A comprehensive study on the effect of bentonite fining on wine charged model molecules.

In bottled wines, haze and turbidity are phenomena to be avoided. Since bentonite fining is a common process to clarify wines removing heat unstable proteins, a theoretical study on the adsorption of three Charged Model Molecules (CMMs, egg albumin, polyphenols and riboflavin) was carried out to deep comprehend this chemical phenomenon. Four bentonites were adopted and finely characterized together with the potential release of Na+ and Ca2+ cations, revealing suitable for RT albumin removal within 120 min. Better results in terms of adsorbed quantity were achieved by adopting 12%v/v EtOH/H2O solvent and by swelling bentonites for 24 h before use. With the most performing sample (Na/Ca_0.27), a comprehensive study on simultaneous adsorption of the three CMMs was performed, resulting in polyphenols adsorption increase due to their interactions with albumin. Notwithstanding the majority of albumin and riboflavin was successfully removed, ca. 40-50% of tested polyphenols was preserved.

Inulin-based polymer coated SPIONs as potential drug delivery systems for targeted cancer therapy.

This paper deal with the synthesis and characterization of PEGylated squalene-grafted-inulin amphiphile capable of self-assembling and self-organizing into nanocarriers once placed in aqueous media. It was exploited as coating agent for obtaining doxorubicin loaded superparamagnetic iron oxide nanoparticles (SPIONs) endowed with stealth like behavior and excellent physicochemical stability. Inulin was firstly modified in the side chain with primary amine groups, followed in turn by conjugation with squalenoyl derivatives through common amidic coupling agents and PEGylation by imine linkage. Polymer coated SPIONs were so obtained by spontaneous self-assembling of inulin copolymer onto magnetite surface involving hydrophobic-hydrophobic interactions between the metallic core and the squalene moieties. The system was characterized in terms of hydrodynamic radius, zeta potential, shape and drug loading capacity. On the whole, the stealth-like shell stabilized the suspension in aqueous media, though allowing the release of the doxorubicin loaded in therapeutic range. The cytotoxicity profile on cancer (HCT116) cell line and in vitro drug uptake were evaluated both with and without an external magnetic field used as targeting agent and uptake promoter, displaying that magnetic targeting implies advantageous therapeutic effects, that is amplified drug uptake and increased anticancer activity throughout the tumor mass.

Study for the quality assessment of abstracts presented to Italian public health national conferences: a six years survey.

BACKGROUND: Oral and poster presentations at congresses are essential to spread scientific knowledge among the medical community. Many scientific societies have analyzed the quality of papers presented at their meetings but no information on abstracts' evaluation has been presented in Public Health field. DESIGN AND METHODS: This study aims to examine the quality of abstracts presented at annual meetings of Italian Public Health Society (SItI) in the period 2005-2010 through a validated checklist grid, evaluating eight dimensions: Inherency, Structure, Originality, Objectives, Study design, Sources, Results, Conclusions. Each item was scored from 0 to 3 points (max score: 24) and we used the average score in our study (15) as threshold of good quality. A multivariate analysis was performed in order to investigate predictors of score of abstracts presented. RESULTS: A total of 4,399 abstracts (1,172 oral communications, 3,227 posters) was examined. Around 60% were submitted by Universities and around 40% were from Central Italy. The highest quality was found in the fields of Vaccines (average score 18.9), Infectious Diseases (18) and in abstracts submitted by Universities (16.4). Predictors of lower quality identified were geographical area and affiliation (p= 0.002). Abstracts containing well-written Results, Conclusions and Objectives (3 points) were more likely to be of high quality(OR=55.6, OR=41.9, and OR=157.4; p>0.001) CONCLUSIONS: This is the first European study evaluating the quality of abstracts in the public health field. A reliable evaluation tool is fundamental to offer a transparent methodology of assessment and to improve the quality of research.

Amphiphilic polyaspartamide copolymer-based micelles for rivastigmine delivery to neuronal cells.

