Biomedical subjects

F Villani

Publications and source records attributed to F Villani.

At least 73 records · Page 4Linked to original sources

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

Maternally inherited myopathy and cardiomyopathy: association with mutation in mitochondrial DNA tRNA(Leu)(UUR).

Different point mutations of the mitochondrial genome, which all affect the ability of mitochondria to translate their own genes and lead to partial defects of mtDNA-dependent respiratory complexes, are related to distinct clinical mitochondrial disorders. A new maternally inherited disorder, characterised by a combination of adult-onset myopathy and cardiomyopathy, with no clinical involvement of the nervous system, was found in members of a single large pedigree. A heteroplasmic new mutation was identified in the mtDNA gene specifying tRNA(Leu)(UUR). This mutation segregated specifically with the disorder, and there were significant correlations between the proportion of the mtDNA that was of the mutant form and the activities (normalised for citrate synthase activity) of the two mtDNA-dependent respiratory enzymes (complex I, r = -0.71, p less than 0.005: complex IV r = -0.77, p less than 0.005) and the maximum oxygen consumption (r = -0.82, p less than 0.005), a physiological index of aerobic metabolism. These findings strongly suggest that the tRNA(Leu)(UUR) mutation is the genetic cause of this disorder, and that lesions of mtDNA should be considered in the differential diagnosis of the hereditary cardiomyopathies.

Adult↗

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

Beta-nerve growth factor (beta-NGF) mRNA expression in the parkinsonian adrenal gland.

The adrenal gland is a well-demonstrated source for different neurotrophic factors. The presence of the beta-nerve growth factor (beta-NGF) mRNA in the adrenal tissue used for grafting in a Parkinsonian patient is reported here. Adrenal samples were obtained on the day of implantation, and a specific cDNA was synthesized after the extraction of total RNA using a synthetic oligonucleotide as a reverse transcription primer. A 168-bp portion of the cDNA was amplified using two other oligonucleotides as Taq polymerase primers in a polymerase chain reaction. Thirty-two cycles of amplification were performed. The amplification products were identified by agarose gel electrophoresis and Southern blot analysis as a single DNA band hybridizing with a third beta-NGF specific oligonucleotide. The identity of the fragment was confirmed by DNA sequencing. Quantitative analysis demonstrated a beta-NGF mRNA concentration exceeding 5 fg/micrograms of total adrenal RNA. These findings add NGF to the other neurotrophic factors produced by the gland (i.e., basic fibroblast growth factor) and demonstrate the retained functional capacity of the Parkinsonian adrenal to express the beta-NGF mRNA. All these data may assume relevant meaning for neurotransplantation research.

Adrenal Glands↗

PubMed1991

Early cardiac toxicity of 4'-iodo-4'-deoxydoxorubicin.

4'-iodo-4'-deoxydoxorubicin was administered intravenously to 35 patients with advanced malignant neoplasms. The doses were escalated as follows: 2, 4, 6, 7, 10, 14, 19, 26, 52, 70, 80 and 90 mg/m2. Myocardial function was assessed by Holter monitoring and echocardiography. The prevalence of arrhythmias that could be attributed to the drug in the 24 h following infusion was 14.3% (supraventricular) and 10.6% (ventricular). Echocardiographic heart function variables were unchanged at 24 h and 21 days from drug injection. The data indicate the absence of significant, acute cardiotoxic effects of 4'-iodo-4'-deoxydoxorubicin.

Adolescent↗

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

[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↗

PubMed1991

[Angiocardioscintigraphy in the cardiological surveillance of chemotherapy with anthracyclines].

Equilibrium angiocardioscintigraphy is a noninvasive nuclear medical method which allows cardiac function to be assessed. It is widely used in oncology since some clinically important drugs used in antitumor chemotherapy have a marked cardiotoxic effect. Angiocardioscintigraphy enables several parameters characteristic of cardiac function to be assessed, namely the left ventricular ejection fraction whose alterations during chemotherapy allow possible cardiotoxic side effects to be revealed before the development of irreversible heart failure.

