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Biomedical subjects

S Poli

Publications and source records attributed to S Poli.

At least 19 recordsLinked to original sources
PubMed2001

Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone.

PURPOSE: The NK1-receptor antagonist MK-869 (L-754,030) has demonstrated antiemetic activity in humans receiving chemotherapy. Objectives of the present trial included the first assessment of oral MK-869 plus dexamethasone compared with a 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis after high-dose cisplatin. Furthermore, the study sought to confirm that addition of MK-869 to a 5HT(3) antagonist plus dexamethasone was more effective than just the 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis. METHODS: This multicenter, double-blind, parallel-group trial in 351 cisplatin-naïve patients evaluated prevention of acute (0 to 24 hours) and delayed emesis (primary efficacy parameter; days 2 to 5) after cisplatin (> or =70 mg/m(2)). Patients were randomized to four groups (I to IV) (n = number randomized; number evaluable): granisetron (10 microg/kg intravenously) pre-cisplatin followed by placebo on days 2 to 5 (group I) (n = 90; 90); granisetron and MK-869 (400 mg PO [by mouth]) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group II) (n = 86; 84); MK-869 (400 mg PO) the evening before and pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group III) (n = 89; 88); or MK-869 (400 mg PO) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group IV) (n = 86; 84). All patients also received dexamethasone (20 mg PO) before cisplatin. Additional medication was available to treat emesis or nausea at any time. RESULTS: In the acute period, 57%, 80%, 46%, and 43% of patients were without emesis in groups I, II, III, and IV, respectively (P <.01 for group II v group I). In the delayed period, the proportion of patients without emesis in groups I, II, III, and IV was 29%, 63%, 51%, and 57%, respectively (P <.01 for groups II, III, and IV v group I). The distribution of nausea scores in the delayed period was lower when comparing group II with group I (P <.05 for days 1 to 5 and days 2 to 5). One serious adverse event (dizziness) was rated as possibly related to MK-869. CONCLUSION: Once daily oral administration of MK-869 was effective in reducing delayed emesis and nausea after high-dose cisplatin. However, the combination of the 5HT3 antagonist plus dexamethasone was numerically superior to MK-869 plus dexamethasone in reducing acute emesis. Confirming and extending previous findings, the triple combination of a 5HT(3) antagonist, MK-869, and dexamethasone provided the best control of acute emesis.

Adult↗
PubMed1999

Endogenous proteins controlling amyloid beta-peptide polymerization. Possible implications for beta-amyloid formation in the central nervous system and in peripheral tissues.

We report that certain plasma proteins, at physiological concentrations, are potent inhibitors of amyloid beta-peptide (Abeta) polymerization. These proteins are also present in cerebrospinal fluid, but at low concentrations having little or no effect on Abeta. Thirteen proteins representing more than 90% of the protein content in plasma and cerebrospinal fluid were studied. Quantitatively, albumin was the most important protein, representing 60% of the total amyloid inhibitory activity, followed by alpha1-antitrypsin and immunoglobulins A and G. Albumin suppressed amyloid formation by binding to the oligomeric or polymeric Abeta, blocking a further addition of peptide. This effect was also observed when the incorporation of labeled Abeta into genuine beta-amyloid in tissue section was studied. The Abeta and the anti-diabetic drug tolbutamide apparently bind to the same site on albumin. Tolbutamide displaces Abeta from albumin, increasing its free concentration and enhancing amyloid formation. The present results suggest that several endogenous proteins are negative regulators of amyloid formation. Plasma contains at least 300 times more amyloid inhibitory activity than cerebrospinal fluid. These findings may provide one explanation as to why beta-amyloid deposits are not found in peripheral tissues but are only found in the central nervous system. Moreover, the data suggest that some drugs that display an affinity for albumin may enhance beta-amyloid formation and promote the development of Alzheimer's disease.

Amyloid beta-Peptides↗
PubMed1996

Interaction of sulfaphenazole derivatives with human liver cytochromes P450 2C: molecular origin of the specific inhibitory effects of sulfaphenazole on CYP 2C9 and consequences for the substrate binding site topology of CYP 2C9.

