Biomedical subjects

M Del Tacca

Publications and source records attributed to M Del Tacca.

At least 91 records · Page 5Linked to original sources

PubMed1995

Role of peripheral GABAB receptors in the regulation of pepsinogen secretion in anaesthetized rats.

The purpose of the present study was to investigate the role played by GABAB receptors in the regulation of gastric basal pepsinogen secretion in anaesthetized rats. Following parenteral administration, the GABAB receptor agonists (-)-baclofen and 3-aminopropylphosphinic acid (3-APPA) caused a dose-dependent increase in basal pepsinogen secretion which was associated with a parallel increment in acid output. The gastric stimulant effects induced by both agonists were not affected by intracerebroventricular injection of the GABAB receptor antagonists 2-hydroxy-saclofen, 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348) or phaclofen, whereas the excitatory actions were antagonized by intravenously administered 2-hydroxy-saclofen or CGP 35348, but not phaclofen. In addition, the (-)-baclofen-induced increases in both pepsinogen and acid output, were fully prevented by omeprazole or cimetidine, partly reduced by atropine and unaffected by pretreatment with capsaicin. When tested on rats undergoing bilateral cervical vagotomy, both (-)-baclofen and 3-APPA were still able to stimulate the basal pepsinogen and acid secretions, although at a lesser extent than in animals with intact vagus nerves. The stimulant actions elicited by (-)-baclofen in vagotomized rats were antagonized by 2-hydroxy-saclofen or CGP 35348, but not phaclofen. Moreover, these gastric excitatory effects were prevented by cimetidine or compound 48/80, while being unaffected by atropine. The present results show that peripheral GABAB receptors mediate an excitatory effect on gastric pepsinogen secretion which totally depends on an increase in acid output. It is also suggested that both vagal cholinergic and extravagal pathways, probably histaminergic in nature, take part in these GABAB receptor-mediated gastric stimulant actions.

Anesthesia↗

PubMed1995

Central administration of cholecystokinin stimulates gastric pepsinogen secretion from anaesthetized rats.

Intracerebroventricular administration of CCK-8S was associated with a stimulation of gastric pepsinogen secretion from anaesthetized rats; similar effects were induced by CCK-8S given intravenously. The excitatory effect of intracerebroventricular CCK-8S was not modified by central injection of L-364,718 or L-365,260, whereas both these antagonists, given by intravenous route, prevented the pepsigogue action of parenteral CCK-8S. Intracerebroventricular or intravenous CCK-8S also increased basal acid secretion, this latter effect being prevented by parenteral L-365,260 but not L-364,718. It is suggested that centrally applied CCK-8S evokes pepsinogen secretion through the activation of peripheral CCK-A and CCK-B receptors.

Anesthesia↗

PubMed1995

Characterization of alpha 2-adrenoceptor subtypes involved in the modulation of gastric acid secretion.

The effects of several alpha 2-adrenoceptor agonists and antagonists were examined on gastric acid secretion from reserpinized rats undergoing electrical stimulation of the left vagus nerve. Both detomidine and oxymetazoline inhibited vagal acid hypersecretion, their effects being fully prevented by idazoxan, 7,8-(methylenedioxy)-14-alpha-hydroxyalloberbane (CH 38083), or 2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline (RX 821002), and partly antagonized by yohimbine or rauwolscine. 2-(2,4-(O-methoxy-phenyl)-piperazin-1-yl)-ethyl-4,4-dimethyl-1,3-( 2H,4H)-isoquinolindione (ARC 239) did not affect the antisecretory action of the two agonists, while prazosin at the highest dose was partly effective only against detomidine. Atropine markedly reduced vagally evoked acid output. It is suggested that acid secretion induced by vagal cholinergic stimulation is modulated by alpha 2A-like adrenoceptor subtypes.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1995

Suramin in patients with metastatic colorectal cancer pretreated with fluoropyrimidine-based chemotherapy. A phase II study.

