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Biomedical subjects

M Del Tacca

Publications and source records attributed to M Del Tacca.

At least 127 records · Page 7Linked to original sources
PubMed1991

Anthracycline cardiotoxicity: in vivo and in vitro effects on biochemical parameters and heart ultrastructure of the rat.

The premise of this study is that mitochondrial lesions caused by anthracyclines lead directly to cardiotoxicity. We compared several biochemical parameters, including endogenous cellular respiration, adenosine and guanosine triphosphate levels, and 14C-amino acid incorporation, of rat hearts treated with doxorubicin and some of its derivatives, recent products of pharmacological research aimed at selecting less toxic antiblastic agents. In rats treated in vivo, we further examined the ultrastructural changes induced by anthracycline antibiotics in order to elucidate which biochemical parameters were consistent with the morphological lesions. Our data indicate that mitochondria are the target of the anthracycline effects and that oxygen uptake and nucleotide levels may be regarded as markers of the toxicity when evaluating new drugs before their clinical use. The lack of cytoplasmatic or endoplasmatic reticulum alterations may account for the failure of anthracyclines to affect amino acid incorporation. In any event, the rate of protein synthesis cannot serve as a marker of cardiac toxicity. In this context, epidoxorubicin and iododoxorubicin are two derivatives characterized by less cardiotoxic potential than doxorubicin and thus appear to be promising antiblastic agents.

Adenosine Diphosphate↗
PubMed1991

[The evaluation of the cardiotoxicity of 4'-epidoxorubicin at high doses].

Twenty-eight patients with small cell lung cancer were treated with high dose 4'-epidoxorubicin (EDX). Fifteen patients underwent EDX monotherapy (cumulative dose: 800 mg/m2) while 13 were treated with EDX (cumulative dose: 660 mg/m2) associated with cyclophosphamide, etoposide and cisplatin. A 2D-echo was performed in basal condition, after the third and sixth dose and 2 months after the end of the therapy. In the patients without cardiovascular disease (n = 19) left ventricular end-diastolic volume (EDV), end systolic volume (ESV) and ejection fraction (EF) were unchanged. The patients with coronary artery disease (n = 5) showed a statistically significant decrease in EF with an increase of ESV. All patients with systemic hypertension (n = 4) showed a significant reduction of EF and a significant increase of ESV and EDV.

Aged↗
PubMed1991

[The clinical efficacy of roxithromycin in patients with acute odontogenic infections].

The clinical efficacy of a macrolide antibiotic, roxithromycin, was evaluated in 24 patients affected by acute odontogenic infections. Patients were treated with a first dose of 300 mg p.o. which was followed by 150 mg p.o. 12-hourly for the following two days. Total responses were evaluated by an arbitrary scale. The results showed that an excellent and good response was obtained in 99.96% of treated patients. On the basis of clinically compared data and the drug safety it may be concluded that roxithromycin can be successfully used in the treatment of odontogenic infections.

Acute Disease↗
PubMed1990

Central GABAA excitatory and GABAB inhibitory receptors regulate gastric acid secretion in rats.

The present study investigates the effects of GABAA- and GABAB-receptor agonists and antagonists on gastric secretion after their i.c.v. administration to conscious pylorus-ligated rats and anaesthetized stomach lumen-perfused rats. Muscimol was without effect in pylorus-ligated rats, whereas baclofen produced a significant decrease in acid secretion, which was fully prevented by phaclofen. Under these conditions, a significant decrease in acid secretion was also obtained with bicuculline. In stomach lumen-perfused rats, muscimol caused a marked, dose-dependent increase in acid secretion, which was antagonized by bicuculline. Under the same conditions, baclofen induced a moderate, but significant, bicuculline-sensitive increase in acid secretion. Overall, our results suggest the presence of two central GABA pathways which mediate opposite effects: (a) a bicuculline-sensitive GABAA-receptor, the stimulation of which increases acid secretion under pharmacological depression of central vagal tone (anaesthetized rats); (b) a phaclofen-sensitive GABAB-receptor, the activation of which decreases vagally stimulated acid secretion (pylorus-ligated rats).

