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Search Results: 1 - 10 of 461893 matches for " A. Gervasini "
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Comparative Cytochrome P450 In Vitro Inhibition by Atypical Antipsychotic Drugs
Guillermo Gervasini,Maria J. Caballero,Juan A. Carrillo,Julio Benitez
ISRN Pharmacology , 2013, DOI: 10.1155/2013/792456
Abstract:
Comparative Cytochrome P450 In Vitro Inhibition by Atypical Antipsychotic Drugs
Guillermo Gervasini,Maria J. Caballero,Juan A. Carrillo,Julio Benitez
ISRN Pharmacology , 2013, DOI: 10.1155/2013/792456
Abstract: The goal of this study was to assess in human liver microsomes the inhibitory capacity of commonly used antipsychotics on the most prominent CYP450 drug metabolizing enzymes (CYP1A2, CYP2C9, CYP2D6, and CYP3A). Chlorpromazine was the only antipsychotic that inhibited CYP1A2 activity ( ?μM), whilst levomepromazine, chlorpromazine, and thioridazine significantly decreased CYP2D6-mediated formation of -hydroxybufuralol (IC50 range, 3.5–25.5?μM). Olanzapine inhibited CYP3A-catalyzed production of , and -hydroxymidazolam ( and 42.20?μM, resp.). In contrast, risperidone ( ?μM) and levomepromazine ( ?μM) showed selectivity towards the inhibition of midazolam -hydroxylation reaction, and haloperidol did so towards -hydroxylation (IC50 of 2.76?μM). Thioridazine displayed a of 1.75?μM and an inhibitory potency of 1.57 on CYP2D6, suggesting a potential to induce in vivo interactions. However, with this exception, and given the observed values, the potential of the assayed antipsychotics to produce clinically significant inhibitions of CYP450 isoforms in vivo seems limited. 1. Introduction In contrast to conventional neuroleptics, atypical antipsychotics have been shown to be effective against both positive and negative symptoms of schizophrenia while showing a reduced propensity to induce extrapyramidal effects [1]. The cytochrome P450 (CYP) 1A2, CYP2C9, CYP2D6, and CYP3A enzymes are responsible for the metabolism of many of these and other psychoactive compounds [2–8]. Traditionally, studies on pharmacological interactions involving antipsychotics have examined the inhibition of these isoforms by drugs that are concomitantly administered, especially serotonin reuptake inhibitors [9–13]. However, there is still limited information on the capacity of antipsychotics to inhibit the metabolism of other coadministered drugs and the potentially clinically significant interactions that could arise [14]. In this paper we have assessed the potential for nine of the most commonly used atypical antipsychotics (clozapine, olanzapine, iloperidone, quetiapine, haloperidol, chlorpromazine, levomepromazine, thioridazine, and risperidone) and abaperidone (7-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidin-1-yl]propoxy]-3-(hydroxymethyl)chromen-4-one; FI-8602), an underdevelopment compound with a potentially atypical antipsychotic profile [15, 16], to cause significant drug-drug interactions by using in vitro inhibition techniques in human liver microsomes. 2. Methods 2.1. Reference Substances Abaperidone and iloperidone were gifts from Centro de Investigación Farmacéutica, Grupo
Property and Activity of Molybdates Dispersed on Silica Obtained from Various Synthetic Procedures  [PDF]
Antonella Gervasini, Laura Wahba, Manuel Dario Finol, Jean-Fran?ois Lamonier
Materials Sciences and Applications (MSA) , 2012, DOI: 10.4236/msa.2012.34030
Abstract: The synthesis and characterization of several dispersed molybdena catalysts on silica support (MoO3-SiO2) prepared from a variety of precursors (Mo(VI)-acetylacetonate, oxo-peroxo Mo-species, hydrated ammonium heptamolybdate) and preparation methods (deposition of the Mo-phase on finite SiO2 support by aqueous and methanol impregnations, by adsorption, by oxo-peroxo route-like, and by one-step synthesis of MoO3-SiO2 system with molecular precursors) are presented. The molybdena concentration on silica was comprised in a large interval (1.5 - 14 wt%) depending on the preparation method which governed the Mo-loading on silica. Convenient comparisons among samples at similar Mo-concentration have been made discussing the morphologic-structural (XRD, XPS, UV-vis-DRS, and N2-adsorption) and physicochemical (TG-DTG, TPR, and n-butylamine-TPD) sample properties. Polymeric octahedral polymolybdate aggregates predominated in the samples prepared by aqueous and methanol impregnations, which were at high Mo-concentration. On the contrary, isolated Mo(VI) species in distorted Td symmetry predominated in the sample prepared by adsorption which was at very low Mo-concentration. The sample acidity was composed of a weak acidy site population, associated with the silica support, and a strong acid site population associated with the Mo-dispersed phase. Oxidation tests of formaldehyde, an oxygen-containing VOC (Volatile Organic Compound), were performed to determine the prevalent redox or acidic function of the Mo-species at the surface of the catalysts.