BACKGROUND: The results of conventional chemotherapy in metastatic colorectal cancer are discouraging, making it a logical target for new treatment approaches a necessary consideration. Suramin is a polysulfonated naphthylurea that binds to several cellular growth factors and has in vitro activity against human colorectal cancer cells. Therefore, this Phase II study of patients with metastatic colorectal cancer was conducted to evaluate its clinical activity. METHODS: Suramin was administered as a 6-day continuous infusion every week for 8 consecutive weeks by using a computer-assisted dosing of Bayesan pharmacokinetics to maintain suramin plasma concentrations of 200-250 micrograms/ml. Twenty patients with metastatic colorectal cancer who were not responsive or in progression within 6 months after completing fluoropyrimidine-based chemotherapy entered the study. RESULTS: Toxicities included mostly Grade 1 and 2 fatigue, nausea and vomiting, peripheral neurotoxicity, creatinine elevation, and proteinuria. No objective responses were observed, but three of three patients who received 5-fluorouracil plus folinic acid after suramin achieved a partial response. CONCLUSIONS: These results indicate that suramin is inactive in patients with metastatic colorectal cancer pretreated with fluoropyrimidines. Pretreatment with suramin may have changed the biology of the tumor, sensitizing it to fluoropyrimidines. Studies to investigate this possibility are in progress.

Adult↗

PubMed1995

Trapidil inhibits endothelial cell proliferation and angiogenesis in the chick chorioallantoic membrane and in the rat cornea.

The effects of trapidil, a coronaro-active drug which has been shown to inhibit the mitogenic activity of platelet derived growth factor (PDGF), have been investigated on the proliferation of the human endothelial cells (HUV-EC-C), on the neovascularization in the chorioallantoic membrane of the chick embryo (CAM) as well as on the angiogenesis of rat cornea following chemical injury. The proliferation of HUV-EC-C in the presence of trapidil (25 and 250 micrograms/mL) was significantly inhibited by 19 and 25% respectively, compared to controls. On 2-days old CAMs, agarose disks containing 100-150 micrograms of trapidil produced an avascular zone indicating significant antiangiogenic activity, while control agarose disks were without effect. Corneal neovascularization was induced by applying a silver nitrate/potassium nitrate applicator to the rat eyes. A 6-day-treatment with eye drops of a solution of 10 mg/mL trapidil significantly decreased the rate of vessel growth compared with vehicle controls. The antiangiogenic activity of trapidil was markedly increased by the association with hydrocortisone (1.34 mg/mL). These results suggest that trapidil, alone or in combination with a steroid, could be a promising candidate for the therapy of corneal diseases in which alterations induced by neovascular growth play a substantial role.

Allantois↗

PubMed1995

Central GABA-A receptors exert a tonic inhibitory control on gastric pepsinogen secretion in anaesthetized rats.

1. The purpose of the present study was to analyse the role played by central gamma-aminobutyric acid (GABA-A) receptors in the regulation of gastric basal pepsinogen secretion in anaesthetized rats. 2. The central, but not parenteral, administration of the GABA-A receptor antagonist bicuculline or SR-95531 caused a significant and dose-dependent increase in basal pepsinogen secretion without changes in acid output. The stimulant effect exerted by bicuculline was prevented by atropine or pirenzepine, but not by vagotomy. 3. The central, but not parenteral, administration of the GABA-A receptor agonist muscimol or THIP induced a significant and dose-dependent stimulation of both basal pepsinogen and acid secretion. The excitatory effect exerted by muscimol was prevented by atropine, pirenzepine, or pretreatment with omeprazole, but not by vagotomy. 4. These results suggest that central GABA-A receptors mediate a tonic inhibitory control on gastric pepsinogen secretion, while their phasic activation leads to an excitatory effect on acid output. However, the agonist-induced pepsigogue action appears to be generated peripherally as an indirect consequence of the increase in acid secretion. 5. It is also suggested that central GABA-A receptors affect the gastric secretory functions through non-vagal pathways that are sensitive to the blockade of peripheral cholinergic receptors.

Anesthesia↗

PubMed1995

Mechanisms of protection by omeprazole against experimental gastric mucosal damage in rats.

