Randomized controlled trial of Tesomet for weight loss in hypothalamic obesity.

Context: Hypothalamic injury often leads to rapid, intractable weight gain causing hypothalamic obesity, which is associated with increased risk of cardiovascular and metabolic morbidity and mortality. There are no approved or effective pharmacological treatments for hypothalamic obesity, and conventional lifestyle management remains ineffective.

Objective: To investigate the safety and efficacy of Tesomet (0.

NS 1231, a novel compound with neurotrophic-like effects in vitro and in vivo.

NS 1231 [5-(4-chlorophenyl)-6,7,8,9-tetrahydro-1H-pyrrolo-[3.2-h]naphthalene-2,3-dione-3-oxime] belongs to a chemical series of compounds, which exhibit neurotrophic-like activities. In vitro, NS 1231 rescued nerve growth factor (NGF)-differentiated PC12 cells from death induced by withdrawal of trophic factors.

NS-417, a novel compound with neurotrophic-like effects.

NS-417 (5-(4-Chlorophenyl)-8-methyl-6-7-8-9-tetrahydro-1-H-pyrrolo[3.2-h]isoquinoline-2,3-dione-3-oxim hydrochloric acid salt) belongs to a new chemical series of compounds. NS-417 rescued differentiated PC12 cells from death induced by withdrawal of serum and nerve growth factor.

Neuroprotection by a novel compound, NS521.

NS521 (1-(1-butyl)-4-(2-oxo-1-benzimidazolinyl)piperidine) belongs to a group of novel benzimidazolones, which exhibit neurotrophic-like activities. In vitro, NS521 rescued neuronal PC12 cells from death induced by serum and nerve growth factor deprivation. The survival effect of NS521 appeared to reflect a delay of the apoptotic process, because the extent of DNA fragmentation was attenuated transiently by NS521.

SPD 502: a water-soluble and in vivo long-lasting AMPA antagonist with neuroprotective activity.

Accumulating preclinical data suggest that compounds that block the excitatory effect of glutamate on excitatory amino acid receptors may have neuroprotective effects and utility for the treatment of neurodegeneration after brain ischemia. In the present study, the in vitro and in vivo pharmacological properties of the novel glutamate antagonist SPD 502 [8-methyl-5(4-(N,N-dimethylsulfamoyl)phenyl)-6,7, 8,9,-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2, 3-dione-3-O-(4-hydroxybutyric acid-2-yl)oxime] are described. In binding studies, SPD 502 was shown to display selectivity for the [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-binding site (IC50 = 0.

Characterization of NS 2028 as a specific inhibitor of soluble guanylyl cyclase.

1 The haeme-containing soluble guanylyl cyclase (alpha1beta1-heterodimer) is a major intracellular receptor and effector for nitric oxide (NO) and carbon monoxide (CO) and mediates many of their biological actions by increasing cyclic GMP. We have synthesized new oxadiazolo-benz-oxazins and have assessed their inhibitory actions on guanylyl cyclase activity in vitro, on the formation of cyclic GMP in cultured cells and on the NO-dependent relaxation of vascular and non-vascular smooth muscle. 2 Soluble guanylyl cyclase, purified to homogeneity from bovine lung, was inhibited by 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one (NS 2028) in a concentration-dependent and irreversible manner (IC50 30 nM for basal and 200 nM for NO-stimulated enzyme activity).

Pharmacological characterisation of voltage-sensitive calcium channels and neurotransmitter release from mouse cerebellar granule cells in culture.

Using subtype-specific Ca-channel blockers, we have characterised the voltage-sensitive Ca2+ currents as well as neurotransmitter release from cultured mouse cerebellar granule cells. The whole cell version of the patch clamp technique was adapted to monitor the isolated Ca-channel currents. The currents were activated at potentials more positive than -40 mV and were composed of at least four pharmacological distinct components being sensitive to nifedipine (35%), omega-conotoxin GVIA (10%), and omega-agatoxin IVA (42%) corresponding to L-, N-, and P-channel-mediated currents.

Selective reduction in domoic acid toxicity in vivo by a novel non-N-methyl-D-aspartate receptor antagonist.

Our objective was to characterize the neurotoxic actions of systemically administered domoic acid on different excitatory amino acid receptors, and to compare the receptor selectivity of domoate with the related compound kainic acid. Groups of mice were injected with various ligands selective for N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid-kainate (AMPA/kainate) receptors prior to injection of equitoxic doses of domoic acid or kainic acid. Domoic acid toxicity was not significantly altered by pretreatment with any NMDA receptor selective antagonists, with the exception of 3-(2-carboxypiperazine-4-yl)propyl-1 -phosphonic acid.

