Biomedical subjects

M Guarneri

Publications and source records attributed to M Guarneri.

At least 19 recordsLinked to original sources

PubMed2001

Potential of pyrazolooxadiazinone derivatives as serine protease inhibitors.

As a part of an investigation on molecular hybrids as new serine protease inhibitors, the pyrazolo [4,3-c][1,2,5]oxadiazin-3(5H)-one ring system was selected as a model of potential mechanism-based inhibitors. Due to the inherent reactivity of this system an optimal balance between susceptibility to nucleophilic attack and stability in solvents was sought prior to development as therapeutic agents. Substitutions on N5 and C7 of the supporting pyrazole ring with either aliphatic or aromatic groups (compounds 2 a-m) and the replacement of the carbonyl oxygen on the reactive oxadiazinone ring with sulfur (compounds 3a,i) were explored. Two members (2i and 2k) of this class of inhibitors displayed time-dependent inhibition of HLE suggesting mechanism-based inhibition. The observation that HLE generated a product(s) from compound 2i which displayed an identical UV-Visible spectrum to that observed during non-enzymatic hydrolysis further supports this proposal. FlexX-based docking of these compounds into a model of the human leukocyte elastase (HLE) active site produced a molecular model of the inhibitor-enzyme interaction.

Binding Sites↗

PubMed2001

A multicenter Italian study of patients' relatives' beliefs about schizophrenia.

This study explored patients' relatives' beliefs about schizophrenia in Italy, a country with a long history of community-based psychiatry. The study was conducted among 709 key relatives of patients with schizophrenia who were recruited in 30 mental health departments. Relatives seemed to believe that mental hospitals are not appropriate places in which to treat their loved ones, even though most of them felt that they were alone in coping with the burden of their ill relative's disease. Most of the relatives agreed that people who have schizophrenia should be allowed to vote, but they appeared to have a stricter attitude toward affective rights, such as the patient's right to get married and have children, and tended to perceive their loved ones as being subject to social discrimination. The findings of this study may be useful for developing psychoeducational intervention and sensitization campaigns for the general population.

Adult↗

PubMed2000

Family burden and coping strategies in schizophrenia: 1-year follow-up data from the BIOMED I study.

BACKGROUND: To date, only few data are available on how family burden in schizophrenia changes over time. In addition, no study has explored how such factors as coping styles and social support influence burden over time. This paper presents the 1-year follow-up data from the BIOMED I study on family burden and coping strategies in schizophrenia. METHODS: A sample of 159 relatives of patients with schizophrenia living in five European countries was followed up prospectively for 1 year with regard to burden and coping strategies, using validated questionnaires. RESULTS: In the sample as a whole, the burden was stable. A reduction of family burden over time was found among relatives who adopted less emotion-focused coping strategies and received more practical support from their social network. In addition, family burden decreased in relation to the improvement of patient's social functioning. CONCLUSIONS: When relatives of patients with schizophrenia are able to improve their coping strategies, it is possible for burden to be reduced even after several years. This points to the necessity to provide families of chronic psychotic patients with psychoeducational interventions emphasising the adoption of an effective coping style.

Adaptation, Psychological↗

PubMed2000

Pregnenolone sulfate, a naturally occurring excitotoxin involved in delayed retinal cell death.

The present study was designed to investigate the neurosteroid pregnenolone sulfate (PS), known for its ability to modulate NMDA receptors and interfere with acute excitotoxicity, in delayed retinal cell death. Three hours after exposure of the isolated and intact retina to a 30-min PS pulse, DNA fragmentation as assessed by genomic DNA gel electrophoresis and a modified in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method appeared concurrently with an increase in superoxide dismutase (SOD) activity and thiobarbituric acid-reactive substances (TBARS) levels. At 7 h, the increased amount of DNA laddering was accompanied by a higher number of TUNEL-positive cells in the inner nuclear and ganglion cell layers. Necrotic signs were characterized by DNA smear migration, lactate dehydrogenase (LDH) release, and damage mainly in the inner nuclear layer. PS-induced delayed cell death was markedly reduced by the NMDA receptor antagonists 4-(3-phosphonopropyl)-2-piperazinecarboxylic acid and 3alpha-hydroxy-5beta-pregnan-20-one sulfate but completely blocked after concomitant addition of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Steroids with antioxidant properties (progesterone, dehydroepiandrosterone and its sulfate ester, and 17beta-estradiol) differently prevented PS-induced delayed cell death. Cycloheximide treatment protected against DNA fragmentation and LDH release but failed to prevent the rise in SOD activity and TBARS level. We conclude that a brief PS pulse causes delayed cell death in a slowly evolving apoptotic fashion characterized by a cycloheximide-sensitive death program downstream of reactive oxygen species generation and lipid peroxidation, turning into secondary necrosis in a retinal cell subset.

