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Biomedical subjects

S Garattini

Publications and source records attributed to S Garattini.

At least 325 records · Page 18Linked to original sources
PubMed1977

Role of brain monoamines in the anorectic activity of mazindol and d-amphetamine in the rat.

The interaction of mazindol and d-amphetamine with brain monoamines was studied in rats. At each dose used, both compounds markedly counteracted the decrease of brain noradrenaline induced by 6-hydroxydopamine while only at high doses they did significantly reduce the effect of 6-hydroxydopamine on brain dopamine. Unlike d-amphetamine, mazindol significantly counteracted the decrease of brain serotonin induced by fenfluramine. The anorectic effect of mazindol and of d-amphetamine was markedly reduced by an electrolytic lesion at the level of the ventral noradrenergic bundle but not by an electrolytic lesion of the nucleus raphe medianus. An intrastriatal injection of 6-hydroxydopamine significantly reduced the effect of mazindol but not that of d-amphetamine. The results indicate that both compounds may block noradrenaline uptake in the brain while their effect on dopamine uptake is less evident. Ulike d-amphetamine, mazindol appears to inhibit serotonin uptake also. In addition, the integrity of the noradrenergic neurons in the brain appears to be an important condition for these drugs to exert their anorectic effect.

Animals↗
PubMed1977

Possible storage of (+)-amphetamine in catecholaminergic terminals of the striatum and brainstem.

6-Hydroxydopamine, given intraventricularly, did not affect the high concentrations of (+)-amphetamine present in the rat striatum and brainstem 1 h after its administration but considerably reduced the small amounts of (+)-amphetamine remaining after 5 h. In contrast, 5,6-dihydroxytryptamine did not modify the (+)-amphetamine concentrations at the times tested. These findings suggest that (+)-amphetamine might be stored in the catecholaminergic but not in the serotonergic central terminals.

5,6-Dihydroxytryptamine↗
PubMed1977

Hydroxylation of three benzodiazepines in vitro.

Three structurally related benzodiazepines were studied as substrates for hydroxylation by liver microsomal enzymes of rats and mice. The Vmax was comparable for dechlorodesmethyldiazepam, desmethyldiazepam, and 2'-chlorodesmethyldiazepam in the two animal species. The apparent Km decreased from dechlorodesmethyldiazepam to 2'-chlorodesmethyldiazepam for liver microsomal enzymes from both animal species. The hydroxylation of desmethyldiazepam and 2'-chlorodesmethyldiazepam yielded two pharmacologically active metabolites, oxazepam and lorazepam, respectively.

Animals↗
PubMed1977

Plasma concentrations and cardiotoxic effects of desipramine and protriptyline in the rat.

1 Desipramine and protriptyline were administered to anaesthetized rats by two consecutive intravenous infusions in order to obtain a peak level (first infusion) followed by lower steady state concentrations (second infusion) (Wagner, 1974). Theoretical plasma level time courses were confirmed experimentally.2 Desipramine and protriptyline were measured in atria and ventricles. Increasing infusion rates led to proportional increases in plasma and atrial concentrations. The tissue/medium ratio ranged from 57 to 21 for desipramine and from 43 to 11 for protriptyline according to the time of determination during infusions.3 Heart rate changes, deviation of the electrical axis of the heart and prolongation of atrioventricular conduction were recorded at fixed times during infusion.4 Positive chronotropic effects were noted at plasma concentrations ranging from 0.035 to 0.1 mug/ml for desipramine and from 0.04 to 1.2 mug/ml for protriptyline. At higher plasma concentrations the positive chronotropic effect decreased and bradycardia developed. Both drugs induced right rotation of the electrical axis of the heart. Threshold plasma levels giving 40 degrees rotation were 1.35 mug/ml (desipramine) and 1.75 mug/ml (protriptyline). Atrioventricular conduction was prolonged at threshold plasma concentrations of 2.2 mug/ml for desipramine and 3.6 mug/ml for protriptyline.5 Desipramine is more cardiotoxic than protriptyline. This difference is discussed in relation to the plasma and heart concentration of the two drugs.

Animals↗
PubMed1977

Plasma nortriptyline and cardiac responses in young and old rats.