Evaluation of the importance of transamination versus deamination in astrocytic metabolism of [U-13C]glutamate.

Glutamate metabolism was studied in primary cultures of cerebral cortical astrocytes to determine the significance of transamination for the oxidative metabolism of glutamate. Cultures were incubated with [U-13C]glutamate (0.5 mM) in the presence and absence of the transaminase inhibitor aminooxyacetic acid (AOAA) and in some cases with methionine sulfoximine, an inhibitor of glutamine synthetase.

Characterization of a chemical anoxia model in cerebellar granule neurons using sodium azide: protection by nifedipine and MK-801.

Induction of chemical anoxia, using sodium azide in cerebellar granule cells maintained in primary culture, was evaluated as an in vitro assay for screening of potential neuroprotective compounds. The purpose of this study was to evaluate sodium azide as an alternative to cyanide salts, compounds which, despite their unfavorable characteristics, are often used in assays for chemical anoxia. The viability of neuronal cultures after treatment with azide, with or without preincubation with calcium channel blockers, tetrodotoxin (TTX), or glutamate receptor antagonists, was monitored by subsequent incubation with the tetrazolium dye MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), followed by isopropanol extraction and spectrophotometric quantification of cellularly reduced MTT.

Pharmacological profile and anti-ischemic properties of the Ca(2+)-channel blocker NS-638.

Included in the sequence of events leading to neuronal death in ischemic tissue following stroke is an excessive and toxic rise in the intracellular Ca(2+)-concentration, predominantly due to an influx of Ca2+ through nonselective cation-channels as well as Ca(2+)-channels. In the present study we have characterized the pharmacological profile and anti-ischemic effects of 2-amino-1-(4-chlorobenzyl)-5-trifluoromethylbenzimidazole (NS-638), a small nonpeptide molecule with Ca(2+)-channel blocking properties. NS-638 dose dependently inhibited K(+)-stimulated [45Ca2+]-uptake in chick cortical synaptosomes and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA)-stimulated [3H]GABA-release from cultured cortical neurons with IC50 values of 2.

Low-field MR imaging of the spine. A comparative study of a traditional and a new, completely balanced gradient-echo sequence.

Purpose: To evaluate a new steady-state sequence in the delineation of the various structures in the spine at low-field MR imaging with a very high homogeneity of the main field.

Methods: 49 patients underwent 53 examinations with both a traditional T1-weighted gradient-echo (PS) sequence and a new completely balanced steady-state 3-D (CBASS3D) sequence; 20 examinations included the cervical spine, 8 the thoracic spine and 25 the lumbar spine. All 106 examinations were reviewed twice regarding visibility of selected structures in the spinal region and diagnostic usefulness.

Characterization of the binding of [3H]NS 257, a novel competitive AMPA receptor antagonist, to rat brain membranes and brain sections.

The binding of [3H]NS 257 (1,2,3,6,7,8-hexahydro-3-(hydroxyimino)-N,N-[3H]dimethyl-7-methyl- 2- oxobenzo[2,1-b:3,4-c']dipyrrole-5-sulfonamide) to rat cortical membranes was characterized in the absence and presence of thiocyanate. Specific [3H]NS 257 binding was saturable and reversible, and the stimulating effect of thiocyanate on binding was optimal at 100 mM. In the presence of thiocyanate [3H]NS 257 bound to a single population of binding sites with an affinity of 225 +/- 8 nM and a binding site density of 0.

Selective block of recombinant glur6 receptors by NS-102, a novel non-NMDA receptor antagonist.

The diversity of neuronal glutamate receptors continues to increase with the discovery of multiple subunits and subunit families. The significance of this potential receptor heterogeneity is unknown because pharmacological tools that could clearly distinguish between different structural isoforms have not yet been identified. A novel glutamate receptor antagonist, 5-nitro-6,7,8,9-tetrahydrobenzo[g]indole-2,3-dione-3-oxime (NS-102), has been shown previously to selectively block the low affinity [3H]kainate binding site in rat brain.

NS 004--an activator of Ca(2+)-dependent K+ channels in cerebellar granule cells.

The large-conductance Ca(2+)-dependent K+ channels or BK channels in cerebellar granule cells were studied by patch-clamp technique, and the effects on channel activity of the molecule NS 004 (1-(2-hydroxy-5-chlorophenyl)-5-trifluoromethyl-2- benzimidazolone) were investigated. The channels had a unit conductance of 187 pS, were blocked by charybdotoxin and activated by internal Ca2+. NS 004 (10-30 microM) significantly increased the single channel opening frequency as well as the mean open time.

Selective activation of Ca(2+)-dependent K+ channels by novel benzimidazolone.