The effects of sulfaphenazole, 1, on typical activities catalyzed by human cytochromes P450 of the 1A, 3A, and 2C subfamilies expressed in yeast were studied. 1 acts as a strong, competitive inhibitor of CYP 2C9 (K(i) = 0.3 +/- 0.1 microM); it is much less potent toward CYP 2C8 and 2C18 (K(i) = 63 and 29 microM, respectively) and fails to inhibit CYP 1A1, 1A2, 3A4, and 2C19. From difference visible spectroscopy experiments using microsomes of yeast expressing various human P450s, 1 selectively interacts only with CYP 2C9 with the appearance of a peak at 429 nm as expected for the formation of a P450 Fe(III)-nitrogenous ligand complex (Ks = 0.4 +/- 0.1 microM). Comparative studies of the spectral interaction and inhibitory effects of twelve compounds related to 1 with CYP 2C9 showed that the aniline function of 1 is responsible for the formation of the iron-nitrogen bond of the 429 nm-absorbing complex and is necessary for the inhibitory effects of 1. The study of two new compounds synthesized during this work, in which the N-phenyl group of 1 was replaced with either an ethyl group or a 3,4-dichlorophenyl group, showed that the presence of an hydrophobic substituent at position 1 of the pyrazole function of 1 is required for a strong interaction with CYP 2C9. A model for the binding of 1 in the CYP 2C9 active site is proposed; that takes into account three major interactions that should be at the origin of the high-affinity and specific inhibitory effects of 1 toward CYP 2C9: (i) the binding of its nitrogen atom to CYP 2C9 iron, (ii) an ionic interaction of its SO2N- anionic site with a cationic residue of CYP 2C9, and (iii) an interaction of its N-phenyl group with an hydrophobic part of the protein active site.

Aryl Hydrocarbon Hydroxylases↗
PubMed1995

[Health education and the prevention of HIV infection in schools].

This review describes the HIV prevention strategies adopted since 1990 by the Italian Ministry of Health and Ministry of Education, coordinated by the National Health Institute, for use in Italian schools. It sets out reasons for believing that action in schools is essential in containing the spread of the HIV epidemic and presents teaching materials prepared for school use. An analysis is made of the IV national HIV information campaign, in which the Ministry of Health trained 4,000 middle and senior schools principals. The prospects for continuing the work with these 4,000 principals in the V information campaign, are also reported.

Adolescent↗
PubMed1994

The chloroperoxidase-catalyzed oxidation of phenols. Mechanism, selectivity, and characterization of enzyme-substrate complexes.

The reactivity of a series of para-substituted phenolic compounds in the peroxidation catalyzed by chloroperoxidase was investigated, and the results were interpreted on the basis of the binding characteristics of the substrates to the active site of the enzyme. Marked selectivity effects are observed. These operate through charge, preventing phenolic compounds carrying amino groups on the substituent chain to act as substrates for the enzyme, and through size, excluding potential substrates containing bulky substituents to the phenol nucleus. Also, chiral recognition is exhibited by chloroperoxidase in the oxidation of N-acetyltyrosine, where only the L isomer is oxidized. Kinetic measurements show that, in general, the efficiency of chloroperoxidase in the oxidation of phenols is lower than that of horseradish peroxidase. Paramagnetic NMR spectra and relaxation rate measurements of chloroperoxidase-phenol complexes are consistent with binding of the substrates close to the heme, in the distal pocket, with the phenol group pointing toward the iron atom. On the other hand, phenolic compounds which are not substrates for chloroperoxidase bind to the enzyme with a much different disposition, with the phenol group very distant from the iron and probably actually outside the active-site cavity.

Catalysis↗
PubMed1992

Mechanism of enantioselective oxygenation of sulfides catalyzed by chloroperoxidase and horseradish peroxidase. Spectral studies and characterization of enzyme-substrate complexes.

The binding of a series of alkyl aryl sulfides to chloroperoxidase (CPO) and horseradish peroxidase (HRP) has been investigated by optical difference spectroscopy, circular dichroism, paramagnetic NMR spectroscopy, and NMR relaxation measurements. The data are consistent with binding of the sulfides in the distal side of the heme pocket with CPO and near the heme edge with HRP. A linear correlation between the binding constants of para-substituted sulfides to CPO and the Taft sigma I parameter suggests that these substrates act as donors in donor-acceptor complexes involving some residue of the protein chain. Spectral studies during turnover show that high enantioselectivity in the CPO-catalyzed oxidation of sulfides results from a reaction pathway that does not involve the accumulation of compound II enzyme intermediate.

Catalysis↗
PubMed1991

Spectroscopic and binding studies on the stereoselective interaction of tyrosine with horseradish peroxidase and lactoperoxidase.

