PubMed Health⌕ Search

Biomedical subjects

G Vitale

Publications and source records attributed to G Vitale.

At least 73 records · Page 4Linked to original sources

Quinoxaline chemistry. Part 9. Quinoxaline analogues of trimetrexate (TMQ) and 10-propargyl-5,8-dideazafolic acid (CB 3717) and its precursors. Synthesis and evaluation of in vitro anticancer activity.

Eighteen quinoxalines bearing a methyleneanilino or methyleneaminobenzoylglutamate group on position 6 of the ring and various lipophilic substituents on positions 2 and 3 were prepared in order to discover if their structural analogy with both trimetrexate (TMQ) and 10-propargyl-5,8-dideazafolic acid (CB 3717) might display in vitro anticancer activity. Among these, 12 compounds were selected at the National Cancer Institute, Bethesda, MD, USA; they exhibited moderate (4b,d,i,l,m and 8) to strong (4f,h and 5a,e) cell-growth inhibition at a concentration of 10(-4) M. Interesting selectivities were also recorded between 10(-8) and 10(-6) M. These analogues proved to be less potent inhibitors of tumor cells than other classical and non-classical antifolate analogues previously described by us.

Antineoplastic Agents↗

Quinoxaline chemistry. Part 10. Quinoxaline 10-oxa-analogues of trimetrexate (TMQ) and of 5,8-dideazafolic acid. Synthesis and evaluation of in vitro anticancer activity.

Among twenty-eight novel compounds (twenty-two 2,3-disubstituted-6-[(substituted-phenoxy)methyl-quinoxalines and six 4-[(2,3-disubstituted-quinoxalin-6-yl)methoxy]benzoylglutamates ) only thirteen were selected at NCI for evaluation of their in vitro anticancer activity. The results have shown that compounds 3l,c,b,e and 4b were endowed with significantly high values of percent tumor growth inhibition on several tumor cell lines at 10(-4) M, while compound 3t was characterized by a high selectivity, being still strongly inhibiting on three cell lines at 10(-5) M. Comparison of the presently observed activity with that of the previously described aza-analogues confirms that the effected isosteric substitution is highly valuable in some cases.

Antineoplastic Agents↗

Effect of acetylsalicylic acid on formalin test and on serotonin system in the rat brain.

1. Acetylsalicylic acid (ASA; 400 mg/kg, i.p.) increased serotonin (5-HT) content in rat brain but did not modify the number or the affinity of 5-HT1A receptors in the pons and the cerebral cortex, whereas the number of cortical 5-HT2 receptors decreased significantly. 2. Pretreatment with parachlorophenylaline (100 mg/kg/day for 4 days) depleted 5-HT brain content but modified neither the serum levels of salicylates nor the 5-HT2 cortical receptor characteristics, and it abolished the antinociceptive effect of ASA, 400 mg/kg, in the first phase of the formalin test. 3. These data support the involvement of the central serotonergic system in the antinociceptive activity of ASA.

Animals↗

Modifications of general parameters of immune activation in the sera of Sicilian patients with Boutonneuse fever.

The serum levels of beta2-microglobulin (beta2-M), soluble HLA class I antigen (sHLA-I), soluble CD4 (sCD4) and CD8 (sCD8) were studied in 98 Sicilian patients with Boutonneuse fever (BF). In different stages of infection all markers were significantly increased in sera from Sicilian patients with acute BF compared with healthy controls. sCD8 and sHLA-I reached the peak in the second week after the onset of symptoms, whereas sCD4 and beta2-M reached the peak in the first week. Afterwards sCD8 decreased to the levels of controls within the third week, the other parameters decreased later and were unmodified until the third week of infection. Significant correlations were found between sCD4 and sCD8 and the sIL-2R, as well as between serum levels of beta2-M and sCD8. The reduction of CD3+ and CD4+ and the increase of CD8+ T cells in the blood indicate that these cells are involved in the response to rickettsia, and their activation might be in part responsible for the release of sCD4 and sCD8. Our data suggest that these soluble markers, indexes of immune activation of T cells both in the circulation and the affected tissues, may be used in monitoring BF evolution.

Adult↗

[New developments in the treatment of medullary thyroid carcinoma].