Anesthesia↗
PubMed1990

Protective effects of fructose-1,6-diphosphate on acute and chronic doxorubicin cardiotoxicity in rats.

The effects of fructose-1,6-diphosphate, an intermediate metabolite of glycolysis, on acute and chronic cardiotoxicity of doxorubicin were investigated in rats. In the acute study, urethane-anaesthetized Wistar female rats treated with 10 mg/kg i.v. doxorubicin developed a widening of the S alpha T segment, an impairment of +dP/dtmax, and tachycardia. Pretreatment with 375 and 750 mg/kg i.p. fructose-1,6-diphosphate prevented the S alpha T segment from widening, whereas only 750 mg/kg i.p. significantly attenuated the heart rate increase. Chronic cardiomyopathy was induced over a 6-week period by weekly doses of 3 mg/kg i.v. doxorubicin, being characterized in vivo by the progressive enlargement of the S alpha T segment and the occurrence of histological alterations and in vitro by a marked impairment of the inotropic response elicited by adrenaline in isolated hearts from treated rats. Concurrent treatment with 150 and 300 mg/kg i.p. fructose-1,6-diphosphate thrice a week for 6 weeks did not lessen the chronic heart damage, whereas 600 mg/kg given i.p. significantly reduced the widening of the S alpha T segment and the severity of histological damage in vivo, as well as significantly improving the contractile responses of hearts in vitro. These findings suggest that the administration of fructose-1,6-diphosphate plays a protective role in the acute and chronic cardiotoxicity of doxorubicin in the rat.

Acute Disease↗
PubMed1990

Cardiac toxicity and antitumor activity of 4'-deoxy-4'-iodo-doxorubicinol.

The acute and chronic cardiotoxicity as well as the cytotoxicity of 4'-deoxy-4'-iodo-doxorubicinol (I-DXRol), the major metabolite of the doxorubicin (DXR) derivative 4'-deoxy-4'-iodo-DXR (I-DXR), were compared with those of I-DXR and DXR. In the acute study, anesthetized rats received i.v. DXR (10 mg/kg), I-DXR (4 mg/kg), or I-DXRol (4 mg/kg) and were monitored for ECG (S alpha T segment and T wave), systolic (SBP) and diastolic (DBP) blood pressure, the first derivative of the systemic arterial pressure (SA dP/dtmax), and heart rate. Treatments induced a significant widening of the S alpha T segment, but I-DXRol was significantly less toxic than I-DXR or DXR. As compared with control values, DXR induced a marked increase in SBP and DBP and a decrease in SA dP/dtmax, whereas I-DXR and I-DXRol induced modest changes in hemodynamic parameters. In the chronic study, 3 mg/kg DXR given to rats by i.v. bolus once a week for 3 weeks resulted in severe chronic cardiotoxicity that lasted 6 weeks and was characterized by S alpha T-segment widening, T-wave flattening, and severe cardiac histological damage. Doses of 1.2 mg/kg I-DXR and 1.2 and 2.4 mg/kg I-DXRol, given i.v. once a week for 3 weeks, and 3.6 mg/kg I-DXRol given as a single dose were associated with a significant T-wave voltage reduction; I-DXR and 2.4 mg/kg I-DXRol induced significant histological alterations of cardiac tissue as compared with control values, whereas modest alterations of heart tissue were observed after injections of 1.2 and 3.6 mg/kg I-DXRol in three doses and in a single dose, respectively. The cytotoxicity of the three anthracyclines against one glioblastoma cell line and two human small-cell lung cancer lines was similar. Results indicate that the acute cardiotoxicity of I-DXRol is lower than that of I-DXR and DXR, whereas the chronic heart damage is similar to that induced by I-DXR and significantly lower compared than that caused by DXR. Moreover, the cytotoxicity of the metabolite appears to be similar to that of I-DXR and DXR. The lack of additional cardiac toxicity due to I-DXRol further supports the lower overall cardiac toxicity of I-DXR, which retains a cytotoxic activity similar to that of the parent drug.

