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Biomedical subjects

M Del Tacca

Publications and source records attributed to M Del Tacca.

At least 163 records · Page 9Linked to original sources

Pirenzepine versus ranitidine in gastroprotection during antiblastic chemotherapy: a double-blind study.

Corticosteroids and cytostatic drugs possess a documented lesive action on upper digestive mucosa, making epigastric pain and/or pyrosis common complaints among patients on antitumor treatment. The selective antimuscarinic pirenzepine and the H2-receptor antagonist ranitidine were tested against the ulcerogenic action of antiblastic chemotherapy. Thirty-eight patients affected with malignant lymphoproliferative disorders were endoscopically examined and the endoscopic pictures were quantified by using an arbitrary score. According to a double-blind randomized sequence, 19 out of the 38 patients received pirenzepine 100 mg/die/p.o. and the other 19 received ranitidine 300 mg/die/p.o. along with antitumoral therapy for periods of 3-6 months. Seven patients died of hematologic complications before ending the treatment. In the 31 surviving patients (13 pirenzepine- and 18 ranitidine-treated) a second endoscopic examination was performed at the end of the treatment and the lesion score repeated. No significant difference was found between initial and final scores in both groups. The antisecretive action of the two drugs may account for their effectiveness, but other mechanisms such as cytoprotection cannot be ruled out.

Adult↗

Central and peripheral involvement of mu receptors in gastric secretory effects of opioids in the dog.

The effects of dermorphin and morphine on gastric acid secretion were studied in conscious dogs with both gastric fistulas (GF) and Heidenhain pouches (HP). Under basal conditions dermorphin and morphine, infused systemically at graded doses, produced a significant increase in acid secretion from both GF and HP. This increase was significantly inhibited by naloxone, naltrexone methylbromide and N-methyl-levallorphan methanesulphonate. Dermorphin did not modify the acid output stimulated by 2-deoxy-D-glucose from GF, while morphine significantly inhibited it; on the contrary acid secretion from HP was increased in this test by both dermorphin and morphine. Acid secretion from GF stimulated by pentagastrin was unaffected by morphine and significantly enhanced by dermorphin. Under these conditions a significant increase in acid secretion from HP was recorded with dermorphin and morphine. Naloxone and N-methyl-levallorphan methanesulphonate, given during pentagastrin-stimulated secretion, significantly inhibited acid output 'per se' from GF and HP and prevented the stimulatory effect of dermorphin and morphine. Bethanechol-induced secretion from GF and HP was significantly increased by both dermorphin and morphine. The present results demonstrate that opioids have simultaneous yet opposite effects on acid secretion in the dog and that mu receptors are involved in both the excitatory and inhibitory effects. Excitatory effects do not seem to be mediated via a vagal pathway (peripheral ?), in contrast to the inhibitory effects (central ?). The inhibitory effects of opiate antagonists on pentagastrin-stimulated secretion suggest a physiological role of peripheral opioid receptors in gastric acid secretion.

Animals↗

[Recent pharmacotoxicologic and clinical findings on adriamycin].

Anthracycline derivative adriamycin (ADR) is one of the most important anticancer drugs with major clinical application in carcinomas of the brest, endometrium, ovary, testicle, thyroid, lung and in treatment of many sarcomas. It is useful also in haematological cancers including acute leukaemia, multiple myeloma, Hodgkin's disease and the diffuse non-Hodgkin lymphomas. A factor limiting ADR clinical practice is represented by a severe dose-dependent cardiac toxicity, the mechanism of which is still under study, but appears to involve excessive intracellular production of free radicals within myocardium: this is rarely seen at ADR dosage below 500 mg/m2. A series of new anthracycline analogues has recently entered clinical trials: they include 4'-epiadriamycin, 4'-deoxy-adriamycin, aclacynomycin A, carminomycin and N-trifluoroacetyladriamycin-14-valerate. These new agents appear to have different spectrum of action and somewhat less toxicity, however antitumor activity in only now being defined, consequently major clinical interest is still concentrated in the use of ADR. The present article reviews the most relevant data from literature concerning the pharmacology, the toxicology and the clinical use of ADR.

Alcohol Oxidoreductases↗

Gastric pharmacological activities of tripotassium dicitrato bismuthate in rats and dogs.