In the present study, the protective effect of omeprazole on gastric mucosa injury induced by ethanol.HCl in rats and the putative mechanisms involved in this action were investigated. Misoprostol and ranitidine were used as reference drugs. The morphometric analysis of histological sections showed that omeprazole caused a significant reduction of mucosal necrotic damage, this effect being associated with a marked increase in Alcian blue recovery from gastric bound mucus. In addition, omeprazole elicited a significant inhibition of gastric acid secretion from pylorus-ligated rats. Misoprostol exerted similar effects to those obtained with omeprazole, even if the Alcian blue recovery and the acid output were affected to a lesser extent. By contrast, ranitidine failed to influence both the mucosal damage and the Alcian blue recovery, while it exerted a marked inhibition on acid secretion. The present results indicate that omeprazole is effective in protecting gastric mucosa from necrotic damage induced by ethanol.HCl and suggest that an enhancement of gastric mucus barrier may account for this protective action.

Animals↗

PubMed1995

Plasma and tissue disposition of paclitaxel (taxol) after intraperitoneal administration in mice.

The pharmacokinetics of single intraperitoneal doses of paclitaxel (18 and 36 mg/kg) in mice were investigated in the present study. The analysis of drug concentrations by HPLC indicated that the plasma Cmax (13.0 +/- 3.1 and 25.7 +/- 2.8 micrograms/ml, respectively) were reached at the 2nd hr. The values of CL were low (0.06 and 0.1 ml/min, respectively), and t1/2 beta values of 3.0 and 3.7 hr were found, after 18 and 36 mg/kg, respectively. The highest tissue concentrations were observed in the liver (50.2 +/- 3.1 and 92.0 +/- 9.5 micrograms/g respectively), followed by the pancreas (39.3 +/- 9.9 micrograms/g) and the ovary (53.4 +/- 5.6 micrograms/g) after 18 and 36 mg/kg, respectively. In the case of the colic tissue, paclitaxel Cmax were 14.4 +/- 0.8 and 32.8 +/- 3.5 micrograms/g at the 3rd hr, respectively, with sustained drug levels still detectable 24 hr after treatment. Paclitaxel Cmax values of 12.7 +/- 3.0 and 53.4 +/- 5.6 micrograms/g were detected in the ovary after 18 and 36 mg/kg, respectively. The overall results provide evidence that, after intraperitoneal administration, paclitaxel concentrates in peritoneal organs; however, the intraperitoneal route does not prevent systemic drug exposure, allowing high and sustained levels of paclitaxel also in several extraperitoneal tissues.

Animals↗

PubMed1994

MCF-10A cells infected with the int-2 oncogene induce angiogenesis in the chick chorioallantoic membrane and in the rat mesentery.

A growing body of evidence demonstrates the relevant role of the int-2 (FGF-3) oncogene in human carcinomas. To investigate its angiogenic activity, the human epithelial mammary cell line MCF-10A was infected with a retroviral expression vector carrying the int-2 oncogene. Infected cells were entrapped in an alginate pellet and placed on the chorioallantoic membrane of chick embryos. After 7 days, a dense capillary network was found to grow toward the pellet, whereas parental cells did not show any angiogenic activity. Conditioned medium from int-2-infected cells was injected i.p. twice daily into rats over a period of 10 days. The mesentery of treated rats showed numerous small blood vessels originating from larger vascular arcades and growing through the stromal layer of the mesentery. In control experiments, neither medium for cell culture nor conditioned medium from parental cells was found to induce angiogenesis. In conclusion, the stimulation of blood vessel growth by int-2-infected cells suggests that the production of the int-2 protein is associated with the acquisition of the angiogenic phenotype.

Allantois↗

PubMed1994

Protective action of omeprazole against gastric mucosal injury induced by hemorrhagic shock in rats.

The efficacy of omeprazole in preventing gastric mucosal injury induced by hemorrhagic shock in rats and the putative mechanisms involved in this effect were investigated in the present study. Omeprazole did not affect mean arterial blood pressure under both basal conditions and induction of hemorrhagic shock, but it evoked a marked increase in Alcian blue recovery from gastric preepithelial mucus. The morphometric analysis of histological sections revealed that omeprazole caused a significant reduction of hemorrhagic shock-induced damage of gastric mucosa. Ranitidine, used as the reference drug, failed to affect mean arterial blood pressure, Alcian blue recovery from gastric mucus, or hemorrhagic shock-induced damage of gastric mucosa. Both omeprazole and ranitidine exerted a significant inhibition of gastric acid output from anesthetized pylorus-ligated rats. Overall, the present results indicate that omeprazole is effective in protecting gastric mucosa from necrotic damage induced by hemorrhagic shock and suggest that an enhancement of gastric mucus secretion contributes to this protective action.

