Zn- vs Bi-based oxides for o-toluidine photocatalytic treatment under solar light.

The photodegradation of the highly toxic o-toluidine pollutant was deeply investigated both under UV and solar irradiations by using three different semiconductors: pure ZnO, Bi-impregnated ZnO, and Bi2O3 nanopowders (synthesized by precipitating method). All the samples were deeply characterized on structural, morphological, surface, and optical points of view. The disappearance and the relative mineralization of o-toluidine molecules were followed by linear sweep voltammetry (LSV) and total organic carbon (TOC) determinations, respectively. Hence, correlations between their physico-chemical properties and the photocatalytic performances, passing from UV to solar light, were drawn and a hypothesis on the photodegradation mechanism has been proposed, on the basis of the HPLC/MS results. Bare Bi2O3 samples, due to the exploitation of both their visible light absorption and the negligible intermediates formation, resulted to be higher performing under solar irradiation than either pure or Bi-doped ZnO nanopowders. Graphical abstract.

Encapsulation and modified-release of thymol from oral microparticles as adjuvant or substitute to current medications.

The aim of this study was to encapsulate, thymol, in natural polymers in order to obtain (i) taste masking effect and, then, enhancing its palatability and (ii) two formulations for systemic and local delivery of herbal drug as adjuvants or substitutes to current medications to prevent and treat several human and animal diseases. Microspheres based on methylcellulose or hydroxypropyl methylcellulose phthalate (HPMCP) were prepared by spray drying technique. Microparticles were in vitro characterized in terms of yield of production, drug content and encapsulation efficiency, particle size, morphology and drug release. Both formulations were in vivo orally administered and pharmacokinetic analysis was carried out. The polymers used affect the release and, then, the pharmacokinetic profile of thymol. Encapsulation into methylcellulose microspheres leads to short half/life but bioavailability remarkably increases compared to the free thymol. In contrast, enteric formulation based on HPMCP shows very limited systemic absorption. These formulations could be proposed as alternative or adjuvants for controlling pathogen infections in human or animal. In particular, methylcellulose microspheres can be used for thymol systemic administration at low doses and HPMCP particles for local treatment of intestinal infections.

Targeting alphavbeta3 integrin: design and applications of mono- and multifunctional RGD-based peptides and semipeptides.

The outstanding physio-pathological role played by integrin receptors in living subjects motivates the enormous interest shown by scientists worldwide for this topic. More than twenty years of research has spanned across the structural and functional elucidation of these proteins and over their antagonism-based biomedical applications. The proof-of concept stage, aimed at identifying potent inhibitors, covered a decade of studies, and paved the way for a more advanced era of research where these antagonist molecules were thrown into the deep end of applicative studies. This review intends to summarize the major efforts conducted thus far and focuses on the design, synthesis and biomedical applications of cyclic RGD-containing alpha(v)beta(3) integrin antagonists, in both their small and macromolecular formats. In particular, Chapters 1 and 2 offer a comprehensive outlook on the rational basis for the design of integrin inhibitors, Chapter 3 chronicles the biological and medical applications of monofunctional RGD integrin ligands both in their monomeric and multimeric asset, and Chapter 4 illustrates the potential of RGD-based multifunctional systems in molecular medicine.

Nasal administration of carbamazepine using chitosan microspheres: in vitro/in vivo studies.

The nasal route is used both for local therapies and, more recently, for the systemic administration of drugs, as well as for the delivery of peptides and vaccines. In this study the nasal administration of Carbamazepine (CBZ) has been studied using microspheres constituted by chitosan hydrochloride (CH) or chitosan glutamate (CG). Blank microspheres were also prepared as a comparison. The microspheres were produced using a spray-drying technique and characterized in terms of morphology (scanning electron microscopy, SEM), drug content, particle size (laser diffraction method) and thermal behaviour (differential scanning calorimetry, DSC). In vitro drug release studies were performed in phosphate buffer (pH 7.0). In vivo tests were carried out in sheep using the microparticles containing chitosan glutamate, chosen on the basis of the results of in vitro studies. The results were compared to those obtained after the nasal administration of CBZ (raw material) alone. For the evaluation of in vivo data statistical analysis was carried out using the unpaired t-test. Spray-drying was a good technique of preparation of CBZ-loaded microspheres. The loading of the drug into the polymeric network always led to an increase in the dissolution rate compared to CBZ raw material. The microspheres obtained using chitosan glutamate had the best behaviour both in vitro and in vivo. They increased the drug concentration in the serum when compared to the nasal administration of the pure drug (Cmax 800 and 25 ng/ml for microspheres and pure drug, respectively). The results obtained indicate that the loading of CBZ in chitosan glutamate microspheres increases the amount of the drug absorbed through the nose.