1. The relationship between plasma concentrations and cardiac effects of nortriptyline was studied in anaesthetized young and old rats. 2. Nortriptyline was administered by two consecutive intravenous infusions which resulted in a peak plasma concentration followed by steady state values. Increasing infusion rates were followed by proportional increases in the drug plasma concentrations ranging from 0.15 to 6.0 microgram/ml. 3. In young rats, nortriptyline induced an increase in the heart rate, a right rotation of the electrical axis and a prolongation of the PQ interval. Heart rate changes were not correlated with nortriptyline plasma concentrations, while significant correlations were found for the other two parameters. Plasma concentrations inducing 20% increase of the PQ interval and 40 degrees rotation of the electrical axis were 1.65 microgram/ml respectively. Arrhythmias occurred at concentrations higher than 5.2 microgram/ml. 4. Nortriptyline caused more severe cardiac effects in old than in young animals. However, plasma concentrations of nortriptyline in old rats were two to five times higher than those found in young rats at similar infusion rates. A higher concentration of the drug at its sites of action seems to be responsible for the more severe cardiac toxicity of nortriptyline observed in old rats.

Aging↗
PubMed1977

Effect of two non tricyclic antidepressant drugs on [14C]5-hydroxytryptamine uptake by rat platelets.

The uptake of 14C-5-HT by rat blood platelets was examined in vitro in experimental conditions which allowed measurement of the initial velocity and excluded other passive processes across the cell membrane. In these conditions, the effect of two non tricyclic antidepressant drugs (Lilly 110140 and trazodone) was investigated. Lilly 110140 was as active as chlorimipramine and several times more active than imipramine as an inhibitor of 14C-5-HT uptake. Like chlorimipramine, Lilly 110140 appeared to be either a non-competitive or an uncompetitive inhibitor, according to the concentration of drug used. Trazodone also inhibited 14C-5-HT uptake by platelets but to a lesser extent than chlorimipramine, imipramine or Lilly 110140. m-Chlorophenylpiperazine, a possible metabolite of trazodone, was about 3 times more potent an inhibitor than the parent molecule. Both compounds acted non-competitively. Compared with published data on the effect of Lilly 110140 and trazodone on brain 5-HT, the present results support the suggestion that rat platelets are a useful pharmacological model of serotoninergic nerve endings.

Animals↗
PubMed1977

Biochemical and pharmacological studies on amineptine (S 1694) and (+)-amphetamine in the rat.

The pharmacological activities of amineptine (S 1694) and (+)-amphetamine and their interaction with biogenic amines have been examined in rats. The locomotor activity, stereotyped behaviour and hypothermia induced by amineptine were similar to but not as marked as those produced by (+)-amphetamine, and there was little or no anorectic action. Amineptine does not modify the concentrations of brain noradrenaline or acetylcholine which are respectively reduced and increased by (+)-amphetamine. Moreover, amineptine does not affect significantly the decrease of brain noradrenaline induced by an intraventricular injection of 6-hydroxydopamine, an effect significantly antagonized by (+)-amphetamine. On the other hand, like amphetamine, amineptine significantly reduces the effect of 6-hydroxy-dopamine on brain dopamine. Both drugs increase the striatal concentrations of homovanillic acid and show a cross tolerance in this action. Therefore they could act similarly on the striatal dopaminergine system. Amineptine thus appears to be a new type of antidepressant with a brain biochemical profile differing from that of other drugs used in depressive disorders.

Animals↗
PubMed1977

Antineoplastic activity and pharmacokinetics of adriamycin and daunomycin in tumor bearing mice.

In C57B1/6 mice bearing the intramuscular Lewis lung carcinoma, single intravenous doses of Adriamycin showed an higher antineoplastic effectiveness on the primary tumor and its lung metastasis than equal doses of its analog Daunomycin. The in vitro cell-binding of Daunomycin to these tumor cells was higher than that of Adriamycin, but no differences in cytotoxicity were found between the two agents. Pharmacokinetic studies revealed that Adriamycin (and/or its metabolites) accumulated in the neoplastic tissue more promptly, in significantly greater quantities and for longer periods than Daunomycin. The possible importance of these findings in explaining the greater therapeutic activity of Adriamycin in experimental animals is discussed.

Animals↗
PubMed1977

Differential distribution of antitumor agents in primary and secondary tumors.