Animals↗

PubMed1994

Synergistic antiproliferative activity of suramin and alpha 2A-interferon against human colorectal adenocarcinoma cell lines: in vitro studies.

Suramin, a polysulphonated naphthylurea proven to be an effective anticancer agent against selected tumours, and alpha 2A-interferon (alpha 2A-IFN) were investigated for their combined effects on HCT-8, HCT-15, CL-D, SW-480 and SW-620 human colorectal adenocarcinoma cell lines. All lines were sensitive to clinically achievable concentrations of suramin in a dose-dependent manner, while alpha 2A-IFN alone induced only a modest reduction of cell growth. Concomitant treatment with suramin and alpha 2A-IFN resulted in a synergistic inhibition of cell viability in each cell line at all doses tested. However, when suramin and alpha 2A-IFN were administered sequentially, inhibition of cell viability was clearly dependent on the timing of treatment schedule, with maximum effect obtained when alpha 2A-IFN was administered prior to suramin. In contrast, pretreatment with suramin was markedly inferior to the former one. In conclusion, suramin and alpha 2A-IFN exert a synergistic effect on human colorectal cell proliferation in vitro at clinically achievable concentrations. This observation may have clinical relevance although the mechanisms of interaction remain to be elucidated.

Adenocarcinoma↗

PubMed1994

Effect of low molecular weight heparan sulphate on angiogenesis in the rat cornea after chemical cauterization.

Vascularization of the cornea occurs in many pathological conditions and can result in loss of visual acuity. It is also thought that vascularization predisposes the cornea to reject grafts by facilitating the detection of foreign antigens in donor material. A rat corneal assay for angiogenesis was adopted in the present study to evaluate the possible angiostatic activity of a low molecular weight heparan sulphate (LMW-HS). Corneal lesions were induced by chemical cauterization at 2 mm from the corneoscleral limbus. Rats were randomized to receive two drops/eye four times daily, for 6 days, of a solution of LMW-HS in vehicle (2.5% carboxymethylcellulose), heparin, heparin plus hydrocortisone, or vehicle alone. After a 6 day-treatment period, the eyes were perfused with india ink and the degree of neovascularization was evaluated. In rats treated with vehicle alone a dense vascular network extending from the corneoscleral limbus to the cauterized site was observed; on the contrary, a markedly reduced vascular network was evidenced in animals treated with LMW-HS. The distribution of basic fibroblast growth factor (bFGF) in the cauterized cornea was also evaluated by using an immunohistochemical method. A marked bFGF immunoreactivity was demonstrated in corneal epithelium and stroma of control rats 12-48 hours after the cautery. These results lead to the assumption that LMW-HS could be used in ophthalmology to inhibit corneal neovascularization.

Animals↗

PubMed1994

Dissociation between in vitro cytotoxicity and in vivo cardiotoxicity of two new anthracyclines: 3'-deamino-3'-(2-methoxy-4-morpholinyl)doxorubicin and 4'-deoxy-4'-iodo-doxorubicin.

The purpose of this study was to examine the cytotoxicity and cardiotoxicity of new doxorubicin (DXR) derivatives, 3'-deamino-3'-(2-methoxy-4- morpholinyl)DXR (MRA-MT), and 4'-deoxy-4'-iodo-doxorubicin (IDXR), comparing them to doxorubicin (DXR). Both anthracycline derivatives were approximately 1.5- to 9-fold more active than DXR in inhibiting the colony-formation ability of DU145, HOS, and A2780 human cancer cell lines. Anesthetized rats given a single intravenous (i.v.) dose of DXR 10 mg/kg showed significant changes in both ECG (S alpha T segment and QRS complex widening) and hemodynamic parameters (impairment in systemic arterial dP/dtmax systolic and diastolic blood pressure), whereas animals that received MRA-MT (0.1 and 0.3 mg/kg) had no significant signs of acute cardiotoxicity. In this case the animals treated with IDXR 1.2 mg/kg showed alterations in the ECG as the animals treated with DXR. In the chronic cardiotoxicity study, some animals received MRA-MT (0.03 mg/kg i.v. once a week for 3 weeks) and others IDXR (4 mg/kg once a week for 3 weeks). They did not show any alteration in ECG and cardiac histological picture. By contrast, DXR (3 mg/kg i.v. once a week for 3 weeks) induced a severe cardiomyopathy, characterized by progressive widening of S alpha T segment, increase in T wave, and histological damage consisting of vacuolations and loss of myofibrils. These results suggest that MRA-MT and IDXR are more active in vitro and markedly less cardiotoxic in vivo than DXR.

