Search PubMed⌕ Search

Biomedical subjects

S Garattini

Publications and source records attributed to S Garattini.

At least 217 records · Page 12Linked to original sources
PubMed1983

Clinical correlates of in vitro drug sensitivities of ovarian cancer cells.

Of 89 samples of cancer cells from ovarian cancer patients primary cultures representative of the cancer cell population could be established in 17. The clinical response to polychemotherapy was studied in relation to the inhibition of thymidine uptake by the cultured cells. Cultures of each patient's tumour were exposed to concentrations of the drugs the patients had been given for long enough to reproduce the area under the curve (AUC) of the plasma levels resulting from in vivo dosage. Full agreement was observed between the degree of thymidine uptake inhibition induced by at least one of the drugs administered to the cultured cells and the degree of clinical response. This approach may prove useful in pharmacological studies as a means of obtaining ovarian cancer cell populations representative of human tumours, even though the number of tumours that can be successfully evaluated in vitro is still too small to serve as a sound basis for prediction.

Adult↗
PubMed1983

Differences between d-fenfluramine and d-norfenfluramine in serotonin presynaptic mechanisms.

The abilities of d-fenfluramine (d-F) and that of d-norfenfluramine (d-NF) to inhibit [3H]serotonin ([3H]5-HT) accumulation in normal and reserpinized synaptosomes were compared to establish to what extent the serotonin-releasing activity of the two drugs might contribute to reduced accumulation of [3H]5-HT. The results indicate that the inhibitory action of (d-NF) on [3H]5-HT accumulation is due principally to its ability to release [3H]5-HT. In contrast, the interference of release in accumulation studies does not seem to play an important role for d-F, suggesting that release from the granular pool and true uptake inhibition are two different mechanisms by which d-F affects serotonin neurons in vitro.

Animals↗
PubMed1983

Disposition and metabolism of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in the rat.

After i.v. injection (10 mg/kg) to rats, buspirone is rapidly cleared from blood with a t1/2 (beta) or 30 min. After the same dose is given orally, the drug is not detectable in blood or brain within the limits of sensitivity of the method. The metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) has a longer t1/2 than buspirone. It is present to about the same extent in rat plasma and brain after either i.v. or p.o. buspirone. Unlike buspirone, 1-PP accumulates in the brain reaching concentrations between four-and five times those in plasma. Its brain AUC is higher than that of buspirone even when buspirone is given i.v. The results suggest that 1-PP may contribute to the pharmacological effect of the parent drug.

Animals↗
PubMed1983

Ovarian reticular cell sarcoma of the mouse (M5076) made resistant to cyclophosphamide.

Resistance of mouse M5076 (M5) ovarian reticular cell sarcoma to cyclophosphamide (CTX) was obtained in vivo by repeated drug treatment followed by transplantation of the regrowing tumor. After 16 passages, we obtained an M5 subline resistant to CTX (M5-CTX-16R). Median survival times were approximately 29 and 39 days for M5 and M5-CTX-16R, respectively. Survival of M5-bearing mice given a single i.p. dose of 200 or 300 mg/kg was 160 and 168% of controls, respectively, whereas in M5-CTX-16R it ws 103 and 123%, respectively. The resistance was not reversible after 14 additional passages with no further CTX treatment. M5 and M5-CTX-16R appear similar in histological features, pattern of metastasis formation, and DNA content, as assessed by flow cytometry (hypotetraploid). Metastases of M5-CTX-16R were also resistant to CTX. Flow cytometry studies 12 and 24 hr after CTX treatment revealed a block in S and G2-M phases in both tumors. After 48 hr and at subsequent times, no cytokinetic pertubation was evident in M5-CTX-16R, whereas in M5 marked accumulation of cells in G2-M was observed at 48, 72, 96, and 120 hr. Cross-resistance was found between CTX, L-phenylalanine mustard, chlorambucil, and hexamethylmelamine. M5-CTX-16R was sensitive, but less so than M5, to cis-platinum, 1,3-bis(2-chloroethyl)-1-nitrosourea, and imidazole-4-carboxamide,5-(3,3-dimethyl-1-triazene). Adriamycin was equally active on M5 and M5-CTX-16R, while 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidine-beta-D-glucopyranoside) was inactive. This model appears to be suitable for studies on the mechanism of resistance to CTX and alkylating agents and for screening new, non-cross-resistant drugs.

