Biomedical subjects

M Sabatino

Publications and source records attributed to M Sabatino.

At least 19 recordsLinked to original sources

PubMed2004

UFT/leucovorin and oxaliplatin alternated with UFT/leucovorin and irinotecan in metastatic colorectal cancer.

A total of 41 metastatic colorectal cancer (CRC) patients received tegafur/uracil (UFT)+leucovorin (LV)+oxaliplatin alternated with UFT/LV+irinotecan. The overall response rate was 58.5% (95% confidence interval, 42.2-73.3%), and the median progression-free survival was 8.8 months. There were no grade 4 toxicities; 12 patients (29%) experienced grade 3 diarrhoea. There were no cases of hand-foot syndrome. This alternating regimen seems to be effective and well tolerated in the first-line treatment of patients with metastatic CRC.

Administration, Oral↗

PubMed2003

A novel biweekly pancreatic cancer treatment schedule with gemcitabine, 5-fluorouracil and folinic acid.

Pancreatic adenocarcinoma is a common disease considered to be poorly responsive to antiblastic treatment. Recent clinical and preclinical results suggest that a combined treatment of gemcitabine (GEM), 5-flurouracil (5-FU) and folinic acid (FA) offers a clinical benefit in patients with advanced pancreas adenocarcinoma. The aim of this phase II clinical trial was to evaluate the antitumour activity and toxicity of a novel biweekly schedule of this combination in patients with pancreatic adenocarcinoma. A total of 42 patients received a 30 min infusion of FA (100 mg m(-2)) and 5-FU (400 mg m(-2)) (FUFA) on days 1-3, and GEM 1000 mg m(-2) on day 1 every 15 days. We observed 13 objective responses (two complete, 11 partial) and 23 stable diseases. The median time to progression was 9.75 months (95% Confidence Interval (CI), 6.88-12.62) and the median overall survival was 13.10 months (95% CI 9.64-16.56). There were seven cases of each grade III gastroenteric and haematological toxicity. The GEM plus FUFA combination appears to be well tolerated and very active in patients with pancreatic carcinoma.

Adenocarcinoma↗

PubMed2003

Gemcitabine increases systemic 5-fluorouracil exposure in advanced cancer patients.

A number of recent clinical trials testing the combination of 5-fluorouracil (5-FU) and gemcitabine in patients with advanced pancreatic adenocarcinoma have shown a significant clinical response rate, but also significant toxicity. As the two antimetabolites may interact at several biochemical levels along their pathways of activation, we investigated whether gemcitabine (GEM) affects 5-FU pharmacokinetics in cancer patients. Thus, we compared 5-FU pharmacokinetics in two groups of patients with various cancers who received the same schedule of 5-FU and folinic acid (FUFA), with or without GEM. There was a significant increase in systemic (5-FU) exposure and toxicity in the FUFA plus GEM group. Our finding may be useful in designing future studies of the combination in order to reduce the occurrence of side-effects and to maximise the antitumour activity.

Adult↗

PubMed2002

Weekly epirubicin in patients with hormone-resistant prostate cancer.

The aim of this study was to investigate the benefit of weekly epirubicin in the treatment of metastatic hormone-resistant prostate cancer. One hundred and forty-eight patients with metastatic hormone-resistant prostate cancer received weekly 30-min intravenous infusions of epirubicin 30 mg m(2) of body surface area. The primary end-point was palliative response, defined as a reduction in pain intensity and an improvement in performance status. The secondary end-points were the duration of the palliative response, quality of life and survival. Fifty-seven (44%) of the 131 evaluable patients met the primary criterion of palliative response after six treatment cycles and 73 (56%) after 12 cycles; the median duration of the response was 9 months (range 1-11). The median global quality of life improved in 52% of the patients after six cycles and in 68% after 12 cycles. The 12- and 18-month survival rates were respectively 56 and 31%, with a median survival of 13+ months (range 1-36). The treatment was well tolerated: grade 3 neutropenia was observed in 8% of the patients, grade 3 anaemia in 7%, and grade 3 thrombocytopenia in 3%. None of the patients developed grade 4 toxicity or congestive heart failure. Weekly epirubicin chemotherapy can lead to a rapid and lasting palliative result in patients with metastatic HRPC, and have a positive effect on the quality of life and survival.

