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M Del Tacca

Publications and source records attributed to M Del Tacca.

209 records · Page 12Linked to original sources
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[Preclinical pharmacology and clinical uses of topotecan].

Topotecan, a soluble semisynthetic derivative of camptothecin, is a specific inhibitor of topoisomerase I and is endowed of potent antiproliferative effect in vitro and in vivo on tumoral cell lines as well as on endothelial cells. Moreover, topotecan is able to interfere with the development of blood vessels in many in vivo experimental models. During the last years, several phase I clinical studies have demonstrated that the five-daily schedule is the most effective for the treatment of neoplastic diseases of children and adults. In particular, the best clinical results have been obtained in patients affected by metastatic ovarian cancer, small cell (SCLC) and non-small cell lung carcinoma (NSCLC), as well as mammary and gastrointestinal neoplasms. High response rates have been observed in myelodysplastic syndromes and myeloma. The clinical effectiveness of topotecan has been also demonstrated in ovarian carcinoma, even after failure of first or second line chemotherapy and in SCLC, where the response rate is 39%, while the percentage decreases up to 7% in case of drug resistance, with a median survival of 5.4 months. Toxicologic profile of topotecan is foreseeable and manageable, and the most frequent and severe toxicity is represented by myelosuppression. Leukopenia and neutropenia, which follow the administration of topotecan, are non-cumulative and self-limiting and unfrequently complicated by infections, whereas non-hematologic toxicities are uncommon and generally of mild-to-moderate degree. Topotecan is under continuous clinical evaluation for the treatment of neoplasms other than those reported above, alone or in combination with antineoplastic drugs in poly-chemotherapeutic protocols.

Antineoplastic Agents↗
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Evidence for both inhibitory and excitatory effects of morphine on gastric secretion in the rat.

The relationship between a wide range of doses of i.p. morphine and the effects of gastric secretion in several rat experimental models was investigated. In unoperated rats, morphine 5-15 mg/kg dose-dependently decreased gastric acidity, but an excitatory effect was observed with 0.5-1.5 mg/kg. A dose-dependent inhibition was also obtained in conscious pylorus-ligated rats with morphine 5-15 mg/kg, whereas no significant effects were found at lower doses. By contrast, acid concentration was enhanced with morphine 0.5-15 mg/kg in anaesthetized pylorus-ligated rats and in stomach lumen perfused rats. The changes of pepsin concentration correlated with the changes in gastric secretory volume. An increase in the volume was associated with a decrease in pepsin concentration, while pepsin amount per stomach was dose-dependently increased in all the conditions under which morphine increased gastric acidity. All the effects of morphine on acid and pepsin secretion were prevented by naloxone 1 mg/kg i.p. Overall results indicate that morphine may induce both excitatory and inhibitory effects on gastric secretion in the rat: these effects depend on the dose of morphine and the experimental conditions.

Anesthesia↗
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Effects of thymostimulin on chemotherapy-induced toxicity and long-term survival in small cell lung cancer patients.

The effects of hymostimulin on chemotherapy-induced toxicity and long-term survival were studied in 26 evaluable patients with small cell lung cancer. Patients were randomly treated with six cycles of two alternating regimens (cyclophosphamide, 4'-epidoxorubicin, and etoposide; cisplatin and etoposide), with (n = 15) or without (n = 11) thymostimulin (1 mg/Kg i.m., days 7-14 of every cycle). Only complete responders received maintenance treatment, consisting of thymostimulin administered 1 mg/Kg i.m., twice weekly, until tumor relapse. Myelosuppression, fever and documented infectious episodes were significantly less severe in thymostimulin-treated patients, allowing the administration of significantly higher drug doses at shorter intervals between chemotherapy cycles; a significant improvement in complete response rate and survival were also observed. Results suggest that the addition of thymostimulin to standard chemotherapeutic regimens might be of benefit, in view of its favourable effects on toxicity and long-term survival.

Adjuvants, Immunologic↗
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[A selective antimuscarinic agent: pirenzepine. Review of its pharmacologic and clinical properties].

The heterogeneity of muscarinic receptors has been well supported by differential characteristics between pirenzepine and atropine both in receptor binding and in whole tissue pharmacology studies. Under these conditions pirenzepine has been classified as a selective receptor antagonist with high affinity for M1 receptors. The antisecretory properties of pirenzepine on gastric acid and pepsin secretion may be attributed to the antagonistic activity of the drug on muscarinic M1 receptors of gastric intramural plexuses, whereas the effect on parietal muscarinic M2 receptors seems of less importance. Additional inhibitory mechanisms on gastric secretion may be represented by pirenzepine-induced increase in somatostatin release from gastrointestinal system. Significant cytoprotective properties of pirenzepine have been observed on a variety of experimentally induced peptic ulcerations. This protective activity may be due to pirenzepine-induced increase in gastric mucosal blood flow as well as to the increase in gastric transmural electric potential difference. In accordance with this pharmacodynamic profile of pirenzepine, numerous clinical studies have revealed its efficacy in the treatment of both duodenal and gastric ulcerations. In addition to this, the clinical usefulness of the drug has been demonstrated in Zollinger-Ellison syndrome, in stress ulceration, in acute gastrointestinal bleeding as well as in gastritis, duodenitis and non-ulcer dyspepsia. In most of the studies pirenzepine has been found to be well tolerated with a low incidence of antimuscarinic effects which may occur at salivary, ocular, cardiac and urinary sites. The clinical use of pirenzepine alone or in association with H2 blockers is recommended in the treatment of peptic ulcer patients, in the case of acute gastrointestinal haemorrhage and in patients non responders to H2 antagonists.