Genetic variability in CYP3A4 and CYP3A5 in primary liver, gastric and colorectal cancer patients
Guillermo Gervasini, Elena García-Martín, José M Ladero, Rosa Pizarro, Javier Sastre, Carmen Martínez, Monserrat García, Manuel Diaz-Rubio, José AG Agúndez
BMC Cancer , 2007, DOI: 10.1186/1471-2407-7-118
Abstract: CYP3A4 and CYP3A5 genotypes were determined in 574 individuals including 178 patients with primary liver cancer, 82 patients with gastric cancer, 151 patients with colorectal cancer, and 163 healthy individuals.The variant allele frequencies for patients with liver cancer, gastric cancer, colorectal cancer and healthy controls, respectively, were: CYP3A4*1B, 4.8 % (95% C.I. 2.6–7.0), 3.7 % (0.8–6.6) 4.3% (2.0–6.6) and 4.3% (2.1–6.5); CYP3A5*3, 91.8 % (93.0–97.4), 95.7% (92.6–98.8), 91.7% (88.6–94.8) and 90.8% (87.7–93.9). The association between CYP3A4*1B and CYP3A5*3 variant alleles did not significantly differ among patients and controls. No differences in genotypes, allele frequencies, or association between variant alleles were observed with regard to gender, age at diagnosis, tumour site or stage.Common polymorphisms on CYP3A4 and CYP3A5 genes do not modify the risk of developing digestive cancers in Western Europe.The identification of low penetrance genes able to increase the risk of developing cancer could constitute a major tool for the identification of individuals with inheritable altered susceptibility. In this regard, the role of drug-metabolizing enzymes in cancer risk has been the object of several hundreds of studies performed over the last decade [1]. The main hypothesis underlying the link between drug-metabolizing enzymes and chemical carcinogenesis is based on the enzymatic activation of procarcinogens to biologically reactive metabolites. These reactive metabolites would interact with DNA, thereby causing altered gene expression or function, and eventually carcinogenesis. The primary metabolism of a variety of xenobiotic carcinogens is mainly mediated by cytochrome P450 (CYP) enzymes belonging to the CYP 1, 2 or 3 families, which together comprise 25 different isoenzymes. Among them, the most relevant are CYP1A1, CYP1A2, CYP1B1, CYP2E1, CYP3A4 and CYP3A5 [2-4]. Most of the latter enzymes are polymorphic, mutated alleles causing abolished, reduce
Novel C16orf57 mutations in patients with Poikiloderma with Neutropenia: bioinformatic analysis of the protein and predicted effects of all reported mutations
Elisa A Colombo, J Fernando Bazan, Gloria Negri, Cristina Gervasini, Nursel H Elcioglu, Deniz Yucelten, Ilknur Altunay, Umram Cetincelik, Anna Teti, Andrea Del Fattore, Matteo Luciani, Spencer K Sullivan, Albert C Yan, Ludovica Volpi, Lidia Larizza
Orphanet Journal of Rare Diseases , 2012, DOI: 10.1186/1750-1172-7-7
Abstract: We characterize six PN patients expanding the clinical phenotype of the syndrome and the mutational repertoire of the gene. We detect the two novel C16orf57 mutations, c.232C>T and c.265+2T>G, as well as the already reported c.179delC, c.531delA and c.693+1G>T mutations. cDNA analysis evidences the presence of aberrant transcripts, and bioinformatic prediction of C16orf57 protein structure gauges the mutations effects on the folded protein chain.Computational analysis of the C16orf57 protein shows two conserved H-X-S/T-X tetrapeptide motifs marking the active site of a two-fold pseudosymmetric structure recalling the 2H phosphoesterase superfamily. Based on this model C16orf57 is likely a 2H-active site enzyme functioning in RNA processing, as a presumptive RNA ligase.According to