Background: Current drugs for epilepsy affect seizures, but no antiepileptogenic or disease-modifying drugs are available that prevent or slow down epileptogenesis, which is characterized by neuronal cell loss, inflammation and aberrant network formation.Ghrelin and ghrelin receptor (ghrelin-R) agonists were previously found to exert anticonvulsant, neuroprotective and anti-inflammatory effects in seizure models and immediately after status epilepticus (SE). Therefore, the aim of this study was to assess whether the ghrelin-R agonist macimorelin is antiepileptogenic in the pharmacoresistant intrahippocampal kainic acid (IHKA) mouse model. Methods: SE was induced in C57BL/6 mice by unilateral IHKA injection. Starting 24 h after SE, mice were treated intraperitoneally with macimorelin (5 mg/kg) or saline twice daily for 2 weeks, followed by a 2-week wash-out. Mice were continuously electroencephalogram-monitored, and at the end of the experiment neuroprotection and gliosis were assessed.Results: Macimorelin significantly decreased the number and duration of seizures during the treatment period, but had no antiepileptogenic or disease-modifying effect in this dose regimen. While macimorelin did not significantly affect food intake or body weight over a 2-week treatment period, its acute orexigenic effect was preserved in epileptic mice but not in sham mice. Conclusions:While the full ghrelin-R agonist macimorelin was not significantly antiepileptogenic nor disease-modifying, this is the first study to demonstrate its anticonvulsant effects in the IHKA model of drug-refractory temporal lobe epilepsy. These findings highlight the potential use of macimorelin as a novel treatment option for seizure suppression in pharmacoresistant epilepsy.
Introduction. Molecular order and the ratio between crystalline and amorphous portions are important factors determining the macroscopic properties of polymeric materials.1 Spatial variations of the molecular parameters, depending on the processing conditions, lead to nonuniform and spatial-dependent macroscopic behavior. For a systematic improvement of the manufacturing process, methods which record the spatial dependence of order and crystallinity are in need. On a phantom of deuterated polyethylene we have recently shown that solid-state 2H NMR spectroscopy, in combination with magneticfield gradients for spatial encoding, can indeed provide the desired information for bulk samples.2 It is the purpose of this paper to demonstrate that spectroscopic images with 13C in natural abundance can be recorded for a "real" polymer material, where spatial heterogeneities are known to exist.
In search of novel antitumor agents natural macrocyclic polyketides called Disorazols have been isolated from myxobacterium Sorangium cellulosum[1,2,3]. Here we show that Disorazol Z specifically produced by strain So ce427, possesses outstanding cytotoxicity with single digit to even subnanomolar EC50 values in a highly diverse panel of more than 60 different tumor cell lines. Interestingly, the maximum efficacy by which Disorazol Z inhibited cell growth increased with the incubation time, e.g. in the endometrium carcinoma cell line Hec1A reaching a maximum efficacy of about 25% after 24 hours, but about 75% efficacy after 72 hours at a saturating concentration of 100 nM, being approximately 100–200 fold above the respective EC50 values. Based on this observation, it was speculated that the mechanism of action of Disorazol Z is dependent on progressing through cell cycle. Indeed, this was supported by showing that in the cell line RKOp27Kip inducible expression of the cell cycle inhibitor p27Kip led to a complete loss of Disorazol Z cytotoxicity up to a concentration of 100 nM. In contrast, without cell cycle arrest Disorazol Z demonstrated high cytotoxic activity with an EC50 value of 0.54 nM in the same cell line. Furthermore, cell cycle analysis revealed that Disorazol Z arrested KB/HeLa cells in the G2/M phase of the cell cycle with an IC50 value of 0.8 nM. As expected this Disorazol Z-induced G2/M arrest induced apoptotic events, as demonstrated by Caspase 3/7 activation in HCT-116 cells with an EC50 value of 0.25 nM. In agreement with the above described behaviour Disorazol Z could be identified as tubulin binding agent by inhibiting in vitro tubulin polymerisation with a mean IC50 value of 3.3 μM as well as inducing multipolar spindle formation at low nanomolar concentrations in U-2 OS cells. The high divergence of the in vitro tubulin activity compared to the cellular efficacy may point to additional mechanisms of action for Disorazol Z. This working hypothesis may be supported by the fact that synergistic cytotoxic action of Disorazol Z and the tubulin binding agent Colchicin could be observed with combination indices down to about 0.5. Neither Taxol nor Vinblastine showed such synergism, both tubulin binders behaved nearly additive in combination with Disorazol Z. Currently, experiments are under way to identify the tubulin binding site for Disorazol Z. Additional ongoing studies focus on the evaluation of the mechanisms of action of this novel highly potent agent with antitumor properties. Further, we aim at evaluating the utility of Disorazol Z as cytotoxic component in a drug-targeting approach utilizing GPCR ligands as the targeting moieties for the treatment of GPCR overexpressing cancers. References: 1. Jansen et al. (1994), Liebigs Ann. Chem. 1994, 759–773 2. Irschik et al., (1995), Journal of Antibiotics 48, 31–35 2. Elnakady et al. (2004), Biochemical Pharmacology 67, 927–935 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C214.