Analysis of Variance↗

PubMed1993

Macrolide antibiotics as antiinflammatory agents: roxithromycin in an unexpected role.

The antiinflammatory activity of a new 14-membered macrolide antibiotic, roxithromycin, was evaluated in various rat models including carrageenan- and poly-L-arginine-induced hind-paw oedema, croton oil inflamed ear assay and polyester sponge granuloma. When administered orally to animals, roxithromycin displayed an atypical profile in the assays utilized, including: (1) marked antioedema activity similar to that of indomethacin in poly-L-arginine assay, (2) significant inhibition of lambda-carrageenan hind-paw oedema and croton-oil-induced inflammation in the ear, although indomethacin was more effective, and (3) failure to reduce the development of granuloma induced by implanted polyester sponges, while indomethacin significantly reduced the chronic inflammatory reaction. Based on these results, it is concluded that roxithromycin is active in reducing the acute inflammatory reaction in rat models through mechanisms different from conventional nonsteroidal antiinflammatory agents such as indomethacin. Therefore, roxithromycin may have a favorable impact on skin inflammatory reactions accompanying microbial infections.

Analysis of Variance↗

PubMed1993

3'-Deamino-3'-(2-methoxy-4-morpholinyl)-doxorubicin (FCE 23762): a new anthracycline derivative with enhanced cytotoxicity and reduced cardiotoxicity.

The purpose of this study was to examine the cytotoxicity and cardiotoxicity of the new doxorubicin derivative, 3'-deamino-3'-(2-methoxy-4-morpholinyl)-doxorubicin (FEC 23762). The concentration of FCE 23762 that resulted in a 50% reduction in colony formation of DU 145, COLO 320DM, A549 and A2780 human cancer cell lines ranged from 1.1 and 3.2 nmol/l and was 3-9 times as low as doxorubicin. In the isolated perfused rat hearts, doxorubicin 10(-5) mol/l induced a significant prolongation of S alpha T segment and Q-Fmax interval, and reduction in dF/dtmax and coronary flow while only FCE 23762 10(-5) mol/l induced a widening of QRS complex. Anaesthetised rats given a single intravenous (i.v.) dose of doxorubicin 10 mg/kg showed significant changes in both ECG (S alpha T segment and QRS complex enlargement) and haemodynamic parameters (increase in mean arterial blood pressure and reduction in systemic arterial dP/dtmax), while animals given FCE 23762 (0.1 and 0.3 mg/kg) had a significant increase in QRS complex duration after the highest dose. In the chronic cardiotoxicity study animals receiving FCE 23762 (0.03 mg/kg i.v. once a week for 3 weeks) did not show any significant alteration of ECG and minor changes of cardiac histological picture; by contrast doxorubicin (3 mg/kg i.v. once a week for 3 weeks) induced a severe cardiomyopathy, characterised by progressive widening of S alpha T segment, increase in T wave and histological damage consisting of vacuolations and loss of myofibrils. These results indicate that FCE 23762 is more active in vitro than doxorubicin and markedly less cardiotoxic in vivo at the doses used in the present study.

Animals↗

PubMed1993

Involvement of basic fibroblast growth factor in suramin-induced inhibition of V79/AP4 fibroblast cell proliferation.