bioinformatic prediction, all known C16orf57 mutations, including the novel mutations herein described, impair the protein structure by either removing one or both tetrapeptide motifs or by destroying the symmetry of the native folding.Finally, we analyse the geographical distribution of the recurrent mutations that depicts clusters featuring a founder effect.In cohorts of patients clinically affected by genodermatoses with overlapping symptoms, the molecular screening of C16orf57 gene seems the proper way to address the correct diagnosis of PN, enabling the syndrome-specific oncosurveillance.The bioinformatic prediction of the C16orf57 protein structure denotes a very basic enzymatic function consistent with a housekeeping function. Detection of aberrant transcripts, also in cells from PN patients carrying early truncated mutations, suggests they might be translatable. Tissue-specific sensitivity to the lack of functionally correct protein accounts for the main cutaneous and haematological clinical signs of PN patients.Biallelic mutations of the C16orf57 (OMIM*613276) gene underlie Poikiloderma with Neutropenia (PN; OMIM#604173), an inherited genodermatosis characterized by early onset po
CYP1A1 gene polymorphisms increase lung cancer risk in a high-incidence region of Spain: a case control study
Carmen San Jose, Agustin Cabanillas, Julio Benitez, Juan Carrillo, Mercedes Jimenez, Guillermo Gervasini
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-463
Abstract: One-hundred-and-three cases of lung cancer and 265 controls participated in the study. The participants were screened for the presence of four CYP1A1 polymorphisms, namely MspI, Ile462Val, T3205C, and Thr461Asn. Lung cancer risk was estimated as odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression models adjusting for age, sex, and smoking.The distribution of the variant CYP1A1 alleles was different from that described for other Caucasian populations, with CYP1A1*2A showing an uncommonly high frequency (p < 0.01). The CYP1A1*2B allele (carrying MspI and Ile462Val mutations) was strongly associated with high lung cancer risk (OR = 4.59, CI:1.4-12.6, p <0.01). The Ile462Val polymorphism was also shown to increase the risk for the disease (OR = 4.51, CI:1.8-11.9; p <0.01) and particularly for squamous-cell (OR = 5.01; CI: 1.6-14.3, p < 0.01) and small-cell lung carcinoma (SCLC) (OR = 6.97, CI: 1.2-81.3; p = 0.04). Moreover, the Thr461Asn polymorphism was found to be associated with SCLC in a Caucasian population for the first time to our knowledge (OR = 8.33, CI: 1.3-15.2, p = 0.04).The results suggest that CYP1A1 polymorphisms contribute to increase lung cancer susceptibility in an area with an uncommon high incidence rate.In the late eighties, a group of oncologists working at the Merida hospital, which is located in an agricultural region situated in south-west Spain, started to notice the unusually high number of lung cancer patients being diagnosed. This prompted the creation of a local lung cancer registry in accordance with the guidelines issued by the International Agency for Research on Cancer (IARC) and the International Association of Cancer Registries (IACR). Quite shockingly, in a 10-year follow-up this registry revealed one of the highest standardized incidence rates of male lung cancer in Spain (58 cases per 100 000 inhabitants in the 1986-1990 period, Cabanillas et al., unpublished observations). This figure, which
Functional analysis of splicing mutations in exon 7 of NF1 gene