Variable strategy toward carbasugars and relatives. 2. Diversity-based synthesis of beta-D-xylo, beta-D-ribo, beta-L-arabino, and beta-L-lyxo 4a-carbafuranoses and (4a-carbafuranosyl)thiols.

The silyloxy diene-based construction of carbasugars, previously exploited for the synthesis of four carbocyclic furanose and pyranose analogues, has been investigated further. By introducing a novel silylative cycloaldolization protocol and by adjusting a couple of minor transformations, the efficiency of this synthetic sequence was greatly improved. Through a series of lactone/thiolactone aldehyde cyclization precursors, four carbafuranoses (4a-carba-beta-D-xylofuranose, 4a-carba-beta-D-ribofuranose, 4a-carba-beta-L-arabinofuranose, and 4a-carba-beta-L-lyxofuranose) and four (carbafuranosyl)thiols [(4a-carba-beta-D-xylofuranosyl)thiol, (4a-carba-beta-D-ribofuranosyl)thiol, (4a-carba-beta-L-arabinofuranosyl)thiol, and (4a-carba-beta-L-lyxofuranosyl)thiol] were assembled. From this study, it was shown that these constructions tolerate a variety of precursors, and in many instances, they are suitable for scaling-up.

Variable strategy toward carbasugars and relatives. 1. Stereocontrolled synthesis of pseudo-beta-D-gulopyranose, pseudo-beta-D-xylofuranose, (pseudo-beta-D-gulopyranosyl)amine, and (pseudo-beta-D-xylofuranosyl)amine.

Four novel, chiral nonracemic carbasugars have been synthesized from 1,2-O-isopropylidene-D-glyceraldehyde. Furan- and pyrrole-based 2-silyloxy dienes--mimics of the alpha,gamma-dianions of gamma-hydroxy- and gamma-aminobutanoic acid, respectively--nicely served to complete the syntheses of two all-oxygen compounds, pseudo-beta-D-gulopyranose and pseudo-beta-D-xylofuranose, and two "anomeric" amino derivatives, (pseudo-beta-D-gulopyranosyl)amine (1,2,4-tri-epi-validamine) and (pseudo-beta-D-xylofuranosyl)amine. Two sequential, highly diastereoselective carbon-carbon bond-forming maneuvers, i.e., a vinylogous crossed aldol addition and an intramolecular aldolization, proved central to these constructions. The fact that readily available heterocyclic diene scaffolds can be employed in the assembly of a varied repertoire of carbasugars and analogues widens the prospects of dienoxy silane chemistry.

The utility of furan-, pyrrole-, and thiophene-based 2-silyloxy dienes as demonstrated by modular synthesis of annonaceous acetogenin core units and their pyrrolidine and thiolane analogues.

We report a modular strategy for obtaining the core units of annonaceous acetogenins and their nitrogen and sulfur analogues, which generates great structural diversity. This synthesis is based on the application of a reiterative vinylogous addition protocol involving a unique triad of silyloxy diene modules, 2-[(tert-butyldimethylsilyl)oxy]furan (TBSOF), N-(tert-butoxycarbonyl)-2-[(tert-butyldimethylsilyl)oxy]pyrrole (TBSOP), and 2-[(tert-butyldimethylsilyl)oxy]thiophene (TBSOT) and suitable heteroatom-stabilized carbenium ions. By combining TBSOF, TBSOP, and TBSOT nucleophilic synthons with certain tetrahydrofuran, pyrrolidine, and thiolane acceptors, the construction of varied, adjacently linked oligo-heterocyclic motifs related to the core segments of the annonaceous acetogenins is assured. At first, the reliability of the pivotal coupling maneuver was certified, by assembling a collection of 18 model constructs, covering all oxygen, nitrogen, and sulfur heteroatom combinations (i.e., compounds 7-9, 13-15, and 19-21). This uniformed protocol was then suited to forge advanced bis-tetrahydrofuran, bis-pyrrolidine, and bis-thiolane scaffolds encompassing the heterocyclic core portion of various binuclear annonaceous acetogenins and relatives. The utility of this synthesis was demonstrated by the preparation of a repertoire of eight isomeric bis-tetrahydrofuran units, 41-48, two bis-pyrrolidine units, 62 and 63, and four bis-thiolane units, 78-81.

Expeditious syntheses of sugar-modified nucleosides and collections thereof exploiting furan-, pyrrole-, and thiophene-based siloxy dienes.