Medullary thyroid carcinoma arises from the C cells, which produce a characteristic hormone, calcitonin. At present, surgery is the main treatment modality. Medullary thyroid carcinoma is usually treated with total thyroidectomy and with removal of nodes in the central portion of the neck and upper mediastinum. Cervical nodes dissection may be required for cancers affecting lateral neck nodes. Substitutive therapy with levo-thyroxine is indicated after surgery. External beam radiation therapy is not effective against advanced medullary thyroid carcinoma, while chemotherapy has a marginal activity. Biological therapy induces its anti-tumour activity through the inhibition of tumour cell growth without cytolysis and stimulating the antitumour immune response, in the absence of relevant side effects. On these bases, it can be suggested that chemo-refractory tumours could be still responsive to biological agents. In the last years somatostatin analogues and interferon have been used in the therapy of advanced and symptomatic medullary thyroid carcinoma, demonstrating an efficacious effect on neuroendocrine symptoms and on the production of calcitonin and an improving in quality of life. Even if there are no consistent data on the effects of biological agents on the reduction of tumour mass, the combined use of chemotherapy and biological therapy needs to be experimented in medullary thyroid carcinoma.

Carcinoma, Medullary↗

Gonadotropin-releasing hormone agonists administration in polycystic ovary syndrome. Effects on bone mass.

Women with amenorrhea and polycystic ovaries (PCO) seem to present a relative degree of protection against bone loss caused by hypoestrogenism. We treated 20 patients affected by polycystic ovary syndrome (PCOS) with a gonadotropin-releasing hormone agonist (GnRH-a) for 6 months. After treatment mean bone mineral density (BMD) significantly decreased. We concluded that patients with PCOS have to be considered at risk of developing osteopenia when treated with GnRH-a. The relative protection against osteoporosis, that is present in amenorrheic patients with PCO, might be attributed to the characteristics of amenorrhea in these patients.

Acne Vulgaris↗

Pre- and postoperative intra-articular analgesia for arthroscopic surgery of the knee and arthroscopy-assisted anterior cruciate ligament reconstruction. A double-blind randomized, prospective study.

We tested the effectiveness of different intra-articular analgesics and of pre-emptive intra-articular analgesia for arthroscopy-assisted anterior cruciate ligament reconstruction (ACLR) and for operative knee arthroscopy. Eighty-two patients underwent operative knee arthroscopy under selective subarachnoid anaesthesia (group A), and 60 patients underwent arthroscopy-assisted ACLR under general anaesthesia (group B). Patients were randomly assigned to intra-articular analgesic treatment as follows. Group A: 1, morphine 2 mg; 2, preoperative morphine 2 mg; 3, morphine 5 mg; 4, preoperative morphine 5 mg; 5, bupivacaine 0.25% 20 ml; 6, bupivacaine 0.25% 20 ml + morphine 2 mg; 7, saline solution 20 ml. Group B: 1, morphine 2 mg; 2, morphine 5 mg; 3, preoperative morphine 5 mg; 4, bupivacaine 0.25% 20 ml; 5, bupivacaine 0.25% 20 ml + morphine 2 mg; 6, saline solution 20 ml. All opioids were diluted in 20 ml of saline solution. After postoperative administration the tourniquet was left in place for 10 min. After preoperative administration the intra-articular surgical procedure was delayed for about 5-10 min. In the postoperative period we recorded: total consumption of ketoprofen given i.v. on demand as rescue analgesic treatment; pain scores before surgery and at 1st, 3rd, 6th, 12th and 24th h; occurrence of local anaesthetic or opioid side-effects. Group A (operative knee arthroscopy): all morphine groups (A1, A2, A3, A4) and the bupivacaine group (A5) did not require ketoprofen postoperatively (P < 0.01 vs both groups A6 and A7). Pain scores did not differ significantly among groups. The percentage of patients reporting higher pain scores than before surgery was larger in control group A7 and in bupivacaine groups A5, A6 (83%, 40%, 60%, respectively) and lower in morphine groups A1, A2, A3, A4 (25%, 16%, 27%, 23%, respectively). Group B (ACLR): total consumption of ketoprofen was lowest in groups B2 and B3 (P < 0.001 vs all other treatments and vs control group). The percentage of patients who did not require any rescue analgesic was 60% in group B3, 50% in group B2, 32% in group B5 and 0% in all other groups. No-side effects occurred in any patient. Intra-articular analgesia is safe and effective for arthroscopic knee surgery. Morphine provides a better pain control both in operative knee arthroscopy patients and in ACLR. A 2 mg dose is adequate for operative knee arthroscopy but not for ACLR, where higher dosages are required (5 mg). Pre-emptive intra-articular morphine provides better analgesia than postoperative administration.

Adult↗

Streptozotocin-induced diabetes provokes changes in serotonin concentration and on 5-HT1A and 5-HT2 receptors in the rat brain.

