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E Monti

Publications and source records attributed to E Monti.

At least 55 records · Page 3Linked to original sources
PubMed1991

Effect of flunarizine on the delayed cardiotoxicity of doxorubicin in rats.

The calcium antagonist flunarizine (FLN) was tested for its ability to prevent doxorubicin (DXR)-induced cardiotoxicity in the rat. A cumulative dose of 9.0 mg/kg of DXR was administered i.v. over a period of 1 week. FLN (10 mg/kg/day i.p., 6 days/week) was administered according to two different time schedules, covering respectively the first and last 4 weeks after the beginning of DXR treatment. The two schedules were adopted to assess whether early and/or delayed DXR-induced cardiotoxic effects were affected by FLN. The development of cardiac toxicity was monitored by ECG recordings. The animals were sacrificed 8 weeks after the beginning of DXR treatment. The contractile performance of isolated atria and the morphological pattern of left ventricular fragments were subsequently evaluated. The early administration schedule of FLN was shown to be ineffective in preventing DXR-induced cardiotoxicity and in some cases was actually found to potentiate the effects of DXR. In contrast, the histological evaluation of ventricular preparations from rats treated with DXR and FLN according to the delayed time schedule showed a significant improvement with respect to hearts from animals treated with DXR alone. An inhibition of the delayed calcium overload occurring after DXR administration has been proposed as a possible mechanism for this protective action.

Animals↗
PubMed1991

Protective effects of spin-trapping agents on adriamycin-induced cardiotoxicity in isolated rat atria.

Adriamycin (ADR) is known to exert a severe negative inotropic effect on isolated myocardial preparations; a role for free radical generation has been hypothesized. Spin-trapping of free radicals has been extensively exploited in ESR studies, both in cell-free systems and in intact tissues. The interaction between spin-traps and free radicals should in principle stop the reaction cascade leading to cellular damage. Based on this hypothesis, the possible cardioprotective action of three spin-trapping agents, 5,5-dimethyl-l-pyrroline-N-oxide (DMPO), N-tert-butyl-alpha-phenylnitrone (PBN) and alpha-(4-pyridyl 1-oxide) N-tert-butylnitrone (POBN), was tested on isolated rat atria incubated in the presence of ADR; maximal non-cardiotoxic concentrations were used (50, 10 and 50 mM respectively) in order to achieve a maximal spin-trapping effect. A varying degree of protection was observed with the three compounds, directly correlated to their hydrophobicity, as assessed by chloroform/water partition coefficients. It is proposed that ADR-induced free radical generation is responsible for the acute cardiotoxic effects of the drug; this seems to be a site-specific mechanism restricted to one or more hydrophobic cellular compartment/s, since only lipophilic spin-trapping agents are able to prevent the development of the negative inotropic effect of ADR.

Animals↗
PubMed1990

Effect of angiotensin II on the antitumor activity and cardiotoxicity of doxorubicin.

The effects of angiotensin II (AII) on the antitumor activity and cardiotoxicity of doxorubicin (DXR) were tested in rats bearing Walker 256/A carcinoma. The animals received 2, 4 or 6 mg/kg of DXR as a bolus i.v. injection, with or without a concurrent i.v. infusion of 2 micrograms/kg/min of AII, starting 1 h prior to DXR administration for a total of 6 h. Neither the antitumor activity, nor the myocardial toxicity of DXR, as assessed by ECG evaluation (Q alpha T duration), were affected by AII at the tested dose. 100% of the animals receiving 6 mg/kg of DXR with or without AII were cured from the tumor, but subsequently some of them developed toxic signs and eventually died within the 12th week after treatment. Rats receiving DXR + AII showed a higher long-term survival than those receiving DXR alone; therefore, a possible interference with other DXR-induced side effects, such as nephrotoxicity, is hypothesized.

Angiotensin II↗
PubMed1990

Cardiotoxicity and antitumor activity of a copper(II)-doxorubicin chelate.

The cardiotoxic and cytotoxic effects of the Cu(II)-doxorubicin (DXR) complex [Cu(DXR)]n are compared with those of the parent drug. It is shown that 10(-4) M [Cu(DXR)]n has no depressant effects on isolated rat atria, in contrast with an equimolar concentration of the parent drug. No differences were found between the cytotoxic activities of the Cu(II) complex and free DXR on B16 melanoma and HeLa cells. A reduced penetration of the polymeric [Cu(DXR)]n into the myocardial cells as compared with the free drug was invoked to account for the absence of cardiotoxicity of the DXR complex. On the other hand, the observation that copper-complexation does not affect the cytotoxicity of the drug suggests that extracellular as well as intracellular mechanisms may be involved in the development of its antitumor activity.

Animals↗
PubMed1990

Effect of amrinone on anthracycline-induced lethal and cardiac toxicity in mice and rats.