Animals↗
PubMed1990

Phase II study of high-dose epirubicin in untreated patients with small-cell lung cancer.

Eighteen previously untreated patients with histologically confirmed small-cell lung cancer were treated with high-dose epirubicin (course 1, 100 mg/m2; courses 2-6, 140 mg/m2, day 1), every 3 weeks. Overall response rate was 33% (95% confidence limits, 14-52%), including two complete and four partial responses. The response rates for limited (n = 11) and extensive (n = 7) disease patients were 45% and 14%, respectively. With a median follow-up of 18 months, estimated 2-year survival of all patients was 29% and the median duration of response 18.5 months. The dose-limiting toxicity was myelosuppression, with a median granulocyte nadir of 1,150/mm3; 39% of patients had neutropenic fever. Nausea/vomiting, alopecia, and stomatitis were the most common nonhematological toxicities, usually mild to moderate. Acute cardiac toxicity was unusual and no episodes of congestive heart failure were observed. Cumulative doses of 800 mg/m2 were associated with moderate cardiotoxicity (grade 2), as assessed by endomyocardial biopsy and electron microscopy analysis. These results indicate that epirubicin, at the present doses and schedule, is an active single agent in patients with small-cell lung cancer, with acceptable general and moderate cardiac toxicity.

Aged↗
PubMed1990

Modulation of gastric acid secretion by peripheral presynaptic alpha 2-adrenoceptors at both sympathetic and parasympathetic pathways.

1. The effects of the alpha 2-adrenoceptor agonist detomidine, and the antagonists idazoxan and CH-38083 were examined on gastric acid secretion from non-vagotomized and vagotomized stomach lumen-perfused rats. The effects of detomidine on acid secretion from isolated guinea-pig gastric fundus were also evaluated. 2. In both non-vagotomized and vagotomized rats i.p. administration of detomidine significantly increased acid secretion, whereas i.c.v. detomidine was without effect. The stimulant action of i.p. detomidine was antagonized by both i.p. idazoxan and CH-38083 as well as by pretreatment with reserpine. 3. In vagotomized and reserpinized rats whose acid secretion was increased by electrical stimulation of the left vagus nerve, i.p. injection of detomidine caused inhibitory effects on acid secretion which were fully antagonized by both i.p. idazoxan and CH-38083. 4. Both idazoxan and CH-38083 caused a significant increase in acid secretion induced by vagal stimulation. At higher doses the two antagonists displayed a potentiating effect on vagally induced acid secretion only when they were associated to i.v. infusion of prazosin and propranolol. 5. Detomidine was without effect on acid secretion from isolated guinea-pig gastric fundus, whereas histamine or bethanechol caused a marked and dose-dependent stimulant action. 6. Overall, these results provide evidence that peripheral presynaptic alpha 2-adrenoceptors modulate both adrenergic inhibitory and cholinergic excitatory influences on rat gastric acid secretion.

Adrenergic alpha-Antagonists↗
PubMed1990

Differential affinities of AF-DX 116, atropine and pirenzepine for muscarinic receptors of guinea pig gastric fundus, atria and urinary bladder: might atropine distinguish among muscarinic receptor subtypes?