Aged↗

PubMed2001

A parathyroid-hormone-related-protein (PTH-rP)-specific cytotoxic T cell response induced by in vitro stimulation of tumour-infiltrating lymphocytes derived from prostate cancer metastases, with epitope peptide-loaded autologous dendritic cells and low-dose IL-2.

Bone metastases are one of the most common events in patients with prostate carcinoma. PTH-rP, a protein produced by prostate carcinoma and other epithelial cancers, is a key agent for the development of bone metastases. A PTH-rP-derived peptide, designated PTR-4 was identified, which is capable to bind HLA-A2.1 molecules and to generate PTH-rP-specific cytotoxic T cell (CTL) lines from healthy HLA-A2.1(+) individual peripheral-blood-mononuclear-cells (PBMC). In this model, we investigated the in vitro possibility of generating an efficient PTH-rP specific CTL response by cyclical stimulations with IL-2 and PTR-4 peptide-pulsed autologous dendritic cells (DC), of HLA-A2.1(+) tumour infiltrating lymphocytes (TIL) derived from a patient with metastatic prostate carcinoma. A T cell line generated in this way (called TM-PTR-4) had a CD3(+), CD5(+), CD4(-), CD8(+), CD45(Ro+), CD56(-) immunophenotype and a HLA-A2.1 restricted cytotoxic activity to PTR-4-peptide pulsed CIR-A2 (HLA-A2.1(+)) target cells, PTH-rP(+)/HLA-A2.1(+) CIR-A2 transfected with PTH-rP gene, prostate carcinoma LNCaP cells, and autologous metastatic prostate cancer cells (M-CaP). These lymphocytes were not cytotoxic to HLA-A2.1(+) targets not producing PTH-rP, such as peptide-unpulsed CIR-A2 and colon carcinoma SW-1463, cell lines. Our results provide evidence that PTR-4 peptide-pulsed autologous DC may break the tolerance of human TIL against the autologous tumour by inducing a PTH-rP-specific CTL immune reaction. In conclusion PTR-4 peptide-pulsed autologous DC may be a promising approach for vaccine-therapy and antigen-specific CTL adoptive immunotherapy of hormone-resistant prostrate cancer.

Antineoplastic Agents↗

PubMed2001

Comparative study of the immune response in mice immunized with four live attenuated strains of mumps virus by intranasal or intramuscular route.

The observation of many cases of mumps and mumps-associated CNS complications in vaccinees prompted us to perform an evaluation of the efficacy of four attenuated mumps virus (Urabe, Jeryl Lynn, Rubini and S12) vaccines. Two doses of vaccine were necessary to induce a good immunity in animals. The humoral and cell-mediated response induced in mice immunized intramuscularly or intranasally with these vaccines has been evaluated. Although the Urabe and Jeryl Lynn strains appear more immunogenic than the other strains and induce higher levels of IgG when administered intramuscularly, the S-12 strain administered intranasally induces a good IgG response. A marked specific CTL activity against mumps virus was observed in mice immunized intranasally with all the strains and, particularly, with the S12 strain. Thus, the intranasal immunization could be considered a possible alternative and efficient route of vaccination against mumps.

Administration, Intranasal↗

PubMed2001

Recruitment of dendritic cells and enhanced antigen-specific immune reactivity in cancer patients treated with hr-GM-CSF (Molgramostim) and hr-IL-2. results from a phase Ib clinical trial.

Experimental findings suggest that granulocyte-monocyte-colony stimulating factor (GM-CSF) synergistically interacts with interleukin-2 (IL-2) in generating an efficient antigen-specific immune response. We evaluated the toxicity, antitumour activity and immunobiological effects of human recombinant (hr)-GM-CSF and hr-IL-2 in 25 cancer patients who subcutaneously (s.c.) received hr-GM-CSF 150 microg/day for 5 days, followed by hrIL-2 s.c. for 10 days and 15 days rest. Two of the most common side-effects were bone pain and fever. Of the 24 patients evaluable for response, 3 achieved partial remission, 13 experienced stable disease, and 8 progressed. Cytokine treatment increased the number of monocytes, dendritic cells (DC), and lymphocytes (memory T cells) in the peripheral blood and enhanced the antigen-specific immunoreactivity of these patients. Our results show that the hr-GM-CSF and hr-IL-2 combination is active and well tolerated. Its biological activity may support tumour associated antigen (TAA)-specific anticancer immunotherapy by increasing antigen presenting cell (APC) activity and T cell immune competence in vivo.

