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Biomedical subjects

L Favalli

Publications and source records attributed to L Favalli.

At least 19 recordsLinked to original sources
PubMed1992

K-opioid receptor changes in experimental models of cerebral ischaemia and atherosclerosis in the rabbit.

Thromboembolic phenomena and transient ischaemic attacks (TIA) are considered the basis of ischaemic pathologies. The aim of the present research is to investigate the involvement of k-opioid receptors in cerebral blood flow (CBF) impairment which results in experimental stroke or dietary atherosclerosis in rabbits. CBF measurement showed a significant decrease in rabbits submitted to embolization and/or atherosclerosis. Binding studies showed that massive cerebral ischaemia and atherosclerosis produced a significant increase in the number of k-opioid receptors (Bmax), without changing (KD) affinity values. In conclusion, the results obtained seem to indicate that the increase in k-opioid receptors might play a crucial role in a common cerebral biochemical mechanism both in ischaemic and atherosclerotic pathologies.

Animals↗
PubMed1992

[The effect of superoxide dismutase and catalase on the delayed toxicity of doxorubicin].

The production of oxygen-free radicals has been proposed as a determinant of the delayed toxicity of doxorubicin. The aim of the present investigation was to evaluate the potential cardioprotective effect of superoxide dismutase (SOD) and catalase (CAT) against the delayed cardiomyopathy induced by doxorubicin (DXR) in a rat model. Female Sprague Dawley rats received 3 mg/kg of DXR intravenously weekly for 4 weeks. SOD or CAT were administered intravenously at the dose of 10000 U/kg 2 min before and 30 min after each DXR administration. Cardiac toxicity was monitored by means of electrocardiography (QaT interval) and by light and electron microscopy evaluation of left ventricle fragments. DXR treated rats showed, in comparison with control animals, a decrease of body weight gain, a progressive and irreversible prolongation of QaT and significant morphologic lesions consisting in myocyte vacuolization and myofibrillar loss. SOD significantly prevented the impairment of body weight gain and QaT prolongation. Moreover, morphologic lesions were significantly reduced in rats receiving DXR + SOD. On the contrary, CAT seems to be completely devoid of protective effect.

Animals↗
PubMed1991

Prevention of doxorubicin-induced cardiomyopathy by reduced glutathione.

The aim of the present investigation was to evaluate the potential cardioprotective effect of reduced glutathione (GSH) against the delayed cardiomyopathy induced by doxorubicin (DXR) in a well-documented rat model. DXR was administered i.v. at a weekly dose of 3 mg/kg for a total of 4 doses; 250 or 500 mg/kg of GSH was given i.v. 10 min before and 2 h after each DXR injection, resulting in a total weekly dose of 500 or 1000 mg/kg, respectively. The development of cardiotoxicity was monitored in vivo by means of electrocardiography (QaT duration), and was evaluated by measuring the contractile performance of isolated atria and by light and electron microscopy of left ventricular samples excised 5 weeks after the last DXR administration. DXR was found to impair body weight gain and to produce an irreversible and time-dependent prolongation of QaT, a decrease in myocardial contractility of isolated atria and typical morphologic alterations, including myocyte vacuolization and myofibrillar loss. Pretreatment with GSH at a dose of 500 mg/kg x 2, but not at 250 mg/kg x 2, partially prevented the impairment of body weight gain, QaT prolongation in ECG and the decrease in myocardial contractility of isolated atria induced by DXR. Alterations of the morphologic pattern were also significantly reduced in animals receiving the higher dose of GSH. Determinations of the cardiac non-protein sulfhydryl group content showed that GSH, at doses higher than or equal to 500 mg/kg, significantly increased this parameter, irrespective of the presence of DXR. In conclusion, the present data indirectly support the hypothesis that oxidative damage is involved in DXR cardiotoxicity and indicate that maintenance of the reduced thiol pool could be an important issue in myocardial protection.

Animals↗
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

Ischemic cerebral pathologies and K opioid receptors in rabbits.

Recently it has been suggested that endogenous k-opioid receptors may have a physiopathological role in ischemia induced neurodegeneration. The aim of this research is to show that in experimental thromboembolic (obtained mechanically using microspheres injected in the carotid) and atherosclerotic pathologies (obtained through a special diet) there is a common mechanism which involves mediation by dynorphine and the receptor compartment considered. The results, obtained using receptor binding techniques, showed a statistically significant increase in the number of k-opioid receptors (Bmax) without variations in the affinity (Kd) for the 3H dynorphine. We can therefore support the hypothesis that these changes in the modulation of the dynorphinergenic system may be part of a mechanism causing early cerebrovascular damage which results from embolic insults and is a consequence of such metabolic risk factors as are activated by atherogenesis.

Animals↗
PubMed1991

[The prevention of the myocardial toxicity of doxorubicin with superoxide dismutase].