The interaction of a series of derivatives of tyrosine with horseradish peroxidase (HRP) and lactoperoxidase (LPO) was studied by using optical difference spectroscopy, c.d. and proton n.m.r. spectroscopy in order to reveal differences in the mode of binding of L-tyrosine and D-tyrosine, which are substrates of but react at different rates with the two peroxidases, to HRP and LPO. All the donor molecules form 1:1 complexes with HRP and LPO, but they display a range of affinities for the enzymes. Whereas D-tyrosine binds to HRP more strongly than does L-tyrosine, the opposite holds for the binding to LPO. The distances of the protons of bound tyrosine molecules from the haem iron atoms of HRP and LPO indicate that the site of binding of these substrates is the same as that of simple phenols. This involves the interaction of the phenol nucleus with a protein tyrosine residue [Sakurada, Takahashi & Hosoya (1986) J. Biol. Chem. 261, 9657-9662; Modi, Behere & Mitra (1989) Biochim. Biophys. Acta 996, 214-225]. However, for the present substrates the additional interaction of the carboxylate group with a protein residue (probably an arginine residue) provides further stabilization for the adducts HRP-D-tyrosine and LPO-L-tyrosine with respect to the corresponding complexes with the opposite enantiomers. The differences in the mode of binding of L-tyrosine and D-tyrosine to HRP and LPO is thus determined by the fact that the spatial arrangement of the interacting protein residues can recognize the chirality of the C(alpha)-CO2- and C(beta)-C6H4OH attachment bonds of the substrates.

Animals↗
PubMed1984

Diagnostic approach to pulmonary embolism: our strategy.

The nonspecificity and variety of clinical features in acute pulmonary embolism account for a high suspicion rate, with a further exclusion of the diagnosis in up to 80% of cases. Arterial blood gas analysis and other laboratory tests are highly non-specific, and suggestive signs on the electrocardiogram are uncommon. The plain chest X-ray often yields valuable information. Lung scan, when normal, has the great advantage of excluding pulmonary embolism. At present, no procedure has superseded pulmonary angiography to attest the presence of emboli. Angiography will probably gain widespread acceptance with the larger use of thrombolysis.

Acute Disease↗
PubMed1983

[Streptococcus (S. pyogenes) group A septicemia. Analysis of 20 cases in adults].

From 1976 to 1981, 25 cases of S. pyogenes septicemia were diagnosed at the University Medical Center, Lausanne, Switzerland, in 5 children and 20 adults. The twenty adult patients are described. The age range was from 24 to 94 years. The portal of entry was the skin (erysipelas, skin ulcers, surgical wounds) in 12 cases, the respiratory tract (upper 3, lower 3) in 6 cases, and the vagina in 2 cases. All except 3 patients were acutely ill with high temperature (39 degrees C) and toxic appearance. None had an underlying malignancy. The clinical course was complicated in 5 patients, i.e. septic arthritis (2), pulmonary abscess (1), endocarditis (1) and acute rheumatic fever (1). After initiation of penicillin therapy, temperature and symptoms resolved only slowly (mean 11 days). Four patients died from infection. In 2 of them the antibiotic treatment had been delayed. When a patient exhibits clinical signs of septicemia and muco-cutaneous lesions suggestive of a portal of entry, S. pyogenes septicemia should be suspected. Complications are frequent and the prognosis remains poor despite early adequate antibiotic treatment.

Adult↗
PubMed1980

Large scale fractionation of calf brain by double run zonal centrifugation.

A previously described method for the subfractionation of subcellular particles by zonal centrifugation (Spanner, 1972), gives an unsatisfactory resolution when applied to calf brain, particularly when large amounts of subcellular particles are required. We succeeded in subfractionating 30-45 g of gray matter by modifying the procedure for preparing the P2 fraction (crude mitochondrial fraction) and introducing a new stepwise sucrose gradient on double run zonal centrifugation. Satisfactory resolution can also be achieved by single run zonal centrifugation when the starting material does not exceed 15 g of gray matter. The following fractions were separated as characterized chemically morphologically and by their enzyme markers: a) light myelin (0.4-0.6 M sucrose); b) heavy myelin (0.7 M); c) plasmamembranes (0.9-1.0 M); d) nerve endings (1.0-1.2 M); e) mitochondria (1.3 M); f) lysosomes (1.4 M).

Animals↗