Antibiotics, Antineoplastic↗

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

Variable angiographic findings in patients with stroke and neurosyphilis.

We describe four patients with cerebral infarction and active neurosyphilis who had variable angiographic findings. Patients 1 and 2 had evidence of arteritis and an atheromatous ulcerated stenosis of the extracranial carotid artery, respectively. The third and fourth patients had symptoms of lacunar infarction, but cerebral angiography was normal in patient 3, whereas patient 4 had evidence of concomitant atheromatous and arteritic lesions. Neither age nor presence of cerebrovascular risk factors was of aid in predicting angiographic features. The concomitance of cerebral infarction and active neurosyphilis does not imply a cause-and-effect relation, since atherosclerotic lesions may coexist with arteritis or may even represent the only angiographic feature. Our findings underscore the importance of angiography to confirm the diagnosis in cases of suspected syphilitic arteritis.

Adult↗

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

Synthesis of a new anti-anaemic iron lysozyme glutarate complex and pharmacological studies in animals.

Iron lysozyme glutarate (ABC 1020) is a new soluble complex with an anti-anaemic activity superior to that of ferritin, ferrous sulphate and iron succinyl protein. Iron serum concentrations after treatment with ABC 1020 are higher than after ferritin and iron succinyl protein and lower than after ferrous sulphate treatment. Anaemic adult rats and rats born from dams with anaemia induced by an iron-deficient diet and by repeated bleeding showed considerable, dose-related improvement when treated with ABC 1020, which gave markedly better results than ferritin, iron succinyl protein and ferrous sulphate. Treatment with all four compounds improved the hematological and blood chemistry parameters considered, and reversed cardio- and splenomegaly. Preliminary data show that ABC 1020 is well tolerated, does not induce gastric lesions and has a high bioavailability.

Anemia, Hypochromic↗

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

A phase II study of the administration of recombinant interleukin 2 (rIL-2) plus lymphokine activated killer (LAK) cells in stage IV melanoma patients.

From January 1987 to February 1988, 15 stage IV melanoma patients were treated with two courses of bolus injection of rIL-2 plus LAK cell infusions at the National Cancer Institute of Milan. The original treatment regimen included a first course of rIL-2 administration (400 micrograms/m2 bolus injection 3 times a day [TID] for 4 days) and a second course of rIL-2 administration (800 micrograms/m2 bolus injection TID for 7 days) separated by 4 consecutive daily leukaphereses. Autologous lymphokine activated killer (LAK) cells were reinfused into each patient on three occasions during the second period of rIL-2 administration. Due to the appearance of grade III-IV neurological, hepatic and cardiopulmonary toxicity, 7 patients discontinued dosing before the end of treatment, one patient desired to be withdrawn and one patient died from rapidly progressive disease, although complications of rIL-2 administration may have contributed to her death. Only 6 patients completed the schedule without evidence of major intolerance, even though the planned dose during the second course of rIL-2 was reduced to 400 micrograms/m2. The complete duration of treatment ranged from 11 to 19 days. The total dose of rIL-2 injected ranged from 12.6 to 30.4 mg. The number of infused LAK cells ranged from 15.5 x 10(9) to 60 x 10(9)/patient. Two of the 14 evaluable patients showed a minor anti-tumor response. In 5 patients new metastases in other sites were documented from 2 to 5 months after completion of dosing. No apparent association was found between progression of the disease (or the appearance of new metastases) and the total dose of rIL-2 injected, the number of LAK cells administered or the number of days of treatment. By December 1988, all patients had died of their disease in a period ranging from 3 to 14 months from the last injection of rIL-2. The lack of significant clinical responses in this study and the high toxicity of this treatment lead us to conclude that at least as far as melanoma patients are concerned, adoptive immunotherapy with rIL-2 plus LAK cells (as described here) is not a justifiable treatment option unless new evidence presents itself.

