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G Fabbri

Publications and source records attributed to G Fabbri.

At least 19 recordsLinked to original sources
PubMed2002

In vitro and in vivo activity of analogues of the kinin B2 receptor antagonist MEN1 1270.

In this study, we describe the in vitro and in vivo activities of a series of cyclic peptide analogues of the selective kinin B2 receptor antagonist MEN11270 on Chinese hamster ovary cells expressing the human B2 receptor (hB2R), the human isolated umbilical vein (hUV), the isolated guinea pig ileum (gpI), and bradykinin (BK) induced bronchoconstriction (BC) and hypotension in anaesthetized guinea pigs. Substitutions in the backbone of MEN1 1270 (H-DArg-Arg-Pro-Hyp-Gly-Thi-c(Dab-DTic-Oic-Arg)c(7gamma-10alpha)) aimed to increase the potency in inhibiting bronchospasm versus hypotension following the topical (intratracheal (i.t.)) or systemic (intravenous (i.v.)) application of these antagonists. A series of analogues were left unprotected from N-terminal cleavage by aminopeptidases (MEN12739, MEN13052, MEN13346, and MEN13371): these compounds maintained sizeable affinities for the hB2R (pKi = 9.4, 9.6, 9.7, and 8.6, respectively) and antagonist activities toward BK in the hUV (pA2 = 7.9, 8.3, 8.2, and 7.5) and gpI assays (pK(B) = 7.4, 7.8, 7.9, and 7.9), but the inhibition of BK-induced BC and hypotension in vivo was negligible following either i.v. or i.t. administration. Two analogues (MEN12388 and MEN13405) could be potential substrates of angiotensin-converting enzyme: these have good activity in the hB2R (pKi = 9.5 and 8.9, respectively), hUV (pA2 = 8.2 for MEN12388), and gpI assays (pK(B) = 8.4 and 8.0) but an in vivo activity 10- to 30-fold lower than the parent compound MEN1 1270 (pKi = 9.4, pA2 = 8.1, pKB = 8.3) when given by either the i.v. or the i.t. route. Other analogues were functionalized with a quaternary ammonium Lys derivative (MEN13031, MEN12374, and the previously mentioned MEN13052) or with an ethyl group on Arg (MEN13655 and the previously mentioned MEN13346 and MEN13405) in order to hinder or facilitate local absorption. MEN13346 and MEN13031 (pKi = 9.7and 9.5, pA2 = 8.2 and 7.9, pKB = 7.9 and 8.5, respectively) were 10- to 30-fold less active in vivo than MEN1 1270, without improving the discrimination between BK-induced BC and hypotension after either systemic or topical administration. It is concluded that the decreased in vivo activities of cyclic analogues of MEN11270 on BK-induced BC and hypotension following either their intratracheal or their intravenous routes of administration might be due in large part to metabolic degradation.

Adult↗
PubMed2002

Cardiovascular effects of peptide kinin B2 receptor antagonists in rats.

Bradykinin (BK) is a vasoactive peptide reputed to play an important role in cardiovascular homeostasis. In this study, we describe the cardiovascular changes (mean blood pressure (BP) and heart rate (HR)) induced by the i.v. administration (left jugular vein) of two selective kinin B2 receptor antagonist, namely icatibant (0.1-1 micromol/kg as a bolus) and MEN1 1270 (0.1-1 micromol/kg as a bolus or 1 micromol/kg infused in 15 or 60 min), in urethane-anaesthetized or conscious rats with an indwelling catheter implanted in the right carotid artery for BP measurements. In conscious rats, icatibant at 0.1 or 0.3 micromol/kg did not change BP but at 0.1 micromol/kg increased HR at 30 min from administration. MEN1 1270 at 0.1 or 0.3 micromol/kg induced a dose-related increase in BP and a concomitant bradycardia (significant at 0.3 micromol/kg) lasting for 5 or 30 min, respectively. Icatibant at 1 micromol/kg induced a slight (P < 0.05) increase in BP that resolved in 5 min and a biphasic tachycardia (peaks at 30 and 90 min from administration). MEN1 1270 at 1 micromol/kg induced a triphasic change in HR (tachycardia in the first 5 min, bradycardia at 30 min, and tachycardia at 90 and 120 min) and a biphasic change in BP (hypotension at 15 min and hypertension at 30 min). The i.v. infusion of MEN1 1270 (1 micromol/kg in 15 or 60 min) produced hypertension, whereas HR was increased only following the 15-min infusion. In urethane-anaesthetized rats, both icatibant and MEN1 1270 (0.1 micromol/kg as a bolus) increased BP and the onset for this effect was correlated with the time course of the antagonism of BK-induced hypotension, where the effect of MEN1 1270 was more rapid than that of icatibant. These results indicate that kinin B2 receptor antagonists can induce acute cardiovascular effects, and the reason for the different haemodynamic profile between icatibant and MEN1 1270 could be putatively attributed to kinetic characteristics.