Animals↗
PubMed1983

Metabolic and pharmacological studies with N-methyl-N'-methyl-2'-allyl-2-benzoyl-4-chloro-glycinanilide (F 1797).

Three metabolites (F 1756, diazepam and N-desmethyl-diazepam) of N-methyl-N'-methyl-2'-allyl-2-benzoyl-4-chloro-glycinanilide (F 1797), a new potential anxiolytic agent, are formed by N-desmethylation or cyclisation in the rat. They were compared with F 1797 for their antileptazol activity in order to assess their contribution to the effect of the parent compound. F 1756 had little effect in this test. However, diazepam and N-desmethyl-diazepam formed after F 1797 certainly contributed to its antileptazol effect.

Anilides↗
PubMed1983

Is it necessary to measure plasma levels of anticancer drugs?

Variability in plasma drug levels in patients given the same doses of anticancer agents suggests that the efficacy of the drugs may also differ. Stress is laid on the need in clinical trials to make concomitant measurements of the plasma levels of drugs used.

Animals↗
PubMed1982

Effect of dimethylamino-2-ethoxyimino-2-adamantane (CM 54903), a non-polar dimethylaminoethanol analog, on brain regional cholinergic neurochemical parameters.

CM 54903, a new psychotropic drug with a particular pharmacological profile, produced a widespread but short-lasting decrease in acetylcholine content in rat brain hemispheric regions but not in the midbrain-hindbrain or cerebellum at the dose of 40 mg/kg, i.p. The decrease was most conspicuous in the striatum. Brian regional choline contents were unaltered as were the acetylcholine turnover rates in the striatum and hippocampus. Neither choline acetyltransferase nor acetylcholinesterase activities were altered after the in vitro incubation or the in vivo administration of high amounts of the drug. CM 54903 was found to be a competitive, reversible inhibitor of the sodium-dependent high affinity uptake of choline by crude hippocampal and striatal synaptosomal preparations showing an IC50 of 10 microM in vitro. Despite the fact that the drug readily crosses the blood-brain barrier and achieves brain concentrations several-fold greater than its in vitro IC50, CM 54903 did not inhibit choline uptake in vivo although it was capable of preventing the pentylenetetrazol-stimulated choline uptake by hippocampal synaptosomes. The changes in striatal acetylcholine content induced by the blockade or the stimulation of muscarinic cholinergic receptors or dopaminergic receptors did not interfere with the effect of CM 54903 on striatal acetylcholine content while pentylenetetrazol completely prevented the decrease. The results taken together indicate that the major effect of CM 54903 on the cholinergic neurons is at the presynaptic level to compete with choline at its uptake sites.

Acetylcholine↗
PubMed1982

Brain levels of tofizopam in the rat and relationship with benzodiazepine receptors.

The effect of tofizopam on 3H-flunitrazepam binding was studied in rat hippocampus and cerebellum. Tofizopam (at a concentration of 10(-7) M) increased 3H-Flu binding through a 30% rise in the Bmax with no modification of Kd in either brain area. Similar results were obtained when the binding was measured in tofizopam (50 mg/kg p.o.) pretreated rats. Even though tofizopam has no anticonvulsive action against pentetrazol-induced convulsions, it significantly potentiated the action of diazepam but with no modification of brain diazepam levels and metabolism. The brain levels of tofizopam are reported and compared to plasma levels after oral administration of 5 and 50 mg/kg to rats.

Animals↗
PubMed1982

Antileptazol activity and kinetic of CP 1414 S (7-nitro-2-amino-5-phenyl-3-H-,1,5-benzodiazepine-4-one) in the rat and mouse.