Adjuvants, Immunologic↗

PubMed1999

A new questionnaire assessing the opinions of the relatives of patients with schizophrenia on the causes and social consequences of the disorder: reliability and validity.

This paper describes the development and the validation of a questionnaire assessing the opinions of the relatives of patients with schizophrenia on the causes and the social consequences of the disorder. The final version of the questionnaire includes 28 items, grouped in four sub-scales (social restrictions, social distance, utility of treatments, biopsychosocial causes of schizophrenia), whose intra-rater reliability ranges from 0.36 to 0.84. Cronbach's alpha coefficient, which tests the content validity of the sub-scales, ranges from 0.56 to 0.66. Factor analysis identifies two factors (opinions on social consequences and the utility of treatments, and the beliefs on the causes of schizophrenia), which account for the 73% of the total variance. This questionnaire may be particularly useful to assess relatives'beliefs about schizophrenia and to target psychosocial interventions in the families of patients with schizophrenia.

Adaptation, Psychological↗

PubMed1998

Burden on the families of patients with schizophrenia: results of the BIOMED I study.

The burden, the coping strategies and the social network of a sample of 236 relatives of patients with schizophrenia, living in five European countries, were explored by well-validated assessment instruments. In all centres, relatives experienced higher levels of burden when they had poor coping resources and reduced social support. Relatives in Mediterranean centres, who reported lower levels of social support, were more resigned, and more often used spiritual help as a coping strategy. These data indicate that family burden and coping strategies can be influenced by cultural factors and suggest that family interventions should have also a social focus, aiming to increase the family social network and to reduce stigma.

Adaptation, Psychological↗

PubMed1998

Social and clinical factors influencing the choice of coping strategies in relatives of patients with schizophrenia: results of the BIOMED I study.

The impact of social and clinical factors on the choice of coping strategies of a sample of 236 relatives of patients with schizophrenia, living in five European countries, was explored using well-validated questionnaires. The adoption of problem-focused coping strategies was more frequent among young relatives and among relatives of younger patients, and was associated with higher levels of practical and emotional social support and of professional help. In contrast, emotion-focused strategies were more frequently adopted by relatives who had been living longer with the patient and who had poorer social support. It is suggested that supportive and educational interventions should be provided as early as possible to relatives of patients with schizophrenia, which, in addition to having a practical focus, should also have a social focus, aiming at extending the family's social network.

Adaptation, Psychological↗

PubMed1996

A new questionnaire assessing coping strategies in relatives of patients with schizophrenia: development and factor analysis.

This paper describes the development and validation of a questionnaire assessing the coping strategies adopted by relatives of patients with schizophrenia. The final version of the questionnaire includes 27 items, grouped into seven subscales (information, positive communication, social interests, coercion, avoidance, resignation and patient's social involvement), the intra-rater reliability of which ranges from 0.46 to 0.76. Cronbach's alpha coefficient, which tests the content validity of the subscales, ranges from 0.68 to 0.83. Factor analysis identifies three factors (problem-oriented coping strategies, emotionally focused strategies, and maintenance of social interests in association with patient's avoidance), accounting for 70.9% of the total variance. This questionnaire may be particularly useful for targeting and monitoring psychoeducational interventions in the families of patients with schizophrenia.

Adaptation, Psychological↗

PubMed1995

Synthesis of N1-substituted benzamidines. Effects on blood coagulation, platelet aggregation and antiarrhythmic activity.