The pA2 values and the Schild plots of the antimuscarinic drugs AF-DX 116, atropine and pirenzepine for muscarinic receptors of isolated guinea pig gastric fundus (acid secretion) and atrial and urinary bladder preparations (contractile force) obtained from the same animals were calculated against bethanechol as the agonist. The antimuscarinic drugs concentration-dependently shifted the concentration-response curves to bethanechol to the right without any change in the maximum response. The analysis of data based on Schild plots was consistent with a simple competitive antagonism, since regression slopes did not differ significantly from unity. The pA2 values indicated a significantly higher affinity of AF-DX 116 and atropine for atrial muscarinic receptors with respect to those of the gastric mucosa or urinary bladder. By contrast, in the case of pirenzepine the pA2 values for the three tissues did not differ significantly. These results suggest that each examined tissue apparently contains homogeneous population of acetylcholine muscarinic (M2) receptors. The pA2 values found for AF-DX 116 and atropine suggest, however, that the putative M2 subtype of atrial muscarinic receptor differs from both those of the gastric fundus and those of the urinary bladder.

Animals↗
PubMed1990

Roxithromycin penetration into gingiva and alveolar bone of odontoiatric patients.

The concentrations of the new macrolide antibiotic roxithromycin in plasma, saliva, gingiva, and alveolar bone were studied in 24 odontoiatric patients treated with a first dose of 300 mg p.o. followed by three maintenance doses of 150 mg p.o., 12-hourly. Samples of blood, saliva, gingiva, and bone were collected at various time points up to 24 h after the last dosing, and the roxithromycin concentration was measured microbiologically, using Bacillus subtilis ATCC 6633 as the reference organism. Pharmacokinetic analysis was performed according to a two-compartment open model with first-order absorption. The plasma, gingiva, and alveolar bone peak concentrations were 6.12 +/- 1.94 mg/l, 6.55 +/- 2.54 mg/kg, and 5.09 +/- 1.60 mg/kg, respectively. Low levels of roxithromycin were detected in saliva (0.67 +/- 0.12 mg/l at the 3rd h). The values of the area under the concentration-time curve for plasma, gingiva, and bone were 59.47 mg/l.h, 51.88 mg/kg.h and 46.80 mg/kg.h, respectively; the half-life values were 7.52 h for plasma and 6.36 and 5.20 h for gingiva and bone, respectively. These results indicate that roxithromycin reaches high levels in periodontal tissues.

Adult↗
PubMed1990

Superoxide anion production by doxorubicin analogs in heart sarcosomes and by mitochondrial NADH dehydrogenase.

This study investigates the effects of daunorubicin, 4-demethoxy-daunorubicin, 11-deoxydaunorubicin, 5-imino-daunorubicin, doxorubicin, 4'-epidoxorubicin and the new derivative 4'-iodo-4'-deoxydoxorubicin, on superoxide anion production in heart sarcosomes and by mitochondrial NADH dehydrogenase. In cardiac sarcosomes all the anthracyclines tested enhanced NADPH-dependent superoxide formation which followed Michaelis-Menten kinetics and their Vmax were similar to that of doxorubicin except 5-iminodaunorubicin which did not affect superoxide production and 4'-iodo-4'-deoxydoxorubicin which showed significantly lower Vmax and Km. The superoxide formation by NADH dehydrogenase in the presence of anthracyclines appeared to follow saturation kinetics, depending by NADH. 4-Demethoxydaunorubicin and 4'-epidoxorubicin showed Vmax higher than that of doxorubicin although the Km values were similar. By contrast 5-iminodaunorubicin failed to increase superoxide production over control levels and 4'-Iodo-4'-deoxydoxorubicin hardly enhanced superoxide production by NADH dehydrogenase. A marked difference of superoxide formation rate was shown for the molecules tested in our in vitro system. The behaviour displayed in vitro by the imino- and iodo-derivatives well correlate to their moderate cardiotoxicity in vivo. For the other molecules tested, the poor correlation between the in vitro production of superoxides and the in vivo cardiotoxicity degree might depend on the pharmacokinetic steps which may modify the cardiac effects of these anthracyclines.

Animals↗
PubMed1989

GABA-A-mediated gastrin release induced by baclofen in the isolated vascularly perfused rat stomach.