Animals↗
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Pirenzepine prevents cysteamine-induced formation of gastroduodenal ulcers and reduction of mesenteric circulation.

The effects of pirenzepine on gastric and duodenal ulceration and barrier mucus levels, as well as on changes of superior mesenteric artery diameter caused by cysteamine, were investigated in rats and compared with those of atropine. Cysteamine induced severe gastric and duodenal ulcers and decreased both barrier mucus levels and mesenteric blood flow. Pirenzepine reduced gastric and duodenal ulceration induced by cysteamine. Moreover, pirenzepine significantly increased basal mesenteric artery diameter and fully prevented cysteamine-induced decrease in mesenteric blood flow. Under the same conditions, atropine failed to prevent gastric and duodenal ulceration or mesenteric artery changes caused by cysteamine. Both pirenzepine and atropine were without any effect on cysteamine-induced inhibition of gastric and duodenal barrier mucus levels. The present results are consistent with the view that pirenzepine protects against gastroduodenal ulceration caused by cysteamine by increasing blood flow at the level of the ulcerated mucosa. The higher affinity of pirenzepine for the muscarinic receptors of sympathetic ganglia may explain the difference between the effects of pirenzepine and atropine. In addition to this, the measurement of superior mesenteric artery diameter changes may represent an accurate and reproducible method, suitable for studying the gastrointestinal protective mechanisms of the drugs.

Animals↗
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Effects of 4'-O-tetrahydropyranyl-doxorubicin on isolated perfused rat heart and cardiac mitochondrial cytochrome C oxidase activity.

The acute cardiac effects of the antitumour anthracycline 4'-O-tetrahydropyranyl-doxorubicin (THP) were studied on isolated, perfused, spontaneously beating rat hearts and on cardiac mitochondrial cytochrome c oxidase activity. Perfusion for 1 hour with 2.5 or 5.0 micrograms/ml of THP was associated with a marked widening of the QRS complex and the S alpha T segment, as well as with a reduction of the R- and T-wave amplitude, the heart rate, the isometric systolic tension and the coronary flow. Heart perfusion with equimolar doses of doxorubicin (2.2 or 4.4 micrograms/ml) induced a significant enlargement of the SaT segment and a reduction in the heart rate and the coronary flow. Both anthracyclines inhibited the cytochrome c oxidase activity in a dose-dependent manner; however, THP exerted a significant inhibition at concentrations higher than doxorubicin (20 microM). Results demonstrate that THP induces a higher degree of acute cardiotoxicity on isolated rat hearts compared with doxorubicin. The reduced inhibitory effect of THP on the cytochrome c oxidase activity of isolated heart mitochondria is consistent with the lower degree of chronic cardiotoxicity displayed by THP in animals and humans.

Animals↗
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Superoxide anion production by adriamycinol from cardiac sarcosomes and by mitochondrial NADH dehydrogenase.

This study investigates the effects of both adriamycin and its 13-hydroxylated metabolite adriamycinol on superoxide anion production from cardiac sarcosomes and by mitochondrial NADH dehydrogenase. Superoxide anion production was determined by using the succinoylated cytochrome c reduction assay. Both adriamycin and adriamycinol stimulated superoxide formation in cardiac sarcosomes and by mitochondrial NADH dehydrogenase. In the first case only NADPH was required as a co-factor and in the second case only NADH. From sarcosomes as well as by NADH dehydrogenase, the superoxide production followed Michaelis-Menten kinetics. With both activating enzymatic systems, the Vmax of adriamycinol was found to be similar to that of adriamycin, but the Km for the former anthracycline was higher than for the latter. Adriamycinol also increased the rate of NADPH and NADH consumption, by sarcosomal fractions and by NADH dehydrogenase respectively. At equimolar consentrations, adriamycinol consumed less NADPH and NADH than adriamycin. These results suggest that adriamycinol could contribute to the chronic cardiac toxicity of adriamycin by forming superoxide anions in cardiac cells constituents.

Animals↗
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General and cardiac toxicity of adriamycinol in rats.

The toxic effects of adriamycinol, the main metabolite of adriamycin, were studied during repeated treatment in rats, by evaluating survival, body growth, electrocardiographic parameters and cardiac histopathology. Different groups of animals were treated with 3 mg/kg weekly of adriamycinol or adriamycin for the first 3 weeks of the experiment and were observed for a further period of 4 weeks. One adriamycinol-treated rat and two adriamycin-treated ones died during the experiment. Adriamycinol inhibited rat body weight increase and induced the appearance of ECG alterations (especially S alpha T widening) as well as moderate histological cardiac lesions, but to a lesser extent and severity compared with adriamycin, which, in turn, markedly affected rat body growth, ECG parameters (especially the S alpha T segment and the T-wave) and the histological cardiac picture. The data of the present study indicate that adriamycinol induces an adriamycin-like toxic syndrome mainly affecting the heart, although to a lesser degree of severity than the parent drug. The lower toxic potential displayed by the metabolite might be due to its greater polarity compared with adriamycin, which implies a lower uptake of adriamycinol into tissues, especially the heart.

Animals↗