Biomedical subjects

Stefano Evangelista

Publications and source records attributed to Stefano Evangelista.

8 recordsLinked to original sources

PubMed2006

Effects of angiotensin-converting-enzyme inhibitors in combination with diuretics on blood pressure and renal injury in nitric oxide-deficiency-induced hypertension in rats.

The present study investigates the effects of chronic administration of ACEIs (angiotensin-converting-enzyme inhibitors; either zofenopril or enalapril) in combination with a diruetic (hydrochlorothiazide) on BP (blood pressure) increase and renal injury induced by L-NAME (NG-nitro-L-arginine methyl ester), an inhibitor of NO (nitric oxide) synthesis. Rats were untreated or received L-NAME alone, L-NAME+zofenopril+hydrochlorothiazide or L-NAME+enalapril+hydrochlorothiazide for 8 weeks. L-NAME treatment resulted in marked elevation in BP and mortality. Treatment with either ACEI and diuretic prevented the increase in BP induced by L-NAME, reduced the death rate and improved excretory parameters. Renal injury in the L-NAME group was severe, but, in the groups treated with either ACEI and diuretic, glomerular and tubulointerstitial lesions were not observed and the intensity, number and size of vessels affected was reduced. However, the efficacy of zofenopril+diuretic was superior to that of enalapril+diuretic in reducing vascular alterations. Oxidative stress indices and the expression of NO synthase and nitrotyrosine were normalized by the treatments. In conclusion, the combined treatment of zofenopril or enalapril with hydrochlorothiazide completely prevented the development of arterial hypertension induced by L-NAME. Renal morphological and functional alterations in the hypertensive animals were also almost completely normalized, but the treatment with zofenopril+diuretic produced a more complete organ protection. The protective effect is related to an activation of endothelial NO synthase expression and to a normalization of the oxidative stress parameters due to the inhibition of angiotensin II.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2006

Fibrinolytic efficacy of Amediplase, Tenecteplase and scu-PA in different external plasma clot lysis models: sensitivity to the inhibitory action of thrombin activatable fibrinolysis inhibitor (TAFI).

In this study, the in-vitro fibrinolytic efficacy of Tenecteplase, Amediplase and scu-PA was investigated in different external lysis models by measuring the lysis of human plasma clots after the addition of the plasminogen activators (PAs) to the surrounding plasma. The effect of TAFI was examined for each PA by neutralising TAFIa with potato carboxypeptidase inhibitor (PCI). The lytic efficacy of Amediplase was lower than that of Tenecteplase at low PA concentrations but slightly higher at therapeutic concentrations. The activity of scu-PA was clearly lower than that of either Tenecteplase or Amediplase. The TAFI system inhibited external clot lysis mediated by all the PAs when thrombomodulin was present in the model. In the therapeutic range (5-10 mug/ml) however, the TAFIa effect was negligible for both Amediplase and Tenecteplase. At lower PA concentrations the effect of TAFI on Amediplase was slightly stronger than that on Tenecteplase. Under static conditions the lysis rates were lower than with stirring. The role of TAFI was similar under both conditions. In conclusion, at therapeutic concentrations Amediplase was slightly more active than Tenecteplase and scu-PA under all conditions used. Therefore, Amediplase might possibly be a more potent thrombolytic agent at these concentrations and increase the efficacy of thrombolysis. The potential of TAFI for inhibiting thrombolytic therapy is probably low. However in conditions where the local PA concentrations are sub-optimal TAFI might affect the lysis rate.

Blood Coagulation↗

PubMed2005

Involvement of nitric oxide in both central and peripheral haemodynamic effect of D/L-nebivolol and its enantiomers in rats.