Since reduced levels of brain serotonin are known to cause behavioural abnormalities, to which diabetics are also prone, we investigated the effect, in rats, of chronic diabetes on brain serotonin concentration and on the numbers of 5-HT(1A) and 5-HT2 receptors in cerebral cortex and brainstem. Our data show that streptozotocin induces a longlasting hyperglicemia that is associated with a decrease in cerebral concentration of serotonin and with an accompanying increase in the maximum number of 5-HT(1A) and 5-HT2 receptors in the brain areas studied. Our results may suggest that changes in serotonergic transmission in the CNS play a role in diabetes-related behavioural abnormalities.

Animals↗

Effect of liver cirrhosis on the systemic availability of naltrexone in humans.

BACKGROUND/AIMS: Naltrexone is a competitive opiate antagonist with high hepatic extraction. It is used for detoxification treatment for heroin addicts and has been proposed as a possible treatment of pruritus in cholestasis. Such patients are likely to have impaired liver function, underscoring the need to understand the pharmacokinetic behavior of naltrexone in liver disease. These studies were undertaken to evaluate the effect of liver cirrhosis on the plasma time-course of naltrexone. METHODS: A total of 18 patients were investigated: seven migraine patients with normal liver function regarded as controls and 11 patients with liver cirrhosis (six with decompensated disease and five with preserved liver function). A bolus of 100 mg of naltrexone was administered orally in the morning, after an overnight fast. Blood samples were taken in basal conditions and at fixed intervals, up to 24 h after administration. Serum levels of naltrexone and of its major active metabolite, 6 beta-naltrexol, were assayed by reversed-phase HPLC analysis. RESULTS: In control subjects, circulating concentrations of naltrexone were always much lower than those of 6 beta-naltrexol (area under the curve: naltrexone, 200 +/- 97 ng/ml x 24 h; 6 beta-naltrexol, 2467 +/- 730 ng/ml x 24 h, p < 0.01). In severe cirrhosis serum levels of 6 beta-naltrexol increased more slowly, so that circulating levels of naltrexone during the first 2-4 h after drug intake were higher than those of 6 beta-naltrexol (6 beta-naltrexol/naltrexone ratio at 2 h: controls, 10.91 +/- 4.80; cirrhosis, 0.39 +/- 0.18, p < 0.01). The area under the curve for naltrexone (1610 +/- 629 ng/ml x 24 h) was significantly greater than in controls, whereas that for 6 beta-naltrexol (2021 +/- 955 ng/ml x 24 h) was not significantly different. Patients with compensated cirrhosis showed an intermediate pattern. No differences in elimination half-life of the two drugs were detected among the groups. CONCLUSIONS: Our data suggest the occurrence of important changes in the systemic availability of naltrexone and 6 beta-naltrexol in liver cirrhosis; such alterations are consistent with lesser reduction of naltrexone to 6 beta-naltrexol and appear to be related to the severity of liver disease. This must be considered when administering naltrexone in conditions of liver insufficiency.

Adult↗

Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study.

BACKGROUND & AIMS: The efficacy of currently available therapeutic agents for cholestatic pruritus is often disappointing. The aim of this study was to assess the antipruritic effect of naltrexone, an oral opiate receptor antagonist. METHODS: Sixteen patients with pruritus of chronic cholestasis were randomized to receive naltrexone (4-week course of 50 mg naltrexone daily) or placebo. Pruritus, quality of sleep, fatigue (using visual analogue scales), side effects, and liver function were assessed every 2 weeks. Serum naltrexone and 6 beta-naltrexol concentrations in all patients and 5 healthy controls were measured during the first day of naltrexone treatment. RESULTS: Mean changes with respect to baseline were significantly different, in favor of the naltrexone group, for daytime itching (-54% vs. 8%; P < 0.001) and nighttime itching (-44% vs. 7%, P = 0.003). In 4 naltrexone-treated patients, side effects (transient in 3 cases) consistent with an opiate withdrawal syndrome were noted. No deterioration of the underlying disease was observed. Naltrexone and 6 beta-naltrexol levels did not differ between patients and controls, and there was no significant association with treatment response. CONCLUSIONS: For patients with cholestatic liver disease and itching, refractory to regular antipruritic therapy, oral naltrexone may be an effective and well-tolerated alternative.

Administration, Oral↗

Alteration of interleukin-2 (IL-2) and soluble IL-2 receptor secretion in the sera and urine of patients with rickettsial boutonneuse fever.