The effects of tripotassium dicitrato bismuthate (TDB) on gastric acid, pepsin and mucoprotein secretion in rats and on hydrochloric-peptic secretion and plasma gastrin levels in dogs were investigated. In Shay rats, TDB did not affect acid secretion but significantly lowered pepsin concentration and increased the amount of bound mucoproteins. In addition, gastric mucosal lesions were significantly prevented by the drug. In dogs, chronically fitted with both gastric fistulae and Heidenhain pouches, acid secretion and plasma gastrin levels stimulated by a meat meal were unaffected by TDB, while pepsin concentration and pepsin output were significantly decreased. On the basis of these results, the antiulcer activity of TDB appears to be ascribed to the protection of the gastric mucosa through an increase in mucoprotein synthesis and a decrease of pepsin activity.

Animals↗

Might adriamycinol contribute to adriamycin-induced cardiotoxicity?

The pharmacokinetics of adriamycin (ADR) and its 13-hydroxylated-metabolite adriamycinol (ADR-ol) was investigated during treatment with ADR in rats at a dose of 2 mg/kg i.v., once a week for 3 weeks. At various times, samples of blood and cardiac and pulmonary tissues were collected to measure the amount of ADR and ADR-ol by an HPLC procedure. Periodical ECG monitoring was performed during the study; the severity of cardiac lesions was histologically evaluated at the end of treatment. During the first 180 min after ADR administration, plasma levels of ADR and ADR-ol rapidly decreased; ADR levels in cardiac and in pulmonary tissues increased between the 15th and 30th min and than decreased between the 60th and 180th min; on the contrary, ADR-ol was undetectable in either cardiac or pulmonary tissues during the first 3 hours following ADR administration. Between the 1st and 3rd weeks of treatment, plasmatic levels of ADR and ADR-ol were unchanged; in a similar way, both cardiac and pulmonary tissue levels of ADR were constant during the period of treatment. By contrast, the cardiac tissue level of ADR-ol significantly increased between the 2nd and 3rd weeks. ECG tracings showed maximal enlargement of both QRS and S alpha T at the end of the 3rd week. The histological examination of cardiac tissue indicated the occurrence of degenerative changes in 20% of rats at the end of the experiment. Overall results seem to indicate that ADR-ol is produced and stored in cardiac tissue during repeated ADR administration; as a consequence the cytotoxic metabolite might contribute to the cardiotoxic effect of ADR.

Animals↗

Cardiotoxic effects of adriamycin and mitochondrial oxidation in rat cardiac tissue.

Rats were subjected to chronic treatment with adriamycin (ADR). Significant alterations of ECG tracings were induced, starting from the third week of treatment. These alterations were related to mitochondrial damage of the heart tissue. A decrease of respiration rate in phosphorylating conditions was observed in isolated organelles over a period of three weeks. Meanwhile, adriamycinol (ADRol) concentration in heart extracts increased during chronic treatment.

Animals↗

Clinical study on the efficacy of clofoctol in the treatment of infectious respiratory diseases.

The effectiveness and the safety of a new chemotherapeutic phenol derivative, clofoctol, was evaluated in adult hospitalized patients affected by infectious diseases of the bronchopulmonary tract. The clinical diagnosis included acute exacerbation of chronic bronchitis, acute bronchitis, bronchiectasis, pneumonia, bronchopneumonia and lung cavitary neoplasm. Expectoration, cough, dyspnoea, respiratory murmur and body temperature were considered as clinical factors to which an arbitrary score was given. Functional respiratory parameters including FVC, FEV1 and FEV1/FVC X 100 were also evaluated. All the patients were treated rectally with clofoctol 1500 mg daily for five days. Bacterial evidence of infection was obtained by sputum culture, which was repeated at the end of treatment. At that time, bacteriological results were 72.4% disappearance of baseline pathogens, 20.7% persistence of baseline pathogens and 6.9% presence of different organisms. Functional respiratory parameters were found to be significantly improved by treatment. Clinical results, arbitrarily evaluated on the basis of the overall assessment of laboratory and functional data, were excellent in 33.3%, good in 44.4%, fair in 5.6% and poor in 16.7% of patients. Tolerance was generally good; side-effects included maculopapular rash in 2 patients and rectal disturbances in 10 patients. In conclusion, for the treatment of bronchopulmonary diseases clofoctol offers an interesting alternative to antibiotic therapy.

Adult↗

[A case of acute clonidine poisoning].

A case of voluntary intoxication by clonidine (3.9 mg per os for a suicide purpose) is reported. The drug caused subjectively sleepiness and headache. Cardiovascular symptoms consisted of a marked bradycardia which was well controlled by atropine (1.04 mg i.v.) and a moderate decrease of the blood pressure. A "discontinuation syndrome" during 72 hours after the intoxication was not observed.