The V79/AP4 Chinese hamster fibroblasts were densely stained with the anti-basic fibroblast growth factor (bFGF) antibody demonstrating an endogenous production of the peptide. The in vitro proliferation of these cells was stimulated by exogenous bFGF and the maximum growth (259% increase in 3H-thymidine incorporation into DNA) was reached with bFGF 10 ng ml-1. Inhibition of bFGF-mediated mitogenic pathway was obtained with a 15-mer antisense oligodeoxynucleotide targeted against bFGF mRNA and with suramin, a drug which blocks the biological activity of heparin-binding growth factors. bFGF antisense oligomer reduced the synthesis of DNA by 79.5 and 89.5% at 20 and 60 microM, respectively; this effect was reversed by the addition of exogenous bFGF to the culture medium. A short-term exposure to suramin 300 micrograms ml-1 produced a modest reduction in 3H-thymidine incorporation but suppressed the mitogenic effect of bFGF on V79/AP4 cells. In cells treated with suramin 300 micrograms ml-1 the drug concentration increased linearly over 3 days, reaching 13.15 micrograms mg-1 of protein; cell proliferation was inhibited in a dose-related manner as evaluated by the colony formation assay (IC50: 344.22 micrograms ml-1) and by the number of mitoses observed in culture. Furthermore, the drug induced ultrastructural alterations, consisting of perinuclear cisternae swelling, chromatin condensation, nucleolar segregation and cytoplasmic vacuolations. These findings demonstrated that the endogenous production of bFGF plays an important role in V79/AP4 fibroblasts proliferation, and the inhibition of bFGF-mediated mitogenic signalling with bFGF antisense oligomer or suramin is an effective mean of reducing cell growth.

Animals↗

PubMed1993

Suramin inhibits bFGF-induced endothelial cell proliferation and angiogenesis in the chick chorioallantoic membrane.

The effects of suramin, an inhibitor of growth factor mitogenic activity, were evaluated on basic fibroblast growth factor (bFGF)-induced proliferation of bovine aortic endothelial cells and on angiogenesis in the chorioallantoic membrane (CAM) of chick embryos. The role of bFGF gene expression in endothelial cell growth was also investigated by using an antisense oligodeoxynucleotide to bFGF. The 4-fold increase in [3H]-thymidine uptake in endothelial cells in vitro upon stimulation with 10 ng ml-1 of bFGF was inhibited by suramin 300 micrograms ml-1. bFGF antisense oligomer (10 microM) reduced [3H]-thymidine incorporation in exponentially growing cells by 76%; this effect was reversed by bFGF 10 ng ml-1. In the CAM of chick embryos suramin 50 micrograms was a more potent inhibitor of angiogenesis than the combination of heparin 60 micrograms/hydrocortisone 50 micrograms; the mean value of the area with reduced vascularity was significantly larger in suramin-treated CAMs (2.4 cm2) than in heparin/hydrocortisone (0.6 cm2), while the reduction of vascular density was similar (- 35 and - 29% compared to controls, respectively), In conclusion, the effects of treatments with bFGF and bFGF antisense oligomer demonstrate that bFGF plays a relevant role in endothelial cell proliferation and may be the target of suramin since the drug is able to suppress basal and bFGF-induced endothelial cell growth; in addition to this, suramin is a more potent angiogenesis inhibitor in the CAM than the combination of heparin/hydrocortisone.

Allantois↗

PubMed1993

Inhibitory cholinergic effects of esaprazole on gastric secretion and plasma gastrin levels in the dog.

The effects of esaprazole, a novel antiulcer drug, on gastric acid secretion and plasma gastrin levels were investigated in dogs provided with a gastric fistula or Heidenhain pouch. Esaprazole affected in a different extent the tests performed on dogs with a gastric fistula. The greatest inhibitory effect was obtained against 2-deoxy-D-glucose-induced acid output and gastrin release. An intermediate inhibition by esaprazole was detected on bethanechol-evoked secretion, and the lowest activity was found versus histamine-stimulated secretion. All these responses were strongly inhibited by the antimuscarinic drug pirenzepine used as reference drug. Moreover, both esaprazole and pirenzepine prevented the acid secretory response to a test meal in dogs with a Heidenhain pouch, without significantly affecting plasma gastrin levels. The present results suggest that the depressant action of esaprazole on gastric secretion depends on its peripheral anticholinergic activity, consisting of a partial blockade of acid output and a main reduction of vagally mediated gastrin release. On the basis of these findings, the antiulcer activity of esaprazole might be in part ascribed to its inhibitory effects on gastric secretion.

Animals↗