The cardiovascular profile of the racemate D/L-nebivolol and its enantiomers administered by intravenous (i.v.) or by intracerebroventricular (i.c.v.) route was investigated in anaesthetized normotensive rats. D/L-Nebivolol (0.1-0.5 mg/kg) induced a dose-related reduction in blood pressure when administered by i.c.v. route. These hypotensive effects were more marked as compared to those achieved by peripheral administration of D/L-nebivolol (0.1-1 mg/kg i.v.). Both enantiomers contributed to the hypotensive effect of D/L-nebivolol by i.c.v. route, while the effects of the drug on blood pressure by i.v. route were due to the d-enantiomer. The bradycardic effect of the racemic form given i.v. was dose-related and, at the highest dose (1 mg/kg), was more pronounced as compared to i.c.v. route. D-Nebivolol was responsible for chronotropic effects by both the i.v. and i.c.v. route, although by i.c.v. route L-nebivolol also induced a reduction in heart rate. The nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) administered at 5 mg/kg i.v. bolus + 0.1 mg/kg/min infusion or at 2.5 mg/kg i.c.v. counteracted the effects of D/L-nebivolol (either 1 mg/kg i.v. or 0.5 mg/kg i.c.v.) on blood pressure, while it did not inhibit the cardiovascular changes induced by isoprenaline (300 ng/kg i.v.) or calcitonin gene-related peptide (CGRP; 400 ng/kg i.v.). In addition, i.c.v. effects of D/L-nebivolol on blood pressure and heart rate were not affected by pre-treatment with atropine (2 mg/kg i.v.). The present findings demonstrate that D/L-nebivolol produced haemodynamic changes following both peripheral and central administration; these latter findings are mainly due to its L-enantiomer and these effects involve the L-arginine/nitric oxide pathway.

Animals↗

PubMed2005

Talnetant GlaxoSmithKline.

Talnetant (SB-223412) is a selective, orally active NK3 antagonist based on 4-quinolinecarboxamide, and is under development by GlaxoSmithKline (formerly SmithKline Beecham) for the potential treatment of several disorders, including urinary incontinence, irritable bowel syndrome and schizophrenia. By November 2004, the compound had completed phase II trials.

Animals↗

PubMed2004

Spatial and temporal pattern of expression of interstitial collagenase, stromelysin/transin, gelatinase A, and TIMP-1 during experimental gastric ulcer healing.

BACKGROUND/AIM: Controlled proteolysis is a prerequisite for cell migration, angiogenesis, and matrix remodelling during gastric ulcer healing. We studied the temporal and spatial expression of three matrix metalloproteinases, gelatinase A (MMP-2), interstitial collagenase (MMP-13), stromelysin (MMP-3), and their major inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1) during experimental gastric ulcer healing induced in rats by acetic acid injection. METHODS: Gastric tissue specimens were hybridized with antisense (35)S-labelled RNA probes and the autoradiographic signal was analyzed by a computer aided image system. Gelatinase activity was analyzed by in situ and gel zymography. RESULTS: During gastric ulcer healing, MMP-2, MMP-3, and MMP-13 RNA expression was increased in stromal cells of the gastric mucosa bordering the ulcer, suggesting a prevalent role of non-epithelial cells in pericellular proteolysis. Gelatinolytic activity was increased during ulcer healing and it was associated with extracellular matrix of the healing mucosa and newly formed vessels. In contrast to MMP-2 RNA, which was homogeneously distributed in all layers of the ulcer bed, MMP-3 and MMP-13 RNAs were confined to the upper layers of the granulation tissue. TIMP-1 RNA was detected in both epithelial and stromal cells of the gastric mucosa adjacent to the ulcer, as well as in the granulation tissue of the ulcer bed. Both MMP and TIMP-1 expression returned to basal levels during the late stages of tissue remodeling. CONCLUSION: Gastric ulcer repair is associated with a transient expression of specific metalloproteinases and their inhibitors in a distinct anatomical pattern pointing to complex cellular and cell/matrix interactions in the various layers of the healing mucosa.

Animals↗

PubMed2002

Zofenopril inhibits the expression of adhesion molecules on endothelial cells by reducing reactive oxygen species.

Hypertension and coronary artery disease are intimately connected. The migration of circulating monocytes into the subendothelial occurs through the expression of some adhesion molecules on endothelial cells. The nuclear factor (NF)-kappaB, a redox-sensitive element, plays a key role in adhesion molecule gene induction. In this study we have compared the effects of two different angiotensin converting enzyme (ACE) inhibitors, one possessing an active sulfhydryl group (zofenopril) and one lacking this group (enalapril) on the cellular redox state (monitored by measuring intracellular reactive oxygen species and thiol status), expression of adhesion molecules, and activation of NF-kappaB in human umbilical vein endothelial cells (HUVECs). Zofenoprilat, the active form of zofenopril, significantly and dose dependently reduced the intracellular reactive oxygen species (ROS) and superoxide formation induced by oxidized low-density lipoprotein (ox-LDL) (P <.001) and tumor necrosis factor-alpha (TNF-alpha) (P <.001). Enalaprilat, the active form of enalapril, was ineffective. Zofenoprilat but not enalaprilat also decreased the consumption of the intracellular GSH induced by ox-LDL (P <.01) and TNF-alpha (P <.01). Although zofenoprilat significantly and dose dependently reduced the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and E-selectin induced by ox-LDL (P <.01) and TNF-alpha (P <.01) on HUVECs, enalaprilat did not. Ox-LDL and TNF-alpha increased the activation of NF-kappaB and the preincubation of HUVECs with zofenoprilat, but not with enalaprilat, dose dependently reduced its activation (P <.001). The conclusion is that the sulfhydryl (SH)-containing ACE inhibitors may be useful in inhibiting foam cell formation and thus slow the development of atherosclerosis.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2002

The colon-selective spasmolytic otilonium bromide inhibits muscarinic M(3) receptor-coupled calcium signals in isolated human colonic crypts.