Animals↗
PubMed2001

[General anaesthesia for orthopaedic pediatric surgery].

When there are no precise indications or contraindications, the choice between general anaesthesia and locoregional anaesthesia is not clear-cut, especially in paediatrics where there are not enough prospective studies about the safety and main complications with the two techniques. This study aims at providing some clarification concerning this problem by outlining the practice of anaesthetics in the Children's Orthopaedic Ward of Rizzoli Orthopaedic Institute which, for logistical reasons and based on past experience, was carried out by the exclusive use of general anaesthesia. The organizational aspects of pre- and post-operative management of the patients are described. In addition, the data of 836 general anaesthetics carried out in the year 2000 were recorded prospectively on a daily basis. The data included the characteristics of the patient, type of surgery, anaesthesiological methods, and intra- and postoperative complications (first 24 hours). No major complications occurred. There was a small incidence of minor complications (13,3%), which all resolved without sequelae. In the group of younger children, where the lowest number of adverse events were recorded (9,7%), halothane was prevalently used, analgesic opiates were excluded, and breathing was maintained spontaneously. The authors deem the results satisfactory with regards to safety and morbidity, and recommend that anaesthetists use the anaesthesiological methods with which they are more experienced and that are most compatible with the logistical and organisational conditions in which they must work.

Adolescent↗
PubMed2000

Solid-phase synthesis of MEN 11270, a new cyclic peptide kinin B2 receptor antagonist.

An efficient synthesis of the cyclic decapeptide MEN 11270 [H-DArg1-Arg2 Pro3-Hyp4-Gly5-Thi6-Dab7-DTic8-Oic9-Arg10 c(7gamma - 10alpha)] was developed. Two three-dimensional orthogonal strategies were applied and compared: Fmoc/Tos/Boc (procedure A) and Fmoc/Pmc/Dde (procedure B). Both resulted in a 23-step strategy comprising the stepwise solid-phase chain assembly of the linear protected peptide, partial deprotection, solution-phase cyclization and final full deprotection. The stepwise assembly of the linear peptide was optimized by double coupling and acylation time prolongation for critical residues (Tic, Dab, Thi, Pro). O-(7-azabenzotriazol-1-yl)-N,N,N',N' tetramethyluronium (HATU) was preferred as coupling reagent for Dab. In the cyclization step, the partial racemization of Arg10 (31% using 1-ethyl-3-(3'-dimethyl-aminopropyl) carbodiimide/1-hydroxybenzotriazole (EDC/HOBt) as activation system) was reduced to 3% with HATU. The final deprotection was performed in the presence of dimethylsulfide (procedure A) and thiocresol (procedure B) as scavengers, to avoid the sulfation of Hyp side chain. The final compound and the main by-products were characterized by mass spectroscopy (MS), nuclear magnetic resonance (NMR) and racemization test. Procedure B produced operationally simpler and more efficient results than A (28% overall yield versus 4%).

Amino Acids↗
PubMed2000

[BRING-UP 2: presentation of the study].

The BRING-UP 2 (ANMCO) is an observational study which evaluates the applicability, safety and efficacy profiles of beta-blockers in elderly patients and in those with severe heart failure. In this last category the recommendations for beta-blockers should be expanded, but in routine conditions of care the administration of these drugs still needs careful guide and observation.

Adrenergic beta-Antagonists↗
PubMed1999

Supratentorial atrophy in spinocerebellar ataxia type 2: MRI study of 20 patients.

