Brief Critical Time Intervention to Reduce Psychiatric Rehospitalization.

Objective: The study investigated the association between implementation of a brief critical time intervention (BCTI) model and occurrence of early and long-term psychiatric readmission of adults with serious mental illness.

Methods: A sample of 149 adults with a psychiatric inpatient readmission within 30 days of a prior psychiatric hospitalization was referred to an acute level of service coordination (ASC) available at six provider organizations implementing BCTI. Activities important to the delivery of BCTI were monitored and supported.

Inhibition of voltage-dependent sodium channels by Ro 31-8220, a 'specific' protein kinase C inhibitor.

We find that several protein kinase C (PKC) inhibitors, previously considered to be specific, directly inhibit voltage-dependent Na(+) channels at their useful concentrations. Bisindolylmaleimide I (GF 1092037), IX (Ro 31-8220) and V (an inactive analogue), but not H7 (a non-selective isoquinolinesulfonamide protein kinase inhibitor), inhibited Na(+) channels assessed by several independent criteria: Na(+) channel-dependent glutamate release and [(3)H]batrachotoxinin-A 20-alpha-benzoate binding in rat cortical synaptosomes, veratridine-stimulated 22Na(+) influx in CHO cells expressing rat CNaIIa Na(+) channels and Na(+) currents measured in isolated rat dorsal root ganglion neurons by whole cell patch-clamp recording. These findings limit the usefulness of the bisindolylmaleimide class PKC inhibitors in excitable cells.

Differential effects of anesthetic and nonanesthetic cyclobutanes on neuronal voltage-gated sodium channels.

Background: Despite their key role in the generation and propagation of action potentials in excitable cells, voltage-gated sodium (Na+) channels have been considered to be insensitive to general anesthetics. The authors tested the sensitivity of neuronal Na+ channels to structurally similar anesthetic (1-chloro-1,2,2-trifluorocyclobutane; F3) and nonanesthetic (1,2-dichlorohexafluorocyclobutane; F6) polyhalogenated cyclobutanes by neurochemical and electrophysiologic methods.

Methods: Synaptosomes (pinched-off nerve terminals) from adult rat cerebral cortex were used to determine the effects of F3 and F6 on 4-aminopyridine- or veratridine-evoked (Na+ channel-dependent) glutamate release (using an enzyme-coupled spectrofluorimetric assay) and increases in intracellular Ca2+ ([Ca2+]i) (using ion-specific spectrofluorimetry).

Suppression of central nervous system sodium channels by propofol.

Background: Previous studies have provided evidence that clinical levels of propofol alter the functions of voltage-dependent sodium channels, thereby inhibiting synaptic release of glutamate. However, most of these experiments were conducted in the presence of sodium-channel activators, which alter channel inactivation. This study electrophysiologically characterized the interactions of propofol with unmodified sodium channels.

Distinct molecular sites of anaesthetic action: pentobarbital block of human brain sodium channels is alleviated by removal of fast inactivation.

Fast inactivation of sodium channel function is modified by anaesthetics. Its quantitative contribution to the overall anaesthetic effect is assessed by removing the fast inactivation mechanism enzymatically. Sodium channels from human brain cortex were incorporated into planar lipid bilayers.

Volatile anesthetics significantly suppress central and peripheral mammalian sodium channels.

1. Voltage-dependent sodium channels are important for neuronal signal propagation and integration. 2.

Steady-state properties of sodium channels from healthy and tumorous human brain.

This extensive bilayer study of unpurified human brain channels from non-diseased and tumorous human brain involves more than 300 lipid bilayer experiments. Single channel conductances and subconductances, single channel fractional open times, the voltage-dependence of tetrodotoxin (TTX) block and the steady-state activation behavior of four different human brain synaptosomal preparations have been examined. Reproducible values have been obtained for the molecular electrophysiological parameters and their standard deviations, providing a database for future comparisons involving disease or drug-related changes in molecular sodium channel functions.

Blocking effects of the anaesthetic etomidate on human brain sodium channels.

Sodium channels from human brain tissue were incorporated into voltage-clamped planar lipid bilayers in presence of batrachotoxin and exposed to increasing concentrations of the intravenous anaesthetic drug etomidate (0.03-1.02 mM).

Central nervous system sodium channels are significantly suppressed at clinical concentrations of volatile anesthetics.