The protective role of amrinone against toxicity of anthracyclines was examined in both mice and rats. These two anthracyclines were selected since they are characterized by different patterns of toxicity. In contrast to doxorubicin, the 4'-deoxy derivative did not cause delayed mortality. The results of this investigation indicate that amrinone is an effective protective agent against acute lethal events induced by both anthracyclines. However, the inotropic agent did not reduce the delayed mortality produced by doxorubicin. This parallels the apparent lack of prevention of doxorubicin-induced myocardial toxicity in CD rats, as determined by ECG changes and by morphologic alterations following multiple drug administrations. The administration of amrinone did not interfere with the antitumor activity of 4'-deoxy-doxorubicin against C-26 colon tumor.

Amrinone↗
PubMed1990

Effect of ICRF-187 pretreatment against doxorubicin-induced delayed cardiotoxicity in the rat.

Doxorubicin (DXR), administered iv in rats at the weekly dose of 3 mg/kg for 5 weeks, significantly impaired body weight gain and induced irreversible ECG alterations, mainly consisting of a progressive prolongation of ST and QT intervals. Five weeks after the last DXR administration, the contractile performance of atria isolated from treated animals was significantly reduced. At the same time, relevant morphologic lesions, consisting of myocyte vacuolization and myofibrillar loss, were also present in the myocardium of the same rats. The study showed that ICRF-187, administered ip at a dose of 125 mg/kg, significantly prevented body weight loss. QT and ST prolongation, and the decreased contractile force induced by DXR. In addition, ICRF-187 caused a significant reduction in incidence and severity of myocardial lesions. The cardioprotective effect of ICRF-187 is not mediated by a modification in DXR pharmacokinetics in heart, since the drug was actually found to increase DXR uptake in myocardial cells.

Animals↗
PubMed1990

A new approach to the direct detection of free radicals in the intact myocardium.

A new method for the direct ESR detection of free radicals in rat myocardial tissue is described. Isolated rat atria are continuously monitored for heart rate and contractile force; at the end of the experimental period the beating organs are inserted into quartz ESR tubes and immediately frozen in liquid nitrogen. Spectra obtained from these preparations show the presence of very weak radical signals. When ESR spectra are recorded on samples obtained from pools of rat atria pulverized under liquid nitrogen, the radical lines are markedly stronger than those observed for intact organs; contaminating metals are also frequently detected. These findings indicate that crushing or grinding procedures carried out under liquid nitrogen produce artifactual ESR active species. The new method described in the present paper does not involve mechanical interventions and therefore should yield reliable artifact-free results.

Animals↗
PubMed1990

Effect of glutathione and N-acetylcysteine on in vitro and in vivo cardiac toxicity of doxorubicin.

The effects of two sulfhydryl compounds, glutathione (GSH) and N-acetylcysteine (NAC), on the cardiotoxicity of doxorubicin (DXR) were tested on in vitro and in vivo models. DXR was administered to rats as 4 weekly i.v. doses of 3 mg/kg. GSH (1.5 mmoles/kg), given i.v. 10 min before and 1 hr after DXR, was found to prevent the development of the delayed cardiotoxic effects of DXR, as assessed by electrocardiographic and mechanical parameters, as well as by histological examination of left ventricular preparations. In contrast, equimolar oral doses of NAC (1 hr before and 2 hrs after DXR) were found to be ineffective. Both GSH and NAC prevented the negative inotropic effect produced by DXR on isolated rat atria. A good correlation exists between the cardioprotective effects of the two agents and their ability to enhance the non-protein sulfhydryl group content of the myocardium. Differences observed in vivo between GSH and NAC might be accounted for by pharmacokinetic factors.

Acetylcysteine↗
PubMed1990

Potentiation of doxorubicin cytotoxicity by (+)-1,2-bis-(3,5-dioxopiperazinyl-1-yl) propane (ICRF-187) in human leukemic HL-60 cells.

The bisdioxopiperazine propane, ICRF-187, has been reported to potentiate doxorubicin cytotoxicity in certain tumor cell lines; however, the mechanism of this interaction is not known. In order to define the mechanism of this interaction, we examined the effects of ICRF-187 on doxorubicin cytotoxicity, free radical formation, and drug accumulation in human leukemia HL-60 cells. Studies show that ICRF-187 synergistically potentiated doxorubicin cytotoxicity in HL-60 cells. This potentiation of doxorubicin cytotoxicity by ICRF-187 appeared to result from enhanced drug dependent free radical formation without effecting doxorubicin uptake in HL-60 cells.

Biological Transport↗
PubMed1990

[Epidural sacral anesthesia with 3% mepivacaine in rectal surgery].

The authors think that the sacral epidural anaesthesia effected with Mepivacaine 3%, 6 ml (180 mg) and Fentanyl 2 ml (100 mcg) is perfectly indicated for the proctologic surgery as it is of simple execution and presents a short latency (12 min.), good deepness and perfect haemodynamic stability. Besides, it does not endanger the lower limbs innervation. No urinary retention.