Aged↗

PubMed2001

Tumour-associated antigen (TAA)-specific cytotoxic T cell (CTL) response in vitro and in a mouse model, induced by TAA-plasmids delivered by influenza virosomes.

We investigated influenza virosomes as a TAA-gene delivery system for use in TAA-directed anti-cancer vaccine therapy. An engineered plasmid (GC90) expressing the parathyroid hormone-related peptide (PTH-rP), a protein secreted by prostate and lung carcinoma cells, was included in influenza virosomes (GC90V). The ability of GC90V to elicit a PTH-rP-specific cytotoxic T cell (CTL) response was demonstrated in BALB/c mice immunised with intranasal (i.n.) GC90V+/-adjuvant subcutaneous (s.c.) interleukin-2 (IL-2). A PTH-rP-specific CTL response with antitumour activity was also demonstrated in human peripheral blood mononuclear cells (PBMC) stimulated in vitro with GC90V infected autologous dendritic cells (DC). These results provide a rationale for investigating GC90V in clinical trials of anticancer vaccine therapy.

Administration, Intranasal↗

PubMed2001

In vitro generation of cytotoxic T lymphocytes against HLA-A2.1-restricted peptides derived from human thymidylate synthase.

5-Fluorouracil (5-FU) is a pyrimidine antimetabolite active against colorectal carcinoma and other malignancies of the digestive tract. Over-expression or mutation of thymidylate synthase (TS), the target enzyme of the 5-FU metabolite, 5-fluorodeoxyuridine monophosphate, is strictly correlated with cancer cell resistance to 5-FU. On this basis we investigated whether TS is a potential target for active specific immunotherapy of human colon carcinoma, which acquires resistance to 5-FU. Three TS-derived epitope peptides which fit defined amino acid consensus motifs for HLA-A2.1 binding were synthesized and investigated for their ability to induce human TS-specific cytotoxic T cell (CTL) responses in vitro. CTL lines specific for each peptide were established by stimulating peripheral blood mononuclear cells (PBMC) from an HLA-A2.1+ healthy donor with autologous dendritic cells loaded with TS peptide. Specific CTL lines showed HLA-A2.1-restricted cytotoxicity in vitro to HLA-A2.1+ target cells pulsed with the specific TS peptide and to HLA-class I matching colon carcinoma target cells over-expressing TS enzyme after exposure to 5-FU. Recognition by CTL lines suggests that these TS peptides may be potential candidates for use in a peptide-based vaccine against 5-FU resistant colon carcinoma.

Antimetabolites, Antineoplastic↗

PubMed1999

Acetylcholine receptor activation enhances NMDA-mediated responses in the rat neostriatum.

The influence of acetylcholine (ACh) upon N-methyl-D-aspartate (NMDA) receptor activation of neostriatal neurons is unknown. In the present study, we used both in vitro intracellular and in vivo electroencephalographic recordings in rats to examine this question. In vitro, iontophoretic application of carbachol, a cholinergic receptor agonist, significantly increased the NMDA-mediated response of neostriatal projection neurons. Carbachol alone had mild excitatory effects. In vivo, intrastriatal NMDA produced focal epileptiform activity restricted to the neostriatum. NMDA applied in conjunction with carbachol produced significantly greater epileptiform activity which propagated to the neocortex. These results suggest that ACh and NMDA receptor co-activation leads to potentiation of the neuronal responses both at the site of the interaction and at the endpoint of the cortico-striato-cortical circuit.

Animals↗

PubMed1995

Effects of desipramine and alprazolam on forced swimming behaviour of adult rats exposed to prenatal diazepam.

Pregnant rats were treated with a single daily s.c. injection of diazepam (2 mg/kg) over gestation days 14-20. This treatment led to a reduction in GABA receptor complex function since adult male offspring showed a strong decrease in electrographic hippocampal responses to alprazolam and a strongly increased response to picrotoxin after intra-locus coeruleus injection of the two compounds. No difference in immobility time in the forced swimming test and in spontaneous motor activity was observed between prenatally vehicle- and diazepam-exposed offspring. Conversely, prenatal exposure to diazepam potentiated the anti-immobility effect of subchronic desipramine (10 mg/kg i.p.) and made active a dose of desipramine (5 mg/kg i.p.) that was ineffective in prenatally vehicle-exposed rats. This effect was observed only in pretested rats. Prenatal exposure to diazepam blocked the anti-immobility effect of subchronic alprazolam (15 mg/kg i.p.) in both non-pretested and pretested rats. Spontaneous motor activity was strongly reduced in all groups. These findings suggest that a persistent reduction in GABA receptor complex function, induced by prenatal exposure to diazepam, does not alter the mobility of adult progeny in the forced swimming test, but it may have consequences when drugs acting on the GABA receptor complex are used.