Irene Bottillo, Alessandro De Luca, Annalisa Schirinzi, Valentina Guida, Isabella Torrente, Stefano Calvieri, Cristina Gervasini, Lidia Larizza, Antonio Pizzuti, Bruno Dallapiccola
BMC Medical Genetics , 2007, DOI: 10.1186/1471-2350-8-4
Abstract: In this study we investigated the expression of exon 7 transcripts using bioinformatic identification of splicing regulatory sequences, and functional minigene analysis of four sequence changes [c.910C>T (R304X), c.945G>A/c.946C>A (Q315Q/L316M), c.1005T>C (N335N)] identified in exon 7 of three different NF1 patients.Our results detected the presence of three exonic splicing enhancers (ESEs) and one putative exonic splicing silencer (ESS) element. The wild type minigene assay resulted in three alternative isoforms, including a transcript lacking NF1 exon 7 (NF1ΔE7). Both the wild type and the mutated constructs shared NF1ΔE7 in addition to the complete messenger, but displayed a different ratio between the two transcripts. In the presence of R304X and Q315Q/L316M mutations, the relative proportion between the different isoforms is shifted toward the expression of NF1ΔE7, while in the presence of N335N variant, the NF1ΔE7 expression is abolished.In conclusion, it appears mandatory to investigate the role of each nucleotide change within the NF1 coding sequence, since a significant proportion of NF1 exon 7 mutations affects pre-mRNA splicing, by disrupting exonic splicing motifs and modifying the delicate balance between aberrantly and correctly spliced transcripts.Alternative splicing, the process by which exons are included or excluded in the mature mRNA, is an important mechanism whereby different transcripts are generated from the same gene unit. In fact, most human genes are transcribed in multiple alternative mRNAs, according to different regulatory programs, resulting in functionally different protein isoforms [1]. In the best characterized models of vertebrate cell-specific alternative splicing, post-transcriptional regulation is tissue or developmental stage specific and may be mediated by intronic and exonic cis elements. These elements, which are important for the correct splice-site identification, can act by stimulating (exonic splicing enhancers, ESEs) or
Formation Of A Cold Antihydrogen Beam in AEGIS For Gravity Measurements
G. Testera,A. S. Belov,G. Bonomi,I. Boscolo,N. Brambilla,R. S. Brusa,V. M. Byakov,L. Cabaret,C. Canali,C. Carraro,F. Castelli,S. Cialdi,M. de Combarieu,D. Comparat,G. Consolati,N. Djourelov,M. Doser,G. Drobychev,A. Dupasquier,D. Fabris,R. Ferragut,G. Ferrari,A. Fischer,A. Fontana,P. Forget,L. Formaro,M. Lunardon,A. Gervasini,M. G. Giammarchi,S. N. Gninenko,G. Gribakin,R. Heyne,S. D. Hogan,A. Kellerbauer,D. Krasnicky,V. Lagomarsino,G. Manuzio,S. Mariazzi,V. A. Matveev,F. Merkt,S. Moretto,C. Morhard,G. Nebbia,P. Nedelec,M. K. Oberthaler,P. Pari,V. Petracek,M. Prevedelli,I. Y. Al-Qaradawi,F. Quasso,O. Rohne,S. Pesente,A. Rotondi,S. Stapnes,D. Sillou,S. V. Stepanov,H. H. Stroke,G. Tino,A. Vairo,G. Viesti,H. Walters,U. Warring,S. Zavatarelli,A. Zenoni,D. S. Zvezhinskij,for the AEGIS Proto-Collaboration
Physics , 2008, DOI: 10.1063/1.2977857
Abstract: The formation of the antihydrogen beam in the AEGIS experiment through the use of inhomogeneous electric fields is discussed and simulation results including the geometry of the apparatus and realistic hypothesis about the antihydrogen initial conditions are shown. The resulting velocity distribution matches the requirements of the gravity experiment. In particular it is shown that the inhomogeneous electric fields provide radial cooling of the beam during the acceleration.