Activators and blockers of specific ion channels are important pharmacological tools for characterizing ion channels and their influence on cell function. The large-conductance Ca(2+)-dependent K+ channel (BK channel) is blocked by peptides such as charybdotoxin and iberiotoxin, but no selective activator of the channel has been described. Here we report single-channel and whole-cell patch-clamp experiments on the specific activation of BK channels in aortic smooth muscle cells with a new heterocyclic molecule, NS 1619 (1-(2'-hydroxy-5'-trifluoromethylphenyl)-5-trifluoromethyl- 2(3H)benzimidazolone).

A novel non-NMDA receptor antagonist shows selective displacement of low-affinity [3H]kainate binding.

5-Nitro-6,7,8,9-tetrahydrobenzo[G]indole-2,3-dione-3-oxime (NS-102), a new competitive glutamate receptor antagonist displaced binding to non-N-methyl-D-aspartate (non-NMDA) binding sites with no activity at the NMDA and strychnine-insensitive glycine binding sites. Under experimental conditions in which both high- and low-affinity sites were labelled, NS-102 only partially inhibited the binding of [3H]kainate. Studies of NS-102 displacement of high-affinity versus low-affinity [3H]kainate binding showed a high selectivity of NS-102 for the low-affinity [3H]kainate binding site (Ki = 0.

[Assessment of the diagnostic yield of cerebral CT in children].

In order to show if an excessive use of cerebral computed tomography of children (aged 0 to 15 years) existed, scans from 157 patients from a single X-ray-department was examined. The clinical information which was presented on referral of the patients was also investigated. No excessive use was proven, as 26.

Development of binding sites for excitatory amino acids in cultured cerebral cortex neurons.

Binding of [3H]glutamate, [3H]AMPA (RS-alpha-amino-3-hydroxy-5-methyl-4-isoxazolo-propionate) and [3H]kainate was investigated in membranes prepared from cerebral cortex of 4-day-old and adult mice and from cerebral cortex neurons cultured for different periods of time (2, 4, 8 and 14 days). For all ligands, the number of binding sites increased as a function of development both in vivo and in culture. A significant number of binding sites for the ligands could be demonstrated on the cultured neurons already after 2 days in culture.

Autoradiographic characterization and localization of quisqualate binding sites in rat brain using the antagonist [3H]6-cyano-7-nitroquinoxaline-2,3-dione: comparison with (R,S)-[3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid binding sites.

Using quantitative autoradiography, we have investigated the binding sites for the potent competitive non-N-methyl-D-aspartate (non-NMDA) glutamate receptor antagonist [3H]6-cyano-7-nitro-quinoxaline-2,3-dione ([3H]-CNQX) in rat brain sections. [3H]CNQX binding was regionally distributed, with the highest levels of binding present in hippocampus in the stratum radiatum of CA1, stratum lucidum of CA3, and molecular layer of dentate gyrus. Scatchard analysis of [3H]CNQX binding in the cerebellar molecular layer revealed an apparent single binding site with a KD = 67 +/- 9.

A potent antagonist of the strychnine insensitive glycine receptor has anticonvulsant properties.

5.7-Dinitro-quinoxaline-2.3-dione (MNQX) displaced [3H]glycine binding to cortical membranes but had no effect n [3H]3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid ([3H]CPP) binding.

Glutamate-induced 45Ca2+ uptake into immature cerebral cortex neurons shows a distinct pharmacological profile.

Glutamate-induced 45Ca2+ uptake was studied in cerebral cortex neurons cultured for 4 days, i.e., at a developmental stage where the neurons are sensitive to the mixed agonist glutamate but not to the actions of N-methyl-D-aspartate or other excitatory amino acids.

Non-NMDA glutamate receptor antagonist 3H-CNOX binds with equal affinity to two agonist states of quisqualate receptors.

Binding of 3H-CNQX to rat cortical membranes is saturable and reversible. Apparently, 3H-CNQX binds to a single site with KD = 39 nM. However, studies using AMPA as inhibitor revealed a biphasic inhibition of 3H-CNQX binding.

Glutamate-induced increase in intracellular Ca2+ in cerebral cortex neurons is transient in immature cells but permanent in mature cells.

The free cytosolic Ca2+ concentration ([Ca2+]i) of cultured cerebral cortex neurons was determined using a fluorescent Ca2+ chelator (Fluo-3) after exposure of the neurons to glutamate. Mature neurons (8 days in culture) responded within 45 s to 100 microM glutamate by an increase in [Ca2+]i from 75 to 340 nM, an increase that during the following 6 min of exposure reached 400 nM. This increase in [Ca2+]i could not be reversed by removal of glutamate.