A novel polysorbate-80 (PS(80))-attached amphiphilic copolymer comprising a hydrophilic α,ß-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) backbone and hydrophobic squalenyl-C(17) (Sq(17)) portions was synthesized and characterized; the formation of polymeric micelles was also evaluated. Rivastigmine free-base (Riv), a hydrophobic drug employed to treat Alzheimer's disease, was chosen as model drug to investigate micelle's ability to incorporate hydrophobic molecules and target them to neuronal cells. Micelle formation was studied through analyses including fluorescence spectroscopy and 2D (1)H-NMR NOESY experiments. Finally, the capacity of Riv-loaded micelles, versus free drug, to penetrate mouse neuroblastoma cells (Neuro2a) was evaluated. 2D (1)H-NMR NOESY experiments demonstrated that the PHEA-EDA-Sq(17)-PS(80) copolymer self-assembles into micelle structures in water, with a micelle core formed by hydrophobic interaction between Sq(17) alkyl chains. Fluorescence probe studies revealed the CAC of PHEA-EDA-Sq(17)-PS(80) micelles, which was 0.25 mg mL(-1). The micelles obtained had a nanometric hydrodynamic diameter with narrow size distribution and negative surface charge. The PHEA-EDA-Sq(17)-PS(80) micelles incorporated a large amount of Riv, and the system maintained the stability of Riv after incubation in human plasma. An in vitro biological assay evidenced no cytotoxic effects of either empty or loaded micelles on the neuronal cell lines tested. Moreover, the micelles are internalized by neuroblastoma cell lines with drug uptake depending on the micelles concentration.

[Role of the Web on behaviors and health choices in six Italian cities: results of a multicenter study]. / Ruolo del web sui comportamenti e sulle scelte sanitarie in sei città italiane: risultati di uno studio multicentrico.

A cross-sectional, multicenter study was carried out in 6 Italian cities (Cassino, Chieti, Naples, Rome, Siena, Turin) in order to highlight differences in Web use to find out health information and its related consequences on behavioral choices and to describe the distribution of the phenomenon in Italy. Data were collected from October 2009 to September 2010 on a sample of volunteers recruited from laboratory analysis, with face-to-face interview, including information about socio-demographic, health, and Web use to health. Data analysis shows that e-health use is greater in Northern Italy, in women aged 30-41 years, in chronic patients and those who have been caught up medical malpractice. Behavioral changes are associated with the Region; in particular Rome and Cassino show to choose/change professionals and facilities, engaging in alternative therapies and buy drugs online more frequently. Living in Southern Italy, a lower educational level and the infrequent drugs use are associated with a greater probability of incurring in negative behaviors. Positive results on the behavior are instead low and not significant. Given the regional differences, the potentiality and the risks of e-health use, it will be important to identify strategies for risks containment and implementation of the web in prevention.

[The Italian legislation on Health Impact Assessment: the current national and regional regulatory framework]. / La legislazione Italiana in materia di health impact asses- sment: il corrente quadro normativo nazionale e regionale.

The scientific literature on HIA is particularly rich in Anglo-Saxon countries (United Kingdom, Canada, New Zealand), in Sweden and in the Netherlands, while in Italy there are not many scientific studies published on this theme. The study conducted showed that in Italy no laws relating to HIA have been enacted yet and that all laws enacted so far considered only EIA. Actually, legislation on environmental impact is in continuous expansion, even if at present, some regions have not yet passed a specified EIA-dealing law. In Italy the protection of health is promoted almost exclusively at a strictly medical level; decisions with strong social and environmental impact are not normally designed with particular regard to health issues. To increase in our country the interest for HIA, it would seem appropriate to discuss the usefulness of introducing health impact assessment in national and regional legislation. A possible law may indeed sensitize non-health decision makers to HIA, bringing Italy among the most innovative countries.

Depression after lung transplantation: causes and treatment.

During the postoperative course of lung transplantation, patients may experience depressive symptoms that negatively influence their ability to cope with the new organ, their adherence to rehabilitation and pharmacologic therapy, and their overall quality of life (QoL). To date, no review has explored the causes of depression following transplantation or the efficacy and safety of therapeutic interventions in this patient group. We conducted a comprehensive 1966-2006 MEDLINE, EMBASE, and PsycINFO search for studies of the causes and treatments of depression in lung transplant recipients. We identified 25 studies of variable methodologic quality. Depression rates are high among candidates for lung transplantation. In the short term, after surgery depressive symptoms remain low with an improvement in QoL, whereas in the long term (>3 years), the decline of functional status is associated with a dramatic increase in such symptomatology. Personality disorders, coping strategies, stressful life events, physical complications, corticosteroid medications, age, gender, and psychosocial support all play a central role in causing depressive states in lung transplant recipients. Serotonin reuptake inhibitors (SSRIs) and new-generation antidepressants (mirtazapine) represent the best therapeutic choices for this group of patients. The risk of serious drug-drug interactions should be carefully monitored by experienced clinicians. Complementary therapies and psychoeducational intervention also help recipients to strengthen their coping strategies, offering further advantages after transplantation. Additional well-conducted randomized controlled trials are needed to clarify the epidemiologic course of depression following lung transplantation and to tailor effective pharmacologic or psychological interventions accordingly.