Background For drug-targeting aimed at the treatment of LHRH receptor overexpressing cancers the LHRH receptor agonistic peptide D-Lys6-LHRH has been conjugated to the novel highly cytotoxic natural compound Disorazol Z. As shown previously by early proof of concept in an ovary cancer xenograft model, differentially linked conjugates possess a high potential regarding the treatment of LHRH-R positive tumors [1]. Here we present further characterization of these conjugates with respect to PK/PD parameter and provide evidence that LHRH receptor targeting significantly contributes to their mechanism of action. Materials and Methods LHRH-R competitive binding, calcium release and cytotoxic activity were measured by Tag-Lite technology (Cisbio), and Fluo-4 (Invitrogen) or Resazurin-based detection, respectively. PK parameter were assessed by standard procedures followed by LC-MS/MS analysis. For the xenograft studies, tumor fragments were transplanted subcutaneously in female nude mice and treatment was started at a tumor size of approx. 100 mm3. Results Disorazol Z - D-Lys6-LHRH conjugates showed varying cytotoxic activity from single digit nanomolar to higher submicromolar EC50 values but comparable LHRH receptor binding and activation in the low nanomolar EC50 range. Comparison in ovarian and triple negative breast cancer xenograft models revealed potent inhibition of tumor growth for the conjugates, whereas equimolar dosing of Disorazol Z failed to reach statistical significance. PK analysis showed substantial plasma levels for the conjugates with only minor release of Disorazol Z, pointing to stabilization by conjugation and demonstrating reasonable half-life of the intact conjugates as prerequisite for tumor targeting. In the same tumor models, competition by previous administration of D-Lys6-LHRH provides evidence for LHRH receptor targeting as mechanism of action. Increased sensitivity of LHRH receptor overexpressing cells towards conjugate cytotoxicity, i.e. leading to about 30 fold decreased EC50 values for the conjugate AEZS-125, further supports the LHRH-R dependency of conjugate efficacy. Conclusions The presented LHRH receptor-dependent efficacies of Disorazol Z - D-Lys6-LHRH conjugates in vitro and in mouse xenograft models support the principle of tumor targeting by the LHRH receptor as already employed by the drug candidate AEZS-108, which is currently in phase II clinical studies. Preclinical development of Disorazol Z conjugates will be started in the first half of 2013. Citation Format: Babette Aicher, Tilmann Schuster, Lars Blumenstein, Antje Schubert, Carsten Gründker, Joerg B. Engel, Olaf Ortmann, Rolf Mueller, Eckhard Guenther, Matthias Gerlach, Michael Teifel. LHRH receptor targeting as mechanism of anti-tumor activity for cytotoxic conjugates of Disorazol Z with the LHRH receptor agonistic peptide D-Lys6-LHRH. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5476. doi:10.1158/1538-7445.AM2013-5476
Preparation of Novel 2,3,8-Trisubstituted Pyrido[3,4-b]pyrazines and Pyrido[2,3-b]pyrazines. -An efficient synthetic approach to the preparation of the title compounds (VIII) and (XVI) is developed. -(ANTOINE, M.; CZECH, M.; GERLACH, M.; GUENTHER, E.; SCHUSTER, T.; MARCHAND*, P.; Synthesis 2011, 5, 794-806, http://dx.doi.org/10.1055/s-0030-1259429 ; Lab. Chim. Ther., Fac. Pharm., CNRS, Univ. Nantes, F-44035 Nantes, Fr.; Eng.) -C. Gebhardt 26-174
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