Background: Although voltage-dependent sodium channels have been proposed as possible molecular sites of anesthetic action, they generally are considered too insensitive to be likely molecular targets. However, most previous molecular studies have used peripheral sodium channels as models. To examine the interactions of volatile anesthetics with mammalian central nervous system voltage-gated sodium channels, rat brain IIA sodium channels were expressed in a stably transfected Chinese hamster ovary cell line, and their modification by volatile anesthetics was examined.

Potentiation of radiation therapy by vinorelbine (Navelbine) in non-small cell lung cancer.

Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Medicament, Paris, France), a semisynthetic vinca alkaloid that is a potent inhibitor of mitotic microtubule polymerization, was recently approved for the treatment of non-small cell lung cancer. Radiotherapy also has been widely used to treat this malignancy. Since other antitumor agents that act on microtubules, such as paclitaxel and estramustine, have been shown to act as radiosensitizers, we studied the ability of vinorelbine to potentiate radiation.

Enhanced antitumor activity for the thymidylate synthase inhibitor 1843U89 through decreased host toxicity with oral folic acid.

The purpose of this investigation was to determine whether antitumor selectivity of the third generation thymidylate synthase inhibitor 1843U89 could be enhanced by a combination of the drug with folic acid. The effects of folic acid on toxicity of 1843U89 to the dog and mouse and on antitumor efficacy of 1843U89 in the mouse were studied. These data were compared to the effect of folic acid on the in vitro cell culture antitumor activity of 1843U89.

[Do general anesthetics act on specific receptors?].

First of all, the meanings of the terms anaesthesia, anaesthetic and receptor are defined. Examples of anaesthetic actions in model systems are then described and compared with clinical actions of anaesthetics. When anaesthetics achieve a certain membrane concentration, they begin to influence membrane protein function in a nonspecific manner.

Voltage- and frequency-dependent pentobarbital suppression of brain and muscle sodium channels expressed in a mammalian cell line.

The voltage- and frequency-dependent interactions of pentobarbital with voltage-gated sodium channels were examined in whole-cell patch-clamp recordings. Using rat brain IIA and rat muscle rSkM1 sodium channels expressed in stably transfected Chinese hamster ovary cell lines, it was found that pentobarbital reduced peak inward sodium currents with IC50 values of 1.2 mM (brain) and 1.

The membrane lipid cholesterol modulates anesthetic actions on a human brain ion channel.

Background: Molecular theories of general anesthesia often are divided into two categories: (1) Anesthetics may bind specifically to proteins, such as ionic channels, and alter their function directly, and (2) anesthetics may alter the functions of integral membrane proteins indirectly through modification of the physical properties of the membrane. Recent studies have provided evidence that anesthetics can bind to proteins and modify their function directly, bringing into question the role of the membrane in anesthetic interactions. To reexamine the role of membrane lipids in anesthetic interactions, an experimental approach was used in which the membrane lipid composition could be systematically altered and the impact on anesthetic interactions with potential targets examined.

Synchronization of cells in the S phase of the cell cycle by 3'-azido-3'-deoxythymidine: implications for cell cytotoxicity.

The mechanism of synergy between 3'-azido-3'-deoxythymidine (AZT) and anticancer agents was investigated with emphasis on cell-cycle events. Exposure of exponentially growing WiDr human colon carcinoma cells to AZT resulted in synchronization of cells in the S phase of the cell cycle. Following treatment with AZT at 50 or 200 microM, 62% +/- 3% or 82% +/- 4% of the cells were in the S phase as compared with 36% +/- 2% in the control.

Dissecting pentobarbitone actions on single voltage-gated sodium channels.

In order to begin separating the roles of membrane protein structure and membrane protein milieu in anaesthetic interactions a new planar lipid bilayer technology is being used. Membrane proteins such as sodium channels from diverse tissue sources are inserted into identical lipid and aqueous environments where they can be examined and compared electrophysiologically in great detail. The results obtained with pentobarbitone suggest that some anaesthetic interactions may be general and conserved, while other anaesthetic interactions may depend on the particular sodium channel isoform.

The voltage-dependent action of pentobarbital on batrachotoxin-modified human brain sodium channels.