Sera and urine samples from 115 Sicilian patients with boutonneuse fever (BF), obtained at the time of diagnosis and after clinical recovery, were analyzed for concentrations of interleukin (IL)-2 and soluble IL-2 receptor (sIL-2R). There were significantly high levels of sIL-2R in the urine and sera of patients with acute BF compared with healthy controls, and the values returned to normal following successful chemotherapy. The data indicate that the sIL-2R urine concentrations correlated directly with the sIL-2R sera levels. In contrast, in all tested sera and urine samples, IL-2 levels were normal. Furthermore, a reduction in IL-2 production by peripheral blood mononuclear cells from acute BF patients was also observed. sIL-2R represents an unspecific marker useful to monitor the evolution of BF.

Boutonneuse Fever↗

Serotonin and opiate involvement in the antinociceptive effect of acetylsalicylic acid.

Acetylsalicylic acid (ASA), 400 mg/kg i.p., displayed antinociceptive activity in both the hot-plate and the formalin test. ASA significantly increased brain serotonin (5-HT) content and reduced the number of 5-HT2 receptors in cortical brain membranes 30 min after drug administration. Pretreatment with naloxone abolished the antinociceptive activity of both ASA and morphine in the hot-plate and formalin tests and prevented the increase in cerebral 5-HT concentration and the reduction in 5-HT2 receptors in cortical membranes induced by ASA. The serum salicylate concentrations were not affected by pretreatment with naloxone. These data indicate a central antinociceptive activity of ASA and suggest that ASA may exert its antinociceptive action through serotonergic and opiatergic pathways.

Analgesics, Non-Narcotic↗

Naloxone-reversible antinociception by paracetamol in the rat.

Paracetamol at the dose of 400 mg/kg i.p. displayed antinociceptive activity in the hot-plate test and the formalin test. Moreover, it induced a significant increase in brain serotonin (5-HT) concentration and a reduction in the number of 5-HT2 receptors in cortical membranes. Pretreatment with naloxone abolished this antinociceptive activity both in the hot-plate test and in the first phase of the formalin test without affecting the serum concentration of paracetamol. At the same time, naloxone prevented the increase in 5-HT concentration in the central nervous system and the reduction in 5-HT2 receptors in cortical membranes. Competition experiments demonstrated that paracetamol possesses affinity for [3H]naloxone binding sites. The action of morphine on nociception and on the serotonergic system was similar to that of paracetamol; all morphine-induced effects were blocked by naloxone. These data provide further evidence for a central antinociceptive effect of paracetamol and support the hypothesis that paracetamol exerts its antinociceptive activity through the serotonergic system. Moreover, our results point to the relationship between serotonergic and opiatergic systems in the antinociceptive activity of paracetamol.

Acetaminophen↗

Treatment of acute respiratory failure secondary to pulmonary oedema with bi-level positive airway pressure by nasal mask.

We report the successful outcome of first-line intervention of noninvasive positive pressure ventilation (NPPV) in four patients, three of whom had hypercapnic acute respiratory failure (ARF) and one hypoxaemic ARF, secondary to pulmonary oedema. The clinical condition showed rapid improvement and the NPPV, performed together with aggressive medical treatment, was effective in decreasing the respiratory frequency, and in correcting gas exchange abnormalities within the first 3 h. The average duration of nasal mask ventilation was 11 h (range 6-15 h). The patients were weaned, following ARF, by removing the ventilator whenever inspiratory positive airway pressure (IPAP) was 5 cmH2O. NPPV was applied, by nasal mask, using a bi-level positive airway pressure (BiPAP) delivering pressure support ventilation (PSV). We conclude that application of noninvasive positive pressure ventilation may be effective in correcting gas exchange abnormalities, in relieving respiratory distress and, perhaps, in avoiding endotracheal intubation in selected patients with acute respiratory failure secondary to reversible medical condition such as pulmonary oedema.

Aged↗

NBP35 encodes an essential and evolutionary conserved protein in Saccharomyces cerevisiae with homology to a superfamily of bacterial ATPases.

We have cloned a novel and essential gene, NBP35, from Saccharomyces cerevisiae that encodes a putative Nucleotide Binding Protein of 35 kDa. Sequence analysis revealed structural homology of Nbp35p with a family of bacterial ATPases involved in cell division processes and chromosome partitioning. A search in databases identified closely related sequences from yeast and higher eukaryotes, suggesting a conserved function for this family of proteins. By indirect immunofluorescence, a tagged version of Nbp35p carrying two immunoglobulin G-binding domains derived from Staphylococcus aureus Protein A was localised to the nucleus. A single amino-acid substitution in the conserved nucleotide-binding motif of Nbp35p renders the protein non-functional. Furthermore, a conserved cluster of four cysteines in the N-terminal end of the protein is also required for an essential role of Nbp35p.