Alprazolam↗

PubMed1995

Cortical stimulation and reflex excitability of spinal cord neurones in man.

The H reflex technique was used to evaluate the influence exerted by cortical conditioning on the excitability of the alpha-motoneurone pool and on IA interneuronal activity (reciprocal inhibition). In ten subjects at absolute rest electrical and magnetic stimulation of the motor cortex was transcranially applied during flexor carpi radialis H reflex eliciting and in conditions of reciprocal inhibition induced by radial nerve stimulation. The time courses showed that at intensities below motor threshold, electrical brain conditioning induced an increase in the amplitude of the test reflex when the cortical shock was given 4 ms after the test H reflex. On the contrary, reciprocal inhibition was reduced by electrical cortical conditioning when the scalp stimulation was applied 2-3 ms after the test stimulus. Magnetic transcranial stimulation induced an increase of H reflex amplitude when the test shock was administered 5 and 2 ms prior to the scalp shock; it did not modify the degree of reciprocal inhibition. The experimental findings could be considered the electrophysiological manifestation of a differential cortico-spinal control on the pathway alpha-motoneurone/IA interneurone. Considerations on the delay allow the hypothesis of a further synapse between the cortico-spinal ending and the IA interneurone. Discrepancies with magnetic conditioning might be ascribed to a preferential transsynaptic action of magnetic mode of neural activation.

Adult↗

PubMed1994

Anticonvulsant activity of the noradrenergic locus coeruleus system: role of beta mediation.

Many experimental observations have demonstrated the modulatory role exerted by several neural structures and neurotransmitters on spontaneous and paroxysmal bioelectric activity of the hippocampus. Recently, the control exerted by locus coeruleus (LC) and its noradrenergic (NA) efferent pathway on different experimental models of epilepsy (e.g. cortical cobalt chronic epilepsy, amygdaloid and hippocampal kindling) was emphasised. On this basis, a series of experiments was performed to elucidate the functional role of LC-NA system on the hippocampal penicillin (PCN) focus and the type of adrenergic receptor involved. The experiments were carried out on 25 rats in which an epileptiform hippocampal focus was obtained through intrahippocampal PCN administration (100-200 I.U.). In these conditions, LC, ipsilateral to PCN hippocampal focus, was stimulated before and after intraperitoneal (i.p.) administration of a beta-adrenergic receptor antagonist propranolol (2 mg/kg). Results showed a significant reduction of hippocampal spiking frequency during LC stimulation; after i.p. propranolol injection, LC stimulation, at the same parameters, failed to induce any sort of modification of PCN hippocampal spiking frequency. Furthermore, intrahippocampal application of a beta-selective agonist 2-fluoro-noradrenaline (2-FNA) mimics the inhibitory effects of LC stimulation. All data suggest that the LC-NA system is able to induce a net reduction of hippocampal epileptiform focus and the inhibitory NA control involves the activation of adrenergic beta receptors.

Animals↗

PubMed1994

Bilateral reciprocal organisation in man: focus on IA interneurone.

The H reflex of flexor carpi radialis and radial-induced reciprocal inhibition were recorded in normal subjects during conditioning stimulation of the contralateral median or radial nerves. It was found that stimulation of the contralateral median nerve enhanced the degree of reciprocal inhibition exerted by the radial nerve on the median nerve, while contralateral radial nerve stimulation reduced the reciprocal inhibition exerted by the extensor on the flexor. In two subjects in which a pure extensor H reflex was recorded specular features were observed following contralateral median and radial stimulation. These findings are considered to be the electrophysiological manifestation of contralateral modulation of reciprocal inhibition, which is likely to act at the level of the IA interneurone.

Adult↗

PubMed1994

Locus coeruleus noradrenaline system and focal penicillin hippocampal epilepsy: neurophysiological study.