Rubinstein-Taybi Syndrome: spectrum of CREBBP mutations in Italian patients
Angela Bentivegna, Donatella Milani, Cristina Gervasini, Paola Castronovo, Federica Mottadelli, Stefano Manzini, Patrizia Colapietro, Lucio Giordano, Francesca Atzeri, Maria T Divizia, Maria Uzielli, Giovanni Neri, Maria F Bedeschi, Francesca Faravelli, Angelo Selicorni, Lidia Larizza
BMC Medical Genetics , 2006, DOI: 10.1186/1471-2350-7-77
Abstract: Our study is based on the mutation analysis of CREBBP in 31 Italian RSTS patients using segregation analysis of intragenic microsatellites, BAC FISH and direct sequencing of PCR and RT-PCR fragments.We identified a total of five deletions, two of the entire gene and three, all in a mosaic condition, involving either the 5' or the 3' region. By direct sequencing a total of 14 de novo mutations were identified: 10 truncating (5 frameshift and 5 nonsense), one splice site, and three novel missense mutations. Two of the latter affect the HAT domain, while one maps within the conserved nuclear receptor binding of (aa 1–170) and will probably destroy a Nuclear Localization Signal. Identification of the p.Asn1978Ser in the healthy mother of a patient also carrying a de novo frameshift mutation, questions the pathogenetic significance of the missense change reported as recurrent mutation. Thirteen additional polymorphisms, three as of yet unreported, were also detected.A high detection rate (61.3%) of mutations is confirmed by this Italian study which also attests one of the highest microdeletion rate (16%) documented so far.Rubinstein-Taybi syndrome (RSTS; MIM 180849) is a congenital disorder characterized by growth retardation and psychomotor developmental delay, broad and duplicated distal phalanges of thumbs and halluces, and a wide range of typical dysmorphic features. Facial dysmorphology includes down-slanted palpebral fissures, broad nasal bridge, beaked nose and micrognathia [1]. In addition, patients with RSTS have an increased, although not well documented, risk of tumor formation [2,3]. RSTS was shown to be associated with microdeletions and point mutations in the gene encoding the CREB-binding protein (CREBBP, also known as "CBP"), located in 16p13.3 [4]. CREBBP is a transcriptional coactivator and possesses acetyltransferase activity on lysine residues of histones and nonhistone proteins [5]. CREBBP partecipates in basic cellular functions, including growth, d
Recurrent microdeletion at 17q12 as a cause of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome: two case reports
Laura Bernardini, Stefania Gimelli, Cristina Gervasini, Massimo Carella, Anwar Baban, Giada Frontino, Giancarlo Barbano, Maria Divizia, Luigi Fedele, Antonio Novelli, Frédérique Béna, Faustina Lalatta, Monica Miozzo, Bruno Dallapiccola
Orphanet Journal of Rare Diseases , 2009, DOI: 10.1186/1750-1172-4-25
Abstract: we report on two patients affected by MRKH syndrome in which array-CGH analysis disclosed an identical deletion spanning 1.5 Mb of genomic DNA at chromosome 17q12. One patient was affected by complete absence of uterus and vagina, with bilaterally normal ovaries, while the other displayed agenesis of the upper part of vagina, right unicornuate uterus, non cavitating rudimentary left horn and bilaterally multicystic kidneys. The deletion encompassed two candidate genes, TCF2 and LHX1. Mutational screening of these genes in a selected group of 20 MRKH females without 17q12 deletion was negative.Deletion 17q12 is a rare albeit recurrent anomaly mediated by segmental duplications, previously reported in subjects with developmental kidney abnormalities and diabetes. The present two patients expand the clinical spectrum associated with this imbalance and suggest that this region is a candidate locus for a subset of MRKH syndrome individuals, with or without renal defects.Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (MIM 277000) affects about 1 in 4500 female births, presenting with congenital aplasia of the uterus and the upper part of vagina, in association with unremarkable development of secondary sexual characteristics and normal 46, XX karyotype. This disorder can be isolated (type I; OMIM 277000) and comprises the so-called CAUV (Congenital Absence of the Uterus and Vagina) and MA (Müllerian Aplasia), or associated with renal, skeletal and/or hearing defects. Cardiac and digital anomalies are rare. Patients with associated anomalies are classified as MURCS association (Müllerian duct aplasia, Renal Dysplasia and Cervical Somite anomalies), also indicated as MRKH type II syndrome (OMIM 601076), or GRES (Genital Renal Ear Syndrome)(OMIM 267400) if the middle ear is also affected [1]. The most common coexisting defects affect the upper urinary tract, including unilateral renal agenesis, ectopia of one or both kidneys, renal hypoplasia, horseshoe kidney and hydronephr
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