Adenosine Triphosphatases↗

Treatment of advanced medullary thyroid carcinoma with a combination of recombinant interferon alpha-2b and octreotide.

BACKGROUND: The medical treatment of advanced medullary thyroid carcinoma (MTC) is still questionable. Results of chemotherapy are disappointing with almost no curative responses, few partial responses, and many side-effects. A recent report has suggested the activity of combination recombinant interferon alpha-2b (rIFN-alpha-2b) and octreotide, a somatostatin analogue, in the treatment of a metastatic carcinoid tumor. This new therapeutic schedule may be used in other neuroendocrine tumors. In this study we evaluated the therapeutic effectiveness of octreotide and rIFN-alpha-2b in patients with advanced MTC. METHODS: Eight patients affected by advanced MTC received octreotide at a daily dose of 150 micrograms for 6 months and subsequently at a daily dose of 300 micrograms for another 6 months, subcutaneously, and rIFN-alpha-2b at a daily dose of 5.000.000 IU intramuscularly 3 times a week for 12 months. Plasma calcitonin, carcinoembryonic antigenic levels, and morphologic staging were evaluated at 0, 1, 3, 6, and 12 months. RESULTS: The therapy was stopped in two patients because of diarrhea and toxicity of drugs used. Pre-existing diarrhea in four patients and flushing in one significantly improved during treatment. A maximum decrease of calcitonin was reached after 1 month in 2 patients and after 3 months in 4. In all of the patients carcinoembryonic antigen levels decreased during treatment. No significant changes of size of metastases were observed. CONCLUSIONS: The combination of octreotide and interferon is well tolerated and can be recommended for the treatment of advanced MTC.

Adult↗

The antinociceptive action of paracetamol is associated with changes in the serotonergic system in the rat brain.

The antinociceptive activity of paracetamol in the hot plate and formalin tests was studied to establish the relationship between antinociceptive activity and the central serotonergic system. Significant antinociceptive activity of paracetamol was observed in the formalin test at the dose of 300 mg/kg, while, at the dose of 400 mg/kg, the drug was active both in the formalin and in the hot-plate test. Serum paracetamol levels remained sub-toxic and the behavioral profile remained unchanged. Depletion of brain serotonin with p-chlorophenylalanine prevented the antinociceptive effect of paracetamol in the hot-plate test and in the first phase of the formalin response. Paracetamol significantly increased the serotonin content in the pontine and cortical areas (by 75 and 70%, respectively). The pretreatment with p-chlorophenylalanine reduced the 5-hydroxytryptamine (5-HT) content in cortical and pontine areas to 12 and 19% of baseline values, respectively, and prevented the enhancement induced by paracetamol. The maximum number of cortical 5-HT2 receptors was reduced by paracetamol, while the number of 5-HT1A receptors in both cortical and pontine areas was unchanged. Pre-treatment with p-chlorophenylalanine prevented the reduction in the number of 5-HT2 receptors induced by paracetamol. These results provide evidence for the involvement of the central serotonergic system in the antinociceptive effect of paracetamol in the hot plate and formalin tests.

Acetaminophen↗

Effect of acute and chronic treatment with triiodothyronine on serotonin levels and serotonergic receptor subtypes in the rat brain.

Hyperthyroidism is often associated with behavioral disorders, and thyroid hormones modify receptor sensitivity as well as the synthesis and/or turnover rate of many neurotransmitters. We evaluated the influence in adult rats of triiodothyronine (T3), administered s.c. (100 micrograms/kg) acutely (once only) or chronically (once a day for 3 or 7 consecutive days), on brain serotonin concentration and on the density and affinity of two brain serotonin (5-HT) receptor subtypes mainly involved in behavioral effects. After both acute and chronic T3 treatment, serotonin levels increased in the cerebral cortex but not in the hippocampus. The density and affinity of 5-HT1A receptors (using [3H]-8-OH-DPAT as ligand) were not affected, while there was a significant decrease in the number of 5-HT2 receptors in the cerebral cortex (using [3H]ketanserin as ligand). This observation might indicate that thyroid hormones enhance 5-HT concentration in certain brain areas, thus causing a down-regulation of 5-HT2 receptors. The serotonergic system could be involved in the complex brain-neurotransmitter imbalance underlying hyperthyroidism-linked behavioral changes.

Animals↗