Synthesis, glycine/NMDA and AMPA binding activity of some new 2,5,6-trioxopyrazino[1,2,3-de]quinoxalines and of their restricted analogs 2,5-dioxo- and 4,5-dioxoimidazo[1,5,4-de]quinoxalines.

The synthesis of some new 1,2,3,5,6, 7-hexahydro-2,5,6-trioxopyrazino[1,2,3-de]quinoxalines 1c-g and of their restricted analogs 2,4,5,6-tetrahydro-2,5-dioxo-1H- 2a-g and 5,6-dihydro-4,5-dioxo-4H-imidazo[1,5,4-de]quinoxalines 3a-d is reported. Compounds 1c-g, 2a-g, and 3a-d were tested for their binding activity at the glycine/NMDA and AMPA receptors. The results show that only the 6,6,6-tricyclic derivatives 1c-g are able to bind to the glycine/NMDA and AMPA receptors, although with lower affinity than the previously reported lead compounds 1a-b.

4,5-Dihydro-1,2,4-triazolo[1,5-a]quinoxalin-4-ones: excitatory amino acid antagonists with combined glycine/NMDA and AMPA receptor affinity.

A series of 4,5-dihydro-1,2,4-triazolo[1,5-a]quinoxalin-4-ones bearing different substituents on the benzo-fused ring and at position 2 were synthesized and biologically evaluated for their binding at glycine/NMDA and AMPA receptors. Most of the reported compounds show combined glycine/NMDA and AMPA receptor binding activity providing further evidences of the structural similarities of the binding pockets of both receptor recognition sites. Moreover, this study has pointed out some differences for the binding at each receptor type.

Synthesis of 2-substituted-6,8-dichloro-3,4-dihydro-3-oxo-2H-1,4-benzothiazine-1,1-d ioxides and -1-oxides as glycine-NMDA receptor antagonists.

A number of 2-substituted-3,4-dihydro-3-oxo-6,8-dichloro-2H-1, 4-benzothiazine-1,1-dioxides (1-2a-b) and -1-oxides (3-4a-b) bioisosters of RPR 104632 in which the 3-carboxylic group was replaced by a carbonyl group were synthesized. Comparative in vitro pharmacological studies on this series of RPR 104632 analogs were performed using receptor binding assays. None of these compounds showed detectable binding affinity for the glycine-NMDA receptor.

High-level expression of rat class I alcohol dehydrogenase is sufficient for ethanol-induced fat accumulation in transduced HeLa cells.

The mechanisms by which ethanol causes fatty liver are complex. Reducing equivalents generated during ethanol oxidation inhibit tricarboxylic acid cycle activity and fatty acid oxidation. In addition, ethanol inhibits lipoprotein export and increases fatty acid uptake and lipid peroxidation.

Ethanol-induced alterations of matrix network in the duodenal mucosa of chronic alcohol abusers.

Excessive consumption of alcoholic beverages may be associated with gastrointestinal symptoms, including dyspepsia and diarrhoea. It is not clear whether or not chronic alcohol ingestion damages the mucosa of the small intestine. We investigated the effect of chronic alcohol abuse on the duodenal mucosa, and particularly on its extracellular matrix (ECM) network.

[Potential of ultrasonography and ultrasonography-guided biopsy in the diagnosis of local recurrence following radical prostatectomy].

Introduction: [corrected] We investigated the diagnostic role of combined transrectal US (TRUS) and biopsy to detect recurrent cancer after radical prostatectomy, in patients with negative bone scintigraphy and elevated prostate specific antigen (PSA) levels.

Materials And Methods: From March, 1997, to May, 1998, we examined 12 patients with persistently detectable serum PSA levels and negative bone scintigraphy. At the time of diagnosis, an average 36 months had elapsed since prostatectomy.

Inhibition of the Mr 70,000 S6 kinase pathway by rapamycin results in chromosome malsegregation in yeast and mammalian cells.

The antifungal and immunosuppressive drug rapamycin arrests the cell cycle in G1-phase in both yeast and mammalian cells. In mammalian cells, rapamycin selectively inhibits phosphorylation and activation of p70 S6 kinase (p70(S6K)), a protein involved in the translation of a subset of mRNAs, without affecting other known kinases. We now report that rapamycin causes chromosome malsegregation in mammalian and yeast cells.

Neuro- and ototoxicity of high-dose carboplatin treatment in poor prognosis ovarian cancer patients.