Previous experimental investigations have shown that several neuronal systems modulate the spontaneous and paroxysmal electric activity of the hippocampus. The locus coeruleus-noradrenaline (LC-NA) system exerts an inhibitory influence on several brain areas including the ipsilateral hippocampus. Selective destruction of the LC increases the susceptibility to epileptiform phenomena in different models of experimental epilepsy. Our experiments were conducted on 34 rats in which a steady epileptiform interictal activity of the hippocampus was obtained by means of intrahippocampal administration of penicillin. Electrical stimulation of LC caused a significant decrease of penicillin spiking of hippocampus. Stimulation sessions given 10-15 min after i.p. propranolol administration (2 mg/kg) failed to induce any significant modification in the hippocampal spiking frequency. Intrahippocampal injection of L-noradrenaline mimicked the inhibitory effect of LC electrical stimulation on hippocampus. Finally, intrahippocampal administration of isoproterenol HCl, a beta-adrenoceptor agonist, caused a significant decrease of hippocampal penicillin spiking; this effect was antagonised by i.p. propranolol administration. The experimental data show a modulating influence of the LC-NA system on penicillin focal hippocampal epilepsy that probably involves beta-adrenoceptors.

Animals↗

PubMed1994

NMDA-GABA interactions in an animal model of behaviour: a gating mechanism from motivation toward psychotic-like symptoms.

We studied the effects of desipramine, alprazolam, muscimol and dizocilpine (MK-801) (alone or associated with desipramine) in the forced swimming test in rats after long-lasting termination of chronic exposure to vehicle and pentylenetetrazol. Sensitisation with pentylenetetrazol was ineffective in changing immobility time in the forced swimming test compared to vehicle treatment; pentylenetetrazol enhanced the anti-immobility effect of desipramine, abolished the anti-immobility effect of alprazolam and did not affect the anti-immobility effect of muscimol. MK-801 at the dose that did not modify immobility time in vehicle-treated rats and in pentylenetetrazol-treated animals strongly potentiated the anti-immobility effect of desipramine in pentylenetetrazol-treated rats. MK-801 in association with desipramine induced a marked hyperlocomotion and hyperexcitability, with swaying movements and oral stereotypies in pentylenetetrazol-sensitised rats. Results are considered the experimental representation of a 'gating mechanism' toward psychotic-like symptoms.

Alprazolam↗

PubMed1993

Effects of desipramine and alprazolam in the forced swim test in rats after long-lasting termination of chronic exposure to picrotoxin and pentylenetetrazol.

Rats were treated for 5 weeks with three subconvulsant doses of picrotoxin (PTX) and pentylenetetrazol (PTZ) per week to induce a persistent reduction of the GABAA receptor function which results in chemical kindling. Fifteen days after termination of this treatment schedule, the effect of desipramine (DMI) and alprazolam (ALP) on immobility time in the forced swim test (FST) was evaluated. Chronic PTX and PTZ did not alter the immobility time. Acute PTX and PTZ reduced the immobility of rats chronically treated with vehicle but not of those exposed chronically to PTX and PTZ. Chronic PTX did not influence the anti-immobility effect of DMI, but blocked that of ALP. Chronic PTZ markedly potentiated the anti-immobility effect of DMI but blocked that of ALP. Concomitant administration of chlordiazepoxide prevented the effects of chronic PTX and PTZ. These findings suggest that a long-lasting reduction in GABAA receptor function, unlike acute reduction, does not play an important role in the mobility of rats in the FST and in the anti-immobility effect of DMI while it blocks that of ALP.

Alprazolam↗

PubMed1992

Evidence of a contralateral motor influence on reciprocal inhibition in man.

The role of contralateral movement on both H reflex and reciprocal inhibition was studied. In normal men H reflex was induced by median nerve stimulation. Reciprocal inhibition was achieved through stimulation of the antagonist radial nerve. On this basis the effects of contralateral arm movement were analyzed. Furthermore the putative influence of exteroceptive origin was also verified by means of digit stimulation. Results showed that contralateral arm movement did not affect H reflex amplitude; on the contrary, it was able to enhance reciprocal inhibition induced by extensors on flexors. Study of cutaneous afferents demonstrated that contralateral digit stimulation failed to elicit modifications on both H reflex and reciprocal inhibition. On the other hand, ipsilateral digit stimulation lowered H reflex amplitude and increased the degree of reciprocal inhibition. Experimental findings underline the possibility that an informational array reaches the contralateral IA interneuron: therefore a mutual (bilateral) interaction among IA interneurones may accordingly be hypothesised.

Adolescent↗