The differential distribution of a series of antineoplastic agents in metastatic tissues compared to their respective primary tumors has been investigated in one rat and two mouse experimental tumor systems, ie, the intramuscular Lewis lung carcinoma (3LL) of C57BL/6 mice, which gives rise to spontaneous lung metastases, the intratibial Sarcoma 180 (S180) of CD1 mice, which induces macroscopic metastases to the lymph nodes, and the Walker 256 carcinosarcoma of CD rats, which also metastasizes to the lymph nodes. The results described in this paper show that the concentrations of adriamycin, daunorubicin, cyclophosphamide and its alkylating metabolites, hydroxyurea, 1-methyl-1-nitrosourea, and 6-mercaptopurine are much higher in the pulmonary metastases of 3LL and/or in the lymph node metastases of S180 than the concentrations measured in the primary tumor. In the Walker 256 tumor system the distribution of adriamycin appears to follow the same pattern observed for the mouse tumors. Only for methotrexate (in the 3LL tumor) is the difference in the concentrations at the two sites not so evident. These findings are discussed in relation to the comparatively greater sensitivity of metastases to chemotherapy.

Animals↗
PubMed1977

Blood coagulation changes in mice bearing Lewis lung carcinoma, a metastasizing tumor.

In view of the possible role of platelets and coagulation mechanisms in the growth and dissemination of solid tumors, a number of hematological parameters were followed during development of an experimental syngeneic tumor in mice, Lewis lung carcinoma. This tumor, when transplanted i.m. in C57BL/6 mice, grows locally and spontaneously metastasizes to the lungs. The transplanted animals survive for about 4 weeks. Metastases are visible from the third week. A slight but constant increase in plasma fibrinogen level and marked thrombocytopenia were first observed during the second week after tumor implantation. No other significant changes in coagulation and fibrinolysis parameters were detected. Moreover, the animals developed marked hemolytic anemia, possibly microangiopathic in origin. 125I-labelled fibrinogen survival was decreased by about 20% during the second week after tumor implantation and was not further reduced later. Fibrinogen turnover was progressively accelerated, being more than doubled by the end of the third week. Labeled fibrinogen accumulated in the primary tumor and in the lungs (its rate of disappearance from the tumor was much slower than that from lungs or blood). 51Cr-labeled platelet survival did not change throughout the observation period, whereas platelet turnover was markedly reduced from the end of the second week, suggesting defective platelet production. 51Cr-labeled RBC survival was drastically reduced to about 30% of the controls starting from the second week. The occurence of low-grade, localized intravascular coagulation could be suggested on the basis of these data. Moreover, when Lewis lung carcinoma cells were abruptly injected i.v. through the tall vein, more impressive signs of intravascular coagulation could be seen. Indeed, there was a rapid decrease in the number of platelets, a reduction in fibrinogen, and an increase in fibrin-fibrinogen degradation products. The effects of i.v. injection of Lewis lung carcinoma cells indicate a relevant interference of cancer cells with the hematostatic system. In contrast, the tenuous evidence fo coagulation disorders in animals receiving injections of tumor cells i.m. seems to indicate a limited effect on hemostasis of the same cells during i.m. tumor growth.

Animals↗
PubMed1977

Interference by fenfluramine with the storage of 14C-5-hydroxytryptamine in rat platelets.

(+)Fenfluramine decreases the 14C-5HT stored in rat platelets both in in vitro and in in vivo systems, indicating a release of the amine. The effect of (+) fenfluramine in vitro increases by increasing the concentration of the drug, the time of incubation with platelets and the temperature. It is not accompanied by loss of lactate dehydrogenase thus excluding an unspecific damage to the platelet membrane induced by the drug. In addition it is not inhibited either by inhibitors of the uptake of 5HT (chlorimipramine, Lilly 110140) or by inhibitors of the platelet 'release reaction' (acetylsalicylic acid) or by an excess of cold 5HT in the incubation medium. The effect of (+) fenfluramine in vivo is dose-dependent and increases gradually up at least 18 hr after i.p. drug's administration. It is significantly inhibited in rats pretreated by either chlorimipramine or Lilly 110140, but not by acetylsalicyclic acid. In analogy with the effect of (+) fenfluramine on rat brain 5HT, it is suggested that this drug could enter platelets by utilizing the 5HT uptake mechanism, at least in vivo.

Animals↗