Adult↗
PubMed1989

The rat model in the comparative evaluation of anthracyclines cardiotoxicity.

In the present investigation, the cardiotoxic effects of three anthracycline analogs (doxorubicin, 4'-epi-doxorubicin and 4'-deoxy-doxorubicin) were compared. For this purpose, 9.0 mg/kg of doxorubicin, divided into three closely spaced subdoses, were injected intravenously in rats. The two derivatives were administered according to the same time schedule and their doses were chosen on the basis of the clinically adopted ratio, doxorubicin: 4'-epidoxorubicin: 4'-deoxy-doxorubicin = 1:1:0.5. The degree of cardiomyopathy induced by the three anthracyclines was evaluated by ECG changes and morphological alterations. Doxorubicin was found to produce a significant degree of cardiotoxicity, thus confirming the validity of the experimental model adopted. Both 4'-substituted derivatives proved to be less cardiotoxic than the parent compound, although not completely devoid of this side effect.

Animals↗
PubMed1989

Hypoxia as a risk factor for doxorubicin-induced cardiotoxicity: a NMR evaluation.

Previous studies suggested that one possible mechanism of doxorubicin (DXR)-induced cardiomyopathy involves the depletion of high-energy phosphate stores. In this study, we used 31P nuclear magnetic resonance to assess the high-energy phosphate content in Langendorff perfused rat hearts. Hearts were perfused in normoxic conditions (spontaneous flow) or in partially hypoxic conditions obtained by perfusing at 50% of the spontaneous flow. DXR was used at the subtoxic conditions of 50 mg/l for 15 min and at the cardiotoxic concentration of 100 mg/l for 60 min. Left ventricular pressure (dP/dt), heart rate, myocardial ATP and PCr levels and PCr/ATP ratio were measured. We found that, in normoxic conditions, DXR (50 mg/l, 15 min) does not impair cellular high-energy phosphate metabolism. However, in mild hypoxic conditions, DXR induces a significant decrease in PCr/ATP ratio, due to a decrease in PCr and to a simultaneous increase in ATP. Similar results are obtained after 60 min perfusion with the cardiotoxic dose of DXR. This study suggests that hypoxia may represent a risk factor for the development of DXR-induced acute cardiotoxicity.

Adenosine Triphosphate↗
PubMed1989

Inhibition of tyrosine protein kinases by the antineoplastic agent adriamycin.

Adriamycin, a lipid-interacting anti-cancer agent, was found to inhibit the phosphorylation of polyGlu/Tyr (4:1) by tyrosine protein kinases either from spleen or expressed by the oncogene of Abelson murine leukemia virus. The dose dependent inhibition by adriamycin is accounted for by competition for the ATP binding site, but it is also deeply influenced by the nature and concentration of the phosphorylatable substrate, suggesting multiple interactions with the enzyme. The phosphorylation at tyrosine residues of cytosolic proteins from cells transformed by Abelson leukemia virus and the autophosphorylation of tyrosine protein kinases are also inhibited by adriamycin. Unlike tyrosine protein kinases most serine/threonine specific protein kinases, with the notable exception of protein kinase-C, appear to be relatively insensitive to adriamycin.

Abelson murine leukemia virus↗
PubMed1989

Reduction of myofibrillar ATPase activity and isomyosin shift in delayed doxorubicin cardiotoxicity.

The aim of this study was to determine whether variations of isomyosin expression occurred during doxorubicin-induced cardiomyopathy. A suitable experimental model in which pure delayed cardiotoxic effects could be easily studied was adopted. Young adult female Sprague Dawley rats received 9 mg/kg of doxorubicin (DXR) i.v. divided into three subdoses of 3 mg/kg every third day. Control animals received equal volumes of saline. The animals were examined 9 weeks after treatment. At this time the animals treated with DXR showed ECG alterations, reduction of body weight and a marked decrease of both atrial and ventricular mass, but were still fully hemodynamically compensated. Loss of myofibrillar material could be documented by the reduced recovery of myofibril and myosin. The contractile response of papillary muscles isolated from the right ventricle of treated animals was markedly impaired. Ca-Mg-activated and Mg-activated myofibrillar ATPase activity and Ca-activated myosin ATPase activity were determined on ventricular myocardium of control and treated animals. Both myofibrillar and myosin ATPase activities were found to be significantly reduced. Pyrophosphate gel electrophoresis of purified myosin was carried out. The isomyosin pattern of DXR-treated animals showed a pronounced shift towards V3, the percent of alpha heavy chains being 54.6% in treated rats (80.5% in control rats). This isomyosin shift can explain the reduced myofibrillar and myosin ATPase activity found in treated animals.

Adenosine Triphosphatases↗