[Training individuals of the construction sector in the province of Bergamo: a shared path division and an operative proposal]. / La formazione delle figure di sistema del comparto edilizia nella provincia di Bergamo: un percorso condiviso ed una proposta operativa.

With this presentation it will be introduced the experience of the work group native of Bergamo who is taken care to plan the formation course for the professional figures of system in building. The group is formed from the greater agencies present on the territory, their work is to ensure the protection of the health and the emergency of the workers in the field of the constructions. The objective is to use the formation course in order to diffuse one culture of the emergency. In the specific one they will come to describe the various planning phases of the course of formation for employers that mean to elect himself Responsible of the Service of Prevention and Protection (RSPP).

From conventional to stealth liposomes: a new Frontier in cancer chemotherapy.

In this review, the different types of liposome used in medicine, in particular in the field of antitumor therapy, are focalised, emphasizing their structures, pharmacological action, pharmacokinetics and biodistribution, toxicity profiles and in the main clinical applications. The first-generation liposomes (conventional liposomes) comprised a liposome-containing amphotericin B, Ambisome, and Myocet, doxorubicin-containing liposome used in clinical trials to treat metastatic breast cancer. The last generation liposomes were pegylated liposomal doxorubicin (Caelix), called "stealth liposomes" because of their ability to evade interception by the immune system, characterized by very long-circulation half-life, favourable pharmacokinetic behaviour and specific accumulation in tumor tissues.

Melphalan monitoring during hyperthermic perfusion of isolated limb for melanoma: pharmacokinetic study and 99mTc-albumin microcolloid technique.

BACKGROUND: The kinetics of melphalan leakage from extracorporeal fluid to the peripheral blood was studied in ten patients undergoing hyperthermic isolation perfusion of the lower limbs as an adjuvant treatment in high-risk melanoma. MATERIALS AND METHODS: Systemic leakage was monitored by a new technique using 99mTc-albumin microcolloid. Serial samples were drawn from a peripheral vein and from the perfusion circuit during surgical treatment and analysed by HPLC. RESULTS: The leakage measured with 99mTc-albumin microcolloid ranged from 1.5 to 18%/h (mean 8%/h). The average concentrations in the perfusate were 200-300-fold those found in the systemic circulation. A good correlation (R=0.945) was obtained between systemic AUC (0 to 1 hour) and leakage measured through the 99mTc procedure. Negligible toxicity was found and the survival rate yielded 92% of objective response. CONCLUSION: By studying the pharmacokinetic data of melphalan in the circuit and in the systemic circulation, we were able to validate the 99mTc procedure used during clinical perfusion. Moreover, considering the efficiency of the system as well as the minimum toxicity and the high survival rate, a reduction of perfusion time may be considered.

Vinyl sulfide derivatives of truncated oxidosqualene as selective inhibitors of oxidosqualene and squalene-hopene cyclases.

Various vinyl sulfide and ketene dithioacetal derivatives of truncated 2,3-oxidosqualene were developed. These compounds, having the reactive functions at positions C-2, C-15 and C-19 of the squalene skeleton, were studied as inhibitors of pig liver and Saccharomyces cerevisiae oxidosqualene cyclases (OSC) (EC 5.4.99.7) and of Alicyclobacillus acidocaldarius squalene hopene cyclase (SHC) (EC 5.4.99.-). They contain one or two sulfur atoms in alpha-skeletal position to carbons considered to be cationic during enzymatic cyclization of the substrate and should strongly interact with enzyme nucleophiles of the active site. Most of the new compounds are inhibitors of the OSC and of SHC, with various degrees of selectivity. The methylthiovinyl derivative, having the reactive group at position 19, was the most potent and selective inhibitor of the series toward S. cerevisiae OSC, with a concentration inhibiting 500% of the activity of 50 nM, while toward the animal enzyme it was 20 times less potent. These results could offer new insight for the design of antifungal drugs.