1. Otilonium bromide (OB) is a smooth muscle relaxant used in the treatment of irritable bowel syndrome. Otilonium bromide has been shown to interfere with the mobilization of calcium in intestinal smooth muscle, but the effects on other intestinal tissues have not been investigated. We identified the muscarinic receptor subtype coupled to calcium signals in colonic crypt derived from the human colonic epithelium and evaluated the inhibitory effects of OB. 2. Calcium signals were monitored by fluorescence imaging of isolated human colonic crypts and Chinese hamster ovary cells stably expressing the cloned human muscarinic M(3) receptor subtype (CHO-M(3)). Colonic crypt receptor expression was investigated by pharmacological and immunohistochemical techniques. 3. The secretagogue acetylcholine (ACh) stimulated calcium mobilization from intracellular calcium stores at the base of human colonic crypts with an EC(50) of 14 micro M. The muscarinic receptor antagonists 4-DAMP, AF-DX 384, pirenzepine and methroctamine inhibited the ACh-induced calcium signal with the following respective IC(50) (pK(b)) values: 0.78 nM (9.1), 69 nM (7.2), 128 nM (7.1), and 2510 nM (5.8). 4. Immunohistochemical analyses of muscarinic receptor expression demonstrated the presence of M(3) receptor subtype expression at the crypt-base. 5. Otilonium bromide inhibited the generation of ACh-induced calcium signals in a dose dependent manner (IC(50)=880 nM). 6. In CHO-M(3) cells, OB inhibited calcium signals induced by ACh, but not ATP. In addition, OB did not inhibit histamine-induced colonic crypt calcium signals. 7. The present studies have demonstrated that OB inhibited M(3) receptor-coupled calcium signals in human colonic crypts and CHO-M(3) cells, but not those induced by stimulation of other endogenous receptor types. We propose that the M(3) receptor-coupled calcium signalling pathway is directly targeted by OB at the level of the colonic epithelium, suggestive of an anti-secretory action in IBS patients suffering with diarrhoea.

Acetylcholine↗

PubMed2002

Extended analysis of a double-blind, placebo-controlled, 15-week study with otilonium bromide in irritable bowel syndrome.

BACKGROUND/OBJECTIVE: In order to follow the most recent developments and recommendations in trial methodology for drug evaluation in patients with irritable bowel syndrome, we performed an extended analysis of a large clinical trial from a previously published study of otilonium bromide, using an assessment that integrates the key symptoms of irritable bowel syndrome. MATERIALS AND METHODS: A large-scale clinical trial with a double-blind, placebo-controlled, parallel-group study design was conducted in 378 patients, treated for 15 weeks with the recommended standard dose of 40 mg otilonium bromide or placebo three times daily. The study was based on the collection of 12 single efficacy endpoints. The new efficacy assessment was based on the data reported by the patients. Rather than demonstrating score differences between the treatment groups of the study, we carried out an assessment that integrates the most frequent symptoms reported (pain frequency and intensity, presence of meteorism and distension) by the patient. RESULTS: The rate of response to treatment within 2-4 months (the primary efficacy outcome measure) was significantly higher in the otilonium bromide group (36.9%) than in the placebo group (22.5%; P = 0.007). In each month of treatment, the rate of monthly response was higher in the otilonium bromide group as compared to the placebo group (P < 0.05). The total monthly and weekly responses to the single endpoints (intensity and frequency of pain and discomfort, meteorism/abdominal distension, severity of diarrhoea or constipation and mucus in the stool) were significantly more frequent in the group treated with otilonium bromide than in the placebo-treated group, with differences ranging from 10% to 20%. The subgroup analysis of the intestinal habits endpoint indicates that patients with diarrhoea have an additional benefit. CONCLUSION: The present re-evaluation of a previously published study confirms that otilonium bromide is more effective than placebo for the treatment of irritable bowel syndrome, being very efficient in relieving pain and discomfort.

Adult↗