A series of N1-substituted-4-alkoxybenzamidines was synthesized and tested in vitro for their inhibitory effects on blood coagulation and agonist induced platelet aggregation. The antiarrhythmic activity against chloroform-induced arrhythmias in mice was also evaluated. The biological activity of the title compounds is reported in comparison with that of procainamide; among the new products described, IVi and IVe were found to have the most potent anti-platelet and antiarrhythmic activity, respectively. The structure-activity relationships are discussed.

Action Potentials↗

PubMed1995

Cholinergic agents structurally related to furtrethonium. 3. Synthesis and antimuscarinic activity of a series of N-(5-methyl-2-furfuryl and-tiophenyl)-dialkyl amines and of 2-dimethylamino methyl-4-(1'-substituted-acetoxy-methyl)-1,3-dioxolanes.

The introduction of an homologous series of cyclic amines at position 2 of 5-methylfurane and its isoster 5-methylthiophene induced a weak antagonist behaviour, probably depending on the steric hindrance of the substituents at the nitrogen, in the case of the cardiac tissue. Surprisingly, when evaluated on guinea-pig ileum preparatons, these compounds showed non-muscarinic effects, not-related either to nicotinic or istaminergic effects, the nature of which awaits to be explained. Substitution of the furane ring on the structure of the lead 2a, b, obtained in a previous study, with the bioisoster 1,3-dioxolane moiety gave potent but not selective analogues (17 and 18).

Animals↗

PubMed1994

Cholinergic agents structurally related to furtrethonium. 2. Synthesis and antimuscarinic activity of a series of N-[5-[(1'-substituted-acetoxy) methyl]-2-furfuryl]dialkylamines.

In the first part of this study, devoted to the discovery of selective antimuscarinic agents, (+/-)- N-[5-[(1'-phenyl-1'-cyclohexylacetoxy)methyl]-2-furfuryl]dimeth yla mine (5a) proved to be at least 20 times more potent in the rat ileum and bladder than in guinea pig atria. Several (+/-)-N- [5-[(1'-substituted-acetoxy)methyl]-2-furfuryl]dialkylamine analogs of 5a were subsequently prepared. This involved exploration of the tertiary nitrogen substituents and modulation of the lipophilic side chain at position 5 of the furan ring, using the Hansch approach. A QSAR study was conducted to correlate activity with physicochemical properties of substituents. The possibility of describing all compounds in a single model indicates that variations of nitrogen and the lipophilic side chain contribute independently to activity. Compounds 5b, c,j, with bulky lipophilic substituents at the tertiary nitrogen, showed unprecedented selectivity between the two smooth muscle tissues, their antimuscarinic potency being from 10 to 90 times higher in the ileum than in the bladder. It is suggested that their interesting tissue selectivity is probably related to nonspecific phenomena involving the receptor environment, rather than real differences between the muscarinic receptors in the two tissues.

Animals↗

PubMed1994

Geiparvarin analogues. 4. Synthesis and cytostatic activity of geiparvarin analogues bearing a carbamate moiety or a furocoumarin fragment on the alkenyl side chain.

As a continuation of previous studies on the synthesis and antitumor activity of geiparvarin analogues bearing a carbamate moiety in the alkyl side chain, a series of N-substituted [(E)-3-(4,5-dihydro-5,5-dimethyl-4-oxo-2-furanyl)-2- butenyl]carbamates (15a-f) were synthesized and tested with the objective to investigate the reason for the marked difference of cytostatic activity found between alkyl and phenyl derivatives. A series of compounds, characterized by different physicochemical properties, were designed in order to study this hypothesis. Moreover, to further investigate the modification of the alkenyl side chain, (E)- and (Z)-[2-(4,5-dihydro-5,5-dimethyl-4-oxo-2-furanyl)propenyl]-7H-furo[3,2- g][1]benzopyran-7-one (11a,b) were synthesized, the latter compounds being the combination of two units, namely, the 3(2H)-furanone ring system endowed with potent alkylating properties and the furocoumarin portion which binds to DNA resulting in potential DNA-targeted alkylating agents. The compounds were tested for their cytostatic activity against proliferation of murine (L1210) and human (Molt/4, CEM, or MT-4) tumor cells. The highest cytostatic activity found within both series of carbamic derivatives (15a-d,k and 15e,g-j) was associated with the highest global lipophilicity. With regard to compounds 11a,b, the cytostatic activity of (Z)-furocoumarin 11b might be related to a specific interaction with DNA (i.e., intercalation).

