Synthesis and biological evaluation of new potential inhibitors of N-acylethanolamine hydrolyzing acid amidase.

N-Acylethanolamines, including N-palmitoyl-ethanolamine (PEA), are hydrolyzed to the corresponding fatty acids and ethanolamine by fatty acid amide hydrolase (FAAH). Recently, N-acylethanolamine-hydrolyzing acid amidase (NAAA) was identified as being able to specifically hydrolyze PEA. In order to find selective and effective inhibitors of this enzyme, we synthesized and screened several amides, retroamides, esters, retroesters and carbamates of palmitic acid (1-21) and esters with C15 and C17 alkyl chains (22-27). Cyclopentylhexadecanoate (13) exhibited the highest inhibitory activity on NAAA (IC(50)=10.0 microM), without inhibiting FAAH up to 50 microM. Compound 13 may become a useful template to design new NAAA inhibitors.

Interaction of a beta-sheet breaker peptide with lipid membranes.

Aggregation of beta-amyloid peptides into senile plaques has been identified as one of the hallmarks of Alzheimer's disease. An attractive therapeutic strategy for Alzheimer's disease is the inhibition of the soluble beta-amyloid aggregation using synthetic beta-sheet breaker peptides that are capable of binding Abeta but are unable to become part of a beta-sheet structure. As the early stages of the Abeta aggregation process are supposed to occur close to the neuronal membrane, it is strategic to define the beta-sheet breaker peptide positioning with respect to lipid bilayers. In this work, we have focused on the interaction between the beta-sheet breaker peptide acetyl-LPFFD-amide, iAbeta5p, and lipid membranes, studied by ESR spectroscopy, using either peptides alternatively labeled at the C- and at the N-terminus or phospholipids spin-labeled in different positions of the acyl chain. Our results show that iAbeta5p interacts directly with membranes formed by the zwitterionic phospholipid dioleoyl phosphatidylcholine and this interaction is modulated by inclusion of cholesterol in the lipid bilayer formulation, in terms of both peptide partition coefficient and the solubilization site. In particular, cholesterol decreases the peptide partition coefficient between the membrane and the aqueous medium. Moreover, in the absence of cholesterol, iAbeta5p is located between the outer part of the hydrophobic core and the external hydrophilic layer of the membrane, while in the presence of cholesterol it penetrates more deeply into the lipid bilayer.

Assessment of fluid-responsiveness parameters for off-pump coronary artery bypass surgery: a comparison among LiDCO, transesophageal echochardiography, and pulmonary artery catheter.

OBJECTIVE: To verify the reliability of different markers of fluid-responsiveness during off-pump cardiac surgery (OPCAB). DESIGN: A clinical prospective, nonblinded, nonrandomized study. SETTING: A community hospital. PARTICIPANTS: Nineteen patients. INTERVENTIONS: Pulmonary artery catheter (PAC), LiDCO (LiDCO, London, UK), and transesophageal echocardiography (TEE) parameters were measured before (t0) and after (t1) a fluid challenge was performed 20 minutes after induction of anesthesia, but before sternotomy and without inotropic infusion. A Student t test and Spearman test were performed for statistical analysis. MEASUREMENTS AND MAIN RESULTS: According to the variation of cardiac index after the fluid challenge (DeltaCI%), 2 groups of patients were identified: the responders (Re, DeltaCI% > 15%) and the nonresponders (nRe). Mean pulse pressure variation (PPV) and mean stroke volume variation (SVV) before the fluid challenge (t0) were significantly different between the 2 groups. No significant differences were shown in systolic pressure variation (SPV), left ventricular end-diastolic area, left ventricular end-diastolic volume, and peak changes of aortic flow (DeltaVAo). A statistically significant correlation was observed between DeltaCI% and PPV (R = 0.793), DeltaCI% and SVV (R = 0.809), and DeltaCI% and SPV (R = 0.766). No correlation with central venous pressure and pulmonary capillary wedge pressure was found. CONCLUSIONS: Dynamic parameters of fluid responsiveness by LiDCO are highly sensitive for assessment of intravascular volume status during OPCAB surgery. In contrast, even if static parameters by TEE reflect changes in ventricular diastolic volume, they are poor indicators of fluid responsiveness. Surprisingly, no significant correlation between DeltaVAo (TEE) and DeltaCI% was found.

Chemistry and biology of chromatin remodeling agents: state of art and future perspectives of HDAC inhibitors.

Chromatin remodeling is a fundamental phenomenon in the life of eukaryotic cells, bearing implications to numerous physiological and pathological phenomena. This review outlines the chemistry of natural and synthetic agents endowed with the ability to interfere with such biological function, with a particular emphasis on histone deacetylase (HDAC) inhibitors. Other aspects covered in this article comprise structure activity relationships (SAR) and modes of action at molecular level, including the description of crystal structures of enzyme-inhibitor complexes.

[What's the best assessment of preload after cardiac surgery?]. / La valutazione del precarico post-intervento cardiochirurgico: quale monitoraggio?

