic treatment. 9c was effective in reducing the immobility time in FST even after acute treatment. These findings identify these compounds as a new class of antidepressants with a rapid onset of action.

An experimental comparison between several pneumatic position control methods

In this paper an experimental comparison is made between six different techniques to control the position of a pneumatic actuator. Six different reference signals have been tested on each control technique. The methods considered are: (A) PID, (B) fuzzy, (C) PID with pressure feedback, (D) fuzzy with pressure feedback, (E) sliding mode and (F) neuro-fuzzy control. In the last method, proposed by the authors, the differential pressure sensor has been replaced by a neural network based estimator. Details of each control method and the results obtained are given and finally a global comparison is made with several critical considerations.

The wheeleg robot

This article describes a hybrid wheeled/legged robot, called the Wheeleg robot. The Wheeleg robot consists of wheels and legs separated but always acting together to locomote the system. A detailed description of the Wheeleg robot from a mechanical and electrical point of view is provided. Some considerations concerning the computing architecture are made, and some experimental results obtained in the laboratory and on volcanic terrain are given.

ROBOVOLC: a robot for volcano exploration result of first test campaign

ROBOVOLC is a new robotic system that has been designed to help scientists in the exploration of volcanoes. It is composed of three subsystems: a rover platform with six articulated and independently actuated wheels; a manipulator arm to collect rock samples, drop and pick up sensors and sample gas; and a pan‐tilt turret with a high resolution camera, video‐camera, infrared camera and a doppler radar for gas speed measurement. This paper contains a short description of the system, following an introduction to the problem and review of the state‐of‐the‐art. Finally, results from the first test campaign on Mount Etna during September 2002 are briefly described.

Design, synthesis and binding properties of novel and selective 5-HT3 and 5-HT4 receptor ligands.

This work reports the synthesis and the binding tests on the 5-HT3 and 5-HT4 receptors of new thienopyrimidopiperazine and piperazinylacylaminodimethylthiophene derivatives, in order to identify potent and selective ligands for each receptor. The 3-amino-2-(4-benzyl-1-piperazinyl)-5,6-dimethyl-thieno[2,3-d]pyrimidin-4(3H)-one derivative 28 showed the highest affinity and selectivity for the 5-HT3 over the 5-HT4 receptor (5-HT3 Ki=3.92 nM, 5-HT4 not active), whereas the 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butanoylamino]-4,5-dimethyl-3-thiophenecarboxylic acid ethyl ester (41) showed the highest affinity and selectivity for the 5-HT4 over the 5-HT3 receptor (5-HT4 Ki=81.3 nM, 5-HT3 not active). Conformational analyses were carried out on the compounds of the piperazinylacylaminodimethylthiophene series (39-42) taking compound 41 as the template.

Pyrazolothiazolopyrimidine derivatives as a novel class of anti-inflammatory or antinociceptive agents: synthesis, structural characterization and pharmacological evaluation☆

Abstract As a part of a research program on anti-inflammatory-analgesic compounds, pyrazolothiazolopyrimidines 5a-f and 5g-i were prepared by cyclodehydration in 98% H 2 SO 4 or PPA of the corresponding 6-thioketomethylene-substituted-4-hydroxy-pyrazolo[3,4- d ]pyrimidines 2a-i and 2g-i . The results of the pharmacological in vivo screening indicate an interesting dissociation of the analgesic from the anti-inflammatory activity depending on aromatic or aliphatic substitution at the C4 of the thiazole ring. Analgesic activity was not associated with any narcotic effect; in addition, all the active compounds showed a remarkable systemic and gastric tolerance. This indicated a mode of action different from that of the classical nonsteroidal anti-inflammatory drugs, acting on prostaglandin biosynthesis. To clarify the mechanism or the mechanisms underlying the pharmacological activity of these and other closely related compounds, we initiated a ‘file chemical approach’ to various systems involved in the inflammatory process. At present, some of the more active in vivo compounds tested as substance P antagonists showed a moderate and possibly non-specific effect on NK 1 and NK 2 receptors.

Interactions of imidazoline ligands with the active site of purified monoamine oxidase A

The two forms of monoamine oxidase, monoamine oxidase A and monoamine oxidase B, have been associated with imidazoline‐binding sites (type 2). Imidazoline ligands saturate the imidazoline‐binding sites at nanomolar concentrations, but inhibit monoamine oxidase activity only at micromolar concentrations, suggesting two different binding sites [Ozaita A, Olmos G, Boronat MA, Lizcano JM, Unzeta M & García‐Sevilla JA (1997) Br J Pharmacol121, 901–912]. When purified human monoamine oxidase A was used to examine the interaction with the active site, inhibition by guanabenz, 2‐(2‐benzofuranyl)‐2‐imidazoline and idazoxan was competitive with kynuramine as substrate, giving Ki values of 3 µm, 26 µm and 125 µm, respectively. Titration of monoamine oxidase A with imidazoline ligands induced spectral changes that were used to measure the binding affinities for guanabenz (19.3 ± 3.9 µm) and 2‐(2‐benzofuranyl)‐2‐imidazoline (49 ± 8 µm). Only one type of binding site was detected. Agmatine, a putative endogenous ligand for some imidazoline sites, reduced monoamine oxidase A under anaerobic conditions, indicating that it binds close to the flavin in the active site. Flexible docking studies revealed multiple orientations within the large active site, including orientations close to the flavin that would allow oxidation of agmatine.

Synthesis and pharmacological properties of pyrazolotriazolopyrimidine derivatives

Abstract As a part of research on anti-inflammatory-analgesic compounds, pyrazolotriazolopyrimidines were prepared by cycling the corresponding 2-phenylamino-3-aminopyrazolo[3,4- d ]pyrimidin-4-one derivatives 3a–h with triethylorthoformate, in the presence of p -toluenesulfonic acid. The results of the pharmacological screening indicate that some of the derivatives which were tested, especially 3c and 6e , showed a good anti-inflammatory activity associated with non-narcotic analgesic properties and a remarkable systemic and gastric tolerance.