Animals↗

PubMed1994

Validity of rapid cycling as a course specifier for bipolar disorder.

OBJECTIVE: This study's aim was to test the validity of rapid cycling, defined by criteria consistent with those proposed in the DSM-IV draft, as a course specifier for bipolar disorder. METHOD: The study was conducted at a university center for affective disorders on patients fulfilling Research Diagnostic Criteria for bipolar disorder. Thirty-seven rapid-cycling patients, i.e., patients with at least four affective episodes during the previous year, were compared with 74 nonrapid-cycling patients on several demographic and clinical variables. All patients were then followed up prospectively for 2-5 years by monthly personal interviews. RESULTS: The rapid-cycling group was significantly older and had a significantly longer illness duration than the nonrapid-cycling group but did not have a significantly higher percentage of women or frequency of current hypothyroidism. During each year of follow-up, the mean number of affective episodes and the percentage of patients with at least four affective episodes were significantly higher among rapid-cycling patients. Rapid-cycling patients with a pole-switching pattern during the year preceding intake were significantly more likely than other rapid-cycling patients to have at least four affective episodes during each of the first 4 years of follow-up. CONCLUSIONS: These findings support the practical usefulness of rapid cycling as a course modifier for bipolar disorder, since it identifies a patient subgroup with a high recurrence rate. The predictive value of the modifier may be enhanced by the requirement of a pole-switching pattern. Since no external (i.e., unrelated to course) validator was found, the idea that rapid cycling represents one extreme of a continuum of episode frequency in bipolar disorder remains viable.

Adult↗

PubMed1992

Pyrazole-related nucleosides. Synthesis and antiviral/antitumor activity of some substituted pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one nucleosides.

Several pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one ribonucleosides were prepared and tested for antiviral/antitumor activities. Appropriate heterocyclic bases were prepared by standard methodologies. Glycosylation of pyrazoles 6a-e,g,i and of pyrazolo[4,3-d]-1,2,3-triazin-4-ones 12f-1 mediated by silylation with hexamethyldisilazane, with 1-beta-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose, gave in good yields the corresponding glycosides 7a-e,g, 8g,i, 13f,h,k, and 14f, but could not be applied to compounds 12g,i,j,l. To overcome this occurrence, a different strategy involving the preparation, diazotization, and in situ cyclization of opportune pyrazole glycosides 9 and 10 was required. Moreover derivatives having the general formula 5 were considered not only as synthetic intermediates in the synthesis of 3 but also as carbon bioisosteres of ribavirin 4. All compounds were evaluated in vitro for cytostatic and antiviral activity. The pyrazolo[4,3-d]-1,2,3-triazin-4-one nucleosides that resulted were substantially devoid of any activity; only 15h,k showed a moderate cytostatic activity against T-cells. However, pyrazole nucleosides 9b,c,e were potent and selective cytotoxic agents against T-lymphocytes, whereas 9e showed a selective, although not very potent, activity against coxsackie B1.

Animals↗

PubMed1992

Effect of basic cholane derivatives on intestinal cholic acid metabolism: in vitro and in vivo activity.

A representative series of hydroxy-5 beta-cholanyl-24-amines were tested both in vitro and in vivo with respect to their activity against the intestinal bacteria responsible for bile acid metabolism. For the in vitro studies, radiolabeled [14C]cholic acid was incubated with human stools both in aerobic and anaerobic conditions in the presence of the title compounds at a dose of 10 micrograms/mL, and the biotransformation of cholic acid into radiolabeled deoxycholic acid and other metabolites was followed by TLC-radiochromatography. Of the compounds studied, 3 alpha, 12 alpha-dihydroxy-5 beta-cholan-24-N-methylamine showed the highest activity. This compound was used for the in vivo studies and was shown to inhibit the formation of endogenous secondary bile acids when chronically administered to rats at a dose of 60 micrograms/day for 15 days. The treated rats showed an increased ratio of taurocholic acid (primary bile acid) to taurodeoxycholic acid (secondary bile acid) in bile, a fact further suggesting a potent antibacterial activity of the compound toward bacteria responsible for bile acid metabolism.