The production of oxygen free radicals during anthracycline therapy has been proposed as a determinant of the toxicity of anthracyclines. Oxygen radical generation might specifically affect the myocardium because of the low antioxidant defense systems in cardiac tissue. The aim of the present investigations was to evaluate the potential cardioprotective effect of superoxide dismutase (SOD) against the delayed cardiomyopathy induced by doxorubicin (DXR) in a rat model. Female Sprague Dawley rats received 3 mg/kg of DXR intravenously weekly for 4 weeks. SOD was administered intravenously at the dose of 10,000 U/Kg one minute before and 30 minutes after each DXR administration. Cardiac toxicity was monitored in vivo by means of electrocardiography (QaT interval), by determining the contractile properties of isolated atria, and by light and electron microscopy evaluation of left ventricle fragments excised 5 weeks after the last DXR administration. The degree of morphologic lesions was quantitated according to the score system proposed by E. Billingham. DXR treated rats showed, in comparison with control animals treated with saline a decrease of body weight gain, a progressive and irreversible prolongation of QaT, decrease of contractility of isolated atria, and significant morphologic lesions consisting in myocyte vacuolization and myofibrillar loss. SOD significantly prevented the impairment of body weight gain, QaT prolongation and the impairment of myocardial contractility. Moreover morphologic lesions were significantly reduced in rats receiving DXR + SOD. The present data indicate that SOD could represent an important issue in myocardial protection against DXR cardiotoxicity.

Animals↗
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

Kappa-opioid receptor changes and neurophysiological alterations during cerebral ischemia in rabbits.

Endogenous opioids have been shown to produce beneficial effects in experimental stroke. To evaluate both neurophysiological and biochemical parameters, we induced massive cerebral ischemia in 11 rabbits according to the method standardized in our laboratory, using microspheres injected through the internal carotid artery. Binding studies were performed in the 11 embolized, in nine control, and in five sham-operated rabbits using the appropriate concentration of [3H]dynorphin A (1-8). Neurophysiological parameters were evaluated under baseline conditions and 1 hour after embolization, surgical preparation, or sham operation in 17 rabbits. Comparison of visual readings of the electroencephalograms and analyses of the quantified electroencephalograms under baseline conditions and after embolization indicated a marked and statistically significant (p less than 0.01) increase in bilateral delta activity; histologic examination confirmed bilateral brain edema. Binding studies on kappa-opioid receptors indicate that 1 hour after embolization there were significantly more (28%) kappa-opioid receptors (Bmax) in six embolized rabbits than in five sham-operated animals. No significant changes were observed in the affinity parameters, particularly in the dissociation constant (Kd). Our results indicate a role for endogenous dynorphin peptides in the pathogenesis of stroke.

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↗
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↗
PubMed1988

Evaluation of cardiotoxicity of a new anthracycline derivative: 4'-deoxy-4'-iodo-doxorubicin.

The present study in rats was performed to evaluate the cardiotoxic activity of 4'-deoxy-4'-iodo-doxorubicin (4'-deoxy-4'-I-DXR), a new anthracycline derivative with interesting antineoplastic properties and possible lower cardiotoxicity than doxorubicin (DXR). DXR produced ECG alterations consisting of a progressive and irreversible prolongation of SaT and QaT. In contrast, in 4'-deoxy-4'-I-DXR-treated rats the increase in SaT and QaT duration was significantly lower than that observed in DXR-treated rats and slightly increased over controls. DXR produced significant histologic changes in myocardium consisting of myocyte vacuolization and myofibrillar loss. No significant modifications were observed in mitochondria. In contrast, no significant cardiac lesions were observed in 4'-deoxy-4'-I-DXR-treated rats. These results suggest that this new anthracycline derivative has a significantly lower degree of cardiotoxic activity than DXR.

Animals↗
PubMed1986

Relationship between doxorubicin-induced ECG changes and myocardial alterations in rats.

The aim of the present study was to evaluate the dose- and time-dependence of the effect displayed by doxorubicin (DXR) on the electrocardiogram (ECG) and to establish the relationship between structural alterations of the myocardium and ECG changes in rats administered DXR, at a dose of 1.5 or 3.0 mg/kg, every 3 days for a total of three administrations. The most interesting findings consisted of a dose-dependent, but reversible prolongation of the QRS complex, and in a dose-dependent and progressive irreversible increase in QaT and, in particular, in SaT duration. Furthermore, animals treated with the higher DXR dose showed a slight increase in serum K+ concentration and a significant decrease in serum Ca2+ levels. A good correlation was found between the morphologic score indicating the degree of observed tissue damage and SaT prolongation. These results therefore support the usefulness of measuring this ECG parameter for monitoring the development of DXR-induced cardiotoxicity in rats.

Animals↗
PubMed1986

Myocardial contractility and heart pharmacokinetics of adriamycin following a single administration in rat.

A single administration of adriamycin (DXR) 6.0 mg/kg i.v. to rats brings about a biphasic impairment of the maximal myocardial contractile performance, measured as dF/dt of ex vivo isolated atria incubated in the presence of calcium concentrations varying up to 12 mM. The initial impairment of the contractile performance peaks 1 week after DXR administration and recovers within 3 weeks (acute phase of cardiotoxicity). After this time and up to the end of the observation period (8 weeks after treatment), delayed cardiotoxicity occurs, showing a progressive and irreversible impairment of the contractile performance of the atria. This behaviour parallels the previously shown ECG and morphological abnormalities. Tissue determinations of DXR showed that the drug is present in myocardium during the acute phase of cardiotoxicity, while the metabolite adriamycinol is not detectable 1 week after DXR administration. These data show that the presence of DXR and/or metabolites in heart muscle is not necessary for the delayed form of cardiotoxicity to become apparent and suggest that this form of cardiotoxicity is related to a mechanism different from that involved in acute cardiotoxicity.

Animals↗