There have been only few studies of brain magnetic resonance imaging (MRI) in spinocerebellar ataxia (SCA) type 2. We investigated 20 SCA2 patients, from 11 Sicilian families, and 20 age-matched control subjects using MRI. Our data confirm that olivopontocerebellar atrophy (OPCA) is the typical pattern in SCA2. We found no significant correlation between infratentorial atrophy, disease duration, or the number of CAG repeats in our SCA2 patients, but there was supratentorial atrophy in 12 patients, with a significant correlation between supratentorial atrophy and disease duration. OPCA appears to represent the "core" of the SCA2: however, central nervous system involvement is not limited to pontocerebellar structures. We therefore consider central nervous system degeneration in SCA2 as a widespread atrophy. MRI is helpful in diagnosing SCA, but it is not diagnostic in the absence of clinical and molecular studies. We suggest that serial MRI may play a role in evaluating "in vivo" the progressive steps of neurodegeneration in SCA2, for a better comprehension of the pathophysiology of this disorder.

Adult↗
PubMed1998

Epidemiology of post-infarction risk stratification strategies in a country with a low volume of revascularization procedures. GISSI-Prognosis Investigators.

AIMS: The aims of the GISSI Prognosis Registry were to describe the diagnostic strategies initiated in acute myocardial infarction patients by a representative sample of Italian cardiological centres, and to determine which clinical or hospital characteristics were associated with the initiation of invasive diagnostic or therapeutic procedures. METHODS AND RESULTS: Baseline characteristics, major in-hospital events and the indication and results of invasive and non-invasive procedures were collected on 1489 acute myocardial infarction patients discharged alive from 65 Italian cardiological centres over a period of 3 months. Twenty-five percent of centres had on site catheterization laboratories while the rest did not. Statistical significance was analysed by chi-square tests for categorical variables. A two-sample Student t-test was used to compare continuous variables. The adjusted analysis was performed utilizing multiple logistic regression models. The most performed procedures were standard, non-invasive: 57.8% of the patients underwent an exercise stress test, 70.8% ambulatory ECG monitoring and 95.6% two-dimensional echocardiography. Nuclear or echocardiographic imaging tests were performed in 40% of acute myocardial infarction survivors. Overall, coronary angiography was planned in 549 patients (36.9%). Variables independently associated with the indication for coronary angiography were residual ischaemia, younger age, contraindication to exercise stress testing, level of patients' education, higher volume of non-invasive diagnostic tests, and male sex. Overall, during a 6-month follow-up period, coronary angiography, percutaneous transluminal coronary angioplasty and coronary artery bypass surgery were performed, respectively in 35%, 10% and 8% of the study population. CONCLUSIONS: The setting where cardiologists practise determines the patterns of care in acute myocardial infarction patients more than the characteristics of the patient. The absence of evidence-based guidelines on the more complex and expensive procedures favour empirical attitudes and practices. The confirmation in a prospective cohort of patients, which aims to represent the care of a whole country, suggests that more effort should be given to the implementation of controlled studies rather than periodical reformulation of guidelines not supported by hard data.

Aged↗
PubMed1997

Synthesis of a series of Homopterocarpane derivatives with potential antitumor and anti-AIDS activity.

The synthesis of a series of derivatives related to (+/-) cis 6a, 12a-dihydro-6H,7H-[1]-benzopyrano-[4,3-b]-[1]-benzopyran (Homopterocarpane) is described. The synthesized derivatives have been tested at National Cancer Institute in its in vitro anti-cancer and anti-AIDS screening programs. The synthesized compounds are inactive in anti-HIV assay, while some show a GI50 < 100 microM (and < 50 microM in several cell lines) in NCI antitumor screening.

Anti-HIV Agents↗
PubMed1996

1,4-Dihydropyridines bearing a pharmacophoric fragment of lidoflazine.