Aerobiosis↗

PubMed1992

Basic cholane derivatives. XI: Comparison between acid and basic derivatives.

A series of hydroxycholan-24-amines was synthesized; the carboxyl group of starting unconjugated bile acids was transformed into a basic moiety [-NH2, -NHCH3, -N(CH3)2, or -NHCH2C6H5] at C-24. Solubilities, acidities, partition coefficients, and critical micellar concentrations were measured and compared with those of the corresponding bile acids. Because the steroid nucleus in the amines is the same as that in the bile acids, most of the physical-chemical properties of the two compound classes were similar. The amines were more soluble than the corresponding acids; solubilities depended mainly on the number of steroid hydroxyls and, to a lesser extent, on the side chain. Amines are strong bases in water, whereas unconjugated bile acids can be classified as weak acids. N-Benzylamino derivatives have higher log P (P is partition coefficient) values, as a consequence of the bulky hydrophobic substituent; the log P values were almost the same for the amines and the bile acids and depended on the steroid hydroxyls. Amines can self-aggregate at an acidic pH and form cationic micelles; the critical micellar concentrations of amines were of the same order of magnitude as those of bile acids. The introduction of a basic function in the side chain of the cholane moiety increased the antimicrobial activity toward most gram-positive strains.

Bile Acids and Salts↗

PubMed1992

Inhibition of human alpha-, beta- and gamma-thrombin by mono-, bis-, tris- and tetra-benzamidine structures: thermodynamic study.

The inhibitory effect of mono-, bis-, tris- and tetra-benzamidine structures (benzamidine, DAPP, TAPB and TAPP, respectively) on the catalytic properties of human alpha-, beta- and gamma-thrombin (alpha-, beta- and gamma-thrombin, respectively) was investigated (between pH 2.0 and 7.0, I = 0.1 M; T = 37.0 +/- 0.5 degrees C). The affinity of DAPP, TAPB and TAPP for alpha- and beta-thrombin is higher than that found for benzamidine association around neutrality, converging in the acidic pH limb; in contrast, benzamidine, DAPP, TAPB and TAPP show the same value of the association inhibition constant (Ki; M-1) for gamma-thrombin over the whole pH range explored. On lowering the pH from 5.5 to 3.0, the decrease in affinity for benzamidine binding to alpha-, beta- and gamma-thrombin, as well as for DAPP, TAPB and TAPP association to gamma-thrombin reflects the acidic-pK shift, upon inhibitor binding of a single ionizing group. On the other hand, values of Ki for DAPP, TAPB and TAPP binding to alpha- and beta-thrombin appear to be modulated by the acidic-pK shift, upon inhibitor association, of two equivalent proton-binding residues over the same pH range. By considering molecular models of the serine proteinase:inhibitor complexes, the observed binding behaviour of benzamidine, DAPP, TAPB and TAPP to alpha-, beta- and gamma-thrombin has been related to the inferred stereochemistry of the enzyme:inhibitor contact region(s).

Amidines↗

PubMed1991

Antimicrobial activity of basic cholane derivatives. X. Synthesis of 3 alpha- and 3 beta-amino-5 beta-cholan-24-oic acids.

A simple and convenient route to 3 alpha- and 3 beta-amino-5 beta-cholan-24-oic acids was developed via Leuckart-Wallach amination reduction and subsequent acid hydrolysis. Two epimeric formylamino derivatives were produced (alpha and beta), approximately in a 1:1 ratio, as determined by 13C nuclear magnetic resonance spectroscopy. The two isomers were separated by making use of their different solubilities in ethyl ether. The absolute configuration of the two amino acids was assigned by comparison with authentic reference samples.

Lithocholic Acid↗