Stereospecific syntheses of trans-vinyldioxidosqualene and 3-hydroxysulfide derivatives, as potent and time-dependent 2,3-oxidosqualene cyclase inhibitors.

trans-Vinyldioxidosqualene and beta-hydroxysulfide derivatives were synthesized stereospecifically and evaluated as inhibitors of animal and yeast oxidosqualene cyclases. Only trans-vinyldioxidosqualene and 2,3-epoxy-vinyl-beta-hydroxysulfides, having the reactive function at crucial positions 14,15 and 18,19, were active as inhibitors of animal and yeast cyclases. (14-trans)-28-Methylidene-2,3: 14,15-dioxidoundecanorsqualene 27 was the most potent inhibitor of the series of pig liver cyclase, with an IC50 of 0.4 microM, and it behaved also as the most active time-dependent inhibitor of the animal enzyme.

Pharmacokinetic monitoring of mycophenolate mofetil in kidney transplanted patients.

Mycophenolate mofetil (MMF) is a new immunosuppressant drug used in association with cyclosporin and oral corticosteroids to prevent acute rejection following renal allograft transplantation. MMF is an ester pro-drug of mycophenolic acid (MFA), the true active species, into which it is completely transformed after oral administration. The recommended initial dose to prevent kidney transplant rejection is 2 g/day irrespective of body weight, 1 g twice daily. The goal of this study was to correlate dosage (fixed or by body weight) and toxic effects to some non-compartmental values such as peak level (Cmax), time to peak level (Tmax) and trough level (Cmin). In a small number of patients who had already reached the plasma steady state, we found a large inter-patient variability, while the same qualitative pharmacokinetic profile (as Tmax) was conserved. At plasma trough level > 4 microg/ml some serious toxic effects were observed, whereas at Cmin < 2 microg/ml, there were some cases of interstitial rejection. There was also a negative correlation between dosage and body weight, suggesting that dosages related to body weight might be better than fixed ones. Finally, monitoring plasma level of drug from transplantation to at least 12 months after surgery, at fixed MFA dosage, a small but significant decline of MFA plasma levels was found.

Rationally designed inhibitors as tools for comparing the mechanism of squalene-hopene cyclase with oxidosqualene cyclase.

The inhibition of squalene-hopene cyclase (SHC) (E.C. 5.4.99.-), an enzyme of bacterial membranes catalyzing the formation of pentacyclic sterol-like triterpenes, was studied by using different classes of compounds originally developed as inhibitors of oxidosqualene cyclase (OSC) (E.C. 5.4.99.7), the enzyme of eukaryotes responsible for the formation of tetracyclic precursors of sterols. The mechanism of cyclization of squalene by SHC, beginning with a protonation of the 2,3 double bond by an acidic residue of the enzyme, followed by a series of electrophilic additions of the carbocationic intermediates to the double bonds, is similar to the mechanism of cyclization of 2,3-oxidosqualene by OSC. The inhibitors studied included: (i) analogs of the carbocationic intermediates formed during cyclization, such as aza-analogs of squalene and 2,3-oxidosqualene; (ii) affinity-labeling inhibitors bearing a methylidene reactive group; and (iii) vinyldioxidosqualenes and vinylsulfide derivatives of the substrates. Comparison of the results obtained with the two enzymes, SHC and OSC, showed that many of the most effective inhibitors of OSC were also able to inhibit SHC, while some derivatives acted as specific inhibitors. Differences could be easily explained on the basis of the different substrate specificity of the two enzymes.

Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes.

Paclitaxel (Taxol) is a diterpenoid isolated from Taxus brevifolia, approved by the FDA for the treatment of ovarian and breast cancers. Due to its low solubility in water, it is clinically administered dissolved in Cremophor EL, (polyethoxylated castor oil) and ethanol, which cause serious side effects. Inclusion of paclitaxel in liposomal formulations has proved to be a good approach to eliminating this vehicle and improving the drug's antitumor efficacy. We prepared different conventional and PEGylated liposomes containing paclitaxel and determined encapsulation efficiency, physical stability and drug leakage in human plasma. The best conventional liposome formulation was composed of ePC/PG 9:1, while for PEGylated liposomes the best composition was ePC/PG/CHOL/PEG(5000)-DPPE 9:1:2:0.7. PEGylated liposomes were found to be less stable during storage than the corresponding conventional liposomes and to have lower drug release in human plasma at 37 degrees C. In vitro cytotoxic activities were evaluated on HT-29 human colon adenocarcinoma and MeWo melanoma cell lines. After 2 and 48 h, conventional liposomes had the same cytotoxicity as free paclitaxel, while PEGylated liposomes were as active as free drug, only after 48 h. Pharmacokinetics and biodistribution were evaluated in Balb/c mice after i.v. injection of paclitaxel, formulated in Cremophor EL or in conventional or in PEGylated liposomes. Encapsulation of paclitaxel in conventional liposomes produced marked differences over the free drug pharmacokinetics. PEGylated liposomes were long-circulating liposomes, with an increased t(1/2) beta 48.6 h, against t(1/2) beta 9.27 h of conventional liposomes. Biodistribution studies showed a considerable decrease in drug uptake in MPS-containing organs (liver and spleen) at 0.5 and 3 h after injection with PEGylated compared to conventional liposomes.

Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing water-soluble prodrugs of paclitaxel.

Paclitaxel (Taxol) is a diterpenoid isolated from Taxus brevifolia, used clinically for the treatment of ovarian and breast cancer. Due to its aqueous insolubility it is administered dissolved in ethanol and Cremophor EL (polyethoxylated castor oil), which has serious side effects. In order to eliminate this vehicle, in previous work we entrapped paclitaxel in conventional and in polyethylene glycol coated liposomes. However, in neither formulation did we obtain satisfactory entrapment efficiency. In this study we increased the paclitaxel concentration entrapped in liposomes by incorporating different water-soluble prodrugs, such as the 2'-succinyl, 2'-methylpyridinium acetate and 2'-mPEG ester paclitaxel derivatives, in the lipid vesicles. Liposomes containing 2'-mPEG (5000)-paclitaxel showed the best performance in terms of stability, entrapment efficiency and drug concentration (6.5 mgml(-1)). The in vitro cytotoxic activity of this liposomal prodrug was similar to that of the parent drug. The pharmacokinetic parameters for the free and for the liposomal prodrugs fitted a bi-exponential plasma disposition. The most important change in pharmacokinetic values of the prodrug vs. the free drug liposomal formulations was t(1/2)beta, plasma lifetime, which was longer in liposomes containing 2'-mPEG (5000)-paclitaxel.

19-Azasqualene-2,3-epoxide and its N-oxide: metabolic fate and inhibitory effect on sterol biosynthesis in Saccharomyces cerevisiae.

19-Azasqualene-2,3-epoxide was more inhibitory than the corresponding N-oxide against 2,3-oxidosqualene cyclase (OSC) solubilized from Saccharomyces cerevisiae (IC50 7+/-2 and 25+/-5 microM, respectively). Both compounds showed a reversible, noncompetitive-type inhibition on solubilized OSC. Different inhibitory properties between the compounds were especially evident when measuring [14C]acetate incorporation into nonsaponifiable lipids extracted from treated cells. In cells treated with 19-azasqualene-2,3-epoxide at 30 microM, the radioactivity associated with the oxidosqualene fraction, which was negligible in the controls, rose to over 40% of the nonsaponifiable lipids, whereas it remained at a slightly appreciable level in cells treated with the N-oxide derivative under the same conditions. 19-Azasqualene-2,3-epoxide was also more effective than the N-oxide as a cell growth inhibitor (minimal concentration of compound needed to inhibit yeast growth: 45 and >100 microM, respectively). The two inhibitors underwent different metabolic fates in the yeast: while 19-azasqualene-2,3-epoxide did not undergo any transformation, its N-oxide was actively reduced to the corresponding amine in whole and in "ultrasonically stimulated" cells. The N-oxide reductases responsible for this transformation appear to be largely confined within the microsomal fractions and require NADPH for their activity. A possible relationship between the inhibitory properties of the two compounds and their metabolic fates is discussed.

Docetaxel in combination with epirubicin in metastatic breast cancer: pharmacokinetic interactions.

Epirubicin (75 mg/m2) and docetaxel (75 mg/m2) were administered to 16 patients affected by metastatic breast cancer following two different schedules: (1) docetaxel as infusion administered 1 h after epirubicin administration (schedule A); and (2) docetaxel as infusion immediately (10 min) after the end of epirubicin i.v. bolus administration (schedule B). Experimental non-compartmental analyses such as AUC and Css, were affected very little by the drug combination, irrespective of whether the administration of docetaxel was immediately after the epirubicin bolus (10 min) or delayed (1 h). However, serum levels showed evidence of transient drug interaction: in schedule A, docetaxel infusion was associated with a transient increase of plasma epirubicin in correspondence with Cssmax of docetaxel. Bi-compartmental analysis showed a significant difference in epirubicin clearance between protocols A and B. It is suggested that polysorbate 80, used in minimal amounts to formulate docetaxel, may interfere with epirubicin plasma level.