A series of 1,4-dihydropyridines bearing a pharmacophoric fragment of lidoflazine was synthesized. The compounds were evaluated for inotropic, chronotropic, and calcium antagonist activities. All compounds behave as inotropic and chronotropic agents, except for compounds 4b, 5a, and 5b, which exhibit a rather weak calcium antagonism in vascular smooth muscle (like aorta). Compound 5b is about twofold more potent in decreasing both chronotropy and inotropy, while compound 5c is about fivefold more potent in decreasing inotropy than nifedipine. Moreover, compound 5b is the most potent calcium antagonist derivative of the series.

Animals↗
PubMed1996

Synthesis and antitumor activity of some analogues of flavone acetic acid.

Some coumarin-, flavonol- and flavanon-acetic acids are described. The cytotoxicity of the synthesized compounds was determined on a human colon carcinoma cell line (LoVo) through evaluation of neutral red uptake, performed by the Riddel method. All tested derivatives were able to induce a statistically significant reduction of lysosomal neutral red uptake at 5 x 10(-5) M concentration. Some compounds were more active than the reference compound flavon-8-acetic acid.

Acetates↗
PubMed1995

Synthesis and pharmacological characterization of some benzazepinone derivatives.

A series of some benzazepinone derivatives were prepared. The compounds were evaluated for inotropic, chronotropic and calcium antagonist properties. For the compounds bearing well-known alpha-blocking fragments, the antagonist potency at postsynaptic alpha-adrenoceptors was assessed. The new compounds were less effective as bradycardic agents and calcium antagonists but show remarkable negative inotropic activity.

Adrenergic alpha-Antagonists↗
PubMed1994

Influence of lipophilicity on the biological activity of cyclic pseudopeptide NK-2 receptor antagonists.

A series of cyclic pseudopeptides of the formula cyclo(Leu psi[CH2NH]Xaa-Gln-Trp-Phe-beta Ala), where Xaa represents the residue of an alpha-amino acid, has been synthesized in order to establish the role of the Xaa side chain for tachykinin NK-2 receptor antagonist activity. Syntheses have been carried out in solid phase with either Fmoc or Boc strategy. The antagonist potency on NK-2 receptors in the hamster isolated trachea (HT) and the rabbit isolated pulmonary artery (RPA) bioassays increases with Xaa lipophilicity; cyclo(Leu psi[CH2NH]Cha-Gln-Trp-Phe-beta Ala) and cyclo(Leu psi[CH2NH]Asp(NHBzl)-Gln-Trp-Phe-beta Ala) resulted in being the two most active antagonists (pA2 = 9.06 and 9.26 on HT, respectively). A significant linear correlation was found between pA2 values determined in HT and RPA bioassays and capacity factors measured in reversed phase HPLC. The comparison between the biological activities of cyclic hexapeptides containing or not containing the aminomethylene moiety proved the crucial role of the pseudopeptide bond for determining high antagonist potency at the NK-2 receptor.

Alkylation↗
PubMed1994

Evidence by magnetic resonance imaging of cerebral alterations of atrophy type in young insulin-dependent diabetic patients.

Aim of this study was to investigate a) if through Magnetic Resonance Imaging (MRI) it was possible to reveal cerebral alterations in patients with insulin-dependent diabetes mellitus (IDDM); b) if there was any correlation with hypoglycemic episodes, glycometabolic control, microvascular alterations and diabetic peripheral neuropathy. For this purpose ten ID-DM patients under treatment with human insulin, aged 19-30 yr with the disease, the duration being from 1 to 19 yr, were investigated by MRI using a Philips Gyroscan. Spin Echo sequences were used with images in T1 T2 in sagittal and axial planes. To measure the ventricular dilatation the cerebroventricular index (CVI) was evaluated. The MRI has put in evidence in 7/10 patients a dilatation in the lateral ventricles and subarachnoidal spaces of the cerebral vault and the cerebellum clearly due to cerebral atrophy. The CVI mean values (34.78 +/- 2.92) were statistically (p < 0.001) higher in diabetic patients respect to control subjects (CVI mean values 27.5 +/- 1.58). These alterations did not present clear correlations with the degree of glycometabolic control, duration of disease, number of symptomatic hypoglycemic episodes and threshold for hypoglycemic symptoms, retinal microvascular alterations, microalbuminuria, diabetic peripheral neuropathy. The clinical or functional relevance of CVI changes and the exact pathogenic mechanism remains to be clarified.

Adult↗