Adult↗

Evidence for two opposite effects of clonidine on gastric acid secretion in the dog.

The effects of clonidine on gastric acid secretion were studied in conscious dogs with both gastric fistulae and Heidenhain pouches. Clonidine infused systemically at graded doses under basal conditions produced a significant increase in acid secretion from both gastric fistulae and Heidenhain pouches. Acid secretion from gastric fistulae submaximally stimulated by pentagastrin was dose-dependently reduced by clonidine while 2-deoxy-D-glucose-induced secretion was completely suppressed. Under these conditions a significant enhancement of secretion from Heidenhain pouches was recorded. An increase in acid secretion from both main stomachs and Heidenhain pouches was observed for clonidine with submaximal doses of bethanechol and histamine as stimulants, though clonidine showed no effect on maximal stimulation by histamine. The stimulant effect of clonidine from gastric fistulae and Heidenhain pouches under basal conditions was fully prevented by cimetidine, while the inhibitory effect of clonidine on acid secretion stimulated by pentagastrin from gastric fistulae was reversed by yohimbine. The present results suggest that clonidine displays two simultaneous yet opposite effects on dog gastric secretion. The inhibitory effect might be mediated through a decrease of vagally released acetylcholine following the activation of alpha 2-adrenoceptors both at central and peripheral sites, while the stimulatory effect probably depends on the histamine-like properties of the drug.

Animals↗

Comparative study of pA2 values of pirenzepine and atropine for guinea-pig gastric fundus and gastric smooth muscle.

Concentration-response curves of bethanechol were obtained from isolated guinea pig gastric fundus and gastric circular smooth muscle strips before and after exposure to pirenzepine or atropine. In the presence of pirenzepine and atropine these curves were shifted parallel to the right with no change in maximum response. Against bethanechol, mean pA2 values were 7.06 for pirenzepine and 8.16 for atropine on gastric fundus, with slopes of Schild plots close to unity for both antagonists, whereas in the case of gastric smooth muscle pA2 values were 6.52 for pirenzepine and 8.52 for atropine, with the slope of the Schild plot significantly less than -1 in the case of pirenzepine. The values of the Schild slope seem to indicate that pirenzepine interacts with a single, apparently homogeneous population of muscarinic receptors on gastric mucosa, at variance with the behaviour of pirenzepine on receptors of gastric smooth muscle.

Animals↗

Short-term and long-term effects of ranitidine and oxmetidine on gastrointestinal motility in sheep.

Short-term and specific motor effects of ranitidine on gastrointestinal motility of conscious sheep were recorded. These effects were prevented by atropine, but tachyphylaxis was observed after a second injection. Short-term effects on motility were not obtained with oxmetidine. Long-term effects for both ranitidine and oxmetidine, at high doses, were reducing the frequency of reticular contractions and shortening the interval between MMCs in a similar manner.

Animals↗

Comparative study with oxmetidine and ranitidine on acid secretion and gastrin release in the dog.

The antisecretory potency of oxmetidine was compared with that of ranitidine for its action against gastric acid secretion induced by histamine and by 2-deoxy-D-glucose (2DG) in the conscious gastric-fistula dog. Oxmetidine, administered i.v. during histamine stimulation, was nearly as effective as ranitidine, with a similar duration of action, but it was about twice as potent as ranitidine against 2DG-stimulated acid secretion. In experiments with bombesin, both oxmetidine and ranitidine significantly decreased gastric acid secretion to a similar extent, without affecting plasma gastrin levels.

Animals↗

Gastric cytoprotection by pirenzepine: role of endogenous catecholamines.

Acute gastric ulcerations were produced in fasted rats by pylorus ligation or by administration of polymyxin B or absolute ethanol. In pylorus-ligated rats pirenzepine 25 mg/kg per os decreased by about 50% the ulceration score, without affecting gastric acid and pepsin output. A similar percentage inhibition of ulceration score with no change of gastric acidity was obtained with pirenzepine 5 mg/kg per os in the case of gastric lesions provoked by polymyxin B. Ethanol-induced gastric lesions were also markedly reduced by pirenzepine, with 50% inhibition occurring with the dose of 25 mg/kg. The release of catecholamines from rat isolated gastric tissue during stimulation of sympathetic periarterial nerves was significantly reduced by pirenzepine 1 X 10(-6) g/ml. The present results indicate that pirenzepine significantly reduced gastric lesions induced by various stimulants; the protective effect of pirenzepine did not appear to be related to increased sympathetic tone.