Background: Hematopoietic toxicity of high-dose carboplatin (HD-CBDCA) chemotherapy can be managed effectively with autologous blood cell support, but no conclusive data are available on its neuro- and ototoxicity.

Patients And Methods: We determined the neuro- and ototoxicity of HD-CBDCA in 10 patients affected by advanced ovarian cancer. HD-CBDCA was delivered as 24-hour continuous infusion or as 5-day schedules.

Relationship between chronic nasal obstruction and craniofacial growth: an experimental model.

The aim of this paper was to verify if the growth of the nasomaxillary complex can be influenced by a purely functional alteration such as nasal obstruction, which was induced experimentally in a genetically controlled animal model. Sixty albino rats were employed. Twenty of them had the right nostril occluded by a synthetic resin; another twenty had both nostrils occluded; the other 20 were taken as control group.

Acute regulation of norepinephrine transport: I. protein kinase C-linked muscarinic receptors influence transport capacity and transporter density in SK-N-SH cells.

Using SK-N-SH cells, we observe that muscarinic acetylcholine receptor activation by methacholine (MCh) rapidly and selectively diminishes l-NE transport capacity (Vmax) with little or no change in norepinephrine (NE) Km and without apparent effects on membrane potential monitored directly under current clamp. Over the same time frame, MCh exposure reduces the density of [3H]nisoxetine binding sites (Bmax) in intact cells but not in total membrane fractions, consistent with a loss of transport capacity mediated by sequestration of transporters rather than changes in intrinsic transport activity or protein degradation. Similar changes in NE transport and [3H]nisoxetine binding capacity are observed after phorbol ester (beta-PMA) treatment.

Effect of Salmonella assay negative and positive carcinogens on intrachromosomal recombination in S-phase arrested yeast cells.

A wide variety of carcinogens including Ames assay (Salmonella) positive as well as Salmonella negative carcinogens induce intrachromosomal recombination (DEL recombination) in Saccharomyces cerevisiae. We have shown previously that the Salmonella positive carcinogens, ethyl methanesulfonate (EMS), methyl methanesulfonate (MMS) and 4-Nitroquinoline-N-oxide (4-NQO, and the Salmonella negative carcinogens, safrole, benzene, thiourea, carbon tetrachloride, and urethane, induced DEL recombination in growing, in G1 and in G2 arrested yeast cells. Since we found interesting differences in response between dividing and arrested cells, we wanted to find out whether these differences were due to the difference between cell division versus cell cycle arrest or to any particular cell cycle phase.

Patch-clamp and amperometric recordings from norepinephrine transporters: channel activity and voltage-dependent uptake.

Transporters for the biogenic amines dopamine, norepinephrine, epinephrine and serotonin are largely responsible for transmitter inactivation after release. They also serve as high-affinity targets for a number of clinically relevant psychoactive agents, including antidepressants, cocaine, and amphetamines. Despite their prominent role in neurotransmitter inactivation and drug responses, we lack a clear understanding of the permeation pathway or regulation mechanisms at the single transporter level.

Fluctuation analysis of norepinephrine and serotonin transporter currents.

Findings from an electrophysiological analysis of neurotransmitter transporters show that transmitter-induced currents are associated with these transporters: For charged transmitters, such as NE and 5-HT, a fraction of the total current is carried by the transmitter itself; however, the transmitter also induces an extra current in analogy to an ligand-gated ion channel. An additional conductance not discussed in this article is the so-called leak, in which neurotransmitter transporters generate an ionic current in the absence of transmitter. Using a combination of flux measurements, voltage clamp, and fluctuation analysis has shown that, for norepinephrine and serotonin transporters, the transmitter-induced current greatly exceeds the transmitter current.

A countrywide programme of continuing professional development in Argentina. Argentine Society of Paediatrics, Subcommittee of Continuing Paediatric Education.

The Argentinean Society of Paediatrics introduced in 1993 a continuing professional development (CPD) programme to raise standards of clinical practice. The aims of the project were to introduce a structured, distance learning programme accessible to all paediatricians in the country, but especially for those working far from centres of paediatric excellence. The programme is planned on an annual basis.

Bactericidal activity of chlorine dioxide against Escherichia coli in water and on hard surfaces.

The efficacy of chlorine dioxide as a disinfectant was evaluated against cells of Escherichia coli ATCC 11229 in aqueous suspension and adhering to the surfaces of stainless steel AISI 304 and PVC. The concentrations tested ranged from 0.7 to 14 mg/liter; the exposure times investigated were 30 s and 1, 2, 4, and 8 min.