The antileptazol effect of CP 1414 S (7-nitro-2-amino-3-phenyl-3H-1,5-benzodiazepine-4-one) a newly developed 1,5 benzodiazepine, lasts longer in mice than in rats. After intraperitoneal injection (10 mg/kg) brain levels of the drug were higher and persisted for longer in the mouse than in the rat. Although it cannot be excluded tht possible metabolites of CP 1414 S may contribute to the anticonvulsant effect of CP 1414 S, in both species the protective effect correlates well with the brain concentrations of the drug.

Animals↗
PubMed1982

Species differences in phenazepam kinetics and metabolism.

The kinetic profiles of phenazepam and its hydroxylated derivative were compared in rat, dog, cat and man after administration of single oral doses of the parent compound. The absorption of phenazepam was reasonably rapid in all the species studied. Blood peak concentrations (Cmax) were reached at 1 h in rats (0.32 +/- 0.03 microgram/ml), at 0.5 h in dogs 0.54 +/- 0.10 microgram/ml), at about 2 h in cats (1.65 +/- 0.23 microgram/ml), about only at 4 h in man (0.038 microgram/ml) at the highest dose tested. The largest normalized (value/dose) Cmax and area under the curve (AUC) were observed in man, while the rat gave the lowest values. The half-life of phenazepam was about 60 h in man, 13.72 +/- 2.09 h in the cat, 6.35 +/- 2.32 h in the dog and 7.49 +/- 1.88 h in the rat (beta-half-life). 3-OH-phenazepam was rapidly detected in cat, rat, and dog blood but no measurable amounts (less than 3 ng/ml) were found in human blood. At the oral doses tested, the ratio of the AUC for 3-OH-phenazepam to phenazepam was 0.01, 0.48, and 0.53 in the dog, rat, and cat, respectively. The half-life of the metabolite was shorter than that of the parent compound in the dog, but it was comparable in the rat and longer in the cat. The results suggest that 3-OH-phenazepam might contribute to the overall pharmacological effects of the parent compound in those species in which it accumulates in significant amounts.

Animals↗
PubMed1982

Plasma and brain levels of glutamate and pyroglutamate after oral monosodium glutamate to rats.

Plasma and brain levels of pyroglutamate (Py), a compound connected with the pathway of glutamate (GA) metabolism, were measured in rats after oral administration of monosodium glutamate (MSG) or Py. Oral MSG (1 g/kg) was followed by only a small rise in plasma Py levels. No increase of Py or GA brain levels was observed in these experimental conditions. Oral administration of Py (0.05, 0.5 and 1 g/kg) resulted in a marked dose-dependent increase of plasma Py, but no increase of plasma or brain GA levels. However, Py accumulated in brain in a dose-related manner. After 0.05 mg/kg the basal brain levels remained unchanged at all the times considered. Rat brain Py levels significantly increased when the oral dose of Py was raised to 0.5 g/kg. Peak brain levels were reached at 240 min, and were about 3 and 4 times the basal levels after 0.5 and 1 g/kg, respectively.

Administration, Oral↗
PubMed1982

In vitro and in vivo cytotoxicity of 6 amino-5-formyl-methylamino-1,3-dimethyl uracil, a uracilic metabolite of caffeine.

The in vitro cytotoxicity of 6 amino-5 formylmethylamino-1,3 dimethyluracil (ADMU) a major metabolite of caffeine in rats was studied by cell counts or [3H]thymidine incorporation in the murine Lewis lung carcinoma (3LL) and L929 fibroblast cells and in the human E cell line derived from an ovarian carcinoma. Unlike 5-fluorouracil (5FU) which was markedly cytotoxic, ADMU concentrations up to 60 micrograms/ml were devoid appreciable cytocidal action. Similarly, 1-10 micrograms 5FU markedly inhibited the blastogenic response of rat lymphocytes to PHA, whereas lymphoproliferation was not affected at ADMU concentrations up to 100 micrograms/ml. In vivo administration of ADMU (40 mg/kg, twice a day on day 1 to 3) to L1210 leukaemia-bearing mice caused a transient short-lasting reduction of tumour cell numbers only on day 6 after leukaemia inoculation.U

Animals↗