In order to investigate the role of peripheral GABA-B receptors, the effects of the putative GABA-B agonist baclofen on immunoreactive gastrin release from an isolated vascularly perfused rat stomach preparation were examined. The vascular infusion of baclofen at graded concentrations induced a dose-dependent increase in gastrin release; this was unaffected by the GABA-B antagonist delta-aminovaleric acid, but was fully prevented by the selective GABA-A antagonist bicuculline as well as by atropine or tetrodotoxin. These results suggest that the stimulant effects of baclofen are mediated by nervous cholinergic structures associated with GABA-A receptors, and indicate that this GABA-B agonist must be regarded as a partial agonist of peripheral GABA-A receptors.

Amino Acids↗
PubMed1989

Evaluation of the JT and corrected JT intervals as a new ECG method for monitoring doxorubicin cardiotoxicity in the dog.

A comparison was made of the sensitivity of ECG, ultrastructural heart pathology, and plasma enzymes CK-MB and alpha-HBDH as methods to assess doxorubicin cardiotoxicity in adult beagle dogs given doxorubicin 30 mg/m2 i.v. once a week for three times. A progressive increase in JT and QT intervals, in corrected JT (JTc) and QT (QTc) intervals as well as a reduction in both T wave amplitude and RR duration, were observed in doxorubicin-treated dogs; the electrocardiogram (ECG) abnormalities were associated with doxorubicin-induced ultrastructural changes in cardiac tissue, consisting of dilation of the sarcoplasmic reticulum, multiform, flasklike invaginations of T-tubules containing electrondense material, and interruption of the junctional sarcoplasmic reticulum, which became more severe as the observation period progressed. On the contrary, doxorubicin treatment was associated with transient changes in plasma CK-MB and alpha-HBDH, which were unrelated to the severity of chronic cardiotoxicity. Overall results suggest that the monitoring of the ECG parameters related to the repolarization of the cardiac muscle, and particularly JT and JTc, might be regarded as a noninvasive method for the study of doxorubicin cardiotoxocity in the dog.

Animals↗
PubMed1988

Fructose-1,6-diphosphate reduces acute ECG changes due to doxorubicin in isolated rat heart.

Doxorubicin (DXR) (0.17 x 10(-4) M) induces an acute cardiotoxicity in isolated rat heart; there is a progressive widening of the S alpha T segment, with a decrease in force derivatives and in the coronary flow. Concurrent perfusion with fructose-1,6-diphosphate (FDP) (10(-5)-10(-4) M) dose-dependently reduces the S alpha T enlargement but fails to affect the reduction in force derivatives and coronary flow. The target of cardiac protection by FDP might be the ionic mechanisms underlying the action potential configuration.

Animals↗
PubMed1988

Cytofluorescence localization and disposition of doxorubicin and doxorubicinol in rat cardiac tissue.

The localization of cardiac cytofluorescence and tissue levels of doxorubicin (DXR) and doxorubicinol (DXR-ol) were studied in rats treated with a single (9 mg/kg: 1-day study) or 3 weekly doses (3 mg/kg: 7-week study) of the compounds. A striking orange-red fluorescence was observed in cardiac cell nuclei from DXR 1-day rats, whilst heart cells from DXR-ol 1-day rats displayed a faint, diffuse fluorescence. Neither cardiac tissue from DXR nor from DXR-ol 7-week animals showed any drug-specific fluorescence. HPLC assay showed that in DXR 1-day rats the drug was concentrated in the heart, which also contained the endogenously produced DXR-ol. Plasma levels of DXR-ol were initially high in DXR-ol 1-day rats but rapidly decreased with time; cardiac levels of DXR-ol remained low. Hearts from DXR 7-week rats contained appreciable amounts of DXR and DXR-ol, while very low levels of DXR-ol were found in DXR-ol 7-week animals. The data correlated well with the ECG alterations recorded during the study, which were more severe in DXR- than in DXR-ol-treated rats. These results indicate that the lower tissue uptake of exogenously administered DXR-ol might explain its lower toxic cardiac potential compared with DXR.

Animals↗