Regulated phosphorylation and trafficking of antidepressant-sensitive serotonin transporter proteins.

Presynaptic serotonin (5-hydroxytryptamine, 5-HT) transporters (SERTs) mediate antidepressant-sensitive clearance of 5-HT following release. Although we have been aware for decades that SERT-mediated 5-HT clearance can be modulated by exogenous agents including serotonin-selective reuptake inhibitors, amphetamines, and cocaine, we have had little reason to speculate that SERT activity was actively controlled through endogenous pathways. Recent studies indicate that SERTs are likely to be trafficked to specific plasma membrane subdomains to achieve localized clearance of 5-HT, and that the number of SERTs resident in the plasma membrane is controlled through kinase- and phosphatase-linked pathways.

Effects of DNA double-strand and single-strand breaks on intrachromosomal recombination events in cell-cycle-arrested yeast cells.

Intrachromosomal recombination between repeated elements can result in deletion (DEL recombination) events. We investigated the inducibility of such intrachromosomal recombination events at different stages of the cell cycle and the nature of the primary DNA lesions capable of initiating these events. Two genetic systems were constructed in Saccharomyces cerevisiae that select for DEL recombination events between duplicated alleles of CDC28 and TUB2.

High-level expression of RXRalpha and the presence of endogenous ligands contribute to expression of a peroxisome proliferator-activated receptor-responsive gene in hepatoma cells.

Genes containing peroxisome proliferator-activated receptor (PPAR) binding sites are both inducible by peroxisome proliferators and expressed in a tissue-specific fashion. A PPAR-responsive reporter gene cotransfected with a PPARalpha expression vector was highly expressed in H4IIEC3 hepatoma cells. Addition of clofibrate resulted in a modest further induction of the reporter gene.

Inhibition of cholinesterase-associated aryl acylamidase activity by anticholinesterase agents: focus on drugs potentially effective in Alzheimer's disease.

The potency of a series of anticholinesterase (anti-ChE) agents and serotonin-related amines as inhibitors of the aryl acylamidase (AAA) activity associated with electric eel acetylcholinesterase (AChE) (EC 3.1.1.

Tricyclic heteroaromatic systems. 1,2,4-triazolo[4,3-a]quinoxalines and 1,2,4-Triazino[4,3-a]quinoxalines: synthesis and central benzodiazepine receptor activity.

Some 1,2,4-triazolo[4,3-a]quinoxalines 1-10, and 1,2,4-triazino[4,3-a]quinoxalines 11-12 were prepared and biologically evaluated for their binding at the benzodiazepine receptor (BZR) in rat cortical membranes. The BZR affinity of 1-10 demonstrates that the presence of a proton acceptor at position-1 is important for the potency of a BZR ligand. On the other hand, the BZR inactivity of the 1,2,5-trione derivatives 11-12 shows that the right collocation of the essential L2 lipophilic substituent is of paramount importance for receptor-ligand interaction.

Tricyclic heteroaromatic systems. Pyrazolo[3,4-c]quinolin-4-ones and pyrazolo[3,4-c]quinoline-1,4-diones: synthesis and benzodiazepine receptor activity.

Some pyrazolo[3,4-c]quinoline-4-ones 1-14 and pyrazolo[3,4-c]-quinoline-1,4-diones 15-17 were prepared and biologically evaluated for their binding at the benzodiazepine receptor (BZR) in rat cortical membranes. The moderate binding activity of 1-5, 7, 9-10, 13 is attributable to the lack of the optional proton acceptor at position-1, while the inactivity of the 1,4-dione derivatives 15-17 is due to the lack of the essential proton acceptor at position-3. These conclusions confirm the validity of our proposed pharmacophoric model.

Salivary nitrate, nitrite and N-nitroso compounds in patients with cancer of the upper aerodigestive tract.

N-nitroso compounds are carcinogens that can be ingested directly or synthesized from nitrites and nitrates. The possible role of N-nitroso compounds in the induction of upper aerodigestive tract tumours was considered in a case-control study conducted in the Valle d'Aosta, an Italian region with a high incidence of these neoplasms. Nitrate, nitrite, labile and stable N-nitroso compounds were analysed in the saliva of 36 patients with cancers of the upper aerodigestive tract and 23 healthy individuals.