Animals↗

Gastric cytoprotection by pirenzepine is not mediated by catecholamines.

The effects of pirenzepine (in a dose of 25.0 mg X kg-1) and atropine (2.5 mg X kg-1) were studied on the development of gastric ulceration produced by pylorus ligation, polymyxin B and absolute ethanol, as well as on the gastric secretory responses and plasma level of noradrenaline. It was found that: (1) pirenzepine significantly decreased the development of ulcer formation produced by pylorus ligation, polymyxin B and absolute ethanol without any antisecretory response; (2) atropine inhibited gastric acid secretion, but no effect was obtained on ulcus produced by pylorus ligation, polymyxin B and absolute ethanol; (3) the plasma level of noradrenaline could be decreased by atropine and pirenzepine, although the difference did not reach statistical significance. It has been concluded that catecholamines are not involved in the gastric cytoprotective mechanism of pirenzepine.

Animals↗

Conformational effects on the activity of drugs. 10. Synthesis, conformation, and pharmacological properties of 1-(2,5-dimethoxyphenyl)-2-aminoethanols and their morpholine analogues.

In order to obtain a better understanding of the effects that structural parameters have on the changes of adrenergic activity when 1-aryl-2-aminoethanol derivatives are converted into their corresponding 2-arylmorpholine cyclic analogues, we synthesized 1-(2,5-dimethoxyphenyl)-2-aminoethanol derivatives 5-7 and their morpholine analogues 8-10. The preferred conformation of amino alcohols and their cyclic analogues have been determined through an H NMR and IR study. Compounds 5 and 6 showed both alpha-stimulating and alpha-blocking activity on rat vas deferens, the effect depending on the concentration employed; on the same isolated tissue, N-isopropyl derivative 7 and the morpholine analogues 8-10 exhibited only alpha-blocking activity. As for the beta-adrenergic activity, only the open-chain compound 7 possessed a moderate blocking effect on isolated guinea pig atria. The results of this work seem to indicate that the changes of pharmacological activity involved in the transformation of the adrenergic drugs into their morpholine analogues are influenced more by characteristic features of the aromatic moiety than by the ethanolamine or propanolamine structure of the drugs.

Animals↗

Pirenzepine in long-term therapy for duodenal ulcer.

A total of 60 patients with endoscopically diagnosed duodenal ulcer were treated with pirenzepine or cimetidine for 8-10 weeks until endoscopic healing of the ulcer. After ulcer healing 20 random patients received 50 mg pirenzepine per os daily for 6 months, 20 received 400 mg cimetidine per os daily for 6 months, and the remaining 20 received topic antacids for 6 months whenever they complained of pyrosis and/or epigastric pain. Endoscopic checks were repeated after 6 months (or earlier, if clinical picture was consistent with relapsing ulcer). Relapsing duodenal ulcer or erosive duodenitis was observed in 5 patients treated with pirenzepine (25%), in 4 patients treated with cimetidine (20%), and in 13 patients treated with occasional antacids (65%). Differences were significant between the antacid-treated patients and each of the other two groups, but not significant between pirenzepine-treated and cimetidine-treated groups.

Adult↗

Pharmacological studies on the mechanisms underlying the inhibitory and excitatory effects of clonidine on gastric acid secretion.

The effects of clonidine on gastric acid secretion were investigated using various pharmacological preparations both in vivo and in vitro. In conscious pylorus-ligated rats clonidine produced a marked reduction of gastric secretion which was prevented by yohimbine, while in anesthetized pylorus-ligated rats the drug failed to affect gastric secretion. In stomach lumen-perfused rats, insulin-stimulated secretion was inhibited by clonidine; in contrast, the drug markedly potentiated bethanechol-evoked gastric secretion; this increase was fully prevented by cimetidine. In isolated preparations of guinea-pig gastric fundus, both spontaneous and bethanechol-induced hypersecretion were significantly enhanced by clonidine; this enhancement was also inhibited by cimetidine. The release of acetylcholine, measured at rest and during vagus nerve stimulation of both guinea-pig and rat isolated stomachs, was significantly inhibited by clonidine: this effect was prevented by yohimbine. Overall results indicate that clonidine possesses both inhibitory and excitatory effects on gastric acid secretion. The inhibitory effect appears to be mediated through the activation of presynaptic alpha 2-receptors which modulate acetylcholine release from the vagus nerve, while the excitatory action seems to depend on histamine-like properties of the drug.

Acetylcholine↗