The voltage-dependent action of the intravenous anesthetic pentobarbital on human brain sodium channels activated by batrachotoxin was examined using planar lipid bilayer methods. Fractional open time-data were fitted by Boltzmann functions to yield simple parameters characterizing the voltage-dependence of the fractional open time. Pentobarbital caused a dose-dependent reduction of the maximum fractional open time of the sodium channel and a shift of the potential of half-maximal open time towards hyperpolarized potentials, whereas the slope parameter of the Boltzmann-fits was unaffected.

Thienyl and thiazolyl acyclic analogues of 5-deazatetrahydrofolic acid.

Analogues of N-[4-[[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]amino] benzoyl]-L-glutamic acid (5-DACTHF), in which the phenylene group is replaced by either a thienoyl or a thiazolyl group were synthesized. These compounds were prepared by reductive amination of suitably protected pyrimidinylpropionaldehyde with the aminoaroyl glutamates. These glutamates were in turn synthesized from the corresponding nitroaroyl carboxylic acids by condensation with protected glutamic acid followed by catalytic reduction.

Molecular actions of pentobarbitone on sodium channels in lipid bilayers: role of channel structure.

The molecular mechanisms by which anaesthetics interfere with neuronal function are controversial. We have examined the effects of pentobarbitone on muscle-derived (eel electroplax) sodium channels incorporated into planar bilayers under exactly the same experimental conditions that we used previously to study the anaesthetic modification of human brain channels. This technique allows examination of protein-mediated similarities and differences.

Benzo[f]quinazoline inhibitors of thymidylate synthase: methyleneamino-linked aroylglutamate derivatives.

Syntheses of several new inhibitors of thymidylate synthase (TS) structurally related to folic acid are described in which the pterin portion of the folate molecule is replaced by a benzo[f]quinazoline moiety, but which retain the natural methyleneamino link to the benzoylglutamate side chain. The effect on enzyme activity and cytotoxicity of various changes in the structure of the (p-aminobenzoyl)glutamate side chain are reported. Replacement of the benzamide portion of the (p-aminobenzoyl)glutamate moiety with 2-fluorobenzamido, 2-isoindolinyl, 1,2-benzisothiazol-2-yl, and 2-thenamido moieties varied in effect from a 9-fold diminution of TS activity to a 5-fold enhancement, while cytotoxic potency on SW-480 and MCF-7 tumor lines showed increases ranging from 3.

Effect of purine synthesis inhibition on WiDr spheroids in vitro or on WiDr or colon 38 tumors in vivo. Complete growth inhibition but not regression.

Clinical responses for anticancer agents are based upon tumor regression. We have investigated the potential of glycineamide ribonucleotide transformylase (GAR TFase) inhibitors to produce regressions in multiple preclinical models of colon carcinoma. The growth of multicellular tumor spheroids of WiDr human colon carcinoma was inhibited by the GAR TFase inhibitors 5-deazaacyclotetrahydrofolate (5-DACTHF), its 2'-fluoro, 3'-fluoro, 10-deaza, and 10-thia analogs as well as 5,10-dideazatetrahydrofolate, but none of the compounds caused spheroid regressions.

Benzoquinazoline inhibitors of thymidylate synthase: enzyme inhibitory activity and cytotoxicity of some sulfonamidobenzoylglutamate and related derivatives.

Several folate-like thymidylate synthase inhibitors are described in which the pteridine nucleus of the folic acid molecule is replaced by a benzoquinazoline moiety, which in turn is attached to the benzoylglutamate side chain by a sulfonamide link. The most potent compounds had Ki values as low as 2.5 nM against the human enzyme, were good substrates for the cellular reduced folate transport system and for folylpolyglutamate synthetase, and had IC50 values for growth inhibition of tumor cell lines as low as 70 nM.

Benzoquinazoline inhibitors of thymidylate synthase: enzyme inhibitory activity and cytotoxicity of some 3-amino- and 3-methylbenzo[f]quinazolin-1(2H)-ones.

The synthesis and thymidylate synthase (TS) inhibitory activity of a series of simple benzo[f]-quinazolin-1(2H)-ones are described. Fully aromatic 3-amino compounds with compact lipophilic substituents in the 9-position were found to have I50 values as low as 20 nM on the isolated enzyme, and represent the first examples of potent, folate-based TS inhibitors that completely lack any structural feature corresponding to the (p-aminobenzoyl)glutamate moiety of the cofactor. A number of the compounds also showed moderate growth inhibitory activity against a human colon adenocarcinoma cell line (SW480), with IC50 values as low as 2 microM.