A series of individual sugar-modified pyrimidine nucleosides including enantiomerically enriched 2',3'-dideoxynucleosides 14a-c (alpha and beta anomers of L- and D-series), 2',3'-dideoxy-4'-thionucleosides 21a-c (alpha and beta anomers of L- and D-series), and 2',3'-dideoxy-4'-azanucleosides 28a-c (beta anomers of L- and D-series) were synthesized, with uniform chemistry and high stereochemical efficiency, exploiting a triad of versatile heterocyclic siloxy dienes, namely, 2-(tert-butyldimethylsiloxy)furan (TBSOF), 2-(tert-butyldimethylsiloxy)thiophene (TBSOT), and N-(tert-butoxycarbonyl)-2-(tert-butyldimethylsiloxy)pyrrole (TBSOP). The synthetic procedure advantageously used both enantiomers of glyceraldehyde acetonide (D-1 and L-1) as sources of chirality and as synthetic equivalents of the formyl cation. The outlined chemistry also allowed for the rapid assemblage of a 30-member collection of racemic nucleosides (D,L-L) as well as one 15-member ensemble of chiral analogues (L-L), along with some related sublibraries.

Management, therapy and outcome of treatment in women with pelvic endometriosis.

Sixty-four cases of endometriosis treated between 1980 and 1985 were reclassified according to the R-A.F.S. Twenty-eight of the patients (43.7%) were followed for 24-39 months: in this group we evaluated the efficiency of medical treatment (Danazol), combined medical and conservative surgical or definitive surgical treatment on the basis of the persistence, complete or partial regression of the symptoms. In this group of patients the symptoms regressed completely in 39.28% of the cases; in 28.57% there was a partial regression and persistence or recurrence of the symptoms were reported in 32.14%. These results suggest that the classification system is a key to interpreting treatment.

Progesterone and LH variations after LH-RH administration in the luteal phase of the menstrual cycle.

We have investigated the pituitary and luteal responses to LH-RH and their related changes. 11 normal women were studied during the luteal phase (day +4/+11). Blood samples were collected every 15 min for a basal period of 180 and 120 min after the intravenous administration of 25 micrograms of LH-RH. Progesterone (P) and LH were assayed by radioimmunoassay. Data were analyzed as maximum peak and its percent increase (delta max), integrated secretory area (ISA) and percent increase of ISA (delta A) in respect to basal values for both P and LH. LH-RH elicited a secretory response of both hormones in all cases. ISA of LH was significantly greater after LH-RH administration in respect to basal values (p less than 0.001) and delta max accounted to 475 +/- (SE) 36% of the basal concentration. Luteal responsiveness varied from about 115-130% to more marked increments. ISA of P differed from basal to stimulated conditions (p less than 0.05) and delta max was 166 +/- (SE) 14%. The analysis of temporal relationship between P and LH secretion showed that LH promptly rose after LH-RH, while the enhancement of P plasma levels occurred within 31 +/- 19 min after LH rise. Then P levels reached a plateau, values of which were statistically different from those observed before LH-RH administration. In two cases where luteal function was blunted or absent, in spite of marked increments of LH, P secretion did not occur. These data are consistent with the presence of close relationships between hypothalamic, pituitary and luteal functions and strengthen the contention about the usefulness of LH-RH during luteal phase for the lifespan and maintenance of corpus luteum.

Pulsatile Gn-Rh induced ovulatory cycles: echographic and endocrine aspects.

Five patients with primary hypogonadotrophic amenorrhea were treated for the induction of ovulation with I.V. pulsatile Gn-Rh doses ranging from 2.5 to 12.5 micrograms/90 min) for 15 cycles. Ovulation occurred during Gn-Rh treatment in 7 cycles (A) or after i.m. HGC administration (5,000-10,000 IU) (B = 6) (ovulation rate = 86%). Four pregnancies (A = 2; B = 2) were obtained (in one case there was a twin pregnancy). Echographic and endocrine patterns were evaluated. Ovulatory follicular diameter was 18.3 +/- 6.0 mm, no difference between A and B (21.8 +/- 5.6 and 16.0 +/- 5.1 mm, respectively) was observed. In addition E2 preovulatary plasma levels were similar in the two groups examined (334 +/- 131 and 300 +/- 89 pg/ml, respectively). Also endocrine and echographic profiles of conceptive (C) and non conceptive (NC) cycles were similar. Furthermore all doses resulted effective in determining the ovarian response and no difference was found at different dosage used. It is concluded that pulsatile GnRh is a "physiological" way of inducing ovulation in PHA patients. By analysis of the present data we consider it advisable to induce ovulation by the enhancement of the endogenous LH peak which occurs during Gn-Rh administration (A group) and then periodic injections of HCG can be used for maintaining the luteal function.