Adult↗

PubMed1989

Mitoxantrone as first-salvage chemotherapy in relapsed breast cancer.

Mitoxantrone was administered at the dose of 14 mg/m2 i.v. every 3 weeks to 25 consecutive women with measurable progressive disease who relapsed after adjuvant CMF and endocrine therapy. The treatment plan consisted in the delivery of 6 cycles, unless disease progression or severe toxicity occurred. All patients were evaluable for drug response and toxicity. One patient achieved complete remission and 6 partial remission, for a total response rate of 28%. Objective tumor response was observed in all major sites of disease. The median time to achieve remission was 3 months. The median duration of response was 7 months (range, 5-39+), and the median survival for the entire group was 10 months (range, 3-39+). Results were influenced only by the duration of disease-free status from the end of adjuvant CMF chemotherapy. In fact, all tumor responses were documented in woman with free intervals exceeding 1 year (7 of 17 or 41%). Treatment was generally well tolerated, with 10 patients developing leukopenia at some time during treatment. Only 2 patients received less than 75% of the projected dose because of granulocytopenia. Complete alopecia occurred in only 2 cases. Three patients developed a fall greater than 15% in left ventricular ejection fraction, but no episode of congestive heart failure was observed. We conclude that mitoxantrone is an effective and safe drug which can be utilized in women relapsing after adjuvant CMF.

Adult↗

PubMed1989

Evaluation of cardiac toxicity of idarubicin (4-demethoxydaunorubicin).

Cardiac toxicity of idarubicin (4-demethoxydaunorubicin), a new daunorubicin derivative, was tested in 49 phase II patients with advanced malignancies. In 26 patients the drug was given intravenously at a dose of 13 mg/m2 and in 23 orally at a dose of 45 mg/m2. Cardiac toxicity was evaluated by means of electrocardiography, left ventricular systolic time intervals, echocardiography and radionuclide cineangiography. The type and incidence of ECG abnormalities were comparable to those observed with other anthracycline analogs. Other functional parameters, serially measured to evaluate delayed cardiotoxicity in patients who received more than 65 mg/m2 intravenously or 225 mg/m2 orally, were not significantly different from pretreatment values. No patient developed clinical congestive heart failure. Only one patient exhibited a drop in the left ventricular ejection fraction of more than 15% from pretreatment values. These data indicate that idarubicin given orally or intravenously at the tested doses has no significant cardiotoxic activity in the range of the cumulative doses attained.

Administration, Oral↗

PubMed1989

Evaluation of ventricular function by echocardiography and radionuclide angiography in patients treated with mitoxantrone.

Mitoxantrone, an anthracenedione derivative structurally similar to anthracycline, was tested in 25 Phase II patients with advanced breast cancer, previously treated with different cycles of 5-fluorouracil. Cardiac toxicity was evaluated by means of electrocardiography, echocardiography and radionuclide left-ventricular ejection fraction. Ten patients received a cumulative dose less than 70 mg/m2 (median 33.6, range 28-63) and 15 a dose equal to or more than 70 mg/m2 (median 81, range 70-84). ECG abnormalities in the form of dysrhythmias and ST-T changes were observed in 41% of the patients. Echocardiographic myocardial function parameters recorded in 10 of the 15 patients who received more than 70 mg/m2 demonstrated a trend to deterioration, whereas the nuclear angiographic ejection fraction recorded in all 15 patients who had more than 70 mg/m2 had significantly decreased. No patients developed congestive heart failure but almost one-quarter of them had a fall in myocardial function parameters of more than 15% compared to pretreatment values. These data indicate that mitoxantrone has a significant toxic effect on myocardial cells also at cumulative doses of less than 85 mg/m2 which is generally considered beyond the limit of safety for patients without risk factors.

Adult↗