OBJECTIVE: The assessment of the role of transesophageal echocardiography and invasive tests with pulmonary modified catheter to monitor the preload indexes in patients in intensive-care-unit after cardiac coronary surgery. MATERIALS AND METHODS: Between January and December 2004 24 patients (14 male, 10 female) with coronary artery disease were prospectively enrolled for preload assessment during off-pump myocardial revascularization. Pulmonary Capillary Wedge Pressure (PCWP), Left Ventricular End Diastolic Indexed Area (LVEDAI), delta Aortic Velocity (deltaVAo), Right Ventricular End Diastolic Volume (RVEDVI) as preload indexes were evaluated. Transesophageal echocardiography and pulmonary modified catheter monitoring were performed during the preoperative period at T1 and after fluid infusion (T2). Patients were considered Responders (R) or No Responders (NR) if the Stroke Volume Index increase at T2 was >20% with respect to T1. RESULTS: Mean T1 PCWP was similar in both groups (12.8+/-2.2 in R vs. 11.4+/-3 mmHg in NR; p=NS) and mean increase of PCWP at T2 was similar in both groups (1.5+/-0.3% in R vs. 1.2+/-3% in NR; p=NS). Mean T1 RVEDVI was similar in both groups (97.33+/-34 in R vs. 101+/-21 ml/m2 in NR; p=NS); T2 RVEDVI was similar in R and NR Groups (122.11+/-49 vs. 138.54+/-30 ml/m2; p=NS); mean T1 and T2 LVEDAI was similar in R and NR (11.2+/-3.5 vs. 10.2+/-2.3 at T1 and 14.04+/-3.35 vs. 14.67+/-2.1 cm2/m2 at T2 respectively; p=NS). Higher mean value of T1 deltaVAo (20+/-7% in R vs. 10+/-2% in NR; p=0.006) were recorded while similar mean value of T2 deltaVAo were observed (11+/-3% in R vs. 5+/-2% in NR; p=0.743). Correlation index between T1 and T2 deltaVAo (R=0.82) in R was significant (p=0.0002), while correlation index between T1 and T2 deltaVAo (R=0.11) in NR was not significant. CONCLUSIONS: Our study showed in patients soon after coronary cardiac surgery deltaVAo is the only predictor of "fluid responsiveness" and of ventricular compliance.

In vitro anti-acanthamoeba action by thioureidic derivatives.

The anti-amoebic power of a series of bis-thioureidic derivatives against amoeba, responsible for a serious form of keratitis of the cornea, has been analysed. The synthesis of these products is also described.

Antioxidant activity of thioureidic derivatives I.

Recent developments in biomedical science have shown that free radicals are involved in many diseases. They attack the unsaturated fatty acids in the biomembrane resulting in membrane lipid peroxidation, which is strongly connected to aging, carcinogenesis and atherosclerosis. Free radicals also attack DNA and cause mutation leading to cancer. In addition lipid peroxidation is an important factor of deterioration in the processing and storage of food. Therefore, it is important to search for new effective radical scavengers (Sci. Rev. 2 (1997) 152; J. Nat. Prod. Rev. 63 (2000) 1035). In this manuscript we describe the antioxidant activity of new thioureidic compounds.

New metabolically stable fatty acid amide ligands of cannabinoid receptors: Synthesis and receptor affinity studies.

We investigated the structure-activity relationships for the interactions of fatty acid amide analogs of the endocannabinoid anandamide with human recombinant cannabinoid receptors. Thirty-five novel fatty acid amides were synthesized using five different types of acyl chains and 11 different aromatic amine 'heads.' Although none of the new compounds was a more potent ligand than anandamide, we identified three amine groups capable of improving the metabolic stability of arachidonoylamides and their CB(1)/CB(2) selectivity ratio to over 20-fold, and several aromatic amines capable of improving the affinity of short chain or monosaturated fatty acids for cannabinoid CB(1) receptors. For the first time a tertiary amide of arachidonic acid was found to possess moderate affinity (K(i)=300 nM) for cannabinoid CB(1), but not CB(2), receptors.

Synthesis and biological evaluation of 3-benzyl-1-methyl- and 1-methyl-3-phenyl-isothioureas as potential inhibitors of iNOS.

Novel benzyl- and phenyl-isothioureidic derivatives have been synthesised and evaluated as inhibitors of nitric oxide synthesis, induced in lipopolysaccharide (LPS)-activated J774.A1 macrophage cell line. The most potent iNOS inhibitor resulting was 1-methyl-3-phenyl-S-methyl isothiourea 5l.

Pharmacological studies and synthesis of morpholino alkyl derivatives.

Seven morpholin derivatives were synthesized (compounds 1-7) and their behavioural effects were evaluated; the elements considered were locomotor activity, motor coordination, catalepsy, stereotyped behaviour and antinociception. All the compounds, at doses of 10-20-40 mg/kg/i.p., induced a reduction of all behavioural elements without a significant antinociceptive effect. These results indicate that these morpholin derivatives affect the central nervous system.